Assessment of the safety of long-term bazedoxifene treatment on the reproductive tract in postmenopausal women with osteoporosis: Results of a 7-year, randomized, placebo-controlled, phase 3 study



      To evaluate the clinical safety of bazedoxifene (BZA) on the reproductive tract in postmenopausal women with osteoporosis over 7 years.

      Study design

      This was a second, blinded, 2-year extension of a 3-year, randomized, double-blind, placebo (PBO)- and active-controlled phase 3 trial. In the core study, subjects were randomized to receive BZA 20 or 40 mg, raloxifene 60 mg, or PBO. During years 4–5, the raloxifene arm was discontinued and subjects receiving BZA 40 mg were transitioned to BZA 20 mg. Subjects continued to receive BZA 20 mg or PBO during years 6–7.

      Main outcome measures

      The primary endpoint was the incidence of new vertebral fractures at 7 years (reported separately). Reproductive tract safety findings at 7 years are reported here. Endometrial thickness was assessed by transvaginal ultrasonography for subjects in the endometrial safety substudy. Adverse events (AEs) were recorded throughout the study.


      At 7 years, the adjusted mean (±standard error) change in endometrial thickness was similar with BZA and PBO (−0.11 ± 0.21 and 0.07 ± 0.32 mm, respectively). The incidence of endometrial hyperplasia was low (0.1% for both groups). BZA showed significantly lower rates than PBO of endometrial carcinoma (0.1% vs. 0.4%; P = 0.020) and vaginitis (6.1% vs. 7.6%; P = 0.035). There were more cases of ovarian carcinoma with BZA (n = 4 [0.1%]) than PBO (n = 0); the difference was not statistically significant. Rates of breast-related and other gynecologic AEs were similar among groups.


      BZA was associated with a favorable reproductive safety profile in postmenopausal women with osteoporosis over 7 years.


      AE (adverse event), ANCOVA (analysis of covariance), ANOVA (analysis of variance), BMD (bone mineral density), BZA (bazedoxifene), ER (estrogen receptor), EU (European Union), PBO (placebo), SERM (selective estrogen receptor modulator), TVU (transvaginal ultrasonography)


