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Summary: Increased fracture risk due to oral glucocorticoids (GCs) rapidly decreases with GC discontinuation. However, evidence for this is limited. We found that fracture risk decreased rapidly in the first year after GC discontinuation, while hip fracture risk remained higher than reference levels for about two years after GC discontinuation. Purpose: We investigated changes in fracture risk following discontinuation of long-term oral glucocorticoids (GCs) using Japan's nationwide health insurance claims database (NDBJ). Methods: We identified patients aged ≥ 50 years who initiated GC therapy in 2012–2019. Those receiving ≥ 5 mg (prednisolone or equivalent, PSL)/day for ≥ 72 days in the initial 90 days of GC therapy were classified as the GC-exposure group, and those receiving < 5 mg PSL/day for < 30 days were classified as the reference group. Patients discontinuing GC after 90 days of GC therapy were classified as the GC-discontinuation group; all others were classified as the GC-continuation group. We tracked the incidence rates of hip and clinical vertebral fractures for up to 990 days, and assessed fracture risk after GC discontinuation by hazard ratios (HR) adjusted by inverse probability weighting using propensity scores for GC discontinuation. Results: There was a total of 52,179 GC-discontinuation, 91,969 GC-continuation, and 43,138 reference group women, and 57,560, 93,736, and 33,696 men in the corresponding groups, respectively. According to adjusted HRs, incidence rates of fractures were significantly lower in the GC-discontinuation group than in the GC-continuation group in the initial 90 days after GC discontinuation and remained significant for 360 days, except for hip fracture in men. HRs for hip fractures remained significantly higher in the GC-discontinuation group compared to the reference group for 720 days post-discontinuation. Conclusion: Fracture risk declines rapidly in the first year after GC discontinuation, but vigilance is necessary as the increased risk persists for two years post-discontinuation. [ABSTRACT FROM AUTHOR]

The nuclear factor-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) pathway, as a crucial intracellular anti- oxidative stress mechanism, prevents various bone formation related cells from ferroptosis damage and represents a potential pathogenic mechanism of glucocorticoid-induced osteoporosis (GIOP). The pathogenesis of GIOP syndrome caused by blood stasis is closely associated with this system. The efficacy of blood stasis treatment can be observed through the microscopic regulation of this pathway. Treatment with traditional Chinese medicine for GIOP emphasizes syndrome differentiation and stasis syndrome treatment, typically utilizing clinical medicine to promote blood circulation, to dissipate blood stasis, and to invigorate qi. Therefore, based on the Nrf2/GPX4 regulation of ferroptosis, this paper discusses the scientific basis for treating GIOP from the perspective of blood stasis, highlighting that traditional Chinese medicine intervention aiming to promote blood circulation and remove blood stasis is involved in regulating ferroptosis in BMSCs, ECs, and OB to treat GIOP. This study offers a novel perspective for comprehending the pathophysiological process of GIOP. [ABSTRACT FROM AUTHOR]

Background: The increasing prevalence of glucocorticoid-induced osteoporosis (GIOP) due to long-term glucocorticoid therapy underscores the need for effective treatment options. Denosumab and bisphosphonates, both key in managing GIOP, require further comparative evaluation to determine their relative efficacy and safety profiles. Methods: We conducted a systematic review and meta-analysis, adhering to PRISMA guidelines. Our analysis included randomized controlled trials (RCTs) comparing denosumab with bisphosphonates in GIOP management. The outcomes were percent changes in bone mineral density (BMD) at various sites, bone turnovers markers (BTMs) and the incidence of adverse events. Results: Our study comprised five RCTs with 1,043 participants. The results showed a significant mean difference in BMD percentage change from baseline at LS of 2.87% (95% CI: 1.86 to 3.87, p <0.001) and at TH of 1.39% (95% CI: 0.15 to 2.64, p =0.03). Additionally, the safety profile of denosumab was found to be comparable to bisphosphonates, with no significant increase in the incidence of adverse events or serious adverse reactions. Conclusions: Denosumab proved more effective in enhancing BMD than bisphosphonates in GIOP, maintaining a comparable safety profile. However, the study's limitations, including heterogeneity and the need for longer-term research, were noted. [ABSTRACT FROM AUTHOR]

