Raloxifene

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Bruce H Mitlak - One of the best experts on this subject based on the ideXlab platform.

  • Long-term Raloxifene for postmenopausal osteoporosis
    Current medical research and opinion, 2011
    Co-Authors: Robert R. Recker, Bruce H Mitlak, John H. Krege
    Abstract:

    AbstractBackground:Due to the chronic nature of osteoporosis and the risk of invasive breast cancer, Raloxifene 60 mg/day (Raloxifene) is intended to be used for long-term treatment (treatment >3 years).Scope:We review available information concerning long-term use of Raloxifene, present several new analyses, and report new data from patients who underwent iliac crest bone biopsies after 8 years of Raloxifene therapy. The most important studies were the Multiple Outcomes of Raloxifene Evaluation (MORE) followed by the Continued Outcomes of Raloxifene Evaluation (CORE).Findings:The primary endpoint in MORE was incidence of vertebral fracture, and the difference between the Raloxifene and placebo groups for this endpoint widened during 4 years of therapy, with the relative risk reduction during the fourth year of the study being similar to the relative risk reduction during years 0 to 3 of the study. Continued Raloxifene treatment is necessary to preserve bone mineral density (BMD). In MORE, Raloxifene lowe...

  • Effect of Raloxifene on all-cause mortality.
    The American journal of medicine, 2010
    Co-Authors: Deborah Grady, Bruce H Mitlak, Jane A Cauley, John L Stock, David A Cox, Jingli Song, Steven R. Cummings
    Abstract:

    Raloxifene, a selective estrogen receptor modulator, reduces osteoporosis and invasive breast cancer risk but increases risk for venous thromboembolism and fatal stroke in women with or at high risk for coronary heart disease. To assess the risk/benefit of Raloxifene as a preventative treatment, we analyzed treatment effects on overall and cause-specific mortality. A pooled analysis of mortality data was performed from large clinical trials of Raloxifene (60 mg/day) versus placebo, including the Multiple Outcomes of Raloxifene Evaluation/Continuing Outcomes Relevant to Evista studies (7705 postmenopausal osteoporotic women followed for 4 years and a subset of 4011 participants followed for an additional 4 years; 110 deaths) and the Raloxifene Use for the Heart trial (10,101 postmenopausal women with coronary disease or multiple risk factors for coronary disease followed for 5.6 years; 1149 deaths). Cause of death was assessed by blinded adjudicators. Cox proportional hazards regression models compared mortality by treatment assignment in a pooled analysis of trial data from the Multiple Outcomes of Raloxifene Evaluation/Continuing Outcomes Relevant to Evista and Raloxifene Use for the Heart trials. All-cause mortality was 10% lower among women assigned to Raloxifene 60 mg/day versus placebo (relative hazard 0.90; 95% confidence interval, 0.80-1.00; P=.05). Lower overall mortality was primarily due to lower rates of noncardiovascular deaths, especially a lower rate of noncardiovascular, noncancer deaths. All-cause mortality was 10% lower in pooled analyses among older postmenopausal women receiving Raloxifene 60 mg/day compared with placebo, due primarily to a reduction in noncardiovascular, noncancer deaths. The mechanism whereby Raloxifene might reduce the risk of noncardiovascular death is unclear. Published by Elsevier Inc.

  • Raloxifene and risk for stroke based on the framingham stroke risk score
    The American Journal of Medicine, 2009
    Co-Authors: Elizabeth Barrettconnor, Bruce H Mitlak, Lori Mosca, David A Cox, Jingli Song, Deborah Grady
    Abstract:

