Bisphosphonate Mechanism of Action
Gideon A. Rodan and Alfred A. Reszka
Affiliation: Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories,West Point, PA 19486, USA
Nitrogen-containing bisphosphonates (N-BPs) are potent inhibitors of bone resorption widely used in the treatment of osteoporosis and other bone degrading disorders. At the tissue level, N-BPs reduce bone turnover, increase bone mass and mineralization, measured clinically as a rise in bone mineral density, increase bone strength and reduce fracture risk. At the cellular level, N-BPs, localize preferentially at sites of bone resorption, where mineral is exposed, are taken up by ostoclasts and inhibit osteoclast activity. The bone formation that follows incroporates the N-BP in the matrix, where it becomes pharmacologically inactive until released at a future time during bone remodeling. At the molecular level, N-BPs inhibit an enzyme in the cholesterol synthesis pathway, farnesyl diphosphate synthase. As a result, there is a reduction in the lipid geranylgeranyl diphosphate, which prenylates GTPases required for cytoskeletal organization and vesicular traffic in the osteoclast, leading to osteoclast inactivation.
Keywords: bisphosphonate, potent inhibitors, osteoporosis, mineralization, bone resorption, osteoclast activity, cholesterol synthesis, cytoskeletal organization, pharmacokinetics, cellular level
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