The pathogenesis, diagnosis, and treatment of glucocorticoid-induced osteoporosis were analyzed under the guidance of the "phase fire theory". It was concluded that excessive hormone levels damage the body, leading to wild movement of phase fire and result ing in an imbalance of Yin and Yang, dysfunction of marrow osteogenesis, and the development of GIOP. The fundamental pathogenesis of GIOP is related to the overreaction of fire. Treatment should be based on regulating the phase fire, adjusting Yin and Yang as a framework, strengthening water as the main focus, nourishing Yin and replenishing essence, supplementing Zuo-Gui Pills or returning phase fire to reduce excess fire energy, while warming Yang energy and supplementing Jin- Gui-Shen-Qi Pills. Differentiating and treating GIOP based on the theory of "phase fire" has unique practical value and deserves further discussion in order to provide new insights for clinical prevention and treatment of GIOP. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction This report presents the recommendations of the European Calcified Tissue Society (ECTS) for the prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) in adults. Our starting point was that the recommendations be evidence based, focused on non-bone specialists who treat patients with glucocorticoid (GC) and broadly supported by ECTS. Methods The recommendations were developed by global experts. After a comprehensive review of the literature, 25 recommendations were formulated, based on quality evidence. For stratifying fracture risk and the most appropriate first line of treatment, we have classified patients into 3 categories: those at medium risk of fractures, ie, adults without a recent (in the last 2 years) history of fracture; those at high risk of fractures, ie, adults with recent history of fracture, and/or at least one vertebral fracture (grade ≥ 2 according to Genant classification); and those at very high risk of fractures, ie, adults aged ≥70 years with a recent hip fracture, pelvis fracture, and/or at least one vertebral fracture (grade ≥ 2 according to Genant classification). The subtopics in the recommendations include who to assess, how to assess, who to treat, how to treat, and follow-up and monitoring. Results General measures are recommended for all patients who are being prescribed GCs for ≥3 months, ie, calcium and protein intake should be normalized, a 25(OH) vitamin D concentration of 50-125 nmol/L should be attained, and the risk of falls be minimized. (1) Who to assess? (R1-2) A preliminary assessment of fracture risk should be routinely performed in patients likely to receive oral GCs for ≥3 months: (i) women and men ≥ 50 years and (ii) patients at increased risk of fracture (history of fragility fracture and/or have comorbidities or are on medications that are frequently associated with osteoporosis. (2) How to assess (fracture risk)? (R3-6) Clinical risk factors include history of fragility fracture, systematic vertebral imaging, and GC dose-adjusted FRAX, measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), fall risk, and biochemical testing. (3) Who to treat? (R7-12) Anti-osteoporosis treatment is indicated for women and men ≥ 50 years with (i) the presence of a recent history of vertebral and/or non-vertebral fracture (less than 2 years), (ii) and/or a GC dosage ≥ 7.5 mg/day, (iii) and/or age ≥ 70 years, (iv) and/or a T -score ≤ −1.5, (v) and/or 10-year probability risk above the country specific GC dose-adjusted FRAX® thresholds. In premenopausal women and men < 50 years with a Z -score ≤ −2 and/or a history of fragility fracture, it is recommended to refer the patient to a bone specialist. (4) How to treat? (R13-18) In women and men ≥ 50 years, (i) alendronate or risedronate is preferred as the first line of treatment in patients at medium risk of fractures, (ii) zoledronic acid or denosumab in patients at high risk of fractures, and (iii) teriparatide in patients at very high risk of fractures. It is imperative that sequential therapy be implemented in individuals receiving denosumab or teriparatide as their first-line treatment regimen. (5) Follow-up and monitoring (R19-25): in patients receiving anti-osteoporosis treatment, monitoring of clinical risk factors (eg, history of fragility fracture), systematic vertebral imaging, fall risk, BMD measurement using DXA, and biochemical testing should be performed regularly during follow-up. Conclusions The new, evidence-based recommendations by the ECTS for the prevention and treatment of GIOP provide clear and pragmatic advice to all health practitioners especially those who are not bone specialists. [ABSTRACT FROM AUTHOR]

Abstract 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

Introduction. Glucocorticoid-induced osteoporosis (GIOP) is a bone metabolic disease that develops as a result of glucocorticoid (GC) use, is one of the most frequent causes of secondary osteoporosis, leads to an increase in the risk of low-energy fractures, disability and mortality of GC users. Despite the few stu­dies conducted in Ukraine on the epidemiology and treatment of GIOP, there have been no national recommendations for its ma­nagement until now, which has become the background for their creation. The purpose was to develop national guidelines for the diagnosis, prevention, and treatment of GIOP based on the analytical analysis of modern literary sources to improve the awareness of the medical community of Ukraine, improve management, and reduce the socio-economic burden of the disease. Materials and ­methods. A group of 18 experts, leading Ukrainian scientists in various fields, was created to develop the guideline. An analysis of current literary sources on epidemiology, risk factors, diagnosis, prevention and treatment of GIOP, and monitoring of the effectiveness and safety of its treatment was carried out. Evidence was synthesized ­using the GRADE system, and a critical assessment of the quality of the recommendations was carried out using the AGREE II tool. ­Results. The guideline consists of 12 provisions on screening, diagnosis, prevention, and treatment of GIOP. The authors emphasized the need to increase the awareness of the medical community of Ukraine regarding the problem, as well as patients regarding the possible side effects of GC. They presented the features of the clinical assessment of the osteoporotic fracture risk in GC users, as well as modern and available in Ukraine methods of diagnosis and treatment of GIOP. Conclusion. The first Ukrainian guideline for screening, diagnosis, prevention, and treatment of GIOP is an important national tool for its management, which is recommended by the Board of the Ukrainian Association of Osteoporosis for use in practical health care by doctors of various specialties.

This review presents a current perspective on the association between rheumatoid arthritis (RA) and osteoporosis. Many factors contribute to the increased risk of osteoporosis and fracture in RA patients. These factors include advanced age, duration of disease, long-term glucocorticoid use, and poor inflammation control inflammation in RA. This review discusses current guidelines and their limitations in assessing bone health in RA-related osteoporosis. Available anti-osteoporotic treatments, their mechanisms of action, and their potential benefits in managing the interaction between RA and osteoporosis are discussed. We also consider potential advancements, including areas of future development in RA and osteoporosis diagnosis and management. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BackgroundThe increasing prevalence of glucocorticoid-induced osteoporosis (GIOP) due to long-term glucocorticoid therapy underscores the need for effective treatment options. Denosumab and bisphosphonates, both key in managing GIOP, require further comparative evaluation to determine their relative efficacy and safety profiles.MethodsWe conducted a systematic review and meta-analysis, adhering to PRISMA guidelines. Our analysis included randomized controlled trials (RCTs) comparing denosumab with bisphosphonates in GIOP management. The outcomes were percent changes in bone mineral density (BMD) at various sites, bone turnovers markers (BTMs) and the incidence of adverse events.ResultsOur study comprised five RCTs with 1,043 participants. The results showed a significant mean difference in BMD percentage change from baseline at LS of 2.87% (95% CI: 1.86 to 3.87, p

Abstract 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.

