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Background: Raloxifene and bazedoxifene are selective estrogen receptor modulators (SERMs) used to prevent and treat osteoporosis in postmenopausal women. Raloxifene is also known for its preventive effect against invasive breast cancer; however, its effect on other cancer types is unclear. This study investigated the incidence of various cancers in osteoporosis patients receiving SERM therapy to determine its association with the risk of developing specific cancer types., Methods: This retrospective cohort study examined the association between SERM use and the incidence of cervical, endometrial, ovarian, and colorectal cancers in postmenopausal women using data from the Korean National Health Insurance Service. Propensity score matching ensured group comparability by analyzing 95,513 participants. Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the cancer risk associated with SERM therapy, differentiating between the effects of raloxifene and bazedoxifene., Results: SERM therapy was associated with a reduced risk of cervical (adjusted HR = 0.47, 95% CI = 0.31-0.71), ovarian (adjusted HR = 0.61, 95% CI = 0.42-0.88), and colorectal cancer (adjusted HR = 0.49, 95% CI = 0.42-0.57). No significant risk reduction was observed for endometrial cancer (adjusted HR = 1.05, 95% CI = 0.70-1.59). A comparison between raloxifene and bazedoxifene revealed no significant differences in their cancer prevention effects., Conclusion: SERM therapy administration is associated with a decreased incidence of cervical, ovarian, and colorectal cancers. Notably, the effects of raloxifene and bazedoxifene were consistent. Further investigations are crucial to elucidate the mechanisms underlying these observations and their clinical implications.

Introduction: Several studies indicated the ameliorating effects of raloxifene supplementation on apolipoproteins and blood pressure, although others have conflicting findings. Therefore, the present study was conducted in order to accurately and definitively understands the effect of raloxifene on apolipoprotein AI (Apo-AI), apolipoprotein B (APoB), lipoprotein (a) (Lp (a)), systolic blood pressure (SBP) and diastolic blood pressure (DBP) in postmenopausal women., Methods: A systematic literature search was conducted using scientific databases including PubMed, Scopus, Embase, and Web of Science and the Cochrane Library, through May 2024. The quality of studies was assessed using Cochrane tool. Random-effects meta-analysis was used to pool standardized mean differences (SMD) and 95 % CI for the outcomes., Results: Twenty trials, with interventions ranging from 6 to 144 weeks and 2825 participants, were included. Raloxifene supplementation demonstrated significant reductions in ApoB (SMD: -0.92; 95 % CI: -1.49 to -0.35; P = 0.001), and Lp (a) (SMD: -0.25; 95 % CI: -0.39 to -0.11; P < 0.001) while increasing Apo-AI levels (SMD: 0.29; 95 % CI: 0.22-0.36; P < 0.001). Conversely, no significant effects were observed on SBP (WMD: -0.49 mmHg; 95 % CI: -3.01-2.04; P = 0.706), and DBP (WMD: -0.81 mmHg; 95 % CI: -4.04-2.41; P = 0.621). Moreover, subgroup analysis indicated that raloxifene significantly decreased DBP in studies with intervention durations of >12 weeks., Conclusions: This meta-analysis has shown that raloxifene supplementation may have beneficial effects on apolipoproteins in postmenopausal women. Future studies are needed to investigate the effect of raloxifene on health status in in postmenopausal women., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Osteogenesis imperfecta (OI) increases fracture risk due to changes in bone quantity and quality caused by mutations in collagen and its processing proteins. Current therapeutics improve bone quantity, but do not treat the underlying quality deficiencies. Male and female G610C+/- mice, a murine model of OI, were treated with a combination of raloxifene and in vivo axial tibial compressive loading starting at 10 weeks of age and continuing for 6 weeks to improve bone quantity and quality. Bone geometry and mechanical properties were measured to determine whole bone and tissue-level material properties. A colocalized Raman/nanoindentation system was used to measure chemical composition and nanomechanical properties in newly formed bone compared to old bone to determine if bone formed during the treatment regimen differed in quality compared to bone formed prior to treatment. Lastly, lacunar geometry and osteocyte apoptosis were assessed. OI mice were able to build bone in response to the loading, but this response was less robust than in control mice. Raloxifene improved some bone material properties in female but not male OI mice. Raloxifene did not alter nanomechanical properties, but loading did. Lacunar geometry was largely unchanged with raloxifene and loading. However, osteocyte apoptosis was increased with loading in raloxifene treated female mice. Overall, combination treatment with raloxifene and loading resulted in positive but subtle changes to bone quality., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy of combined therapy of teriparatide and raloxifene on the osseointegration of titanium dental implants in a rabbit model of osteoporotic bone., Materials and Methods: Sixty female rabbits were randomly divided into six groups. The sham ovariectomy group (control) consisted of animals that received no medication. Animals in the ovariectomy group (OVX) underwent ovariectomy and received no medication. The combined group consisted of ovariectomized animals that received combined teriparatide (10 mg/kg) for 12 weeks and raloxifene (10 mg/kg) for 12 weeks. The sequential group (SEQ) consisted of ovariectomized animals that received teriparatide (10 mg/kg) for the first 6 weeks and raloxifene therapy (10 mg/kg) for the following 6 weeks sequentially. The parathormone (PTH) and raloxifene (RAL) groups consisted of ovariectomized animals that received only teriparatide (10 mg/kg) for 12 weeks or raloxifene (10 mg/kg) for 12 weeks, respectively. Dental implants (Bilimplant) were placed in the proximal metaphysis of both tibias in all rabbits. Histomorphometric and microCT studies were performed on the specimens obtained from the right tibia bone. Removal torque (RTQ) and implant stability quotient (ISQ) tests were performed on the specimens obtained from the left tibia bone. The results were compared and evaluated statistically., Results: RTQ analysis revealed a statistically significant difference between the mean values of the combined group (93.01 ± 27.19 Ncm) and the OVX group (49.6 ± 12.5 Ncm) (P = .015). The highest mean T0 (implantation day) value was obtained in the control group (67.1 ± 3.4 Ncm), and the lowest mean value was obtained in the OVX group (61.4 ± 3.8 Ncm). The highest T1 mean (3 months after implantation) was obtained by the combined group (76.6 ± 3.8 Ncm), and the lowest mean was obtained by the OVX group (68.9 ± 6.2 Ncm). Histomorphometric analyses showed that the mean percentage of bone-to-implant contact (BIC%) of the combined group (51.2%) was significantly higher than that of the OVX group (28.6%) (P =.006). In the microCT examinations, it was found that the mean BIC% value of the combined group (41.1%) was significantly higher than that of the OVX group (24.1%) (P < .001)., Conclusions: According to the results of the current study, combined therapy of teriparatide and raloxifene improves the BIC and osseointegration of titanium dental implants in osteoporotic bone compared with sequential or independent therapy with these agents.

