EVISTA - GENERIC
Substance: Raloxifene

Endocrinology. 2005 Apr 28;
Raloxifene, a Selective Estrogen Receptor Modulator, Reduces Carrageenan-induced Acute Inflammation in Normal and Ovariectomized Rats.
Esposito E, Iacono A, Raso GM, Pacilio M, Coppola A, DI Carlo R, Meli R.
Department of Experimental Pharmacology, University of Naples Federico II, 80131 Naples, Italy.

Raloxifene (RAL) is a selective estrogen receptor modulator (SERM), presenting tissue-specific agonist activity. The aim of this study was to examine whether RAL has an estrogenic effect on carrageenan-induced acute inflammation. Adult female rats were ovariectomized seven weeks before edema or pleurisy to deplete circulating estrogens. Edema formation and selected inflammatory markers in inflamed paw tissue were measured in intact (SHAM) and ovariectomized (OVX) rats. Groups of OVX rats were treated with RAL (1, 3 or 10 mg/kg) or 17beta-estradiol (E2, 25 microg/kg) and these treatments began 2 days after surgery and continued until carrageenan paw edema or pleurisy. Ovariectomy amplifies the inflammation and we found that RAL, as well as E2, attenuates inflammation and tissue damage associated with paw edema and pleurisy. In treated rats there is a decrease in edema development and formation, and in polymorphonuclear cell infiltration and migration, as shown by myeloperoxidase measurement and cell counting. RAL and E2 treatments decrease COX-2 and iNOS expression in inflamed areas, and counteract the inhibition of PPAR-gamma expression caused by ovariectomy, restoring this receptor protein expression to SHAM levels and identifying a possible PPAR-dependent anti-inflammatory effect of these drugs. Moreover, RAL and E2 increase cytoprotective hsp72 protein expression, which seems to be closely associated with the remission of the inflammatory reaction. In addition, we confirm the anti-inflammatory effect of RAL in male rats using a single administration of RAL or E2.

Obstet Gynecol. 2005 May;105(5):1278-80.
Malignant mixed mullerian tumor of the uterus in a patient taking raloxifene.
Goldman NA, de Los Angeles MM, Jones JG, Goldberg GL.
Department of Obstetrics and Gynecology and Women's Health, Division of Gynecologic Oncology; and Department of Pathology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.

BACKGROUND: Uterine malignant mixed mesodermal tumor is a rare variant of uterine cancer. Data suggest that tamoxifen is involved in the pathogenesis. We report a case of a women in whom a malignant mixed mesodermal tumor was diagnosed while she was taking raloxifene, which is also a selective estrogen receptor modulator. CASE: A malignant mixed mesodermal tumor was diagnosed in a 64-year-old woman with a bicornuate uterus while she was taking raloxifene for osteoporosis prevention. Diagnosis had been delayed secondary to sampling of the other uterine horn. CONCLUSION: There may be an association between raloxifene and the development of malignant mixed mesodermal tumor. Special attention should be paid when attempting to sample the endometrium in patients with mullerian abnormalities.

Curr Med Res Opin. 2005 Jan;21(1):135-40.
Year-by-year analysis of cardiovascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial.
Keech CA, Sashegyi A, Barrett-Connor E.
Eli Lilly and Company, Indianapolis, IN, USA.

OBJECTIVE: To assess the effect of raloxifene 60 mg/day (RLX) on year-by-year cardiovascular (CV) events in postmenopausal women participating in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a double-blind, placebo-controlled osteoporosis treatment trial. RESEARCH DESIGN AND METHODS: Post hoc analysis, using data from participants receiving placebo (N = 2576) or RLX 60 mg/day (N = 2557) in MORE, was performed to determine the relative risk (RR, 95% CI) of CV events in each individual trial year. Analyses were performed for the overall cohort and for women in high and low risk subsets. Women were retrospectively assessed as high CV risk using established criteria and the remaining women were considered low CV risk. RESULTS:The incidence of CV events did not differ between the RLX and placebo groups in the overall cohort (RR 0.86, 95% Cl 0.64-1.15), or the low CV risk subset (RR 1.01, 95% Cl 0.70-1.46). In the high-risk subset, the incidence of CV events was less in the RLX group (RR 0.60, 95% Cl 0.38-0.95). There was no significant increase in CV risk during any single year in the RLX group for either the overall cohort or the low or high CV risk subsets. CONCLUSION: In this post hoc analysis, the risk of CV events was not increased in any single year of MORE in women taking RLX, either in the overall cohort or in the low and high CV risk subsets.