    Abstract Purpose Raloxifene reduces vertebral fracture and invasive breast cancer risks, but increases fatal strokes in postmenopausal women at increased coronary risk. We assessed whether this risk is concentrated in postmenopausal women already at high stroke risk. Methods Raloxifene Use for The Heart (RUTH) enrolled 10,101 postmenopausal women (mean age 67 years) with or at increased coronary heart disease risk; Multiple Outcomes of Raloxifene Evaluation (MORE) enrolled 7705 osteoporotic postmenopausal women (mean age 66 years). A Framingham Stroke Risk Score (FSRS) was calculated for all women with no prior cerebrovascular events (n=16,858). The validity of the FSRS was assessed in the placebo groups, and then Raloxifene-associated stroke risk was analyzed by FSRS subgroups. Results FSRS predicted an increased stroke risk in the placebo group of both clinical trials. There was no difference in the incidence of nonfatal strokes between the Raloxifene and placebo groups in MORE or RUTH, regardless of baseline Framingham stroke risk. In RUTH, women with FSRS P =.33). In MORE, where 80% of women had a FSRS Discussion Risk of fatal stroke associated with Raloxifene was greater in women at high stroke risk. These results might be useful for identifying postmenopausal women at high risk of first stroke who should avoid Raloxifene therapy.

  • relationships between bone mineral density and incident vertebral fracture risk with Raloxifene therapy
    Obstetrical & Gynecological Survey, 2002
    Co-Authors: Somnath Sarkar, Bruce H Mitlak, Dennis M Black, John L Stock, Mayme Wong, Kristine D Harper
    Abstract:

    Low bone mineral density (BMD) in osteoporotic patients predicts an increased risk of bone fracture, but it is not clear whether increasing BMD in those given antiresorptive drugs predicts a reduced risk. The investigators explored this relationship after 1 or 3 years of treatment with Raloxifene or placebo in 7705 postmenopausal women with osteoporosis who participated in the MORE (Multiple Outcomes of Raloxifene Evaluation) trial. Raloxifene was given in a daily dose of 60 or 120 mg. Logistic regression models were used to relate baseline BMD and changes in BMD to the risk of new vertebral fractures (Figs. 1 and 2). All women received supplemental calcium and vitamin D. BMD was estimated by dual-energy x-ray absorptiometry in the femoral neck and lumbar spine at yearly intervals. The risk of a new vertebral fracture was greatest in women having the lowest baseline BMD values at either measurement site. Raloxifene reduced the risk of incident vertebral fractures by 41% compared with the placebo group, regardless of baseline BMD at the femoral neck, but women with relatively low baseline lumbar spine BMD had the most marked reduction in fracture risk from Raloxifene. After 3 years, Raloxifene therapy was associated with increases of only 2% to 3% in BMD. Raloxifene-treated women had a significantly lower risk of spinal fracture than placebo patients regardless of the change in femoral neck BMD, and they also had a lower fracture risk at any percentage change in lumbar spine BMD. At the 75th percentile of the population, with a 6.1% increase in lumbar spinal BMD, the risk of incident vertebral fracture was reduced 52% by Raloxifene therapy. With lesser increases in lumbar spine BMD at the 25th and 50th centiles, Raloxifene lowered the risk of incident spinal fracture by 39% and 46%, respectively. These findings indicate that the percentage change in BMD in postmenopausal women treated with Raloxifene account for only 4% of the observed reduction in risk of vertebral fracture. Not unexpectedly, changes in BMD during treatment are a poor predictor of risk reduction.

  • relationships between bone mineral density and incident vertebral fracture risk with Raloxifene therapy
    Journal of Bone and Mineral Research, 2002
    Co-Authors: Somnath Sarkar, Bruce H Mitlak, Dennis M Black, John L Stock, Mayme Wong, Kristine D Harper
    Abstract:

    Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of Raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or Raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the Raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, Raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with Raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving Raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, Raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with Raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with Raloxifene therapy are poor predictors of vertebral fracture risk reduction with Raloxifene therapy.

Kristine D Harper - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of Raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis four year results from a randomized clinical trial
    The Journal of Clinical Endocrinology and Metabolism, 2002
    Co-Authors: Pierre D Delmas, Kristine E. Ensrud, Robert R. Recker, Kristine D Harper, Jonathan D. Adachi, S Sarkar, C Gennari, Jeanyves Reginster, Huibert A P Pols, Steven T Harris
    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.

