To evaluate the efficacy of the tissue-selective estrogen complex, bazedoxifene/conjugated estrogens (BZA/CE), for postmenopausal osteoporosis prevention.Multicenter, randomized, double-blind, placebo- and active-controlled, phase 3 trial (Selective estrogen Menopause And Response to Therapy [SMART]-1).Outpatient clinical study.Women (n = 3,397) more than 5 years and 1–5 years postmenopause were enrolled in the Osteoporosis Prevention I and II Substudies, respectively.Single tablets of BZA (10, 20, or 40 mg) each with CE (0.625 or 0.45 mg), raloxifene (60 mg), or a placebo taken daily for 2 years.The primary outcome for both substudies was change in bone mineral density of the lumbar spine; bone mineral density was also measured at the hip.In both substudies, bone mineral density increased significantly more with all BZA/CE doses compared with placebo at the lumbar spine and total hip, and for most BZA/CE doses compared with raloxifene at the lumbar spine. Osteocalcin and N-telopeptide significantly decreased with all BZA/CE doses vs. placebo and most BZA/CE doses vs. raloxifene.BZA/CE combinations decreased bone turnover and bone loss in postmenopausal women at increased risk for osteoporosis.