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Glucocorticoid-induced osteoporosis (GIOP) lacks fully effective treatments. This study investigated the role of Piezo1, a mechanosensitive ion channel component 1, in GIOP. We found reduced Piezo1 expression in cortical bone osteocytes from patients with GIOP and a GIOP mouse model. Yoda1, a Piezo1 agonist, enhanced the mechanical stress response and bone mass and strength, which were diminished by dexamethasone (DEX) administration in GIOP mice. RNA-seq revealed that Yoda1 elevated Piezo1 expression by activating the key transcription factor Hes1, followed by enhanced CaM kinase II and Akt phosphorylation in osteocytes. This improved the lacuno-canalicular network and reduced sclerostin production and the receptor activator of NF-κB/osteoprotegerin ratio, which were mitigated by DEX. Comparative analysis of mouse models and human GIOP cortical bone revealed downregulation of mechanostimulated osteogenic factors, such as osteocrin, and cartilage differentiation markers in osteoprogenitor cells. In human periosteum-derived cells, DEX suppressed differentiation into osteoblasts, but Yoda1 rescued this effect. Our findings suggest that reduced Piezo1 expression and activity in osteocytes and periosteal cells contribute to GIOP, and Yoda1 may offer a novel therapeutic approach by restoring mechanosensitivity.

Glucocorticoid-induced osteoporosis (GIOP) is a widespread disease characterized by low bone density. There remains a lack of effective means for osteoporosis. Rehmannioside A (ReA), an iridoid glycoside, exhibits various pharmacological activities. This study aimed to explore the role and mechanism of ReA in osteogenic differentiation of osteoblasts. Cell viability, reactive oxygen species (ROS) generation, and cell apoptosis were assessed using corresponding assay kits. Real-time quantitative polymerase chain reaction, Western blotting, and alkaline phosphatase (ALP) staining were performed to evaluate the osteogenic differentiation of MC3T3-E1 cells. Alizarin red S staining was used to assess the mineralization of MC3T3-E1 cells. Protein expression associated with the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway was analyzed using Western blotting. Micro-computed tomography, histopathological, and immunohistochemical analyses were performed to determine the therapeutic effect of ReA on GIOP in vivo.The results showed that ReA promoted the osteogenic differentiation of MC3T3-E1 cells by regulating the PI3K/AKT signaling pathway and protected mice against glucocorticoid-induced bone loss by promoting osteoblast-mediated bone formation in vivo. The findings of the current study revealed that ReA is a potential therapeutic agent for osteoporosis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To compare the efficacy of romosozumab (ROMO) and denosumab (DEN) in prevalent long-term glucocorticoid (GC) users., Methods: Adult patients receiving oral prednisolone (≥5 mg/day) with high risk of fracture were randomized to receive subcutaneous ROMO (210 mg monthly) or DEN (60 mg 6-monthly) for 12 months, followed by DEN for two more doses. The primary end point was the change in spine bone mineral density (BMD) from Months 0 to 12. Secondary end points included changes in BMD of the spine/hip/femoral neck and bone turnover markers at various time points and adverse events., Results: Seventy patients (age 62.6 ± 9.1 years; 96% women; median prednisolone dose 5.0 mg/day; duration of therapy 10.7 ± 7.4 years) were enrolled, and 63 completed the study. At Month 12, the spine BMD increased significantly in both ROMO (+7.3% ± 4.5%; p < 0.001) and DEN (+2.3% ± 3.1%; p < 0.001) groups. The absolute spine BMD gain from Months 0 to 12 was significantly greater in ROMO-treated patients (p < 0.001). Although the total hip BMD at Month 12 also increased significantly in the ROMO (+1.6% ± 3.3%; p = 0.01) and DEN groups (+1.6% ± 2.6%; p = 0.003), the absolute BMD gain was not significantly different between the groups. At Month 24, the spine BMD continued to increase in both the ROMO (+9.7% ± 4.8%; p < 0.001) and DEN group (+3.0% ± 3.0%; p < 0.001) compared to baseline, and the absolute BMD gain remained significantly greater in ROMO-treated patients. The total hip BMD continued to increase in both groups (ROMO +2.9% ± 3.7%; p < 0.001; DEN +2.2% ± 3.4%; p = 0.001), but the changes from baseline were similar. Injection site reaction was more frequently reported in ROMO-treated patients., Conclusion: ROMO was superior to DEN in raising the spine BMD at Month 12 in chronic GC users. After switching to DEN, ROMO-treated patients continued to gain spine BMD to a greater extent than DEN until Month 24., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

Osteoporosis (OP) is a metabolic disease characterized by low bone mineral mass owing to osteoblast dysfunction. Eucommia ulmoides Oliver (EuO) is a Chinese herbal medicine traditionally used to treat OP. Here, a polysaccharide purified from the EuO cortex (EuOCP3) was administered to OP mice constructed with dexamethasone (Dex) to investigate its anti-OP activity. EuOCP3 significantly improved Dex-induced bone microarchitecture destruction, increased osteoblast numbers and surface, and stimulated an increase in the expression of osteoblast differentiation markers in the femurs of OP mice. Furthermore, EuOCP3 was applied to MC3T3-E1 cells to further explore its effects on osteoblast differentiation. EuOCP3 significantly promoted osteoblast differentiation and increased the level of phosphorylated extracellular signal-regulated kinase1/2 (ERK1/2) and SMAD1/5/8. The EuOCP3-mediated enhancement of osteoblast differentiation-related proteins and phosphorylated SMAD1/5/8 expression levels was strongly suppressed by an ERK inhibitor (PD98059), which confirmed the critical role of ERK signaling in EuOCP3-induced osteoblast differentiation. In summary, EuOCP3 can stimulate bone formation by improving osteoblast differentiation via ERK/BMP-2/SMAD signaling, indicating the potential use of EuOCP3 as a functional ingredient in food products for anti-OP treatment., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Glucocorticoid-induced osteoporosis (GIOP) is the leading cause of iatrogenic osteoporosis due to the widespread clinical use of glucocorticoids (GC) as immunosuppressants. Previous research identified the proline-rich tyrosine kinase 2, Pyk2, as a critical mediator of GC-induced bone loss, and that blocking Pyk2 could protect the skeleton from adverse GC actions. However, systemic administration of current Pyk2 inhibitors causes harmful side effects, such as skin lesions. To address this, we developed bone-targeted (BT) Pyk2 inhibitors by conjugating them with bisphosphonates (BP), ensuring adherence to the bone matrix and reducing impact on noncalcified tissues. We synthesized BT-Amide by linking a derivative of TAE-226, a Pyk2 inhibitor, with alendronic acid. Oral administration (gavage) of BT-Amide prevented GC-induced bone loss in mice without causing skin lesions, or elevation of any organ toxicity markers. These findings introduce BT-Amide as the first orally effective bone-targeted Pyk2 inhibitor for preventing GC-induced bone loss while minimizing off-target effects.

