The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results From the MORE Randomized Trial

Context Raloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting.

Objective To determine whether women taking raloxifene have a lower risk of invasive breast cancer.

Design and Setting The Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe.

Participants A total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded.

Intervention Raloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets.

Main Outcome Measures New cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review.

Results Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor–positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor–negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7).

Conclusion Among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene.

Adenocarcinoma of the breast is the most common cancer and the second leading cause of cancer death among women in the United States. About 43,500 women in the United States died of breast cancer in 1998.¹ Estrogen plays an important role in the pathogenesis of breast cancer. Postmenopausal women with high serum concentrations of estradiol have the highest risk of breast cancer.^2-5 A number of other risk factors associated with longer or greater exposure to estrogen increase the risk of developing breast cancer.⁶

Tamoxifen citrate, which inhibits the action of estrogen on breast tissue, improves disease-free survival among women who have estrogen receptor– positive breast cancer⁷ and reduces the risk of contralateral breast cancer.^8,9 Three trials^10-12 have tested tamoxifen for primary prevention of breast cancer. Two found no effect, but the study with the most participants, the Breast Cancer Prevention Trial (BCPT),¹² reported that tamoxifen reduced breast cancer risk by about 50% among women who had a high risk of breast cancer because of age (older than 60 years) or a combination of other risk factors. However, most breast cancers occur in women who are not identified to be at increased risk.¹³ To substantially reduce the rate of breast cancer in the whole population, a preventive intervention would need to be safe and effective for long periods to be acceptable for use among women who have an average or low risk of breast cancer. In addition to increasing the risk of thromboembolic disease, tamoxifen increases the risk of endometrial cancer,^12,14 which may limit its use for primary prevention of breast cancer.

Raloxifene hydrochloride is a selective estrogen receptor modulator, chemically distinct from tamoxifen and estradiol, that binds to estrogen receptors to competitively block estrogen-induced DNA transcription in the breast and endometrium.^15,16 In animal studies, raloxifene inhibits estrogen-stimulated growth of mammary cancers^17,18 and antagonizes the mitogenic effects of both estrogen and tamoxifen in the uterus.^19,20

To determine whether treatment with raloxifene reduces the risk of breast cancer and to assess the safety of treatment with raloxifene, we analyzed the effect of raloxifene on rates of breast cancer after 3 years of follow-up in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial that included 7705 women who had postmenopausal osteoporosis.

The MORE trial is a multicenter, randomized, double-blind trial designed to test whether 3 years of raloxifene reduces the risk of fracture in postmenopausal women with osteoporosis. Participants were also monitored for the occurrence of breast cancer, a secondary end point of the trial. If a participant was diagnosed as having breast cancer, her study treatment was stopped and the treatment was unblinded to the sponsor and to the US Food and Drug Administration.

The MORE trial is being conducted at 180 clinical centers in 25 countries, mainly in the United States and Europe, and was planned to continue for 3 years. We enrolled 7705 women who were at least 2 years postmenopausal and no older than 80 years (Figure 1). Participants had osteoporosis, defined as bone density at least 2.5 SDs below the mean for normal young women²¹ at either the lumbar spine or femoral neck or had at least 1 moderate or 2 mild vertebral fractures that were detected by lateral spine radiography. For each woman with a vertebral fracture, approximately 2 women without vertebral fractures were enrolled. The protocol called for enrollment of 6500 participants to afford a power of 0.90 to detect a 40% reduction in risk of vertebral fractures after 36 months of treatment.

Potential participants underwent breast examination and mammography or breast ultrasonography if they refused mammography. Women were excluded if they had a known, suspected, or history of breast cancer; invasive endometrial cancer; abnormal uterine bleeding; a history of stroke or venous thromboembolic disease during the past 10 years; any type of cancer besides superficial skin cancer in the previous 5 years; secondary causes of osteoporosis; or other types of bone disease. We also excluded women who, during the previous 6 months, had taken systemic estrogen (except estriol ≤2 mg/d) or topical estrogen more often than 3 times a week; progestins, androgens, or systemic corticosteroids of more than 50,000 IU of cholecalciferol a week; or who currently drank more than 4 alcoholic drinks per day. If participants started taking excluded estrogen while in the MORE trial, they were instructed to stop taking the study drug.

