Multiple Outcomes Of Raloxifene Evaluation Research Articles

Psychometric properties of the osteoporosis assessment questionnaire (OPAQ) 2.0: results from the multiple outcomes of raloxifene evaluation (MORE) study.

BackgroundWe explored psychometric properties of the Osteoporosis Assessment Questionnaire 2.0 in terms of reliability, validity, and responsiveness with generic, clinical, demographic, and preference-based data collected from a population of postmenopausal women with osteoporosis.MethodsThe Multiple Outcomes of Raloxifene Evaluation study was a randomized, placebo-controlled, multinational clinical trial evaluating efficacy and safety of raloxifene. The Osteoporosis Assessment Questionnaire 2.0, a generic quality of life measure (Nottingham Health Profile), and a preference-based measure (Health Utilities Index) were administered at baseline and annually. Psychometric properties of the 14 Osteoporosis Assessment Questionnaire 2.0 domains were evaluated by standard statistical techniques.ResultsThis study included a subset of 1477 women from the Multiple Outcomes of Raloxifene Evaluation study population completing the questionnaires. Mean (standard deviation) age was 68.4 (6.8) years. Prevalent vertebral fractures were found in 70% (n =1038) of women. Internal consistency was >0.7 in 9 Osteoporosis Assessment Questionnaire 2.0 domains. Correlations were moderate and significant for similar Osteoporosis Assessment Questionnaire 2.0 domain scores, Nottingham Health Profile domains, and Health Utilities Index scores. All but 2 Osteoporosis Assessment Questionnaire 2.0 domains distinguished between patients with or without prevalent vertebral fractures and detected worsening with increased number of vertebral fractures. Women with ≥1 incident vertebral fracture generally had a greater worsening in Osteoporosis Assessment Questionnaire 2.0 scores (excluding social activity and support of family and friends) from baseline to study endpoint compared with women without incident vertebral fractures.ConclusionsMost domains in the Osteoporosis Assessment Questionnaire 2.0 demonstrated robust psychometric properties; however, several domains not showing these criteria may need to be reassessed and removed for a potentially shorter and validated version of the Osteoporosis Assessment Questionnaire.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2474-15-374) contains supplementary material, which is available to authorized users.

Estrogen Replacement Therapy and Cardiac Function Under Metabolic Syndrome

See related article, pp 694–704 Regardless of age, race, and ethnicity, cardiovascular disease is the number 1 cause of death for women, and its prevalence rises rapidly after menopause.1–4 This postmenopausal increase is believed to result from the loss of endogenous estrogen. Although estrogen replacement therapy (ERT) has long been thought to protect against menopause-associated cardiovascular anomalies, osteoporosis, hot flashes, and thinning of the vaginal epithelium,3–5 findings from the Heart and Estrogen/Progestin Replacement Study and the Women's Health Initiative Study5 do not support the notion that ERT protects the cardiovascular system. Instead, the data indicate just the opposite, that is, increased risk of cardiovascular disease, in addition to the apparent higher risk of breast cancer and deep vein thrombosis.1,2,4 Although results from clinical trials have substantiated the beneficial role of ERT in the management of menopausal symptoms, the unexpected finding of exacerbated cardiovascular function after ERT has made women hesitant to initiate ERT after menopause.1 Further analysis of the clinical trials revealed that the age of a woman and especially the number of years after menopause onset may be primary factors that contribute to the ultimate cardiovascular outcome of ERT. Although estrogen-progesterone therapy was found beneficial in young postmenopausal women, it increased cardiovascular risk when initiated in older postmenopausal women with established coronary artery disease.2,4 It is, thus, recommended that ERT be limited to the shortest duration consistent with treatment goals (eg, relief of menopausal symptoms).1 In contrast to the generalized recommendation for short duration of menopausal hormone treatment,2,4 careful scrutiny of the data from the Women's Health Initiative Estrogen Plus Progestin Trial reveal a reduced coronary heart disease risk after 5 to 6 years of ERT treatment. Accordingly, the …

Effects of Raloxifene on Bone Metabolism in Hemodialysis Patients

Effects of Raloxifene on Bone Metabolism in Hemodialysis Patients

A meta-analysis of the efficacy of raloxifene on all clinical and vertebral fractures and its dependency on FRAX®

