title: A new vitamin D analog, 2MD, restores trabecular and cortical bone mass and strength in ovariectomized rats with established osteopenia.
abstract: An orally active, highly potent analog of 1alpha,25-dihydroxyvitamin D3, 2MD, restores trabecular and cortical bone mass and strength by stimulating periosteal bone formation and decreasing trabecular bone resorption in OVX rats with established osteopenia.
  
  
  BACKGROUND
  The purposes of this study were to determine the effects of long-term treatment with 2-methylene-19-nor-(20S)-1alpha,25(OH)2D3 (2MD) on restoring bone mass and bone strength in ovariectomized (OVX) rats with established osteopenia and 2MD effects on bone formation and bone resorption on trabecular and cortical bone surfaces.
  
  
  METHODS
  Sprague-Dawley female rats were sham-operated (sham) or OVX at 4 months of age. Beginning at 8 weeks after OVX, OVX rats were orally dosed with 2MD at 0.5, 1, 2.5, 5, or 10 ng/kg/day for 16 weeks. Serum calcium was measured at 6, 13, and 16 weeks after treatment, and bone mass and structure, bone formation, bone resorption, and bone strength were determined at the end of the study.
  
  
  RESULTS
  Serum calcium did not change significantly with 2MD at 0.5 or 1 ng/kg/day, whereas it significantly increased at 2.5, 5, or 10 ng/kg/day. 2MD significantly and dose-dependently increased total body BMD, total BMC, and stiffness of femoral shaft (FS), maximal load and stiffness of femoral neck, and toughness of the fifth lumbar vertebral body (L5) at all doses compared with OVX controls. In 2MD-treated OVX rats, there was a dose-dependent increase in total BMD and total BMC of the distal femoral metaphysis (DFM), trabecular bone volume of L3, ultimate strength and stiffness of L5, and maximal load of FS compared with OVX controls at dosages>or=1 ng/kg/day. At dosages>2.5 ng/kg/day, most of the bone mass and bone strength related parameters were significantly higher in 2MD-treated OVX rats compared with sham controls. Bone histomorphometric analysis of L3 showed dose-dependent decreases in osteoclast number and osteoclast surface on trabecular bone surface and a dose-dependent increase in periosteal bone formation associated with 2MD treatment.
  
  
  CONCLUSIONS
  2MD not only restored both trabecular and cortical bone mass but also added bone to the osteopenic OVX rats beyond that of sham controls by stimulating bone formation on the periosteal surface and decreasing bone resorption on the trabecular surface. 2MD increased bone mass and strength at doses that did not induced hypercalcemia.
authors.affiliation: Osteoporosis Research, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, USA. huazhu.ke@Pfizer.com
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.forename: Hong
authors.initials: H
authors.lastname: Qi
authors.forename: D Todd
authors.initials: DT
authors.lastname: Crawford
authors.forename: Hollis A
authors.initials: HA
authors.lastname: Simmons
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Lori
authors.initials: L
authors.lastname: Plum
authors.forename: Margaret
authors.initials: M
authors.lastname: Clagett-Dame
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
authors.forename: David D
authors.initials: DD
authors.lastname: Thompson
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Brown
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000188:drug therapy*; D001862:Bone Resorption; D002117:Calcitriol / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives; D002118:Calcium / Q000097:blood; D005260:Female; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D002117:Calcitriol; D002118:Calcium