Bisphosphonates in Bone Disease: From the Laboratory to the Patient

Bisphosphonates in Bone Disease

To My wife, Maria Pia My children, Marie-Gabrielle, Isabelle DSsirde, and Marie-Laure My father, Alfred Fleisch, who taught me scientific thinking and experimental rigor William F. Neuman, who introduced me to the bone

Bisphosphonates in Bone Disease From the Laboratory to the Patient

Herbert Fleisch Professor Emeritus University of Berne Berne, Switzerland

ACADEMIC PRESS A Harcourt Science and Technology Company

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NOTICE The information contained in this book has been compiled from the available literature. Although every effort has been made to report faithfully, the author and publisher cannot be held responsible for its correctness. The book is not intended to be and should not be construed as medical advice. For any use the package inserts of the various drugs should be consulted. The author and publisher disclaim any liability arising directly or indirectly from the use of the compounds, drugs, techniques or procedures described in this book.

This b o o k is printed on acid-free paper. |

Copyright 9 2000, 1997, 1995, 1993 by Herbert Fleisch All Rights Reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Requests for permission to make copies of any part of the work should be mailed to: Permissions Department, Harcourt Inc., 6277 Sea Harbor Drive, Orlando, Florida 32887-6777 A c a d e m i c Press A Harcourt Science and Technology Company 525 B Street, Suite 1900, San Diego, California 92101-4495, USA http://www.academicpress.com A c a d e m i c Press Harcourt Place, 32 Jamestown Road, London NW1 7BY, UK http://www.hbuk.co.uk/ap/ Library of Congress Catalog Card Number: 00-100337 International Standard Book Number: 0-12-260371-0 (casebound) International Standard Book Number: 0-12-260370-2 (paperback) PRINTED IN THE UNITED STATES OF AMERICA 00 01 02 03 04 05 CO 9 8 7 6 5 4

3

2

1

Contents

Note: The arrows (~) that appear in the margins indicate the text to which the reader is referred by the captions, also in the margins. Preface

.....................................................

xi

1

lo

Bone and mineral

1.1. 1.1.1. 1.1.2.

Bone physiology ......................................... Morphology ............................................ C o m p o s i t i o n of b o n e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mineral ............................................. Organic matrix ....................................... B o n e cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Osteoblasts ........................................ L i n i n g cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Osteocytes ........................................ Osteoclasts ........................................ O t h e r cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Modeling and remodeling ................................ Calcium homeostasis .................................... B o n e as a n o r g a n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A s s e s s m e n t of b o n e t u r n o v e r . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R e c o m m e n d e d selected r e a d i n g . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 3 3 4 5 5 7 7 8 12 12 16 19 21 21

Bisphosphonates

27

1.1.3. 1.1.4. 1.1.5. 1.1.6.

o

2.1.

2.2.

metabolism

mpreclinical

.........................

.......................

1

B a c k g r o u n d to t h e p h a r m a c o l o g i c a l d e v e l o p m e n t . . . . . . . . . . . . . .

27

R e c o m m e n d e d selected reading . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29

Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30 33

R e c o m m e n d e d selected r e a d i n g . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.

Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34

2.3.1.

P h y s i c o c h e m i c a l effects

34

..................................

Contents

2.3.2.

Biological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I n h i b i t i o n of b o n e r e s o r p t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . In vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.4. 2.4.1. 2.4.2. 2.4.3. 2.4.4.

2.5. 2.5.1. 2.5.2.

0

Intact animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A n i m a l s w i t h e x p e r i m e n t a l l y increased b o n e resorption ..................................... Relative activity of b i s p h o s p h o n a t e s . . . . . . . . . . . . . . . . . . . . M e c h a n i s m s of a c t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D i r e c t effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I n d i r e c t effect t h r o u g h o t h e r cells . . . . . . . . . . . . . . . . . . . I n h i b i t i o n of m i n e r a l i z a t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ectopic m i n e r a l i z a t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Normal mineralization .............................. M e c h a n i s m s of a c t i o n in the inhibition of calcification . . . . . . O t h e r effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R e c o m m e n d e d selected r e a d i n g . . . . . . . . . . . . . . . . . . . . . . . . . . . .

39 40 41 43 45 48 48 49 50 50 51

Pharmacokinetics ....................................... Intestinal a b s o r p t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Distribution ........................................... Renal clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . O t h e r m o d e s of a p p l i c a t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R e c o m m e n d e d selected r e a d i n g . . . . . . . . . . . . . . . . . . . . . . . . . . . .

56 56 57 59 60 60

Animal toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N o n a c u t e toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alendronate ........................................ Clodronate ......................................... Etidronate .......................................... Pamidronate ........................................ Other bisphosphonates ................................ R e c o m m e n d e d selected r e a d i n g . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63 63 63 64 64 65 65 65 66

Bisphosphonates--

67

3.1.

Introduction

3.2.

Paget's disease

3.2.1. 3.2.2. 3.2.3. 3.2.4.

3.2.5. 3.2.6.

34 34 34 36

clinical ..........................

...........................................

......................................... Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology .......................................... Pathophysiology ........................................ Clinical m a n i f e s t a t i o n s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signs a n d s y m p t o m s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory ......................................... Dia g n o s i s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F o l l o w - u p of p r o g r e s s i o n of the disease . . . . . . . . . . . . . . . . . . . . T r e a t m e n t w i t h drugs o t h e r t h a n b i s p h o s p h o n a t e s . . . . . . . . . . . . . . Treatment with bisphosphonates ........................... Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

vi

67 68 68 68 68 69 69 70 71 71 72 72 72

Contents Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73

Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment regimens ................................

73 76

Alendronate ....................................

78

Clodronate

....................................

79

Etidronate ..................................... Olpadronate ................................... Pamidronate ................................... Risedronate .................................... Tiludronate ....................................

79 80 80 81 82

Other bisphosphonates

83

...........................

Conclusion ....................................... R e c o m m e n d e d selected r e a d i n g . . . . . . . . . . . . . . . . . . . . . . . . . .

83 84

3.3.

O s t e o l y t i c t u m o r - i n d u c e d b o n e disease . . . . . . . . . . . . . . . . . . . . . . .

88

3.3.1.

Definition .............................................

88

3.3.2.

Pathophysiology ........................................ Local bone destruction ................................ Generalized bone destruction ........................... M e c h a n i s m s of h y p e r c a l c e m i a . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signs a n d s y m p t o m s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88 88 90 90 92 92

3.3.3.

3.3.4. 3.3.5.

3.4. 3.4.1. 3.4.2. 3.4.3. 3.4.4. 3.4.5.

Laboratory ......................................... F o l l o w - u p of p r o g r e s s i o n of t h e disease . . . . . . . . . . . . . . . . . . . . Treatment with drugs other than bisphosphonates .............. Treatment with bisphosphonates ........................... Preclinical s t u d i e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypercalcemia .................................. Urinary parameters .............................. O t h e r effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment regimens ............................... Clodronate ................................... Etidronate .................................... Ibandronate ................................... Pamidronate .................................. Other bisphosphonates .......................... C o m p a r i s o n of t h e v a r i o u s b i s p h o s p h o n a t e s . . . . . . . . . . . .

93 94 94 95 95 98 98 98 99 101 104 104 105

Conclusion ........................................ R e c o m m e n d e d selected r e a d i n g . . . . . . . . . . . . . . . . . . . . . . . . . . .

110 111

Non-tumor-induced hypercalcemia ........................ Definition ............................................

118

Pathophysiology .......................................

118

Clinical manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

118 119 119 119

Treatment with drugs other than bisphosphonates ............. Treatment with bisphosphonates .......................... Preclinical s t u d i e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

vii

106 106 108 109

118

Contents

3~ 3.5.1. 3.5.2. 3.5.3. 3.5.4.

Clinical s t u d i e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

119

Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment regimens ............................... Conclusion ........................................ R e c o m m e n d e d selected r e a d i n g . . . . . . . . . . . . . . . . . . . . . . . . .

120 120 121 121

Osteoporosis ......................................... Definition ............................................ Epidemiology ......................................... Pathophysiology ....................................... Clinical m a n i f e s t a t i o n s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signs a n d s y m p t o m s Laboratory Diagnosis

.................................

........................................ .........................................

123 123 123 124 128 128 128 129

F o l l o w - u p of p r o g r e s s i o n of the disease . . . . . . . . . . . . . . . . . . . Treatment with drugs other than bisphosphonates ............. Treatment with bisphosphonates .......................... Preclinical s t u d i e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical s t u d i e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effect on b o n e m i n e r a l d e n s i t y . . . . . . . . . . . . . . . . . . . . . Effect o n b o n e t u r n o v e r . . . . . . . . . . . . . . . . . . . . . . . . . . Effect o n f r a c t u r e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects a f t e r d i s c o n t i n u a t i o n of the d r u g . . . . . . . . . . . . . . V a r i o u s o t h e r effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment regimens ............................... Alendronate ................................... Clodronate ................................... Etidronate .................................... Ibandronate ................................... Pamidronate .................................. Risedronate ................................... Tiludronate ................................... Conclusion ...................................... R e c o m m e n d e d selected r e a d i n g . . . . . . . . . . . . . . . . . . . . . . . . .

129 130 133

3.6.2. 3.6.3.

H e t e r o t o p i c calcification and ossification . . . . . . . . . . . . . . . . . . . . Definition ........................................... Pathophysiology ....................................... Clinical m a n i f e s t a t i o n s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

160 160 160 160

3.6.4.

Treatment with drugs other than bisphosphonates .............

161

3.6.5.

Treatment with bisphosphonates

161 161 161

3.5.5. 3.5.6.

3.6. 3.6.1.

..........................

Preclinical s t u d i e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical s t u d i e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H e t e r o t o p i c calcification . . . . . . . . . . . . . . . . . . . . . . . . . . . Soft tissue c a l c i f i c a t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . Urolithiasis ................................... Dental calculus

................................

viii

133 136 136 137 143 144 148 148 149 149 150 150

151 151 151 152 152 152

161 161 162 162

Contents

3.7.

H e t e r o t o p i c ossification . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fibrodysplasia (previously myositis) ossificans p r o g r e s s i v a . . . . . . . . . . . . . . . . . . . . . . . . . . O t h e r h e t e r o t o p i c ossifications . . . . . . . . . . . . . . . . . . . . Conclusion ........................................ R e c o m m e n d e d selected reading . . . . . . . . . . . . . . . . . . . . . . . . . . .

162

Other diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

166 166

Diseases with enhanced resorption Osteogenesis imperfecta

......................

..............................

162 163 164 164

166

O t h e r diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R e c o m m e n d e d selected reading . . . . . . . . . . . . . . . . . . . . . . . . . . .

166 167

3.8.

Adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.8.1.

B i s p h o s p h o n a t e s in g e n e r a l

168 168

3.8.2.

Individual bisphosphonates .............................. Alendronate ....................................... Clodronate ........................................ Etidronate ......................................... Pamidronate .......................................

..............................

169 169 170

171 173

Risedronate ........................................ Tiludronate ........................................ Other bisphosphonates ............................... R e c o m m e n d e d selected reading . . . . . . . . . . . . . . . . . . . . . . . . . . .

174 175 175 175

3.9.

Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R e c o m m e n d e d selected reading . . . . . . . . . . . . . . . . . . . . . . . . . . .

178 180

3.10.

Future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

181

0

Index

Commercially

available bisphosphonates

....................................................

ix

..............

182 207

This Page Intentionally Left Blank

Preface

The bisphosphonates are a new class of drug that has been developed in the past three decades for use in various diseases of bone and calcium metabolism. Seven bisphosphonates are commercially available today. Those available, as well as the indications for which they are registered, vary from country to country. A substantial number are in preclinical or clinical development, so in the near future, specialists and practitioners will have the opportunity to choose the most suitable drug and the best regimen to treat an individual patient. Information for the doctor is available today in original articles, reviews, and documentation distributed by the companies selling the various compounds. No complete, easy-to-read publication is available where the practicing doctor can quickly find the necessary information on all bisphosphonates. This book has been written to cover this deficit. It starts with a chapter giving a small aper~u of the physiology of bone. In the preclinical section, it then covers the chemistry, mechanisms of action, and animal toxicology of these compounds. Before addressing the use of the bisphosphonates, which is the main aim of this book, the clinical section discusses the diseases treated by these compounds with respect to their pathophysiology, clinical picture, and treatment with other drugs. After a chapter on adverse events, the book ends with a table containing the trade names of the commercially available bisphosphonates, the registered indications, and the available forms for each country. In order to keep this book concise, it was necessary to simplify many of the issues and therefore to make choices. It is hoped that the result nevertheless faithfully represents the state of the art. Literature had to be kept very restricted, the reader being referred when possible to ones, for further information, the references of original articles being limited to the earliest ones, for historical background, and to the most current articles on the subject.

xi

Preface I express here my gratitude to the late Professor W. F. Neuman, Radiation Biology Department, Rochester, New York, USA, where the seeds of this work were planted; to the late Professor A. Fleisch; to Professor M. Allg6wer; to Professor M. E. Miiller; and to the Canton of Berne, who gave me the opportunity to pursue and develop this research in the Department of Physiology of the University of Lausanne, the Laboratory for Experimental Surgery, Davos, and the Department of Pathophysiology of the University of Berne. I also thank Dr. M. D. Francis, with whose collaboration the bisphosphonates were born; my collaborators over these many years, who have allowed an idea to become reality; my colleagues S. Adami, J. P. Bilezikian, J.-J. Body, P. D. Delmas, T. A. Einhorn, J. L. Ferretti, J. A. Kanis, T. J. Martin, P. J. Meunier, G. R. Mundy, S. E. Papapoulos, L. G. Raisz, R. Rizzoli, G. A. Rodan, R. Rubens, R. G. G. Russell, R. K. Schenk, E. Seeman, F. R. Singer, and E. S. Siris, who have read and improved various parts of this work. The first edition appeared in 1993. Since then second and third updated English versions, as well as Italian, Japanese, Spanish, and German versions, have been published. In view of the very rapid development in this field, it seemed appropriate to prepare an updated fourth English edition.

Herbert Fleisch Av. Ddsertes 5 CH-1009 Pully, Switzerland

xii

1.

1.1. 1.1.1.

Bone and mineral metabolism

BONE

PHYSIOLOGY

Morphology

Macroscopically, bone can be divided into an outer part called cortical or compact bone, which makes about 80% of the total skeleton, and an inner part named cancellous, trabecular, or spongy bone. This structure, an outer cortical sheath and an inner three-dimensional trabecular network, allows optimal mechanical function under customary loads.

Biomechani, adaptation pp. 19-20

Bone is a superb engineering construction with an outer compact sheath and an inner trabecular scaffold allowing optimal mechanical properties. -+

Microscopically, woven and lamellar bone can be distinguished. Woven bone is the type formed initially in the embryo and during growth, and is characterized by an irregular array of loosely packed collagen fibrils. It is then replaced by lamellar bone, so that it is practically absent from the -+ adult skeleton, except under pathological conditions of rapid bone formation, such as occur in Paget's disease, fluorosis, or fracture healing. In contrast, lamellar bone is the form present in the adult, both in cortical and in cancellous bone. It is made of well-ordered parallel collagen fibers, organized in a lamellar pattern.

Histologically bone formed during growth is of the woven type; in the adult it is lamellar, except in certain diseases with rapid formation.

Paget's disea p. 71

1. Bone and mineral metabolism

Bone is made of basic units called bone structural units (BSUs). In cortical bone these are called osteons or Haversian systems, which represent its basic structural building blocks. These are hollow cylinders of a median length of 2 mm, but which can reach 8 mm, and 200 btm in diameter, made of concentric lamellae, between which the osteocytes are located. In the center is a canal containing the nutrient blood vessels. These anastomose with vessels from other osteons so that the various osteons are in communication with one another. The diameter of the osteon is always about 200 ~tm, regardless of species, the maximal distance of any part from the central vessel being no more than 100 btm, this being the largest transport distance for nutrients. Osteons are separated from one another by so-called cement lines.

Compact bone Interstitial

Vascular canal

I

~ ~'2~J ' "t ,,a'~ ' ~ ,

, ~ ; ~ " ~' ~i~' , X q g .~ -~" ." ,.f., ;- ol

Fig. 1.1-1 Cross section of compact bone showing osteons with osteocytes (left), and--in polarized lightmwith collagen lamellae (right). [From Schenk, R. K., et al. (1993). Reproduced from Royce, P. M., and Steinmann, B. (eds.) (1993 ). Connective Tissue and Its Heritable Disorders. Molecular Genetic, and Mineral Aspects, pp. 85-101, with copyright permission from the author and John Wiley & Sons, Inc.]

4b.

The osteon is the basic u n i t o f the Haversian bone o f the cortex.

Remodeling packets and BMUs p. 13

Osteoporosis p. 124

The trabeculae also consist of structural units, which in this location § are called packets. They are separated, as are the osteons of the cortex, by cement lines. When they are on the surface and not yet terminated, they are called bone multicellular units (BMUs). However, BMUs and packets are also found on the inner surface of the cortex, which therefore looks very much like trabecular bone. These two locations, trabeculae and inner cortex, are those that are affected predominantly by osteoporosis. Trabeculae generally possess no vessels and are therefore nourished from the surface. This explains why they cannot become much thicker than about 2 0 0 - 3 0 0 btm, twice the distance of 100 ~tm over which transport of nutrients is possible.

1.1. Bone physiology Fig. 1.1-2 Trabecular bone showing individual packets separated by cement lines. (Courtesy of Dr. R. K. Schenk.)

Trabecular bone ~

,~

,

~.~

Packets

Cement lines

1.1.2.

Composition of bone

Bone is made up of mineral, a fibrillar organic matrix, cells, and water. Fig. 1.1-3 of bone.

Composition

Composition of bone Mineral -65%

Matrix -35% Cells

Hydroxyapatite

Collagen -90% Other prQteins Lipids Osteoblasts Lining cells Osteocytes Osteoclasts

Water

Mineral Mineral accounts for about two-thirds of the total dry weight of bone. It is made of small crystals of about 2 0 0 - 4 0 0 A x 35-75 fii x 1 0 - 4 0 ~i in the shape of plates, located within and between the collagen fibrils. Chemically it is a calcium deficient apatite, containing, however, many other constituents, among others H P O 4 - , carbonate, citrate, magnesium, sodium, fluoride, and strontium. These are either incorporated into the crystal lattice, or adsorbed onto the crystal surface. For this reason, the more general term calcium phosphate will be used in this book for bone mineral. Some substances, such as tetracyclines, polyphosphates, and bisphosphonates, have a special affinity for calcium phosphate and hence for bone. They are deposited in preference on the mineral at sites of new bone formation, but can also be deposited at other sites such as resorption areas. This bone seeking property has been utilized in the case of tetracyclines

Deposition of bisphosphonates in bone p. 57

1. Bone and mineral metabolism

Paget's disease p. 70

in order to label newly formed bone, thus enabling the assessment of bone formation. Indeed, by administering tetracycline, a fluorescent molecule, twice or more at known time intervals, it is possible to measure in bone biopsies the distance between the two lines of deposition of the fluorochrome, thus enabling the quantification of the bone formed during the time interval. The binding of polyphosphates and bisphosphonates, when linked to 99mTc, is used in nuclear medicine to visualize hot spots of bone formation by scintigraphy. This technique is especially useful for detecting skeletal metastases and the bone lesions in Paget's disease. Lastly, the strong binding of bisphosphonates to bone mineral is fundamental to their pharmacological activity. The binding of these substances is usually reversible at sites where the bone surface is accessible to the extracellular fluid. However, it is irreversible at sites which become buried by new bone formation, until the bone with the bone seeker is destroyed again during modeling or remodeling.

The bone mineral is made essentially of impure calcium apatite. Foreign substances such as tetracyclines, polyphosphates, and bisphosphonates can also be incorporated with high affinity.

M D and bone turnover p. 136

The mineral crystals are deposited within and between the collagen crystals in a manner which gives the bone tissue its compressive strength and stiffness. The process of mineralization proceeds rapidly initially, to proceed subsequently over months and years with decreasing speed, a process called secondary mineralization. This property explains why old bone is more mineralized and has a higher mineral density when measured by DXA than a younger one, and why a decrease in bone turnover is accompanied by an increase in bone density. The mineralization process is under the modulation of both activators and inhibitors. Thus, the collagen fibrils themselves as well as other proteins can act as activators, while pyrophosphate and proteins such as matrix gla-protein can act as inhibitors.

Organic matrix

Measurement of bone turnover p. 21

The matrix amounts to about 35 % of the dry weight of bone. It consists of 90% collagen, which is thus by far the most abundant bone protein. Its complex three-dimensional structure, comparable to that of a rope, gives bone tissue its tensile strength. The remainder of the bone matrix is made up of various noncollagenous proteins, the role of which is not yet well understood. The most abundant are osteonectin, osteocalcin, previously called bone gla-protein (BGP), osteopontin, and bone sialoprotein. Because some of them are synthesized and deposited almost exclusively in bone, their urinary excretion and plasma or serum levels are used clinically to assess bone turnover.

1.1. Bone physiology The organic matrix also contains a large amount of various growth factors, especially transforming growth factor [3 (TGF[3) and insulin-like growth factor II (IGF II). These are thought to play a role after their release during bone resorption in the local modulation of bone formation during the turnover of the BSUs, and in the growth of tumor cells in bone metastases.

Effect on bone metastases p. 89

Bone matrix is made up of 90% collagen and about 10% ol:various noncollagenous proteins. It contains many growth factors which may play a role, when released, in bone turnover and in tumorinduced bone disease. Bone cells Osteoblasts The osteoblasts, which derive from mesenchymal progenitors, are the cells that synthesize the bone matrix. They form an epithelial-like structure at the surface of the bone and are connected by gap junctions containing connexins. These and the cell adhesion molecules of the cadherin superfamily are thought to play an essential role in the control of osteoblast formation and function. The osteoblasts secrete unidirectionally the osseous organic matrix which, in a second step, then calcifies extracellularly. As a consequence of the time lag between the formation of the matrix and its calcification, there is a layer of unmineralized matrix osteoid under the osteoblasts. This osteoid seam diminishes in width when the rate of bone matrix formation decreases, but it widens when mineralization is delayed. This widening is most prominent when there is an arrest in mineralization, such as in osteomalacia.

Bone formation Marrow Osteoblasts ,

~ o~';~t ..

Osteoid.....f..-'r ~ - ~ , ,

..

~.

~,

Calcified bone Fig. 1.1-4 Lamellar bone formation with osteoblasts and osteoid seam. (Courtesy of Dr. R. K. Schenk.)

Osteomalacia pp. 171-172

1. Bone and mineral metabolism

Remodeling and modeling p. 12

Fluoride in osteoporosis p. 132

Corticosteroidinduced osteoporosis p. 126

The modulation of bone formation is still poorly understood. Histologically it seems to occur at the level of the recruitment of new osteoblasts as well as through modification of the activity of the mature osteoblasts. Although many hormones and cytokines influence osteoblasts in vitro, among them the insulin-like growth factors (IGFs), transforming growth factor [3 (TGFf3), acidic and basic fibroblast growth factors (FGFs), platelet-derived growth factor (PDGF), bone morphogenetic proteins (BMPs), and prostaglandins, their individual roles in vivo are not yet clear. Some of them are thought to mediate cell to cell messages that stimulate or inhibit bone formation and resorption in specific sites. They are the consequence to the strains produced in bone by mechanical use. This results not only in bone remodeling, but also in bone modeling, both during growth and in the adult. Very recently it was found that a peptide made by fat cells, called leptin, decreases bone formation through a yet unknown central hypothalamic pathway. This opens a fascinating new aspect in our understanding of the regulation of bone mass. One of the main aims of current research is to develop molecules that will increase bone formation. Up to now the only substances that are active in this direction, when given systemically, are fluoride, parathyroid hormone, and certain cytokines such as prostaglandins and IGF-1. Of these only fluoride has been used therapeutically to date in clinical practice, namely, in osteoporosis. However, the increase in bone mass produced by fluoride did not induce a decrease in fracture incidence. Parathyroid hormone is under investigation and looks very promising. When locally administered in the proximity of bone in animals, various growth factors such as TGFf3, basic FGF, PDGF, and BMPs induce bone formation at the site of injection. These, as well as others, such as the IGFs, could prove useful in the future for such indications as improving fracture healing, filling osseous defects, and possibly inducing ridge augmentation in periodontology. Whether systemic administration will become possible is unknown. Effects on other organs are likely to make this development difficult. However, it might be possible to modulate their local synthesis. Thus, HMG Co-A reductase inhibitors, compounds called statins which reduce serum cholesterol, increase bone formation in vitro and in vivo, apparently by increasing BMP-2 production. Recently it was reported that the use of statins may be associated with higher BMD and lower fracture risk in older women. It is also hoped that the discovery of transcription factors for osteoblast differentiation, such as Cbfal, will open new aspects in our search for stimulators of bone formation. In contrast, corticosteroids inhibit bone formation, possibly because they induce osteoblast apoptosis (programmed cell death), explaining why chronic administration of these compounds leads to osteoporosis both in animals and in humans.

1.1. Bone physiology Fig. 1.1-5 Possible physiological and pharmacological modulators of bone formation.

S~ste~e Fluoride PTH Prostaglandins Cytokines

BMPs TGF[3 IGFs

Corticosteroids

FGFs PDGF Prostaglandins

Bone is formed by the osteoblasts. Their modulation and therefore

the modulation of bone formation are still little understood. Lining cells When the osteoblasts are not in the process of forming bone, they are flat and are called resting osteoblasts or lining cells. Active and resting osteoblasts form a membrane at the surface of the bone tissue, which may be important in constituting some kind of blood-bone barrier able to assure a characteristic osseous milieu intSrieur.

Resting osteoblasts at the surface of the bone are called lining cells and constitute a blood-bone barrier. Osteocytes At a certain moment some of the osteoblasts stop synthesizing matrix and become embedded within bone. They are then called osteocytes. Despite the fact that the osteocytes are the most numerous cells in bone, their function is still poorly understood. They are located in lacunae and are interconnected by long cytoplasmic processes among themselves and with the osteoblasts and the lining cells. Gap junctions at the membrane contact sites make a functional syncytium, allowing bone to respond to stimuli over large areas. These cell processes are located within canaliculi, which contain, together with the lacunae, the so-called bone fluid. As the surface

Morphology of cell connections p. 2

1. Bone and mineral metabolism of these lacunae and canaliculi is very large, in humans about 1000 m 2, the bone fluid is in immediate contact with the mineral, with which it is in equilibrium. The osteocytes are thought to influence the composition of this bone fluid. Since the latter is also related to the extracellular fluid and therefore to blood, the osteocytes may play a role in the regulation of plasma minerals, especially calcium. Osteocytes are also well located for responding to mechanical strain and are thought today to play a key role in transducing mechanical loads into changes in bone formation and bone resorption. Like other cells osteocytes undergo apoptosis.

The role of the osteocytes is still little understood. They are probably involved in the homeostasis of bone fluid and consequently in the homeostasis or:plasma calcium, and in the adaptation of bone in response to mechanical influences. Osteoclasts

Remodeling p. 13

The fourth type of cell in bone is the osteoclast. It originates from a different lineage to that of the other bone cells, namely from the hemopoietic compartment, more precisely from the granulocyte-macrophage colonyforming unit (GM-CFU). Osteoclasts are usually large multinucleated, sometimes mononucleated cells that are situated either on the surface of the cortical or trabecular bone, often in depressions called Howship's lacunae, or within the cortical bone. They are located at the tip of the remodeling units, drilling the vascular canals in which the new osteons will be formed. The role of osteoclasts is to resorb bone. This is performed in a closed, sealed-off microenvironment located between the cell and the bone, delimited by a peripheral actin-rich ring of tight adherence between the cell membrane and bone matrix. This specialized adhering site of the cell, called the clear zone, involves cell membrane receptors, called integrins, which recognize specific peptide sequences in the matrix. Covering this microenvironment is another specialized part of the cell membrane, called the ruffled border, which secretes two types of products, both leading to bone destruction. The first, the H § ions, which dissolve the bone mineral, originate from HECO 3 as a result of the action of carbonic anhydrase and are secreted by means of a proton ATPase. The second category includes various proteolytic enzymes, such as cathepsins, especially cathepsin K, and possibly collagenases, such as matrix metalloproteinase 1, which digest the matrix. Current investigations are directed toward the development of specific inhibitors of these various processes, with the aim to develop drugs that will decrease bone destruction.

1.1. Bone physiology

Osteodast

Clear zone Nucleus Ruffled border Bone Fig. 1.1-6 Electron micrograph of an osteoclast. [Reproduced from Schenk, R. K. (1974). Verh. Dtsch. Ges. Pathol., 58, 72-83, with permission from the author and publisher.] Nucleus

? .~--~7-------.~:~ Ca, P, Peptides

Mitochondrion~~

. .-~

Clear z o n e - . . . - _ . ~ ~ : ~ ~ ~ / ! ~ ,.,~,.~:. g l ? ' / / A ~ 9

'~:"

'" ....

"

..... ,

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Fig. 1.1-7 Diagram of an osteoclast. N, nucleus. [Adapted from Schenk, R. K. (1974). Verh. Dtsch. Ges. Pathol., 58, 72-83, with permission from the author and publisher.] Bone resorption can be modulated by altering three basic processes, namely the recruitment of new osteoclasts, the life span of the latter which is programmed by the time when they will undergo apoptosis, and the activity of mature osteoclasts. All three processes are influenced by a series of cytokines and hormones. Recent results indicate that all three processes seem to be under the control of cells of osteoblastic lineage, which synthesize factors influencing directly the osteoclasts and their precursors.

Bone resorption is modulated by altering recruitment of osteoclasts, their life span, and their activity.

1. Bone and mineral metabolism

Osteoclast recruitment and activation

Fig. 1.1-8 Modulation of bone resorption: role of the osteoblast lineage cells.

Recruitment Precursor

~i

ResorbingOsteoclast ~) Osteoblast lineage cell

Activation Inactive Osteoclast

Resorbing Osteoclast

The three main hormones modulating bone resorption are parathyroid *hormone (PTH), 1,25(OH)2 D (calcitriol), and calcitonin, the first two increasing, the latter decreasing resorption. Furthermore, estrogens in women and testosterone in men inhibit bone resorption. This is why menopause and ovariectomy, as well as orchidectomy, induce an increase in bone resorption, mediated possibly in part by an increase in IL-1, IL6, and tumor necrosis factor a (TNFa). PTH-related protein, a peptide which has a resemblance to PTH, and binds to one of its receptors, also increases bone resorption. Its main role is probably during fetal life where it modulates, among others, chondrocyte differentiation in the growth plate. In the adult it plays a major role Tumor bone in tumor bone disease, favoring bone resorption and hypercalcemia. disease Whether it contributes to plasma calcium homeostasis and to bone homepp. 88, 91 ostasis in the adult is not known. Among the most important cytokines that can increase bone resorption, at least in vitro, and are possibly involved in this process in vivo, are the interleukins 1, 3, 6, and 11 (IL-1, IL-3, IL-6, IL-11), tumor necrosis factor a and 13 (TNFa, TNFf3), macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF), and prostaglandins. Interferon T (IFNT), TGFf3, IL-4, and IL-13 as well as IL-1 receptor antagonist on the other hand, decrease bone resorption. Some of these cytokines are produced by the cells of the osteoblastic lineage and are therefore possibly involved in the "osteoblast- osteoclast axis. Recently a novel factor inhibiting osteoclast formation and activity, called osteoprotegerin (OPG), has been discovered. It is a soluble glycoprotein of the TNF superfamily, which is produced by stromal cells, osteoblastic lineage cells, and pre-B cells. Acting as a decoy receptor, it binds Calcium homeostasis pp. 17-18

10

1.1. Bone physiology to an osteoclastic differentiation factor called RANK ligand (RANKL), or ODF, which is located on the membrane of the osteoblastic lineage cells. By doing so, it inhibits the binding of the latter to its transmembrane receptor on the osteoclast (RANK), an osteoclast differentiation and activation stimulator, and thus inhibits osteoclast recruitment, involving the transcription factor NF-•I3. Osteoprotegerin inhibits bone resorption both in vitro and in vivo. Its synthesis, and that of RANKL, are modulated by hormones and cytokines affecting bone resorption, and it is likely that they play a major role in the modulation of osteoclastic bone resorption. All these proteins have various names in the literature, the above being used most commonly today. Fig. 1.1-9 Possiblemodulators of bone resorption.

Bone resorption Increase

Decrease Systemic

PTH PTHrP Calcitriol Thyroxin

Calcitonin Estrogen Testosterone

Local IL-1 IL-6 IL-11 IL-17 FGFs Prostaglandins RANKL

TNF(z TNFI3 TGF(z M-CSF GM-CSF SCF

TGF]3 IFN7 IL-4 IL-10 IL-13 IL-18 IL-lra Osteoprotegerin

Bone resorption is performed by the osteoclast. Its recruitment, activity, and apoptosis are under the modulation of a series of hormones and cytokines and under the control of the cells of osteoblastic lineage. Recently a new inhibiting mechanism involving a glycoprotein from the TNF superfamily called osteoprotegerin has been described.

11

1. Bone and mineral metabolism

Other cells Bone marrow contains many other cells, among them hemopoietic, immune, and stromal cells. They are not only important for the formation of the osteoclasts, but also interrelate with the bone cells through various cytokines and appear to be involved thus in the modulation of both the formation and resorption of bone. Thus it is not fortuitous that bone marrow and bone are in close proximity.

1.1.3. Modeling and remodeling

Biomechanical adaptation p. 19

Calcium homeostasis p. 17

Osteoporosis pp. 124-125

Bone is built during fetal life, youth, and adolescence by two fundamental mechanisms: endochondral ossification, whereby bone is built on a cartilaginous scaffold, and intramembranous ossification where it is formed directly without the latter. The correct elaboration of the definitive form is under the control of numerous genes which are gradually being elucidated. Once formed, the shape and structure of the bones is continuously renovated and modified by the two processes of modeling and remodeling. In the modeling, which takes place principally during growth, new bone is formed at a location different from the one destroyed. This therefore results in a change in the shape of the skeleton. It allows not only the development of a normal architecture during growth, but also the modulation of this architecture in the adult when the mechanical conditions change. Furthermore it is the cause of the increase in size of the bones during life. Modeling is the main process by which the skeleton can increase its volume and its mass. In remodeling, which is the main process in the adult, the two processes are coupled in space and time, so that no change occurs in the shape of the bone. Both modeling and remodeling, however, result in the replacement of old bone by new bone. This allows the maintenance of the mechanical integrity of the skeleton, which is illustrated by the fact that in diseases where bone resorption is impaired, such as in osteopetrosis, bone becomes fragile and fractures occur. The turnover also allows the bone to play its role as an ion bank. The remodeling rate is between 2 and 10% of the skeletal mass per year. It can be either a systemic process which occurs more or less randomly, or a targeted one, occurring at special sites of the skeleton. The former is increased by parathyroid hormone, thyroxin, growth hormone, and 1,25(OH)2 D, and decreased by calcitonin, estrogen, and glucocorticosteroids. It is also stimulated by microfractures and modulated by the mechanical strain environment. The cancellous bone, which represents about 20% of the skeletal mass, makes up 80% of the turnover, while the cortex, which represents 80% of the bone, makes up only 20% of the turnover. This explains why osteoporosis, which is the result of

12

1.1. Bone physiology an abnormal turnover and balance, is seen first and mainly in cancellous bone.

Bone is continuously turned over by modefing and remodeling, the rates of which are under hormonal and mechanical influence. Cancellous bone accounts for 80% of the turnover, although it represents only 20% of the skeleton. The morphological dynamic structure of turnover is the basic multicellular unit (BMU), also called bone remodeling unit (BRU). The morphological entity formed when the process is terminated is called the bone structural unit (BSU), which corresponds to the packet in cancellous bone and to the osteon in cortical bone. Both in the cortex and in the trabeculae, the process of remodeling starts in the same way by bone being eroded by osteoclasts. In a second step, the resorption sites are refilled by the osteoblasts. The tight coupling of bone resorption followed by bone formation emphasizes the necessity for a previous occurrence of bone resorption to trigger bone formation at the same site. The linear resorption rate of osteoclasts is about 50 ~tm per day. The formation rate is slower, about 1 ~tm per day for lamellar, more for woven bone. The time required for the completion of a new BSU is between 3 and 5 months.

Cortical remodeling unit Old bone

Osteoclasts Vasculargap Osteoblasts Osteoid "~ Fig. 1.1-10 Cortical bone remodeling. Osteoclasts located at the tip of the cutter cone erode a canal within the bone. Osteoblasts present on the lateral walls will refill it and form the osteon. [From Schenk, R. K. et al. (1993). Reproduced from Royce, P. M., and Steinmann, B. (eds.) Connective Tissue and Its Heritable Disorders. Molecular Genetic, and Mineral Aspects, pp. 85-101. Copyright 9 1993, by permission of the author and John Wiley & Sons, Inc.]

13

BMUs BSUs p. 2

1. Bone and mineral metabolism Trabecular remodeling Osteoclast

, ~r g

| ,. ",~

~

a,~ ~ "

.,.

Bone

Fig. 1.1-11 Cancellous bone remodeling. The process is similar to that in the cortex but occurs at the surface. Osteoclasts erode a burrow which is then refilled by osteoblasts. [From Schenk, R. K., et al. (1993). Reproduced from Royce, P. M., and Steinmann, B. (eds.) Connective

Tissue and Its Heritable Disorders. Molecular Genetic, and Mineral Aspects, Osteoblasts

.... ,

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......"

~- f ~ .~ ~.

~:

pp. 85-101. Copyright 9 1993, by permission of the author and John Wiley & Sons, Inc.]

Osteoid ~

Cement line "Packet" of

~ ~

ewbone

tDone structural unit)

~.~ .~,.~,

The basic dynamic unit of bone remodeling is the basic multicellular unit, called usually just BMU.

It was generally t h o u g h t in the past that, while the erosion in the cortex was a longitudinal process along the long axis of the bone, this was not the case for the trabeculae. There the osteoclasts w o u l d just erode a pit perpendicularly to the surface, which w o u l d then be refilled by osteoblasts. Recent evidence showed that this is not the case and was due to a misinterpretation of the morphological appearance. Indeed, the osteoclasts also erode bone longitudinally in the trabeculae, excavating a burrow, this time at the surface of the bone. Once refilled, this is called a

14

1.1. Bone physiology hemiosteon by analogy with the intracortical osteon. This new concept has important practical implications. The amount of bone resorbed will depend not only on the number of new BMUs formed and on the depth of the burrow, but also on its length, that is on the duration of life of the osteoclasts.

At the surface of the trabeculae the erosion process is similar to that occurring in the cortex, namely, the formation followed by refilling of a burrow, called then a bemiosteon. Normally the amount of bone formed during bone remodeling equals the amount destroyed, so that the balance is zero. The mechanism underlying the balance and the coupling between the resorption and the formation processes is still unknown and the subject of intensive investigation. It is thought that both local formation of cytokines and their local release during resorption play a major role in healthy as well as in diseased bone. The elucidation of these mechanisms may help to explain the cause of bone loss in osteoporosis, in which more bone is being destroyed than formed, resulting in a negative balance. This imbalance is seen, for example, after the menopause or during immobilization. Similarly this local interplay also probably has a major role in the development of osseous metastases.

Osteoporosi p. 127 Tumor bon~ disease p. 88

In the steady state, the amount of bone formed in the remodeling process equals the amount destroyed. If more bone is destroyed than formed, bone loss occurs and osteoporosis may develop. A special situation arises in periods where turnover rates change, for example, after the administration of an inhibitor of bone resorption. Since there is a time interval between the beginning of the inhibition of the resorption process and the start of the secondary decrease in formation, the ongoing bone formation will produce a transient net gain of bone whenever the turnover rate decreases. This time interval explains why after the administration of an inhibitor of bone resorption, such as a bisphosphonate, markers of bone resorption such as urinary hydroxyproline and pyridinium cross-links decrease sooner than markers of bone formation such as plasma alkaline phosphatase and osteocalcin. The amount of bone gained in this way, sometimes called the remodeling space, may account for up to a total of 2%, more for trabecular bone volume, or when the turnover is rapid, less for the cortex.

15

Turnover m arkers

p. 21

1. Bone and mineral metabolism Fig. 1.1-12 Influence of changes in turnover on calcium balance.

Inhibition of bone turnover Resorption inhibitor Bone formation .

.

.

.

/ ! .

.

.

.

.

I

J

Bone resorption

+

Balance

\

. . . . . .

Time

Inhibition of resorption and BMD p. 15

Furthermore, after inhibition of turnover, osteons have more time to complete their mineralization, so that some calcium will still be taken up by the not yet completely mineralized matrix, accounting for another 1 - 2 % increase in calcium. Thus a total elevation of 3 - 4 % in skeletal calcium, and therefore of bone mineral density, usually called BMD, may occur, possibly more if turnover is higher. However this increase of BMD does not represent faithfully an increase of bone mass, since part of it is due just to an increase in the mineralization of the bone present, and not to an increase of the whole bone tissue. Thus some of the increase in BMD seen with various inhibitors of bone resorption such as estrogens, calcitonin, and bisphosphonates are a true durable augmentation neither of bone mass, nor density, and will be reversed if the inhibition is stopped. This fact has often been neglected in the literature. In contrast, the gain in BMD may remain if bone turnover is maintained at the lower level.

When turnover rate is decreased, a transient increase of bone mineral density, called BMD, occurs, which is, however, at least partially reversed when turnover normalizes again.

1.1.4.

C a l c i u m homeostasis

Calcium concentration in plasma is around 10 mg per 100 ml. About 40% of this amount is bound to proteins and 10% to ultrafilterable ions, so that approximately only one-half is ionized. The level of ionized plasma calcium and not of total calcium is the fraction that is tightly controlled throughout the animal world. This has led some authors to call ionized

16

1.1. Bone physiology calcium one of nature's physiological constants. This constancy is explained by the importance of extracellular calcium for many biological processes. Nevertheless, for clinical purposes, and as long as there is no disturbance in plasma proteins and plasma pH, measurement of total calcium is usually sufficient. In some conditions, however, such as in tumor bone disease, plasma proteins are disturbed to such an extent that a correction is necessary.

Plasma ionized calcium, and not total calcium, is the fraction that is tightly controlled. The level of ionized calcium, and therefore of plasma calcium, is set by the interaction of the three target organs: intestine, bone, and kidney. The level will depend on the fluxes between extracellular fluid and therefore blood, and these three organs. For bone the relative roles played by bone resorption and by the equilibrium at the surface of the apatite crystals is still debated. Probably the latter is more relevant for the short-term steady state regulation. Fig. 1.1-13 Calcium homeostasis in the body.

Calcium homeostasis

Gastrointestinal Tract Blood

~

Bone

Kidney I

The level of ionized calcium is set by the interaction of the three target organs: intestine, bone, and kidney. In bone, the equilibrium at the surface of the crystals is probably also important. The fluxes of calcium are controlled mainly by three hormones, parathyroid hormone (PTH), the vitamin D metabolite 1,25(OH)2 D (calcitriol), and possibly calcitonin, although the last has not yet been proved to act physiologically. All three are directly regulated by plasma calcium levels through a feedback mechanism. Whether the three hormones, or at least some of them, also control the bone surface equilibrium is likely, but not proven.

17

Correction t plasma proteins p. 93

1. Bone and mineral metabolism Blood calcium is regulated mainly by the three hormones parathyroid hormone, 1,25(0H)2 D, and possibly calcitonin. Of the three hormones, the most important is parathyroid hormone, which increases plasma calcium by action on all three target organs. Thus it increases bone resorption, increases the intestinal absorption of calcium, although indirectly through an elevation of 1,25(OH)z D, and increases renal tubular reabsorption of calcium. Since the production of parathyroid hormone is inversely related to plasma calcium and is rapidly modulated through a calcium-sensing receptor located in the parathyroid gland, this hormone provides an excellent rapidly working negative feedback mechanism. The hormone 1,25(OH)2 D increases intestinal calcium absorption and bone resorption and enhances the capacity of PTH to increase renal Ca reabsorption. Since its production is also stimulated by low plasma calcium, it provides a regulatory feedback mechanism too. However, in contrast to parathyroid hormone, which is modulated and acts within minutes, 1,25(OH)2 D requires hours. Vitamin D metabolites are also required for normal mineralization of bone, 1,25(OH)2 D and possibly 24,25(OH)z D forms being the most important. Finally, calcitonin inhibits bone destruction. This property is used therUse in Paget's apeutically in diseases with increased bone resorption, such as Paget's disease disease and osteoporosis. Since its production is rapidly modulated by p. 72 plasma calcium through positive feedback, this hormone could also theUse in oretically provide good feedback regulation. Its relevance in humans for osteoporosis p. 132 calcium homeostasis is, however, not yet established. Bone resorption p. lO

Fig. 1.1-14 Roleof parathyroid hormone, 1,25(OH)2 D, and calcitonin in calcium homeostasis.

Hormones and calcium homeostasis

Gastrointestinal Tract ~, ~" 1,25D+

1,25D+ one

~;'"/" ~

PTH+I~

PTH+ 1,25D+ CT-

Kidney ~

Plasma calcium levels regulate parathyroid hormone, 1,25(0H) 2D as well as calcitonin, providing an excellent homeostatic feedback mechanism for maintaining plasma calcium homeostasis. 18

1.1. Bone physiology Thus the three target organs, intestine, kidney, and bone, are intimately linked with respect to calcium homeostasis. Consequently, a disturbance in one of these organs will affect the others. Because 99% of the body cal-+ cium is located in the skeleton, this organ will act as a reserve of the ion. In the case of calcium shortage, the homeostatic mechanisms will work to the detriment of the bone in order to maintain plasma calcium, which seems to have absolute priority. It is not yet clear what the daily intake of calcium should be for humans. It is thought today that at least I g is necessary in adult life, somewhat more in adolescents, and 1.5 g in the elderly as well as during pregnancy and lactation. If this is true, a large part of the population would be chronically calcium deficient, since its daily intake is usually only about 0.5 g. It is interesting that in the animal kingdom, humans have by far the lowest calcium intake in relation to body weight, and that our ancestors in the Stone Age ate apparently about three times as much calcium as we do. Calcium deficiency may possibly explain in part the bone loss during the second part of life, since calcium absorption decreases in the elderly, who may have vitamin D deficiency or a disturbance in its metabolism and action. A decrease in calcium absorption due to malabsorption, or a loss in the urine such as in renal hypercalciuria, may also induce bone loss. 1.1.5.

B o n e as an o r g a n

In addition to these homeostatic mechanisms at the service of plasma calcium, other mechanisms exist which allow bone to maintain its own in-+ tegrity. First, bone architecture is under the control of a biomechanical cybernetic system, called a mechanostat, that controls bone's modeling of its spatial organization, and its load carrying capacity and ability to transfer loads. To allow this, the strains induced by external mechanical influences appear to play an essential role by altering both modeling and remodeling. This system also has a feed-back loop. Indeed, a loss of bone, or a deterioration of the mechanical property of the bone tissue itself, will increase the strains induced, leading to increased bone formation and/or decreased bone resorption, and therefore a subsequent change in bone mass. These mechanisms allow bone to adapt its structure to function and to fulfill its mechanical role optimally. They explain why the trabeculae of cancellous bone are oriented along the prevailing lines of pressure and traction and why they change if these are altered, for example, after an orthopedic operation that alters the axis, or locally after destruction of individual trabeculae (Fig. 1.1-15). Besides these mechanisms, the bone ensures its own integrity during aging. Apart of the generalized remodeling, which is under endocrine control, the microcracks, which occur constantly during life, stimulate bone remodeling and therefore their own repair. This allows old bone to 19

Calcium in osteoporosis p. 132

1. Bone and mineral metabolism be replaced by young bone and permits the skeleton to keep its mechanical strength.

Bone structure and function

R/

]vl,! i

-'3"

~

o.~

Osteocytes p. 8

Fig. 1.1-15 Adaptation of bone structure to mechanical function along lines of compression and tension. M, muscle pull; R, down direction of load. [Adapted from Pauwels, F. (1960). Z. Anat. Entwickl. Gesch., 121,478-515, with permission from the publisher.]

,,,

,

If the mechanostat does not sense sufficient input, such as in immobi- *-lization, rapid and massive bone loss will occur. The magnitude of the bone loss can be such as to disturb calcium homeostasis and lead to hypercalciuria and even hypercalcemia. Some bone loss also occurs during weightlessness in astronauts. Therefore, one of the rules in osteoporotic patients is to avoid immobilization. The cellular mechanisms underlying these events are yet little understood but are likely to involve the osteocytes and local cytokines. It has been proposed that the mechanostat can be disturbed in some of the metabolic diseases, an interesting hypothesis which deserves further study.

Mechanical forces influence bone turnover and allow the skeleton to maintain an optimal structure to fulfill its mechanical function. Immobilization induces bone loss.

