Glucocorticoid-induced Osteoporosis Research Articles

Lactobacillus plantarum attenuates glucocorticoid-induced osteoporosis by altering the composition of rat gut microbiota and serum metabolic profile.

Osteoporosis, one of the most common non-communicable human diseases worldwide, is one of the most prevalent disease of the adult skeleton. Glucocorticoid-induced osteoporosis(GIOP) is the foremost form of secondary osteoporosis, extensively researched due to its prevalence.Probiotics constitute a primary bioactive component within numerous foods, offering promise as a potential biological intervention for preventing and treating osteoporosis. This study aimed to evaluate the beneficial effects of the probiotic Lactobacillus plantarum on bone health and its underlying mechanisms in a rat model of glucocorticoid dexamethasone-induced osteoporosis, using the osteoporosis treatment drug alendronate as a reference. We examined the bone microstructure (Micro-CT and HE staining) and analyzed the gut microbiome and serum metabolome in rats. The results revealed that L. plantarum treatment significantly restored parameters of bone microstructure, with elevated bone density, increased number and thickness of trabeculae, and decreased Tb.Sp. Gut microbiota sequencing results showed that probiotic treatment increased gut microbial diversity and the ratio of Firmicutes to Bacteroidota decreased. Beneficial bacteria abundance was significantly increased (Lachnospiraceae_NK4A136_group, Ruminococcus, UCG_005, Romboutsia, and Christensenellaceae_R_7_group), and harmful bacteria abundance was significantly decreased (Desulfovibrionaceae). According to the results of serum metabolomics, significant changes in serum metabolites occurred in different groups. These differential metabolites were predominantly enriched within the pathways of Pentose and Glucuronate Interconversions, as well as Propanoate Metabolism. Furthermore, treatment of L. plantarum significantly increased serum levels of Pyrazine and gamma-Glutamylcysteine, which were associated with inhibition of osteoclast formation and promoting osteoblast formation. Lactobacillus plantarum can protect rats from DEX-induced GIOP by mediating the "gut microbial-bone axis" promoting the production of beneficial bacteria and metabolites. Therefore L. plantarum is a potential candidate for the treatment of GIOP.

Τhe story of sclerostin inhibition: the past, the present, and the future.

Sclerostin inhibits osteoblast activity by hampering activation of the canonical Wnt signaling pathway and simultaneously stimulates osteoclastogenesis through upregulation of the receptor activator of NFκB ligand (RANKL). Thus, antibodies against sclerostin (Scl-Abs), besides promoting bone formation, suppress bone resorption and dissociate bone formation from resorption. This dual action results in remarkable increases of bone mineral density which are of a greater magnitude compared to the other antiosteoporotic treatments and are accompanied by decreases of fracture risk at all skeletal sites. The anabolic effect subsides after the first few months of treatment and a predominantly antiresorptive effect remains after this period, limiting its use to 12months. Furthermore, these effects are largely reversible upon discontinuation; therefore, subsequent treatment with antiresorptives is indicated to maintain or further increase the bone gains achieved. Romosozumab is currently the only Scl-Ab approved for the treatment of severe postmenopausal osteoporosis. Indications for use in other populations, such as males, premenopausal women, and patients with glucocorticoid-induced osteoporosis, are pending. Additionally, the efficacy of Scl-Abs in other bone diseases, such as osteogenesis imperfecta, hypophosphatasia, X-linked hypophosphatemia, and bone loss associated with malignancies, is under thorough investigation. Cardiovascular safety concerns currently exclude patients at high cardiovascular risk from this treatment.

Effects of Denosumab and Bisphosphonates on Glucocorticoid-induced Osteoporosis in Patients with Neuroimmunological Disorders.

Objective Although patients with neuroimmunological disorders often need to be treated with glucocorticoids and are at risk of developing glucocorticoid-induced osteoporosis, no research has focused on the treatment of glucocorticoid-induced osteoporosis in such patients. Methods We compared the efficacy of denosumab and bisphosphonates in glucocorticoid-induced osteoporosis in neuroimmunological diseases. In 57 patients with neuroimmunological disorders treated with corticosteroids (34 with neuromyelitis optica spectrum disorders, 16 with myasthenia gravis, and 7 with others), we retrospectively studied the long-term effects of denosumab (n=23) and bisphosphonates (n=34) on spine and total hip bone mineral density (BMD) measured by dual energy X-ray absorptiometry. Results There were no significant differences in the age, lumbar spine BMD, or mean dose or duration of prednisolone administration at baseline between the denosumab and bisphosphonate groups. During the follow-up period of up to 6 years, the increase in the lumbar spine and total hip BMD was greater in the denosumab group than in the bisphosphonate group (p<0.01). Insufficient bone fractures were observed in 2 (9%) of the 23 patients in the denosumab group and in 2 (6%) of the 34 patients in the bisphosphonate group (not significant). Conclusion Denosumab is more effective than bisphosphonates in increasing the BMD of patients with neuroimmunological disorders receiving glucocorticoids.

