JOURNAL OF BONE AND MINERAL RESEARCH Volume 13, Number 11, 1998 Blackwell Science, Inc.

1998 American Society for Bone and Mineral Research

Treatment of Established Postmenopausal Osteoporosis with Raloxifene: A Randomized Trial

EDWARD G. LUFKIN,1 MICHAEL D. WHITAKER,2 THOMAS NICKELSEN,3 RODOLFO ARGUETA,2 ROBERT H. CAPLAN,4 RONALD K. KNICKERBOCKER,3 and B. LAWRENCE RIGGS1

ABSTRACT Raloxifene is a selective estrogen receptor modulator that in experimental animals acts as an estrogen receptor antagonist in breast and endometrium but as an estrogen receptor agonist in the skeletal and cardiovascular systems. We conducted a 1-year prospective, randomized, double-blind trial in 143 postmenopausal osteoporotic women (mean SD age, 68.4 5.0 years) with at least one prevalent vertebral fractures and low bone mineral density (BMD), comparing groups receiving raloxifene at 60 mg/day (RLX60) or 120 mg/day (RLX120) and a control group receiving supplements of 750 mg/day of calcium and 400 IU/day of vitamin D. There were no differences among groups in the occurrence of uterine bleeding, thrombophlebitis, breast abnormalities, or increased endometrial thickness (assessed by ultrasonography). As compared with controls, the changes in values over 1 year for RLX60 and RLX120, respectively, were significant for serum bone alkaline phosphatase ( 14.9%, 8.87%), serum osteocalcin ( 20.7%, 17.0%), and urinary C-telopeptide fragment of type I collagen/creatinine ( 24.9%, 30.8%), markers of bone turnover; for serum total cholesterol ( 7.0% for RLX60) and low density lipoprotein cholesterol (LDL) ( 11.4% for RLX60) and for the LDL/HDL cholesterol ratio ( 13.2%, 8.3%). BMD increased significantly in the total hip (1.66% for RLX60) and ultradistal radius (2.92%, 2.50%). There were nonsignificant trends toward increases over controls in BMD for lumbar spine, total body, and total hip (for RLX120). Using a >15% cutoff definition, raloxifene had no effect on incident fractures, but using a >30% cutoff, there was a dose-related reduction (p 0.047). We conclude that raloxifene therapy is well tolerated, reduces serum lipids, and does not stimulate the uterus or breasts. It has beneficial effects on bone, although, under the conditions of this study, these appear to be of a smaller magnitude than have been reported with estrogen therapy. (J Bone Miner Res 1998;13:17471754)

INTRODUCTION
ALOXIFENE HYDROCHLORIDE is a benzothiophene derivative, originally investigated as a treatment for advanced breast cancer.(1) It is related pharmacologically, but not chemically, to the more widely used antiestrogen tamoxifen. These drugs are now classified as selective estrogen receptor modulators based on their tissue-specific effects in classical target tissue for estrogen action(2) and, at least for raloxifene, on the presence of a specific response element in

DNA that differs from the classical estrogen response element.(3) This selective action was first associated with tamoxifen treatment. Despite its action as an antiestrogen on breast tissue, tamoxifen was reported to maintain bone mass in postmenopausal women, to lower serum cholesterol, and to stimulate endometrial proliferation.(4 6) However, clinical use of tamoxifen to treat osteoporosis is limited by its toxicity, including induction of endometrial hyperplasia and carcinoma, thrombophlebitis, abnormal hepatic function and, in rodents, hepatic tumors.(5)

1 2 3

Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota, U.S.A. Division of Endocrinology, Mayo Clinic, Scottsdale, Arizona, U.S.A. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, U.S.A. 4 Section of Endocrinology, Gundersen Clinic, La Crosse, Wisconsin, U.S.A.