20

1.1. Bone physiology 1.1.6.

Assessment of bone turnover

Bone turnover can be assessed in vivo, although only indirectly. For bone formation the measurements most commonly used are serum alkaline phosphatase, preferentially the bone isoenzyme, and serum osteocalcin. Alkaline phosphatase is produced by the osteoblasts during bone formation. Osteocalcin is specific to bone and is liberated during the formation of matrix by the osteoblasts. Its level in serum is a good index for bone formation, except, for unknown reasons, in Paget's disease. More recently the appearance of certain propeptides liberated during collagen synthesis, such as procollagen I N-terminal extension peptides (PINP), has been used. Bone resorption is evaluated by measuring the urinary excretion of bone collagen breakdown products such as hydroxyproline, pyridinium cross-links, and certain collagen fragments. Collagen contains 10% hydroxyproline. When bone is destroyed, some of this amino acid is excreted in the urine, so that urinary hydroxyproline can be used as an index of bone destruction. However, because urinary hydroxyproline can also originate from nonosseous collagen, and because some of the amino acid is metabolized, this index is not ideal. Furthermore hydroxyproline is also absorbed from dietary collagen, so that the measurements must be performed under a collagen-free diet. The procedure can be simplified by measuring the hydroxyproline/creatinine ratio of the first 2-h morning fasting urine specimen obtained after the urine of the night is voided, and with no intake of collagen the evening before. Better markers of bone resorption, which have now practically replaced hydroxyproline, are the pyridinium cross-links present in collagen. These are formed by the linkage of two collagen molecules to form pyridinoline and deoxypyridinoline. Of the two, the latter is more specific to bone, but both measurements seem to give similar results, so that often both are measured together. No dietary precautions are necessary. Until recently this determination was performed only in specialized laboratories by means of high-pressure liquid chromatography, but the development of immunoassays makes it now more widely available. More recently antibodies have been developed against pyridinium-containing peptides both from the N-terminal and C-terminal telopeptide. These appear in the urine, and their measurement gives excellent results. They appear to be the most useful markers available today. Very recently, assays in plasma have also been developed. Bone formation is assessed by measuring serum alkaline phospha-

tase and osteocalcin; bone resorption previously by measuring urinary hydroxyproline, which has been replaced by pyridinoline cross-links or preferentially peptides containing these cross-links. 21

Markers in Paget's dise~ p. 70

1. Bone and mineral metabolism

Recommended selected reading Books Avioli, L. V., and Krane, S. M. (eds.) (1998). Metabolic Bone Disease and Clinically Related Disorders. (San Diego: Academic Press) Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) (1996). Principles of Bone Biology. (San Diego, London: Academic Press) Favus, M. J. (ed.) (1999). Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th Ed. (Philadelphia: Lippincott Williams & Wilkins) Marcus, R., Feldman, D., and Kelsey, J. (eds.) (1996). Osteoporosis. (San Diego: Academic Press) Mundy, G. R. (1995). Bone Remodeling and Its Disorders. (London: Martin Dunitz) Mundy, G. R., and Martin, T. J. (eds.) (1993). Physiology and Pharmacology of Bone. Handbook of Experimental Pharmacology, vol. 107. (Berlin, Heidelberg, New York: Springer-Verlag) Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) (1999). Dynamics of Bone and Cartilage Metabolism. (San Diego, London: Academic Press)

Reviews

Morphology Einhorn, T. A. (1996). Biomechanics of bone. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 25-37. (San Diego, London: Academic Press) Einhorn, T. A. (1996). The bone organ system: Form and function. In Marcus, R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 3-22. (San Diego: Academic Press) Eriksen, E. F., Vesterby, A., Kassem, M., Melsen, F., and Mosekilde, L. (1993). Bone remodeling and bone structure. In Mundy, G. R., and Martin, T. J. (eds.) Physiology and Pharmacology of Bone. Handbook of Experimental Pharmacology, vol. 107, pp. 67109. (Berlin, Heidelberg, New York: Springer-Verlag) Marks, S. C., Jr., and Hermey, D. C. (1996). The structure and development of bone. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 314. (San Diego, London: Academic Press) Monier-Faugere, M.-C., Langub, M. C., and Malluche, H. H. (1998). Bone biopsies: A modern approach. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 237-273. (San Diego: Academic Press) Ott, S. (1996). Theoretical and methodological approach. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 231-241. (San Diego, London: Academic Press) Parfitt, A. M. (1992). The physiologic and pathogenetic significance of bone histomorphometric data. In Coe, F. L., and Favus, M. J. (eds.) Disorders of Bone and Mineral Metabolism, pp. 475-489. (New York: Raven) Parfitt, A. M., Mundy, G. R., Roodman, G. D., Hughes, D. E., and Boyce, B. F. (1996). A new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates. J. Bone Miner. Res., 11,150-159 Schenk, R. K., Felix, R., and Hofstetter, W. (1993). Morphology of connective tissue: Bone. In Royce, P. M., and Steinmann, B. (eds.) Connective Tissue and Its Heritable Disorders. Molecular, Genetic, and Medical Aspects, pp. 85-101. (New York: Wiley-Liss)

Chemistry Boskey, A. L. (1999). Mineralization, structure, and function of bone. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 153-164. (San Diego, London: Academic Press)

22

1.1. Bone physiology Gehron Robey, P., and Boskey, A. L. (1996). The biochemistry of bone. In Marcus, R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 95-183. (San Diego: Academic Press) Glimcher, M. J. (1998). The nature of the mineral phase in bone: Biological and clinical implications. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 23-50. (San Diego: Academic Press) Gundberg, C. M., and Nishimoto, S. K. (1999). Vitamin K-dependent proteins of bone and cartilage. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 43-57. (San Diego, London: Academic Press) Hardingham, T. E. (1999). Proteoglycans and glycosaminoglycans. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 7181. (San Diego, London: Academic Press) Heinegard, D., Saxne, T., and Lorenzo, P. (1999). Noncollagenous proteins: Glycoproteins and related molecules. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 59-69. (San Diego, London: Academic Press) Robins, S. P. (1999). Fibrillogenesis and maturation of collagens. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 591604. (San Diego, London: Academic Press) Von der Mark, K. (1999). Structure and biosynthesis of collagens. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 3-29. (San Diego, London: Academic Press)

Cells Aarden, E. M., Burger, E. H., and Nijweide, P. J. (1994). Function of osteocytes in bone. J. Cell. Biochem., 55,287-299 Clark, I. M., and Murphy, G. (1999). Matrix proteases. In Seibel, M. J., Robins, S. P., and Bilezikian, J. p. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 137-150. (San Diego, London: Academic Press) Helfrich, M. H., and Horton, M. A. (1999). Integrins and adhesion molecules. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 111-126. (San Diego, London: Academic Press) Henthorn, P., Mill~n, J. L., and Leboy, P. (1999). Acid and alkaline phosphatases. In Seibel, M. J., Robins, S. P., and Bilezikian, J. p. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 127-136. (San Diego, London: Academic Press) Lian, J. B., and Stein, G. S. (1996). Osteoblast biology. In Marcus, R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 23-59. (San Diego: Academic Press) Lian, J. B., and Stein, G. S. (1999). The cells of bone. In Seibel, M. J., Robins, S. P., and Bilezikian, J. p. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 165-185. (San Diego, London: Academic Press) Martin, T. J., Findlay, D. M., Heath, J. K., and Ng, K. W. (1993). Osteoblast: Differentiation and function. In Mundy, G. R., and Martin, T. J. (eds.) Physiology and Pharmacology of Bone. Handbook of Experimental Pharmacology, vol. 107, pp. 149-183. (Berlin, Heidelberg, New York: Springer-Verlag) Martin, T. J., Romas, E., and Gillespie, M. T. (1998). Interleukins in the control of osteoclast differentiation. Crit. Rev. Eukariot. Gene Expr. 8, 107-123 Nijweide, P. J., Burger, E. H., Klein Nulend, J., and Van der Plas, A. (1996). The osteocyte. In Bilezikian, J. p., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 115-126. (San Diego, London: Academic Press) Raisz, L. G., and Rodan, G. A. (1998). Embryology and cellular biology of bone. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 1-22. (San Diego: Academic Press) Roodman, G. D. (1996). Advances in bone biology: The osteoclast. Endocr. Rev., 17, 3083a2. Suda, T., Takahashi, N., Udagawa, N., Jimi, E., Gillespie, M. T., and Martin, T. J. (1999). Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr. Rev., 20, 345-357 Teitelbaum, S. L., Tondravi, M. M., and Ross, F. P. (1996). Osteoclast biology. In Marcus,

23

1. Bone and mineral metabolism R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 61-94. (San Diego: Academic Press)

Mechanism of bone formation and resorption and its modulation Canalis, E. (1996). Skeletal growth factors. In Marcus, R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 261-279. (San Diego: Academic Press) Croucher, P. I., and Russell, R. G. G. (1999). Growth factors. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 83-95. (San Diego, London: Academic Press) Dempster, D. W. (1999). New concepts in bone remodeling. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 261-273. (San Diego, London: Academic Press) Khosla, S., Spelsberg, T. C., and Riggs, B. L. (1999). Sex steroid effects on bone metabolism. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 233-245. (San Diego, London: Academic Press) Lorenzo, J. A., and Raisz, L. G. (1999). Cytokines and prostaglandins. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 97-109. (San Diego, London: Academic Press) Manolagas, S. C., and Jilka, R. L. (1995). Bone marrow, cytokines, and bone remodeling. N. Engl. J. Med. 332, 305-311 Martin, T. J., Findlay, D. M., and Moseley, J. M. (1996). Peptide hormones acting on bone. In Marcus, R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 185-204. (San Diego: Academic Press) Mundy, G. R. (1993). Hormonal factors which regulate bone resorption. In Mundy, G. R., and Martin, T. J. (eds.) Physiology and Pharmacology of Bone. Handbook of Experimental Pharmacology, vol. 107, pp. 185-214. (Berlin, Heidelberg, New York: SpringerVerlag) Mundy, G. R., Boyce, B. F., Yoneda, T., Bonewald, L. F., and Roodman, D. G. (1996). Cytokines and bone remodeling. In Marcus, R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 302-313. (San Diego: Academic Press) Oursler, M. J., Kassem, M., Turner, R., Riggs, B. L., and Spelsberg, T. C. (1996). Regulation of bone cell function by gonadal steroids. In Marcus, R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 237-260. (San Diego: Academic Press) Raisz, L. G., and Rodan G. A. (1998). Embryology and cellular biology of bone. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 1-22. (San Diego: Academic Press) Reddi, A. H., and Sampath, T. K. (1996). Bone morphogenetic proteins: Potential role in osteoporosis. In Marcus, R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 281-287. (San Diego: Academic Press) Rodan, G. A. (1996). Coupling of bone resorption and formation during bone remodeling. In Marcus, R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 290-299. (San Diego: Academic Press) C a l c i u m homeostasis Azria, M., and Avioli, L. V. (1996). Calcitonin. In Bilezikian, J. p., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 1083-1097. (San Diego, London: Academic Press) Carmeliet, G., Verstuyf, A., Daci, E., and Bouillon, R. (1999). The vitamin D hormone and its nuclear receptor: Genomic mechanisms involved in bone biology. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 217-231. (San Diego, London: Academic Press) Civitelli, R., Ziambaras, K., and Leelawattana, R. (1998). Pathophysiology of calcium, phosphate, and magnesium absorption. In Avioli, L. V., and Krane, S. M. (eds.) Meta-

24

1.1. Bone physiology bolic Bone Disease and Clinically Related Disorders, pp. 165-205. (San Diego: Academic Press) Feldman, D., Mallon, P. J., and Gross, C. (1996). Vitamin D: Metabolism and action. In Marcus, R., Feldman, D., and Kelsey, J. (eds.) Osteoporosis, pp. 205-235. (San Diego: Academic Press) Fitzpatrick, L. A., and Bilezikian, J. P. (1996). Actions of parathyroid hormone. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 339346. (San Diego, London: Academic Press) Fitzpatrick, L. A., and Bilezikian, J. P. (1999). Parathyroid hormone: Structure, function, and dynamic actions. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 187-202. (San Diego, London: Academic Press) Holick, M. F., and Adams, J. S. (1998). Vitamin D metabolism, and biological function. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 123-164. (San Diego: Academic Press) Hruska, K., and Gupta, A. (1998). Disorders of phosphate homeostasis. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 207236. (San Diego: Academic Press) Karaplis, A. C., and Goltzman, D. (1999). PTHrP: Of molecules, mice and men. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 203-216. (San Diego, London: Academic Press) Martin, T. J., Findlay, D. M., Moseley, J. M., and Sexton, P. M. (1998). Calcitonin. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 95-121. (San Diego: Academic Press) Moseley, J. M., and Martin, T. J. (1996). Parathyroid hormone-related protein: Physiological actions. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 363-376. (San Diego, London: Academic Press) Parfitt, A. M. (1993). Calcium homeostasis. In Mundy, G. R., and Martin, T. J. (eds.) Physiology and Pharmacology of Bone. Handbook of Experimental Pharmacology, vol. 107, pp. 1-65. (Berlin, Heidelberg, New York: Springer-Verlag) Potts, J. T., Jr., and J~ippner, H. (1998). Parathyroid hormone and parathyroid hormonerelated peptide in calcium homeostasis, bone metabolism, and bone development: The proteins, their genes, and receptors. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 51-84. (San Diego: Academic Press) Rizzoli, R., and Bonjour, J.-P. (1999). Physiology of calcium and phosphate homeostasis. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 247-260. (San Diego, London: Academic Press)

Measurement of bone t u r n o v e r Brixen, K., and Eriksen, E. F. (1999). Validation of local and systemic markers of bone turnover. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 427-436. (San Diego, London: Academic Press) Christiansen, C., Hassager, C., and Riis, B. J. (1998). Biochemical markers of bone turnover. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 313-326. (San Diego: Academic Press) Eyre, D. (1996). Biochemical basis of collagen metabolites as bone turnover markers. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 143153. (San Diego, London: Academic Press) Garnero, P., and Delmas, P. D. (1996). Measurements of biochemical markers: Methods and limitations. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 1277-1291. (San Diego, London: Academic Press) Kraenzlin, M. E., and Seibel, M. J. (1999). Measurement of biochemical markers of bone resorption. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 411-426. (San Diego, London: Academic Press) Naylor, K. E., and Eastell, R. (1999). Measurement of biochemical markers of bone forma-

25

1. Bone and mineral metabolism tion. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 401-410. (San Diego, London: Academic Press) Risteli, J., and Risteli, L. (1999). Products of bone collagen metabolism. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 275-287. (San Diego, London: Academic Press) Seibel, M. J., and Pols, H. A. P. (1996). Clinical application of biochemical markers of bone metabolism. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 1293-1311. (San Diego, London: Academic Press) B o n e as an o r g a n

Rodan, G. A. (1997). Bone mass homeostasis and bisphosphonate action. Bone, 20, 1-4

26

2. Bisphosphonates preclinical

2 . 1 . BACKGROUND TO THE PHARMACOLOGICAL DEVELOPMENT Our knowledge of the biological characteristics of bisphosphonates dates from nearly 30 years ago, the first report having appeared in 1968. The concept was derived from earlier studies in our laboratory on inorganic pyrophosphate. We had found that plasma and urine contained compounds inhibiting calcium phosphate precipitation, and that part of this inhibitory activity was due to inorganic pyrophosphate, a substance that had not been described previously in these fluids. Fig. 2.1-1 Chemical structure of inorganic pyrophosphate.

Pyrophosphate O-I

O-I

o-P-O-P=O I

I

o-

o-

Pyrophosphate is the simplest of the polyphosphates, also called condensed phosphates, compounds which have been used extensively in industry because of their property of inhibiting the precipitation of calcium carbonate. Their main applications were as antiscaling additives in washing powders or water and oil brines to prevent deposition of calcium carbonate scale. 27

2. Bisphosphonatesmpreclinical

Polyphosphates as antiscaling agents

Fig. 2.1-2 Effectof polyphosphates on the deposition of calcium carbonate in a water pipe. [Adapted from Rudy, H. (1960). Altes und Neues

iiber kondensierte Phosphate. (Ludwigshafen am

Rhein: J.A. Benckiser, GmbH). Reproduced with permission from the publisher.]

No addition

With addition

Inorganic pyrophosphate, a compound of the family of the polyphosphates, used industrially [:or their property or: inhibiting calcium carbonate, is present in biological fluids. We then found that pyrophosphate binds very avidly to calcium phos- *-phate and impairs both the formation of calcium phosphate crystals in vitro and their dissolution. Pyrophosphate was then shown to inhibit calcification, also in vivo. Various types of ectopic calcification were efficiently prevented by the parenteral but not the oral administration of the compound. In contrast, no effect was found on bone resorption. This was explained by the possible hydrolysis of pyrophosphate when given orally and at the sites of bone destruction. These results led us to propose that pyrophosphate might be a physiological regulator of calcification and perhaps also of decalcification in vivo, its local concentration being determined by the activity of local phosphatases and other pyrophosphatases.

Inorganic pyrophosphate inhibits both the formation and the dissolution of calcium phosphate in vitro. In vivo it prevents ectopic calcification. It might be a physiological regulator of mineral deposition and dissolution. Because of its failure to act when given orally as a result of its rapid hydrolysis, pyrophosphate found a therapeutic use only in two indications. In view of its strong affinity for calcium phosphate and therefore for bone mineral, it is used, when linked to 99roTc, in skeletal scintigraphy. Furthermore, it is used as antitartar agents in toothpastes.

Pyrophosphate is used in scintigraphy and as an antitartar agent in toothpastes.

28

2.1. Background

This restricted use prompted us to search for analogs which would display similar physicochemical activity, but which would resist enzymatic hydrolysis and would therefore not be broken down metabolically. We found that the bisphosphonates fulfilled these conditions. In the last 30 years our group has worked, in collaboration with various pharmaceutical companies, on the development of the bisphosphonates and the elucidation of their mode of action, which is primarily the inhibition of bone resorption. In the 1980s and 1990s various companies have synthesized new bisphosphonates and developed them for clinical use in diseases c h a r a c t e r i z e d by increased b o n e r e s o r p t i o n , a n d by b o n e loss.

The bisphosphonates are analogs o f pyrophosphate and are used today primarily in diseases with increased bone resorption and with bone loss.

Recommended selected reading Reviews Fleisch, H., and Russell, R. G. G. (1970). Pyrophosphate and polyphosphate. In Ency-

clopaedia (Int.) of Pharmacology and Therapeutics, Section 51. Pharmacology of the Endocrine System and Related Drugs, pp. 61-100. (Oxford, New York: Pergamon) Original articles Fleisch, H., and Bisaz, S. (1962). Isolation from urine of pyrophosphate, a calcification inhibitor. Am. J. Physiol., 203,671-675 Fleisch, H., and Neuman, W. F. (1961). Mechanisms of calcification: Role of collagen, polyphosphates and phosphatase. Am. J. Physiol., 200, 1296-1300 Fleisch, H., Russell, R. G. G., and Straumann, F. (1966). Effect of pyrophosphate on hydroxy-apatite and its implications in calcium homeostasis. Nature (London), 212, 901-903 Fleisch, H., Russell, R. G. G., Bisaz, S., Casey, P. A., and M/ihlbauer, R. C. (1968). The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution of calcium phosphate in vitro and in vivo. Calcif. Tissue Res., 2(Suppl.), 10-10A Russell, R. G. G., Bisaz, S., Donath, A., Morgan, D. B., and Fleisch, H. (1971). Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta and other disorders of bone. J. Clin. Invest., 50, 961-969 Schibler, D., Russell, R. G. G., and Fleisch, H. (1968). Inhibition by pyrophosphate and polyphosphate of aortic calcification induced by vitamin D3 in rats. Clin. Sci., 35, 363372

29

2.2. CHEMISTRY Bisphosphonates, formerly called diphosphonates, are compounds characterized by two CroP bonds. If the two bonds are located on the same carbon atom, resulting in a P - - C ~ P structure, the compounds are called geminal bisphosphonates. They are therefore analogs of pyrophosphate that contain a carbon instead of an oxygen atom. For the sake of simplicity, and since so far only P ~ C - - P bisphosphonates have been found to exert strong activity on the skeleton, the geminal bisphosphonates will simply be called bisphosphonates in this book. This simplification is usually also made in the literature. Fig. 2.2-1 Chemical structure of pyrophosphate and bisphosphonates.

Chemical structure OI

OI

O=P-O-P=O I O-

I O-

Pyrophosphate

OI

R' I

0I

O=P-C-P=O I O-

I I R" O-

Geminal bisphosphonate

Geminal bisphosphonates, simply called bisphosphonates in this book and the literature, are synthetic compounds characterized by a PmC--P bond.

Commercial index pp. 182-206

The geminal bisphosphonates have been known for a long time, the first synthesis by German chemists dating back to 1865. Etidronate was synthesized as early as 1897. They were used for a variety of industrial applications, among them as antiscaling agents. The P--CroP structure allows a great number of possible variations, either by changing the two lateral chains on the carbon atom, or by esterilying the phosphate groups. Many bisphosphonates have been investigated in animals and humans with respect to their effect on bone. Alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, and tiludronate are commercially available in some countries for use in human bone disease (Fig. 2.2-2). Each bisphosphonate has its own physicochemical and biological characteristics. This variability in effect makes it impossible to extrapolate with certainty from data for one compound to others, so that each compound has to be considered on its own, with respect to both its use and its toxicology.

30

2.2. Chemistry Bisphosphonates used in humans NH 2 OI

I O - (CH2)3 O-

I

I

O--P

I

O:P--C--P:O

I

I

I

O - OH

O-

CI

I

O-

I

-- C - - P - - O

I

I

I

O-

CI

o-

(Dichloromethylene)bis-phosphonate

(4-Amino-1-hydroxybutylidene)bis-phosphonate

clodronate* Abiogen; Astra Leiras; Rhdne-Poulenc Rorer; Roche

alendronate* Abiogen; Merck Sharp & Dohme

9 I O - (CH2)2 0 -

I

I

O--P

I

-- C - - P - - O

I

I

O-

t

O--P

O-

!

-- C - - P - - O

I

OH

CH 3 O-

O-

I

I

I

t

O-

OH

o-

[1-Hydroxy-3-(1-pyrrolidinyl)propylidene]bis-phosphonate

(1-Hydroxyethylidene)bis-phosphonate

EB-1053

etidronate* Abiogen; Procter & Gamble

Leo /CH3 C~H3N / (0H2)4

I

I

O - (CH2)2 O -

O-

NH

I

I

I

I

O--'P

I

-- C-- P-'-O

O'-P

OI

-- C - - P - - O

I

1

I

I

I

1

O-

OH

O-

O-

H

o-

[1-Hydroxy-3-(methylpentylamino) propylidene]bis-phosphonate

[(Cycloheptylamino)methylene]bis-phosphonate

ibandronate* Roche

incadronate Yamanouchi NH 2

I Ol O--P--

I O-

I

CH2 O -

I

O - (CH2)s O -

t

I

C--P--O

O--P

1

I

--C--P--O

I

I

i

I

1

OH

O-

O-

OH

o-

[1-Hydroxy-2-imidazo-(1, 2-a) pyridin3-ylethylidene]bis-phosphonate

(6-Amino-l-hydroxyhexylidene)bis-phosphonate

minodronate Yamanouchi- Hoechst

neridronate Abiogen

Fig. 2.2-2 Chemical structure of bisphosphonates investigated for their effect on bone in humans. *Commercially available.

31

2. Bisphosphonatesmpreclinical H3C\ N / CH3

Y

NH 2

I

I

O- (CH2)2 O-

O - (CH2)2 O-

I

I

O--P

I

I

O--P

--C--P--O

I

I

I

O-

OH

o-

I

I

--C--P--O

I O-

I

I

OH

o-

[3-(Dimethylamino)-l-hydroxypropylidene]bis-phosphonate

(3-Amino-l-hydroxypropylidene)bis-phosphonate

olpadronate Gador

pamidronate* Gador; Novartis

cI I

9

9

1

I

O- CH2 OI I I O-----P -- C - - P - - O

I

I

I

O-

OH

o-

o-

s

o-

I

t

I

O--P

--C--P=O

I

I

I

O-

H

o-

[1-Hydroxy-2-(3-pyridinyl)ethylidene]bis-phosphonate

[[(4-Chlorophenyl)thio]methylene]bis-phosphonate

risedronate* Procter & Gamble

tiludronate* Sanofi

I O- CH 2 OI I I O - - P -- C - - P = O

I

t

O-

OH

I O-

[1-Hydroxy-2-(1H-imidazole-1-yl) ethylidene]bis-phosphonat zoledronate Novartis

Fig. 2.2-2 (continued)

Many bisphosphonates have been investigated. Each has its characteristic profile of activity.

own

The P ~ C ~ P bonds of the bisphosphonates are stable to heat and most *chemical reagents, and completely resistant to enzymatic hydrolysis, but can be hydrolyzed in solution by ultraviolet light. These compounds have a strong affinity for metal ions, among them calcium, with which they can form both soluble and insoluble complexes and aggregates, depending on *-

32

2.2. Chemistry the pH of the solution and the metal present. This can occur in vivo when large amounts are infused rapidly, so that great care has to be taken when these compounds are given intravenously. Some uncertainty still exists as to the state of bisphosphonates when in solution. In plasma they are only partially ultrafilterable, because of binding to proteins and possibly of other causes. The ultrafilterability varies greatly between compounds. This is of importance when renal clearance is calculated.

Bisphosphonates are resistant to chemical and enzymatic hydrolysis. They can l:orm insoluble complexes with metal ions.

Recommended selected reading Reviews Blomen, L. J. M. J. (1995). History of bisphosphonates: Discovery and history of the nonmedical uses of bisphosphonates. In Bijvoet, O. L. M., Fleisch, H. A., Canfield, R. E., and Russell, R. G. G. (eds.) Bisphosphonate on Bones, pp. 111-124. (Amsterdam: Elsevier)

Original articles Menschutkin, N. (1865). Ueber die Einwirkung des Chloracetyls auf phosphorige SZiure. Ann. Chem. Pharm., 133,317-320

33

Adverse events p. 168 Ultrafilterability p. 57 Renal clearance p. 59

2.3. ACTIONS 2.3.1.

Physicochemical effects

The physicochemical effects of many of the bisphosphonates are very similar to those of pyrophosphate. Thus, they inhibit the formation, delay the aggregation, and also slow down the dissolution of calcium phosphate crystals. All these effects are related to the marked affinity of these compounds for solid-phase calcium phosphate, on the surface of which they bind strongly. This property is of great importance, because it is the basis for the use of these compounds as skeletal markers in nuclear medicine and the basis for their selective localization in bone when used as drugs.

Effects on calcium phosphate 9Bind stronglyto crystals 9Inhibit crystal formation 9Inhibit crystal aggregation 9Inhibit crystal dissolution

Fig. 2.3-1 Physicochemical effects of bisphosphonates on calcium phosphate.

Bisphosphonates also inhibit the formation and the aggregation of calcium oxalate crystals.

Bisphosphonates bind avidly to calcium phosphate crystals and inhibit their growth, aggregation, and dissolution. The affinity for bone mineral is the basis for their use as skeletal markers and as inhibitors of ectopic calcification and of bone resorption. 2.3.2.

Biological effects

Inhibition o f bone resorption The main effect of the pharmacologically active bisphosphonates is to inhibit bone resorption. Indeed these compounds proved to be extremely powerful inhibitors of resorption when tested in a variety of conditions, both in vitro and in vivo.

In vitro Bisphosphonates block bone resorption induced by various means in cell and organ culture. In the former, they inhibit the formation of pits by isolated osteoclasts cultured on mineralized substrata. In organ culture they

34

2.3. A c t i o n s

decrease the destruction of bone in embryonic long bones and in neonatal calvaria. This inhibition is present whether resorption is stimulated or not. Up to now, the effect of all the stimulators of bone resorption, such as parathyroid hormone, 1,25(OH)2 D, and prostaglandins, as well as the products of tumor cells, has been inhibited. Fig. 2.3-2 Effectof bisphosphonates on resorption of rat calvaria in culture, assayed by 4sCa release. Open circles, etidronate; filled circles, clodronate. [Adapted from Reynolds, J. J., et al. (1972). Reproduced from Calcified Tissue Res., 10, 302-313, with copyright permission from the author and SpringerVerlag, Heidelberg.]

Resorption of calvaria Bisphosphonate ~tg P/ml 0.007 l

0.12 I

I

2 I

8 16

a

I

i

v 9 4-~

90

~

80

~

70

~

60

v

o " onate

Clodronate

In the past, the correlation between the results obtained in calvaria in vitro and those obtained in v i v o was rather poor. However, a more recent study performed with nine compounds varying in their activity by 5 - 6 orders of magnitude showed a satisfactory correlation using the 4 - 7 day-old mouse calvaria assay. Fig. 2.3-3 Inhibitory activity of various bisphosphonates in vitro in mouse calvariae and in vivo in the TPTX rat. [Adapted from Green, J. R., et al. (1994), J. Bone Miner. Res. 9, 745751, with permission from the author and publisher.]

Bisphosphonates in o

. ,~

1

0

Neri ronate. Pamidrona~.~" Alendronat~Olpadronate Risedronate~_ _ ~ 9Ibandronate

~ ~

--1"

0 ~

--2"

0

~

vitro and in vivo

-3- 7

~

-2

mClodronate

9Zoledronate 0 2 Log EDs0 TPTX assay in vivo

35

4

2. Bisphosphonatesmpreclinical Bisphosphonates inhibit bone resorption in cell and organ culture. Intact animals In growing rats, bisphosphonates can block the degradation of both primary and secondary trabeculae, thus arresting the modeling and remodeling of the metaphysis. The latter therefore becomes club-shaped and radiologically more dense than normal, leading to a picture similar to that seen in congenital osteopetrotic animals. This effect is often used as an experimental assay to estimate the potency of new compounds.

Inhibition of bone resorption Control

With clodronate

Bone resorption

Bone resorption blocked

Fig. 2.3-4 Inhibition of metaphyseal modeling and remodeling by a bisphosphonate in the growing rat. Upper panel: Diagram of the locations of bone resorption in the rat tibia during longitudinal growth (left): osteoclasts resorb calcified cartilage (1), subperiosteal bone (2), and primary spongiosa (3), therefore enlarging the marrow cavity. Effect of clodronate (right). Lower panel: Microradiograph of a normal tibia (left) and of a bone from an animal treated with clodronate (right). [Adapted from Schenk, R. K., et al. (1973). Reproduced from Calcified Tissue Res., 11, 196-214, with copyright permission from the author and Springer-Verlag, Heidelberg.] 36

2.3. Actions The inhibition of bone r e s o r p t i o n by b i s p h o s p h o n a t e s has also been d o c u m e n t e d using 4s Ca kinetic studies and h y d r o x y p r o l i n e excretion, as well as by other means. The effect occurs within 2 4 - 4 8 h and is therefore slower than that of calcitonin. Fig. 2.3-5 Inhibition of bone resorption by subcutaneous (sc) administration of clodronate in the rat, as assessed by 45Ca kinetics.

Effect of clodronate on bone resorption 60+1

40-

k)

0

"= 200

r 0

0.01

0.1

1

1.0

Clodronate (mg P/kg/day sc)

Fig. 2.3-6 Effect of one injection of 0.1 mg P/kg subcutaneously of alendronate on bone resorption, assessed by monitoring the urinary excretion of radioactive tetracycline from prelabeled rats. [Adapted from Miihlbauer, R. C., and Fleisch, H. (1990). A method for continuing monitoring of bone resorption in rats: Evidence for a diurnal rhythm. Am. J. Physiol., 259, R679-R689, with permission from the authors and publisher.]

Inhibition of bone resorption Alendronate

+i o 1-o

o 100 o

.,..~

.,.~

~

O-

I

2

I

I

4

I

I

6 Days

I

I

8

Bisphosphonates inhibit bone resorption in intact animals.

37

' 1'0

2. Bisphosphonates--preclinical

Calcium balance pp. 15-16

Coupling p. 15

Bisphosphonates in osteoporosis models pp. 133-136

The decrease in resorption is accompanied, at least in the growing animal, by a positive calcium balance, and an increase in the mineral content of bone and in bone mass. This is possible because of an increase in intestinal calcium absorption, consequent to an elevation of 1,25(OH)2 D. The increase is, however, smaller than expected considering the dramatic decrease in bone resorption. This is due to the fact that, after a certain § time, bone formation also decreases, because of the so-called coupling between formation and resorption characteristic of a decrease in remodeling and therefore of turnover. The main effect of bisphosphonates is therefore a reduction in bone turnover. It is not known how long the increase in balance lasts after discontinuation of the bisphosphonate. This increase is the basis for the administration of these compounds to prevent and treat osteoporosis in humans. Fig. 2.3-7 Effect of 1 Ftg P/kg sc daily of ibandronate on calcium metabolism in the rat. Bone resorption was decreased and calcium balance increased. [Data from Fleisch, H. (1996)].

Calcium metabolism I-7 Controls ~! Ibandronate l~tgP/kg sc daily 50 40 +1

-I-

30

"

eq

20

210

Bone resorption

Intestinal absorption

Balance

Bisphosphonates increase calcium balance in normal growing animals.

Mechanostat pp. 1 9 - 2 0

Less is known about the effect in the normal adult animal. In dogs and minipigs, the long-term administration of alendronate did not lead to an increase in bone mass. This might be explained by the physiological biomechanical homeostasis of bone structure, which would eliminate a biomechanically unnecessary excess of bone. This fact suggests that the fear of the dangers of long-term use of therapeutic doses may not be warranted. Some studies have addressed the question of the effect of the bisphosphonates on the mechanical properties of the skeleton. This issue is of importance, since it is known that a long-lasting, strong inhibition of bone 38

2.3. Actions

resorption can lead to increased bone fragility both in animals and in humans. This is well illustrated in the human osteopetrosis described by Albers-Sch6nberg. Many studies have shown that clinically relevant doses of bisphosphonates have a positive effect on mechanical characteristics in various experimental osteoporosis models. In normal animals there is either a positive effect or no effect, but not negative. Bisphosphonates proven to have this action include alendronate, clodronate, etidronate, ibandronate, incadronate, olpadronate, pamidronate, tiludronate, minodronate, and zoledronate. However, under very high and long-term, clinically not relevant dosage, increased fractures have been reported in the dog given clodronate. Etidronate at high doses may also induce an opposite effect, probably because of an inhibition of mineralization.

Effect in experiment~ osteoporosi~ p. 134 Chemistry c bisphosphonates pp. 31-32

Animals with experimentally increased bone resorption Bisphosphonates can also prevent an experimentally induced increase in bone resorption. Thus, they impair resorption induced by many bone resorbing agents such as parathyroid hormone, 1,25(OH)2 D and retinoids, the latter effect having been used to develop a powerful and rapid screening assay for new compounds. --~ Fig. 2.3-8 Assessmentof the action of inhibitors of bone resorption by means of retinoid-induced hypercalcemia in thyroparathyroidectomized rats.

Retinoid

E 10-

. . ~

O O

E

assay

No effect

8-

.- 100% ~

6-

~ ~

Maximal

4I

0

I

I

Days

- - B..Retinoidalone

t

Inhibition

I

3 ~ Retinoid + bisphosphonate

They also inhibit bone loss induced by different procedures such as immobilization, ovariectomy, corticosteroids, or lactation combined with a low calcium diet. This aspect will be discussed in the chapter on osteoporosis in Section 3.5. Bisphosphonates also inhibit bone resorption induced experimentally by implantation of various t u m o r cells. They reduce both the local destruction of bone near the invading tumor cells, as well as the resorption induced by systemically circulating factors. These effects lead to a partial 39

Osteoporos models pp. 133-13

Effect on experiment: tumors pp. 95-97

2. Bisphosphonatesmpreclinical Tumor bone disease p. 95

or total prevention of hypercalcemia and hypercalciuria. This effect is the basis for their use in tumor-related bone disease and is discussed in Section 3.3. Of interest in the dental field is the fact that they also slow down periodontal bone destruction in rats susceptible to periodontal disease and in experimental periodontitis in monkeys. Furthermore, they inhibit tooth movement induced by orthodontic procedures, and these effects can be achieved even when the compounds are administered topically.

Bisphosphonates very efficiently prevent experimentally induced bone resorption. Relative activity of bisphosphonates The activity of bisphosphonates on bone resorption varies greatly from compound to compound. For etidronate, the dose required to inhibit resorption is relatively high, in the rat above 1 mg/kg parenterally per day. This dose is very near that which impairs normal mineralization. One of the aims of bisphosphonate research has therefore been to develop compounds with a more powerful antiresorptive activity, without a stronger inhibition of mineralization. This has proven to be possible. Clodronate was already more potent than etidronate, and pamidronate was found to be even more active. In more recent years, compounds have been developed that are up to 10,000 times more powerful than etidronate in the inhibition of bone resorption in experimental animals without being more active in inhibiting mineralization.

Potency to inhibit bone resorption

Chemistry of

-lx

--lOx

Etidronate

Clodronate Neridronate Alendronate Tiludronate Pamidronate EB-1053 Incadronate Olpadronate

-100 x

>100 <1000 x

>1000 <10 000 x

>10 000 •

Ibandronate Minodronate Risedronate Zoledronate

bisphosphonates pp. 31-32

Fig. 2.3-9 Potencyof some bisphosphonates to inhibit bone resorption in the rat. The compounds in each column are listed in alphabetical order. For the development of future compounds it is of relevance that, so far, the potency evaluated in the rat corresponds quite well with that found in humans, at least with respect to their relative place in the scale of potency. However, the difference of activity between the least and the most potent compound is less in humans and depends on the disease for which the compounds are used. It is much smaller for osteoporosis, less so for Paget's disease and tumor-induced hypercalcemia.

40

2.3. Actions The potency of different bisphosphonates on bone resorption varies from 1 for etidronate to approximately 10,000 for zoledronate in the rat, about 10 or more times less in humans. There is quite a good correlation between the potencies found in the rat and those in humans as to their place in the scale. At present, the structural requirements for activity are only partially defined. The length of the aliphatic carbon chain is important, the effect on bone resorption increasing and then decreasing again with increasing chain length. Adding a hydroxyl group to the carbon atom at position 1 increases potency, and compounds with a nitrogen atom in the side chains are more active. The first compound of the latter kind to be described, pamidronate, has an amino group at the end of the alkyl chain. When the chain is altered in its length, the highest activity is present with a backbone of four carbons, as seen in alendronate. A primary amine is not necessary for this activity, as dimethylation of the amino nitrogen of pamidronate, as seen in olpadronate, increases potency. The latter can still be further increased when other groups are added to the nitrogen, as is the case, for example, in ibandronate, [1-hydroxy-3(methylpentylamino)propylidene]bisphosphonate, which is extremely potent. Geminal bisphosphonates containing cyclic substituents are also very potent, especially those containing a nitrogen atom in the ring, such as risedronate. The most active compounds described so far, zoledronate and minodronate, belong to this class and contain an imidazole ring. It must be noted that at present, all effective compounds have a P - - C - - P structure, which appears to be a prerequisite for activity. The intensity of the effect is, however, also dependent on the side chain. A threedimensional structural requirement appears to be involved. Indeed stereoisomers of the same chemical structure have shown 10-fold differences in activity. This opens the possibility of binding onto some kind of receptor.

No clear structure-effect relationship has yet emerged. The binding to the mineral appears to be due to the P m C m P structure, while the antiresorptive activity is influenced both by the P m C ~ P part and by the structure of the side chains, therefore by the threedimensional structure.

Mechanisms of action Our understanding of the mode of action of the bisphosphonates has made great progress in the last few years. There is no doubt that the action in vivo is mediated mostly, if not completely, through mechanisms other than the physicochemical inhibition of crystal dissolution, as was initially

41

Chemistry of bisphosphonates pp. 31-32

2. Bisphosphonates--preclinical postulated. However, the exact nature of these mechanisms is still not entirely unraveled. It may well be that several mechanisms are operating simultaneously.

The action of bisphosphonates on b o n e resorption is not mediated, as thought earlier, by their pbysicochemical effect on crystal dissolution, but mostly if not entirely through cellular mechanisms.

Osteoporosis p. 127

The mechanism of action of the bisphosphonates can be considered at three levels which are, however, tightly linked one to another: At the tissue level their main effect is a decrease in bone turnover, which is secondary to the inhibition of bone resorption. This effect is due to a decrease in the number and the activity of osteoclasts destroying bone, which leads to a decrease in the number of new BMUs. Since bone loss is intimately linked to turnover in diseases like tumor-induced bone disease and osteoporosis, this loss will be reduced by the bisphosphonates. Furthermore the bisphosphonates act to a certain extent at the individual BMU level by decreasing the depth of the resorption site. Since the amount of new bone formed in the BMU is not decreased, but possibly even increased, the local and consequently the whole body bone balance will be less negative or possibly sometimes even positive.

Bisphosphonates decrease bone turnover and therefore bone loss. At the cellular level four mechanisms appear to be possibly involved: (1) inhibition of osteoclast recruitment; (2) possibly inhibition of osteoclastic adhesion; (3) shortening of the life span of osteoclasts due to earlier apoptosis; (4) inhibition of osteoclast activity. The former three will lead to a decrease in the number of osteoclasts which is usually seen after treatment. The fourth will lead to inactive osteoclasts.

Bisphosphonates decrease the number of osteoclasts by inhibiting the recruitment and activating apoptosis. Furthermore they inhibit osteoclast activity.

Effect on mevalonate pathway p. 45

At the molecular level, the low concentrations necessary for activity suggests some sort of "pocket" which induces a cellular transduction mechanism. This site could be either on the cell membrane or within the cell and might be an enzyme, a pump, or some other intracellular protein involved in the signaling cascade. As discussed below, one of them could be farnesyl pyrophosphate synthase, which has recently been found to be inhibited by N-containing bisphosphonates and responsible for at least some of their effects.

42

2.3. Actions Direct effect The bisphosphonates can influence osteoclasts either directly as a result of their cellular binding or intracellular uptake, as well as indirectly via other cells. The direct effects are made possible by the uptake of these compounds by the osteoclasts during the resorption process, a process favored by the fact that the bisphosphonates also deposit preferentially under the osteoclasts where they can attain very high concentrations, in the range of 10 -4 M or higher. Fig. 2.3-10 Directmechanism of action. The osteoclast is inhibited directly after having taken up bisphosphonate from bone.

Direct effect on osteoclast

Active

Osteoclast

Inactive

Bisphosphonate Bone

Bisphosphonates may directly affect the osteoclast when it dissolves bisphosphonate-coated mineral, or when they deposit under the osteoclasts. The direct effects of the bisphosphonates are many. Thus it has been known for a long time that they alter the morphology of osteoclasts both in vitro and in vivo. The changes are numerous and include alterations in the cytoskeleton, among others in actin and vinculin as well as disruption of the ruffled border (Fig. 2.3-11).

Bisphosphonates induce morphological changes in the osteoclasts both in vitro and in vivo. A great number of different biochemical effects on various cell types have been described in vitro, but only few data exist on the osteoclasts themselves. Some of the changes which are possibly relevant to bone resorption, are reduction in lactic acid production, proton secretion, lysosomal enzyme activity, and prostaglandin synthesis. Experiments on osteoclasts themselves have shown an inhibition of the acid extrusion performed by a sodium-independent mechanism, and of the vacuolar-type proton ATPase present in the ruffled border. An inhibition of certain protein tyrosine phosphatases (PTPase), namely PTPase e and o, has also been described. But unfortunately, in many cases there is no structure-effect

43

Deposition i bone pp. 57-58

2. Bisphosphonates--preclinical Fig. 2.3-11 An osteoclast of a normal rat (above) and of an animal treated with a bisphosphonate (below). (Courtesy of Dr. R. K. Schenk.)

Effect on osteoclasts

,.,~' , ...~

D

correlation between these effects in vitro and those on bone resorption in vivo.

Bisphosphonates induce in vitro many biochemical and enzymatic changes, some of them decreasing acid production. This might be one of the causes o1:decreased bone destruction. Very recently it was found that nitrogen containing bisphosphonates *-. can inhibit the mevalonate pathway, by inhibiting farnesyl pyrophosphate synthase. This inhibition is due to the docking of the bisphosphonates into the pyrophosphate Mg 2+ binding site of the enzyme, while the charged side chains act as inhibiting transition state analogs. This leads to a decrease of the formation of isoprenoid lipids such as farnesyl- and geranylgeranylpyrophosphates. These are required for the post-translational prenylation (transfer of fatty acid chains) of proteins, including the GTP-binding proteins Ras, Rho, Rac, and Rab. These proteins are important for many cell functions, including cytoskeletal assembly and intracellular signaling. Therefore, disruption of their activity will induce a series of changes lead44

2.3. Actions ing to decreased activity, probably the main effect, and to earlier apoptosis in several cell types, including osteoclasts. In osteoclasts the lack of geranylgeranylpyrophosphate is probably responsible for the effects. Fig. 2.3-1.2 Effectof bisphosphonates on the mevalonate pathway.

The mevalonate pathway HMG-CoA ~ ~ mevalonate

Statins

C10 geranylpyrophosphate ,,FarnesylPP ....SYnthase I ~ ~ ~ i"Bisph~176 squalene ~ C15 farnesylpyrophosphate~Farnesylated proteins ~ Ras, Rho, Rac, Rab, Lamins cholestrol C20 geranylgeranylpyrophosphate--~ geranylgeranylated proteins

Some bisphosphonates inhibit the mevalonate pathway which can lead to altered cell activity and apoptosis. It was also shown recently that some non-nitrogen-containing bisphosphonates that closely resemble pyrophosphate, such as etidronate, tiludronate, and clodronate, can be incorporated into the phosphate chain of ATP-containing compounds so that they become nonhydrolyzable. The new P m C - - P containing ATP analogs inhibit cell function and may lead to apoptosis and cell death. Thus, the bisphosphonates can be classified into two major groups with different modes of action. The latter may explain the various cellular changes described above (Fig. 2.3-13).

The bisphosphonates can be divided into two groups. The nitrogencontaining compounds can inhibit the mevalonate pathway and hence inhibit protein prenylation. Others, like etidronate, clodronate, and tiludronate, can be incorporated in ATP-containing compounds. Both may act by inhibiting cell function and inducing apoptosis.

Indirect effect through other cells It is likely that bisphosphonates act, at least in part, also through other cells. One candidate is the osteoblast. It is now generally accepted that 45

2. Bisphosphonates--preclinical Molecular mechanisms of action of bisphosphonates Risedronate Zoledronate Ibandronate Alendronate Pamidronate

Clodronate Etidronate Tiludronate

Incorporated into intracellular analogues of A TP NH2 0 C1 0 0 " o,p,~/l'._..P, .

6_ o 6 _ o

C1

~

'{)',,,__.~_

HO OH N

o

o

0-6.

Inhibit the prenylationand function of GTP-bindingproteins required for osteoclastformation, function and survival

NNI~~q < O' N ~ .I

NH2 N

o

o O 6_o OH

Fig. 2.3-13

HO OH The two classes of bisphosphonates. Courtesy of Dr. M. Rogers.

cells of osteoblastic lineage control the recruitment and activity of osteoclasts. One of the modulators involved in this mechanism appear to be the bisphosphonates. Indeed these compounds induce the osteoblasts to synthesize inhibitor(s) for osteoclast recruitment and therefore of bone resorption. Fig. 2.3-14 Indirect mechanism of action. The inhibition of the osteoclast is secondary to an increase in production by osteoblast lineage cells of an inhibitor(s) of osteoclast recruitment. The primary target is therefore the osteoblastic cell type.

Effect t h r o u g h o s t e o b l a s t

~ Recruitment

Osteoclast

Osteoblasts

Bone

Bisphosphonates also inhibit osteoclasts by stimulating the secretion of an inhibitor(s) of osteoclast recruitment by osteoblast lineage cells. Therefore the target cells may include members of the osteoblastic cell family.

46

2.3. Actions Another candidate target cell population are the macrophages which release many cytokines which are able to modulate the osteoclasts, and which are influenced by the bisphosphonates. Thus, under certain conditions, bisphosphonates inhibit their release of IL-113, IL-6, and TNFa in vitro. Alternatively, at high concentrations such as after intravenous administration, the release of these cytokines can be stimulated, producing an acute phase reaction. It is not known at present to which extent these mechanisms, the direct effect on the osteoclast or indirect action through osteoblastic or other cells, are operating in vivo and, if both do, which of the two is more important.

Acute phase reaction p. 173

It is not yet known which of the mechanisms, the direct effect on the osteoclast or indirect action through the osteoblastic cells, is more important in vivo.

Fig. 2.3-15 Summary of the effects of bisphosphonates on the osteoclast.

Mode of action of bisphosphonates Binding to apatite crystals Preferential accumulation under osteoclasts ~b Local release during bone resorption .

.

.

[ '~ osteoclast activity ! Decreased ruffled border Altered cytoskeleton Decreased acid production Decreased enzyme activity Decreased prenylation Incorporation into nucleotides

.

.

] ~osteoclast nu, number[ Increased apoptosis Decreased recruitment Osteoblast lineage cells

In view of the large array of their effects on cells, it is surprising that the bisphosphonates act almost exclusively on calcified tissues. This selectivity is explained by the strong affinity of these compounds for calcium phosphate, which allows them to be cleared very rapidly from blood and to be incorporated into calcified tissues, especially bone.

Bisphosphonates act specifically on bone, because of their affinity for bone mineral.

47

Pharmacokinetics p. 57

2. Bisphosphonates--preclinical I n h i b i t i o n o/r m i n e r a l i z a t i o n Ectopic

mineralization

Like pyrophosphate, bisphosphonates inhibit calcification in vivo very efficiently. Thus, they prevent experimentally induced calcification of many soft tissues such as arteries, kidneys, and skin. In contrast to pyrophosphate, which acts only when given parenterally, they are also active when administered orally. In the arteries they decrease not only mineral deposition, but also the accumulation of cholesterol, elastin, and collagen.

Experimental aortic calcification ~-80+l e 60-

fl

>-. r

40-

Fig. 2.3-16 Effectof 10 mg P/kg body weight of bisphosphonates on vitamin D3-induced aortic calcification in the rat. Subcutaneous (sc) compared with oral (po)administration. [Adapted from Fleisch, H., et al. (1970). Reproduced with permission from the author and the publisher.]

era =I. o

=oa 2 0 ka

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Control Vit.D3 Vit.D3 Vit.D3 Etidronate Clodronate sc po sc po

Clinical use in ectopic calcification and ossification pp. 162-164 Human urolithiasis p. 162

A possibly interesting future use of bisphosphonates could arise from the finding that some of them, such as etidronate, can also inhibit the calcification of bioprosthetic heart valves, either when administered subcutaneously or when released locally from various matrices. Investigations are in progress to bind bisphosphonates covalently to the valves. Etidronate also inhibits ectopic ossification, when given either systemically or locally. This effect has led to the clinical use of etidronate in ectopic ossification, but unfortunately normal mineralization is inhibited as well. Similarly, certain bisphosphonates such as etidronate decrease the formation of experimental urinary stones. However the active dose also leads to the inhibition of normal mineralization of bone. Lastly, topical administration of etidronate induces a decrease in the formation of dental calculus, a property which is made use of in some toothpastes.

48

2.3. Actions Bisphosphonates in vivo inhibit experimentally induced soft tissue calcification and ossification, urinary stones, and dental calculus. Normal mineralization "+ The dose, at least of etidronate, which inhibits experimental ectopic mineralization, also impairs the mineralization of normal calcified tissues such as bone, cartilage, dentine, and enamel. The amount required to have this effect varies according to the animal species and the length of treatment. In contrast to bone resorption, where the different compounds vary greatly in their activity, this does not seem to be so much the case for the inhibition of mineralization. For most species, and most compounds, the effective daily parenteral dose is in the order of 1-10 mg of compound phosphorus per kilogram. Interestingly, clodronate inhibits normal mineralization somewhat less than does etidronate, despite the fact that it is more active on bone resorption. This may be due to the fact that clodronate has no hydroxyl side chain and is therefore less bound to the mineral. The inhibition of calcification with high doses can lead to fractures and to an impairment of fracture healing. The mineralization defect is eventually reversed after discontinuation of the drug. Nevertheless, the propensity to inhibit the mineralization of normal bone has hampered the therapeutic use of bisphosphonates in ectopic calcification. This is not the case for their use in bone resorption, since compounds have been developed that inhibit this process at doses at least 1000 times lower than those that inhibit mineralization. .~ 9 Fig. 2.3-17 Inhibitionof mineralization of bone and cartilage in the growing rat by 10 mg P/kg subcutaneously of etidronate, but not clodronate, daily for 7 days. (Courtesy of Dr. R. K. Schenk.)

Effect on growth plate

Bisphosphonates, if given at high doses, inhibit the mineralization of normal calcified tissues inducing rickets and osteomalacia. While this is a problem in humans when it is used to prevent ectopic calcification or ossification, it is not the case for most bisphosphonates when they are used to decrease bone resorption.

49

Adverse eve pp. 171-17

Heterotopic calcification and ossific, pp. 162-16

2. Bisphosphonates--preclinical Mechanisms of action in the inhibition of calcification Physicochemical effects p. 34

There is a close relationship between the ability of an individual bisphosphonate to inhibit the formation of calcium phosphate in vitro and its effectiveness on calcification in vivo, strongly suggesting that the latter can be explained in terms of a physicochemical mechanism. The inhibition of calcium phosphate formation is closely related to the affinity of the bisphosphonate to the solid-phase calcium phosphate. The binding can be bidentate through the two phosphates, as is the case for clodronate. Or it can be tridentate through a third moiety, such as a hydroxyl or a nitrogen attached to the carbon atom. This is the case for most bisphosphonates used clinically today. The third binding site increases the affinity and hence the inhibitory effect on calcification. However, additional effects on matrix formation, involving changes in glycosaminoglycan and collagen synthesis, may occur. These may be direct via cellular effects, or mediated indirectly by effects on crystals.

The inhibition of mineralization in vivo, both on normal and ectopic calcification, is most probably explained by a physicochemical mechanism involving the binding of the bisphosphonate on the surface of the mineral. Other effects

Use in osteoporosis p. 136

Another interesting finding is that several bisphosphonates, including clodronate, risedronate, and zoledronate, inhibit local bone and cartilage resorption, preserve the joint architecture, and decrease the inflammatory reaction in various types of experimental arthritis, such as that induced by Freund's adjuvant or by carrageenan. This effect is especially pronounced when the bisphosphonates are encapsulated in liposomes. Similar results were obtained with a new bisphosphonate, TRK-530, which furthermore inhibits splenomegaly and inflammation. Furthermore, clodronate and newer bisphosphonates also inhibit the delayed-type hypersensitivity granuloma response. Moreover, bisphosphonates or phosphonosulfonates linked to an isoprene chain are potent inhibitors of squalene synthase and hence are cholesterol-lowering agents in the animal. These results may open some interesting new therapeutic possibilities for these drugs. It is worth mentioning that very low concentrations of bisphosphonates were found to increase colony formation, nodule formation, mineralization, and osteocalcin synthesis in bone cell cultures in vitro. Furthermore, when administered in vivo, the amount of bone formed at each individual BMU is not decreased, but may possibly be somewhat increased. Lastly, since statins, which are inhibitors of the mevalonate pathway, increase bone formation at least in vitro, probably through an elevation of

50

2.3. A c t i o n s

BMP-2, it could be conceivable that the bisphosphonates have a similar action. Thus, it could be that bisphosphonates might, under certain conditions, increase bone formation in vivo. However, this still needs to be verified. Under some conditions, bisphosphonates may increase bone formation, at least in vitro. Whether this is true in vivo, needs confirmation.

