| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Article |
University of Claude Bernard of Lyon (P.D.D.), Hôpital Edouard Herriot, Service de Rhumatologie et de Pathologie Osseuse, Lyon 69437, France; Department of Medicine (K.E.E.), Minneapolis VA Medical Center, Minneapolis, Minnesota 55417; St. Joseph’s Hospital (J.D.A.), McMaster University, Hamilton, Ontario, L8N 1Y2 Canada; Lilly Research Laboratories (K.D.H., S.S., W.W.), Eli Lilly and Company, Indianapolis, Indiana 46285; Institute of Internal Medicine and Medical Pathology (C.G.), University of Siena, 53100 Siena, Italy; Bone/Cartilage Metabolism Unit (J.-Y.R.), Centre Hôpital Universitaire Centre-Ville, Liege 04020, Belgium; Department of Internal Medicine (H.A.P.P.), Erasmus University Medical School, Rotterdam DR 3000, The Netherlands; Osteoporosis Research Center (R.R.R.), Creighton University, Omaha, Nebraska 68131; Departments of Medicine (S.T.H.), Epidemiology and Biostatistics (D.M.B.), and Musculoskeletal Radiology (H.K.G.), University of California at San Francisco, San Francisco, California 94117; and Northern General Hospital (R.E.), Clinical Science Center, University of Sheffield, Sheffield, Yorkshire S5 7AU United Kingdom
Address all correspondence and requests for reprints to: Pierre D. Delmas, M.D., Ph.D., University Claude Bernard of Lyon, Hôpital Edouard Herriot, Pavillon F, Lyon, Cedex 03 69437, France. E-mail: . delmas{at}lyon151.inserm.fr
Abstract
The Multiple Outcomes of Raloxifene Evaluation trial studied 7705 postmenopausal women with osteoporosis randomized to placebo, or raloxifene 60 or 120 mg/d [JAMA 282(1999): 637]. This report assesses the efficacy of raloxifene on the long-term cumulative incidence new vertebral fractures through 4 yr.
New vertebral fractures was assessed from radiographs taken at baseline, yr 2–4. The primary analysis was the cumulative incidence of new vertebral fractures through 4 yr. A posthoc analysis compared the vertebral fracture risk in yr 4 alone with that observed in the first 3 yr.
The 4-yr cumulative relative risks (RR) for one or more new vertebral fractures were 0.64 [95% confidence interval (CI) 0.53, 0.76] with raloxifene 60 mg/d and 0.57 (95% CI 0.48, 0.69) with raloxifene 120 mg/d. In yr 4 alone, raloxifene 60 mg/d reduced the new vertebral fracture risk by 39% [RR 0.61 (95% CI 0.43, 0.88)], which was not found to be significantly different from the RR observed in the first 3 yr in both raloxifene groups, irrespective of prevalent fracture status. The nonvertebral fracture risk was not significantly reduced [RR 0.93 (95% CI 0.81, 1.06)]. The safety profile after 4 yr was similar to that observed after 3 yr.
Raloxifene 60 and 120 mg/d through 4 yr decreased the cumulative risk of new vertebral fractures in postmenopausal women with osteoporosis. The decreased vertebral fracture risk in yr 4 alone was not different from that observed in the first 3 yr.
RALOXIFENE, A SELECTIVE estrogen receptor modulator, decreases bone loss in healthy postmenopausal women (1, 2), women with osteopenia (3), and women with osteoporosis (4, 5). The Multiple Outcomes of Raloxifene (MORE) trial studied the effects of raloxifene in 7705 postmenopausal women with osteoporosis defined by bone mineral density (BMD) and/or radiographically apparent prevalent vertebral fractures. Raloxifene decreased the cumulative risk of new vertebral fractures, increased BMD, and decreased biochemical markers of bone turnover in the 36-month core treatment phase of MORE (5). The MORE study had a 12-month blinded extension phase to further assess multiple outcomes, including bone endpoints, breast cancer, cardiovascular disease, and uterine safety. In clinical trials of skeletal antiresorptive agents, fracture efficacy was assessed as cumulative fracture incidence. Fracture efficacy could vary between time intervals during the study, and this variation would not be apparent in a cumulative baseline to endpoint analyses. Noncumulative interval analyses have not been used in fracture efficacy trials; however, such analyses may provide some indication about the consistency or lack of consistency of the fracture efficacy results between time intervals. The primary objective of this report is to present the final 48-month results of the cumulative effects of raloxifene on the incidence of fractures, changes in BMD and bone turnover. Although the MORE study was designed to assess cumulative fracture efficacy, the fracture data were assessed in yr 4 alone using exploratory noncumulative interval analyses, as a secondary endpoint.
