MECHANISMS OF ACTION OF ETIDRONATE AND OTHER BISPHOSPHONATES

The bisphosphonates were discovered to be useful modulators of bone me tabolism in vivo in the 1960s. Etidronate was the first analogue to be extensively studied and utilized clinically in a variety of diseases characterized by abnormal bone metabolism, including Pagers disease an d heterotopic ossification. Etidronate is now widely used as a therape utic option for osteoporosis in 22 countries. This continued success o f etidronate and other bisphosphonates has led to detailed studies of the mechanisms of action of this class of drugs. In general, the bisph osphonates are safe and well tolerated, but in some cases particular c hemical features have adverse effects associated with them, such as up per gastrointestinal tract irritation with the alkyl amino series. The geminal bisphosphonate moiety (P-C-P) has a unique three dimensional structure facilitating both bidentate and tridentate binding to calciu m in bone. Etidronate thus exhibits high selectivity for bone compared with other tissues, due to this adsorption to calcium phosphate. Bisp hosphonates may affect both extracellular and intracellular calcium co ncentrations in the environment of the relevant bone cells. Multiple s ubstituent changes and the effects of overall three-dimensional struct ure have been studied and wide variations in potency have been observe d. Compounds with nitrogen substituents in the side chain can be highl y potent and several are in clinical use. Cellular effects are likely to play a major role in the overall mechanisms by which etidronate and other bisphosphonates modulate bone metabolism. These cellular effect s may include the metabolic incorporation of some bisphosphonates into ATP analogues in osteoclasts, and the inhibition by other bisphosphon ates of metabolic pathways and of cell signalling, particularly by int erfering with prenylation by inhibiting mevalonate metabolism. This ma y therefore be a partial explanation for the subtle differences betwee n bisphosphonate compounds in terms of their biological and clinical e ffects.