Bisphosphonates: mechanisms of action.

T bisphosphonates have been known to chemists since the middle of the 19th century, when the first synthesis occurred in 1865 in Germany (1). Etidronate, the first bisphosphonate to be used to treat a human disease (2), was synthesized exactly 100 yr ago (3). Bisphosphonates were used in industry, mainly as corrosion inhibitors or as complexing agents in the textile, fertilizer, and oil industries. Their ability to inhibit calcium carbonate precipitation, similar to polyphosphates, was put to good use in the prevention of scaling (4). Only in the past three decades have bisphosphonates been developed as drugs for use in various diseases of bone, tooth, and calcium metabolism. Our knowledge of the biological characteristics of bisphosphonates dates back 30 yr. The first report was done by the author’s group and published in 1968 (5). The concept was derived from our earlier studies on inorganic pyrophosphate. We had found that plasma and urine contained compounds that inhibit calcium phosphate precipitation and that part of this inhibitory activity was due to inorganic pyrophosphate, a compound that had not been described previously in the scientific literature (6). Pyrophosphate was then shown to impair in vitro the formation and dissolution of calcium phosphate crystals. This effect was therefore similar to that on calcium carbonate and, for this reason, had been used in washing powders. Since pyrophosphate was able to inhibit ectopic calcification in vivo, it was suggested that it might act as a physiological regulator of calcification and perhaps also of decalcification in vivo, its local concentration being determined by the activity of local pyrophosphatases (7). 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.