1747

1748 In contrast to results with tamoxifen, studies in experimental animals and in humans treated with raloxifene have not demonstrated major adverse actions. Moreover, like tamoxifen, it has antiresorptive effects on bone, but, unlike tamoxifen, it does not cause endometrial stimulation. Thus, Black et al.(7) found that raloxifene treatment of ovariectomized rats prevented bone loss, reduced serum cholesterol, and prevented estrogen-induced endometrial hyperplasia. In an 8-week study in early postmenopausal women, Draper et al.(8) found that raloxifene in dosages of 200 mg/day or 600 mg/day and conjugated equine estrogen both had similar effects on reducing biochemical markers of bone turnover versus placebo. Raloxifene also decreased serum lipids and, as assessed by endometrial biopsies, did not stimulate the endometrium. There were no adverse effects except for hot flushes, which were common, especially in the group receiving the highest dosage of raloxifene. Based on these favorable results, raloxifene appears to be a promising candidate drug for the treatment of postmenopausal osteoporosis. We therefore initiated a 1-year prospective, randomized, double-blind clinical trial in women with established postmenopausal osteoporosis comparing parallel treatment groups of controls and two dosages of raloxifene.

LUFKIN ET AL.

Experimental design
Candidates for the trial were seen for a screening visit to determine eligibility, at which time they had a general medical examination that included physical examination, including breast examination, general laboratory studies, radiographic evaluation of the thoracic and lumbar spine, and mammograms. All details of the study were explained, and informed written consent was obtained from all participants. One hundred and forty-three women were then assigned to parallel groups receiving no drug (control, CON), 60 mg/day of raloxifene HCl (RLX60), or 120 mg/ day of raloxifene HCl (RLX120) by blocked random allocation. All women concomitantly received a supplemental dosage of 750 mg/day elemental calcium and supplements of vitamin D, to bring daily intake to 800 IU. During a 12-month treatment period, they were evaluated four times: at baseline, 1 month, 6 months, and 12 months. At each visit, the women received interviews, determination of vital signs, and measurements of bone densitometry, bone biochemical markers, serum lipids, and serum intact parathyroid hormone (PTH). Serum vitamin D metabolites were measured at baseline, 1 month, and 1 year. Transvaginal ultrasonography to determine endometrial thickness was obtained at baseline and 12 months. At 1 year, spinal radiographs and mammograms were repeated.

MATERIALS AND METHODS Study population

One hundred and forty-three women with postmenopausal osteoporosis were enrolled in the clinical trial. All of them were studied at the Mayo Clinic, Rochester, MN, or the Mayo Clinic, Scottsdale, AZ, including the women recruited at the Gundersen Clinic in La Crosse, WI, who were studied at the Mayo Clinic, Rochester. Subjects were eligible if they were in good health except for osteoporosis, free of any serious acute or chronic medical condition that might affect bone or calcium metabolism, fully ambulatory, between the ages of 45 and 75 years, and postmenopausal (no menses for 5 years or levels of serum estradiol 73 pmol/l and serum follicle-stimulating hormone [FSH] 30 IU/l). Specific exclusion criteria included patients with a history of deep venous thrombosis, thromboembolic disorders, or cerebral vascular accident, also patients with a history of cancer within the previous 5 years, except for superficial skin cancer. The criteria for the diagnosis of osteoporosis were a bone mineral density (BMD) value for either the lumbar spine or proximal femur of 10th percentile for normal premenopausal females and one or more nontraumatic vertebral fractures, defined as a decrease in vertical height of 15% compared with adjacent vertebrae. (Two women were inadvertently entered whose BMD values were slightly above the entry criteria.) Calcium supplements of 500 mg/day or vitamin D 800 IU/day were allowed. Patients with previous estrogen replacement therapy (ERT) or calcitonin therapy were accepted after a 6-month washout interval before enrollment, and, for larger dosages of calcium supplements or vitamin D supplements, after a 3-month washout interval. Patients were ineligible if they had been previously treated with sodium fluoride or bisphosphonates.

