Mechanisms of action of the bisphosphonates

Abstract

Geminal bisphosphonates, usually called bisphosphonates, are synthetic compounds characterized by a P-C-P bond. Many such bisphosphonates have been synthesized, each of them having its own physicochemical and biologic characteristics. This implies that it is not possible to extrapolate from the results of one compound to others with respect to their actions. Bisphosphonates can exert physicochemical effects very similar to those of polyphosphates, binding to the surface of calcium phosphate crystals and inhibiting their formation and aggregation as well as their dissolution. Many of the bisphosphonates are very powerful inhibitors of bone resorption. This is seen both in normal animals and in animals where bone resorption is simulated by various means. Thus, they are active in various models of human diseases, such as hyperparathyroidism, tumoral bone disease and osteoporosis. They not only prevent bone loss, but actively increase bone mass and improve the biomechanical properties of the skeleton. The activity varies greatly from compound to compound, the newest bisphosphonates being 5,000 to 10,000 times more active than etidronate, the first bisphosphonate described. The mechanism of action appears to be complex. It involves: a) a direct effect on the osteoclast activity. b) A direct and indirect effect on the osteoclast recruitment. The latter is mediated by cells of the osteoblastic lineage and involves their production of an inhibitor of osteoclastic recruitment. c) A shortening of osteoclast survival by apoptosis. Large amounts of bisphosphonates can also inhibit mineralization through a physicochemical inhibition of crystal growth. Bisphosphonates are used therapeutically in humans to decrease bone resorption, among others in Paget's disease, tumor bone disease, and recently osteoporosis. Etidronate is also sometimes used to prevent ectopic calcification.