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Kidney transplant (KT) requires long-term glucocorticoid (GC) treatment against acute and/or chronic rejection. Glucocorticoid-induced osteoporosis (GIOP) is one of the major concerns in kidney transplant recipients (KTRs). Therefore, it is essential to accumulate GIOP data from paediatric KTRs to aid in their healthy growth. A serial observational study of bone strength was carried out in an 8-year-old girl with bilateral hypoplastic kidney who underwent ABO-compatible living-donor KT and GC treatment over 2 years. Bone strength was evaluated by bone mineral density (BMD) and serum bone turnover markers (BTMs), including serum alkaline phosphatase (S-ALP), serum tartrate-resistant acid phosphatase 5b (S-TRACP-5b), and serum undercarboxylated osteocalcin (S-ucOC). All the levels of BTMs and BMD from 1 M to 4 M remained lower than the levels at 0 months (0 M: baseline). After gradual reduction of GC dose (4 M-24 M), S-ALP levels increased from baseline and S-TRACP-5b levels remained lower than the baseline level, but BMD recovered to baseline and increased. The S-ucOC levels did not increase from baseline. The patient's height growth velocity SDS was +3.99 for 23 months, and no fracture occurred during this observation period. A consistent, predominantly formative state of bone, which maintained higher S-ALP levels and lower S-TRACP-5b levels compared to baseline, could contribute to increased BMD. In addition, no increase in S-ucOC levels from baseline could be associated with no deterioration of bone strength. This case suggests that measurement of BMD and, S-ALP, TRACP-5b and ucOC could be useful for evaluating the trend on bone strength in a paediatric KTR.
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Glucocorticoids (GCs) are extensively used as anti-inflammatory and immunosuppressive medications in the long-term treatment of rheumatic disorders, respiratory diseases, renal diseases, and organ transplantation. Prolonged use of GCs can reduce bone mineral density, leading to osteoporosis (Glucocorticoid Induced Osteoporosis, GIOP) and fracture. All-trans retinoic acid (ATRA) is an active vitamin A metabolite that regulates embryonic development and adult organ function. ATRA has been found in studies to enhance osteogenesis. To examine the interventional effects of ATRA on GIOP and the mechanisms of ATRA activities, we first performed bioinformatic analysis to identify potential gene targets of ATRA. Zebrafish larvae were recruited as experimental animals, and the frequently used GC, prednisolone, was administered to larvae to construct a GIOP model. We evaluated the influence of exogenous ATRA on the activities of bone metabolic enzymes, the expression of genes linked to osteoblasts and osteoclasts, and the restoration of bone mineral density and bone mass in GIOP zebrafish larvae. Furthermore, we studied the influence of RBM14, a transcriptional coactivator and negative reciprocal factor of ATRA, on the regulation of osteoblastic gene expression during the anti-GIOP process of ATRA using the morpholino knockdown approach. The findings of bone metabolic enzyme activity (alkaline phosphatase, ALP and tartrate-resistant acid phosphatase, TRAP) and expression assays of osteoblastic marker genes (Runx2a, Runx2b, SP7, Csf1a, RANKL, and CTSK) indicated that ATRA had bidirectional effects on osteogenesis. However, in the GIOP model, ATRA reversed the GIOP-induced osteoporosis phenotype by inhibiting the GIOP-induced suppression of osteoblastic metabolic enzyme (ALP) activities and osteoblastic marker gene expression (Runx2a, Runx2b, and SP7), and this antagonism was concentration-dependent. We also observed that ATRA inhibited RBM14 expression in zebrafish larvae, while ATRA alone and RBM14 knockdown showed a consistent induction of osteoblast marker gene expression, implying that ATRA's inhibitory effect on RBM14 expression may underlie ATRA's osteogenic effects. Based on these data, we postulated that ATRA may ameliorate GIOP by decreasing RBM14 expression, thereby enhancing osteoblastic marker gene expression.
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BACKGROUND: Glucocorticoid-induced osteoporosis is a leading secondary cause of osteoporosis. Cullin-1 (CUL1) levels are abnormally elevated in patients with osteoporosis, but the underlying mechanism remains unclear. The purpose of this study was to elucidate the mechanism of action of CUL1 in a glucocorticoid (dexamethasone, Dex)-induced osteoporosis model. METHODS: C57BL/6J mice were intraperitoneally injected with Dex to establish an osteoporosis model. Mouse femur bone injury and bone formation were detected using hematoxylin-eosin or Masson staining. Apoptosis and cell cycle distribution were determined by flow cytometry. Alkaline phosphatase (ALP) activity and calcified nodules were monitored using ALP and Alizarin Red S staining. The molecular mechanism was validated by co-immunoprecipitation (Co-IP) and ubiquitination assays. RESULTS: CUL1 expression was enhanced in the Dex-induced osteoporosis mouse model. CUL1 silencing moderated the Dex-induced cell proliferation and osteogenesis inhibition. Moreover, CUL1 promoted the ubiquitination and degradation of ASAP1 via the SKP1-CUL1-F-box (SCF)-FBXW7 complex. CUL1 induced apoptosis and repressed osteogenesis by ASAP1. CUL1 silencing alleviated the Dex-induced osteoporosis in mice. CONCLUSION: CUL1 suppressed osteoblast proliferation and osteogenesis by promoting ASAP1 ubiquitination via the SCF-FBXW7 complex in glucocorticoid-induced osteoporosis.
