Bisphosphonates--history and experimental basis.

This paper reviews the mechanisms of action of the bisphosphonates, a new class of recently developed drugs. The geminal bisphosphonates are characterized by a P-C-P bond and are thus analogs of pyrophosphate. They bind strongly to hydroxyapatite crystals and in vitro inhibit both crystal formation and dissolution. In vivo, they inhibit soft tissue calcification and in some instances normal calcification. Furthermore, they are very potent inhibitors of bone resorption. The mechanism of action for the inhibition of calcification probably involves an inhibition of calcium phosphate crystal growth. However, the mode of action on bone resorption is not yet known, but is more likely to be cellular. The bisphosphonates are accumulated specifically in mineralized tissues. They are released when bone is resorbed so that osteoclasts and their precursors may be exposed to high local concentrations. Both inhibition of calcification and the effect on bone resorption is highly dependent upon the specific chemical structure of the individual bisphosphonate, so that each bisphosphonate must be considered as a compound per se. The only common characteristic is the tropism to mineral, which is due to the P-C-P group. This opens interesting possibilities for the development of new compounds.