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The Multiple Outcomes of Raloxifene Evaluation trial included postmenopausal women with osteoporosis randomized to placebo, raloxifene 60 mg/day, or raloxifene 120 mg/day for 4 years. The protocol specified subgroups based on whether or not patients had a vertebral fracture at baseline. Absolute differences between placebo and raloxifene 60 mg/day (the approved dose) for endpoints in these groups were defined as the incidence in the raloxifene group minus the incidence in the placebo group.
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Nationwide cohort study from Denmark with all users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) as exposed group and three age- and gender-matched controls from the general population (n = 310,683). Adjustments were made for prior fracture, use of systemic hormone therapy, and use of systemic corticosteroids.
Seven and fourteen days after wounding, samples from OVX rats showed a decrease in transforming growth factor-beta1, tissue transglutaminase 2 and vascular endothelial growth factor compared to samples from sham OVX rats. Oestradiol, raloxifene and genistein all significantly modified this decrease, but the lowest genistein dose exerted a greater effect than the other treatments. Moreover, the lowest dose of genistein was the most effective in improving skin healing and wound tensile strength.
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The importance of statins for the prevention and treatment of coronary artery disease (CAD), the recent paradoxical effects of hormone replacement therapy on prevention of CAD, and the role of nontraditional risk factors in CAD in women are examined.
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Postmenopausal women (n=10 101; mean age, 67 years) were randomized to raloxifene 60 mg/d or placebo for a median of 5.6 years. Coronary outcomes were assessed by treatment group in women with coronary heart disease risk factors and those with established coronary heart disease. Raloxifene had no effect on the incidence of coronary events in any subgroup except in the case of a post hoc age subgroup analysis using age categories defined in the Women's Health Initiative randomized trials. The effect of raloxifene on the incidence of coronary events differed significantly by age (interaction P=0.0118). The incidence of coronary events in women <60 years of age was significantly lower in those assigned raloxifene (50 events) compared with placebo (84 events; hazard ratio, 0.59; 95% confidence interval, 0.41 to 0.83; P=0.003; absolute risk reduction, 36 per 1000 women treated for 1 year). No difference was found between treatment groups in the incidence of coronary events in women > or =60 and <70 or > or =70 years of age.
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Women of minority race/ethnicity have been underrepresented in United States-based breast cancer chemoprevention trials. Searches of Medline between 1966 and 2004 were done with priority given to recent reports (1996-2004), and references from bibliographies of relevant articles. Large chemoprevention trials have reported significant breast cancer risk reduction and increased risk of serious adverse events in tamoxifen-treated, high-risk women, which illustrates the need to carefully assess the risk/benefits of this therapy. The mathematical model used for this purpose in the United States-based trials has resulted in the inclusion of very few women of minority racial/ethnic backgrounds. The continued use of this risk assessment that has not been adequately validated for its usefulness in non-Caucasian populations, should be reviewed, especially given that adequate alternative nonmathematical models exist. Current and future chemoprevention trials should also use nonmathematical selection criteria to ensure that eligible underrepresented minorities are adequately included in these trials.
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Hip fracture is a devastating outcome associated with postmenopausal osteoporosis. This fracture causes considerable pain, disability, diminished quality of life, and mortality. Although bone loss is an important factor associated with hip fracture, there are other demographic and clinical factors such as those that increase the risk of falling (e.g., unsteady gait, medications) that contribute to the likelihood of experiencing a hip fracture. Nonpharmacological interventions to reduce hip fracture risk include regular weight-bearing exercise, fall intervention programs, and external hip protectors. Patients should receive calcium and/or vitamin D supplementation as necessary. Among available pharmacologic options, the bisphosphonates, risedronate (Actonel) and alendronate (Fosamax), have reduced the risk of hip fracture in postmenopausal women with osteoporosis. Raloxifene (Evista), salmon calcitonin nasal spray (Miacalcin), and teriparatide (Forteo) have not demonstrated hip fracture risk reduction in controlled clinical trials. Hormone therapy (HT) reduced hip fracture risk in a recent large placebo-controlled trial; however, the risk/benefit profile of HT has resulted in recommendations to consider alternatives for the management of osteoporosis. Postmenopausal women with osteoporosis should receive adequate calcium/vitamin D supplementation, be encouraged to exercise, and institute risk factor interventions. Treatment with a bisphosphonate should be considered for those who are also at increased risk for hip fracture.
