ORIGINAL INVESTIGATION. Long-term Effects of Raloxifene on Bone Mineral Density, Bone Turnover, and Serum Lipid Levels in Early Postmenopausal Women

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1 ORIGINAL INVESTIGATION Long-term Effects of Raloxifene on Bone Mineral Density, Bone Turnover, and Serum Lipid Levels in Early Postmenopausal Women Three-Year Data From 2 Double-blind, Randomized, Placebo-Controlled Trials C. Conrad Johnston, Jr, MD; Nina H. Bjarnason, MD; Fredric J. Cohen, MD; Aarti Shah, PhD; Robert Lindsay, MD; Bruce H. Mitlak, MD; William Huster, PhD; Michael W. Draper, MD, PhD; Kristine D. Harper, MD; Hunter Heath III, MD; Carlo Gennari, MD; Claus Christiansen, MD, PhD; Claude D. Arnaud, MD; Pierre D. Delmas, MD, PhD Background: In postmenopausal women, raloxifene hydrochloride has favorable effects on bone and lipid metabolism and does not stimulate reproductive tissues. The studies reported herein evaluated the long-term (3- year) effects of raloxifene treatment on bone mineral density (BMD), serum lipid levels, and drug tolerability in healthy postmenopausal women. Methods: A total of 1145 healthy European and North American postmenopausal women aged 45 through 60 years were enrolled in 2 parallel, double-blind, randomized, placebo-controlled trials of identical design and randomly assigned to receive raloxifene hydrochloride, 30, 60, or 150 mg, or placebo daily; all groups received 400 to 600 mg of elemental calcium. Assessments included measurements for BMD by dual-energy x-ray absorptiometry, markers of bone turnover, and serum lipid levels. Results: Lumbar spine BMD changed from baseline to 36 months as follows: placebo (mean percentage change±se), 1.32%±0.22%; raloxifene, 30 mg, 0.71% ±0.23%; raloxifene, 60 mg, 1.28% ±0.23%; and raloxifene, 150 mg, 1.20%±0.24%. Comparable BMD changes were observed in the hip and total body. Biochemical markers of bone turnover were suppressed by raloxifene to normal premenopausal ranges through 3 years. Serum low-density lipoprotein cholesterol was reduced 7% to 12% below baseline through 3 years. Study withdrawals due to any reason (37%) and withdrawals due to adverse events (14%) were not different among groups. The only significant adverse effect of therapy was hot flashes (25% in the 60-mg raloxifene group vs 18% in the placebo group); hot flashes were typically reported as mild and were not associated with study withdrawal (1.7% for 60-mg raloxifene vs 2.4% for placebo). Conclusions: Raloxifene preserves BMD at important skeletal sites, lowers serum low-density lipoprotein cholesterol levels, and has a tolerability profile comparable to placebo. These results indicate a favorable benefitrisk profile of raloxifene for long-term use in healthy postmenopausal women. Arch Intern Med. 2000;160: The affiliations of the authors appear in the acknowledgment section at the end of the article. RALOXIFENE hydrochloride is a nonsteroidal benzothiophene that has been classified as a selective estrogen receptor modulator (SERM) based on its demonstrated ability to affect bone and lipid metabolism similarly to estrogen, while simultaneously antagonizing the effects of estrogen in the uterus and breast. 1-4 Raloxifene given to healthy postmenopausal women for 2 years suppressed bone turnover to the normal premenopausal range; increased bone mineral density (BMD) in the spine, hip, and total body; lowered serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels; and did not stimulate proliferation of the endometrium. 5 Results from the Multiple Outcome of Raloxifene Evaluation (MORE) study indicate that raloxifene treatment reduces new vertebral fracture incidence by about half relative to placebo in older postmenopausal women with osteoporosis treated for 3 years, 6 a magnitude of effect comparable to that of bisphosphonates. 7 The potential utility of raloxifene for both prevention and treatment of osteoporosis mandates long-term study. Two clinical trials, each of 5 years total duration, were identically designed to determine the longterm effects of raloxifene treatment on BMD and lipid levels in healthy postmenopausal women. 5 Herein we report results from a planned 3-year analysis from these 2 double-blind trials comparing placebo with raloxifene doses of 30, 60, or 150 mg/d. 3444

