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2002 Selected Articles

Raloxifene Versus Standard Hormone Replacement
How to Counsel Your Postmenopausal Patients

Owen P. Phillips, MD

Today, women in the United States can expect to live into their 80s and beyond. Many of the health risks that characterize these later years are a result of estrogen deficiency, and therefore may be preventable. For example, postmenopausal osteoporosis leads to fractures that can debilitate otherwise healthy women with chronic pain, hospitalization, rehabilitation, and need for long-term care. Osteoporosis is a major health problem that causes 1.5 million fractures annually.¹ Indeed, a postmenopausal woman’s risk of hip fracture is equal to her risks for breast, uterine, and ovarian cancer combined.²

The incidence of cardiovascular disease increases dramatically in women after menopause. Because estrogen use in postmenopausal women produces a more favorable lipid profile by decreasing low-density lipoprotein (LDL) cholesterol levels and increasing high-density lipoprotein (HDL) cholesterol levels, it has been assumed that estrogen- or hormone-replacement therapy (ERT, HRT) would prevent heart disease in women. Although some recent studies have failed to show a significant benefit from ERT/HRT in preventing myocardial infarction in certain populations,^3,4 randomized studies are still ongoing. Other possible benefits of ERT/HRT that are under investigation include decreasing the risks for Alzheimer’s disease and colorectal cancer.

While ERT/HRT has certain health benefits and is effective for the treatment of postmenopausal symptoms such as hot flashes and vaginal dryness, physicians face many challenges when prescribing it for their patients. Side effects such as vaginal bleeding and breast tenderness often cause discontinuation of therapy, and many women have complaints related to the progestin component of HRT prescribed for women with a uterus (eg, weight gain, mood changes). Perhaps most importantly, the fear of a potential association between ERT/HRT and breast cancer is causing women to be wary.^5-7 As a result, only 20% of all postmenopausal women are using ERT/HRT, and fewer than half of those prescribed ERT/HRT remain compliant after a year.⁸

SELECTIVE ESTROGEN RECEPTOR MODULATORS

The ideal replacement for estrogen would be one with osteoporosis prevention properties, beneficial effects on menopausal symptoms and the cardiovascular system, a low side-effect profile, and no adverse physiologic impact on the uterus or breast. As this ideal agent does not currently exist, physicians must individualize therapy for each patient, keeping in mind the patient’s complaints, concerns, and risks for serious diseases. Standard HRT with an estrogen and a progestin (if the uterus is intact) may be the best choice for some women. Other women may be better candidates for treatment with selective estrogen receptor modulators (SERMs), which should be an important part of every gynecologist’s armamentarium.

Advantages

The SERMs are a group of structurally diverse compounds that interact with the estrogen receptors. They can act either as an estrogen agonist or an estrogen antagonist, depending on the target tissue and the properties of the particular SERM. Therefore, classifying SERMs as antiestrogens is misleading. Clomiphene, tamoxifen, and raloxifene, the most familiar SERMs, are used according to their specific estrogen receptor-agonist or -antagonist properties. While several SERMs are under investigation for use in menopause, only raloxifene (Evista) is approved for the prevention and treatment of postmenopausal osteoporosis, and will therefore be the focus of this discussion. Table 1 compares the effects of raloxifene with those of ERT/HRT.

Bone Effects.–Both raloxifene and tamoxifen have estrogen-like effects on skeletal tissue. In oophorectomized rats, raloxifene prevented bone loss and produced a dose-related increase in lumbar spine bone mineral density (BMD).^9,10 Clinical studies in humans have confirmed these effects. A reduction in bone turnover variables has been found in raloxifene-treated patients at all doses studied.^11,12 In a European multicenter osteoporosis prevention study,¹³ 601 postmenopausal women were randomized to several regimens of raloxifene or placebo. Using BMD changes as the endpoint, raloxifene was shown to increase bone mass over placebo. Interestingly, the increase in bone mass was evident at all sites measured: lumbar spine, total hip, and total body. This finding may actually be an improvement over the effects of conjugated estrogens and the antiresorptive bisphosphonates (eg, alendronate), which have more significant effects on the spine.¹⁴