Maturitas. 2005 Mar 14;50(3):182-8.
Effects of raloxifene on serum malondialdehyde, erythrocyte superoxide dismutase, and erythrocyte glutathione peroxidase levels in healthy postmenopausal women.
Kaya H, Ozkaya O, Sezik M, Arslanoglu E, Yilmaztepe A, Ulukaya E.
Department of Obstetrics and Gynecology, School of Medicine, Suleyman Demirel University, Isparta, Turkey.

Objective: To investigate the relationship between raloxifene administration and serum malondialdehyde (MDA), erythrocyte superoxide dismutase (SOD), erythrocyte glutathione peroxidase (GPx) levels in healthy postmenopausal women. Methods: In a randomized and placebo-controlled design, 80 women received either 60mg/day raloxifene or placebo for 24 weeks. MDA, SOD, and GPx levels were assessed at 0,4,12, and 24 weeks. Wilcoxon signed-rank test and Mann-Whitney U test were used for comparisons. Results: Six women in the treatment arm and eight women in the placebo group discontinued the study. Mean serum MDA levels were significantly (p = 0.001) decreased from 11.4nmol/ml at baseline to 8.9nmol/ml at week 12 with raloxifene treatment. Mean erythrocyte SOD activity was significantly (p = 0.02) reduced from 1472U/gHb at baseline to 1173U/gHb at week 12 following raloxifene administration. Lowered serum MDA and erythrocyte SOD levels persisted during treatment. On contrary, erythrocyte GPx levels did not change significantly with raloxifene administration. Conclusions: Raloxifene (60mg/day) lowers serum MDA levels and erythrocyte SOD activity in postmenopausal women after 12 weeks of treatment. The clinical implications of these findings need to be determined.

Neuroimage. 2005 Mar;25(1):63-75. Epub 2005 Jan 12.
Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior.
Goekoop R, Duschek EJ, Knol DL, Barkhof F, Netelenbos C, Scheltens P, Rombouts SA.
Department of Neurology, VU University Medical Center, De Boelelaan 1117 1081 HV, Amsterdam, The Netherlands.

Raloxifene is a selective estrogen receptor modulator (SERM) that is prescribed in females only, but its use in male subjects is increasingly considered. With a growing number of patients having potential benefit from raloxifene, the need for an assessment of its effects on brain function is growing. Effects of estrogens on brain function are very subtle and difficult to detect by neuropsychological assessment. Functional imaging techniques, however, have been relatively successful in detecting such changes. This study used functional magnetic resonance imaging (fMRI) to examine effects of raloxifene treatment on memory function. Healthy elderly males (n = 28; mean age 63.6 years, SD 2.4) were scanned during performance on a face encoding paradigm. Scans were made at baseline and after 3 months of treatment with either raloxifene (n = 14) or placebo (n = 14). Treatment effects were analyzed using mixed-effects statistical analysis (FSL). Activation during task performance involved bilateral parietal and prefrontal areas, anterior cingulate gyrus, and inferior prefrontal, occipital, and mediotemporal areas bilaterally. When compared to placebo, raloxifene treatment significantly enhanced activation in these structures (Z > 3.1), except for mediotemporal areas. Task performance accuracy diminished in the placebo group (P = 0.02), but remained constant in the raloxifene group (P = 0.60). In conclusion, raloxifene treatment enhanced brain activation in areas spanning a number of different cognitive domains, suggesting an effect on cortical arousal. Such effects may translate into small effects on behavior, including effects on attention and working memory performance, executive functions, verbal skills, and episodic memory. Further neuropsychological assessment is necessary to test the validity of these predictions.

