Bisphosphonates: mechanisms of action

The geminal bisphosphonates are a class of drug, developed in the last 30 years, characterised by a P-C-P bond. Consequently, they are analogues of pyrophosphate but are resistant to chemical and enzymatic hydrolysis. The bisphosphonates bind strongly to hydroxyapatite crystals and inhibit their formation and dissolution. This physicochemical effect on crystal growth is the cause, in vivo, of the prevention of soft tissue calcification and, in some instances when given in large amounts, the inhibition of normal calcification. However, the main effect is to inhibit bone resorption, the mechanism involved in which is cellular and not physicochemical. The action is mediated by a direct effect on the osteoclasts, which become inhibited after engulfing the compounds during the process of dissolution of drug-containing mineral, and possibly by an inhibitory effect on the recruitment of osteoclasts. The inhibition of bone resorption is useful for the treatment of diseases characterised by an elevated bone destruction, such as Paget’s disease, tumour bone disease, as well as osteoporosis. This review will describe today’s preclinical knowledge on these compounds, with special emphasis on the patent claims, and on the latest developments in the field. In view of the orientation of this series, the clinical part was not reviewed, with the exception of the areas related to the patents. For more information about the bisphosphonates, their mechanism of action, and their therapeutic use, the reader can consult a recent book [1] and various reviews [2-4].