What is the mechanism of action of bisphosphonates?

Bisphosphonates act primarily on osteoclasts to reduce bone resorption. Their mechanism involves intracellular accumulation within osteoclasts: nitrogen-containing bisphosphonates (alendronate, risedronate, zoledronic acid) inhibit farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway, which disrupts osteoclast cytoskeletal function and induces osteoclast apoptosis. Non-nitrogen bisphosphonates (clodronate, etidronate) form toxic ATP analogs within osteoclasts. The net result is decreased osteoclast number and activity, reduced bone resorption, and increased bone density. Clinically, bisphosphonate-related osteonecrosis of the jaw (BRONJ/MRONJ) is a serious complication relevant to dentistry.