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AMA Osteoporosis Report

First posted April 17, 2002 Last updated April 17, 2002

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Hormone Replacement Therapy Falls Out of
Favor With Expert Committee

Brian Vastag
Journal of the American Medical Association

Medical News & Perspectives
Vol 287, No. 15 April 17, 2002
Bethesda, MD

Falling in line with the evidence-based medicine trend, an international team of women's health experts is discouraging the use of hormone replacement therapy (HRT) for many postmenopausal conditions. Coronary heart disease, fractures, depression, urinary incontinence all cited in the past as prime reasons to initiate HRT are losing favor as valid indications for it, as evidence from high-quality clinical trials accumulates.

In 1992, three major organizations threw their collective weight behind guidelines that pushed physicians to prescribe HRT for women with or at risk of heart disease and osteoporosis. Endorsed by the American College of Physicians, the American College of Family Medicine, and the US Preventive Services Task Force, the guidelines relied almost exclusively on soft data from observational studies and clinical experience.

A decade later, those recommendations seem quaint. At a symposium sponsored by the Office of Women's Health Research at the National Institutes of Health (NIH) here, experts on the Committee of the International Position Paper on Women's Health and Menopause sketched the dramatic shift on best clinical practices for treating patients during menopause. Their views are to be published in June as an "international position paper," or monograph. Further information is available at the Office of Women's Health Research Web site. The Giovanni Lorenzini Medical Science Foundation, Milan, collaborated with the NIH on the project.


At the symposium, University of California, San Francisco, Medical School researcher Deborah Grady, MD, MPH, renounced her earlier recommendation to prescribe HRT for heart disease. The studies that formed the foundation of the 1992 guidelines, which Grady coauthored, showed that women who took estrogen, or estrogen with progesterone, reduced their risk for heart attack by 35% to 50%. "But the problem with these studies is that we [now] know that the women who take estrogen are just different from the women who don't," said Grady. "They're healthier, they're wealthier, they have a better health profile."

In addition to this selection bias, the estrogen users in the cohort studies differed from nonusers in another critical way. As Grady sees it, "People who do what you tell them to do are special." Patients who listen to their physician, fill their prescription, and continue taking medicines despite uncomfortable adverse effects do "markedly better" on overall health measures than those who ignore physicians and forget prescriptions. Grady calls this phenomenon "adherence bias," which was "exactly what we were looking at in the observational studies," she said.

Four years ago, results from the first large, randomized clinical trial of HRT for cardiovascular disease shocked researchers. In the Heart and Estrogen/Progestin Replacement Study (JAMA. 1998;280:605-613), HRT failed to reduce risk of coronary heart disease events in postmenopausal women with established coronary disease. In fact, during the first 18 months of the study HRT increased risk over placebo by nearly 50%. "Those of us running the trial were so surprised that we actually went out and had the pills tested to make sure we hadn't mixed them up," said Grady. After confirming the pills' identities and confirming the results with other trials, including the 27 500-participant Women's Health InitiativeGrady is left with one conclusion. "The . . . very disturbing possibility, disturbing to epidemiologists like me, is that those observational studies were just all wrong."


During the 4 years it took to compile and synthesize the evidence, that fills the upcoming monograph, dozens of experts drew similar though less stark conclusions about fractures precipitated by osteoporosis. "[A]ggressive pharmacotherapy should be reserved for women who are at high risk" for fractures, states the monograph's executive summary, released at the symposium. Further information is available from the Office of Women's Health Research Web site, http://www4.od.nih.gov/orwh/.

It remains true that HRT helps prevent bone loss, said the Lorenzini Foundation's Rodolfo Paoletti, MD, PhD, but whether that benefit translates into reduced risk of fractures remains questionable, as quality data from clinical trials are lacking. In addition, trials show that HRT must be taken continuously to preserve bone mass, not just for 5 or 10 years after menopause, as previously thought. Given the hormone's adverse effect profile, including a three-fold risk of blood clots (although the absolute risk remains fairly low, Paoletti said), and somewhat increased risk of biliary disease and possibly breast cancer, patients are usually better off with other drug options, according to the monograph.

Selective estrogen receptor modulators (tamoxifen and raloxifene) and bisphosphonates (alendronate and risedronate) both show promise, but not equally. An influential trial funded and touted by raloxifene maker Eli Lilly & Co, Indianapolis, did show that raloxifene reduces risk for vertebral fractures by 40% over placebo (JAMA. 1999;281:2189-2197). However, Grady pointed out that in that study, raloxifene did not have an impact on risk for any other fractures, including serious hip and leg breaks.

For women with osteoporosis, then, bisphosphonates become a more attractive option, according to the monograph: "Older women, particularly those with severe osteoporosis and prior fracture(s), may prefer alendronate or risedronate for their rapid acting bone-specific effects and reduction in nonspine as well as spine fractures."


In addition to dealing with heart disease and fractures, the monograph also details the dearth of trials data for HRT's purported ability to retard early Alzheimer disease, alleviate major depression, and improve urinary incontinence. For hot flashes, various estrogen formulations alone and various high-dose progestogens alone do stand up as effective. But, the monograph notes, selective serotonin reuptake inhibitors venlafaxine and paroxetine can also reduce hot flashes substantially, with diet and other lifestyle changes, such as wearing layered clothing, another viable option.

While the monograph offers a wealth of substantiated clinical pointers, some doubt physicians' willingness to incorporate such evidence-based changes into their care of older patients. A survey conducted in January by the nonprofit Merck Institute of Aging and Health, Washington, DC, found that primary care physicians question their colleagues' ability to adequately diagnose and treat common problems among patients over age 60 (Merck Institute of Aging & Health physician study. Available at http://www.miahonline.org).


"It's not surprising that we continue to see that practicing physicians find the care of older people less comfortable than the care of younger people," said Patricia Barry, MD, a geriatrician and director of the Merck Institute. She said the ideas behind the monograph, which she has not seen, are "great," but that providing such information is not enough to sway physician behavior. "Information is necessary, the first step to changing behavior. But it's not sufficient. Lots of good data show that," said Barry, who has spent the past year working on a project to find improved methods, such as small-group workshops, of helping physicians update their knowledge and caring skills.

The survey, although small (250 respondents), elicited another issue that the monograph echoed: patient compliance. The survey report concludes that compliance is "the greatest challenge physicians face when treating older patients." The monograph nudges physicians to consider hownot just whetherto prescribe. For instance, starting with a low dose of raloxifene helps overcome its hot flash effects, while doing the same with estrogen can reduce breast pain.

Barry said that she is not trying to indict physicians' ability to treat older patients. Rather, she said, she wants to encourage more interaction between geriatricians and primary care physicians. "There will never be enough geriatricians to meet the need," she said. "But most primary care physicians are more than capable of taking care of older patients." If the international committee gets its wish, its efforts will help physicians to do just that.

© 2002 American Medical Association. All rights reserved.

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