All participants received daily supplements containing 500 mg of calcium and 400 to 600 IU of cholecalciferol. Eligible subjects were randomly assigned to take 2 tablets daily of 1 of the following: 2 placebo; 1 placebo and a 60-mg tablet of raloxifene hydrochloride; or 2 60-mg tablets of raloxifene hydrochloride. Thus, twice as many women received raloxifene as placebo.

The sponsor produced randomly numbered kits that contained raloxifene or placebo tablets that were identical in appearance. Trial centers dispensed the kits in numerical order to the women enrolled in the study.

Participants were followed up every 6 months. Mammography screenings were optional after the first year but were mandatory after 2 years and after 3 years of treatment. Participants who declined mammography screening could have a breast ultrasonography instead. At every visit, participants were also asked if they had been diagnosed as having breast cancer, had an abnormal mammogram or breast sonogram result or a breast biopsy specimen, or had had surgery since the previous visit. If breast cancer was suspected, records of procedures were obtained.

The diagnosis of breast cancer was confirmed by the oncology adjudication review board consisting of 5 physician specialists in breast cancer or breast surgery and chaired by a pharmacological scientist; none of the board members are employees of the sponsor. The panel reviewed local records of histopathology, estrogen receptor status, and other clinical data, as needed, for all reported cases. The diagnosis was made blinded to treatment assignment.

Seventeen of the clinical centers were designated to perform annual transvaginal ultrasonography in all participants who still had a uterus. In addition, some centers elected to perform transvaginal ultrasonography in a subset of their participants. Results were similar when the analysis was limited to participants in the centers that were assigned to test all participants, so the analysis includes all participants who underwent ultrasonography. Of 1936 women tested at baseline, 1781 (92%) completed at least 1 follow-up sonogram. Endometrial biopsy specimens were recommended for women with bleeding, endometrial thickness of more than 8 mm on any ultrasound examination, or an increase in thickness of at least 5 mm. A panel of gynecologists confirmed diagnoses of endometrial cancer. All assessments were blinded to treatment assignment.

We obtained medical records and reports of radiographs and scans for any participant reported to have had a possible deep vein thrombosis or pulmonary embolism. A panel of 3 physician adjudicators, who were blinded to treatment assignment, confirmed diagnoses. All reported cases of thromboembolic disease are included in this report because the panel has not completed adjudication of all cases.

Investigators queried participants at every visit about potential adverse events and use of medications and obtained fasting plasma glucose specimens at annual examinations.

Using an intention-to-treat analysis, we compared the crude incidence of invasive breast cancer in women assigned to raloxifene with the incidence in women assigned to the placebo. The main analyses were repeated after including cases of noninvasive breast cancer (and cases for which the degree of invasion could not be determined). Cumulative incidence of all breast cancer was plotted by treatment assignment, and the statistical significance of the difference was assessed by the log-rank test. We also compared the incidence of invasive breast cancer in the treated and untreated groups by raloxifene dose and stratified by estrogen receptor status. Relative risks (RRs) are reported with 95% confidence intervals (CIs).

We report the rates and excess risks for adverse events that occurred in more than 1% of any treatment group, and the difference between the combined raloxifene and placebo groups was statistically significant at P<.05. We also report the rates of conditions known to be associated with estrogen or tamoxifen (vaginal bleeding, breast tenderness, and endometrial cancer).