Laboratory methods
Serum osteocalcin (ELSA-OSTED, CIS BioInternational, Gifs-sur-Yvette, France), serum bone-specific alkaline phosphatase (ALP; Hybritech, Inc., San Diego, CA, U.S.A.), and C-terminal telopeptide of type I collagen (CTx; ACTIVE CrossLaps; Diagnostic Systems Laboratories, Inc., Webster, TX, U.S.A.) in a first-morning voided urine sample were measured by enzyme-linked immunosorbent assay kits. Four serum lipid variables were measured (serum total cholesterol, serum triglycerides, serum high density lipoprotein [HDL], and low density lipoprotein [LDL] cholesterol). Serum PTH was measured by a two-site immunoradiometric assay (Incstar Corp., Stillwater, MN, U.S.A.). Serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were measured by the method of Kao and Heser.(9) Serum and urine samples were stored at 70C until measured in a central laboratory (Covance Central Laboratory Services, Inc., Indianapolis, IN, U.S.A.). BMD at the anteroposterior and lateral lumbar spine, total hip, distal one-third radius, and ultradistal radius, and total body bone mineral were measured by dual-energy X-ray absorptiometry using a scanner (QDR-2000; Hologic, Inc., Waltham, MA, U.S.A.). For assessment of vertebral fractures, lateral radiographs of the lumbar and thoracic spine were obtained at a standard target-to-film distance of 122 cm. For the vertebrae from T4 to L5, eight points were placed to define the anterior, posterior, right lateral, and left lateral heights of the vertebrae. The points were electronically digitized, and the heights were assessed by computer as previously described.(10) A prevalent (present at baseline) fracture was defined as a decrease in one or more of the four vertical heights of 15% compared with those of adjacent verte-

RALOXIFENE TREATMENT OF OSTEOPOROSIS TABLE 1. CHARACTERISTICS

OF

1749 PARTICIPANTS
AT

BASELINE (MEAN

SE)

Treatment groups Variables n Age (years) Years postmenopause Hysterectomy Previous estrogen therapy Calcium intake (mg/day) Family history of osteoporosis Current smoker Alcohol use ( 3 drinks/week) BMI (kg/m3) CON 48 68.2 22.2 15 24 704 19 8 16 25.3 0.7 1.0 73 RLX60 48 69.9 22.0 14 27 589 15 14 7 24.8 0.5 0.9 54 RLX120 47 67.2 23.5 19 22 580 18 7 6 26.2 0.9 1.3 52 p 0.028 0.569 0.467 0.644 0.262 0.183 0.135 0.022 0.311

0.55

0.61

0.70

brae. An incident (new) fracture (change between baseline and 1 year), was defined as 15% decrease in the same vertebra between baseline and 1 year. A more stringent definition of incident and prevalent fractures was also applied, defined as a 30% decrease in the same four vertical heights. Precision of densitometry was monitored using a phantom exchanged between the two sites. The coefficient of variation for the Rochester site was 0.46, and 0.44 for the Scottsdale site.

Statistical methods
All data analyses were performed with the intent to treat population with missing values handled by carrying their last value forward. Continuous laboratory data were analyzed using an analysis of variance model including treatment and investigative site. This model was fit using the raw change and percentage change from baseline to the end of the study for BMD and fracture rates. The change and percentage change data were ranked and analyzed in the model above for the biochemical markers, which are sometimes skewed. All p values and inferences were based on pairwise comparisons using the percentage change data for the model described above. Categorical data were analyzed across treatment groups using Pearsons chi-square test. Additionally, for the vertebral fracture analysis, trend tests were performed using a linear contrast for the fracture rates and the gamma statistic for the categorical data. To assess the possibility of a differential treatment effect in the two investigational sites, both change and percentage change from baseline to endpoint were modeled using analysis of variance with terms for treatment, site, and treatment-by-site interaction. In no case was the treatment-bysite interaction term significant, thus it was removed from the model. Baseline BMD levels were generally slightly higher in the Scottsdale site.

alcohol usage ( Table 1). Thirteen patients did not complete the first year of study. One woman in the RLX60 group died of unrelated causes (pneumonia), two discontinued for personal reasons, two because of protocol variance, and eight because of adverse effects. The percentage of patients reporting at least one serious adverse event (as defined by Food and Drug Administration criteria) was not significantly different among the three groups. Specifically, there were no differences in the occurrence of uterine bleeding, thrombophlebitis, pulmonary embolism, breast abnormalities, or increased endometrial thickness or other endometrial pathological findings. Results of mammography showed no adverse effects of raloxifene treatment on breast tissue. The mean SE for endometrial thickness as assessed by ultrasonography was not significantly different among treatment groups (CON, 3.39 0.34 mm; RLX60, 2.76 0.34 mm; and RLX120, 2.83 0.39 mm at baseline; and CON, 3.67 0.66 mm; RLX060, 3.03 0.40 mm; and RLX120, 2.55 0.31 mm at 1 year).