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BACKGROUNDS: The use of large language models (LLMs) in medicine can help physicians improve the quality and effectiveness of health care by increasing the efficiency of medical information management, patient care, medical research, and clinical decision-making. METHODS: We collected 34 frequently asked questions about glucocorticoid-induced osteoporosis (GIOP), covering topics related to the disease's clinical manifestations, pathogenesis, diagnosis, treatment, prevention, and risk factors. We also generated 25 questions based on the 2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis (2022 ACR-GIOP Guideline). Each question was posed to the LLM (ChatGPT-3.5, ChatGPT-4, and Google Gemini), and three senior orthopedic surgeons independently rated the responses generated by the LLMs. Three senior orthopedic surgeons independently rated the answers based on responses ranging between 1 and 4 points. A total score (TS) > 9 indicated 'good' responses, 6 ≤ TS ≤ 9 indicated 'moderate' responses, and TS < 6 indicated 'poor' responses. RESULTS: In response to the general questions related to GIOP and the 2022 ACR-GIOP Guidelines, Google Gemini provided more concise answers than the other LLMs. In terms of pathogenesis, ChatGPT-4 had significantly higher total scores (TSs) than ChatGPT-3.5. The TSs for answering questions related to the 2022 ACR-GIOP Guideline by ChatGPT-4 were significantly higher than those for Google Gemini. ChatGPT-3.5 and ChatGPT-4 had significantly higher self-corrected TSs than pre-corrected TSs, while Google Gemini self-corrected for responses that were not significantly different than before. CONCLUSIONS: Our study showed that Google Gemini provides more concise and intuitive responses than ChatGPT-3.5 and ChatGPT-4. ChatGPT-4 performed significantly better than ChatGPT3.5 and Google Gemini in terms of answering general questions about GIOP and the 2022 ACR-GIOP Guidelines. ChatGPT3.5 and ChatGPT-4 self-corrected better than Google Gemini.
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Glucocorticoides , Osteoporosis , Humanos , Osteoporosis/inducido químicamente , Glucocorticoides/efectos adversos , Encuestas y CuestionariosRESUMEN
Objective: Glucocorticoid-induced osteoporosis (GIOP) represents a major complication arising from the long-term use of glucocorticoids, which are widely prescribed for various inflammatory and autoimmune conditions. Despite its prevalence, the current therapeutic options for GIOP are limited in terms of efficacy, safety profiles, and patient compliance. The Modified Danggui Buxue Decoction (DGBXD), a traditional Chinese herbal formulation, has shown promise in preliminary studies for its potential osteoprotective effects. The present study aimed to explore the mechanistic underpinnings of DGBXD's action on GIOP using network pharmacology and molecular docking approaches, bridging traditional medicine with modern pharmacological insights. Method: Network pharmacology is applied to screen drug-active compounds and potential core target proteins for disease treatment and to explore the drugs' therapeutic mechanisms. Result: Altogether, 78 DGBXD active compounds and 223 DGBXD-related, 146 component-disease common, and 2168 GIOP-associated target genes were obtained. The PPI network had 43 nodes and 462 edges, and a total of 10 core target genes, including TP53, JUN and MAPK3, were identified. The results of the GO enrichment analysis implied that DGBXD might participate in biological activities, including responses to oxidative stress and nutrient levels. The outcomes of the KEGG pathway enrichment analysis showed that DGBXD may treat GIOP through TNF, IL-17, and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathways. Based on to the molecular docking results, biologically active compounds (beta-carotene, formononetin, luteolin, and isorhamnetin) exhibited good binding to AKT1 and ESR1. Conclusion: DGBXD may aid in GIOP treatment by modulating multiple therapeutic targets and signaling pathways.