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., Competing Interests: Conflict of interest: J.P.: occasional work (consultancies, advice, conferences, clinical studies, courses) for Amgen, Lilly, Synadiet, Theramex, Kyowa Kirin, and UCB; M.P.Y.: lecture fees from Galenica, Genesis S.A., and Amgen; M.C.: honoraria for speaking engagements from Amgen and Kyowa Kirin; A.D.A.: lecture fees from Amgen, Bianex, Eli-Lilly, Galenica, ITF, Unifarma, and UCB and advisory boards from Amgen; W.F.L.: speakers fee and advisory boards from Amgen, UCB, Pfizer, and Galapagos, (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., (© 2024 John Wiley & Sons, Ltd.)

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., (© 2024. The Author(s).)

Glucocorticoid-induced osteoporosis (GIOP) represents the most prevalent form of secondary osteoporosis. Aucubin (AU), a principal active component found in traditional herbal medicines such as Eucommia ulmoides, has been demonstrated to enhance osteoblast differentiation. Nonetheless, the precise therapeutic effects of AU on GIOP and the complex underlying regulatory mechanisms warrant further investigation. We first established a GIOP model in female mice and then assessed the therapeutic effects of AU using micro-CT analysis, biomechanical testing, measurements of serum calcium (Ca) and phosphorus (P) levels, and histological analyses using Hematoxylin and Eosin (HE) and Masson staining. Subsequently, non-targeted metabolomics was employed in order to study the effects of AU on serum metabolites in GIOP mice. The levels of the factors related to these metabolites were quantified using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot analyses. Finally, the effects of AU on osteoblastic and osteoclastic differentiation were examined. We found that AU significantly ameliorated bone microarchitecture and strength in GIOP mice. It mitigated pathological damages such as impairment of trabecular bone structure and reduction in collagen fibers, while concurrently elevating serum levels of Ca and P. Non-targeted metabolomics revealed that Arachidonic acid (AA) metabolism serves as a common pathway between the control and GIOP groups, as well as between the high-dose AU (AUH) and GIOP groups. AU notably upregulates prostaglandin-endoperoxide synthase 2 (PTGS2) and microsomal prostaglandin-E synthase 1 (PTGES) expression and downregulates prostaglandin-H2 D-isomerase (PTGDS) expression. Furthermore, AU treatment increased the expression of runt-related transcription factor 2 (Runx2) and transcription factor Sp7 (Osterix), enhanced serum alkaline phosphatase (ALP) activity, and reduced osteoclast expression. These results indicate that AU is a potential drug for treating GIOP, and its mechanism is related to regulating AA metabolism and promoting osteoblast differentiation. However, the key targets of AU in treating GIOP still need further exploration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Osteoporosis is a common condition worldwide, affecting millions of people. Women are more commonly affected than men, and the risk increases with age. Inflammatory reaction plays a crucial role in the expansion of osteoporosis. Osteoporosis is characterized by a gradual decline in bone density and bone tissue quality, which increases fragility and raises the risk of fractures. We scrutinized the anti-osteoporosis effect of hydroxysafflor yellow A (HYA) against glucocorticoid-induced osteoporosis (GIOP) in rats. In-silico study was carried out on EGFR receptor (PDBID: 1m17), Estrogen Alpha (PDB id: 2IOG), MTOR (PDB id: 4FA6), RANKL (PDB id: 1S55), and VEGFR2 (PDB id: 1YWN) protein. For this investigation, Sprague-Dawley (SD) rats were used, and they received an oral dose of HYA (5, 10, and 20 mg/kg, b.w.) along with a subcutaneous injection of dexamethasone (0.1 mg/kg/day) to induce osteoporosis. The biomechanical, bone parameters, antioxidant, cytokines, inflammatory, nutrients, hormones, and urine parameters were estimated. HYA treatment significantly suppressed the body weight and altered the organ weight. HYA treatment remarkably suppressed the level of alkaline phosphatase, acid phosphatase, and improved the level of bone mineral density (total, proximal, mild, and dis). HYA treatment restored the level of calcium (Ca), phosphorus (P), estradiol (E 2 ), and parathyroid hormone near to the normal level. HYA treatment remarkably altered the level of biomechanical parameters, antioxidant, cytokines, urine, and inflammatory parameters. HYA treatment altered the level of osteoprotegerin (OPG), receptor activator of nuclear factor kappa beta (RANKL) and RANKL/OPG ratio. The result clearly showed the anti-osteoporosis effect of HYA against GIOP-induced osteoporosis in rats via alteration of antioxidant, cytokines, inflammatory, and bone protective parameters., (© 2024 Wiley Periodicals LLC.)

Introduction: Bone homeostasis depends on the regulation of β-catenin in osteoblasts. Glucocorticoids (GCs) are known to diminish β-catenin activity via Wnt pathway signaling, leading to osteoporosis. Conversely, activating β-catenin in osteoblasts through mitogen-activated protein kinase kinase kinase 2 (Mekk2) offers an innovative approach to combat GC-induced osteoporosis (GIOP). Fufang Zhenshu Tiaozhi (FTZ) capsules have shown effectiveness in treating GIOP, but the mechanisms behind this are still unclear., Materials and Methods: In this study, Mekk2 knockout mice (Mekk2 -/- ) was generated by CRISPR/Cas9. These mice were then subjected to Alcian Blue-Alizarin Red staining and immunofluorescence to assess their bone and cartilage development. To establish models of GIOP, both Mekk2 -/- and wild-type (WT) mice were treated with dexamethasone (DXMS) and subsequently given FTZ capsules. We analyzed the resulting phenotypic changes in these mice using Micro-CT scans and histomorphological studies. Primary osteoblasts, isolated from both Mekk2 -/- and WT mice, underwent qRT-PCR to measure key osteogenesis markers, including Runx2, Sp7, Bgalp, Col1a1 and Alp. Cells were then exposed to treatments with either FTZ or Wnt3a and the phosphorylation levels of β-catenin and Mekk2, along with the protein expression of Runx2, were evaluated using Western blotting and immunoprecipitation. Additionally, C3H10T1/2 cells transfected with TOPflash-luciferase and Renilla luciferase reporters were treated with FTZ and Wnt3a to measure β-catenin activity., Results: In our study, administering FTZ in vivo effectively prevented bone loss typically induced by GCs. However, it's important to note that this protective effect was substantially reduced in mice lacking Mekk2. Additionally, FTZ showed a significant ability to enhance osteogenic differentiation in primary osteoblasts, doing so by altering the expression of Mekk2. Intriguingly, the impact of FTZ on Mekk2 appears to function through a pathway separate from the traditional Wnt signaling route. Furthermore, our findings indicate that FTZ also promotes the deubiquitination of β-catenin, contributing further to its positive effects on bone health., Conclusions: This study suggests that FTZ plays a significant role in protecting bone mass in cases of GIOP. The mechanism through which FTZ confers this benefit involves the activation of Mekk2/β-catenin signaling pathways, which represents a promising alternative strategy to counteract the deleterious effects of GIOP by augmenting osteoblastogenesis., (© 2024. The Japanese Society Bone and Mineral Research.)

