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Journal of Clinical Densitometry : the... 2014The number needed to treat is a valuable metric to determine the benefit of therapy, but it must be viewed against the respective number needed to harm. Denosumab and... (Review)
Review
The number needed to treat is a valuable metric to determine the benefit of therapy, but it must be viewed against the respective number needed to harm. Denosumab and teriparatide (TPTD) have proven antifracture efficacy at vertebral and nonvertebral sites, whereas raloxifene has proven antifracture efficacy at the spine only. Denosumab use has been associated with a small, yet statistically significant, increased incidence of eczema and serious cellulitis. Raloxifene use has been associated with statistically significant increases in the risk of venous thromboembolism and possibly deadly stroke, although not an increase in total strokes. No significant, nontransient adverse events have been reported with TPTD use. When used for the treatment of postmenopausal osteoporosis, denosumab, raloxifene, and TPTD all generally have favorable risk-to-benefit profiles, but therapy-specific contraindications necessitate thoughtful consideration of all available clinical information and individualization of treatment decisions.
Topics: Antibodies, Monoclonal, Humanized; Bone Density Conservation Agents; Denosumab; Female; Humans; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Patient Education as Topic; Physician-Patient Relations; Raloxifene Hydrochloride; Risk Assessment; Teriparatide
PubMed: 24206867
DOI: 10.1016/j.jocd.2013.09.018 -
Clinical Pharmacology in Drug... May 2022Osteoporosis is a common skeletal disorder, often leading to fragility fracture. Combination therapy with raloxifene, a selective estrogen receptor modulator, and... (Randomized Controlled Trial)
Randomized Controlled Trial
Osteoporosis is a common skeletal disorder, often leading to fragility fracture. Combination therapy with raloxifene, a selective estrogen receptor modulator, and cholecalciferol (vitamin D ) has been proposed to improve the overall efficacy and increase compliance of raloxifene therapy for postmenopausal osteoporosis. To our knowledge, there has been no report of any study on the pharmacokinetic interaction between raloxifene and cholecalciferol. This study aimed to evaluate the possible pharmacokinetic interactions between raloxifene and cholecalciferol in healthy adult male Korean volunteers. Twenty subjects completed this open-label, randomized, single-dose, 3-period, 6-sequence, crossover phase 1 study with a 14-day washout period. Serial blood samples were collected from 20 hours before dosing to 96 hours after dosing. The plasma concentrations of raloxifene and cholecalciferol were determined using a validated method for high-performance liquid chromatography with tandem mass spectrometry. The geometric mean ratios (90%CIs) for area under the plasma concentration-time curve from time 0 to the last quantifiable time point and maximum plasma concentration of raloxifene with or without cholecalciferol were 1.02 (0.87-1.20) and 0.87 (0.70-1.08), respectively. For baseline-corrected cholecalciferol, geometric mean ratios (90%CIs) of area under the plasma concentration-time curve from time 0 to the last quantifiable time point and maximum plasma concentration with or without raloxifene were 1.01 (0.93-1.09) and 0.99 (0.92-1.06), respectively. Concurrent treatment with raloxifene and cholecalciferol was generally well tolerated. These results suggest that raloxifene and cholecalciferol have no clinically relevant pharmacokinetic drug-drug interactions when administered concurrently. All treatments were well tolerated, with no serious adverse events.
Topics: Adult; Cholecalciferol; Cross-Over Studies; Drug Interactions; Healthy Volunteers; Humans; Male; Raloxifene Hydrochloride
PubMed: 34984851
DOI: 10.1002/cpdd.1062 -
Mayo Clinic Proceedings Apr 2021Breast cancer remains the most common cancer in women in the United States. For certain women at high risk for breast cancer, endocrine therapy (ET) can greatly decrease... (Review)
Review
Breast cancer remains the most common cancer in women in the United States. For certain women at high risk for breast cancer, endocrine therapy (ET) can greatly decrease the risk. Tools such as the Breast Cancer Risk Assessment Tool (or Gail Model) and the International Breast Cancer Intervention Study risk calculator are available to help identify women at increased risk for breast cancer. Physician awareness of family history, reproductive and lifestyle factors, dense breast tissue, and history of benign proliferative breast disease are important when identifying high-risk women. The updated US Preventive Services Task Force and American Society of Clinical Oncology guidelines encourage primary care providers to identify at-risk women and offer risk-reducing medications. Among the various ETs, which include tamoxifen, raloxifene, anastrozole, and exemestane, tamoxifen is the only one available for premenopausal women aged 35 years and older. A shared decision-making process should be used to increase the usage of ET and must be individualized. This individualized approach must account for each woman's medical history and weigh the benefits and risks of ET in combination with the personal values of the patient.