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. Highlight: • BACH1 was gradually reduced during osteogenic differentiation and induced by Dex. • Loss of BACH1 impaired Dex-induced osteogenic differentiation and autophagy inhibition. • BACH1 transcriptionally inhibited ATG7 expression. • The helpful effect of BACH1 silence on osteogenic differentiation and autophagy in Dex-induced BMSCs were reversed by ATG7 inhibition. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction. Glucocorticoid-induced osteoporosis (GIOP) is a bone metabolic disease that develops as a result of glucocorticoid (GC) use, is one of the most frequent causes of secondary osteoporosis, leads to an increase in the risk of low-energy fractures, disability and mortality of GC users. Despite the few studies conducted in Ukraine on the epidemiology and treatment of GIOP, there have been no national recommendations for its management until now, which has become the background for their creation. The purpose was to develop national guidelines for the diagnosis, prevention, and treatment of GIOP based on the analytical analysis of modern literary sources to improve the awareness of the medical community of Ukraine, improve management, and reduce the socio-economic burden of the disease. Materials and methods. A group of 18 experts, leading Ukrainian scientists in various fields, was created to develop the guideline. An analysis of current literary sources on epidemiology, risk factors, diagnosis, prevention and treatment of GIOP, and monitoring of the effectiveness and safety of its treatment was carried out. Evidence was synthesized using the GRADE system, and a critical assessment of the quality of the recommendations was carried out using the AGREE II tool. Results. The guideline consists of 12 provisions on screening, diagnosis, prevention, and treatment of GIOP. The authors emphasized the need to increase the awareness of the medical community of Ukraine regarding the problem, as well as patients regarding the possible side effects of GC. They presented the features of the clinical assessment of the osteoporotic fracture risk in GC users, as well as modern and available in Ukraine methods of diagnosis and treatment of GIOP. Conclusion. The first Ukrainian guideline for screening, diagnosis, prevention, and treatment of GIOP is an important national tool for its management, which is recommended by the Board of the Ukrainian Association of Osteoporosis for use in practical health care by doctors of various specialties. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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

Glucocorticoids (GC) have been used in medicine since the middle of the twentieth century, including for the treatment of various systemic rheumatic diseases. However, long-term use of GC may be accompanied by the development of serious complications, one of which is secondary osteoporosis, leading to low-energy fractures, which affects the quality of life of patients and may lead to an increased risk of death. This article presents an overview with a discussion of the new edition of the guideline of the American College of Rheumatology (ACR) 2022 for the prevention and treatment of glucocorticoid-induced osteoporosis in adult patients.

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. Summary: 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. [ABSTRACT FROM AUTHOR]

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. Key message What is already known on this topic—   The treatment of glucocorticoid-induced osteoporosis (GIOP) in patients with autoimmune diseases primarily relies on oral BPs. What this study adds—   Zoledronic acid is emerging as the preferred alternative for GIOP in patients with autoimmune diseases, with high patient satisfaction, comparable efficacy to oral bisphosphonates in bone mineral density changes, and fracture prevention. How this study might affect research, practice, or policy—   This study suggests that zoledronic acid is a viable, patient-preferred option for GIOP in patients with autoimmune diseases, which may impact treatment decisions and guidelines. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Bone remodeling is a process that involves osteoblasts, osteoclasts, and osteocytes, and different intracellular signaling, such as the canonical Wnt/β‐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/β‐catenin pathway. Dexamethasone challenge reduced bone formation in primary osteoblasts and bone mineralization in osteocytes; moreover, canonical Wnt/β‐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 β. These data suggest that genistein could induce bone remodeling through Wnt/β‐catenin pathway activation. [ABSTRACT FROM AUTHOR]

Abstract Background Glucocorticoid-induced osteoporosis (GIOP) is a disease in which long-term use of glucocorticoid causes bone loss, deterioration of bone microstructure and fracture. Currently, clinical drugs targeting this disease have certain side effects. There is still a need to find effective drugs with fewer side effects. The theory of traditional Chinese medicine suggests that YGJ has therapeutic effect on GIOP, but it has not been explained. Therefore, this study aims to explore the protective effect of YGJ on GIOP mouse models and elucidate the underlying mechanism through LC–MS-based metabolomics analysis. Methods The general condition of 8 week age male C57BL/6J mice was recorded after 8 weeks of treatment with dexamethasone (DEX) and YGJ. Bone-related parameters and bone morphology were determined by Micro-CT. HE staining was used to observe the pathological changes of bone tissue. Serum levels of bone metabolism markers were detected by ELISA. Liver metabolomics analysis was conducted to search for the significant markers of anti-GIOP of YGJ and the metabolic pathway affecting it. Results After treatment, YGJ significantly reversed the weight loss caused by DEX; increase the number of bone trabecular in ROI region, significantly improve the bone-related parameters of GIOP mice, and increase the levels of alkaline phosphatase and osteocalcin. In the study of metabolic mechanism, YGJ reversed 24 potential markers in GIOP mice. These included cortisol, 3-hydroxybutyric acid, taurine, esculin and uric acid, which are closely associated with osteoporosis. Topological analysis results showed that YGJ had the most significant effect on taurine and hypotaurine metabolism, with − log10 (P) > 2.0 and Impact > 0.4. Conclusions Yi-Guan-Jian decoction can increase bone density and improve bone microstructure by regulating the levels of alkaline phosphatase and osteocalcin and reverse bone loss in GIOP mouse model. The underlying metabolic mechanism may be related to taurine and hypotaurine metabolic pathway.

