Use of bisphosphonates in the prevention of bone loss and fractures

Abstract

The bisphosphonates, formerly diphosphonates, are a class of synthetic analogues of pyrophosphate, with a phosphate-calcium-phosphate (PCP) instead of a phosphate-oxygen-phosphate (POP) backbone, which renders them resistant to hydrolysis [l]. They are poorly absorbed and bind avidly to bone mineral and are either retained in mineralized tissue or excreted in the urine. Many members of the class have been synthesized and tested in animals, and some have been used in human subjects. All bisphosphonates are capable of inhibiting bone mineralization and bone resorption [l], but with more recent compounds, the relative potency has shifted in favor of inhibition of resorption; the ambiguity of this term will be explained later. The mechanisms of action are poorly understood, and the profile of mechanisms is probably different for each member of the class [Z]. Bisphosphonates are retained in bone by at least two mechanisms. Like other bone-seeking substances, they are irreversibly trapped at sites of new bone formation, a property that has permitted their use as bone-scanning agents. With prolonged administration, all bone adjacent to the cancellous surface will eventually contain the drug to an average depth of approximately 50 pm and at a concentration that depends on the average blood level. A steady state will be attained when resorbed bone contains as much bisphosphonate as the new bone formed in its place. The time taken to attain this steady state will depend upon the prevailing rate of remodeling activation and whether the drug is given continuously or intermittently. The drug will also be reversibly bound to the most superficial layer of mineral that is accessible to exchange with the extracellular fluid. When administration is halted, the surface-bound drug will diffuse out of bone back into the circulation, in accordance with adsorptionidesorption kinetics [3], and most of the surface-bound bisphosphonate will have left the bone within a week. There is evidence for binding to some constituent of bone matrix [4], and small