Smart trials: effects of a tissue selective estrogen complex (TSEC) comprised of bazedoxifene (BZA) and conjugated estrogens (CEs) on bone mineral density (BMD) in postmenopausal women

Abstract

The first member of the TSEC class of menopausal therapy (pairing of a selective estrogen receptor modulator with estrogens) in clinical development pairs CE with BZA, a new selective estrogen receptor modulator with a unique endometrial profile. The effect of this combination on BMD was evaluated in 2 of the Selective estrogens Menopause And Response to Therapy (SMART) trials. Osteoporosis substudies of 2 randomized double-blind, placebo-controlled, multicenter, phase III trials—SMART-1 and SMART-4. SMART-1 trial randomized postmenopausal women (40–75 years) to 2 years of daily therapy with 6 doses of a TSEC comprised of BZA 10, 20, or 40 mg paired with CE 0.45 or 0.625 mg; raloxifene 60 mg (RLX); or placebo. Endpoints included the rate of endometrial hyperplasia and lumbar spine and hip BMD assessed by dual energy x-ray absorptiometry. SMART-4 trial, the first to compare BZA/CE with hormone therapy, randomized postmenopausal women (aged 40–64 years) to 2 years of daily therapy with 2 doses of a TSEC (BZA 20 mg/CE 0.45 or BZA 20 mg/CE 0.625 mg); hormone therapy (CE 0.45/medroxyprogesterone acetate 1.5 mg); or placebo. The primary endpoints were the rate of endometrial hyperplasia and prevention of osteoporosis at 1 year. SMART-1 osteoporosis substudy enrolled 2315 women (861 women ≤5 years postmenopause and 1454 women >5 years postmenopause). Among women ≤5 years postmenopause, the mean increase from baseline in lumber spine BMD at 2 years was significantly greater with all TSECs (range, 1.15%-2.61%) compared to RLX (0.15%; P<0.05) or placebo (−1.92%; P<0.001). Among women >5 years postmenopause, the increase from baseline in lumbar spine BMD at 2 years was significantly greater with TSECs containing BZA 10 and 20mg (range, 1.57%–2.42%) than with RLX (0.73%; P<0.05); all TSECs were significantly greater than placebo (−1.51%; P<0.001). Similar results were observed for hip BMD. Results will be also presented for the SMART-4 trial osteoporosis substudy, which enrolled >500 postmenopausal women (<5 years postmenopausal). BZA/CE, the first TSEC, significantly improves lumbar spine and hip BMD in postmenopausal women. Together with its favorable endometrial safety profile and efficacy for vasomotor symptoms (reported elsewhere), the clinical profile of BZA/CE may change the way women and physicians approach menopausal symptoms.