Glucocorticoid-induced osteoporosis (GIOP), one of the most common and serious adverse effects associated with glucocorticoid administration, manifests as decreased bone formation and increased bone resorption, eventually culminating in bone loss. Galangin (GAL) is a flavonoid extracted from the medicinal herbal galangal that possesses a variety of pharmacological activities and can inhibit osteoclastogenesis. However, the effects of GAL on GIOP remain unclear. Our study aims to explore the effects of GAL on GIOP in mice and the underlying mechanism. Our results show that GAL markedly mitigates the severity of dexamethasone (Dex)-induced osteoporosis in mice and potentiates osteogenic differentiation in mouse bone marrow-derived mesenchymal stem cells (BMSCs). Furthermore, GAL also significantly counteracts Dex-mediated suppression of osteogenic differentiation and autophagy in human BMSCs. GAL augments PKA/CREB-mediated autophagic flux in BMSCs and the bones of osteoporotic mice. GAL-mediated osteogenic differentiation in Dex-treated BMSCs is significantly decreased by the PKA inhibitor H89 and autophagy inhibitor 3-methyladenine. Collectively, our data indicate that GAL can ameliorate GIOP, partly by augmenting the mineralization of BMSCs by potentiating PKA/CREB-mediated autophagic flux, highlighting its potential therapeutic use in treating glucocorticoid-related osteoporosis.

Objective To predict and preliminarily verify the potential targets and related signaling pathways of Artemisia annua L. in treating glucocorticoid-induced osteoporosis (GIOP) with kidney-yin deficiency by network pharmacology and in vitro experiments. Methods The pharmacological targets of Artemisia annua L. were obtained from TCMSP database and were converted to gene names through Uniprot database. The target genes of GIOP with kidney-yin deficiency were obtained from GeneCards database, OMIM database and Drugbank database, and the common target genes were obtained by cross analysis with drug target gene. Protein-protein interaction (PPI) network was constructed by String database, and visualization analysis and core targets screening were performed by Cytoscape 3.9.0. All common targets were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis through Metascape database. Finally, the prediction results were verified by in vitro experiments. Results Ninety-eight targets of Artemisia annua L. to GIOP with kidney-yin deficiency were screened, including 17 core genes. The results of GO and KEGG functional enrichment analysis indicated that Artemisia annua L. treating GIOP with kidney-yin deficiency was related to biological processes such as hormonal response, positive regulation of cell death and extracellular stimulation response, et al, as well as signaling pathways such as PI3K/AKT, AGE/ RAGE, MAPK and IL-17 et al. The number of genes enriched in PI3K/AKT signaling pathway was the largest. In vitro experiment results showed that Artemisia annua L. promoted the proliferation of osteoblasts damaged by dexamethasone (DEX), increased alkaline phosphatase activity, activated PI3K/AKT pathway, and promoted the phosphorylation of AKT. Conclusion Artemisia annua L. treating GIOP with kidney-yin deficiency has the characteristics of multi-targets and multi-pathway, which could promote the proliferation and differentiation of osteoblasts through multiple pathways. The PI3K/AKT signaling pathway is an important pathway. Artemisia annua L. treating GIOP with kidney-yin deficiency might be related to its ability to promote the PI3K/AKT signaling pathway and promote the phosphorylation of AKT. [ABSTRACT FROM AUTHOR]

Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis in children.?Because it affects the development of children's bones and leads to growth development disorders, and reduces the quality of life in children, it has gradually attracted wide attention worldwide.?GIOP is classified to the category of bone loss and bone impotence in traditional Chinese medicine. Its occurrence is closely related?to warm kidney qi.?Kidney is the bank of water. Water is conquered by fire. When heat causes marrow exhaustion, the bone is suffered from non-nourishment. Glucocorticoid is the source of GIOP. It belongs to the hot and acrid in traditional Chinese medicine. Overdose?of glucocorticoids may cause consumption of kidney?essence?due to?intense heat, which is consistent with the theory of marrow loss and bone exhaustion caused by warm kidney qi. Based on this theory, this paper explores the pathogenesis of GIOP in traditional Chinese medicine combined with modern medical research, in order to provide ideas for clinical dialectical treatment. [ABSTRACT FROM AUTHOR]