Clin Calcium. 2004 Oct;14(10):1570-4.
[Safety profile of raloxifene.]
[Article in Japanese]
Morii H.
Osaka City University, Japan Osteoporosis Society.

Selective estrogen receptor modulators (SERMs) are a diverse group of non-steroidal (non hormonal) compounds developed to offer the postmenopausal women many of the advantages of estrogen therapy (ET) while avoiding undesired effects on reproductive and other tissues. Tamoxifen and toremifene, first generation SERMs are used for the adjuvant treatment of breast cancer worldwide, but their stimulatory effect on the uterus prevents their widespread use in other indications. A second generation SERM, raloxifene hydrochloride, a benzothiophene SERM is fully safe for the uterus and significantly reduces the risk of vertebral fractures in postmenopausal women with osteoporosis. The safety and efficacy of raloxifene in postmenopausal women have been studied extensively in more than 40,000 women over 50 clinical trials in 30 countries. The majority of the trials have been large double-blind placebo-controlled trials, including Asia and Japan. Raloxifene is well tolerated, with the only common side effects significantly higher than placebo being hot flushes and minor leg cramps. Venous thromboembolism was the only adverse events of clinical significance but rare associated with raloxifene in Caucasian women, but was not observed so far in Asian countries.

Clin Calcium. 2004;14(10):1551-1554.
[Effects of SERM on breast cancer and cardiovascular disease:making a comparison between raloxifene use and hormone replacement therapy about the risks of the diseases.]
[Article in Japanese]
Higuchi T, Mizunuma H.
Department of OB/GYN Hirosaki University School of Medicine.

According to the report of MORE trial, raloxifene (RLX) compensate for the faults of hormone replacement therapy with the reasons following below;1) RLX inhibits onset of breast cancer with estrogen receptor remarkably, 2) RLX inhibits onset of cardiovascular disease in its high risk group. However, because RLX has a elevated risk of venous thrombosis as same as hormone replacement therapy, we should give attention to this disease at the use of RLX.

Clin Calcium. 2004 Oct;14(10):1543-50.
[Defining the role of raloxifene as a therapeutic agent for postmenopausal osteoporosis:focus on its pharmacological properties.]
[Article in Japanese]
Ohta H.
Department of Obstetrics and Gynecology, Tokyo Women's Medical University.

In this semiar, I propose to describe the pharmacological properties of raloxifene that provide a basis for its role in the treatment of postmenopausal osteoporosis. These pharmacological properties can be described as providing therapeutic benefits in the following three areas:1) reduction in bone turnover, 2) increases in bone mineral density, and 3) risk reduction in fractures. While reloxifene shares these effects with conventional bisphosphonates that are in common use for postmenopausal osteoporosis, it exerts its antiresorptive effects through a different mechanism of action from those of the bisphosphonates. Furthermore, raloxifene exerts its stimulatory or inhibitory effects on estrogen in a tissue-specific fashion as a selective estrogen-receptor-modulator (SERM), thereby providing a wide range of clinical benefits that result from its ability to exert estrogen-like beneficial effects in tissues other than bone while at the same time inhibiting estrogen-like deleterious effects in other tissues. I therefore propose to define the role of raloxifene as a viable therapeutic option in the treatment of postmenopausal osteoporosis in light of these unique pharmacological features. Current data suggests that raloxifene can be positioned somewhere in between hormone replacement therapy (HRT) and bisphosphonates, and is highly likely to be suitable for use in patients between the ages of 55 and 70, while other agents may be indicated in special populations, such as premenopausal patients, postmenopausal patients with hot flushes, or elderly patients who may be placed at accelerated risk of developing femoral neck fractures. Thus, as a novel therapeutic option with unique clinical benefits, a far greater role may be expected for raloxifene in the treatment of postmenopausal osteoporosis than for other conventional therapeutic agents.

