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Kidney transplant (KT) requires long‐term glucocorticoid (GC) treatment against acute and/or chronic rejection. Glucocorticoid‐induced osteoporosis (GIOP) is one of the major concerns in kidney transplant recipients (KTRs). Therefore, it is essential to accumulate GIOP data from paediatric KTRs to aid in their healthy growth. A serial observational study of bone strength was carried out in an 8‐year‐old girl with bilateral hypoplastic kidney who underwent ABO‐compatible living‐donor KT and GC treatment over 2 years. Bone strength was evaluated by bone mineral density (BMD) and serum bone turnover markers (BTMs), including serum alkaline phosphatase (S‐ALP), serum tartrate‐resistant acid phosphatase 5b (S‐TRACP‐5b), and serum undercarboxylated osteocalcin (S‐ucOC). All the levels of BTMs and BMD from 1 M to 4 M remained lower than the levels at 0 months (0 M: baseline). After gradual reduction of GC dose (4 M–24 M), S‐ALP levels increased from baseline and S‐TRACP‐5b levels remained lower than the baseline level, but BMD recovered to baseline and increased. The S‐ucOC levels did not increase from baseline. The patient's height growth velocity SDS was +3.99 for 23 months, and no fracture occurred during this observation period. A consistent, predominantly formative state of bone, which maintained higher S‐ALP levels and lower S‐TRACP‐5b levels compared to baseline, could contribute to increased BMD. In addition, no increase in S‐ucOC levels from baseline could be associated with no deterioration of bone strength. This case suggests that measurement of BMD and, S‐ALP, TRACP‐5b and ucOC could be useful for evaluating the trend on bone strength in a paediatric KTR. [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]

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]

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]

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]

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]

Administration of glucocorticoids is an effective strategy for treating many inflammatory and autoimmune diseases. However, glucocorticoid treatment can have adverse effects on bone, leading to glucocorticoid‐induced osteoporosis (GIO), the most common form of secondary osteoporosis. Although the pathogenesis of GIO has been studied for decades, over the past ten years the autophagy machinery has been implicated as a novel mechanism. Autophagy in osteoblasts, osteocytes, and osteoclasts plays a critical role in the maintenance of bone homeostasis. Herein, we specifically discuss how osteoblast autophagy responds to glucocorticoids and its role in the development of GIO. Although the pathogenesis of glucocorticoid‐induced osteoporosis (GIO) has been studied for decades, over the past ten years the autophagy machinery has been implicated as a novel mechanism. Autophagy in osteoblasts, osteocytes, and osteoclasts plays a critical role in the maintenance of bone homeostasis. Herein, we specifically discuss how osteoblast autophagy responds to glucocorticoids and its role in the development of GIO. [ABSTRACT FROM AUTHOR]

