MECHANISMS OF ACTION OF BISPHOSPHONATES

Bisphosphonates (BPs) are pyrophosphate analogs in which the oxygen br idge has been replaced by carbon and diverse carbon side chains have g enerated a large family of compounds. Several are potent inhibitors of bone destruction (resorption) and are in clinical use for the treatme nt and prevention of osteoporosis, Paget's disease, hypercalcemia caus ed by malignancy, tumor metastases in bone, and other bone ailments. S elective action on bone is based on the binding of the BP moiety to th e bone mineral. The molecular mode of action of BPs, which may differ from compound to compound, is unknown. However, at the tissue level, a ll BPs inhibit bone destruction and lead to an increase in bone minera l density by decreasing bone resorption and bone turnover. At the cell ular level, the ultimate target of BP action is the osteoclast, the bo ne resorbing cell. In vitro evidence shows BP inhibition of osteoclast formation, via action on osteoblasts, and there is in vitro and in vi vo evidence for BP inhibition of osteoclast activity. There is in vivo and in vitro evidence for increased apoptosis. The relative contribut ion of these various effects on the therapeutic action of BPs remains to be established. At the molecular level, it is not known if BPs act on a single or multiple targets. Enzymes in the cholesterol biosynthes is pathway and protein tyrosine phosphatases were shown to be inhibite d by BPs.