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Efficacy of raloxifene hydrochloride for the prevention of health care problems in patients who undergo surgery for endometrial cancer: a multicenter randomized clinical trial.
Nakamura, K, Sawada, K, Sugiyama, M, Mabuchi, S, Hisamatsu, T, Nishio, Y, Ito, K, Kimura, T, Kamiura, S, Morishige, K
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2015;(2):288-95
Abstract
OBJECTIVE Removal of the ovaries is common during surgery for endometrial cancer. However, because loss of the ovaries can cause several health problems in patients, strategies for the prevention of such problems need to be established. Hence, we decided to conduct a multicenter randomized clinical trial to assess the effect of raloxifene on bone mineral density (BMD), bone metabolism, and the lipid profile of patients who had undergone surgery for patients with endometrial cancer. MATERIALS AND METHODS Patients with endometrial cancer were enrolled after treatment. The participants were randomized into 2 groups: group 1 included 39 women who received alfacalcidol (1 μg/d) alone and group 2 included 37 women who received alfacalcidol and the test drug, raloxifene hydrochloride, at a dose of 60 mg/d. The BMD of lumbar spine and femoral neck, serum bone markers, as well as lipid profile parameters were evaluated at enrollment as well as 6, 12, and 24 months after the enrollment. The primary efficacy end point was the percentage change from baseline to 24 months in lumbar spine (L2-L4) and femoral neck BMD. RESULTS Sixty-four women completed the 24-month study. At 24 months, the lumbar and femoral neck BMDs were significantly increased in group 2 compared with group 1 (3.5% vs -0.8% and 2.3% vs -2.8%, respectively). In group 2, low-density lipoprotein-cholesterol levels were significantly reduced by 13.6% and serum N-terminal telopeptide of type I collagen as well as bone-specific alkaline phosphatase values were significantly reduced by 16.7% and 25.7%, respectively. The patients who received adjuvant therapy for endometrial cancer showed a significantly higher response to raloxifene (5.8% vs 1.9%). Recurrence was detected in 2 (2.6%) patients in group 1. No severe adverse events were noted in any patient during the study period. CONCLUSIONS Raloxifene exerts positive effects on BMD, bone metabolism, and lipid profile parameters and could provide an improved therapeutic option for patients with endometrial cancer.
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Overlapping and continued alendronate or raloxifene administration in patients on teriparatide: effects on areal and volumetric bone mineral density--the CONFORS Study.
Muschitz, C, Kocijan, R, Fahrleitner-Pammer, A, Pavo, I, Haschka, J, Schima, W, Kapiotis, S, Resch, H
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014;(8):1777-85
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Abstract
Nine month teriparatide (TPTD) monotherapy followed by co-administration of raloxifene (RAL) or alendronate (ALN) for another nine 9 months resulted in incremental bone mineral density (BMD) increase. The aim of this study was to investigate the effects of continued antiresorptive treatments for 12 months in the extension phase. Postmenopausal women (n = 125) with severe osteoporosis on ongoing TPTD treatment for 9 months were randomized into three open-label groups for another 9 months: ALN (70 mg/week, n = 41), RAL (60 mg/d, n = 37) in addition to TPTD or no additional medication (n = 47) except Ca and vitamin D. After discontinuation of TPTD the respective antiresorptives were continued for a further 12 months, while patients in the TPTD monotherapy group received Ca and vitamin D. Amino-terminal propeptide of type I procollagen (P1NP) and cross-linked C-telopeptide (CTX), areal and volumetric BMD at the lumbar spine (LS) and hip were assessed. ALN resulted in continued BMD increase in LS (4.3 ± 1.5%; mean ± SD), femoral neck (4.2 ± 1.6%) and total hip (4 ± 1.6%; p < 0.001 for all), while RAL was only effective at the LS (2.4 ± 1.7%, p < 0.001) but no changes at the femoral neck (0.4 ± 1.4%) or total hip (-0.8 ± 1.5%) were observed. Cortical bone only increased in the ALN group (femoral neck 6.7 ± 2.7% and -1.3 ± 2.5%; total hip 13.8 ± 2.9% and -2.3 ± 2.5% for ALN and RAL, p < 0.001 for all; respectively). Analyzing the entire 30 months of therapy, the ALN group revealed the largest BMD increase in all regions. Our results suggest that the addition of ALN to ongoing TPTD and continuing ALN after TPTD was stopped may be beneficial for patients in terms of areal and volumetric BMD increase. Further research is warranted to determine the optimal timing of the initiation of the combination treatment, the respective antiresorptive medication and the potential benefit of this BMD increase regarding fracture prevention.
