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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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Comparison of alendronate and raloxifene for the management of primary hyperparathyroidism.
Akbaba, G, Isik, S, Ates Tutuncu, Y, Ozuguz, U, Berker, D, Guler, S
Journal of endocrinological investigation. 2013;(11):1076-82
Abstract
AIM: To evaluate and compare the efficacy of alendronate sodium (ALN) and raloxifene (RLX) for the management of primary hyperparathyroidism (PHPT) in postmenopausal female patients (pts) with osteoporosis. METHODS Twenty-four postmenopausal women with osteoporosis who were diagnosed with PHPT, but refused the option of surgery, were enrolled. Participants were sequentially randomized into two groups: an ALN-group of 12 pts (70 mg/week) and a RLX-group of 12 pts (60 mg/day). The control group consisted of 10 pts with PHPT who did not have any indications for surgery. RESULTS The decrease in ionized calcium levels was significantly more pronounced in the ALN group compared to the RLX and control groups (p<0.001). In terms of difference from baseline in bone mineral density (BMD) of the lumbar area in percentages over a period of 12 months, pts in the ALN and RLX groups both showed statistically significant improvements compared to pts in the control group (control vs ALN, p<0.001; control vs RLX, p<0.001). BMD measurements of the femoral and radial areas were comparable in all three groups. CONCLUSIONS ALN and RLX may improve bone density in the lumbar area of osteoporotic post-menopausal women with PHPT. The more significant decrease in serum calcium levels which was observed in the ALN group compared to both RLX and control groups, suggests that ALN could be used for the short-term control of calcium levels in patients awaiting surgery.
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A randomized phase II presurgical trial of weekly low-dose tamoxifen versus raloxifene versus placebo in premenopausal women with estrogen receptor-positive breast cancer.
Serrano, D, Lazzeroni, M, Gandini, S, Macis, D, Johansson, H, Gjerde, J, Lien, E, Feroce, I, Pruneri, G, Sandri, M, et al
Breast cancer research : BCR. 2013;(3):R47
Abstract
INTRODUCTION We previously demonstrated that 1 or 5 mg per day of tamoxifen (T) given for four weeks before surgery reduces Ki-67 in breast cancer (BC) patients to the same extent as the standard 20 mg/d. Given the long half-life of T, a weekly dose (10 mg per week (w)) may be worth testing. Also, raloxifene (R) has shown Ki-67 reduction in postmenopausal patients in a preoperative setting, but data in premenopausal women are limited. We conducted a randomized trial testing T 10 mg/w vs. R 60 mg/d vs. placebo in a presurgical model. METHODS Out of 204 screened subjects, 57 were not eligible, 22 refused to participate and 125 were included in the study. The participants were all premenopausal women with estrogen receptor-positive BC. They were randomly assigned to either T 10mg/w or R 60 mg/d or placebo for six weeks before surgery. The primary endpoint was tissue change of Ki-67. Secondary endpoints were modulation of estrogen and progesterone receptors and several other circulating biomarkers. RESULTS Ki-67 was not significantly modulated by either treatment. In contrast, both selective estrogen receptor modulators (SERMs) significantly modulated circulating IGF-I/IGFBP-3 ratio, cholesterol, fibrinogen and antithrombin III. Estradiol was increased with both SERMs. Within the tamoxifen arm, CYP2D6 polymorphism analysis showed a higher concentration of N-desTamoxifen, one of the tamoxifen metabolites, in subjects with reduced CYP2D6 activity. Moreover, a reduction of Ki-67 and a marked increase of sex hormone-binding globulin (SHBG) were observed in the active phenotype. CONCLUSIONS A weekly dose of tamoxifen and a standard dose of raloxifene did not inhibit tumor cell proliferation, measured as Ki-67 expression, in premenopausal BC patients. However, in the tamoxifen arm women with an extensive phenotype for CYP2D6 reached a significant Ki-67 modulation.
