ReviewBisphosphonates: The first 40 years
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 PC bonds, linked through a single carbon to give a geminal bisphosphonate with the core structure made up of PCP 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 PCP 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
References (246)
- et al.
Bisphosphonates: from the laboratory to the clinic and back again
Bone
(1999) Bisphosphonates: a review of their pharmacokinetic properties
Bone
(1996 Feb)Excretion of inorganic pyrophosphate in hypophosphatasia
Lancet
(1965)- et al.
Purinergic signalling and bone remodelling
Curr Opin Pharmacol
(Jun 2010) - et al.
Sustained osteomalacia of long bones despite major improvement in other hypophosphatasia-related mineral deficits in tissue nonspecific alkaline phosphatase/nucleotide pyrophosphatase phosphodiesterase 1 double-deficient mice
Am J Pathol
(2005) - et al.
Autosomal dominant familial calcium pyrophosphate dihydrate deposition disease is caused by mutation in the transmembrane protein ANKH
Am J Hum Genet
(Oct 2002) - et al.
Mutations in ANKH cause chondrocalcinosis
Am J Hum Genet
(2002) - et al.
Autosomal dominant craniometaphyseal dysplasia is caused mutations in the transmembrane protein ANK
Am J Hum Genet
(2001) - et al.
Vascular pathology of medial arterial calcifications in NT5E deficiency: implications for the role of adenosine in pseudoxanthoma elasticum
Mol Genet Metab
(May 2011) - et al.
Continuous alendronate treatment throughout growth, maturation, and aging in the rat results in increases in bone mass and mechanical properties
Calcif Tissue Int.
(1993 Oct)
Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: what we think we know and what we know that we don't know
Bone
Zoledronic acid causes enhancement of bone growth into porous implants
J Bone Joint Surg Br
Bisphosphonates and implants. An overview
Acta Orthop
Zoledronic acid prevents osteopenia and increases bone strength in a rabbit model of distraction osteogenesis
J Bone Miner Res
Ueber die Einwirkung des Chloracetyls auf phosphorige Saure
Ann Chem Pharmacol
Acetodiphosphorige Saure
Berichte Dtsch Chem Ges
Discovery and history of the non-medical uses of bisphosphonates. Chapter 7
Bisphosphonates in bone disease. From the laboratory to the patient
Bisphosphonates: mechanisms of action
Endocr Rev
Bisphosphonates: preclinical review
Oncologist
Bisphosphonates: structure–activity relationships and therapeutic implications
Bone Miner Res
Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy
Osteoporos Int
The chemical dynamics of bone mineral
Mechanisms of calcification: role of collagen, polyphosphates, and phosphatase
Am J Physiol
Isolation from urine of pyrophosphate, a calcification inhibitor
Am J Physiol
The urinary excretion of inorganic pyrophosphate by normal subjects and patients with renal calculus
Clin Sci
Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta and other disorders of bone
J Clin Invest
Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis
Nature
The uptake and metabolism of 32P-pyrophosphate by mouse calvaria in vitro
Biochem J
Evolutionary origins of the purinergic signalling system
Acta Physiol (Oxf)
Pathophysiology of articular chondrocalcinosis—role of ANKH
Nat Rev Rheumatol
It ANKH necessarily so
J Clin Endocrinol Metab
Inorganic pyrophosphate generation and disposition in pathophysiology
Am J Physiol Cell Physiol
Genetic studies of disorders of calcium crystal deposition
Rheumatology (Oxford)
Hypophosphatasia: molecular diagnosis of Rathbun's original case
J Bone Miner Res
Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia
J Bone Miner Res
Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene
Hum Mutat
Physiological role of alkaline phosphatase explored in hypophosphatasia
Ann NY Acad Sci
The mutational spectrum of ENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI)
Hum Mutat
Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL)
Hum Genet
Role of the mouse ank gene in control of tissue calcification and arthritis
Science
Association of sporadic chondrocalcinosis with a − 4-basepair G-to-A transition in the 5′-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate
Arthritis Rheum
Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia
Nat Genet
Craniometaphyseal dysplasia with severe craniofacial involvement shows homozygosity at 6q21-22.1 locus
Am J Med Genet A
Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family
J Clin Endocrinol Metab
NT5E mutations and arterial calcifications
N Engl J Med
Inhibition by pyrophosphate of aortic calcification induced by Vitamin D3 in rats
Clin Sci
The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals
Calcif Tissue Res
Cited by (920)
Synthesis and preliminary anticancer evaluation of photo-responsive prodrugs of hydroxymethylene bisphosphonate alendronate
2024, European Journal of Medicinal ChemistryTowards the synthesis of new sequestring hexadentate bisphosphonic ligands for iron ion chelation
2024, Phosphorus, Sulfur and Silicon and the Related ElementsFollow-up bone mineral density testing: 2023 official positions of the International Society for Clinical Densitometry
2024, Journal of Clinical DensitometryHarvesting phosphorus-containing moieties for their antibacterial effects
2023, Bioorganic and Medicinal ChemistryAn updated review of chemical compounds with anti-Toxoplasma gondii activity
2023, European Journal of Medicinal Chemistry