Summary
Bisphosphonates (BPs) are well established as the leading drugs for the treatment of osteoporosis. There is new knowledge about how they work. The differences that exist among individual BPs in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness.

Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy

Bisphosphonates are primary agents in the current pharmacological arsenal against osteoclast-mediated bone loss due to osteoporosis, Paget disease of bone, malignancies metastatic to bone, multiple myeloma, and hypercalcemia of malignancy. In addition to currently approved uses, bisphosphonates are commonly prescribed for prevention and treatment of a variety of other skeletal conditions, such as low bone density and osteogenesis imperfecta. However, the recent recognition that bisphosphonate use is associated with pathologic conditions including osteonecrosis of the jaw has sharpened the level of scrutiny of the current widespread use of bisphosphonate therapy. Using the key words bisphosphonate and clinical practice in a PubMed literature search from January 1, 1998, to May 1, 2008, we review current understanding of the mechanisms by which bisphosphonates exert their effects on osteoclasts, discuss the role of bisphosphonates in clinical practice, and highlight some areas of concern associated with bisphosphonate use.

https://www.mayoclinicproceedings.org/article/S0025-6196(11)60607-1/pdf

Bisphosphonates: Mechanism of Action and Role in Clinical Practice

I. Introduction II. Chemistry III. Effects in Vivo A. Inhibition of calcification B. Inhibition of bone resorption C. Effects on bone formation D. Effects on noncalcified tissues IV. Mechanisms of Action A. Calcification B. Bone resorption C. Other effects V. Pharmacokinetics VI. Animal Toxicology and Human Adverse Events A. Animal toxicology B. Human adverse events VII. Conclusion

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Bisphosphonates: Mechanisms of Action

Because of its failure to act when given orally and its rapid hydrolysis when given parenterally, pyrophosphate was used therapeutically only in scintigraphy and against dental calculus. This prompted us to search for analogs that showed similar physicochemical activity but resisted enzymatic hydrolysis and, therefore, would not be degraded metabolically. The bisphosphonates fulfilled these conditions. This review will deal with the mechanisms of action of these compounds. In vitro results, as well as results both in animals and humans, will be integrated in an attempt to deduce the current state of the art. Various reviews have been published recently on bisphosphonates and may be consulted also for information on other aspects (8 ‐14). Since the literature in this field is plentiful, selective citation was necessary. Priority is given to papers dealing with the mechanisms of action. Since many papers often deal with the same finding, in most cases only the first ones are quoted. Subsequent papers are quoted only if they convey new knowledge.

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Bisphosphonates: mechanisms of action.

Studies of the mode of action of the bisphosphonate alendronate showed that 1 d after the injection of 0.4 mg/kg [3H]alendronate to newborn rats, 72% of the osteoclastic surface, 2% of the bone forming, and 13% of all other surfaces were densely labeled. Silver grains were seen above the osteoclasts and no other cells. 6 d later the label was 600-1,000 microns away from the epiphyseal plate and buried inside the bone, indicating normal growth and matrix deposition on top of alendronate-containing bone. Osteoclasts from adult animals, infused with parathyroid hormone-related peptide (1-34) and treated with 0.4 mg/kg alendronate subcutaneously for 2 d, all lacked ruffled border but not clear zone. In vitro alendronate bound to bone particles with a Kd of approximately 1 mM and a capacity of 100 nmol/mg at pH 7. At pH 3.5 binding was reduced by 50%. Alendronate inhibited bone resorption by isolated chicken or rat osteoclasts when the amount on the bone surface was around 1.3 x 10(-3) fmol/microns 2, which would produce a concentration of 0.1-1 mM in the resorption space if 50% were released. At these concentrations membrane leakiness to calcium was observed. These findings suggest that alendronate binds to resorption surfaces, is locally released during acidification, the rise in concentration stops resorption and membrane ruffling, without destroying the osteoclasts.

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Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure.