Osteogenesis imperfecta (OI) is a hereditary bone disease in which gene mutations affect collagen formation, leading to a weak, brittle bone phenotype that can cause severe skeletal deformity and increased fracture risk. OI interventions typically repurpose osteoporosis medications to increase bone mass, but this approach does not address compromised tissue-level material properties. Raloxifene (RAL) is a mild anti-resorptive used to treat osteoporosis that has also been shown to increase bone strength by a-cellularly increasing bone bound water content, but RAL cannot be administered to children due to its hormonal activity. The goal of this study was to test a RAL analog with no estrogen receptor (ER) signaling but maintained ability to reduce fracture risk. The best performing analog from a previous analog characterization project, named RAL-ADM, was tested in an in vivo study. Female wildtype (WT) and Col1a2 G610C/+ (G610C) mice were randomly assigned to treated or untreated groups, for a total of 4 groups (n = 15). Starting at 10 weeks of age, all mice underwent compressive tibial loading 3×/week to induce an anabolic bone formation response in conjunction with RAL-ADM treatment (0.5 mg/kg; 5×/week) for 6 weeks. Tibiae were scanned via microcomputed tomography then tested to failure in four-point bending. RAL-ADM had reduced ER affinity, and increased post-yield properties, but did not improve bone strength in OI animals, suggesting some properties can be improved by RAL analogs but further development is needed to create an analog with decidedly positive impacts to OI bone., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Breast cancer is the second leading cause of death for women worldwide. Raloxifene (RLX) is a somewhat effective drug in lowering cholesterol, preventing and treating invasive breast cancer in postmenopausal women with osteoporosis, and does not interfere with breast tissue. Nevertheless, considering the possibility of risk in biological function due to excessive use of anticancer drugs and the adverse effects of drugs in wastewater on plants, animals, and aquatic, it is useful to determine the concentration of RLX in water and human body fluids. Here, a fluorescent metal-organic framework (MOF) nanoparticle based on trinuclear zinc clusters called Zn-MOF was presented, which is a high-performance and fast-response fluorescent chemosensor that can be used to detect RLX based on the fluorescence quenching medium in water. FTIR, XRD, SEM, and EDS analyses were used to identify the functional group and determine the structure and morphology of Zn-MOF. pH range 3-10. The prepared nanoparticles showed symmetric emission with excitation at a wavelength of 310.0 nm. The performance of the proposed fluorescent nanosensor was proportional to the quenching of the fluorescent signal with increasing RLX concentration at 404.0 nm; the quenching fluorescence response was linear in RLX concentration from 0.7 to 350 ng/mL with a significant detection limit equal to 0.485 nM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Drug repurposing provides a cost-effective approach to address the need for breast cancer prevention and therapeutics. We aimed to identify actionable druggable targets using Mendelian randomization (MR) and then validate the candidate drugs using population-based analyses., Methods: We identified genetic instruments for 1406 actionable targets of approved non-oncological drugs based on gene expression, DNA methylation, and protein expression quantitative trait loci (eQTL, mQTL, and pQTL, respectively). Genome-wide association study (GWAS) summary statistics were obtained from the Breast Cancer Association Consortium (122,977 cases, 105,974 controls). We further conducted a nested case-control study using data retrieved from Swedish registers to validate the candidate drugs that were identified from MR analyses., Findings: We identified six significant MR associations with gene expression levels (TUBB, MDM2, CSK, ULK3, MC1R and KCNN4) and two significant associations with gene methylation levels across 21 CpG islands (RPS23 and MAPT). Results from the nested case-control study showed that the use of raloxifene (targeting MAPT) was associated with 35% reduced breast cancer risk (odds ratio, OR, 0.65; 95% confidence interval, CI, 0.51-0.83). However, usage of estradiol, tolterodine, and nitrofurantoin (also targeting MAPT) was associated with increased breast cancer risk, with adjusted ORs and 95% CI of 1.10 (1.07-1.13), 1.16 (1.09-1.24), and 1.09 (1.05-1.13), respectively. The effect of raloxifene and nitrofurantoin lost significance in further validation analyses using active-comparator and new-user design., Interpretation: This large-scale MR analysis, combined with population-based validation, identified eight druggable target genes for breast cancer and suggested that raloxifene is an effective chemoprevention against breast cancer., Funding: Swedish Research Council, Cancerfonden, Crafoordska Stiftelsen, Allmänna Sjukhusets i Malmö Stiftelsen för bekämpande av cancer, 111 Project and MAS cancer., Competing Interests: Declaration of interests The authors declare that they have no relevant conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The study aimed to assess the efficacy of using Raloxifene with ultrasonic processing to enhance Bio-Oss ® , a bone graft substitute, for maxillary sinus bone height reconstruction. A total of 24 rabbit maxillary sinuses were distributed into three groups, each receiving different treatments: Bio-Oss ® only, sonicated Bio-Oss, and sonicated Bio-Oss ® with Raloxifene. Surgical procedures and subsequent histomorphometric and immunohistochemistry analyses were conducted to evaluate the bone formation, connective tissue, and remaining biomaterial, as well as the osteoblastic differentiation and maturation of collagen fibers. Results indicated that the sonicated Bio-Oss ® and Bio-Oss ® groups showed similar histological behavior and bone formation, but the Raloxifene group displayed inflammatory infiltrate, low bone formation, and disorganized connective tissue. The statistical analysis confirmed significant differences between the groups in terms of bone formation, connective tissue, and remaining biomaterial. In conclusion, the study found that while sonicated Bio-Oss ® performed comparably to Bio-Oss ® alone, the addition of Raloxifene led to an unexpected delay in bone repair. The findings stress the importance of histological evaluation for accurate bone repair assessment and the necessity for further investigation into the local application of Raloxifene. Future research may focus on optimizing bone substitutes with growth factors to improve bone repair.

Renal ischemia-reperfusion injury is caused by a temporary reduction in oxygen-carrying blood flow to the kidney, followed by reperfusion. During ischemia, kidney tissue damage induces overproduction of reactive oxygen species, which produces oxidative stress. The blood flow restoration during the reperfusion period causes further production of reactive oxygen species that ends with apoptosis and cell death. This study aimed to investigate the potential renoprotective effects of Raloxifene on bilateral renal ischemia-reperfusion injury in rats by looking into kidney function biomarkers, urea and creatinine, inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). Additionally, antioxidant markers such as total antioxidant capacity (TAC) and the pro-apoptotic marker caspase-3 were assessed. Histopathological scores were also employed for evaluation. Our experimental design involved 20 rats divided into four groups: the sham group underwent median laparotomy without ischemia induction, the control group experienced bilateral renal ischemia for 30 minutes followed by 2 hours of reperfusion, the vehicle group received pretreatment with a mixture of corn oil and dimethyl sulfoxide (DMSO) before ischemia induction, and the Raloxifene-treated group was administered Raloxifene at a dose of 10 mg/kg before ischemia induction, followed by ischemia-reperfusion. Urea and creatinine, TNF-α, IL-1β, and caspase-3 in the Raloxifene group were significantly lower compared to the control and vehicle groups. On the other hand, TAC levels in the Raloxifene group were significantly higher than in the control and vehicle groups. This study concluded that Raloxifene had a renoprotective impact via multiple actions as an anti-inflammatory, anti-apoptotic, and antioxidant agent., Competing Interests: The authors declare no conflict of interest., (©2023 JOURNAL of MEDICINE and LIFE.)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice. Patients with high-risk breast lesions (HRLs) or preinvasive breast cancers face an elevated risk of future breast cancer diagnoses. Endocrine therapy in this setting reduces the risk of a future diagnosis but does not confer improved survival, thus the side effects of primary/secondary prevention must be considered relative to the benefits. Here, we discuss the available chemoprevention regimens for patients with HRLs and considerations for selecting a regimen, as well as the decision making surrounding use of adjuvant endocrine therapy for patients with ductal carcinoma in situ (DCIS). For patients with HRLs, available chemoprevention regimens differ by menopausal status, including tamoxifen 20 mg once daily for 5 years and more recently tamoxifen 5 mg once daily for 3 years in both premenopausal and postmenopausal women as well as raloxifene or aromatase inhibitors for postmenopausal women. We recommend a shared decision-making approach with attention to patient preferences related to risk tolerance and side-effect profiles. Low-dose tamoxifen appears to be a particularly favorable choice that is well tolerated, without risk of serious adverse events and offers comparable risk reduction to other regimens. For DCIS, the benefit of endocrine therapy in addition to radiation is small, and appears to be driven mainly by a reduction in contralateral breast diagnoses or new breast cancers. A strategy that reduces the side-effect profile of chemoprevention such as low-dose tamoxifen may be especially appealing in the setting of secondary prevention.

To assess the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs; bazedoxifene, raloxifene) or placebo, for the treatment of osteoporosis in postmenopausal women (PMW). Systematic searches were run in PubMed, Embase & Cochrane Library on 27-April-2022. Randomized controlled trials (RCTs) that included osteoporotic PMW allocated to denosumab, SERMs, bisphosphonates, or placebo were eligible for inclusion. RCTs were appraised using Cochrane Risk of Bias 2.0. Bayesian network and/or pairwise meta-analyses were conducted on predetermined outcomes (i.e. vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, adverse events [AEs], serious AEs (SAEs), withdrawals due to AEs, AEs caused by denosumab discontinuation). A total of 12 RCTs (k = 22 publications; n = 25,879 participants) were included in the analyses. Denosumab, reported a statistically significant increase in lumbar spine (LS) and total hip (TH) BMD, compared to placebo. Similarly, denosumab also resulted in a statistically significant increase in TH BMD compared to the raloxifene and bazedoxifene. However, relative to denosumab, alendronate, ibandronate and risedronate resulted in significant improvements in both femoral neck (FN) and LS BMD. With regards to vertebral fractures and all safety outcomes, there were no statistically significant differences between denosumab and any of the comparator. Relative to placebo, denosumab was associated with significant benefits in both LS and TH BMD. Additionally, denosumab (compared to placebo) was not associated with reductions in vertebral and nonvertebral fractures. Finally, denosumab was not associated with improvement in safety outcomes, compared to placebo. These findings should be interpreted with caution as some analyses suffered from statistical imprecision., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011., (© 2023. The Author(s).)