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Despite the potentially protective effects of estrogen on bone and cardiovascular tissue as well as against kidney diseases, its effects on diabetic nephropathy are unknown. Here, we examined the therapeutic effectiveness of 17beta-estradiol and raloxifene, a selective estrogen receptor modulator, for preventing functional and histological alterations in the kidneys of db/db mice, a model of type 2 diabetes. In the first experiment, ovariectomized female db/db mice were treated with 17beta-estradiol for 8 weeks. The treatment significantly ameliorated albuminuria, attenuated weight gain, and reduced hyperglycemia in diabetic ovariectomized db/db mice. Histologically, the increases in mesangial area and the accumulation of fibronectin were significantly inhibited by 17beta-estradiol. In the second experiment, mice were administered vehicle or raloxifene hydrochloride (3 mg/kg/day) for 8 weeks. Raloxifene significantly reduced mesangial expansion and fibronectin accumulation in db/db mice, but in contrast to 17beta-estradiol, it failed to affect body weight or hyperglycemia. An in vitro experiment further demonstrated that raloxifene inhibited transforming growth factor beta-1-induced fibronectin transcription and AP-1 activity. Thus, our findings suggest that raloxifene, which lacks the harmful effects of estrogen, is useful for the treatment of diabetic nephropathy.
This article reviews lasofoxifene, a new-generation selective estrogen receptor modulator (SERM) that is currently in Phase III development for the prevention and treatment of osteoporosis in postmenopausal women. This compound selectively binds to both of the estrogen receptors with a high affinity and a median inhibitory concentration that is similar to that seen with estradiol and > or = 10-fold higher than those reported for other SERMs (raloxifene and tamoxifen). Lasofoxifene has a remarkably improved oral bioavailability with respect to other SERMs due to increased resistance to intestinal wall glucuronidation. In both preclinical and short-term studies, the compound showed a favourable safety profile and demonstrated a proven efficacy in preventing bone loss and lowering cholesterol levels. Dose modelling from Phase II studies allowed the selection of lasofoxifene 0.25 mg/day as the lowest fully effective dose.
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An increase in blood pressure after menopause has been documented. The renin-angiotensin-aldosterone system (RAAS) plays a central role in the regulation of blood pressure and in the pathophysiology of hypertension. This study investigated the effects of raloxifene, a selective estrogen receptor modulator, on components of the RAAS and blood pressure in hypertensive and normotensive osteoporotic postmenopausal women.
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Antiestrogens such as tamoxifen are one of the most effective methods of treating estrogen receptor (ERalpha) positive breast cancers; however, the effectiveness of this therapy is limited by the almost universal development of resistance to the drug. If antiestrogens are recognized differently by the cell as it has been suggested, then in disease conditions where tamoxifen fails to function effectively, a mechanistically different antiestrogen might yield successful results. Although many antiestrogens have been developed, a direct comparison of their mechanisms of action is lacking, thus limiting their utility. Therefore, to determine if there are mechanistic differences among available antiestrogens, we have carried out a comprehensive analysis of the molecular mechanisms of action of 4-hydroxy-tamoxifen (40HT), idoxifene, raloxifene, GW7604, and ICI 182,780. Using a novel set of peptides that recognize different surfaces on ERalpha, we have found that following binding to ERalpha, each ligand induces a distinct ERalpha-ligand conformation. Furthermore, transcriptional assays indicate that each ERalpha-ligand complex is recognized distinctly by the transcription machinery, and consequently, antiestrogens vary in their ability to inhibit estradiol- and 40HT-mediated activities. Relative binding assays have shown that the affinity of these ligands for ERalpha is not always representative of their inhibitory activity. Using this assay, we have also shown that the pharmacology of each antiestrogen is influenced differently by hormone binding proteins. Furthermore, GW7604, like ICI 182,780, but unlike the other antiestrogens evaluated, decreases the stability of the receptor. Overall, our results indicate that there are clear mechanistic distinctions among each of the antiestrogens studied. However, GW7604 and ICI 182,780 differ more significantly from tamoxifen than idoxifene and raloxifene. These data, which reveal differences among antiestrogens, should assist in the selection of compounds for the clinical regulation of ERalpha function.