Introduction Multiple Outcomes of Raloxifene Evaluation (MORE), a placebo controlled phase III study of raloxifene in postmenopausal osteoporosis, showed that both doses tested (60 mg and 120 mg daily) reduced the risk of vertebral fracture. There was no significant effect on non-vertebral fracture. Aims The aim of the present study was to evaluate the distribution of fracture risk assessed at baseline using the FRAX® tool in MORE and to determine the efficacy of raloxifene as a function of baseline fracture risk. The effects of raloxifene (60 and 120 mg daily combined) with placebo on the risk of all clinical fractures as well as the risk of morphometric vertebral fracture were examined as a function of baseline fracture risk. Methods Baseline clinical risk factors and BMD were entered in the FRAX® model to compute the 10-year probability of major osteoporotic fractures. The interaction between fracture probability and treatment efficacy was examined by Poisson regression. Results The 10-year probability of major osteoporotic fractures (with BMD) ranged from 0.9% to 77.2%. The incidence of clinical fractures and morphometric vertebral fractures increased with increasing baseline fracture probabilities. Treatment with raloxifene was associated with an 18% decrease in all clinical fractures compared to placebo treatment (hazard ratio HR = 0.82; 95% CI = 0.71–0.95; p = 0.0063) and a 42% decrease in incident morphometric vertebral fractures (HR = 0.58; 95% CI = 0.48–0.69; p < 0.001). Efficacy was shown over the whole range of fracture probability and the interaction between fracture probability and treatment was not significant. The efficacy or raloxifene on vertebral fracture risk was significantly greater at lower ages. At the 90th percentile of age (75 years) vertebral fracture risk was reduced by 31% irrespective of FRAX® probabilities. In contrast at younger ages, efficacy was higher and increased further still with decreasing fracture probability. Conclusion We conclude that raloxifene (60 and 120 mg doses combined) significantly decreased the risk of all clinical fractures and morphometric fractures in women. Overall, there was no significant interaction between efficacy and fracture probability. In the case of morphometric vertebral fractures efficacy decreased significantly with increasing age.

Serum calcium, phosphorus and cardiovascular events in post-menopausal women

Background There is increasing evidence linking phosphorus and calcium levels to a higher risk of cardiovascular morbidity and mortality in the general population. Methods We performed a post hoc data analysis from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial of raloxifene treatment in 7259 postmenopausal women with osteoporosis to test the hypothesis that higher baseline calcium and phosphorus levels are associated with a higher risk of incident cardiovascular events during 4 years of follow-up. Results Baseline mean (SD) values were 2.3 (0.1) mmol/L for serum calcium, 1.2 (0.2) mmol/L for serum phosphorus. Adjusted for multiple covariates including 25(OH)D, parathyroid hormone, and phosphorus, adjusted hazard ratios (AHR) (95% confidence interval (CI)) per SD of calcium were: 1.17(1.01–1.35), p = 0.03 for combined cardiovascular outcome, 1.22(0.99–1.49), p = 0.06 for cerebrovascular events, 1.12(0.92–1.37), p = 0.25 for coronary heart disease, and 1.18(0.94–1.48), p = 0.16 for death. While there was some evidence that higher serum phosphorus levels were associated with higher rate of combined cardiovascular outcome ( p = 0.07) and cerebrovascular events ( p = 0.03) in pauci-variable analysis, these associations did not persist after adjustment for additional confounders. Adjusted for multiple covariates including 25(OH)D, parathyroid hormone, and calcium, AHR(95% CI) per SD of phosphorus were 0.88(0.77–1.01), p = 0.07 for combined cardiovascular outcome, 0.86(0.70–1.06), p = 0.15 for ceverbrovascular events, 0.92(0.76–1.10), p = 0.35 for coronary heart disease, and 1.00(0.80–1.25) for death. Conclusion We found an independent association between higher baseline serum calcium levels and higher rate of cardiovascular events. Our findings did not support an independent association between serum phosphorus levels and cardiovascular events.

