HRT enhances bone density, but what about breast cancer risk?

Latest study spells out concerns for long-term users

You read one journal, and it warns you about the risks of long-term use of estrogen and breast cancer in post-menopausal women. You pick up another journal, and it touts the benefits of estrogen against heart disease. In the meantime, you have a 45-year-old woman with a family history of breast cancer who wants to start taking hormone replacement therapy (HRT). What’s a family planner to do?

Start reading now about the pros and cons of HRT. With the abundance of new research on the subject, there’s no better time to become informed if you are to successfully guide your patients through the peri- and post-menopausal years.

Two studies published in the Journal of the American Medical Association (JAMA) offer good news for your patients. The two studies find that estrogen has a positive effect on bone mineral density.1,2

But a third article in the same issue calls long-term exposure to estrogen as measured by bone mineral density an important risk factor for breast cancer.3 The researchers conclude in this article, however, that this hypothesis needs further study.

Help your patients to evaluate this new information in the context of their own family history, health risks, and symptoms so they can make an informed decision about HRT.

Bone mineral density serves as an important predictor for osteoporosis and a woman’s risk for fractures. Such fractures, particularly when they occur in the hip or spine, are associated with chronic pain, loss of mobility and independence, and death. Approximately 20% of white women older than 50 years have osteoporosis in both the hip and spine, according to information cited in one of the JAMA studies.

That study is the third installation of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, the largest completed study of the effects of estrogen and estrogen-progestin treatments on spine and hip bone mineral density in post-menopausal women.

Another report included in the Nov. 6, 1996, issue looks at a new combination HRT dosing regimen that may provide the benefits of estrogen without the side effects of cyclical bleeding for many post-menopausal women. Family planning clinicians may recognize this ethinyl estradiol/norethindrone acetate combination as one used in low-dose oral contraceptives. In this trial (dubbed the CHART study), though, the amount of ethinyl estradiol ranges from 1 to 10 mcg, while the dosage in current low-dose oral contraceptives (OCs) varies from 20 to 50 mcg.

"The major thing that I would see here is compared to [a] placebo, over a 12-month, 24- [and] 36-month period, women who were on estrogen compared to placebo always gained bone mineral density," says David F. Archer, MD, professor of OB/GYN at The Jones Institute for Reproductive Medicine at The Eastern Virginia Medical School in Norfolk. "That’s the positive," Archer says.

Andrew M. Kaunitz, MD, professor and assistant chair of the department of OB/GYN at the University of Florida Health Sciences Center in Jacksonville, concurs. "Both of these studies reinforce that combination HRT has a positive impact on bone density. As new formulations become available, some may have more positive impact than others," Kaunitz says.

Compare and contrast the two studies

The PEPI report was based on a three-year multicenter, randomized, double-blinded, placebo-controlled study. A total of 875 post-menopausal women, 45 to 64 years, were recruited at seven clinical centers and were given placebo or one of four hormone replacement strategies. The CHART study was a two-year, double-blind, placebo-controlled, parallel-group clinical trial that randomly assigned 1,265 post-menopausal women, age 40 or older, to one of eight treatment groups or placebo. A total of 695 women completed the trial.

In the PEPI study, the combined estrogen- progestin therapy did not prove statistically more effective in enhancing bone mineral density than the estrogen-only treatment. Hormones in this trial included conjugated equine estrogen, used alone or with medroxyprogesterone acetate or micronized progesterone.

"The big difference between the two studies is that when using estrogen alone, conjugated equine estrogen had a positive impact in PEPI, while ethanol estradiol didn’t in the CHART study," notes Kaunitz. "The two higher-dose combinations in CHART and the combination in PEPI both had a positive impact."

"Ethanol estradiol and norethindrone acetate appear to enhance bone mineral density when they use the 5 mcg of ethanol estradiol or greater, as in contrast to 5 mcg of ethanol estradiol alone," comments Archer of the CHART study. "So what that says is that norethindrone has a positive effect on bone, and that has been known for some time."

Bone mineral density-breast cancer link?

The study of the possible link between bone mineral density (BMD) and breast cancer is an interesting one, because it suggests that the BMD may be a marker for the disease, says Archer. Conducted by researchers from the University of Pittsburgh, the prospective cohort trial included 6,854 non-black women, age 65 years or older, who participated in the study of osteoporotic fractures at four clinical centers.

High bone mineral density can double the risk for breast cancer, the study found. The age-adjusted incidence rate of breast cancer was lowest among those with low BMD. Women with the highest BMD had 2 to 21¼2 times increased risk of breast cancer compared with those with the lowest BMD, researchers concluded.

"What comes out in this study is the intriguing fact that these women who had breast cancer seemed to have a denser bone and now the question is, is there some underlying factor or factors that links this together?" Archer asks. "And the question is, what could that factor or factors be? It is as yet unidentified. We’re just at the beginning here."

Until there is a clinical utility to clearly measure this correlation, clinicians and women should continue their normal course of vigilance in breast cancer detection, he notes.

"Whether your bone mineral density is high or low, you still need annual mammograms, you still need to see a doctor, you still should do breast self-examinations," says Archer.

Another thing to remember in reviewing this study is that the rate of breast cancer was 4.3 cases per 1,000 people per year, the same as it is in any woman over the age of 65, Archer points out.

"Even if there is this increase in risk with increasing bone mineral density, at the maximum in their table, they show it’s 5.2 cases per 1,000 persons per year, so that the actual incidence is only slightly changed," he says.

With research now showing HRT’s positive effects on cardiovascular risk factors, patients and their physicians now perform a balancing act in weighing HRT’s benefits against its risks.

More women die of heart disease than from breast cancer, says Archer. For women who are at risk for this disease, clinicians may want to evaluate information published in 1995 from the same PEPI trial, which shows that HRT has a positive impact on cardiovascular risk factors.4

A study published in 1996 in Obstetrics and Gynecology revealed that post-menopausal women who took estrogen for at least five years reduced their risk of fatal heart attack by 60% and their risk of dying from other cardiovascular diseases by 73%.5 This investigation, conducted by the Kaiser Permanente Medical Care Program, compared these women to those who took estrogen for one year or less.


1. The Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density: Results from the postmenopausal estrogen/progestin interventions (PEPI) Trial. JAMA 1996; 276:1,389-1,396.

2. Speroff L, Rowan J, Symons J, et al. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART Study): A randomized controlled trial. JAMA 1996; 276:1,397-1,403.

3. Cauley JA, Lucas FL, Kuller FH, et al. Bone mineral density and risk of breast cancer in older women: The study of osteoporotic fractures. JAMA 1996; 276:1,404-1,408.

4. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in post-menopausal women: The post-menopausal estrogen/progestin interventions (PEPI) trial. JAMA 1995; 273(3):199-207. 5. Ettinger B, Friedman GD, Bush T, et al. Reduced mortality associated with long-term postmenopausal estrogen therapy. Obstet Gynecol 1996; 87:6-12.