Elsevier

Bone

Volume 49, Issue 1, July 2011, Pages 2-19
Bone

Review
Bisphosphonates: The first 40 years

https://doi.org/10.1016/j.bone.2011.04.022Get rights and content

Abstract

The first full publications on the biological effects of the diphosphonates, later renamed bisphosphonates, appeared in 1969, so it is timely after 40 years to review the history of their development and their impact on clinical medicine.

This special issue of BONE contains a series of review articles covering the basic science and clinical aspects of these drugs, written by some of many scientists who have participated in the advances made in this field.

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, and is a paradigm of a successful journey from ‘bench to bedside’.

Bisphosphonates are chemically stable analogues of inorganic pyrophosphate (PPi), and it was studies on the role of PPi as the body's natural ‘water softener’ in the control of soft tissue and skeletal mineralisation that led to the need to find inhibitors of calcification that would resist hydrolysis by alkaline phosphatase.

The observation that PPi and BPs could not only retard the growth but also the dissolution of hydroxyapatite crystals prompted studies on their ability to inhibit bone resorption. Although PPi was unable to do this, BPs turned out to be remarkably effective inhibitors of bone resorption, both in vitro and in vivo experimental systems, and eventually in humans.

As ever more potent BPs were synthesised and studied, it became apparent that physico-chemical effects were insufficient to explain their biological effects, and that cellular actions must be involved. Despite many attempts, it was not until the 1990s that their biochemical actions were elucidated.

It is now clear that bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalised by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen containing bisphosphonates (such as etidronate and clodronate) can be metabolically incorporated into non-hydrolysable analogues of ATP, which interfere with ATP-dependent intracellular pathways. The more potent, nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zoledronate) are not metabolised in this way but inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway. The major enzyme target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS), and the crystal structure elucidated for this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. Inhibition of FPPS prevents the biosynthesis of isoprenoid compounds (notably farnesol and geranylgeraniol) that are required for the post-translational prenylation of small GTP-binding proteins (which are also GTPases) such as rab, rho and rac, which are essential for intracellular signalling events within osteoclasts. The accumulation of the upstream metabolite, isopentenyl pyrophosphate (IPP), as a result of inhibition of FPPS may be responsible for immunomodulatory effects on gamma delta (γδ) T cells, and can also lead to production of another ATP metabolite called ApppI, which has intracellular actions. Effects on other cellular targets, such as osteocytes, may also be important.

Over the years many hundreds of BPs have been made, and more than a dozen have been studied in man. As reviewed elsewhere in this issue, bisphosphonates are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, the skeletal complications of malignancy, and osteoporosis. Several of the leading BPs have achieved ‘block-buster’ status with annual sales in excess of a billion dollars.

As a class, BPs share properties in common. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various BPs. Each BP has a unique profile in terms of mineral binding and cellular effects that may help to explain potential clinical differences among the BPs.

Even though many of the well-established BPs have come or are coming to the end of their patent life, their use as cheaper generic drugs is likely to continue for many years to come. Furthermore in many areas, e.g. in cancer therapy, the way they are used is not yet optimised. New ‘designer’ BPs continue to be made, and there are several interesting potential applications in other areas of medicine, with unmet medical needs still to be fulfilled.

The adventure that began in Davos more than 40 years ago is not yet over.

This article is part of a Special Issue entitled Bisphosphonates.

Research highlights

► The biological effects of bisphosphonates (BPs) were first published in 1969. ► The potency of BPs on bone resorption depends on binding to bone mineral and osteoclast inhibition. ► Nitrogen-BPs inhibit farnesyl pyrophosphate synthase(FPPS) and protein prenylation. ► BPs are the major drugs for treating Paget’s disease, bone metastases, and osteoporosis. ► Knowledge of structure-activity enables rational design of new BP drugs.

Introduction

All the bisphosphonates (BPs) currently in use as drugs in clinical medicine possess two Psingle bondC bonds, linked through a single carbon to give a geminal bisphosphonate with the core structure made up of Psingle bondCsingle bondP bonds. They are chemically stable analogues of pyrophosphate compounds, which are found widely in nature. The simplest of the naturally occurring pyrophosphates is inorganic pyrophosphate (PPi), and it was the discovery that this compound circulates in the body as an endogenous ‘water softener’ that led on to the work with bisphosphonates.

Chemically the bisphosphonates were first synthesised in the 1800s [1], but it is only in the past 40 years that they have been used to treat disorders of calcium metabolism. Even etidronate, which was the first bisphosphonate to be used in humans, was originally synthesised over 100 years ago [2].

The early uses of bisphosphonates were mainly as corrosion inhibitors, also as complexing agents in the textile, fertiliser and oil industries, as well as for many other industrial processes [3]. Their use as ‘water softeners’ was based on their ability to act as sequestering agents for calcium, and in particular their ability to inhibit calcium carbonate precipitation, as do polyphosphates. This has been applied in the prevention of scaling in domestic and industrial water installations.

A recent search in PubMed under the term ‘bisphosphonates’ revealed over 19,000 publications, and even this large list this does not cite abstracts, nor all publications and the many books and review articles available that describe the chemistry, pharmacology, and clinical applications of bisphosphonates [4], [5], [6], [7], [8], [9], [10], [11], [12].