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Effects of raloxifene on lipid and bone metabolism in postmenopausal women with type 2 diabetes.
Mori, H, Okada, Y, Kishikawa, H, Inokuchi, N, Sugimoto, H, Tanaka, Y
Journal of bone and mineral metabolism. 2013;(1):89-95
Abstract
Evidence suggests that bone quality is poorer and fracture risk is higher in patients with diabetes, even those with normal bone mineral density. The aim of this study was to determine the effects of raloxifene on lipid, bone, and glucose metabolism in postmenopausal women with type 2 diabetes. The study subjects (144 postmenopausal women aged less than 80 years with type 2 diabetes) were randomly assigned into three groups: no medication, alfacalcidol 1 μg/day, or raloxifene hydrochloride 60 mg/day. The primary endpoint was the change in LDL-C at 6 months. Raloxifene significantly decreased the levels of bone metabolism markers NTX and BAP at 6 months in patients with diabetes. The primary endpoint, LDL-C at 6 months, was significantly lower in the raloxifene group than in the other two groups. However, percent changes in HDL-C were not significantly different among the three groups. Although glucose metabolism was unaffected, homocysteine, a bone quality marker, was significantly decreased at 6 months in the raloxifene group. The percent improvement in LDL-C did not correlate with percent improvement in any bone metabolism or bone quality markers. Raloxifene, unlike estrogen, improved LDL-C and decreased homocysteine, indicating that raloxifene can potentially improve LDL-C as well as bone quality in postmenopausal women with type 2 diabetes.
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Effects of teriparatide on serum calcium in postmenopausal women with osteoporosis previously treated with raloxifene or alendronate.
Wermers, RA, Recknor, CP, Cosman, F, Xie, L, Glass, EV, Krege, JH
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2008;(7):1055-65
Abstract
UNLABELLED The effect of teriparatide (20 microg/day) on serum calcium was examined in postmenopausal women previously treated with alendronate or raloxifene. Women previously treated with alendronate or raloxifene who added teriparatide or switched to teriparatide did not have clinically meaningful increases in mean predose serum calcium. INTRODUCTION The effects of a 6-month treatment with teriparatide (20 microg/day; rhPTH(1-34), TPTD) on serum calcium (Ca) was examined in a prospective study of postmenopausal women previously treated with alendronate (70 mg/week or 10 mg/day [ALN] or raloxifene 60 mg/d [RLX]) for > or =18 months. METHODS Women continued their usual ALN or RLX during a 2-month antiresorptive phase. Women previously treated with ALN were randomized to add TPTD (n = 52) or switch to TPTD (n = 50) and women previously treated with RLX were randomized to add TPTD (n = 47) or switch to TPTD (n = 49). All were to take at least 500 mg/day of elemental Ca and 400-800 IU/day of vitamin D. RESULTS Predose mean serum Ca did not significantly change in groups adding TPTD to either RLX or ALN treatment. In patients who switched from RLX or ALN to TPTD, mean serum Ca increased by 0.05 mmol/L and 0.04 mmol/L respectively. Only 1 patient had the predefined calcium endpoint of serum calcium > 2.76 mmol/L (11 mg/dL) at more than one visit. CONCLUSIONS Women previously treated with ALN or RLX who added TPTD or switched to TPTD did not have clinically meaningful increases in mean predose serum Ca.
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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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Vitamin D insufficiency does not affect bone mineral density response to raloxifene.
Antoniucci, DM, Vittinghoff, E, Blackwell, T, Black, DM, Sellmeyer, DE
The Journal of clinical endocrinology and metabolism. 2005;(8):4566-72
Abstract
CONTEXT Vitamin D insufficiency and osteoporosis are common and often coexist in postmenopausal women. OBJECTIVE The objective of this study was to test whether the presence of vitamin D insufficiency at the initiation of raloxifene therapy affected the subsequent response of bone mineral density (BMD). DESIGN, SETTING, AND PARTICIPANTS We studied 7522 postmenopausal participants of the Multiple Outcomes of Raloxifene Evaluation, a placebo-controlled trial of the effects of raloxifene on BMD and fracture. INTERVENTION After enrollment, all participants began daily supplements of 500 mg calcium and 400-600 IU cholecalciferol; 1 month later, women were randomly assigned to placebo or raloxifene. MAIN OUTCOME MEASURE Serum levels of vitamin D [25-hydroxy vitamin D (25OHD)] were measured at enrollment, randomization, and 6 months later. We categorized participants' vitamin D status (deficient, insufficient, or sufficient) based on their randomization 25OHD level. We estimated the effects of treatment on BMD within these subgroups using linear regression models. RESULTS At enrollment, 3.2% of participants were vitamin D deficient, and 51.8% were insufficient; after 7 months of cholecalciferol supplementation, 0.2% of all participants remained D deficient, and 23.6% remained insufficient. The effects of raloxifene on hip and spine BMD did not vary by vitamin D status at randomization (P = 0.08 and P = 0.7, respectively). CONCLUSION We conclude that vitamin D status at initiation of raloxifene therapy does not affect the subsequent BMD response when coadministered with cholecalciferol and calcium. After 7 months of cholecalciferol therapy, very few women continued to have 25OHD levels in the deficient range; however, 25OHD levels remained suboptimal in nearly one fourth of the cohort. Additional research is needed to determine whether these observations can be generalized to other antiresorptive agents.