It is now generally accepted that raloxifene can prevent bone loss in postmenopausal women, but other studies are now investigating whether it is effective as a treatment for existing osteoporosis.^12-15 Meunier and colleagues¹⁵ found significant increases in bone mass in women with osteoporotic fractures randomized to raloxifene compared with placebo. The Multiple Outcomes of Raloxifene Evaluation (MORE) study¹⁶ also evaluated women with established osteoporosis using new fractures as an endpoint, and found a significant decrease in fractures among raloxifene users over placebo. In a 1-year prospective study of 143 postmenopausal women with osteoporosis, Lufkin and associates¹² found significant increases in bone mass in the hip and radius and a significant decrease in fracture risk in raloxifene users compared with placebo. Thus, raloxifene has been shown to augment bone mass in women with osteoporosis and to reduce the risk of future fractures in these women.

There is evidence that HRT/ERT plus biphosphonates has an additive positive effect on bone density, over that of either agent alone, in women with postmenopausal osteoporosis.¹⁷ Recently, the same has been found for raloxifene and alendronate. In combination, the two agents decreased bone turnover markers over placebo and over either agent alone. ¹⁸ Fracture prevention data are lacking, however. In addition, risks of side effects and costs will certainly be higher with combination therapy.

Lipid Effects.–Raloxifene promotes favorable lipid profile changes. Like estrogens, it lowers total cholesterol, LDL cholesterol, apolipoprotein B, and lipoprotein(a) in postmenopausal women.^19,20 In contrast to ERT, which significantly increases triglyceride levels, raloxifene does not adversely affect triglycerides. However, raloxifene has no significant effect on HDL cholesterol, a clear benefit of ERT. And finally, raloxifene improves vascular endothelial function, helping prevent plaque formation.²¹

Cardiovascular Effects.–Although the positive effects of raloxifene on the lipid profile may indicate a potential benefit in preventing heart disease, only large-scale, controlled clinical trials can provide conclusive evidence. To that end, the Raloxifene Use for the Heart (RUTH) study has been undertaken.²² This multicenter, randomized, double-blind study of raloxifene versus placebo in more than 10,000 postmenopausal women with coronary heart disease or with risk factors for coronary artery disease will analyze effects on the incidence of fatal and nonfatal cardiovascular events. The results of this study will not be available for several years.

However, cardiovascular data has been published from the MORE study.¹⁹ After 4 years of follow-up, the incidence of cardiovascular events among the 7,705 participants did not differ between raloxifene- and placebo-treated groups. In the subgroup of 1,035 women with significant risk factors for coronary heart disease, though, there were significantly fewer cardiovascular events among women assigned to raloxifene, with a relative risk (RR) of 0.60. Furthermore, this beneficial effect was apparent in women with established cardiovascular disease. There were also fewer strokes in the raloxifene group, with an RR of 0.38. Importantly, there was no increase in cardiovascular events during the first year of use.

These findings are in contrast to results of studies on ERT and cardiovascular disease. In the HERS study³ and in preliminary data from the Women’s Health Initiative,⁴ women with cardiovascular disease using HRT/ERT experienced an increased risk of acute coronary events, particularly in the first year of use. Nonetheless, results from the prospective, randomized studies in progress on HRT may find long-term benefit in women with established disease or in women at low risk.

Breast Effects.–Although raloxifene mimics the effects of estrogen on the bone and cholesterol metabolism, it acts as an estrogen antagonist in reproductive tissues. In breast cancer cell lines, it inhibits estrogen-induced proliferation.²³ Postmenopausal women treated for osteoporosis with raloxifene had a significantly decreased incidence of breast cancer compared with women receiving the placebo.⁵ The RR was 0.35 for all breast cancer and 0.10 for estrogen receptor-positive breast cancer. In a 4-year follow-up of this population, Cauley and colleagues²⁴ found a significant decrease in the risk of breast cancer, reducing the risk of estrogen-receptor positive invasive breast malignancies by 84%. The US National Institutes of Health Study of Tamoxifen and Raloxifene trial of 22,000 postmenopausal women is currently underway to investigate the use of SERMs as preventive therapy for breast cancer in high-risk women, and breast cancer prevention is a primary outcome measurement in the ongoing RUTH trial as well.