Subjects and Methods
Subjects and treatment
Subject recruitment and follow-up for the MORE trial are summarized in Fig. 1
. Complete inclusion and exclusion criteria for the MORE trial were previously described in the results of the 3-yr core treatment phase for skeletal efficacy (5). Briefly, a total of 7705 women who were at least 2 yr postmenopausal, and who had osteoporosis, defined by BMD T-score of -2.5 or less and/or the presence of radiographically apparent vertebral fracture, were randomly assigned to raloxifene 60 or 120 mg/d, or an identically appearing placebo. All women received daily supplements of calcium (500 mg) and vitamin D (400–600 IU). Use of sex hormones, systemic estrogens, combined hormone replacement therapy, phytoestrogens, anabolic androgens or any sex hormone agonists/antagonists, such as selective estrogen receptor modulators, was not allowed.
|
Fracture assessment
Spine radiographs were taken at baseline, 2, 3, and 4 yr, and vertebral fractures were assessed at a central quality assurance center (Osteoarthritis Research Group, University of California, San Francisco) by radiologists blinded to treatment group assignment but not to temporal sequence. The same radiologist was not always used to assess spinal radiographs. However, all radiologists were trained and validated on their ability to diagnose baseline and postbaseline fractures consistently, so that the diagnostic reliability between radiologists was similar to that obtained within radiologists. For confirmation of diagnoses, radiologists had access to previously read radiographs and associated scores. Prevalent vertebral fractures were identified using semiquantitative (SQ) analysis of spinal radiographs taken at baseline. The presence of incident vertebral fractures was determined by comparing spinal radiographs taken at 2, 3, and 4 yr to baseline radiographs. A new vertebral fracture was defined as a vertebral fracture occurring in a vertebra that was not fractured at baseline. The fracture adjudication process consisted of SQ visual assessments and quantitative morphometry (QM) (6). If the first SQ assessment found a fracture, then a binary SQ assessment and QM analysis were also performed. The binary SQ assessment was a second, independent visual inspection in which new vertebral fracture was only considered as present or absent. The QM analysis defined a new vertebral fracture as an electronically measured decrease from baseline of at least 20% and at least 4 mm in the anterior, mid, or posterior vertebral height. An adjudicated fracture was reported if it was confirmed by at least two of the three determinations, consisting of two independent SQ assessments and one QM measurement.
Women were assigned into study groups based upon the absence or presence of vertebral fractures in nonadjudicated baseline radiographs (5). After radiographs were adjudicated, approximately 10% of the women in each study group were found to have a baseline vertebral fracture status different from the initial assignment. To facilitate understanding of the present analysis, women were further categorized according to the presence or absence of an adjudicated baseline vertebral fracture. In the present report, prevalent vertebral fracture status was based upon the adjudicated fracture determination.
Osteoporotic nonvertebral fractures, a secondary endpoint, were determined by direct questioning at each clinic visit (5).
Assessment of BMD, biochemical markers of bone turnover, and adverse events
Lumbar spine and femoral neck BMD were measured at baseline and at each yearly interval using dual-energy x-ray absorptiometry. A central reading facility (Osteoarthritis Research Group, University of California, San Francisco) provided correction factors to adjust for between-site differences and performance of densitometers over time. According to the protocol’s early completion rules, women with excessive bone loss (5) and/or more than two new vertebral fractures identified at up to and including 36 months, were required to discontinue the study. Early completion rules were not applied in yr 4.
Biochemical markers of bone metabolism were measured at baseline, 6 months, and each yearly interval in a subset of 2622 women. These markers included serum osteocalcin (ELSA-OSTEO IRMA, CIS Biointernational, Gif-sur-Yvette, France), serum bone-specific alkaline phosphatase (Ostase IRMA, Hybritech, San Diego, CA), and urinary excretion of type I collagen fragment, normalized to creatinine (CrossLaps, Osteometer A/S, Herlev, Denmark).
All women were questioned about adverse events at every 6-month interim visit. Serious and treatment-emergent nonserious adverse events were defined as previously described (5).
Statistical methods
Vertebral fractures were assessed in scheduled adjudicated radiographs. The primary efficacy endpoint was the cumulative proportion of women with at least one new vertebral fracture from baseline to yr 4, identified from the last available postbaseline radiograph. Women with at least one postbaseline follow-up radiograph were included in the primary analysis. Binary fracture data were analyzed using Pearson’s 
2 test. Cumulative analyses were performed as intention-to-treat, with missing postbaseline data imputed by carrying the last observation forward.
The cumulative distribution function of the time to first fracture through yr 4 was plotted using the Kaplan-Meier method, and the statistical significance of the difference between the raloxifene groups and placebo was determined using the log-rank test. The time to first new postbaseline vertebral fracture was calculated by subtracting the time between randomization and the observation of this fracture in a radiograph. However, scheduled radiographs were only performed at yr 2, 3, and 4.