Clin Calcium. 2004 Oct;14(10):1525-30.
[The effects of Raloxifene on other organs without bone:Uterus.]
[Article in Japanese]
Nozaki M.
Department of Obsterics and Gynecology Graduate School of Medical Sciences Kyushu University.

Tamoxifen and Toremifene act as agonistic on uterine myometrium and endometrium. Tamoxifen leads re-enlargement of uterine myomas, recurrence of adenomyosis, atypical genital bleeding for endometrial hyperplasia and endometrial carcinoma in postmenopausal women. Therefore, it is necessary to evaluate the stage of pathological change on myometrium and endometrium, both before and during the period of administration of tamoxifen or toremifene. Unlike these drugs, raloxifene has an antagonistic action on uterine myometrium and endometrium. From these standpoints, we consider that raloxifene use lower the risks of uterine myomas, adenomyosis, endometrial hyperplasia and endometrial carcinoma.

Clin Calcium. 2004 Oct;14(10):1551-60.
Effect of hormone therapy and raloxifene on serum VE-cadherin in postmenopausal women.
Christodoulakos G, Lambrinoudaki I, Panoulis C, Papadias C, Economou E, Creatsas G.
Second Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, Athens, Greece.

OBJECTIVE: To investigate the effect of continuous combined hormone therapy and raloxifene on serum VE-cadherin. DESIGN: The study was double blinded, with a placebo run-in period of 28-50 days. SETTING: University menopause clinic. PATIENT(S): Twenty-eight healthy postmenopausal women devoid of climacteric complaints. INTERVENTION(S): Subjects were randomized to 17beta-estradiol (2 mg) + norethisterone acetate (1 mg; E(2)-NETA) or raloxifene hCL (60 mg) for a period of 6 months. MAIN OUTCOME MEASURE(S): Serum VE-cadherin, which was estimated at baseline and at month 6. RESULT(S): Serum VE-cadherin decreased significantly in both E(2)-NETA and raloxifene groups (raloxifene baseline +/- SD: 1.17 +/- 0.44 ng/mL, 6 months: 0.82 +/- 0.29 ng/mL; E(2)-NETA baseline: 1.19 +/- 0.47 ng/mL, 6 months: 0.92 +/- 0.49 ng/mL). Percentage changes from baseline were -21.7 +/- 24.3 for E(2)-NETA and -26.0 +/- 20.6 for raloxifene. CONCLUSION(S): The effect of E(2)-NETA and raloxifene suggests that these drugs may preserve interendothelial junction integrity and control vascular permeability. Although this effect may influence the progress of the atheromatous lesion, its clinical impact on coronary artery disease (CAD) remains uncertain.

Clin Calcium. 2004 Apr;14(4):632-7.
[Bone quality and raloxifene.]
[Article in Japanese]
Nakamura T.
Department of Orthopaedic Surgery, University of Occupational and Environmental Health.

Bone turnover affects fracture risk. Degrees of fracture risk reduction by antiresorptive agents are larger than those expected from the rates of BMD increase. Actually, fracture risk reduction by raloxifene is largely dependent on the effects of bone turnover regulation. Raloxifene stabilizes the trabecular structure, maintains the activities of micro-injury repair and healing of fracture, and increases the mean values of the degrees of tissue mineralization and the distribution of their ranges. The relationship between the fracture risk reduction and the changes in these parameters of bone quality is not clear. Further information is necessary based on the data of clinical practice.

Biol Reprod. 2004 Dec 1;
Differential Effects of Estrogen and Raloxifene on Messendger RNA and Matrix Metalloproteinase 2 Activity in Rat Uterus.
Helvering LM, Adrian MD, Geiser AG, Estrem ST, Wei T, Huang S, Chen P, Dow ER, Calley JN, Dodge JA, Grese TA, Jones SA, Halladay DL, Miles RR, Onyia JE, Ma YL, Sato M, Bryant HU.

