The Pairing of a Selective Estrogen Receptor Modulator, Bazedoxifene, with Conjugated Estrogens as a New Paradigm for the Treatment of Menopausal Symptoms and Osteoporosis Prevention

Abstract

The menopausal transition is associated with decreased ovarian function and concomitant decline in estrogen production, which may result in physiological effects such as hot flashes, reduced bone mass, and altered lipid profile. It is well established that these unfavorable changes are effectively offset with estrogen therapy (ET) or, in women with a uterus, estrogens in combination with a progestin (hormone therapy). Selective estrogen receptor (ER) modulators (SERMs), which exhibit both ER agonist and antagonist activities depending on the target tissue, have been regarded as offering the potential to provide the benefits of ET and hormone therapy with an improved safety and tolerability profile. To date, no SERM alone has demonstrated an ideal benefit-risk profile for menopausal therapy. The tissue-selective estrogen complex, or the pairing of a SERM with estrogens, may provide an optimal blend of ER agonist and antagonist activities. We evaluated the physiological profile of this novel therapeutic paradigm by using various in vivo models to assess uterine, vasomotor, lipid, and skeletal responses to a tissue-selective estrogen complex partnering bazedoxifene with conjugated estrogens (CE). Bazedoxifene at 3.0 mg/kg effectively antagonized CE-induced uterine stimulation without reversing the positive effects of CE on vasomotor instability. When paired with CE, bazedoxifene at 3.0 mg/kg reduced total cholesterol levels by up to 20% compared with CE alone and significantly increased total bone density relative to control. These preclinical findings showed that the appropriate dose combination of bazedoxifene/CE exhibits positive vasomotor, lipid, and skeletal responses with minimal uterine stimulation.

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…Preclinical data have suggested that the combination treatment of bazedoxifene and conjugated estrogens (CE) might lead to a more favorable benefit-risk profile in the treatment of menopause symptoms, including favorable vasomotor, lipid, and skeletal response with minimal stimulation in the uterus (Kharode et al, 2008;Peano et al, 2009). This combination therapy also shows efficacy in the treatment of osteoporosis in a manner that prevents uterine growth, with decreased uterine wet weight and lower cholesterol levels .…”

Recent Developments in Pharmacotherapy for Vasomotor Symptoms

“…A tissue-selective estrogen complex (TSEC) partners bazedoxifene (BZA), a novel estrogen agonist/antagonist, with conjugated estrogens (CE), with the goal of designing a novel menopausal therapy that combines the beneficial effects of both [28]. Ideally, a TSEC would relieve menopausal symptoms such as hot flushes and vaginal atrophy, prevent osteoporosis, and have a favorable safety and tolerability profile, including a neutral effect on the breast and uterus.…”

“…Ideally, a TSEC would relieve menopausal symptoms such as hot flushes and vaginal atrophy, prevent osteoporosis, and have a favorable safety and tolerability profile, including a neutral effect on the breast and uterus. BZA is a novel estrogen agonist/antagonist that has shown efficacy in preventing fractures and preserving bone mineral density (BMD) in postmenopausal women, without any evidence of endometrial or breast stimulation [28], [ …”

Pharmacological Treatment of Osteoporosis

“…(Stovall & Pinkerton, 2008) Preclinical studies have shown that bazedoxifene antagonizes estrogen-induced uterine and mammary gland stimulation more effectively than other SERMs like raloxifene and lasofoxifene. (Peano et al, 2009;Kharode et al, 2008) A randomized, double-blind, placebocontrolled Phase III trial in 3,397 postmenopausal women examined the effect of bazedoxifene 10, 20, or 40 mg combined with conjugated estrogens 0.625 mg or 0.45 mg on bone and endometrium. In this trial, the bazedoxifene plus conjugated estrogen combination therapy showed a statistically significant increase in BMD and a decrease in bone biochemical turnover markers compared with placebo.…”