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The effects of selective estrogen receptor modulator treatment following hormone replacement therapy on elderly postmenopausal women with osteoporosis.
Hayashi, T, Ina, K, Maeda, M, Nomura, H
Nitric oxide : biology and chemistry. 2011;(4):199-203
Abstract
OBJECTIVES A comparison between the atheroprotective and osteoprotective effects of the selective estrogen receptor modulator (SERM) raloxifene and those of hormone replacement therapy (HRT) has not been made in elderly women. METHODS A randomized prospective controlled trial was performed in a cohort of 32 elderly Japanese women with osteoporosis receiving HRT (estriol plus medroxyprogesterone) for more than 1 year. In 16 randomly selected subjects, HRT was changed to raloxifene therapy (60mg/day, 71.4±3.4 years, SERM group). The other 16 patients were continued on HRT (71.8±2.9 years, HRT group). As a control group, 14 subjects were enrolled, did not take any medications and were age-matched to experimental patients (72.5±3.3 years, control group). Plasma lipids, TNFα, adiponectin, NO metabolites (NOx:NO2(-) and NO3(-)), cyclicGMP and bone-mineral density (BMD) were evaluated at baseline and at 26 and 52 weeks after enrollment. RESULTS SERM (Raloxifene) increased high-density-lipoprotein cholesterol levels and tended to decrease low-density-lipoprotein cholesterol levels (P=0.058) compared with baseline. Adiponectin, NOx and cGMP levels were significantly increased after 6 months compared with baseline or the HRT group. TNFα was decreased by raloxifene. In control subjects, no significant changes were observed in any of these markers. Bone-mineral density was higher at baseline in the raloxifene and HRT groups than in the control group, and BMD increased 12 months after baseline in the HRT and control group. CONCLUSION SERM improved BMD and endothelial function in elderly postmenopausal women with osteoporosis who had received HRT, and these effects were comparable to or slightly stronger than those of HRT. Changes in adiponectin and TNFα may underlie the improvements in endothelial function, such as NO signaling.
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Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study.
Miller, PD, Chines, AA, Christiansen, C, Hoeck, HC, Kendler, DL, Lewiecki, EM, Woodson, G, Levine, AB, Constantine, G, Delmas, PD
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2008;(4):525-35
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Abstract
UNLABELLED Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2-yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD. INTRODUCTION Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24-mo, randomized, double-blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis. MATERIALS AND METHODS Healthy postmenopausal women with a BMD T-score at the lumbar spine or femoral neck between -1.0 and -2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism. RESULTS The intent-to-treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 +/- 0.28%, 1.41 +/- 0.28%, 1.49 +/- 0.28%, and 1.49 +/- 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C-telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain. CONCLUSIONS Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.
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Effect of raloxifene -- a selective oestrogen receptor modulator -- on kidney function in post-menopausal women with Type 2 diabetes: results from a randomized, placebo-controlled pilot trial.
Hadjadj, S, Gourdy, P, Zaoui, P, Guerci, B, Roudaut, N, Gautier, JF, Chabin, M, Mauco, G, Ragot, S, ,
Diabetic medicine : a journal of the British Diabetic Association. 2007;(8):906-10
Abstract
AIMS: Epidemiological and experimental data suggest that activation of the oestrogen receptor pathway limits the incidence and the progression of diabetic nephropathy. We tested the hypothesis that raloxifene protects against increasing urinary albumin excretion in post-menopausal women with Type 2 diabetes in a randomized pilot clinical trial. METHODS We included 39 post-menopausal women with Type 2 diabetes and micro- or macro-albuminuria in a 6-month, double-blind, placebo-controlled trial: 20 received placebo and 19 received 60 mg raloxifene per day. The albumin : creatinine ratio (ACR) in urine was determined on three consecutive days during the week before randomization and during the week before the final visit. RESULTS One patient in each group dropped out in the first 3 weeks, leaving 37 patients for the analysis (19 on placebo and 18 on raloxifene). From randomization to the final visit, mean ACR was unchanged in the placebo group {277 microg/mg (67; 651) [median (interquartile range)] vs. 284 microg/mg (79; 1508)} but decreased slightly in the raloxifene group [376 microg/mg (67; 615) vs. 243 microg/mg (103; 549)]. This corresponds to a change of +24 (-37; +517) for the placebo group vs. -10 microg/mg (-36; +16) for the raloxifene group (P = 0.11). In multivariate analysis, raloxifene treatment (P(adjusted) = 0.013), baseline low-density lipoprotein (LDL) cholesterol (P(adjusted) = 0.023) and change in LDL cholesterol (P(adjusted) = 0.008) were related to the absolute change in ACR. Adverse effects were similar in the two groups. CONCLUSIONS These results suggest that raloxifene may limit the progression of albuminuria in post-menopausal women with diabetes; further studies in a larger population are warranted.