Laboratory measurements
The results of BMD measurements are given in Table 2 for the groups receiving no drug (CON), raloxifene HCl 60 mg/day (RLX60), and raloxifene HCl 120 mg/day (RLX120). Compared with the CON group, the RLX60 group improved significantly at the total hip scanning site, and both RLX groups improved at the distal and ultradistal radius scanning site. There were nonsignificant trends toward increased BMD or decreased bone loss with RLX versus CON treatment at all scanning sites except at the lateral lumbar spine. The effects of RLX treatment on biochemical markers for bone turnover and for serum intact PTH are shown in Table 3. Compared with the CON group, there were significant decreases in both treatment groups in both serum bone-specific ALP and serum osteocalcin, markers of bone formation, and in the urinary CTx/Cr ratio, a marker of bone resorption. Consistent with the decrease in bone resorption, there was a significant compensatory increase in serum PTH. These changes were significant at 6 months but not maximal until 12 months. Values for serum 25-

RESULTS Clinical findings

The groups did not differ at baseline regarding the general characteristics, except for minor variations in age and

1750 TABLE 2. BASELINE VALUES

AND

LUFKIN ET AL. GROUP CHANGES

FROM

BASELINE (MEAN SE) VARIOUS SCANNING SITES

AT

6 MONTHS

AND

12 MONTHS SE)

FOR

BMD

AT

Treatment group (mean Variables Total hip (g/cm )

2

CON baseline 6 months 12 months change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* 0.67 (0.002) 0.001 (0.003) 0.42 (0.48) 0.004 (0.003) 0.71 (0.48) 0.77 (0.02) 0.002 (0.004) 0.33 (0.50) 0.01 (0.004) 0.96 (0.55) 0.54 (0.01) 0.003 (0.004) 0.78 (0.89) 0.01 (0.004) 1.44 (0.74) 0.93 (0.01) 0.004 (0.005) 0.35 (0.55) 0.007 (0.004) 0.64 (0.45) 0.54 (0.01) 0.009 (0.002) 1.63 (0.30) 0.009 (0.002) 1.75 (0.35) 0.32 (0.01) 0.007 (0.002) 1.80 (0.51) 0.01 (0.002) 2.70 (0.56)

RLX60 0.64 (0.010) 0.002 (0.003) 0.43 (0.48) NS 0.006 (0.004) 0.95 (0.62) 0.027 0.75 (0.02) 0.01 (0.003) 1.25 (0.47) NS 0.01 (0.004) 1.78 (0.57) NS 0.52 (0.01) 0.01 (0.004) 2.16 (0.81) NS 0.01 (0.005) 1.34 (1.02) NS 0.91 (0.01) 0.004 (0.005) 0.37 (0.51) NS 0.002 (0.005) 0.11 (0.53) NS 0.52 (0.01) 0.003 (0.002) 0.59 (0.32) 0.031 0.01 (0.002) 1.05 (0.34) NS 0.30 (0.01) 0.002 (0.002) 0.14 (0.71) NS 0.001 (0.002) 0.22 (0.71) 0.002

RLX120 0.69 (0.01) 0.004 (0.002) 0.55 (0.48) NS 0.004 (0.003) 0.47 (0.48) NS 0.81 (0.02) 0.02 (0.004) 1.89 (0.52) 0.025 0.02 (0.004) 2.07 (0.52) NS 0.56 (0.01) 0.004 (0.004) 0.52 (0.78) NS 0.01 (0.007) 1.41 (1.20) NS 0.95 (0.01) 0.004 (0.003) 0.41 (0.32) NS 0.002 (0.004) 0.23 (0.43) NS 0.56 (0.01) 0.002 (0.002) 0.25 (0.40) 0.005 0.01 (0.002) 0.92 (0.38) NS 0.33 (0.01) 0.002 (0.002) 0.33 (0.60) NS 0.002 (0.002) 0.19 (0.63) 0.007

AP lumbar spine (g/cm2)

baseline 6 months 12 months

Lateral lumbar spine (g/cm2)

baseline 6 months 12 months

Total body bone mineral (g)

baseline 6 months 12 months

Radius distal 1/3 (g/cm)

baseline 6 months 12 months

Radius ultradistal (g/cm)

baseline 6 months 12 months

* For significance of difference from CON group, using % change. NS, not significant; AP, anteroposterior.

hydroxyvitamin D and 1,25-dihydroxyvitamin D did not change with treatment. The effects on serum lipids are given in Table 4. As compared with the CON group, serum total cholesterol and LDL cholesterol decreased significantly in both treatment groups and the LDL cholesterol/HDL cholesterol ratio also decreased significantly in both treatment groups. The HDL cholesterol and triglyceride levels were not significantly altered.