2 SUBJECTS AND METHODS SUBJECTS This analysis includes 36-month data from 1145 women enrolled in 2 double-blind, placebo-controlled clinical trials. Study 1 was conducted in Western Europe (N=601) and study 2 was conducted in the United States and Canada (N=544). Both trials enrolled healthy women, aged 45 through 60 years, and between 2 and 8 years (inclusive) beyond their last menstrual period at baseline. For both studies, systemic hormone replacement therapy was permitted before, but not during, the study, and only if it had been discontinued at least 6 months before entry. Use of vaginal estrogens, except estradiol, was permitted up to an average of 3 times per week during the study. Concomitant use of progestins, androgens, boneactive agents, or other SERMs was not permitted. Complete inclusion and exclusion criteria have been published previously. 5 A randomized block design was used to assign women equally to receive daily either raloxifene hydrochloride, 30, 60, or 150 mg, or an identical placebo. All women were provided with supplemental elemental calcium (400 to 600 mg/d). Dietary vitamin D was not supplemented. Study visits were scheduled every 3 months for the first 2 years and every 6 months thereafter. The protocols were approved by local ethical review boards, and all women provided written informed consent for participation in accordance with the principles outlined in the Declaration of Helsinki. LABORATORY EVALUATION Blood samples were obtained after at least a 6-hour fast every 3 months during the first 2 years, and every 6 months thereafter. Bone turnover was assessed by measurements of serum osteocalcin (ELISA-OSTEO IRMA; CIS Biointernational, Gif-sur-Yvette, France), serum bone-specific alkaline phosphatase (Ostase IRMA; Hybritech, San Diego, Calif), and urine type I collagen C-telopeptide fragments corrected for creatinine excretion (CrossLaps ELISA; Osteometer Biotech A/S, Herlev, Denmark). These analyses were performed centrally (Hôpital Edouard Herriot, Lyon, France, and Covance Laboratories, Indianapolis, Ind, and Geneva, Switzerland). Analyses of serum lipid concentrations and routine laboratory measurements were performed centrally using routine methods (Covance, Indianapolis and Geneva). BONE DENSITOMETRY Bone mineral density of the spine (L1-L4), hip, and total body (subset of women) was measured twice yearly during the first 2 years and annually thereafter by dual energy x-ray absorptiometry using Hologic QDR-1000, 1500, 2000, or 4500 machines (Hologic, software version 7.10B, Waltham, Mass). Bone mineral density of the nondominant forearm was determined in a subset of women in study 1 by single energy x-ray absorptiometry (Osteometer DTX-100, software version 1.51B; Osteometer Meditech A/S, Roedovre, Denmark) and study 2 (dual energy x-ray absorptiometry, Hologic QDR-1000 and 2000). All scans were checked for quality by a central reader (Quality Assurance Center, Herlev, Denmark, or Osteoporosis Research Group, San Francisco, Calif). Scans for a subset of women in study 1 were reanalyzed to determine BMD in the new region of interest (N-ROI), a region in the ultradistal forearm with a high content of trabecular bone. 8 ASSESSMENT OF ADVERSE EVENTS At each scheduled visit (no less than every 6 months), women were asked in general terms about the occurrence and severity of adverse events. An adverse event that occurred for the first time or worsened in severity after randomization was considered treatment-emergent, which does not imply causality. Only treatment-emergent adverse events were analyzed. Women were also asked to grade adverse events as mild, moderate, or severe. If a woman withdrew from the study because of adverse event(s), the predominant adverse event contributing to the