Topics: Adult; Aged; Aged, 80 and over; Anastrozole; Breast Neoplasms; Curriculum; Decision Making, Shared; Education, Medical, Continuing; Estrogen Antagonists; Female; Health Personnel; Humans; Middle Aged; Preventive Medicine; Raloxifene Hydrochloride; Risk Assessment; Risk Factors; Selective Estrogen Receptor Modulators; Tamoxifen; United States
PubMed: 33814072
DOI: 10.1016/j.mayocp.2021.01.028 -
JCO Oncology Practice Dec 2021Agency breast cancer prevention guidelines for other than hereditary cancers have not materially changed in 20 years; endocrine-targeted agents (then, tamoxifen; now,...
Agency breast cancer prevention guidelines for other than hereditary cancers have not materially changed in 20 years; endocrine-targeted agents (then, tamoxifen; now, adding raloxifene and aromatase inhibitors) reduce good prognosis estrogen receptor (ER)-positive, progesterone receptor (PR)-positive cancers without reducing deaths from breast cancer. Across three tamoxifen placebo-controlled prevention trials (N = 23,360) begun almost 30 years ago, although there were 226 fewer breast cancer cases, there were nine more deaths from breast cancer in the tamoxifen groups. Following clinical advances, currently more than half of breast cancer cases are solved problems with extremely low risk of death. As endocrine-targeted agents commonly prevent these cancers, widespread implementation of current prevention strategies may not reduce deaths from breast cancer. Compared with other breast cancers, ER-positive, PR-negative cancers and triple-negative cancers have inferior survival (90.6% 83.8% 78.1%, respectively; < .001). Against this background, in the Women's Health Initiative Dietary Modification randomized trial (N = 48,835), ER-positive, PR-negative cancers were statistically significantly reduced in the intervention group (hazard ratio, 0.77; 95% CI, 0.64 to 0.94) and deaths from breast cancer were reduced 21% ( = .02). In the Women's Health Initiative randomized, placebo-controlled trial evaluating conjugated equine estrogen (N = 10,739), ER-positive, PR-negative cancers were statistically significantly reduced in the intervention group (hazard ratio, 0.44; 95% CI, 0.27 to 0.74) and deaths from breast cancer were reduced 40% ( = .04). These findings suggest that reexamination of breast cancer risk reduction strategies and clinical practice is needed.
Topics: Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Raloxifene Hydrochloride; Tamoxifen
PubMed: 34319769
DOI: 10.1200/OP.21.00343 -
Schizophrenia Bulletin Nov 2023Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND HYPOTHESIS
Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum Disorders (SSD). We aimed to assess the effects of adjunctive raloxifene in women and men with SSD.
STUDY DESIGN
This parallel, randomized, double-blind, placebo-controlled trial included adult SSD patients across the Netherlands and Belgium. Participants were stratified by age, sex, and global functioning and randomly assigned 1:1 to 12-week add-on raloxifene or placebo. Primary outcomes were symptom severity at 6, 12, and 38 weeks and cognition at 12 and 38 weeks, as measured with the Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia, respectively. Intention-to-treat analyses were performed using linear mixed-effect models.
STUDY RESULTS
We assessed 261 patients for eligibility, of which 102 (28% female) were assigned to raloxifene (n = 52) or placebo (n = 48). Although we found no main effect of raloxifene, secondary sex-specific analysis showed that in women, raloxifene had beneficial effects on negative symptoms at week 6 (LSM -2.92; adjusted P = 0.020) and week 12 (LSM -3.12; adjusted P = 0.030), and on working memory at week 38 (LSM 0.73; adjusted P = 0.040), while having negative effects on working memory at week 38 in men (LSM -0.53; adjusted P = 0.026). The number of adverse events was similar between groups.
CONCLUSIONS
Our results do not support the use of raloxifene in patients with SSD in general, but suggest female-specific beneficial effects of raloxifene on negative symptoms and working memory. Our findings encourage further research on sex-specific pharmacotherapeutic treatment.