Breast pain is a common complaint in women using HRT. In a review of eight comparison trials of standard HRT, raloxifene, and placebo, breast pain was reported more often in women using HRT than in women using raloxifene.²⁵

Uterine Effects.–Raloxifene produces similar estrogen-antagonist effects in the endometrium. In studies on endometrial thickness in women using raloxifene versus placebo, no difference was seen after 1 or 2 years of observation.^26,27 The occurrence of menstrual irregularities between the raloxifene and placebo groups was no different;²³ however, when compared with women receiving HRT, the incidence of irregular vaginal bleeding was higher in women receiving HRT.²⁵ In one study, the incidence of endometrial hyperplasia and cancer was not increased in women taking raloxifene versus placebo after 40 months of follow-up;⁵ and in a study comparing raloxifene with continuous-combined HRT, raloxifene did not cause endometrial proliferation after a 24-month trial.²⁷

For women with a uterus, bleeding irregularities on standard HRT are a major source of concern for both patient and physician. Because raloxifene has no proliferative effect on the endometrium, concomitant progestin use is not necessary, and bleeding irregularities would not be expected.

Disadvantages

Raloxifene does not alleviate menopausal hot flashes. In a review of eight clinical trials of raloxifene, Davies and colleagues²⁵ found that users of raloxifene had a higher incidence of hot flashes than did women on ERT/HRT. They also found a higher incidence than in placebo groups, indicating an increased incidence of new hot flashes among raloxifene users. However, this finding was only observed during the first 6 months of therapy; after 6 months, the incidence was no higher among raloxifene users versus placebo controls. It is clear that women seeking relief of postmenopausal hot flashes will not respond to raloxifene therapy. On the other hand, the apparent increase in hot flashes did not lead to higher rates of discontinuation of therapy in the above studies.

Finally, raloxifene is associated with an increase in the incidence of venous thromboembolic events. In the 4-year follow-up study from the MORE trial,²⁴ raloxifene was associated with a significantly higher risk of deep venous thrombosis and a trend toward a greater risk of pulmonary emboli. However, the risk may be comparable to that seen in some studies of women using ERT/HRT.^3,28 According to the package insert,²⁹ raloxifene is contraindicated in women with current or previous venous thromboembolic events.

COUNSELING PATIENTS

Although most women seek postmenopausal ERT/HRT for symptom relief, continuing therapy to prevent osteoporosis is a primary goal of care. The choice of standard ERT/HRT versus raloxifene should depend on a number of factors, with the patient helping to make the decision.

Candidates for raloxifene therapy include women who decline ERT/HRT because of a fear of breast cancer or who have a significant family history of the disease. Other candidates are women who cannot tolerate the progestin component of HRT and those with intolerable bleeding irregularities. Women with hypertriglyceridemia should not use standard ERT, whereas raloxifene may actually decrease triglyceride levels. Hot flashes may prevent some women from using raloxifene successfully, but the overall discontinuation rate in comparison trials was no higher in women using raloxifene. And finally, raloxifene is not recommended for women with a history of venous thromboembolic disease.

Armstrong and colleagues³⁰ approached the issue of individualizing therapy using a cost-effectiveness model. They assumed that ERT increases the risk of breast cancer, and that raloxifene may not be as effective in preventing heart disease because it does not significantly affect HDL levels. Their conclusions were that in women with average risks for coronary artery disease and breast cancer, lifetime ERT was slightly more effective in prolonging life (1.75 versus 1.32 quality-adjusted life years) and cheaper than raloxifene. However, if the patient had one or more breast cancer risk factors or refused ERT, raloxifene was more effective. Finally, the authors added that if prospective studies show less benefit from ERT in preventing coronary heart disease than is currently postulated, raloxifene will be cost-effective in almost all scenarios considered.

CONCLUSION

More studies are needed to precisely define the benefits of both ERT/HRT and raloxifene use in postmenopausal women. But for now, it is clear that women should be given information about both options. The hope is that a new SERM will be developed that has all the benefits of raloxifene, ERT, and HRT and with few side effects.

Owen P. Phillips, MD, is an associate professor, Department of Obstetrics and Gynecology, and chief, genetics, both at the University of Tennessee Memphis.

REFERENCES

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