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Psychoneuroendocrinology Dec 2019There is currently no treatment available for the cognitive symptoms of schizophrenia, but evidence suggests that selective estrogen receptor modulators (SERMs) may...
There is currently no treatment available for the cognitive symptoms of schizophrenia, but evidence suggests that selective estrogen receptor modulators (SERMs) may provide relief. Our recent animal model data showed that a lack of female sex hormones in mice impairs the ability of hippocampal neurons to synchronise and generate oscillations within the frequency range of 30-80 Hz (gamma power) leading to cognitive impairment, while both estradiol and the SERM, raloxifene, recovered this. Given that cognitive impairment is accompanied by abnormal gamma power in schizophrenia, this study aimed to determine the effects of raloxifene on gamma power during spatial memory tasks in the prenatal immune challenged (poly-I:C) mouse model with relevance to schizophrenia. Pregnant dams received the viral mimetic poly-I:C (20 mg/kg, i.p.) at gestational day 17. Male and female offspring were treated with placebo or raloxifene implants at adulthood. Local field potentials from the CA1 hippocampus were simultaneously recorded during the Y-maze test of short term spatial memory and the cheeseboard maze test of long-term spatial learning and memory and cognitive flexibility. In female but not male mice, poly I:C exposure reduced gamma power during decision making and prolonged the time spent in the centre (decision making phase) during the Y-maze task. Female poly-I:C exposed mice also showed increased gamma power during acquisition of the cheeseboard long term memory task and perseverative behaviour. Treatment with raloxifene recovered gamma power and decision making deficits in the Y-maze and restored gamma power changes during the cheeseboard maze task as well as perseverative behaviour. Male mice showed no electrophysiological or behavioural effects of poly-I:C or raloxifene treatment. In summary, poly-I:C exposure induced female specific cognitive impairments accompanied by altered neural oscillations in the gamma frequency and raloxifene recovered these abnormalities.
Topics: Animals; Behavior, Animal; Biological Clocks; Cognition; Disease Models, Animal; Female; Gamma Rhythm; Immune System; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Psychomotor Performance; Raloxifene Hydrochloride; Schizophrenia
PubMed: 31546114
DOI: 10.1016/j.psyneuen.2019.104448 -
Climacteric : the Journal of the... Apr 2019Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have variable estrogen agonist and antagonist activities in different target... (Review)
Review
Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have variable estrogen agonist and antagonist activities in different target tissues. Tamoxifen is an anti-estrogen in the breast used for treatment and prevention of breast cancer, with estrogen agonist activity in the uterus. Raloxifene prevents and treats osteoporosis and prevents breast cancer, and can be safely combined with vaginal but not systemic estrogen. The tissue selective estrogen complex combines conjugated equine estrogens (CEE) with the SERM bazedoxifene (BZA). The five Selective Estrogen Menopause and Response to Therapy studies, with up to 2 years of data, demonstrated that CEE/BZA 0.45 mg/BZA 20 mg improved vasomotor symptoms and vulvovaginal atrophy, prevented bone loss, and was neutral on breast tenderness, breast density, with breast cancer incidence similar to placebo. Protection against estrogen-induced endometrial hyperplasia and cancer was found, with similar amenorrhea rates to placebo. Ospemifene is approved to treat dyspareunia, with potential benefits on bone and the breast, while lasofoxifene is being developed to treat resistant estrogen receptor-positive breast cancer in women. Estetrol is an estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered a weak estrogen, but it appears to have dual weak estrogenic/anti-estrogenic features.
Topics: Adult; Aged; Atrophy; Breast Neoplasms; Estrogens, Conjugated (USP); Female; Female Urogenital Diseases; Hot Flashes; Humans; Indoles; Middle Aged; Osteoporosis, Postmenopausal; Postmenopause; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Vagina
PubMed: 30895900
DOI: 10.1080/13697137.2019.1568403 -
Osteoporosis International : a Journal... Jul 2022Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover... (Observational Study)
Observational Study
UNLABELLED
Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover markers. The decrease in lumbar bone mineral density was particularly evident when the body mass index was low, there were previous vertebral fractures, or lumbar bone mineral density before denosumab administration was low.
INTRODUCTION
Selective estrogen receptor modulators may be an alternative to bisphosphonates for treating rebound resorption after discontinuing denosumab. This study aimed to investigate the effects of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women.
METHODS
This retrospective observational study included 61 patients who received 12-month follow-up raloxifene therapy after denosumab discontinuation. The primary endpoint was the bone mineral density change. The secondary endpoints were the changes in bone turnover markers and the incidence of new vertebral fractures.
RESULTS
Raloxifene administration for 12 months after denosumab discontinuation resulted in a significantly lower bone mineral density at all sites compared to the level at 6 months after the last denosumab treatment (lumbar spine, - 5.48%; femoral neck, - 2.95%; total hip, - 3.52%; all, p < 0.001). The decrease in lumbar bone mineral density was particularly evident when the body mass index was low, there were previous vertebral fractures, or lumbar bone mineral density before denosumab administration was low. Marked increases in the bone turnover markers from baseline were noted after switching to raloxifene. However, no new vertebral fractures occurred during raloxifene treatment.
CONCLUSIONS
Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover markers. Therefore, raloxifene administered sequentially after denosumab discontinuation was not effective in preventing rebound phenomenon.
Topics: Bone Density; Bone Density Conservation Agents; Denosumab; Female; Follow-Up Studies; Humans; Osteoporosis, Postmenopausal; Postmenopause; Raloxifene Hydrochloride; Spinal Fractures
PubMed: 35376989
DOI: 10.1007/s00198-022-06388-w -
Ginekologia Polska 2017This study aims to asses the effects of estradiol vs. raloxifene on the levels of osteoprotegerin and soluble Receptor Activator of Nuclear Factor kB Ligand (sRANKL) in...
OBJECTIVES
This study aims to asses the effects of estradiol vs. raloxifene on the levels of osteoprotegerin and soluble Receptor Activator of Nuclear Factor kB Ligand (sRANKL) in Human Umbilical Vein Endothelial Cells (HUVEC) culture in standard and calcifying medium.
MATERIAL AND METHODS
Human Umbilical Vein Endothelial Cells were isolated from human umbilical vein by standard method. The supernatant concentrations of osteoprotegerin (OPG) and sRANKL (ELISA) were determined after incubation with glicerophosphate, estradiol , raloxifene, glicerophoshate and estradiol, glicerophosphate and raloxifene in comparison with control group at four designated time points (0, 1, 2 and 4 days of incubation).
RESULTS
Incubation of estradiol with HUVEC colony lowered the OPG level significantly after day 2 and 4. Meantime, the level of sRANKL was stable. Raloxifene added to standard growth medium also significantly lowered OPG concentration after day 4 only, with no impact on sRANKL concentration. When added to calcifying medium, both estradiol and raloxifene significantly changed OPG level during the experiment. In all treated groups OPG levels were lower than in groups exposed to calcifying medium only. Neither estradiol, nor raloxifene changed sRANKL levels during the experiment.
CONCLUSIONS
Estradiol and raloxifene affect OPG secretion from endothelial cells in vitro which may suggest their modifying role in pathogenesis of vascular calcification in postmenopausal women.
Topics: Endothelial Cells; Estradiol; Estrogens; Female; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Osteoprotegerin; Postmenopause; RANK Ligand; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Vascular Calcification
PubMed: 28509316
DOI: 10.5603/GP.a2017.0033 -
Bone Jul 2024Osteogenesis imperfecta (OI) increases fracture risk due to changes in bone quantity and quality caused by mutations in collagen and its processing proteins. Current...
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.
Topics: Animals; Raloxifene Hydrochloride; Osteogenesis Imperfecta; Female; Male; Disease Models, Animal; Mice; Bone and Bones; Biomechanical Phenomena; Apoptosis; Anabolic Agents; Weight-Bearing; Osteocytes
PubMed: 38641232
DOI: 10.1016/j.bone.2024.117106 -
Clinical Oral Investigations Jan 2018Alendronate and raloxifene, a bisphosphonate and a selective estrogen modulator, respectively, are established osteoporosis therapies. Current evidence suggests that...
OBJECTIVES
Alendronate and raloxifene, a bisphosphonate and a selective estrogen modulator, respectively, are established osteoporosis therapies. Current evidence suggests that simultaneous application of osteoporosis therapies modulates osseointegration. However, alendronate shows inconsistent findings and raloxifene has not been studied comprehensively. This study aimed to evaluate the bone dynamics and molecular and microstructural features at the peri-implant bone interface in osteoporotic rats.
MATERIALS AND METHODS
Thirty female rats underwent ovariectomy and were fed a diet low in calcium and phosphate and treated with alendronate or raloxifene for 30 days or underwent fictional ovariectomy surgery (SHAM) prior to implant insertion in the tibia; osteoporosis therapies continued thereafter. After 42 days, peri-implant bone was evaluated by histometric and micro-CT analysis. Fluorochrome incorporation and gene expression was determined to evaluate bone turnover.
RESULTS
We report here that alendronate had no impact on bone-to-implant contacts and the mineral apposition rate. The RANKL/OPG ratio and local bone volume, however, were increased compared to the untreated osteoporotic rats. Even though signaling to bone resorption activity through RANKL production was observed in the alendronate group, the blockade of bone resorption activity that occurs in decorrence to alendronate activity took place and resulted in an increase in bone volume. Raloxifene significantly increased osseointegration in osteoporotic rats, as indicated by bone-to-implant contacts, mineral apposition, and local bone volume. Raloxifene, however, had no considerable impact on the RANKL/OPG ratio compared to untreated osteoporotic rats. As expected, the SH group showed higher bone-to-implant contacts and mineral apposition rates than the untreated osteoporotic rats.
CONCLUSIONS
These findings suggest that raloxifene but not alendronate can compensate for the impaired osseointegration in osteoporotic rats.
CLINICAL RELEVANCE
Regarding the superiority of raloxifene observed in the improvement of bone dynamics response, this statement suggests that raloxifene could be a good option for osteoporosis patients in oral rehabilitation procedures.
Topics: Alendronate; Animals; Bone Density; Dental Implants; Disease Models, Animal; Female; Immunoenzyme Techniques; Implants, Experimental; Microscopy, Confocal; Osseointegration; Osteoporosis; Ovariectomy; Raloxifene Hydrochloride; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Tibia; X-Ray Microtomography
PubMed: 28357643
DOI: 10.1007/s00784-017-2106-2 -
Connective Tissue Research Dec 2018This study proposes to evaluate, by means of microtomographic analysis, the topical potential of raloxifene combined with BioGran® through the sonochemical method in...
OBJECTIVE
This study proposes to evaluate, by means of microtomographic analysis, the topical potential of raloxifene combined with BioGran® through the sonochemical method in the repair of critical bone defects in the calvaria of rats. The hypothesis was that the homogenization of Raloxifene to Biogran at the 20% concentration would improve the bone repair at the grafted site.
MATERIALS AND METHODS
A 5-mm calvaria bone defect was induced in three groups: CTR (100% BioGran®); RAL10 (90% BioGran® and 10% raloxifene), and RAL20 (80% BioGran® and 20% raloxifene). The animals were euthanized after 30 days and the microCT analysis was then performed to evaluate the parameters bone volume (BV), bone volume percentage (BV/TV), trabecular bone thickness (Tb.Th), and the separation and number of trabeculae (Tb.Sp and Tb.N). The obtained results were compared using ANOVA and Tukey test (p < 0.05).
RESULTS
The best results were found for the CTR and RAL20 groups, in which the BV, BV/TV, Tb.Sp, and Tb.N parameters were statistically significant in comparison with RAL10 (p < 0.05).
CONCLUSIONS
In view of the results obtained in this experiment, we can conclude that BioGran® alone or in an 80/20 mass concentration with raloxifene can lead to favorable bone formation.
Topics: Animals; Bone Density; Bone Regeneration; Ceramics; Male; Nanocomposites; Raloxifene Hydrochloride; Rats; Rats, Wistar; Skull
PubMed: 29745810
DOI: 10.1080/03008207.2018.1430143 -
JAMA Jul 2020
Topics: Adult; Age Factors; Anastrozole; Androstadienes; Anticarcinogenic Agents; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Raloxifene Hydrochloride; Risk Factors; Selective Estrogen Receptor Modulators; Tamoxifen
PubMed: 32692388
DOI: 10.1001/jama.2020.11784 -
Bioanalysis Jun 2023A reliable, sensitive, HPLC method was developed and validated to simultaneously quantify raloxifene (RLX) and cladrin (CLD). The C18 column was used to analyze RLX...
A reliable, sensitive, HPLC method was developed and validated to simultaneously quantify raloxifene (RLX) and cladrin (CLD). The C18 column was used to analyze RLX and CLD at λ 285 and 249 nm. The mobile phase was composed of acetonitrile and 35:65% v/v aqueous solution of 0.1% formic acid. The method was linear over the linearity range of 0.078-20 μg/ml, and the limit of detection and limit of quantification for RLX and CLD were 0.191 and 0.228 and 0.581 and 0.69 μg/ml, respectively. In accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines, the developed method is precise and accurate for simultaneous estimation of RLX and CLD with applications in liver microsomal stability in mice, rabbits, dogs, monkeys and humans.
Topics: Mice; Humans; Animals; Dogs; Rabbits; Chromatography, High Pressure Liquid; Raloxifene Hydrochloride; Isoflavones
PubMed: 37254752
DOI: 10.4155/bio-2023-0046 -
Genes Jan 2023The present study analyzed the effect of vitamin D receptor () gene polymorphisms (ApaI, TaqI, BsmI, FokI, and Cdx2) on bone mineral density (BMD), biochemical...
The present study analyzed the effect of vitamin D receptor () 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 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 gene in personalized pharmacotherapy of osteoporosis.
Topics: Female; Humans; Receptors, Calcitriol; Raloxifene Hydrochloride; Ibandronic Acid; Polymorphism, Genetic; Osteoporosis; Fractures, Bone
PubMed: 36672934
DOI: 10.3390/genes14010193