Two diphosphonates containing the P-C-P bond, Cl(2)C(PO(3)HNa)(2), and H(2)C(PO(3)HNa)(2) retard the rate of dissolution of apatite crystals in vitro. They inhibit bone resorption induced by parathyroid extract in mouse calvaria in tissue culture and in thyroparathyroidectomized rats in vivo.

http://science.sciencemag.org/content/sci/165/3899/1262.full.pdf

Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo.

Two diphosphonates containing the P-C-P bond, CH(3)C(OH)(PO(3)HNa)(2) and H(2)C(PO(3)HNa)(2), inhibit the crystallization of calcium phosphate in vitro and prevent aortic calcification of rats given large amounts of vitamin D(3). The diphosphonates therefore have effects similar to those described for compounds containing the P-O-P bond but are active when administered orally.

http://science.sciencemag.org/content/sci/165/3899/1264.full.pdf

Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo.

Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis.

Earlier studies have shown that inorganic pyrophosphate (PPi) inhibits the dissolution of hydroxyapatite crystalsin vitro and it has been suggested that PPi might be a physiological regulator of bone resorption. In this study PP1 and other phosphate compounds have been tested for their ability to inhibit bone resorption induced by parathyroid hormone in mouse calvaria and to inhibit the rise in plasma calcium induced by parathyroid hormone in thyroparathyroidectomised rats on a low calcium diet. Orthophosphate, pyrophosphate, polyphosphate and two polymeric phosphate inhibitors of phosphatases did not inhibit the resorption of calvaria or the rise in plasma calcium. In contrast, several phosphonates containing P-C-P bonds retarded the dissolution of hydroxyapatite crystalsin vitro, and, at concentrations down to 1.6×10−6M, inhibited bone resorption in tissue culture. Some diphosphonates also inhibited the rise in plasma calcium in thyroparathyroidectomised rats. One reason for the difference between the effects of compounds containing P-O-P and P-C-P bonds may be related to the greater resistance of the latter to chemical and enzymic hydrolysis. Phosphonates may provide a model for the effect of endogenous PP1 in bone, and might be of use in elucidating provide a model for the effect of endogenous PP1 in bone, and might be of use in elucidating mechanisms of bone formation and resorption and in the therapy of diseases that involve increased resorption of bone.

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.

1. Various phosphonates, which are compounds containing C-P bonds, have been studied to see whether they are able to inhibit, in a manner similar to that of pyrophosphate and the condensed phosphates, the crystallization of calcium phosphate in vitro and the pathological calcification of the aorta and the kidneys of rats given large amounts of vitamin D3.



2. Six of the ten compounds studied markedly increased the minimum product, [Ca] × [P], required to induce the precipitation of calcium phosphate in vitro under physiological conditions of pH, ionic strength and temperature. Inhibition was observed at concentrations as low as 10-7—106M.



3. Most of the diphosphonates, particularly those possessing P-C-P bonds, showed some ability to inhibit the calcification of the aortas and kidneys of rats treated with large amounts of vitamin D3. The most effective inhibitors were methylene diphosphonate (MDP), ethane-1-hydroxy-1: I-diphosphonate (EHDP) and diehloromethylene diphosphonate (Cl2MDP).



4. The phosphonates that possess P-C-P bonds thus appear to have effects on the deposition of calcium phosphate in vitro and in vivo similar to those of inorganic pyrophosphate and the condensed phosphates, which possess P-O-P bonds. These phosphonates differ from the condensed phosphates in that they inhibit kidney calcification as well as aortic calcification and are active by mouth as well as parenterally. The wider spectrum of activity of the phosphonates in vivo may be due to the fact that they are more resistant to chemical and enzymic breakdown.



5. Phosphonates might be used therapeutically in man against diseases in which calcium salts deposit in soft tissues.

H. Fleisch

Papers

Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo.

Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo.

Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis.

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.

The Inhibitory Effect of Phosphonates on the Formation of Calcium Phosphate Crystals in vitro and on Aortic and Kidney Calcification in vivo