The study was aimed at evaluating therapeutic efficacy of vitamin D3 (VD3, 1000 IU/kg of b.w., 30 days) and sodium salt of methylenebisphosphonic acid (MBPA, 17 mg/kg of b.w., 30 days) monotherapies as well as their effect in combination in preventing mineral metabolism and bone remodeling disturbances associated with glucocorticoid(GC)-induced osteoporosis. Osteoporosis in rats was induced by long-term (30 days) administration of the synthetic glucocorticoid prednisolone (5 mg/kg of b.w.). Calcium and inorganic phosphate levels, the activity of alkaline phosphatase (ALP) in serum, bone tissue and bone marrow were determined spectrophotometrically. The protein levels of VD3 receptor (VDR), receptor activator of nuclear factor kappa-B (RANK), its ligand (RANKL), and osteoprotegerin (OPG) in bone tissue were determined by Western blotting. Serum 25-hydroxyvitamin D3 (25OHD3) content was assayed by ELISA. It was shown that prednisolone caused the development of hypocalcemia and hypophosphatemia, increased the alkaline phosphatase activity in the blood serum, while downregulating its activity in bone tissue and bone marrow. GC-induced osteoporosis was accompanied by a profound deficiency of VD3 and a decrease in the content of VDR. Evaluation of the NF-κB-associated cytokine axis RANK/RANKL/OPG, which regulates the balance of osteoblasts/osteoclasts, showed a simultaneous decrease in the RANK content and OPG/RANKL ratio. Vitamin D3 restored mineral metabolism and 25OHD3 level that led to the normalization of VDR-mediated signaling­ and RANK/RANKL/OPG functions in bone tissue. It has been shown that the administration of MBPA had a corrective effect on the content of mineral components in the blood serum and bone tissue, as well as on the activity­ of alkaline phosphatase only in combination with vitamin D3, indicating a low efficiency of bisphosphonate monotherapy in GC-induced vitamin D3 deficiency and osteoporosis.

Context Morinda officinalis F.C. How. (MO) (Rubiaceae) can strengthen bone function.Objective To examine the functional mechanism and effect of MO polysaccharides (MOPs) in rats with glucocorticoid-induced osteoporosis (GIOP).Materials and methods Rats with GIOP were treated with 5, 15 or 45 mL/kg of MOP [n = 15 for each dose, intraperitoneal (i.p.) injection every other day for 8 weeks]. The body weight of rats and histomorphology of bone tissues were examined. Bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (Exo) were collected and identified. Bone marrow-derived macrophages (BMMs) were induced to differentiate into osteoclasts and treated with BMSC-Exo for in vitro studies.Results MOP reduced the body weight (5, 15, or 45 mg/kg MOP vs. phosphate-buffered saline: 8%, 15% and 25%, p

There is still a lack of high-quality evidence-based studies on the efficacy of drug treatment for glucocorticoid-induced osteoporosis (GIOP). The purpose of this umbrella review is to comprehensively evaluate the existing evidence to determine the efficacy and safety of pharmacological interventions for GIOP. We searched PubMed, Embase, and the Cochrane Library for systematic reviews and/or meta-analyses (SRs) of randomized controlled trials (RCTs) aimed at evaluating drug therapy for GIOP. Both the methodological quality and the strength of recommendation of the endpoints included in the SRs were evaluated by using the AMSTAR-2 tool and GRADE system, respectively. Six SRs involving 7225 GIOP patients in 59 RCTs were included in this umbrella review. The results of the methodological quality evaluation showed that 2 high-quality, 2 low-quality and 2 critically low-quality SRs were included. The GRADE evaluation results showed that the quality of evidence and the strength of recommendation of 46 outcome indicators were evaluated in the umbrella review; there were 3 with high-level evidence, 20 with moderate-level evidence, 15 with low-level evidence, and 8 with very low-level evidence. Moderate- to high-level evidence suggests that teriparatide, bisphosphonates, and denosumab can improve the bone mineral density in patients with GIOP. The findings of this umbrella review can enable patients and clinical healthcare professionals to choose the best drug prescription. [ABSTRACT FROM AUTHOR]

Prednisolone, used as a standard initial treatment for immune thrombocytopenia (ITP), is an important risk factor for osteoporosis. Recently, we found that prescription of bisphosphonate during initial loading of prednisolone may prevent reduction in bone mineral density and development of glucocorticoid-induced osteoporosis (GIO) in older patients with ITP receiving prolonged steroid therapy. In this review, I describe the treatment options for older patients with ITP, and present the best practices for screening, evaluating, and diagnosing ITP. I also summarize the literature from 2017 to 2022 on the treatment options for ITP, including discussions on the contraindications and side effects, with an emphasis on GIO, and the relative merits of bisphosphonates as a co-treatment for prevention of GIO. Finally, I present a perspective and an expert recommendation on how older patients with ITP would best be served in the future. [ABSTRACT FROM AUTHOR]

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.