Recommended selected reading Reviews Ebetino, F. H., Francis, M.D., Rogers, M. J., and Russell, R. G. G. (1998). Mechanisms of action of etidronate and other bisphosphonates. Rev. Contemp. Pharmacother., 9, 233243 Fleisch, H. (1998). Bisphosphonates: Mechanisms of action. Endocr. Rev., 19, 80-100 Rodan, G. A. (1998). Mechanisms of action of bisphosphonates. Annu. Rev. Pharmacol. Toxicol., 38, 375-388 Rodan, G. A. and Fleisch, H. A. (1996). Bisphosphonates: Mechanisms of action. J. Clin. Invest., 97, 2692-2696 Roldan, E. J. A., P6rez-Llore, A., and Ferretti, J. L. R. (1998). Olpadronate: A new aminobisphosphonate for the treatment of medical osteopathies. Exp. Opin. Invest. Drugs, 7, 1521-1538 Russell, R. G. G., Rogers, M. J., Frith, J. C., Luckman, S. P., Coxon, F. P., Benford, H. L., Croucher, P. I., Shipman, C., and Fleisch, H. A. (1999). The pharmacology of bisphosphonates and new insights into their mechanisms of action. J. Bone Miner. Res., 14(Suppl. 2), 53-65 O r i g i n a l articles Physical

chemistry

Fleisch, H., Russell, R. G. G., Bisaz, S., Miihlbauer, R. C., and Williams, D. A. (1970). The inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur. J. Clin. Invest., 1, 12-18 Francis, M. D. (1969). The inhibition of calcium hydroxyapatite crystal growth by polyphosphonates and polyphosphates. Calcif. Tissue Res., 3, 151-162 Jung, A., Bisaz, S., and Fleisch, H. (1973). The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calcif. Tissue Res., 11,269-280 Russell, R. G. G., M/ihlbauer, R. C., Bisaz, S., Williams, D. A., and Fleisch, H. (1970). The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatite in vitro and on bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomised rats. Calcif. Tissue Res., 6, 183-196

Bone resorption Adachi, H., Igarashi, K., Mitani, H., and Shinoda, H. (1994). Effects of topical administration of a bisphosphonate (risedronate) on orthodontic tooth movements in rats. J. Dent. Res., 73, 148-184 Balena, R., Markatos, A., Seedor, J. G., Gentile, M., Stark, C., Peter, C. P., and Rodan, G. A. (1996). Long-term safety of the aminobisphosphonate alendronate in adult dogs. II. 51

2. B i s p h o s p h o n a t e s ~ p r e c l i n i c a l Histomorphometric analysis of the L5 vertebrae. J. Pharmacol. Exp. Tber., 276,277-283 Ferretti, J. L., Cointry, G., Capozza, R., Montuori, E., Roldfin, E., and P~rez Lloret, A. (1990). Biomechanical effects of the full range of useful doses of (3-amino-l-hydroxy propylidene)-l,l-bisphosphonate (APD) on femur diaphyses and cortical bone tissue in rats. Bone Miner., 11,111-122 Ferretti, J. L., Mondelo, N., Capozza, R. F., Cointry, G. R., Zanchetta, J. R., and Montuori, E. (1995). Effects of large doses of olpadronate (dimethyl-pamidronate) on mineral density, cross-sectional architecture, and mechanical properties of rat femurs. Bone, 16 (Suppl. 4), 285S-293S Fleisch, H. (1996). The bisphosphonate ibandronate, given daily as well as discontinuously, decreases bone resorption and increases calcium retention as assessed by 4s Ca kinetics in the intact rat. Osteoporosis Int., 6, 166-170 Fleisch, H., Russell, R. G. G., and Francis, M. D. (1969). Diphosphonates inhibit hydroxy apatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science, 165, 1262-1264 Gasser, A. B., Morgan, D. B., Fleisch, H. A., and Richelle, L. J. (1972). The influence of two diphosphonates on calcium metabolism in the rat. Clin. Sci., 43, 31-45 Geusens, P., Nijs, J., van der Perre, G., van Audekercke, R., Lowet, G., Goovaerts, S., Barbier, A., Lacheretz, F., Remandet, B., Jiang, Y., and Dequeker, J. (1992). Longitudinal effect of tiludronate on bone mineral density, resonant frequency, and strength in monkeys. J. Bone Miner. Res., 7, 599-609 Green, J. R., Miiller, K., and Jaeggi, K. A. (1994). Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound. J. Bone Miner. Res., 9, 745-751 Guy, J. A., Shea, M., Peter, C. P., Morrissey, R., and Hayes, W. C. (1993). Continuous alendronate treatment throughout growth, maturation, and aging in the rat results in increases in bone mass and mechanical properties. Calcif. Tissue Int., 53,283-288 Igarashi, K., Adachi, H., Mitani, H., and Shinoda, H. (1996). Inhibitory effect of the topical administration of a bisphosphonate (risedronate) on root resorption incident to orthodontic tooth movements in rats. J. Dent. Res., 75, 1644-1659 Lafage, M. H., Balena, R., Battle, M. A., Shea, M., Seedor, J. G., Klein, H., Hayes, W. C., and Rodan, G. A. (1995). Comparison of alendronate and sodium fluoride effects on cancellous and cortical bones in minipigs. J. Clin. Invest., 95, 2127-2133 Miihlbauer, R. C., Bauss, F., Schenk, R., Janner, M., Bosies, E., Strein, K., and Fleisch, H. (1991). BM 21.0955, a potent new bisphosphonate to inhibit bone resorption. J. Bone Miner. Res., 6, 1003-1011 Peter, C. P., Guy, J., Shea, M., Bagdon, W., Kline, W. F., and Hayes, W. C. (1996). Longterm safety of the aminobisphosphonate alendronate in adult dogs. I. General safety and biomechanical properties of bone. J. Pharmacol. Exp. Tber., 276, 271-276 Reitsma, P. H., Bijvoet, O. L. M., Verlinden-Ooms, H., and van der Wee-Pals, L. J. A. (1980). Kinetic studies of bone and mineral metabolism during treatment with (3amino-l-hydroxypropylidene)-l,l-bisphosphonate (ADP) in rats. Calcif. Tissue Int., 32, 145-157 Reynolds, J. J., Minkin, C., Morgan, D. B., Spycher, D., and Fleisch, H. (1972). The effect of two diphosphonates on the resorption of mouse calvaria in vitro. Calcif. Tissue Res., 10, 302-313 Reynolds, J. J., Murphy, H., Miihlbauer, R. C., Morgan, D. B., and Fleisch, H. (1973). Inhibition by diphosphonates of bone resorption in mice and comparison with grey-lethal osteopetrosis. Calcif. Tissue Res., 12, 59-71 Russell, R. G. G., Miihlbauer, R. C., Bisaz, S., Williams, D. A., and Fleisch, H. (1970). The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatite in vitro and on bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomised rats. Calcif. Tissue Res., 6, 183-196 Schenk, R., Eggli, P., Fleisch, H., and Rosini, S. (1986). Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat. Calcif. Tissue Int., 38,342-349 Shoji, K., Horiuchi, H., and Shinoda, H. (1995). Inhibitory effects of a bisphosphonate (risedronate) on experimental periodontitis in rats. J. Periodont. Res., 30, 27-84 Trechsel, U., Stutzer, A., and Fleisch, H. (1987). Hypercalcemia induced with an arotinoid

52

2.3. Actions in thyroparathyroidectomized rats. New model to study bone resorption in vivo. J. Clin. Invest., 80, 1679-1686

van der Pluijm, G., Binderup, L., Bramm, E., van der Wee-Pals, L., de Groot, H., Binderup, E., L6wik, C., and Papapoulos, S. (1992). Disodium 1-hydroxy-3-(1-pyrrolidinyl)propylidene-l,l-bisphosphonate (EB-1053) is a potent inhibitor of bone resorption in vitro and in vivo. J. Bone Miner. Res., 7, 981-986

Mechanisms of resorption van Beek, E. R., L6wik, C. W. G. M., Ebetino, F. H., and Papapoulos, S. E. (1998). Binding and antiresorptive properties of heterocycle-containing bisphosphonate analogs: Structure-activity relationships. Bone, 23, 437-442 van Beek, E., L6wik, C. van der Pluijm, G., and Papapoulos, S. (1999). The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates. J. Bone Miner. Res., 14, 722-729 van Beek, E., Pieterman, E., Cohen, L., L6wik, C., and Papapoulos, S. (1999). Nitrogencontaining bisphosphonates inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo. Biochem. Biophys. Res. Commun., 255,491-494 van Beek, E., Pieterman, E., Cohen, L., L6wik, C., and Papapoulos, S. (1999). Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem. Biophys. Res. Commun., 264, 108-111 Boonekamp, P. M., van der Wee-Pals, L. J. A., van Wijk-van Lennep, M. M. L., Thesing, C. W., and Bijvoet, O. L. M. (1986). Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner., 1, 27-39 Carano, A., Teitelbaum, S. L., Konsek, J. D., Schlesinger, P. H., and Blair, H. C. (1990). Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. J. Clin. Invest., 85,456-461 Cecchini, M. G., Felix, R., Fleisch, H., and Cooper, P. H. (1987). Effects of bisphosphonates on proliferation and viability of mouse bone marrow-derived macrophages. J. Bone Miner. Res., 2, 135-142 Colucci, S., Minielli, V., Zambonin, G., Cirulli, N., Mori, G., Serra, M., Patella, V., Zambonin Zallone, A., and Grano, M. (1998). Alendronate reduces adhesion of human osteoclast-like cells to bone and bone protein-coated surfaces. Calc. Tissue Int., 63, 230-235 David, P., Nguyen, H., Barbier, A., and Baron, R. (1996) The bisphosphonate tiludronate is a potent inhibitor of the osteoclast vacuolar H+-ATPase. J. Bone Miner. Res., 11, 1498-1507 Endo, N., Rutledge, S. J., Opas, E. E., Vogel, R., Rodan, G. A., and Schmidt, A. (1996). Human protein tyrosine phosphatase-o: Alternative splicing and inhibition by bisphosphonates. J. Bone Miner. Res., 11,535-543 Fast, D. K., Felix, R., Dowse, C., Neuman, W. F., and Fleisch, H. (1978). The effects of diphosphonates on the growth and glycolysis of connective-tissue cells in culture. Biochem. J., 172, 97-107 Felix, R., Russell, R. G. G., and Fleisch, H. (1976). The effect of several diphosphonates on acid phosphohydrolases and other lysosomal enzymes. Biochim. Biophys. Acta, 429, 429-438 Felix, R., Bettex, J. D., and Fleisch, H. (1981). Effect of diphosphonates on the synthesis of prostaglandins in cultured calvaria cells. Calcif. Tissue Int., 33,549-552 Fisher, J. E., Rogers, M. J., Halasy, J. M., Luckman, S. P., Hughes, D. E., Masarachia, P. J., Wesolowski, G., Russell, R. G. G., Rodan, G. A., and Reszka, A. A. (1999). Alendronate mechanism of action: Gernylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc. Natl. Acad. Sci. U.S.A., 96, 133-138 Flanagan, A. M., and Chambers, T. J. (1989). Dichloromethylenebisphosphonate (C12MBP) inhibits bone resorption through injury to osteoclasts that resorb C12MBP-coated bone. Bone Miner., 6, 33-43

53

2. B i s p h o s p h o n a t e s - - p r e c l i n i c a l

Frith, J. C., M6nkk6nen, J., Blackburn, G. M., Russell, R. G. G., and Rogers, M. J. (1997). Clodronate and liposome-encapsulated clodronate are metabolised to a toxic ATP analog, adenosine5'([3,3/-dichloromethylene)triphosphate, by mammalian cells in vitro. J. Bone Miner. Res., 12, 1358-1367 Hughes, D. E., Wright, K. R., Uy, H. L., Sasaki, A., Yoneda, T., Roodman, G. D., Mundy, G. R., and Boyce, B. F. (1995). Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J. Bone Miner. Res., 10, 1478-1487 Luckman, S. P., Coxon, F. P., Ebetino, F. H., Russell, R. G. G., and Rogers, M. J. (1998). Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation: Evidence from structure-activity relationships in J774 macrophages. J. Bone Miner. Res., 13, 1668-1678 Luckman, S. P., Hughes, D. E., Coxon, F. P., Russell, R. G. G., and Rogers, M. J. (1998). Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent posttranslational prenylation of GTP-binding proteins, including Ras. J. Bone Miner. Res., 13,581-589 Martin, M. B., Arnold, W., Heath III, H. T., Urbina, J. A., and Oldfield, E. (1999). Nitrogencontaining bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis. Biochem. Biophys. Res. Commun., 263,754-758 Masarachia, P., Weinreb, M., Balena, R., and Rodan, G. A. (1996). Comparison of the distribution of 3H-alendronate and 3H-etidronate in rat and mouse bones. Bone, 19, 281-290 Murakami, H., Takahashi, N., Sasaki, T., Udagawa, N., Tanaka, S., Nakamura, I., Zhang, D., Barbier, A., and Suda, T. (1995). A possible mechanism of the specific action of bisphosphonates on osteoclasts: Tiludronate preferentially affects polarized osteoclasts having ruffled borders. Bone, 17, 137-144 Nishikawa, M., Akatsu, T., Katayama, Y., Yasutomo, Y., Kado, S., Kugai, N., Yamamoto, M., and Nagata, N. (1996). Bisphosphonates act on osteoblastic cells and inhibit osteoclast formation in mouse marrow cultures. Bone, 18, 9-14 Sahni, M., Guenther, H. L., Fleisch, H., Collin, P., and Martin, T. J. (1993). Bisphosphonates act on rat bone resorption through the mediation of osteoblasts. J. Clin. Invest., 91, 2004-2011 Sato, M., and Grasser, W. (1990). Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. J. Bone Miner. Res., 5, 31-40 Sato, M., Grasser, W., Endo, N., Akins, R., Simmons, H., Thompson, D. D., Golub, E., and Rodan, G. A. (1991). Bisphosponate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J. Clin. Invest., 88, 2095-2105 Schmidt, A., Rutledge, S. J., Endo, N., Opas, E. E., Tanaka, H., Wesolowski, G., Leu, C. T., Huang, Z., Ramachandaran, C., Rodan, S. B., and Rodan, G. A. (1996). Protein-tyrosine phosphatase activity regulates osteoclast formation and function: Inhibition by alendronate. Proc. Natl. Acad. Sci. U.S.A., 93, 3068-3073 Vitt~, C., Fleisch, H., and Guenther, H. L. (1996). Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology, 137, 2324-2333 Zimolo, Z., Wesolowski, G., and Rodan, G. A. (1995). Acid extrusion is induced by osteoclast attachment to bone: Inhibition by alendronate and calcitonin. J. Clin. Invest., 96, 2277-2283

Mineralization Briner, W. W., Francis, M. D., and Widder, J. S. (1971). The control of dental calculus in experimental animals. Int. Dent. J., 21, 61-73 Fleisch, H., Russell, R. G. G., Bisaz, S., Miihlbauer, R. C., and Williams, D. A. (1970). The inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur. J. Clin. Invest., 1, 12-18 Francis, M. D., Russell, R. G. G., and Fleisch, H. (1969). Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science, 165, 1264-1266 King, W. R., Francis, M. D., and Michael, W. R. (1971). Effect of disodium ethane-l-hydroxy-l,l-diphosphonate on bone formation. Clin. Orthop., 78, 251-270

54

2.3. A c t i o n s

Schenk, R., Merz, W. A., Miihlbauer, R., Russell, R. G. G., and Fleisch, H. (1973). Effect of ethane-l-hydro• (EHDP) and dichloromethylene diphosphonate (C12MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calcif. Tissue Res., 11,196-214 Shinoda, H., Adamek, G., Felix, R., Fleisch, H., Schenk, R., and Hagan, P. (1983). Structure-activity relationships of various bisphosphonates. Calcif. Tissue Int., 35, 8799 O t h e r effects Boyce, R. W., Paddock, C. L., Gleason, J. R., Sietsema, W. K., and Eriksen, E. F. (1995). The effects of risedronate on canine cancellous bone remodeling: Three-dimensional kinetic reconstruction of the remodeling site. J. Bone Miner. Res., 10, 211-221 Ciosek, C. P., Magnin, D. R., Harrity, T. W., Logan, J. V. H., Dickson, J. K., Gordon, E. M., Hamilton, K. A., Jolibois, K. G., Kunselman, L. K., Lawrence, R. M., Mookhtiar, K. A., Rich, L. C., Slusarchyk, D. A., Sulsky, R. B., and Biller, S. A. (1993). Lipophilic 1, 1-bisphosphonates are potent squalene synthase inhibitors and orally active cholesterol lowering agents in vivo. J. Biol. Chem., 268, 24832-24837 Dunn, C. J., Galinet, L. A., Wu, H., Nugent, R. A., Schlachter, S. T., Staite, N. D., Aspar, D. G., Elliott, G. A., Essani, N. A., Rohloff, N. A., and Smith, R. J. (1993). Demonstration of novel anti-arthritic and anti-inflammatory effects of diphosphonates. J. Pharmacol. Exp. Ther., 266, 1691-1698 Endo, Y., Nakamura, M., Kikuchi, T., Shinoda, H., Takeda, Y., Nitta, Y., and Kumagai, K. (1993). Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase machrophages, granulocytes, and osteoclasts in vivo. Calcif. Tissue Int., 52, 248-254 Francis, M. D., Hovancik, K., and Boyce, R. W. (1989). NE-58095: A diphosphonate which prevents bone erosion and preserves joint architecture in experimental arthritis. Int. J. Tissue React., 11,239-252 Giuliani, N., Pedrazzoni, M., Negri, G., Passeri, G., Impicciatore, M., and Girasole, G. (1998). Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo. Bone, 22, 455-461 Goziotis, A., Sukhu, B., Torontali, M., Dowhaniuk, M., and Tenenbaum, H. C. (1995). Effects of bisphosphonates APD and HEBP on bone metabolism in vitro. Bone, 16(Suppl.), 317S-327S Guenther, H. L., Guenther, H. E., and Fleisch, H. (1981). The effects of 1-hydroxyethane1, 1-diphosphonate and dichloromethanedisphosphonate on collagen synthesis by rabbit articular chondrocytes and rat bone cells. Biochem. J., 196, 293-301 Kinne, R. W., Schmidt-Weber, C. B., Hoppe, R., Buchner, E., Palombo-Kinne, E., Niirnberg, E., and Emmrich, F. (1995). Long-term amelioration of rat adjuvant arthritis following systemic elimination of macrophages by clodronate-containing liposomes. Arthritis Rheum., 38, 1777-1790 Osterman, T., Kippo, K., Laur8n, L., Hannuniemi, R., and Sellman, R. (1994). Effect of clodronate on established adjuvant arthritis. Rheumatol. Int., 14, 139-147 Tanahashi, M., Funaba, Y., Itoh, M., Kawabe, N., and Nakadate-Matsushita, T. (1998). Inhibitory effects of TRK-530 on rat adjuvant arthritis. Pharmacology, 56, 242-251 Tsuchimoto, M., Azuma, Y., Higuchi, O., Sugimoto, I., Hirata, N., Kiyoki, M., and Yamamoto, I. (1994). Alendronate modulates osteogenesis of human osteoblastic cells in vitro. Jpn. J. Pharmacol., 66, 25-33

55

2.4. PHARMACOKINETICS

dechanism of action p. 45

Bisphosphonates are synthetic compounds, which have not yet been found to occur naturally in animals or humans. No enzymes able to cleave the P - - C - - P bonds have been described. The bisphosphonates on which data have been published so far, appear to be absorbed, stored, and excreted unaltered from the body. Therefore, these bisphosphonates seem to be nonbiodegradable, in solution and in animals. However, it cannot be excluded that some bisphosphonates may be metabolized, especially in their side chains. Some of them may be incorporated in ATP-containing compounds. Bisphosphonates are not biodegradable, at least not at their P - - C m P bond.

Data from relatively few pharmacokinetic studies are available. Most of the published data have been obtained with alendronate, clodronate, etidronate, pamidronate, and tiludronate. 2.4.1.

Inhibition of lineralization pp. 171-172

Intestinal absorption

The bioavailability of an oral dose of a bisphosphonate in animals as well as in humans is low, probably because of their low lipophilicity which prevents transcellular transport, and their high negative charge which prevents paracellular transport. It lies between less than 1 and 10%. Absorption is proportionally greater when large doses are given, such as with etidronate and clodronate. This is possibly the reason why it is generally lower for the more potent bisphosphonates which are administered in lower amounts. It is in general higher in the young and shows great inter- and intraspecies variation. This variability can present a problem in humans, especially for compounds such as etidronate where the dose which shows an adverse event, such as an inhibition of mineralization, is close to that which inhibits bone resorption. The location of the absorption in the gastrointestinal tract is not yet elucidated, although it can occur in the stomach as well as in the small intestine. It appears to occur by passive diffusion, probably through a paracellular pathway. Absorption is substantially diminished when the drug is given with meals, especially in the presence of calcium and iron. The mechanism of this reduction may be due to the conversion of the bisphosphonate into a nonabsorbable form, or to a decrease of the absorption process itself. Therefore, bisphosphonates should never be given at mealtimes and never together with milk or dairy products or with iron supplements. For some unknown reasons, orange juice and coffee also decrease absorption.

56

2.4. Pharmacokinetics Bisphosphonates are poorly absorbed, especially in the presence of food and of calcium.

2.4.2.

Distribution

In the blood, only part of the bisphosphonates are ultrafilterable. The values vary between about two-thirds to only a few percent and are strongly species-dependent, being low for the rat, higher for larger animals and humans. The nonfilterable fraction is either bound to proteins, especially albumin, or present in very small calcium-containing aggregates. Some 2 0 - 8 0 % of the absorbed bisphosphonate is then taken up by bone, the remainder being rapidly excreted in the urine. The skeletal uptake varies with species, sex, and age and with the dose and nature of the compound. In humans receiving clinical doses, the values are about 20% for clodronate, 50% for etidronate, and more for alendronate and pamidronate. Sometimes bisphosphonates, especially pamidronate, can deposit in other organs, mostly the liver and the spleen. The deposition is proportionally greater when large amounts of the compounds are given. At least part of this extraosseous deposition appears to be due to the formation of complexes with metals or to aggregates after too high or too rapid intravenous injection. These complexes are then phagocytosed by the macrophages of the reticuloendothelial system. Therefore, data obtained from studies using large amounts of labeled bisphosphonate given rapidly intravenously should be interpreted with caution. The formation of aggregates in the blood is thought to occur in humans following rapid intravenous injections of large quantities, possibly explaining the renal failure that can ensue.

Bisphosphonates should not be infused rapidly in large quantities, as this can cause the formation of insoluble aggregates or complexes which may impair kidney function. The half-life of circulating bisphosphonates is short, in the order of minutes in the rat. In humans it is somewhat longer, 0.5-2 h. The rate of entry into bone is very fast, similar to that of calcium and phosphate. Bone clearance is compatible with a complete extraction by the skeleton after the first passage, so that skeletal uptake might be determined to a large extent by skeletal vascularization and blood flow. The areas of deposition were generally thought to be mostly those of bone formation. This property is used to measure areas of high bone turnover in nuclear medicine by means of 99mTc-linked bisphosphonates. However, alendronate, when

57

Adverse eve p. 168

2. Bisphosphonates~preclinical

Deposition in bone p. 43

given in therapeutic doses, has been found to accumulate preferentially under the osteoclasts. This is also the case, although to a lesser extent, for etidronate when given in the same amount. When given at a therapeutic dose, the latter, however, accumulates equally under both cells. This suggests that when a bisphosphonate is given in small doses, which is the case for all newer compounds, it is likely to deposit preferentially in locations of bone resorption. The rapid uptake by bone means that the soft tissues are exposed to bisphosphonates for only short periods, explaining why practically only bone is affected in vivo.

Bisphosphonates deposit rapidly into bone, in areas of both bone formation and bone destruction. The half-life in plasma is therefore very short.

Effect in humans p. 143

When bisphosphonates are given in clinically effective doses, there seems to be no saturation in their total skeletal uptake in humans, at least within periods as long as years or decades. In contrast, with continuous administration, the antiresorbing effect reaches a maximum relatively rapidly, both in animals and in man. The level of this maximal effect depends on the dose administered, as does the duration of the effect after discontinuation of the drug. The fact that a plateau of activity is reached, despite the fact that the bisphosphonate continues to be incorporated, suggests that the compounds are buried in the bone and become inactive (Fig. 2.4-1).

The accumulation in the skeleton reaches a plateau with chronic administration only after a very long time, possibly decades. In contrast, the plateau of biological response on resorption is attained more rapidly and is dose-dependent. Once deposited in the skeleton, part of the bisphosphonate is liberated again by physicochemical mechanisms. Once buried under new layers of bone, they will be released to a large extent only when the bone in which they were deposited is resorbed. Thus the half-life in the body depends on the rate of bone turnover itself. As the bisphosphonates slow down the resorption of the bone in which they are deposited, their half-life may be even longer than the normal half-life of the skeleton. The half-life of various bisphosphonates is between 3 months and up to a year in mice or rats, clodronate being cleared somewhat faster than etidronate and pamidronate. For humans it is much longer, for some bisphosphonates over 10 years, and it is possible that a portion of the administered compounds remains in the body for life. However, this is also true for other bone seekers such as tetracyclines, heavy metals, and fluoride. There is no indication that the bisphosphonate buried in the skeleton has any pharmacological activity. On the contrary, in the rat, bone formed

58

2.4. Pharmacokinetics --~ Fig. 2.4-1 Effectof various doses of pamidronate administered daily subcutaneously on urinary hydroxyproline excretion in the rat. The maximal effect is obtained rapidly and depends on the dose given. [Adapted and reproduced from Reitsma, P. H., et al. (1980). Calcif. Tissue Int., 32, 145-157, with copyright permission from the author and SpringerVerlag, Heidelberg.]

Effect of dose on bone resorption 100 80 0.16 ~moles/day +1

"-6

60

4..a O

100

9

~

80

9

x

60

"=

100

1.6 pmoles/day -+

....

+-+

........

80 60 0

5

16 ~moles/day 1() 1~5 Days

under administration of even high doses of alendronate can be resorbed normally. However, at the sites where the bisphosphonate is deposited in large amounts, such as in high turnover locations of patients with bone metastases or with Paget's disease, the long skeletal retention may explain why one single administration of a bisphosphonate can be active for long periods of time, both in animals and in humans.

Tumor hypercalcen p. 100 Paget's dise~ p. 76

The skeletal retention of bisphosphonates is very long, possibly life-long.

2.4.3.

Renal clearance

The renal clearance of bisphosphonates is high. When taking into account their only partial ultrafilterability, it can be, at least in animals, higher than that of inulin, indicating active secretion. The secretory pathway involved is not yet characterized. Urinary excretion is decreased in renal failure and the removal by peritoneal dialysis is poor, which has to be accounted for when the compounds are administered in patients with kidney disease.

59

Administrat:

in renal faih p. 178

2. Bisphosphonates--preclinical Fig. 2.4-2 Pharmacokinetics of bisphosphonates.

Bisphosphonate kinetics Gastrointestinal Tract ~ <1-10%

20-80%

Blood

Z ~"

one

z/, ], .~,,_~,

Kidney Urine

2.4.4.

Other modes of application

Bisphosphonates are also bioavailable to some extent when given intranasally and through the skin. This may open new modes of administration in clinical practice.

Recommended selected reading Reviews Lin, J. H. (1996). Bisphosphonates: A review of their pharmacokinetic properties. Bone, 18, 75-85 Papapoulos, S. E. (1995). Pharmacodynamics of bisphosphonates in man; implications for treatment. In Bijvoet, O. L. M., Fleisch, H. A., Canfield, R. E., and Russell, R. G. G. (eds.) Bisphosphonate on Bones, pp. 231-263. (Amsterdam: Elsevier)

Original articles Bisaz, S., Jung, A., and Fleisch, H. (1978). Uptake by bone of pyrophosphate, diphosphonates and their technetium derivatives. Clin. Sci. Mol. Med., 54, 265-272 Boulenc, X., Marti, E., Joyeux, H., Roques, C., Berger, Y., and Fabre, G. (1993). Importance of the paracellular pathway for the transport of new bisphophonate using the human CACO-2 monolayers model. Biochem. Pharmacol., 46(9), 1591-1600 Cheung, W. K., Brunner, L., Schoenfeld, S., Knight, R., Seaman, J., Brox, A., Batist, G., John, V., and Chan, K. (1994). Pharmacokinetics of pamidronate disodium in cancer patients after a single intravenous infusion of 30-, 60- or 90-mg dose over 4 or 24 hours. Am. J. Ther., 1,228-235 Conrad, K. A., and Lee, S. M. (1981). Clodronate kinetics and dynamics. Clin. Pharmacol. Ther., 30, 114-120 Daley-Yates, P. T., Dodwell, D. J., Pongchaidecha, M., Coleman, R. E., and Howell, A. (1991). The clearance and bioavailability of pamidronate in patients with breast cancer and bone metastases. Calcif. Tissue Int., 49, 433-435 Gertz, B. J., Holland, S. D., Kline, W. F., Matuszewski, B. K., Freeman, A., Quan, H., Lasseter, K. C., Mucklow, J. C., and Porras, A. G. (1995). Studies of the oral bioavailability of alendronate. Clin. Pharmacol. Ther., 58, 288-298 Gural, R. P. (1975). Pharmacokinetics and Gastrointestinal Absorption Behavior of Etridronate. Dissertation, Lexington: University of Kentucky

60

2.4. Pharmacokinetics Gural, R. P., Chungi, V. S., Shrewsbury, R. P., and Dittert, L. W. (1985). Dose-dependent absorption of disodium etidronate. J. Pharm. Pharmacol., 37, 443-445 Hanhij/irvi, H., Elomaa, I., Karlsson, M., and Lauren, L. (1989). Pharmacokinetics of disodium clodronate after daily intravenous infusions during five consecutive days. Int. J. Clin. Pharmacol. Tber. Toxicol., 27, 602-606 Hyldstrup, L., Flesch, G., and Hauffe, S. A. (1993). Pharmacokinetic evaluation of pamidronate after oral administration: A study on dose proportionality, absolute bioavailability, and effect of repeated administration. Calcif. Tissue Int., 53, 297-300 Kasting, G. B., and Francis, M. D. (1992). Retention of etidronate in human, dog and rat. J. Bone Miner. Res., 7, 513-522 Koopmans, S. J., van der Wee-Pals, L., L6wick, C. W. G. M., and Papapoulos, S. E. (1994). Use of a rat model for the simultaneous assessment of pharmacokinetic and pharmacodynamic aspects of bisphosphonate treatment: Application to the study of intravenous 14C-labeled 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1, 1-bisphosphonate. J. Bone Miner. Res., 9, 241-246 Lin, J. H., Chen, I.-W., and Duggan, D. E. (1992). Effects of dose, sex, and age on the disposition of alendronate, a potent antiosteolytic bisphosphonate, in rats. Drug Metab. Dispos., 20, 473-478 Lin, J. H., Chen, I.-W., Florencia, A., Deluna, A., and Hichens, M. (1992). Renal handling of alendronate in rats: An uncharacterized renal transport system. Drug Metab. Dispos., 2O, 608 -613 Lin, J. H., Chen, I.-W., and DeLuna, F. A. (1994). On the absorption of alendronate in rats. J. Pharm. Sci., 83, 1741-1746 Masarachia, P., Weinreb, M., and Rodan, G. A. (1996). Comparison of the distribution of 3H-alendronate and 3H-etidronate in rat and mouse bones. Bone, 19, 281-290 Michael, W. R., King, W. R., and Wakim, J. M. (1972). Metabolism of disodium ethane-1hydroxy-l,l-diphosphonate (disodium etidronate) in the rat, rabbit, dog and monkey. Toxicol. Appl. Pharmacol., 21,503-515 Mitchell, D. Y., Eusebio, R. A., Dunlap, L. E., Pallone, K. E., Nesbitt, J. D., Russell, D. A., Clay, M. E., and Bekker, P. J. (1998). Risedronate gastrointestinal absorption is independent of site and rate of administration. Pharmacol. Res., 15,228-232 M6nkk6nen, J., Koponen, H. M., and Ylitalo, P. (1990). Comparison of the distribution of three bisphosphonates in mice. Pharrnacol. Toxicol., 66, 294-298 O'Rourke, N. P., McCloskey, E. V., Neugebauer, G., and Kanis, J. A. (1994). Renal and nonrenal clearance of clodronate in patients with malignancy and renal impairment. Drug Invest., 7, 26-33 (Ssterman, T., Juhakoski, A., Laur6n, L., and Sellman, R. (1994). Effect of iron on the absorption and distribution of clodronate after oral administration in rats. Pharmacol. Toxicol., 74, 267-270 Pongchaidecha, M., and Daley-Yates, P. T. (1993). Clearance and tissue uptake following 4-hour and 24-hour infusions of pamidronate in rats. Drug Metab. Dispos., 21, 100103 Powell, J. H., and DeMark, B. R. (1985). Clinical pharmacokinetics of diphosphonates. In Garattini, S. (ed.) Bone Resorption, Metastasis, and Diphosphonates, pp. 41-49. (New York: Raven) Recker, R. R., and Saville, P. D. (1973). Intestinal absorption of disodium ethane-l-hydroxy-l,l-diphosphonate (disodium etidronate) using a deconvolution technique. Toxicol. Appl. Pharmacol., 24, 580-589 Saha, H., Castren-Kortekangas, P., Ojanen, S., Juhakoski, A., Tuominen, J., Tokola, O., and Pasternack, A. (1994). Pharmacokinetics of clodronate in renal failure. J. Bone Miner. Res., 9, 1953-1958 Saha, H. H. T., Ala-Houhala, I. O., Liukko-Sipi, S. H., Ylitalo, P., and Pasternack, A. I. (1998). Pharmacokinetics of clodronate in peritoneal dialysis patients. Peritoneal. Dial. Int., 18, 204-209 Sansom, L. N., Necciari, J., and Thiercelin, J. F. (1995). Human pharmacokinetics of tiludronate. Bone, 17, 479S-483S Troehler, U., Bonjour, J. p., and Fleisch, H. (1975). Renal secretion of diphosphonates in rats. Kidney Int., 8, 6-13

61

2. Bisphosphonates--preclinical Usui, T., Watanabe, T., and Higuchi, S. (1995). Pharmacokinetics of YM175, a new bisphosphonate, in rats and dogs. Drug Metab. Dispos., 23, 1214-1219 Wingen, F., and Schm~ihl, D. (1987). Pharmacokinetics of the osteotropic diphosphonate 3-amino-l-hydroxypropane-1, 1-diphosphonic acid in mammals. Arzneim.-Forsch., 37, 1037-1042 Yakatan, G. J., Poynor, W. J., Talbert, R. L., Floyd, B. F., Slough, C. L., Ampulski, R. S., and Benedict, J. J. (1982). Clodronate kinetics and bioavailability. Clin. Pharmacol. Ther., 31,402-410

62

2.5.

ANIMAL

TOXICOLOGY

Published animal toxicological data are scanty and deal mostly with alendronate, clodronate, etidronate, incadronate, pamidronate, and tiludronate. Unfortunately, little is published about other compounds. Acute, subacute, and chronic administration in several animal species have in general revealed little toxicity. Teratogenicity, mitogenicity, and carcinogenicity tests have been negative. When bisphosphonates are administered subcutaneously, local toxicity can occur, with local necrosis. This is especially the case for the amino derivatives such as pamidronate.

Bisphosphonates have in general little toxicity. 2.5.1.

Acute toxicity

Acute toxicity can include induction of hypocalcemia and appears to be due mainly to the formation of complexes or aggregates with calcium, which lead to a decrease in ionized calcium. Toxicity therefore varies with the speed of infusion when the compounds are administered intravenously, so that the rate of infusion in humans must be carefully controlled when given in high doses. In contrast, it appears that very potent bisphosphonates, such as ibandronate, may be safely given in doses up to 2 - 3 mg as an i.v. injection. In the event of hypocalcemia, calcium infusion can rapidly correct the signs and symptoms. Some acute toxicity can also be due to renal tubular effects.

Formation of aggregates pp. 3 2 - 3 3

Infusion in humans p. 168

Acute toxicity is due in the first instance to hypocalcemia. 2.5.2.

Nonacute toxicity

In view of the large array of cellular effects obtained in vitro with the bisphosphonates, one would have expected a large number of toxic effects. This is not the case, and when administered in pharmacological doses, the bisphosphonates seem to act almost exclusively on calcified tissues, and secondarily on plasma calcium, but are very well tolerated otherwise. This selectivity is explained by the strong affinity of these compounds for calcium phosphate, which allows them to be rapidly incorporated into calcified tissues, especially bone, and therefore to be cleared quickly from the blood.

Bisphosphonates have low toxicity. They act specifically on bone, because of their affinity for bone mineral. The nonskeletal toxicity associated with the compounds used clinically occurs only when doses substantially larger than those which inhibit bone resorption are used. In general, the first organ to show cellular alterations 63

Pharmacokinetics p. 57

2. Bisphosphonatesmpreclinical with all bisphosphonates, as well as with polyphosphates and phosphate itself, is the kidney. The liver, as well as the testis, the epididymis, the prostate and possibly the lung, can in some cases also show alterations. Some inflammatory gastrointestinal changes have been described, even with parenteral administration at high doses, although this has not been observed in humans. Developmental disturbances of enamel can also appear at high systemic doses. Lastly, at least certain bisphosphonates, such as etidronate and pamidronate, cross the placenta and can affect the fetus.

The first organ, apart l:rom bone, to show alterations is the kidney. At least some bisphosphonates can cross the placenta and affect the [etus. It must be stressed that the results with one bisphosphonate cannot necessarily be extrapolated to other bisphosphonates. Indeed toxicity, both in cell and organ culture and in vivo, varies greatly from one compound to another.

Toxicity, both in vitro and in vivo, varies greatly from one bisphosphonate to another. Alendronate

GI effects in humans p. 169

Alendronate when given orally to rats at suprapharmacological doses has been reported to occasionally induce gastric and esophageal erosions and ulcerations and delay healing of indomethacin induced gastric erosions. These effects are not attributable to changes in gastric acid secretion, or prostaglandin synthesis, but are thought to be due to a topical irritant effect. No esophageal irritation occurred when the pH was above 3.5 in a dog model. Similar effects were reported with etidronate, risedronate, and tiludronate when given at pharmacologically equivalent doses. All these effects were obtained at doses much larger than the ones given in humans.

Bisphosphonates given at suprapharmacological doses and at low pH can induce gastric and esophageal ulcerations. Clodronate Inhibition of mineralization can also occur with clodronate, but requires higher doses than with etidronate. At very high doses, fractures can occur, without signs of osteomalacia or rickets. The fractures may be caused

64

2.5. Animal toxicology by the extreme long-term decrease in bone turnover, which can itself lead to an increased fragility, as is well known in human congenital osteopetrosis, or by bone cell toxicity. Kidney alterations are seen at high doses, and with very high doses atrophy of the thymus and some immunological alterations can occur in newborn animals. None of these alterations, which were obtained at very high dosage, have however been seen in humans. Six-month toxicology studies with clodronate have shown that a daily oral amount of 200 mg/kg and 40 mg/kg are the highest nontoxic doses in the rat and dog, respectively.

Etidronate The most relevant toxicity associated with this bisphosphonate is the inhibition of bone and cartilage calcification. This starts to occur at parenteral doses of approximately 5-10 mg/kg daily. The radiological appearance resembles rickets or osteomalacia, although there are some histological differences. Fractures can occur after long-term administration of high doses and are probably the result of the defective mineralization. Renal lesions can be induced after rapidly administered intravenous doses. Very large doses (200 mg/kg subcutaneously) of etidronate, given to -~ pregnant rats, that is about 300 times the maximal oral dose of 20 mg/kg used in humans, lead to fetal abnormalities of the skeleton and the skin and induce malformations and hemorrhages.

The most relevant toxicity associated with etidronate is an inhibition of the mineralization of calcified tissues. At higher doses renal lesions appear, as is generally the case for bisphosphonates. Pamidronate Pamidronate also can lead to kidney alterations, the safety margin between the toxic dose and that inhibiting bone resorption being somewhat smaller than with etidronate and clodronate. Large doses of pamidronate "~ (60 mg/kg per day and more orally) can decrease the number of live pups and pup viability in rats. Intravenous administration of 1 mg/kg per day and more produce alterations in the skeleton and the kidneys of the offspring.

Other bisphosphonates A toxic dose of incadronate has induced in the dog the formation of immature woven bone in the marrow of various bones. This observation, for which no explanation has yet been found, is a unique finding in the field of bisphosphonates.

65

Inhibition o mineralizati p. 49 Effect in humans

p. 171

2. Bisphosphonatesmpreclinical

Recommended selected reading Reviews Neer, R. M. (1995). Skeletal safety of tiludronate. Bone, 17(Suppl. 5), 501S-503S Roldan, E. J. A., P~rez-Llore, A., and Ferretti J. L. R. (1998). Olpadronate: A new aminobisphosphonate for the treatment of medical osteopathies. Exp. Opin. Invest. Drugs 7, 1521-1538

Original articles Alden, C. L., Parker, R. D., and Eastman, D. F. (1989). Development of an acute model for the study of chloromethanediphosphonate nephrotoxicity. Toxicol. Pathol., 17, 27-32 Cal, J. C., and Daley-Yates, P. T. (1990). Disposition and nephrotoxicity of 3-amino-1hydroxypropylidene-l,l-bisphosphonate (APD) in rats and mice. Toxicology, 65, 179197 Eguchi, M., Yamaguchi, T., Shiota, E., and Handa, S. (1982). Fault of ossification and calcification and angular deformities of long bones in the mouse fetuses caused by high doses of ethane-l-hydroxy-l,l-diphosphonate (EHDP) during pregnancy. Cong. Anom., 22, 47-52 Elliott, S. N., McKnight, W., Davies, N. M., MacNaugthton, W. K., and Wallace, J. L. (1998). Alendronate induces gastric injury and delays ulcer healing in rodents. Life Sci. 62, 77-91 Flora, L., Hassing, G. S., Parfitt, A. M., and Villanueva, A. R. (1980). Comparative skeletal effects of two diphosphonates in dogs. Metab. Bone Dis. Relat. Res., 2, 389-407 Graepel, P., Bentley, P., Fritz, H., Miyamoto, M., and Slater, S. R. (1992). Reproduction toxicity studies with pamidronate. Arzneim.-Forsch. Drug Res., 42, 654-667 Nii, A., Fujimoto, R., Okazaki, A., Narita, K., and Miki, H. (1994). Intramembranous and endochondral bone changes induced by a new bisphosphonate (YM175) in the beagle dog. Toxicol. Pathol., 22(5), 536-544 Nixon, G. A., Buehler, E. V., and Newmann, E. A. (1972). Preliminary safety assessment of disodium etidronate as an additive to experimental oral hygiene products. Toxicol. Appl. Pharmacol., 22, 661-671 Okazaki, A., Matsuzawa, T., Takeda, M., York, R. G., Barrow, P. C., King, V. C., and Bailey, G. P. (1995). Intravenous reproductive and developmental toxicity studies of cimadronate (YM175), a novel bisphosphonate, in rats and rabbits. J. Toxicol. Sci., 20, 1-13 Okazaki, A., Sakai, H., Matsuzawa, T., Perkin, C. J., and East, P. W. (1995). Intravenous single and repeated dose toxicity studies of cimadronate (YM175), a novel bisphosphonate, in rats. J. Toxicol. Sci., 20, 15-26 Okazaki, A., Matsuzawa, T., Perkin, C. J., and Barker, M. H. (1995). Intravenous single and repeated dose toxicity studies of cimadronate (YM175), a novel bisphosphonate, in beagle dogs. J. Toxicol. Sci., 20, 27-36 Nolen, G. A., and Buehler, E. V. (1971). The effects of disodium etidronate on the reproductive functions and embryogeny of albino rats and New Zealand rabbits. Toxicol. Appl. Pharmacol., 18, 548-561 Peter, C. P., Handt, K. K., and Smith, S. M. (1998). Esophageal irritation due to alendronate sodium tablets. Digest. Dis. Sci., 43, 1998-2002 Peter, C. P., Kindt, M. V., and Majka, J. A. (1998). Comparative study of potential for bisphosphonates to damage gastric mucosa of rats. Digest. Dis. Sci., 43, 1009-1015 Sakiyama, Y., Yamamoto, H., Soeda, Y., Tada, I., Oda, M., Nagasawa, S., and Ikeo, T. (1986). The effect of ethane-l-hydroxy-l,l-diphosphonate (EHDP) on fetal mice during pregnancy. Part 2: External anomalies. J. Osaka Dent. Univ., 20, 91-100

66

Bisphosphonates clinical

3.1. INTRODUCTION The clinical applications of bisphosphonates have focused on four areas. They are used as: (a) Skeletal markers in the form of 99mWcderivatives for diagnostic purposes in nuclear medicine; (b) Antiosteolytic agents in patients with increased bone destruction, especially Paget's disease, tumor-induced bone disease, and more recently osteoporosis; (c) Inhibitors of calcification in patients with ectopic calcification and ossification; and (d) Antitartar agents added to toothpastes. Only applications (b) and (c) are discussed in this book.

67

3.2. 3.2.1.

PAGET'S

DISEASE

Definition

Paget's disease is a localized and progressive disorder of bone, characterized by increased bone remodeling, bone hypertrophy, and abnormal bone structure. Originally called osteitis deformans, it was first described in 1876 by Sir James Paget. 3.2.2.

Epidemiology

It is a fairly common disease, actually the second most common metabolic bone disease after osteoporosis in some countries. It has been estimated that in the countries where the ailment is prevalent, up to 3 % of the population over the age of 50, more in later years, is affected. A recent study suggests a decrease in the prevalence of the disease in the last 20 years. The disease is frequent in Europe, with the exception of the Scandinavian countries, and is frequent in regions inhabited by European immigrants, such as North America and Australia. In contrast, it is rare in the Arab countries, as well as among blacks and Asians. It is almost always diagnosed in patients over the age of 40 and is probably somewhat more common in men than in women. Recent work shows that there is a genetic predisposition, as a family history is often present. Possibly a gene abnormality on chromosome 18q causes Paget's disease in some families.

Paget's disease is fairly common and presents itself clinically after the age o[40. There is often a positive family history. 3.2.3.

Coupling p. 13

Pathophysiology

For as yet unknown reasons, bone turnover becomes abnormally increased at certain sites of the skeleton, with an increase in local remodeling and modeling. The cause is probably a slow paramyxovirus infection, in view of the presence of cellular inclusions in the osteoclasts which appear to be paramyxovirus nucleocapsids, of positive reactions with antisera raised against the measles virus, and the presence of RNA for measles and other viruses in the cells. It has been suggested that in some cases the patients are infected by dogs afflicted by distemper virus, the canine equivalent of measles. The initial event is a marked elevation of bone resorption, probably because of, among other reasons, an increase in IL-6 production by marrow and/or bone cells, leading to osteolytic lesions. A compensatory increase in formation occurs secondarily and induces an abnormally positive bone balance with sclerotic lesions and local deformations of the skeleton. 68

3.2. Paget's disease The disorder is clue to localized loci of increased bone turnover following a local increase in resorption. The etiology is uncertain, possibly viral with a genetic predisposition. 3.2.4.

Clinical manifestations

Signs a n d s y m p t o m s The condition is most commonly asymptomatic and is often discovered fortuitously during a routine measurement of serum alkaline phosphatase activity, an X-ray, or more rarely a scintigraphic examination. The lesions appear as lytic or sclerotic foci in the X-ray or as hot spots during scintigraphy. Localization occurs mainly in the pelvis, the vertebrae, the scapulae, the larger long bones, and the skull. They can be mono- or polyostotic. Sometimes a deformation of the bone, especially bone enlargement, is present.

The disease is often asymptomatic and discovered during a routine measurement of serum alkaline phosphatase or an X-ray examination. Only approximately 5 % of patients present with symptoms. The most common complaint is pain, which may be very intense, and is most commonly secondary to a Pagetic localization in the back, the hip, or a long bone. It can be caused, among others, by a fissure-fracture, or secondary joint disease. In the latter case it will not respond to treatment, in contrast to the pain resulting from a Pagetic lesion itself. Another complaint is bone deformity, especially bending of long bones and the spine, and enlargement of bones, such as the skull. An increase in the cranium has led to the term disease of the too small hat. Deformities can lead to a variety of neurovascular symptoms, such as a vertebrobasilar artery syndrome and sometimes spinal cord dysfunction, although the latter is due more commonly to Pagetic bone stealing blood from neural tissue. Deafness, a common complication, is due to damage of the cochlear capsule. It is speculated that Paget's disease was the cause of Beethoven's deafness. There can be an increase in vascularization in the afflicted bones, which may even lead very rarely to cardiac failure due to diversion of substantial cardiac output. Lastly, it must be remembered that some Pagetic patients (about 1% or less) may develop osteosarcoma.

Pain, bone deformities, fractures, and neurovascular symptoms are observed and may seriously affect quality of life. 69

3. Bisphosphonates~clinical Laboratory Assessment of turnover p. 21

Laboratory findings reflect increased bone turnover, the indices of both bone formation and resorption being elevated. There is a direct relationship between the increase of the biochemical markers of formation and destruction of bone and the extension of the disease in the skeleton. Bone formation indices are reflected by increased total and bone-specific serum alkaline phosphatase activity. Serum osteocalcin (BGP) is poorly correlated with the activity of the disease, despite the fact that it too is a marker of bone formation. Bone resorption is indicated by an increase in the fasting urinary hydroxyproline, replaced today by urinary pyridinium crosslinks, especially the C-terminal and N-terminal cross-linked telopeptides of type I collagen. There is a positive correlation between the progression of the disease and the increase of the biochemical markers. In monostotic disease, they can therefore be normal. The markers are also used for evaluation of the effect of treatment and the detection of a relapse.

Useful chemical investigations are serum alkaline phosphatase, fasting urinary hydroxyproline, replaced increasingly today by urinary pyridinium cross-links, especially their C- and N-terminal telopeptides. X-ray pictures show, besides osseous deformations and enlargement of the size of certain bones, an accentuated trabecular pattern and local areas of increased bone density alternating with lytic lesions. The sclerotic changes can be so marked that they lead to the so-called ivory vertebrae, which are sometimes difficult to distinguish from skeletal metastases. Scintigraphy with 99mtechnetium-labeled compounds, in which the lesions show up as hot spots, is of great diagnostic value. It is the best method for showing the map of Pagetic sites in the patient. Fig. 3.2-1 99mTc-labeled bisphosphonate scintigram of a patient with Paget's disease. Intense hot spots are seen in the tibia, which is deformed. (Courtesy of Drs. P. J. Meunier and P. D. Delmas.)

Paget's disease

J

70

3.2. Paget's disease Usel:ul radiophysical investigations are radiography and scintigraphy. The histology of Pagetic bone is characterized by the features of extremely rapid turnover. The lesions comprise a mosaic structure of areas of resorption, with a large number of osteoclasts, often of abnormal shape and with many nuclei, and of formation sites with osteoblasts producing an increased amount of bone matrix. Characteristically, the new bone is not lamellar but woven, which explains its brittleness despite the osteosclerosis. The marrow adjacent to the bone lesions shows an increase in fibrous tissue. --* Fig. 3.2-2 Histology of Pagetic bone. Left: Picture of high bone turnover with many osteoclasts. Right: New bone of woven type. (Courtesy of Dr. P. J. Meunier.)

Woven bon~ p. 1

Bone histology in Paget's disease

7oven bone Osteoclasts

Diagnosis The diagnosis ol: Paget's disease is made by radiography, scintigraphy, the laboratory evaluation of bone turnover, and the clinical features. Follow-up of progression of the disease The evolution of the disease is followed by assessing the symptoms, the -+ biochemical indices of bone turnover, and the X-rays. From the biochemical indices of bone formation, serum alkaline phosphatase is more reliable than osteocalcin in this disease. For assessing bone resorption, collagen pyridinium cross-links and especially their N- and C- telopeptides are excellent. They are particularly useful in monostotic forms of the disease where serum total alkaline phosphatase may be normal. Most often it is sufficient to follow only one parameter, the least expensive one being serum alkaline phosphatase.

71

Assessment turnover p. 21

3. Bisphosphonates--clinical Fig. 3.2-3 Boneturnover indices most often used today to monitor treatment in Paget's disease.

Indices of bone turnover Formation Serum alkaline phosphatase

Resorption Urinary pyridinium cross-links

The evolution of the disease and its treatment are usually monitored by following one of the biochemical indices of bone turnover. The least expensive and most used is serum alkaline phosphatase. 3.2.5.

T r e a t m e n t with drugs other than b i s p h o s p h o n a t e s

Treatment should be offered to all symptomatic patients as well as to asymptomatic patients with involvement of skeletal areas that have a potential to give rise to complications, such as the skull, vertebral bodies, long bones, and near major joints. Practically the only treatment, apart from bisphosphonates, is calcitonin. This hormone can be effective in decreasing bone turnover in Pagetic patients and in improving clinical signs and symptoms. Calcitonin has, however, some drawbacks in comparison with bisphosphonates. Its effect is less pronounced than with bisphosphonates and resistance can develop. Bone turnover relapses occur earlier and almost invariably after discontinuation of treatment. In addition, some patients show unpleasant adverse reactions, such as vascular symptoms with parenteral administration. Calcitonin is useful in cases where a rapid effect on blood flow is desired, such as in progressive paraparesis. Plicamycin is virtually never used anymore because of its toxicity.

The only treatment other than bisphosphonates is calcitonin. 3.2.6.

T r e a t m e n t with b i s p h o s p h o n a t e s

Preclinical studies Inhibition of bone resorption pp. 35-40

No well-established animal model exists for Paget's disease. However, resuits obtained with bisphosphonates in animals with normal or experimentally increased bone resorption have proved to be good predictors of the effect in humans.

72

3.2. Paget's disease Clinical studies The bisphosphonates are now the therapy of choice in Paget's disease. All bisphosphonates that have been tested so far have proven to be active in decreasing bone turnover. The difference between the compounds lies in their potency and in their adverse event profile. They are all focally concentrated in the involved areas because of the high local bone turnover. This is probably a major cause of their long-lasting effect.

Pharmacokinetics p. 57

The therapy of choice/:or Paget's disease are the bisphosphonates. Effects Most clinical studies in Paget's disease deal with alendronate, clodronate, etidronate, pamidronate, risedronate, and tiludronate. Other bisphosphonates showing clinical efficacy include ibandronate, neridronate, olpadronate, and zoledronate. The effects observed are qualitatively very similar, but differ with respect to the rapidity with which they develop, the absolute reduction of turnover, and the duration of effect.