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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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Predictors of hot flushes in postmenopausal women who receive raloxifene therapy.
Aldrighi, JM, Quail, DC, Levy-Frebault, J, Aguas, F, Kosian, K, Garrido, L, Bosio-Le Goux, B, Saráchaga, M, Graebe, A, Niño, AJ, et al
American journal of obstetrics and gynecology. 2004;(6):1979-88
Abstract
OBJECTIVE In a previous report, we described the results of a randomized, controlled trial that evaluated the potential of raloxifene to induce or exacerbate hot flushes. Here, we provide additional analyses that were undertaken to identify potential predictors of hot flushes and to assess the clinical usefulness of various therapeutic strategies for the reduction of hot flushes in postmenopausal women who receive raloxifene therapy. STUDY DESIGN In this randomized, double-blind, placebo-controlled study, 487 unselected postmenopausal women were assigned randomly to receive treatment for 8 months with raloxifene, which was administered either at a dose of 60 mg/d every other day for 2 months followed by 60 mg/d (slow-dose escalation) or 60 mg/d throughout (raloxifene), or placebo. Data on the number, duration, intensity, and severity of hot flushes and awakenings because of night sweats were collected. Logistic regression models were used to examine the predictive value of various demographic and menopausal factors on the development or worsening of hot flushes. RESULTS At baseline, 40.4% of all randomly assigned patients had hot flushes. The mean number of hot flushes (3-5 per week) was low. Fewer years postmenopause, surgical menopause, and previous estrogen or estrogen/progestin therapy were significant predictors of hot flushes at baseline but were not predictive of incident hot flushes during treatment with raloxifene. Of the women who received raloxifene therapy who had pre-existing hot flushes at baseline, 36% women had none at the end point. Early postmenopause and surgical menopause were significant predictors of a biologically relevant increase in hot flushes (≥14 flushes/week). Early postmenopause, previous estrogen/progestin therapy, high body mass index, and greater duration of hot flushes at baseline were significant predictors of the need for symptomatic treatment. After 2 months of treatment, women in early postmenopause had significantly more hot flushes with raloxifene therapy than with slow-dose escalation ( P = .042), whereas there was no significant difference between raloxifene therapy and slow-dose escalation among women in later postmenopause. In the 50 patients who requested symptomatic treatment during the study, phytohormones or veralipride did not reduce the number of hot flushes markedly. CONCLUSION A shorter time since menopause and surgical menopause are important predictors of hot flushes both before and during treatment with raloxifene. Previous estrogen/progestin therapy also increases the risk of hot flushes at baseline. For women in early postmenopause, slow-dose escalation of raloxifene therapy may be a suitable therapeutic strategy for the reduction of the risk of hot flushes.
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Compliance and satisfaction with raloxifene versus alendronate for the treatment of postmenopausal osteoporosis in clinical practice: An open-label, prospective, nonrandomized, observational study.