Xing Rong,1,2 Yuying Kou,1,2 Yuan Zhang,1,2 Panpan Yang,1,2 Rong Tang,1,2 Hongrui Liu,1,2 Minqi Li1,2 1Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, People’s Republic of China; 2Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Minqi Li; Hongrui Liu, Center of Osteoporosis and Bone Mineral Research, Shandong University, Department of Bone Metabolism, School of Stomatology, Shandong University, Wenhua West Road 44-1, Jinan, 250012, People’s Republic of China, Tel +86-531-88382095 ; +86-531-88382493, Fax +86-531-8838 2923, Email liminqi@sdu.edu.cn; yf1blhr@126.comPurpose: Long-term glucocorticoid- usage can lead to glucocorticoid-induced osteoporosis (GIOP). The study focused on the preventative effects of a novel active vitamin D3 analog, eldecalcitol (ED-71), against GIOP and explored the underlying molecular mechanisms.Methods: Intraperitoneal injection of methylprednisolone (MPED) or dexamethasone (DEX) induced the GIOP model within C57BL/6 mice in vivo. Simultaneously, ED-71 was orally supplemented. Bone histological alterations, microstructure parameters, novel bone formation rates, and osteogenic factor changes were evaluated by hematoxylin-eosin (HE) staining, micro-computed tomography, calcein/tetracycline labeling, and immunohistochemical (IHC) staining. The osteogenic differentiation level and mineralization in pre-osteoblast MC3T3-E1 cells were evaluated in vitro using alkaline phosphatase (ALP) staining, alizarin red (AR) staining, quantitative polymerase chain reaction (qPCR), Western blotting, and immunofluorescence staining.Results: ED-71 partially prevented bone mass reduction and microstructure parameter alterations among GIOP-induced mice. Moreover, ED-71 also promoted new bone formation and osteoblast activity while inhibiting osteoclasts. In vitro, ED-71 promoted osteogenic differentiation and mineralization in DEX-treated MC3T3-E1 cells and boosted the levels of osteogenic-related factors. Additionally, GSK3-β and β-catenin expression levels were elevated after ED-71 was added to cells and were accompanied by reduced Notch expression. The Wnt signaling inhibitor XAV939 and Notch overexpression reversed the ED-71 promotional effects toward osteogenic differentiation and mineralization.Conclusion: ED-71 prevented GIOP by enhancing osteogenic differentiation through Notch and Wnt/GSK-3β/β-catenin signaling. The results provide a novel translational direction for the clinical application of ED-71 against GIOP.Keywords: glucocorticoid-induced osteoporosis, eldecalcitol, osteoblasts, Notch signaling, Wnt/GSK-3β/β-catenin signaling

Prednisolone, used as a standard initial treatment for immune thrombocytopenia (ITP), is an important risk factor for osteoporosis. To investigate the prevention of glucocorticoid-induced osteoporosis (GIO) in elderly ITP patients receiving prolonged steroid therapy, associations between GIO prevention and the real-world data of score changes of a dual-energy X-ray absorptiometry (DXA) scan, FRAX® and the Garvan tool during the initial loading of prednisolone were examined. In our institute, 22 ITP patients aged ≥ 70 years received 0.5–1.0 mg/kg prednisolone for 2–3 weeks as the initial ITP treatment between 2014 and 2021. The femoral neck bone mineral density (BMD) measured by DXA scan was entered into FRAX® to define the risk-adapted approach to bisphosphonate during the initial loading of prednisolone. Bisphosphonate was administered according to ® and the Garvan tool were associated with bisphosphonate use for short-term fracture prevention in primary GIO; however, there were no incidents of fracture or significant differences in probabilities determined by FRAX® and the Garvan tool. During the initial loading of prednisolone, prescribing bisphosphonate might prevent the reduction in BMD in elderly patients with ITP receiving prolonged steroid therapy.

Glucocorticoid (GC)‐induced osteoporosis (GIO) is a concurrent disease commonly appeared in chronic inflammatory and autoimmune disease patients. Stereoselective recognition between chiral drugs and homochiral biological molecules could directly affect their distribution, adhesion and transport. Herein, trace element selenium (Se) with bone formation‐regulating activity, is employed to construct cysteine‐decorated chiral nanoparticles (Cys@SeNPs) to attenuate GIO. Interestingly, comparing with the racemic (DL‐Cys@SeNPs) and D‐Cys@SeNPs, the L‐Cys@SeNPs displays higher uptake in osteoblast cells and could lessen reactive oxygen species overproduction to block dexamethasone (Dex)‐induced osteoblasts cells apoptosis. Intracellular L‐Cys@SeNPs could be predominantly transformed to selenocystine to upregulate the expression levels of antioxidative selenoproteins to effectively scavenge Dex‐induced excessive ROS accumulation in osteoblasts, and thus reduce the undesirable apoptosis through activating Wnt/β‐catenin pathway. Consistently, L‐Cys@SeNPs significantly alleviates the main osteoporosis symptoms of bone trabeculae destruction and decreased bone density in vivo, and also reduces the weight gain and fatty liver formation in Dex‐exposed mice, thus suppressing the overall side effects of Dex. This study not only demonstrates an effective strategy for treatment of GIO by using chiral Se nanomedicine, but also elucidates the important roles of selenoproteins in alleviating osteoporosis, which could help for future Se‐based drug design through chirality control engineering. [ABSTRACT FROM AUTHOR]