Chemical structures pp. 31-32

The effects o1:the various bisphosphonates are qualitatively similar, the differences lying in their potency and adverse event profile. The earliest studies were performed with etidronate. The initial report, which was also the first report in which an effect of a bisphosphonate on bone resorption in a human was demonstrated, dates back to 1971. Both bone resorption and formation were decreased. This action on bone turnover has been well documented in numerous subsequent studies with many other bisphosphonates (Fig. 3.2-4). The effect on resorption precedes that on formation, suggesting that, as in animals, the decrease in formation is secondary, due to the coupling between the two processes. This time differential has a practical consequence in that markers of bone resorption are a better way to assess the acute effect of treatment than alkaline phosphatase. The latter will give useful information only after about 4 weeks, and sometimes even longer (Fig. 3.2-5).

Coupling p. 13

Bisphosphonates decrease both bone resorption and bone formation. The effect on formation occurs somewhat later and is probably secondary to the physiological coupling between the two processes. The decrease in bone turnover can be accompanied by a small decrease in serum ionized calcium and of phosphorus, and an elevation of serum PTH and 1,25(OH)2 D. The latter are often seen when patients with very

73

Effect on calcemia

p. 39

3. Bisphosphonates--clinical

E f i ~ o n a t e in Paget's disease Urinary hydroxyproline

Plasma alkaline phosphatase

%

O

100 60

20

10 mg/kg daily

100 0060 ~

60

. . . .

I

....

I

I

I

....

0 2 4 6 0 2 4 6 Months 20

, , , ,5mg~kgdaily , , , , 0

2

4

6 0 Months

2

4

6

Fig. 3.2-4 Effect of various doses of etidronate on the indices of bone formation and bone resorption in Paget's disease, expressed in percentage of initial values. [Adapted from Russell, R. G. G., et al. (1974). Lancet, 1,894-898. Reproduced with permission from the author and the publisher.]

Effect on:b:.one t u r n ~ e r Clodronate !

~oo

+& 80 >

60

,.~

40

t~

0

0

[

t

,

Pre 1 2

,

I

~

3 4 5 i 2 3 '~ 5 X 7 8' Days Weeks

o Serum alkaline phosphatase 9 Urinary fasting hydroxyproline/creatinine

74

Fig. 3.2-5 Effect of 300 mg/day of clodronate given intravenously for 5 days on bone turnover. Note that bone resorption (urinary hydroxyproline) decreases before bone formation (alkaline phosphatase). [Adapted from Kanis, J. A., and McCloskey, E. V. (1990). Reproduced from Kanis, J. A. (ed.) Calcium Metabolism. Progress in Basic and Clinical Pharmacology, vol. 4, pp. 89-136, with copyright permission from the author and S. Karger AG, Basel.]

3.2. Paget's disease

active osteolysis are treated with a powerful inhibitor of bone resorption. In order to avoid the secondary increase in PTH, some advise administration of the bisphosphonates, especially in patients with severe disease, or elderly people, together with 0.5-1.0 g calcium. In addition, 4 0 0 800 units of vitamin D per day may also be used. In contrast to other bisphosphonates, and for an unknown reason, etidronate increases renal tubular phosphate reabsorption and therefore plasma phosphate when given at daily oral doses of 300 mg or more, as is also the case with this bisphosphonate in other indications. Morphological studies confirm the reduction in turnover. The number of osteoclasts is diminished, but the virus-like cellular inclusions in the nuclei and the measles-type viral antigens in the osteoclasts persist unmodified. It is interesting that the bone formed under treatment with bisphosphonates returns to a lamellar organization, in contrast to the woven bone formation typical of this disease.

Effect on bone histology

New lamellar bone

9

.

New lamellar bone

Fig. 3.2-6 Effect of etidronate (above) and clodronate (below) on bone histology in Paget's disease. The new bone formed is now lamellar with no more woven bone, either in the cortex (above) or in the trabeculae (below). [Courtesy of Dr. P. J. Meunier. Reproduced from Meunier, P. J., et al. (1987). Am. J. Med., 82 (Suppl. 2A), 71-78, with permission from the author and publisher.] 75

Effect on plasma phosphate p. 172

3. Bisphosphonatesmclinical Bisphosphonates improve the morphology of bone. The number of osteoclasts is decreased, and the new bone formed is lameUar instead o1:woven.

Acute-phaselike effects p. 173

Bone pain usually decreases and can disappear completely, except when it is due to arthritic changes, in which case it does not respond or responds less well. It can, however, sometimes be transiently increased within the first few days of treatment with N-containing bisphosphonates like pamidronate. This effect may be related to the acute-phase-like syndrome often observed with these compounds. It resolves spontaneously and does not require reduction of the dose.

Bone pain is usually decreased or even disappears. Occasionally it may be transiently increased at the beginning of treatment. The finding that bone deformities, for example, in the face, as well as neurological spinal syndromes can be improved, suggests that treatment not only stops the progression of the disease, but can also lead to an amelioration of pre-existing lesions. Elevated cardiac output can be normalized. Lastly, treatment with bisphosphonates markedly reduces the pathological uptake of radioactive technetium. Radiologically, although major changes are mostly not striking, the reconstitution of the V-shaped lesions of long bones or of osteoporosis circumscripta of the skull is not uncommon.

Neurological spinal syndromes as well as scintigraphic scans of the skeleton and certain radiological changes are improved. The decrease in bone turnover, as well as the other improvements, can § last for a long time after the discontinuation of treatment, often years. Some patients have actually not relapsed for over 10 years. This is very unusual with calcitonin treatment.

The therapeutic effect on bone turnover can last for a long time, often years, after treatment has been discontinued. Treatment

regimens

Dosage has often been calculated in Paget's disease, as well as in other disorders, according to body weight. This is only meaningful if the latter gives a good reflection of the weight of the skeleton, which is true in children, but most often not in adults. Adjusting the dose according to the fat content of the body has no scientific rationale. If a correction is to be 76

3.2. Paget's disease made, which is in general not useful, it would be better to consider the ideal weight or the height of the patient.

Prescribing a dose per kg of body weight is in most cases not useful in the adult. The effect of treatment is monitored, as mentioned above, by one of the biochemical parameters of bone turnover, serum alkaline phosphatase being currently the simplest and least expensive. Pyridinium cross-links and peptides containing them are becoming increasingly used. It must, however, be remembered that the indices of bone formation respond later than those of bone resorption. The aim of the treatment is to decrease bone turnover to the normal range. Indeed, a relationship appears to exist between the decrease in turnover obtained during treatment and the duration of the effect. If a normalization of turnover is not possible with a specific bisphosphonate, even after longer therapy, a more potent compound should be used if available. The plateau is usually reached within 3 - 6 months for alkaline phosphatase in the case of oral administration, faster for the parameters of bone resorption. Treatment is then discontinued until the indices of bone turnover start to increase again or symptoms recur. At what point one should resume treatment is difficult to determine. An increase above normal range, or if the latter was not attained, of at least 25%, seems a reasonable guideline.

Effect on turnover p. 74

Treatment should aim to normalize turnover, as assessed by o n e of the biochemical markers, for example, alkaline phosphatase. This occurs usually within 6 months after the first course, but normalization may be obtained only after 2, 3, or more courses. Treatment is resumed when symptoms recur, or when the biochemical markers rise again above normal range or by at least 25 %. Recent results show that, as in tumor-induced bone disease, patients with more active forms of the disease require higher total amounts of bisphosphonates. One explanation is that the bisphosphonate administered is distributed into more areas of high turnover, so that the amount deposited in each focal lesion is smaller.

Patients with more severe disease may require higher amounts of bisphosphonates. In some patients resistance to the bisphosphonate may develop with time. The cause of this is unknown. Sometimes it can be overcome by increasing the dose, in other cases the switch to another bisphosphonate, if possible a more potent one, will be successful. 77

Tumor born disease p. 107

3. Bisphosphonatesmclinical If resistance to the treatment develops, either increasing the dose, or a switch to another, preferably more potent bisphosphonate, may solve the problem.

Alendronate Intravenous administration of 2.5, 5, and 10 mg for 5 consecutive days showed a dose-dependent effect. With 10 mg, all patients normalized their serum alkaline phosphatase levels, and the duration of the remission was the longest. In oral studies, administration of 40 mg daily for 6 months induced a decrease of about 70% in alkaline phosphatase, more in resorption markers, approximately half of the patients reaching normal levels. In another study, 40 mg normalized the alkaline phosphatase in approximately 80% of the patients when given for 3 or 6 months, and the urinary hydroxyproline in 100%. Eighty milligrams of alendronate after 3 or 6 months normalized the alkaline phosphatase in 70 and 100%, and the hydroxyproline in 80 and 100%, respectively. Alendronate treatment was also associated with radiological improvement and normal bone histology. Forty milligrams of alendronate orally for 6 months is the dose recommended by the manufacturer. This treatment regimen led to biochemical remission rates of 82 and 66% after 18 and 30 months off-therapy respectively.

Effect of alendronate 20 N-27 _

+l

a= ~ -20.=

-40 -

-60

v

N=47

-

9 Placebo ~ - " ~ N=27 -80 - i Etidronate 400 m g / d a y ~ - ~ N=41 9 Alendronate 40 mg/day - Multinational Study 9 Alendronate 40 mg/day - U.S.Study -100 u i i 0 3 6 Time (months)

78

Fig. 3.2-7 Effect of 40 mg of alendronate and 400 mg of etidronate administered orally daily for 6 months on serum alkaline phosphatase. [Adapted and reproduced from Lombardi, A. (1999), Bone 24 (Suppl.), 59S-61S. Reproduced with permission of the author and Elsevier Science.]

3.2. Paget's disease A daily dose ofalendronate of 40 mg orally for 6 months, the dose recommended by the manufacturer, normalizes the turnover in most of the patients within 6 months. Alendronate is available in an oral form in the United States for the treatment of Paget's disease.

Commercial index pp. 182-206

Clodronate Various oral doses up to 1600 mg daily have been investigated. It appears that the latter dose is preferred and that the treatment should be not less than 6 months. With this therapy 71% of the patients normalized their turnover and the duration of the effect was the longest. A total dose of 1500 mg has been given intravenously either once, or as 300 mg daily for 5 days, or as 300 mg once a month for 5 months. The response of the three treatments was similar, but only 1 5 - 3 2 % of the patients normalized their turnover. This treatment is therefore insufficient.

A daily dose of 1600 mg per os for 6 months normalizes turnover in 73% of the patients. Clodronate is available for this indication in some countries.

Etidronate The dose of etidronate necessary to inhibit bone resorption in patients with Paget's disease is, as in animals, not too different from the dose that inhibits normal bone mineralization. Since intestinal absorption is variable between patients, and even within the same person, the optimal dosage is sometimes difficult to establish. The currently recommended dose of etidronate is 5 mg/kg daily orally, which corresponds usually to 400 mg, for no longer than 6 months. It is effective in decreasing bone turnover substantially and is usually very well tolerated, although mineralization can be impaired under these circumstances. However, more than 70% of the patients do not normalize turnover with this regimen. If this is the case, or if resistance develops during a later course of therapy, as is the case in many patients, higher doses, such as 10 mg/kg, have been proposed. However, impaired mineralization becomes a greater problem, so that this dose is rarely used today. Despite the fact that this defect is repaired relatively quickly, probably within months, when treatment is stopped, it is preferable to switch to a more potent bisphosphonate, if available. Another possibility suggested by some is the oral administration of 20 mg/kg for I month or the intravenous infusion of 3 0 0 - 6 0 0 mg daily for 5 days. In

79

Commercial index pp. 182-206 Effect on turnover p. 74 Intestinal absorption p. 56 Inhibition of mineralization pp. 171-172

3. Bisphosphonatesmclinical general after completion of a course of treatment, a second course should not be started before 3 months, preferably longer. Because of the weak potency of etidronate, other more potent bisphosphonates are usually preferred if available.

The dosage recommendation [or etidronate is difficult, since the active dose required in some patients is near that which induces a mineralization del:ect. The most commonly used dose, which is the o n e approved by regulatory authorities, is 400 rag/day orally [or not longer than 6 months. However, the majority ol:patients do not normalize their turnover at this dose and may develop resistance after a few courses. Therefore more potent bisphosphonates are usually preferred il: available. Commercial index pp. 182-206

Etidronate is widely available for the treatment of Paget's disease.

Olpadronate The daily administration of 200 mg orally or of 4 mg intravenously of this newer bisphosphonate for 10 days or longer resulted in excellent results with a recurrence-free period of over 2 years. In the patients treated intravenously, the determination of the cross-linked N-telopeptides of collagen I (NTx) after 10 days reflected serum alkaline phosphatase after 1 year.

Olpadronate given at 200 mg orally or 4 mg intravenously for 10 days gives good results. Pamidronate

Intravenous administration, p. 168

Pamidronate has recently been introduced in many countries for use in Paget's disease. Many different regimens have been used in the past, and are still used. It appears that the total dose administered is of more importance than the frequency of the administration or the amount of the individual dose. Furthermore it appears that patients with more disseminated disease need a higher dosage. Nevertheless, for the sake of simplicity, the manufacturer proposes in all patients infusions of 30 mg 3 days in a row. However most physicians would give one 90 mg infusion for the same effect. Such a treatment regimen normalizes bone turnover in up to 90% of the patients with mild to moderate disease and between 25 and 66% in patients with severe disease. Treatment can be repeated after 6 months if the result is not satisfactory. In some patients, higher doses, up to a total of 180 mg given in 3 or 6 infusions, are required, according to some investigators. Even with those secondary resistance can sometimes

80

3.2. Paget's disease develop. Pamidronate must always be dissolved in at least 250 ml. It should not be infused faster than over 1 h for 60 mg and 2 h for higher amounts. Fig. 3.2-8 Effect of 180 mg intravenously of pamidronate given by infusions of 30 mg once a week for 6 weeks in patients with mild to moderate and severe Paget's disease. SAP, serum alkaline phosphatase. (Based on patients reported in Richardson, D. C., et al. (1990). Cal-

cium Reg. Bone Metab., 10, 509-514. Reproduced with permission from the author.)

Intravenous administration p. 168

P a m i d r o n a t e in Paget's disease

~ 1000- I "= 800 ~ ~ ~ 600

-i- SAP < 500 IU/1 (n=15) =12)

~ +l ~ ~ 400 ~ -_E 200 0

~~____L~ , ~ (~

, Months

.,. Ii2

,

I Normal 118 range

Successful regimens also include 250 mg or more orally for 6 months, lower doses being less effective. However, in view of a potential for severe gastrointestinal adverse events, parenteral administration is vastly preferred.

Pamidronate is very effective in decreasing bone turnover. In view of the gastrointestinal disturbances at high doses with oral use, the intravenous route is usually used today. While one infusion of 30 mg may be sufficient in mild cases, higher total doses, usually 180 mg given in three infusions of 60 rag, are required in more severe ones. The manufacturer recommends doses of 30 rag, 3 days in a row. However, most physicians would give one 90 mg infusion [or the same effect. Pamidronate is commercially available for Paget's disease in many countries.

Risedronate In a first study an oral daily dose of 30 mg for 12 weeks to 13 patients with severe disease, followed, if necessary, by a second 12 weeks treatment after a 16-week interval, decreased serum alkaline phosphatase by at least 77% and urinary hydroxyproline by 79%. A later study on 162 patients with moderate to severe disease showed similar results. Recently, 30 mg

81

Commercial index pp. 182-206

3. Bisphosphonates--clinical given daily for 2 months were compared with 400 mg of etidronate given daily for 6 months. With risedronate, 73% normalized serum alkaline phosphatase within 12 months and 15% with etidronate; 87 and 57% normalized urinary deoxypyridinoline, respectively. After 16 months off therapy, 53 % of the residronate and 14% of the etidronate patients were still in remission. The dose now recommended by the manufacturer is 30 mg daily for 2 months, followed by another course 2 months later, if necessary. Effect of risedronate 1.0

-

......... "'"m....

0.9 0.8

Etidronate ........

m ..........

ii m ...............

= .~,.~ ~N0.7

~" ~ 0.6 =~0.5 ~' ~O 0.4 O o

0.3

Risedronate

0.2 0.1

.

0

'

89

'~

'

;

'

8

.

.

.

'

i

10

"f"

/

.....

12

T i m e (months)

Fig. 3.2-9 Effect of risedronate given for 2 months at 30 mg daily orally (n = 62) and etidronate for 6 months given at 400 mg daily orally (n = 61) on the time and percentage of normalization of serum alkaline phosphatase. [Reproduced from Miller et al. (1999), Am. J. Med. 106, 513-520, with the permission of the author and Excerpta Medica.]

Risedronate, administered orally at 30 mg daily for 2 months, followed if necessary by a second course, is very effective and is the dose recommended by the manufacturer. Commercial index pp. 182-206

Risedronate is available for Paget's disease in the United States, Canada, and Sweden.

Tiludronate Previously the oral dose of tiludronate ranged between 400 and 800 rag/day for 3 months, 800 mg being considered optimal. Higher doses, such as 1200 mg, were accompanied by gastrointestinal side effects. Today, with a new formulation, the daily oral administration of 400 mg for 3 - 6 months was found to be as effective as 800 mg of the previous formulation. This dosage normalizes the biochemical parameters in 2 5 40% of the patients, and the effects were found to be more pronounced 82

3.2. Paget's disease than with 400 mg of etidronate. This is the dosage recommended by the manufacturer. Fig. 3.2-10 Effectof tiludronate former formulation given orally for 3 months on bone turnover in Paget's disease. [Adapted from Reginster, J. Y., et al. (1992). Reproduced from Arthritis Rheum., 35,967-974, with copyright permission from the author and J. B. Lippincott Company, Philadelphia, Pennsylvania.]

Tiludronate in Paget's disease % --- +40

~

"~ .~ .=r

0

100 mg/d Placebo 200 mg/d

-~ -40

400 mg(d 800 m~d r

-80

0

60

120

180

Days

Oral doses of 400 rag/day of tiludronate given for 3 months are effective and are recommended by the manufacturer. Tiludronate is available in many countries.

Other bisphosphonates Neridronate administered orally at 400 mg daily for 3 months, at 2 0 50 mg intravenously daily for 5 days, or in one intravenous dose of 200 mg, was effective. Recently ibandronate given in a single intravenous dose of 2 mg and zoledronate given in a single intravenous dose 0.4 mg have also been shown to be very active.

Ibandronate, neridronate, and zoledronate are all active at very low doses. Conclusion

Today bisphosphonates are the drugs of choice in Paget's disease. The first commercially available compound was etidronate. Today clodronate and tiludronate or the more potent compounds, especially alendronate, pamidronate, and risedronate, are taking its place.

83

Commercial index pp. 182-206

3. Bisphosphonates--clinical

Recommended selected reading Paget's disease Books Kanis, J. A. (1998). Pathophysiology and Treatment of Paget's Disease of Bone, 2nd Ed. (London: Martin Dunitz)

Reviews Delmas, P. D., and Meunier, P. J. (1997). The management of Paget's disease of bone. N. Engl. J. Med., 336, 558-566 Grauer, A., and Siris, E. (1999). Paget's disease of bone. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 581-589. (San Diego, London: Academic Press) Hamdy, R. C. (1995). Clinical features and pharmacological treatment of Paget's disease. Endocr. Metab. Clin. North Am., 24, 421-437 Papapoulos, S. E. (1997). Paget's disease of bone: Clinical, pathogenic and therapeutic aspects. Baillikre's Clin. Endocrinol. Metab., 11,117-143 Proceedings of the third international symposium on Paget's disease. Napa, California, U.S.A. November 29-30, 1998 (1999). J. Bone Miner. Res. 14(Suppl. 2), 1-104 Singer, F. R., and Krane, S. M. (1998). Paget's disease of bone. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 545-605. (San Diego: Academic Press) Singer, F. R., and Roodman, G. D. (1996). Paget's disease of bone. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 969-977. (San Diego, London: Academic Press) Siris, E. S. (1998). Paget's disease of bone. J. Bone Miner. Res., 13, 1061-1065

Bisphosphonates Reviews Kanis, J. A. (1998). Drugs used for the treatment of Paget's disease. In Kanis, J. A. (ed.) Pathophysiology and Treatment of Paget's Disease of Bone, pp. 159-216. (London: Martin Dunitz) Siris, E. S., and Arden-Cordone, M. (1995). The bisphosphonates in treatment and secondary prevention of Paget's disease of bone. In Bijvoet, O. L. M., Fleisch, H. A., Canfield, R. E., and Russell, R. G. G. (eds.) Bisphosphonate on Bones, pp. 293-303. (Amsterdam: Elsevier)

Alendronate Original articles Adami, S., Mian, M., Gatti, P., Rossini, M., Zamberlan, N., Bertoldo, F., and Lo Cascio, V. (1994). Effects of two oral doses of alendronate in the treatment of Paget's disease of bone. Bone, 15,415-417 Khan, S. A., Vasikaran, S., McCloskey, E. V., Ben&on, M. N. C., Rogers, S., Coulton, L., Orgee, J., Coombes, G., and Kanis J. A. (1997). Alendronate in the treatment of Paget's disease of bone. Bone, 20, 263-271 Lombardi, A. (1999). Treatment of Paget's disease of bone with alendronate. Bone, 24, Suppl., 59S-61S. O'Doherty, D. P., Bickerstaff, D. R., McCloskey, E. V., Hamdy, N. A. T., Beneton, M. N. C., Harris, S., Mian, M., and Kanis, J. A. (1990). Treatment of Paget's disease of bone with aminohydroxybutylidene bisphosphonate. J. Bone Miner. Res., 5,483-491 84

3.2. Paget's disease O'Doherty, D. P., McCloskey, E. V., Vasikaran, S., Khan, S., and Kanis, J. A. (1995). The effects of intravenous alendronate in Paget's disease of bone. J. Bone Miner. Res., 10, 1094-1100 Reid, I. R., Nicholson, G. C., Weinstein, R. S., Hosking, D. J., Cundy, T., Kotowicz, M. A., Murphy, W. A., Yeap, S., Dufresne, S., Lombardi, A., Musliner, T. A., Thompson, D., and Yates, A. J. (1996). Biochemical and radiological improvement in Paget's disease of bone treated with alendronate: A randomized, placebo-controlled trial. Am. J. Med., 101,341-347 Siris, E., Weinstein, R. S., Altman, R., Conte, J. M., Favus, M., Lombardi, A., Lyles, K., Mcllwain, H., Murphy, W. A., Jr., Reda, C., Rude, R., Seton, M., Tiegs, R., Thompson, D., Tucci, J. R., Yates, A. J., and Zimering, M. (1996). Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone. J. Clin. Enclocrinol. Metab., 81,961-967 Clodronate

Reviews Plosker, G. L., and Goa, K. L. (1994). Clodronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs, 47, 945-982

Original articles Delmas, P. D., Chapuy, M. C., Vignon, E., Charhon, S., Brianqon, D., Alexandre, C., Edouard, C., and Meunier, P. J. (1982). Long term effects of dichloromethylene diphosphonate in Paget's disease of bone. J. Clin. Endocrinol. Metab., 54, 837-844 Douglas, D. L., Duckworth, T., Kanis, J. A., Preston, C., Beard, D. J., Smith, T. W. D., Underwood, I., Woodhead, J. S., and Russell, R. G. G. (1980). Biochemical and clinical responses to dichloromethylene diphosphonate (CI2MDP) in Paget's disease of bone. Arthritis Rheum., 23, 1185-1192 Khan, S. A., McCloskey, E. V., Eyres, K. S., Nakatsuka, K., Sirtori, P., Orgee, J., Coombes, G., and Kanis, J. A. (1996). Comparison of three intravenous regimens of clodronate in Paget disease of bone. J. Bone Miner. Res., 11, 178-182 Khan, S. A., McCloskey, E. V., Nakatsuka, K., Orgee, J., Coombes, G. M., and Kanis, J. A. (1996). Duration of response with oral clodronate in Paget's disease of bone. Bone, 18, 185-190 Yates, A. J. P., Percival, R. C., Gray, R. E. S., Atkins, R. M., Urwin, G. H., Hamdy, N. A. T., Preston, C. J., Beneton, M. N. C., Russell, R. G. G., and Kanis, J. A. (1985). Intravenous clodronate in the treatment and retreatment of Paget's disease of bone. Lancet, 1, 14741477

Etidronate Reviews Dunn, C. J., Fitton, A., and Sorkin, E. M. (1994). Etidronic acid. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs Aging, 5, 446-474

Original articles Alexandre, C., Meunier, P. J., Edouard, C., Khairi, R. A., and Johnston, C. C. (1981). Effects of ethane-1 hydroxy-1, 1-diphosphonate (5 mg/kg/day dose) on quantitative bone histology in Paget's disease of bone. Metab. Bone Dis. Related Res., 4 and 5, 309-316 Altman, R. D., Johnston, C. C., Khairi, M. R. A., Wellman, H., Serafini, A. N., and Sankey, R. R. (1973). Influence of disodium etidronate on clinical and laboratory manifestations of Paget's disease of bone (osteitis deformans). N. Engl. J. Med., 289, 1379-1384 85

3. Bisphosphonates--clinical Boyce, B. F., Smith, L., Fogelman, I., Johnston, E., Ralston, S., and Boyle, I. T. (1984). Focal osteomalacia due to low-dose diphosphonate therapy in Paget's disease. Lancet, 1, 821-824 de Vries, H. R., and Bijvoet, O. L. M. (1974). Results of prolonged treatment of Paget's disease of bone with disodium ethane-l-hydroxy-l,l-diphosphonate (EHDP). Neth. J. Med., 17, 281-298 Nagant de Deuxchaisnes, C., Rombouts-Lindemans, C., Huaux, J. P., Devogelaer, J. P., Malghem, J., and Maldague, B. (1979). Roentgenologic evaluation of the action of the diphosphonate EHDP and of combined therapy (EHDP and calcitonin) in Paget's disease of bone. Mol. Endocrinol., 1,405-433 Russell, R. G. G., Smith, R., Preston, C., Walton, R. J., and Woods, C. G. (1974). Diphosphonates in Paget's disease. Lancet, 1 894-898 Smith, R., Russell, R. G. G., and Bishop, M. (1971). Diphosphonates and Paget's disease of bone. Lancet, 1,945-947

Pamidronate Reviews Chakravarty, K., and Crisp, A. (1998). Pamidronate disodium in Paget's disease of bone. Rev. Contemp. Pharmacother., 9, 165-181

Original articles Frijlink, W. B., Bijvoet, O. L. M., te Velde, J., and Heynen, G. (1979). Treatment of Paget's disease with (3-amino-l-hydroxypropylidene)-l,l-bisphosphonate (A.ED.). Lancet, 1, 799-803 Gallacher, S. J., Boyce, B. F., Patel, U., Jenkins, A., Ralston, S. H., and Boyle, I. T. (1991). Clinical experience with pamidronate in the treatment of Paget's disease of bone. Ann. Rheum. Dis., 50, 930-933 Ryan, P. J., Sherry, M., Gibson, T., and Fogelman, I. (1991). Treatment of Paget's disease by weekly infusions of 3-aminohydroxypropylidene-l,l-bisphosphonate (APD). Br. J. Rheumatol., 31, 97-101 Thi~baud, D., Jaeger, P., Gobelet, C., Jacquet, A. F., and Burckhardt, P. (1988). Single infusion of the bisphosphonate AHPrBP (APD) as treatment of Paget's disease of bone. Am. J. Med., 85,207-212

Risedronate Reviews Goa, K. L., and Balfour, J. A. (1998). Risedronate. Drugs Aging, 13, 83-91

Original articles Hosking, D. J., Eusebio, R. A., and Chines, A. A. (1998). Paget's disease of bone: Reduction of disease activity with oral risedronate. Bone, 22, 51-55 Miller, P. D., Brown, J. P., Siris, E. S., Hoseyni, M. S., Axelrod, D. W., and Bekker, P. J. (1999). A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Am. J. Med., 106, 513-520 Singer, F. R., Clemens, T. L., Eusebio, R. A., and Beckker, P. J. (1998). Risedronate, a highly effective oral agent in the treatment of patients with severe Paget's disease. J. Clin. Endocr. Metab., 83, 1906-1910 Siris, E. S., Chines, A. A., Altman, R. D., Brown, J. P., Johnston, C. C., Lang, R., McClung, M. R., Mallette, L. E., Miller, P. D., Ryan, W. G., Singer, F. R., Tucci, J. R., Eusebio, R. A., and Bekker, P. J. (1998). Risedronate in the treatment of Paget's disease of bone: An open label, multicenter study. J. Bone Miner. Res., 13, 1032-1038 86

3.2. Paget's disease

Tiludronate O r i g i n a l articles Audran, M., Clochon, P., Ethgen, D., Mazi~res, B., and Renier, J. C. (1989). Treatment of Paget's disease of bone with (4-chlorophenyl)thiomethylene bisphosphonate. Clin. Rheumatol., 8, 71-79 Fraser, W. D., Stamp, T. C., Creek, R. A., Sawyer, J. P., and Picot, P. (1997). A double-blind, multicentre, placebo-controlled study of tiludronate in Paget's disease of bone. Postgrad. Med. J., 73,496-502 Reginster, J. Y., Colson, F., Morlock, G., Combe, B., Ethgen, D., and Geusens, P. (1992). Evaluation of the efficacy and safety of oral tiludronate in Paget's disease of bone. A double-blind, multiple-dosage, placebo-controlled study. Arthritis Rheum., 35,967-974 Reginster, J. Y., Treves, R., Renier, J. C., Amor, B., Sany, J., Ethgen, D., Picot, C., and Franchimont, P. (1994). Efficacy and tolerability of a new formulation of oral tiludronate (tablet) in the treatment of Paget's disease of bone. J. Bone Miner. Res., 9, 615-619 Roux, C., Gennari, C., Farrerons, J., Devogelaer, J. P., Mulder, H., Kruse, H. P., Picot, C., Titeux, L., Reginster, J. Y., and Dougados, M. (1995). Comparative prospective, doubleblind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget's disease of bone. Arthritis Rheum., 6, 851-858

Other bisphosphonates O r i g i n a l articles Arden-Cordone, M., Siris, E. S., Lyles, K. W., Knieriem, A., Newton, R. A., Schaffer, V., and Zelenakas, K. (1997). Antiresorptive effect of a single infusion of microgram quantities of zoledronate in Paget's disease of bone. Calcif. Tissue Int., 60, 415-418 Atkins, R. M., Yates, A. J. P., Gray, R. E. S., Urwin, G. H., Hamdy, N. A. T., Beneton, M. N. C., Rosini, S., and Kanis, J. A. (1987). Aminohexane diphosphonate in the treatment of Paget's disease of bone. J. Bone Miner. Res., 2, 273-279 Buckler, H., Fraser, W., Hosking, D., Ryan, W., Maricic, M. J., Singer, F., Davie, M., Fogelman, I., Birbara, C. A., Moses, A. M., Lyles, K., Selby, P., Richardson, P., Seaman, J., Zelenakas, K., and Siris, E. (1999). Single infusion of zoledronate in Paget's disease of bone: A placebo-controlled, dose-ranging study. Bone, 24, 81S-85S Delmas, P. D., Chapuy, M. C., Edouard, C., and Meunier, P. J. (1987). Beneficial effects of aminohexane diphosphonate in patients with Paget's disease of bone resistant to sodium etidronate. Am. J. Med., 83,276-282 Filipponi, P., Cristallini, S., Policani, G., Casciari, C., and Gregorio, F. (1998). Paget's disease of bone: Benefits of neridronate as a first treatment and in cases of relapse after clodronate. Bone, 23,543-548 Garnero, P., Gineyts, E., Schaffer, A. V., Seaman, J., and Delmas, P. D. (1998). Measurement of urinary excretion of nonisomerized and ~3-isomerized forms of type I collagen breakdown products to monitor the effects of the bisphosphonate zoledronate in Paget's disease. Arthritis Rheum., 41,354-360 Papapoulos, S. E., and Fr6hlich, M. (1996). Prediction of the outcome of treatment of Paget's disease of bone with bisphosphonates from short-term changes in the rate of bone resorption. J. Clin. Endocr. Metab., 81, 3993-3997 Schweitzer, D. H., Zwinderman, A. H., Vermeij, P., Bijvoet, O. L. M., and Papapoulos, S. E. (1993). Improved treatment of Paget's disease with dimethylaminohydroxypropylidene bisphosphonate. J. Bone Miner. Res., 8, 175-182

87

3.3.

OSTEOLYTIC TUMOR-INDUCED BONE DISEASE

3.3.1.

Definition

This is a condition in which tumors of various origins induce bone destruction, which can lead to fractures, pain, and hypercalcemia. 3.3.2. PTH-related protein p. 10

Pathophysiology

The tumors leading to bone disease destroy bone either through local invasion, or at a distance by secreting bone-resorbing products, mostly PTH- ~-related protein, into the bloodstream. Often they work through both mechanisms. i,:

Fig. 3.3-1 Mechanismsof ,., Bone destruction by,..~i,,,iii!,ii!i:iiii',iiiiiiii!!i..:-i malignant bone destruction.

Tumor

Metastasis Localized resorption

Systemic cytokines Tumor

(5 Generalized resorption

Tumors can induce bone resorption locally when present in the bone, as well as by the systemic secretion of osteolytic ]:actors, mostly PTH-related protein, when found outside the skeleton. Local bone destruction

Bone resorption pp. 10-11

Local skeletal erosion is seen mostly in metastases of the breast and lung cancer and in hematological malignancies, especially multiple myeloma. Breast cancer is frequently associated with bone metastases; 90% of patients who die of this disease have such metastases. The mechanism of resorption of bone is not well elucidated. It appears that tumor cells can secrete, or stimulate other local cells to secrete, a series of bone-resorbing cytokines such as PTH-related protein, TGFa, TNFa, TNFI3, M-CSF, *interleukins such as IL-la, IL-113, and IL-6, prostaglandins, and others, which induce osteoclasts to resorb bone. In multiple myeloma, the malignant plasma cells induce localized osteolysis probably by means of the 88

3.3. Osteolytic tumor-induced bone disease production of IL-6, IL-113, TNFI3, MlPla, and PTH-related protein. It is possible, although not yet proven, that certain tumor cells can themselves also directly destroy bone. Tumor cells destroy bone mainly through the production or the induction of bone resorbing cytokines.

The apparently preferential growth of certain tumors within the bone microenvironment may be explained by the so-called seed and soil concept. Cancer cells find in bone a fertile environment in which their growth and survival is nurtured by growth factors present in bone, such as TGF[3 and IGF's. These are growth factors released when bone is resorbed, a process which is stimulated by bone-resorbing factors released from the tumor cells. This establishes a self-supporting cycle for tumor replication and bone destruction. It is thought that bisphosphonates decrease tumor burden by inhibiting the liberation of these factors, thus blocking the positive feedback. Fig. 3.3-2 Seedand soil mechanisms and the possible effect of bisphosphonates.

Effect of bisphosphonates through "seed an~tSoil" mecham:'sms Bisphosphonates Osteoclastic bone resorption Liberation of matrix growth factors (TGF/3, IGF's) Tumor cell multiplication Bone resorption

During osteolysis the bone releases stored growth factors which form a fertile environment ]:or tumor cell growth, a mechanism called seed and soil. Bisphosphonates are supposed to act at this level. Localized bone resorption can lead to pathological fractures and pain, which are the most common features of tumor-induced bone disease. Another consequence is hypercalcemia, cancer being the most common cause of this disturbance in hospitalized patients.

Localized bone resorption can lead to fractures, pain and hypercalcemia. 89

Bisphospho nates and tumor burd p. 97

3. Bisphosphonates--clinical Generalized bone destruction Generalized bone destruction occurs associated with carcinoma of the lung, breast, head and neck, kidney, and ovary. Bone resorption is induced via the systemic production of osteolytic factors by a tumor localized elsewhere in the body. The most important of these factors is PTH-related protein. If generalized bone destruction is accompanied by hypercalcemia the term humoral hypercalcemia of malignancy (HHM) is used. Both mechanisms, local and generalized bone destruction, can be operative simultaneously. In fact the two mechanisms are best considered as a continuum rather than as two distinct entities.

A consequence o[ tumors, especially cancer o/: the breast and lung, and myeloma, is hypercalcemia. When caused by a tumor outside the bone it is called humoral hypercalcemia o1:malignancy. Mechanisms of hypercalcemia The tumors most frequently associated with hypercalcemia are carcinoma of the breast, lung and upper respiratory tract, kidney, myeloma, and lymphomas. Up to 20% of patients with bone metastases from breast cancer develop hypercalcemia, and about one-quarter of patients with malignant hypercalcemia have carcinoma of the breast. It is believed that the frequency of tumor hypercalcemia has recently decreased, possibly because of the widespread use of bisphosphonates before the patients become hypercalcemic. Tumors inducing hypercalcemia

Fig. 3.3-3 Tumorsthat induce hypercalcemia of malignancy most frequently.

9Breast 9Respiratorytract 9Myelomaand lymphomas 9Kidney

The mechanisms inducing hypercalcemia are complex, the increase in blood calcium not being due to bone lysis alone. Three main mechanisms are involved: Calcium homeostasis pp. 17-18

(1) Increased bone destruction, either local or generalized, which brings about a release of calcium from the skeleton and consequently an increase in the flow of calcium through the extracellular space. This mechanism ap-

90

3.3. Osteolytic tumor-induced bone disease

pears to be the main cause of hypercalcemia in patients with hematological malignancies such as myeloma and in many patients with metastases; (2) Increased tubular reabsorption of calcium in the kidney, as a result of factors produced by tumor cells, such as PTH-related protein. This protein, which is also produced by certain nontumor tissues and probably plays a main role in fetal life, among others in the differentiation of chondrocytes in the growth plate, and during lactation, has a small aminoterminal sequence that resembles parathyroid hormone in both primary and secondary structure. Like PTH, it acts on the PTH-1 receptor. The renal mechanism occurs with solid tumors such as squamous cell carcinoma of the lung and carcinomas of other organs. In many solid tumors with bone metastases both the osseous and renal mechanisms coexist; (3) Tumor disease is often accompanied by dehydration, which can be severe and lead to renal failure. The dehydration is due in part to an increase in sodium excretion induced by the hypercalcemia, in part because hypercalcemia leads to an impairment of water reabsorption. The volume depletion, can in turn induce hypercalcemia by mechanisms such as decrease in glomerular filtration, which leads to impairment of calcium excretion and enhancement of proximal tubular reabsorption of calcium. Therefore, rehydration is always the first therapeutic step in cases of severe hypercalcemia. It can be followed by a substantial reduction in plasma calcium and improvement of symptoms. (4) Less frequent mechanisms include, as in myeloma, a decrease in bone formation, which can contribute to hypercalcemia through the diminished efflux of calcium from the extracellular space to bone. In granulomatous disease and in some lymphomas, intestinal absorption of calcium can be increased due to elevated 1,25(OH)2 D. ---* Fig. 3.3-4 Mechanismsof hypercalcemia in tumor bone disease.

Calcium homeostasis

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Calcium homeostasis pp. 17-18

3. Bisphosphonatesmclinical Hypercalcemia in tumor bone disease is caused essentially by increased osteolysis, as well as by increased renal reabsorption of calcium and dehydration.

Experimental tumor hypercalcemia p. 96

The fact that hypercalcemia is produced by various mechanisms has therapeutic consequences. Because only bone resorption is influenced by bisphosphonates, plasma calcium will be less influenced by these compounds in patients where nonosteolytic mechanisms are prominent. This is the case, for example, in humoral hypercalcemia of malignancy. Because blood levels of PTH-related protein are high in this condition, and because this protein increases renal reabsorption of calcium, the response to bisphosphonates will be less pronounced. In fact, the measurement of the latter hormone helps to predict the therapeutic effect of the bisphosphonates. In contrast, hypercalciuria, which is in most cases the consequence of elevated bone resorption only, will be corrected more often.

Bisphosphonates appear to most effectively correct hypercalcemia due to osteolytic tumors located in bone and producing no circulating cytokines. They are often less effective in hypercalcemia caused by circulating/:actors from tumors outside the skeleton, such as PTH-related protein, which also affect other organs, especially the kidney. 3.3.3.

Clinical manifestations

Signs and symptoms The clinical manifestations are those of tumor osteolysis, namely pain and fractures, and of hypercalcemia and its multiple metabolic consequences. Fig. 3.3-5 Main clinical manifestations in tumor bone disease.

T u m o r bone disease 9Pain

9Fractures 9Hypercalcemiasyndrome

Symptoms of hypercalcemia appear mainly in the nervous, gastrointestinal, cardiovascular, and renal systems. In some cases, the hypercalcemia can be life-threatening and must be dealt with immediately.

92

3.3. Osteolytic tumor-induced bone disease .+ 9 Fig. 3.3-6 Clinicalfeatures of the hypercalcemic syndrome.

Signs and symptoms of hypercalcemia 9Psychiatric 9Neurological 9Gastrointestinal 9Cardiovascular 9Renal

Unspecific Drowsiness, lethargy Constipation, vomiting, anorexia ECG changes, arrhythmias Hyposthenuria, nephrocalcinosis, renal failure

9Hypercalcemic crisis

The other symptoms are those of the underlying tumor disease.

The main clinical manifestations of tumor osteolysis are pain, fractures, and those of the hypercalcemic syndrome. Sometimes lifethreatening hypercalcemic crises may occur. Laboratory The main biochemical investigations useful in osteolytic bone disease are, besides the tumor markers, serum calcium and urinary excretion of calcium. Markers of bone turnover are useful in certain cases, but it is not yet clearly established how useful they are in routine practice. For bone --~ resorption these would be urinary and serum pyridinium cross-links and their peptides, especially the C-terminal and N-terminal cross-linked telopeptides of type I collagen, which have replaced urinary hydroxyproline. In sclerotic or mixed (lytic/blastic) metastases, such as in metastases of prostate and sometimes of breast carcinoma, measurement of serum alkaline phosphatase, or preferably bone-specific alkaline phosphatase to distinguish from changes due to liver metastases, is helpful. It should be -+ remembered that ionized calcium, which is the physiologically relevant form, can be underestimated in the presence of hypoalbuminemia, which is often present in cancer patients, if merely serum calcium is measured. Indeed albumin influences the relative distribution between ionized and bound calcium. A simple correction factor is to add to the measured total calcium 0.08 mg/100 ml for each gram of albumin lower than 40 g/liter. In multiple myeloma, serum IL-6, soluble IL-6 receptor, and [32-microglobulin are all increased and are prognostic factors for the disease. The radiophysical examinations used are mainly X-rays, scintigraphy, computed tomography, and, more recently, magnetic resonance imaging, which is particularly sensitive for marrow metastases.

93

Assessment resorption p. 21

3. Bisphosphonates~clinical The main biochemical investigations of skeletal disturbances are measurement of serum calcium and urinary calcium. Markers of bone turnover such as bone specific alkaline phosphatase and pyridinium cross-links and their peptides may be sometimes useful. The radiophysical techniques used are X-rays, scintigraphy, computer tomography, and magnetic resonance imaging. Follow-up of progression of the disease The parameters most often monitored are pain, fractures, and the radiological evolution of osteolytic foci, as well as blood calcium, urinary excretion of calcium, and pyridinium cross-links and their peptides. The most frequent investigation, plasma calcium, is easy to perform. Furthermore, hypercalcemia is one of the disturbances in tumor-induced bone disease with the most severe clinical consequences and which, therefore, has to be treated. M a i n investigations

, Serum calcium 9Urinary calcium 9Urinary pyridinium cross-links * Pain 9Fractures 9Bone scintigraphy 9Osteolytic foci

Fig. 3.3-7 Parameters most often monitored during treatment.

The parameters usually followed during the treatment of tumorinduced bone disease are most of all pain, fractures, and osteolytic loci, as well as plasma calcium, urinary calcium, and pyridinium cross-links or their peptides. 3.3.4.

T r e a t m e n t with drugs other than bisphosphonates

Initially treatment of tumor-induced hypercalcemia included besides excision of the primary tumor, chemo-, hormonal, or radiotherapy, and plicamycin (mythramycin), an inhibitor of RNA synthesis. However, because of its high toxicity, plicamycin is not used anymore. The same is true for gallium nitrate, the dosage of which is limited because of nephrotoxicity. Hypercalcemia in the acute stage is first treated with fluid repletion.

94

3.3. Osteolytic tumor-induced bone disease Volume repletion ( 2 - 4 liters over the initial 2 4 - 4 8 h) is the first therapy when dehydration is present. However, care must be taken to avoid overhydration. Other interventions are less efficacious. Calcitonin, possibly in combination with glucocorticoids, has sometimes been given in both acute and chronic hypercalcemia. It can be useful, preferably given together with a bisphosphonate, in severe life-threatening hypercalcemia because of its rapid, although transient and incomplete, calcium-lowering effect. The use of loop diuretics, such as furosemide, is of uncertain efficacy in decreasing blood calcium and may lead to a serious disturbance of fluid and electrolyte balance. Today bisphosphonates have become the drugs of choice for treatment of hypercalcemia and tumor bone disease in general.

Dehydratioi p. 91

The bisphosphonates have become the drugs of choice, and have virtually replaced other less satisfactory treatments.

3.3.5.

T r e a t m e n t with b i s p h o s p h o n a t e s

Preclinical studies In organ culture, bisphosphonates added to the culture medium inhibit the resorption of mouse calvaria induced by supernatants of breast or other cancer cells. -~ In vivo, three types of models have been investigated, namely, the subcutaneous implantation of tumor cells leading to tumoral hypercalcemia, their intracardiac injection inducing osseous metastases, and their implantation next to bone inducing local erosion. These studies are today often performed in immune-deficient animals. All three models are influenced by bisphosphonates. Fig. 3.3-8 Experimental models of tumor bone disease.

Experimental tumoral bone disease Administration of tumor cells Subcutaneous: Tumoralhypercalcemia Intra-arterial: Metastases Bone vicinity: Localinvasion and resorption

Thus, bisphosphonates normalize or prevent the increased calciuria induced in rats by subcutaneous implantation of various tumor cells. In contrast they do not always entirely prevent or correct hypercalcemia. The cause of this discrepancy is, as discussed above, due to the fact that in some

95

Mechanism~ hypercalcerr pp. 90-91

3. Bisphosphonatesmclinical of these models, hypercalcemia is induced by the systemic production of PTH-related protein, which not only increases bone resorption but also tubular reabsorption of calcium, on which bisphosphonates are inactive. Fig. 3.3-9 Effect of clodronate administered daily on tumoral hypercalcemia and hypercalciuria in the rat implanted subcutaneously with Walker carcinosarcoma cells. [Adapted from Rizzoli, R., and Fleisch, H. (1987).

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Bisphosphonates prevent hypercalcemia partially, and prevent hypercalciuria completely, in rats implanted subcutaneously with t u m o r cells. Bisphosphonates also prevent or retard bone resorption due to actual tumor invasion. Thus, etidronate, clodronate, and pamidronate all decrease bone destruction induced by Walker carcinosarcoma cells injected into the iliac artery of the rat, a procedure whereby the cells are seeded into the bone. Incadronate, risedronate, and minodronate decrease the

96

3.3. Osteolytic tumor-induced bone disease development of bone metastases after intracardiac inoculation of human breast cancer cells into nude mice. In contrast, bisphosphonates have no effect on the development of the various tumors in soft tissues. Bisphosphonates are also effective when various tumor cell types are directly implanted into the bone or in the vicinity of the bone.

Bis_phosphonates inhibit local bone destruction by tumors and decrease tumor burden in bone. It used to be thought that bisphosphonates had no direct effect on tumor cells. However, recent results show that they inhibit the adhesion and the spreading of tumor cells on bone in vitro. This was the case both when the bone matrix was pretreated, or when the tumor cells were exposed to the bisphosphonate. There was a good correlation between the effect on adhesion and the antiosteolytic potency of the compounds tested. In vitro bisphosphonates also induce apoptosis of myeloma and other tumor cells and inhibit their proliferation. For nitrogen-containing bisphosphonates this effect is analogous to the effect in osteoclasts in that it involves the mevalonate pathway. Furthermore, bisphosphonates may also induce an inhibition of osseous tumor invasion by decreasing locally growth factors and other cytokines released when bone is resorbed, and which may stimulate replication of cancer cells. One of the questions is whether bisphosphonates can decrease the skeletal tumor burden. While earlier results showed no effect or even possibly an increase, newer ones displayed on the contrary a clear reduction. The above mechanisms may explain this fact.

The bisphosphonates may act directly on tumor cells by inhibiting their adhesion onto bone and by altering their multiplication and apoptosis. They may also act indirectly by decreasing the release ]from bone of cytokines that stimulate tumor cell multiplication, as a result o[ the lower bone resorption. These mechanisms may explain the decrease in tumor burden in the bone.

Methotrexate-bisphosphonate conjugates have been synthesized and found to be active in the rat Walker carcinosarcoma model. Furthermore rhenium-186- and rhenium-188-etidronate decrease pain in metastatic bone disease in humans. Using bisphosphonates to bring chemostatic agents or therapeutic radionuclides to the skeleton is an interesting new approach.

97

Mevalonate pathway an apoptosis pp. 4 4 - 4 5 Seed and so mechanism p. 89

3. Bisphosphonates--clinical Binding chemostatic agents or radionuclides to bisphosphonates could be an interesting new approach to deliver them selectively to the skeleton. Clinical studies Despite a large number of studies showing the antiosteolytic effect of bisphosphonates and the widespread clinical use in tumor-induced bone disease, it has for a long time been difficult to draw clear conclusions about which bisphosphonate to use in which patient as well as the optimal regimen to administer. This was due to many factors. First, as seen above, the malignant tumors are extremely heterogeneous with respect to their type and to the mechanisms involved. Therapy is also not necessarily identical for the various effects desired, such as the reduction of hypercalcemia, reduction of pain, or the prevention of new osteolytic foci. Furthermore many studies were not controlled, involved too few patients with too many dosage regimens, or involved other treatments, especially chemotherapy, so that valid conclusions could often not be drawn. Last, many studies, especially the early ones, used rehydration together with the bisphosphonate, so that it was not always possible to draw reliable conclusions about the relative effect of the two. Recently, however, a series of well-designed controlled trials has provided new knowledge to fill this gap in part. Effects The great majority of the earlier studies were performed with clodronate and pamidronate on tumor hypercalcemia, with a fewer employing etidronate. Recently, studies have focused also on the development of bone metastases and the skeletal morbidity. As with Paget's disease, it seems that the main discrepancies between the different compounds are related to their respective potencies.

Hypercalcemia

Mechanisms of hypercalcemia pp. 90-91 Hyperparathyroidism p. 120

Bisphosphonates will effectively reduce hypercalcemia. With intravenous administration, the effect starts to be clinically significant after 2 - 3 days, normocalcemia being obtained after 3 - 5 days and the full effect after about a week. As discussed above, the effect is more pronounced in patients in whom hypercalcemia is completely or largely a result of bone resorption only, as is the case, for example, in myeloma. In some cases hypocalcemia can occur, and can occasionally be symptomatic. Bisphosphonates can also be helpful in parathyroid carcinoma, although their effect is transient when treatment is stopped.

98

3.3. Osteolytic tumor-induced bone disease -+

Fig. 3.3-10 Effect of clodronate infused in most cases for 5 days intravenously at a dose of 300 mg on hypercalcemia of malignancy. *p < 0.01; ':* *p
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~9 0 Pre' i

' 3 ' } ' 7E)ays

=

Pre

Post

B i s p h o s p h o n a t e s are n o w the drugs of choice for the t r e a t m e n t of tum o r a l h y p e r c a l c e m i a in patients in w h o m cancer t h e r a p y is not effective.

Bisphosphonates decrease and often normalize plasma calcium in tumor hypercalcemia, their effect depending on the type of the tumor. In this condition they are the drugs of choice in patients in whom cancer therapy alone was not effective.

Urinary parameters Plasma p h o s p h a t e a n d t u b u l a r r e a b s o r p t i o n of p h o s p h a t e can decrease, as seen in Paget's disease. This might be, at least partially, the c o n s e q u e n c e

99

3. Bisphosphonatesmclinical of the observed increase in previously suppressed parathyroid hormone and of positive skeletal phosphate balance. While parathyroid hormone and 1,25(OH)2 D are increased under treatment with bisphosphonate, the levels of PTH-related protein are not altered in average. Hypercalciuria is greatly decreased by treatment in all types of tumor. Urinary hydroxyproline is also diminished, although sometimes less than predicted. The reason for this is unclear and has been attributed to assay problems and to tumor-induced nonosseous collagen turnover in soft tissues, a process that is not influenced by bisphosphonates. In contrast the urinary pyridinium cross-links and their C- and N-terminal telopeptides, which are more specific for bone collagen, are markedly decreased and are today increasingly used. Serum alkaline phosphatase is usually unchanged, at least acutely, showing that the effect of the drug is on the resorption process. Finally, renal function can improve.