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Glucocorticoid-induced osteoporosis (GIOP) commonly accelerates bone loss, increasing the risk of fractures and osteonecrosis more significantly than traditional menopausal osteoporosis. The extracellular environment influenced by glucocorticoids heightens fracture and osteonecrosis risks. Fraxin (Fra), a key component of the traditional Chinese herbal remedy Cortex Fraxini, is known for its wide-ranging pharmacological effects, but its impact on GIOP remains unexplored. This investigation aims to delineate the effects and underlying mechanisms of Fra in combating dexamethasone (Dex)-induced ferroptosis and GIOP. We established a mouse model of GIOP via intraperitoneal injections of Dex and cultured osteoblasts with Dex treatment for in vitro analysis. We evaluated the impact of Fra on Dex-treated osteoblasts through assays such as C11-BODIPY and FerroOrange staining, mitochondrial functionality tests, and protein expression analyses via Western blot and immunofluorescence. The influence of Fra on bone microarchitecture of GIOP in mice was assessed using microcomputerized tomography, hematoxylin and eosin staining, double-labeling with Calcein-Alizarin Red S, and immunohistochemistry at imaging and histological levels. Based on our data, Fra prevented Dex-induced ferroptosis and bone loss. In vitro, glutathione levels increased and malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species decreased. Fra treatment also increases nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and COL1A1 expression and promotes bone formation. To delve deeper into the mechanism, the findings revealed that Fra triggered the activation of Nrf2/GPX4 signaling. Moreover, the use of siRNA-Nrf2 blocked the beneficial effect of Fra in osteoblasts cultivated with Dex. Fra effectively combats GIOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.
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BACKGROUND: Glucocorticoid-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis. Recently, autophagy has been found to be related with the development of various diseases, including osteoporosis and osteoblast differentiation regulations. BTB and CNC homology 1 (BACH1) was a previously confirmed regulator for osteoblast differentiation, but whether it's could involve in glucocorticoid-induced human bone mesenchymal stem cells (hBMSCs) differentiation and autophagy regulation remain not been elucidated. METHODS: hBMSCs were identified by flow cytometry method, and its differentiation ability were measured by ARS staining, oil O red, and Alcian blue staining assays. Gene and proteins were quantified via qRT-PCR and western blot assays, respectively. Autophagy activity was determined using immunofluorescence. ChIP and dual luciferase assay validated the molecular interactions. RESULTS: The data revealed that isolated hBMSCs exhibited positive of CD29/CD44 and negative CD45/CD34. Moreover, BACH1 was abated gradually during osteoblast differentiation of hBMSCs, while dexamethasone (Dex) treatment led to BACH1 upregulation. Loss of BACH1 improved osteoblast differentiation and activated autophagy activity in Dex-challenged hBMSCs. Autophagy-related proteins (ATG3, ATG4, ATG5, ATG7, ATG12) were repressed after Dex treatment, while ATG3, ATG7 and BECN1 could be elevated by BACH1 knockdown, especially ATG7. Moreover, BACH1 could interact ATG7 promoter region to inhibit its transcription. Co-inhibition of ATG7 greatly overturned the protective roles of BACH1 loss on osteoblast differentiation and autophagy in Dex-induced hBMSCs. CONCLUSION: Taken together, our results demonstrated that silencing of BACH1 mitigated Dex-triggered osteogenic differentiation inhibition by transcriptionally activating ATG7-mediated autophagy, suggesting that BACH1 may be a therapeutic target for GIOP treatment.
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Autofagia , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Diferenciación Celular , Dexametasona , Glucocorticoides , Células Madre Mesenquimatosas , Osteoblastos , Osteogénesis , Humanos , Autofagia/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Glucocorticoides/farmacología , Glucocorticoides/efectos adversos , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Dexametasona/farmacología , Células Cultivadas , Osteoporosis/inducido químicamente , Osteoporosis/genética , Osteoporosis/patologíaRESUMEN
BACKGROUND: The effects of Isopsoralen (ISO) in promoting osteoblast differentiation and inhibiting osteoclast formation are well-established, but the mechanism underlying ISO's improvement of Glucocorticoid- Induced Osteoporosis (GIOP) by regulating metabolism remains unclear. METHODS: This study aims to elucidate the mechanism of ISO treatment for GIOP through non-targeted metabolomics based on ISO's efficacy in GIOP. Initially, we established a GIOP female mouse model and assessed ISO's therapeutic effects using micro-CT detection, biomechanical testing, serum calcium (Ca), and phosphorus (P) level detection, along with histological analyses using hematoxylin and eosin (HE), Masson, and tartrate-resistant acidic phosphatase (TRAP) staining. Subsequently, non-targeted metabolomics was employed to investigate ISO's impact on serum metabolites in GIOP mice. RT-qPCR and Western blot analyses were conducted to measure the levels of enzymes associated with these metabolites. Building on the metabolomic results, we explored the effects of ISO on the cyclic Guanosine Monophosphate (cGMP)/Protein Kinase G (PKG) pathway and its role in mediating osteoblast differentiation. RESULTS: Our findings demonstrate that ISO intervention effectively enhances the bone microarchitecture and strength of GIOP mice. It mitigates pathological damage, such as structural damage in bone trabeculae, reduced collagen fibers, and increased osteoclasts, while improving serum Ca and P levels in GIOP mice. Non-- targeted metabolomics revealed purine metabolism as a common pathway between the Control and GIOP groups, as well as between the ISO high-dose (ISOH) group and the GIOP group. ISO intervention upregulated inosine and adenosine levels, downregulated guanosine monophosphate levels, increased Adenosine Deaminase (ADA) expression, and decreased cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5) expression. Additionally, ISO intervention elevated serum cGMP levels, upregulated PKGI and PKGII expression in bone tissues, as well as the expression of Runt-related transcription factor 2 (Runx2) and Osterix, and increased serum Alkaline Phosphatase (ALP) activity. CONCLUSION: In summary, ISO was able to enhance the bone microstructure and bone strength of GIOP mice and improve their Ca, P, and ALP levels, which may be related to ISO's regulation of purine metabolism and promotion of osteoblast differentiation mediated by the cGMP/PKG pathway. This suggests that ISO is a potential drug for treating GIOP. However, further research is still needed to explore the specific targets and clinical applications of ISO.