Inhibitory effect of hydroxychloroquine on glucocorticoid‐induced osteoporosis in lupus therapy

AbstractObjectivesSystemic lupus erythematosus (SLE) is a chronic and severe autoimmune disease characterised by persistent inflammation. Hydroxychloroquine (HCQ) and glucocorticoids (GCs) are the primary agents commonly used in combination as the first‐line treatment for SLE. Nevertheless, the specific mechanisms responsible for the effectiveness of this combined therapy with HCQ and GCs have not been fully elucidated. This study aimed to reveal the mechanism behind combined HCQ and GC treatment in lupus.MethodsAn SLE IgG‐induced inflammation model was used to investigate the anti‐inflammatory effects of HCQ and dexamethasone (DXM). A glucocorticoid‐induced osteoporosis (GIOP) model was used to investigate the inhibitory effect of HCQ on osteoclastogenesis. Inflammation was assessed by haematoxylin and eosin staining. Bone metabolism was determined structurally via microcomputer tomography and in bone marrow‐derived osteoclast cultures.ResultsAn SLE IgG‐induced inflammation model demonstrated that HCQ could not ameliorate inflammation alone but could enhance the anti‐inflammatory effect of GCs by decreasing the expression of FcγRI on macrophages. HCQ inhibited osteoclastogenesis induced by GCs and RANKL by upregulating nuclear factor erythroid 2‐related factor 2 and limiting reactive oxygen species formation, which mitigated GC‐induced bone loss.ConclusionThe results indicate that HCQ improved the anti‐inflammatory effects of GCs and inhibits the osteoclastogenesis in experimental lupus. This study offers valuable insights into the mechanisms underlying the combined treatment of lupus with HCQ and GCs.

The Therapeutic Potential of Two Egyptian Plant Extracts for Mitigating Dexamethasone-Induced Osteoporosis in Rats: Nrf2/HO-1 and RANK/RANKL/OPG Signals.

The prolonged use of exogenous glucocorticoids, such as dexamethasone (Dex), is the most prevalent secondary cause of osteoporosis, known as glucocorticoid-induced osteoporosis (GIO). The current study examined the preventative and synergistic effect of aqueous chicory extract (ACE) and ethanolic purslane extract (EPE) on GIO compared with Alendronate (ALN). The phytochemical contents, elemental analysis, antioxidant scavenging activity, and ACE and EPE combination index were evaluated. Rats were randomly divided into control, ACE, EPE, and ACE/EPE MIX groups (100 mg/kg orally), Dex group (received 1.5 mg Dex/kg, Sc), and four treated groups received ACE, EPE, ACE/EPE MIX, and ALN with Dex. The bone mineral density and content, bone index, growth, turnover, and oxidative stress were measured. The molecular analysis of RANK/RANKL/OPG and Nrf2/HO-1 pathways were also evaluated. Dex causes osteoporosis by increasing oxidative stress, decreasing antioxidant markers, reducing bone growth markers (OPG and OCN), and increasing bone turnover and resorption markers (NFATc1, RANKL, ACP, ALP, IL-6, and TNF-α). In contrast, ACE, EPE, and ACE/EPE MIX showed a prophylactic effect against Dex-induced osteoporosis by modulating the measured parameters and the histopathological architecture. In conclusion, ACE/EPE MIX exerts a powerful synergistic effect against GIO by a mode of action different from ALN.