The percentage of women in each group who experienced new vertebral fractures in yr 4 alone was also analyzed using Pearson’s 2 test. These exploratory analyses were performed only on those women who had a spinal radiograph in yr 4, and were referred to as noncumulative analyses in this report. Several factors in the study design should be considered when interpreting the results of these analyses. The MORE trial was designed to analyze the 4-yr cumulative data, and there could be limited statistical power to detect certain significant differences in the risk of new vertebral fractures between the raloxifene and placebo groups in yr 4 alone. Statistical power is further limited when analyses are done on subgroups of women with and without prevalent vertebral fractures. Power calculations will be provided for the yr 4 noncumulative analyses. Furthermore, demographic characteristics will be different between the placebo and raloxifene groups at the end of yr 3, as a result of discontinuations and active treatment. These differences may confound the interpretation of the yr 4 results. Finally, some women chose to use other bone-active agents in yr 4. To account for this difference, cumulative and noncumulative analyses will also be performed on women who reported no use of other bone-active agents in yr 4.
A generalized linear model, with treatment group and study phase as independent variables, was used to determine whether the risk reduction for new vertebral fractures in the extension phase (yr 4 alone) was similar to the risk reduction observed in the core treatment phase (yr 0–3). If the interaction between treatment group and study phase was not found to be statistically significant (P > 0.1), then the risk reduction for new vertebral fractures in yr 4 extension phase was considered to be similar to the cumulative risk reduction in the 3-yr core treatment phase. To determine whether concomitant use of other bone-active agents in yr 4 had any significant effect on the raloxifene results, these calculations were repeated in women who reported no use of other bone-active agents in yr 4.
Other binary data, such as use of other bone-active agents, study discontinuations and adverse events, were analyzed using Pearson’s 2 test. Relative risks and 95% confidence intervals were calculated using large sample procedures (Mantel Haenzel). Continuous data, such as BMD, were analyzed using ANOVA, with terms for treatment group and country as fixed effects in the model. For continuous data that were not normally distributed, such as biochemical markers of bone turnover, inference was based upon analysis of ranked data. All other comparisons were performed at a two-sided, P = 0.05 level of significance. To determine whether concomitant use of other bone-active agents in yr 4 had any significant effect on the raloxifene results, a logistic model was used for fracture data and an ANOVA model was used on unranked BMD or ranked bone marker data. Both models had an interaction effect for bone-active agent use by treatment group, which was tested at the P = 0.10 level of significance.
Results
Baseline characteristics of the women who had a baseline and at least one postbaseline follow-up radiograph were not significantly different between the treatment groups (Table 1).
|
The primary efficacy endpoint was determined in the 6828 women (89%) who had paired baseline and at least one postbaseline follow-up radiograph through 4 yr (Fig. 1
). After 4 yr, the cumulative relative risks (RR) for new vertebral fractures were reduced in the total study population with both raloxifene doses (Fig. 2A). Raloxifene decreased the cumulative risk of new vertebral fractures in women with and without prevalent vertebral fractures. The cumulative risk reductions for new vertebral fractures at 4 yr were not significantly different between raloxifene doses, nor between women with prevalent vertebral fractures and women without prevalent vertebral fractures. A Kaplan-Meier plot (Fig. 3) determined the time to occurrence of the first new postbaseline vertebral fracture, was significantly different between the placebo and raloxifene groups (P < 0.001). The plot showed continuing divergence between the raloxifene groups and placebo.
|
|
). Because these other bone-active agents could influence the cumulative 4-yr vertebral fracture efficacy, the above analyses were repeated in those women who reported no use of other bone-active agents. Irrespective of reported use of other bone-active agents, the baseline demographic characteristics listed in Table 1 were not significantly different between treatment groups. The proportion of women who experienced new vertebral fractures in yr 4 was not found to be significantly different between women who reported either use or no use of other bone-active agents (interaction effect, P = 0.82), though there may be limited statistical power to observe a difference. The cumulative incidence of new vertebral fractures was similar in the 5077 women who reported no use of other bone active agents (Fig. 2B), as observed in the total study population (Fig. 2A).
The cumulative relative risks of multiple (
2) new vertebral fractures through 4 yr were 0.54 (95% CI 0.38, 0.77) with raloxifene 60 mg/d and 0.39 (95% CI 0.26, 0.58) with raloxifene 120 mg/d, and were not different (P = 0.13) between the raloxifene doses. For women with prevalent vertebral fractures, the RR were 0.63 (95% CI 0.43, 0.91) with raloxifene 60 mg/d and 0.40 (95% CI 0.26, 0.62) with raloxifene 120 mg/d. In women without prevalent vertebral fractures, the RR were 0.12 (95% CI 0.03, 0.50) with raloxifene 60 mg/d and 0.29 (95% CI 0.11, 0.77) with raloxifene 120 mg/d.
