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.

Bone remodeling markers and bone metastases: From cancer research to clinical implications

“…[31][32][33][34][35][36][37][38][39][40][41] In addition, in nonhuman primate models, serum markers of bone resorption were also consistent with the observed phenotype. [42][43][44][45][46] Biomarkers of bone remodeling can also be used in in vitro models. 47 These cellular models can be reliably used for enhancing preclinical evaluation of pharmacological agents in metastatic bone disease.…”

Tissue selective effects of bazedoxifene on the musculoskeletal system in female mice

“…While such clinical investigations have shown several positive effects of BZA, additional pre-clinical studies are necessary to further determine effects on targeted and nontargeted tissues, as well as the mechanisms through which BZA elicits these effects independent of a simultaneous estrogen treatment. In terms of efficacy on the skeleton, both rodent and primate models show treatment with BZA following ovariectomy (OVX) increases total bone mineral density (BMD), reduces OVX-induced bone turnover, and increases bone volume and trabecular thickness, particularly of the vertebrae (Kharode et al 2008, Komm et al 2011, Saito et al 2015, Smith et al 2015. Work by Borjesson et al implicates estrogen receptor alpha (ERα), specifically the ERα-activation function-1, as a mechanism through which BZA elicits its effects in bone (Borjesson et al 2013, Börjesson et al 2016.…”

Suppression of Bone Resorption by miR-141 in Aged Rhesus Monkeys

“…Rhesus monkeys ( Macaca mulatta ) have many valuable features that highlight their potential as experimental animals in biomedical research, including their genetic, anatomical, and biomechanical similarities with humans . Mature female rhesus monkeys exhibit a menstrual cycle of 26 to 32 days and a natural menopause, which is similar to humans; thus, the aged female rhesus monkey (>20 years old) is regarded as an ideal model for OP study . In our study, we investigated the pharmacological role of OC‐targeted delivery of miR‐141 in aged osteoporotic rhesus monkeys.…”