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., (© 2024. The Author(s).)

Introduction: Currently, little is known regarding bone health surveillance for glucocorticoid-exposed non-infectious uveitis (NIU) patients or their baseline risks of skeletal fragility outcomes., Methods: Using claims data, we calculated rates of dual-energy x-ray absorptiometry (DXA) screening for glucocorticoid-exposed NIU and rheumatoid arthritis (RA) patients. Separately, we compared risks of skeletal fragility metrics amongst NIU patients, RA patients, and controls, independent of glucocorticoid use., Results: The adjusted hazard ratio (aHR) of NIU patients to have a DXA scan was 0.64 (95% CI, 0.63-0.65; p < .001) compared to RA patients. The aHR for any skeletal fragility outcome amongst NIU patients was 0.97 ( p < .02) compared to normal controls, while RA patients had excess risk (aHR, 1.15; p < .001)., Conclusions: NIU patients are 36% less likely to receive a DXA scan after high-dose glucocorticoid exposure compared with RA patients. No elevated risk of osteoporosis for NIU patients was found compared to normal controls.

Glucocorticoid-induced osteoporosis (GIOP) is the common reason for secondary osteoporosis. Dendrobine (DEN) is the major biologically active component of Dendrobium officinale with anti-inflammatory and antiaging properties. Whether DEN could alleviate osteogenic inhibition in GIOP rats is still unknown. The influence on osteogenic function caused by DEN on dexamethasone-treated bone marrow mesenchymal stem cells and rats was observed. The in vitro results showed that DEN reversed the inhibition of osteogenic differentiation by dexamethasone. Moreover, DEN supplementation attenuated dexamethasone-induced bone loss in vivo . DEN activated JNK and p38 MAPK pathways and restrained GR nuclear translocation, which could be prevented by the JNK (SP600125) or p38 (SB203580) pathway inhibitor. This study verified that DEN alleviated dexamethasone-induced nuclear translocation of GR, and inhibition of osteogenesis via JNK and p38 pathways, laying the foundation for DEN as a therapeutic agent for GIOP.

Glucocorticoids (GCs) are steroid hormones that are extensively used in the treatment of autoimmune diseases, inflammation, and cancer. The major ill effect of administering GCs is that it has a deleterious effect on bone, which leads to GC-induced osteoporosis. GC therapy induces bone loss and is associated with the risk of nonvertebral and vertebral fractures, as it works in combination by increasing bone reabsorption and suppressing bone formation during the initial phase of therapy. It is seen and established that GC in excess or in low dose for 3 months or more can be a risk factor for fracture, and the risk increases with an increase in dose and duration of usage. The most common cause of secondary osteoporosis is the administration of GC inside the body to treat various diseases. The degree of bone loss is directly proportional to the GC dose and the exposure duration. The first step is to evaluate the patients' risk factors for the development of glucocorticoids that induce osteoporosis, which include the dose, duration of use, patient age, sex, previous fractures, and other medical conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Osteoporotic fractures are a major complication of long-term glucocorticoid therapy. Glucocorticoids transiently increase bone resorption, but they predominantly inhibit bone formation and induce osteocyte apoptosis, leading to bone loss. Current treatments of glucocorticoid-induced osteoporosis aim mainly at reducing bone resorption and are, therefore, inadequate. We previously showed that signaling via the NO/cGMP/protein kinase G pathway plays a key role in skeletal homeostasis. Here, we show that pharmacological PKG activation with the guanylyl cyclase-1 activator cinaciguat or expression of a constitutively active, mutant PKG2R242Q restored proliferation, differentiation, and survival of primary mouse osteoblasts exposed to dexamethasone. Cinaciguat treatment of WT mice or osteoblast-specific expression of PKG2R242Q in transgenic mice prevented dexamethasone-induced loss of cortical bone mass and strength. These effects of cinaciguat and PKG2R242Q expression were due to preserved bone formation parameters and osteocyte survival. The basis for PKG2's effects appeared to be through recovery of Wnt/β-catenin signaling, which was suppressed by glucocorticoids but critical for proliferation, differentiation, and survival of osteoblast-lineage cells. Cinaciguat reduced dexamethasone activation of osteoclasts, but this did not occur in the PKG2R242Q transgenic mice, suggesting a minor role in osteoprotection. We propose that existing PKG-targeting drugs could represent a novel therapeutic approach to prevent glucocorticoid-induced osteoporosis.

Fractures often cause irreversible harm in Duchenne muscular dystrophy (DMD). This study investigated the trajectory of bone mineral density (BMD) using group-based trajectory modeling and identified that BMD acts as an early-stage indicator of clinically significant bone fragility. The greater the early-stage BMD, the better the 4-year bone health outcome., Purpose: Most Duchenne muscular dystrophy (DMD) children suffer bone loss after long-term glucocorticoid (GC) exposure, which induces scoliosis and fragility fractures. To assess the BMD progression pattern and individual medical risk markers for these phenotypes in young ambulatory boys with DMD, and provide evidence-based suggestions for clinical management of bone health., Methods: A retrospective longitudinal cohort study of 153 boys with DMD in West China Second University Hospital (2016-2023) was performed. Group-based trajectory modeling was used to study the BMD progression pattern, and potential predictors were further analyzed by logistic regression and survival analysis., Results: One hundred and fifty-three participants were included, 71 of which had more than 3 BMD records. Three BMD trajectories were identified. Baseline BMD and age-started GC and were independent predictors of trajectory attribution. The median survival time of the first observation of low BMD in GC-treated DMD boys was 5.32 (95% CI 4.05-6.59) years, and a significant difference was tested (P < 0.001) among the three trajectory groups., Conclusion: BMD may serve as a novel early indicating marker for monitoring bone fragility for DMD. We proposed a bone health risk stratification through BMD progression trajectory that allows us to adapt the osteoporosis warning sign in DMD from a fixed threshold approach to a more individualized strategy, where baseline BMD and age of glucocorticoid initiation can provide an earlier prediction of bone loss. Better management of primary BMD may be able to delay or avoid the onset of adverse bone health outcomes in the fifth year in children with DMD., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

For a wide range of chronic autoimmune and inflammatory diseases in both adults and children, synthetic glucocorticoids (GCs) are one of the most effective treatments. However, besides other adverse effects, GCs inhibit bone mass at multiple levels, and at different ages, especially in puberty. Although extensive studies have investigated the mechanism of GC-induced osteoporosis, their target cell populations still be obscure. Here, our data show that the osteoblast subpopulation among Gli1 + metaphyseal mesenchymal progenitors (MMPs) is responsive to GCs as indicated by lineage tracing and single-cell RNA sequencing experiments. Furthermore, the proliferation and differentiation of Gli1 + MMPs are both decreased, which may be because GCs impair the oxidative phosphorylation(OXPHOS) and aerobic glycolysis of Gli1 + MMPs. Teriparatide, as one of the potential treatments for GCs in bone mass, is sought to increase bone volume by increasing the proliferation and differentiation of Gli1 + MMPs in vivo. Notably, our data demonstrate teriparatide ameliorates GC-caused bone defects by targeting Gli1 + MMPs. Thus, Gli1 + MMPs will be the potential mesenchymal progenitors in response to diverse pharmaceutical administrations in regulating bone formation.