Exploratory analyses were used to examine the noncumulative incidence of new vertebral fractures in 5394 women who had follow-up radiographs at the end of yr 4 (Fig. 1), and considered only new vertebral fractures that were not present in radiographs taken at baseline, 2 or 3 yr. The risks for new vertebral fractures in yr 4 alone were significantly reduced with both raloxifene doses (Fig. 4, A and B), and in women with and without prevalent vertebral fractures treated with raloxifene 60 mg/d (Fig. 4, C and D). In women treated with raloxifene 60 mg/d, there was over 70% statistical power to detect the observed RR 0.61 (Fig. 4A) and 55% and 45% statistical power to detect the observed RR 0.62 (Fig. 4C) and RR 0.50 (Fig. 4D) in subgroups of women with and without prevalent vertebral fractures, respectively. Raloxifene 120 mg/d decreased the risk of new vertebral fractures in women with [RR 0.61 (95% CI 0.40, 0.95)] and women without [RR 0.53 (95% CI 0.28, 1.01)] (P = 0.048) prevalent vertebral fractures. In additional exploratory analyses, the risk reductions for new vertebral fractures in yr 4 alone (noncumulative) were not found to be statistically different from those in the first 3 yr (cumulative) for either raloxifene dose (Fig. 4, A and B). The risk reductions with raloxifene 60 mg/d in women with and without prevalent vertebral fractures were similar in yr 4 alone as in the first 3 yr (Fig. 4, C and D). Similar results were demonstrated with raloxifene 120 mg/d (data not shown).
|
, C and D). Nonvertebral fractures
Through 4 yr, there was no evidence that raloxifene treatment lowered the risk for nonvertebral fractures. At least one new nonvertebral fracture was reported in 296 women (11.5%) in the placebo group and 548 (10.7%) in the pooled raloxifene groups [RR 0.93 (95% CI 0.81, 1.06)]. Wrist fractures occurred in 109 (4.2%) and 180 (3.5%) women in the placebo and pooled raloxifene groups, respectively [RR 0.83 (95% CI 0.66, 1.05)]. Ankle fractures occurred in 29 (1.1%) and 54 (1.1%) women in the placebo and pooled raloxifene groups, respectively [RR 0.94 (95% CI 0.60, 1.47)]. Twenty-nine women (1.1%) in the placebo group and 56 (1.1%) in the pooled raloxifene groups experienced hip fractures [RR 0.97 (95% CI 0.62, 1.52)].
BMD and bone turnover
BMD at the lumbar spine and femoral neck was increased by 2.6% and 2.1% with raloxifene 60 mg/d, respectively, and by 2.5% and 2.3% with raloxifene 120 mg/d, respectively, compared with placebo at 4 yr (P < 0.001). While the change in femoral neck BMD with raloxifene 60 mg/d was statistically significant between yr 2 and 3, the change between yr 3 and 4 was not significant (P = 0.11). The differences in femoral neck BMD between placebo and each raloxifene group remained constant from yr 2–4. As very few women concomitantly used other bone-active agents in yr 4, the BMD increases were not found to be significantly different between women who did and women who did not use other bone-active agents at the lumbar spine (interaction P = 0.78) and femoral neck (interaction P = 0.95).
In the placebo, raloxifene 60 mg/d and raloxifene 120 mg/d groups, respectively, the median changes from baseline for osteocalcin were -8.6%, -26.2% and -31.1%, for bone-specific alkaline phosphatase were -19.9%, -35.2% and -35.6% and for the ratio of urinary type I collagen fragment normalized to creatinine were -8.2%, -34.2%, and -31.7%. For all biochemical markers of bone turnover, the decreases in the raloxifene groups were significantly different from placebo (P < 0.001), and the values remained in the premenopausal range throughout the 4-yr study (7).
Discontinuations and adverse events
More women in the placebo group (5.5%) met the early completion rules for study discontinuation (5), compared with raloxifene 60 mg/d (1.8%) or raloxifene 120 mg/d (1.6%) groups (P < 0.001 for both comparisons).
Table 2 lists the incidences of adverse events that were significantly different (P < 0.05) between placebo and pooled raloxifene, including only those reported by at least 2% of women in each group. The incidence of flu syndrome, vasodilatation (hot flashes), leg cramps, endometrial cavity fluid, and peripheral edema was significantly higher with raloxifene compared with placebo. The pooled raloxifene groups had a significantly lower incidence of hypertension and hypercholesterolemia compared with placebo. With raloxifene 60 mg/d, the RR was 1.78 (95% CI 0.99, 3.19) for all venous thromboembolic events including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. The RR were 2.76 (95% CI 1.30, 5.86) for deep vein thrombosis, 2.76 (95% CI 0.95, 8.01) for pulmonary embolisms and 0.50 (95% CI 0.15, 1.73) for retinal vein thrombosis in the pooled raloxifene groups (Table 2). Breast pain was reported by 80 women (3.1%) in the placebo and 153 women (3.0%) in the pooled raloxifene groups, respectively. Endometrial cancer was diagnosed in 5 (0.3%) and 9 (0.2%) women in the placebo and pooled raloxifene groups, respectively. The adjudication board confirmed 77 cases of breast cancer, with 44 (1.7%) and 33 (0.6%) cases in the placebo and pooled raloxifene groups, respectively (P < 0.001 between groups), with a RR of 0.38 (95% CI 0.24, 0.58) (8).
|
lists the reasons for discontinuation from this study.
|
Raloxifene treatment at 60 or 120 mg/d for 4 yr significantly decreased the risks for new vertebral fractures in postmenopausal women with osteoporosis. The relative risk reductions for new vertebral fractures in yr 4 alone were not found to be different than the relative risk reductions observed in the first 3 yr. These reductions were consistent across raloxifene doses and within subgroups defined by prevalent vertebral fracture status. Raloxifene treatment did not reduce the risk of total nonvertebral fractures. This trial was not powered to determine the effects of raloxifene on the risks of specific types of nonvertebral fractures. The safety profile for raloxifene through 4 yr was similar to that reported at 3 yr (5).