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Epimedium is thought to enhance the integrity of tendons and bones, ease joint discomfort and rigidity and enhance kidney function. Although glucocorticoids are commonly used in clinical practice, the mechanism by which the active compound Epimedin C (EC) alleviates glucocorticoid-induced osteoporosis (GIOP) is not well understood. The therapeutic potential of EC in treating GIOP was evaluated using alizarin red S staining, calcein immersion and fluorescence imaging, and bone mineralization, bone mass accumulation and bone density in zebrafish larvae were determined. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the key signalling pathways related to bone development were identified. A protein-protein interaction network (PPIN) was constructed to identify osteoclast characteristic genes and the findings were verified using real-time quantitative PCR (RT-qPCR). The bone tissue damage caused by prednisolone was reduced by EC. It also altered physiological processes, improved bone density, boosted mineralization and increased bone mass and activity. Subsequent empirical investigations showed that EC impacted the major signalling pathways involved in bone development, such as osteoclast differentiation, oestrogen, MAPK, insulin resistance, PPAR and AMPK signalling pathways. It also decreased the expression of genes typical of osteoclasts. The results of our study uncover a previously unknown function of EC in controlling bone formation and emphasize the potential of EC as a therapeutic target. The osteoprotective effect of EC indicates its potential as a cost-effective strategy for treating GIOP.
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Modelos Animales de Enfermedad , Flavonoides , Glucocorticoides , Osteoclastos , Osteoporosis , Transducción de Señal , Pez Cebra , Animales , Osteoporosis/inducido químicamente , Osteoporosis/metabolismo , Osteoporosis/genética , Osteoporosis/patología , Osteoporosis/tratamiento farmacológico , Flavonoides/farmacología , Glucocorticoides/efectos adversos , Glucocorticoides/farmacología , Osteoclastos/metabolismo , Osteoclastos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Mapas de Interacción de Proteínas , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Calcificación Fisiológica/efectos de los fármacosRESUMEN
Glucocorticoids (GCs) are the leading cause of secondary osteoporosis. The emerging perspective, derived primarily from 2D histological study of trabecular bone, is that GC-induced bone loss arises through the uncoupling of bone formation and resorption at the level of the basic multicellular unit (BMU), which carries out bone remodeling. Here we explore the impact of GCs on cortical bone remodeling in the rabbit model. Based upon the rapid reduction of bone formation and initial elevation of resorption caused by GCs, we hypothesized that the rate of advance (longitudinal erosion rate; LER) of cortical BMUs would be increased. To test this hypothesis we divided 20 female New Zealand White rabbits into four experimental groups: ovariohysterectomy (OVH), glucocorticoid (GC), OVH + GC and SHAM controls (n = 5 animals each). Ten weeks post-surgery (OVH or sham), and two weeks after the initiation of dosing (daily subcutaneous injections of 1.5 mg/kg of methylprednisolone sodium succinate in the GC-treated groups and 1 ml of saline for the others), the right tibiae were scanned in vivo using Synchrotron Radiation (SR) in-line phase contrast micro-CT at the Canadian Light Source. After an additional 2 weeks of dosing, the rabbits were euthanized and ex vivo images were collected using desktop micro-CT. The datasets were co-registered in 3D and LER was calculated as the distance traversed by BMU cutting-cones in the 14-day interval between scans. Counter to our hypothesis, LER was greatly reduced in GC-treated rabbits. Mean LER was lower in GC (4.27 µm/d; p < 0.001) and OVH + GC (4.19 µm/d; p < 0.001), while similar in OVH (40.13 µm/d; p = 0.990), compared to SHAM (40.44 µm/d). This approximately 90 % reduction in LER with GCs was also associated with an overall disruption of BMU progression, with radial expansion of the remodeling space occurring in all directions. This unexpected outcome suggests that GCs do not simply uncouple formation and resorption within cortical BMUs and highlights the value of the time-lapsed 4D approach employed.
