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Arkadi Chines - One of the best experts on this subject based on the ideXlab platform.
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Bridging analysis of the efficacy and safety of Bazedoxifene in Japanese and global populations of postmenopausal women with osteoporosis.
Journal of bone and mineral metabolism, 2014Co-Authors: Akira Itabashi, Takami Miki, Arkadi Chines, Kousei Yoh, Masahiko Takada, Hiroshi Sato, Itsuo Gorai, Toshitsugu Sugimoto, Hideki Mizunuma, Hiroshi OchiAbstract:This study examined whether the global clinical data for Bazedoxifene could be extrapolated to a Japanese population by evaluating the results of a phase 2 study in postmenopausal Japanese women with osteoporosis as compared to those of a pivotal, phase 3 study. The efficacy of Bazedoxifene 20 and 40 mg versus placebo on lumbar spine bone mineral density (BMD), bone turnover markers, lipid profile, incidence of fractures, and safety parameters was compared between the Japanese phase 2 study (N = 429) and the global phase 3 study (N = 7,492) during a 2-year period. In the primary population for assessment of bridging, differences in the mean percent change from baseline in lumbar spine BMD at 2 years relative to placebo were greater for women treated with Bazedoxifene 20 and 40 mg in the phase 2 study than in the phase 3 study. BMD changes in the Bazedoxifene groups were confirmed to be similar between the phase 2 study population and a subset of the phase 3 study population with similar baseline characteristics. The effects of Bazedoxifene on incidence of fractures, bone turnover markers, and lipid metabolism were similar between studies. There were no major differences in safety parameters between studies. The greater improvement in lumbar spine BMD and similar results in bone turnover markers, fracture incidence, and safety profile observed with Bazedoxifene in the phase 2 study compared with the phase 3 study confirmed the feasibility of extrapolating the global clinical data to a Japanese population.
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A double‐blind, randomized, ascending, multiple‐dose study of Bazedoxifene in healthy postmenopausal women
Clinical pharmacology in drug development, 2014Co-Authors: William Mckeand, Gayle P. Orczyk, Ermer James C, Arkadi ChinesAbstract:Bazedoxifene is a novel selective estrogen receptor modulator in clinical development for the prevention and treatment of postmenopausal osteoporosis. This phase 1, double-blind, randomized, placebo-controlled study (N = 107) of healthy postmenopausal women examined the pharmacokinetics and safety/tolerability profile of multiple doses of Bazedoxifene (1, 2.5, 5, 10, 20, 40, and 80 mg) administered orally once daily for 30 days. Bazedoxifene demonstrated a half-life of 25 to 30 hours, reached steady state within 7 days, and exhibited linear pharmacokinetics over a dose range of 5-80 mg. Fibrinogen levels decreased with Bazedoxifene doses of 5 mg and greater; these changes were significant for Bazedoxifene 20, 40, and 80 mg (P ≤ .05 vs placebo), but were not dose dependent. Bazedoxifene was associated with increased levels of sex hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin (CBG); only increases in the levels of CBG appeared to be dose related. Bazedoxifene was safe and well tolerated within the tested dose range. Bazedoxifene showed no differences from placebo in adverse event reports, vital sign measurements, or electrocardiogram findings.
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Relationships Between Changes in Bone Mineral Density or Bone Turnover Markers and Vertebral Fracture Incidence in Patients Treated with Bazedoxifene
Calcified Tissue International, 2012Co-Authors: Olivier Bruyère, Arkadi Chines, Johann Detilleux, Jean-yves ReginsterAbstract:We analyzed the relationships between bone mineral density (BMD) or bone turnover marker (BTM) changes and vertebral fracture incidence in women treated with Bazedoxifene using a post hoc analysis from a 3-year randomized, placebo-controlled study evaluating the effect of Bazedoxifene (20 or 40 mg) on fracture risk reduction. BMD was assessed at baseline and every 6 months for 3 years. Osteocalcin and C-telopeptide of type I collagen were assessed at baseline and at 3, 12, and 36 months. Vertebral fractures were assessed with a semiquantitative visual assessment. Data were available for 5,244 women, of whom 3,476 were treated with Bazedoxifene. Using a logistic regression analysis and the classical Li approach, the proportion of fracture incidence explained by BMD change after 3 years of Bazedoxifene treatment was 29 % for the total hip and 44 % for the femoral neck. The proportion of treatment explained by lumbar BMD change could not be quantified accurately because of the significant interaction between treatment and change in BMD. With the same model, the 12-month BTM changes explained up to 29 % of the fracture risk reduction observed with the two forms of Bazedoxifene. In women treated with Bazedoxifene, changes in femoral neck BMD, hip BMD, or BTMs explained a moderate proportion of the fracture risk reduction observed during the 3 years of follow-up. However, BMD or BTM changes cannot be recommended for individual monitoring of women treated with Bazedoxifene.