Случай многоочагового асептического некроза костей с вторичным остеоартритом и глюкокортикоидным остеопорозом у взрослой пациентки с ювенильным дебютом системной красной волчанки — факторы риска и современная тактика терапевтического лечения

The article presents the case analysis concerning the successful therapeutic treatment of multiple osteonecrosis in an adult female patient with the juvenile form of systemic lupus erythematosus (SLE), including an analysis of the risk factors for their development. A comprehensive approach, including limiting axial load on the hip joints, the use of bisphosphonates, teriparatide, nonsteroidal anti-inflammatory drugs (NSAIDs), and disease-modifying osteoarthritis drugs, resulted in pain reduction, slowing of structural progression of femoral head changes, and improved functional status of the patient. Disease-modifying treatment of osteoarthritis was conducted with alternating injectable and oral medications. The success in treating osteonecrosis in this female patient was also enabled by the adjustment of basic SLE therapy and the reduction of prednisone dosage to 1.25 mg/day. This case serves as a vivid illustration of what is referred to as "complicated comorbidity.» The comprehensive approach allowed for achieving sustained positive outcomes, thus postponing surgical intervention in a physically active young female patient. KEYWORDS: systemic lupus erythematosus, SLE, aseptic necrosis, risk factors, osteoarthritis, osteoporosis, basic therapy of osteoarthritis, DMOAD, bisphosphonates, glucocorticoids. FOR CITATION: Gaydukova I.Z., Musiychuk M.M., Bombina M.V., Aparkina A.V., Petukhova A.A., Filonenko E.P., Inamova O.V., Rebrov A.P. Сase of multi-focal osteonecrosis with secondary osteoarthritis and glucocorticoid-induced osteoporosis in an adult patient with juvenile- onset systemic lupus erythematosus — risk factors and modern treatment tactics. Russian Medical Inquiry. 2024;8(7):406–412 (in Russ.). DOI: 10.32364/2587-6821-2024-8-7-6.

Nationwide prevalence of glucocorticoid prescriptions over 17 years and osteoporosis prevention among long-term users.

Glucocorticoid steroids are frequently prescribed, and side effects are well-known, such as glucocorticoid-induced osteoporosis. Our aim was to estimate the nationwide trend in the prevalence of glucocorticoid steroid prescriptions over 17 years and to elucidate the proportion of patients on long-term glucocorticoid steroid therapy who receive active bone protective therapy. As well as to examine which medical specialties prescribe glucocorticoid steroids the most. This study was a retrospective observational registry study extended over 17 years (2003-2020). Data were retrieved from the Icelandic Prescription Medicine Register on all delivered glucocorticoid steroids (Anatomic therapeutic chemical code: H02AB) for oral use. Long-term users were defined as those who annually received ⩾90 defined daily doses of glucocorticoid steroids. Annually, 3.8% of the population received oral glucocorticoid steroids, from 3.3% in 2006 to 4.3% in 2017. Prednisolone was most frequently prescribed. Females dispatched glucocorticoid steroid prescriptions more often than males (55.8%). Males and females reached their peak prevalence between the ages of 60 and 70. General practitioners most often prescribe glucocorticoid steroids, followed by physicians in training, rheumatologists, internists, and medical students. Of those who received prescriptions for glucocorticoid steroids, 12.2%-18.1% were classified as long-term users. A declining number of patients have been receiving bone-protective therapy in recent years. Only 13.0% of chronic users received bone protective therapy in 2020. The use of glucocorticoid steroids has increased during the last 2 decades despite improvements in treatment for inflammatory disorders. The prevalence of long-term users has remained stable. Meanwhile, the use of parallel active bone-protective therapy among long-term users of glucocorticoid steroids is declining. Thus, improvements in prophylaxis for corticosteroid-induced osteoporosis are urgently needed for patients who require long-term treatment with glucocorticoid steroids.

Narlumosbart: First Approval.

Narlumosbart () is a recombinant, fully human, anti-receptor activator of nuclear factor kappa-Β ligand (RANKL) IgG4 monoclonal antibody being developed by CSPC Pharmaceutical and its wholly owned subsidiary Shanghai Jinmante Biotechnology for the treatment of giant cell tumour of bone (GCTB), bone metastases from solid tumours and osteoporosis. The RANK/RANKL signalling pathway plays a pivotal role in osteoclastogenesis and in the pathogenesis of GCTB. Narlumosbart specifically binds to RANKL and blocks the interaction of RANKL with RANK, thus inhibiting osteoclastogenesis and bone resorption by osteoclasts. In September 2023, narlumosbart received conditional first approval in China for the treatment of adults with GCTB that is unresectable or when surgical resection would result in severe functional disability. Clinical studies of narlumosbart for bone metastases, postmenopausal osteoporosis and glucocorticoid-induced osteoporosis are underway in China. This article summarizes the milestones in the development of narlumosbart leading to this first approval for the treatment of adults with GCTB.

