Current issues of ACP Journal Club are published in Annals of Internal Medicine


Transdermal estrogen lowered the vertebral fracture rate in postmenopausal women with osteoporosis

ACP J Club. 1993 Jan-Feb;118:8. doi:10.7326/ACPJC-1993-118-1-008

Source Citation

Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med. 1992 Jul 1;117:1-9.



To investigate the effectiveness of transdermal estradiol therapy in postmenopausal women with vertebral fractures and to evaluate the effect of baseline characteristics on response to treatment.


1-year, randomized, double-blind, placebo-controlled trial.


A referral-based outpatient clinic.


75 women (median age 65 y) with osteoporosis, which was defined as lumbar-spinal and femoral bone mineral density below the 10th percentile of premenopausal women, and with ≥ 1 vertebral fracture (a decrease in vertebral height of > 15%). 89% were evaluated after 1 year.


36 women were randomized to 20-cm2 transdermal patches delivering 0.1 mg estradiol for days 1 to 21 and oral medroxyprogesterone acetate (10 mg/d) for days 11 to 21 of a 28-day cycle, regardless of previous hysterectomy. Calcium supplementation, estrogen, and vitamin D were discontinued 3 to 6 months before the beginning of the study. 39 women were assigned to placebo. Both groups were given a weight maintenance diet containing calcium, 800 mg/d.

Main outcome measures

Occurrence of vertebral fractures measured in lateral radiographs as anterior wedge, central biconcave, or compression fractures (a decrease of > 15% since baseline); bone mineral density; and bone turnover measured by biochemical and histomorphometric values.

Main results

8 new fractures occurred in 7 women in the estrogen group compared with 20 fractures in 12 women in the placebo group (relative risk [RR] in the estrogen group for vetebral fracture rate 0.39, 95% CI 0.16 to 0.95, P = 0.04). The RR reduction for a woman taking estrogen having ≥ 1 fracture is in the table. The median increase in bone density was greater at each site except the femoral neck for the estrogen group (P ≤ 0.03 for the comparisons). Bone turnover decreased in the estrogen group but remained constant in the placebo group (P < 0.001 for all comparisons). Differences between the groups in changes in bone mineral density were smaller for women with a baseline serum estradiol concentration > 25.7 pmol/L and for heavier women and were greater for women who consumed more decaffeinated coffee. Older age did not affect response to estrogen. 20 women (56%) had breast tenderness, and 3 (8%) developed endometrial hyperplasia among the estrogen group; 1 woman in each group developed breast cancer. All women in the estrogen group had vaginal bleeding.


Transdermal estrogen treatment lowered the rate of vertebral fractures among women with established osteoporosis.

Source of funding: Ciba-Geigy Corporation.

For article reprint: Dr. E.G. Lufkin, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. FAX 507-284-8018.

Table. Estrogen vs placebo at 1 year in postmenopausal women with osteoporosis*

Outcome Estrogen Placebo RRR (95% CI) NNT
≥ 1 new fracture 21% 35% 42% (-26 to 74) Not significant

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


The study by Lufkin and colleagues extends the understanding of the use of estrogen replacement therapy in women with established postmenopausal osteoporosis. Many researchers have advocated that estrogen therapy is best initiated in the immediate postmenopausal period, but not after 10 years of menopause. Recent studies have suggested that estrogens may be effective in women after menopause (1-3). Until recently, research experience with estrogen replacement has been limited to conjugated equine estrogens. The current study shows that transdermal estrogens with oral progesterone retards or even increases bone density.

Several methodological issues in the current study may require clarification. First, treatment with transdermal patches was not clearly described as to the frequency of changing patches during treatment. Second, for the vertebral fracture end point, no mention was made that the x-ray readers were blinded to treatment arm. Finally, it is not clear that the authors can explain the lack of bone density loss from the spine and femur in the placebo group on the basis of precision of dual photon absorptiometry measurements in these regions, because these measurements were precise enough to detect a rise in bone density in the estrogen group.Another probability raised by the authors was that calcium intake differed between the estrogen and placebo groups. Notwithstanding the above questions, this study and a 2-year extension showing that those women who remained on estrogen had a 12% increase in spinal bone mineral density (BMD) (4), as well as results from the PEPI Trial (5), confirm that estrogen is an effective anti-resorptive therapy for postmenopausal osteoporosis at all ages. In general, across the studies of estrogen replacement, greater increases in BMD are reported in older women than younger women because they start with lower BMDs. Other than the study by Lufkin, no estrogen trials have shown fracture reduction. Data such as these should be forthcoming from the Women's Health Study.

Douglas P. Kiel, MD, MPH
Harvard Medical SchoolBoston, Massachusetts, USA


1. Lindsay R, Tohme JF. Estrogen treatment of patients with established postmenopausal osteoporosis. Obstet Gynecol. 1990;76:290-5.

2. Quigley ME, Martin PL, Burnier AM, Brooks P. Estrogen therapy arrests bone loss in elderly women. Am J Obstet Gynecol. 1987;156:1516-23.

3. Jensen GF, Christiansen C, Transbol I. Treatment of postmenopausal osteoporosis. A controlled therapeutic trial comparing oestrogen/gestagen, 1.25-dihydroxy-vitamin D3 and calcium. Clin Endocrinol (Oxf). 1982;16:515-24.

4. Lufkin EG, Riggs BL. Three-year follow-up on effects of transdermal estrogen [letter]. Ann Intern Med. 1996;125:77.

5. Anonymous. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI. JAMA. 1996;276:1389-96.