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Bazedoxifene: the evolving role of third-generation selective estrogen-receptor modulators in the management of postmenopausal osteoporosis.
Therapeutic advances in musculoskeletal disease, 2011Co-Authors: Barry S. Komm, Arkadi ChinesAbstract:Osteoporosis is a significant public health concern, particularly for postmenopausal women. Current treatment options may not be appropriate for all women. Selective estrogen-receptor modulators (SERMs) are a class of molecules with tissue-selective activity. Bazedoxifene is currently in clinical development for the prevention and treatment of postmenopausal osteoporosis. In a 2-year, phase III, osteoporosis prevention study (N = 1583), Bazedoxifene 10, 20, and 40 mg was shown to preserve bone mineral density and decrease biochemical markers of bone turnover compared with placebo in postmenopausal women at risk for osteoporosis. In a pivotal 3-year, phase III, osteoporosis treatment study (N = 7492), Bazedoxifene 20 and 40 mg significantly reduced the incidence of new vertebral fractures compared with placebo (p
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Sustained efficacy and safety of Bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteopor, 2011Co-Authors: Stuart L Silverman, Arkadi Chines, Ginger D. Constantine, David L. Kendler, Awc Kung, Christence S. Teglbjaerg, D. Felsenberg, N. Mairon, Jonathan D. AdachiAbstract:Summary In this 2-year extension of a 3-year study, Bazedoxifene showed sustained efficacy in preventing new vertebral fractures in postmenopausal women with osteoporosis and in preventing non-vertebral fractures in higher-risk women. Bazedoxifene significantly increased bone mineral density and reduced bone turnover versus placebo and was generally safe and well tolerated.
Ginger D. Constantine - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE Open Access Research article
2013Co-Authors: Claus Christiansen, Santiago Palacios, Amy B. Levine, Jacques P. Brown, Annie W. C. Kung, Charles H. Chesnut, Jonathan D. Adachi, Arkadi A Chines, César E Fern, Ginger D. ConstantineAbstract:Safety of Bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosi
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Sustained efficacy and safety of Bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteopor, 2011Co-Authors: Stuart L Silverman, Arkadi Chines, Ginger D. Constantine, David L. Kendler, Awc Kung, Christence S. Teglbjaerg, D. Felsenberg, N. Mairon, Jonathan D. AdachiAbstract:Summary In this 2-year extension of a 3-year study, Bazedoxifene showed sustained efficacy in preventing new vertebral fractures in postmenopausal women with osteoporosis and in preventing non-vertebral fractures in higher-risk women. Bazedoxifene significantly increased bone mineral density and reduced bone turnover versus placebo and was generally safe and well tolerated.
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Safety of Bazedoxifene in a randomized, double-blind, placebo- and active-controlled Phase 3 study of postmenopausal women with osteoporosis.
BMC musculoskeletal disorders, 2010Co-Authors: Claus Christiansen, Arkadi Chines, Santiago Palacios, Amy B. Levine, Jacques P. Brown, Annie W. C. Kung, Charles H. Chesnut, Jonathan D. Adachi, César Eduardo Fernandes, Ginger D. ConstantineAbstract:We report the safety findings from a 3-year phase 3 study (NCT00205777) of Bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis. Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of Bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination. Overall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the Bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with Bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with Bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with Bazedoxifene 20 and 40 mg versus raloxifene or placebo. Reductions in total and low-density lipoprotein levels and increases in high-density lipoprotein levels were seen with Bazedoxifene versus placebo; similar results were seen with raloxifene. Triglyceride levels were similar among groups. Bazedoxifene showed a favorable safety and tolerability profile in women with postmenopausal osteoporosis. Trial registration number: NCT00205777; Trial registration date: September 16, 2005
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Efficacy and safety of Bazedoxifene in postmenopausal Asian women.