We randomly assigned 2576 women to receive placebo and 5129 to receive raloxifene (2557 took dosages of 60 mg/d and 2572 took dosages of 120 mg/d; Figure 1). Their mean age was 66.5 years, almost all (96%) were white, and 12.3% reported a family history of breast cancer. There were no significant differences in the characteristics of women assigned to receive placebo or raloxifene at baseline (Table 1). Forty-eight percent (3725) of all participants elected to have optional mammography or breast sonography screening during the first year of follow-up. Of the 6932 participants (90% of randomized subjects) who continued in the study past the first annual visit, 6333 (91%) had mammography screenings and 177 (3%) had breast sonography screenings during the second year of follow-up; of the 6381 subjects (83% of randomized subjects) who continued in the study past the second annual visit, 5642 (88%) had mammography screenings and 176 (3%) had breast sonography screenings during the third year of follow-up. A total of 1924 (75%) of the 2576 women assigned to placebo and 3977 (78%) of the 5129 women assigned to the raloxifene groups completed all 3 years of follow-up (Figure 1). Of those women who were randomized, 92% of both raloxifene and placebo patients took at least 80% of the study medication during the duration of the follow-up.

Within a median of 40 months of follow-up, breast cancer was reported in 56 women of the 7705 women originally enrolled in the study. The adjudication board ruled that 1 subject in the 60-mg raloxifene group did not have cancer. The board could not determine the primary source of the metastatic adenocarcinoma of another woman in the placebo group. Thus, 54 cases of breast cancer are included in the analyses. Twelve cases were classified as ductal carcinoma in situ (5 in the placebo, 3 in the 60-mg, and 4 in the 120-mg group), 40 were classified as invasive; and there was insufficient information to classify the degree of invasion for 2 subjects (1 in the 60-mg group and 1 in the 120-mg raloxifene group). Thirteen cases of invasive breast cancer were confirmed in the 5129 women assigned to take raloxifene and 27 in the 2576 women assigned to take placebo (RR, 0.24; 95% CI, 0.13-0.44; P<.001; Table 2). About 126 women would need to be treated for a median of 40 months to prevent 1 case of invasive breast cancer. Inclusion of all women with confirmed breast cancer (invasive, noninvasive, or uncertain invasiveness) did not substantially change the results (Figure 2; RR, 0.35; 95% CI, 0.21-0.58; P<.001). The reduction in risk of invasive cancer was similar for those taking 60 mg/d (RR, 0.22; 95% CI, 0.10-0.50) and 120 mg/d (RR, 0.26; 95% CI, 0.12-0.56) of raloxifene. Of the 54 women with breast cancer, 1 (assigned to 60 mg of raloxifene) died, and vital status was not available for 3 others.

Estrogen receptor status was available for 35 of the invasive cancer cases: 24 were estrogen receptor–positive and 11 were estrogen receptor–negative. Raloxifene reduced the risk of invasive estrogen receptor–positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24; Table 2). Raloxifene did not influence the risk of estrogen receptor–negative invasive cancer (RR, 0.88), but the CI was very wide (95% CI, 0.26-3.00).

Hot flashes, influenzalike syndromes, endometrial cavity fluid, peripheral edema, and leg cramps were reported more frequently in the raloxifene group than in the placebo group (Table 3). Thirty-three women (0.6%) assigned to the raloxifene group and 2 (0.1%) assigned to the placebo group discontinued treatment due to hot flashes (P<.001).

By 40 months of follow-up, there was a higher rate of deep venous thrombosis (38 cases, 0.7%) and pulmonary embolus (17 cases, 0.3%) in the combined raloxifene groups than in the placebo group (5 cases, 0.2%; 3 cases, 0.1%, respectively). One case of venous thromboembolism occurred per 155 women treated with raloxifene for 3 years. The risk of venous thromboembolic disease (deep venous thrombosis or pulmonary embolism) was 3.1 times higher (95% CI, 1.5-6.2) in women assigned to the raloxifene group than to the placebo group. One woman (in the 60-mg raloxifene group) died due to pulmonary embolism. No significant difference in the rate of venous thromboembolic disease existed between the 60- and 120-mg groups. In addition, 5 women assigned to raloxifene (0.1%) and 3 women assigned to placebo (0.1%) had retinal vein thrombosis.