A detailed analysis of the differential effects of estrogen (E) compared to raloxifene (Ral), a selective estrogen receptor modulator (SERM), following estrogen receptor binding in gynecological tissues was conducted using gene microarrays, northern analysis and MMP2 activity studies. We profiled gene expression in the uterus following acute (1 day) and prolonged daily treatment (5 weeks) of E and Ral in ovariectomized rats. E regulated twice as many genes as Ral, largely those associated with catalysis and metabolism, whereas Ral treatment induced genes associated with cell death and negative cell regulation. Follow-up studies confirmed that genes associated with matrix integrity were differentially regulated by Ral and E at various timepoints in uterine and vaginal tissues. Additional experiments were conducted to determine the levels of MMP2 activity in uterus explants from ovariectomized rats following 2 weeks of treatment with E, Ral, or one of two additional SERMs: lasofoxifene, and levormeloxifene. E and lasofoxifene stimulated uterine MMP2 activity to a level twice that of Ral while levormeloxifene elevated MMP2 activity to a level 12 times that of Ral. These data show that one of the significant differences between E and Ral signaling in the uterus is the regulation of genes and proteins associated with matrix integrity. This may be a potential key difference between the action of SERMs in the uterus of postmenopausal women.

J Natl Cancer Inst. 2004 Dec 1;96(23):1751-61.
Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene.
Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, Secrest RJ, Cummings SR; CORE Investigators.
Cancer Institute Medical Group, 2001 Santa Monica Blvd., Ste. 560W, Santa Monica, CA 90404, USA. smartino@cimg.org

BACKGROUND: The randomized, double-blind Multiple Outcomes of Raloxifene Evaluation (MORE) trial found that 4 years of raloxifene therapy decreased the incidence of invasive breast cancer among postmenopausal women with osteoporosis by 72% compared with placebo. We conducted the Continuing Outcomes Relevant to Evista (CORE) trial to examine the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer in women in MORE who agreed to continue in CORE. METHODS: Women who had been randomly assigned to receive raloxifene (either 60 or 120 mg/day) in MORE were assigned to receive raloxifene (60 mg/day) in CORE (n = 3510), and women who had been assigned to receive placebo in MORE continued on placebo in CORE (n = 1703). Breast cancer incidence was analyzed by a log-rank test, and a Cox proportional hazards model was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: During the CORE trial, the 4-year incidences of invasive breast cancer and estrogen receptor (ER)-positive invasive breast cancer were reduced by 59% (HR = 0.41; 95% CI = 0.24 to 0.71) and 66% (HR = 0.34; 95% CI = 0.18 to 0.66), respectively, in the raloxifene group compared with the placebo group. There was no difference between the two groups in incidence of ER-negative invasive breast cancer during CORE (P = .86). Over the 8 years of both trials, the incidences of invasive breast cancer and ER-positive invasive breast cancer were reduced by 66% (HR = 0.34; 95% CI = 0.22 to 0.50) and 76% (HR = 0.24; 95% CI = 0.15 to 0.40), respectively, in the raloxifene group compared with the placebo group. During the CORE trial, the relative risk of thromboembolism in the raloxifene group compared with that in the placebo group was 2.17 (95% CI = 0.83 to 5.70). This increased risk, also observed in the MORE trial, persisted over the 8 years of both trials. CONCLUSIONS: The reduction in invasive breast cancer incidence continues beyond 4 years of raloxifene treatment in postmenopausal women with osteoporosis. No new safety concerns related to raloxifene therapy were identified during CORE.

Am J Cardiol. 2004 Dec 1;94(11):1453-6.
Effects of hormone replacement therapy or raloxifene on ambulatory blood pressure and arterial stiffness in treated hypertensive postmenopausal women.
da Costa LI, de Oliveira MA, Rubim VS, Wajngarten M, Aldrighi JM, Rosano GM, Neto CD, Gebara OC.
General Hospital, Santa Casa Misericordia of Rio de Janeiro, Rio de Janeiro, Brazil.