Introduction: Glucocorticoid therapy is the most common cause for secondary osteoporosis leading to a resurgence of interest in traditional medicine that could have bone sparing effects by naturally occurring bioactive molecules. Therefore, this study was done to evaluate the effect of Ormocarpum sennoides DC through immunohistological evidence in the expression of Bax and Bcl2 in glucocorticoid-induced Osteoporosis in Wister albino rats. Materials and Methods: Rats were divided into five groups (Control, MPA (Osteoporosis), Alendronate (2 mg/kg), 100 mg (EOS), and 200 mg (EOS). The treatment was conducted for 45 days the Bax and Bcl2 expressions were evaluated in osteoclast of distal femur diaphysis. Results: When compared the MPA to control group (P < 0.05) Bax increased and Bcl2 reduced, when compared with MPA (P < 0.05) Alendronate, EOS 100 mg and EOS 200 mg increased the Bcl2 expressions, Alendronate, EOS 100 mg, and EOS 200 mg reduced the Bax expression. Discussion and Conclusion: EOS 100 mg and EOS 200 mg increased Bcl2 expression and reduced the Bax expression Ormocarpum sennoides prevents glucocorticoid-induced Apoptosis of preosteoblast; therefore, Bcl2 may be an important regulator of bone growth thus reporting antiapoptotic property of Ormocarpum sennoides DC. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP) is characterized as decreased bone mineral density (BMD) and increased risk of bone fracture. Secondary OP resulting from excess endogenous or exogenous glucocorticoid is defined as glucocorticoid-induced osteoporosis (GIOP). Current therapeutic strategies for GIOP are similar to menopausal osteoporosis, including calcium and vitamin D supplementation, bisphosphonates, and parathyroid hormone (PTH) analogues (teriparatide). Previously, several published meta-analyses compared anti-osteoporotic agents for the menopausal or aging-dependent OP. However, the physiopathologic bone metabolism of GIOP is different. In this study, we investigated the efficacy of BMD enhancement, bone fracture rate and safety of bisphosphonates versus teriparatide in the therapy of GIOP. We searched databases including PubMed, Embase, and the Cochrane Library until Jan 2023, and selected ten random clinical trials (RCT)s that compared the efficacy and/or safety of bisphosphonate versus teriparatide for GIOP patients. Teriparatide therapy increased lumber spinal BMD by 3.96% (95% CI 3.01–4.9%, p<0.00001), 1.23% (95% CI 0.36–2.1%, p=0.006) at total hip, and 1.45% (95% CI 0.31–2.58%, p=0.01) at femoral neck, respectively, compared to bisphosphonates at 18-month therapy for GIOP. Teriparatide also reduced bone fracture especially in vertebral bone (p=0.0001, RR 6.27, 95% CI 2.44–16.07), and increased bone formation and resorption marker levels. There was no difference in the incidence of adverse effects in bisphosphonate and teriparatide groups. Teriparatide showed better performance over bisphosphonate in BMD enhancement, bone fracture reduction, and bone remodeling improvement, without increasing the incidence of adverse effects. [ABSTRACT FROM AUTHOR]

Glucocorticoid-induced osteoporosis（GIOP） is one of the most common adverse reactions of glucocorticoids, severe cases can cause osteoporotic fracture. Its treatmentand prevention are the focus of current research. Denosumab is a nuclear factor κ B receptor activator ligand（RANKL） monoclonal antibody. In China, it was approved to treat bone metastasis from solid tumors, multiple myeloma, giant cell tumor of bone and postmenopausal women with high risk of fracture, but it has not been approved to treat glucocorticoid-induced osteoporosis. This article reviews the pathogenesis of glucocorticoid-induced osteoporosis, and updates the result of clinical trials related to denosumab in the treatment of glucocorticoid-induced osteoporosis, so as to provide reference for the treatment of glucocorticoid-induced osteoporosis. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoid‐induced osteoporosis is the most common secondary cause of osteoporosis, which increases the risk of fracture. Long non‐coding RNA telomerase RNA elements (TERC) has been proven to be closely related to osteoporosis. However, the role of TERC in glucocorticoid‐induced osteoporosis and its underlying molecular mechanism remains unclear. Methods: The in vitro model of osteoporosis was established after bone marrow mesenchymal stem cells (BMSCs) were exposed to dexamethasone (DEX). The cell viability, alkaline phosphatase (ALP) activity and mineralized nodules of BMSCs were evaluated. The messenger RNA and protein levels were detected by quantitative real‐time polymerase chain reaction and Western blot. The interaction between TERC, enhancer of zeste homolog 2 (EZH2) and dickkopf‐1 (DKK1) was confirmed by chromatin immunoprecipitation and RNA immunoprecipitation assays. Results: Bone marrow mesenchymal stem cells were isolated, identified and induced osteogenic differentiation. The findings showed that the levels of osteogenic marker genes, including ALP, Runt‐related transcription factor 2 (RUNX2) and osteocalcin (OCN) in BMSCs were increased dependent on the osteogenic induction time. Similarly, TERC was significantly increased, but DKK1 was significantly decreased during BMSC osteogenic differentiation. Functional research showed that TERC overexpression promoted cell viability, ALP activity and mineralized nodules of BMSCs and increased the levels of osteogenic differentiation‐related genes (ALP, RUNX2 and OCN), and TERC overexpression increased EZH2 protein level. Moreover, the decrease of cell viability, ALP activity and mineralized nodules induced by DEX was reversed by TERC overexpression. Furthermore, TERC inhibited DKK1 expression by promoting the histone modification of DKK1, and TERC overexpression alleviated DEX suppressed osteogenic differentiation of BMSCs by interaction with EZH2 to regulate DKK1. Conclusion: Our findings illustrated that TERC overexpression alleviated DEX‐induced osteoporosis by recruiting EZH2 to regulate DKK1. Our research provided a novel direction for the treatment of glucocorticoid‐induced osteoporosis. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP) is the most prevalent metabolic bone disease, characterized by the low bone mass and microarchitectural deterioration of bone tissue. Glucocorticoid (GC) clinically acts as one of the anti-inflammatory, immune-modulating, and therapeutic drugs, whereas the long-term use of GC may cause rapid bone resorption, followed by prolonged and profound suppression of bone formation, resulting in the GC-induced OP (GIOP). GIOP ranks the first among secondary OP and is a pivotal risk for fracture, as well as high disability rate and mortality, at both societal and personal levels, vital costs. Gut microbiota (GM), known as the "second gene pool" of human body, is highly correlated with maintaining the bone mass and bone quality, and the relation between GM and bone metabolism has gradually become a research hotspot. Herein, combined with recent studies and based on the cross-linking relationship between GM and OP, this review is aimed to discuss the potential mechanisms of GM and its metabolites on the OP, as well as the moderating effects of GC on GM, thereby providing an emerging thought for prevention and treatment of GIOP. [ABSTRACT FROM AUTHOR]