More women in the raloxifene group (1.2%) reported new or worsening diabetes mellitus compared with participants in the placebo group (0.5%) (P=.009). However, there was no difference between the placebo and raloxifene groups in median changes in levels of fasting plasma glucose (0.2 mmol/L [36 mg/dL] in both groups; P=.15) or hemoglobin A_1c (0.1% in both groups; P=.75); or in the proportion of participants who had at least 1 annual fasting plasma glucose level that exceeded 7.0 mmol/L (126 mg/dL) (5.7% placebo vs 6.4% in the combined raloxifene treatment group; P=.26). Furthermore, there was no significant difference in the proportion of participants who began using insulin or oral hypoglycemic agents (0.8% placebo vs 0.5% in the combined raloxifene treatment group; P=.45).

Hypertension, hypercholesterolemia, hematuria, and bradycardia were reported less frequently among women assigned to the raloxifene groups than the placebo group. There were no differences in the rates of occurrence of vaginal bleeding or breast pain. Overall mortality rates did not differ between the placebo (1.0%) and combined raloxifene group (0.8%), and there were no differences by cause of death.

Among the 5957 women who had not had a hysterectomy, endometrial cancer occurred in 4 (0.20%) assigned to placebo and in 6 (0.25%) assigned to the combined raloxifene group (RR, 0.8; 95% CI, 0.2-2.7) by 40 months of follow-up. In the 1781 women who underwent transvaginal ultrasonography at baseline and had at least 1 follow-up test, endometrial thickness increased by an average of 0.01 mm in the raloxifene group and decreased 0.27 mm in the placebo group after 3 years of follow-up (P<.01 for the difference between the groups). Of these 1781 women, 60 participants (10.1%) in the placebo and 168 participants (14.2%) in the raloxifene group (P=.02) had endometrial thickness that was more than 5 mm on at least 1 follow-up ultrasound. Nine women (1.5%) in the placebo group and 39 women (3.3%) in the raloxifene group had at least 1 endometrial thickness measurement that had increased by more than 5 mm compared with their baseline measurements (P=.03).

Among women who still had a uterus, 196 (148 in the raloxifene and 48 in the placebo group) had an endometrial biopsy. There were 3 cases of hyperplasia and 2 cases of endometrial carcinoma in the placebo group and 3 cases of hyperplasia and 2 cases of endometrial carcinoma in the combined raloxifene group. Fluid was seen in the endometrial cavity of 5.7% of controls and 8.4% in the combined raloxifene group (P=.02, Table 3).

Raloxifene reduced the risk of newly diagnosed invasive breast cancer by 76% during a median of 40 months of treating postmenopausal women for osteoporosis. This was attributable to a 90% reduction in the risk of estrogen receptor–positive breast cancer. There was no apparent decrease in the risk of estrogen receptor–negative breast cancer. This supports the concept that raloxifene acts by interacting with estrogen receptors in the breast to competitively inhibit estrogen-induced DNA transcription.^15,16

The BCPT¹² found that a median of 55 months of treatment with tamoxifen decreased the risk of invasive breast cancer by 49% and estrogen receptor–positive breast cancer by 69% (Table 4). Although it appears that raloxifene reduces the risk of breast cancer more than tamoxifen does, the results of these 2 studies cannot be directly compared. Women in the BCPT were, on average, at higher risk for breast cancer and were younger than the subjects in our study (Table 4). Selective estrogen receptor modulators might be more effective in women at average or low risk of breast cancer than in women who have risk factors for breast cancer and, perhaps, an increased risk of breast cancer due to genetic factors that may not involve estrogen. Another study, the National Surgical Adjuvant Breast and Bowel Project, Part 2, will compare the effects of raloxifene and tamoxifen in women at high risk of breast cancer, although this study will not have a placebo group.