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Association of bone metabolism related genes polymorphisms with the effect of raloxifene hydrochloride on bone mineral density and bone turnover markers in postmenopausal women with osteoporosis.
Zhang, ZL, He, JW, Qin, YJ, Huang, QR, Liu, YJ, Hu, YQ, Li, M
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2006;(2):129-33
Abstract
OBJECTIVE To investigate the association of bone metabolism related genes polymorphisms with the effect of raloxifene hydrochloride(RLX) on bone mineral density (BMD) and bone turnover markers in postmenopausal women with osteoporosis. METHODS A total of 68 unrelated postmenopausal women with osteoporosis of Han ethnicity aged 47-74 years were randomly divided into 2 groups of 34 women: RLX group (60 mg were given daily for 12 months) and placebo group. BMD and bone turnover markers were measured at baseline, 6 and 12 months after treatment. The polymorphisms of Xba I and Pvu II sites in estrogen receptor 1 gene(ESR1), Ras I site in ESR2 gene, and start codon (Fok I) and CDX2 binding sites in vitamin D receptor gene (VDR) were analyzed. RESULTS A total of 58 patients completed 12 months of study period. By the end of study, the increased percentage of BMD in lumbar spine 2-4 (L2-4), total hip, and trochanter were found significantly different between RLX group and placebo group(P<0.05), and the decreased percentage of C-telopeptide and osteocalcin were significantly different between the two groups (P<0.01). The BMD of total hip and trochanter of women with FF genotypes of VDR Fok I site were decreased by 1.98%+/-4.86% and 2.26%+/-4.73% respectively in the RLX group, but those of women with Ff/ff genotypes were increased by 2.52%+/-2.75% and 2.74 %+/-2.97%, respectively(P<0.05). Moreover, the total hip BMD of women with PP/Pp genotypes of ESR1 Pvu II site was increased by 2.12%+/-2.78%, and of women with pp genotype it was decreased by 1.34%+/-3.73%(P<0.05). However, no significant association was observed of the polymorphisms of five sites with the changes of BMD and bone turnover markers in the placebo group. CONCLUSION The effect of RLX on BMD in postmenopausal women with osteoporosis is regulated by the polymorphisms of Fok I of VDR gene and Pvu II of ESR1 gene. The study is valuable to select this drug according to genotype of patients in clinical.
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Effects of raloxifene on lipid and lipoprotein levels in postmenopausal osteoporotic women with and without hypertriglyceridemia.
Dayspring, T, Qu, Y, Keech, C
Metabolism: clinical and experimental. 2006;(7):972-9
Abstract
This post hoc analysis reports the effects of raloxifene on lipids and lipoproteins in 2659 women with either normal (< or =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 beta-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.
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Does raloxifene treatment influence back pain and disability among postmenopausal women with osteoporosis?