The main objective of the present analysis was to determine the cumulative effects of raloxifene on vertebral fracture risk reduction through yr 4. The cumulative results at 4 yr were not significantly different from the effects observed through 3 yr (5). Because the primary endpoint of the MORE fracture efficacy was the 3-yr analysis, and the 1-yr extension phase was intended for monitoring of extraskeletal endpoints, women were allowed to use other bone-active agents in yr 4. This adds complexity to the analysis and interpretation of the yr 4 fracture efficacy data. Because more women in the placebo group reported use of other bone-active agents, the original placebo group was no longer maintained, and this imbalance could introduce a selection bias. In particular, the differences between the placebo and raloxifene groups may be diminished with the reported use of other bone-active agents, and would be biased against raloxifene. In an attempt to address this bias, fracture efficacy analyses were also performed excluding those women who reported use of other bone-active agents.
To date, most clinical trials of skeletal antiresorptive agents have evaluated fracture efficacy as the cumulative fracture incidence in endpoint radiographs compared with baseline. The same cumulative relative risk reduction results could be achieved in different scenarios. For example, fracture efficacy could be similar within each treatment interval, or perhaps greater efficacy in the early years could be offset by lesser efficacy, reflected by an increasing fracture incidence in the treatment group, in later years. Noncumulative analysis of new vertebral fractures, in which the incidence of new vertebral fractures in each postbaseline radiograph are compared with those in the previous radiograph, could determine if early effects on overall fracture efficacy were sustained or waned over time. To date, noncumulative interval analyses have not been used in studies with antiresorptive agents. In the current paper, the yr 4 MORE data were assessed noncumulatively in exploratory analyses as a secondary endpoint.
There are limitations to noncumulative analysis of fracture efficacy in yr 4. For cumulative analyses, treatment groups must be balanced with respect to baseline characteristics at randomization, and ideally, this balance would be maintained during the course of the study. The MORE study had an early completion rule, which required women who experienced excessive bone loss to discontinue the study. The proportion of women who were required to discontinue the study was statistically significantly greater in the placebo group than in the raloxifene groups, which could lead to an imbalance and introduce a potential bias against the raloxifene group at the beginning of yr 4. Even if study discontinuation was balanced between groups, the study group characteristics will still have diverged during 3 yr of treatment, assuming that the active treatment is effective. In the present study, a divergence in disease criteria between the placebo and raloxifene groups at yr 3 would result from early study discontinuation in the placebo group, and also to the effects of raloxifene. The divergence between study groups during yr 4 is further complicated by the use or nonuse of other bone-active agents. A second, major limitation of noncumulative analysis is the possibility of limited statistical power to show differences in treatment effects on vertebral fractures within one yearly interval, and may be particularly evident when comparisons are made between treatment groups, with additional subgroup analyses based upon baseline vertebral fracture status. There was adequate statistical power to detect the observed differences in the total study population, and in women who reported no use of other bone-active agents in yr 4, who constitute the majority of the total study population. When the total study population was separated by baseline vertebral fracture status, the relative risk reductions in yr 4 alone remained statistically significant, despite the limited statistical power. The significant reductions in vertebral fracture risk with raloxifene in yr 4 alone are supported by the observation that the fracture incidence rates in the treated groups are continuing to decline in consecutive time intervals.
In conclusion, raloxifene significantly reduced the risk of vertebral fractures in the 4-yr MORE study of postmenopausal women with osteoporosis, although there was no evidence that raloxifene reduced the risk of nonvertebral fractures. The present analyses provide the first evidence demonstrating that vertebral fracture risk reduction with raloxifene in yr 4 alone was not significantly different from that observed in the first 3 yr.
Acknowledgments
We acknowledge Mayme Wong, Ph.D., for her contributions to the content of this paper, and for preparation of this manuscript, and Jeannette Love for editorial assistance. All authors participated in the interpretation of data, and in the writing and editing of the manuscript for intellectual content. P.D.D., K.E.E., J.D.A., C.G., J.Y.R., H.A.P.P., R.R.R., S.T.H., and R.E. participated in data collection; and K.D.H., S.S., and W.W. performed the data analyses.