withdrawal was specifically captured. STATISTICAL ANALYSES All analyses were performed using an intent-to-treat approach. The data set included all women who had at least 1 follow-up visit after randomization. For women who withdrew from the study before the 3-year visit (referred to as end point), the last available observation was carried forward to subsequent visits. The changes and percentage changes in BMD from baseline to 6, 12, 18, 24, and 36 months were evaluated by analysis of variance, including a term for therapy and study. Initially, a term for therapy-by-study interaction was included and tested for significance at the.10 level. Since this interaction was not significant, it was deleted from all models. For BMD measurements wherein the therapy effect was significant at the.029 level of significance, a pairwise comparison was also performed at the.029 two-sided level of significance, reflecting adjustment for an interim analysis at 2 years. The changes and percentage changes for biochemical markers of bone turnover and serum lipid levels were not normally distributed (Shapiro-Wilk s test of normality). 9 Therefore, these data were ranked and analyzed using the analysis of variance described above. Median changes were used to represent the central tendency, and SEs for median changes were estimated using the d-delete jackknife method. 10 These measures were tested at the.05 two-sided level of significance for overall therapy effect and for each pairwise comparison. For measures determined to be normally distributed, means and SDs are presented. For those that were not normally distributed, medians and jackknife SEs are presented. Safety measurements having continuous distribution (eg, laboratory results, vital signs) were analyzed in a manner similar to efficacy measurements. Study discontinuations and safety assessments having binary responses (eg, adverse events) were analyzed using the Cochran- Mantel-Haenszel tests for general association stratified by study. 3445

3 Table 1. Patient Baseline Characteristics and Number Discontinued* Placebo Group (n = 286) 30 mg/d (n = 288) 60 mg/d (n = 286) 150 mg/d (n = 285) Discontinued, No. (%) 94 (32.9) 108 (37.5) 101 (35.3) 120 (42.1) Age, mean ± SE, y 54.6 ± ± ± ± 0.01 BMI, mean ± SE, kg/m ± ± ± ± 0.27 BMD, mean ± SE, g/cm 2 Lumbar spine 0.94 ± ± ± ± 0.01 Hip 0.86 ± ± ± ± 0.01 Total body 1.05 ± ± ± ± 0.01 Ultradistal radius 0.38 ± ± ± ± 0.01 Cholesterol, median ± SE, mmol/l Total 5.88 ± ± ± ± 0.05 LDL-C 3.81 ± ± ± ± 0.05 HDL-C 1.53 ± ± ± ± 0.01 Triglycerides, median ± SE, mmol/l 1.06 ± ± ± ± 0.03 *BMI indicates body mass index; BMD, bone mineral density; LDL-C, low-density lipoprotein cholesterol; and HDL-C, high-density lipoprotein cholesterol. Raloxifene was given as raloxifene hydrochloride. To convert cholesterol values from millimoles per liter to milligrams per deciliter, divide by To convert triglyceride values from millimoles per liter to milligrams per deciliter, divide by A B Mean % Change From Baseline Placebo Raloxifene, 30 mg Raloxifene, 60 mg Raloxifene, 150 mg Months of Treatment Mean percentage changes from baseline in spine (A) and total hip (B) bone mineral density through 36 months of treatment. The differences between each raloxifene hydrochloride group and placebo group and from baseline were statistically significantly different at all time points. RESULTS The randomization procedure and identical inclusion and exclusion criteria contributed to similar study groups being enrolled in the 2 trials, as evidenced by the baseline characteristics of enrolled women (Table 1). Treatment responses for key end points were also comparable between studies, and there was no difference between studies in the proportion of women who had withdrawn after 3 years. Throughout the follow-up interval, about 90% of participants in each treatment group were compliant with study medication, defined as taking at least 80% of dispensed tablets (data not shown). Bone mineral density decreased by 1% to 2% from baseline at all body sites (and by 3% at the wrist) in the placebo group. In the raloxifene groups, there was an increase in spine and total hip BMD during the first 2 years, which was maintained during the third year (Figure). The response to raloxifene at the femoral neck was similar to the total hip (data not shown). The BMD responses to raloxifene, compared with placebo, were similar across anatomic sites (Figure and Table 2). There were no statistically significant differences in the mean percentage changes in spine and hip BMD among raloxifene groups at end point, although the response to 30-mg raloxifene tended to be less than that of the 2 higher doses. Total body BMD was increased at 3 years by an average of 1.7% with raloxifene therapy compared with placebo (Table 2). Raloxifene, 60 and 150 mg, significantly attenuated, but did not completely prevent, BMD decline at the ultradistal radius or the forearm new region of interest (Table 2). Raloxifene therapy significantly decreased bone turnover to premenopausal levels, as reflected by decreases of serum osteocalcin, serum bone-specific alkaline phosphatase, and urine CrossLaps/creatinine 11,12 (Table 3). The placebo group also had a slight, but significant, decrease in most markers (Table 3). The responses of serum CrossLaps, serum N-mid osteocalcin, and urine and serum type I collagen fragment N-telopeptide were similar to those of the other bone turnover markers (Table 3). Raloxifene treatment significantly decreased serum total and LDL-C levels (Table 4) throughout 3 years, whereas high-density lipoprotein cholesterol (HDL-C) 3446

4 Table 2. Percentage Change for Bone Mineral Density* Placebo Group 30 mg/d 60 mg/d 150 mg/d Lumbar spine No. (end point, 12 mo) Mean % change ± SE 0.71 ± ± ± ± 0.18 No. (end point, 24 mo) Mean % change ± SE 1.08 ± ± ± ± 0.21 No. (end point, 36 mo) Mean % change ± SE 1.32 ± ± ± ± 0.24 Radius ultradistal No. (end point, 24 mo) Mean % change ± SE 2.28 ± ± ± ± 0.35 No. (end point, 36 mo) Mean % change ± SE 3.05 ± ± ± ± 0.38 Forearm N-ROI No. (end point, 12 mo) Mean % change ± SE 1.37 ± ± ± ± 0.54 No. (end point, 24 mo) Mean % change ± SE 3.82 ± ± ± 0.50 # 1.90 ± 0.48 # Total body No. (end point, 12 mo) Mean % change ± SE 0.40 ± ± 0.24 # 0.68 ± ± 0.38 No. (end point, 24 mo) Mean % change ± SE 0.69 ± ± ± ± 0.26 No. (end point, 36 mo) Mean % change ± SE 1.06 ± ± ± ± 0.32 *N-ROI indicates new region of interest. Raloxifene was given as raloxifene hydrochloride. P.001 compared with baseline. P.01 compared with placebo. P.001 compared with placebo. P.01 compared with baseline. P.029 compared with baseline. #P.029 compared with placebo. and triglyceride concentrations were unchanged from baseline after 3 years of raloxifene treatment. During 3 years of treatment, the tolerability of raloxifene was comparable to that of placebo. Overall, 37% of women withdrew from the study at or before the 3-year visit. The study discontinuation rates were similar across treatment groups, and there were no treatment differences in the reasons for early study withdrawal. A total of 164 (14%) women withdrew due to an adverse event, the most common reason for study withdrawal. At least 1 adverse event was reported by 88% of the participants, with no difference among treatment groups overall. The only adverse event for which there was both a statistically significant treatment difference and a higher reported incidence among raloxifene-treated women was hot flashes (25% in the 60-mg raloxifene group vs 18% in the placebo group) (Table 5). Hot flashes were generally mild and did not increase study withdrawals (1.7% for 60-mg raloxifene vs 2.4% for placebo). Symptoms usually accompanying hot flashes, such as insomnia and sweating, were not reported more frequently by raloxifene-treated women (data not shown). Other adverse events that have been associated with menopause, therapy with other SERMs, estrogens, or estrogen-progestin replacement therapies were also not reported more frequently during raloxifene therapy compared with placebo (Table 5). COMMENT