First fractures among postmenopausal women with osteoporosis

After the occurrence of the first fracture, osteoporosis is no longer a "silent" disease, and the patient's risk for future fracture is increased several fold. We assessed the location of first osteoporotic fractures among women with osteoporosis. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a fracture outcomes study of postmenopausal women with osteoporosis. All subjects received supplements containing 500 mg elemental calcium and 400-600 IU vitamin D. We assessed the location of first fractures among women with osteoporosis and no previous fractures at baseline from the placebo group of this trial after 3 years of follow-up. Prespecified fracture sites included vertebral fractures and nonvertebral fractures as defined in the MORE study protocol. Among 875 women (mean age, 64.5 +/- 7.4 years) with no prevalent vertebral or nonvertebral fractures, 9% experienced their first fracture event during the trial. Fractures of radius and spine each occurred in 3% of patients. Fractures at other individual sites included ankle (0.6%), metatarsal (0.6%), humerus (0.5%), rib (0.5%), patella (0.3%), leg (0.2%), hip (0.2%), and clavicle (0.1%). These data suggest that for postmenopausal women with osteoporosis but no previous fractures, skeletal care should include a focus on preventing spine and radius fractures.

Raloxifene and Risk for Stroke Based on the Framingham Stroke Risk Score

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 <13 showed no increase in raloxifene-associated fatal stroke risk (hazard ratio [HR] 1.08; 95% confidence interval [CI], 0.49-2.37). Those with FSRS ≥13 had a 75% increased risk of raloxifene-associated fatal stroke (HR 1.75; 95% CI, 1.01-3.02; interaction P = .33). In MORE, where 80% of women had a FSRS <13, no increase in fatal (HR 0.57; 95% CI, 0.19-1.68) stroke risk was observed. 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.

Incidence of Invasive Breast Cancer in Postmenopausal Women After Discontinuation of Long-Term Raloxifene Administration

Background Postmenopausal women with osteoporosis had a 66% relative risk reduction for invasive breast cancer over 8 years of raloxifene therapy in the randomized, placebo-controlled 4-year MORE (Multiple Outcomes of Raloxifene Evaluation) trial and the CORE (Continuing Outcomes Relevant to Evista) trial, a 4-year follow-up to MORE. Patients and Methods The first post hoc analysis examined the effects of raloxifene on the cumulative incidence of invasive breast cancer on a yearly basis. Another analysis compared the incidence of invasive breast cancer in 3967 patients who continued raloxifene for 8 years (RLX-C, n = 2280), discontinued raloxifene after 4 years in MORE (RLX-D, n = 401), or took placebo (n = 1286) for a mean 2.9 years' treatment duration (57,338 patient-years). Results The unadjusted breast cancer incidence rate was 5.39 per 1000 patient-years in the placebo group compared with 2.26 in the RLX-C group (hazard ratio [HR], 0.41 [95% CI 0.21–0.81]) and 3.59 in the RLX-D group (HR, 0.69 [95% CI 0.23–2.01]). Because the choice of taking the study drug was not randomized in CORE, propensity scores were used to adjust for potential imbalances in baseline characteristics before CORE. Results after adjustment by the propensity score method were similar to the unadjusted results. Conclusion This analysis suggests a persistent effect for breast cancer risk reduction in patients who discontinued raloxifene, although this conclusion is limited by the small sample size.

Reduced Incidence of Invasive Breast Cancer With Raloxifene Among Women at Increased Coronary Risk

In the Raloxifene Use for The Heart trial, 10 101 postmenopausal women with coronary heart disease (CHD) or multiple CHD risk factors were randomly assigned to 60 mg/d raloxifene or to placebo and followed for a median of 5.6 years. Raloxifene, a selective estrogen receptor modulator, was found to reduce the risk of invasive breast cancer and vertebral fractures but not the risk of cardiovascular events. Here, we provide further details about breast cancer incidence by tumor characteristics, duration of treatment, and subgroup. Reported breast cancer was adjudicated by an independent committee based on medical records and pathology reports. The primary analyses used Cox proportional hazards models with time to first breast cancer as the outcome. Subgroup effects were analyzed using similar models with terms for treatment by subgroup. All statistical tests were two-sided. As previously reported, raloxifene reduced the incidence of invasive breast cancer by 44% (hazard ratio [HR] = 0.56; 95% confidence interval [CI] = 0.38 to 0.83; absolute risk reduction = 1.2 invasive breast cancers per 1000 women treated for 1 year). The lower incidence of invasive breast cancer reflected a 55% lower incidence of invasive estrogen receptor (ER)-positive tumors (HR = 0.45; 95% CI = 0.28 to 0.72). However, raloxifene treatment did not reduce the incidence of noninvasive breast cancer or of invasive ER-negative breast cancer. The reduced incidence of invasive breast cancer was similar across subgroups, including those defined by age, body mass index, family history of breast cancer, prior use of postmenopausal hormones, and 5-year estimated risk of invasive breast cancer. Raloxifene reduces risk of invasive ER-positive breast cancer regardless of a woman's baseline breast cancer risk but does not reduce risk of noninvasive or ER-negative breast cancers. These results confirm those of the Multiple Outcomes of Raloxifene Evaluation, a previous randomized trial among women with osteoporosis.

