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.

SummaryRats were given Graham salt (a long chain polyphosphate) at dose levels which prevent calciphylactic reactions in skin and the ectopic calcification of the aorta caused by large doses of vit. D. Graham salt given at this dose level to growing rats had no effect upon the normal calcification sequences in the epiphyses, nor did it affect the cure of rickets by physiological doses of vit. D. The significance of these results is discussed.

Bone formation in normal and vitamin D-treated rachitic rats during the administration of polyphosphates.

The origin of inorganic pyrophosphate in urine.

Pyrophosphate, phosphonates and pyrophosphatases in the regulation of calcification and calcium homeostasis.

In previous work it was shown that urine contains a compound inhibiting calcium phosphate and calcium oxalate precipitation in vitro . This inhibitor was identified as inorganic pyro

Influence of Pyrophosphate on the Crystallisation of Uric Acid and Magnesium Ammonium Phosphate and its Implications in Phosphate Therapy for Urolithiasis

H. Fleisch

Papers

Bone formation in normal and vitamin D-treated rachitic rats during the administration of polyphosphates.

The origin of inorganic pyrophosphate in urine.

Pyrophosphate, phosphonates and pyrophosphatases in the regulation of calcification and calcium homeostasis.

Influence of Pyrophosphate on the Crystallisation of Uric Acid and Magnesium Ammonium Phosphate and its Implications in Phosphate Therapy for Urolithiasis

Influence of diphosphonates on the deposition and dissolution ofccalcium phosphate in vitro and in vivo