Two European trials of tamoxifen for the prevention of breast cancer, the Italian Tamoxifen Prevention Study (Italian Trial)¹⁰ and the Royal Marsden Hospital Tamoxifen Chemoprevention Trial (Marsden Trial),¹¹ have reported that tamoxifen had no significant influence on the risk of breast cancer (Table 4). These trials, however, were smaller than the BCPT. Compared with participants in the BCPT, those in the Marsden Trial were younger, more likely to have a strong family history of breast cancer, and 26% of the subjects took estrogen during the trial.¹¹ Participants in the Italian trial had undergone hysterectomy, 48% had bilateral oophorectomies, and 14% took estrogen.^10,22 It is not clear whether the differences in the characteristics of the participants might account for the differences in results. However, because of its greater statistical power, the BCPT provides the strongest evidence that tamoxifen reduces the risk of breast cancer among women at high risk of the disease.²²

Women with low bone density probably have a decreased risk of breast cancer.^23,24 The rates of breast cancer observed in the placebo group in the MORE study, however, were similar to rates expected among average 65-year-old white women.²⁵ Perhaps the decreased risk of breast cancer associated with osteoporosis was offset by an increased detection of breast cancer by mammographic screening during the trial.

Because breast cancer generally requires several years to grow to a clinically or radiographically detectable size,²⁶ the cancers that were diagnosed during this trial were probably present when the study began. Therefore, the reduction in the risk of breast cancer within the first 40 months of treatment with raloxifene probably represents suppression or regression of subclinical cancer.

It is important to determine the long-term effects of raloxifene and other selective estrogen receptor modulators because metastatic breast cancers can develop resistance to tamoxifen after long-term exposure.^27-29 The effectiveness of tamoxifen for prevention of primary breast cancer beyond 5 years of treatment is uncertain. The NSABP B-14 trial¹⁴ found that 5 years of tamoxifen treatment for estrogen receptor–positive breast cancer reduced the risk of new primary cancer in the contralateral breast; continuation for an additional 5 years did not reduce this risk more.^8,9 If a treatment reduces the risk of breast cancer for only a few years, then it should be reserved for women who have a high near-term risk of breast cancer. If a treatment continues to reduce safely the risk of breast cancer as long as it is taken, then it may be worthwhile for longer-term use in a broader spectrum of women than what is currently practiced.

The vast majority of women in the MORE trial were white. Black women tend to have a lower rate of estrogen receptor–positive breast cancer, but there is no indication that raloxifene would have a different effect on the risk of estrogen receptor–positive cancer in various racial groups.

Unopposed, estrogen and tamoxifen substantially increase the risk of endometrial cancer.^12,30 Estrogen and tamoxifen (but not raloxifene) stimulate the endometrium of animals and their effects are blocked by raloxifene.^19,20,31 Raloxifene did not increase the risk of endometrial cancer during the first 3 years of the MORE trial treatment, but the total number of cases was small. For those women who had transvaginal ultrasonography performed, we observed a slight (0.3 mm) difference in the endometrial thickness changes between women assigned to raloxifene and placebo, with endometrial thickness exceeding 5 mm in 4.1% more of those in the raloxifene group than those in the placebo group. However, we found no evidence for an increased risk of endometrial hyperplasia among women who underwent endometrial biopsy. Fluid in the endometrial cavity was seen in 2.7% more of the women in the raloxifene group than in the placebo group. Tamoxifen increases the prevalence of endometrial fluid.³² Fluid in the endometrial cavity is generally regarded as a benign finding that sometimes occurs in healthy postmenopausal women due to cervical retention of normal endometrial secretions.^33,34 In the absence of evidence that raloxifene increases the risk of cancer or hyperplasia, we believe that routine periodic endometrial monitoring with ultrasonography or biopsy is not warranted for women taking raloxifene.