Objectives: We conducted a comprehensive meta-analysis of all available trials to evaluate the efficacy and safety of estrogen and selective estrogen receptor modulators as adjunctive treatment for women with schizophrenia., Methods: Multiple databases were searched from the inception until March 2022. Only randomized, double-blind, placebo-controlled studies (randomized controlled trials) were included. Mean differences (MDs) and their 95% confidence intervals (CIs) were calculated using random effects models., Results: The meta-analysis included six estradiol versus placebo studies (n = 724) and seven raloxifene versus placebo studies (n = 419), covering a total of 1143 patients. Adjunctive estradiol outperformed the placebo in terms of the Positive and Negative Syndrome Scale (PANSS) total score (MD = -7.29; 95% CI = -10.67 to -3.91; I 2  = 59.1%; p < 0.001; k = 9; N = 858), positive symptom score (MD = -1.54; 95% CI = -3.04 to -0.72; I 2  = 45.8%; p < 0.001; k = 7; N = 624), negative symptom score (MD = -1.9; 95% CI = -1.77 to -0.34; I 2  = 37.6%; p < 0.05; k = 14; N = 1042), and general psychopathology score (MD = -4.27; 95% CI = -7.14 to -1.41; I 2  = 76.3%; p < 0.005; k = 7; N = 624). Adjunctive raloxifene outperformed the placebo in terms of the PANSS total score (MD = -6.83; 95% CI = -11.69 to -1.97; I 2  = 67.8%; p = 0.006; k = 8; N = 432) and general psychopathology score (MD = -3.82; 95% CI = -6.36 to -1.28; I 2  = 65.3%; p < 0.005; k = 8; N = 432)., Conclusions: Our meta-analysis showed that estradiol and raloxifene are effective and safe adjunctive treatments that improve schizophrenia symptoms in women. Moreover, the effects of estradiol and raloxifene differed in terms of timing and dosage. Both are promising adjunctive treatments that merit further study., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Thermoneutral housing and Raloxifene (RAL) treatment both have potential for improving mechanical and architectural properties of bone. Housing mice within a 30 to 32 °C range improves bone quality by reducing the consequences of cold stress, such as shivering and metabolic energy consumption (Chevalier et al. in Cell Metab 32(4):575-590.e7, 2020; Martin et al. in Endocr Connect 8(11):1455-1467, 2019; Hankenson et al. in Comp Med 68(6):425-438, 2018). Previous work suggests that Raloxifene can enhance bone strength and geometry (Ettinger et al. in Jama 282(7):637-645, 1999; Powell et al. in Bone Rep 12:100246, 2020). An earlier study in our lab utilized long bones to examine the effect of thermoneutral housing and Raloxifene treatment in mice, but no significant interactive effects were found. The lack of an impact is hypothesized to be connected to the short 6-week duration of the study and the type of bone analyzed. This study will examine the same question within the axial skeleton, which has a higher proportion of trabecular bone. After 6 weeks of treatment with RAL, vertebrae from female C57BL/6 J mice underwent microcomputed tomography (μCT), architectural analysis, and compression testing. Most of the tested geometric properties (bone volume/tissue volume percent, trabecular thickness, trabecular number, trabecular spacing) improved with both the housing and RAL treatment. The effect sizes suggested an additive effect when treating mice housed under thermoneutral conditions. While ultimate force was enhanced with the treatment and housing, force normalized by bone volume fraction was not significantly different between groups. For longer pre-clinical trials, it may be important to consider the impacts of temperature on mice to improve the accuracy of these models., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The present study analyzed the effect of vitamin D receptor ( VDR ) gene polymorphisms (ApaI, TaqI, BsmI, FokI, and Cdx2) on bone mineral density (BMD), biochemical parameters and bone turnover markers, fracture prevalence, and response to three types of antiresorptive therapy (estrogen-progesterone, raloxifene, and ibandronate) in 356 postmenopausal women from Slovakia. Association analysis revealed a significant effect of BsmI polymorphism on lumbar spine BMD, serum osteocalcin (OC), and β-CrossLaps levels. While ApaI and Cdx2 polymorphisms were associated with OC and alkaline phosphatase, TaqI polymorphism affected all turnover markers. ApaI, TaqI, and BsmI genotypes increased the risk of spinal, radial, or total fractures with odds ratios ranging from 2.03 to 3.17. Each of therapy types evaluated had a beneficial effect on all osteoporosis-related traits; however, the VDR gene affected only ibandronate and raloxifene treatment. ApaI/aa, TaqI/TT, and BsmI/bb genotypes showed a weaker or no response to ibandronate therapy in femoral and spinal BMD. The impact of aforementioned polymorphisms on turnover markers was also genotype dependent. On the contrary, only TaqI and BsmI polymorphisms influenced raloxifene therapy, even only in lumbar spine BMD. These results point to the potential of using the VDR gene in personalized pharmacotherapy of osteoporosis.

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Published literature on physicians' preferences and sequential treatment patterns of osteoporosis therapy is scarce., Methods: A retrospective cohort study of patients who received bisphosphonates, denosumab, and/or raloxifene for at least 3 consecutive years or teriparatide for at least 18 months for osteoporosis. Data collection spanned 10 years, from October 2007 to September 2016, at a tertiary care center in the United States., Results: In total, 12 885 patients were identified on the basis of receiving at least 1 treatment at any point in time; 1814 patients were randomly reviewed, and 274 patients met the inclusion criteria. The mean age was 68.8 ± 10.7 years, and women represented 90.9% of all the cases. Primary care physicians and rheumatologists constituted 65.7% and 22.6% of the prescribers, respectively. Before instituting a drug holiday, alendronate was the most common initial treatment (percentage, mean duration ± standard deviation in years: 69%, 5.4 ± 2.4 years) followed by ibandronate (9.5%, 4.9 ± 2.1 years) and raloxifene (9.1%, 5.2 ± 1.6 years). Denosumab was the most common second course of treatment, accounting for 29.3% of 82 patients who were subsequently prescribed another therapy, followed by alendronate (24.4%) and zoledronate (20.7%). Among patients who were placed on a drug holiday and eventually restarted on osteoporosis therapy, denosumab was the most common treatment instituted (n = 21), accounting for 40% of the total patients, followed by alendronate (32%) and zoledronate (16%). There was a progressive decline in osteoporosis therapy over the duration of the study., Conclusion: Alendronate was the most common initial therapy. Denosumab was the most common second course of treatment prescribed., (Copyright © 2022 AACE. Published by Elsevier Inc. All rights reserved.)

Treatment persistence was higher among the patients who initially received an anti-osteoporosis medication (AOM) with a long-dose-interval., Purpose: With long-dose-interval anti-osteoporosis medications (AOMs) available for osteoporosis management, it is important to evaluate persistence of any AOM as long as it is continuously used. The purpose of this study was to investigate the treatment pattern and persistence of AOMs, allowing for medication switch., Methods: This study was an observational retrospective cohort study using Taiwan's National Health Insurance claims data. We selected patients who first initiated an AOM between January 1, 2013, and June 30, 2016. AOM therapy included alendronate, raloxifene, teriparatide, denosumab, zoledronate, and ibandronate; the latter three were categorized as long-dose-interval medications. Persistence was defined as continual prescription of any AOM at a given time point with a grace period of 45 days within which to obtain prescription refill. The competing risk model was used to examine the factors affecting patients switching their initial AOM., Results: During the study period, 126,539 patients with mean age of 75 years met the inclusion criteria; 85% were female. For initial AOM, 43.3%, 25.6%, 14.6%, 9.3%, 5.3%, and 1.9% of the patients received alendronate, denosumab, raloxifene, zoledronate, ibandronate, and teriparatide, respectively. During a mean 36-month follow-up, 29.6% of the patients who received at least two AOM pharmacy claims throughout the study period have ever switched their initial medication. Long-dose-interval medications, mainly denosumab and zoledronate, were the preferred choice for medication switch. Treatment persistence was higher in patients who initiated with long-dose-interval AOMs., Conclusion: The real-world data reveal long-dose-interval therapy as an initial treatment or at the first switch stage may improve management of persistent AOM treatment., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Discontinuation of denosumab (DMab) is associated with decline in bone density. Whether raloxifene can be effective to attenuate bone loss after DMab discontinuation in certain conditions when other antiresorptives cannot be used remains unclear. Data on postmenopausal women with osteoporosis who discontinued DMab treatment after short-term use (1-to-4 doses) at Severance Hospital, Seoul, Korea, between 2017 and 2021 were reviewed. Changes in bone mineral density (BMD) at 12 months after DMab discontinuation was compared between sequential raloxifene users (DR) and those without any sequential antiresorptive (DD) after 1:1 propensity score matching. In matched cohort (66 patients; DR n = 33 vs. DD n = 33), mean age (69.3 ± 8.2 years) and T-score (lumbar spine - 2.2 ± 0.7; total hip - 1.6 ± 0.6) did not differ between two groups at the time of DMab discontinuation. Sequential treatment to raloxifene in DR group attenuated the bone loss in lumbar spine after DMab discontinuation compared to DD group (DR vs. DD; - 2.8% vs. - 5.8%, p = 0.013). The effect of raloxifene on lumbar spine BMD changes remained robust (adjusted β + 2.92 vs. DD, p = 0.009) after adjustment for covariates. BMD loss at femoral neck (- 1.70% vs. - 2.77%, p = 0.673) and total hip (- 1.42% vs. - 1.44%, p = 0.992) did not differ between two groups. Compared to BMD at DMab initiation, DR partially retained BMD gain by DMab treatment in lumbar spine (+ 3.7%, p = 0.003) and femoral neck (+ 2.8%, p = 0.010), whereas DD did not. Raloxifene use after DMab treatment attenuated lumbar spine BMD loss in postmenopausal women with short exposures (< 2 years) to DMab., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite a remarkable improvement in health care and continued drug discovery efforts, malaria control efforts are continuously challenged by the emergence of drug-resistant parasite strains. Given a long and risky development path of new drugs, repurposing existing drugs for the treatment of malaria is an attractive and shorter path. Tamoxifen, a selective estrogen receptor modulator (SERM) for the treatment and prevention of estrogen receptor-positive breast cancer, possesses antibacterial, antifungal, and antiparasitic activities. Hence, we assessed tamoxifen, raloxifene, and bazedoxifene, which represent the first-, second-, and third-generation SERMs, respectively, for antimalarial activity. Raloxifene and bazedoxifene inhibited the erythrocytic development of Plasmodium falciparum with submicromolar 50% inhibitory concentration (IC 50 ) values. Among the three, bazedoxifene was the most potent and also decreased P. berghei infection in female mice but not in male mice. However, bazedoxifene similarly inhibited P. falciparum growth in erythrocytes of male and female origin, which highlights the importance of sex-specific host physiology in drug efficacy. Bazedoxifene was most potent on early ring-stage parasites, and about 35% of the treated parasites did not contain hemozoin in the food vacuole. Bazedoxifene-treated parasites had almost 34% less hemozoin content than the control parasites. However, both control and bazedoxifene-treated parasites had similar hemoglobin levels, suggesting that bazedoxifene inhibits hemozoin formation and that toxicity due to accumulation of free heme could be a mechanism of its antimalarial activity. Because bazedoxifene is in clinical use and bazedoxifene-chloroquine combination shows an additive antiparasitic effect, bazedoxifene could be an adjunctive partner of currently used antimalarial regimens. IMPORTANCE The emergence and spread of drug-resistant strains of the human malaria parasite Plasmodium falciparum has necessitated new drugs. Selective estrogen receptor modulators are in clinical use for the prevention and treatment of breast cancer and postmenopausal osteoporosis. We demonstrate that bazedoxifene, a third-generation selective estrogen receptor modulator, has potent inhibitory activity against both susceptible and drug-resistant strains of Plasmodium falciparum. It also blocked the development of Plasmodium berghei in mice. The inhibitory effect was strongest on the ring stage and resulted in the inhibition of hemozoin formation, which could be the major mechanism of bazedoxifene action. Hemozoin is a nontoxic polymer of heme, which is a by-product of hemoglobin degradation by the malaria parasite during its development within the erythrocyte. Because bazedoxifene is already in clinical use for the treatment of postmenopausal osteoporosis, our findings support repurposing of bazedoxifene as an antimalarial.