  • relationships between bone mineral density and incident vertebral fracture risk with Raloxifene therapy
    Obstetrical & Gynecological Survey, 2002
    Co-Authors: Somnath Sarkar, Bruce H Mitlak, Dennis M Black, John L Stock, Mayme Wong, Kristine D Harper
    Abstract:

    Low bone mineral density (BMD) in osteoporotic patients predicts an increased risk of bone fracture, but it is not clear whether increasing BMD in those given antiresorptive drugs predicts a reduced risk. The investigators explored this relationship after 1 or 3 years of treatment with Raloxifene or placebo in 7705 postmenopausal women with osteoporosis who participated in the MORE (Multiple Outcomes of Raloxifene Evaluation) trial. Raloxifene was given in a daily dose of 60 or 120 mg. Logistic regression models were used to relate baseline BMD and changes in BMD to the risk of new vertebral fractures (Figs. 1 and 2). All women received supplemental calcium and vitamin D. BMD was estimated by dual-energy x-ray absorptiometry in the femoral neck and lumbar spine at yearly intervals. The risk of a new vertebral fracture was greatest in women having the lowest baseline BMD values at either measurement site. Raloxifene reduced the risk of incident vertebral fractures by 41% compared with the placebo group, regardless of baseline BMD at the femoral neck, but women with relatively low baseline lumbar spine BMD had the most marked reduction in fracture risk from Raloxifene. After 3 years, Raloxifene therapy was associated with increases of only 2% to 3% in BMD. Raloxifene-treated women had a significantly lower risk of spinal fracture than placebo patients regardless of the change in femoral neck BMD, and they also had a lower fracture risk at any percentage change in lumbar spine BMD. At the 75th percentile of the population, with a 6.1% increase in lumbar spinal BMD, the risk of incident vertebral fracture was reduced 52% by Raloxifene therapy. With lesser increases in lumbar spine BMD at the 25th and 50th centiles, Raloxifene lowered the risk of incident spinal fracture by 39% and 46%, respectively. These findings indicate that the percentage change in BMD in postmenopausal women treated with Raloxifene account for only 4% of the observed reduction in risk of vertebral fracture. Not unexpectedly, changes in BMD during treatment are a poor predictor of risk reduction.

  • bone histomorphometric and biochemical marker results of a 2 year placebo controlled trial of Raloxifene in postmenopausal women
    Journal of Bone and Mineral Research, 2002
    Co-Authors: M Susan M D Ott, Kristine D Harper, Anna Oleksik, Paul Lips
    Abstract:

    Raloxifene is a selective estrogen receptor modulator that has been shown to increase bone density. The purpose of this study was to examine the effects of Raloxifene on bone tissue by studying bone biopsy specimens before and after 2 years of Raloxifene or placebo therapy. The women in this study were participants of the double-blind, placebo-controlled, multicenter study, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Subjects from two U.S. sites and two European sites were included if they consented to a bone biopsy. Iliac crest bone biopsies were performed at baseline and after 2 years. Tetracycline labeling preceded each biopsy. A total of 65 paired biopsy specimens were evaluated with 25, 22, and 18 patients in the placebo, Raloxifene HCl (60 mg) and Raloxifene HCl (120 mg) treatment groups, respectively. They were analyzed using standard histomorphometry. None of the biopsy specimens showed evidence of toxic effects on bone or bone cells or met criteria for osteomalacia. Biopsy specimens in the placebo and Raloxifene groups had the appearance of normal bone, with no evidence of marrow fibrosis or increases in the amount of woven bone or numbers of empty osteocyte lacunae. Compared with the baseline, the bone formation rate (BFR) decreased significantly in both Raloxifene groups. The change in BFR in the group treated with 120 mg of Raloxifene was -62.3%, which was significantly lower than the change in the placebo group of -21.0% (p = 0.03). No change in resorption parameters could be measured by histomorphometry, but there was a decrease in urinary type I collagen excretion. The results from this study suggest that Raloxifene has actions on bone tissue that are similar to those observed with estrogen. The depressive effects on bone remodeling are less marked than the effects seen with alendronate.