Objective: To determine the signaling pathways mediated by teriparatide in MLO‐Y4 cell lines based on the evaluation of reactive oxygen species (ROS) through AKT pathways, which regulate apoptosis of bone cells. Methods: We performed the DCFH‐DA assay to investigate the role of ROS in MLO‐Y4 cells caused by dexamethasone (Dex). Four groups were included: Dex group, Dex+NAC, Dex+ teriparatide group and control group (without any dispose). Real‐time reverse transcriptase polymerase chain reaction was used to test the SOD2 and Cat mRNA expression. Western blot (WB) was used to investigate the AKT and caspase‐3 protein expression. A Cell Counting Kit‐8 (CCK‐8) assay test was conducted to explore the cell viability, and we also studied the apoptosis through western blot assay. A glucocorticoid‐induced osteoporosis (GIOP) model was used to confirm the anti‐ROS and anti‐apoptosis ability of teriparatide. Results: The CCK‐8 assay revealed that Dex reduced the proliferative capability of cells significantly, whereas incubation with teriparatide resulted in a remarkable increase in the proliferation of osteocytes. In addition, teriparatide can rescue the effect of inhibiting cell proliferation due to Dex treatment. Immunofluorescence analysis showed that ROS levels increased in Dex‐treated MLO‐Y4 cells when compared with control groups. However, the Dex+Teriparatide group showed less ROS when compared with the Dex group. The expression of Sod2 and Cat, two antioxidant enzymes crucial for ROS elimination, was decreased in the Dex group, indicating a defect of the enzymatic antioxidant system. Compared to the Dex group, incubation with teriparatide resulted in a significant decrease in caspase‐3 level; when compared with the control group, the caspase‐3 level was not significantly different, indicating that teriparatide can rescue apoptosis during Dex exposure. Moreover, teriparatide promotes the expression of AKT, and rescues the apoptosis effect caused by Dex. The results of immunofluorescence also showed that Akt was highly expressed in the teriparatide group when compared with the Dex group. The microstructural parameters Tb.Th, BV/TV, and Tb.N in the methylprednisolone (MPS) group were markedly reduced compared with the control group, but additional treatment with teriparatide could remarkably reverse the methylprednisolone‐induced reduction of these parameters. Moreover, the parameter Tb.Sp was significantly increased in the methylprednisolone group compared to the control group, and this increase could be inhibited by teriparatide. Conclusions: Teriparatide can reduce the cellular ROS level caused by glucocorticoids to facilitate the proliferation of osteocytes through activating the AKT pathway. Meanwhile, the activated AKT can inhibit the activity of proteolytic enzyme caspase‐3 and prevent the activation of apoptosis cascade. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Glucocorticoid therapy is associated with an appreciable risk of bone loss leading to fractures that require expensive treatments. This study aimed to evaluate the cost‐effectiveness of bisphosphonates for prevention of hip fracture in glucocorticoid‐induced osteoporosis (GIOP) in Malaysia. Method: Retrospective data were collected from GIOP patients referred to the Universiti Kebangsaan Malaysia Medical Centre. Fracture events and direct medical costs were compared between bisphosphonates and calcium/vitamin D combination. Results: Fracture events were reported in 28 out of 93 included patients, with hip and vertebral fractures representing 42.9% and 35.7%, respectively. Overall, the use of bisphosphonates could not be considered cost‐effective for treatment of all GIOP patients. The presence of certain fracture risk factors was able to modify the cost‐effectiveness of bisphosphonates. Bisphosphonates was considered cost‐effective if started in patients more than 60 years old. However, the use of bisphosphonates was not cost‐effective in GIOP patients with secondary osteoporosis. The incremental cost‐effectiveness ratios (ICER) of bisphosphonates in patients with risk factors of previous fracture or rheumatoid arthritis were Malaysian Ringgits (MYR) 108 603.40 and MYR 25 699.21, respectively. Conclusion: Fracture risk factors of age, previous fracture, rheumatoid arthritis and secondary osteoporosis may modify the cost‐effectiveness outcomes of bisphosphonates. Bisphosphonates would be considered cost‐effective in patients more than 60 years old as compared to calcium/vitamin D treatments. Further evaluation of the impact of fracture risk factors in larger populations would provide more precise information to better assist rational and economical use of anti‐osteoporosis treatment in GIOP patients. [ABSTRACT FROM AUTHOR]

Long-term effects of glucocorticoid treatment in humans induce bone loss and increase the risk of fracture in the skeleton. The pathogenic mechanisms of glucocorticoid-induced osteoporosis ( GIOP) are still unclear. The GIOP and its effects have been reproduced in several animal models including Danio rerio (zebrafish) embryo. The treatment of adult fish with prednisolone ( PN) has shown a dose-dependent decrease of mineralized matrix in the scales. Large resorption lacunae are characterized by single TRAP-positive cells which migrate to the margin of the scale merging into a multinucleated structures. The treatment with PN of cultured scales did not increase TRAP activity suggesting that the massive presence of osteoclasts in the resorption sites could be likely the result of a systemic recruitment of monocyte-macrophage precursors. We observed that treatment with PN induced a significant decrease of the alkaline phosphatase ( ALP) activity in scale scleroblasts if compared with untreated controls. Then, we investigated the total mineral balance under prednisolone treatment using a time-dependent double live staining. The untreated fish fully repaired the resorption lacuna induced by prednisolone, whereas treated fish failed. The presence of osteoclast resorption fingerprints on new matrix suggested that the osteoclast activity counterbalances the osteodepositive activity exerted by scleroblasts. The treatment with PN in association with alendronate ( AL) has surprisingly resulted in a significant decrease of TRAP activity and increase of ALP compared to PN-treated fish in biochemical and histological assays confirming the action of alendronate against GIOP in fish as well in humans. [ABSTRACT FROM AUTHOR]