The new coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which so far has caused over 6 million deaths in 2 years, despite new vaccines and antiviral medications. Drug repurposing, an approach for the potential application of existing pharmaceutical products to new therapeutic indications, could be an effective strategy to obtain quick answers to medical emergencies. Following a virtual screening campaign on the most relevant viral proteins, we identified the drug raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a new potential agent to treat mild-to-moderate COVID-19 patients. In this paper we report a comprehensive pharmacological characterization of raloxifene in relevant in vitro models of COVID-19, specifically in Vero E6 and Calu-3 cell lines infected with SARS-CoV-2. A large panel of the most common SARS-CoV-2 variants isolated in Europe, United Kingdom, Brazil, South Africa and India was tested to demonstrate the drug's ability in contrasting the viral cytopathic effect (CPE). Literature data support a beneficial effect by raloxifene against the viral infection due to its ability to interact with viral proteins and activate protective estrogen receptor-mediated mechanisms in the host cells. Mechanistic studies here reported confirm the significant affinity of raloxifene for the Spike protein, as predicted by in silico studies, and show that the drug treatment does not directly affect Spike/ACE2 interaction or viral internalization in infected cell lines. Interestingly, raloxifene can counteract Spike-mediated ADAM17 activation in human pulmonary cells, thus providing new insights on its mechanism of action. A clinical study in mild to moderate COVID-19 patients (NCT05172050) has been recently completed. Our contribution to evaluate raloxifene results on SARS-CoV-2 variants, and the interpretation of the mechanisms of action will be key elements to better understand the trial results, and to design new clinical studies aiming to evaluate the potential development of raloxifene in this indication., (© 2022. The Author(s).)

Visual deficits after ocular blast injury (OBI) are common, but pharmacological approaches to improve long-term outcomes have not been identified. Blast forces frequently damage the retina and optic nerves, and work on experimental animals has shown the pro-inflammatory actions of microglia can further exacerbate such injuries. Cannabinoid type-2 receptor (CB2) inverse agonists specifically target activated microglia, biasing them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state. We previously found that treating mice with CB2 inverse agonists after traumatic brain injury, produced by either focal cranial air blast or dorsal cranial impact, greatly attenuated the visual deficits and pathology that otherwise resulted. Here we examined the consequences of single and repeat OBI and the benefit provided by raloxifene, an FDA-approved estrogen receptor drug that possesses noteworthy CB2 inverse agonism. After single OBI, although the amplitudes of the A- and B-waves of the electroretinogram and pupil light response appeared to be normal, the mice showed hints of deficits in contrast sensitivity and visual acuity, a trend toward optic nerve axon loss, and significantly increased light aversion, which were reversed by 2 weeks of daily treatment with raloxifene. Mice subjected to repeat OBI (5 blasts spaced 1 min apart), exhibited more severe visual deficits, including decreases in contrast sensitivity, visual acuity, the amplitudes of the A- and B-waves of the electroretinogram, light aversion, and resting pupil diameter (i.e. hyperconstriction), accompanied by the loss of photoreceptor cells and optic nerve axons, nearly all of which were mitigated by raloxifene. Interestingly, optic nerve axon abundance was strongly correlated with contrast sensitivity and visual acuity across all groups of experimental mice in the repeat OBI study, suggesting optic nerve axon loss with repeat OBI and its attenuation with raloxifene are associated with the extent of these two deficits while photoreceptor abundance was highly correlated with A-wave amplitude and resting pupil size, suggesting a prominent role for photoreceptors in these two deficits. Quantitative PCR (qPCR) showed levels of M1-type microglial markers (e.g. iNOS, IL1β, TNFα, and CD32) in retina, optic nerve, and thalamus were increased 3 days after repeat OBI. With raloxifene treatment, the overall expression of M1 markers was more similar to that in sham mice. Raloxifene treatment was also associated with the elevation of IL10 transcripts in all three tissues compared to repeat OBI alone, but the results for the three other M2 microglial markers we examined were more varied. Taken together, the qPCR results suggest that raloxifene benefit for visual function and pathology was associated with a lessening of the pro-inflammatory actions of microglia. The benefit we find for raloxifene following OBI provides a strong basis for phase-2 efficacy testing in human clinical trials for treating ocular injury., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aim: Raloxifene treatment has been reported to be associated with cardiovascular benefits if prescribed to women during the postmenopausal period. However, a final conclusion regarding this hypothesis has not yet been achieved. We conducted a systematic review and meta-analysis to evaluate the effect of raloxifene on the endothelial function and inflammation in postmenopausal women., Methods: We systematically searched the following 4 databases from inception to 23 January 2021 without any language restrictions: Web of Science, PubMed/Medline, Embase and Scopus. The eligible randomized controlled trials (RCTs) reporting the effects of raloxifene on the flow-mediated dilatation (FMD), C-reactive protein (CRP), carotid intima-media thickness (CIMT), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin levels, were included in the final meta-analysis., Results: A total of 16 RCTs were included in the final analysis. Raloxifene administration had no significant effect on ICAM-1 and E-selectin levels. However, we observed a decrease of the CIMT (WMD: -0.071 mm, 95% CI: -0.09 to -0.04, P = 0.000), CRP (WMD: -0.342 mg/L, 95% CI: -0.591, -0.094, p = 0.007), and VCAM-1 (WMD: -197.90 mg/L, 95% CI: -269.58 to -126.23, P = 0.000) levels in the intervention versus control groups following the prescription of this pharmacological agent. Moreover, raloxifene treatment resulted in a significant elevation of the FMD (WMD: 1.64%, 95% CI: 0.46 to 2.81, P = 0.006), particularly if the intervention was equal to or exceeded 12 weeks., Conclusion: Raloxifene might emerge as a potential therapeutic option in the management of endothelial dysfunction and inflammation in postmenopausal women., (Copyright © 2021. Published by Elsevier Inc.)

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates strategies to identify prophylactic and therapeutic drug candidates to enter rapid clinical development. This is particularly true, given the uncertainty about the endurance of the immune memory induced by both previous infections or vaccines, and given the fact that the eradication of SARS-CoV-2 might be challenging to reach, given the attack rate of the virus, which would require unusually high protection by a vaccine. Here, we show how raloxifene, a selective estrogen receptor modulator with anti-inflammatory and antiviral properties, emerges as an attractive candidate entering clinical trials to test its efficacy in early-stage treatment COVID-19 patients., (© 2021. The Author(s).)

