Effects of bazedoxifene alone and with conjugated equine estrogens on coronary and peripheral artery atherosclerosis in postmenopausal monkeys

Abstract

Objective The objective was to evaluate the effects of bazedoxifene acetate (BZA), a new selective estrogen receptor modulator, on coronary and peripheral artery atherosclerosis and to determine if it would antagonize the atheroprotective effects of conjugated equine estrogens (CEE) in a monkey model. Methods Ninety-eight surgically postmenopausal monkeys (Macaca fascicularis) were fed a moderately atherogenic diet and then randomized to receive no treatment, or women’s equivalent doses of BZA (20 mg/day), CEE (0.45 mg/day) or BZA+CEE. The experiment period was for 20 months (approximately equivalent to 5 years of patient experience) during which interim measures were made of cardiovascular risk factors. At the end of the experimental period, the extent and severity of coronary and iliac artery atherosclerosis was quantified. Results Body weight, adiposity, fasting glucose concentrations and plasma lipid profiles were not different among treatment conditions. BZA had no adverse effects on coronary artery nor common iliac artery atherosclerosis extent or severity when compared to no-treatment. CEE, administered soon after inducing menopause, had a robust atheroprotective effect on both iliac and coronary artery extent and severity. The addition of BZA to the CEE treatment antagonized the atheroprotective effect of the CEE. Conclusions In this nonhuman primate trial, treatment with BZA alone, CEE alone and BZA and CEE in combination did not have significant effects on plasma lipid profiles. CEE markedly inhibited the progression and complication of both coronary and iliac artery atherosclerosis. BZA had no adverse effects on atherosclerosis but attenuated the atheroprotective effects of CEE.

Effects of bazedoxifene, conjugated equine estrogens, and a tissue-selective estrogen complex containing both bazedoxifene and conjugated equine estrogens on cerebral artery atherosclerosis in postmenopausal monkeys

“…We have reported separately that BZA was an estrogen antagonist capable of abrogating the effects of CEE on the monkey breast 18 , and endometrium 19 . We have also reported that BZA had no adverse effects on coronary and iliac artery atherosclerosis when given alone, but did attenuate the atheroprotective effects of CEE when given in combination 20 . In this communication we report on the effect of these interventions on the extent and severity of cerebral artery atherosclerosis.…”

“…The mean plasma lipid and lipoprotein concentrations for the control and treatment groups over the experimental period were reported previously 20 and are presented in Table 1. There were no significant differences among the groups.…”

“…However, beneficial effects of estrogen treatment in the monkey model, and probably among women as well, are thought to be mainly due to direct effects on the artery wall and not due to changes in plasma lipids and lipoproteins. Therefore it seems doubtful that the atherosclerosis outcomes of the monkey study would have been different had the monkey’s plasma lipid responses been more like those of women, since 20 ; in the common carotid artery, there was no significant effect of BZA on plaque extent (size). There was also no significant effect of CEE on plaque size; however, the prevalence of atherosclerosis was affected beneficially (11 of 24 unaffected with CEE compared with only 1 of 23 unaffected in the control group).…”

The role of estrogen in adipose tissue metabolism: insights into glucose homeostasis regulation [Review]

“…Bazedoxifene-CE combination therapy in postmenopausal women and rodents results in a significant increase in bone mineral density [111,112] and a decrease in the frequency of hot flashes [113,114] while protecting the endometrium. In a postmenopausal monkey model, this TSEC treatment did not affect the adiposity and plasma lipid profile, but bazedoxifene was found to attenuate the atheroprotective effects of CE [115]. A molecular study of bazedoxifene function on energy and glucose homeostasis in OVX mice demonstrated that injection of recombinant RBP4 in normal mice results in insulin resistance [96].…”

Raloxifene hydrochloride treatment leads to better outcomes than medroxyprogesterone acetate when paired with estrogen in ovariectomized cholesterol-fed rabbits

“…However, in a preclinical trial, treatment with bazedoxifene acetate (BZA), a new third-generation SERM, and conjugated equine estrogen (CEE) in combination did not show significant effects on plasma lipid profiles, and BZA treatment had no adverse effects on atherosclerosis but attenuated the atheroprotective effects of CEE in both the coronary and iliac arteries [6]. Raloxifene hydrochloride (RLX), a benzothiophene SERM, confers estrogen-like effects on lipids but anti-estrogenic effects on breast tissue and uterine endometrium.…”