Background and Purpose: Glucocorticoid-induced osteoporosis (GIO) is the leading cause of secondary osteoporosis. Clinical evidence suggests a role for genistein aglycone in the treatment of post-menopausal osteopenia although proof of efficacy in comparison with currently available treatments is still lacking. To clarify this issue, we investigated the effects of genistein on bone compared with alendronate in experimental GIO.Experimental Approach: A total of 28 female Sprague-Dawley rats were used. GIO was induced by daily injections of methylprednisolone (MP; 30 mg x kg(-1) s.c.) for 60 days. Sham GIO animals (Sham-MP) were injected daily with the MP vehicle. At the end of the osteoporosis development period, MP rats were randomized to receive: vehicle (n= 7), genistein aglycone (5 mg x kg(-1) s.c.; n= 7) or alendronate (0.03 mg x kg(-1) s.c.; n= 7). Treatment lasted 60 days. Sham-MP animals were treated with vehicle for an additional 60 days. At the beginning and at the end of treatments, animals were examined for bone mineral density and bone mineral content. Bone-alkaline phosphatase and carboxy-terminal collagen cross links were determined; femurs were removed and tested for breaking strength and histology.Key Results: Genistein aglycone showed a greater increase in bone mineral density, bone mineral content and in breaking strength than alendronate and significantly increased bone-alkaline phosphatase (bone formation marker), reduced carboxy-terminal collagen cross links (bone resorption marker), compared with alendronate. Both treatments improved bone histology and the histological score.Conclusion and Implications: The results strongly suggest that the genistein aglycone might be an alternative therapy for the management of secondary osteoporosis. [ABSTRACT FROM AUTHOR]

Aim: To assess the quality of care of patients beginning corticosteroid therapy with respect to bone protection. Methods: Practicing rheumatologists in Australia were approached countrywide to recruit patients beginning corticosteroid therapy under their care. Use of bone-active medications in the ensuing year was recorded prospectively. Baseline and follow-up bone mineral density and fracture data were collected. Results: Ninety-two patients (64% female) were enrolled by 18 rheumatologists. Seven patients reported a medical history of osteoporosis and 14 had already sustained a low-trauma fracture. The median corticosteroid dose at commencement of therapy was 20 mg of prednisone. Bone-active medications were commenced in 47% of patients within 3 months of commencing steroid therapy. These included calcium supplements (33%), vitamin D supplements (21%), hormone replacement therapy (11%), selective estrogen receptor antagonists (5%) and bisphosphonates (15%). Calcium and vitamin D supplementation usually accompanied bisphosphonate therapy. Median change in bone mineral density at the lumbar spine was −0.20 SD units over 12 months (range: −1.16–0.70, P = 0.007), and at the hip −0.10 SD units over 12 months (range −1.66–0.93, P = 0.24). There were 21 new fractures in 13 patients over the study period, with a vertebral fracture incidence of 0.16 per patient year. Of those patients taking bisphosphonate therapy, two had incident low-trauma fractures but there was no significant change in bone mineral density at the hip or spine. Conclusions: Rheumatologists in Australia appear informed about the need for bone-active medications in patients who are commencing steroid therapy. However there remains room for improved awareness, as is seen by the low use of bisphosphonates. [ABSTRACT FROM AUTHOR]

The adverse effects of glucocorticoids on bone health are well recognized. In adults, evidence-based guidelines exist to base management of patients with glucocorticoid-induced osteoporosis. Osteoporosis is also recognized in children and adolescents with chronic disease requiring steroid treatment. Additional complexities in the assessment and management of growing children mean that evidence-based guidelines for this complex patient group have not been produced. Factors, which need to be taken into account, include defining osteoporosis in childhood and addressing the effects of chronic disease and glucocorticoid treatment on a number of parameters including the skeleton, growth, puberty, nutrition and vitamin D status. In the absence of randomized controlled trials to guide clinical practice, we provide proposals for the prevention and management of steroid-induced osteoporosis, drawing on the available evidence and our clinical experience of managing children and adolescents with steroid-induced osteoporosis. [ABSTRACT FROM AUTHOR]