Manufacturer seeking FDA approval: ultralow-dose estradiol patch boosts bone mineral density

OB/GYN News, June 1, 2004 by Mitchel L. Zoler

PHILADELPHIA -- A quarter of the standard, hormone-therapy estradiol dose was safe and effective for boosting bone mineral density in women aged 60-80 years in a controlled study with 417 women.

Two years of treatment of postmenopausal women with an unopposed, ultralow dose of estradiol delivered through a transdermal patch led to a significant rise in bone mineral density (BMD) compared with placebo, with virtually no adverse effects on the endometrium or breast and no vaginal bleeding. Dr. Bruce Ettinger reported at the annual meeting of the American College of Obstetricians and Gynecologists.

"This is very promising and important, but we need to know what happens with 3 or 5 years of treatment," commented Dr. Isaac Schiff, chief of the ob.gyn. service at Massachusetts General Hospital in Boston.

This month, the Food and Drug Administration is expected to announce whether it will approve the new patch with an indication for preventing osteoporosis in postmenopausal women, said a spokeswoman for Berlex, the company that makes the patch and sponsored this study.

This is the first study to look at the efficacy of an unopposed estradiol patch in women with an intact uterus, said Dr. Ettinger, a clinical professor of medicine at the University of California, San Francisco. A prior study examined the safety and efficacy of an ultralow dose of unopposed, oral estradiol in postmenopausal women (JAMA 290[8]:1042-48, 2003).

The concept originated with results from epidemiologic studies showing that postmenopausal women with serum estradiol levels higher than 5 pg/mL seemed to be protected against developing osteoporosis, while those with serum levels of 5 pg/mL or lower had the biggest problem with lost BMD. The ultralow-dose patch formulation was designed to boost a woman's serum estradiol level by about 5 pg/mL.

The study enrolled 417 women at nine centers in the United States. Each woman had an intact uterus and normal BMD for her age. The average age of the women was about 67 years, and their average body mass index was 28 kg/[m.sup.2]. About 15% of the women had osteoporosis; at baseline, their median level of plasma estradiol was about 5.3 pg/mL.

The 208 women randomized to receive transdermal estradiol used one patch per week that was formulated to deliver a daily estradiol dosage of 14 [micro]g. In contrast, a standard-dose estradiol patch delivers a daily dosage of 50 [micro]g. All women in the study also received a daily supplement of 400 mg of calcium b.i.d. and 400 IU of vitamin D per day.

After 1 year of treatment, the average serum estradiol level among the women who received the active patch rose to 8.9 pg/mL, and reached an average of 9.6 pg/mL after 2 years. The level was unchanged from baseline among the 209 women who received placebo patches.

After 1 year, spinal BMD rose by 2.3% in the women who received estradiol, and by 3% after 2 years. Hip BMD rose by 0.9% after 1 year and by 0.8% after 2 years. In the placebo group, spinal BMD rose by 0.5% after both 1 and 2 years, and hip BMD was below baseline levels at both follow-up times. Serum markers of bone turnover showed that significantly less turnover occurred in the women treated with estradiol compared with the controls. Fractures were recorded as adverse events, but were not rigorously followed using scheduled x-ray examinations. There were 4 identified fractures in the estradiol group and 10 in the placebo group, a difference that was not statistically significant.

After 2 years of treatment, 1.9% of women in the estradiol group showed signs of endometrial proliferation, detected by biopsy, and one woman in this group (0.5%) had focal, atypical endometrial hyperplasia. No women in the control group had proliferation or hyperplasia, but this difference was not statistically significant. In contrast to this very low level of endometrial proliferation with ultralow estradiol dosage, proliferation is usually seen in about 50% of women who receive an estradiol dosage that is half the standard level, said Dr. Ettinger, who is now a consultant for Berlex but was not at the time of the study.

"I'm a little concerned about the one case of endometrial hyperplasia. It would be ideal if there were no cases," commented Dr. Schiff, who also chairs ACOG's Task Force on Hormone Therapy. Ultralow-dose hormone therapy makes sense because it appears to provide an osteoporosis benefit while perhaps avoiding the need for a progestin, he told this newspaper. But periodic monitoring of patients would be necessary to confirm that they were not having endometrial hyperplasia.

During both years of the study, women on the ultralow estradiol dosage showed no excess of abnormal mammograms, troublesome breast tenderness, or vaginal bleeding compared with the control group. About 10% of the women in the estradiol group had vaginal discharges, which probably reflected a uterine-lining change, in which cells changed from very atrophic to less atrophic, he said.

If the patch comes onto the U.S. market, it may be reasonable for a physician to check a woman's serum estradiol level before prescribing it, as the patch would be most likely to help women who have serum levels lower than 5 pg/mL. Dr. Ettinger said.