title: Bisphosphonate mechanism of action.
abstract: 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.
authors.affiliation: Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA. gideon_rodan@merck.com
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Rodan
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Reszka
mesh_terms: D019386:Alendronate / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption; D002784:Cholesterol / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004164:Diphosphonates / Q000737:chemistry* / Q000378:metabolism*; D004224:Diterpenes; D006801:Humans; D050356:Lipid Metabolism; D008954:Models, Biological; D009584:Nitrogen / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D017368:Protein Prenylation
chemical_list: D004164:Diphosphonates; D004224:Diterpenes; D011106:Polyisoprenyl Phosphates; D002784:Cholesterol; C002963:geranylgeranyl pyrophosphate; D009584:Nitrogen; D019386:Alendronate