Background: Lung tumors express high levels of aromatase enzyme compared to surrounding normal tissue. Inhibition of aromatase has emerged as a recent therapeutic approach for the treatment of breast cancer. However, the role of aromatase inhibition in lung cancer treatment requires further investigation., Methods: The anti-proliferative effects of aromatase inhibitors were evaluated by MTT assay. Cell migration was assessed using a wound healing assay. The mechanism of cell death was determined using the annexin VFITC/ propidium iodide staining flow cytometry method. The soft agar colony formation assay evaluated cells' capability to form colonies., Result: Exemestane and curcumin significantly inhibited the growth of lung cancer cell lines in a dose- and timedependent manner. The IC 50 values after 48 hours of treatment with exemestane were 176, 180, and 120 μM in A549, H661, and H1299, respectively. Curcumin IC 50 values after 48 hours were 80, 43, and 68 μM in A549, H661, and H1299, respectively. The combined treatment of exemestane or curcumin with cisplatin, raloxifene, and celecoxib resulted in a synergistic effect in the A549 lung cell line with a combination index of less than 1, suggesting synergism. Exemestane resulted in approximately 96% inhibition of wound closure at 100 μM, while curcumin resulted in approximately 63% inhibition of wound closure at 50 μM. Exemestane and curcumin inhibited the formation of cell colonies by reducing the number and size of formed colonies of A549, H661, and H1299 cell lines in a concentration dependent manner. Exemestane and curcumin had significantly induced apoptosis in A549 cells compared to control of untreated cells., Conclusion: Aromatase inhibition by exemestane or curcumin had significantly inhibited the growth of lung cancer cell lines, synergized with cisplatin, raloxifene, and celecoxib, suppressed lung cancer cell migratory potential, induced apoptosis, and reduced colony formation of lung cancer cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Chronic inflammation plays a crucial role in the initiation, promotion, and invasion of tumors, and thus the antiproliferative effects of numerous anti-inflammatory drugs have been frequently reported in the literature. Upregulation of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) has been linked to various human cancers, including breast cancer., Objectives: This research aims to investigate the antiproliferative activity of different Non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 selective and non-selective agents, against various breast cancer cell lines and to elucidate possible molecular pathways involved in their activity., Methods: The antiproliferative and combined effects of NSAIDs with raloxifene were evaluated by MTT assay. Cell migration was assessed using a wound-healing assay. The mechanism of cell death was determined using the Annexin V-FITC/ propidium iodide staining flow cytometry method. A mass spectrometry-based targeted metabolomics approach was used to profile the metabolomic changes induced in the T47d cells upon drug treatment., Results: Our results have demonstrated that celecoxib, a potent and selective COX-2 inhibitor, resulted in significant antiproliferative activity against all examined breast cancer cell lines with IC50 values of 95.44, 49.50. and 97.70 μM against MDA-MB-231, T47d, and MCF-7, respectively. Additionally, celecoxib exhibited a synergistic effect against T47d cells combined with raloxifene, a selective estrogen receptor modulator. Interestingly, celecoxib treatment increased cell apoptosis and resulted in substantial inhibition of cancer cell migration. In addition, the metabolomic analysis suggests that celecoxib may have affected metabolites (n = 43) that are involved in several pathways, including the tricarboxylic acid cycle, amino acids metabolism pathways, and energy production pathways in cancer cells., Conclusion: Celecoxib may possess potential therapeutic utility for breast cancer treatment as monotherapy or in combination therapy. The reported metabolic changes taking place upon celecoxib treatment may shed light on possible molecular targets mediating the antiproliferative activity of celecoxib in an independent manner of its COX-2 inhibition., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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% v 83.8% v 78.1%, respectively; P < .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% ( P = .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% ( P = .04). These findings suggest that reexamination of breast cancer risk reduction strategies and clinical practice is needed., Competing Interests: Rowan T. ChlebowskiHonoraria: Novartis, AstraZenecaConsulting or Advisory Role: Novartis, Genentech, Amgen, AstraZeneca, ImmunomedicsSpeakers' Bureau: Novartis, AstraZenecaNo other potential conflicts of interest were reported.

Objectives: To evaluate the anticancer effects of calcitriol and cholecalciferol against different cell lines of breast cancer in monotherapy settings and in combination with raloxifene., Methods: The antiproliferative, anti-migratory, and apoptotic induction effects were assessed by MTT, wound healing, and flow cytometry assays, respectively., Results: Calcitriol and cholecalciferol exhibited antiproliferative effects against T47D, MCF-7, and MDA-MB-231 in a time and concentration-dependent manner. The IC 50 values of calcitriol were in the range of 0.05-0.25 μM while that for cholecalciferol were in the range of 3-100 μM. Furthermore, the results showed that calcitriol and cholecalciferol exhibited anti-migratory effects on MDA-MB-231, an apoptotic induction effect on MCF-7 cells, and a synergistic effect when combined with raloxifene., Conclusions: Calcitriol and cholecalciferol exhibited anticancer effects and may be used as chemosensitizers., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

As a selective estrogen receptor modulator (SERM), raloxifene is used in healthy postmenopausal women to prevent bone loss and reduce fractures. However, the benefit of raloxifene is uncertain in the treatment of osteoporosis among patients with end-stage renal disease (ESRD) or those who require maintenance dialysis. We assessed the safety and efficacy of raloxifene in this particular population. Studies were selected from PubMed, Springer, CNKI (Chinese National Knowledge Infrastructure) and Wanfang Database. Randomized controlled trials (RCTs) and prospective studies with control/placebo groups were included. Five studies were included with a total of 244 participants (121 patients in the raloxifene group and 123 patients in the placebo/control group). The median duration of treatment was 12 months. The incidence rate of side effects of raloxifene was 0/121 (0%). There was a significant improvement of lumbar spine bone mineral density (BMD) levels in the raloxifene group compared with the placebo group (MD: 33.88, 95% CI: 10.93, 56.84, p=0.004). There was no significant difference concerning the improvement of femoral neck BMD (MD: 8.42, 95% CI: -10.21, 27.04, p=0.38), intact parathyroid hormone (iPTH) (MD: -12.62, 95% CI: -35.36, 10.13, p=0.28), calcium (MD: -0.08, 95% CI: -0.61, 0.44, p=0.76), phosphorus (MD: 0.18, 95% CI: -0.12, 0.48, p=0.23) or bone alkaline phosphatase (BAP) (MD: -4.33, 95% CI: -14.44, 5.79, p=0.40). Raloxifene seems to be effective in improving the lumbar spine BMD in postmenopausal women with ESRD. More large RCTs are necessary to evaluate the long-term safety of raloxifene in uremic patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Ethnopharmacological Relevance: The increasing use of "kidney"-nourishing Traditional Chinese Medicine (TCM) like Er-xian decoction (EXD) for management of menopausal symptoms and osteoporosis has aroused concerns about their safety, and whether they interact with prescription drugs as both of them act via estrogen receptors (ERs) and regulate serum estradiol., Aim of the Study: The present study aimed to evaluate whether EXD selectively exerted estrogenic activities and interacted with Selective Estrogen Receptor Modulators (SERMs)., Materials and Methods: In vivo, mature ovariectomized (OVX) rats were administrated with EXD or combined treatment of EXD and SERMs for 12 weeks. The tissue-selective effect of EXD and its interaction of SERMs were studied in four estrogen sensitive tissues, bone, brain, breast and uterus. In vitro, the interaction of extracts of EXD-treated serum and SERMs in four ER-positive cell lines., Results: In OVX rats, EXD selectively alleviated estrogen deficiency-induced changes in the bone and brain without inducing any estrogenic effects in the breast or uterus. Two-way ANOVA indicated the presence of interactions between EXD and SERMs in OVX rats but EXD did not significantly alter the tissue responses to SERMs in the bone, breast or brain. Indeed, the combined use of EXD and SERMs appeared to suppress the estrogenic effect of raloxifene and tamoxifen in the uterus. Extract of EXD-treated serum directly stimulated cell proliferation or differentiation in human osteosarcoma MG-63, neuroblastoma SHSY5Y, breast cancer MCF-7, and endometrial Ishikawa cells. Two-way ANOVA revealed that EXD-treated serum interacted with SERMs at various concentrations and altered the effects of tamoxifen in MG-63 and MCF-7 cells., Conclusions: EXD exerted estrogenic effects in a tissue-selective manner and interacted with SERMs. Combined treatment of EXD and SERMs did not hamper the beneficial effects of SERMs on the bone or brain but appeared to moderate the estrogenic effect of SERMs in the uterus., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than among people who do not have CKD. Although several drugs have been used to effectively treat osteoporosis in the general population, it is unclear whether they are also effective and safe for people with CKD, who have altered systemic mineral and bone metabolism., Objectives: To assess the efficacy and safety of pharmacological interventions for osteoporosis in patients with CKD stages 3-5, and those undergoing dialysis (5D)., Search Methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov., Selection Criteria: Randomised controlled trials comparing any anti-osteoporotic drugs with a placebo, no treatment or usual care in patients with osteoporosis and CKD stages 3 to 5D were included., Data Collection and Analysis: Two review authors independently selected studies, assessed their quality using the risk of bias tool, and extracted data. The main outcomes were the incidence of fracture at any sites; mean change in the bone mineral density (BMD; measured using dual-energy radiographic absorptiometry (DXA)) of the femoral neck, total hip, lumbar spine, and distal radius; death from all causes; incidence of adverse events; and quality of life (QoL). Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Main Results: Seven studies involving 9164 randomised participants with osteoporosis and CKD stages 3 to 5D met the inclusion criteria; all participants were postmenopausal women. Five studies included patients with CKD stages 3-4, and two studies included patients with CKD stages 5 or 5D. Five pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide). All studies were judged to be at an overall high risk of bias. Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95% CI 0.39 to 0.69; low certainty evidence). Anti-osteoporotic drugs probably makes little or no difference to the risk of clinical fracture (RR 0.91, 95% CI 0.79 to 1.05; moderate certainty evidence) and adverse events (RR 0.99, 95% CI 0.98 to 1.00; moderate certainty evidence). We were unable to incorporate studies into the meta-analyses for BMD at the femoral neck, lumbar spine and total hip as they only reported the percentage change in the BMD in the intervention group. Among patients with severe CKD stages 5 or 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture (RR 0.33, 95% CI 0.01 to 7.87; very low certainty evidence). It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low (MD 0.01, 95% CI 0.00 to 0.02). Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine (MD 0.03, 95% CI 0.03 to 0.04, low certainty evidence). No adverse events were reported in the included studies. It is uncertain whether anti-osteoporotic drug reduces the risk of death (RR 1.00, 95% CI 0.22 to 4.56; very low certainty evidence)., Authors' Conclusions: Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture in low certainty evidence. Anti-osteoporotic drugs make little or no difference to the risk of clinical fracture and adverse events in moderate certainty evidence. Among patients with CKD stages 5 and 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture and death because the certainty of this evidence is very low. Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine in low certainty evidence. It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low. Larger studies including men, paediatric patients or individuals with unstable CKD-mineral and bone disorder are required to assess the effect of each anti-osteoporotic drug at each stage of CKD., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: To identify predictors for incident fractures in patients on pharmaceutical treatment for osteoporosis by a secondary analysis of the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04), which was a 2-year, randomized, parallel-group, controlled trial of minodronate and raloxifene in women with primary osteoporosis., Materials and Methods: This was a prospective, observational study using JOINT-04 data, in which biomarkers, such as undercarboxylated osteocalcin (ucOC), N-telopeptide of type 1 collagen, tartrate-resistant acid phosphatase 5b (TRACP-5b), bone alkaline phosphatase, homocysteine, and pentosidine in blood, and physical functions, such as the timed up and go test and one-leg standing test with eyes open (OLST), and the fall risk index, were measured. The relationships of incident morphometric vertebral fractures during the treatment period, as well as prevalent vertebral fractures, and baseline data were analyzed., Results: The full analysis set of the JOINT-04 included 3247 patients (1623 in the minodronate group and 1624 in the raloxifene group). The hazard ratio (95% confidence interval) for incident vertebral fractures over 2 years of pharmacotherapy, adjusted for confounders, was 0.93 (0.90-0.96) for ucOC, 1.15 (1.08-1.23) for TRACP-5b, 1.02 (1.01-1.03) for pentosidine, 0.91 (0.88-0.94) for the OLST, and 1.27 (1.01-1.60) for the fall risk index, which were all independent predictors., Conclusion: Evaluating fracture risk for patients with osteoporosis considering these potential risk factors for fracture in addition to the established risk factors may be useful when starting pharmaceutical treatment.