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteopor, 2010Co-Authors: Keh-sung Tsai, Ghi Su Kim, Pascale Vincendon, Arkadi Chines, Ginger D. ConstantineAbstract:Summary This 6-month study examined the efficacy and safety of Bazedoxifene 20 mg in postmenopausal Asian women. Bazedoxifene showed statistically significant improvements over placebo in bone mineral density at all skeletal sites evaluated. Bazedoxifene significantly reduced bone turnover and had favorable effects on lipid parameters. Bazedoxifene was safe and well tolerated.
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Bazedoxifene a selective estrogen receptor modulator effects on the endometrium ovaries and breast from a randomized controlled trial in osteoporotic postmenopausal women
Menopause, 2009Co-Authors: David F Archer, Joann V. Pinkerton, Arkadi Chines, Amy B. Levine, Tobie De Villiers, Wulf H Utian, Jose C Menegoci, Chui Kin Yuen, Ginger D. ConstantineAbstract:OBJECTIVE The aim of this study was to evaluate the endometrial, ovarian, and breast safety of Bazedoxifene used as a treatment for postmenopausal osteoporosis. METHODS Healthy women (aged 55-85 y) with osteoporosis were enrolled in a randomized, double-blind, placebo-controlled phase 3 trial. Participants were randomized to treatment with Bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo daily for 3 years. Endometrial and ovarian safety was assessed by periodic transvaginal ultrasonography and endometrial biopsy through 24 months. Gynecologic and breast-related adverse events were recorded throughout the study. RESULTS Among 753 participants with available transvaginal ultrasonography data, there were no significant between-group differences in overall endometrial thickness or in the percentage of participants with endometrial thickness greater than 5 mm at 12 or 24 months. Changes in the mean endometrial thickness (+/-SE) from baseline were -0.07 +/- 0.11 mm (Bazedoxifene 20 mg), 0.10 +/- 0.11 mm (Bazedoxifene 40 mg), 0.16 +/- 0.12 mm (raloxifene 60 mg), and -0.08 +/- 0.11 mm (placebo) at 24 months. There was one report of endometrial hyperplasia in each group, and there were zero, two, two, and three reports of endometrial carcinoma with Bazedoxifene 20 and 40 mg, raloxifene 60 mg, and placebo, respectively. There were no clinically important changes from baseline in the number or size of ovarian cysts among groups. There was a significantly lower incidence of fibrocystic breast disease (P
Masaaki Inaba - One of the best experts on this subject based on the ideXlab platform.
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Bazedoxifene improves renal function and increases renal phosphate excretion in patients with postmenopausal osteoporosis
Journal of Bone and Mineral Metabolism, 2020Co-Authors: Hideki Masaki, Yuki Nagata, Masanori Emoto, Masafumi Kurajoh, Katsuhito Mori, Takami Miki, Yasuo Imanishi, Hiroshi Naka, Masaaki InabaAbstract:Introduction Because aging is a predictor of renal insufficiency in the general population, renal function is a concern in postmenopausal patients undergoing treatment for osteoporosis. Although high serum phosphate concentration is a predictor of renal insufficiency, the effect of selective estrogen receptor modulator (SERM) on renal function and phosphate homeostasis remains to be established. Materials and Methods We administered 20 mg/day Bazedoxifene to 48 postmenopausal osteoporotic women who had been taking alfacalcidol for ≥ 6 months, and assessed lumbar spine bone mineral density (LS-BMD), renal function (by calculating estimated glomerular filtration rate using serum cystatin-C levels [eGFRcys] [range 38.0–98.2 mL/min/1.73 m^2]), and phosphate homeostasis. Results LS-BMD was significantly higher 6 months after the initiation of Bazedoxifene administration. eGFRcys had increased by 3 months after initiation and was stable until 12 months. Serum phosphate gradually decreased after initiation, reaching statistical significance at 6 months. The changes in serum phosphate were also significant when the maximum tubular reabsorption rate of phosphate was normalized to glomerular filtration rate (TmP/GFR), indicating that Bazedoxifene treatment reduces serum phosphate by increasing the urinary excretion of phosphate. The change in eGFRcys after the initiation of Bazedoxifene was significantly negatively correlated with the change in serum phosphate, suggesting that a reduction in serum phosphate improves renal function. Conclusion Bazedoxifene improves renal function, possibly by increasing renal phosphate excretion, in postmenopausal osteoporotic women without severe renal insufficiency.
