Safety Of Raloxifene Research Articles

Could in-vitro studies on Ishikawa cell lines explain the endometrial safety of raloxifene? Systematic literature review and starting points for future oncological research.

To evaluate all the in-vitro raloxifene (RAL) mechanisms of action on normal, Ishikawa, and different endometrium-derived cell lines to explain the in-vivo RAL endometrial effects, a systematic literature search was performed in the electronic databases MEDLINE, EMBASE ScienceDirect, and the Cochrane Library for the time period between 2002 and 2012. Outcomes were considered in relation to in-vitro stimulatory, inhibitory, or neutral actions of RAL in Ishikawa cell lines compared with different endometrial-derived cell lines (both cancerous and normal endometrium). We also considered all the RAL molecular mechanisms responsible for the in-vitro effects observed. More than 150 articles were available in the scientific database literature, but only 21 fulfilled our selection criteria. Although in-vitro studies appear to yield conflicting results, most evidence has shown that RAL seems to induce endometrial cell mitochondria-mediated apoptosis, and to inhibit estrogen-related cell proliferation and endometrial carcinogenesis by inducing antiangiogenic factors, and reducing cytoskeletal reorganization. If the endometrial safety profile of RAL is confirmed, in the near future, selective estrogen receptor modulators could represent an efficient alternative adjuvant treatment to tamoxifen (TAM) in women with breast cancer considered to be at an increased risk of endometrial disease. The confirmation of the endometrial safety profile could enable the proposal of RAL by clinicians as the most appropriate treatment for BRCA1-2 patients after prophylactic salpingo-oophorectomy.

Psychometric properties of the osteoporosis assessment questionnaire (OPAQ) 2.0: results from the multiple outcomes of raloxifene evaluation (MORE) study.

BackgroundWe explored psychometric properties of the Osteoporosis Assessment Questionnaire 2.0 in terms of reliability, validity, and responsiveness with generic, clinical, demographic, and preference-based data collected from a population of postmenopausal women with osteoporosis.MethodsThe Multiple Outcomes of Raloxifene Evaluation study was a randomized, placebo-controlled, multinational clinical trial evaluating efficacy and safety of raloxifene. The Osteoporosis Assessment Questionnaire 2.0, a generic quality of life measure (Nottingham Health Profile), and a preference-based measure (Health Utilities Index) were administered at baseline and annually. Psychometric properties of the 14 Osteoporosis Assessment Questionnaire 2.0 domains were evaluated by standard statistical techniques.ResultsThis study included a subset of 1477 women from the Multiple Outcomes of Raloxifene Evaluation study population completing the questionnaires. Mean (standard deviation) age was 68.4 (6.8) years. Prevalent vertebral fractures were found in 70% (n =1038) of women. Internal consistency was >0.7 in 9 Osteoporosis Assessment Questionnaire 2.0 domains. Correlations were moderate and significant for similar Osteoporosis Assessment Questionnaire 2.0 domain scores, Nottingham Health Profile domains, and Health Utilities Index scores. All but 2 Osteoporosis Assessment Questionnaire 2.0 domains distinguished between patients with or without prevalent vertebral fractures and detected worsening with increased number of vertebral fractures. Women with ≥1 incident vertebral fracture generally had a greater worsening in Osteoporosis Assessment Questionnaire 2.0 scores (excluding social activity and support of family and friends) from baseline to study endpoint compared with women without incident vertebral fractures.ConclusionsMost domains in the Osteoporosis Assessment Questionnaire 2.0 demonstrated robust psychometric properties; however, several domains not showing these criteria may need to be reassessed and removed for a potentially shorter and validated version of the Osteoporosis Assessment Questionnaire.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2474-15-374) contains supplementary material, which is available to authorized users.