Introduction: Evidence on second-line agents for osteoporosis and osteopenia associated with glucocorticoid use after first-line bisphosphonate therapy is limited. We, therefore, examine the efficacy of denosumab on bisphosphonate-treated osteoporosis and osteopenia in Japanese systemic rheumatic disease (SRD) patients receiving glucocorticoids. Materials and methods: Glucocorticoid-treated SRD patients with a pre-existing fragility fracture, either lumbar spine (LS) or femoral neck (FN) bone mineral density (BMD) T-score of ≤ −2.5 or of ≤ −1.5 without a significant increase in BMD in the past year despite oral bisphosphonate therapy were enrolled in this study. They were randomized to switch to 60 mg subcutaneous denosumab every six months (switching group) or to continue the bisphosphonate (continuing group). The primary endpoint was the percent change from baseline in BMD at the LS and FN at week 52. Results: Of the 39 subjects, 19 were assigned to the switching group and 20 to the continuing group. The switching group showed significant increases in LS BMD (5.7% vs. 1.1%, p = 0.002) and FN BMD (4.2% vs. −0.3%, p = 0.008) at week 52 than the continuing group, with a significant decrease in serum tartrate-resistant acid phosphatase 5b (−28.1% vs. 7.0%, p < 0.001) and improved patient satisfaction. Conclusion: Switching to denosumab demonstrated greater efficacy than continuing bisphosphonates in increasing BMD, inhibiting osteoclast activation, and enhancing patient satisfaction in Japanese bisphosphonate-treated osteoporosis and osteopenia patients with concomitant SRD receiving glucocorticoids. [ABSTRACT FROM AUTHOR]

This randomized, open-label, multicenter, parallel study imitating real-world clinical practice assessed the effect of switching to weekly teriparatide in patients with glucocorticoid-induced osteoporosis (GIO) with a lumbar spine/proximal femur bone mineral density (BMD) T-score ≤ −2.0 or ≤−1.0 and a fragility fracture. Forty-four patients were randomized. The mean durations of the corticosteroid and bisphosphonate administrations were 90.0 and 51.3 months. The baseline BMD at L1–L4 was 0.828 and 0.826 g/cm2 in Groups B (bisphosphonate) and T (teriparatide); at the femur (total), these values were 0.689 and 0.661 g/cm2. The mean change in BMD was numerically higher with teriparatide vs. bisphosphonate but not statistically significant. The mean percentage changes from baseline in BMD at L1–L4 after a 72-week treatment were 0.5% and 4.1% in Groups B and T. The incidence of new fractures was higher in the patients taking bisphosphonates vs. those receiving once-weekly teriparatide at 72 weeks (18.2% vs. 11.8%) and 144 weeks (22.7% vs. 17.6%). The mean percentage change in femur (trochanter) BMD (0.035 [0.007–0.063]; p = 0.02) was significantly greater with teriparatide vs. bisphosphonates. Adverse events (AEs) were more frequent with teriparatide vs. bisphosphonates. Switching to once-weekly teriparatide tended to increase lumbar spine BMD and reduce the occurrence of new fractures vs. bisphosphonates. [ABSTRACT FROM AUTHOR]

Objectives Due to their pronounced anti-inflammatory and immunosuppressive effects, glucocorticoids (GCs) are widely used in inflammatory conditions and organ transplants. Unfortunately, GC-induced osteoporosis is one of the most common causes of secondary osteoporosis. The aim of the present systematic review and meta-analysis was to determine the effect of exercise added to GC therapy on BMD at the lumbar spine or femoral neck in people on GC therapy. Methods A systematic literature search of five electronic databases included controlled trials with a duration of >6 months and at least two study arms [glucocorticoids (GCs) and GCs and exercise (GC + EX)] were conducted up to 20 September 2022. Studies involving other pharmaceutical therapies with relevant effects on bone metabolism were excluded. We applied the inverse heterogeneity model. Outcome measures were standardized mean differences (SMDs) with 95% CIs for BMD changes at the lumbar spine (LS) and femoral neck (FN). Results We identified three eligible trials with a total of 62 participants. In summary, the GC + EX intervention indicated statistically significantly higher SMDs for LS-BMD [SMD 1.50 (95% CI 0.23, 2.77)] but not for FN-BMD [0.64 (95% CI −0.89, 2.17)] compared with GC treatment alone. We observed substantial heterogeneity (LS-BMD I 2 = 71%, FN-BMD I 2 = 78%) between the study results. Conclusion Although more well-designed exercise studies are needed to address the issue of exercise effects on GC-induced osteoporosis (GIOP) in more detail, upcoming guidelines should pay more attention to the aspect of exercise for bone strengthening in GIOP. Registration number PROSPERO: CRD42022308155 [ABSTRACT FROM AUTHOR]