Bisphosphonates in Bone Disease: From the Laboratory to the Patient

By Herbert Fleisch

This book is an essential handbook on bisphosphonates, the most widely used new class of drugs for osteoporosis therapy. It reviews basic physiology in addition to the indications and adverse reactions of these drugs.

Bisphosphonates in Bone Disease, Fourth Edition, discusses the compounds' chemistry, mechanisms of action, and animal toxicology before presenting a clinical picture of the diseases treated by bisphosphonates. The book provides a table listing the trade names of the commercially available bisphosphonates, registered indications, and the available forms for various countries. The revised Fourth Edition contains approximately 50% new material, including information on all of the latest drugs.

• The revised fourth edition contains approximately 50% new material
• Includes information on all the latest drugs

• Language: English
• Publisher: Academic Press
• Release date: Jun 12, 2000
• ISBN: 9780080573908

Book preview

Bisphosphonates in Bone Disease

From the Laboratory to the Patient

Fourth Edition

Herbert Fleisch

Professor Emeritus, University of Berne Berne, Switzerland

ACADEMIC PRESS

A Harcourt Science and Technology Company

San Diego  San Francisco  New York  Boston  London  Sydney  Tokyo

Table of Contents

Cover image

Title page

Dedication

Copyright page

Preface

1: Bone and mineral metabolism

1.1 Bone physiology

2: Bisphosphonates—preclinical

2.1 Background to the Pharmacological Development

2.2 Chemistry

2.3 Actions

2.4 Pharmacokinetics

2.5 Animal Toxicology

3: Bisphosphonates—clinical

3.1 Introduction

3.2 Paget’s Disease

3.3 Osteolytic Tumor-Induced Bone Disease

3.4 Non-Tumor-Induced Hypercalcemia

3.5 Osteoporosis

3.6 Heterotopic Calcification and Ossification

3.7 Other Diseases

3.8 Adverse Events

3.9 Contraindications

3.10 Future prospects

4: Commercially available bisphosphonates

Index

Dedication

To

My wife, Maria Pia

My children, Marie-Gabrielle, Isabelle Désirée, and Marie-Laure

My father, Alfred Fleisch, who taught me scientific thinking

and experimental rigor

William F. Neuman, who introduced me to the bone

Copyright

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.

Copyright © 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.

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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 aperçu 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.

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. Allgöwer; to Professor M. E. Müller; 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. Désertes 5 CH-1009 Pully, Switzerland

1

Bone and mineral metabolism

Herbert Fleisch

1.1 Bone physiology

1.1.1 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.

Biomechanical 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.

Paget’s disease p. 71

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

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 μm 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 μm, regardless of species, the maximal distance of any part from the central vessel being no more than 100 μm, this being the largest transport distance for nutrients. Osteons are separated from one another by so-called cement lines.

Fig. 1.1-1 Cross section of compact bone showing osteons with osteocytes (left), and—in polarized light—with 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.]

The osteon is the basic unit of the Haversian bone of the cortex.

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.

Remodeling packets and BMUs p. 13

Trabeculae generally possess no vessels and are therefore nourished from the surface. This explains why they cannot become much thicker than about 200–300 μm, twice the distance of 100 μm over which transport of nutrients is possible.

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

Osteoporosis p. 124

1.1.2 Composition of bone

Bone is made up of mineral, a fibrillar organic matrix, cells, and water.

Fig. 1.1-3 Composition of bone.

Mineral

Mineral accounts for about two-thirds of the total dry weight of bone. It is made of small crystals of about 200−400 Å × 35−75 Å × 10−40 Å 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 HPO4−, 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 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.

Deposition of bisphosphonates in bone p. 57

Paget’s disease p. 70

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.

MD 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

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.

Measurement of bone turnover p. 21

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.

Effect on bone metastases p. 89

The organic matrix also contains a large amount of various growth factors, especially transforming growth factor β (TGFβ) 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.

Bone matrix is made up of 90% collagen and about 10% of various noncollagenous proteins. It contains many growth factors which may play a role, when released, in bone turnover and in tumor-induced bone disease.

Bone cells

Osteoblasts

Osteomalacia pp. 171–172

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 super-family 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.

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

Remodeling and modeling p. 12

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 β (TGFβ), 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.

Fluoride in osteoporosis p. 132

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 TGFβ, 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 Cbfa1, will open new aspects in our search for stimulators of bone formation.

Corticosteroid-induced osteoporosis p. 126

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.

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

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 intérieur.

Resting osteoblasts at the surface of the bone are called lining cells and constitute a blood–bone barrier.

Osteocytes

Morphology of cell connections p. 2

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 of these lacunae and canaliculi is very large, in humans about 1000 m², 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