The occurrences of prevalent and incident fractures are given in Table 5. For vertebral fractures, there were no significant differences among groups using the 15% cutoff fracture definition. However, using a 30% cutoff definition, there was a dose-related reduction in vertebral fracture for the RLX groups which was significantly different from CON ( p 0.047). There were no differences or trends for differences among groups for nonvertebral fractures.

RALOXIFENE TREATMENT OF OSTEOPOROSIS TABLE 3. MEAN ( SE)

AND

1751
AT

RANGE FOR BASELINE VALUES AND GROUP CHANGES FROM BASELINE BIOCHEMICAL MARKERS OF BONE TURNOVER AND FOR SERUM PTH

AND

12 MONTHS

FOR

Treatment group Serum variables Bone-specific ALP ( g/l) baseline 6 months 12 months Osteocalcin ( g/l) baseline 6 months 12 months CTx/Cr Ratio ( g/mmol) baseline 6 months 12 months PTH (pg/ml) baseline 6 months 12 months change % change p change % change p* change % change p change % change p* change % change p* change % change p* change % change p* change % change p* CON 14.6 (0.94) 2.10 (0.69) 10.9 (4.7) 3.69 (0.69) 21.1 (4.8) 24.5 (1.4) 2.77 (1.1) 10.6 (3.8) 3.62 (1.1) 12.4 (4.3) 349 (32) 63.6 (26) 11.4 (8.3) 91.5 (28) 11.0 (9.8) 3.70 (0.16) 0.53 (0.14) 10.8 (3.8) 0.49 (0.16) 9.70 (4.3) RLX60 14.2 (0.92) 4.14 (0.76) 24.5 (5.7) 0.015 6.16 (0.89) 36.0 (5.8) 0.006 22.3 (1.2) 7.49 (0.77) 31.4 (2.7) 0.001 7.91 (0.83) 33.1 (3.0) 0.001 251 (21) 94.9 (20) 31.0 (7.6) 0.037 114 (19) 35.9 (8.0) 0.009 3.48 (0.19) 0.11 (0.16) 7.87 (5.2) 0.002 0.10 (0.17) 10.8 (5.5) 0.006 RLX120 13.8 (1.0) 3.97 (0.74) 24.1 (5.5) 0.027 5.21 (0.84) 30.0 (7.7) 0.026 24.0 (1.4) 6.62 (0.79) 28.3 (2.8) 0.001 7.31 (0.86) 29.4 (3.0) 0.005 295 (28) 130 (22) 39.1 (5.9) 0.005 127 (18) 41.8 (4.6) 0.026 3.16 (0.14) 0.25 (0.14) 12.9 (4.9) 0.001 0.28 (0.17) 15.3 (5.9) 0.001

* For signifiance of difference from CON group, using ranked % change.

Adverse events
Of 124 minor symptoms or signs occurring in individual patients, there were significant differences over CON in the patients receiving raloxifene only in the higher occurrence of arthralgia ( p 0.027) and dizziness ( p 0.024). The only significant physical finding was a 6 mm Hg decrease in systolic blood pressure in the two groups receiving raloxifene ( p 0.028 overall). None of the patients who reported dizziness were found to be hypotensive. Eight patients discontinued the study because of adverse events. None of these adverse events were thought to be drug related, and there was no significant difference between groups in the number of these adverse events.

DISCUSSION
These data clearly demonstrate that at the tissue level, raloxifene has estrogen-like activities in bone. Compared with controls, there were significant decreases in serum bone-specific ALP and serum osteocalcin, markers for bone

formation, and urinary excretion of CTx, a marker of bone resorption, indicating that raloxifene was effective in decreasing overall bone turnover. There was also a substantial decrease in these values in the control group itself, suggesting that the 750 mg/day of calcium supplement received by all patients also reduced bone turnover. The decreases over controls in these markers was somewhat less than the decreases in serum osteocalcin and serum bone-specific ALP and in urine hydroxyproline that we previously reported in patients with postmenopausal osteoporosis receiving 0.1 mg/day of 17 -estradiol by transdermal patches.(11) The patients in that trial, however, did not receive calcium supplementation as did those in the present trial. The decreases in biochemical markers of bone turnover were similar to those in the 2-month treatment trial reported by Draper et al.(8) for normal early postmenopausal women. Our results are also quite comparable to those of Delmas et al. who evaluated the effect of three dosages of RLX in younger, healthy postmenopausal women.(12) We also were able to document an effect on retardation of the rate of bone loss in the raloxifene treatment groups