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Bazedoxifene improves renal function and increases renal phosphate excretion in patients with postmenopausal osteoporosis.
Journal of bone and mineral metabolism, 2020Co-Authors: Hideki Masaki, Yuki Nagata, Masanori Emoto, Masafumi Kurajoh, Katsuhito Mori, Takami Miki, Yasuo Imanishi, Hiroshi Naka, Masaaki InabaAbstract:Because aging is a predictor of renal insufficiency in the general population, renal function is a concern in postmenopausal patients undergoing treatment for osteoporosis. Although high serum phosphate concentration is a predictor of renal insufficiency, the effect of selective estrogen receptor modulator (SERM) on renal function and phosphate homeostasis remains to be established. We administered 20 mg/day Bazedoxifene to 48 postmenopausal osteoporotic women who had been taking alfacalcidol for ≥ 6 months, and assessed lumbar spine bone mineral density (LS-BMD), renal function (by calculating estimated glomerular filtration rate using serum cystatin-C levels [eGFRcys] [range 38.0–98.2 mL/min/1.73 m2]), and phosphate homeostasis. LS-BMD was significantly higher 6 months after the initiation of Bazedoxifene administration. eGFRcys had increased by 3 months after initiation and was stable until 12 months. Serum phosphate gradually decreased after initiation, reaching statistical significance at 6 months. The changes in serum phosphate were also significant when the maximum tubular reabsorption rate of phosphate was normalized to glomerular filtration rate (TmP/GFR), indicating that Bazedoxifene treatment reduces serum phosphate by increasing the urinary excretion of phosphate. The change in eGFRcys after the initiation of Bazedoxifene was significantly negatively correlated with the change in serum phosphate, suggesting that a reduction in serum phosphate improves renal function. Bazedoxifene improves renal function, possibly by increasing renal phosphate excretion, in postmenopausal osteoporotic women without severe renal insufficiency.
Jiayuh Lin - One of the best experts on this subject based on the ideXlab platform.
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Bazedoxifene exhibits anti inflammation and anti atherosclerotic effects via inhibition of il 6 il 6r stat3 signaling
European Journal of Pharmacology, 2021Co-Authors: Pengcheng Luo, Wei Shi, Tianshu Liu, Dan Yan, Shengqi Huo, Junyi Guo, Yina Wang, Chongqiang Zhao, Moran Wang, Jiayuh LinAbstract:Abstract Atherosclerosis is regarded as chronic inflammatory disease. The IL-6/STAT3 pathway plays an important role in inflammation. We previously described a small-molecule compound, Bazedoxifene, which target IL-6/STAT3 pathway and has been approved for clinical use for osteoporosis in postmenopausal women. The aim of this study is to evaluate the effect of Bazedoxifene in the progression of atherosclerosis in apolipoprotein E-deficient (ApoE−/−) mice. Five-week-old male ApoE−/− mice were fed with High-fat diet (HFD) containing 5 mg/kg Bazedoxifene or a matching control for 12 weeks. Oil red O (ORO) staining was used to detect plaque size; immunohistochemical staining was used to detect the presence of endothelial cells, vascular muscle cells and phosphorylated STAT3 (P-STAT3) in localized plaques. The potential underlying mechanisms in human umbilical vein endothelial cells (HUVECs) and vascular muscle cells (VSMCs) was detected by Western blot analysis, Wound healing assay and Elisa assay. In the ApoE−/− mice fed with HFD, daily Bazedoxifene administration effectively attenuated atherosclerotic plaque area (P Bazedoxifene is an attractive novel therapeutic reagent for atherosclerosis diseases. This mechanism may be partially attributed to regulating IL-6/IL-6R/STAT3 signaling pathway.
