Ultra-low dose estrogen patch improves bone, appears safe for the uterus

(This article was first printed in the January, 2005 issue of the Harvard Women’s Health Watch. For more information or to order, please go to http://health.harvard.edu/women.)

Estrogen was approved for osteoporosis prevention in the 1980s, but in the past couple of years, postmenopausal women who are worried about bone loss have been urged to try other drugs instead. That’s because results from the Women’s Health Initiative (WHI) hormone trials suggest that over the long term, a standard dose of oral estrogen poses certain health risks — especially when combined with a progestin. (For more details, visit www.whi.org.)

Rather than give up on estrogen as an osteoporosis fighter, some scientists are trying to determine the lowest amount needed to protect bone and the safest way to deliver it long-term. A new study suggests that a skin patch containing a tiny amount of estrogen, and no progestin, can increase bone density without harmful side effects.

Several studies have already shown that lower-than-standard doses of hormone therapy can relieve menopausal symptoms and prevent bone loss (although even at half-strength, estrogen taken “unopposed,” that is, without a progestin, may increase the risk for cancer of the uterine lining). Researchers are also interested in different preparations of estrogen and different ways of administering it. The only estrogen preparation used in the WHI was Premarin, which contains many forms of estrogen as well as several other compounds. Furthermore, the WHI trials only used oral estrogen; the hormone can also be delivered transdermally (through the skin) or through the vagina.

Researchers at the University of California at San Francisco tested whether an ultra-low dose of estrogen would work in older postmenopausal women, who need less circulating estrogen to protect their bones than younger postmenopausal women do. For two years, more than 400 healthy women ages 60–80 wore a transdermal patch containing either a placebo or 17beta-estradiol (an estrogen preparation different from Premarin) released at the rate of 0.014 mg per day — about one-quarter the standard dose. Bone mineral density (BMD) was measured and endometrial biopsies were taken during the study period. Both groups received calcium and vitamin D supplements.

The results were reported in the September 2004 issue of Obstetrics and Gynecology. Blood levels of estradiol nearly doubled in the treated women and were unchanged in the placebo group. BMD at the lumbar spine increased fourfold in the women taking estradiol, compared with those taking a placebo. Hip BMD increased in the estradiol group and decreased in the placebo group; markers of bone turnover (the rate at which bone breaks down and builds up) were also better for women taking estradiol. After two years, one woman in the estradiol group developed abnormal endometrial cell growth (endometrial hyperplasia), which cleared up after short-term treatment with a progestin.

The finding that ultra-low dose estradiol without a progestin improves bone density and is relatively safe in older postmenopausal women may be good news for women who can’t tolerate other osteoporosis drugs, such as bisphosphonates, which can cause digestive upset. But some caution is in order. We don’t know whether the treatment will remain safe and effective longer than two years. The findings don’t necessarily apply to younger postmenopausal women, who are likely to need higher levels of estrogen because of accelerated bone loss in early menopause. And we still don’t know whether the observed improvements in BMD actually translate into a reduced risk of fracture.