Estrogen therapy is known to prevent osteoporosis, but studies have
shown that conventional doses increase adverse events. Whether lower doses,
one quarter of standard treatment, prevent bone loss is not known.
To examine the effect of 3 years of treatment with 0.25 mg/d of micronized
17β-estradiol on bone mineral density (BMD) and bone turnover in healthy
older postmenopausal women.
Design, Setting, and Participants
Randomized, double-blind, placebo-controlled trial conducted from July
24, 1998, through June 14, 2002, at a university general clinical research
center in the United States. Healthy, community-dwelling women (N = 167) who
were older than 65 years at enrollment.
Dosage of 0.25 mg/d of micronized 17β-estradiol (n = 83) or placebo
(n = 84); all women who had not had a hysterectomy received 100 mg/d of oral
micronized progesterone for 2-week periods every 6 months.
Main Outcome Measures
The BMD of the hip, spine, wrist, and total body measured annually for
3 years. Serum and urine biochemical markers of bone resorption and formation
and sex hormones were measured at baseline, 3 months, and during years 1 and
3 of treatment.
Mean BMD increased at all sites for participants taking low-dose estrogen
(17β-estradiol) compared with placebo (P<.001).
Compared with participants receiving placebo, participants taking low-dose
estrogen had BMD increases of 2.6% for the femoral neck; 3.6%, total hip;
2.8%, spine; and 1.2%, total body. Markers of bone turnover, N-telopeptides
of type 1 collagen, and bone alkaline phosphatase decreased significantly
(P<.001) in participants taking low-dose estrogen
compared with placebo. Estradiol, estrone, and sex hormone–binding globulin
levels increased in the estrogen-treated group compared with placebo. The
adverse effect profile was similar; specifically, there were no statistically
significant differences in breast tenderness, changes in endometrial thickness
or pathological effects, or annual mammographic results between the 2 groups.
The number of abnormal mammograms over 3 years was 15 for the low-dose estrogen
group and 10 for the placebo group (8 occurred at baseline) (P = .26). There were no reports of breast cancer during the study.
In older women, a dosage of 0.25 mg/d of 17β-estradiol increased
bone density of the hip, spine, and total body, and reduced bone turnover,
with minimal adverse effects. Future studies evaluating the effect of low-dose
estrogen on fractures are indicated.