Bisphosphonates: structure-activity relations from a clinical perspective

Bisphosphonates, synthetic compounds containing two phosphonate groups bound to a central (geminal) carbon (P-C-P) and two additional chains (R1 and R2, respectively) bind strongly to calcium crystals, inhibit their growth and suppress osteoclast-mediated bone resorption. The availability of two side chains allows numerous substitutions and the development of a variety of analogs with different pharmacological properties. The R1 structure together with the P-C-P are primarily responsible for binding to bone mineral and for the physicochemical actions of the bisphosphonates and a hydroxyl group at R1 provides optimal conditions for these actions. The R2 is believed to be responsible for the antiresorptive action of the bisphosphonates and small modifications or conformational restrictions of this part of the molecule may result in marked differences in antiresorptive potency. The presence of a nitrogen function in an alkyl chain or in a ring structure in R2 greatly enhances the antiresorptive potency and specificity of bisphosphonates for bone resorption and most of the newer potent bisphosphonates contain a nitrogen in their structure. Recent evidence, however, suggests that the whole bisphosphonate molecule is essential for antiresorptive action. Thus, although the basic structural requirements for bisphosphonate actions have been defined, precise structure-activity relations have not been defined yet. These are essential for elucidating their molecular mechanism of action and for the rational design of compounds for various clinical indications.