title: Vitamin D receptor ligands for osteoporosis.
abstract: 1alpha,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the biologically active metabolite of vitamin D, mediates its actions via the vitamin D receptor (VDR), a member of the superfamily of steroid/thyroid hormone/retinoid receptors. 1,25-(OH)2D3 is required for calcium and phosphorus homeostasis, and for normal skeletal development as well as maintenance of skeletal architecture. Two VDR ligands, calcitriol (1,25-(OH)2D3) and its synthetic analog alfacalcidol (1alpha-hydroxyvitamin D3), have been approved for the treatment of osteoporosis. However, the use of calcitriol and alfacalcidol is limited by their major side effect, hypercalcemia, which is mediated mainly by VDR activity in the small intestine. In order to identify VDR ligands with less hypercalcemia liability, a number of pharmaceutical companies are pursuing efforts to develop synthetic vitamin D analogs. This review discusses the mechanism of action of vitamin D, and summarizes the currently approved anti-osteoporotic VDR agonists and compounds that are under development. The future directions of vitamin D research for the discovery of novel VDR agonists for osteoporosis are also discussed.
authors.affiliation: Wyeth Research, VVomen's Health and Musculoskeletal Biology, 500 Arcola Road, Collegeville, PA 19426, USA.
authors.forename: Boris J
authors.initials: BJ
authors.lastname: Cheskis
authors.forename: Leonard P
authors.initials: LP
authors.lastname: Freedman
authors.forename: Sunil
authors.initials: S
authors.lastname: Nagpal
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001842:Bone and Bones / Q000502:physiology; D006801:Humans; D008024:Ligands; D010024:Osteoporosis / Q000188:drug therapy*; D018167:Receptors, Calcitriol / Q000187:drug effects* / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology
chemical_list: D050071:Bone Density Conservation Agents; D008024:Ligands; D018167:Receptors, Calcitriol; D014807:Vitamin D