Turbí, C, Herrero-Beaumont, G, Acebes, JC, Torrijos, A, Graña, J, Miguélez, R, Sacristán, J, Marín, F
Clinical therapeutics. 2004;(2):245-56
Abstract
BACKGROUND The treatment of osteoporosis among postmenopausal women represents a major public health challenge because long-term therapy is needed to prevent fractures and chronic disability. Low patient compliance with prescribed osteoporosis treatments can severely distort the validity of controlled clinical trials. Raloxifene and alendronate have been shown to reduce the incidence of osteoporotic fracture in postmenopausal women in well-conducted randomized trials, but few data are available on the rate of adherence to these treatments in routine clinical practice. OBJECTIVE The primary aim of this study was to assess the compliance of postmenopausal women at risk for osteoporotic fractures who were treated with raloxifene hydrochloride (RLX) versus alendronate sodium (ALN) during a 12-month observational period in a routine clinical setting. Secondary objectives were the assessment of factors that might contribute to noncompliance and patient satisfaction. METHODS This open-label, prospective, multicenter, nonrandomized, observational, comparative study was conducted at 154 centers across Spain. Assignment to either RLX or ALN treatment was determined by the physician and was based on each patient's clinical profile. Compliance with RLX (60-mg tablet once daily) versus ALN (10-mg tablet once daily) was assessed using 3 different compliance assessment tools: the Morisky-Green test, the Autocompliance test, and the Compliance Questionnaire. A logistic regression model was used to assess different factors affecting compliance. Patient satisfaction was also assessed using a questionnaire. Adverse events (AEs) were collected as reasons for discontinuation in the Compliance Questionnaire and at the discontinuation visit. RESULTS A total of 902 women (RLX group, n = 476; ALN group, n = 426) were included in the study (mean age, 64.4 [6.9] years). Overall, patients in the RLX group reported significantly better compliance than patients in the ALN group, as collected either by the Morisky-Green test (68.7% vs 54.0%; P < 0.001) or the Autocompliance test (94.7% vs 90.6%; P = 0.033). More patients discontinued treatment prematurely in the ALN group compared with the RLX group (25.8% vs 16.4%; P < 0.001). The age-adjusted relative risk for discontinuation was 1.4-fold higher for women treated with ALN than for those treated with RLX (95% CI, 1.21-1.61). The main reason for premature discontinuation was due to AEs (RLX 4.8% vs ALN 11.0%; P < 0.001). The proportion of patients with gastrointestinal AEs was 9.9% in the ALN group and 3.4% in the RLX group (P < 0.001). Only treatment and type of physician were independent covariates of treatment compliance. After 12 months of observation, significantly more patient in the RLX group were satisfied or very satisfied with their treatment than patients in the ALN group (P < 0.001). CONCLUSION In this study of postmenopausal women at risk for osteoporotic fractures, compliance with 12-month treatment with daily RLX was higher than with daily ALN in clinical setting. RLX showed significant benefits compared with ALN in terms of compliance assessed by means of the Morisky-Green and Autocompliance tests and the patients' self-reported satisfaction.
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A comparison of the effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women.
Reid, IR, Eastell, R, Fogelman, I, Adachi, JD, Rosen, A, Netelenbos, C, Watts, NB, Seeman, E, Ciaccia, AV, Draper, MW
Archives of internal medicine. 2004;(8):871-9
Abstract
BACKGROUND Although many studies have assessed the effects of estrogen and raloxifene hydrochloride on bone mineral density and serum lipid concentrations, there are few direct comparative data. METHODS Randomized placebo-controlled trial for 3 years, intention-to-treat analysis. Six hundred nineteen postmenopausal women with prior hysterectomy (mean age, 53.0 years) were studied in 38 centers in Europe, North America, Australasia, and South Africa. They were randomized to 60 mg/d or 150 mg/d of raloxifene, 0.625 mg/d of conjugated equine estrogen (CEE), or placebo. Bone density of the lumbar spine and proximal femur, biochemical markers of bone turnover, and fasting serum lipid concentrations were assessed for 3 years. RESULTS Compared with baseline, bone density in the lumbar spine progressively declined by 2.0% in the placebo group (P <.05), was stable in the 2 raloxifene groups, and increased 4.6% in the subjects receiving CEE (P <.001). Effects in both raloxifene groups were different from those observed in the CEE and placebo groups (P <.001). Bone density in the total hip showed similar results. Conjugated equine estrogen produced significantly greater depression of serum osteocalcin, bone-specific alkaline phosphatase, and urine C-telopeptide, compared with raloxifene. Each of the active treatments caused comparable depression of low-density lipoprotein cholesterol below placebo levels (P <.001 at most time points). Raloxifene did not affect high-density lipoprotein cholesterol, whereas CEE increased it by 13.4% compared with placebo at 3 years (P <.001). Triglyceride concentrations increased 24.6% in the CEE group at 3 years (P <.003), a significantly greater change than in the raloxifene groups, which were 4.9% and 8.0% above baseline (P < or =.002) but not different from placebo. Urinary incontinence was reported in 11 women receiving CEE, but in only 1 or 2 in each of the other groups (P < or =.01 compared with the other groups). Hernias occurred less frequently in those receiving 150 mg/d of raloxifene or CEE (P =.03 vs placebo). CONCLUSIONS Raloxifene and CEE have beneficial effects on bone density and bone turnover, although effects of CEE are more marked. Raloxifene and CEE produce different patterns of lipid responses and have distinct adverse effect profiles.