title: Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial.
abstract: OBJECTIVE
  Because small increments in levels of endogenous plasma estradiol are associated with higher postmenopausal bone mineral density, we investigated the safety and effectiveness in preventing bone loss of unopposed, very-low-dose transdermal estradiol for postmenopausal women.
  
  
  METHODS
  This was a randomized, placebo-controlled, double-blind trial with 2-year follow-up at 9 United States clinical centers. The study population comprised 417 postmenopausal women, aged 60-80 years, with intact uterus and bone mineral density z scores of -2.0 or higher, who were randomly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d (n = 208) or placebo (n = 209). All participants received calcium and vitamin D supplementation. Lumbar spine and total hip bone mineral density change was measured by dual-energy X-ray absorptiometry; endometrial hyperplasia incidence was assessed by endometrial biopsy.
  
  
  RESULTS
  Median plasma estradiol level in the estradiol group increased from 4.8 pg/mL at baseline to 8.5 pg/mL at 1 year (P <.001 versus baseline) and to 8.6 pg/mL at 2 years (P <.001 versus baseline) and was unchanged in the placebo group. Lumbar spine bone mineral density increased 2.6% in the estradiol group and 0.6% in the placebo group (between-group difference 2.0%, P <.001). Mean total hip bone mineral density increased 0.4% in the estradiol group and decreased 0.8% in the placebo group (between-group difference 1.2%, P <.001). Osteocalcin levels and bone-specific alkaline phosphatase were lower in the estradiol group than the placebo group (P <.001 each). Endometrial hyperplasia developed in 1 woman in the estradiol group but in none of the placebo group (difference in 2-year rates 0.5%, 95% confidence interval 0-7.3%).
  
  
  CONCLUSIONS
  Postmenopausal treatment with low-dose, unopposed estradiol increased bone mineral density and decreased markers of bone turnover without causing endometrial hyperplasia.
authors.affiliation: Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Ettinger
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Ensrud
authors.forename: Robert
authors.initials: R
authors.lastname: Wallace
authors.forename: Karen C
authors.initials: KC
authors.lastname: Johnson
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yankov
authors.forename: Eric
authors.initials: E
authors.lastname: Vittinghoff
authors.forename: Deborah
authors.initials: D
authors.lastname: Grady
mesh_terms: D000279:Administration, Cutaneous; D000368:Aged; D015519:Bone Density / Q000187:drug effects*; D004311:Double-Blind Method; D004958:Estradiol / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D020249:Hormone Replacement Therapy / Q000009:adverse effects; D006801:Humans
chemical_list: D004958:Estradiol