1752 TABLE 4. BASELINE VALUES

AND

LUFKIN ET AL. GROUP CHANGES

FROM

BASELINE

AT

AND

12 MONTHS (MEAN

SE)

FOR

SERUM LIPID

Treatment group Serum variables Total cholesterol (mmol/l) baseline 6 months 12 months HDL cholesterol (mmol/L) baseline 6 months 12 months LDL cholesterol (mmol/l) baseline 6 months 12 months Triglycerides (mmol/l) baseline 6 months 12 months LDL cholesterol/HDL cholesterol ratio baseline 6 months 12 months change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* change % change p* CON 5.99 (0.12) 0.14 (0.10) 1.92 (1.6) 0.19 (0.09) 2.77 (1.4) 1.46 (0.05) 0.008 (0.02) 0.53 (1.6) 0.002 (0.03) 0.84 (1.8) 3.89 (0.12) 0.11 (0.09) 2.31 (2.1) 0.17 (0.08) 3.70 (1.9) 1.47 (0.11) 0.05 (0.07) 2.49 (4.8) 0.06 (0.08) 0.40 (4.6) 2.78 (0.12) 0.06 (0.07) 1.42 (2.4) 0.10 (0.06) 3.18 (2.1) RLX60 6.05 (0.16) 0.41 (0.10) 6.10 (1.6) 0.049 0.47 (0.10) 7.04 (1.5) 0.042 1.48 (0.05) 0.021 (0.03) 1.96 (2.0) NS 0.05 (0.03) 4.65 (2.1) NS 3.91 (0.15) 0.39 (0.09) 8.76 (2.4) 0.019 0.50 (0.10) 11.4 (2.3) 0.009 1.45 (0.11) 0.03 (0.08) 1.09 (4.7) NS 0.03 (0.12) 1.48 (7.4) NS 2.78 (0.14) 0.26 (0.09) 8.96 (3.0) 0.005 0.42 (0.09) 13.2 (3.0) 0.001 RLX120 5.81 (0.14) 0.54 (0.14) 8.37 (2.3) 0.009 0.29 (0.11) 4.28 (2.0) NS 1.47 (0.04) 0.018 (0.03) 1.85 (1.9) NS 0.03 (0.03) 2.21 (1.8) NS 3.71 (0.12) 0.45 (0.11) 10.7 0.004 0.31 (0.10) 7.13 (2.8) NS 1.36 (0.10) 0.04 (0.10) 3.57 (5.4) NS 0.02 (0.08) 4.57 (5.6) NS 2.64 (0.12) 0.35 (0.08 11.4 (2.9) 0.001 0.26 (0.07) 8.34 (2.8) 0.032

*For significance of difference from CON group, using ranked % change. NS, not significant.

as compared with the control group. This reached significance for the measurements at the total hip for the 60 mg/day dosage and at the distal and ultradistal radius for both dosages. However, there was a clear trend toward lower rates of loss at all measurement sites except that for the lateral lumbar spine, a site which has a relatively poor precision because of the large amount of soft tissue in the beam pathway.(13) This suggests that there was a generalized effect of treatment on preventing skeletal bone loss but that we may not have had the statistical power to assess rates of change over controls in the remaining sites in which the 1-year changes over controls ranged from 0.5% to 1.1%. Even at the measurement sites at which there were significant differences, the 1-year changes over controls which ranged from 1.7% to 2.9% in the present study were less than those in our previous study with transdermal estro-

gen,(11) which ranged from 1.2% to 5.5%. At least part of this difference may have been due to the cotreatment with calcium and the somewhat lesser degree of osteoporosis in the present study. However, it is also possible that the effect of raloxifene on bone loss may more resemble that of tamoxifen, in which bone mass is maintained over the initial years of treatment,(4) than that of estrogen, in which there is a 10 12% increase in bone density during the initial 23 years of treatment followed by a further maintenance at that level,(11) even in elderly women.(14,15) To resolve this issue, more data are needed in a larger number of patients undergoing parallel treatment limbs with control, raloxifene, and estrogen. Our findings also indicate that raloxifene HCl is a safe and efficacious treatment for women with established postmenopausal osteoporosis. In keeping with studies in exper-