The discovery of the biological effects of the BPs has its origin in studies of calcification mechanisms and the role of pyrophosphate. It is instructive to trace the steps by which this came about. This review will focus on the historical aspects, and on topics not covered elsewhere in this issue, including aspects of pharmacology, and the inter-relationship between BPs and pyrophosphate metabolism, bearing in mind that disturbances in pyrophosphate metabolism have an important role in several diseases.

Section snippets

How studies on calcification mechanisms and the role of pyrophosphate led to the discovery of the bisphosphonates

The beginning of this story can be traced back to 1962, when Herbert Fleisch spent a postdoctoral year at the University of Rochester with Bill Neuman. W F Neuman (1919–1981)1 headed the biochemistry section in the Department of Radiation Biology in conjunction with the U.S. Atomic Energy Commission at the

Dating the anniversary

The first publications appeared as abstracts [50], [51] in 1968, and were followed by the two full papers in Science in 1969, in which the effects of two representative bisphosphonates, etidronate and clodronate, on crystal formation and dissolution, and on vascular calcification and bone resorption were described [52], [53]. These early studies with bisphosphonates were the result of a very fruitful collaboration between the Davos laboratory with Dave Francis (Marion D Francis) of the Procter

Bisphosphonates inhibit bone resorption in many different experimental systems, and this enabled the pharmacological development of bisphosphonates

Many studies using a variety of experimental systems showed that bisphosphonates inhibit osteoclast-mediated bone resorption, not only in organ cultures of bone in vitro, but also both in normal animals and in those with experimentally increased resorption. The first experimental model studied was in thyroparathyroidectomized rats treated with parathyroid hormone to stimulate bone resorption in vivo [49], [53].

In growing intact rats, the bisphosphonates block the removal of both bone and

Special features of the pharmacology of bisphosphonates

As drugs bisphosphonates display a few unusual features. Their remarkable selectivity for their target organ of bone is paramount among these and accounts for much of the efficacy and safety of the drug class, as reviewed by Cremers and Papapoulos [67] in this issue. Secondly unlike many drugs, BPs are not metabolised to inactive products, and drug derivatives do not appear in urine. Intracellular conversion of some non-N-BPs to ATP derivatives does occur however, as discussed elsewhere.

Thirdly

Defining structure activity relationships

The evolution of concepts about the structure activity relationships among BPs has been reviewed in detail elsewhere in this issue [107]. Some of the key historical aspects will be summarised here.

Several of the features of the bisphosphonate molecule necessary for biological activity were well defined in the early studies. The Psingle bondCsingle bondP moiety is responsible for the strong affinity of the bisphosphonates for binding to hydroxyapatite (HAP) and allows for a number of variations in structure based on

Understanding the mechanisms of action of bisphosphonates at a cellular level

The remarkable selectivity of bisphosphonates for bone rather than other tissues is the basis for both their efficacy and safety in clinical medicine. Their preferential uptake by and adsorption to mineral surfaces in bone bring them into close contact with osteoclasts. During bone resorption, bisphosphonates appear to be internalised by endocytosis, along with other products of resorption. The uptake of bisphosphonates by osteoclasts in vivo has been confirmed using radiolabeled [117] and

Understanding the mechanisms of action of bisphosphonates at a biochemical level

Over the years there were many attempts made to explain how bisphosphonates work on cells, especially via inhibitory effects on enzymes. Various studies suggested possible effects on glycolysis [139], or direct or indirect inhibition of the osteoclast proton pumping H+ATPase [140], [141], [142], phosphatases [143], [144], or lysosomal enzymes [145], [146], and even effects on osteoblasts to produce an osteoclast-inhibitory factor [147], [148], [149], [150].

Since the early 1990s there has been a

Clinical applications of bisphosphonates

The most impressive clinical application of bisphosphonates has undoubtedly been as inhibitors of bone resorption, often for diseases where no effective treatment existed previously, but it took many years for them to become well established.

However, the first clinical uses of bisphosphonates were as inhibitors of calcification. Etidronate was the only BP to be used in this way, first in fibrodysplasia ossicans progressiva (FOP, formerly known as myositis ossificans) [180], [181]. Etidronate

Current challenges and new directions with bisphosphonates

There are many ongoing issues with clinical aspects of the treatment of bone diseases. In osteoporosis, issues under consideration with bisphosphonates include the choice of therapeutic regimen, e.g. the use of intermittent dosing rather than continuous, intravenous versus oral therapy, the optimal duration of therapy, the combination with other drugs such as teraparatide, and their extended use in related indications e.g. glucocorticosteroid-associated osteoporosis, male osteoporosis,

Reflections on the past, present and future

It is now 40 years since the discovery of the profound effects of the bisphosphonates on calcium metabolism. It has taken a long time for them to become well established as clinically successful anti-resorptive agents, which has enabled new approaches to the therapy of bone diseases.

Studies of the structure–activity relationships over many years have led to a much better understanding of the unique properties of bisphosphonates and how they work. These studies have culminated in the

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