Topics: Adult; Male; Female; Humans; Infant, Newborn; Raloxifene Hydrochloride; Schizophrenia; Antipsychotic Agents; Postmenopause; Selective Estrogen Receptor Modulators; Double-Blind Method; Treatment Outcome
PubMed: 37116866
DOI: 10.1093/schbul/sbad058 -
Expert Opinion on Pharmacotherapy Jun 2018Reduced estrogen levels at menopause mean a loss of the neuroprotection that is conferred, from puberty until menopause, on women with schizophrenia. The postmenopausal... (Review)
Review
INTRODUCTION
Reduced estrogen levels at menopause mean a loss of the neuroprotection that is conferred, from puberty until menopause, on women with schizophrenia. The postmenopausal stage of schizophrenia requires therapeutic attention because women with this diagnosis almost invariably experience increased symptoms and increased side effects at this time. So far, few targeted therapies have been successfully developed.
AREAS COVERED
This non-systematic, narrative review is based on the relevant published literature indexed in PubMed. A digital search was combined with a manual check of references from studies in the field of gender differences, menopause and schizophrenia. Aside from the inclusion of a few early classic papers, the review focuses on 21st century basic, psychopharmacologic, and clinical literature on the treatment of women with schizophrenia after menopause.
EXPERT OPINION
Beyond a relatively low dose threshold, all antipsychotic medications have adverse effects, which become more prominent for women at the time of menopause. Estrogen modulators may not help all symptoms of schizophrenia but are, nevertheless, relatively safe and, when used as adjuncts, help to keep antipsychotic doses low, thus reducing the side effect burden. The field is currently moving towards precision medicine and individual genetic profiles will help to determine the efficacy of available treatments in the future.
Topics: Antipsychotic Agents; Female; Humans; Phytoestrogens; Postmenopause; Raloxifene Hydrochloride; Receptors, Estrogen; Schizophrenia; Venous Thromboembolism
PubMed: 29676942
DOI: 10.1080/14656566.2018.1465563 -
Human serum albumin-based nanoparticles alter raloxifene administration and improve bioavailability.Drug Delivery Dec 2022Osteoporosis is a disease that reduces bone mass and microarchitecture, which makes bones fragile. Postmenopausal osteoporosis occurs due to estrogen deficiency....
Osteoporosis is a disease that reduces bone mass and microarchitecture, which makes bones fragile. Postmenopausal osteoporosis occurs due to estrogen deficiency. Raloxifene is a selective estrogen receptor modulator used to treat postmenopausal osteoporosis. However, it has a low bioavailability, which requires long-term, high-dose raloxifene administration to be effective and causes several side effects. Herein, raloxifene was encapsulated in human serum albumin (HSA)-based nanoparticles (Ral/HSA/PSS NPs) as an intravenous-injection pharmaceutical formulation to increase its bioavailability and reduce the treatment dosage and time. results indicated that raloxifene molecules were well distributed in HSA-based nanoparticles as an amorphous state, and the resulting raloxifene formulation was stabile during long-term storage duration. The Ral/HSA/PSS NPs were both biocompatible and hemocompatible with a decreased cytotoxicity of high-dose raloxifene. Moreover, the intravenous administration of the prepared Ral/HSA/PSS NPs to rats improved raloxifene bioavailability and improved its half-life in plasma. These raloxifene-loaded nanoparticles may be a potential nanomedicine candidate for treating postmenopausal osteoporosis with lower raloxifene dosages.
Topics: Animals; Biological Availability; Female; Humans; Nanoparticles; Osteoporosis, Postmenopausal; Raloxifene Hydrochloride; Rats; Selective Estrogen Receptor Modulators; Serum Albumin, Human
PubMed: 35975329
DOI: 10.1080/10717544.2022.2111479 -
Drug Delivery and Translational Research Mar 2022Transdermal administration of raloxifene hydrochloride (RLX)-loaded nanostructured lipid carriers (NLCs) has been proposed to circumvent its low oral bioavailability...
Transdermal administration of raloxifene hydrochloride (RLX)-loaded nanostructured lipid carriers (NLCs) has been proposed to circumvent its low oral bioavailability (2%). Preformulation studies were carried out to evaluate drug-excipient compatibility of various adjuvants commonly used for NLC preparation (waxes, cholesterol, compritol, gelucire, span 60, span 80, span 85, tween 80, poloxamer 188, oleic acid, caprylic/capric triglyceride, and castor oil). It was used differential scanning calorimetry (DSC), isothermal stress testing (IST), and solubility studies. The most promising excipients were chosen for NLC obtention, and full characterization was done, including in vitro skin permeation. DSC curves suggested drug-excipient interaction among some compounds, and the IST study showed incompatibility of RLX with waxes, compritol, cholesterol, span 60, and poloxamer 188. Solubility studies helped select gelucire, caprylic/capric triglyceride, span 80, and tween 80 for NLC production. Twelve NLCs were obtained (NLC1 to NLC12), but NLC7 and NLC8 were the most promising ones. In vitro release studies demonstrated that NLC7 and NLC8 were able to control RLX release (14.74 and 9.07% at 24 h, respectively) compared with the unloaded drug (> 90% at 24 h). Unloaded RLX did not permeate the diffusion cells' receptor medium and showed higher drug skin retention (11-fold) than RLX-loaded NLC. NLC reduced RLX skin retention, favoring drug permeation to deeper skin layers. NLC7 increased drug flux is 2.4-fold. NLC7 is a promising formulation for RLX transdermal drug delivery.
