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Bisphosphonate Mechanism of Action

[ Vol. 2 , Issue. 6 ]


Gideon A. Rodan and Alfred A. Reszka   Pages 571 - 577 ( 7 )


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.


bisphosphonate, potent inhibitors, osteoporosis, mineralization, bone resorption, osteoclast activity, cholesterol synthesis, cytoskeletal organization, pharmacokinetics, cellular level


Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories,West Point, PA 19486, USA

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