Urinary calcium is often normalized. Urinary hydroxyproline is diminished but less than expected, for reasons which are not yet clear, but pyridinium cross-links, especially their peptides are markedly decreased. The duration of the effect after discontinuation of the drug is difficult to predict. The time to recurrence varies greatly from patient to patient, and depends on the type of tumor, the accompanying treatment, the dosage, and the compound used. The effect lasts longer in focal bone disease, such as in the presence of metastases. This has been explained by the preferential deposition of bisphosphonates in the locations invaded by the tumor cells. In contrast, recurrence occurs much faster when bone resorption is more generalized, such as in humoral hypercalcemia of malignancy or carcinoma of the parathyroid. In general recurrence is seen between a few days and 1 month, sometimes more. If therapy is resumed, the effect is usually obtained again. The most practical procedure is therefore to monitor plasma calcium and to resume treatment when hypercalcemia resumes. However, some patients respond less well on retreatment. The cause of this resistance is unknown (Fig. 3.3-12).

The duration o]: the effect after discontinuation o[ treatment is variable, usually less than a month. It seems to depend on the potency o[: the bisphosphonate, the total dose administered, and the type o[ bone disease. In patients with focal involvement, resorption appears to be inhibited [:or longer than in those with humoral hypercalcemia.

100

3.3. Osteolytic tumor-induced bone disease --~ Fig. 3.3-12 Effect of a median dose of 0.5 (0.25-0.75), 1.0 (exactly), and 1.5 (1.25-4.5) mg/kg of pamidronate administered intravenously for 1-3 days in 160 hypercalcemic tumor patients. [Adapted from Body, J. J., and Dumon, J. C. (1994). Ann. Oncol., 5, 359-363. Reproduced with permission from the author and Kluwer Academic Publishers.]

Effect of pamidronate on hypercalcemia 16 ~" +l

14

1 0.5 mg/kg O 1.0mg/kg

~...

,

o~ --~" 12 "-" ~ 10

_ _ _

E

_.

8 -5

'~

i

0

5

10 Days

15

20

25

Other effects Bisphosphonates, at least clodronate and pamidronate, diminish bone pain, leading sometimes to a marked improvement in the quality of life. The onset of this effect is relatively slow. It should, however, be understood that the bisphosphonates should not be used as analgetics per se. With long-term therapy these bisphosphonates, as shown primarily in patients with breast cancer and with myeloma, also decrease the number of skeletal-related events, such as the appearance of new osseous metastases, the occurrence of pathological fractures, vertebral collapse, spinal cord compression, and the requirement of radiation and bone surgery. The effects are present also when patients receive chemotherapy or h o r m o n e therapy. The efficacy is lost after discontinuation of the drug. Fig. 3.3-13 Effect of 1600 mg of clodronate given daily for up to 18 months on skeletal complications in patients with carcinoma of the breast. [Adapted from Paterson, A. H. G., et al. (1993). Picture courtesy of Dr. J. A. Kanis.]

Effect of clodronate in breast cancer m

....~

100 0 0

~ 50 0 Nonvertebral fractures Placebo

101

Vertebral Hypercalcemia fractures [---1 Clodronate

3. B i s p h o s p h o n a t e s - - c l i n i c a l

Fig. 3.3-14 Effectof 90 mg pamidronate given intravenously every 34 weeks for 2 years on skeletal complications in patients with metastatic breast cancer. [Data from Hortobagyi et al. (1998).]

Effect of pamidronate in breast cancer 70

p< 0.001

H Placebo H Pamidronate

60 ._. 50 g "-" 40

p = 0.001

1

9" 30 20 10

p < 0.001

p=0.8

001

..........., !

|

w

All Non- Vertebral Radiation Hyperskeletal vertebral fractures calcaemia complications fractures

In animals, the d e v e l o p m e n t of metastases in other tissues is usually n o t altered. The same is true for the survival rate. H o w e v e r , in one very recent study, c l o d r o n a t e induced b o t h a decrease of the d e v e l o p m e n t of bone and soft tissue metastases and a longer survival time in patients with breast cancer treated for a m e d i a n time of 2 years. An i m p r o v e m e n t in survival has also been f o u n d in some s u b g r o u p s with p a m i d r o n a t e . In contrast, other studies s h o w e d no such effect so that the situation is unclear.

Effect of clodronate in breast cancer 5o r ....~ 4,a

p < 0.001

40

~ 30

p = 0.003

P = 0.001

O

.~

20

~ ~0

p = 0.004

Z

0 Metastases

[l

p = 0.001

Fig. 3.3-15 Effect of 1600 mg clodronate orally for 2 years on visceral and other metastases and survival in patients with primary breast cancer and tumor cells in bone marrow. Data from Diel et al. (1998).

Bone Bone Visceral Deaths metastases metastases metastases per patient

In view of these results, t r e a t m e n t with b i s p h o s p h o n a t e s in patients with t u m o r - a s s o c i a t e d bone disease has become established widely.

102

3.3. Osteolytic tumor-induced bone disease Clodronate and pamidronate decrease the occurrence of skeletalrelated events, such as bone pain, the development of new osteolytic loci, and the events they induce in patients with tumor bone disease. Visceral metastases and survival have improved in some studies. Recent results suggest that bisphosphonates also diminish the formation of bone metastases in patients who have not developed them yet. Their potential use in tumors such as carcinoma of the breast to prevent skeletal dissemination has become an interesting possibility, but still requires further investigation. Various bisphosphonates, such as clodronate, pamidronate, and recently also risedronate, are effective in multiple myeloma. They reduce hypercalcemia and the number of hypercalcemic episodes, bone pain, the number of fractures, of radiotherapy courses and of surgical interventions, prevent skeletal deterioration, and improve quality of life. In one study with clodronate one subgroup of patients showed also a borderline significant longer survival. Bisphosphonates are used today extensively in myeloma. Fig. 3.3-16 Effect of 1600 mg clodronate administered daily orally for up to 7.5 years in patients with multiple myeloma. The median time of follow-up was 2.8 years in both groups. Data from McCloskey et al. (1998).

Effect of clodronate in myeloma 60 ,_, 50 ~ 40

p=0.02

= 30 ~ 20 ~" 10 0

p=0.05

Vertebral fractures

Fig. 3.3-17 Effect of 90 mg pamidronate infused every 4 weeks, for 21 cycles, in patients with multiple myeloma. Median time of followup was 28.2 months for pamidronate and 28.7 months for placebo. Data from Berenson et al. (1998).

II Placebo [] Clodronate

p=0.05

p-0.06

Other Severe Poor fractures hypercalcemia performance status

Effect of pamidronate in myeloma p<0.015

9 Placebo [] Pamidronate

~: 50] 40| ]

p=0.225

30]

p=0.06 p=0.05

=201 ~2 0"

All All Vertebral Radiation H.vperevents fractures fractures treatment calcemia

103

3. Bisphosphonatesmclinical Bisphosphonates are also effective in myeloma and are used extensively today in this disease. Lastly, it is of interest that bisphosphonates improve clinical symptoms, including bone pain, in patients with cancer of the prostate, in some, although not in all the studies. This is probably due to the fact that the metastases, despite being essentially osteoblastic, also have an osteoclastic component which is inhibited by the bisphosphonates. Controlled studies to establish an effect on bone-related events in prostate cancer are still necessary.

Bisphosphonates appear to be effective in prostate cancer, but this effect needs to be confirmed. It must be clear, however, that in most patients under treatment with bisphosphonates, the skeletal-related events do not disappear entirely, but are only reduced. Treatment

regimens

One should distinguish between the treatment of hypercalcemia, the treatment directed toward a long-term decrease of skeletal morbidity (new osteolytic lesions and fractures), and an improvement in the quality of life. Hypercalcemia is usually treated by intravenous administration of the bisphosphonate until blood calcium reaches a plateau. If this plateau is higher than desired, it is possible either to increase the dose, if this is acceptable from the toxicological point of view, or to change to a more potent compound. Once the desired plasma calcium is reached, administration is discontinued until plasma calcium increases again to an unacceptable level. Another option is to repeat the infusion periodically to prevent the recurrence of the hypercalcemia, and hopefully decrease the frequency of other skeletal-related events, or to proceed with an oral therapy with a bisphosphonate that can be given in this way, such as clodronate.

Clodronate Intravenous administration p. 168

For the treatment of patients with hypercalcemia, 300 mg of clodronate given as an intravenous infusion daily for about 5 days was originally proposed. Because it appears that the total dose is relevant, this regimen can easily be replaced by one infusion of 900-1500 mg, most often the latter, in no less than 500 ml. Oral clodronate is also effective. But because clodronate has a low potency, a high dose, generally 1600-3200 rag/day, is needed.

104

3.3. Osteolytic tumor-induced bone disease Intravenous infusions of 300 mg/day 01:clodronate for S clays or of a single infusion of 1500 mg in 500 ml is usually given. Sometimes oral treatment of 1600 to 3200 mg is used. The duration of the effect is very variable, relapse usually occurring within 1 - 4 weeks. As in Paget's disease, it appears that the duration is related not only to the severity of the disease, but also to the total administered dose. Treatment should be resumed when plasma calcium rises again. Another possibility is to administer clodronate orally as maintenance therapy after the initial intravenous treatment. A daily dose of 1600 mg is the standard maintenance therapy today, since lower doses are suboptimal and higher ones do not appear to give added effects.

Paget's disease p. 77

For long-term therapy of hypercalcemia, one can use either repeated courses of intravenous infusions, or oral administration of 1600 rng daily. For the long-term therapy of other complications of tumor bone disease, the daily oral administration of 1600 mg of clodronate has been shown in various randomized multicenter studies to reduce the formation of new osteolytic lesions, the further progression of existing lesions, and the occurrence of pathological fractures in patients with breast cancer and with myeloma. A possible effect on survival has yet to be proved in a large study.

Effect on complications pp. 101-104

Chronic oral administration of 1600 mg of clodronate daily is effective in decreasing the morbidity rate from skeletal metastases and is the dosage usually used. Clodronate is commercially available in many countries in both intravenous and oral forms.

Commercial index pp. 182-206

Etidronate Although the first report of the effect of etidronate on tumor-induced bone disease was published in 1980 and the activity was then confirmed by later investigations, the number of studies are fewer than those with clodronate and pamidronate. Nearly all patients have received the same dose of 7.5 mg/kg intravenously, given mostly for 3 days, in fewer cases somewhat longer. The compound is diluted in about 500 ml of liquid and administered over a few hours, in order to prevent precipitation or the formation of aggregates.

105

Intravenous administration p. 168

3. Bisphosphonates--clinical This dose leads to a normalization of hypercalcemia in 7-10 days in one-quarter of the patients, longer treatments being apparently somewhat more effective. The effect disappears within a month, sometimes already within days after discontinuation of the drug. If the effect is not satisfactory, or if plasma calcium rises again, the treatment can be repeated after an interval of 1 week. However, the long-term effect of repeated dosing on bone mineralization is unknown. There are only few results with regimens other than this, so that it is not known whether improvement is possible. Etidronate could not prevent the occurrence of skeletal complications in multiple myeloma. Among the various bisphosphonates used, the effect of etidronate, being the least potent, is the least satisfactory and the compound is very little used today.

Etidronate given daily at ZS rng/kg intravenously for 3 days can decrease hypercalcemia, as well as urinary calcium. Its effect is weaker than that of other bisphosphonates, so that this compound is not the bisphosphonate of choice. Commercial index pp. 182-206

Etidronate is commercially available in several countries for intravenous administration.

Ibandronate Ibandronate has been found to be active at low dosage when given in a single 2-h infusion of 500 ml. In one study, 49% of the patients reached normocalcemia, defined as albumin-corrected values below 10.8 mg%, when given 1.1 mg, 54% with 2 mg, 76% with 4 mg, and 78% with 6 mg. The manufacturer recommends 2 mg when the plasma calcium is below 12 mg% and 4 mg when it is above this value. Six milligrams are sometimes given in cases of severe hypercalcemia. Doses up to 3 mg can also be administered as an intravenous injection (Fig. 3.3-18). When given orally, doses from 10 to 50 mg daily were active in decreasing calciuria and markers of bone turnover. Some gastrointestinal disturbances were observed.

Ibandronate is very active even with a single dose of 2 - 4 rag. Doses up to 3 mg can be given by intravenous injection rather than infusion. Commercial index pp. 182-206

Ibandronate is available in various countries for hypercalcemia of malignancy.

Pamidronate Most studies in hypercalcemia have been performed using intravenous in- * fusions, and many different doses for different durations have been tried. 106

3.3. Osteolytic tumor-induced bone disease Effect of ibandronate on serum calcium

=-14 E o o

- ~ 2mg -a- 4 mgg

~ 12 .,,,~

~ 10 0

i

i

i

1

2

3

,

,

;

.

.

.

.

4 5 10 14 21 28 Days after infusion

Fig. 3.3-18 Effectof various doses of ibandronate, given once intravenously, on albumin-corrected serum calcium. [Adapted from Ralston, S. H., et al. (1997) with permission from the author and the publisher.] When it was realized that similar effects can be obtained when the same total dose is given once instead of divided over several days, the protocol with a single infusion gained popularity. The optimal dose ranges between 15 and 90 mg and should be adapted to the initial hypercalcemia, severely hypercalcemic patients requiring the larger dose. Thus, according to the manufacturer's guidelines in some countries, 1 5 - 3 0 mg is usually sufficient for hypercalcemia up to 12 mg/100 ml, while 3 0 - 6 0 mg is suggested for hypercalcemia between 12 and 14 rag/100 ml, 6 0 - 9 0 mg for values between 14 and 16 rag/100 ml, and 90 mg for values above 16 rag/100 ml. For the sake of simplicity many centers today use just 60 mg for plasma calcium levels below 13.5 rag/100 ml and 90 mg for plasma calcium above this concentration. However, many clinicians always use just the dose of 90 rag. When correctly dosed, normocalcemia can be obtained in 90% or more of the cases. As for the other bisphosphonates, treatment is resumed when blood calcium increases again. The compound must always be dissolved in at least 250 ml of fluid and be infused not faster than over 1 h for up to 60 mg and 2 h for higher amounts. Infusing the drug over 24 h does not improve the results. In myeloma an infusion time of 4 h in 500 ml is recommended.

One infusion of pamidronate is usually sufficient to normalize plasma calcium in hypercalcemia. The dose can be adapted to the degree of hypercalcemia and lies between 30 and 90 rag, mostly either 60 or 90 rag. Treatment is repeated when plasma calcium rises again. 107

3. Bisphosphonatesnclinical

Adverse events p. 174

Various trials have addressed the question of the optimal long-term therapy to reduce skeletal morbidity, and especially to prevent the development of new osteolytic foci, pathological fractures, and other complications in metastatic bone disease. Doses between 45 and 90 mg every 3 - 4 weeks, given in a single infusion, were shown to slow down the progression of the skeletal disease and to reduce bone pain. The equivalent of weekly doses of 20 mg seem to be necessary to improve pain. The effects of chronic oral therapy with 300 mg daily are ambiguous and are often accompanied by gastrointestinal side effects. This dose has not been active in one study on myeloma. Recently, in two large double-blind studies in patients with metastases of breast cancer, who received chemo- or hormone therapy, as well as in a study on patients with multiple myeloma, 90 mg infused once every 4 weeks for 2 years was successful in reducing skeletal complications, bone pain, and in improving performance status and quality of life. Therefore today one monthly infusion of 90 mg is most often recommended to prevent the development of skeletal related events and is the dose recommended by the manufacturer.

For chronic therapy to prevent complications, infusions of 90 mg monthly are effective and most often used today. Commercial index pp. 182-206

Pamidronate is available in many countries for intravenous administration.

Other bisphosphonates Chemical structures pp. 31-32

Commercial index pp. 182-206

Data on other bisphosphonates are still scanty. Alendronate and incadronate effectively reduce hypercalcemia at 10 mg (Fig. 3.3-19). Neridronate was effective with single infusions of 125 mg. Olpadronate given at 4 mg intravenously for 5 days, followed in some cases by daily oral administration of 200 mg for 3 months to patients with metastatic carcinoma of the prostate, decreased hypercalcemia, bone resorption, as well as bone pain. Risedronate decreased bone resorption in myeloma when given orally at 30 mg daily for 6 months. When investigated for the calcium-lowering effect, tiludronate has an activity similar to that of etidronate. Lastly, zoledronate given in single infusions of 0.02-0.04 mg/kg can also reduce the serum calcium. Alendronate and incadronate are available in Japan for intravenous administration in tumoral hypercalcemia.

Alendronate, incadronate, olpadronate, risedronate, and zoledronate on a milligram basis are very potent bisphosphonates.

108

3.3. Osteolytic tumor-induced bone disease Fig. 3.3-19 Effectof a single infusion of alendronate in tumor hypercalcemia. Some patients given the lower doses received a second infusion on day 3. (Adapted from Rizzoli, R., et al. (1992). Int. J. Cancer, 50, 706-712. Reproduced with permission from the author and publisher.)

Effect of alendronate on hypercalcemia

14+1 o o

IN) E

, ~k,~ "~.. ~g-C.~..._

,

Alendronate .... a, .... 2.5 mg - - e - - 5.0mg 'El lOmg

12-

.._... t~

IOE

Time (days)

Comparison of the various bisphosphonates From the available data, there is no indication that there are any fundamental differences in the qualitative effect of the various bisphosphonates in tumor-induced bone disease. There is, however, a great difference in their quantitative effect. From the results reported above, it appears that the total parenteral dose of bisphosphonate that effectively reduces hypercalcemia in tumor-induced bone disease ranges from roughly I to over 1000. It is of interest that the order of potency, as defined by the a m o u n t of drug necessary to reduce hypercalcemia found in humans is the same as that observed in the rat, but that the range of potency is s o m e w h a t --, shorter, about 1000 instead of 10,000. Fig. 3.3-20 Approximate relative potency of various bisphosphonates in tumoral hypercalcemia.

Relative potency in humans Etidronate Tiludronate Clodronate Neridronate Pamidronate Incadronate Alendronate Ibandronate Risedronate Zoledronate

1

>1000

The potency o1: the various bisphosphonates used [:or tumorinduced bone disease increases from 1 to about 1000.

109

Potency in the rat p. 40

3. Bisphosphonates--clinical Because a more potent substance is not necessarily a better one, it is difficult to decide which bisphosphonate to use if more than one is available. From the commercially available ones, etidronate appears to be the least suitable. Because of its relatively low potency, it is often not efficacious in cancer patients. Furthermore the effective doses are those that can lead to an inhibition of normal mineralization, a potential drawback if therapy is of long duration. Therefore, if available, the other four are preferred. Clodronate and pamidronate are both good choices, the latter may possibly have a somewhat stronger and more sustained effect, at least at the doses investigated up to now. However, clodronate is better tolerated when given orally, at least in comparison with the oral formulations of pamidronate used in the past. Thus, while pamidronate is for most the preferred choice when intravenous treatment is used, clodronate is the choice when oral administration is desired. Ibandronate appears, in view of its potency, to be an interesting new alternative, particularly with the potential for injections rather than infusions of doses up to 3 mg.

Alendronate, clodronate, pamidronate, and ibandronate appear to be the compounds of choice today in acute hypercalcemia. For chronic treatment of hypercalcemia and of the other complications, clodronate and pamidronate are the most used, clodronate being preferred for oral therapy, and pamidronate for parenteral therapy. Resistance to bisphosphonates p. 77

As in Paget's disease some patients develop resistance to the bisphosphonate with time. The cause of this is unknown. Sometimes it can be overcome by increasing the dose, in other cases the switch to another bisphosphonate, if possible a more potent one, will be successful.

It: resistance to the treatment develops, either increasing the dose, or a switch to another, prel:erably more potent bisphosphonate, may solve the problem.

Conclusion Besides classic antineoplastic treatments, bisphosphonates are today the drugs 01:choice to treat tumor bone disease. By inhibiting bone resorption, they correct hypercalcemia, reduce pain, prevent the development of new osteolytic lesions, and reduce the occurrence o[[ractures, and as a consequence improve the quality ol:lil:e.

110

3.3. Osteolytic t u m o r - i n d u c e d bone disease

Recommended selected reading Tumor bone disease Books Body, J.-J. (ed.) (1999). Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy. (New York, Basel: Dekker)

Reviews Bataille, R., and Harousseau, J.-L. (1997). Multiple myeloma. N. Engl. J. Med., 336, 16571664 Body, J.-J. (1999). Metastatic bone disease. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 591-604. (San Diego, London: Academic Press) Coleman, R. E. (1998). Monitoring of bone metastases. Eur. J. Cancer, 34, 252-259 Fontana, A., Garnero, P., and Delmas P. D. (1999). Markers of bone turnover in diagnosis and monitoring of bone metastases. In Body, J.-J. (ed.) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy, pp. 213-226. (New York, Basel: Dekker) Goltzman, D., and Henderson, J. E. (1996). Expression of PTHrP in disease. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 809-826. (San Diego, London: Academic Press) Goltzman, D., and Rabbani, S. A. (1999). Pathogenesis of osteoblastic metastases. In Body, J.-J. (ed.) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy., pp. 71-84. (New York, Basel: Dekker) Grill, V., Rankin, W., and Martin, T. J. (1998). Parathyroid hormone-related protein (PTHrP) and hypercalcemia. Eur. J. Cancer, 34, 222-229 Guise, T. A., and Mundy, G. R. (1998). Cancer and bone. Endocr. Rev., 19, 18-54 Koutsilieris, M. (1995). Skeletal metastases in advanced prostate cancer: Cell biology and therapy. Crit. Rev. Oncol. Hematol., 8, 51-64 Mundy, G. R. (1996). Role of cytokines, parathyroid hormone, and growth factors in malignancy. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 827-836. (San Diego, London: Academic Press) Mundy, G. R. (1998). Hypercalcemia of malignancy. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 637-649. (San Diego: Academic Press) Rubens, R. D. (1999). Clinical aspects of bone metastases. In Body, J.-J. (ed.) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy, pp. 85-96. (New York, Basel: Dekker) Thtirlimann, B., and de Stoutz, N. D. (1996). Causes and treatment of bone pain of malignant origin. Drugs, 51,383-398 Vinholes, J., Coleman, R., and Eastell, R. (1996). Effects of bone metastases on bone metabolism: Implications for diagnosis, imaging and assessment of response to cancer treatment. Cancer Treat Rev., 22, 289-331 Yoneda, T., Williams, P. J., Myoi, A., Michigami, T., and Mbalaviele, G. (1999). Cellular and molecular mechanisms of development of skeletal metastases. In Body, J.-J. (ed.) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy, pp. 41-69. (New York, Basel: Dekker)

Bisphosphonates, preclinical Reviews Fleisch, H. (1998). Bisphosphonates: Mechanisms of action. Endocr. Rev., 19, 80-100 Fleisch, H. (1999). Bisphosphonates: Introduction and mechanisms of action in tumor

111

3. B i s p h o s p h o n a t e s m c l i n i c a l

prevention. In Body, J.-J. (ed.) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy, pp. 357-376. (New York, Basel: Dekker) Russell, R. G., Croucher, P. J., and Rogers, M. J. (1999). The clinical pharmacology of bisphosphonates. In Body, J.-J. (ed.) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy, pp. 377-392. (New York, Basel: Dekker) O r i g i n a l articles

Aparicio, A., Gardner, A., Tu, Y., Savage, A., Berenson, J., and Lichtenstein, A. (1998). In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia, 12, 220-229 Boissier, S., Magnetto, S., Frappart, L., Cuzin, B., Ebetino, F. H., Delmas, P. D., and Clezardin, P. (1997). Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer Res., 57, 3890-3894 Guaitani, A., Polentarutti, N., Filippeschi, S., Marmonti, L., Corti, F., Italia, C., Coccioli, G., Donelli, M. G., Mantovani, A., and Garattini, S. (1984). Effects of disodium etidronate in murine tumor models. Eur. J. Cancer Clin. Oncol., 20, 685-693 Hall, D. G., and Stoica, G. (1994). Effect of the bisphosphonate risedronate on bone metastases in a rat mammary adenocarcinoma model system. J. Bone Miner. Res., 9, 221-230 Hiraga, T., Tanaka, S., Yamamoto, M., Nakajima, T., and Ozawa, H. (1996). Inhibitory effects of bisphosphonate (YM175) on bone resorption induced by a metastatic bone tumor. Bone, 18, 1-7 Jung, A., Mermillod, B., Barras, C., Baud, M., and Courvoisier, B. (1981). Inhibition by two diphosphonates of bone lysis in tumor-conditioned media. Cancer Res., 41, 3233-3237 Jung, A., Bornand, J., Mermillod, B., Edouard, C., and Meunier, P. J. (1984). Inhibition by diphosphonates of bone resorption induced by the Walker tumor of the rat. Cancer Res., 44, 3007-3011 Martodam, R. R., Thornton, K. S., Sica, D. A., D'Souza, S. M., Flora, L., and Mundy, G. R. (1983). The effects of dichloromethylene diphosphonate on hypercalcemia and other parameters of the humoral hypercalcemia of malignancy in the rat Leydig cell tumor. Calcif. Tissue Int., 35, 512-519 Pluijm van der, G., Vloedraven, H., Beek van, E., Wee-Pals van der, L., L6wik, C., and Papapoulos, S. (1996). Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J. Clin. Invest., 98, 698-705 Sasaki, A., Boyce, B. F., Story, B., Wright, K. R., Chapman, M., Boyce, R., Mundy, G. R., and Yoneda, T. (1995). Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res., 55,3551-3557 Sasaki, A., Kitamura, K., Alcalde, R. E., Tanaka, T., and Suzuki, A. (1998). Effect of a newly developed bisphosphonate, YH529, on osteolytic bone metastases in nude mice. Int. J. Cancer, 77, 279-285 Shipman, C. M., Rogers, M. J., Apperley, J. F., Russell, R. G. G., and Croucher, P. I. (1997). Bisphosphonates induce apoptosis in human myeloma cell lines: A novel anti-tumour activity. Br. J. Haematol., 98,665-672. Shipman, C. M., Croucher, P. I., Russell, R. G. G., Helfrich, M. H., and Rogers, M. J. (1998). The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway. Cancer Res. 58, 5294-5297 Sturtz, G., Couthon, H., Fabulet, O., Mian, M., and Rosini, S. (1993). Synthesis of gembisphosphonic methotrexate conjugates and their biological response towards Walker's osteosarcoma. Eur. J. Med. Chem., 28, 899-903

Bisphosphonates, clinical Reviews

Adami, S. (1997). Bisphosphonates in prostate cancer. Cancer, 80, 1674-1679 Berenson, J. R., and Lipton, A. (1998). Pharmacology and clinical efficacy of bisphosphonates. Curr. Opin. Oncol., 10, 566-571 112

3.3. Osteolytic t u m o r - i n d u c e d bone disease Bloomfield, D. J. (1998). Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from other cancers? An evidence-based review. J. Clin. Oncol., 16, 1218-1225 Body, J.-J. (1998). Bisphosphonates. Eur. J. Cancer, 34, 263-269 Body, J.-J., Bartl, R., Burckhardt, P., Delmas, P. D., Diel, I. J., Fleisch, H., Kanis, J. A., Kyle, R. A., Mundy, G. R., Paterson, A. H. G., and Rubens, R. D. (1998). Current use of bisphosphonates in oncology. J. Clin. Oncol., 16, 3890-3899 Coleman, R. E. (1999). Treatment of tumor-induced osteolysis and prevention of skeletalrelated events in patients with bone metastases. In Body, J.-J. (ed.) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy, pp. 409-434. (New York, Basel: Dekker) Kanis, J. A., and McCloskey, E. V. (1999). Bisphosphonates in the treatment of multiple myeloma. In Body, J.-J. (ed.) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy, pp. 457-481. (New York, Basel: Dekker) Paterson, A. H. G. (1999). Prospects of bisphosphonates for the prevention of bone metastases. In Body, J.-J. (ed.) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy, pp. 435-455. (New York, Basel: Dekker). Ralston, S. H. (1999). Treatment of tumor induced hypercalcemia. In Body, J.-J. (ed.) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Pathophysiology, Diagnosis, and Therapy, pp. 393-408. (New York, Basel: Dekker)

Alendronate O r i g i n a l articles Adami, S., Bolzicco, G. P., Rizzo, A., Salvagno, G., Bertoldo, F., Rosini, M., Suppi, R., and Lo Cascio, V. (1987). The use of dichloromethylene bisphosphonate and aminobutane bisphosphonate in hypercalcemia of malignancy. Bone Miner., 2, 395-404 Nussbaum, S. R., Warrell, R. P., Jr., Rude, R., Glusman, J., Bilezikian, J. p., Stewart, A. F., Stepanavage, M., Sacco, J. F., Averbuch, S. D., and Gertz, B. J. (1993). Dose-response study of alendronate sodium for the treatment of cancer-associated hypercalcemia. J. Clin. Oncol., 11, 1618-1623 Rizzoli, R., Buchs, B., and Bonjour, J.-p. (1992). Effect of a single infusion of alendronate in malignant hypercalcaemia: Dose dependency and comparison with clodronate. Int. J. Cancer, 50, 706-712

Clodronate Reviews Elomaa, I., and Blomqvist, C. (1995). Clodronate and other bisphosphonates as supportive therapy in osteolysis due to malignancy. Acta Oncol., 34, 629-636 Hurst, M., and Noble, S. (1999). Clodronate. A review of its therapeutic potential in breast cancer. Drugs Aging, 15. Kanis, J. A., O'Rourke, N., and McCloskey, E. V. (1994). Consequences of neoplasia induced bone resorption and the use of clodronate. Int. J. Oncol., 5,713-731 Plosker, G. L., and Goa, K. L. (1994). Clodronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs, 47, 945-982 O r i g i n a l articles Bonjour, J.-p., Philippe, J., Guelpa, G., Bisetti, A., Rizzoli, R., Jung, A., Rosini, S., and Kanis, J. A. (1988). Bone and renal components in hypercalcemia of malignancy and responses to a single infusion of clodronate. Bone, 9, 123-130 Delmas, P. D., Charhon, S., Chapuy, M. C., Vignon, E., Brian~on, D., Edouard, C., and Meunier, P. J. (1982). Long-term effects of dichloromethylene diphosphonate (C12MDP) on skeletal lesions in multiple myeloma. Metab. Bone Dis. Related Res., 4, 163-168 Diel, I. J., Solomayer, E.-F., Costa, S. D., Gollan, C., Goerner, R., Wallwiener, D., Kauf!13

3. Bisphosphonates--clinical mann, M., and Bastert, G. (1998). Reduction in new metastases in breast cancer with adjuvant clodronate therapy. N. Engl. J. Med., 339, 357-363 Douglas, D. L., Duckworth, T., Russell, R. G. G., Kanis, J. A., Preston, C. J., Preston, F. E., Prenton, M. A., and Woodhead, J. S. (1980). Effect of dichloromethylene diphosphonate in Paget's disease of bone and in hypercalcaemia due to primary hyperparathyroidism or malignant disease. Lancet, 1, 1043-1047 Elomaa, I., Blomqvist, C., Gr6hn, P., Porkka, L., Kairento, A. L., Selander, K., LambergAllardt, C., and Holmstr6m, T. (1983). Long-term controlled trial with diphosphonate in patients with osteolytic bone metastases. Lancet, 1,146-149 Heim, M. E., Clemens, M. R., Queisser, W., Pecherstorfer, M., Boewer, C., Herold, M., Franke, A., Herrmann, Z., Loose, R., and Edler, L. (1995). Prospective randomized trial of dichloromethylene bisphosphonate (clodronate) in patients with multiple myeloma requiring treatment. A multicenter study. Onkologie, 18,439-448 Jacobs, T. P., Siris, E. S., Bilezikian, J. P., Baquiran, D. C., Shane, E., and Canfield, R. E. (1981). Hypercalcemia of malignancy: Treatment with intravenous dichloromethylene diphosphonate. Ann. Intern. Med., 94, 312-316 Kanis, J. A., Powles, T., Paterson, A. H. G., McCloskey, E. V., and Ashley, S. (1996). Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone, 19, 663-667 Kym/il/i, T., Taube, T., Tammela, T. L. J., Risteli, L., Risteli, J., and Elomaa, I. (1997). Concomitant i.v. and oral clodronate in the relief of bone pain--a double-blind placebocontrolled study in patients with prostate cancer. Br. J. Cancer, 76, 939-942 Lahtinen, R., Laakso, M., Palva, I., Virkkunen, P., and Elomaa, I. (1992). Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet, 340, 1049-1052 McCloskey, E. V., MacLennan, I. C. M., Drayson, M. T., Chapman, C., Dunn, J., and Kanis, J. A. (1998). A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. Br. J. Haematol., 100, 317-325 O'Rourke, N. P., McCloskey, E. V., Vasikaran, S., Eyres, K., Fern, D., and Kanis, J. A. (1993). Effective treatment of malignant hypercalcaemia with a single intravenous infusion of clodronate. Br. J. Cancer, 67, 560-563 Paterson, A. H. G., Powles, T. J., Kanis, J. A., McCloskey, E., Hanson, J., and Ashley, S. (1993). Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J. Clin. Oncol., 11, 59-65 Shane, E., Jacobs, T. P., Siris, E. S., Steinberg, S. F., Stoddart, K., Canfield, R. E., and Bilezikian, J. P. (1982). Therapy of hypercalcemia due to parathyroid carcinoma with intravenous dichloromethylene diphosphonate. Am. J. Med., 72, 939-944 Siris, E. S., Sherman, W. H., Baquiran, D. C., Schlatterer, J. P., Osserman, E. F., and Canfield, R. E. (1980). Effects of dichloromethylene diphosphonate on skeletal mobilization of calcium in multiple myeloma. N. Engl. J. Med., 302, 310-315 Urwin, G. H., Yates, A. J. P., Gray, R. E. S., Hamdy, N. A. T., McCloskey, E. V., Preston, F. E., Greaves, M., Neil, F. E., and Kanis, J. A. (1987). Treatment of the hypercalcaemia of malignancy with intravenous clodronate. Bone, 8(Suppl 1), $43-$51

Etidronate

Reviews Dunn, C. J., Fitton, A., and Sorkin, E. M. (1994). Etidronic acid. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs Aging, 5, 446-474

Original articles Gucalp, R., Ritch, P., Wiernik, P. H., Sarma, P. R., Keller, A., Richman, S. P., Tauer, K., Neidhart, J., Mallette, L. E., Siegel, R., and VandePol, C. J. (1992). Comparative study of pamidronate and etidronate disodium in the treatment of cancer-related hypercalcemia. J. Clin. Oncol., 10, 134-142

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3.3. Osteolytic tumor-induced bone disease Jung, A. (1982). Comparison of two parenteral diphosphonates in hypercalcemia of malignancy. Am. J. Med., 72, 221-226 Kanis, J. A., Urwin, G. H., Grab R. E. S., Beneton, M. N. C., McCloskey, E. V., Hamdy, N. A. T., and Murray, S. A. (1987). Effects of intravenous etidronate disodium on skeletal and calcium metabolism. Am. J. Med., 82(Suppl. 2A), 55-70 Ryzen, E., Martodam, R. R., Troxell, M., Benson, A., Paterson, A., Shepard, K., and Hicks, R. (1985). Intravenous etidronate in the management of malignant hypercalcemia. Arch. Intern. Med., 145,449-452 Singer, F. R., Ritch, P. S., Lad, T. E., Ringenberg, Q. S., Schiller, J. H., Recker, R. R., and Ryzen, E. (1991). Treatment of hypercalcemia of malignancy with intravenous etidronate. A controlled, multicenter study. Arch. Intern. Med., 151,471-476

Ibandronate Reviews Dooley, M., and Balfour, J. A. (1999). Ibandronate. Drugs, 57, 101-108

Original articles Coleman, R. E., Purohit, O. P., Black, C., Vinholes, J. J. F., Schlosser, K., Huss, H., Quinn, K. J., and Kanis, J. (1999). Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease. Ann. Oncol., 10, 311-316. Pecherstorfer, M., Herrmann, Z., Body, J.-J., Manegold, C., Degardin, M., Clemens, M. R., Thiirlimann, B., Tubiana-Hulin, M., Steinhauer, E. U., van Eijkeren, M., Huss, H.-J. and Thi~baud, D. (1996). Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. J. Clin. Oncol., 14, 268-276 Pecherstorfer, M., Ludwig, H., Schlosser, K., Buck, S., Huss, H.-J., and Body, J.-J. (1996). Administration of the bisphosphonate ibandronate (BM 21.0955) by intravenous bolus injection. J. Bone Miner. Res., 11,587-593 Ralston, S. H., Thidbaud, D., Herrmann, Z., Steinhauer, E. U., Thiirlimann, B., Walls, J., Lichinitser, M. R., Rizzoli, R., Hagberg, H., Huss, H. J., Tubiana-Hulin, M., and Body, J.-J. (1997). Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia. Br. J. Cancer, 75, 295-300 Wiister, C., Sch6ter, K. H., Thi6baud, D., Manegold, C., Krahl, D., Clemens, M. R., Ghielmini, M., Jaeger, P., and Scharla, S. H. (1993). Methylpentylaminopropylidene bisphosphonate (BM 21.0955): A new potent and safe bisphosphonate for the treatment of cancer-associated hypercalcemia. Bone Miner., 22, 77-85

Pamidronate Books Thiirlimann, B. (1999). Bisphosphonates in Clinical Oncology. The Development of Pamidronate. (Berlin: Springer-Verlag)

Reviews Berenson, J. R. (1998). The efficacy of pamidronate disodium in the treatment of osteolytic lesions and bone pain in multiple myeloma. Rev. Contemp. Pharmacother., 9, 195-203 Brincker, H., Westin, J., Abildgaard, N., Gimsing, P., Turesson, I., Hedenus, M., Ford, J., and Kandra, A. (1998). Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: A double-blind placebo-controlled trial. Br. J. Haematol., 101,280-286 Clarke, N. W. (1998). The effects of pamidronate disodium treatment in metastatic prostate cancer. Rev. Contemp. Pharmacother., 9, 205-212

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3. B i s p h o s p h o n a t e s - - c l i n i c a l Coleman, R. E. (1998). Pamidronate disodium in the treatment and management of hypercalcaemia. Rev. Contemp. Pharmacother., 9, 147-164 Coukell, A. J., and Markham, A. (1998). Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone. Drugs Aging, 12, 149-168 Iddon, J., Bundred, N., and Howell, T. (1998). Pamidronate sodium in the treatment of osteolytic lesions and bone pain in patients with bone metastases associated with breast cancer. Rev. Contemp. Pharmacother., 9, 183-193

O r i g i n a l articles Berenson, J. R., Lichtenstein, A., Porter, L., Dimopoulos, M. A., Bordoni, R., George, S., Lipton, A., Keller, A., Ballester, O., Kovacs, M. J., Blacklock, H. A., Bell, R., Simeone, J., Reitsma, D. J., Heffernan, M., Seaman, J., and Knight, R. D. (1996). Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N. Engl. J. Med., 334, 488-493 Berenson, J. R., Lichtenstein, A., Porter, L., Dimopoulos, M. A., Bordoni, R., George, S., Lipton, A., Keller, A., Ballester, O., Kovacs, M. J., Blacklock, H., Bell, R., Simeone, J. F., Reitsma, D. J., Heffernan, M., Seaman, J., and Knight, R. D. (1998). Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J. CIin. Oncol., 16, 593-602 Body, J.-J. and Dumon, J. C. (1994). Treatment of tumour-induced hypercalcaemia with the bisphosphonate pamidronate: Dose-response relationship and influence of turnout type. Ann. Oncol., 5,359-363 Body, J.-J., Magritte, A., Seraj, F., Sculier, J. P., and Borkowski, A. (1989). Aminohydroxypropylidene bisphosphonate (APD) treatment for tumor-associated hypercalcemia: A randomized comparison between a 3-day treatment and single 24-hour infusions. J. Bone Miner. Res., 4, 923-928 Body, J.-J., Dumon, J. C., Piccart, M., and Ford, J. (1995). Intravenous pamidronate in patients with tumor-induced osteolysis: A biochemical dose-response study. Bone Miner. Res., 10, 1991-1995 Body, J.-J., Dumon, J. C., and Delmas, P. D. (1997). Comparative evaluation of markers of bone resorption in patients with breast cancer-induced osteolysis before and after bisphosphonate therapy. Br. J. Cancer, 75,408-412 Conte, P. F., Latreille, J., Mauriac, L., Calabresi, F., Santos, R., Campos, D., Bonneterre, J., Francini, G., and Ford, J. M. (1996). Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: Results from a multinational randomized controlled trial. J. Clin. Oncol., 14, 2552-2559 Glover, D., Lipton, A., Keller, A., Miller, A. A., Browning, S., Fram, R. J., George, S., Zelenakas, K., Macerata, R. S., and Seaman, J. J. (1994). Intravenous pamidronate disodium treatment of bone metastases in patients with breast cancer. Cancer, 74, 2949-2955 Gucalp, R., Ritch, P., Wiernik, P. H., Sarma, P. R., Keller, A., Richman, S. P., Tauer, K., Neidhart, J., Mallette, L. E., Siegel, R., and VandePol, C. J. (1992). Comparative study of pamidronate and etidronate disodium in the treatment of cancer-related hypercalcemia. J. Clin. Oncol., 10, 134-142 Harinck, H. I. J., Bijvoet, O. L. M., Plantingh, A. S. T., Body, J.-J., Elte, J. W. F., Sleeboom, H. P., Wildiers, J., and Neijt, J. P. (1987). Role of bone and kidney in tumor-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride. Am. J. Med., 82, 1133-1142 Hortobagyi, G. N., Theriault, R. L., Porter, L., Blayney, D., Lipton, A., Sinoff, C., Wheeler, H., Simeone, J. F., Seaman, J. J., Knight, R. D., Heffernan, M., and Reitsma D. J. (1996). Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N. Engl. J. Med., 335, 1785-1791 Hortobagyi, G. N., Theriault, R. L., Lipton, A., Porter, L., Blayney, D., Sinoff, C., Wheeler, H., Simeone, J. F., Seaman, J. J., Knight, R. D., Heffernan, M., Mellars, K., and Reitsma D. J. (1998). Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J. Clin. Oncol., 16, 2038-2044

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3.3. Osteolytic t u m o r - i n d u c e d bone disease Nussbaum, S. R., Younger, J., VandePol, C. J., Gagel, R. F., Zubler, M. A., Chapman, R., Henderson, I. C., and Mallette, L. E. (1993). Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: Comparison of 30-, 60-, and 90-mg dosages. Am. J. Med., 95,297-304 Purohit, O. P., Radstone, C. R., Anthony, C., Kanis, J. A., and Coleman, R. E. (1995). A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br. J. Cancer, 72, 1289-1293 Theriault, R. L., Lipton, A., Hortobagyi, G. N., Left, R., Gliick, S., Stewart, J. F., Costello, S., Kennedy, I., Simeone, J., Seaman, J. J., Knight, R. D., Mellars, K., Heffernan, M., and Reitsma, D. J. (1999). Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial. J. Clin. Oncol., 17, 846-854 Thi6baud, D., Portmann, L., Jaeger, p., Jacquet, A. F., and Burckhardt, P. (1986). Oral versus intravenous AHPrBP (APD) in the treatment of hypercalcemia of malignancy. Bone, 7, 247-253 Thi~baud, D., Jaeger, P., Jacquet, A. F., and Burckhardt, P. (1988). Dose-response in the treatment of hypercalcemia of malignancy by a single infusion of the bisphosphonate AHPrBP. J. Clin. Oncol., 6, 762-768 Thi6baud, D., Leyvraz, S., von Fliedner, V., Perey, L., Cornu, P., Thi6baud, S., and Burckhardt, P. (1991). Treatment of bone metastases from breast cancer and myeloma with pamidronate. Eur. J. Cancer, 27, 37-41 Thiirlimann, B., Morant, R., Jungi, W. F., and Radziwill, A. (1994). Pamidronate for pain control in patients with malignant osteolytic bone disease: A prospective dose-effect study. Support Care Cancer, 2, 61-65 van Breukelen, F. J. M., Bijvoet, O. L. M., and van Oosterom, A. T. (1979). Inhibition of osteolytic bone lesions by (3-amino-l-hydroxypropylidene)-l,l-bisphosphonate (A.P.D.). Lancet, 1,803-805 van Holten-Verzantvoort, A. T. M., Kroon, H. M., Bijvoet, O. L. M., Cleton, F. J., Beex, L. V. A. M., Blijham, G., Hermans, J., Neijt, J. p., Papapoulos, S. E., Sleeboom, H. P., Vermey, P., and Zwinderman, A. H. (1993). Palliative pamidronate treatment in patients with bone metastases from breast cancer. J. Clin. Oncol., 11,491-498

Tiludronate Dumon, J. C., Magritte, A., and Body, J.-J. (1991). Efficacy and safety of the bisphosphonate tiludronate for the treatment of tumor-associated hypercalcemia. Bone Miner., 15, 257-266 Other bisphosphonates Body, J.-J., Lortholary, A., Romieu, G., Vigneron, A. M., and Ford, J. (1999). A dose-finding study of zoledronate in hypercalcemic cancer patients. J. Bone Miner. Res., 14, 15571561 Fukumoto, S., Matsumoto, T., Takebe, K., Onaya, T., Eto, S., Nawata, H., and Ogata, E. (1994). Treatment of malignancy-associated hypercalcemia with YM175, a new bisphosphonate: Elevated threshold for parathyroid hormone secretion in hypercalcemic patients. J. Clin. Endocrinol. Metab., 79, 165-170 O'Rourke, N. P., McCloskey, E. V., Rosini, S., Coleman, R. E., and Kanis, J. A. (1994). Treatment of malignant hypercalcemia with aminohexane bisphosphonate (neridronate). Br. J. Cancer, 69, 914-917 pelger, R. C. M., Hamdy, N. A. T., Zwinderman, A. H., Lycklama, A. A. B., Nijeholt, A., and Papapoulos, S. E. (1998). Effects of the bisphosphonate olpadronate in patients with carcinoma of the prostate metastatic to the skeleton. Bone, 22, 403-408 Roux, C., Ravaud, P., Cohen-Solal, M., de Vernejoul, M. C., Guillemant, S., Cherruau, B., Delmas, P., Dougados, M., and Amor, B. (1994). Biologic, histologic and densitometric effects of oral risedronate on bone in patients with multiple myeloma. Bone, 15, 41-49

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3.4. 3.4.1.

NON-TUMOR-INDUCED

HYPERCALCEMIA

Definition

All hypercalcemias due to causes other than malignant bone disease fall within this category. 3.4.2. Calcium homeostasis p. 91

Pathophysiology

An increase in blood calcium can be due to increased flux of calcium from bone or the intestine, to an increase in tubular reabsorption of calcium in the kidney, or both. An increase in calcium flux from bone, following accelerated bone destruction, is by far the most common mechanism. Examples are hyperparathyroidism, the most frequent cause, thyrotoxicosis, and certain cases of acute osteoporosis, as during immobilization. Increased intestinal calcium absorption is a less frequent cause of hypercalcemia. It occurs, for example, in vitamin D intoxication or in sarcoidosis, in which macrophages produce 1,25(OH)2 D. An increase in tubular reabsorption of calcium is usually due to abnormally high levels of parathyroid hormone as encountered in primary hyperparathyroidism. In familial hypocalciuric hypercalcemia the recently discovered Ca2§ receptor appears to be involved. Often more than one mechanism is involved, such as in primary hyperparathyroidism, where the increase in blood calcium originates from both bone and kidney.

Hypercalcemia can result from an increase in the efflux of calcium from bone or the intestine to the blood, from an increase in tubular reabsorption of calcium in the kidney, or to both. 3.4.3. Hypercalcemic syndrome p. 93

Clinical manifestations

The clinical picture is that of the hypercalcemic syndrome. Disturbances involve the central and peripheral nervous system, the digestive, cardiovascular and renal systems, and the muscles. Dangerous complications are acute hypercalcemic crisis, which can be fatal, and ectopic calcification. The latter occurs especially in the kidney, where renal failure can result, and in the urinary tract in the form of urolithiasis.

Hypercalcemia induces a large variety of disturbances and can be life threatening.

118

3.4. Non-tumor-induced hypercalcemia

3.4.4.

Treatment with drugs other than bisphosphonates

M o s t hypercalcemias are relatively resistant to t r e a t m e n t other than that which is directed to the underlying disease. Drugs used include corticosteroids, prostaglandin inhibitors, calcitonin, and furosemide, but the resuits are most often disappointing, except for corticosteroids in granulom a t o u s diseases and in vitamin D toxicity.

3.4.5.

Treatment with bisphosphonates

Preclinical studies The animal experiments which give the basis for the use of bisphosphonates in hypercalcemia in humans have been discussed extensively in the preclinical section. These compounds prevent or decrease hypercalcemia induced by agents such as parathyroid hormone, vitamin D and its metabolites, and retinoids. Fig. 3.4-1 Effect of 10 mg phosphorus/kg of clodronate on the hypercalcemia induced in the rat by parathyroid extract. [Adapted from Fleisch, H., Russell, R. G. G., and Francis, M.D. (1969). Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science, 165, 1262-1264, with copyright permission from the author and the American Association for the Advancement of Science.]

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3 6 Time (days)

9

Bisphosphonates prevent or reverse hypercalcemia induced by various means in the animal.

Clinical studies Only few data are available concerning the use of bisphosphonates in nontumor-induced hypercalcemia. Most of the reports are on hyperparathyroidism.

119

Bone resorption p. 39

3. Bisphosphonates--clinical Effects

Effect of PTH p. 18

BMU p. 13

Various bisphosphonates reduce serum calcium to some degree in some patients with hyperparathyroidism, whether primary or tertiary. The older bisphosphonates like etidronate and clodronate are relatively weak and have a short duration of action. The newer more potent bisphosphonates have not been well studied. Some positive effects have also been seen in the hypercalcemias accompanying immobilization, thyrotoxicosis, sarcoidosis, and vitamin D intoxication. In general it appears that the bisphosphonates have only limited effects in the great majority of patients with non-tumor-induced hypercalcemia, especially those with hyperparathyroidism. This is not surprising, as the increase in serum calcium is due in most patients to an increase in parathyroid hormone, which acts in part through the kidney. Furthermore, the bisphosphonates are not as long acting as, for example, in Paget's disease. It has been suggested that the long-lasting effect in this disease, as well as in other conditions characterized by focal involvement, is due to the specific accumulation of bisphosphonates at sites of local resorption. These compounds would be less active in diseases with generalized resorption, such as hyperparathyroidism, where new BMUs form constantly throughout the skeleton, so that the bisphosphonate will be present in a much lower concentration at resorption sites. Furthermore, new BMUs formed after cessation of treatment will not be exposed to drug at all. It has been reported that patients treated with more potent bisphosphonates do normalize their fasting hypercalcemia, but may become sensitive to calcium ingestion.

Bisphosphonates are relatively less active on nontumor hypercalcemia such as in hyperparathyroidism, because part o[ the elevation in plasma calcium is due to increased reabsorption in the kidney. They are also active ]:or a shorter time. Little is known about other diseases. Treatment regimens

Intravenous administration p. 168

Clodronate decreases hypercalcemia when given intravenously at 3 0 0 600 mg daily for a few days or orally at 1600-3200 mg daily. From our knowledge on tumor bone disease, it appears preferable to infuse 9 0 0 1500 mg once when given intravenously. Etidronate can be effective when given intravenously at 7.5 mg/kg daily, but appears mostly inactive when given orally. For pamidronate 4 5 - 6 0 mg intravenously, given as a single infusion, is usually given. The highest recommended dose, 90 mg, should be employed with caution because of the possible development of "over-

120

3.4. Non-tumor-induced hypercalcemia s h o o t " hypocalcemia. The infusion should always be p e r f o r m e d with no less t h a n 500 ml of fluid a n d last for at least 2 h. Daily oral doses of 2 0 40 mg of risedronate for 1 w e e k are also effective. H o w e v e r , the effect of all c o m p o u n d s disappears relatively rapidly after d i s c o n t i n u a t i o n of treatment, so that it should be continued.

Clodronate, etidronate, pamidronate, and risedronate can decrease plasma calcium in some cases ol: non-tumor-induced hypercalcemia. In general, dosages similar to those acting in tumor bone disease are recommended. In hyperparathyroidism the effect often disappears rapidly after discontinuation ol: treatment.

Conclusion Bisphosphonates can occasionally be useful in non-tumor-induced hypercalcemia. The compounds mostly used are pamidronate and cloclronate.

