Efficacy of Tissue-Selective Estrogen Complex of Bazedoxifene/Conjugated Estrogens for Osteoporosis Prevention in At-Risk Postmenopausal Women

Abstract

Several large placebo-controlled trials have demonstrated that conjugated estrogens with or without progestins significantly reduce the risk of vertebral and nonvertebral fractures and increase bone mineral density in postmenopausal women. The occurrence of endometrial stimulation and other unwanted hormonal-related side-effects with hormone therapy led to combined use with selective estrogen receptor modulators (SERMs) such as raloxifene, in an attempt to prevent bone loss while sparing the endometrium. Because raloxifene failed to reduce important vasomotor symptoms such as hot flashes and night sweats, other more selective SERMS were investigated. In animal studies and clinical studies, a new SERM, bazedoxifene (BZA), was shown to have effects on bone metabolism similar to raloxifene but showed no evidence of vasomotor symptoms. The present trial was part of a multicenter, randomized, double-blind, placebo- and active-controlled, phase 3 trial (Selective estrogen Menopause And Response to Therapy-1). The Selective estrogen Menopause And Response to Therapy-1 trial was designed to evaluate the effectiveness of treatment with a combination of a CE with BZA in a tissue-selective estrogen complex in preventing postmenopausal bone loss, relieving menopausal hot flashes, and treating vaginal and vulvar atrophy. The present study assessed the efficacy of BZ/CE to prevent bone loss in postmenopausal women. The study subjects in the Osteoporosis Prevention I and II substudies were 3397 women who were >5 years postmenopausal and 1 to 5 years postmenopausal, respectively. All participants were randomly assigned to receive once daily doses for up to 2 years of one of 8 regimens: BZA and CE (BZA: 10, 20, or 40 mg) each with CE, 0.625 or 0.45 mg), raloxifene (60 mg), or placebo. The primary study outcome was change in bone mineral density of the lumbar spine. Secondary outcomes included changes in BMD measured at the hip. Compared with placebo, the increase in BMD of the lumbar spine and total hip for all BZA/CE doses was significantly greater in both substudies (P < 0.001). The percent increase in lumbar spine BMD was significantly higher compared to raloxifene for most BZA/CE treatment groups (P < 0.05). In addition, serum concentrations of the bone turnover markers osteocalcin and C–telopeptide were significantly greater with all BZA/CE doses than with placebo (P < 0.001) and for most doses compared to raloxifene. These findings demonstrate that treatment of postmenopausal women at increased risk for osteoporosis with tissue-selective estrogen complex containing various BZA/CE combinations was associated with decreased bone turnover and bone loss.