Topics: Administration, Cutaneous; Drug Carriers; Excipients; Liposomes; Nanoparticles; Nanostructures; Particle Size; Poloxamer; Polysorbates; Raloxifene Hydrochloride; Triglycerides; Waxes
PubMed: 33682031
DOI: 10.1007/s13346-021-00949-y -
Medical Oncology (Northwood, London,... Dec 2022Triple-negative breast cancers (TNBCs) are characterized by a lack of approved targeted therapies and remain a challenge in the clinic. Several overexpressed proteins,...
Triple-negative breast cancers (TNBCs) are characterized by a lack of approved targeted therapies and remain a challenge in the clinic. Several overexpressed proteins, including epidermal growth factor receptor (EGFR), have been associated with TNBCs and are considered potential therapeutic targets. However, EGFR inhibitors alone failed to demonstrate a cutting-edge advantage for treating TNBCs over conventional chemotherapies. Studies have shown that selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene also affect TNBC cell viability. The combination of gefitinib and raloxifene was assessed against TNBC cell lines in vitro. Two TNBC cell lines, MDA-MB-231 and MDA-MB-468, were used to investigate the combination of gefitinib and raloxifene on cell viability, DNA synthesis, and apoptosis. The combination was assessed on intracellular signaling pathways, colony formation, migration, and angiogenesis. In the present study, raloxifene, in combination with gefitinib, decreased cell viability. The combination potentiates apoptosis and affects the expression and phosphorylation pattern of proteins involved in cell proliferation, such as NFκB, β-catenin, and EGFR. Furthermore, evidence of apoptosis activation was also observed, along with a decreased cell migration and tumorigenicity of TNBC cells. Moreover, the combined treatment decreased the ability of neovascularization as assessed by tube formation of endothelial cells. These results suggested the potential of the combination of raloxifene and gefitinib for the prevention of TNBC growth and the appearance of metastatic events. Our findings provide the basis for future studies on the mechanism involved in raloxifene-gefitinib inhibition of ER-negative tumor growth.
Topics: Humans; Gefitinib; Triple Negative Breast Neoplasms; Raloxifene Hydrochloride; Quinazolines; Endothelial Cells; Protein Kinase Inhibitors; Cell Line, Tumor; Cell Proliferation; Apoptosis
PubMed: 36494506
DOI: 10.1007/s12032-022-01909-3 -
Archives of Women's Mental Health Feb 2018The aim of this study is to meta-analytically assess the efficacy and safety of adjunctive raloxifene for postmenopausal women with schizophrenia. Six studies with 440... (Review)
Review
The aim of this study is to meta-analytically assess the efficacy and safety of adjunctive raloxifene for postmenopausal women with schizophrenia. Six studies with 440 patients, including 225 (51.14%) patients on raloxifene and 215 (48.86%) on placebo who completed 13.71 ± 5.09 weeks of treatment, were included in this study. Meta-analysis of Positive and Negative Syndrome Scale total scores and positive, negative, and general symptom scores [standard mean difference (SMD) -0.22 to -0.55, 95% confidence interval (CI) -1.01 to -0.02, p = 0.04-0.01; I = 74-79%] revealed an advantage of adjunctive raloxifene treatment over placebo treatment. There was no significant difference regarding discontinuation rate [risk ratio (RR) = 1.38, p = 0.51] and adverse drug reactions (RR = 1.27, p = 0.57) between the two groups. This meta-analysis showed that adjunctive raloxifene appears to be efficacious and safe for postmenopausal women with schizophrenia. Moreover, raloxifene may be efficacious for patients with less severe symptoms. Future studies with a large sample size are needed to confirm these findings.
Topics: Adult; Aged; Estrogen Receptor Modulators; Female; Humans; Middle Aged; Postmenopause; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Schizophrenia
PubMed: 28849318
DOI: 10.1007/s00737-017-0773-2