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Combined Bazedoxifene and paclitaxel treatments inhibit cell viability, cell migration, colony formation, and tumor growth and induce apoptosis in breast cancer.
Cancer letters, 2019Co-Authors: Xiang Chen, Jiayuh LinAbstract:Abstract Breast cancer, especially triple-negative breast cancer (TNBC), has limited treatment options. We repurposed the FDA-approved drug Bazedoxifene as a novel inhibitor of interleukin 6/glycoprotein 130 signaling. In this study, we investigated the inhibitory effects of Bazedoxifene alone or in combination with paclitaxel on several estrogen receptor positive and TNBC cells. Bazedoxifene inhibited the cell viability of these cells, as well as tumor growth of TNBC cells in a xenograft tumor model. Furthermore, Bazedoxifene combined with paclitaxel exhibited more potent inhibition of cell viability, colony formation, and cell migration and induced more apoptosis in vitro, and generated stronger inhibition of tumor growth of TNBC in vivo than either drug alone. Western blotting showed that Bazedoxifene inhibited estrogen receptor positive breast cancer cells by suppressing the expression of estrogen receptor, Cyclin D1, p-P70S6K, Survivin, c-Myc, and Bcl-2, and Bazedoxifene inhibited TNBC cells by inhibiting the expression of phosphorylated STAT3 (Tyr705), Cyclin D1, p-P70S6K, c-Myc, p-AKT (Ser473) and p-ERK 1/2 (T202/Y 204) without changing the expression of total STAT3. When combined with paclitaxel, Bazedoxifene may be a potential small molecule for the treatment of both estrogen receptor positive and triple-negative breast cancer.
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Bazedoxifene as a novel GP130 inhibitor for Colon Cancer therapy
BMC, 2019Co-Authors: Jia Wei, Yi-hui Lai, Ruijie Zhang, Jiayuh LinAbstract:Abstract Background Interleukin-11 (IL-11), a dominant IL-6 family cytokine, is involved in tumorigenesis, tumor progression and differentiation in colon cancer cells. IL-11 signaling has been recently identified as a potential therapeutic target in colon cancer. Bazedoxifene, a third- generation selective estrogen modulator approved by the Food and Drug Administration (FDA), is a novel inhibitor of IL-11/GP130 signaling discovered by docking modeling. Methods In this study, the inhibition efficacy of Bazedoxifene in colon cancer cells and its potential mechanism were investigated in vitro and in vivo by using MTT cell viability assay, BrdU cell proliferation assay, colony formation assay, wound-healing/cell migration assay, immunofluorescence, western blot assay and the mouse xenograft tumor model. Results Bazedoxifene inhibits phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and its nuclear translocation induced by IL-11 in colon cancer cells. It also inhibits p-STAT3 induced by IL-6 and IL-11 but not by OSM or STAT1 phosphorylation induced by INF-γ in human colon cancer cells. In addition, Bazedoxifene can significantly inhibit phosphorylation of AKT and STAT3 downstream targets. Furthermore, Bazedoxifene alone or together with oxaliplatin can significantly induce apoptosis, inhibit cell viability, cell colony formation and cell migration in colon cancer cells. Knock-down of IL-11R can reduce the sensitivity of colon cancer cells to Bazedoxifene. IL-11 can reduce the efficacy of oxaliplatin-mediated inhibition of cell viability. Consistent with in vitro findings, Bazedoxifene alone also attenuated HCT-15 xenograft tumor burden and reduced p-STAT3, p-AKT and p-ERK in vivo. Its combination with oxaliplatin attenuated DLD-1 xenograft tumor burden and reduced p-STAT3 in vivo. Conclusions Taken together, these results support Bazedoxifene as a novel and effective therapeutic agent targeting IL-11/GP130 signaling for human colorectal cancer therapy