Ginsenoside Rg1 modulates PI3K/AKT pathway for enhanced osteogenesis via GPER

BackgroundOsteoporosis is a systemic skeletal disorder characterized by decreased bone density and the degradation of bone tissue microarchitecture. Ginsenoside Rg1, derived from Panax ginseng, has been a part of traditional Chinese medicine in China for centuries, particularly for treating osteoporosis. However, there remains limited research on the osteogenic potential of Rg1 within the glucocorticoid-induced osteoporosis (GIOP) model and its specific mechanisms. PurposeThe primary objective of this study is to investigate the osteogenic potential of Rg1 within the GIOP model and explore the signaling pathways associated with its in vivo and in vitro effects. MethodsCell proliferation, differentiation and mineralization were evaluated by the Cell counting kit 8(CCK8) assay, alkaline phosphatase (ALP) test and Alizarin Red S staining, respectively. The qPCR technique was used to determine the relative expression of mRNA and the western blot was used to determine the relative expression of protein. In vivo experiments, spinal vertebrae staining in zebrafish larvae was accomplished by alizarin red S staining. ResultsZebrafish larvae's hatching, survival, malformation, and heart rate were unaffected by 50 μM of Rg1 in vivo, while the MEC3T3-E1 cell line's proliferation was unaffected by 50 μM of Rg1 in vitro. Meanwhile, Rg1 was shown to improve osteogenic differentiation or bone formation as well as the level of mRNA expression of osteogenic markers in vivo and in vitro. Treatment with Rg1 significantly increased the expression of G protein-coupled estrogen receptor (GPER) and pAKT. In addition, the GPER inhibitor G15 could significantly reduce the mRNA and protein expression levels of GPER and phosphorylated AKT, LY294002, a PI3K/AKT pathway inhibitor, markedly suppresses the expression of phosphorylated AKT, yet shows no significant impact on GPER expression. Both G15 and LY294002 can significantly blocked the Rg1-mediated enhancement of osteogenesis capacity in the GIOP model. In contrast, when both the agonists G1 of GPER and LY294002 were added, G1 increased the relative expression of mRNA and protein of GPER, but not the expression of osteogenic capacity and osteogenic markers. ConclusionsThis study investigates the mineralization effects and mechanisms of Ginsenoside Rg1 both in vitro and in vivo. For the first time, we propose that Rg1 might regulate osteogenesis by modulating AKT phosphorylation through mediating GPER expression within the PI3K/AKT pathway in the GIOP model. This discovery introduces novel targets and avenues for osteoporosis treatment.

ATP-induced cell death: a novel hypothesis for osteoporosis.

ATP-induced cell death has emerged as a captivating realm of inquiry with profound ramifications in the context of osteoporosis. This study unveils a paradigm-shifting hypothesis that illuminates the prospective involvement of ATP-induced cellular demise in the etiology of osteoporosis. Initially, we explicate the morphological attributes of ATP-induced cell death and delve into the intricacies of the molecular machinery and regulatory networks governing ATP homeostasis and ATP-induced cell death. Subsequently, our focus pivots towards the multifaceted interplay between ATP-induced cellular demise and pivotal cellular protagonists, such as bone marrow-derived mesenchymal stem cells, osteoblasts, and osteoclasts, accentuating their potential contributions to secondary osteoporosis phenotypes, encompassing diabetic osteoporosis, glucocorticoid-induced osteoporosis, and postmenopausal osteoporosis. Furthermore, we probe the captivating interplay between ATP-induced cellular demise and alternative modalities of cellular demise, encompassing apoptosis, autophagy, and necroptosis. Through an all-encompassing inquiry into the intricate nexus connecting ATP-induced cellular demise and osteoporosis, our primary goal is to deepen our comprehension of the underlying mechanisms propelling this malady and establish a theoretical bedrock to underpin the development of pioneering therapeutic strategies.