Objective. To provide a framework for healthcare professionals managing pediatric patients who are on active glucocorticoid (GC) therapy and to develop recommendations for the prevention and treatment of GC-induced osteoporosis in the pediatric population. Methods. A panel of experts on bone and pediatric diseases developed a series of PICO questions that address issues related to the prevention and treatment of osteoporosis in patients on GC therapy. In accordance with the GRADE approach, we conducted a systematic review of the literature, summarized effect estimations, and classified the quality of the evidence. Then, voting and the formulation of recommendations followed. Results. Seven recommendations and six general principles were developed for GC-induced osteoporosis in the pediatric population. Conclusion. These recommendations provide guidance for clinicians who must make decisions concerning pediatric patients undergoing treatment with GC., (Sociedad Argentina de Pediatría.)

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Context: Morroniside (MOR) possesses antiosteoporosis (OP) effects, but its molecular target and relevant mechanisms remain unknown., Objective: We investigated the effects of MOR on glucocorticoid-induced OP and osteoblastogenesis and its underlying mechanisms., Materials and Methods: The effects of MOR (10-100 μM) on the proliferation and differentiation of MC3T3-E1 cells were studied in vitro . The glucocorticoid-induced zebrafish OP model was treated with 10, 20 and 40 μM MOR for five days to evaluate its effects on vertebral bone density and related osteogenic markers. In addition, molecular targets prediction and molecular docking analysis were carried out to explore the binding interactions of MOR with the target proteins., Results: In cultured MC3T3 - E1 cells, 20 μM MOR significantly increased cell viability (1.64 ± 0.12 vs. 0.95 ± 0.16; p  < 0.01) and cell differentiation (1.57 ± 0.01 vs. 1.00 ± 0.04; p  < 0.01) compared to the control group. MOR treatment significantly ameliorated vertebral bone loss in the glucocorticoid-induced OP zebrafish model (0.86 ± 0.02 vs. 0.40 ± 0.03; p  < 0.01) and restored the expression of osteoblast-specific markers, including ALP, Runx2 and Col-І. Ligand-based target prediction and molecular docking revealed the binding interaction between MOR and the glucose pockets in sodium-glucose cotransporter 2 (SGLT2)., Discussion and Conclusions: These findings demonstrated that MOR treatment promoted osteoblastogenesis and ameliorated glucocorticoid-induced OP by targeting SGLT2, which may provide therapeutic potential in managing glucocorticoid-induced OP.

Mitochondrial dysfunction plays a crucial role in the development of glucocorticoid-induced osteoporosis (GIO). Cytidine monophosphate kinase 2 (Cmpk2), an essential mitochondria-associated gene, promotes the production of free mitochondrial DNA, which leads to the formation of inflammasome-mediated inflammatory factors. However, the specific role of Cmpk2 in GIO remains unclear. In this study, we report that glucocorticoids induce cellular senescence within the bone, particularly in bone marrow mesenchymal stem cells and preosteoblasts. We discovered that glucocorticoids cause mitochondrial dysfunction in preosteoblasts, increasing cellular senescence. Moreover, we observed elevated expression of Cmpk2 in preosteoblasts following glucocorticoid exposure. Inhibiting Cmpk2 expression alleviates glucocorticoid-induced cellular senescence and promotes osteogenic differentiation by improving mitochondrial function. Our study uncovers new mechanisms underlying glucocorticoid-induced senescence in stem cells and preosteoblasts, highlighting the potential of inhibiting the mitochondrial gene Cmpk2 to reduce senescence and enhance osteogenic differentiation. This finding offers a potential therapeutic approach for the treatment of GIO., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The research aimed to discuss the action mechanism of the treatment of glucocorticoid-induced osteoporosis (GIOP) by denshensu. In the research, 60 rats were purchased and divided into a control group, model group, estradiol group, and denshensu treatment group. Except for the control group, GIOP models were established for all other groups, and then the structural changes of osseous tissues as well as osteoprotegerin (OPG), expression of receptor activator of nuclear factor-κB ligands (RANKL) were detected. Besides, the changes in osteoclasts were observed by bone marrow-derived mononuclear phagocytes in vitro. The results showed that the micro-structure of bone trabeculae, bone mineral density (BMD), and bone metabolic markers of rats in the denshensu treatment group were enhanced significantly, while trabecular separation and structural model index were reduced (P<0.05). OPG messenger ribonucleic acid (mRNA) and protein levels in the hypothalamus and femur tissues were increased, while RANKL content was remarkably decreased (P<0.05). In addition, in vitro experiments revealed that denshensu inhibited the differentiation of positive osteoclasts, and osteoclast-related genes were reduced (P<0.05). To conclude, denshensu might inhibit the expressions of OPG and RANKL and further play a role in treating GIOP.

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 Ⅰ, 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)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier GmbH.)

Objective: The negative effects of glucocorticoids on bone depend on dose and treatment duration. However, it is unclear whether a safe dose exists, especially for patients with inflammatory rheumatic musculoskeletal diseases (iRMDs). We undertook this study to determine the effects of glucocorticoid doses on bone health in iRMD patients., Methods: We conducted a longitudinal cohort study on women with iRMD. Bone mineral density (BMD) and fractures were assessed prospectively and compared to a matched cohort without iRMD. Kaplan-Meier curves with log rank test were made for iRMD patients (stratified for glucocorticoid use and dose) and the matched cohort. Multivariable Cox regression survival models were also employed to analyze the effect of glucocorticoids on fracture., Results: A total of 884 women with iRMD and 1,766 controls (matched for age, T score, and 10-year fracture risk) were included in the study and followed up for up to 6 years. BMD decreased significantly in all patients receiving glucocorticoids who were not receiving anti-osteoporosis treatment (-4.26% for ≥5 mg/day of prednisone equivalent, P = 0.0011; -4.23% for 2.5-5 mg/day, P = 0.0422; -2.66% for 0-2.5 mg/day, P = 0.0006). Anti-osteoporosis treatment (largely bisphosphonates) prevented bone loss only in patients receiving <5 mg/day of prednisone equivalent. Fracture incidence was higher in patients with iRMD compared to controls, but only glucocorticoid doses ≥5 mg/day were associated with significantly higher risk of fracture., Conclusion: Glucocorticoid doses as low as 2.5 mg/day were associated with BMD loss in iRMD patients, but this effect was preventable. BMD loss in patients receiving ≥5 mg/day was not totally prevented by anti-osteoporosis medications currently used in clinical practice, resulting in higher risk of fracture., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: The aim of this study was to provide an evidence-based framework to guide health care professionals treating patients under glucocorticoid (GC) therapy and develop guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis (GIO) in postmenopausal women and men aged ≥50 years., Methods: An expert panel on bone diseases designed a series of clinically meaningful questions following the PICO (Population, Intervention, Comparator, and Outcome) structure. Using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology, we made a systematic literature review, extracted and summarized the effect estimates, and graded the quality of the evidence. The expert panel voted each PICO question and made recommendations after reaching an agreement of at least 70%., Results: Seventeen recommendations (9 strong and 8 conditional) and 8 general principles were developed for postmenopausal women and men aged ≥50 years under GC treatment. Bone mineral density (BMD), occurrence of fragility fractures, probability of fracture at 10 years by Fracture Risk Assessment Tool, and other screening factors for low BMD are recommended for patient evaluation and stratification according to fragility fracture risk. The treatment of patients under GC therapy should include counseling on lifestyle habits and strict control of comorbidities. The goal of GIO treatment is the nonoccurrence of new fragility fractures as well as to increase or maintain BMD in certain clinical situations. This was considered for the therapeutic approach in different clinical scenarios., Conclusions: This GIO guideline provides evidence-based guidance for health care providers treating patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