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Hueso Cortical , Glucocorticoides , Tibia , Microtomografía por Rayos X , Animales , Conejos , Glucocorticoides/farmacología , Femenino , Tibia/efectos de los fármacos , Tibia/diagnóstico por imagen , Tibia/patología , Hueso Cortical/efectos de los fármacos , Hueso Cortical/diagnóstico por imagen , Remodelación Ósea/efectos de los fármacosRESUMEN
Glucocorticoid-induced osteoporosis (GIOP) is a side effect of glucocorticoid (GC) treatment; however, despite established prevention guidelines in various countries, a gap persists between these guidelines and clinical practice. To address this gap, we implemented a collaborative intervention between hospitals and community pharmacists, aiming to assess its effectiveness. Pharmacists recommended to the prescribing doctor osteoporosis treatment for patients who did not undergo osteoporosis treatment with a fracture risk score of ≥3 via tracing reports (TRs), between 15 December 2021, and 21 January 2022. Data were extracted from electronic medical records, including prescriptions, concomitant medications, reasons for not pursuing osteoporosis treatment, and TR contents. Of 391 evaluated patients, 45 were eligible for TRs, with 34 (75.6%) being males. Prednisolone was the most common GCs administered, and urology was the predominant treatment department. Among the 45 patients who received TRs, prescription suggestions were accepted for 19 (42.2%). After undertaking the intervention, guideline adherence significantly increased from 87% to 92.5%. This improvement indicates that TRs effectively bridged the evidence-practice gap in GIOP prevention among GC patients, suggesting their potential utility. Expansion of this initiative is warranted to further prevent GIOP.
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BACKGROUND: Glucocorticoids and sclerostin act as inhibitors of the Wnt signaling pathway, thereby hindering bone formation. Given the pathway's intricate association with mesenchymal stem cells, the hypothesis suggests that heightened sclerostin levels may be intricately linked to an augmentation in marrow adiposity induced by glucocorticoids. This study endeavored to delve into the nuanced relationship between circulating sclerostin and bone marrow adipose tissue in postmenopausal women grappling with glucocorticoid-induced osteoporosis (GIO). METHODS: In this cross-sectional study, 103 patients with autoimmune-associated diseases underwent glucocorticoid treatment, boasting an average age of 61.3 years (standard deviation 7.1 years). The investigation encompassed a thorough assessment, incorporating medical history, anthropometric data, biochemical analysis, and dual-energy X-ray absorptiometry measurements of lumbar and femoral bone mineral density (BMD). Osteoporosis criteria were established at a T-score of -2.5 or lower. Additionally, MR spectroscopy quantified the vertebral marrow fat fraction. RESULTS: BMD at the femoral neck, total hip, and lumbar spine showcased an inverse correlation with marrow fat fraction (r = -0.511 to - 0.647, P < 0.001). Serum sclerostin levels exhibited a positive correlation with BMD at various skeletal sites (r = 0.476 to 0.589, P < 0.001). A noteworthy correlation emerged between circulating sclerostin and marrow fat fraction at the lumbar spine (r = -0.731, 95% CI, -0.810 to -0.627, P < 0.001). Multivariate analysis brought to light that vertebral marrow fat fraction significantly contributed to sclerostin serum concentrations (standardized regression coefficient ß = 0.462, P < 0.001). Even after adjusting for age, body mass index, physical activity, renal function, BMD, and the duration and doses of glucocorticoid treatment, serum sclerostin levels maintained a significant correlation with marrow fat fraction. CONCLUSIONS: Circulating sclerostin levels exhibited a noteworthy association with marrow adiposity in postmenopausal women grappling with GIO.
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Proteínas Adaptadoras Transductoras de Señales , Adiposidad , Densidad Ósea , Médula Ósea , Glucocorticoides , Posmenopausia , Humanos , Femenino , Persona de Mediana Edad , Glucocorticoides/efectos adversos , Estudios Transversales , Adiposidad/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Anciano , Marcadores Genéticos , Biomarcadores/sangre , Biomarcadores/análisis , Osteoporosis Posmenopáusica/sangre , Absorciometría de FotónRESUMEN
INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.