Differences in prior estrogen exposure may explain the difference in magnitude of breast cancer risk reduction observed in raloxifene breast cancer prevention trials

1519 Background: Sep 2007, raloxifene (RLXF) approved for invasive breast cancer (IBC) risk reduction (RR) in postmenopausal women (PMW) with osteoporosis (OP) based on two placebo-controlled trials: RLXF Use for The Heart (RUTH) in PMW at increased risk of coronary events and Multiple Outcomes of RLXF Evaluation (MORE) in PMW with OP, later: Continuing Outcomes Relevant to Evista (CORE). Each trial showed statistically significant reduction in IBC risk, but Number Needed to Treat (NNT: women who need to take RLXF for 1 year to prevent one IBC) was 862 and 323 in RUTH and MORE: a difference >500. Impressive MORE results, attributed to RLXF, later on, led to Study of Tamoxifen and Raloxifene (STAR trial). Methods: IRs of IBC in RLXF and placebo (PLCB) arms of RUTH and MORE were compared and trial publications searched for history of prior estrogen exposure. Results: IRs of IBC in RUTH and MORE = 2.66 and 4.36 in PLCB arms & 1.50 and 1.26 in RLXF arms; corresponding absolute RR = 1.16 and 3.10 per 1,000 person-years, respectively. IRs of IBC are similar in RLXF arms but remarkably different in PLCB arms, and derive the observed difference in RR magnitude: 2.66 to 1.50 (RUTH) vs 4.36 to 1.26 (MORE). Prior to enrollment, a smaller fraction of women was on estrogen replacement in RUTH than MORE: 20% vs 28%; differences in duration of estrogen therapy and estrogen exposure free time prior to randomization are not known. Conclusions: It is the higher IBC IR in MORE PLCB arm that seems to derive the effect size of the observed risk reduction. High IBC IR in MORE PLCB arm is unexpected: publications show lower IBC incidence in women with OP (attributed to lower lifetime estrogen exposure) or no difference. Differences in prior OP estrogen treatment might have led to different IBC IRs in RUTH and MORE PLCB arms, ie, the observed remarkable RR of IBC in MORE resulted from interplay of two factors: 1) Persisting estrogen exposure effect in MORE PLCB arm with the consequent higher than expected IBC IR, & 2) Starting RLXF in RLFX arms. Possibility remains that impressive RR in MORE was a random finding: IBC IR was a safety endpoint in MORE. Notably, since Women's Health Initiative publication, lowering of IBC IR has been reported: attributed to a decline in estrogen use. No significant financial relationships to disclose.

Raloxifene: an agent for breast cancer prevention

On 13 September 2007, raloxifene was approved by the US FDA for reducing the risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer and in women with osteoporosis. This approval was the result of the findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial and the Study of Tamoxifen And Raloxifene (STAR). MORE, an osteoporosis treatment trial, suggested that raloxifene reduced the incidence of breast cancer in average-risk postmenopausal women with osteoporosis. STAR compared the proven preventive agent tamoxifen with raloxifene, a selective estrogen receptor modulator that had been suggested to have a preventive benefit with fewer side effects. The results of STAR showed that raloxifene is equivalent to tamoxifen in the prevention of invasive breast cancer. Postmenopausal women now have a second option to reduce their risk of invasive breast cancer.

Relationship between bone mass, invasive breast cancer incidence and raloxifene therapy in postmenopausal women with low bone mass or osteoporosis