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.

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., (© 2023. The Author(s).)

Purpose of Review: This review seeks to summarize the literature relevant to the treatment of glucocorticoid-induced osteoporosis in premenopausal women; an issue commonly encountered by rheumatologists and yet lacking good clinical practice guidelines., Recent Findings: Although most of the relevant literature on osteoporosis includes postmenopausal women only, data from both randomized controlled trials and case reports suggest bisphosphonates can be an effective and well tolerated treatment for premenopausal patients. Data for other medications to treat premenopausal osteoporosis is less robust., Summary: The use of bisphosphonates in young women may be safer than initially thought and should likely be used for the treatment of glucocorticoid-induced osteoporosis in rheumatology clinics. Further research is needed to continue to understand long-term risk., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To explore pathogenesis of glucocortocoid-induced osteoporosis(GIOP) based on label-free mass proteomics., Methods: Twevle female Sprague-Dawley(SD) rats were randomly divided into two groups, named as sham group and GIOP group. After one-week adaptive feeding, the rats of GIOP group were administered with dexamethasone via intramuscular injection according to 2.5 mg/kg weighting, while the rats of sham group were administered with the same amount of saline, twice a week. The tibias of each group were collected after 8-week modeling and made pathological sections to confirm the success of modeling. Three samples of each group were picked up to perform label-free mass proteomics. After quality control, differentially expressed proteins were identified according to qualitative and quantitative analyses. Then gene ontology(GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, cluster analysis as well as protein-protein interaction analysis were performed using bioinformatics analysis., Results: Compared with sham group, the structure of bone trabecular in GIOP group showed abnormal arrangement, uneven distribution and obvious fragmentation, which could demonstrate successful modeling. A total of 47 differentially expressed proteins (DEPs) were identified including 20 up-regulated and 27 down-regulated proteins. The expression of protein nucleophosmin 1(NPM1), adipocyte plasma membrane associated protein (APMAP), cytochromec oxidase subunit 6A1 (COX6A1) and tartrate-resistant acid phosphatase (ACP5) showed a significant difference between two groups. KEGG results showed DEPs were enriched on metabolism-related pathways, immune-related pathways and AMP-activated kinase (AMPK) signaling pathway., Conclusion: Protein NPM1, APMAP, COX6A1 and ACP5 showed a close relationship with pathogenesis of GIOP, which could serve as potential biomarkers of GIOP. AMPK signaling pathway played an important role in the occurrence and development of GIOP, which could be regarded as potential signaling pathway to treatment GIOP.

Glucocorticoid (GC) is one of the most prescribed medicines to treat various inflammatory and autoimmune diseases. However, high doses and long-term use of GCs lead to multiple adverse effects, particularly glucocorticoid-induced osteoporosis (GIO). Excessive GCs exert detrimental effects on bone cells, including osteoblasts, osteoclasts, and osteocytes, leading to impaired bone formation and resorption. The actions of exogenous GCs are considered to be strongly cell-type and dose dependent. GC excess inhibits the proliferation and differentiation of osteoblasts and enhances the apoptosis of osteoblasts and osteocytes, eventually contributing to reduced bone formation. Effects of GC excess on osteoclasts mainly include enhanced osteoclastogenesis, increased lifespan and number of mature osteoclasts, and diminished osteoclast apoptosis, which result in increased bone resorption. Furthermore, GCs have an impact on the secretion of bone cells, subsequently disturbing the process of osteoblastogenesis and osteoclastogenesis. This review provides timely update and summary of recent discoveries in the field of GIO, with a particular focus on the effects of exogenous GCs on bone cells and the crosstalk among them under GC excess., Competing Interests: Declaration of Competing Interest All authors disclose no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Osteoporosis is a common consequence of long-term oral glucocorticoid therapy and the resulting fractures cause significant morbidity. Bone loss occurs rapidly after initiation of glucocorticoid therapy; the accompanying increase in risk of fracture is dose-dependent and occurs within a few months of starting therapy. The adverse effects of glucocorticoids on bone are mediated by inhibition of bone formation accompanied by an early but transient increase in bone resorption, due both to direct and indirect effects on bone remodelling. Fracture risk assessment should be performed as soon as possible after long-term glucocorticoid therapy (≥3 months) is initiated. FRAX can be adjusted for the dose of prednisolone but does not currently take fracture site, recency, or number into account and therefore may underestimate fracture risk, particularly in individuals with morphometric vertebral fractures. Vertebral fracture assessment should therefore be regarded as a routine part of fracture risk estimation in individuals receiving long-term glucocorticoid therapy. Bone protective therapy should be started promptly in individuals at high-risk, together with calcium and vitamin D supplements. Bisphosphonates are generally regarded as first-line options on the grounds of their low cost, but anabolic therapy should be considered as an alternative first-line option in very high-risk individuals., Competing Interests: Conflicts of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology.)