Raloxifene, tamoxifen, and estrogen increase the risk of venous thromboembolic disease to a similar degree.^12,35 We included all reported cases of venous thromboembolism and did not limit the analysis to "idiopathic" cases as have some studies. Because venous thromboembolism is an uncommon disease, the 3-fold increase in risk translated to a 0.6% excess risk of venous thromboembolic disease during 3 years of treatment. Investigation is under way to find the reason for this adverse effect and ways to identify women who are prone to thromboembolic complications of estrogenic therapies. Women with a history of venous thrombosis or pulmonary embolism should not take raloxifene, tamoxifen, or estrogen, and women currently taking any of these medications should discontinue them before major surgery or during periods of immobilization.

Raloxifene decreases low-density lipoprotein cholesterol levels, but it does not alter high-density lipoprotein cholesterol levels.^36,37 Tamoxifen has shown similar effects on plasma lipid levels, and previous studies suggest that tamoxifen might decrease the risk of coronary heart disease.^38-40 Tamoxifen did not, however, significantly reduce the risk of heart disease in the BCPT.¹² The effect of selective estrogen receptor modulators on the risk of heart disease needs further study.

Raloxifene decreases bone turnover and increases bone density.³⁷ In the MORE trial, 3 years of treatment decreased the risk of vertebral fractures but not other types of fractures. These findings have recently been corroborated (B. Ettinger, MD, et al, unpublished data, 1999). Tamoxifen also improves bone density⁴¹ and may reduce the combined risk of hip, wrist, and spine fractures; however, this effect was not statistically significant after 4 years of treatment in the BCPT.¹²

In general, raloxifene was well tolerated. Our results confirm that raloxifene does not cause vaginal bleeding or breast pain, which often limits the use of postmenopausal estrogen therapy. We confirmed previous findings of an increased rate of hot flashes and leg cramps with raloxifene; however, few women discontinued treatment for these symptoms. The 1.5% excess occurrence of peripheral edema with raloxifene might indicate fluid retention or venous insufficiency; this association needs to be confirmed in other trials. Although influenzalike syndromes were reported more frequently in the treatment group, it is not clear how raloxifene might cause such symptoms. It is possible that some of these associations and the decreased incidence of hypertension, hematuria, and bradycardia with raloxifene might be due to chance because we tested rates of more than 400 adverse experiences for statistical significance.

New or worsening diabetes mellitus was reported by 0.7% more participants in the raloxifene group than in the placebo group. There were 0.6% more participants taking raloxifene with fasting plasma glucose levels of at least 7.0 mmol/L (126 mg/dL) compared with placebo; however, this was not statistically significant. There was no significant change in median fasting plasma glucose or hemoglobin A_1c concentrations and no increase in the use of treatments for diabetes among women taking raloxifene. A daily dose of estradiol and 0.625 mg of conjugated estrogen might slightly improve fasting plasma glucose levels but not postprandial glucose tolerance,^42,43 and tamoxifen has no impact on fasting plasma glucose levels.⁴⁴ If raloxifene increases fasting glucose levels in a few women, the mechanism is not clear.

Tamoxifen and raloxifene may be useful preventive therapies for women who have an increased risk of estrogen receptor–positive breast cancer and vertebral fractures. Unfortunately, bone density alone may have limited value in identifying women most likely to have overall benefit from these drugs because women with low bone density have a high risk of fractures but a low risk of breast cancer.^23,24 Both tamoxifen and raloxifene increase hot flashes and, therefore, may be best tolerated by women who are no longer having hot flashes after menopause. If additional follow-up confirms that raloxifene continues to decrease the risk of breast cancer and does not increase the risk of endometrial cancer, then raloxifene might be preferred over tamoxifen for reduction in the risk of breast cancer and fractures in women who have a uterus.

We conclude that a median of 40 months of treatment with raloxifene decreases the risk of newly diagnosed breast cancer in postmenopausal women who have osteoporosis and who have no prior history of breast cancer. This effect is largely due to a substantial reduction in the risk of developing estrogen receptor–positive breast cancer. The MORE trial is continuing to assess the effectiveness and safety of longer-term use of raloxifene.