ABSTRACTObjective: To evaluate the relationship between bone mass and risk of breast cancer and to determine the effect of raloxifene therapy on breast cancer incidence in women categorized by bone mass into low bone mass and osteo­porosis subgroups.Design: In this post hoc analysis, data were analyzed from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, enrolling postmenopausal women with low bone mass (N = 7705), and the Continuing Outcomes Relevant to Evista (CORE) trial, a follow-up to MORE enrolling 4011 MORE participants. Total follow-up was for up to 8 years. Women with a total hip bone mineral density (BMD) T-score < –1 to > –2.5 or T-score ≤ –2.5 (referent, NHANES III database) were classified as having low bone mass or osteoporosis, respectively. Women with a pre-existing vertebral fracture were considered as having osteoporosis irrespective of BMD T-score. Analyses were performed for invasive breast cancers and invasive estrogen-receptor (ER) positive breast cancers.Results: Women with low bone mass (N = 3829) had a twofold higher incidence of invasive ER-positive breast cancer than those with osteoporosis (N = 3836) (HR 2.13, 95% CI 1.12–4.03). The incidence of all invasive breast cancers did not differ significantly between the bone mass groups. The incidences of invasive and invasive ER-positive breast cancers were 65–78% lower in women assigned raloxifene versus placebo in both the low bone mass and osteoporosis groups ( p < 0.05).Conclusions: In this post hoc analysis of postmeno­pausal women participating in MORE and CORE, bone mass was a predictor of invasive ER-positive breast cancer. Raloxifene treatment reduced the risk of invasive and invasive ER-positive breast cancers in women with low bone mass and those with osteoporosis. Since participants were older postmenopausal women with low bone mass, whether these findings can be generalized to other postmenopausal women is unclear.

Impact of prevalent and incident vertebral fractures on utility: results from a patient-based and a population-based sample

Data are scarce on the impact of vertebral fractures (VFX) on utility. The objective of this study was to assess the impact of prevalent and incident VFX on utility in both a patient-based and population-based sample. Data from the Multiple Outcomes of Raloxifene Evaluation (MORE) study (n = 550 for prevalent VFX and n = 174 for incident VFX) and the European Prospective Osteoporosis Study (EPOS) (n = 236) were used. Utility was assessed by the index score of the EQ-5D. In the MORE study, highly statistically significant associations were found between utility and the presence of prevalent VFX (p < 0.001), number of prevalent VFX (p < 0.001), severity of prevalent VFX (p < 0.001), the combination of number and severity of prevalent VFX (p = 0.001) and location of prevalent VFX (p = 0.019). The mean utility was significantly lower among women who suffered an incident VFX (utility = 0.67) than among women who did not (utility = 0.77) (p = 0.005), although utility loss was not significantly different between the two groups (p = 0.142). In EPOS, the combination of number and severity of incident VFX was significantly related to utility (p = 0.030). In conclusion, utility is lower among persons with prevalent and incident VFX, especially in a patient-based sample. Utility loss was not significantly different between women without and with incident VFX.

Carotid Artery Intima-Media Thickness after Raloxifene Treatment

Raloxifene, a selective estrogen receptor modulator (SERM), decreases total and low-density lipoprotein cholesterol (LDL-C) in postmenopausal women and inhibits increases in intima-media thickness (IMT) in animal models. We tested whether up to 8 years exposure to raloxifene had an effect on subclinical atherosclerosis in the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial and the follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial. A subsample of postmenopausal women with osteoporosis, who had completed the MORE and CORE trials and were on average 68 years of age and 19 years postmenopausal at randomization into MORE, participated in this substudy. Within 6 months of cessation of study drug in CORE, right common carotid artery IMT (CIMT) and carotid artery stiffness and arterial compliance were measured at one of two sites (San Diego and San Francisco) using high-resolution B-mode ultrasound. CIMT and arterial stiffness measures were compared between women who had received raloxifene vs. placebo; the primary analysis included only women who were >or=80% drug compliant and had used <or=6 months of lipid-lowering medication during CORE. For the primary analysis dataset (n = 89), there was no significant difference in mean CIMT between the raloxifene and placebo groups (0.83 and 0.81 mm, respectively, p = 0.62). Carotid artery stiffness and compliance were not significantly different between treatment groups (p = 0.33 and 0.59, respectively). These preliminary data suggest that in this self-selected group of elderly post-menopausal women with osteoporosis who were evaluated within 6 months of cessation of study medication, there were no differences between long-term raloxifene treatment and placebo groups in several measures of subclinical atherosclerosis.