Papadokostakis, G, Katonis, P, Damilakis, J, Hadjipavlou, A
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2005;(10):977-81
Abstract
Clinical studies have suggested that postmenopausal women on estrogen replacement treatment are more likely to experience back pain and related disability compared to women who do not take estrogens. Raloxifene, a selective estrogen receptor modulator has estrogen-like effects on bone tissue, and antagonize the action of estrogens on endometrium and breast tissue. It is unknown if the treatment of osteoporosis with raloxifene has estrogen-like or opposite effects on back pain and functional capacity among postmenopausal women with osteoporosis. A total of 120 postmenopausal women with osteoporosis and chronic back pain were randomized to receive raloxifene 60 mg with 1,000 mg calcium, and 800 IU vitamin D daily or 1,000 mg calcium and 800 IU vitamin D daily. Pain intensity and pain-related disability were measured before treatment at 6 months and after 1 year. Repeated measures of ANOVA, did not reveal statistically significant differences over time, on pain intensity and disability scores, between groups studied. There was a trend in pain intensity changes during the follow-up period, but the differences between the groups were not statistically significant. It seems that treatment with raloxifene does not influence back pain and disability among postmenopausal women with osteoporosis. Raloxifene may have estrogenic agonist effects on nociceptive processing in the central nervous system.
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A comparison of raloxifene and calcium plus vitamin D on vaginal atrophy after discontinuation of long-standing postmenopausal hormone therapy in osteoporotic women. A randomized, masked-evaluator, one-year, prospective study.
Checa, MA, Garrido, A, Prat, M, Conangla, M, Rueda, C, Carreras, R
Maturitas. 2005;(1):70-7
Abstract
OBJECTIVES We assessed the effects of the discontinuation of long-standing transdermal estrogen replacement therapy (>4 years) and substitution of this treatment by calcium or raloxifene on the vaginal epithelium and climateric symptoms in a study population of osteoporotic women. METHODS A total of 136 women (mean age 55.5 years) were randomized to calcium (500 mg elemental calcium, 400 IU Vitamin D3) (n=40), raloxifene (60 mg/day) (n=48), or estrogen patches (3.9 mg estradiol) and progesterone (100 mg/day) (n=48). Treatment was given for 1 year. The vaginal maturation value (VMV), serum estradiol levels, and climateric symptoms using a 12-item modification of the SF-36 quality of life questionnaire were evaluated at baseline and at 6 and 12 months. RESULTS At 6 months, mean VMV decreased significantly (P<0.001) in the calcium (-51.8%) and raloxifene (-18.6%) groups compared with baseline and the estrogen/progesterone group. At 12 months, significant decreases of mean VMV in the calcium (-38.7%) and raloxifene groups (-32%) (P<0.001) were also observed. Serum estradiol levels and changes of VMV correlated significantly at 6 months (rho=0.361, P<0.01) and at 12 months (rho=0.269, P<0.035). A significantly higher number of patients complained of hot flushes and palpitations in the calcium and raloxifene groups than in the estrogen/progesterone group. Raloxifene-treated women reported a significantly higher number of adverse events at 6 months compared to the other treatment groups. CONCLUSIONS Withdrawal and change of long-standing transdermal hormone replacement therapy by treatment with calcium or raloxifene resulted in worsening of vaginal atrophy assessed by the VMV, although it was not clinically perceived by the patients. However, increases in dyspareunia and urinary leaks were reported. Menopausal complaints related to vasomotor symptoms worsened in the calcium- and raloxifene-treated groups and persisted throughout the study period.
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Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal women.
Francucci, CM, Daniele, P, Iori, N, Camilletti, A, Massi, F, Boscaro, M
Journal of endocrinological investigation. 2005;(7):623-31
Abstract
The aim of our prospective, randomised, controlled and open-label clinical study was to evaluate in healthy post-menopausal women the effects of raloxifene (RLX) on body fat distribution and lipids, and the correlations between these parameters. The fat distribution, by dual energy X-ray absorptiometry, and lipids were evaluated at baseline and after 1 yr in 50 post-menopausal women: 25 were treated with RLX 60 mg/die, while 25 served as control group (CG). After 1 yr, we observed in RLX-users a slight reduction of fat mass in trunk and central region and an increase in legs and, in relation to CG, significantly lower values of adiposity in trunk and abdominal region (p < 0.05). At the same time, HDL-cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) were significantly increased in relation to baseline values and CG (p < 0.05) and apolipoprotein B (ApoB), total cholesterol/HDL-C, LDL cholesterol/ HDL-C, and ApoB/ApoA1 ratios significantly decreased compared to baseline values and CG (p < 0.05). No correlation was underlined among lipids and regional fat distribution. These results highlight the positive effect of RLX on lipids and suggest, for the first time, that RLX promotes the shift from android to gynoid fat distribution, and prevents the uptrend of abdominal adiposity and body weight compared with untreated women.