Investigators for the MORE trial: Argentina—Carlos Mautalen, M.D.; and Jose R. Zanchetta, M.D. Australia—Michael J. Hooper, M.B., B.S., F.R.A.C.P.; Geoffrey Nicholson, M.B.B.S., Ph.D., M.R.C.P., F.R.A.C.P.; Kong Wah Ng, F.R.A.C.P., M.D.; Ego Seeman, B.Sc., M.B.B.S., F.R.A.C.P., M.D.; Richard L. Prince, M.D., F.R.A.C.P.; Anthony P. Roberts, M.D.; and Margaret M. Williamson, M.B.Ch.B., M.R.C.P., F.R.A.C.P. Austria—Ewald Boschitsch, M.D.; and Georg Leb, M.D. Belgium—Thierry Appelboom, M.D.; Jean J. Body, M.D.; Anne Peretz, M.D.; Jean-Pierre Devogelaer, M.D.; Jan Dequeker, M.D.; Piet Geusens, M.D.; Jean-Marc Kaufman, M.D.; and Jean-Yves Reginster, M.D. Canada—David A. Hanley, M.D., F.R.C.P.C.; John P. Wade, M.D.; William Leslie, M.D., M.Sc., F.R.C.P.C.; Carol A. Joyce, M.D.; Roger S. Rittmaster, M.D.; Jack R. Wall, M.D., Ph.D.; Angela M. Cheung, M.D., Ph.D., F.R.C.P.; Gillian A. Hawker, M.D., F.R.C.P.C.; William C. Sturtridge, M.D.; Anthony B. Hodsman, M.D.; Theodore C. Monchesky, M.D.; Jonathan D. Adachi, M.D.; William G. Bensen, M.D., F.R.C.P.C.; Alfred A. Cividino, B.A.Sc., M.D., F.R.C.P.; Jacques P. Brown, M.D., F.R.C.P.C.; Alan Tenenhouse, M.D.; Wojciech P. Olszynski, M.D., Ph.D., F.R.C.P.; Kerry G. Siminoski, M.D; and Louis G. Ste-Marie, M.D. Czech Republic—Jan J. Stepan, M.D., D.Sc. Denmark—Claus Christiansen, M.D.; Henrik Lawaetz, M.D.; Erik F. Eriksen, M.D.; Lars Hyldstrup, M.D.; and Ole H. Sorensen, M.D. Finland—Esko Alhava, M.D.; Martti Kormano, M.D., Ph.D., Laakariasema Vagus, Turku; Pasi Salmela, M.D.; Jorma Salmi, M.D., Ph.D., and Matti Valimaki, M.D., Ph.D. France—Christian Alexandre, M.D.; Maurice Audran, M.D.; Chu D’Angers; Daniel Briancon, M.D.; Pierre Delmas, M.D., Ph.D.; Marie C. DeVeine Joul, M.D.; Patrice Fardellone, M.D.; D. Kuntz, Jacques LeClere, M.D.; and Claude Ribot, M.D. Germany—J. Beyer, H. Franck, Claus C. Glüer, M.D.; Elmar Keck, M.D.; Peter Maier, M.D.; Gerhard Scholz, M.D.; J. Semler; and Christian Wuster, M.D. Hungary—Geza Balint, M.D.; Janos Szuecs, M.D.; Adam Balogh, M.D.; and Jonas Julesz, M.D., Ph.D. Israel—Avraham Karasik, M.D.; Iris Vered, M.D.; and Uri Liberman, M.D., Ph.D. Italy—Maria Luisa Brandi, M.D., Ph.D.; Antonio Del Puente, M.D.; Pasquale Oriente, M.D.; Carmelo Fiore, M.D.; Andrea R. Gennari M.D.; Mario Passeri, M.D.; and Leonardo Sartori, M.D., Ph.D. Mexico—Ricardo Carrea-Rotter, M.D.; and Alfonso Murillo-Uribe, M.D. The Netherlands—Paul Lips, M.D., Ph.D.; Henk Mulder, M.D.; and Huibert A. Pols, M.D., Ph.D. New Zealand—Nigel Gilchrist, M.D. Norway—Johan Halse, M.D., Ph.D.; Rolf Jorde, M.D.; and Joacob A. Stakkestad, M.D., Ph.D. Poland—Janusz Badurski, M.D.; Krzysztof Hoszowski, M.D.; and Jaroslaw