Safety of Raloxifene in Hemodialysis Patients

Dear Editor, With interest I read the article from Saito and colleagues about “the effects of raloxifene on bone metabolism in hemodialysis patients with type 2 diabetes” (1). The article addresses the possibility of treatment with raloxifene for osteoporosis in these patients. Raloxifene, a selective estrogen receptor modulator could be a good option, because it has no known renal side effects like bisphosphonates. Additionally, bisphosphonate use in chronic kidney disease is associated with adynamic bone disease, compared with a low bone turnover (2). In another trial in a group of 17 postmenopausal hemodialysis patients raloxifene improved lumbar spine Bone Mineral Density (BMD) by 2.6% in 53% of the patients while 70% of the control group consisting of 10 aged-matched women showed a reduction in BMD by 4%. The effects of raloxifene on serum calcium and serum iPTH level suggest it improves bone resorption (3). Primary, in these patients treatment of secondary hyperparathyroidism should be performed as is recommended (4). However of concern is the safety of raloxifene treatment in this patient group with multimorbidity. Long term studies should be performed to determine the efficacy and safety of raloxifene in hemodialysis patients. Diabetes mellitus and chronic kidney disease both have a negative effect on bone metabolism and there is an increased risk of vascular complications. In the dialysis population the incidence of myocardial infarction and stroke is 5- to 15 fold higher (5) and cardiovascular mortality is 10- to 30-fold higher (6) than seen in the general population (7-9). In this hemodialysis population with or without diabetes mellitus I would expect an increased risk of fatal stroke with raloxifene therapy. Taking into account the data of the RUTH-trial in 10101 postmenopausal women with a mean age of 67 years, with a high Framingham Stroke Risk Score (FSRS) ( ≥ 13), a 75% increased risk of raloxifene–associated fatal stroke was found. (HR 1.75; 95% CI, 1.01-3.02) (10). The FSRS includes the classical risk factors for cardiovascular disease including age, sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, smoking and echocardiogram based left ventricular hypertrophy (11-13). This score was originally validated for people aged up to 75 years (14). The FSRS also seems to underestimate the vascular risk in hemodialysis patients. The prevalence of traditional cardiovascular disease risk factors is very high in this hemodialysisgroup, but seems not to explain all of the increased cardiovascular risk (15). I would recommend a longer term randomized, double-blind, placebo-controlled trial in hemodialysis patients (subgroup analysis with or without diabetes mellitus). Raloxifene versus placebo should be given for 3 years with attention to the change in BMD and monitoring fractures and vascular complications. First it should be shown that the number needed to treat to prevent fracture is clearly smaller than the number needed to harm in a clinical trial of the duration of the required raloxifene treatment before raloxifene can be safely recommended as common practice in the treatment of osteoporosis in hemodialysis patients. Saito et al. performed an important preliminary study that warrants the investment of such a trial to reach the quality standard of safe and evidence based therapy in this vulnerable patient group.

Effect of Intestinal Glucuronidation in Limiting Hepatic Exposure and Bioactivation of Raloxifene in Humans and Rats

Raloxifene (Evista) is a second generation selective estrogen receptor modulator used in the treatment of osteoporosis and for chemoprevention of breast cancer. It is bioactivated to reactive intermediates, which covalently bind to proteins and form GSH conjugates upon incubation with NADPH and GSH-supplemented human and rat liver microsomes. Despite these in vitro findings, no major raloxifene-related toxic events have been reported upon its oral administration to humans. This disconnect between safety of raloxifene and its in vitro bioactivation is attributed to its presystemic metabolism via glucuronidation. Current studies investigated the effect of hepatic and intestinal glucuronidation in modulating hepatic availability of raloxifene and its subsequent bioactivation, in vitro. The study design involved preincubation of raloxifene with intestinal microsomes followed by a sequential incubation with liver microsomes. The degree of bioactivation of raloxifene was assessed from the percentage of GSH conjugate formed in liver microsomal incubations or the amount of covalent binding of raloxifene-related material to liver microsomal proteins. The results indicated that human intestinal glucuronidation limited the hepatic exposure of raloxifene that underwent bioactivation in the liver. Similar experiments with rat microsomal preparations showed very little effect of intestinal glucuronidation. This effect of intestinal glucuronidation and the observed species difference were explained by comparing the efficiency (Cl(int)) of glucuronidation and oxidation in the two species. These findings suggested that even though the rate of bioactivation in the two species was similar, the Cl(int) of glucuronidation was 7.5-fold higher in the human intestine as compared to rats. These results support the hypothesis that intestinal glucuronidation modulates the amount of raloxifene undergoing bioactivation by liver and corroborate the importance of assessing other competitive metabolic pathways and species differences in metabolism prior to extrapolation of bioactivation results from rats to humans.

Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes<SUBTITLE>The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial</SUBTITLE>

Tamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis. To compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes. The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial, a prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America, with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed. Patients were 19,747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk (mean risk, 4.03% [SD, 2.17%]). Data reported are based on a cutoff date of December 31, 2005. Oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years. Incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events. There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1000; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death. Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. clinicaltrials.gov Identifier: NCT00003906.

