title: Gynecologic Safety of Conjugated Estrogens Plus Bazedoxifene: Pooled Analysis of Five Phase 3 Trials.
abstract: OBJECTIVE
  To evaluate gynecologic safety of conjugated estrogens/bazedoxifene treatment for menopausal symptoms and osteoporosis prevention in nonhysterectomized women.
  
  
  METHODS
  We pooled data from five randomized, placebo-controlled trials of conjugated estrogens 0.625 mg/bazedoxifene 20 mg (n = 1583), conjugated estrogens 0.45 mg/bazedoxifene 20 mg (n = 1585), and placebo (n = 1241). Gynecologic safety was evaluated by pelvic examination, Papanicolaou smear, endometrial biopsy, transvaginal ultrasound, mammogram, adverse events, and diary records of vaginal bleeding and breast pain/tenderness. Incidence rates and relative risks (RR) versus placebo were calculated with inverse variance weighting. Data for conjugated estrogens 0.45 mg/medroxyprogesterone acetate 1.5 mg, an active comparator in two trials (n = 399), are included for comparison.
  
  
  RESULTS
  Endometrial hyperplasia occurred in <1% (n = 4 [0.3%], 2 [0.2%], 1 [0.5%], and 2 [0.2%] for conjugated estrogens 0.625 mg/bazedoxifene 20 mg, conjugated estrogens 0.45 mg/bazedoxifene 20 mg, conjugated estrogens/medroxyprogesterone acetate, and placebo). There was one endometrial cancer, which occurred with conjugated estrogens 0.45 mg/bazedoxifene 20 mg (0.44/1000 woman-years [95% confidence interval (CI), 0.00-2.37]; RR versus placebo 0.91 [95% CI, 0.17-4.82]). There were seven cases of breast cancer: four with conjugated estrogens 0.45 mg/bazedoxifene 20 mg (1.00/1000 woman-years [95% CI, 0.00-3.21] RR 1.11 [95% CI, 0.33-3.78]), two with placebo, and one with conjugated estrogens/medroxyprogesterone acetate. Unlike conjugated estrogens/medroxyprogesterone acetate, conjugated estrogens/bazedoxifene did not increase breast density, breast pain/tenderness, or vaginal bleeding versus placebo. No active treatment increased ovarian cysts.
  
  
  CONCLUSIONS
  Conjugated estrogens/bazedoxifene provides endometrial protection without increasing breast pain/density, vaginal bleeding, or ovarian cysts in nonhysterectomized postmenopausal women studied up to 2 years.
authors.affiliation: 1 Pfizer Inc , Collegeville, Pennsylvania.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mirkin
authors.affiliation: 2 University of Virginia Health System , Charlottesville, Virginia.
authors.forename: JoAnn V
authors.initials: JV
authors.lastname: Pinkerton
authors.affiliation: 3 University of California , San Francisco, California.|4 East Bay Physicians Medical Group , Berkeley, California.
authors.forename: Risa
authors.initials: R
authors.lastname: Kagan
authors.affiliation: 5 Pfizer Inc , Groton, Connecticut.
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.affiliation: 1 Pfizer Inc , Collegeville, Pennsylvania.
authors.forename: Kaijie
authors.initials: K
authors.lastname: Pan
authors.affiliation: 6 Columbia University Medical Center , New York, New York.
authors.forename: James H
authors.initials: JH
authors.lastname: Pickar
authors.affiliation: 1 Pfizer Inc , Collegeville, Pennsylvania.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Komm
authors.affiliation: 7 Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School , Norfolk, Virginia.
authors.forename: David F
authors.initials: DF
authors.lastname: Archer
mesh_terms: D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects; D001940:Breast / Q000187:drug effects; D004359:Drug Therapy, Combination; D004714:Endometrial Hyperplasia / Q000139:chemically induced / Q000453:epidemiology; D004967:Estrogens / Q000008:administration & dosage / Q000009:adverse effects*; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D015994:Incidence; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects*; D008593:Menopause / Q000187:drug effects*; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000517:prevention & control*; D010919:Placebos; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects; D014592:Uterine Hemorrhage / Q000139:chemically induced / Q000453:epidemiology
chemical_list: D050071:Bone Density Conservation Agents; D004967:Estrogens; D004966:Estrogens, Conjugated (USP); D007211:Indoles; D010919:Placebos; D020845:Selective Estrogen Receptor Modulators; C447119:bazedoxifene