Ogonowski, M.D. Singapore—Kamal Bose, M.B.B.S., M.S. Slovak Republic—Rastislav Dzurik, M.D., Ph.D., D.Sc. Slovenia—Andreja Kocijancic, M.D. Spain—Juan J. Garcia Borras, M.D., Ph.D.; Jorge B. Canata-Andia, M.D., Ph.D.; Fernando Escobar, M.D., Ph.D.; Manuel Muñoz-Torres, M.D.; Jardi Farrerons, M.D., Ph.D.; Adolfo Diez-Perez, M.D., Ph.D.; and Frederico Hawkins, M.D., Ph.D. Sweden—Sverker Ljunghall, M.D.; Karin Larsson, M.D.; Dan Mellstrøm, M.D., Ph.D.; Britt-Marie Nyhäll-Wåhlin, M.D.; Mats Palmér, M.D.; and Goran Toss, M.D. United Kingdom—Richard Eastell, B.Sc., M.B., Ch.B.; Ignac Fogelman, B.Sc., M.D.; Robert Landray, M.C.C.H.B.; David W. Purdie, M.B., Ch.B., M.D.; David M. Reid, M.B., Ch.B., N.H.S.; Michael D. Stone, B.A., M.B., B.S. United States—Cora Lewis, M.D., M.S.P.H.; William J. Shergy, M.D.; Robert C. Biesbroeck, M.D.; Michael J. Maricic, M.D.; Thomas T. Aoki, M.D.; Claude D. Arnaud, M.D.; Steven T. Harris, M.D.; Elizabeth Barrett-Connor, M.D.; David J. Baylink, M.D.; Bruce Ettinger, M.D.; Richard O. Kamrath, M.D.; Robert Marcus, M.D.; Sidney Rosenblatt, M.D.; Charles F. Sharp, Jr., M.D.; Stuart L. Silverman, M.D.; Frederick Singer, M.D.; Stuart R. Weiss, M.D.; David A. Podlecki, M.D.; Robert Lang, M.D.; Mark P. Ettinger, M.D.; Marvin A. Heuer, M.D.; Silvina Levis, M.D.; Nelson B. Watts, M.D.; Richard D. Wasnich, M.D.; Sheldon Berger, M.D.; Robert G. Trapp, M.D.; M. Rashid Khairi, M.D.; Randall T. Stoltz, M.D.; Barbara P. Lukert, M.D.; Christine L. Cook, M.D.; Alan Burshell, M.D.; Clifford J. Rosen, M.D.; Michael A. Bolognese, M.D.; Norman S. Koval, M.D.; Philip Levin, M.D.; Nathan Wei, M.D.; Robert M. Neer, M.D.; Kristine E. Ensrud, M.D.; Louis V. Avioli, M.D.; Robert R. Recker, M.D.; Keith S. Usiskin, M.D.; Arnold M. Moses, M.D.; Louis L. Shane, M.D.; Ethel Siris, M.D.; Stuart Weinerman, M.D.; Michelle Hooper, M.D.; James H. Liu, M.D.; David Bacha, M.D.; William C. Orr, Ph.D.; Jane A. Cauley, M.D., Dr.PH.; Solomon Epstein, M.D.; Susan B. Ward, M.D.; Joseph Tucci, M.D.; Norman H. Bell, M.D.; William Applegate, M.D.; Suzanne Satterfield, M.D., Dr.PH.; M. Cedars; Stanley B. Cohen, M.D.; Clark McKeever, M.D.; Veronica K. Piziak, M.D., Ph.D.; Julio Rosenstock, M.D.; Sherwyn L. Schwartz, M.D.; Chad Deal, M.D.; Robert Downs, M.D.; Barbara Drinkwater, Ph.D.; and Neil Binkley, M.D.
Footnotes
Eli Lilly and Company (Indianapolis, IN) sponsored the Multiple Outcomes of Raloxifene Evaluation (MORE) trial.
Abbreviations: BMD, Bone mineral density; CI, confidence interval; MORE, Multiple Outcomes of Raloxifene Evaluation; QM, quantitative morphometry; RR, relative risks; SQ, semiquantitative.
Received October 31, 2001.
Accepted May 1, 2002.