Effect of Raloxifene on the Incidence of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis Categorized by Breast Cancer Risk

To assess the effect of raloxifene, indicated for osteoporosis treatment and prevention, on invasive breast cancer in subgroups of postmenopausal women defined by risk factors for breast cancer. Data from the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial (N=7,705) and a follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial (N=4,011), were analyzed. Prespecified subgroups were defined by age (>or=65 versus<65 years), age at menopause (>or=49 versus<49 years), body mass index (>or=25 versus<25 kg/m2), family history of breast cancer (yes/no), serum estradiol level (5-10 versus<5, >10 versus<5 pmol/L), prior estrogen therapy (yes/no), and bone mass at MORE baseline, and 5-year predicted risk, assessed using the modified Gail model (>or=1.67 versus<1.67%), at CORE baseline. Time-to-first invasive breast cancer was analyzed using Cox proportional hazards models. In the placebo group, older age, higher estradiol level, and a family history of breast cancer were associated with an increased breast cancer risk (P<0.05). Raloxifene therapy was associated with a reduced breast cancer risk in both women at lower and those at higher breast cancer risk. Hazard ratio point estimates were 0.11 to 0.67, corresponding to a 33% to 89% reduction in breast cancer risk with raloxifene versus placebo. The therapy by family history interaction was significant (P=0.04). Raloxifene therapy was associated with a reduced risk of invasive breast cancer in postmenopausal women irrespective of the presence/absence of risk factors; its effect was greater in women with a family history of breast cancer.

Chemoprevention of Breast Cancer in Postmenopausal Women

In the United States, an estimated 211,240 new cases of breast cancer were diagnosed in 2005 and approximately 40,410 deaths occurred. In recent years, a number of randomized prospective trials have investigated the use of antiestrogens as a means to reduce the incidence of breast cancer. We aim to describe the results of these trials as they pertain to postmenopausal women. In the Breast Cancer Prevention Trial and the International Breast Cancer Intervention Study-I, tamoxifen reduced the risk of invasive breast cancer by 55% and 30%, respectively, among older participants. However, tamoxifen is associated with adverse events including thromboembolic disease and endometrial cancer. The Multiple Outcomes of Raloxifene Evaluation, aimed primarily at evaluating the use of raloxifene for the prevention of osteoporosis, demonstrated a 72% decreased breast cancer risk. Side effects of raloxifene include thromboembolic events, but not endometrial cancer. Results from the Study of Tamoxifen and Raloxifene trial comparing these two agents are expected in mid-2006. Ongoing chemoprevention trials are evaluating the use of the aromatase inhibitors. At present, tamoxifen is the only FDA-approved agent for breast cancer risk reduction. Decisions regarding its use must remain highly individualized, involving careful consideration of its risks versus benefits.

Effects of raloxifene on lipid and lipoprotein levels in postmenopausal osteoporotic women with and without hypertriglyceridemia

This post hoc analysis reports the effects of raloxifene on lipids and lipoproteins in 2659 women with either normal (≤150 mg/dL) or high (>150 mg/dL) triglyceride levels from a substudy of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. In both triglyceride subgroups, raloxifene significantly improved low-density lipoprotein cholesterol, total cholesterol, non–high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, apolipoprotein A-I, and fibrinogen compared with placebo ( P < .05). After raloxifene treatment, women with high triglycerides experienced an equal or more robust reduction in cholesterol, lipoprotein parameters, and ratios of total cholesterol to HDL-C and non–HDL-C to HDL-C than was observed in women with normal triglycerides ( P < .05). Mean levels of low-density lipoprotein cholesterol and apolipoprotein B were reduced by 16.5% and 15.8%, respectively, in women with high triglycerides, and by 12.7% and 11.3%, respectively, in women with normal triglycerides. These findings further substantiate that raloxifene improves concentrations of both cholesterol and β-lipoprotein. The subgroup of women with high triglycerides, who have elevated cardiovascular risk, appear to derive at least equal, if not greater, overall effect on lipid and lipoprotein lowering with raloxifene.

New or Worsening Lumbar Spine Vertebral Fractures Increase Lumbar Spine Bone Mineral Density and Falsely Suggest Improved Skeletal Status