RALOXIFENE TREATMENT OF OSTEOPOROSIS TABLE 5. SUMMARY

OF

1753
OVER

PREVALENT FRACTURES AT BASELINE AND INCIDENT FRACTURES TREATMENT GROUP

1 YEAR

IN THE

Treatment group CON Number of patients* Vertebral fractures ( 15% cutoff definition) median prevalent fractures number of patients with 1 incident fracture number of incident fractures mean incident fracture rate (fractures/year) Vertebral fractures ( 30% cutoff definition) median prevalent fractures number of incident fractures mean incident fracture rate (fractures/year) Nonvertebral fractures number of baseline nonvertebral fractures number of atraumatic incident nonvertebral fractures number of baseline hip fractures number of incident hip fractures number of baseline radius fractures number of incident radius fractures
* Number of patients

RLX60 43 5.5 21 38 0.71 1 8 0.14 40 0 2 0 16 0

RLX120 45 5 20 48 0.89 1 4 0.08 29 3 1 1 7 0

45 4.5 18 39 0.72 1 13 0.25 40 3 4 0 13 0

143 because 10 patients discontinued the study and did not have a follow-up spine X-ray at 1 year.

imental animals showing that raloxifene acts as an antiestrogen on the breast and endometrium, there were no significant differences over controls in symptoms of mastodynia or abnormalities detected by mammography or in menstrual bleeding or differences in endometrial thickness. None of the patients had evidence of thromboembolism. The meaning, if any, of the small reported increase in minor symptoms of arthralgia and dizziness in the patients receiving raloxifene is unclear. However, even if such symptoms do occur, we feel they would not be a deterrent to the future use of the drug. We were particularly interested to find that vasomotor symptoms (perspiration or hot flushes) were no more prevalent in the two treatment groups than in controls. Flushing is not uncommon with tamoxifen treatment, and occurred in 22% of patients treated with raloxifene 600 mg/day versus 11% in controls in the previous study by Draper et al.(8) Thus, vasomotor symptoms with raloxifene treatment appear to be dose related. Although we recorded the effect of raloxifene on fracture rate as a secondary variable, our study was not designed to have enough statistical power to detect differences in fracture rate. We found no differences over controls in the combined groups receiving raloxifene in the occurrence of vertebral fractures as defined by the requirement for a 15% decrease in vertebral height. However, when only more severe fractures were assessed using the 30% cutoff definition, the dose-dependent reduction was significant. Based on the new concept that both increases in bone mass and decreases in bone turnover lead to decreases in fracture rate,(16) the reduction of bone turnover that we observed in the raloxifene therapy groups would be expected to lead to a decrease in vertebral fracture rate. Larger studies will be needed to corroborate this prediction.

As in the short-term study by Draper et al.(8) we found that raloxifene significantly decreased the serum LDL cholesterol/HDL cholesterol ratio, a major predictor of coronary heart disease.(17) There were also reductions in serum total cholesterol and serum LDL cholesterol in the 60 mg/day treatment group and trends for raloxifene treatment to be associated with decreases in all lipid fractions except for serum HDL cholesterol which did not change. Similar results were also reported in the ovariectomized rat model.(7) Although these changes in serum lipids suggest that raloxifene therapy will protect against the occurrence of coronary artery ischemic events, it also may have other beneficial preventive effects such as direct effects on blood vessels(18) or on arterial blood flow, which have been reported to occur in experimental animals treated with estrogen.(19) Estrogen replacement is considered to be the treatment of choice for most women with osteoporosis.(20) Physiological replacement dosages administered to postmenopausal osteoporotic women normalize high levels of bone turnover(21) and also reduce the vertebral fracture rate.(14,22) Estrogen deficiency is considered to be one of the main causes of the disease, and ERT in postmenopausal women offers many physiological benefits including a decreased incidence of coronary ischemic events,(23) improved memory, concentration, and attention span.(24) However, many postmenopausal women are unwilling to accept renewed menstruation, breakthrough bleeding, mastodynia, fluid retention, or premenstrual syndrome-like symptoms which may occur with long-term HRT. Most importantly, there are recent data that support strongly the contention that long-term estrogen therapy is associated with an increased risk for breast cancer.(25) Even though this is still a subject of debate,(26) the issue has had wide coverage in the mass media, and a general