Recommended

selected reading

Hypercalcemia

Reviews Bilezikian, J. p. (1992). Hypercalcemic states: Their differential diagnosis and acute management. In Coe, F. L., and Favus, M. J. (eds.) Disorders of Bone and Mineral Metabolism, pp. 493-521. (New York: Raven) Brown, E. M., Bai, M., and Pollak, M. (1998). Familial benign hypocalciuric hypercalcemia and other syndromes of altered responsiveness to extracellular calcium. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 637-649. (San Diego: Academic Press) Peacock, M. (1993). Hyperparathyroid and hypoparathyroid bone disease. In Mundy, G. R., and Martin, T. J. (eds.) Physiology and Pharmacology of Bone. Handbook of Experimental Pharmacology, vol. 107, pp. 443-483. (Berlin, Heidelberg, New York: SpringerVerlag) Potts, J. T., Jr.(1998). Primary hyperparathyroidism. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 411-442. (San Diego: Academic Press)

Original articles B i s p h o s p h o n a t e s , preclinical Fleisch, H., Russell, R. G. G., and Francis, M. D. (1969). Diphosphonates inhibit hydroxy apatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science, 165, 1262-1264

121

3. Bisphosphonates--clinical

Bisphosphonates, clinical Hamdy, N. A. T., Gray, R. E. S., McCloskey, E., Galloway, J., Rattenbury, J. M., Brown, C. B., and Kanis, J. A. (1987). Clodronate in the medical management of hyperparathyroidism. Bone, 8(Suppl. 1), $69-$77 Hamdy, N. A. T., McCloskey, E. V., Brown, C. B., and Kanis, J. A. (1990). Effects of clodronate in severe hyperparathyroid bone disease in chronic renal failure. Nephron, 56, 6-12 Reasner, C. A., Stone, M. D., Hosking, D. J., Ballah, A., and Mundy, G. R. (1993). Acute changes in calcium homeostasis during treatment of primary hyperparathyroidism with risedronate. J. Clin. Endocrinol. Metab., 77, 1067-1071 Rizzoli, R., Stoermann, C., Ammann, P., and Bonjour, J.-P. (1994). Hypercalcemia and hyperosteolysis in vitamin D intoxication: Effects of clodronate therapy. Bone, 15,193198 Selby, P. L., Davies, M. Marks, J. S., and Mawer, E. B. (1995). Vitamin D intoxication causes hypercalcaemia by increased bone resorption which responds to pamidronate. Clin. Endocrinol., 43, 531-536 Shane, E., Baquiran, D. C., and Bilezikian, J. P. (1981). Effect of dichloromethylene diphosphonate on serum and urinary calcium in primary hyperparathyroidism. Ann. Intern. Med., 95, 23-27

122

3.5. OSTEOPOROSIS 3.5.1.

Definition

Osteoporosis is a disease characterized by a decrease in bone mass and a deterioration in the architecture of the bones, which leads to an enhanced fragility of the skeleton and, therefore, to a greater risk of fracture. A study group of the World Health Organization (WHO) has quantified this definition in women. Thus, osteoporosis is defined as being present when the bone mineral density (BMD) or bone mineral content (BMC) is over 2.5 standard deviations below the young adult reference mean ( - 2 . 5 T-scores). If fractures are present, the condition is called severe osteoporosis. This defined threshold has been validated particularly by measurements of BMD and BMC at the hip. Fig. 3.5-1 Definition of osteoporosis. Bone mineral density (BMD) is given as standard deviations (SD) below the peak bone mass.

Definition of osteoporosi s BMD 1 SD

/

Normal

-

,

]~ -

T

-2.5 SD

Osteoporosis is defined as present in women when the bone mass is more than 2.5 standard deviations below that of the young female adult.

3.5.2.

Epidemiology

Osteoporosis is a very common disorder which will become even more common with the increase in life expectancy. The incidence is much higher in women than in men, and higher in whites and Asians than in blacks. It is estimated that close to 1 woman out of two who have reached the age of 50 will sustain an osteoporotic fracture during their remaining life. In recent years it has been realized that osteoporosis is not as rare as previously thought in men. Accordingly, one-third of all hip fractures occur in

123

3. Bisphosphonates~clinical men, and at the age of 60 the fracture risk in men is nearly one-half that of women. This disease is therefore, because of its medical and socioeconomic impact on our society, a major public health issue both in women and in men. This will become even more so in the future because of the rapid increase of the elderly population. Development of preventive and curative treatment will thus be a main concern in the future.

Osteoporosis is a very common condition, especially in w o m e n .

3.5.3.

Pathophysiology

During their lifetime, women lose on the average 3 0 - 4 0 % of their maximum (peak) bone mass, men about 2 0 - 3 0 % . The decrease in bone mass affects both cancellous and cortical bone, the former to a greater extent in the early stages of bone loss. It has been estimated that women lose about 50% of their cancellous bone and 30% of their cortical bone. In women after menopause, the trabeculae become thinner, discontinuous, and can eventually disappear, thus leading to a deterioration of the macroarchitectural spacial design of the bones. The cortex, however, also becomes thinner and can show increased porosity. The overall chemical composition of the bone, and therefore the mechanical quality of the bone tissue, is not altered, in contrast to osteomalacia, a disease typified by a defect of mineralization. In older people who are often vitamin D deficient, both osteoporosis and osteomalacia may be present together, which explains, at least in part, why certain patients often respond very well to vitamin D and its derivatives when BMD is measured. Fig. 3.5-2 The difference between osteoporosis and osteomalacia.

Osteoporosis vs. osteomalacia

~

Normal bone Bone amount

% Mineral

Normal Normal

i

~

~

~.

Osteoporosis Osteomalacia Decreased Normal

Normal Decreased

Osteoporosis is characterized by a loss o]: cancellous and cortical bone.

124

3.5. Osteoporosis The loss of bone has two distinct patterns. One is a continuous agerelated linear decline in bone mass occurring in both women and men of about 0 . 5 - 1 % a year. The age at which this loss starts is still disputed, but it is generally recognized that it is around age 50. Some believe that it can occur earlier, at least at some cancellous bone sites. In women, there is a second pattern of more rapid bone loss of variable intensity after the menopause. This menopausal loss occurs at a at a rate of a few percent a year. It is of variable duration, 5 - 8 years, due to the decrease in estrogen production. In men androgen as well as estrogen deficiency may play a similar role in inducing bone loss, but syndromes of acute androgen deficiency are uncommon in the male. After a certain time, bone mass will have reached a value where the structure becomes fragile and fractures occur. Since this takes place sooner in women than in men, the former will also develop fractures earlier in life. Fig. 3.5-3 Evolution of bone mass with age.

Evolution of bone mass with age Male

Fracture risk

o~

r = 0

I"

I

!

20

I

40 60 Age (years)

I

80

......... i

100

The main cause of osteoporosis is the continuous loss of bone during life, which is exacerbated in women after the menopause. A second predisposing factor for osteoporosis, in some patients, is a failure to achieve optimal peak bone mass during adolescence. Maximum bone mass, is attained around the end of the second decade, later for certain parts of the skeleton. Women achieve less total bone mass than men. This is in part due to a difference in bone size. However, actual bone density as assessed by DXA is not necessarily less than in men. Peak bone mass is determined to some extent by heredity, through various genes the relative role of which is still unknown, and to some extent by other factors such as nutrition. Calcium intake during youth may play a role in some children who are given a calcium deficient diet or have malnutrition, giving a rationale, at least in these, for the administration of calcium during

125

3. Bisphosphonates--clinical growth. Since people with a smaller peak bone mass have less bone to start with, they will reach a point of high risk of fracture earlier in the course of eventual bone loss. Fig. 3.5-4 Mechanisms leading to osteoporosis.

Causes of osteoporosis 9Increase bone loss 9Too little peak bone mass

The second contributory factor in the development of osteoporosis is failure to achieve peak bone mass during adolescence. Thus, osteoporosis can be due to increased bone loss, too little bone built during adolescence, or both. Women are more prone to osteoporosis, because of the rapid loss after the menopause. A distinction used to be made, although this is somewhat artificial, between postmenopausal osteoporosis and senile (age-related) osteoporosis. The former is seen, as its name implies, after the menopause and involves mainly cancellous bone. In contrast the latter, encountered after the age of 70, involves both cancellous and cortical bone. Sometimes osteoporosis is the consequence of other diseases, such as endogenous or exogenous hypercortisolism, hypogonadism, liver diseases, malignant dis- ~eases, and immobilization. It is then called secondary osteoporosis.

One can distinguish between postmenopausal and senile (agerelated) osteoporosis, and osteoporosis secondary to other diseases.

Calcium homeostasis pp. 17-19 Calcium supplement p. 132

The mechanisms leading to the loss of bone are still not well understood. It is clear that in women after menopause, the increased loss is due to elevated bone resorption following the loss of estrogens, possibly mediated, at least in part, by an increase in bone resorbing cytokines. However, it is less clear why most people lose bone after a certain age. Various possibilities have been suggested, one of them being a chronic lack of dietary calcium. The amount of calcium which should be ingested at different ages is not yet completely clear, but it is possible that many elderly *" people ingest too little. Furthermore the aged can also develop a vitamin D deficiency due to a lack of solar exposure and a low dietary intake of vitamin D. In addition, a disturbance in the metabolism of vitamin D and of its active metabolite 1,25(OH)2 D as well as of the intestinal receptors of this hormone may be associated with a decrease in intestinal 126

3.5. Osteoporosis calcium absorption. The decrease in gastrointestinal calcium absorption then induces a secondary hyperparathyroidism and increased bone resorption. It has also been suggested that in men the reduced testosterone production is important, possibly through a concomitant decrease in estrogen produced by aromatization of testosterone. The loss might be related to the general atrophy with age, in particular of muscle mass, which is then accompanied by a decrease of mechanical forces on the skeleton. Lastly, the mechanostat itself may be disturbed.

Bone biomechani~ pp. 19-20

While the cause of osteoporosis in postmenopausal women is lack of estrogens, in men it is less clear. Possibly reduced testosterone production is involved. Other causes of bone loss in the elderly are still unknown. Possibilities are too little calcium in the diet, reduced vitamin D, and less mechanical loading of the skeleton. At the cellular level a discrepancy between bone resorption and formation occurs, the mechanism of which is still unknown. There is a negative balance in each individual element of bone turned over, the BMU, less bone being formed than has been destroyed. The cause of this imbalance can either be an increase in the amount of bone resorbed, or a decrease in the amount formed, or both, as seems to be the case in the elderly. In addition to this imbalance between formation and resorption at the BMU level, estrogen deficiency at the menopause also induces an increase in the formation of new BMUs, thus of remodeling, which amplifies the total amount of bone lost. In contrast to what was thought previously, an increase in bone remodeling occurs in the elderly women. These mechanisms explain why an inhibition of turnover will reduce bone loss and will be beneficial in osteoporotic women regardless of their age. Fig. 3.5-5 Mechanismsof bone loss at the microscopic level of the BMU.

Causes of bone loss

No loss

Loss T Resorption

Loss f Formation

The negative bone balance within the individual basic multicellular unit (BMU) is their structural basis of bone loss. This is why an increase in bone remodeling and therefore turnover, as seen after the menopause or in the elderly, is accompanied by an increase in total bone loss, and why inhibitors of turnover reduce this loss. 127

BMU p. 13

3. Bisphosphonates~clinical 3.5.4.

Clinical manifestations

Signs and symptoms The clinical manifestations of osteoporosis are fractures and their consequences. The fractures occur often spontaneously or after minimal trauma. Their location differs somewhat with age. In the postmenopausal form, the forearm is a common site, following a fall on the outstretched hand. Later in life, they occur mostly in the vertebrae, leading to a decrease in height and to forward bending of the spine. This can give rise to pain. In the age-related form, hip fractures become increasingly important, both in women and in men, and carry significant morbidity and mortality. ~,:e~,,-*~.,~~.'*~,........~:~.............. -~: "i......." ~"~' ofFig'the3"5-6threetypicalOCcurrence osteoporotic fractures. Type.o! fract~e ......... [adapted from the slide Colles' Vertebral Hip kit of the Health Council on Osteoporosis. ReproTypical age (years) >55 >65 >75 duced with permission 4:1 3:1 2:1 of the author and the Women: Men publisher.] Predominent bone Trabecular Trabecular Cortical

Although reduced bone mass and macroarchitectural deterioration are main causes of fracture, other factors like a higher propensity to fall and a decreased capacity to handle falls adequately, contribute to their occurrence. The typical symptom of vertebral osteoporosis is pain, mostly in the back, due to crush fractures. It has, however, to be remembered that microfractures are usually not accompanied by any acute symptoms, and will only induce a progressive shortening and bending which can induce chronic back pain only later.

The consequence of osteoporosis is fractures. They occur first in the forearm and the spine, later in life in the hip. In the spine, crush fractures can induce pain either acutely or only later, as well as shortening and bending. Laboratory Osteoporosis is now diagnosed readily. Besides plain X-rays to detect fractures, techniques such as single energy absorptiometry (SXA), quantitative computed tomography (QCT), and the most widely used dual X-ray absorptiometry (DXA) allow accurate quantification of bone mass. The sites measured are the vertebrae, the forearm, and the hip. However, it 128

3.5. Osteoporosis has to be kept in mind that these techniques all assess the amount of mineral present, which can, but does not necessarily reflect the amount of bone, as the measurement is influenced by the degree of mineralization of the latter. Peripheral devices using SXA, DXA, QCT, and ultrasound are also used widely throughout the world to measure sites such as the finger and heel.

Mineralization and turnover pp. 15-16

Osteoporosis is diagnosed and assessed quantitatively by techniques that measure bone mineral density, most commonly dual X-ray absorptiometry (DXA). Chemical measurements are not used to establish the diagnosis of osteoporosis per se. This is especially the case for serum calcium and phosphate and for markers of bone formation and resorption. The latter are, however, of use to investigate whether the patient is in a phase of rapid turnover and therefore likely to lose bone. But these markers cannot be used to assess precisely the amount of the imbalance between formation and resorption in the individual patient. Furthermore an elevation of alkaline phosphatase may also indicate the presence of osteomalacia, which is frequently associated with osteoporosis, especially in the old. It may also indicate the presence of a recent fracture. Markers of bone turnover are also most useful to assess response to treatment.

Assessment of bone turnover p. 21

Chemical analyses cannot be used to diagnose osteoporosis. Bone markers, however, are useful to determine bone turnover and consequently to identify those patients who are likely to be losing bone rapidly and thus at risk for osteoporosis. Diagnosis The diagnosis of osteoporosis is made by the quantitative measurement of bone mineral density (DXA). Fractures detected by X-rays indicate severe osteoporosis. Biochemical markers of turnover may be useful for the prediction of further bone loss.

Follow-up of progression of the disease The parameter usually followed in the individual patient is bone mineral density, using a central monitoring device. Since bone mass changes relatively slowly, measurements may not reveal significant changes before 2 years. Today therapy is often monitored with biochemical indices of bone turnover. For bone resorption, collagen pyridinium cross-links, today preferably their N- or C-terminal telopeptides, while for bone formation, serum bone specific alkaline phosphatase or osteocalcin are usually 129

Bone mineral density p. 128

Assessment of bone turnover p. 21

3. Bisphosphonatesnclinical used. Indeed they give a good indication of whether an antiresorbing drug is efficacious. In the literature it has often been forgotten that many patients, especially the old, also have some degree of osteomalacia. An improvement in bone mineral density may therefore be due to the healing of the osteomalacic component, especially when vitamin D is administered together with another treatment. Furthermore, the decrease of bone turnover itself, as obtained by most of the drugs used today for the treatment and prevention of osteoporosis, will prolong the life of the bone structural units and hence their mineralization. Lastly, BMD may also be confounded by the development of osteoarthritic changes and ectopic calcifications, particularly with spine measurements using DXA.

to their bone mineral ~ i t y , and the chemical parameters of bone turnover. The f o ~ e r r e ~ c t s , hOwever, tbe evoluaon not only o f bone mass but also ofmineralizafion. It will tberefore also imonitor healing of an osteoma~cic componentand be increased by the inhibition of bone reso~tion, ~en when no effect on bone mass is obtained.

3.5.5.

Treatment with drugs other than bisphosphonates

In general, treatments can be divided into two categories, namely those aimed at inhibiting bone loss, and those aimed at increasing bone mass.

,~ Preventive ~

,

Fracturelimit

Fig. 3.5-7 Preventiveand curative treatment of osteoporosis.

/ Curative

Treatment of osteoporosis can be both preventive and curative. Some treatments are available that inhibit bone destruction and therefore prevent bone loss. The most widely used is estrogen replacement after the menopause. This treatment is very effective in inhibiting bone loss and even leads to some increase in bone density. Moreover, some epidemiological studies indicate that it may reduce the occurrence of fractures of the wrist, hip, and spine when taken for 6 - 1 0 years. The effect on bone 130

3.5. Osteoporosis stops after discontinuation of the treatment, with resorption increasing again rapidly. Thus, long-term therapy is necessary. Many women, however, refuse this therapy for various reasons, not the least being the fear of a possible slight increase in the frequency of breast cancer after long-term treatment. Compliance is most often poor. The majority of women who began estrogen replacement therapy have discontinued it after 3 years. The increased risk of endometrial carcinoma can be greatly reduced by the concurrent administration of a progestagen. Estrogens may also reduce the risk of cardiovascular disease, which otherwise rises after the menopause, although a recent secondary prevention study (HERS, or The Heart and Estrogen/Progestin Replacement Study) was negative, and other prospective controlled studies are lacking. Most women take estrogens to relieve menopausal symptoms, such as hot flushes, nights sweats, and urogenital symptoms, resulting in improved quality of life. Fig. 3.5-8 Effectof estrogen and gestagen on bone loss. [Adapted from Christiansen, C., et al. (1981). Reproduced with permission from the author and the publisher.]

Effect of estrogen on bone loss 9= Placebo

o- Estrogen/gestagen

104 ~a 102

{d3 +I

0

100

ID

!9 98,

~-~ 96' 94'

0

6

12

18 24 Months

30

36

The most often used preventive treatment of osteoporosis in women at risk after the menopause is estrogen. Recently tibolone, a drug which associates the effect of estrogen, progestagen, and of an anabolic agent, has been made available. The results look promising. 131

3. Bisphosphonates--clinical

Dietary calcium p. 126

A therapeutic area of great promise is development of selective estrogen receptor modulators (SERMs). These compounds are partial estrogen agonists and partial estrogen antagonists. Raloxifene, for example, has been shown to prevent bone loss and to reduce the incidence of vertebral fractures. Very recently the incidence of newly diagnosed breast cancer was found to be decreased by 76%, largely due to a 90% decrease in estrogen-receptor-positive invasive breast cancers. Another drug that inhibits bone resorption and decreases bone loss, and in some conditions fractures, is calcitonin. However, parenteral administration has sometimes unpleasant side effects. Nasal calcitonin is well tolerated but is relatively weak in its effect on BMD and fracture incidence. Last, osteoprotegerin is a very new inhibitor of resorption and is in early clinical trials. Calcium can also decrease bone turnover and diminish bone loss in certain conditions. A daily intake of 1-1.5 g is recommended in the adult, especially during lactation and in the elderly. Vitamin D should be present in sufficient amounts. Administration of 1.2 g of calcium and 800 units of vitamin D to elderly institutionalized women decreased the rate of hip and other nonvertebral fractures. How much of this improvement was due to the presence of osteomalacia is not known. Other trials have shown similar results. Calcium and physiological doses of vitamin D, such as 4 0 0 800 units, are therefore recommended in the elderly. Calcium supplementation of at least 500 mg daily is a standard procedure when either an inhibitor of bone resorption or a stimulator of formation is used in the therapy of osteoporosis. Also, derivatives of vitamin D can decrease bone loss and fracture rate in certain patients, most studies having been made on Asian women. However, the benefit over vitamin D is still controversial.

In elderly people, calcium together with vitamin D, especially if they are vitamin D deficient, reduces the fracture rate and should be generally recommended. Today only very few compounds are able to increase bone formation, namely fluoride and PTH. Fluoride administered as sodium fluoride or monofluorophosphate increases cancellous bone, the effect on the cortex being less clear. The earlier regimen of 75 mg of sodium fluoride per day, equal to 34 mg of fluoride ion, gave rise to adverse events, such as bone pain due to microfractures, and gastrointestinal disturbances. Therefore, lower doses of 15-25 mg fluoride ion daily, if possible administered in a slow-release form, are used today. So far it has, however, not been demonstrated that this treatment decreases the occurrence of fractures. PTH looks very promising, as it induces large amounts of spinal cancellous bone in women, receiving estrogen or not. It is currently under clinical investigation. 132

3.5. Osteoporosis Only fluoride and PTH are able to increase bone formation. The effect ol:fluoride on l:ractures is doubtful, and the safety margin of: this drug is relatively narrow. PTH looks promising.

3.5.6.

Treatment with bisphosphonates

Preclinical studies -+ M a n y animal experiments support the use of bisphosphonates in humans. As described earlier, in normal growing rats these compounds decrease bone resorption and increase calcium balance and the mineral content of bone. Besides actually increasing bone mass in normal growing animals, the bisphosphonates are also effective in preventing bone loss in a number of experimental osteoporosis models. The first used was immobilization by sciatic nerve section in the rat. Fig. 3.5-9 Effect of 10 mg phosphorus/kg of clodronate subcutaneously on the bone loss induced by sciatic nerve section in the rat. [Data from Miihlbauer, R. C., et al. (1971).]

Experimental osteoporosis Control

Clodronate

~" 70+I

60Femurs

o ..~ 509~

~

_

40 R Immobilized I-1 Nonimmobilized

Later, similar results were obtained in a number of osteoporosis models not only in the rat, but also in the mouse, rabbit, dog, and monkey. Fig. 3.5-10 Osteoporosis models improved by bisphosphonates.

Osteoporosis models ~ Sciatic nerve section ~ Paraplegia ~ Hypokinesia ~ Ovariectomy ~ Orchidectomy

133

9Heparin ~ Thyroid hormones ~ Corticosteroids ~ Low calcium

Rat studies pp. 36-41

3. Bisphosphonates--clinical

Chemical structures pp. 31-32

Practically all the bisphosphonates tested, such as, in order of increasing potency in animals, etidronate, tiludronate, clodronate, pamidronate, olpadronate, incadronate, alendronate, risedronate, ibandronate, minodronate, and zoledronate have been effective. In the case of etidronate, the effect was blurred when higher doses were used which inhibited mineralization. In the ovariectomized rat the preventive effect was maintained for a long period after discontinuation of the drug. Recently an interesting new model has been developed to mimic osteolysis and aseptic loosening around total hip arthroplasty. Also in this model alendronate inhibited the bone destruction.

Bisphosphonates prevent bone loss in practically all the experimental osteoporosis models.

Chemical structures pp. 31-32

The question of the effect of the bisphosphonates on the mechanical properties of the skeleton has been addressed only recently. This issue is of importance, since it is known that a long-lasting, extreme inhibition of bone resorption can lead to increased bone fragility, the human osteopetrosis described by Albers-Sch6nberg being a good illustration. It appears that, when not given in excess, bisphosphonates have a positive effect on mechanical characteristics both in normal animals and in various experimental osteoporosis models. The bisphosphonates that proved to be active include alendronate, clodronate, etidronate (although at high doses the opposite effect was induced, probably because of an inhibition of mineralization), ibandronate, incadronate, minodronate, neridronate, olpadronate, pamidronate, risedronate, and tiludronate.

Effect of alendronate on mechanical strength and mineral density 30 t"3

r 25-e-

=~ 2 0 -

~ 15-

o ....,

5

"

0.9

!

'

I

I

..... I"

'

!

I

'"

I

! ....

10 11 12 13 Bone mineral density L2-L4 (g/cm2)

134

Fig. 3.5-11 Effectof alendronate given intravenously every 2 weeks for a period of 2 years to ovariectomized baboons on bone mineral density and mechanical strength. Squares, not ovariectomized; triangles, ovariectomized; circles, ovariectomized + 0.05 mg/kg; diamonds, ovariectomized + 0.25 mg/kg; MPa, megapascal. [Adapted from Balena, R., et al. (1993). Reproduced from J. Clin. Invest., 92, 2577-2586, with copyright permission from the author and the American Society of Clinical Investigation.]

3.5. Osteoporosis The mechanisms leading to the improved mechanical strength are still poorly understood. They may not be caused uniquely, as previously thought, by a higher bone mass, but also by an improvement in architecture, and probably a reduction in bone remodeling. Indeed, a higher number of bone remodeling sites, in which there is excessive osteoclastic destruction of bone, leads to the development of areas of stress concentration, and hence to increased fracture risk. Bisphosphonates may serve as a means of reducing these effects, hence reducing the incidence of new fractures. Another mechanism may be related to the increase in the mineral density following the lower bone turnover. This increase is due to the longer life span of the osteons, and thus the time available for their mineralization.

The bisphosphonates can improve the mechanical strength of the bones both in normal animals and in those with experimental osteoporosis. The mechanisms of this effect seem to be due to alterations in bone mass, architecture, and quality. The mechanism of action of the bisphosphonates in osteoporosis is still not completely understood. The prevention of bone loss is probably explained to a large extent by the decrease in bone turnover which slows down bone loss. This decrease also diminishes the fracture rate, since fewer trabeculae are destroyed. In addition the bisphosphonates may also act at the individual BMU. Indeed it has been shown that they decrease the depth of the resorption site, may possibly increase the amount of bone formed, and may increase the bone balance in the BMU. Fig. 3.5-12 Possible effect of bisphosphonates at the level of the individual BMU.

Effect at B M U level ca

Bone resorption

o

"~ .......

r

ca

.,,

Loss of bone

No inhibition

Bone formation

~

N ~

l•r _

~

4

@ Low _Ne

.

No loss of bone

Inhibition

r

.

.

.

.

Stronger inhibition .

.

.

135

.

~

Gain of bone

i/

Low

Low

Mechanisms of bone loss p. 127

3. Bisphosphonates--clinical

Coupling p. 15

BMU p. 13

Effect on formation in vitro p. 50

The actual increase in bone density probably has various causes. One explanation of the initially occurring increase is that the decrease in bone resorption is followed only later by the "coupling-induced" diminution in formation, which brings an initial gain in calcium and bone balance through the reduction of the so-called remodeling space. Another explanation is that a lower turnover will lengthen the life span of the BMU, thus permitting it to mineralize more completely. This has been described in alendronate treated baboons, and on iliac crest biopsies from osteoporotic women after alendronate treatment. The third explanation could be that by decreasing resorption more than formation at the individual BMU level, the bisphosphonates increase bone balance at this site. Whether this occurs is under discussion. Although the morphological data mentioned above speak in favor of this possibility, and an increase in bone mineral density is seen with alendronate for up to seven years, no increase of the trabecular bone has recently been reported. Finally, it has been suggested that bisphosphonates may to some extent increase bone formation in vitro and in vivo in the animal. This hypothesis still needs confirmation.

Bisphosphonates act in osteoporosis by decreasing turnover and therefore bone loss and by increasing the degree of mineralization of bone. Whether they induce an increase in bone mass is possible but not yet proved in humans. Of clinical importance is the recent finding that treatments which increase bone formation, such as prostaglandin, IGF-1, and PTH, are still effective in rats given bisphosphonates, resulting in an additive effect of the two treatments. When given with or after a course of PTH, the bisphosphonates prevent the PTH-induced bone loss that would otherwise occur. The additive effect of stimulators of bone formation and inhibitors of bone destruction opens an interesting possibility for future therapy.

The administration of both a stimulator of bone formation and an inhibitor of bone destruction is an interesting future therapeutic possibility. Clinical studies Effects While there have been quite a number of studies in the past using bisphosphonates in patients with osteoporosis, there were until recently only few that were adequately controlled. The many uncontrolled studies sug-

136

3.5. Osteoporosis gested, however, that various bisphosphonates would not only stop the loss of bone in postmenopausal osteoporosis and other types of the disease, but would actually induce a small increase in bone mineral density.

A series of studies, although inadequately controlled, suggested in the past that various bisphosphonates not only slow clown or stop bone loss, but can actually induce an increase in bone mineral density. The first controlled study (in the 1970s)was performed on calcium balance with etidronate at an oral dose of 20 mg/kg daily for 6 months in senile osteoporosis. The results were not very encouraging, since bone resorption and formation decreased approximately to the same extent, so that the effect on calcium balance was only small. However, at the above dose and regimen an inhibition of mineralization was likely to have occurred. More recently many well-performed controlled studies proved indeed the efficacy of bisphosphonates in decreasing bone turnover, preventing skeletal loss, and sometimes even increasing skeletal calcium. The parameters most frequently measured are bone mineral density (BMD) and bone turnover. However, as mentioned above, the measurement of BMD is not necessarily a true reflexion of actual bone mass, as it is influenced not only by the amount of bone, but also by the degree of mineralization of the bone present. This is explained by the fact that the induced decrease of turnover rate allows bone more time to complete its secondary mineralization. This applies equally to other antiresorptive drugs, such as estrogen.

The parameter most frequently measured to assess the effect o]: a drug in osteoporosis is bone mineral density (BMD), which reflects both bone mass and its mineral content. Effect on bone mineral density The two first well-controlled double-blind studies were performed with -* etidronate. In postmenopausal women discontinuous oral administration of etidronate for 2 weeks was followed by either 10 or 13 weeks of 500 mg daily calcium alone. The cycle was repeated over a period of 3 years. Some patients have been treated for 7 years or more. Both studies showed a significant increase in vertebral bone mineral density, in contrast to a loss in the controls in one study, and no change in the other. Some increase in mineral was still observed after 5 to 7 years of treatment. Increases were also obtained in the hip, especially in the trochanter.

137

Inhibition o mineralizati pp. 171-17

Causes of increase in BMD p. 16

3. Bisphosphonatesmclinical

Etidronate in osteoporosis ~D

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Etidronate administered orally to w o m e n induced a significant increase in bone mineral density for up to 7 years Similar results on bone mineral density were also f o u n d with clodronate given 1 m o n t h out of 3 for 1 year. In a n o t h e r study c l o d r o n a t e was f o u n d to increase bone mineral density for as long as 4 and 6 years.

Clodronate in osteoporosis Placebo - ~ - Clodronate - - o - C l o d r o n a t e +1,25-(OH)2 D3

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Fig. 3.5-14 Effect of clodronate administered at 400 mg/day for 30 days every 3 months in postmenopausal women. [-1 clodronate; o 2 gg/day 1,25(OH)2 vitamin D 3 for 5 days and clodronate for 25 days; A placebo. [Adapted from Giannini, S., et al. (1993). Reproduced from Bone, 14, 137-141, with copyright permission from the author and Elsevier Science.]

P a m i d r o n a t e given orally for 2 years at 150 mg daily or intravenously once every 3 m o n t h s at 30 mg also increased bone density. The latter result is of interest as it opens the possibility of a regimen w h i c h might be attractive to some patients.

138

3.5. Osteoporosis

Clodronate and pamidronate also not only prevent the decrease in bone mass in postmenopausal osteoporosis, but actually induce a small increase in bone mineral density. Both continuous oral administration and discontinuous oral or parenteral administration are effective. The most extensive studies reported so far have been conducted with alendronate. In the first study the c o m p o u n d was given intravenously every 3 months. In two other studies, both multicenter, randomized, and placebo controlled, the drug was administered orally at 5, 10, 20, and 40 mg for 2 years. All studies have shown an increase in bone density both in the vertebrae and in the hip, compared with a reduction or no change in the controls. Since 10 mg were more active than 5 rag, but not less active than 20 rag, 10 mg appears to be the most favorable dose. Two subsequent 3-year studies were performed on 994 w o m e n between 45 and 80 years of age suffering from osteoporosis, defined as a BMD of the lumbar spine at least 2.5 SD below the mean premenopausal level. Patients were given daily either 5 or 10 mg of alendronate orally for 3 years, or 20 mg for 2 years, followed by 5 mg for 1 year. The results with 10 mg showed a significant increase in bone mineral density versus placebo of about 8.8% in the lumbar spine, 5.9% in the femoral neck, and 7.8% in the trochanter. The patients who received a placebo lost on the average about 1% over the 3 years. A subset of these w o m e n have now been followed through seven years with progressive increases in BMD. Similar resuits were obtained in a series of other studies. --* Fig. 3.5-15 Effect of 10 mg of alendronate given daily per os for 3 years on bone mineral density in patients with postmenopausal osteoporosis. [Adapted from Liberman, U. A., et al., N. Engl. J. Med. (1995), 333, 1437-1443, Copyright @ 1995 Massachusetts Medical Society. All rights reserved.]

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3. Bisphosphonatesmclinical Alendronate administered orally at 10 mg per day/or 3 years induced an average 7% increase of bone mineral density in the spine and the hip, compared to the value in controls, who lost about 1%.

Ibandronate has also been found to increase bone mineral density in the lumbar spine and the hip instead of the usual loss in placebo patients. This compound is active both when given orally at 0 . 5 - 5 mg daily, as well as when given discontinuously in intravenous injections of 0 . 2 5 - 2 . 0 mg, once every 3 months.

Ibandronate in postmenopausal osteoporotic women

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Ibandronate increases bone mass in postmenopausal osteoporotic women, both when given orally daily, and in intravenous injections every 3 months.

Recently, in two large placebo-controlled multicenter studies, oral administration of 5mg of risedronate daily, given continuously for 3 years to osteoporotic patients with vertebral fractures, also produced a significant increase in bone mineral density. Differences from controls ranged from 4.3 to 5.8% in the lumbar spine, 4.0 to 6.4% in the trochanter, and 2.8 to 3.1% in the femoral neck. Risedronate is also able to prevent bone loss in patients with artificial menopause.

140

3.5. Osteoporosis Fig. 3.5-17 Effect of 5 mg daily of risedronate, administered orally to women with osteoporosis for 3 years, on BMD of the lumbar spine. * p<0.05 versus baseline. ^ p<0.05 versus control.

Risedronate in osteoporosis 6-

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Risedronate also increases BMD in osteoporotic women. Bisphosphonates are active in Caucasian, Asian, as well as in black osteoporotic women. Alendronate and etidronate are effective not only in postmenopausal women, but also in the elderly. Thus a positive effect on BMD has been shown in 70 to 80-year-old women, the lumbar BMD increasing about 6% in the lumbar spine with 5 mg of alendronate. This is not surprising in view of the fact that bone turnover increases again in old age.

Bisphosphonates are effective in Caucasian, Asian, as well as in black osteoporotic women. Furthermore they are effective in the elderly. Clodronate prevents bone loss due to chemical castration or to antiestrogen therapy in patients with breast cancer. Clodronate and pamidronate decrease bone loss in paraplegia. Recently various studies were performed on patients undergoing glucocorticoid therapy. They showed that alendronate, clodronate, etidronate, pamidronate, and risedronate all induced either no change or an increase in bone mineral density of the spine and the hip rather than the decrease observed in the placebo patients.

Bisphosphonates prevent and partially even reverse the bone loss in glucocorticoid-treated patients. Recently two studies showed that bisphosphonates prevent the bone loss occurring after cardiac transplantation in patients receiving corticosteroids and cyclosporine. Thus, pamidronate given intravenously either directly after operation or 18 months later, at an intravenous dose of 60 mg every 3 months, increased bone mineral density, in contrast to the usually occurring bone loss. 141

Turnover in elderly p. 127

3. Bisphosphonatesmclinical Bisphosphonates prevent bone loss after cardiac transplants. The question arose whether bisphosphonates might be useful also in preventing bone loss in healthy women. This has been shown to be the case. Thus a study involving 1609 healthy postmenopausal women aged 4 5 - 5 9 years, showed that alendronate, administered orally at 2.5 or 5 mg daily, not only prevented bone loss, but again induced an increase in the bone mineral density of the spine, hip, and total body. Five milligrams was more effective than 2.5 mg, but slightly less effective than hormone replacement therapy with estrogen and progestin. In another study 10 mg was somewhat more active than 5 rag. Positive results were also obtained with clodronate, etidronate, tiludronate, and risedronate.

Bisphosphonates also prevent bone loss in normal postmenopausal women, and can therefore be o]: use not only in the treatment but also in the prevention of osteoporosis. Osteoporosis in men p. 123

In recent years more attention has been devoted to male osteoporosis, a disease which has been largely under-diagnosed and inadequately studied in the past. This is of concern because osteoporosis is frequent and has a marked degree of morbidity and mortality also in men. Two studies of adequate size have now shown that bisphosphonates increase BMD also in men. In the first study performed on 241 patients with a mean age of 63 years, oral administration of 10 mg of alendronate daily for 2 years significantly increased BMD at the lumbar spine and at the hip. Treatment also resulted in a significant reduction of height loss. There was also a significant reduction in morphometric vertebral and a trend toward a decrease of nonvertebral fractures. Alendronate was well tolerated. M e n d r o n a t e in male o s t e o p o r o s i s "

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Fig. 3.5-18 Effectof 10 mg daily of alendronate for 2 years in osteoporotic males on BMD of the lumbar spine and the hip. Alendronate, n - 146; placebo, n--95. [Data from Orwoll, E., et al. (1999). J. Bone Miner. Res., 14, Suppl. 1,184.1

3.5. Osteoporosis In the second study, performed on 122 males with osteoporosis with or without fractures, alendronate administered at 10 mg daily for 12 months was compared to 1 tig daily of alfacalcidol. Alendronate induced an increase of BMD of the lumbar spine of 7.7%, compared to 0.9% for alfacaicidol. The effects on the femoral neck were 3.2% versus 1.5%. Both differences were highly significant. Furthermore there was a trend toward a decrease in vertebral and nonvertebral fractures in the alendronate group.

Alendronate increases BMD also in men. Effect on bone turnover All the bisphosphonates induce a marked decrease in bone turnover when given in doses effective on bone mineral density. This is seen both by the biochemical markers and by morphological evaluation. Both bone formation and resorption are decreased. The extent of the decrease is dependent on the dose and the marker used. The most pronounced and earliest effect is seen with markers of bone resorption, especially the collagen type I cross-linked telopeptides which can decrease by more than 80%. The decrease seen within 1 or 6 months is a good prediction for the later effect on bone mineral density. It is interesting that in analogy to what has been seen in rats and baboons, the inhibitory effect on bone destruction reaches a plateau even if the administration is continued, and that this plateau depends on the dose administered. With appropriate dosage, premenopausal levels of turnover can be reached. Furthermore the inhibition of resorption disappears when the drug is discontinued. These results suggest that the bisphosphonate buried in the bone is inactive, and that there is no danger of a progressive decrease of bone turnover with an increase in bone fragility (Fig. 3.5-19).

Effects in ra p. 59

The inhibition of bone resorption reaches a plateau which is dependent on the dosage, even if the administration is continued. Histomorphometric investigations showed that at the level of the BMU, bisphosphonates given at the clinical doses recommended to osteoporotic patients, induced a decrease in bone turnover, which was more marked with alendronate than with etidronate, a decrease in the depth of the resorptive cavities, and no change in the amount of new bone formed and in the trabecular volume. These results can explain the decrease in the loss of BMD, but only partially the increase of the latter, which is probably due to the decrease in turnover and the subsequent increase in remodeling space and mineralization.

143

BMU pp. 13, 15

Causes of increase in BMD pp. 15-16

3. Bisphosphonates~clinical

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Effect on fractures Etidronate study p. 137

The question of whether bisphosphonates will also decrease fracture incidence has been definitively established over the past few years. Some decrease in vertebral fractures was found earlier in the above mentioned etidronate study, but significance was obtained only on patients with lower bone density chosen during the analysis of the data. Other studies with etidronate show a trend to a reduction of fractures but have been performed on too few patients to give significant results. A recent epidemiological study also shows a similar effect. To establish that etidronate decreases significantly fracture risk, which is probable, a new study on a large scale would be necessary (Fig. 3.5-20).

TheeffeciofetidronateonfractureratewasassessedonsmaUstud..... ies and is nbr pet Clear. Itneeds furtberinvestigaaon~

Alendronate on BMD p. 139

More recently it was reported in the above-mentioned study on alendronate on 994 women that, when the various groups were pooled, the daily administration of alendronate led to a decrease of 489'0 in vertebral fractures. This was accompanied by an improvement of the spine deformity index, and a decrease in the loss of height. These results were confirmed in another study on 2027 women between 144

3.5. Osteoporosis Fig. 3.5-20 Effect of etidronate administered for 2 weeks every 3 months for 3 years on vertebral fractures. In the left panel all patients were included, while in the right only those with a low bone mineral density at the start were analyzed. [Adapted from Harris, S. T., et al. (1993). Reproduced from J. Med., 95,557567, with permission from the author and publisher.]

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the ages of 55 and 81, with low bone mineral density and with at least one vertebral fracture. The oral administration of 5 mg daily for 2 years followed by approximately 1 year at 10 mg reduced the risk of vertebral fractures by 47% and the risk of sustaining more than one fracture by 89%. Furthermore, both hip and wrist fractures were significantly decreased by 51 and 44 %, respectively. The incidence of any clinical (symptomatic)fracture was reduced by 28%, and that of multiple new clinical fractures by 48 %. The effect was independent of age, initial bone mineral density, a n d the n u m b e r of pre-existing fractures. The patients w h o h a d an increase of B M D above 3 % in the first year of t r e a t m e n t , h a d a lower incidence of n e w vertebral fractures during the w h o l e study. A decrease in n o n v e r t e b r a l fractures of 4 7 % was also f o u n d in a n o t h e r study on 1908 patients. Fig. 3.5-21 Effect of the daily oral administration of either 5 or 10 mg for 3 years or 20 mg for 2 years, followed by 5 mg for 1 year of alendronate (all data pooled) on new vertebral fractures in postmenopausal osteoporotic women with or without fractures. [Data from Liberman et al., (1995).]

Placebo [--] Alendronate

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Alendronate given orally for 3 years decreases significantly by about one-half the occurrence of vertebral and nonvertebral fractures in patients with low bone mineral density and at least one fracture. In a further study on 4432 w o m e n with a bone mineral density below - 1 . 6 SD, but without a fracture, the treatment mentioned previously with alendronate over 4 years reduced significantly radiographic vertebral fractures by 44 %, as well as height loss, but induced only a trend towards a reduction in clinical fractures. However, if the w o m e n with a T-score below - 2 . 5 were analyzed, the risk of clinical fractures significantly decreased by 3 6 % , nonvertebral fractures by 3 5 % , and hip fractures by 56%. Thus, the effect of the bisphosphonate was dependent upon the severity of the initial osteoporosis. In an additional study on 1908 postmenopausal w o m e n at 153 centers with a T-score of the lumbar spine lower than - 2 SD, 10 mg of alendronate daily for one year also decreased significantly the risk of nonvertebral fractures by 4 7 % .

In patients without any fracture the results were similar for new vertebral fractures but significant/:or nonvertebral fractures only when initial BMD was low.

146

3.5. Osteoporosis

Very recently, risedronate has been shown to reduce the incidence of vertebral and nonvertebral fractures in osteoporotic women with vertebral fractures based upon two 3-year double-blind, placebo-controlled studies. In the multinational study conducted in Europe and Australia, patients receiving 5 mg therapy daily (n=407) had a reduction in the risk of new vertebral fractures by 49% (p<0.001) and nonvertebral fractures by 33% (p=0.06) compared with placebo (n=407). These data were confirmed in a North American study where risedronate 5 mg (n = 813) significantly reduced vertebral and nonvertebral fractures by 41 and 39%, respectively, compared with placebo (n=815). In both studies, a rapid and significant treatment effect was observed in 1 year with reductions in vertebral fractures of over 60%. Consistent with these data, 1 year of treatment with 5 mg risedronate (n=174) significantly reduced vertebral fractures by 70% compared with patients receiving placebo (n= 170) in patients who initiated, or were on long-term corticosteroid treatment. Results are forthcoming of a large multicenter study involving over 9000 patients to determine the effect of risedronate on reducing hip fractures.

3025-

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Fig. 3.5-23 Effectof daily administration of 5 mg of risedronate for 3 years on 813 patients on new vertebral and nonvertebral fractures. [Data from Harris, S. T., et al. (1999)]. In a recent study risedronate reduced vertebral fractures also in patients given corticosteroids.

Since BMD is a good predictor for future fractures, it has been postulated that the effect of inhibitors of bone resorption on fractures was due

147

3. Bisphosphonates--clinical to the increase in BMD. However, a meta-analysis of 13 trials with various inhibitors showed that despite a good correlation between the effect on fracture incidence and the increase of BMD, the former was at least twice as large as would have been expected from the effect on BMD.

The increase in BMD under treatment with inhibitors o]: bone resorption underestimates the effect on fractures. Effects after discontinuation of the drug There are not many studies examining the consequences of discontinuing bisphosphonate administration. It appears that the results depend on the bisphosphonate administered, the dose, and the length of treatment. In general, bone turnover increases again within 3 months and reaches pretreatment levels within a year. The evidence is less clear for bone mineral density. However, BMD also begins to decline within the first or second year after discontinuation of the drug. It is not yet clear whether this decrease occurs at a slower rate or not than that in placebo patients, but it seems to be slower than after estrogen discontinuation. Nevertheless the difference between treated and placebo patients is maintained, at least for the time (1-2 years) investigated up to now. Nothing is known about fracture incidence after treatment is stopped.

After discontinuation o[ treatment bone turnover returns to pretreatment values within months and bone loss appears to resume again, although later. These results raise the question of how long the treatment should be given. No data are available allowing us to answer this question. However, if one extrapolates from the position taken by clinicians giving estrogens, that the treatment should be given at least for 10 years if the bone is considered, a similar strategy is likely to be valid for bisphosphonates. Whether the treatment can or should be interrupted intermittently, is not known.

Various other effects One clinically very relevant question is whether bisphosphonates given with another bone resorption inhibitor shall have additive effects. This has been shown to be the case with estrogen, at least for alendronate, etidronate, and risedronate, opening the possibility of administering hormonal and bisphosphonate treatment together. Raloxifene and alendronate or risedronate also have an additive effect. 148

3.5. Osteoporosis Bisphosphonates given together with hormone replacement therapy or raloxifene have a greater effect on bone mineral density than either treatment given alone. Another question is whether there might be a possibility to give in the future both a stimulator of bone formation and an inhibitor of bone resorption. This idea is supported by the finding that the anabolic effect of PTH, measured by markers of bone formation, is still present when combined with alendronate therapy.

Stimulators of bone formation p. 136

Bisphosphonates might be given in the future together with a drug stimulating bone formation.

Treatment regimens Alendronate In the first published study 5 mg intravenously every 3 months was used. Later, daily oral doses between 5 and 40 mg were given. All regimens were effective in increasing bone density. An oral dose of 10 mg appears to be the optimal regimen to increase bone mineral density at the various sites. Furthermore it decreases vertebral and nonvertebral fractures and it is the regimen recommended by the manufacturer for treatment of osteoporosis. Five and 10 milligrams have also been used in corticosteroid-induced osteoporosis. In contrast a dose of 5 mg daily is used for the prevention of bone loss in younger patients. The efficacious doses are smaller in postmenopausal Japanese women because of a higher bioavailability, 5 mg being the dose recommended today in this country. In order to maximize absorption and minimize the risk of esophageal adverse effects, the compound is taken on an empty stomach with 180240 ml of water in the morning, and the patient should not recline. No food or beverage (except water) is taken for at least 30 minutes.

For treatment the recommended dose of alendronate is 10 mg orally daily. A dose of S mg is used for prevention. The compound must always be taken with about 200 ml of water and the patient should not recline after ingestion. Weekly dosing has been investigated, aimed at improving patient convenience and compliance. A one-year, double-blind multicenter study has just been reported that compared the efficacy and safety of treatment with once weekly 70 mg alendronate (n=519), twice weekly 35 mg (n-369), and daily the usual 10 mg (n-370) in postmenopausal women with osteoporosis. The increase in bone mineral density in the lumbar spine was over 5 % and similar in all groups. It was also similar in the three groups 149

Adverse events pp. 169-170

3. Bisphosphonates--clinical

in other skeletal sites. Furthermore the decrease in bone turnover a with markers was similar. All treatments were well tolerated, evm upper gastrointestinal tract. Alendronate on B M D

_

o

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ta

2-

m Aen ronate3 mgtwicewe ~ Alendronate 70 mg once we 0

6

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Fig. 3.5-24 fect of thr( regimens c dronate or bone mine sity. [Data Bone, H., I (1999). Ak presented : 6 th Interna Symposiur Clinical D: of Bone & eral Metal November Venice, Ita

12

Months

Alendronate as a similar effect on B M D whether given once we at 70 rag, twice weekly at 3S rag, or daily at 10 rag.

Commercial index pp. 182-206

Commercial index pp. 182-206

Alendronate is commercially available in many countries. Clodronate

The first published controlled study was performed in paraplegi~ daily oral doses of 400 and 1600 mg given continuously somewhat ished the bone loss. More recently 400 mg per day was given or 1 month out of 3 for 1 year. Clodronate has also been administer, success as an infusion of 200 mg every 3 or 4 weeks. In elderly 800 mg daily for 3 years prevented the bone loss occurring in the c{ Lastly, it is effective at 1600 mg and 2400 mg, but not 800 mg, give for 1 year in corticosteroid-induced osteoporosis. To our knowledge, clodronate so far is registered for osteoporo in Italy. The recommended regimen is 400 mg daily orally for 1 every 3 months, or the same dose given continuously. Etidronate

Up to now, the only dosage which has been adequately studied is ir tent cyclical treatment with 400 mg daily orally for 14 days, folio 10 or 13 weeks without drug, during which time all patients rec 150

3.5. Osteoporosis supplement of 500 mg of calcium daily. This regimen increases bone mineral density in postmenopausal and corticosteroid-induced osteoporosis. It might reduce vertebral fractures. So far it is not known whether another regimen would give better results. A higher dosage should, however, not be used, since an inhibition of mineralization may occur. It is also not known whether it might be preferable to interrupt treatment from time to time.

Inhibition of mineralization pp. 171-172

The recommended regimen ]:or etidronate is 400 mg daily orally ]:or 2 weeks every 3 months. How long such a treatment should be pursued without interruption has not yet been determined. Etidronate is commercially available in many countries for this indication.

Commercial index pp. 182-206

Ibandronate Recently, ibandronate was found to be effective on bone mineral density at daily oral doses of 0.5-5 mg and, when injected intravenously every 3 months with doses between 0.25 and 2 mg. Two large, placebocontrolled fracture endpoint trials involving almost 6000 women are currently underway, evaluating doses of 0.5 or 1.0 mg intravenously every 3 months and oral doses of 2.5 mg daily or 20 mg intermittently.

Pamidronate In steroid-induced osteoporosis, pamidronate was effective at an oral daily dose of 150 mg for 1 year. This dose also appeared effective in other noncontrolled studies. The same dose was also effective in increasing bone mass in postmenopausal osteoporosis. The latter was also true when the compound was given intravenously in a dose of 30 mg every 3 months. In rheumatoid arthritis, 300 mg per day administered orally also led to an increase in bone mass rather than a decrease. In patients with cardiac transplantation 60 mg given intravenously every 3 months was active. Pamidronate is registered for osteoporosis in some countries of South America and Asia.

Risedronate Risedronate was effective in the prevention of bone loss in early postmenopausal women with normal bone mass, both in the lumbar spine and the hip. The effective dose was 5 mg given orally daily, while 5 mg daily for 2 weeks out of 4 were less effective. Thirty milligrams administered for 2 weeks out of 3 months were effective in patients with artificial menopause. Five milligrams daily is the dose most often used today and the one recommended by the manufacturer and approved by regulatory authorities in the countries where it is available. Dosing instructions are similar 151

Commercial index pp. 182-206

3. Bisphosphonatesmclinical to those of alendronate, namely that the drug should be taken on an empty stomach, with a full glass of water, 3 0 - 6 0 minutes before any food or drink, and patients should not recline after dosing. Risedronate has just been made commercially available in some countries.

Tiludronate In a first study oral administration of 100 mg daily for 6 m o n t h s was effective in preventing bone loss in normal p o s t m e n o p a u s a l w o m e n . H o w ever in a large multicenter study on osteoporotic w o m e n , either 50 or 200 mg given orally for 7 days each m o n t h , were effective neither on bone mineral density nor on the fracture rate.

Conclusion Bisphosphonates not only stop bone loss in various types of osteoporosis, and after the menopause, but also induce an increase in bone mineral density. A t least alendronate decreases vertebral and nonvertebral fractures and risedronate vertebral fractures. Fracture results with ibandronate should be available soon. Thus, bisphosphonates are an important addition to the therapeutic modalities available for the treatment and the prevention of osteoporosis.