References
This article has been cited by other articles:
 |
|
 |
|
  L. Gehrig, J. Lane, and M. I. O'Connor Osteoporosis: Management and Treatment Strategies for Orthopaedic Surgeons J. Bone Joint Surg. Am., June 1, 2008; 90(6): 1362 - 1374. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liu, N. M. Paige, C. L. Goldzweig, E. Wong, A. Zhou, M. J. Suttorp, B. Munjas, E. Orwoll, and P. Shekelle Screening for Osteoporosis in Men: A Systematic Review for an American College of Physicians Guideline Ann Intern Med, May 6, 2008; 148(9): 685 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Barrett, M. J. Fossler, K. D. Cadieu, and M. R. Gastonguay Pharmacometrics: A Multidisciplinary Field to Facilitate Critical Thinking in Drug Development and Translational Research Settings J. Clin. Pharmacol., May 1, 2008; 48(5): 632 - 649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Allen, H. A. Hogan, W. A. Hobbs, A. S. Koivuniemi, M. C. Koivuniemi, and D. B. Burr Raloxifene Enhances Material-Level Mechanical Properties of Femoral Cortical and Trabecular Bone Endocrinology, August 1, 2007; 148(8): 3908 - 3913. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Powles, S. Ashley, A. Tidy, I. E. Smith, and M. Dowsett Twenty-Year Follow-up of the Royal Marsden Randomized, Double-Blinded Tamoxifen Breast Cancer Prevention Trial J Natl Cancer Inst, February 21, 2007; 99(4): 283 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.J. Cloft and M.E. Jensen Kyphoplasty: An Assessment of a New Technology AJNR Am. J. Neuroradiol., February 1, 2007; 28(2): 200 - 203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Meadows, J. Stock, and J. A. Johnston Commentary on Mobley and Others: Importance of Assumptions About VTE Mortality in Modeling the Cost-effectiveness of Osteoporosis Therapies. Med Decis Making, November 1, 2006; 26(6): 633 - 635. [PDF]
|
|
|
|
|
|
A.T. Trout and D.F. Kallmes Does Vertebroplasty Cause Incident Vertebral Fractures? A Review of Available Data AJNR Am. J. Neuroradiol., August 1, 2006; 27(7): 1397 - 1403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Barrett-Connor, L. Mosca, P. Collins, M. J. Geiger, D. Grady, M. Kornitzer, M. A. McNabb, N. K. Wenger, and the Raloxifene Use for The Heart (RUTH) Trial Inve Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N. Engl. J. Med., July 13, 2006; 355(2): 125 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liu, K. Michaud, S. Nayak, D. B. Karpf, D. K. Owens, and A. M. Garber The Cost-effectiveness of Therapy With Teriparatide and Alendronate in Women With Severe Osteoporosis. Arch Intern Med, June 12, 2006; 166(11): 1209 - 1217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nayak, I. Olkin, H. Liu, M. Grabe, M. K. Gould, I. E. Allen, D. K. Owens, and D. M. Bravata Meta-analysis: accuracy of quantitative ultrasound for identifying patients with osteoporosis. Ann Intern Med, June 6, 2006; 144(11): 832 - 841. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Olivier, P. Close, E. Castermans, L. de Leval, S. Tabruyn, A. Chariot, M. Malaise, M.-P. Merville, V. Bours, and N. Franchimont Raloxifene-Induced Myeloma Cell Apoptosis: A Study of Nuclear Factor-{kappa}B Inhibition and Gene Expression Signature Mol. Pharmacol., May 1, 2006; 69(5): 1615 - 1623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. R. Mobley, T. J. Hoerger, J. S. Wittenborn, D. A. Galuska, and J. K. Rao Cost-effectiveness of osteoporosis screening and treatment with hormone replacement therapy, raloxifene, or alendronate. Med Decis Making, March 1, 2006; 26(2): 194 - 206. [Abstract] [PDF]
|
|
|
|
 |
|
 D. Michalska, J. J. Stepan, B. R. Basson, and I. Pavo The Effect of Raloxifene after Discontinuation of Long-Term Alendronate Treatment of Postmenopausal Osteoporosis J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 870 - 877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Antoniucci, E. Vittinghoff, T. Blackwell, D. M. Black, and D. E. Sellmeyer Vitamin D Insufficiency Does Not Affect Bone Mineral Density Response to Raloxifene J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4566 - 4572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Bouxsein, J. Kaufman, L. Tosi, S. Cummings, J. Lane, and O. Johnell Recommendations for Optimal Care of the Fragility Fracture Patient to Reduce the Risk of Future Fracture J. Am. Acad. Ortho. Surg., November 1, 2004; 12(6): 385 - 395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Cholecystitis, Biliary Tract Surgery, and Pancreatitis Obstet. Gynecol., October 1, 2004; 104(4_suppl): 17S - 24S. [Full Text] [PDF]
|
|
|
|
|
|
Osteoporosis Obstet. Gynecol., October 1, 2004; 104(4_suppl): 66S - 76S. [Full Text] [PDF]
|
|
|
|
|
|
P. Neven, D. Quail, M. Levrier, F. Aguas, H. S. The, C. De Geyter, M. D. Glant, H. Beck, B. Bosio-LeGoux, H. Schmitt, et al. Uterine Effects of Estrogen Plus Progestin Therapy and Raloxifene: Adjudicated Results From the EURALOX Study Obstet. Gynecol., May 1, 2004; 103(5): 881 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Adler and M. C. Hochberg Suggested Guidelines for Evaluation and Treatment of Glucocorticoid-Induced Osteoporosis for the Department of Veterans Affairs Arch Intern Med, November 24, 2003; 163(21): 2619 - 2624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Boivin, P. Lips, S. M. Ott, K. D. Harper, S. Sarkar, K. V. Pinette, and P. J. Meunier Contribution of Raloxifene and Calcium and Vitamin D3 Supplementation to the Increase of the Degree of Mineralization of Bone in Postmenopausal Women J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4199 - 4205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. C. Kung, H.-T. Chao, K.-E. Huang, A. G. Need, N. Taechakraichana, F.-H. Loh, F. Gonzaga, U. Sriram, N. M. N. Ismail, A. Farooqi, et al. Efficacy and Safety of Raloxifene 60 Milligrams/Day in Postmenopausal Asian Women J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3130 - 3136. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS |