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Additional file 1: of Bazedoxifene as a novel GP130 inhibitor for Colon Cancer therapy
2019Co-Authors: Jia Wei, Yi-hui Lai, Ruijie Zhang, Jiayuh LinAbstract:Docking modeling of Bazedoxifene to GP130 receptor. GP130 D1 (PDB code: 1P9M) domain is shown in grey Ribbon; Bazedoxifene is rendered in green stick; IL-11 Trp168 and Leu72 are shown in red lines. Picture is made using AutoDockTools (ADT). (TIF 2907 kb
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Abstract 864: Repurposing FDA-approved drug Bazedoxifene as a novel inhibitor of IL-6 signaling for triple-negative breast cancer
Experimental and Molecular Therapeutics, 2018Co-Authors: Xiang Chen, Yang Cao, Jilai Tian, Jiayuh LinAbstract:Triple-negative breast cancer (TNBC) is a major cause of death among breast cancer patients and is the only subtype of breast cancer that is still lacking effective therapeutic options. IL-6 is one of the principal oncogenic mediators in breast cancer and systemic IL-6 levels correlates with poor prognosis, advanced disease, and metastases. Importantly, growth of TNBC cells are replied on autocrine cytokines including IL-6 and TNBC cells secret the highest levels of IL-6 comparing to other subtypes of breast cancer. Therefore, IL-6 signaling represents a novel approach with a potential to improve the therapeutic efficacy. To date, however, no small molecules that target IL-6 signaling are available for clinical cancer therapy. IL-6 binds to IL-6 Rα, then recruits Glycoprotein 130 (GP130) to form hexamer consisting two IL-6/IL-6 Rα/GP130 heterotrimers to trigger a signaling cascade downstream including JAK/STAT3, PI3-K/AKT/mTOR, and MEK/ERK. Therefore, it is possible to target IL-6 signaling by blocking IL-6 binds to GP130 or IL-6 Rα and thus inhibiting its signaling cascade downstream. We have utilized a novel drug discovery approach combining Multiple Ligand Simultaneous Docking and drug repurposing to target GP130 and have identified a FDA-approved drug Bazedoxifene (for the prevention of the osteoporosis in postmenopausal women) with a novel function to inhibit IL-6 and GP130 proteinprotein interactions and thus blocking IL-6 signaling cascade downstream. In this study, we examined the therapeutic efficacy of Bazedoxifene in combination with paclitaxel on human TNBC cells and TNBC tumor model, aiming to provide experimental results of Bazedoxifene and paclitaxel combination for TNBC therapy. Our data showed Bazedoxifene inhibited increased STAT3 phosphorylation induced by IL-6. Bazedoxifene also inhibited phosphorylation of STAT3, AKT, and ERK in TNBC cells that produced IL-6. In addition, combination of Bazedoxifene with paclitaxel exhibited more significant inhibition on cell viability and colony formation and induction of apoptosis than single agent alone in TNBC cells in vitro. Moreover, Bazedoxifene inhibits cell migration and combination of Bazedoxifene with paclitaxel more significantly inhibit cell migration than single agent alone. We also showed Bazedoxifene could inhibit increased proliferation of TNBC cells induced by IL-6. The combination of Bazedoxifene with paclitaxel also showed significantly inhibition of tumor growth of TNBC in vivo furtherly supported the therapeutic effects of Bazedoxifene. The results support the significant therapeutic efficacy of Bazedoxifene and paclitaxel combination for further TNBC therapy. Citation Format: Xiang Chen, Shengling Fu, Jilai Tian, Yang Cao, Chenglong Li, Jiayuh Lin. Repurposing FDA-approved drug Bazedoxifene as a novel inhibitor of IL-6 signaling for triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 864.
Takami Miki - One of the best experts on this subject based on the ideXlab platform.