Background: Adjacent segmental intervertebral disk degeneration (ASDD) is a major complication secondary to lumbar fusion. Although ASSD pathogenesis remains unclear, the primary cause of intervertebral disk degeneration (IVDD) development is apoptosis of nucleus pulposus (NP). Raloxifene (RAL) could delay ASDD by inhibiting NP apoptosis., Methods: An ASDD rat model was established by ovariectomy (OVX) and posterolateral spinal fusion (PLF) on levels 4-5 of the lumbar vertebrae. Rats in the treatment groups were administered 1 mg/kg/d RAL by gavage for 12 weeks, following which, all animals were euthanized. Lumbar fusion, apoptosis, ASDD, and vertebrae micro-architecture were evaluated., Results: RAL maintained intervertebral disk height (DHI), delayed vertebral osteoporosis, reduced histological score, and inhibited apoptosis. The OVX+PLF+RAL group revealed upregulated expression of aggrecan and B-cell lymphoma-2 (bcl2), as well as significantly downregulated expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), metalloproteinase-13 (MMP-13), caspase-3, BCL2-associated X (bax), and transferase dUTP nick end labeling (TUNEL) staining. Micro-computed tomography (Micro-CT) analysis revealed higher bone volume fraction (BV/TV), bone mineral density (BMD), and trabecular number (Tb.N), and lower trabecular separation (Tb.Sp) in OVX+PLF+RAL group than in the OVX+PLF group., Conclusions: RAL can postpone ASDD development in OVX rats through inhibiting extracellular matrix metabolic imbalance, NP cell apoptosis, and vertebral osteoporosis. These findings showed RAL as a potential therapeutic target for ASDD.

The SARS-CoV-2 pandemic has challenged researchers at a global scale. The scientific community's massive response has resulted in a flood of experiments, analyses, hypotheses, and publications, especially in the field of drug repurposing. However, many of the proposed therapeutic compounds obtained from SARS-CoV-2 specific assays are not in agreement and thus demonstrate the need for a singular source of COVID-19 related information from which a rational selection of drug repurposing candidates can be made. In this paper, we present the COVID-19 PHARMACOME, a comprehensive drug-target-mechanism graph generated from a compilation of 10 separate disease maps and sources of experimental data focused on SARS-CoV-2/COVID-19 pathophysiology. By applying our systematic approach, we were able to predict the synergistic effect of specific drug pairs, such as Remdesivir and Thioguanosine or Nelfinavir and Raloxifene, on SARS-CoV-2 infection. Experimental validation of our results demonstrate that our graph can be used to not only explore the involved mechanistic pathways, but also to identify novel combinations of drug repurposing candidates.

Background: Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity. This chronic and recurring condition occurs in women of reproductive age. It is a common cause of pain or infertility and can cause non-specific symptoms such as lower back pain, dyspareunia (pain during or after intercourse), and dysmenorrhoea (menstrual pain). Endometriosis is an oestrogen-dependent disease. Medical treatment aims to relieve symptoms and shrink lesions by suppressing the normal menstrual cycle. In this review, we consider medication specifically aiming to modulate oestrogen receptors as an alternative method of treatment., Objectives: To evaluate the effectiveness and safety of selective oestrogen receptor modulators (SERMs) in the management of endometriosis., Search Methods: We searched for trials in the following databases (from their inception to 28 May 2020): Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies (CRS Online), MEDLINE, Embase, CINAHL, PsycINFO, and registers of ongoing trials. In addition, we searched all reference lists of included trials, and we contacted experts in the field, in an attempt to locate trials., Selection Criteria: We included randomised controlled trials (RCTs) comparing selective oestrogen receptor modulators (SERMs) with placebo, no treatment, other medical treatment, or surgery for endometriosis., Data Collection and Analysis: We used standard methodological procedures recommended by Cochrane. Two review authors independently selected trials for inclusion, assessed risk of bias, and extracted data using data extraction forms. We used risk ratios (RRs) with 95% confidence intervals (CIs) for reporting dichotomous data. Primary review outcomes were relief of pelvic pain and adverse events. Secondary outcomes included quality of life, recurrence rate, and economic and fertility outcomes., Main Results: We included only one RCT, which included 93 women, comparing the SERM raloxifene with placebo in biopsy-proven endometriosis. All women first underwent complete surgical excision of all lesions. Evidence was of very low quality: the main limitation was imprecision - with very sparse data from only one small study, which included only women after surgical treatment. Relief of pelvic pain The included study did not specifically measure the primary outcome of pain relief. Study authors reported that time to return of pelvic pain (defined as two months of pain equal to or more severe than pain at study entry) was more rapid in the raloxifene group (P = 0.03). Adverse events The included study reported adverse events such as pelvic pain, ovarian cyst, headache, migraine, and depression. We are uncertain whether raloxifene improves the incidence of pelvic pain (RR 1.25, 95% CI 0.63 to 2.45), ovarian cysts (RR 1.57, 95% CI 0.55 to 4.43), headache (RR 1.09, 95% CI 0.49 to 2.43), migraine (RR 0.73, 95% CI 0.28 to 1.95), depression (RR 1.96, 95% CI 0.63 to 6.06), or other adverse events (RR 0.08, 95% CI 0.00 to 1.30) (all: 1 study, n = 93; very low-quality evidence). Quality of life The study described a statistically significant difference in mental health quality of life (QoL) by 12 months, in favour of placebo treatment (mean difference 11.1, 95% CI 0.01 to 21.19). Other QoL data did not differ between groups but were not reported in detail. Recurrence rate, fertility, and economic outcomes We are uncertain whether raloxifene improves the recurrence rate of endometriosis, proven by biopsy, when compared to placebo (RR 1.20, 95% CI 0.66 to 2.21; 1 study, n = 93; very low-quality evidence). This suggests that if 28% of women taking placebo have biopsy-proven recurrence of endometriosis, between 19% and 62% of those taking raloxifene will do so. These outcomes are prone to bias, as not all women had an actual second laparoscopy. Recurrence based on symptoms (non-menstrual pain, dysmenorrhoea, or dyspareunia) was described; in these cases, symptoms improved after use of raloxifene as well as after use of placebo. The included study did not report data on economic outcomes. No comparative data were available on pregnancy, as the study included only women who agreed to postpone pregnancy until after the study endpoint; the few pregnancies that did occur were uneventful but were regarded as an adverse event.  AUTHORS' CONCLUSIONS: Based on a single, small RCT and incomplete data, we are uncertain of the effects of SERMs on pain relief in surgically treated patients with endometriosis. The included study was stopped prematurely because of higher pain scores among women who took SERMs when compared to scores among those receiving placebo. Further research is needed to fully evaluate the role of SERMs in endometriosis., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Tocotrienol has been shown to prevent bone loss in animal models of postmenopausal osteoporosis, but the low oral bioavailability might limit its use. A self-emulsifying drug delivery system (SEDDS) could increase the bioavailability of tocotrienol. However, evidence of this system in improving the skeletal effects of tocotrienol is scanty. This study aims to evaluate the therapeutic efficacy of annatto tocotrienol with SEDDS in a rat model of postmenopausal bone loss. Ten-month-old female Sprague Dawley rats were randomized into six groups. The baseline group was euthanatized at the onset of the study. Four other groups underwent ovariectomy to induce estrogen deficiency. The sham underwent similar surgery procedure, but their ovaries were retained. Eight weeks after surgery, the ovariectomized rats received one of the four different regimens orally daily: (a) SEDDS, (b) annatto tocotrienol [60 mg/kg body weight (b.w.)] without SEDDS, (c) annatto-tocotrienol (60 mg/kg b.w.) with SEDDS, (d) raloxifene (1 mg/kg b.w.). After eight weeks of treatment, blood was collected for the measurement of delta-tocotrienol level and oxidative stress markers. The rats were euthanized and their bones were harvested for the evaluation of the bone microstructure, calcium content and strength. Circulating delta-tocotrienol level was significantly higher in rats receiving annatto tocotrienol with SEDDS compared to the group receiving unformulated annatto-tocotrienol (p < 0.05). Treatment with unformulated or SEDDS-formulated annatto tocotrienol improved cortical bone thickness, preserved bone calcium content, increased bone biomechanical strength and increased antioxidant enzyme activities compared with the ovariectomized group (p < 0.05). Only SEDDS-formulated annatto tocotrienol improved trabecular microstructure, bone stiffness and lowered malondialdehyde level (p < 0.05 vs the ovariectomized group). The improvement caused by annatto tocotrienol was comparable to raloxifene. In conclusion, SEDDS improves the bioavailability and skeletal therapeutic effects of annatto tocotrienol in a rat model of postmenopausal bone loss. This formulation should be tested in a human clinical trial to validate its efficacy., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Osteoporosis is a metabolic disease of the skeletal system which currently affects over 200 million patients worldwide. The WHO criteria define osteoporosis as low bone mineral density, with a T-score ≤ -2.5 found in the spine, the neck of the femur, or during a full hip examination. Osteoporosis considerably reduces a patient's quality of life. QoL should be carefully evaluated before fractures occur to enable the development of an appropriate treatment plan. The progression of osteoporosis may be significantly inhibited by following a proper diet, leading a healthy lifestyle, taking dietary supplements, and receiving appropriate treatment. Education and the prevention of the disease play a major role. Potentially modifiable risk factors for osteoporosis are vitamin D deficiency, smoking, alcohol consumption, low calcium intake, low or excessive phosphorus intake, protein deficiency or a high-protein diet, excessive consumption of coffee, a sedentary lifestyle or lack of mobility, and insufficient exposure to the sun. Pharmaceutical treatment for osteoporosis involves bisphosphonates, calcium and vitamin D3, denosumab, teriparatide, raloxifene, and strontium ranelate. Data indicates that 30%-50% of patients do not take their medication correctly. Other methods of treatment include exercise, kinesitherapy, treatment at a health resort, physical therapy, and diet.