1754 concern about this issue is probably the main reason that many postmenopausal women find ERT unacceptable. Thus, there is a need for a compound that would maintain the favorable effects of estrogen but would avoid its unfavorable effects. In conclusion, we found that raloxifene treatment of women with established osteoporosis was safe and well tolerated. Like estrogen, it acted to reduce bone turnover and prevent bone mineral loss and had beneficial lipid effects. But unlike estrogen, it did not stimulate the endometrium, thus preventing uterine bleeding, and was free of breast-stimulating effects. Thus, it appears to be a promising new form of treatment for women with established postmenopausal osteoporosis, particularly for women who are unable or unwilling to take estrogen.

LUFKIN ET AL.
10. Riggs BL, Hodgson SF, OFallon WM, Chao EYS, Wahner HW, Muhs JM, Cedel SL, Melton LJ III 1990 Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 322:802 809. 11. Lufkin EG, Wahner HW, OFallon WM, Hodgson SF, Kotowicz MA, Lane AW, Judd HL, Caplan RH, Riggs BL 1992 Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 117:19. 12. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C 1997 Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:16411647. 13. Mazess RB, Gifford CA, Bisek JP, Barden HS, Hanson JA 1991 DEXA measurement of spine density in the lateral projection. I: Methodology. Calcif Tissue Int 49:235239. 14. Lindsay R, Tohme JF 1990 Estrogen treatment of patients with established postmenopausal osteoporosis. Obstet Gynecol 76: 290 295. 15. Marx CW, Dailey GE III, Cheney C, Vint VC II, Muchmore DB 1992 Do estrogens improve bone mineral density in osteoporotic women over age 65? J Bone Miner Res 7:12751279. 16. Riggs BL, Melton LJ III, OFallon WM 1996 Drug therapy for vertebral fractures in osteoporosis: Evidence that decreases in bone turnover and increases in bone mass both determine antifracture efficacy. Bone 18 (Suppl):197S201S. 17. Kannel WB 1987 Metabolic risk factors for coronary heart disease in women: Perspective from the Framingham Study. Am Heart J 114:413 419. 18. Bjarnason NH, Haarbo J, Byrjalsen I, Kauffman RF, Christiansen C 1997 Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits. Circulation 96:1964 1969. 19. Clarkson TB, Cline JM, Williams JK, Anthony MS 1997 Gonadal hormone substitutes: Effects on the cardiovascular system. Osteoporos Int 7 (Suppl 1):S52S57. 20. Eastell R 1998 Treatment of postmenopausal osteoporosis. N Engl J Med 338:736 746. 21. Seibel MJ, Cosman F, Shen V, Gordon S, Dempster DW, Ratcliffe A, Lindsay R 1993 Urinary hydroxypyridinium crosslinks of collagen as markers of bone resorption and estrogen efficacy in postmenopausal osteoporosis. J Bone Miner Res 8:881 889. 22. Lufkin EG, Riggs BL 1996 Three-year followup on effects of transdermal estrogen. Ann Intern Med 125:77. 23. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR 1992 Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 117:1016 1037. 24. Sherwin BB 1996 Hormones, mood, and cognitive functioning in postmenopausal women. Obstet Gynecol 87 (Suppl 2): 20S 26S. 25. Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE 1995 The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 332: 1589 1593. 26. Seachrist L 1995 What risk hormones? Conflicting studies reveal problems in pinning down breast cancer risks. Science 148:94 95.

ACKNOWLEDGMENTS
We are indebted to Ginny Wong, R.N., Nancy Gilliland, R.N., and Joan Muhs, R.N. for their expert management of the study patients. Dr. Michael Draper, Lilly Research Laboratories, was extremely helpful in the design and prosecution of this clinical trial. This work was supported by a grant from Eli Lilly and Company.

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Address reprint requests to: Edward G. Lufkin, M.D. Mayo Clinic Division of Endocrinology and Metabolism, West 18-A 200 First Street SW Rochester, MN 55905 U.S.A.
Received in original form October 24, 1997; in revised form June 22, 1998; accepted July 2, 1998.