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Double-blind, randomised controlled trial of six-month duration.
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Forty women, 54-59 years of age, in physiological menopause for 6 months to 4 years, were enrolled in the study and treated with raloxifene 60 mg/day for 6 months. All had blood pressure less than 130/85 mm Hg at the start of the study. The women were divided into two groups: the first (group A; 20 women) with normal blood pressure and the second (group B; 20 women) with previous high blood pressure treated with antihypertensive drugs, not angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
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Until recently, calcium supplementation with vitamin D and hormone replacement therapy were the mainstays of treating osteoporosis associated with the menopause. Hormone replacement therapy, indeed, was (and is) effective in preventing fracture, but is no longer to be considered to be a primary indication for this purpose. Thus, while continuing with calcium and vitamin D, drug therapy now consists of the antiresorptive agents: raloxifene, calcitonin, and the bisphosphonates. These drugs reduce bone turnover, and do prevent fractures, but are limited to halting further deterioration of skeletal microarchitecture. The newest agent against osteoporosis is teriparatide, an amino terminal fragment parathyroid hormone containing 34 amino acids. PTH(1-34), or teriparatide, exhibits many of the classical actions of the whole molecule. It is anabolic with respect to bone when used according to well-defined protocols. Bone microarchitecture is restored with increases in cortical thickness and in connectivity. This paper describes the activities as known at present of the bisphosphonates and of teriparatide and reviews studies of their use alone and in combination with each other.
Major advancements in the treatment of osteoporosis have occurred over the last decade. Therapies including the anti-resorptive drugs such as alendronate and risedronate have been shown in randomized placebo-controlled trials to increase bone mineral density and reduce fracture risk. Anabolic therapy in the form of parathyroid hormone has been introduced as the first treatment to build bone mass. However, gaps in our knowledge about specific management issues that arise frequently among primary care providers persist. In this paper, three common clinical scenarios are discussed: a postmenopausal woman with only slightly reduced bone mineral density; an osteoporotic woman on anti-resorptive therapy for more than 5 years; and a woman who continues to fracture despite treatment. Evidence gaps in each treatment scenario are presented, and rational approaches to management are suggested.
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Raloxifene hydrochloride (R-HCl), a BCS class II drug, remains a mainstay in the prevention and pharmacologic therapy of osteoporosis. Its absolute bioavailability, however, is 2% due to poor solubility and extensive first pass metabolism. The present study describes two simultaneous approaches to improve its bioavailability, complexation of R-HCl with cyclodextrin(s), and formulation of mucoadhesive microspheres of the complex using different proportions of carbopol and HPMC. Microspheres were pale yellow in color, free-flowing, spherical, and porous in outline. The particle size ranged between 3 and 15 μm, and entrapment efficiency was found to be within 81.63% to 87.73%. A significant improvement in the solubility of R-HCl was observed, and it differed with the combination of excipients used. X-ray diffraction and differential scanning calorimetry studies revealed that enhancement in drug solubility was resulted due to a change in its crystallinity within the formulation. Microspheres possessed remarkable mucoadhesion and offered controlled drug release, lasting up to 24 h. They produced a sharp plasma concentration-time profile of R-HCl within 30 min post-administration to Wistar rats. [AUC](0-24 h) was found to be 1,722.34 ng h/ml, and it differed significantly to that of pure drug powder (318.28 ng h/ml). More than fivefold increase in AUC and more than twofold increase in MRT were observed. FT-IR studies evidenced no interaction among drug and excipients. The results of this study showed that mucoadhesive microspheres could be a viable approach to improve the pharmacokinetic profile of R-HCl.