During 3 years of treatment, raloxifene, 30 to 150 mg/d, reduced bone turnover to within normal premenopausal ranges 11,12 and preserved BMD above baseline at the spine, hip, and total body, supporting the use of 60 mg/d of raloxifene for long-term prevention of postmenopausal bone loss. Small decreases in markers of bone turnover in the placebo group, possibly attributable to calcium supplementation, were not sufficient to prevent loss of BMD. Data from 2 trials were integrated for this study. The validity of data integration was evidenced by the comparable baseline characteristics and responses to therapy between the 2 studies. Throughout the follow-up period, the random assignment to therapy and the doubleblind were maintained; medication compliance was as expected and was unaffected by drug assignment; and attrition from the study was as expected for an asymptomatic disease prevention study and was unaffected by treatment. The similarity of BMD responses to raloxifene in different body regions that contain either primarily trabecular (ie, spine) or cortical bone (ie, femoral neck) suggests that the effect of raloxifene is similar on these 2 bone types. This is in contrast to other antiresorptive treatment modalities, for example, bisphosphonates, which 3447

5 Table 3. Percentage Changes From Baseline in Markers of Bone Turnover* Placebo Group 30 mg/d 60 mg/d 150 mg/d Serum osteocalcin No. (end point, 36 mo) Median % change ± SE ± ± ± ± 1.88 Serum bone-specific alkaline phosphatase No. (end point, 36 mo) Median % change ± SE 6.99 ± ± ± ± 2.20 Urine CrossLaps/creatinine No. (end point, 36 mo) Median % change ± SE ± ± ± ± 2.45 Urine NTX/Cr No. (end point, 12 mo) Mean % change ± SE 4.53 ± ± ± ± 2.89 Serum NTX No. (end point, 12 mo) Mean % change ± SE 1.56 ± ± ± ± 1.70 N-Mid osteocalcin No. (end point, 24 mo) Median % change ± SE 1.26 ± ± ± ± 3.88 Serum CrossLaps No. (end point, 12 mo) Median % change ± SE ± ± ± ± 3.82 *CrossLaps indicates urinary type I collagen fragment c-telopeptide; NTX/Cr, type I collagen fragment N-telopeptide corrected for creatinine; and NTX, type I collagen fragment N-telopeptide. Raloxifene was given as raloxifene hydrochloride. P.001 compared with baseline. P.001 compared with placebo. P.01 compared with placebo. Table 4. Percentage Changes From Baseline to 36 Months for Serum Lipid Levels* Placebo Group 30 mg/d 60 mg/d 150 mg/d Total cholesterol No Median % change ± SE 2.12 ± ± ± ± 1.38 LDL-C No Median % change ± SE 1.96 ± ± ± ± 0.79 HDL-C No Median % change ± SE 4.65 ± ± ± ± 0.70 Triglycerides No Median % change ± SE 1.00 ± ± ± ± 4.20 *LDL-C indicates low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. Raloxifene was given as raloxifene hydrochloride. P.01 compared with baseline. P.001 compared with baseline. P.01 compared with placebo. P.001 compared with placebo. P.05 compared with baseline. preferentially increase BMD in the spine One hypothesis accounting for the differential effect of bisphosphonates is based on an increase in the amount of mineral per volumetric unit of bone. Animal and human bone microradiography studies indicate that, when bone metabolism is markedly reduced by bisphosphonates, the second phase of mineralization (which accounts for about 30% of mineral deposited into bone) is significantly prolonged, thus increasing the amount of mineral per unit of bone. 16,17 Such an effect is more likely to be observed in sites rich in cancellous bone, such as the lumbar spine, characterized by higher turnover rates than cortical bone. Thus, the relatively large increase in BMD observed with antiresorptive agents that markedly reduce bone turnover (below the normal premenopausal range) could be due initially to filling of the remodeling space (greatest in cancellous bone) and later to an increase in bone mineral per unit volume of bone (also greatest in cancellous 3448