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Conservadores de la Densidad Ósea , Fracturas Óseas , Osteoporosis , Anciano , Humanos , Adolescente , Adulto , Lactante , Glucocorticoides , Conservadores de la Densidad Ósea/uso terapéutico , Calidad de Vida , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Densidad Ósea , Fracturas Óseas/tratamiento farmacológicoRESUMEN
PURPOSE: We evaluated the preference, patient satisfaction, and efficacy of zoledronic acid compared with oral bisphosphonates (BPs) for glucocorticoid-induced osteoporosis (GIOP) in patients with autoimmune diseases. METHODS: We enrolled 50 patients with new fractures or osteoporosis detected on follow-up bone densitometry after at least 1 year of oral BP use among patients diagnosed with GIOP during treatment for autoimmune diseases. After 1 year of zoledronic acid treatment, patients completed a survey for preference and satisfaction assessment. Treatment efficacy was analysed by comparing bone mineral density changes and fractures with those in a control group of patients who continued oral BP use. RESULTS: Age, sex, treatment duration, and medication history did not differ significantly between the two groups. Among the participants, 86.7% preferred and were more satisfied with intravenous zoledronic acid than with oral BPs, primarily because of the convenience of its administration interval. Only two patients (4%) reported infusion-related adverse events with zoledronic acid. Furthermore, no significant differences were observed in the annualized percentage change in the bone mineral density of the lumbar spine, femur neck, and hip between patients receiving zoledronic acid and those receiving oral BPs. The occurrence of new fractures was consistent across both groups, with two cases in each, showing no significant differences. CONCLUSION: Patients showed a preference for and greater satisfaction with zoledronic acid, and its efficacy in treating osteoporosis was comparable to that of oral BPs. Therefore, zoledronic acid is a suitable treatment option for GIOP in patients with autoimmune diseases.
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Enfermedades Autoinmunes , Conservadores de la Densidad Ósea , Densidad Ósea , Glucocorticoides , Osteoporosis , Prioridad del Paciente , Ácido Zoledrónico , Humanos , Ácido Zoledrónico/uso terapéutico , Ácido Zoledrónico/efectos adversos , Osteoporosis/tratamiento farmacológico , Osteoporosis/inducido químicamente , Femenino , Glucocorticoides/efectos adversos , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Masculino , Conservadores de la Densidad Ósea/uso terapéutico , Conservadores de la Densidad Ósea/efectos adversos , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inducido químicamente , Persona de Mediana Edad , Densidad Ósea/efectos de los fármacos , Anciano , Administración Oral , Difosfonatos/uso terapéutico , Difosfonatos/efectos adversos , Difosfonatos/administración & dosificación , Satisfacción del Paciente , Resultado del Tratamiento , Imidazoles/efectos adversos , Imidazoles/uso terapéutico , Imidazoles/administración & dosificaciónRESUMEN
PURPOSE: Fracture risk assessment is recommended at three months after glucocorticoid (GC) therapy initiation. This study aimed to assess whether GC exposure in the initial 90 days of GC therapy is associated with subsequent hip and clinical vertebral fracture risk using the nationwide health insurance claims database of Japan (NDBJ). METHODS: Patients aged ≥ 50 years who were prescribed GC (≥ 70 mg prednisolone or equivalent; PSL) in the initial 90 days of GC therapy and were followed for hip and clinical vertebral fracture incidences for the subsequent 1080 days were selected from NDBJ. Associations of GC exposure with hip or clinical vertebral fracture risk were evaluated by Cox regression analysis adjusted for potential confounders. RESULTS: We selected 316,396 women and 299,871 men for the GC-exposed group and 43,164 women and 33,702 men for the reference group. Higher GC doses and longer prescription days in the initial 90 days of GC therapy were significantly and dose-dependently associated with increased fracture risk relative to the reference group. Patients receiving GC ≥ 5 mg PSL/day had a significantly increased fracture risk in the stratum of 30-59 days of GC prescription. In addition, female patients who received GC (≥ 1 and < 2.5 mg PSL/day) for 90 days in the initial 90 days of GC therapy had a significantly increased fracture risk. CONCLUSIONS: GC exposure in the initial 90 days of GC therapy was dose-dependently associated with hip and clinical vertebral fracture risk. GC may increase fracture risk with lower doses for shorter durations than previously reported. Fracture risk assessment three months after glucocorticoid (GC) therapy initiation is recommended. We found that GC exposure in the initial 90 days of GC therapy at lower daily doses for shorter durations than previously reported were significantly and dose-dependently associated with fracture risk using a nationwide health insurance claims database.