Allolobophora calignosa (Ac) is a folk medicine for millennia, as it possesses many biological activities. This study aimed to investigate the chemo-preventive activity of A.calignosa coelomic fluid (AcCF) and A.calignosa extract (AcE) on glucocorticoid-induced osteoporosis (GIOP) in mice. Characterization and in vitro biological activity of AcE and AcCF has been assessed. Male CD-1 mice were subcutaneously received dexamethasone (DEX) (1 mg/kg, 5 times/week) and concurrently intraperitoneally treated with either AcCF (20 mg/kg) or AcE (45 mg/kg) every other day for 28 days. Serum and bone homogenates were subjected for qPCR and biochemical analysis. AcE and AcCF treatment significantly increased bone mineral density (BMD), bone mineral content (BMC), calcium (Ca), phosphorus (P), and calcitonin levels, whereas activity of serum alkaline phosphatase (ALP), bone alkaline phosphatase (BALP), serum acidic phosphatase (ACP), bone acidic phosphatase (BACP) and parathyroid hormone (PTH) levels were significantly reduced compare with untreated GIOP mice. Treatment with AcE and AcCF modulates oxidative stress and downregulated Rank and Mmp9 expression, as well as increased glycosaminoglycan content in the organic bone matrix, resulting in osteoclastogenesis inhibition. Overall, AcCF and AcE show a chemo-preventive activity against GIOP by inhibiting oxidative stress and regulating expression and/or activity of osteoblast/osteoclast-related markers., (© 2023. The Author(s).)

The widespread use of therapeutic glucocorticoids has increased the incidences of glucocorticoid-induced osteoporosis (GIOP). Oxidative stress and mitochondrial dysfunction are major causes of GIOP; therefore, alleviation of excess oxidative stress in osteoblasts is a potential therapeutic strategy for osteoporosis. Exosomes derived from ADSCs (ADSCs-Exos), as novel cell-free therapeutics, can modulate various biological processes, such as immunomodulation, reduce oxidative damage, and promote tissue repair as well as regeneration. In this study, ADSCs-Exos restored the viability and osteogenic potential of MC3T3-E1 cells by attenuating apoptosis, oxidative damage, intracellular ROS generation, and mitochondrial dysfunction. Moreover, after pretreatment with ADSCs-Exos, Nrf2 expressions were upregulated in Dex-stimulated osteoblasts. Inhibitory assays showed that silencing Nrf2 partially eliminated the protective effects of ADSCs-Exos. The rat model assays confirmed that ADSCs-Exos alleviated the Dex-induced increase in oxidation levels, restored bone mass of the distal femur, and increased the expressions of Nrf2 and osteogenic markers in bone tissues. Thus, ADSCs-Exos alleviated apoptosis and oxidative stress by regulating Nrf2/HO-1 expressions after Dex and prevented the development of GIOP in vivo., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2023 Xue-wei Yao et al.)

Context: Gu-Shu-Kang (GSK) is a clinical traditional Chinese medicine prescription for the treatment of primary osteoporosis., Objective: This study investigates the protection of GSK against dexamethasone (Dex)-induced disturbance of musculoskeletal system in male mice and to identify the underlying mechanism., Materials and Methods: Male C57BL/6 mice in Dex-treated groups were orally administered (i.g.) with vehicle, low dose (0.38 g/kg), middle dose (0.76 g/kg), or high dose (1.52 g/kg) of GSK for 8 weeks. A control group was designed without any treatment. The quadriceps femoris, tibialis anterior and gastrocnemius were harvested. Molecular expression was determined by RT-PCR and immunoblotting., Results: Treatment with GSK enhanced weight-loaded swimming time (from 411.7 ± 58.4 s in Dex group to 771.4 ± 87.3 s in GSK-M) and grip strength (from 357.8 ± 23.9 g in Dex group to 880.3 ± 47.6 g in GSK-M). GSK produced a rise in cross-sectional area of myofibers and promoted a switching of glycolytic-to-oxidative myofiber. The administration with GSK affected expression of muscle regulatory factors shown by the down-regulation in MuRF-1 and atrogin-1 and the up-regulation in myogenic differentiation factor (MyoD) and myosin heavy chain (MHC). GSK stimulated tissue IGF-1 signalling pathway (IGF-1R/PI3K/Akt), not only in skeletal muscle but also in bone associated with the amelioration of trabecular bone mineral density and the improvement of osteogenesis., Conclusions: These findings revealed the potential mechanisms involved in the beneficial effects of Gu-Shu-Kang on musculoskeletal system in mice with challenging to dexamethasone, and this prescription may have applications in management for muscle atrophy and osteoporosis triggered by glucocorticoid.

Long-term exposure to glucocorticoid (GC) contributes to the development of osteoporosis (OP), which is correlated with the risk of fracture. Pathologically, GC-induced bone loss is associated with osteoblast apoptosis. Geniposide (GEN), a natural occurring compound derived from Eucommia ulmoides, has been reported to ameliorate dexamethasone (DEX)-induced OP. Our previous study shows that GEN exhibits protective activity against DEX-induced OP by attenuating endoplasmic reticulum stress and decreasing apoptosis in osteoblasts. However, the molecular mechanisms of GEN in inhibiting DEX-induced osteoblast apoptosis still need further elucidation. In this article, a molecular target network of GEN against OP was screened. It was found that GEN might interact with OP by mediating PI3K/AKT pathway, which is the upstream factor in regulating autophagy. GEN exhibited protective activity against DEX-induced apoptosis by activating autophagy in vivo and in vitro. Blockage of autophagy, activation of PI3K/AKT/mTOR pathway, or inhibition of GLP-1R activity could eliminate the protective effects of GEN against DEX-induced apoptosis. Collectively, GEN ameliorated DEX-induced osteoblast apoptosis by activating autophagy through GLP-1R/PI3K/AKT/mTOR pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chronic glucocorticoid (GC) therapy is the most common cause of iatrogenic osteoporosis and represents an important risk factor for osteoporosis and bone fractures. New therapeutic approaches are required in order to treat osteoporosis and reduce the side effects related to the use of anti-osteoporotic drugs. In this context, previous studies reported the efficacy of some isoflavones and carotenoids, such as lycopene and genistein, on the reduction of the risk of fracture related to osteoporosis. The aim of this study was to investigate the effects of a combined oral treatment, consisting of genistein and lycopene, in an experimental model of glucocorticoid-induced osteoporosis (GIO). GIO was induced by subcutaneous injection of methylprednisolone (MP, 30 mg/kg) for 60 days, whereas the control group (Sham) received saline solution only. Following induction, MP animals randomly were assigned to receive alendronate, genistein, lycopene, or the association of genistein and lycopene or saline solution for additional 60 days together with MP. Femurs obtained from the Sham group were used for osteoblasts extraction; they were then incubated with dexamethasone (DEX) for 24 h to be then treated with lycopene or genistein or the association of lycopene and genistein for an additional 24 h. Treatments with lycopene and genistein restored the impaired mineralization of cells observed following DEX treatment and stimulated osteoblast differentiation by increasing the depressed expression of bALP and RUNX2 (p < 0.0001). Wnt5a, β-catenin, and Nrf-2 expression were significantly increased following genistein and lycopene treatment (p < 0.0001), thus confirming their antioxidant activity as well as their ability in stimulating osteoblast function, mostly when genistein and lycopene were used in association. The combined treatment of genistein and lycopene improved the bone damage induced by glucocorticoids and significantly restored the normal architecture of bones as well as adequate interconnectivity of bone trabeculae, thus increasing bone mineral density parameters. The obtained data demonstrated that genistein and lycopene but in particular their association might prevent GC’s adverse effects, thus stimulating bone formation and reducing bone resorption, improving bone structure and microarchitecture, through different molecular pathways, such as the Wnt/β-catenin and the Nrf-2 signaling.