6 Table 5. Selected Reported Adverse Events* Event Placebo Group (n = 286) 30 mg/d (n = 288) 60 mg/d (n = 286) 150 mg/d (n = 285) P Hot flashes 52 (18.2) 49 (17.0) 72 (25.2) 67 (23.5).04 Leg cramps 8 (2.8) 9 (3.1) 14 (4.9) 14 (4.9).41 Abdominal pain 20 (7.0) 20 (6.9) 16 (5.6) 26 (9.1).43 Nausea 23 (8.0) 17 (5.9) 18 (6.3) 23 (8.1).64 Vaginitis 12 (4.2) 17 (5.9) 11 (3.8) 15 (5.3).64 Breast pain 11 (3.8) 7 (2.4) 11 (3.8) 7 (2.5).60 Peripheral edema 6 (2.1) 7 (2.4) 13 (4.5) 7 (2.5).28 Leukorrhea 3 (1.0) 7 (2.4) 8 (2.8) 7 (2.5).49 Vaginal hemorrhage 10 (4.0) 1 (0.4) 8 (3.3) 4 (1.6).04 Breast carcinoma 2 (0.7) 2 (0.7) 0 1 (0.4).70 Deep thrombophlebitis (0.3) 0.75 *Data are given as number (percentage). Raloxifene was given as raloxifene hydrochloride. Denominators for vaginal hemorrhage are based only on women with a uterus at baseline: placebo, n = 247; 30-mg/d raloxifene, n = 234; 60-mg/d raloxifene, n = 245; and 150-mg/d raloxifene, n = 243. bone). Such a hypothesis is consistent with the difference in bone turnover marker suppression between raloxifene (about 30%) and potent bisphosphonates ( 50%). 14,15 A similar BMD response to raloxifene in the prevention studies was observed in an osteoporosis treatment trial, Multiple Outcomes of Raloxifene Evaluation (MORE), which enrolled osteoporotic women who were about 10 years older at baseline 6 than subjects in the present report. Although these BMD increases seem modest, patients in MORE treated with raloxifene experienced a significant reduction of risk for incident vertebral fracture at 3 years of therapy. 6 Thus, although the BMD response to raloxifene in the spine is substantially less than that observed for bisphosphonates, the reduction in vertebral fracture risk appears to be similar. These and other observations suggest that on-treatment change in BMD does not accurately predict clinical outcomes in response to antiresorptive therapies. Whether bone turnover marker responses will prove to be better predictors of fracture prevention efficacy for antiresorptive therapies remains to be determined. The raloxifene-induced reductions in LDL-C without change in HDL-C or triglyceride concentrations are consistent with previous results, 5,18 and indicate that these effects are sustained long-term. The responses in markers of cardiovascular risk to raloxifene treatment differ from those to oral hormone replacement therapies. In a 6-month study comparing raloxifene with continuouscombined conjugated equine estrogens and medroxyprogesterone acetate (HRT), there was a similar effect of the therapies on LDL-C and total cholesterol, whereas raloxifene had a lesser effect on lipoprotein(a) and no effect on HDL-C. 18 However, raloxifene did not affect serum triglyceride concentrations, which were elevated by HRT. While HRT enhanced fibrinolysis, raloxifene had no effect on fibrinolysis but markedly reduced serum fibrinogen concentration. 18 Although surrogate markers of cardiovascular risk are interesting surrogate end points, only large-scale controlled clinical trials can provide conclusive evidence of coronary heart disease benefit. The recently published Heart and Estrogen/progestin Replacement Study (HERS), 19 which enrolled women with established coronary disease, found no benefit of HRT compared with placebo for nonfatal myocardial infarction or coronary heart disease death. The effects of raloxifene therapy on fatal and nonfatal cardiovascular events are among the primary end points in the Raloxifene Use for The Heart (RUTH) trial, 20 a multicenter, randomized double-blind trial of raloxifene, 60 mg/d, compared with placebo in postmenopausal women who have risk factors for or history of heart disease. The overall tolerability profile of raloxifene in these studies was similar to that of placebo, although a small increase in incident hot flashes was found (excess risk, appoximately 7 of 100 treated). Hot flashes were typically reported as mild, were not associated with other symptoms, and did not contribute to study withdrawal. Importantly, there was no evidence that raloxifene aggravated symptoms or signs of menopause such as vaginitis, and raloxifene therapy was also not associated with symptoms commonly reported during therapy with other SERMs (eg, leukorrhea) 21 and HRT (eg, breast pain, vaginal bleeding). Although reported rarely in these osteoporosis prevention studies, raloxifene therapy has been associated with development of venous thromboembolism in older women, 22 as have HRT 19 and tamoxifen therapy. 