title: The effects of bazedoxifene in the ovariectomized aged cynomolgus monkey.
abstract: Bazedoxifene (BZA) is a novel selective estrogen receptor modulator in clinical development for the prevention and treatment of postmenopausal osteoporosis. This preclinical study evaluated the efficacy and safety of BZA in preventing ovariectomy (OVX)-induced bone loss in aged cynomolgus monkeys. Animals (18 per group) underwent OVX and were administered BZA (0.2, 0.5, 1, 5, or 25 mg/kg/day) or vehicle, or were sham-operated and administered vehicle, by daily oral gavage for 18 months. Biochemical markers of bone turnover were assessed at 6, 12, and 18 months, along with bone densitometry using dual energy X-ray absorptiometry and peripheral quantitative computed tomography. Animals were killed after 18 months. Uterine and pituitary weights were determined, and histomorphometric and biomechanical measurements were performed. OVX vehicle controls showed increases in bone turnover associated with cancellous and cortical bone osteopenia (in vivo), and slight decreases (not statistically significant) in biomechanical strength parameters at the lumbar spine and femoral neck. BZA partially preserved cortical and cancellous bone mass by preventing the OVX-induced increases in bone turnover. Although the response was often similar among BZA-treated groups, the strongest efficacy was generally seen at 25 mg/kg/day. Treatment with BZA did not adversely affect measures of bone strength and was well tolerated; there was no evidence of uterotrophic activity, mammary tissue was unaffected, and there were no adverse effects on plasma lipids. Treatment of ovariectomized animals with BZA partially prevented changes in bone remodeling that correlated with increases in bone mineral density, while maintaining bone strength and a favorable safety profile.
authors.affiliation: Charles River Preclinical Services, 22022 Transcanadienne, Senneville, QC, H9X 3R3, Canada.
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Smith
authors.forename: Jacquelin
authors.initials: J
authors.lastname: Jolette
authors.forename: Luc
authors.initials: L
authors.lastname: Chouinard
authors.forename: Barry S
authors.initials: BS
authors.lastname: Komm
mesh_terms: D015502:Absorptiometry, Photon / Q000379:methods; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects*; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D005269:Femur / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000378:metabolism; D010052:Ovariectomy / Q000379:methods; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism
chemical_list: D007211:Indoles; D020845:Selective Estrogen Receptor Modulators; C447119:bazedoxifene