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Fracturas Óseas , Fracturas de Cadera , Fracturas de la Columna Vertebral , Masculino , Humanos , Femenino , Anciano , Glucocorticoides/efectos adversos , Fracturas de la Columna Vertebral/epidemiología , Fracturas de la Columna Vertebral/etiología , Estudios Retrospectivos , Japón/epidemiología , Seguro de Salud , Fracturas de Cadera/inducido químicamente , Fracturas de Cadera/epidemiología , Factores de RiesgoRESUMEN
Bone remodeling is a process that involves osteoblasts, osteoclasts, and osteocytes, and different intracellular signaling, such as the canonical Wnt/ß-catenin pathway. Dysregulations of this pathway may also occur during secondary osteoporosis, as in the case of glucocorticoid-induced osteoporosis (GIO), which accelerates osteoblast and osteocyte apoptosis by reducing bone formation, osteoblast differentiation and function, accelerates in turn osteoblast, and osteocyte apoptosis. Genistein is a soy-derived nutrient belonging to the class of isoflavones that reduces bone loss in osteopenic menopausal women, inhibiting bone resorption; however, genistein may also favor bone formation. The aim of this study was to investigate whether estrogen receptor stimulation by genistein might promote osteoblast and osteocyte function during glucocorticoid challenge. Primary osteoblasts, collected from C57BL6/J mice, and MLO-A5 osteocyte cell line were used to reproduce an in vitro model of GIO by adding dexamethasone (1 µM) for 24 h. Cells were then treated with genistein for 24 h and quantitative Polymerase Chain Reaction (qPCR) and western blot were performed to study whether genistein activated the Wnt/ß-catenin pathway. Dexamethasone challenge reduced bone formation in primary osteoblasts and bone mineralization in osteocytes; moreover, canonical Wnt/ß-catenin pathway was reduced following incubation with dexamethasone in both osteoblasts and osteocytes. Genistein reverted these changes and this effect was mediated by both estrogen receptors α and ß. These data suggest that genistein could induce bone remodeling through Wnt/ß-catenin pathway activation.
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Genisteína , Isoflavonas , Osteoporosis , Animales , Ratones , beta Catenina/genética , beta Catenina/metabolismo , Diferenciación Celular , Dexametasona/farmacología , Genisteína/farmacología , Glucocorticoides , Isoflavonas/farmacología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteocitos/efectos de los fármacos , Osteocitos/metabolismo , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Glycine max/químicaRESUMEN
A 70-year-old female patient was admitted for close examination and treatment of hypercalcemia (corrected serum calcium levels: 3.04 mmol/L) and renal dysfunction (serum creatinine levels: 254.59 µmol/L). The patient had a history of sarcoidosis, diagnosed based on epithelioid cell granulomas in subcutaneous nodule biopsies, uveitis, and bilateral hilar lymphadenopathy, which had spontaneously remitted 10 years before admission. Because the patient was diagnosed with hypercalcemia associated with recurrent sarcoidosis, prednisone (20 mg/day) was initiated, and its dose was tapered following the decrease in serum calcium and creatinine levels. However, the levels of these parameters increased again when the prednisone dose was reduced to ≤ 4 mg/day. We were concerned about glucocorticoid-induced osteoporosis in the patient but hesitated to use first-line bisphosphonates because of renal dysfunction. Therefore, denosumab was initiated to reduce the risk of hypercalcemia, renal dysfunction, and glucocorticoid-induced osteoporosis. Serum creatinine and corrected serum calcium levels subsequently decreased. The prednisone dose could be reduced following repeated denosumab administration.Thus, denosumab can be a multifaceted, beneficial option for sarcoidosis-induced hypercalcemia, as it alleviates renal dysfunction indirectly by normalizing serum calcium levels, facilitates reduction of the glucocorticoid dose, and ameliorates glucocorticoid-induced osteoporosis.
Asunto(s)
Hipercalcemia , Enfermedades Renales , Osteoporosis , Sarcoidosis , Anciano , Femenino , Humanos , Calcio , Creatinina , Denosumab/uso terapéutico , Glucocorticoides/efectos adversos , Granuloma/complicaciones , Hipercalcemia/inducido químicamente , Hipercalcemia/tratamiento farmacológico , Osteoporosis/inducido químicamente , Osteoporosis/complicaciones , Osteoporosis/tratamiento farmacológico , Prednisona/efectos adversos , Sarcoidosis/complicaciones , Sarcoidosis/tratamiento farmacológicoRESUMEN
OBJECTIVE: To investigate the effects of CA on glucocorticoid-induced osteoporosis (GIOP) and lucubrate the underlying mechanism of CA via the activation of polycystic kidney disease-1(PKD1) in bone marrow mesenchymal stem cells (BMSCs). METHODS: In vivo, a GIOP model in mice treated with dexamethasone (Dex) was established. Biomechanical, micro-CT, immunofluorescence staining of OCN, ALP and PKD1 and others were severally determined. qRT-PCR and Western blot methods were adopted to elucidate the particular mechanisms of CA on GIOP. In addition, BMSCs cultured in vitro were also induced by Dex to verify the effects of CA. Finally, siRNA and luciferase activity assays were performed to confirm the mechanisms. RESULTS: We found that CA could restore the destroyed bone microarchitecture and increase the bone mass in GIOP mice. CA could also upregulate PKD1 protein expression, reduce oxidative stress, and promote mRNA expression of bone formation-associated markers in GIOP mice. Furthermore, it was also observed that CA reduced oxidative stress and promoted osteogenic differentiation in Dex-induced BMSCs. Mechanically, CA could promote protein expression via increasing the activity of PKD1 promoter. CONCLUSION: This study provides important evidences for CA in the further clinical treatment of GIOP, reveals the activation of PKD1 promoter as the underlying mechanism.