  • relationships between bone mineral density and incident vertebral fracture risk with Raloxifene therapy
    Journal of Bone and Mineral Research, 2002
    Co-Authors: Somnath Sarkar, Bruce H Mitlak, Dennis M Black, John L Stock, Mayme Wong, Kristine D Harper
    Abstract:

    Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of Raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or Raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the Raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, Raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with Raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving Raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, Raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with Raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with Raloxifene therapy are poor predictors of vertebral fracture risk reduction with Raloxifene therapy.

  • 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
    JAMA Internal Medicine, 2000
    Co-Authors: Conrad C Johnston, Bruce H Mitlak, Nina Hannover Bjarnason, Fredric J. Cohen, Aarti Shah, Robert Lindsay, William J Huster, Draper Michael William, Kristine D Harper, Hunter Heath
    Abstract:

    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 benefit-risk profile of Raloxifene for long-term use in healthy postmenopausal women.

John H. Krege - One of the best experts on this subject based on the ideXlab platform.

  • Long-term Raloxifene for postmenopausal osteoporosis
    Current medical research and opinion, 2011
    Co-Authors: Robert R. Recker, Bruce H Mitlak, John H. Krege
    Abstract:

    AbstractBackground:Due to the chronic nature of osteoporosis and the risk of invasive breast cancer, Raloxifene 60 mg/day (Raloxifene) is intended to be used for long-term treatment (treatment >3 years).Scope:We review available information concerning long-term use of Raloxifene, present several new analyses, and report new data from patients who underwent iliac crest bone biopsies after 8 years of Raloxifene therapy. The most important studies were the Multiple Outcomes of Raloxifene Evaluation (MORE) followed by the Continued Outcomes of Raloxifene Evaluation (CORE).Findings:The primary endpoint in MORE was incidence of vertebral fracture, and the difference between the Raloxifene and placebo groups for this endpoint widened during 4 years of therapy, with the relative risk reduction during the fourth year of the study being similar to the relative risk reduction during years 0 to 3 of the study. Continued Raloxifene treatment is necessary to preserve bone mineral density (BMD). In MORE, Raloxifene lowe...

  • Original article Benefits and risks of Raloxifene by vertebral fracture status
    2010
    Co-Authors: Angelina Sontag, Xiaohai Wan, John H. Krege
    Abstract:

    Objective: Women without versus those with vertebral fracture may have different benefits and risks during Raloxifene treatment. Our objective was to compare the effects of Raloxifene to decrease risk for vertebral fracture and invasive breast cancer with its effect to increase risk for venous thromboembolism in postmenopausal women without or with baseline vertebral fracture. Research design and methods: The Multiple Outcomes of Raloxifene Evaluation trial included postmenopausal women with osteoporosis randomized to placebo, Raloxifene 60 mg/day, or Raloxifene 120 mg/day for 4 years. The protocol specified subgroups based on whether or not patients had a vertebral fracture at baseline. Absolute differences between placebo and Raloxifene 60 mg/day (the approved dose) for endpoints in these groups were defined as the incidence in the Raloxifene group minus the incidence in the placebo group.

  • Benefits and risks of Raloxifene by vertebral fracture status.
    Current medical research and opinion, 2009
    Co-Authors: Angelina Sontag, Xiaohai Wan, John H. Krege
    Abstract:

    AbstractObjective:Women without versus those with vertebral fracture may have different benefits and risks during Raloxifene treatment. Our objective was to compare the effects of Raloxifene to decrease risk for vertebral fracture and invasive breast cancer with its effect to increase risk for venous thromboembolism in postmenopausal women without or with baseline vertebral fracture.Research design and methods:The Multiple Outcomes of Raloxifene Evaluation trial included postmenopausal women with osteoporosis randomized to placebo, Raloxifene 60 mg/day, or Raloxifene 120 mg/day for 4 years. The protocol specified subgroups based on whether or not patients had a vertebral fracture at baseline. Absolute differences between placebo and Raloxifene 60 mg/day (the approved dose) for endpoints in these groups were defined as the incidence in the Raloxifene group minus the incidence in the placebo group.Results:Raloxifene decreased the incidence of vertebral fracture and invasive breast cancer while increasing th...

