Elsevier

Bone

Volume 25, Issue 1, July 1999, Pages 97-106
Bone

Original Articles
Bisphosphonates: from the laboratory to the clinic and back again

https://doi.org/10.1016/S8756-3282(99)00116-7Get rights and content

Abstract

Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a “P-C-P” structure. The bisphosphonates are therefore stable analogues of naturally occuring pyrophosphate-containing compounds, which now helps to explain their intracellular as well as their extracellular modes of action. Bisphosphonates adsorb to bone mineral and inhibit bone resorption. The mode of action of bisphosphonates was originally ascribed to physico-chemical effects on hydroxyapatite crystals, but it has gradually become clear that cellular effects must also be involved. The marked structure-activity relationships observed among more complex compounds indicate that the pharmacophore required for maximal activity not only depends upon the bisphosphonate moiety but also on key features, e.g., nitrogen substitution in alkyl or heterocyclic side chains.

Several bisphosphonates (e.g., etidronate, clodronate, pamidronate, alendronate, tiludronate, risedronate, and ibandronate) are established as effective treatments in clinical disorders such as Paget’s disease of bone, myeloma, and bone metastases. Bisphosphonates are also now well established as successful antiresorptive agents for the prevention and treatment of osteoporosis. In particular, etidronate and alendronate are approved as therapies in many countries, and both can increase bone mass and produce a reduction in fracture rates to approximately half of control rates at the spine, hip, and other sites in postmenopausal women. In addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce the activation frequency and birth rates of new bone remodeling units, and possibly to enhance osteon mineralisation, may also contribute to the reduction in fractures.

The clinical pharmacology of bisphosphonates is characterized by low intestinal absorption, but highly selective localization and retention in bone. Significant side effects are minimal. Current issues with bisphosphonates include the introduction of new compounds, the choice of therapeutic regimen (e.g., the use of intermittent dosing rather than continuous), intravenous vs. oral therapy, the optimal duration of therapy, the combination with other drugs, and extension of their use to other conditions, including steroid-associated osteoporosis, male osteoporosis, arthritis, and osteopenic disorders in childhood.

Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis. The molecular mechanisms by which these effects are brought about are becoming clearer. Recent studies show that bisphosphonates can be classified into at least two groups with different modes of action. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTPases. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity and induction of apoptosis. These different modes of action might account for subtle differences between compounds in terms of their clinical effects.

In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of bone diseases, and their mode of action is being unravelled. As a result, their full therapeutic potential is gradually being realized.

Introduction

The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating story that has extended over three decades. As the title of this presentation implies, the tale starts with laboratory studies31, 32 related to mechanisms of biological calcification, followed by the clinical exploitation of bisphosphonates as inhibitors of bone resorption, and has recently returned to laboratory studies that are helping to unravel how these drugs work at a cellular level.

There are several recent books and reviews available that describe the chemistry, pharmacology, and clinical applications of bisphosphonates.10, 22, 27, 28, 37, 41, 43, 47, 73, 79, 93

Section snippets

The early days

In the early 1960s, Neuman and Fleisch30 were studying mechanisms of calcification induced by collagen, and showed that body fluids such as plasma and urine contained inhibitors of calcification. Since it had been known since the 1930s that trace amounts of polyphosphates were capable of acting as water softeners by inhibiting the crystallization of calcium salts, such as calcium carbonate, they proposed that compounds of this type might be natural regulators of calcification under

Clinical applications

Exploration of bisphosphonates as inhibitors of calcification showed some promise, and early applications of etidronate included use in myositis ossificans and in patients who had undergone total hip replacement surgery to prevent subsequent heterotopic ossification and to improve mobility.10, 27 It should be emphasized that these effects required very high doses of etidronate, and that inhibition of skeletal mineralization is not a significant clinical problem when etidronate is used at the

The relationship between the chemical structure of bisphosphonates and their biological activity

Bisphosphonates differ from pyrophosphate in that a carbon rather than an oxygen atom bridges the two phosphate residues, which renders bisphosphonates chemically stable and able to withstand incubation in acids or with hydrolytic enzymes (Figure 1). The P-C-P moiety is responsible for the strong affinity of the bisphosphonates for the skeleton and allows for a number of variations in structure based on substitution in the R1 and R2 positions on the carbon atom (Figure 2). The ability of the

Mechanisms of action

Bisphosphonates probably inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, whence they are internalized by osteoclasts. Bisphosphonates affect osteoclast-mediated bone resorption in a variety of ways, which include effects on osteoclast recruitment, differentiation, and resorptive activity.44, 45, 57, 82, 84 Once internalized within osteoclasts, bisphosphonates perturb cellular metabolism and induce apoptosis (Figure 3). Given the structural

Future prospects

It has taken over 30 years since the discovery of the profound effects of the bisphosphonates on calcium metabolism for them to become well established as clinically successful antiresorptive agents, and their availability has enabled new approaches to the therapy of bone diseases.

There have now been many years of mostly favorable experience with the use of bisphosphonates in diseases such as Paget’s disease of bone, myeloma, and bone metastases. Bisphosphonates represent an important class of

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