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Forty-nine patients with cirrhotic ESLD (26 men, 23 women; median age 54 years) had dual energy x-ray absorptiometry preformed at baseline and 4 and 12 months after OLT. Immunosuppression therapy after OLT included a standard transplant protocol of daily tacrolimus to maintain plasma levels between 0.2 to 0.5 ng/mL and daily oral prednisone tapered over 4 months. BMD was measured at the lumbar spine (L-BMD) and left hip (hip BMD) and reported as raw density (g/cm2) and T score (standard deviations from gender-matched young healthy subjects). Results represent total hip measurements. Two-sided paired t test and analysis of variance methods were used for statistical comparisons.
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Evidence from this study supports screening for breast cancer risk in all postmenopausal women by use of risk factors and breast density and considering chemoprevention for those found to be at high risk. Several lifestyle changes with the potential to prevent breast cancer should be recommended regardless of risk.
Raloxifene is a polyaromatic compound which has been reported to form radicals when incubated with horseradish peroxidase resulting in formation of a homo-dimer product. Polyaromatic phenols have also been reported to undergo oxidation by P450 enzymes to form reactive intermediates, presumably through the formation of phenoxy radical species. Recently, we observed that a raloxifene homo-dimer was formed in vitro when incubated with CYP3A4. In response to this finding, a series of experiments were designed to determine whether the observed raloxifene homo-dimer was formed via solution phase chemistry similar to that previously documented with horseradish peroxidase or if generation of the homo-dimer occurred within the P450 active site. To this end, a series of experiments were carried out to determine the structure of the CYP3A4 generated raloxifene homo-dimer using analytical techniques including: high resolution MS, NMR and H/D exchange. In addition, a variety of in vitro techniques were applied to characterize the mechanism responsible for formation of the raloxifene homo-dimer. Collectively, the results of these experiments suggest that unlike the homo-dimer formed by peroxidase enzymes, raloxifene homo-dimer formation mediated by CYP3A4 is a consequence of two raloxifene molecules binding simultaneously within the active site of a catalytically competent P450 enzyme.
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Lumbar spine BMD changed from baseline to 36 months as follows: placebo (mean percentage change + SE), -1. 32% +0.22%; raloxifene, 30 mg, 0.71% +0.23%; raloxifene, 60 mg, 1. 28% +0.23%; and raloxifene, 150 mg, 1.20% +0.24%. Comparable BMD changes were observed in the hip and total body. Biochemical markers of bone turnover were suppressed by raloxifene to normal premenopausal ranges through 3 years. Serum low-density lipoprotein cholesterol was reduced 7% to 12% below baseline through 3 years. Study withdrawals due to any reason (37%) and withdrawals due to adverse events (14%) were not different among groups. The only significant adverse effect of therapy was hot flashes (25% in the 60-mg raloxifene group vs 18% in the placebo group); hot flashes were typically reported as mild and were not associated with study withdrawal (1.7% for 60-mg raloxifene vs 2.4% for placebo).
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The aim of this study was to improve the physicochemical properties and bioavailability of a poorly water-soluble drug, raloxifene by solid dispersion (SD) nanoparticles using the spray-drying technique. These spray-dried SD nanoparticles were prepared with raloxifene (RXF), polyvinylpyrrolidone (PVP) and Tween 20 in water. Reconstitution of optimized RXF-loaded SD nanoparticles in pH 1.2 medium showed a mean particle size of approximately 180 nm. X-ray diffraction and differential scanning calorimetry indicated that RXF existed in an amorphous form within spray-dried nanoparticles. The optimized formulation showed an enhanced dissolution rate of RXF at pH 1.2, 4.0, 6.8 and distilled water as compared to pure RXF powder. The improved dissolution of raloxifene from spray-dried SD nanoparticles appeared to be well correlated with enhanced oral bioavailability of raloxifene in rats. Furthermore, the pharmacokinetic parameters of the spray-dried SD nanoparticles showed increased AUC(0-∞) and C(max) of RXF by approximately 3.3-fold and 2.3-fold, respectively. These results suggest that the preparation of RXF-SD nanoparticles using the spray drying technique without organic solvents might be a promising approach for improving the oral bioavailability of RXF.
Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination.