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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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Responses of urinary N-telopeptide and renal calcium handling to PTH infusion after treatment with estrogen, raloxifene, and tamoxifen.
Kulak, CA, Baz-Hecht, M, Nieves, J, Shen, V, Lindsay, R, Cosman, F
Calcified tissue international. 2012;(4):263-71
Abstract
This prospective, randomized, placebo-controlled study investigated whether estrogen, tamoxifen, and raloxifene protect the skeleton from the acute catabolic effects of continuous PTH(1-34) infusion. It was infused over 24 h in 25 postmenopausal women both before and while on medication for 16-20 weeks (estrogen n = 7, raloxifene n = 5, tamoxifen n = 7, placebo n = 6). Blood and urine samples were collected at baseline and every 4 h during the PTH(1-34) infusion and analyzed for calcium homeostasis, bone remodeling, and specific cytokines. Data for the premedication PTH(1-34) infusions were pooled. During the premedication PTH(1-34) infusions, serum calcium and urine phosphorus increased, while serum phosphorus and urine calcium declined. Osteocalcin decreased (mean 18%), while urine NTX increased (mean 315%). Serum IL-6 increased 260%, but there were no other cytokine changes as a result of the PTH(1-34) infusion. On medication, the mean peak change in NTX with PTH(1-34) infusion was less (77, 59, and 31 nM/mM with raloxifene, tamoxifen, and estrogen, respectively). The reduction in urine calcium excretion was prolonged with each agent but only significantly with estrogen. There was no reduction in the IL-6 elevation induced by PTH(1-34) with any medication. The differential skeletal resorption response to PTH(1-34) infusion after the treatments may reflect different potencies of these agents or variability in interaction with the estrogen receptor. Renal calcium conservation and the blunted response of bone resorption to PTH(1-34) infusion may be mechanisms by which estrogen and estrogen agonist/antagonist agents preserve bone mass.
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Administration of omega-3 fatty acids and Raloxifene to women at high risk of breast cancer: interim feasibility and biomarkers analysis from a clinical trial.
Signori, C, DuBrock, C, Richie, JP, Prokopczyk, B, Demers, LM, Hamilton, C, Hartman, TJ, Liao, J, El-Bayoumy, K, Manni, A
European journal of clinical nutrition. 2012;(8):878-84
Abstract
BACKGROUND/OBJECTIVES The antiestrogen, Raloxifene (Ral) is an effective breast cancer chemopreventive agent. Omega-3 fatty acids (n-3FA) may inhibit mammary carcinogenesis. On the basis of their mechanisms of action, we test the hypothesis that a combination of n-3FA and Ral may be superior in reducing select biomarkers of breast cancer risk in women. SUBJECTS/METHODS Postmenopausal women at increased risk for breast cancer (breast density ≥ 25%) were randomized to: (1) no intervention; (2) Ral 60 mg; (3) Ral 30 mg; (4) n-3FA (Lovaza) 4 g and (5) Lovaza 4 g+Ral 30 mg for 2 years. Reduction in breast density is the primary end point of the study. We report preliminary data on feasibility, compliance and changes in secondary end points related to IGF-I signaling, estrogen metabolism, oxidative stress and inflammation in the first group of 46 women who completed 1 year of the study. RESULTS All interventions were well tolerated with excellent compliance (96 ± 1% overall) by pill count and also supported by the expected rise in both serum n-3FA and n-3FA/Omega-6 fatty acids (n-6FA) ratio in women randomized to groups 4 and 5 (P<0.05). Lovaza decreased serum triglycerides and increased high-density lipoprotein (HDL) cholesterol compared with control (P<0.05 for both). Ral reduced serum IGF-1 in a dose-dependent manner (P<0.05) while Lovaza did not. Lovaza had no effect on IGF-1 or IGFBP-3. None of the other biomarkers were affected by our treatment. CONCLUSION The combination of Lovaza and Ral is a feasible strategy that may be recommended in future breast cancer chemoprevention trials.
