title: Effects of lasofoxifene on bone in surgically postmenopausal cynomolgus monkeys.
abstract: OBJECTIVE
  The purpose of this study was to evaluate the effects on bone of two doses of the selective estrogen receptor modulator lasofoxifene in surgically postmenopausal cynomolgus monkeys for 24 months. The primary endpoint of this study was biomechanical testing of animals treated for 2 years.
  
  
  METHODS
  The design of the study was a five-group (sham-ovariectomy, ovariectomy, conjugated [0.02 mg/kg], and two doses of lasofoxifene [1.0 and 5.0 mg/kg]), parallel arm design, with the treatments lasting for 24 months. Bone biomarker and estradiol data were collected at baseline and 3, 6, 12, 18, and 24 months after surgery. Vertebral bone mineral density was determined at baseline and every 6 months after ovariectomy. Hip bone density was determined at baseline and 12 and 24 months postovariectomy. Iliac bone biopsies were collected at 7 months, and the second lumbar vertebra and left femur were collected at 24 months after initiation of treatment for histomorphometric examination. The third lumbar vertebra and right femur were tested for mechanical strength after 24 months of treatment.
  
  
  RESULTS
  Lasofoxifene and conjugated estrogens prevented ovariectomy-induced increases in serum alkaline phosphatase and CrossLaps and resulted in increased vertebral (all three treatments) and hip (conjugated estrogens and high-dose lasofoxifene only) bone mineral density, although both doses of lasofoxifene exceeded the doses projected to be used in women. In the 7-month iliac biopsy specimens, both doses of lasofoxifene reduced bone turnover rates. These histomorphometric changes were not present in either the vertebral or femoral compartments measured after 24 months of treatment. Lasofoxifene-treated animals did not differ from ovariectomized controls in mechanical strength testing of either the third lumbar vertebra or right femur.
  
  
  CONCLUSIONS
  Lasofoxifene prevented ovariectomy-induced increased bone turnover and loss of bone mineral density without having a detrimental effect on bone strength.
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Winston Salem, NC, USA. clees@wfubmc.edu
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lees
authors.forename: Victor
authors.initials: V
authors.lastname: Shen
authors.forename: Robert
authors.initials: R
authors.lastname: Brommage
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena; D001835:Body Weight; D015519:Bone Density / Q000187:drug effects*; D024042:Collagen Type I / Q000097:blood; D004958:Estradiol / Q000097:blood; D004967:Estrogens / Q000494:pharmacology*; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D008252:Macaca fascicularis; D010024:Osteoporosis / Q000517:prevention & control*; D010052:Ovariectomy; D010455:Peptides / Q000097:blood; D017698:Postmenopause / Q000097:blood / Q000187:drug effects*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D013131:Spine / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D004967:Estrogens; D004966:Estrogens, Conjugated (USP); D010455:Peptides; D011759:Pyrrolidines; D013764:Tetrahydronaphthalenes; C052929:collagen type I trimeric cross-linked peptide; C111332:Lasofoxifene; D004958:Estradiol; D000469:Alkaline Phosphatase