There is robust evidence that the appropriate treatment of dyslipidaemia substantially reduces cardiovascular disease-related morbidity and mortality. Raloxifene is a selective oestrogen receptor modulator that also interferes with the lipid metabolism and may be of aid in the management of lipid abnormalities in females. Therefore, we conducted a systematic review and meta-analysis of the available randomized clinical trials (RCTs) exploring the effect of raloxifene on the lipid profile in women. The Scopus, Web of Science, PubMed/Medline and EMBASE databases were systematically and independently searched by two assessors from inception until 20 November 2020 without time and language restrictions. The overall findings were generated from 30 eligible RCTs. As compared to controls, raloxifene resulted in a significant elevation of the high-density lipoprotein-cholesterol (HDL-C) (WMD: 2.41 mg/dL, 95% CI: 0.84-3.97, P = 0.003) and a significant reduction of the total cholesterol (TC) (WMD:-14.84 mg/dL, 95% CI: -20.37 to -9.317, P = 0.000) and of the low-density lipoprotein-cholesterol (LDL-C) (WMD: -17 mg/dL, 95% CI: -25.77, -8.22, P = 0.000). In the stratified analysis, a significant decrease of serum triglycerides (TG) (WMD: -22.06 mg/dL) was achieved in the RCTs with a duration of ≤ 26 weeks (WMD -8.70 mg/dL) and with baseline TG concentrations of ≥ 130 mg/dL (WMD: -23.02 mg/dL). In conclusion, raloxifene treatment can increase HDL-C and lower LDL-C and TC. In terms of TG, a significant decrease can be observed if the administration of raloxifene lasts ≤ 26 weeks and if the baseline TG concentrations are ≥ 130 mg/dL., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: In patients with primary hyperparathyroidism (PHPT) and severe hypercalcemia, parathyroidectomy remains the only curative therapy. During the coronavirus disease 2019 (COVID-19) pandemic, when many hospital visits are suspended and surgeries cannot be performed, the management of these patients represents a challenging clinical situation. This article presents a literature review and discussion of the pharmacologic management of PHPT and severe hypercalcemia, which can be used as a temporary measure during the COVID-19 pandemic until parathyroidectomy can be performed safely., Methods: This narrative review was conducted by searching literature on the PubMed, Medline, and Google Scholar databases using the terms primary hyperparathyroidism, hypercalcemia, cinacalcet, bisphosphonates, denosumab, vitamin D, raloxifene, hormone replacement therapy, coronavirus, and COVID-19., Findings: Appropriate monitoring and remote medical follow-up of these patients are essential until the resolution of the pandemic. Cinacalcet is the drug of choice for controlling hypercalcemia, whereas bisphosphonate or denosumab is the drug for improving bone mineral density. Combined therapy with cinacalcet and bisphosphonates or cinacalcet and denosumab should be considered when the effects on serum calcium and bone mineral density are simultaneously desired., Implications: Medical management of PHPT and severe hypercalcemia presents a reasonable alternative for parathyroid surgery during the COVID-19 outbreak and should be instituted until the pandemic ends and surgery can be performed safely., Competing Interests: Declaration of Competing Interest The author has indicated no conflicts of interest with regard to the content of this article., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial., Methods and Results: Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6, respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF- α ) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro , we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene., Conclusion: Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Shengqi Huo et al.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused corona virus disease 2019 (COVID-19) pandemic and led to mass casualty. Even though much effort has been put into development of vaccine and treatment methods to combat COVID-19, no safe and efficient cure has been discovered. Drug repurposing or drug repositioning which is a process of investigating pre-existing drug candidates for novel applications outside their original medical indication can speed up the drug development process. Raloxifene is a selective estrogen receptor modulator (SERM) that has been approved by FDA in 1997 for treatment and prevention of postmenopausal osteoporosis and cancer. Recently, raloxifene demonstrates efficacy in treating viral infections by Ebola, influenza A, and hepatitis C viruses and shows potential for drug repurposing for the treatment of SARS-CoV-2 infection. This review will provide an overview of raloxifene's mechanism of action as a SERM and present proposed mechanisms of action in treatment of viral infections.

Several neurodegenerative disorders are characterized by proteasome dysfunctions leading to protein aggregations and pathogenesis. Since we showed that estrogen receptor alpha (ERα) activates the proteasome, drugs able to stimulate ERα in the central nervous system (CNS) could hold potential for therapeutic intervention. However, the transcriptional effects of selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, can be tissue specific. A direct comparison of the effects of different SERMs on gene transcription in the CNS has never been performed. Here, we report an RNA-seq analysis of the spinal cord treated with estrogen, tamoxifen, or raloxifene. We find stark SERM and sex-specific differences in gene expression profiles in the spinal cord. Notably, raloxifene, but not estrogen or tamoxifen, modulates numerous deubiquitinating enzymes, proteasome subunits and assembly factors, and these effects translate into decreased protein aggregates. In the SOD1-G93A mouse model of amyotrophic lateral sclerosis, we found that even a low dose of raloxifene causes a significant decrease in mutant SOD1 aggregates in the spinal cord, accompanied by a delay in the decline of muscle strength in females, but not in males. These results strongly indicate SERM-selective as well as sex-specific effects, and emphasize the importance of sex as a biological variable to be considered for the careful selection of specific SERM for use in clinical trials for neurodegenerative diseases., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD)., Methods: Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure., Results: Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (P = 0.34) or Beck Depression Inventory (P = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (P = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (P = 0.0005), and less consistently with placebo (P = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE-15.3 (4.5), raloxifene-16.0 (3.7), Rimostil-14.0 (2.7), and placebo-15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE-5.2(1.1), raloxifene-5.8(1.2), Rimostil-11.2(1.4), and placebo-7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (P values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo., Conclusions: This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha)., Competing Interests: Financial disclosures/conflicts of interest: D.R.R. reports funding from Sage Therapeutics Advisory Board and Dialogues in Clinical Neuroscience Editorial Board. He is a member of Foundation of Hope Board., (Copyright © 2021 by The North American Menopause Society.)

Background: Limited evidence exists about how to communicate breast density-informed breast cancer risk to women at elevated risk to motivate cancer prevention., Methods: We conducted a randomized controlled trial evaluating a web-based intervention incorporating personalized breast cancer risk, information on chemoprevention, and values clarification on chemoprevention uptake vs active control. Eligible women aged 40-69 years with normal mammograms and elevated 5-year breast cancer risk were recruited from Kaiser Permanente Washington from February 2017 to May 2018. Chemoprevention uptake was measured as any prescription for raloxifene or tamoxifen within 12 months from baseline in electronic health record pharmacy data. Secondary outcomes included breast magnetic resonance imaging (MRI), mammography use, self-reported distress, and communication with providers. We calculated unadjusted odds ratios (ORs) using logistic regression models and mean differences using analysis of covariance models with 95% confidence intervals (CIs) with generalized estimating equations., Results: We randomly assigned 995 women to the intervention arm (n = 492) or control arm (n = 503). The intervention (vs control) had no effect on chemoprevention uptake (OR = 1.04, 95% CI = 0.07 to 16.62). The intervention increased breast MRI use (OR = 5.65, 95% CI = 1.61 to 19.74) while maintaining annual mammography (OR = 0.98, 95% CI = 0.75 to 1.28). Women in the intervention (vs control) arm had 5.67-times higher odds of having discussed chemoprevention or breast MRI with provider by 6 weeks (OR = 5.67, 95% CI = 2.47 to 13.03) and 2.36-times higher odds by 12 months (OR = 2.36, 95% CI = 1.65 to 3.37). No measurable differences in distress were detected., Conclusions: A web-based, patient-level intervention activated women at elevated 5-year breast cancer risk to engage in clinical discussions about chemoprevention, but uptake remained low., (© The Author(s) 2021. Published by Oxford University Press.)