Dennis M Black - One of the best experts on this subject based on the ideXlab platform.

  • associations between baseline risk factors and vertebral fracture risk in the multiple outcomes of Raloxifene evaluation more study
    Journal of Bone and Mineral Research, 2004
    Co-Authors: Olof Johnell, Dennis M Black, Somnath Sarkar, John A Kanis, A Balogh, Gyula Poor, Chunmei Zhou, Imre Pavo
    Abstract:

    Different risk factors may influence the effectiveness of osteoporosis therapies. The interaction of 30 baseline risk factors and the effectiveness of Raloxifene in the MORE study were assessed. The efficacy of Raloxifene in reducing vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fractures. Introduction: The aim of this analysis was to determine the effect of different risk factors on the effectiveness of Raloxifene to reduce vertebral fractures in the Multiple Outcomes of Raloxifene Evaluation (MORE) study using logistic regression models. Materials and Methods: The association was assessed using univariate analyses and a multivariate model between 30 potential risk factors at baseline and the risk of vertebral fractures after 3 years in the placebo group, as well as the interaction of risk factors with Raloxifene therapy (at a dose of 60 or 120 mg/day). Results and Conclusions: In the univariate analysis of the placebo group, after adjusting for baseline lumbar spine BMD (LS BMD), short stature (odds ratio [OR] = 1.18), age (OR = 1.38), years since menopause (OR = 1.38), impaired cognitive function, visuospatial capabilities (OR = 1.19), impaired musculoskeletal strength (OR = 1.23), low femoral neck BMD (OR = 1.21), and prior vertebral fracture (OR = 4.95) were significantly associated with the incidence of new vertebral fractures. In the univariate analysis, significant interactions were observed between Raloxifene treatment and age (p = 0.04), serum triglycerides (p = 0.03), LS BMD (p = 0.08), and diabetes mellitus (p = 0.04). In the multivariate analysis, the effectiveness of Raloxifene was independent of almost all risk factors, with the exception of baseline serum triglyceride level and LS BMD, suggesting an increased efficacy of Raloxifene in patients with increased triglyceride levels (p = 0.006) and lower LS BMD values (p = 0.008) at baseline. These data suggest that the efficacy of Raloxifene in reducing vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fractures.

  • effect of Raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis a reanalysis of the multiple outcomes of Raloxifene evaluation trial
    Bone, 2003
    Co-Authors: John A Kanis, Dennis M Black, Somnath Sarkar, Olof Johnell, Robert W Downs, Thomas Fuerst, Roberta J Secrest, Imre Pavo
    Abstract:

    Raloxifene reduces vertebral fracture risk in postmenopausal women with osteoporosis and established osteoporosis, but its efficacy in women with osteopenia has not been studied. The objective of this study was to evaluate the effect of Raloxifene hydrochloride on the risk of vertebral fractures in postmenopausal women with osteopenia and to compare this effect with that in women with osteoporosis as defined by the bone mineral density (BMD) T-score at the hip. We studied the 3204 postmenopausal women with osteopenia or osteoporosis without vertebral fractures at baseline in the Multiple Outcomes of Raloxifene Evaluation trial. Compared with placebo, 60 mg/day Raloxifene reduced the risk of new vertebral fractures at 3 years independent of baseline total hip BMD. The relative risk for new vertebral fractures for the Raloxifene group compared with placebo was 0.53 (95% CI, 0.32-0.88) for those with osteopenia and 0.31 (0.06-0.71) for those with osteoporosis. In Raloxifene-treated women the rate of vertebral fracture was similar in women with osteoporosis (2%) to that in women with osteopenia (1.9%). For clinically apparent vertebral fractures, the relative risk of fracture in the osteopenia group for Raloxifene was 0.25 (0.04-0.63) compared with placebo. There were no new clinical vertebral fractures in women with osteoporosis receiving Raloxifene, whereas four occurred in the placebo group. We conclude that treatment with 60 mg/day Raloxifene significantly decreases the risk of new vertebral fractures and new clinical vertebral fractures in postmenopausal women without baseline vertebral fracture who have osteopenia or osteoporosis.