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Vascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: incidence, patient characteristics, and effect of raloxifene.
Duvernoy, CS, Kulkarni, PM, Dowsett, SA, Keech, CA
Menopause (New York, N.Y.). 2005;(4):444-52
Abstract
OBJECTIVE To determine the incidence of arterial and venous thromboembolic (VTE) events, to determine the effect of raloxifene on the incidence of combined vascular (arterial and VTE) events, and to identify patient characteristics associated with these vascular events, in women participating in the MORE trial. DESIGN In a post hoc analysis using MORE data, arterial, VTE, and combined vascular event rates were compared between participants receiving placebo (n = 2,576) and those receiving 60 mg/d of raloxifene (n = 2,557). Baseline characteristics were compared between those who did and did not experience an arterial event. The same analysis was performed for VTE events. RESULTS Overall, during a mean follow-up time of 41 months, 178 women experienced an arterial event and 40 experienced a VTE event. In the placebo group, the incidence of arterial events exceeded VTE events by at least sevenfold. Raloxifene had no significant effect on the incidence of combined vascular events in the overall cohort (hazard ratio 0.95, 95% CI, 0.73-1.24). In a subset of women retrospectively determined to be at increased cardiovascular risk, raloxifene was associated with a lower incidence of combined vascular events (hazard ratio 0.63, 95% CI, 0.40-0.97). Baseline characteristics differed between those who did and those who did not experience an arterial event, but this was generally not the case for VTE events. CONCLUSIONS Arterial events were more common than VTE events. The characteristics of women experiencing an arterial event differed from those experiencing a VTE event. Raloxifene had a neutral effect on the risk of combined vascular events in the overall population, and was associated with a reduced combined vascular event rate in women at increased cardiovascular risk. Additional studies are needed to confirm the effect of raloxifene on overall vascular outcomes.
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Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women.
Komi, J, Lankinen, KS, Härkönen, P, DeGregorio, MW, Voipio, S, Kivinen, S, Tuimala, R, Vihtamäki, T, Vihko, K, Ylikorkala, O, et al
Menopause (New York, N.Y.). 2005;(2):202-9
Abstract
OBJECTIVE To compare ospemifene and raloxifene regarding their effects on hormones, lipids, genital tract, and tolerability in postmenopausal women. DESIGN A randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) of ospemifene or 60 mg (n = 29) of raloxifene for 3 months. RESULTS There were no significant differences in the baseline characteristics between study groups. In comparison with raloxifene, follicle-stimulating hormone levels decreased significantly more in the 90-mg ospemifene group and sex hormone-binding globulin levels increased more in all ospemifene groups. Total cholesterol and low-density lipoprotein cholesterol levels decreased more in raloxifene than in ospemifene groups, although the difference in low-density lipoprotein cholesterol between 90-mg ospemifene and raloxifene was not significant. Endometrial thickness did not change in any study group and endometrial biopsies showed atrophy in the majority of subjects at 3 months. All ospemifene groups demonstrated a clear estrogenic effect on the vaginal epithelium, as seen in Pap smears. This was in sharp contrast to the raloxifene group, which had no effect on the vaginal epithelium. Kupperman index decreased in all study groups during treatment. The adverse events were mild, mainly single cases, and no clustering of events was observed. There were no clinically significant abnormal findings in laboratory safety parameters. CONCLUSIONS Ospemifene, at the dose of 90 mg/day, was more estrogenic than raloxifene, as shown by changes in serum follicle-stimulating hormone and sex hormone-binding globulin levels. Neither agent stimulated endometrium, but in contrast to raloxifene, ospemifene had a clear estrogenic effect in the vagina. Further studies with ospemifene are needed in subjects with vaginal atrophy.