Determinants of structure–function relationships among bisphosphonates

Abstract Bisphosphonates are a chemical class of compounds in widespread use since the 1970s for the management of disorders of bone metabolism, such as Paget's disease and osteoporosis. The members of this drug class share a common P–C–P backbone structure, where C is carbon and each P is a phosphonate group; the 2 phosphonate groups act as a “bone hook” and are essential for binding to hydroxyapatite. Individual bisphosphonates exhibit differential binding to hydroxyapatite and exert differential actions within osteoclasts. The unique structure of each bisphosphonate determines its efficacy and relative utility in treating specific disorders of bone resorption. The structure–function profile of individual bisphosphonates is determined by the R1 and R2 side groups. Binding to bone is enhanced when R1 is a hydroxyl group. The R2 side group predominantly determines the antiresorptive potency of the bisphosphonates but has some effect on binding. The presence of nitrogen groups within the R2 side group is associated with the ability of an individual bisphosphonate to inhibit farnesyl pyrophosphate (FPP) synthase, a major enzyme in the mevalonate pathway. Structural differences among bisphosphonates explain the observed differences in mineral binding and antiresorptive potency and may in turn account for some of the clinical differences that have been seen in potency, duration of effect, and antifracture efficacy among members of this drug class.