  • relationships between bone mineral density and incident vertebral fracture risk with Raloxifene therapy
    Obstetrical & Gynecological Survey, 2002
    Co-Authors: Somnath Sarkar, Bruce H Mitlak, Dennis M Black, John L Stock, Mayme Wong, Kristine D Harper
    Abstract:

    Low bone mineral density (BMD) in osteoporotic patients predicts an increased risk of bone fracture, but it is not clear whether increasing BMD in those given antiresorptive drugs predicts a reduced risk. The investigators explored this relationship after 1 or 3 years of treatment with Raloxifene or placebo in 7705 postmenopausal women with osteoporosis who participated in the MORE (Multiple Outcomes of Raloxifene Evaluation) trial. Raloxifene was given in a daily dose of 60 or 120 mg. Logistic regression models were used to relate baseline BMD and changes in BMD to the risk of new vertebral fractures (Figs. 1 and 2). All women received supplemental calcium and vitamin D. BMD was estimated by dual-energy x-ray absorptiometry in the femoral neck and lumbar spine at yearly intervals. The risk of a new vertebral fracture was greatest in women having the lowest baseline BMD values at either measurement site. Raloxifene reduced the risk of incident vertebral fractures by 41% compared with the placebo group, regardless of baseline BMD at the femoral neck, but women with relatively low baseline lumbar spine BMD had the most marked reduction in fracture risk from Raloxifene. After 3 years, Raloxifene therapy was associated with increases of only 2% to 3% in BMD. Raloxifene-treated women had a significantly lower risk of spinal fracture than placebo patients regardless of the change in femoral neck BMD, and they also had a lower fracture risk at any percentage change in lumbar spine BMD. At the 75th percentile of the population, with a 6.1% increase in lumbar spinal BMD, the risk of incident vertebral fracture was reduced 52% by Raloxifene therapy. With lesser increases in lumbar spine BMD at the 25th and 50th centiles, Raloxifene lowered the risk of incident spinal fracture by 39% and 46%, respectively. These findings indicate that the percentage change in BMD in postmenopausal women treated with Raloxifene account for only 4% of the observed reduction in risk of vertebral fracture. Not unexpectedly, changes in BMD during treatment are a poor predictor of risk reduction.

  • relationships between bone mineral density and incident vertebral fracture risk with Raloxifene therapy
    Journal of Bone and Mineral Research, 2002
    Co-Authors: Somnath Sarkar, Bruce H Mitlak, Dennis M Black, John L Stock, Mayme Wong, Kristine D Harper
    Abstract:

    Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of Raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or Raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the Raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, Raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with Raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving Raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, Raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with Raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with Raloxifene therapy are poor predictors of vertebral fracture risk reduction with Raloxifene therapy.

  • reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with Raloxifene results from a 3 year randomized clinical trial
    Obstetrical & Gynecological Survey, 2000
    Co-Authors: Bruce Ettinger, Bruce H Mitlak, Ronald Keith Knickerbocker, Thomas Nickelsen, Dennis M Black, J R Zanchetta, Claus Christiansen, Pierre D Delmas, Harry K. Genant, Jacob A. Stakkestad
    Abstract:

    Raloxifene is a selective estrogen receptor modulator that has been shown to prevent bone loss in postmenopausal women. Whether it also reduces the risk of fracture remains uncertain, prompting the present trial, the Multiple Outcomes of Raloxifene Evaluation (MORE) study. The randomized, blinded, placebo-controlled trial enlisted 7705 women in 25 countries, ranging in age from 31 to 80 years, who had been postmenopausal for 2 years or longer and met World Health Organization criteria for osteoporosis. Participants were assigned to receive Raloxifene in a daily dose of 60 or 120 mg or placebo pills, and, in addition, all of them were given supplemental calcium and cholecalciferol. Follow-up extended for at least 3 years. Baseline and follow-up radiographs were available for 89 percent of women entering the study. One or more new vertebral fractures developed in 7.4 percent of women within 3 years of entry into the study. Those given Raloxifene had fewer new fractures, regardless of whether fractures were present at the outset. No overall dose-related difference was found, although women with baseline fractures had fewer new lesions when given the higher dose of Raloxifene. The rate of nonvertebral fracture at 3 years was 9.3 percent in the placebo group and 8.5 percent for Raloxifene-treated women. Bone mineral density increased by 2 to 3 percent at various sites in the Raloxifene group compared with the placebo group. Nearly one fourth of women had serious adverse effects regardless of treatment assignment, but the only ones considered causally related to Raloxifene were deep thrombophlebitis and pulmonary embolism. This developed in 1 percent of each dose group and in 0.3 percent of placebo patients. Breast cancer was less frequent in women given Raloxifene. Withdrawals due to adverse events were slightly more frequent in the Raloxifene group than in the placebo group (10.3 vs. 8.8 percent). Hot flashes were the most common nonserious adverse event. No clinically important renal, hepatic, or hematological abnormalities were noted. These findings indicate that Raloxifene treatment over 3 years not only preserves bone mass but also lowers the risk of new vertebral fractures in postmenopausal women with osteoporosis, regardless of whether they have had fractures before starting treatment. J Am Med Assoc 1999;282:637–645

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  • skeletal effects of Raloxifene after 8 years results from the continuing outcomes relevant to evista core study
    Journal of Bone and Mineral Research, 2005
    Co-Authors: Ethel S Siris, J R Zanchetta, John L Stock, Jingli Song, Richard Eastell, Steven T Harris, Stefan Goemaere, Adolfo Diezperez, Pandurang M Kulkarni, Suresh Siddhanti
    Abstract:

    In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and Raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of Raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE. Introduction: The multicenter, double-blind Continuing Outcomes Relevant to Evista (CORE) trial assessed the effects of Raloxifene on breast cancer for 4 additional years beyond the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial. Materials and Methods: In CORE, placebo-treated women from MORE continued with placebo (n = 1286), whereas those previously given Raloxifene (60 or 120 mg/day) received Raloxifene 60 mg/day (n = 2725). As a secondary endpoint, new nonvertebral fractures were analyzed as time-to-first event in 4011 postmenopausal women at 8 years. A substudy assessed lumbar spine and femoral neck BMD at 7 years, with the primary analysis based on 386 women (127 placebo, 259 Raloxifene) who did not take other bone-active agents from the fourth year of MORE and who were ≥80% compliant with study medication in CORE. Results: The risk of at least one new nonvertebral fracture was similar in the placebo (22.9%) and Raloxifene (22.8%) groups (hazard ratio {HR}, 1.00; Bonferroni-adjusted CI, 0.82, 1.21). The incidence of at least one new nonvertebral fracture at six major sites (clavicle, humerus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. Posthoc Poisson analyses, which account for multiple events, showed no overall effect on nonvertebral fracture risk, and a decreased risk at six major nonvertebral sites in women with prevalent vertebral fractures (HR, 0.78; 95% CI, 0.63, 0.96). At 7 years after MORE randomization, the differences in mean lumbar spine and femoral neck BMD with Raloxifene were 1.7% (p = 0.30) and 2.4% (p = 0.045), respectively, from placebo. Compared with MORE baseline, after 7 years, Raloxifene treatment significantly increased lumbar spine (4.3% from baseline, 2.2% from placebo) and femoral neck BMD (1.9% from baseline, 3.0% from placebo). BMDs were significantly increased from MORE baseline at all time-points at both sites with Raloxifene. Conclusion: Raloxifene therapy had no effect on nonvertebral fracture risk after 8 years, although CORE had limitations for fracture risk assessment. BMD increases were maintained after 7 years of Raloxifene.

  • efficacy of Raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis four year results from a randomized clinical trial
    The Journal of Clinical Endocrinology and Metabolism, 2002
    Co-Authors: Pierre D Delmas, Kristine E. Ensrud, Robert R. Recker, Kristine D Harper, Jonathan D. Adachi, S Sarkar, C Gennari, Jeanyves Reginster, Huibert A P Pols, Steven T Harris
    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.