The administration of oral raloxifene in 30 postmenopausal hypertensive women was evaluated to demonstrate its effect on arterial stiffness. Casual and ambulatory blood pressure (BP) and pulse-wave velocity (PWV) data were obtained before and after patients received raloxifene, estrogen-progestin replacement therapy, or placebo in a randomized crossover study. It was shown that the 2 therapies decreased BP and carotid-femoral PWV, and the effect of raloxifene on vascular compliance was independent of the effects on BP.

J Pharmacol Exp Ther. 2004 Nov 18;
Raloxifene Relaxes Rat Pulmonary Arteries and Veins: Roles of Gender, Endothelium and Antagonism of Ca2+ Influx.
Chan Y, Leung F, Yao X, Lau C, Vanhoutte PM, Huang Y.
Chinese University of Hong Kong.

Effects of raloxifene have been documented in the systemic circulation. However, its impact on the pulmonary circulation is unclear. The present study investigated the role of gender, endothelial modulation and Ca(2+) channel in relaxations evoked by raloxifene in rat pulmonary arteries and veins. Vascular responses were studied on isolated pulmonary blood vessels mounted in a myograph and constricted by U46619. Constrictions to CaCl2 were studied in Ca(2+)-free, 60 mM K(+) solution. Changes in the intracellular calcium ion concentration ([Ca(2+)]i) in vascular smooth muscle were measured using a calcium fluorescence imaging method. Raloxifene was more effective in relaxing U46619-constricted pulmonary arteries from male than female rats. Raloxifene-induced relaxation was unaffected by ICI 182,780, inhibition of nitric oxide (NO) pathway, or removal of the endothelium. In arteries without endothelium, raloxifene attenuated CaCl2-induced constriction and CaCl2-stimulated increase in [Ca(2+)]i with similar potencies. Raloxifene caused endothelium-independent relaxations in pulmonary veins albeit to a lesser degree than in pulmonary arteries. The venous responses showed a gender difference as raloxifene was more potent in male veins. In summary, raloxifene relaxed rat pulmonary arteries and this effect did not involve the endothelium/NO or ICI 182,780-sensitive estrogen receptors. Raloxifene, like nifedipine, reduced both constriction and [Ca(2+)]i increase in response to CaCl2 in high K(+) solution. Raloxifene also relaxed high K(+)-constricted pulmonary veins. Our data indicate that raloxifene acutely relaxes rat pulmonary blood vessels primarily via inhibition of Ca(2+) influx through voltage-sensitive Ca(2+) channels. Finally, raloxifene induced more relaxation in blood vessels isolated from male than female rats.

Bone. 2004 Nov;35(5):1164-8.
Treatment with raloxifene for 2 years increases vertebral bone mineral density as measured by volumetric quantitative computed tomography.
Genant HK, Lang T, Fuerst T, Pinette KV, Zhou C, Thiebaud D, Diez-Perez A.
Department of Radiology, University of California, San Francisco, CA 94143-0628, United States; Synarc, Inc., San Francisco, CA 94105, United States.

Volumetric quantitative computed tomography (vQCT), using multiple thin-slice acquisition, measures three-dimensional volumetric bone mineral density (BMD, mg/cm(3)). vQCT is often used to measure BMD of lumbar vertebrae and may detect early changes in trabecular, cortical, or integral BMD that extend beyond the technical limits of areal dual X-ray absorptiometry (DXA) BMD measurements. The objective of this study was to determine the effect of 2 years of raloxifene (RLX) treatment on several volumetric BMD measures in a subset of postmenopausal women (n = 58) enrolled in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Patients in this study were randomized to one of three treatment groups: placebo (n = 21), RLX 60 mg/day (n = 17), or RLX 120 mg/day (n = 20), and all patients received daily calcium (500 mg) and vitamin D (400-600 IU) supplementation. Data from the raloxifene treatment groups were pooled for each analysis. Following 2 years of raloxifene treatment, there was a significant percent change from baseline in the vQCT regions of interest (ROIs) of midintegral BMD, total trabecular BMD, and total integral BMD (P < 0.05) compared to placebo, while there was no significant change in the spinal DXA BMD measurement. These data provide the first longitudinal assessment by vQCT of changes in vertebral bone density after 2 years of treatment with raloxifene. vQCT appears to be a valuable technique for measuring the effects of raloxifene treatment in this population of postmenopausal women with osteoporosis.

