In the Women's Health Initiative trial of estrogen-plus-progestin therapy,
women assigned to active treatment had fewer fractures.
To test the hypothesis that the relative risk reduction of estrogen
plus progestin on fractures differs according to risk factors for fractures.
Design, Setting, and Participants
Randomized controlled trial (September 1993-July 2002) in which 16 608
postmenopausal women aged 50 to 79 years with an intact uterus at baseline
were recruited at 40 US clinical centers and followed up for an average of
Women were randomly assigned to receive conjugated equine estrogen,
0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506)
or placebo (n = 8102).
Main Outcome Measures
All confirmed osteoporotic fracture events that occurred from enrollment
to discontinuation of the trial (July 7, 2002); bone mineral density (BMD),
measured in a subset of women (n = 1024) at baseline and years 1 and 3; and
a global index, developed to summarize the balance of risks and benefits to
test whether the risk-benefit profile differed across tertiles of fracture
Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin
group and 896 women (11.1%) in the placebo group experienced a fracture (hazard
ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did
not differ in women stratified by age, body mass index, smoking status, history
of falls, personal and family history of fracture, total calcium intake, past
use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD
increased 3.7% after 3 years of treatment with estrogen plus progestin compared
with 0.14% in the placebo group (P<.001). The
HR for the global index was similar across tertiles of the fracture risk scale
(lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile,
HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24)
(P for interaction = .54).
This study demonstrates that estrogen plus progestin increases BMD and
reduces the risk of fracture in healthy postmenopausal women. The decreased
risk of fracture attributed to estrogen plus progestin appeared to be present
in all subgroups of women examined. When considering the effects of hormone
therapy on other important disease outcomes in a global model, there was no
net benefit, even in women considered to be at high risk of fracture.