Context Lower-than-commonly-prescribed doses of conjugated equine estrogens
(CEEs) with medroxyprogesterone acetate (MPA) improve vasomotor symptoms and
vaginal atrophy, provide acceptable bleeding and lipid profiles, and afford
endometrial protection. This lower-dose therapy's protection against loss
of bone mineral density (BMD) associated with menopause has not been thoroughly
Objective To determine the effects of lower doses of CEEs only or CEEs-MPA on
spine and hip BMD, total body bone mineral content (BMC), and biochemical
markers of bone turnover in postmenopausal women.
Design and Setting Two-year randomized, double-blind, placebo-controlled substudy of the
Women's Health, Osteoporosis, Progestin, Estrogen trial, conducted at 19 US
centers between August 1995 and October 2000.
Participants Eight hundred twenty-two healthy postmenopausal women aged 40 to 65
years who were within 4 years of their last menstrual period.
Interventions Patients were randomly assigned to receive CEEs, 0.625; CEEs, 0.625
and MPA, 2.5; CEEs, 0.45; CEEs, 0.45 and MPA, 2.5; CEEs, 0.45 and MPA, 1.5;
CEEs, 0.3; CEEs 0.3 and MPA, 1.5 (all doses in mg/d); or placebo for 2 years.
All participants also received elemental calcium at 600 mg/d.
Main Outcome Measures Changes from baseline in spine and total hip BMD, total body BMC, and
biochemical markers of bone turnover (serum osteocalcin and urinary cross-linked N-telopeptides of type I collagen), assessed at 6-month
intervals and compared among treatment groups with a modified intention-to-treat
Results At 24 months, women assigned to all of the active treatment groups had
significant gains from baseline (P<.001) in spine
and hip BMD and total body BMC (except total body BMC in the group receiving
CEEs, 0.3 mg/d). These changes were significantly different from those in
the placebo group, in which losses of bone mass in spine and total body were
evident over the course of the study (P<.001).
The loss in hip BMD from baseline in the placebo group was significant at
18 (P = .02) but not at 24 months (P = .06). Osteocalcin and N-telopeptides of
type I collagen were significantly reduced from baseline (P<.001) for all active treatment groups at all time points; no changes
were found for the placebo group. For women treated with CEEs alone, the gains
in spine BMD for the group taking CEEs, 0.625 mg/d, were significantly higher
than those of the group taking CEEs, 0.3 mg/d (P
= .02), but not the group treated with CEEs, 0.45 mg/d (P = .48).
Conclusions Doses of CEEs or CEEs-MPA lower than 0.625 mg/d effectively increase
BMD and BMC in early postmenopausal women.