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1.
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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Antiresorptive treatment of postmenopausal osteoporosis: review of randomized clinical studies and rationale for the Evista alendronate comparison (EVA) trial.
Lufkin, EG, Sarkar, S, Kulkarni, PM, Ciaccia, AV, Siddhanti, S, Stock, J, Plouffe, L
Current medical research and opinion. 2004;(3):351-7
Abstract
Standard pharmacological antiresorptive therapy for the prevention and/or treatment of postmenopausal osteoporosis now consists of four categories of drugs: estrogens, a selective estrogen receptor modulator (SERM), bisphosponates, and calcitonin. All of these drugs have been studied in randomized controlled trials, but meaningful comparisons of the efficacy of drugs have been difficult due to differences in baseline risks for fracture and differences in study design, including calcium and vitamin D supplementation, definition of fracture, and discontinuation rates. The current paper reviews results from pivotal studies of antiresorptive therapies with fracture as a primary endpoint, as well as head-to-head trials comparing these therapies using surrogate markers of fracture risk, and introduces the first head-to-head trial with fracture as a primary endpoint. The Evista Alendronate Comparison (EVA) trial, a multi-center, double-blind, double-dummy, randomized trial with two active treatment arms is currently underway to compare directly the osteoporotic fracture risk reduction efficacy of raloxifene and alendronate in postmenopausal women with osteoporosis as defined by bone mineral density. The results from this trial will permit more informed judgment by practitioners and provider groups concerning the relative clinical utility of these two drugs.
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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
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2004;(6):291-8
Abstract
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.
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The effects of raloxifene and simvastatin on plasma lipids and endothelium.
Sbarouni, E, Flevari, P, Kroupis, C, Kyriakides, ZS, Koniavitou, K, Kremastinos, DT
Cardiovascular drugs and therapy. 2003;(4):319-23
Abstract
PURPOSE Raloxifene is a selective estrogen receptor modulator and an attractive alternative to estrogen replacement as it obviates the need for a progestin and does not increase C-reactive protein levels. We compared the effects of simvastatin and raloxifene treatments on the lipid profile, the levels of adhesion molecules and the endothelium dependent and independent vasoreactivity. SUBJECTS & METHODS We treated 12 postmenopausal women with hypercholesterolemia and coronary artery disease with raloxifene 60 mg/day and simvastatin 20 mg/day in a randomized, double-blind, crossover study. Each treatment period was 8 weeks long with a 4-week washout interval. Plasma lipids and cellular adhesion molecules were evaluated and peripheral blood flow studies with venous occlusion plethysmography were performed. RESULTS Both simvastatin and raloxifene significantly reduced total [33% (27-40), 12% (0-24)] and LDL [44% (36-52), 16% (0-33)] cholesterol compared to baseline values (p < 0.05) but simvastatin was more effective than raloxifene (p < 0.005). None of the treatments had any significant effect on HDL cholesterol and triglyceride levels. Only raloxifene significantly reduced Lp(a) [18% (1-36)] and ICAM-1 [17% (8-25)] and VCAM-1 [24% (15-33)] plasma levels compared to baseline (p = 0.019, p < 0.0001 and p = 0.003, respectively). Hyperemic blood flow response on raloxifene was significantly higher compared to baseline [52% (0-105)], (p < 0.05), whereas no significant change was noted on simvastatin. Endothelium independent blood flow induced by nitroglycerine was not influenced by either active treatment. CONCLUSIONS Raloxifene administration is associated with lower ICAM-1, VCAM-1 and Lp(a) plasma levels and enhanced endothelium dependent dilation compared to simvastatin although simvastatin is more powerful in total and LDL cholesterol reduction.
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Medical treatment of vertebral osteoporosis.
Lippuner, K
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. 2003;(Suppl 2):S132-41
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Abstract
Although osteoporosis is a systemic disease, vertebral fractures due to spinal bone loss are a frequent, sometimes early and often neglected complication of the disease, generally associated with considerable disability and pain. As osteoporotic vertebral fractures are an important predictor of future fracture risk, including at the hip, medical management is targeted at reducing fracture risk. A literature search for randomized, double-blind, prospective, controlled clinical studies addressing medical treatment possibilities of vertebral fractures in postmenopausal Caucasian women was performed on the leading medical databases. For each publication, the number of patients with at least one new vertebral fracture and the number of randomized patients by treatment arm was retrieved. The relative risk (RR) and the number needed to treat (NNT, i.e. the number of patients to be treated to avoid one radiological vertebral fracture over the duration of the study), together with the respective 95% confidence intervals (95%CI) were calculated for each study. Treatment of steroid-induced osteoporosis and treatment of osteoporosis in men were reviewed separately, based on the low number of publications available. Forty-five publications matched with the search criteria, allowing for analysis of 15 different substances tested regarding their anti-fracture efficacy at the vertebral level. Bisphosphonates, mainly alendronate and risedronate, were reported to have consistently reduced the risk of a vertebral fracture over up to 50 months of treatment in four (alendronate) and two (risedronate) publications. Raloxifene reduced vertebral fracture risk in one study over 36 months, which was confirmed by 48 months' follow-up data. Parathormone (PTH) showed a drastic reduction in vertebral fracture risk in early studies, while calcitonin may also be a treatment option to reduce fracture risk. For other substances published data are conflicting (calcitriol, fluoride) or insufficient to conclude about efficacy (calcium, clodronate, etidronate, hormone replacement therapy, pamidronate, strontium, tiludronate, vitamin D). The low NNTs for the leading substances (ranges: 15-64 for alendronate, 8-26 for risedronate, 23 for calcitonin and 28-31 for raloxifene) confirm that effective and efficient drug interventions for treatment and prevention of osteoporotic vertebral fractures are available. Bisphosphonates have demonstrated similar efficacy in treatment and prevention of steroid-induced and male osteoporosis as in postmenopausal osteoporosis. The selection of the appropriate drug for treatment of vertebral osteoporosis from among a bisphosphonate (alendronate or risedronate), PTH, calcitonin or raloxifene will mainly depend on the efficacy, tolerability and safety profile, together with the patient's willingness to comply with a long-term treatment. Although reduction of vertebral fracture risk is an important criterion for decision making, drugs with proven additional fracture risk reduction at all clinically relevant sites (especially at the hip) should be the preferred options.