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Bazedoxifene improves renal function and increases renal phosphate excretion in patients with postmenopausal osteoporosis
Journal of Bone and Mineral Metabolism, 2020Co-Authors: Hideki Masaki, Yuki Nagata, Masanori Emoto, Masafumi Kurajoh, Katsuhito Mori, Takami Miki, Yasuo Imanishi, Hiroshi Naka, Masaaki InabaAbstract:Introduction Because aging is a predictor of renal insufficiency in the general population, renal function is a concern in postmenopausal patients undergoing treatment for osteoporosis. Although high serum phosphate concentration is a predictor of renal insufficiency, the effect of selective estrogen receptor modulator (SERM) on renal function and phosphate homeostasis remains to be established. Materials and Methods We administered 20 mg/day Bazedoxifene to 48 postmenopausal osteoporotic women who had been taking alfacalcidol for ≥ 6 months, and assessed lumbar spine bone mineral density (LS-BMD), renal function (by calculating estimated glomerular filtration rate using serum cystatin-C levels [eGFRcys] [range 38.0–98.2 mL/min/1.73 m^2]), and phosphate homeostasis. Results LS-BMD was significantly higher 6 months after the initiation of Bazedoxifene administration. eGFRcys had increased by 3 months after initiation and was stable until 12 months. Serum phosphate gradually decreased after initiation, reaching statistical significance at 6 months. The changes in serum phosphate were also significant when the maximum tubular reabsorption rate of phosphate was normalized to glomerular filtration rate (TmP/GFR), indicating that Bazedoxifene treatment reduces serum phosphate by increasing the urinary excretion of phosphate. The change in eGFRcys after the initiation of Bazedoxifene was significantly negatively correlated with the change in serum phosphate, suggesting that a reduction in serum phosphate improves renal function. Conclusion Bazedoxifene improves renal function, possibly by increasing renal phosphate excretion, in postmenopausal osteoporotic women without severe renal insufficiency.
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Bazedoxifene improves renal function and increases renal phosphate excretion in patients with postmenopausal osteoporosis.
Journal of bone and mineral metabolism, 2020Co-Authors: Hideki Masaki, Yuki Nagata, Masanori Emoto, Masafumi Kurajoh, Katsuhito Mori, Takami Miki, Yasuo Imanishi, Hiroshi Naka, Masaaki InabaAbstract:Because aging is a predictor of renal insufficiency in the general population, renal function is a concern in postmenopausal patients undergoing treatment for osteoporosis. Although high serum phosphate concentration is a predictor of renal insufficiency, the effect of selective estrogen receptor modulator (SERM) on renal function and phosphate homeostasis remains to be established. We administered 20 mg/day Bazedoxifene to 48 postmenopausal osteoporotic women who had been taking alfacalcidol for ≥ 6 months, and assessed lumbar spine bone mineral density (LS-BMD), renal function (by calculating estimated glomerular filtration rate using serum cystatin-C levels [eGFRcys] [range 38.0–98.2 mL/min/1.73 m2]), and phosphate homeostasis. LS-BMD was significantly higher 6 months after the initiation of Bazedoxifene administration. eGFRcys had increased by 3 months after initiation and was stable until 12 months. Serum phosphate gradually decreased after initiation, reaching statistical significance at 6 months. The changes in serum phosphate were also significant when the maximum tubular reabsorption rate of phosphate was normalized to glomerular filtration rate (TmP/GFR), indicating that Bazedoxifene treatment reduces serum phosphate by increasing the urinary excretion of phosphate. The change in eGFRcys after the initiation of Bazedoxifene was significantly negatively correlated with the change in serum phosphate, suggesting that a reduction in serum phosphate improves renal function. Bazedoxifene improves renal function, possibly by increasing renal phosphate excretion, in postmenopausal osteoporotic women without severe renal insufficiency.
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Bridging analysis of the efficacy and safety of Bazedoxifene in Japanese and global populations of postmenopausal women with osteoporosis.