23 Raloxifene therapy has also been shown to reduce the risk of invasive breast cancer (a secondary end point in an osteoporosis treatment trial) by 76% in women with osteoporosis at a median of 40 months of observation. 24 As with venous thromboembolism, breast cancer was reported rarely in these osteoporosis prevention studies. In conclusion, raloxifene therapy in healthy, relatively young postmenopausal women resulted in continuous and effective skeletal antiresorptive effects, with decreases in markers of bone turnover and preservation of BMD during 3 years. Raloxifene therapy also reduced serum LDL-C level and was well tolerated. For these reasons, raloxifene should be considered as an adjunct to exercise and nutritional optimization for long-term osteoporosis prevention in healthy postmenopausal women with risk factors for osteoporosis. Preliminary results 3449

7 showing favorable effects of raloxifene on the risk of breast cancer and the favorable effects on markers of cardiovascular risk suggest that the indications for raloxifene therapy may be broadened in the future. 20 Accepted for publication June 16, From the Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis (Dr Johnston); Center for Clinical and Basic Research, Ballerup, Denmark (Drs Bjarnason and Christiansen); Eli Lilly and Company, Indianapolis (Drs Cohen, Shah, Mitlak, Huster, and Draper); Helen Hayes Hospital, Clinical Research Center, West Haverstraw, NY (Dr Lindsay); Duke University Medical Center, Durham, NC (Dr Harper); University of Utah School of Medicine, Salt Lake City (Dr Heath); University of Siena, University Hospital of Siena, Siena, Italy (Dr Gennari); University of California, San Francisco (Dr Arnaud); and Hôpital Edouard Herriot and INSERM Research Unit, Lyon, France (Dr Delmas). Drs Cohen, Shah, Mitlak, Huster, Draper, Harper, and Heath are employees and stockholders of Eli Lilly and Co, Indianapolis. Drs Arnaud and Delmas have received honoraria from Eli Lilly Corporation and performed clinical trials of raloxifene supported by Eli Lilly. Dr Cohen is now with R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ. Support was provided by Eli Lilly and Company in the form of research grants to the individual study sites. The following were principal investigators: Austria: J. Huber, MD (Vienna); Belgium: J. P. DeVogelaer, MD (Brussels); Denmark: H. Lawaetz, MD (Ballerup); France: P. D. Delmas, MD (Lyon); Germany: J. Semler, MD (Berlin), J. Happ, MD (Frankfurt); Italy: M. L. Brandi, MD (Florence), C. Gennari, MD (Siena); the Netherlands: S. E. Papapoulos, MD (Leiden), J. I. Puyenbroek, MD (Amsterdam); United Kingdom: I. Smith, MD, and S. Young, MD (Lancashire, England); United States: S. R. Weiss, MD (San Diego, Calif), C. Arnaud, MD (San Francisco, Calif), H. H. McIlwain, MD (Tampa, Fla), C. Johnston, MD (Indianapolis, Ind), T. J. Weber, MD (Durham, NC), R. Lindsay, MD (West Haverstraw, NY), S. S. Miller, MD (San Antonio, Tex), H. Heath III, MD, and T. P. Knecht, MD (Salt Lake City, Utah). We thank Patrick Garnero, Lyon, France, for bone marker analyses; Anette Møllgaard for assistance in forearm bone mass reanalysis; colleagues from Osteometer Biotech for assistance in measurement of serum CrossLaps and N-Mid osteocalcin; Steven D. Watts for statistical programming; and Erin Walls, ELS, for editorial assistance. We also gratefully acknowledge the enthusiastic, steady participation of the women volunteers, and the hundreds of skilled and educated research staff. Reprints: C. Conrad Johnston, Jr, MD, Indiana University School of Medicine, Emerson Hall Room 421, 545 Barnhill Dr, Indianapolis, IN REFERENCES 1. Bryant HU, Dere WH. 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