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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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Back pain during different sequential treatment regimens of teriparatide: results from EUROFORS.
Lyritis, G, Marin, F, Barker, C, Pfeifer, M, Farrerons, J, Brixen, K, del Pino, J, Keen, R, Nickelsen, TN, ,
Current medical research and opinion. 2010;(8):1799-807
Abstract
OBJECTIVE To investigate changes in back pain in postmenopausal women with severe osteoporosis who received teriparatide for 24 months or switched at 12 months to raloxifene or no active treatment. STUDY DESIGN AND METHODS This prospective, controlled, randomised, open-label, 2-year study enrolled 868 postmenopausal women with osteoporosis and a recent fragility fracture. After 12 months of teriparatide (20 microg/day), 507 patients were randomised to further teriparatide (n = 305), raloxifene 60 mg/day (n = 100), or no active treatment (n = 102) for another 12 months (substudy 1); in substudy 2, 199 patients continued teriparatide. All received calcium and vitamin D supplementation. Back pain was self-assessed by patients using a visual analogue scale (0-100 mm). Changes in back pain were analysed using a mixed model for repeated measures. RESULTS During year 1, back pain decreased from a mean (SD) of 48.9 mm (24.0) at baseline by 11.5 mm (p < 0.001) in the total study population. In substudy 1, mean change in back pain from month 12 (randomisation) to 24 months was -2.2, -4.4 and +0.7 mm in the teriparatide (p = 0.076), raloxifene (p = 0.041), and no active treatment groups (p = 0.751). There were no between-group differences from randomization to 18 or 24 months. In a sensitivity analysis excluding patients with low baseline back pain (VAS < 30 mm), mean change from randomisation to endpoint was significant for teriparatide (-3.9 mm, p = 0.006) and raloxifene (-6.3 mm, p = 0.018) groups. Subgroup analyses of 503 patients who received teriparatide for up to 2 years showed that patients with a recent vertebral fracture had a greater decrease in back pain than those without (p < 0.05). Those with and without mild back pain (>or=30 mm), and those with and without severe back pain (>or=60 mm) at baseline all had a statistically significant reduction in back pain after 24 months (p < 0.05). CONCLUSIONS Teriparatide treatment is associated with significant reductions in back pain regardless of the presence of recent vertebral fracture. These results need to be considered with caution due to the open-label design of the study.
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Performance of quantitative ultrasound measurements of bone for monitoring raloxifene therapy.
Paggiosi, MA, Clowes, JA, Finigan, J, Naylor, KE, Peel, NF, Eastell, R
Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry. 2010;(4):441-50
Abstract
Raloxifene increases bone mineral density (BMD) and decreases vertebral fracture risk; the effects on quantitative ultrasound (QUS) variables, however, have been less well studied. We aimed to further evaluate the effectiveness of QUS for monitoring raloxifene treatment and withdrawal effects. Osteopenic, postmenopausal women (age=50-80 yr, n=125), who completed a 96-wk study (phase A) evaluating treatment compliance or monitoring, were invited to participate in a 96-wk raloxifene withdrawal study (phase B). Those originally receiving treatment were then randomized to continue on raloxifene (60 mg/d)+calcium (500 mg/d) (n=23) or to discontinue raloxifene and take placebo+calcium (500 mg/d) (n=23). Previously untreated women remained untreated (n=12). Yearly QUS and BMD measurements were performed. At the end of phase A, lumbar spine BMD (p=0.005), amplitude-dependent speed of sound (Ad-SoS) (p=0.006) and average SoS (p=0.040) decreased in untreated women but remained stable in treated women. Significant changes in Ad-SoS and ultrasonic bone profiler index had occurred in treated women by the end of phase B (p<0.01). All variables, except bone transmission time, were higher for those receiving any raloxifene treatment (p<0.05). Until further knowledge has been acquired, QUS measurement variables should only be used in conjunction with BMD when assessing changes in bone because of raloxifene therapy.