Journal of bone and mineral metabolism, 2014Co-Authors: Akira Itabashi, Takami Miki, Arkadi Chines, Kousei Yoh, Masahiko Takada, Hiroshi Sato, Itsuo Gorai, Toshitsugu Sugimoto, Hideki Mizunuma, Hiroshi OchiAbstract:This study examined whether the global clinical data for Bazedoxifene could be extrapolated to a Japanese population by evaluating the results of a phase 2 study in postmenopausal Japanese women with osteoporosis as compared to those of a pivotal, phase 3 study. The efficacy of Bazedoxifene 20 and 40 mg versus placebo on lumbar spine bone mineral density (BMD), bone turnover markers, lipid profile, incidence of fractures, and safety parameters was compared between the Japanese phase 2 study (N = 429) and the global phase 3 study (N = 7,492) during a 2-year period. In the primary population for assessment of bridging, differences in the mean percent change from baseline in lumbar spine BMD at 2 years relative to placebo were greater for women treated with Bazedoxifene 20 and 40 mg in the phase 2 study than in the phase 3 study. BMD changes in the Bazedoxifene groups were confirmed to be similar between the phase 2 study population and a subset of the phase 3 study population with similar baseline characteristics. The effects of Bazedoxifene on incidence of fractures, bone turnover markers, and lipid metabolism were similar between studies. There were no major differences in safety parameters between studies. The greater improvement in lumbar spine BMD and similar results in bone turnover markers, fracture incidence, and safety profile observed with Bazedoxifene in the phase 2 study compared with the phase 3 study confirmed the feasibility of extrapolating the global clinical data to a Japanese population.
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effects of Bazedoxifene on bone mineral density bone turnover and safety in postmenopausal japanese women with osteoporosis
Journal of Bone and Mineral Research, 2011Co-Authors: Akira Itabashi, Takami Miki, Arkadi Chines, Kousei Yoh, Masahiko Takada, Hiroshi Sato, Itsuo Gorai, Toshitsugu Sugimoto, Hideki Mizunuma, Hiroshi OchiAbstract:This randomized, double-blind, placebo-controlled, dose-response late phase 2 study evaluated the efficacy and safety of Bazedoxifene in postmenopausal Japanese women 85 years of age or younger with osteoporosis. Eligible subjects received daily treatment with oral doses of Bazedoxifene 20 or 40 mg or placebo for 2 years. Efficacy assessments included bone mineral density (BMD) at the lumbar spine and other skeletal sites, bone turnover marker levels, lipid parameters, and incidence of new fractures. Of 429 randomized subjects, 387 were evaluable for efficacy, and 423 were included in the safety analyses (mean age, 64 years). At 2 years, the mean percent changes from baseline in lumbar spine BMD were significantly greater with Bazedoxifene 20 and 40 mg (2.43% and 2.74%, respectively) than with placebo (−0.65%, p < .001 for both). Both Bazedoxifene doses significantly improved BMD at the total hip, femoral neck, and greater trochanter compared with placebo (p < .001 for all). Decreases in bone turnover markers were observed with Bazedoxifene 20 and 40 mg as early as 12 weeks (p < .05 for all) and were sustained throughout the study. Total and low-density lipoprotein cholesterol levels were significantly decreased from baseline with both Bazedoxifene doses compared with placebo (p < .05 for all). Incidences of new vertebral and nonvertebral fractures were similar among the Bazedoxifene and placebo groups. Overall, the incidence of adverse events with Bazedoxifene 20 and 40 mg was similar to that with placebo. Bazedoxifene significantly improved BMD, reduced bone turnover, and was well tolerated in postmenopausal Japanese women with osteoporosis. © 2011 American Society for Bone and Mineral Research.
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Effects of Bazedoxifene on bone mineral density, bone turnover, and safety in postmenopausal Japanese women with osteoporosis.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2011Co-Authors: Akira Itabashi, Takami Miki, Arkadi Chines, Kousei Yoh, Masahiko Takada, Hiroshi Sato, Itsuo Gorai, Toshitsugu Sugimoto, Hideki Mizunuma, Hiroshi OchiAbstract:This randomized, double-blind, placebo-controlled, dose-response late phase 2 study evaluated the efficacy and safety of Bazedoxifene in postmenopausal Japanese women 85 years of age or younger with osteoporosis. Eligible subjects received daily treatment with oral doses of Bazedoxifene 20 or 40 mg or placebo for 2 years. Efficacy assessments included bone mineral density (BMD) at the lumbar spine and other skeletal sites, bone turnover marker levels, lipid parameters, and incidence of new fractures. Of 429 randomized subjects, 387 were evaluable for efficacy, and 423 were included in the safety analyses (mean age, 64 years). At 2 years, the mean percent changes from baseline in lumbar spine BMD were significantly greater with Bazedoxifene 20 and 40 mg (2.43% and 2.74%, respectively) than with placebo (−0.65%, p