Recommended selected reading Osteoporosis Books Kanis, J. A. (1997). Osteoporosis. (London: Blackwell) Marcus, R., Feldman, D., and Kelsey, J. (eds.) (1996). Osteoporosis. (San Diego: Academic Press) Meunier, P. J. (ed.) (1998). Osteoporosis: Diagnosis and Management. (London: Martin Dunitz) Sartoris, D. J. (ed.) (1996). Osteoporosis Diagnosisand Treatment. (New York: Dekker) Stevenson, J. C., and Lindsay, R. (eds.) (1998). Osteoporosis. (London: Chapman & Hall Medical)

Reviews Eastell, R., Reid, D. M., Compston, J., Cooper, C., Fogelman, I., Francis, R. M., Hosking, D. J., Purdie, D. W., Ralston, S. H., Reeve, J., Russell, R. G. G., Stevenson, J. J., and Torgerson, D. J. (1998). AUK consensus group on management of glucocorticoidinduced osteoporosis: An update. J. Int. Med. 244,271-292 Ferretti, J. L. (1995). Effects of bisphosphonates on bone biomechanics. In Bijvoet, O. L. M., Fleisch, H. A., Canfield, R. E., and Russell, R. G. G. (eds.) Bisphosphonate on Bones, pp. 211-229. (Amsterdam: Elsevier) Garnero, P. and Delmas, P. D. (1999). Laboratory assessment of postmenopausal osteo-

152

3.5. Osteoporosis porosis. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 465-477. (San Diego, London: Academic Press) Heaney, R. P. (1996). Calcium. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 1007-1018. (San Diego, London: Academic Press) Kleerekoper, M. (1996). Fluoride and the skeleton. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 1053-1062. (San Diego, London: Academic Press) Kleerekoper, M., and Avioli, L. V. (1998). Osteoporosis, pathogenesis and therapy. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 387-409. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 237-273. (San Diego, London: Academic Press) Lindsay, R., and Cosman, F. (1996). The pharmacology of estrogens in osteoporosis. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 10631067. (San Diego, London: Academic Press) Meunier, P. J. (1999). Evidence-based medicine and osteoporosis: A comparison of fracture risk reduction data from osteoporosis randomised clinical trials. Int. J. Clin. Pract. 53, 122-129 Miller, P. D. (1999). Management of osteoporosis. Adv. Intern. Med. 44, 175-207 Moreira Kulak, C. A., and Shane, E. (1999). Transplantation osteoporosis. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 515-526. (San Diego, London: Academic Press) Mulder, J. E., Moreira Kulak, C. A., and Shane, E. (1999). Secondary osteoporosis. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 527-545. (San Diego, London: Academic Press) Orwoll, E. S. (1999). Osteoporosis in men. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 493-504. (San Diego, London: Academic Press) Reid, I. R. (1999). Steroid-induced osteoporosis. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 505-513. (San Diego, London: Academic Press) Rodan, G. A., Raisz, L. G., and Bilezikian, J. P. (1996). Pathophysiology of osteoporosis. In Bilezikian, J. P., Raisz, L. G., and Rodan, G. A. (eds.) Principles of Bone Biology, pp. 979-990. (San Diego, London: Academic Press) Rosen, C. J. (1999). Age-related osteoporosis and skeletal markers of bone turnover. In Seibel, M. J., Robins, S. P., and Bilezikian, J. P. (eds.) Dynamics of Bone and Cartilage Metabolism, pp. 479-492. (San Diego, London: Academic Press) Seeman, E. (1997). Osteoporosis: Trials and tribulations. Am. J. Med. 103, 74S-89S Uffmann, M., Fuerst, T. P., Jergas, M., and Genant H. K. (1998). Noninvasive assessment of bone. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 275-311. (San Diego: Academic Press) B i s p h o s p h o n a t e s , preclinical

Original articles Ammann, P., Rizzoli, R., Caverzasio, J., Shigematsu, T., Slosman, D., and Bonjour, J. P. (1993). Effects of the bisphosphonate tiludronate on bone resorption, calcium balance, and bone mineral density. J. Bone Miner. Res., 8, 1491-1498 Balena, R., Toolan, B. C., Shea, M., Markatos, A., Myers, E. R., Lee, S. C., Opas, E. E., Seedor, J. G., Klein, H., Frankenfield, D., Quartuccio, H., Fioravanti, C., Clair, J., Brown, E., Hayes, W. C., and Rodan, G. A. (1993). The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized non human primates. J. Clin. Invest., 92, 2577-2586 Binkley, N., Kimmel, D., Bruner, J., Haffa, A., Davidowitz, B., Meng, C., Schaffer, V., and Green, J. (1998). Zoledronate prevents the development of absolute osteopenia following ovariectomy in adult Rhesus monkeys. J. Bone Miner. Res., 13, 1775-1782 Boyce, R. W., Paddock, C. L., Franks, A. F., Jankowsky, M. L., and Eriksen, E. F. (1996). Effects of intermittent hPTH (1-34) alone and in combination with 1,25(OH)2D3 or

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3. Bisphosphonates--clinical risedronate on endosteal bone remodeling in canine cancellous and cortical bone. J. Bone Miner. Res., 11,600-613 Ferretti, J. L., Delgado, C. J., Capozza, R. F., Cointry, G., Montuori, E., Roldfin, E., P~rez Lloret, A., and Zanchetta, J. R. (1993). Protective effects of disodium etidronate and pamidronate against the biomechanical repercussion of betamethasone-induced osteopenia in growing rat femurs. Bone Miner., 20, 265-276 Fleisch, H. (1996). The bisphosphonate ibandronate, given daily as well as discontinuously, decreases bone resorption and increases calcium retention as assessed by 45Ca kinetics in the intact rat. Osteoporosis Int., 6, 166-170 Jee, W. S. S., Black, H. E., and Gotcher, J. E. (1981). Effect of dichloromethane diphosphonate on cortisol-induced bone loss in young adult rabbits. Clin. Orthop., 156, 39-51 Ma, Y., Jee, W. S. S., Chen, Y., Gasser, J., Ke, H. Z., Li, X. J., and Kimmel, D. B. (1995). Partial maintenance of extra cancellous bone mass by antiresorptive agents after discontinuation of human parathyroid hormone (1-38) in right hindlimb immobilized rats. J. Bone Miner. Res., 10, 1726-1734 Meunier, P. J., and Boivin, G. (1997). Bone mineral density reflects bone mass but also the degree of mineralization of bone: Therapeutic implications. Bone, 5,373-377 Monier-Faugere, M.-C., Friedler, R. M., Bauss, F., and Malluche, H. H. (1993). A new bisphosphonate, BM 21.0955, prevents bone loss associated with cessation of ovarian function in experimental dogs. J. Bone Miner. Res., 8, 1345-1355 Motoie, H., Nakamura, T., O'Uchi, N., Nishikawa, H., Kanoh, H., Abe, T., and Kawashima, H. (1995). Effects of the bisphosphonate YM175 on bone mineral density, strength, structure, and turnover in ovariectomized beagles on concomitant dietary calcium restriction. J. Bone Miner. Res., 10, 910-920 Miihlbauer, R. C., Russell, R. G. G., Williams, D. A., and Fleisch, H. (1971). The effects of diphosphonates, polyphosphates, and calcitonin on 'immobilisation' osteoporosis in rats. Eur. J. Clin. Invest., 1,336-344 Murakami, H., Nakamura, T., Tsurukami, H., Abe, M., Barbier, A., and Suzuki, K. (1994). Effects of tiludronate on bone mass, structure, and turnover at the epiphyseal, primary, and secondary spongiosa in the proximal tibia of growing rats after sciatic neurectomy. J. Bone Miner. Res., 9, 1355-1364 Rosen, H. N., Sullivan, E. K., Middlebrooks, V. L., Zeind, A. J., Gundberg, C., DresnerPollak, R., Maitland, L. A., Hock, J. M., Moses, A. C., and Greenspan, S. L. (1993). Parenteral pamidronate prevents thyroid hormone induced bone loss in rats. J. Bone Miner. Res., 8, 1255-1261 Shanbhag, A. S., Hasselman, C. T., and Rubash, H. E. (1997). Inhibition of wear debris mediated osteolysis in a canine total hip arthroplasty model. Clin. Orthop., 344, 33-43. Takano, Y., Tanizawa, T., Mashiba, T., Endo, N., Nishida, S., and Takahashi, H. E. (1996). Maintaining bone mass by bisphosphonate incadronate disodium (YM175) sequential treatment after discontinuation of intermittent human parathyroid hormone (1-34) administration in ovariectomized rats. J. Bone Miner. Res., 11, 169-177 Thompson, D. D., Seedor, J. G., Quartuccio, H., Solomon, H., Fioravanti, C., Davidson, J., Klein, H., Jackson, R., Clair, J., Frankenfield, D., Brown, E., Simmons, H. A., and Rodan, G. A. (1992). The bisphosphonate, alendronate, prevents bone loss in ovariectomized baboons. J. Bone Miner. Res., 7, 951-960 Toolan, B. C., Shea, M., Myers, E. R., Botchers, R. E., Seedor, J. G., Quartuccio, H., Rodan, G., and Hayes, W. C. (1992). Effects of 4-amino-l-hydroxybutylidene bisphosphonate on bone biomechanics in rats. J. Bone Miner. Res., 7, 1399-1406 Wronski, T. J., Dann, L. M., Qi, H., and Yen, C. F. (1993). Skeletal effects of withdrawal of estrogen and diphosphonate treatment in ovariectomized rats. Calcif. Tissue Int., 53, 210-216

Bisphosphonates, clinical Reviews Papapoulos, S. E. (1999). Bisphosphonates. In Rosen, C. J., Glowacki, J., and Bilezikian, J. P. (eds.) The Ageing Skeleton, pp. 541-549. (San Diego, London: Academic Press)

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3.5. Osteoporosis Watts, N. B. (1998). Treatment of osteoporosis with bisphosphonates. Endocrinol. Metab. Clin. North Am., 27, 419-439

Alendronate

Reviews Devogelaer, J.-p. (1998). A risk-benefit assessment of alendronate in the treatment of involutional osteoporosis. Drug Safety, 19, 141-154 Jeal, W., Barradell, L. B., and McTavish, D. (1997). Alendronate. A review of its pharmacological properties and therapeutic efficacy in postmenopausal osteoporosis. Drugs, 53, 415-434

Original articles Adami, S., Passeri, M., Ortolani, S., Broggini, M., Carratelli, L., Caruso, I., Gandolini, G., Gnessi, L., Laurenzi, M., Lombardi, A., Norbiato, G., Pryor-Tillotson, S., Reda, C., Romanini, L., Subrizi, D., Wei, L., and Yates, A. J. (1995). Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis. Bone, 17, 383-390 Black, D. M., Cummings, S. R., Karpf, D. B., Cauley, J. A., Thompson, D. E., Nevitt, M. C., Bauer, D. C., Genant, H. K., Haskell, W. L., Marcus, R., Ott, S. M., Torner, J. C., Quandt, S. A., Reiss, T. F., and Ensrud, K. E. (1996). Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet, 348, 1535-1541 Bone, H. G., Downs, R. W., Tucci, J. R., Harris, S. T., Weinstein, R. S., Licata, A. A., McClung, M. R., Kimmel, D. B., Gertz, B. J., Hale, E., and Polvino, W. J. (1997). Doseresponse relationships for alendronate treatment in osteoporotic elderly women. J. Clin. Endocrinol. Metab., 82, 265-274 Chavassieux, P. M., Arlot, M. E., Reda, C., Wei, L., Yates, A. J., and Meunier, P. M. (1997). Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J. Clin. Invest., 100, 1475-1480 Chesnut III, C. H., McClung, M. R., Ensrud, K. E., Bell, N. H., Genant, H. K., Harris, S. T., Singer, F. R., Stock, J. L., Yood, R. L., Delmas, P. D., Kher, U., Pryor-Tillotson, S., and Santora III, A. C. (1995). Alendronate treatment of the postmenopausal osteoporotic woman: Effect of multiple dosages on bone mass and bone remodeling. Am. J. Med., 99, 144-152 Cosman, F., Nieves, J., Woelfert, L., Shen, V., and Lindsay, R. (1998). Alendronate does not block the anabolic effect of PTH in postmenopausal osteoporotic women. J. Bone Miner. Res., 13, 1051-1055 Cummings, S. R., Black, D. M., Thompson, D. E., Applegate, W. B., Barrett-Connor, E., Musliner, T. A., Palermo, L., Prineas, R., Rubin, S. M., Scott, J. C., Vogt, T., Wallace, R., Yates, A. J., and LaCroix, A. Z. (1998). Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. J. Am. Med. Assoc., 280, 2077-2082 Devogelaer, J. P., Broil, H., Correa-Rotter, R., Cumming, D. C., Nagant de Deuxchaisnes, C., Geusens, P., Hosking, D., Jaeger, P., Kaufman, J. M., Leite, M., Leon, J., Liberman, U., Menkes, C. J., Meunier, P. J., Reid, I., Rodriguez, J., Romanowicz, A., Seeman, E., Vermeulen, A., Hirsch, L. J., Lombardi, A., Plezia, K., Santora, A. C., Yates, A. J., and Yuan, W. (1996). Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis. Bone, 18, 141-150 Garnero, P., Shih, W. J., Gineyts, E., Karpf, D. B., and Delmas, P. D. (1994). Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J. Clin. Endocrinol. Metab., 79, 1693-1700 Gertz, B. J., Shao, P., Hanson, D. A., Quan, H., Harris, S. T., Genant, H. K., Chesnut III, C. H., and Eyre, D. R. (1994). Monitoring bone resorption in early postmenopausal women by an immunoassay for cross-linked collagen peptides in urine. J. Bone Miner. Res., 9, 135-142

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3. B i s p h o s p h o n a t e s - - c l i n i c a l Greenspan, S. L., Parker, R. A., Ferguson, L., Rosen, H. N., Maitland-Ramsey, L., and Karpf, D. (1998). Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: A randomized trial. J. Bone Miner. Res., 13, 1431-1438 Hochberg, M. C., Ross, P. D., Black, D., Cummings, S. R., Genant, H. K., Nevitt, M. C., Barrett-Connor, E., Musliner, T., and Thompson, D. (1999). Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Arthritis Rheum., 42, 1246 -1254 Hosking, D., Chilvers, C. E. D., Christiansen, C., Ravn, P., Wasnich, R., Ross, P., McClung, M., Balske, A., Thompson, D., Daley, M., and Yates, J. (1998). Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N. Engl. J. Med., 338,485-493 Khan, S. A., Kanis, J. A., Vasikaran, S., Kline, W. F., Matuszewski, B. K., McCloskey, E. V., Beneton, M. N. C., Gertz, B. J., Sciberras, D. G., Holland, S. D., Orgee, J., Coombes, G. M., Rogers, S. R., and Porras, A. G. (1997). Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J. Bone Miner. Res., 12, 1700-1707 Liberman, U. A., Weiss, S. R., Br611, J., Minne, H. W., Quan, H., Bell, N. H., RodriguezPortales, J., Downs, R. W., Jr., Dequeker, J., Favus, M., Seeman, E., Recker, R. R., Capizzi, T., Santora II, A. C., Lombardi, A., Shah, R. V., Hirsch, L. J., and Karpf, D. B. (1995). Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N. Engl. J. Med., 333, 1437-1443 Lindsay, R., Cosman, F., Lobo, R. O., Walsh, B. W., Harris, S. T., Reagan, J. T., Liss, C. L., Melton, M. E., and Byrnes, C. A. (1999). Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: A randomized, controlled clinical trial. J. Clin. Endocrinol. Metab., 84, 3076-3081 McClung, M., Clemmesen, B., Daifotis, A., Gilchrist, N. L., Eisman, J., Weinstein, R. S., E1 Hajj Fuleihan, G., Reda, C., Yates, A. J., and Ravn, P. (1998). Alendronate prevents postmenopausal bone loss in women without osteoporosis. Ann. Int. Med., 128, 253-261 Passeri, M., Baroni, M. C., Pedrazzoni, M., Pioli, G., Barbagallo, M., Costi, D., Biondi, M., Girasole, G., Arlunno, B., and Palummeri, E. (1991 ). Intermittent treatment with intravenous 4-amino-l-hydroxybutylidene-l,l-bisphosphonate (AHBuBP) in the therapy of postmenopausal osteoporosis. Bone Miner., 15,237-247 Pols, H. A. P., Felsenberg, D., Hanley, D. A., Stepan, J., Munoz-Torres, M., Wilkin, T. J., Qin-sheng, G., Galich, A. M., Vandormael, K., Yates, A. J., and Stych, B. (1999). Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: Results of the FOSIT study. Osteoporosis Int., 9, 461-468 Saag, K. G., Emkey, R., Schnitzer, T. J., Brown, J. P., Hawkins, F., Goemaere, F., Thamsborg, G., Lieberman, U. A., Delmas, P. D., Malice, M.-P., Czachur, M., and Daifotis, A. G. (1998). Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N. Engl. J. Med., 339, 292-299 Shiraki, M., Kushida, K., Fukunaga, M., Kishimoto, H., Kaneda, K., Minaguchi, H., Inoue, T., Tomita, A., Nagata, Y., Nakashima, M., and Orimo, H. (1998). A placebocontrolled, single-blind study to determine the appropriate alendronate dosage in postmenopausal Japanese patients with osteoporosis. Endocr. J., 45, 191-201 Shiraki, M., Kushida, K., Fukunaga, M., Kishimoto, H., Taga, M., Nakamura, T., Kaneda, K., Minaguchi, H., Inoue, T., Morii, H., Tomita, A., Yamamoto, K., Nagata, Y., Nakashima, M., and Orimo, H. (1999). A double-masked mutlicenter comparative study between alendronate and alfacalcidol in Japanese patients with osteoporosis. Osteoporosis Int., 9, 183-192 Stock, J. L., Bell, N. H., Chesnut, C. H., Ensrud, K. E., Genant, H. K., Harris, S. T., McClung, M. R., Singer, F. R., Yood, R. A., Pryor-Tillotson, S., Wei, L., and Santora, A. C. (1997). Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women. Am. J. Med., 103, 291-297

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3.5. Osteoporosis Clodronate Filipponi, P., Pedetti, M., Fedeli, L., Cini, L., Palumbo, R., Boldrini, S., Massoni, C., and Cristallini, S. (1995). Cyclical clodronate is effective in preventing postmenopausal bone loss: A comparative study with transcutaneous hormone replacement therapy. J. Bone Miner. Res., 10, 697-703 Filipponi, P., Cristallini, S., Rizzello, E., Policani, G., Fedeli, L., Gregorio, F., Boldrini, S., Troiani, S., and Massoni, C. (1996). Cyclical intravenous clodronate in postmenopausal osteoporosis: Results of a long-term clinical trial. Bone, 18, 179-184 Giannini, S., D'Angelo, A., Malvasi, L., Castrignano, R., Pati, T., Tronca, R., Liberto, L., Nobile, M., and Crepaldi, G. (1993). Effects of one-year cyclical treatment with clodronate on postmenopausal bone loss. Bone, 14, 137-141 Herrala, J., Puolijoki, H., Lippo, K., Raitio, M., Impivaara, O., Tala, E., and Nieminen, M. M. (1998). Clodronate is effective in preventing corticosteroid-induced bone loss among asthmatic patients. Bone, 22, 577-582 Minaire, P., BSrard, E., Meunier, P. J., Edouard, C., Goedert, G., and Pilonch~ry, G. (1981). Effects of disodium dichloromethylene diphosphonate on bone loss in paraplegic patients. J. Clin. Invest., 68, 1086-1092 Saarto, T., Blomqvist, C., Valimaki, M., Makela, P., Sarna, S., and Elomaa, I. (1997). Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorourasil chemotherapy causes rapid bone loss that is reduced by clodronate: A randomized study in premenopausal breast cancer patients. J. Clin. Oncol., 15, 1341-1347

Etidronate Reviews Johnson, S., and Johnson, F. N. (eds.) (1998). Etidronate in osteoporosis. Rev. Contemp. Pharmacother., 9, 225-292

O r i g i n a l articles Adachi, J. D., Bensen, W. G., Brown, J., Hanley, D., Hodsman, A., Josse, R., Kendler, D. L., Lentle, B., Olszynski, W., Ste.-Marie, L.-G., Tenenhouse, A., and Chines, A. A. (1997). Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N. Engl. J. Med., 337, 382-387 Diamond, T., McGuigan, L., Barbagallo, S., and Bryant, C. (1995). Cyclical etidronate plus ergocalciferol prevents glucocorticoid-induced bone loss in postmenopausal women. Am. J. Med., 98, 459-463 Harris, S. T., Watts, N. B., Jackson, R. D., Genant, H. K., Wasnich, R. D., Ross, P., Miller, P. D., Licata, A. A., and Chesnut III, C. H. (1993). Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: Three years of blinded therapy followed by one year of open therapy. Am. J. Med., 95,557-567 Heaney, R. P., and Saville, P. D. (1976). Etidronate disodium in postmenopausal osteoporosis. Clin. Pharmacol. Ther., 20, 593-604 Meunier, P. J., Confravreux, E., Tupinon, I., Hardouin, C., Delmas, P. D., and Balena, R. (1997). Prevention of early postmenopausal bone loss with cyclical etidronate therapy (a double-blind, placebo-controlled study and 1-year follow-up. J. Clin. Endocrinol. Metab., 82, 2784-2791 Miller, P. D., Watts, N. B., Licata, A. A., Harris, S. T., Genant, H. K., Wasnich, R. D., Ross, P. D., Jackson, R. D., Hoseyni, M. S., Schoenfeld, S. L., Valent, D. J., and Chesnut, C. H. (1997). Cyclical etidronate in the treatment of postmenopausal osteoporosis: Efficacy and safety after seven years of treatment. Am. J. Med., 103,468-476 Roux, C., Oriente, P., Laan, R., Hughes, R. A., Ittner, J., Goemaere, S., Di Munno, O., Pouill~s, J. M., Horlait, S., and Cortet, B. (1998). Randomized trial of effect of cyclical etidronate in the prevention of corticosteroid-induced bone loss. J. Clin. Endocrinol. Metab., 83, 1128-1133

157

3. B i s p h o s p h o n a t e s - - c l i n i c a l Storm, T., Thamsborg, G., Steiniche, T., Genant, H. K., and Sorensen, O. H. (1990). Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N. Engl. J. Med., 322, 1265-1271 Storm, T., Steiniche, T., Thamsborg, G., and Melsen, F. (1993). Changes in bone histomorphometry after long-term treatment with intermittent, cyclic etidronate for postmenopausal osteoporosis. J. Bone Miner. Res., 8, 199-208 Storm, T., Kollerup, G., Thamsborg, G., Genant, H. K., and Sorensen, O. H. (1996). Five years of clinical experience with intermittent cyclical etidronate for postmenopausal osteoporosis. J. Rheumatol., 23, 1560-1564 Struys, A., Snelder, A. A., and Mulder, H. (1995). Cyclical etidronate reverses bone loss of the spine and proximal femur in patients with established corticosteroid-induced osteoporosis. Am. J. Med., 99, 235-242 Watts, N. B., Harris, S. T., Genant, H. K., Wasnich, R. D., Miller, P. D., Jackson, R. D., Licata, A. A., Ross, P., Woodson, G. C., Yanover, M. J., Mysiw, W. J., Kohse, L., Rao, M. B., Steiger, P., Richmond, B., and Chesnut III, C. H. (1990). Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N. Engl. J. Med., 323, 73-79 Wimalawansa, S. J. (1998). A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am. J. Med., 104, 219-226

Ibandronate Ravn, P., Clemmesen, B., Riis, B. J., and Christiansen, C. (1996). The effect on bone mass and bone markers of different doses of ibandronate: A new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: A 1-year, randomized, double-blind, placebo-controlled dose-finding study. Bone, 19, 527-533 Ravn, P., Christensen, J. O., Baumann, M., and Clemmesen, B. (1998). Changes in biochemical markers and bone mass after withdrawal of ibandronate treatment: Prediction of bone mass changes during treatment. Bone, 22, 559-564 Thi~baud, D., Burckhardt, P., Kiegbaum, H., Huss, H., Mulder, H., Juttmann, J. R., and Sch6ter, K. H. (1997). Three monthly intravenous injections of ibandronate in the treatment of postmenopausal osteoporosis. Am. J. Med., 103,298-307

Pamidronate Nance, P. W., Schryvers, O., Leslie, W., Ludwig, S., Krahn, J., and Uebelhart, D. (1999). Intravenous pamidronate attenuates bone density loss after acute spinal cord injury. Arch. Phys. Rehabil., 80, 243-251 Reid, I. R., King, A. R., Alexander, C. J., and Ibbertson, H. K. (1988). Prevention of steroidinduced osteoporosis with (3-amino- 1-hydroxypropylidene)- 1,1-bisphosphonate (APD ). Lancet, 1,143-146 Reid, I. R., Wattie, D. J., Evans, M. C., Gamble, G. D., Stapleton, J. P., and Cornish, J. (1994). Continuous therapy with pamidronate, a potent bisphosphonate, in postmenopausal osteoporosis. J. Clin. Endrocrinol. Metab., 79, 1595-1599 Thi~baud, D., Burckhardt, P., Melchior, J., Eckert, P., Jacquet, A. F., Schnyder, P., and Gobelet, C. (1994). Two years' effectiveness of intravenous pamidronate (APD)versus oral fluoride for osteoporosis occurring in the postmenopause. Osteoporosis Int., 4, 76-83

Risedronate Cohen, S., Levy, R. M., Keller, M., Boling, E., Emkey, R. D., Greenwald, M., Zizic, T. M., Wallach, S., Sewell, K. L., Lukert, B. P., Axelrod, D. W., and Chines, A. A. (1999). Risedronate therapy prevents corticosteroid-induced bone loss. Arthritis Rheum., 42, 2309-2318. Delmas, P. D., Balena, R., Confravreux, E., Hardouin, C., Hardy, P., and Bremond, A. (1997). Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: A double-blind, placebo-controlled study. J. Clin. Oncol., 15,955-962

158

3.5. Osteoporosis Harris, S. T., Watts, N. B., Genant, H. K., McKeever, C. D., Hangartner, D., Keller, M., Chesnut, C. H., Brown, J., Eriksen, E. F., Hoseyni, M. S., Axelrod, D. W., and Miller, P. D. (1999). Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. JAMA, 14, 1344-1352 Mortensen, L., Charles, P., Bekker, P. J., Digennaro, J., and Johnston, C. C. (1998). Risedronate increases bone mass in an early postmenopausal population: Two years of treatment plus one year follow-up. J. Clin. Endocrinol. Metab., 83, 396-402

Tiludronate Chappard, D., Minaire, P., Privat, C., B6rard, E., Mendoza-Sarmiento, J., Tournebise, H., Basle, M. F., Audran, M., Rebel, A., Picot, C., and Gaud, C. (1995). Effects of tiludronate on bone loss in paraplegic patients. J. Bone Miner. Res., 10, 112-118 Reginster, J. Y., Lecart, M. P., Deroisy, R., Sarlet, N., Denis, D., Ethgen, D., Collette, J., and Franchimont, P. (1989). Prevention of postmenopausal bone loss by tiludronate. Lancet, 2, 1469-1471

159

3.6.

HETEROTOPIC

CALCIFICATION

AND OSSIFICATION 3.6.1.

Definition

Heterotopic, also called ectopic, calcification is a condition in which calcium phosphate crystals deposit in sites that are normally not calcified. If the calcification occurs in the form of osseous or osseous-like tissue, the condition is called heterotopic ossification.

A distinction is made between heterotopic calcification and heterotopic ossification. 3.6.2.

Pyrophosphate and calcification p. 28

Pathophysiology

Ectopic calcification can occur in various tissues. Its mechanism is not understood, except when it occurs during hypercalcemia or in the case of urinary stones. In these cases precipitation occurs, because of the supersaturation of the fluid in calcium and phosphate. Local disturbances of nucleators or of inhibitors of calcium phosphate crystal formation have been proposed as possible mechanisms. The cause of heterotopic ossification is unknown. Here the abnormal formation of bone usually occurs in the muscles. Trauma seems to be involved in some cases. Heterotopic ossification is common after hip operations with implantation of a prosthesis, after paraplegia, and after cerebral trauma. In other cases, such as fibrodysplasia ossificans progressiva, the disorder is congenital. Recently an overproduction of a bone morphogenetic protein has been demonstrated in the latter condition. Another possibility may be a lack of matrix Gla protein, which has been proposed to prevent mineralization in soft tissues. Indeed, knockout mice without this protein develop calcification of muscle cells.

The mechanisms responsible ]:orthe development of the heterotopic calcifications and ossifications are unknown. Sometimes an overproduction of a bone morphogenetic protein may be involved. 3.6.3.

Clinical manifestations

Manifestations are numerous and depend on the localization of the calcium phosphate deposit. In the case of heterotopic calcification, the most frequent location is in the walls of blood vessels, especially the arteries. In the lumen of the urinary tract, they will lead to the formation of urinary stones. Calcification can be widespread throughout the connective 160

3.6. Heterotopic calcification and ossification tissues in conditions such as calcinosis universalis, dermatomyositis, and scleroderma. Heterotopic ossification can be localized, for example, after hip prosthesis, or widespread, as in fibrodysplasia ossificans progressiva, where death as a result of pulmonary insufficiency can occur. 3.6.4.

T r e a t m e n t with

drugs other than bisphosphonates

Many therapies have been tried in heterotopic calcification, but none has proven totally successful. In heterotopic ossification, for example, after hip replacement, the treatments most often used are nonsteroidal antiinflammatory agents and irradiation. 3.6.5.

T r e a t m e n t with

bisphosphonates

The only bisphosphonate investigated up to now is etidronate.

Preclinical studies As mentioned earlier, bisphosphonates very efficiently inhibit mineralization in vivo. They can prevent experimentally induced calcification of many soft tissues such as arteries, kidneys, skin, heart, heart valves, urinary stones when given parenterally or orally, and, when administered topically, experimental dental calculus. Etidronate also inhibits heterotopic ossification induced by various means.

Bisphosphonates prevent experimental heterotopic calcification and ossification in animals. Clinical studies The studies mentioned above led to the hope that bisphosphonates would find a use in preventing ectopic calcification and ossification in humans. Unfortunately, the results obtained so far are less encouraging than expected. The studies all used etidronate, which is therefore the only bisphosphonate investigated so far. They were usually uncontrolled and performed on only very few patients in diseases that undergo spontaneous remission, so that the results are difficult to interpret.

Heterotopic calcification Soft tissue calcification Etidronate has been given in some cases of scleroderma, dermatomyositis, idiopathic infantile arterial calcification, and calcinosis universalis. Efficacy is uncertain, since these disorders often go into spontaneous remission. 161

Effect on calcification p. 48

3. Bisphosphonatesmclinical The efficacy of etidronate in various ectopic soft tissue calcifications is uncertain. Urolithiasis Physicochemical effects p. 50

Adverse events p. 171

The hope that the inhibitory effect on crystal growth and aggregation of both calcium phosphate and calcium oxalate would be useful for the prevention of urinary stones has not been fulfilled, at least with etidronate. Although pilot studies showed an effect in chronic stone formers, the dose necessary to obtain inhibition of crystal growth in urine was high, about 1600 mg/day orally, so that it would also induce inhibition of skeletal mineralization. Furthermore, the clinical benefit is uncertain, large-scale studies having failed to show efficacy. Etidronate can therefore not be recommended for use in urolithiasis.

Etidronate should not be administered in urolitbiasis. However, bisphosphonates which decrease bone resorption may possibly be considered in patients with hypercalciuria due to increased bone resorption. Indeed, alendronate was reported to decrease urinary calcium and saturation with urinary calcium phosphate as well as calcium oxalate in normal males, so that the values after immobilization through bed rest never attained levels above those of normal controls. Further studies on this subject would be desirable.

The hypocalciuric effect of bisphosphonates may possibly be of use in certain patients with increased bone resorption. Dental calculus Many investigations have shown that topical application of etidronate by means of mouthwashes or toothpastes diminishes the development of dental calculus. Toothpastes containing a bisphosphonate are marketed in some countries.

Bisphosphonates are available in toothpastes for use against dental calculus.

Heterotopic ossification Fibrodysplasia (previously myositis) ossificans progressiva The first time a bisphosphonate (etidronate) was given to a human was in this disease. Despite a series of further investigations reporting positive resuits, it remains to be established whether this drug is really active in de162

3.6. Heterotopic calcification and ossification creasing ectopic bone formation. Some retardation in the evolution probably occurs in many cases, but a complete standstill is rarely obtained. Lesions already formed are not influenced. Despite this uncertainty, in view of the often dismal outcome of the disease in many cases and of the lack of alternative treatment, the use of etidronate as an oral dosage of 20 mg/kg per day seems advisable. However, since this dose also inhibits mineralization of normal bone and can lead to rickets in children and osteomalacia in adults, and since lower doses are not effective, the drug should not be given for longer than 3 months, preferably for shorter periods of a few weeks and only when a new exacerbation occurs.

Etidronate can be tried in patients with fibrodysplasia ossificans progressiva. Other heterotopic ossifications Results may be somewhat more encouraging with other types of heterotopic ossification. Etidronate has been found to diminish the appearance of ossifications in patients with spinal cord injury, after cranial trauma, and after total hip replacement. In the latter, although ectopic bone formation reappears, at least partially, after discontinuation of the drug, the mobility of the hip seems nevertheless to be improved in the etidronate-treated patients. However, these results have been questioned by other authors. Fig. 3.6-1 Effectof etidronate administered for 4 months at 20 mg/kg daily in heterotopic ossification after placement of total hip prosthesis. [Adapted from Lowell J. D., et al. (1982). In Ziegler, R. (ed.) EHDP, pp. 173-195. (Miinchen, Wien, Baltimore: Urban & Schwarzenberg), with copyright permission from the publisher.]

Etidronate and hip ossification

Etidronate 6/

Placebo n=40

/

I./~,/11/

+1

/

/

v

o 4! tll

4.a

* p < 0.05

!

O

!

f

r 1

2 o

_L

90

Etidronate n=42

tl p

~

,

O-i Operation

163

I 3 months

II

.....

I

12 months

Adverse events pp. 169-170

3. Bisphosphonates--clinical Etidronate may in some cases inhibit ectopic ossifications.

Commercial index pp. 182-206

Although the efficacy of etidronate is not absolutely established, it seems nevertheless justifiable to administer it preventively in those patients who are particularly liable to develop ectopic ossifications, for example, patients who require a second operation after total hip replacement because of ossifications after the first operation. The daily oral dosage recommended by the manufacturer is 20 mg/kg body weight, starting 1 month before the operation and given for up to 3 months after the intervention. Longer treatment should not be given, because of the possible development of osteomalacia. Etidronate is commercially available for this indication in many countries.

Etidronate appears to be useful in preventing heterotopic ossification under certain conditions. The dosage is 20 mg/kg body weight daily per os for not longer than 4 months. It is commercially available in many countries.

Conclusion Etidronate, the only bisphosphonate investigated so far in ectopic calcification and ossification, appears to be useful for partial prevention of heterotopic ossifications in some instances. However, the effective dose is the same as that inhibiting normal mineralization, which makes its use difficult.

Recommended selected reading Heterotopic calcification

and ossification

Reviews Pak, C. Y. C. (1998). Kidney stones: Pathogenesis, diagnosis, and therapy. In Avioli, L. V., and Krane, S. M. (eds.) Metabolic Bone Disease and Clinically Related Disorders, pp. 739-758. (San Diego: Academic Press) Thomas, B. J. (1992). Heterotopic bone formation after total hip arthroplasty. Orthop. Clin. North Am., 23,347-358 Whyte, M. P. (1998). Skeletal disorders characterized by osteosclerosis or hyperostosis. In Avioli, L. V., and Krane, S. M. (eds.) MetabolicBone Diseaseand ClinicallyRelated Disorders, pp. 697-738. (San Diego: Academic Press)

164

3.6. Heterotopic calcification and ossification B i s p h o s p h o n a t e s , preclinical

Original articles Fleisch, H., Russell, R. G. G., Bisaz, S., Miihlbauer, R. C., and Williams, D. A. (1970). The inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur. J. Clin. Invest., 1, 12-18 B i s p h o s p h o n a t e s , clinical

Original articles Baumann, J. M., Bisaz, S., Fleisch, H., and Wacker, M. (1978). Biochemical and clinical effects of ethane-l-hydroxy-l,l-diphosphonate in calcium nephrolithiasis. Clin. Sci. Mol. Med., 54, 509-516 Finerman, G. A. M., and Stover, S. L. (1981). Heterotopic ossification following hip replacement or spinal cord injury. Two clinical studies with EHDP. Metab. Bone Dis. Related Res., 4, 337-342 Geho, W. B., and Whiteside, J. A. (1973). Experience with disodium etidronate in diseases of ectopic calcification. In Frame, B., Parfitt, A. M., and Duncan, H. (eds.) Clinical Aspects of Metabolic Bone Disease, pp. 506-511. (Amsterdam: Excerpta Medica) Reiner, M., Sautter, V., Olah, A., Bossi, E., Largiad~r, U., and Fleisch, H. (1980). Diphosphonate treatment in myositis ossificans progressiva. In Caniggia, A. (ed.) Etidronate, pp. 237-241. (Pisa: Istituto Gentili) Rural, L. A., Dubois, S. K., Roberts, M. L., and Pak, C. Y. C. (1995). Prevention of hypercalciuria and stone-forming propensity during prolonged bedrest by alendronate. J. Bone Miner. Res., 10, 655-662 Slooff, T. J. J. H., Feith, R., Bijvoet, O. L. M., and Nollen, A. J. G. (1974). The use of a disphosphonate in para-articular ossifications after total hip replacement. A clinical study. Acta Orthop. Belg., 40, 820-828 Thomas, B. J., and Amstutz, H. C. (1985). Results of the administration of diphosphonate for the prevention of heterotopic ossification after total hip arthroplasty. J. Bone Joint Surg. (Am)., 67, 400-403

165

3.7. OTHER DISEASES Bisphosphonates have been administered in other diseases. In some conditions the effects are quite dramatic. But often only a few cases are described, so that it is not possible to evaluate whether the effect is significant or not.

Diseases with enhanced resorption Pamidronate given at 180 mg intravenously twice a year for 18 to 64 months to patients with fibrous dysplasia of bone, a rare osteolytic disease that presents certain histological analogies with Paget's disease, induces an improvement of bone turnover, of the radiological picture, and of pain. Alendronate and pamidronate may improve pain in patients with reflex sympathetic dystrophy syndrome (Sudeck's atrophy), but an evaluation of these results is difficult in this disease characterized by a very variable natural history.

Osteogenesis imperfecta Recently pamidronate, administered to children with osteogenesis imperfecta at a dose of 6.8 mg/kg intravenously twice a year, was found to reduce bone turnover, increase bone mineral density, increase cortical width, and decrease cortical porosity. Clinically the treatment decreased the occurrence of fractures. Since this disease is caused by an inborn abnormality of collagen, and hence of bone strength, the latter effect is probably explained by the increase in bone mass.

Other diseases Ibandronate administered intravenously at 2 mg every 3 months for 2 years to patients with Klinefelter syndrome, induced a decrease in the elevated bone turnover and an increase in BMD. Positive results have been obtained in hereditary hyperphosphatasia, in diabetic Charcot neuroarthropathy, in mastocytosis, and in hypercalcemia of primary oxalosis. Pamidronate diminished clinical skeletal manifestations, such as acute bone crisis episodes and fractures in Gaucher's disease. Furthermore clodronate, administered intra-articularly, has given positive results on pain and articular movement in a study in patients with osteoarthritis of the knee. The resuits in rheumatoid arthritis are controversial. A recent study showed a significant effect of a single infusion of pamidronate both on bone resorption and disease activity assessed by the Ritchie articular index, the number of swollen joints, and also to a lesser degree, sedimentation rate and the Creactive protein. This indication merits further investigation.

166

3.7. Other diseases

Bisphosphonates had positive effects in fibrous dysplasia of bone, reflex sympathetic dystrophy syndrome, and osteogenesis imperrecta. In the other diseases preliminary results need confirmation.

Recommended selected reading Adami, S., Fossaluzza, V., Gatti, D., Fracassi, E., and Braga, V. (1997). Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann. Rheum. Dis., 56, 201-204 Chapurlat, R. D., Delmas, P. D., Liens, D., and Meunier, P. J. (1997). Long-term effects of intravenous pamidronate in fibrous dysplasia of bone. J. Bone Miner. Res., 12, 17461752 Cortet, B., Flipo, R.-M., Coquerelle, P., Duquesnoy, B., and Delcambre, B. (1997). Treatment of severe, recalcitrant reflex sympathetic dystrophy: Assessment of efficacy and safety of the second generation bisphosphonate pamidronate. Clin. Rheumatol., 16, 51-56 Eggelmeijer, F., Papapoulos, S. E., van Paassen, H. C., Dijkmans, B. A. C., and Breedveld, F. C. (1994). Clinical and biochemical response to single infusion of pamidronate in patients with active rheumatoid arthritis: A double blind placebo controlled study. J. Rheumatol., 21, 2016-2020 Glorieux, F. H., Bishop, N. J., Plotkin, H., Chabot, G., Lanoue, G., and Travers, R. (1998). Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N. Engl. J. Med., 339, 947-952 Landsmeer-Beker, E. A., Massa, G. G., Maaswinkel-Mooy, P. D., van de Kamp, J. J. P., and Papapoulos, S. E. (1997). Treatment of osteogenesis imperfecta with the bisphosphonate olpadronate (dimethylaminohydroxypropylidene bisphosphonate). Eur. J. Pediatr., 156, 792-794 Liens, D., Delmas, P. D., and Meunier, P. J. (1994). Long-term effects of intravenous pamidronate in fibrous dysplasia of bone. Lancet, 343,953-954 Samuel, R., Katz, K., Papapoulos, S. E., Yosipovitch, Z., Zaizov, R., and Liberman, U. A. (1994). Aminohydroxy propylidene bisphopsphonate (APD) treatment improves the clinical skeletal manifestations of Gaucher's disease. Pediatrics, 94, 385-389 Selby, P. L., Young, M. J., and Boulton, A. J. M. (1994). Bisphosphonates: A new treatment for diabetic Charcot neuroarthropathy. Diabetic Med., 11, 28-31 Singer, F., Siris, E., Shane, E., Dempster, D., Lindsay, R., and Parisien, M. (1994). Hereditary hyperphosphatasia: 20 year follow-up and response to disodium etidronate. J. Bone Miner. Res., 9, 733-738

167

3 . 8 . ADVERSE EVENTS 3.8.1. Bisphosphonates in general

Insoluble aggregates p. 32

[bandronate ministration p. 106

As in animals, studies in humans have revealed only a few important adverse events. Caution must be taken with the intravenous administration of large amounts of all bisphosphonates. Rapid injection has led to renal failure, probably because of the formation of a solid phase of bisphosphonate in the blood which is then held back in the kidney. No further events of that kind have been observed since care has been taken to administer all bisphosphonates given intravenously in large amounts by slow infusion in a large volume of fluid. The exact amount of fluid necessary is not known. It is generally suggested that etidronate and clodronate should be diluted into at least 250 ml, 500 ml if the amount administered is large. The infusion should be slow, over at least 2 h, longer if the amount administered is high. Pamidronate should be diluted in at least 250 ml and infused in not less than 1 h for 60 mg and 2 h for higher amounts. For the more potent bisphosphonates, which are given in lower amounts, the dilution may be smaller and very potent bisphosphonates, which need very low dosage, may even be injected. Thus, up to 3 rag, ibandronate can be injected in a few milliliters. For all dilutions, the fluid must not contain divalent cations such as in Ringer's solution, which might form an insoluble phase with the bisphosphonate. For exact instructions the package insert should be consulted.

When given intravenously, etidronate, clodronate, and pamidronate must be diluted into 2S0-500 ml and infused slowly, not faster than within 2 h, longer if the amount infused is large. Bisphosphonates can induce hypocalcemia, especially when given intravenously in large amounts. This is usually without clinical consequences, although seizures have been described occasionally. Severe hypocalcemia has been reported in a patient who received aminoglycoside antibiotic therapy. It is possible that this was due to the incapacity of the kidneys damaged by the antibiotic to compensate for the decrease in bone resorption. Therefore, the two drugs should not be administered together. Great care has to be given in patients with hypoparathyroidism.

Bisphosphonates may sometimes induce a certain degree of hypocalcemia, which is usually clinically irrelevant. An exception may be the association with aminoglycoside antibiotics with which very s e v e r e hypocalcemia can occur, so that the two drugs should not be administered together.

168

3.8. Adverse events The oral administration of bisphosphonates can be accompanied by esophageal and gastrointestinal side effects, such as nausea, dyspepsia, vomiting, gastric pain and diarrhea, and sometimes even esophageal erosions or ulcerations. This effect might be due to the inhibitory effect of the nitrogen-containing bisphosphonates on the mevalonate pathway which leads to an inhibition of keratinocyte growth, or to some direct chemical irritant effect.

Oral administration of bisphosphonates, especially those with a nitrogen, can be accompanied by digestive tract disturbances. It must be remembered that all bisphosphonates are bone seekers and therefore accumulate in the skeleton. They will stay there until the bone in which they are buried is destroyed during the process of bone turnover. This can be a very long time, so that it is likely that some of the bisphosphonates may stay in the body for life. Therefore, the very long-term safety of these compounds has to be closely followed.

Kinetics p. 57

Since the bisphosphonates may stay in the body for life, their safety has to be closely followed. 3.8.2.

Individual

bisphosphonates

Alendronate In clinical studies, alendronate was very well tolerated up to a daily oral dose of 20 mg with an overall profile comparable to placebo. This was also the case for the digestive tract. Signs of upper gastrointestinal intolerance occurred in some postmenopausal patients with osteoporosis treated with 40 mg. However, this dose was well tolerated in patients with Paget's disease. Nevertheless, in clinical practice, it seems that alendronate administration is occasionally accompanied by gastrointestinal disturbances in some patients. Furthermore a postmarketing analysis performed by the manufacturer reported that about 0.1%o of patients who had received 10 mg of alendronate daily per os displayed serious or severe adverse esophageal effects. These included symptoms related to esophageal dysfunction, and structural alterations like esophagitis, erosions, and ulcerations.

In clinical studies, alendronate was very well tolerated up to a daily oral dose of 20 rag, in Paget's disease 40 rag. In clinical practice, however, some gastrointestinal disturbances were seen. Furthermore, in about O.1%o of the patients, serious or severe esophageal adverse effects were seen in postmarketing experience.

169

GI effects in animals p. 64

3. Bisphosphonates--clinical An analysis of these patients showed that the majority did not follow the recommendations in the product label to take the drug with a full glass of water and not to recline afterward. In response to these facts, the instructions in the product label were strengthened by the manufacturer and include the recommendation that patients should stop taking their medication if they develop esophageal symptoms. Since the dosing instructions were reinforced, the number of reports of these events has declined, and this despite a substantial increase in the number of patients treated. Whether the other gastrointestinal symptoms were significant under correct administration, and whether they were different from those seen with other bisphosphonates, is not clear.

The potential [or esophageal adverse events can be substantially reduced by taking the drug with a lull glass of water, and by not reclining after the intake and before ingesting the first meal ol: the day. Whether they are significant in these conditions and different from those observed with other bisphosphonates is not known.

Ocular adverse events p. 174

Very recently three patients receiving oral alendronate have developed ocular inflammation with scleritis with and without anterior uveitis, which resolved after anti-inflammatory therapy and discontinuation of the drug. Similar signs and symptoms have been described with pamidronate and risedronate.

Clodronate Except for occasional diarrhea when given orally, and one case of bronchospasm in an aspirin-sensitive patient with asthma, no proven adverse reactions have been described for clodronate. Individual cases of skin reactions have been described, but have not been confirmed in clinical trials. Contrary to etidronate, this compound does not inhibit mineralization of bone at the dosage used.

Clodronate has, except [or occasional diarrhea when given orally, and possibly a special sensitivity in aspirin-sensitive asthma, no proven side effects. In the course of the clinical evaluation of this compound, some of the patients treated who had Paget's disease developed acute leukemia. This prompted the suspension of all clinical trials. Careful analysis of the data and subsequent follow-up of all the patients who had received clodronate over many years, led a panel of experts to conclude that causes other than the drug, especially preselection of patients, were at least as likely or more

170

3.8. Adverse events likely than clodronate to be an explanation for the observed cases. In view of this analysis and the cumulative clinical experience of 17 years now, it is most improbable that there was any relation between the bisphosphonate and the development of the disease in these patients.

The suspicion that clodronate may induce leukemia has not been confirmed. Etidronate Etidronate has been used in humans for 20 years now and has proven to be very well tolerated when not administered in excessive amounts. The most common side effects of etidronate are some gastrointestinal disturbances such as discomfort, pain, and diarrhea. These occur only during oral administration at higher doses and are usually of minor intensity. Most often they disappear spontaneously or can be overcome by dividing the dose. Increased bone pain may occur transiently in patients with Paget's disease.

Oral etidronate can induce gastrointestinal disturbances which are, however, mostly minor. -+

The major and practically only complication of treatment with etidronate is the inhibition of normal skeletal mineralization, which can lead to a clinical and histological picture of osteomalacia. This effect is present at -~ 9 daily oral doses above 800 mg and has been well documented in various conditions. The inhibition regresses after discontinuation of therapy. In Paget's disease, the picture can be that of focal osteomalacia at areas of high bone turnover and can be accompanied by the appearance of radiolucent areas. These seem to be related to bone pain. In this condition, the inhibition of mineralization has been seen at doses as low as 400 mg orally, which normally do not have this effect. The focal nature of Paget's disease, with an increased uptake of bisphosphonate at areas of high turnover, may explain this phenomenon (Fig. 3.8-1). Fractures have occurred in children treated for fibrodysplasia ossificans progressiva, and possibly also in adults in Paget's disease, when high doses are given over longer periods. Lower extremity stress fractures have been described in patients receiving the regimen for osteoporosis. However, since the latter occurred after relatively short periods of treatment, the relation to the drug is doubtful. In children, long-term treatment at an oral dose of 20 mg/kg may also induce proximal muscular weakness, leading to an abnormal gait similar to that seen in rickets.

171

Effect in animals p. 49

Fibrodyspla ossificans p. 162

3. Bisphosphonatesmclinical

Etidronate induced ostemalacia

Fig. 3.8-1 Osteomalacia in a Pagetic patient after treatment with 20 mg/kg orally of etidronate over a long time. The dark areas are nonmineralized osteoid. (Courtesy of Dr. R. K. Schenk.) Osteoid

Etidronate can induce osteomalacia and rickets when given at oral doses over 10 mg/kg daily. The effect of smaller doses in long-term therapy are more difficult to assess. Bone biopsies have been performed in osteoporosis patients receiving etidronate in the intermittent cyclical regimen of 400 mg for 2 weeks every 3 months. A consensus exists that over 3 years this regimen does not lead to any clinical or morphological alterations of mineralization. The situation is less clear when therapy is pursued for longer. One study showed no evidence of histological changes after up to 7 years, while in another study which used sensitive histomorphometric criteria, an increased prevalence of localized areas of inhibition of mineralization was observed in some patients after 4 - 5 years. This was a time when bone turnover was increasing toward baseline levels. The changes did not persist or worsen with longer term exposure. No generalized osteomalacia or clinical problems were reported during the 7 years of treatment.

Very long-term treatment with 400 mg daily for 2 weeks every 3 months does not seem to induce any clinically relevant inhibition of mineralization. Etidronate can cause a conspicuous rise in plasma phosphate, often to high levels, both in healthy persons and in patients. The change is associated with an increase in renal tubular reabsorption of phosphate. While it was first thought that this effect was specific for etidronate, it can also occur occasionally with other bisphosphonates. The effect can, however, be obscured by secondary hyperparathyroidism. It is not associated with any clinical problems.

172

3.8. Adverse events Etidronate induces an increase in plasma phosphate. Intravenous infusions can induce a transient loss or alteration of taste with a metallic flavor which occurs, according to the package insert, in about 5% of the patients. In some individual studies the incidence was somewhat higher. Finally, one case of bronchospasm in an aspirin-sensitive patient has been described.

Pamidronate "~ The intravenous administration of pamidronate induces on the average in about 10% of the patients, but in some trials more often, a transient pyrexia of usually 1~176 sometimes more, accompanied by flu-like symptoms. Occasionally it is also accompanied by pain in the bones. It is maximal within 24 to 48 h and disappears within approximately 3 days, even when treatment is continued. The effect is dose-dependent and is most often only observed once, even if treatment is discontinued and restarted later. The pyrexia is accompanied by a decrease in peripheral lymphocytes, an increase in serum C-reactive protein, and a decrease in serum zinc. The mechanism of these changes, which resemble an acute-phase response, is still not completely understood, but seems to involve the stimulation of macrophages to release IL-6 and TNFa, which increase in plasma. This event occurs also with some other N-containing bisphosphonates, but not with etidronate, clodronate, or tiludronate. Up to now no negative consequences of these episodes have been described, and these appear to bear no clinical relevance, except for the slight discomfort in the first days of treatment.

Pamidronate, like some other N-containing bisphosphonates, induces transientpyrexia in the course of an acute-phase-like reaction. Pamidronate administered intravenously can induce occasional local thrombophlebitis at the infusion site. In this case alternation of the side -~ of infusion or a central venous catheter can be used. Otherwise it is well tolerated when given through this route. Recently it has, however, been reported that in patients with Paget's disease who received pamidronate intravenously at doses equal to or higher than 30 m g a week for 6 continuous weeks, four out of ten have displayed a defect in mineralization in both Pagetic and normal bone. Furthermore, patients who had received 45 mg intravenously every 3 months for 1 year displayed osteoid borders larger than normal. These changes disappeared after cessation of

173

3. Bisphosphonateswclinical

treatment. In an other study, a child with fibrous dysplasia, who was given 60 mg daily intravenously of pamidronate for 3 days in a continuous infusion every 6 months over 18 months, developed a radiological picture of defective mineralization of the epiphyseal plate, but without other clinical consequences. Pamidronate administered at intravenous doses equal to or higher than 180 rag/year can induce a transient inhibition ol: mineralization.