Safety assessment of raloxifene over eight years in a clinical trial setting

ABSTRACTObjective: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting.Methods: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista (CORE) trial. MORE was an international, 4‐year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4‐year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test.† Evista is a registered trade name of Eli Lilly and Company, Indianapolis, USAResults: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups ( p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively ( p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93–3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups ( p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo ( p = 0.028, p < 0.001, and p = 0.008, respectively).Conclusion: These 8‐year data support the known clinical safety profile of raloxifene, established in the MORE trial.

Safety and efficacy of antiestrogens for prevention of breast cancer

The rationale for clinical trials of antiestrogens for prevention of breast cancer, potential concerns with antiestrogens, and clinical trials of antiestrogens for breast cancer prevention are discussed. Extensive preclinical evidence supports clinical investigation and use of tamoxifen for preventing breast cancer. The efficacy of tamoxifen in the treatment of advanced breast cancer and as adjuvant therapy has further strengthened the rationale for use in prevention. Tamoxifen is well tolerated and, like raloxifene, has been associated with non-cancer-related benefits. The major concerns with tamoxifen are an increased risk of thromboembolic events and endometrial cancer and an association with ocular disorders. Little is known about the long-term safety of raloxifene. Three randomized, double-blind, placebo-controlled clinical trials of tamoxifen 20 mg (as the citrate) daily for the prevention of breast cancer and one post hoc analysis and a literature review examining the effect of raloxifene on breast cancer risk (as a secondary endpoint) have been published. In one of the three trials of tamoxifen, the rate of invasive breast cancer was reduced 49%; in the other two trials, no reduction in breast cancer was found. Raloxifene apparently reduced the frequency of breast cancer. On the basis of the positive tamoxifen trial, tamoxifen can be offered to women with a five-year projected risk of breast cancer of > or = 1.67%, as determined by the Gail model. Risks and benefits should be evaluated for each patient. Tamoxifen may offer some women protection against breast cancer. Raloxifene may also have a preventive role, but more study is needed.

Clinical efficacy of raloxifene in postmenopausal women

A new class of compounds known as selective estrogen receptor modulators (SERMs) may possess the optimal combination of characteristics desirable in a drug designed for use in postmenopausal women. Among this class of compounds, raloxifene is the most studied and is currently available for clinical use in some countries for the prevention of osteoporosis in post-menopausal women. Raloxifene is a non-steroidal benzotiophene derivative shown to prevent bone loss at axial and appendicular sites and reduce serum cholesterol, like estrogen, in oophorectomized rats and in postmenopausal women. In animal models, unlike estrogen, raloxifene does not stimulate breast or uterine tissues. These appealing attributes make raloxifene a potential treatment for osteoporosis and other menopause related risks in middle aged and elderly women. Multicenter studies have been performed in early postmenopausal women, randomly assigned to receive raloxifene 30, 60, or 150 mg/day or placebo. All subjects received a calcium supplement. Bone mineral density, which was measured twice a year over 24 months by dual X-ray absorptiometry, decreased significantly at all skeletal sites with placebo, and significantly increased with raloxifene at the spine, hip, and total body at the three doses. At 24 months, the mean increase with raloxifene 60 mg compared with placebo was 2.4% at the lumbar spine and at the total hip, and 2% at the total body. Markers of bone formation (serum osteocalcin and bone specific alkaline phosphatase) and of resorption (urinary CrossLaps™) decreased significantly to the premenopausal range within 3–6 months of treatment with raloxifene. In addition, total serum and low-density lipoprotein cholesterol decreased significantly in all raloxifene therapy groups in a dose-related fashion. Serum HDL-cholesterol and triglycerides were not significantly changed by therapy. The most commonly observed side-effect was hot flushes, with patients taking raloxifene reporting a slightly higher rate of flushes (25%) than those on placebo (18%). This adverse event usually occurred within the first few months of therapy, was generally mild, and did not result in excess study dropout (raloxifene 1.5%, placebo 2.1%). Preliminary 2-year data indicated that raloxifene is not associated with an increased risk of breast cancer. In summary, the clinical efficacy and safety of raloxifene is very promising and this compound will offer a particularly attractive choice for postmenopausal women.