Glioblastoma (GBM) is the most common primary malignant brain tumor, and it has a uniformly poor prognosis. Hypoxia is a feature of the GBM microenvironment, and previous work has shown that cancer cells residing in hypoxic regions resist treatment. Hypoxia can trigger the formation of stress granules (SGs), sites of mRNA triage that promote cell survival. A screen of 1120 FDA-approved drugs identified 129 candidates that delayed the dissolution of hypoxia-induced SGs following a return to normoxia. Amongst these candidates, the selective estrogen receptor modulator (SERM) raloxifene delayed SG dissolution in a dose-dependent manner. SG dissolution typically occurs by 15 min post-hypoxia, however pre-treatment of immortalized U251 and U3024 primary GBM cells with raloxifene prevented SG dissolution for up to 2 h. During this raloxifene-induced delay in SG dissolution, translational silencing was sustained, eIF2α remained phosphorylated and mTOR remained inactive. Despite its well-described role as a SERM, raloxifene-mediated delay in SG dissolution was unaffected by co-administration of β-estradiol, nor did β-estradiol alone have any effect on SGs. Importantly, the combination of raloxifene and hypoxia resulted in increased numbers of late apoptotic/necrotic cells. Raloxifene and hypoxia also demonstrated a block in late autophagy similar to the known autophagy inhibitor chloroquine (CQ). Genetic disruption of the SG-nucleating proteins G3BP1 and G3BP2 revealed that G3BP1 is required to sustain the raloxifene-mediated delay in SG dissolution. Together, these findings indicate that modulating the stress response can be used to exploit the hypoxic niche of GBM tumors, causing cell death by disrupting pro-survival stress responses and control of protein synthesis.

Aims: We conducted a head-to-head randomized trial of minodronate, a bisphosphonate, and raloxifene, a selective estrogen receptor modulator, to obtain clinical evidence and information about their efficacy and safety., Methods: The Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04) trial is a multi-center, open-labeled, blinded endpoints, head-to-head randomized trial of minodronate and raloxifene. Ambulatory elderly women with osteoporosis (age, >60 years) were randomly allocated to the raloxifene or minodronate group by central registration. The co-primary endpoints included any one of osteoporotic fractures (vertebral, humeral, femoral, and radial fractures), vertebral fractures, and major osteoporotic fractures (clinical vertebral, humeral, femoral, and radial fractures). The biological effects of each drug, patients' quality of life, and drug safety were assessed based on the secondary outcomes. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) under trial identification number UMIN000005433., Results: A total of 3896 patients were randomized to the minodronate and raloxifene groups, and drug efficacy assessments were performed for 3247 patients (1623 and 1624 patients, respectively). Among these patients, 1176 and 1187 patients received allocated treatment for 2 years. The incidence rate ratios for osteoporotic, vertebral, and major osteoporotic fractures in the minodronate group were 0.94 (95% CI: 0.78-1.13, p  = .494), 0.86 (95% CI: 0.70-1.05, p  = .147), and 1.22 (95% CI: 0.86-1.74, p  = .274), respectively. Compared to the raloxifene group, the minodronate group showed significantly increased bone mineral density of the lumbar spine for each visit (6 months: p  = .007, 12 months: p  = .0003, 24 months: p <.0001). Also, serious adverse reactions were observed for four and six patients in the minodronate and raloxifene groups, respectively., Conclusions: Overall, there were no statistical differences in the incidence rates of osteoporotic, vertebral, or major osteoporotic fractures between the two groups. Serious adverse reactions were rare in both groups.

Recent studies have shown that the selective estrogen receptor modulator (SERM) raloxifene had pronounced protective effects against progressing brain damage after traumatic brain injury (TBI) in mice. These studies, indicating beneficial effects of raloxifene for brain health, prompted the study of the history and present state of knowledge of this topic. It appears that, apart from raloxifene, to date, four nonrelated compounds have shown comparable beneficial effects-fucoidan, pifithrin, SMM-189 (5-dihydroxy-phenyl]-phenyl-methanone), and translocator protein (TSPO) ligands. Raloxifene, however, is ahead of the field, as for more than two decades it has been used in medical practice for various chronic ailments in humans. Thus, apart from different types of animal and cell culture studies, it has also been assessed in various human clinical trials, including assaying its effects on mild cognitive impairments. Regarding cell types, raloxifene protects neurons from cell death, prevents glial activation, ameliorates myelin damage, and maintains health of endothelial cells. At whole central nervous system (CNS) levels, raloxifene ameliorated mild cognitive impairments, as seen in clinical trials, and showed beneficial effects in animal models of Parkinson's disease. Moreover, with stroke and TBI in animal models, raloxifene showed curative effects. Furthermore, raloxifene showed healing effects regarding multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) in cell culture. The adverse biological signals typical of these conditions relate to neuronal activity, neurotransmitters and their receptors, plasticity, inflammation, oxidative stress, nitric oxide, calcium homeostasis, cell death, behavioral impairments, etc. Raloxifene favorably modulates these signals toward cell health-on the one hand, by modulating gene expression of the relevant proteins, for example by way of its binding to the cell nuclear estrogen receptors ERα and ERβ (genomic effects) and, on the other hand (nongenomic effects) by modulation of mitochondrial activity, reduction of oxidative stress and programmed cell death, maintaining metabolic balance, degradation of Abeta, and modulation of intracellular cholesterol levels. More specifically regarding Alzheimer's disease, raloxifene may not cure diagnosed Alzheimer's disease. However, the onset of Alzheimer's disease may be delayed or arrested by raloxifene's capability to attenuate mild cognitive impairment. Mild cognitive impairment is a condition that may precede diagnosis of Alzheimer's disease. In this review, relatively new insights are addressed regarding the notion that Alzheimer's disease can be caused by bacterial (as well as viral) infections, together with the most recent findings that raloxifene can counteract infections of at least some bacterial and viral strains. Thus, here, an overview of potential treatments of neurodegenerative disease by raloxifene is presented, and attention is paid to subcellular molecular biological pathways that may be involved.

The neurodegenerative Alzheimer's disease (AD) affects more than 30 million people worldwide. There is thus far no cure or prevention for AD. Aggregation of hyperphosphorylated tau in the brain correlates with the cognitive decline of patients of AD and other neurodegenerative tauopathies. Intracerebral injection of tau aggregates isolated from tauopathy brains causes similar pathology in the recipient mice, demonstrating the pathogenic role of abnormally phosphorylated tau. Compounds controlling the aggregation of hyperphosphorylated tau therefore are probable modulators for the disease. Here we report the use of recombinant hyperphosphorylated tau (p-tau) to identify potential tauopathy therapeutics and risk factors. Hyperphosphorylation renders tau prone to aggregate and to impair cell viability. Taking advantage of these two characters of p-tau, we performed a screen of a 1280-compound library, and tested a selective group of prescription drugs in p-tau aggregation and cytotoxicity assays. R-(-)-apomorphine and raloxifene were found to be p-tau aggregation inhibitors that protected p-tau-treated cells. In contrast, a subset of benzodiazepines exacerbated p-tau cytotoxicity apparently via enhancing p-tau aggregation. R-(-)apomorphine and raloxifene have been shown to improve cognition in animals or in humans, whereas benzodiazepines were linked to increased risks of dementia. Our results demonstrate the feasibility and potential of using hyperphosphorylated tau-based assays for AD drug discovery and risk factor identification.

Background: The goal of this study was to review relevant randomized controlled trials or case-control studies to determine the clinical efficacy of minodronate in the treatment of osteoporosis., Method: The relevant studies were identified on PubMed, Cochrane, and Embase databases using appropriate keywords. Pertinent sources in the literature were also reviewed, and all articles published through October 2019 were considered for inclusion. For each study, we assessed odds ratios, mean difference, and 95% confidence interval (95% CI) to evaluate and synthesize outcomes., Result: Thirteen studies comprising 3740 patients were included in this study. Compared with other drugs, minodronate significantly decreased N-telopeptide of type I collagen/creatinine (weighted mean difference [WMD]: -13.669, 95% confidence interval [CI]: -23.108 to -4.229), bone alkaline phosphatase (BAP) (WMD: -1.26, 95% CI: -2.04 to -0.47) and tartrate-resistant acid phosphatase 5b (WMD: -154.11, 95% CI: -277.85 to -30.37). Minodronate combined with other drugs would significantly decrease BAP (WMD: -3.10, 95% CI: -5.20 to -1.00) than minodronate. Minodronate-naïve would significantly decrease BAP (WMD: -3.00, 95% CI: -5.47 to 0.53) and tartrate-resistant acid phosphatase 5b (WMD: -128.20, 95% CI: -198.11 to -58.29) than minodronate-switch. The incidence of vertebral fracture was significantly decreased in the minodronate group than the other drugs (relative risk: 0.520, 95% CI: 0.363-0.744)., Conclusion: Minodronate has better clinical efficacy in the treatment of osteoporosis than other drugs (alendronate, risedronate, raloxifene, or eldecalcitol).