Effects of Transdermal Estradiol Delivered by a Matrix Patch on Bone Density in Hysterectomized, Postmenopausal Women: A 2-year Placebo-Controlled Trial

Abstract

This 2-year, double-masked, randomized, placebo-controlled trial was designed to evaluate the safety and efficacy in preventing bone loss in postmenopausal women of two doses of transdermal 17betaestradiol (estradiol) delivered by a matrix patch, compared with placebo. One hundred and sixty healthy, hysterectomized postmenopausal volunteers aged 40-60 years with serum estradiol levels < 20 pg/ml were started on treatment at four centers in The Netherlands. Every 6 months, bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, non-dominant wrist and left hip, and markers of bone turnover were assessed in urine and serum. The treatment arms were: estradiol, 100 microg/day (E-100, n = 53), oestradiol, 50 microg/day (E-50, n = 54), placebo (P-100, placebo to E-100, n = 27 or P-50, placebo to E-50, n = 26). Treatment was continued for up to 2 years. After 24 months, BMD of the lumbar spine in the E-100 group differed by 7.7% [5.8-9.5%] (mean [95% confidence interval]) from the placebo group and showed a mean (s.e.m.) increase in BMD from baseline of 5.9% (0.69%). For the E-50 group the difference compared with placebo was 6.2% [4.4-8.0%] and the absolute increase was 4.5% (0.62%); in the placebo group, the absolute change was -2.3% (0.48%). In the total wrist, the changes were: E-100: difference compared with placebo 2.5% [1.5 3.6%], absolute increase 0.6% (0.3%); E-50: difference compared with placebo 2.9% [1.8-3.9%], absolute increase 0.7% (0.25%); and absolute change on placebo: -2.5% (0.35%). In the total hip, the changes were: E-100: difference compared with placebo 3.7% [2.2-5.2%], absolute increase 2.8% (0.5%); E-50: difference compared with placebo: 3.2% [1,8-4.7%], absolute change 2.4% (0.36%); and absolute change on placebo -1.4% (0.66%). Three markers of bone turnover--serum bone-specific alkaline phosphatase, serum osteocalcin and urinary CTX--fell significantly during the trial. Breast pain was reported by 8% of women on placebo, by 6% of women on E-50 and by 17% of women on E-100. Estradiol delivered by the E-50 matrix patch effectively reversed bone loss in hysterectomized postmenopausal women with few side-effects. The marginal additional gain in BMD with the higher dose may be offset by a more important side effect profile.

The effect of continuous oestradiol with intermittent norgestimate on bone mineral density and bone turnover in post-menopausal women

“…The difference between treatment and placebo after 1 year of treatment is 3.8%. This is similar to the differences seen in studies of today's standard doses [32] of oestradiol, 1 mg per day oral (in sequential association with dydrogesterone) [27] or 50 g transdermal oestradiol per day oestradiol transdermal in hysterectomised women [33,34]. Thus, neither the progestogen nor its mode administration as used in this study seems to modulate to a noticeable extent the effect of oestradiol on BMD.…”

“…The proportion of BMD losers (18.5%) in the active treatment group is comparable to, e.g. the fraction of 'losers' (16.3%) upon treatment with 50 g per day transdermal oestradiol [33]. The median loss in losers on active treatment is smaller than the median loss on placebo in this and the trial of transdermal E2 [33].…”

“…the fraction of 'losers' (16.3%) upon treatment with 50 g per day transdermal oestradiol [33]. The median loss in losers on active treatment is smaller than the median loss on placebo in this and the trial of transdermal E2 [33]. It is considered likely that women with a high bone turnover profit from active treatment by a reduced loss of BMD, without actually achieving a gain of BMD.…”

“…[27,28,33,34]). The consistency of this observation allows extrapolation to the regimen used in this trial.…”

Low-dose estrogen therapy for prevention of osteoporosis: working our way back to monotherapy

“…Arrenbrecht and Boermans reported that transdermal estradiol in a dose of 50 mg/d significantly increased BMD in the lumbar spine and hip; a dose of 100 mg/d provided only a marginally increased benefit that was offset by a more pronounced side-effect profile. 63 Estrogen monotherapy versus estrogen/progestogen combinations Although it has become standard practice to include a progestin when treating intact postmenopausal women with estrogen, the origin of this practice dates from studies using doses of estrogen higher than those currently utilized. The role of estrogen in the development and course of (receptor positive) endometrioid endometrial cancer, as opposed to estrogenÕs lack of effect on (receptor negative) papilloserous endometrial cancer had not come to light 16 and the side effects of synthetic progestins not yet appreciated.…”