Bisphosphonates: The first 40Â years

► The biological effects of bisphosphonates (BPs) were first published in 1969. ► The potency of BPs on bone resorption depends on binding to bone mineral and osteoclast inhibition. ► Nitrogen-BPs inhibit farnesyl pyrophosphate synthase(FPPS) and protein prenylation. ► BPs are the major drugs for treating Paget's disease, bone metastases, and osteoporosis. ► Knowledge of structure-activity enables rational design of new BP drugs.