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[A randomised clinical trial to study the effects of raloxifene hydrochloride on bone mineral density, biochemical markers of bone metabolism and serum lipids in postmenopausal women].
Zheng, SR, Wu, YY, Zhang, ZL, Yang, X, Hui, Y, Zhang, Y, Chen, SL, Den, WH, Liu, H, Ekangaki, A, et al
Zhonghua fu chan ke za zhi. 2003;(4):226-9
Abstract
OBJECTIVE To determine the effect of raloxifene hydrochloride (RLX) on bone mineral density (BMD), biochemical markers of bone metabolism and lipid metabolism in Chinese postmenopausal women. METHODS This was a multicenter, randomized, double blind placebo controlled study in China with a total of 204 postmenopausal women [mean age (60 +/- 5) years (x +/- s) and weight (63 +/- 9) kg (x +/- s)] treated with either RLX 60 mg (n = 102) or placebo (n = 102) daily for 12 months. BMD, serum lipid and bone markers were determined before and after drug administration. RESULTS Compared to placebo, RLX produced a significant increase in both total lumbar spine and total hip BMD. For the lumbar spine, percentage increase in total BMD was 2.30% with RLX compared to a decrease of 0.08% with placebo (P < 0.001). Corresponding values for total hip BMD were 2.46% increase for RLX and 1.07% for placebo (P < 0.05). For biochemical markers of bone metabolism, serum osteocalcin and C-telopeptide, percentage decrease were 27.6% and 24.0% in raloxifene-treated subjects. Corresponding values in placebo were 10.6% decrease and 15.8% increase (RLX compared to placebo, both P < 0.001). For total cholesterol and low-density lipoprotein cholesterol, percentage decrease were 6.4% and 34.6% in the raloxifene-treated group. Corresponding values in placebo were 1.4% increase and 19.1% decrease (RLX compared to placebo, both P < 0.001). No differences were found for high-density lipoprotein cholesterol or triglyceride levels between the two groups. Only 5 subjects discontinued early due to an adverse event (3 in the RLX group and 2 in the placebo group). CONCLUSIONS This study confirms that RLX exerts positive effects on the skeleton, increasing BMD and decreasing biochemical markers of bone metabolism, and decreased total cholesterol and low-density lipoprotein cholesterol in postmenopausal women in China.
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A rationale for the reinitiation of adjuvant tamoxifen therapy in women receiving fewer than 5 years of therapy.
Gradishar, WJ, Hellmund, R
Clinical breast cancer. 2002;(4):282-6
Abstract
The overview analysis of adjuvant therapy trials in early-stage breast cancer by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) compared 1, 2, and 5 years of adjuvant therapy. The optimal benefit to patients in terms of reduced risk of recurrence and death was clearly conferred by 5 years of therapy with tamoxifen compared to shorter durations of therapy. Many women with early-stage breast cancer treated in the past received a recommendation for shorter durations of tamoxifen therapy. The obvious question is whether reinitiating tamoxifen to complete a full 5-year course would further reduce the risk of recurrence and death. In an attempt to explore this issue, we have analyzed recurrence rates in women who received different durations of tamoxifen therapy in the adjuvant setting. The data used for this analysis are directly from the EBCTCG. Our analysis suggests that women who received 1-2 years of adjuvant tamoxifen therapy may benefit from reinitiation of tamoxifen to complete a 5-year course.
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The effects of estrogen and selective estrogen receptor modulators on cardiovascular risk factors.
Walsh, BW
Annals of the New York Academy of Sciences. 2001;:163-7
Abstract
Raloxifene, a selective estrogen receptor modulator, favorably alters several markers of cardiovascular risk in healthy postmenopausal women. While many of its effects are similar to those of conventional hormone replacement therapy (HRT), there are also important differences. Raloxifene lowered low-density lipoprotein cholesterol levels similarly to estrogen. However, raloxifene lacked the potentially beneficial effects of HRT on high-density lipoprotein cholesterol levels and plasminogen activation inhibitor-1, as well as the potentially adverse effects of HRT on triglycerides and C-reactive protein. Raloxifene also had a potentially beneficial fibrinogen-lowering effect not seen with conventional HRT. The net effect of these differences is unclear. Proof that raloxifene or HRT reduces the risk of heart disease must await the results of ongoing clinical trials with cardiovascular event end points.
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Effects of estrogen and the selective estrogen receptor modulator raloxifene on markers of inflammation in postmenopausal women.
Blum, A, Schenke, WH, Hathaway, L, Mincemoyer, R, Csako, G, Waclawiw, MA, Cannon, RO
The American journal of cardiology. 2000;(8):892-5