Asunto(s)
Células Madre Mesenquimatosas , Osteoporosis , Ratones , Animales , Osteogénesis , Glucocorticoides/efectos adversos , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Osteoporosis/genética , Dexametasona/efectos adversos , Diferenciación Celular , Células Cultivadas , Células de la Médula Ósea/metabolismoRESUMEN
BACKGROUND: Glucocorticoids (GC)-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis, which leads to an increased risk of fracture in patients. The inhibition of the osteoblast effect is one of the main pathological characteristics of GIOP, but without effective drugs on treatment. PURPOSE: The aim of this study was to investigate the potential effects of orcinol glucoside (OG) on osteoblast cells and GIOP mice, as well as the mechanism of the underlying molecular target protein of OG both in vitro osteoblast cell and in vivo GIOP mice model. METHODS: GIOP mice were used to determine the effect of OG on bone density and bone formation. Then, a cellular thermal shift assay coupled with mass spectrometry (CETSA-MS) method was used to identify the target of OG. Surface plasmon resonance (SPR), enzyme activity assay, molecular docking, and molecular dynamics were used to detect the affinity, activity, and binding site between OG and its target, respectively. Finally, the anti-osteoporosis effect of OG through the target signal pathway was investigated in vitro osteoblast cell and in vivo GIOP mice model. RESULTS: OG treatment increased bone mineral density (BMD) in GIOP mice and effectively promoted osteoblast proliferation, osteogenic differentiation, and mineralization in vitro. The CETSA-MS result showed that the target of OG acting on the osteoblast is the p38 protein. SPR, molecular docking assay and enzyme activity assay showed that OG could direct bind to the p38 protein and is a p38 agonist. The cellular study found that OG could promote p38 phosphorylation and upregulate the proteins expression of its downstream osteogenic (Runx2, Osx, Collagen â , Dlx5). Meanwhile, it could also inhibit the nuclear transport of GR by increasing the phosphorylation site at GR226 in osteoblast cell. In vivo GIOP mice experiment further confirmed that OG could prevent bone loss in the GIOP mice model through promoting p38 activity as well as its downstream proteins expression and activity. CONCLUSIONS: This study has established that OG could promote osteoblast activity and revise the bone loss in GIOP mice by direct binding to the p38 protein and is a p38 agonist to improve its downstream signaling, which has great potential in GIOP treatment for targeting p38. This is the first report to identify OG anti-osteoporosis targets using a label-free strategy (CETSA-MS).
Asunto(s)
Glucocorticoides , Osteoporosis , Animales , Ratones , Glucocorticoides/efectos adversos , Osteogénesis , Glucósidos/uso terapéutico , Simulación del Acoplamiento Molecular , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismoRESUMEN
Glucocorticoid-induced osteoporosis (GIOP) represents the foremost cause of secondary osteoporosis and fragility fractures. Novel therapeutic strategies for GIOP are needed, with improved safety profiles and reduced costs compared to current options. Dendrobium officinale (D. officinale) is a traditional Chinese medicine that has been reported to have beneficial effects on bone metabolism. Here, we sought to investigate the impacts of D. officinale polysaccharides (DOP), the main active constituents of D. officinale, on GIOP in vivo models and dexamethasone (DEX)-treated osteoblast lineage cells. We found that low concentrations of DOP are relatively safe in vitro and in vivo, respectively. Importantly, we found that DOP treatment significantly inhibited DEX-induced osteoporosis in two in vivo models, zebrafish and mice, while boosting osteogenic differentiation of hBMSCs exposed to DEX. Futhermore, our data reveal that DOP elevates nuclear Nrf2 levels under DEX treatment, by suppressing of Nrf2 ubiquitination. Leveraging Keap1b knockout zebrafish and RNAi approach, we demonstrated that DOP disrupts the association of Nrf2/Keap1, resulting in the inhibition of Nrf2 ubiquitination. Taken together, these results illuminate that DOP stimulates osteogenesis in the presence of DEX by destabilizing the Nrf2/Keap1 interaction. These findings suggest that DOP may serve as a novel drug against osteoporosis caused by glucocorticoids.