The long-term treatment of glucocorticoids is a common cause of osteoporosis (OP). This study concentrated on inquiring into the regulatory role and potential mechanisms of TRG-AS1 on dexamethasone (Dex)-induced OP in rats. We adopted Dex to treat rat osteoblasts and rats to simulate in-vitro and in-vivo OP models, respectively. Gain-of-function assays of TRG-AS1, miR-802 and CAB39 were constructed in rat osteoblasts to make certain the influence of TRG-AS1, miR-802 and CAB39 on differentiation, proliferation and apoptosis of rat osteoblasts. TRG-AS1 and CAB39 were down-regulated in the Dex-induced OP model in rats, in contrast to miR-802. Overexpression of TRG-AS1 restrained Dex-induced inhibition of osteogenic differentiation, promoted CAB39/AMPK/SIRT-1 and inhibited NF-κB, while overexpression of miR-802 bridled the inhibitory effect of TRG-AS1 on OP. miR-802 was targeted by TRG-AS1, and inhibited CAB39. Inhibition of either AMPK or SIRT-1 abated the osteogenic differentiation-promoting effect of CAB39. Animal experiments displayed that overexpressing TRG-AS1 alleviated Dex-induced OP in rats. In conclusion, up-regulation of TRG-AS1 protected against glucocorticoid-induced OP in rats by modulating the miR-802-mediated CAB39/AMPK/SIRT-1/NF-κB axis., (© 2022. The Author(s) under exclusive licence to Japan Human Cell Society.)

Background: Glucocorticoids (GCs) induce osteoporosis, which results in fractures in the bond, causing significant morbidity. In the conducted study, we examined the antiosteoporosis effect of dieckol against GC-induced osteoporosis in rats., Methods: Sprague-Dawley (SD) rats were used for the current study and dexamethasone (2.5 mg/kg) induced osteoporosis in the rats that received the dieckol (test) and alendronate (standard) for 20 weeks. Bone turnover parameters, microCT, antioxidant, inflammatory cytokines, nutrient, and hormones parameters., Results: Dieckol noticeably suppressed the body weight and boosted the uterine and vagina weight. Dieckol considerably altered the level of trabecular number (Tb. N), the bone volume to total volume (BV/TV), trabecular separation (Tb.Sp), bone surface to bone volume (BS/BV), and t​r​a​b​e​c​u​l​a​r thickness (Tb.Th). Dieckol noticeably (P < 0.001) elevated the level of osteocalcin (OC) and alleviated the level of bone Gla protein (BGP), acid phosphatase (ACP), alkaline phosphatase (ALP), and β-CTx. Dieckol markedly boosted the level of malondialdehyde (MDA) and suppressed the level of glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) along with the suppression of inflammatory cytokines like TNF-α, IL-1β, and IL-6. Dieckol remarkably increased the level of calcium, potassium, magnesium, and 25 (OH) vitamin D. Dieckol substantially (P < 0.001) boosted the level of estradiol and alleviated the level of parathyroid hormone and tartrate-resistant acid phosphatase (TRAP). Dieckol also suppressed the level of receptor activator of nuclear factor κB ligand (RANKL) and boosted the level of osteoprotegerin (OPG)., Conclusion: Taken together, our data suggest that dieckol demonstrated the anti-osteoporosis effect against GC-induced osteoporosis in rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Yang and Chao.)

Introduction: Glucocorticoid-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis. Although many studies related to GIOP have been published, there was no bibliometric analysis in this field. This study aimed to investigate the research trends on GIOP by using bibliometric analysis., Materials and Methods: All data were collected from the Web of Science Core Collection (WoSCC). All original research articles regarding GIOP from 2012 to 2021 were retrieved. CiteSpace was used to analyze the distribution of countries, institutions, journals, authors, and keywords. We revealed hotspots and trends in the field by drawing co-occurrence keyword maps and identifying burst keywords., Results: From 2012 to 2021, 685 relevant articles were published, with a peak in 2018 in the annual number of publications. China and McMaster University were the leading country and institution in this field with 208 and 12 publications, respectively. Osteoporosis International was the journal with the most studies, while Journal of Bone and Mineral Research was the most cited journal. "Bone mineral density", "fracture", "postmenopausal women", "prevention" and "therapy" were the most high-frequency keywords, while "bone mineral density", "bisphosphonate" and "metabolism" were the top high-centrality keywords., Conclusion: The results from this bibliometric study provided insight into the status and research trends in GIOP of the past decade, which could help researchers quickly determine the current hotspots and frontier trends in this field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Feng, Li, Tu and Li.)

Classical monocytes are commonly involved in the innate inflammatory response and are the progenitors of osteoclasts. Excess endogenous glucocorticoids (GCs) can increase the levels of classical monocytes in blood and bone marrow. The role of this cell population in high-dose exogenous GC-induced osteoporosis (GIOP) remains to be elucidated. In this study, GIOP was established in rats and mice by daily methylprednisolone injection, and monocyte subsets were analyzed by flow cytometry. We demonstrated that classical monocytes accumulate in bone marrow during GIOP. Similarly, the monocyte proportion among bone marrow nucleated cells was also increased in patients with steroid treatment history. We sorted classical monocytes and analyzed their transcriptional profile in response to GCs by RNA sequencing. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that classical monocytes isolated from GC-treated rats exhibited osteoclast differentiation potential. Deletion of classical monocytes by clodronate liposome treatment prevented GIOP via inhibition of osteoclastogenesis and restoration of CD31 Hi endomucin Hi vessels. Regarding the molecular mechanism, classical monocytes express high levels of glucocorticoid receptors. In vitro treatment with GCs increased both the percentage and absolute number of monocytes and promoted their proliferation. In summary, classical monocytes mediated GC-induced bone loss and are a potential target for therapeutic intervention in GIOP treatment., (© 2022. The Author(s).)

Objective: Glucocorticoids constitute a considerable risk for developing osteoporosis in both younger and older adults. However, currently available bone imaging modalities and fracture-risk assessment tools do not adequately capture the dramatic changes in bone microarchitecture, heterogeneity of glucocorticoid exposure, the impact of chronic disease and other osteoporosis risk factors on the assessment of osteoporosis in these individuals., Design: A narrative review is presented, following a systematic search of the literature from 2000 to 2021., Results: Our current appreciation of glucocorticoid-induced osteoporosis (GIO) is focused on older populations, with limited evidence to guide the investigation, risk assessment and treatment in premenopausal women and men less than 50 years. The impact of the underlying chronic disease on secondary osteoporosis in these younger adults is also poorly understood., Conclusion: Through this narrative review, we provide a comprehensive overview of and recommendations for optimising the management of this common cause of secondary osteoporosis younger and older adults., (© 2021 John Wiley & Sons Ltd.)