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        • International Osteoporosis Foundation
        Facts and statistics about osteoporosis and its impact.
        • North American Menopause Society
        Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society.
        Menopause. 2010; 17: 25-54
        • Silverman S.
        • Christiansen C.
        Individualizing osteoporosis therapy.
        Osteoporosis International. 2012; 23: 797-809
        • McDonnell D.P.
        • Connor C.E.
        • Wijayaratne A.
        • Chang C.Y.
        • Norris J.D.
        Definition of the molecular and cellular mechanisms underlying the tissue-selective agonist/antagonist activities of selective estrogen receptor modulators.
        Recent Progress in Hormone Research. 2002; 57: 295-316
        • Alexandersen P.
        • Riis B.J.
        • Stakkestad J.A.
        • Delmas P.D.
        • Christiansen C.
        Efficacy of levormeloxifene in the prevention of postmenopausal bone loss and on the lipid profile compared to low dose hormone replacement therapy.
        Journal of Clinical Endocrinology & Metabolism. 2001; 86: 755-760
        • Fleischer A.C.
        • Wheeler J.E.
        • Yeh I.T.
        • Kravitz B.
        • Jensen C.
        • MacDonald B.
        Sonographic assessment of the endometrium in osteopenic postmenopausal women treated with idoxifene.
        Journal of Ultrasound in Medicine. 1999; 18: 503-512
        • Goldstein S.R.
        • Nanavati N.
        Adverse events that are associated with the selective estrogen receptor modulator levormeloxifene in an aborted phase III osteoporosis treatment study.
        American Journal of Obstetrics & Gynecology. 2002; 187: 521-527
        • Pickar J.H.
        • MacNeil T.
        • Ohleth K.
        SERMs: progress and future perspectives.
        Maturitas. 2010; 67: 129-138
        • Miller P.D.
        • Chines A.A.
        • Christiansen C.
        • et al.
        Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study.
        Journal of Bone and Mineral Research. 2008; 23: 525-535
        • Pinkerton J.V.
        • Archer D.F.
        • Utian W.H.
        • et al.
        Bazedoxifene effects on the reproductive tract in postmenopausal women at risk for osteoporosis.
        Menopause. 2009; 16: 1102-1108
        • Silverman S.L.
        • Christiansen C.
        • Genant H.K.
        • et al.
        Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial.
        Journal of Bone and Mineral Research. 2008; 23: 1923-1934
        • Christiansen C.
        • Chesnut III, C.H.
        • Adachi J.D.
        • et al.
        Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis.
        BMC Musculoskeletal Disorders. 2010; 11: 130
        • Archer D.F.
        • Pinkerton J.V.
        • Utian W.H.
        • et al.
        Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women.
        Menopause. 2009; 16: 1109-1115
        • Silverman S.L.
        • Chines A.A.
        • Kendler D.L.
        • et al.
        Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study.
        Osteoporosis International. 2012; 23: 351-363
        • Palacios S.
        • Silverman S.
        • Levine A.B.
        • et al.
        Long-term efficacy and safety of Bazedoxifene in postmenopausal women with osteoporosis: results of a 7-year, randomized, placebo-controlled study.
        in: Presented at: the 13th International Menopause Society World Congress on Menopause, June 8–11, Rome, Italy2011
        • de Villiers T.J.
        • Chines A.A.
        • Palacios S.
        • et al.
        Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial.
        Osteoporosis International. 2011; 22: 567-576
        • European Medicines Agency
        Guideline on clinical investigation of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women. London, October 13, Doc. Ref. EMEA/CHMP/021/97 Rev. 1.
        • US Food and Drug Administration
        FDA guidance for industry: estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms.
        Recommendations for Clinical Evaluation. 2003;
        • Vogel V.G.
        The NSABP study of tamoxifen and raloxifene (STAR) trial.
        Expert Review of Anticancer Therapy. 2009; 9: 51-60
        • Martino S.
        • Disch D.
        • Dowsett S.A.
        • Keech C.A.
        • Mershon J.L.
        Safety assessment of raloxifene over eight years in a clinical trial setting.
        Current Medical Research and Opinion. 2005; 21: 1441-1452
        • Lewis-Wambi J.S.
        • Kim H.
        • Curpan R.
        • Grigg R.
        • Sarker M.A.
        • Jordan V.C.
        The selective estrogen receptor modulator bazedoxifene inhibits hormone-independent breast cancer cell growth and down-regulates estrogen receptor alpha and cyclin D1.
        Molecular Pharmacology. 2011; 80: 610-620
        • Pickar J.H.
        • Yeh I-T.
        • Bachmann G.
        • Speroff L.
        Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy.
        Fertility and Sterility. 2009; 92: 1018-1024
        • Peano B.J.
        • Crabtree J.S.
        • Komm B.S.
        • Winneker R.C.
        • Harris H.A.
        Effects of various selective estrogen receptor modulators with or without conjugated estrogens on mouse mammary gland.
        Endocrinology. 2009; 150: 1897-1903
        • Grady D.
        • Ettinger B.
        • Moscarelli E.
        • et al.
        Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation.
        Obstetrics & Gynecology. 2004; 104: 837-844
        • Fisher B.
        • Costantino J.P.
        • Wickerham D.L.
        • et al.
        Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.
        Journal of the National Cancer Institute. 1998; 90: 1371-1388
        • LaCroix A.Z.
        • Powles T.
        • Osborne C.K.
        • et al.
        Breast cancer incidence in the randomized PEARL trial of lasofoxifene in postmenopausal osteoporotic women.
        Journal of the National Cancer Institute. 2010; 102: 1706-1715
        • Martino S.
        • Cauley J.A.
        • Barrett-Connor E.
        • et al.
        Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene.
        Journal of the National Cancer Institute. 2004; 96: 1751-1761
        • Powles T.J.
        • Diem S.J.
        • Fabian C.J.
        • et al.
        Breast cancer incidence in postmenopausal women with osteoporosis or low bone mass using arzoxifene.
        Breast Cancer Research and Treatment. 2012; 134: 299-306
        • Cohen I.
        Endometrial pathologies associated with postmenopausal tamoxifen treatment.
        Gynecologic Oncology. 2004; 94: 256-266
        • Cummings S.R.
        • Ensrud K.
        • Delmas P.D.
        • et al.
        Lasofoxifene in postmenopausal women with osteoporosis.
        New England Journal of Medicine. 2010; 362: 686-696
        • Goldstein S.R.
        • Neven P.
        • Cummings S.
        • et al.
        Postmenopausal evaluation and risk reduction with lasofoxifene trial: 5-year gynecological outcomes.
        Menopause. 2010; 18: 17-22
      1. Pfizer Inc. FABLYN® (lasofoxifene tartrate) 0.5 mg Tablets. NDA 22-242. Reproductive Health Drugs Advisory Committee Briefing Document, 08 September.
        2008 (