Animal studies p. 64

Effects of alendronate pp. 169-170

When given orally at doses of 300 mg or more daily, pamidronate can induce gastrointestinal disturbances with nausea, vomiting, pain, and diarrhea. Some cases of erosive esophagitis have also been reported. At 300 mg the effect seems to depend on the study. The heterogeneity of the response suggests that the formulation may be crucial, as this has varied a great deal between the studies. The timing of the dose is relevant, and it is important to avoid administration before sleeping, especially in bedridden patients. Finally, the amount of fluid given with the drug is of importance, and it is advised to take it with sufficient liquid, about 150 ml. With these various points taken into account and with the use of enterocoated micropellet capsules, these gastrointestinal side effects have decreased and may even do more so in the future. However, it is wise not to exceed the dose of 300 mg, which is the one used in the current trials. Oral pamidronate as well as other bisphosphonates containing a nitrogen atom can give rise to dose-related gastrointestinal disturbances that may be severe.

Ocular adverse events p. 170

Recently the manufacturer reported that on rare occasions, ocular adverse reactions occurred, which recurred under rechallenging, in patients receiving intravenous pamidronate. These reactions included anterior uveitis, episcleritis or scleritis, and conjunctivitis. The clinical manifestations were usually mild and responded to topical corticosteroid treatment. Pamidronate can in rare cases induce ocular adverse reactions. Risedronate

The safety and tolerance of risedronate has been established from controlled clinical studies involving over 15,000 patients. It has a favorable safety profile with adverse events reported to be similar to placebo. Some cases of iritis have been reported, as has been the case with other bisphosphonates.

174

3.8. Adverse events

Tiludronate Tiludronate appears to be well tolerated. One patient with a personal and family history of allergies was reported to have developed a widespread erythematous skin condition with vesicular and vesiculobullous periphery and a histological picture of epidermal necrosis. The mucous membranes remained unaffected. The condition was diagnosed at first as toxicoderma, later possibly as pemphigus, and required systemic corticosteroid therapy. Some sporadic cases of toxiderma have also been reported with other bisphosphonates. Diminution of renal function has been described in tumor-induced hypercalcemia with a high dose of an intravenous formulation, but the interpretation of these data is difficult, in view of the severe condition of the patients treated.

Other bisphosphonates No data are yet available.

Recommended selected reading Reviews Adami, S., and Zamberlan, N. (1996). Adverse effects of bisphosphonates. Drug Safety, 14, 158-170 Houston, S. J., and Rubens, R. D. (1998). The tolerability and adverse event profile of pamidronate disodium. Rev. Contemp. Pharmacother., 9, 213-224

Original articles Alendronate Graham, D. Y., Malaty, H. M., and Goodgame, R. (1997). Primary aminobisphosphonates: A new class of gastrotoxic drugsmComparison of alendronate and aspirin. Am. J. Gastroenterol., 92, 1322-1325 De Groen, P. C., Lubbe, D. F., Hirsch, L. J., Daifotis, A., Stephenson, W., Freedholm, D., Pryor-Tillotson, S., Seleznick, M. J., Pinkas, H., and Wang, K. K. (1996). Esophagitis associated with the use of alendronate. N. Engl. J. Med., 355, 1.016-1021 Maconi, G., and Porro, G. B. (1995). Multiple ulcerative esophagitis caused by alendronate. Am. J. Gastroenterol., 90, 1889-1890 Mbekeani, J. N., Slamovitz, T. L., Schwartz, B. H., and Sauer, H. L. (1999). Ocular inflammation associated with alendronate therapy. Arch. Ophtalmol., 117, 837-838

Clodronate Pedersen-Bjergaard, U., and Myhre, J. (1991). Severe hypocalcaemia after treatment with diphosphonate and aminoglycoside. Br. Med. J., 302, 295 Rolla, G., Bucca, C., and Brussino, L. (1994). Bisphosphonate-induced bronchoconstriction in aspirin-sensitive asthma. Lancet, 343, 426-427

175

3. B i s p h o s p h o n a t e s - - c l i n i c a l

Etidronate Bounameaux, H. M., Schifferli, J., Montani, J. P., Jung, A., and Chatelanat, F. (1983). Renal failure associated with intravenous diphosphonate (letter). Lancet, 1,471 Boyce, B. F., Smith, L., Fogelman, I., Johnston, E., Ralston, S., and Boyle, I. T. (1984). Focal osteomalacia due to low-dose diphosphonate therapy in Paget's disease. Lancet, 1,821824 de Vries, H. R., and Bijvoet, O. L. M. (1974). Results of prolonged treatment of Paget's disease of bone with disodium ethane-l-hydroxy-l,l-diphosphonate (EHDP). Neth. J. Med., 17, 281-298 Guanabens, N., Peris, P., Monegal, A., Pons, F., Collado, A., and Munoz-Gdmez, J. (1994). Lower extremity stress fractures during intermittent cyclical etidronate treatment of osteoporosis. Calcif. Tissue Int., 54, 431-434 Jowsey, J., Riggs, B. L., Kelly, P. J., Hoffman, D. L., and Bordier, P. (1971). The treatment of osteoporosis with disodium ethane-l-hydroxy-l,l-diphosphonate. J. Lab. Clin. Med., 78,574-584 Khairi, M. R. A., Altman, R. D., DeRosa, G. P., Zimmermann, J., Schenk, R. K., and Johnston, C. C. (1977). Sodium etidronate in the treatment of Paget's disease of bone. A study of long-term results. Ann. Intern. Med., 87, 656-663 Nagant de Deuxchaisnes, C., Rombouts-Lindemans, C., Huaux, J. P., Devogelaer, J. P., Malghem, J., Maldague, B., Withofs, H., and Meersseman, F. (1981). Paget's disease of bone. Br. Med. J., 283, 1054-1055 Recker, R. R., Hassing, G. S., Lau, J. R., and Saville, P. D. (1973). The hyperphosphatemic effect of disodium ethane-l-hydroxy-l,l-diphosphonate (EHDPTM): Renal handling of phosphorus and the renal response to parathyroid hormone. J. Lab. Clin. Med., 81, 258-266 Reiner, M., Sautter, V., Olah, A., Bossi, E., Largiad~r, U., and Fleisch, H. (1980). Diphosphonate treatment in myositis ossificans progressiva. In Caniggia, A. (ed.) Etidronate, pp. 237-241. (Pisa: Istituto Gentili) Rolla, G., Bucca, C., and Brussino, L. (1994). Bisphosphonate-induced bronchoconstriction in aspirin-sensitive asthma. Lancet, 343, 426-427

Pamidronate Adami, S., Bhalla, A. K., Dorizzi, R., Montesanti, F., Rosini, S., Salvagno, G., and Lo Cascio, V. (1987). The acute-phase response after bisphosphonate administration. Calcif. Tissue Int., 41,326-331 Adamson, B. B., Gallacher, S. J., Byars, J., Ralston, S. H., Boyle, J. T., and Boyce, B. F. (1993). Mineralisation defects with pamidronate therapy for Paget's disease. Lancet, 342, 14591460 Dodwell, D. J., Howell, A., and Ford, J. (1990). Reduction in calcium excretion in women with breast cancer and bone metastases using the oral bisphosphonate pamidronate. Br. J. Cancer, 61,123-125 Eggelmeijer, F., Papapoulos, S. E., van Paassen, H. C., Dijkmans, B. A. C., Valkema, R., Westedt, M. L., Landman, J.-O., Pauwels, E. K. J., and Breedveld, F. C. (1996). Increased bone mass with pamidronate treatment in rheumatoid arthritis. Arthritis Rheum., 39, 396-402 Harinck, H. I. J., Papapoulos, S. E., Blanksma, H. J., Moolenaar, A. J., Vermeij, P., and Bijvoet, O. L. M. (1987). Paget's disease of bone: Early and late responses to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD). Br. Med. J., 295, 1301-1305 Liens, D., Delmas, P. D., and Meunier, P. J. (1994). Long-term effects of intravenous pamidronate in fibrous dysplasia of bone. Lancet, 343,953-954 Lufkin, E. G., Argueta, R., Whitaker, M. D., Cameron, A. L., Wong, V. H., Egan, K. S., O'Fallon, W. M., and Riggs, B. L. (1994). Pamidronate: An unrecognized problem in gastrointestinal tolerability. Osteoporosis Int., 4, 320-322 Marcarol, V., and Fraunfelder, F. T. (1994). Pamidronate disodium and possible ocular adverse drug reactions. Am. J. Opthalmol., 118, 220-224

176

3.8. A d v e r s e events

Sauty, A., Pecherstorfer, M., Zimmer-Roth, I., Fioroni, P., Juillerat, L., Markert, M., Ludwig, H., Leuenberger, P., Burckhardt, P., and ThiSbaud, D. (1996). Interleukin-6 and tumor necrosis factor a levels after bisphosphonate treatment in vitro and in patients with malignancy. Bone, 18, 133-139 Schweitzer, D. H., Oostendorp-van de Ruit, M., van der Pluijm, G., L6wik, C. W. G. M., and Papapoulos, S. E. (1995). Interleukin-6 and the acute phase response during treatment of patients with Paget's disease with the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate. J. Bone Miner. Res., 10, 956-962 van Breukelen, F. J. M., Bijvoet, O. L. M., Frijlink, W. B., Sleeboom, H. P., Mulder, H., and van Oosterom, A. T. (1982). Efficacy of amino-hydroxypropylidene bisphosphonate in hypercalcemia: Observations on regulation of serum calcium. Calcif. Tissue Int., 34, 321-327 van Holten-Verzantvoort, A. T., Bijvoet, O. L. M., Cleton, F. J., Hermans, J., Kroon, H. M., Harinck, H. I. J., Vermey, P., Elte, J. W. F., Neijt, J. p., Beex, L. V. A. M., and Blijham, G. (1987). Reduced morbidity from skeletal metastases in breast cancer patients during long-term bisphosphonate (APD) treatment. Lancet, 2, 983-985

Tiludronate Dumon, J. C., Magritte, A., and Body, J. J. (1991). Efficacy and safety of the bisphosphonate tiludronate for the treatment of tumor-associated hypercalcemia. Bone Miner., 15, 257-266 Roux, C., Listrat, V., Villette, B., Lessana-Leibowitch, M., Ethgen, D., Pelissier, C., Dougados, M., and Amor, B. (1992). Long-lasting dermatological lesions after tiludronate therapy. Calcif. Tissue Int., 50, 378-380

177

3.9. CONTRAINDICATIONS Kinetics pp. 57-58

Etidronate on plasma Pi p. 172

Up to now, only a few contraindications have been described for the bisphosphonates. The question is often raised whether these compounds can be administered in renal failure. Because they are cleared from blood to a large extent by the skeleton, there is no theoretical reason to deny bisphosphonates in patients with moderate renal failure. Clodronate and pamidronate have in fact been administered successfully to treat hypercalcemia in patients with renal failure. However, plasma levels are likely to be higher, so that the dose should possibly be reduced. The exact amount of this reduction will only be known when plasma data are available. This is the case for clodronate, for which the following dosages have been recommended: 7 5 - 1 0 0 % for creatinine clearances between 50 and 80 ml per minute; 5 0 - 7 5 % for clearances between 12 and 50 ml per minute; and 50% of the normal dose for clearances below 12 ml per minute. Since the skeletal uptake is less for clodronate than for many other bisphosphonates, these values cannot be extrapolated to other compounds. It is therefore just suggested to reduce the dosage, according to the degree of renal failure. Furthermore, when the compounds are infused, a slower infusion rate is recommended. In addition, caution is indicated with etidronate in advanced renal failure, because of its propensity to increase already increased phosphate levels. For alendronate, the manufacturer advises not to administer the drug when the creatinine clearance is less than 35 ml/minute. In contrast, although plasma levels of pamidronate are higher in patients with a renal creatinine clearance below 30 ml/ minute, it has been suggested not to reduce the doses of this bisphosphonate in patients with cancer as the administration is performed only once every three months.

There is no absolute contraindication to the use of bisphospbonates in renal failure. However, the dose should be reduced.

Inhibition of mineralization p. 171

Another open question is whether bisphosphonates can be given during fracture healing or during stabilization of orthopedic implants such as hip prostheses. Recent data indicate that at least alendronate in the dog and man, clodronate and pamidronate in the rat, and ibandronate in the dog do not significantly hamper fracture healing. In fact the callus can be thicker, contain more calcium, and have greater mechanical strength, but it is remodeled at a later stage to normal bone size. Furthermore bisphosphonates can prevent bone loss under plates or around hip prostheses. It would appear, therefore, that there is no contraindication with the low doses such as those used in osteoporosis which do not inhibit mineralization. In contrast, large doses of etidronate, which are likely to inhibit mineralization, should be avoided. The same applies to patients with vertebral fractures. 178

3.9. Contraindications Fracture healing or new orthopedic implants are no contraindication to the use o[ bisphosphonates, provided they are not given in doses that inhibit mineralization. The question is often raised whether bisphosphonates can be administered in patients with cancer receiving treatment directed against the tumor itself. Up to now no evidence for a specific contraindication seems to have been described.

There appears to be no contraindication to use bisphosphonates together with tumor therapy. In view of the potential for gastrointestinal effects of bisphosphonates during oral administration, great caution should be used when giving these compounds orally, especially the more potent bisphosphonates, to patients with gastrointestinal esophageal disorders, such as ulcers, esophagitis, and esophageal dysmotility.

Gastrointestinal effec[s

pp. 169-170, 174

Oral administration should be used with great caution in patients with inflammatory gastrointestinal and esophageal conditions and with esophageal dysmotility. Since bisphosphonates can cross the placenta and can have deleterious effects on the fetus when given in high doses, they should not be used in pregnant women. Furthermore, since it is not known whether they are excreted in milk, it is also not advisable to give them to lactating women.

Effects on fetus p. 65

Bisphosphonates should not be given during pregnancy and lactation. Few data are available on interrelations with other drugs. Bisphosphonates should not be administered with aminoglycoside antibiotics, because of the possible development of hypocalcemia. No data are available on the effect of the simultaneous administration of different bisphosphonates. Therefore, only one bisphosphonate should be administered at a time. The concomitant use of estramustine phosphate and clodronate increases the serum concentration of the former, apparently because of a higher bioavailability.

A bisphosphonate should not be given together with another compound of the same class or with aminoglycosides.

179

Adverse events p. 168

3. Bisphosphonates~clinical

Recommended selected reading Berenson, J. H., Rosen, L., Vescio, R., Lau, H. S., Woo, M., Sioufi, A., Kowalski, M. O., Knight, R. D. and Seaman, J. J. (1997). Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function. J. Clin. Pharmacol., 37, 285-290 Goodship, A. E., Walker, P. C., McNally, D., Chambers, T., and Green, J. R. (1994). Use of a bisphosphonate (pamidronate) to modulate fracture repair in ovine bone. Ann. Oncol., 5(Suppl. 7), $53-$55 Kylmfil~i, T., Castren-Kortegangas, P., Seppanen, J., Ylitalo, P., and Tammela, T. L. J. (1996). Effect of concomitant administration of clodronate and estramustine phosphate on their bioavailability in patients with metastasized prostate cancer. Pharmacol. Toxicol., 79, 157-160 Nyman, M. T., Paavolainen, P., and Lindholm, T. S. (1993). Clodronate increases the calcium content in fracture callus. An experimental study in rats. Arch. Orthop. Trauma Surg., 112, 228-231 Peter, C. P., Cook, W. O., Nunamaker, D. M., Provost, M. T., Seedor, J. G., and Rodan, G. A. (1996). Effect of alendronate on fracture healing and bone remodeling in dogs. J. Orthop. Res., 14, 74-79 Saha, H., Castren-Kortekangas, P., Ojanen, S., Juhakoski, A., Tuominen, J., Tokola, O., and Pasternack, A. (1994). Pharmacokinetics of clodronate in renal failure. J. Bone Miner. Res., 9, 1953-1958 Tarvainen, R., Olkkonen, H., Nevalainen, T., Hyv6nen, P., Arnala, I., and Alhava, E. (1994). Effect of clodronate on fracture healing in denervated rats. Bone, 6, 701-705

180

3.10. FUTURE PROSPECTS The bisphosphonates represent an important development in the field of treatment of bone diseases, and it is probable that we are only at the beginning of a new era of therapy. Many issues are still unresolved. For example, we do not yet know whether we have found the optimal regimen for the various compounds available. This is especially the case in treatment of osteoporosis. How can the intravenous versus the oral therapy be compared? Is there an advantage to the use of an intermittent therapy? Are the newly proposed regimens of a weekly tablet, or of a 3-monthly injection, just the first step in a new evolution? Could one use longer intervals, possibly even once yearly treatment? Which are in the different cases the optimal regimens for the various bisphosphonates? Will there be an advantage in the future to combine bisphosphonates, or bisphosphonates with another inhibitor of resorption, such as estrogens in hormone replacement therapy, as is already done by some clinicians, SERMs, or with a stimulator of bone formation? Will it be possible in the future to synthesize compounds that have certain specific effects? For example, a compound acting only on ectopic calcification would be most useful. Since the long persistence of bisphosphonates in the body is a concern for some, it may be possible in the future to devise drugs that are similar to the bisphosphonates, have similar effects, but are metabolically broken down. The possible use of bisphosphonates in diseases other than those of bone has not yet been practically investigated. The results on experimental arthritis are most encouraging in this respect. Another interesting application may be in the dental field. Lastly, the results showing that bisphosphonates have an effect on the apoptosis and adherence of tumor cells, open the possibility that these drugs might be of use in tumors other than only those affecting bone metabolism. In addition, the use of bisphosphonates or bisphosphonate analogs as carriers for drugs to be brought to the bone or to other calcified tissues is another line of investigation, although it might be difficult to find appropriate chemical linkages that will allow the selective release of the active compound at the desired location. Lastly, it could be that with a still better knowledge of the mode of action of these compounds at the cellular level, new insight will be gained into the physiological and pathophysiological function of bone, opening up new approaches to therapy.

181

4. Commerciallyavailable bisphosphonates

Country

Bisphosphonate Trade name

Company

Indications

Form

Fosamax

Merck Sharp & Dohme

Osteoporosis ~

po

Argentina Alendronate

Marvil 10

Elisium SA

Osteoporosis

po

Clodronate

Ostac

Roche

Tumoral osteolysis Hypercalcemia of malignancy

po & iv

Pamidronate

Aminomux

Gador SA

Paget's disease Osteoporosis Tumoral osteolysis Hypercalcemia of malignancy

po iv

Pamidronate + calcium

Osteokit

Gador SA

Osteoporosis

po

Tiludronate

Skelid

Sanofi Winthrop

Paget's disease

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Rh6ne-Poulenc Rorer

Hypercalcemia of malignancy

po & iv

Etidronate

Didronel

Upjohn/ Pharmacia

Paget's disease Heterotopic ossification

po

Australia

continued

182

Commercially available bisphosphonates

Country Company

Indications

Form

Osteoporosis

po

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Fresenius

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Lodronat

Roche

Hypercalcemia of malignancy Tumoral osteolysis

p o & ;v

Didronel

HMR

Paget's disease Heterotopic ossification Osteoporosis

po

Bisphosphonate

Trade name

Pamidronate

Didrocal

Austria

Etidronate

Roehm Pharma

Ibandronate

Bondronat

Roche

ftypercalcem.ia of malignancy

iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Tumoral osteolysis Bone metastases Paget's disease

iv

Tiludronate

Skelid

Sanofi Winthrop

Paget's disea~e

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Bahamas Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Bonefos

Schering

Hypercalcemia of malignancy Tumoral ostelysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Azerbaijan

Bahrain Clodronate

continued

183

4. Commercially available bisphosphonates

Country

Bisphosphonate Trade name

Company

Indications

Form

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

UCB Pharma

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis Osteolytic bone metastases

po & iv

Didronel

Procter & Gamble

Hypercalcemia of malignancy Paget's disease Periarticular ossification

po

Barbados Alendronate

Belarus

Belgium

Etidronate

Osteodidronel

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma

iv

Tiludronate

Skelid

Sanofi Winthrop

Paget's disease

po

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Marvil 10

Raices Ltd.

Osteoporosis

po

Belize A lendronate

Bermuda Alendronate

Bolivia Alendronate

continued

184

Commercially available bisphosphonates

Country Trade name

Company

Indications

Form

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Asta Medica

Hypercalcemia of malignancy Bone metastases

po & iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases

Tiludr onate

Skelid

Sanofi Winthrop

Paget's disease

po

A lendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Frosst

Paget's disease Osteoporosis

po

Clodronate

Bonefos

Rh6ne-Poulenc iorer

Hypercalcemia of malignancy

po & iv

Ostac

Roche

Hypercalcemia of malignancy

po & iv

Etidronate

Didronel

Procter & Gamble

Paget's disease Osteoporosis Hypercalcemia of malignancy

po po iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

Risedronate

Actonel

Paget's disease Alliance for Better Bone Health (Procter & Gamble and Aventis)

po

Fosamax

Merck Sharp & Dohme

po

Bisphosphonate

Brazil

Bulgaria

Canada

Cayman Islands Alendronate

Osteoporosis

continued

185

4. Commercially available bisphosphonates

Country Trade name

Company

Indications

Form

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Roche

Hypercalcemia of malignancy Paget's disease

po & iv

Pamidronate

Aminomux

Andromaco

Bone metastases Hypercalcemia of malignancy

iv

Aredia

Novartis

Bone metastases

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis Bone metastases

po & iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Paget's disease

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Roche

Hypercalcemia of malignancy Paget's disease

Bisphosphonate

Chile

P.R. China

Colombia

Griinenthal Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases

Fosamax

Merck Sharp & Dohme

Osteoporosis

Pamidronate

Costa Rica po

Croatia Alendronate

po

continued i

186

Commercially available bisphosphonates Country

Trade name

Company

Indications

Form

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Papaellina

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Lodronat

Roche

Tumoral osteolysis

po & iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Tumoral osteolysis Bone metastases

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Astra Zeneca

Hypercalcemia, Tumoral osteolysis Prevention of vertebral fractures in breast cancer with bone metastasis

po & iv

Ostac

Ercopharm

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Etidronate

Didronate

Roche

Paget's disease Heterotopic ossification Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma

iv

Merck Sharp & Dohme

Osteoporosis

po

Bisphosphonate

Curacao Alendronate

Cyprus

Czech Republic

Denmark

Dominican Republic A lendronate

Fosamax

187

continued

4. Commercially available bisphosphonates

Country Bisphosphonate

Trade name

Company

Indications

Form

Clodronate

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Pamidronate

Aminomux

Sued

Osteoporosis

po

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Gr~inenthal

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Pamidronate

Aminomux

Marco-Med

Paget's disease Osteoporosis

po

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ecuador

Egypt

El Salvador

Estonia

continued

188

Commercially available bisphosphonates Country Trade name

Company

Indications

Form

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Leiras

Hypercalcemia of malignancy Osteolytic bone metastases

po & iv

Etidronate + calcium

Didronate

Roche

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma

iv

Tiludronate

Skelid

Sanofi Winthrop

Paget's disease

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Clastoban

Rh6ne-Poulenc Rorer

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Lytos

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Didronel

Procter & Gamble

Paget's disease Osteoporosis Hypercalcemia of malignancy

po

Bisphosphonate

Finland

France

Etidronate

iv

lbandronate

Bondronat

Roche

Hypercalcemia of malignancy

iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

Tiludronate

Skelid

Sanofi Winthrop

Paget's disease

po

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

French Guiana Alendronate

French Polynesia A lendronate

continued

189

4. Commercially available bisphosphonates

Country Trade name

Company

Indications

Form

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Astra/Medac

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Didronel

Procter & Gamble

Osteoporosis

po

Diphos

Procter & Gamble

Paget's disease Heterotopic ossification

po

Hypercalcemia of malignancy

iv

Bisphosphonate

Germany

Etidronate

Etidronate iv

Ibandronate

Bondronat

Roche

Hypercalcemia of malignancy

iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metaastases Multiple myeloma Paget's disease

iv

Tiludr onate

Skelid

Sanofi Winthrop

Paget'sdisease

po

A lendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Farmalex

Hypercalcemia of malignancy Tumoral osteolysis Paget's disease

po & iv

Greece

Etidronate

Ostopor

Unipharm

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Multiple myeloma Bone metastases

iv

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Guadeloupe Alendronate

continued

190

Commercially available bisphosphonates

Country Trade name

Company

Indications

Form

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

CIodronate

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Roche

H),percalcemia of malignancy Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Lodronat

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Bisphosphonate

Guatemala

Guyana Alendronate

Haiti Alendronate

Honduras

Hong Kong

Pamidronate

Hungary

continued

191

4. Commercially available bisphosphonates Country

Bisphosphonate

Trade name

Company

Indications

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

Alendronate

Fosamax

Osteoporosis

po

Clodronate

Bonefos

Merck Sharp & Dohme Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Loron

Ercopharm

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Aredia

Novartis

Hypercalcemia of malignanc Multiple myeloma Bone metastases

iv

Aminomux

Mac Laboratories

Hypercalcemia of malignancy

Aredia

Novartis

Hypercalcemia of malignancy

Alendronate

Fosamax

Osteoporosis

po

Clodronate

Bonefos

Merck Sharp & Dohme Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases

iv

Aredia

Novartis

Bone metastases Multiple myeloma

Bonefos

Schering

Tumoral osteolysis

Form

Iceland

Pamidronate

India Pamidronate

Indonesia

Pamidronate

Iran Pamidronate

Iraq Clodronate

po & iv

continued

192

Commercially available bisphosphonates Country

Trade name

Company

Indications

Form

Alendronate

Fosamax

Osteoporosis

po

Clodronate

Bonefos

Merck Sharp & Dohme Boehringer I.

po & iv

Etidronate

Didronel

Procter & Gamble

Hypercalcemia of malignancy Tumoral osteolysis Paget's disease Heterotopic ossification Hypercalcemia of malignancy

Bisphosphonate

Ireland

po iv

Didronel PMO Procter & Gamble Aredia Novartis

Osteoporosis Hypercalcemia of malignancy Tumoral osteolysis

po iv

Alendronate

Fosamax

Osteoporosis

po

Clodronate

Bonefos

Merck Sharp & Dohme Agis/Schering

po & iv

Ostac

Abic

Aredia

Novartis

Hypercalcemia of malignancy Osteolytic bone metastases Hypercalcemia of malignancy Tumoral osteolysis Hypercalcemia of malignancy Bone metastases Multiple myeloma

Alendronate

Adronat Alendros Dronal Fosamax

Osteoporosis Osteoporosis Osteoporosis Osteoporosis

po po po po

Clodronate

Clasteon

Neopharmed Abiogen Sigma-Tau Merck Sharp & Dohme Abiogen

Tumoral osteolysis Multiple myeloma Primary hyperparathyroidism Osteoporosis Tumoral osteolysis Multiple myeloma Primary hyperparathyroidism Osteoporosis

po, iv & im

Pamidronate

Israel

Pamidronate

po & iv

iv

Italy

Difosfonal

SPA

po po, iv & im po

continued

193

4. Commercially available bisphosphonates Country Trade name

Company

Indications

Form

Ossiten

Roche

Tumoral osteolysis Multiple myeloma Primary hyperparathyroidism Osteoporosis

po, iv & im

Didronel

Procter & Gamble

Osteoporosis

po

Etidron

Abiogen

Paget's disease

po

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases

iv

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Onclast

Banyu

Hypercalcemia of malignancy

iv

Teiroc

Teijin

Hypercalcemia of malignancy

iv

Etidronate

Didronel

Sumitomo

Paget's disease Heterotopic ossification Osteoporosis

po

Incadronate

Bisphonal

Yamanouchi

Hypercalcemia of malignancy

iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Tumoral osteolysis

po & iv

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Alend

Whan-In Co.

Osteoporosis

po

Bisphosphonate

Etidronate Pamidronate

po

Jamaica Alendronate

Japan Alendronate

po

Jordan

Kazakhstan

Kenya Alendronate

Korea Alendronate

continued

194

Commercially available bisphosphonates

Country Bisphosphonate

Trade name

Company

Indications

Form

Fosamax

Osteoporosis

po

Osteoporosis Hypercalcemia of malignancy Tumoral osteolysis

po

Clodronate

Ostac

Merck Sharp & Dohme Yu-Yu Co. CKD

Pamidronate

Aminomux

Han Lim Co.

Paget's disease Osteoporosis Tumoral osteolysis

po & iv

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

po & iv

Ostac

Roche/ A1-Ganim

Paget's disease Hypercalcemia of malignancy Hypercalcemia of malignancy Tumoral osteolysis

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Tumoral osteolysis

po & iv

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

UCB Pharma

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Marvil

po & iv

Kuwait

po & iv

Latvia

Lebanon Alendronate

Lithuania

Luxemburg

continued

iii iiii

195

4. Commercially available bisphosphonates

Country

Bisphosphonate

Trade name

Company

Indications

Form

Etidronate

Didronel

Procter & Gamble

Paget's disease Hypercalcemia of malignancy

po iv

Ibandronate

Bondronat

Roche

Hypercalcemia of malignancy

iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy

iv

Tiludronate

Skelid

Sanofi Winthrop

Paget's disease

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Roche

Tumoral bone disease po & iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Vivian

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

Malaysia

Malta

Martinique Alendronate

Mexico

Moldova Clodronate

po & iv

continued

196

Commercially available bisphosphonates Country

Trade name

Company

Indications

Form

Didronel

Procter & Gamble

Osteoporosis

po

A lendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy

po & iv

Bisphosphonate

Morocco Etidronate

The Netherlands

Etidronate

Didrokit

Procter & Gamble

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy

iv

Tiludr onate

Skelid

Sanofi Winthrop

Paget's disease

po

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Etidronate

Didronel

Pharmaco (NZ)

Paget's disease Heterotopic ossification Osteoporosis Hypercalcemia of malignancy

po

New Caledonia Alendronate

New Zealand

Clodronate

Ostac

Roche

Tumoral osteolysis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Tumoral osteolysis Bone metastases Multiple myeloma Paget's disease

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases

Nicaragua

continued

197

4. Commercially available bisphosphonates Country

Bisphosphonate Tradename

Company

Indications

Form

Norway AIendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy

po & iv

Ostac

Organon

Hypercalcemia of malignancy

po & iv

Etidronate

Didronate

Roche

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Tumoral osteolysis

po & iv

A lendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Tumoral osteolysis

po & iv

Pamidronate

Aminomux

Seignior Pharma

Osteoporosis Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Quimifar

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

Aminomux

Gador Paraguay SA

Osteoporosis Hypercalcemia of malignancy Tumoral osteolysis

Oman

Pakistan

Panama

Paraguay Pamidronate

po & iv

continued

198

Commercially available bisphosphonates

Country Trade name

Company

Indications

Form

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Marvil

Farmindustria

Osteoporosis

po

Pamidronate

Aminomux

Vitalab S.A.

Paget's disease Osteoporosis Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Rh6ne-Poulenc Rorer

Paget's disease Hypercalcemia of malignancy

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Lodronat

Roche

Tumoral osteolysis

po & iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering Lusitana

Tumoral osteolysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Etidronate

Didronel

Lab Normal

Paget's disease Heterotopic ossification Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Tumoral osteolysis Bone metastases Paget's diseasse

iv

Bisphosphonate

Peru

Philippines

Poland

Portugal

continued

199

4. Commercially available bisphosphonates

Country

Bisphosphonate

Trade name

Company

Indications

Form

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Roche Opsis Pharmacy

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate Pamidronate

Bonefos

Schering

Tumoral osteolysis

po & iv

Aredia

Novartis

Hypercalcemia of malignancy Multiple myeloma Bone metastases Paget's disease

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Osteolytic bone metastases

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering Family Care

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Aredia

Novartis

Hypercalcemia of malignancy

iv

Qatar

Reunion Alendronate

Romania

Russia

Saudi Arabia

Singapore

Pamidronate

continued i

200

Commercially available bisphosphonates

Country Trade name

Company

Indications

Form

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Tumoral osteolysis

po & iv

Lodronat

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Aredia

Novartis

Hypercalcemia of malignancy Tumoral osteolysis

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Osteolytic bone

po & iv

Bisphosphonate

Slovak Republic

Pamidronate

Slovenia

metastases

Tumoral osteolysis Paget's disease Lodronat

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Roche

Hypercalcemia of malignancy

po & iv

Etidronate Pamidronate

Didronel

Roche

Paget's disease

po

Novartis

Hypercalcemia of malignancy Bone metastases Paget's disease

iv

Merck Sharp & Dohme

Osteoporosis

po

Pamidronate

South Africa

Aredia

South West Africa A lendronate

Fosamax

continued

201

4. Commercially available bisphosphonates Country

Trade name

Company

Indications

Form

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Prodesfarma/ Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Mebouat

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Etidronate

Difosphen / Osteum

Rubio/\;~nas

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Paget's disease

iv

Tiludronate

Skelid

Sanofi Winthrop

Paget's disease

po

Ostac

J. L. Morison

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodro nate

Bonefos

Astra Zeneca

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Didronat

Roche

Paget's disease

po

Osteoporosis

po

Bisphosphonate

Spain

Sri Lanka Clodronate

Sweden

Etidronate

Didronat 400 mg + Calcium 500 mg

Ibandronate

Bondronat

Roche

Hypercalcemia of malignancy

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma

continued

202

Commercially available bisphosphonates Country

Bisphosphonate

Trade name

Company

Indications

Risedronate

Optinate

Alliance for Paget's disease Better Bone Health (Procter & Gamble and Aventis)

po

Tiludronate

Skelid

Sanofi Winthrop

Paget's disease

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Astra Zeneca

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Ostac

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Etidronate

Didronel

Procter & Gamble

Paget's disease Heterotopic ossification

po

lbandronate

Bondronat

Roche

Hypercalcemia of malignancy

iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma

iv

Tiludronate

Skelid

Sanofi Winthrop

Paget's disease

po

Alendronate

Fosamax

Osteoporosis

po

Clodronate

Bonefos

Merck Sharp & Dohme Schering

Hypercalcemia of malignancy Osteolytic bone metastases

po & iv

Osteoporosis

po

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Form

Switzerland

Taiwan

Thailand Alendronate

Fosamax

Clodronate

Bonefos

Merck Sharp & Dohme Schering

Ibandronate

Bondronat

Roche

Hypercalcemia of malignancy

iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy

iv

continued i

203

4. Commercially available bisphosphonates

Country

Bisphosphonate Tradename

Company

Indications

Form

po

Trinidad/Tobago A lendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases

Clodronate

Bonefos

Dimas-Tunisie

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Etidronate

Didronel

Procter & Gamble

Osteoporosis

po

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Er-Kim

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

Tiludronate

Skelid

Sanofi Winthrop

Paget's disease

po

Tunisia

Turkey

Ukraine

United Arab Emirates Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Schering

Hypercalcemia of malignancy Osteolytic bone

po & iv

metastases

continued

204

Commercially available bisphosphonates Country

Bisphosphonate

Trade name

Company

Indications

Form

Ostac

Roche/ Pharmatrade

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

A lendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Bonefos

Boehringer I

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Loron

Roche

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Didronel

Procter & Gamble

Paget's disease Hypercalcemia of malignancy

po & iv

Didronel PMO swallowable

Procter & Gamble

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

Tiludronate

Skelid

Sanofi Winthrop

Paget's disease

po

Alendronate

Fosamax

Merck & Co. Inc.

Paget's disease Osteoporosis

po

Etidronate

Didronel

Procter & Gamble

Paget's disease Heterotopic ossification Hypercalcemia of malignancy

po

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

United Kingdom

Etidronate

United States

MGI Pharma

iv

Pamidronate

Aredia

Novartis

Risedronate

Actonel

Paget's disease Alliance for Better Bone Health (Procter & Gamble and Aventis)

po

Tiludronate

Skelid

Sanofi

Paget's disease

po

Marvil

Gador SA

Osteoporosis

po

Uruguay Alendronate

continued

205

4. Commercially available bisphosphonates

Country

Bisphosphonate Trade name

Company

Indications

Form

Pamidronate

Gador SA

Paget's disease Osteoporosis Tumoral osteolysis Hypercalcemia of malignancy

po

Aminomux

iv

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

Venezuela Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Clodronate

Ostac

Laboratorios Vargas

Hypercalcemia of malignancy Tumoral osteolysis

po & iv

Pamidronate

Aminomux

Leti

Hypercalcemia of malignancy Bone metastases

iv

Aredia

Novartis

Hypercalcemia of malignancy Bone metastases Multiple myeloma Paget's disease

iv

Bonefos

Schering

Hypercalcemia of malignancy Osteolytic bone metastases

po & iv

Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Yugoslavia Alendronate

Fosamax

Merck Sharp & Dohme

Osteoporosis

po

Pamidronate

Aredia

Novartis

Hypercalcemia of malignancy

iv

Vietnam Clodronate

Virgin Islands

Note: This list is based on information received from the companies mentioned in it. It is possible that we missed some firms selling bisphosphonates and of which we were not aware. If this was the case, we are sorry for the unintentional omission. ~The term osteoporosis includes various subindications such as prevention, treatment, glucocorticoid-induced osteoporosis. The reader should contact local manufacturers for exact indications in his country.

206

Index

Actonel, see Risedronate Adverse events, 168-175 alendronate, 169-170 clodronate, 170-171 etidronate, 171-173 overview, 168-1_69 pamidronate, 108, 173-174 risedronate, 174 tiludronate, 174-175 Alendronate adverse events, 1.69-170 bone resorption inhibition potency, 4041 commercial availability, 182-206 osteolytic tumor-induced bone disease treatment, 108 -109 osteoporosis treatment, 1.34, 139, 142150 Paget's disease treatment, 78-79 reflex sympathetic dystrophy syndrome treatment, 166 structure, 31 toxicity, 64, ! 69-170 Aminomux, see Pamidronate Animal studies, see Preclinical studies Application, see Pharmacokinetics; specific drugs

Aredia, see Pamidronate Arthritis future research directions, 181 treatment, 166 Basic multicellular units, physio'ogy, 2, 13-15, 127, 135 Biology, see also specific drugs future research directions, 181 preclinical actions, 34-51 bone resorption inhibition, 34-47 direct effects, 43-46

207

experimentally increased bone resorption animal studies, 39-40 indirect effects, 46-47 intact animal studies, 36-39 mechanisms, 41-47 relative activity, 40-41 in vitro studies, 34-36 cartilage resorption inhibition, 50 mineralization inhibition, 48-50 ectopic mineralization, 48 normal mineralization, 49, 56 minor effects, 50-51. Bisphosphonates, see Preclinical studies; specific diseases; specific drugs

Bondronat, see Ibandronate Bone cells, see specific types Bonefos, see Clodronate Bone matrix, composition, 4-5 Bone mineral density, see also Mineralization bisphosphonate effects, 137-143 osteoporosis definition, 123, 13 7 turnover relationship, 4-5, 16, 42 Bone physiology, 1-21 calcium homeostasis, see Calcium homeostasis composition of bone, 3-12 hemopoietic cells, 12 immune cells, 12 lining cells, 7 minerals, 3 - 4 organic matrix, 4-5 osteoblasts, 5-6 osteoclasts, 8-11 osteocytes, 7- 8 stromal cells, 12 modeling, 6, 12-16 morphology, 1-2

Index

Bone physiology (continued) organ function, 19-20 remodeling, 6, 8, 12-16 turnover assessment, see Turnover Bone resorption inhibition, 3 4 - 4 7 direct effects, 43-46 experimentally increased bone resorption animal studies, 39-40 indirect effects, 4 6 - 4 7 intact animal studies, 36-39 mechanisms, 41-47 relative bisphosphonate activity, 40-41,164 in vitro studies, 34-36 local bone destruction osteolytic tumorinduced bone disease, 88-89 Bone turnover, see Turnover Calcifcation, see Heterotopic calcification; Ossification Calcitonin calcium homeostasis regulation, 17-18 Paget's disease treatment, 72 Calcitriol, see 1,25-(OH)2 Vitamin D Calcium homeostasis bone physiology, 10, 12, 16-19 daily calcium requirements, 19, 126127, 132 metabolism, 38-39 non-tumor-induced hypercalcemia relationship, 118 osteolytic tumor-induced bone disease relationship, 90- 91 osteoporosis relationship, 126, 132 Calcium phosphate, bisphosphonate effects, 34 Calculus, treatment, 162 Cancer-induced disease, see Osteolytic tumor-induced bone disease Cartilage, resorption inhibition, 50 Charcot neuroarthropathy, treatment, 166 Chemistry, see also specific drugs future research directions, 181 preclinical studies, 30-33 Clinical studies, see specific diseases; specific drugs

Clodronate adverse events, 170-171 bone resorption inhibition potency, 4041 commercial availability, 182-206 hypercalcemia treatment, 99-105, 109-110, 120 osteolytic tumor-induced bone disease treatment, 99-105, 109-110 osteoporosis treatment, 133, 138, 141, 150 Paget's disease treatment, 74, 79

renal failure treatment, 178-179 structure, 31 toxicity, 64-65, 170-171 Commercial availability, 182-206 Contraindications, 178-179 Corticosteroids hypercalcemia treatment, 119 osteoporosis induction, 6 Coupling, bisphosphonate effects, 73, 136 Cytokines, local bone destruction, 88-89 Dental calculus, treatment, 162 Dermal application, preclinical pharmacokinetics, 60 Diabetic Charcot neuroarthropathy, treatment, 166 Didronel, see Etidronate Distribution, see also Adverse events preclinical pharmacokinetics, 5 7 - 5 9 EB-1053 bone resorption inhibition potency, 4 0 41 structure, 31 Ectopic calcification, see Heterotopic calcification Estrogen replacement, osteoporosis prevention, 130-132 Etidronate adverse events, 171-173 bone resorption inhibition potency, 4041,164 commercial availability, 182-206 fibrodysplasia ossificans progressiva treatment, 163 hypercalcemia treatment, 105-106, 109-110, 121 osteolytic tumor-induced bone disease treatment, 105-106, 109-110 osteoporosis treatment, 138, 145, 150151 Paget's disease treatment, 74, 79-80, 82 structure, 31 toxicity, 65, 171-173 Fibrodysplasia ossificans progressiva, treatment, 162-163 Fibrous dysplasia, treatment, 166-167 Fluoride, bone formation role, 6, 132 Fosamax, see Alendronate Fractures, bisphosphonate effects, 144148, 179 Future research directions, 181 Gastrointestinal effects contraindications, 179 intestinal absorption, 56 Gaucher's disease, treatment, 166

208

Index

Hemopoietic cells, physiology, 12 Hereditary hyperphosphatasia, treatment, 166 Heterotopic calcification description, 160, 164 manifestations, 160-161 mineralization inhibition, 48, 164 pathophysiology, 160 treatment, 161-164 dental calculus, 162 drug availability, 182-206 non-bisphosphonate drugs, 161 preclinical studies, 48-50, 161 soft tissue calcification, 161-162 urolithiasis, 162 Hypercalcemia drug availability, 182-206 non-tumor-induced, 118-121 description, 118 manifestations, 118 pathophysiology, 118 treatment, 119-121 effects, 120 non-bisphosphonate drugs, 119 preclinical studies, 119 regimens, 120-121 tumor-induced, 88-110 mechanisms, 90-92 symptoms, 92-93 treatment, 94-109 alendronate use, 108-109 clodronate use, 99-105, 109110 effects, 98-104 etidronate use, 105-106, 109110 ibandronate use, 106 - 1 1 0 incadronate use, 108-109 neridronate use, 108-109 non-bisphosphonate drugs, 9 4 95 pamidronate use, 102-103, 106-110 potency comparisons, 109-110 preclinical studies, 95-98 regimens, 104-109 risedronate use, 108-109 urinary parameters, 99-100 Hyperphosphatasia, treatment, 166

Paget's disease treatment, 83 structure, 31 Immune cells, physiology, 12 Incadronate bone resorption inhibition potency, 4 0 41 osteolytic tumor-induced bone disease treatment, 108 -109 structure, 31 Injection, adverse events, 168 Intestinal absorption, preclinical pharmacokinetics, 56 Intranasal application, preclinical pharmacokinetics, 60 Klinefelter syndrome, treatment, 166 Lactation contraindications, 179 Lining cells, physiology, 7 Local bone destruction, osteolytic tumorinduced bone disease pathophysiology, 88-89 Lodronat, see Clodronate Marvil 10, see Alendronate Matrix, composition, 4 - 5 Menopause, osteoporosis relationship, 125-127, 140-142, 146 Mevalonate pathway, bisphosphonate effects, 42, 44 - 45 Mineralization, see also Bone mineral density; Ossification inhibition, preclinical biology, 48-50 ectopic mineralization, 48 normal mineralization, 49, 56 Minerals, see also Bone mineral density bone composition, 3 - 4 Minodronate bone resorption inhibition potency, 4 0 41 structure, 31 Modeling, bone physiology, 6, 12-16 Morphology, bone physiology, 1-2 Neridronate bone resorption inhibition potency, 4 0 41 osteolytic tumor-induced bone disease treatment, 108-109 Paget's disease treatment, 83 structure, 31

Ibandronate bone resorption inhibition potency, 4 0 41 commercial availability, 182-206 Klinefelter syndrome treatment, 166 osteolytic tumor-induced bone disease treatment, 106 - 1 1 0 osteoporosis treatment, 140, 151

Olpadronate bone resorption inhibition potency, 4 0 41 Paget's disease treatment, 80 structure, 32 Organic matrix, composition, 4 - 5

209

Index

Ossification description, 160, 164 manifestations, 160-161 pathophysiology, 160 treatment, 161-164 drug availability, 182-206 fibrodysplasia ossificans progressiva, 162-163 hip ossification, 163 inhibition, 48-49, 164 non-bisphosphonate drugs, 161 preclinical studies, 48-50, 161 Ostac, see Clodronate Osteoblasts lining cells, 7 physiology, 5-6 Osteoclasts bisphosphonate effects, 43-44, 4 6 - 4 7 physiology, 8-11 Osteocytes, physiology, 7-8 Osteodidronel, see Etidronate Osteogenesis imperfecta, treatment, 166 Osteokit, see Pamidronate Osteolytic tumor-induced bone disease, 88-110 description, 88, 110 manifestations, 92-94 laboratory indications, 93-94 progression follow-up, 94 signs and symptoms, 92-93 pathophysiology, 88-92 generalized bone destruction, 90 hypercalcemia mechanisms, 90-92 local bone destruction, 88-89 treatment, 94-109 alendronate use, 108-109 clodronate use, 99-105, 109-110 contraindications, 179 drug availability, 182-206 effects, 98 -104 etidronate use, 105-106, 109-110 hypercalcemia, 98-99 ibandronate use, 106 - 1 1 0 incadronate use, 108 -109 neridronate use, 108-109 non-bisphosphonate drugs, 94 - 95 pamidronate use, 102-103, 106 110 potency comparisons, 109-110 preclinical studies, 95-98 regimens, 104-109 risedronate use, 108-109 urinary parameters, 99-100 Osteomalacia description, 5 osteoporosis compared, 124 Osteoporosis, 123-152 calcium requirements, 19, 126-127, 132

corticosteroid-induced, 6 description, 2, 123, 152 epidemiology, 123-124 manifestations, 128-130 diagnosis, 129 laboratory indications, 128-129 progression follow-up, 129-130 signs and symptoms, 1.28 osteomalacia compared, 124 pathophysiology, 124-127 treatment, 130-152 drug availability, 182-206 effects, 136-149 additive effects, 148-149 bone mineral density, 123, 137143 bone turnover, 143 - 144 drug discontinuation, 148 fractures, 144 -148 non-bisphosphonate drugs, 6, 130133 preclinical studies, 133-136 regimens, 149-152 alendronate use, 134, 139, 142150 clodronate use, 133, 138, 141, 150 etidronate use, 138, 145, 150151 ibandronate use, 140, 151 pamidronate use, 138-139, 141, 151 tiludronate use, 152 turnover rate effects, 12-13, 15, 38, 42, 130 Paget's disease, 68-83 description, 68, 83 epidemiology, 68 manifestations, 69-72 diagnosis, 71 laboratory indications, 4, 21, 70-71 progression follow-up, 71-72 signs and symptoms, 69 pathophysiology, 68-69 treatment, 72-83 alendronate use, 78-79 bisphosphonate effectiveness, 59 clodronate use, 74, 79 drug availability, 182-206 effects, 72-76 etidronate use, 74, 79-80, 82 ibandronate use, 83 neridronate use, 83 non-bisphosphonate drugs, 72 olpadronate use, 80 pamidronate use, 80-81 preclinical studies, 72 regimens, 76-83

210

Index

risedronate use, 81-82 tiludronate use, 82-83 zoledronate use, 83 Pamidronate adverse events, 108, 173-174 bone resorption inhibition potency, 4 0 41,59 commercial availability, 182-206 fibrous dysplasia treatment, 166 hypercalcemia treatment, 102-103, 106-110, 121 osteogenesis imperfecta treatment, 166 osteolytic tumor-induced bone disease treatment, 102-103, 106-110 osteoporosis treatment, 138-139, 141, 151 Paget's disease treatment, 80-81 reflex sympathetic dystrophy syndrome treatment, 166 renal failure treatment, 178-179 structure, 32 toxicity, 65, 108, 173-174 Parathyroid hormone calcium homeostasis regulation, 17 osteoporosis treatment, 132-133 Paget's disease treatment, 73, 75 Pharmacokinetics adverse events, 168-175 alendronate, 169-170 clodronate, 170-171 etidronate, 171-173 overview, 168-169 pamidronate, 173-174 risedronate, 174 tiludronate, 174-175 future research directions, 181 preclinical studies, 56-60 dermal application, 60 distribution, 5 7 - 5 9 intestinal absorption, 56 intranasal application, 60 renal clearance, 59-60 Physicochemistry future research directions, 181 preclinical actions, 34 Physiology, see Bone physiology Preclinical studies actions, 34-51 biological effects, 3 4 - 5 1 bone resorption inhibition, 3 4 47 cartilage resorption inhibition, 50 direct effects, 43-46 ectopic mineralization, 48 experimentally increased bone resorption animal studies, 39-40 indirect effects, 4 6 - 4 7

211

intact animal studies, 36-39 mechanisms, 41-47 mevalonate pathway inhibition, 42, 4 4 - 4 5 mineralization inhibition, 48-50 minor effects, 5 0 - 5 1 normal mineralization, 49, 56 relative bisphosphonate activity, 40-41 in vitro studies, 34-36 chemistry, 30-33 non-tumor-induced hypercalcemia treatment, 119 ossification and calcification treatment, 161 osteolytic tumor-induced bone disease treatment, 95-98 osteoporosis treatment, 133-136 Paget's disease treatment, 72 pharmacokinetics, 56-60 dermal application, 60 distribution, 5 7 - 5 9 intestinal absorption, 56 intranasal application, 60 renal clearance, 59-60 pharmacological development, 27-29 toxicology, 63-65 acute toxicity, 63 nonacute toxicity, 6 3 - 6 5 alendronate, 64 clodronate, 64-65 etidronate, 65 minor bisphosphonates, 65 pamidronate, 65 Pregnancy contraindications, 179 Pyrophosphate, characteristics, 27-30 Reflex sympathetic dystrophy syndrome, treatment, 166 Remodeling bone physiology, 6, 8, 12-16 packets, 2 Renal clearance contraindications, 178-179 preclinical pharmacokinetics, 59-60 Resting osteoblasts, see Lining cells Rheumatoid arthritis, treatment, 166 Risedronate adverse events, 174 bone resorption inhibition potency, 4 0 41 commercial availability, 182-206 hypercalcemia treatment, 108-109, 121 osteolytic tumor-induced bone disease treatment, 108-109 osteoporosis treatment, 140-141,147 Paget's disease treatment, 81-82 structure, 32

Index

Selective estrogen receptor modulators, osteoporosis prevention, 131-132 Skelid, see Tiludronate Stromal cells, physiology, 12 Sudeck's atrophy, treatment, 166 Therapeutic effects, see specific bisphosphonates; specific diseases Tibolone, osteoporosis prevention, 131 Tiludronate adverse events, 174-175 bone resorption inhibition potency, 4 0 41 commercial availability, 182-206 osteolytic tumor-induced bone disease treatment, 109 osteoporosis treatment, 152 Paget's disease treatment, 82-83 structure, 32 Toxicology adverse events, 168-175 alendronate, 169-170 clodronate, 170-171 etidronate, 171-173 overview, 168-169 pamidronate, 173-174 risedronate, 174 tiludronate, 174-175 preclinical studies, 63-65 acute toxicity, 63 nonacute toxicity, 63-65

alendronate, 64 clodronate, 64-65 etidronate, 65 other bisphosphonates, 65 pamidronate, 65 Tumor bone disease, see Osteolytic tumorinduced bone disease Turnover assessment, 5, 15, 21, 70-71 bone mineral density relationship, 4-5, 16, 42 osteoporosis relationship, 12-13, 15, 38, 130, 143 Paget's disease relationship, 70-71 Urolithiasis, treatment, 162 Vitamin D, daily requirements, 19, 126127, 132 1,25-(OH)2 Vitamin D calcium homeostasis regulation, 17-19, 39 Paget's disease treatment, 73, 75 Zoledronate bone resorption inhibition potency, 4 0 41 osteolytic tumor-induced bone disease treatment, 108-109 Paget's disease treatment, 83 structure, 32

212