Objective: In traditional Chinese medicine, the herbal pair, Radix Achyranthis Bidentatae (RAB) and Eucommiae Cortex (EC), is widely used to treat osteoporosis. Herein, we determined whether this herbal pair can be used to ameliorate glucocorticoid (GC)-induced osteoporosis (GIOP) and find its optimal dosage in zebrafish., Methods: The characteristics of the aqueous extract of RAB and EC were separately characterized using high-performance liquid chromatography. Osteoporosis was induced in 5-day post-fertilization zebrafish larvae by exposing them to 10 μmol/L dexamethasone (Dex) for 96 h. Seven combinations of different ratios of RAB and EC were co-administered. Treatment efficacy was determined by calculating zebrafish vertebral area and sum brightness, via alizarin red staining, and by detecting alkaline phosphatase (ALP) activity. Multiple regression analysis was conducted to test the optimal dosage ratio., Results: According to the Chinese Pharmacopoeia (2015), β-ecdysone (β-Ecd) is a major bioactive marker in RAB extract, while pinoresinol diglucoside (PDG) is the major marker in EC extract. Both of β-Ecd and PDG content values aligned with the Chinese Pharmacopoeia standards. Treatment with 10 μmol/L Dex reduced zebrafish vertebral area, sum brightness, and ALP activity, but RAB and EC attenuated these effects. Combining 50 µg/mL RAB and 50 µg/mL EC was optimal for preventing GIOP in zebrafish. Reverse transcription-quantitative polymerase chain reaction was used to evaluate the mRNA expression of osteogenesis-related genes. A treatment of 10 μmol/L Dex decreased runt-related transcription factor 2 (Runx2), osteogenic protein-1 (OP-1), bone γ-carboxyglutamic acid-containing protein (BGLAP), and β-catenin levels. This effect was counteracted by RAB and EC co-treatment (P < 0.05). Additionally, the effect of using the two herbal extracts together was better than single-herb treatments separately. These results demonstrated that RAB and EC preserve osteoblast function in the presence of GC. The best mass ratio was 1:1., Conclusion: RAB and EC herbal pair could ameliorate GC-induced effects in zebrafish, with 1:1 as the optimal dosage ratio., (Copyright © 2022 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)

Epidemiological investigations have shown that individuals treated with dexamethasone during pregnancy have an increased risk of osteoporosis after birth. Our studies reported that peak bone mass was decreased in the prenatal dexamethasone exposure (PDE) offspring before chronic stress, while further decrease was observed after chronic stress. Simultaneously, increase of bone local active corticosterone was observed in the PDE offspring, while further increase was also observed after chronic stress. Moreover, the histone H3 lysine 9 acetylation (H3K9ac) level of 11-beta hydroxysteroid dehydrogenase 2 (11β-HSD2) and its expression in bone tissue of PDE offspring rats remained lower than the control before and after birth. Injection of 11β-HSD2 overexpression lentivirus into the bone marrow cavity could partially alleviate the accumulation of bone local active corticosterone and bone loss induced by PDE. In vitro, dexamethasone inhibited the expression of 11β-HSD2 and aggravated the inhibitory effect of corticosterone on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Overexpression of 11β-HSD2 partially alleviated the inhibitory effect of corticosterone. Moreover, dexamethasone promoted the nuclear translocation of glucocorticoid receptor (GR), which resulted in the stimulation of 11β-HSD2 expression due to the binding of GR to the 11β-HSD2 promoter region directly, as well as increasing H3K9ac level in the 11β-HSD2 promoter region by recruiting histone deacetylase 11 (HDAC11). Our results indicated that low expression of 11β-HSD2 in bone tissue is an important mediator for the high susceptibility to osteoporosis in PDE adult offspring., (Copyright © 2021. Published by Elsevier Ltd.)

Clinical and experimental data have shown that prolonged exposure to GCs leads to bone loss and increases fracture risk. Special attention has been given to existing emerging drugs that can prevent and treat glucocorticoid-induced osteoporosis GIOP. However, there is no consensus about the most relevant animal model treatments on GIOP. In this systematic review, we aimed to examine animal models of GIOP centering on study design, drug dose, timing and size of the experimental groups, allocation concealment, and outcome measures. The present review was written according to the PRISMA 2020 statement. Literature searches were performed in the PubMed electronic database via Mesh with the publication date set between April, 2011, and February 2021. A total of 284 full-text articles were screened and 53 were analyzed. The most common animal species used to model GIOP were rats (66%) and mice (32%). In mice studies, males (58%) were preferred and genetically modified animals accounted for 28%. Our work calls for a standardization of the establishment of the GIOP animal model with better precision for model selection. A described reporting design, conduction, and selection of outcome measures are recommended.

Glucocorticoid-induced osteoporosis (GIOP) leads to fractures in up to 40% of patients with chronic glucocorticoid (GC) therapy when left untreated. GCs rapidly increase fracture risk, and thus many patients with anticipated chronic GC exposures should start anti-osteoporosis pharmacotherapy to prevent fractures. In addition to low awareness of the need for anti-osteoporosis therapy among clinicians treating patients with GCs, a major barrier to prevention of fractures from GIOP is a lack of clear guideline recommendations on when to start and stop anti-osteoporosis treatment in patients with GC use. The aim of this narrative review is to summarize current evidence and provide considerations for the duration of anti-osteoporosis treatment in patients taking GCs based on pre-clinical, clinical, epidemiologic, and pharmacologic evidence. We review the pathophysiology of GIOP, outline current guideline recommendations on initiating and stopping anti-osteoporosis therapy for GIOP, and present considerations for the duration of anti-osteoporosis treatment based on existing evidence. In each section, we illustrate major points through a patient case example. Finally, we conclude with proposed areas for future research and emerging areas of interest related to GIOP clinical management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hayes, Baschant, Hauser, Burden and Winter.)

Glucocorticoid-induced osteoporosis (GIOP) is one of the side effects associated with glucocorticoid (GC) therapy. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) provided new guidelines for the management and treatment of GIOP. The aim of the present study was to clarify the prevalence of patients with rheumatoid arthritis (RA) requiring treatment according to the new guidelines and to identify risk factors associated with lack of treatment in these patients. Patients in the 2018 Akita Orthopedic group on Rheumatoid Arthritis (AORA) database were enrolled. Of 2,234 patients with RA in the database, 683 (30.6%) met the 2014 JSBMR guideline treatment criteria, and 480 (70.3%) had been treated. The untreated group included a larger number of males, younger patients, and patients treated in clinics rather than hospital (p<0.001, p=0.015, and p<0.001, respectively). Multivariate analyses found that male sex, younger age, and clinic-based RA care were significant risk factors associated with lack of treatment (p<0.001, p=0.013, and p<0.001, respectively). Thus, male sex, younger age, and clinic-based care were identified as risk factors., Competing Interests: No potential conflict of interest relevant to this article was reported.