title: Mechanism of action of bisphosphonates.
abstract: In recent years, substantial progress has been made in understanding the mechanism for bisphosphonate suppression of bone turnover. Bisphosphonates can now be distinguished based on their molecular and cellular mechanisms of action. Simple bisphosphonates such as clodronate and etidronate inhibit bone resorption through induction of osteoclast apoptosis. Clodronate, and perhaps etidronate, triggers apoptosis by generating a toxic analog of adenosine triphosphate, which then targets the mitochondria, the energy center within the cell. For nitrogen-containing bisphosphonates, the direct intracellular target is the enzyme farnesyl diphosphate synthase in the cholesterol biosynthetic pathway. Its inhibition suppresses a process called protein geranylgeranylation, which is essential for the basic cellular processes required for osteoclastic bone resorption. Although nitrogen-containing bisphosphonates can induce osteoclast apoptosis, this is not necessary for their inhibition of bone resorption.
authors.affiliation: Department of Molecular Endocrinology and Bone Biology, Merck Research Laboratories, West Point, PA 19846, USA. alfred_reszka@merck.com
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Reszka
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Rodan
mesh_terms: D001862:Bone Resorption / Q000517:prevention & control*; D004002:Clodronic Acid / Q000737:chemistry* / Q000627:therapeutic use; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D012968:Etidronic Acid / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D010024:Osteoporosis / Q000517:prevention & control; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
chemical_list: D004164:Diphosphonates; D004002:Clodronic Acid; D012968:Etidronic Acid