Gynecol Endocrinol. 2004 Jun;18(6):291-8.
Comparative vascular effects of hormone replacement therapy and raloxifene in women at increased cardiovascular risk.
Cerquetani E, Vitale C, Mercuro G, Fini M, Zoncu S, Rosano GM.
Department of Internal Medicine, San Raffaele Hospital, Rome, Italy.

Hormone replacement therapy (HRT) improves endothelial function in postmenopausal women while the effects of raloxifene, a selective estrogen receptor modulator, are still under debate. The aim of this study was to evaluate endothelium-dependent flow-mediated vasodilatation in the brachial artery and plasma levels of nitrite, nitrate and endothelin-1 in 20 postmenopausal women with increased cardiovascular risk treated with either HRT or raloxifene for 4 weeks in a randomized double-blind single cross-over study. Patients had an endothelium-dependent flow-mediated dilatation of 4% prior to initiation of the study. Treatment with HRT resulted in a 67% increase in dilatation compared with baseline (from a 7.4% increase to a 12.4% increase, p < 0.01). Raloxifene treatment resulted in no change in vasodilatation from baseline. Endothelium-dependent dilatation was significantly improved by HRT compared with raloxifene treatment (12.4+/-0.6% vs. 6.1+/-2.0%; p < 0.01). Compared with baseline values, nitrate plus nitrite levels increased significantly (p < 0.05) with HRT but not with raloxifene. Similarly, endothelin-1 decreased from baseline with both treatments, but only the HRT-induced decrease was statistically significant (p < 0.05). In conclusion, HRT improved endothelial function and reduced plasma levels of endothelin-1 in postmenopausal women at risk of coronary artery disease. These beneficial effects were not shared by raloxifene.

J Clin Endocrinol Metab. 2004 Oct 19;
Protection of Bone Mass by Estrogens and Raloxifene During Exercise-induced Weight Loss.
Gozansky W, Van Pelt R, Jankowski C, Schwartz R, Kohrt W.
Division of Geriatric Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado.

The aim of this study was to determine whether estrogen and/or raloxifene help to conserve bone mineral density (BMD) during moderate weight loss. Postmenopausal women (n = 68) participated in a 6-month weight loss program that consisted primarily of supervised exercise training. Another 26 women were studied over 6 months of weight stability. All participants were randomized to 3 treatment arms: placebo, raloxifene (60 mg/d), or hormone therapy (HT; conjugated estrogens, 0.625 mg/d; trimonthly medroxyprogesterone acetate, 5 mg/d for 13 days, for women with a uterus). Changes in body weight (mean+/-SE) averaged 0.8 +/- 0.5 kg in the weight stable group and -4.1 +/- 0.4 kg in the weight loss group. Across all measured skeletal sites, average changes in BMD in weight stable women were -0.6 +/- 1.1% (n = 7), 0.9 +/- 0.6% (n = 9), and 3.0 +/- 0.7% (n = 10) in the placebo, raloxifene, and HT groups, respectively; comparable BMD changes in the weight loss groups were -1.5 +/- 0.5% (n = 22), -0.5 +/- 0.5% (n = 23), and 1.1 +/- 0.4% (n = 23). There were no significant interactions between weight loss and drug treatment on changes in BMD, but there were significant main effects of weight loss on lumbar spine (P = 0.022), total hip (P = 0.010), and trochanter BMD (P < 0.001). These findings suggest that weight loss, even when modest in magnitude and induced by exercise training, causes a reduction in BMD, particularly in women not on raloxifene or HT. It is not known whether reductions in BMD of this magnitude increase risk for osteoporotic fracture.

