Extraskeletal effects of the novel selective estrogen receptor modulator (SERM) bazedoxifene acetate (BZA): a 12-month study in ovariectomized rats

Abstract

Bazedoxifene acetate (BZA) is a novel SERM currently in development as monotherapy for the prevention and treatment of postmenopausal osteoporosis and in pair with conjugated estrogens for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis. We examined effects of BZA on body, uterine, and pituitary weights, reproductive tract histology, and serum lipids to assess its safety in ovariectomized (OVX), 6-month-old female rats. In active treatment groups, 3 doses of BZA (0.15, 0.3, and 1.5 mg/kg/day) were administered to OVX animals by oral gavage for 12 months. Control groups included an untreated baseline group, untreated sham-operated animals, untreated OVX animals, and estrogen-treated (17α-ethinylestradiol [EST], 0.03 mg/kg/day) OVX group. Body, uterine, and pituitary weights were recorded as baseline and terminal procedures. The uterus and pituitary were examined macro- and microscopically. Laboratory investigations included serum cholesterol and triglycerides, with blood samples collected at baseline and throughout the study. Although animals in all groups had increased body weights, BZA-treated animals gained less weight than OVX controls and sham and EST-treated animals. Uterine weights were decreased in all BZA groups compared with the sham and EST groups and were slightly increased compared with the OVX control group. BZA-related uterus weight changes were correlated with decreased incidence of small uteri and decreased severity of uterine atrophy vs. OVX controls. Pituitary weights were decreased in all BZA groups compared with the OVX and sham control groups; these decreases were comparable to those in the EST group and were not correlated with macro- or microscopic findings. Total cholesterol levels in BZA-treated groups decreased from baseline at week 3 and remained lower compared to those in the sham-operated and OVX control groups and comparable to those in the EST group through the study's end. From week 25 through study end, animals in the 0.3 and 1.5 mg/kg/day BZA groups had triglyceride levels comparable to those in the sham-operated group and lower than in the EST group. We conclude that bazedoxifene, a novel SERM, has a promising therapeutic profile based on the safety outcomes observed in this animal model of accelerated bone loss: BZA prevented ovariectomy-associated increases in body weight, demonstrated minimal effects on uterine weight, and reduced serum cholesterol levels.