Changes in lumbar spine bone mineral density (BMD) are determined by follow-up dual-energy x-ray absorptiometry (DXA) assessments. Inclusion of new or worsening vertebral fractures in follow-up measurements may increase BMD. To test this hypothesis, we examined pooled data from the placebo groups of two clinical trials that involved postmenopausal women with osteoporosis. DXA measurements of lumbar spine BMD, bone mineral content (BMC), and area were obtained at baseline and at two years in the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial and at baseline and study endpoint in the Fracture Prevention Trial. In these trials, fractured vertebrae identified by expert radiologists during posterioranterior (PA) spine DXA assessment were excluded from the BMD assessment. Lateral spine radiographs were graded using a semi-quantitative (SQ) scale. Most new or worsening vertebral fractures (84%) diagnosed from lateral spine radiographs were not identified by PA spine DXA. While the follow-up BMD of vertebrae without new or worsening fractures did not change significantly, each unit increase in SQ grade was associated with an approximate 7.0% increase in the BMD of affected vertebrae (p < 0.001). Increases in BMD were highly correlated with increases in BMC (r = 0.87, p < 0.001). Inclusion of new or worsening vertebral fractures increased PA spine BMD measurements at follow-up, with the impact being related to the magnitude of change in SQ score. It is difficult to reliably identify vertebral fractures from PA spine DXA assessments. Inclusion of new or worsening vertebral fractures in follow-up DXA measurements may falsely suggest an improvement in spine BMD. Our suggestion is to perform lateral spine imaging concurrently with any assessment of PA spine BMD in patients who, in the opinion of the health care provider, may have vertebral fractures.

Raloxifene: A Selective Estrogen-Receptor Modulator for Postmenopausal Osteoporosis – a Clinical Update on Efficacy and Safety

Selective estrogen-receptor modulators are molecules with specific estrogen-receptor binding affinity. Each selective estrogen-receptor modulator induces a unique conformation in the ligand-receptor complex, which leads to transcriptional activation and/or inhibition. Raloxifene 60 mg/day, a benzothiophene selective estrogen-receptor modulator, is approved for the prevention and treatment of postmenopausal osteoporosis. This article provides an update on new studies and further analyses of clinical trial data for raloxifene. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial of women with osteoporosis has described the efficacy of raloxifene in decreasing vertebral fracture risk over 4 years. The Continuing Outcomes Relevant to Evista((R)) (CORE) trial, designed to assess the effects of raloxifene on breast cancer prevention, is a 4-year continuation of MORE. The skeletal and cardiovascular effects of raloxifene in the CORE study were similar to those observed in MORE. The relative risk of developing breast cancer was significantly decreased in women treated with raloxifene, compared with placebo, after 4 years in MORE and 8 years in the CORE trial. The incidence of uterine bleeding, endometrial hyperplasia and endometrial cancer was similar between raloxifene and placebo after 8 years of treatment. Raloxifene use is associated with a higher incidence of hot flashes and leg cramps, and an increased risk of venous thromboembolic events.

Structural effects of raloxifene on the proximal femur: results from the multiple outcomes of raloxifene evaluation trial

Raloxifene improves spine bone mineral density (BMD), and its ability to reduce vertebral fractures by 40-50% suggests that it increases vertebral strength. Positive effects on hip BMD suggest a similar strengthening of the hip, but dimensional ambiguities in BMD by dual energy x-ray absorptiometry (DXA) make it difficult to infer strength effects directly. Hip fractures may be too infrequent to evaluate in practical clinical trials; even the Multiple Outcomes of Raloxifene Evaluation (MORE) study with 7,705 subjects was insufficiently powered to show a comparable reduction in hip fractures. An alternative evaluation of hip DXA data in structural terms should provide more direct evidence of treatment effects on hip strength. Hip scans from a subset of the MORE study, including 4,806 postmenopausal women with osteoporosis randomized to daily oral doses of placebo, 60 mg, or 120 mg of raloxifene were reanalyzed by the hip structure analysis (HSA) method. Scans acquired at baseline, 1, 2, and 3 years were evaluated to extract BMD and cross-sectional geometry across the narrowest point on the neck (NN), the intertrochanteric region (IT), and the proximal shaft 1.5 times the minimum neck width distal to the intersection of the neck and shaft axes. While femur outer diameter expanded during follow-up at all three regions, there were no differences in expansion between groups; treatment influenced mainly the amount and distribution of bone within cross-sections. Effects were similar at the two dose levels at the NN region although the 120 mg dose produced a greater effect on section modulus (SM) at the IT region and on BMD, bone cross-sectional area (CSA), SM, average cortical thickness (CT), and buckling ratio (BR) at the shaft region. Compared with placebo after 3 years, treatment groups showed 0.4-2% higher BMD, CSA, SM, and CT and 1-2% lower BR. The smallest treatment effects were evident at the shaft at 60 mg. We conclude that raloxifene does not influence periosteal apposition in the proximal femur but it nevertheless produces small but significant improvement in resistance to axial and bending stresses (CSA and SM, respectively) at all analyzed regions. The significant reductions in buckling ratio suggest that additional strength loss due to cortical instability is also ameliorated by treatment.