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a randomized double-blind study was conducted in 33 ovulatory premenopausal women with fibroadenoma. Patients were divided into two groups: Placebo, (n=18) and Raloxifene 60 mg, (n=15). The medication was used for 22 days, beginning on the first day of the menstrual cycle. An excisional biopsy was carried out on the 23rd day of the menstrual cycle and a sample of normal breast tissue adjacent to the fibroadenoma was collected and submitted to immunohistochemical study using anti-Bax polyclonal antibody to evaluate the expression of Bax protein. Immunoreaction for Bax was evaluated taking into consideration intensity and fraction of stained cells, whose combination resulted in a final score ranging from 0 to 6. Cases with a final score >3 were classified as positive for Bax. The c2 test was used for statistical analysis (p<0.05).
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The recognition of selective estrogen receptor modulation in the laboratory has resulted in the development of two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, for clinical application in healthy women. SERMs are antiestrogenic in the breast but estrogen-like in the bones and reduce circulating cholesterol levels. SERMs also have different degrees of estrogenicity in the uterus. Tamoxifen is used specifically to reduce the incidence of breast cancer in premenopausal and postmenopausal women at risk for the disease. In contrast, raloxifene is used specifically to reduce the risk of osteoporosis in postmenopausal women at high risk for osteoporosis. The study of tamoxifen and raloxifene (STAR) trial is currently comparing the ability of these SERMs to reduce breast cancer incidence in high-risk postmenopausal women. There is intense interest in understanding the molecular mechanism(s) of action of SERMs at target sites in a woman's body. An understanding of the targeted actions of this novel drug group will potentially result in the introduction of new multifunctional medicines with applications as preventive agents or treatments of breast cancer and endometrial cancer, coronary heart disease, and osteoporosis.
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Abstract Raloxifene and low-dose simvastatin can each reduce low-density lipoprotein (LDL) cholesterol without affecting high-density lipoprotein (HDL) cholesterol and triglycerides. The objective of this double-blind, 12-week study is to determine whether raloxifene and simvastatin coadministration gives added benefit beyond either monotherapy in affecting fasting lipoproteins and apolipoproteins. Ninety-five postmenopausal women with moderately elevated LDL cholesterol (mean, 146 mg/dL) were randomized to placebo, raloxifene 60 mg/d, simvastatin 10 mg/d, or raloxifene 60 mg/d coadministered with simvastatin 10 mg/d. Raloxifene, simvastatin, and coadministration therapy reduced mean LDL cholesterol by 10.5%, 23.3%, and 31.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo), and mean apolipoprotein B by 10.4%, 24.2%, and 30.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo). Each active treatment decreased non-HDL cholesterol compared with placebo ( P < .01). Coadministration treatment was more effective than either monotherapy in reducing LDL cholesterol ( P < .05). Coadministration treatment reduced mean apolipoprotein B ( P < .001) and non-HDL cholesterol ( P < .001) when compared with raloxifene, but was not significantly different when compared with simvastatin. Coadministration therapy increased HDL cholesterol and apolipoprotein A1 levels compared with placebo ( P < .02). No significant effect on triglycerides, very low density lipoprotein cholesterol, and lipoprotein (a) occurred with any active treatment. Raloxifene, simvastatin, and the coadministration therapy were generally well tolerated with clinical adverse effects similar to placebo. No woman had clinically significant elevated liver function tests requiring drug discontinuation. Further data on safety and lipid-lowering effects are needed before raloxifene and statin coadministration may be considered as therapeutic interventions for treating postmenopausal women to achieve National Cholesterol Education Program-Adult Treatment Panel III treatment guidelines.
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The primary end point was the intrasubject percent change in BMD at 1 yr measured by dual-energy x-ray absorptiometry.
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Based on their perceived risk of breast cancer, the women had higher value scores for the raloxifene risk profile than for both HRT (p = .002) and no therapy (p = .003), with similar results for analyses based on population risks and from utility scores. Regression analysis showed that the risk of breast cancer (p < .001) was the only disease risk that was statistically significantly associated with women's preferences.
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Raloxifene therapy significantly decreases cardiovascular risk markers LDL, total triglyceride and cholesterol. No abnormal change in breast density and in endometrial thickness indicate good safety profile of this agent.
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The results of the present study suggest that tamoxifen and raloxifene may have the potential to produce CTA in breast cancer patients receiving chemoprevention care.