Obstet Gynecol. 2004 Oct;104(4):837-44.
Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation.
Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A, Cummings S; Multiple Outcomes of Raloxifene Evaluation Investigators.
University of California-San Francisco, 1634 Divisadero Street, Suite 600, San Francisco, CA 94115, USA. dgrady@itsa.ucsf.edu

OBJECTIVE: To examine the effect of raloxifene on major adverse events that occur with postmenopausal estrogen therapy or tamoxifen. METHODS: The Multiple Outcomes of Raloxifene Evaluation, a multicenter, randomized, double-blind trial, enrolled 7,705 postmenopausal women with osteoporosis. Women were randomly assigned to raloxifene 60 mg/d or 120 mg/d or placebo. Outcomes included venous thromboembolism, cataracts, gallbladder disease, and endometrial hyperplasia or cancer. RESULTS: During a mean follow-up of 3.3 years, raloxifene was associated with an increased risk for venous thromboembolism (relative risk [RR] 2.1; 95% confidence interval [CI] 1.2-3.8). The excess event rate was 1.8 per 1,000 woman-years (95% CI -0.5-4.1), and the number needed to treat to cause 1 event was 170 (95% CI 100-582) over 3.3 years. Risk in the raloxifene group was higher than in the placebo group for the first 2 years, but decreased to about the same rate as in the placebo group thereafter. Raloxifene did not increase risk for cataracts (RR 0.9; 95% CI 0.8-1.1), gallbladder disease (RR 1.0; 95% CI 0.7-1.3), endometrial hyperplasia (RR 1.3; 95% CI 0.4-5.1), or endometrial cancer (RR 0.9; 95% CI 0.3-2.7). CONCLUSION: Raloxifene was associated with an increased risk for venous thromboembolism, but there was no increased risk for cataracts, gallbladder disease, endometrial hyperplasia, or endometrial cancer. LEVEL OF EVIDENCE: I

Mol Cell Biochem. 2004 Jun;261(1-2):71-5.
Comparison of raloxifene and atorvastatin effects on serum lipids composition of healthy post-menopausal women.
Piperi C, Kalofoutis C, Lagogianni I, Troupis G, Kalofoutis A.
Department of Biological Chemistry, School of Medicine, University of Athens, Athens, Greece.

The aim of this study was to evaluate the effects of the selective oestrogen receptor modulator, raloxifene, and those of statin, atorvastatin, in reducing the cardiovascular risks associated with the post-menopausal status. A detailed study of serum lipid concentrations was performed in four groups of post-menopausal women receiving either placebo, raloxifene or atorvastatin alone or their combination for the period of three months. Group A (raloxifene) showed significant decrease in total cholesterol levels (P < 0.05) and an increase in phospholipids concentration (P < 0.05), followed by a marked reduction in low-density lipoprotein cholesterol (LDL-C) levels (P < 0.01) and ApoB amounts (P < 0.001). Additionally, ApoA-I concentration was significantly increased (P < 0.01). Group B (atorvastatin) presented decreased cholesterol (P < 0.05) and triglycerides levels (P < 0.01), followed by elevated high-density lipoprotein cholesterol (HDL-C) concentration (P < 0.05) and low LDL-C amounts (P < 0.001). ApoA-I was significantly increased (P < 0.001) whereas ApoB was reduced (P < 0.001). The combined treatment in Group C (raloxifene and atorvastatin) showed significant changes in the majority of serum lipids. In particular, total cholesterol was reduced (P < 0.001), as well as triglycerides (P < 0.001) levels. Phospholipids were raised (P < 0.01) whereas LDL-C was reduced (P < 0.001) as was ApoB (P < 0.001). Furthermore, ApoA-I was elevated (P < 0.001). A further attempt to evaluate each treatment group was performed and the significance of these results is discussed.