Effect of internal heat-type acupuncture on bone remodeling in a glucocorticoid-induced osteoporosis model rabbit by regulating the triplet of OPG-RANKL-RANK

Introduction: Internal heat-type acupuncture therapy is a new therapeutic method that integrates acupuncture and heat therapy and effectively reduces local muscle inflammation. It has a good effect on the clinical application of osteoporosis. The purpose of this study was to assess the improvement of glucocorticoid-induced osteoporosis (GIOP) after internal heat-type acupuncture treatment as well as its role in promoting the balance of bone remodeling in the GIOP rabbit model by regulating the triplet of osteoprotegerin(OPG)-receptor activator of nuclear factor-KB ligand (RANKL)-receptor activator of nuclear factor-KB (RANK). Methods: The rabbits were divided into the control, model (GIOP), GIOP+Alendronate, and GIOP+Internal heat-type acupuncture groups, with 8 rabbits in each group. At the end of the treatment, all rabbits were sacrificed. The pathologic changes of lumbar vertebrae were observed by x-ray, the morphology of lumbar trabecular bone was observed by HE staining, and the apoptosis of lumbar vertebrae was detected by Tunel. The protein expressions of OPG, RANKL, and RANK in lumbar vertebrae were detected by immunohistochemistry staining, immunofluorescence staining, and Western blotting. Results: Internal heat-type acupuncture partly prevented osteopenia among GIOP-induced rabbits, improved the morphology of lumbar vertebrae, and inhibited the apoptosis of lumbar vertebrae osteocytes. Moreover, by increasing the protein expression level of OPG and reducing the protein expression of RANKL and RANK, internal heat-type acupuncture effectively promoted the balance of bone remodeling and eventually achieved the treatment of GIOP. Conclusion: Internal heat-type acupuncture therapy may promote the balance of bone remodeling by regulating the triplet of osteoprotegerin-receptor activator of nuclear factor-KB ligand-receptor activator of nuclear factor-KB, thereby treating osteoporosis which was induced by glucocorticoid.

A Pharmacovigilance Study on Steroid Induced Osteoporosis

Background: In elderly people, osteoporosis and low bone density are significant risk factors for morbidity and death. Low bone strength distinguishes these illnesses, which are correlated to an increased risk of fractures from even minor traumas. Objectives: To study pharmacovigilance on steroid induced osteoporosis. Methods: A total of 950 individual who were diagnosed with osteoporosis. These individuals were deemed to be at a high risk of osteoporosis. Patients were given information regarding the risks of steroid-induced osteoporosis, as well as a handout. The patient's steroid duration and any medicines used to control the risks of steroid-induced osteoporosis were the focus of the initial evaluation. Following that, evaluations of the pharmacological therapy being examined. Any problems found were discussed with the patient and/or the prescribing practitioner. Data was gathered at the start of the study and again after 6 months of observation. Results: Glucocorticoids (prednisolone) was the main prescription drug of the entire study sample. Family history of Osteoporosis was reported in 20% of the cases. The history of fracture was reported in 30% of the cases. Low calcium diet was reported in 35% of the cases. Osteoporosis was diagnosed in 17% of the cases, Osteopenia in 22% of the cases. In 88% of the cases the drug prescribed was &gt;5mg daily. The duration of CS intake was high. This shows that the CS drug is being abused mostly in history of allergies and asthma as its easily available OTC leading to an increased risk of osteoporosis. Around 26% were prescribed antiosteoporosis treatment with Bisphosphonate. Estrogen therapy was prescribed in 16% of the cases. Calcium supplement consumption was increased by 17%. There was significant reduction in BMD, Glucocorticoid’s usage and daily dosage and result was statistically significant. Conclusion: Because all cells employ the same glucocorticoid receptor, corticosteroids' antiinflammatory effects cannot be distinguished from their metabolic effects; thus, precautions should be taken when corticosteroids are given. Clearly, the risk of serious adverse effects rises as the amount and duration of therapy increases, thus the smallest dose required to control the condition should be provided.

Glucocorticoid-Induced Osteoporosis (GIOP).

Use of glucocorticoid in various diseases including rheumatology and respiratory diseases is on the rise because of its prompt beneficial effects. This culminates in osteoporosis and fragility fractures. Judicious use of glucocorticoid hence calls for attention with regard to the dose schedule, route of administration and accompanying enhancing factors. Institution of proper therapeutic management as per WHO risk stratification with anabolic and/or resorptive drugs like bisphosphonates, teriparatide or denosumab is necessary to prevent the eventuality of fragility fractures. Even otherwise, knowledge of glucocorticoid, its metabolism, various dose schedules, adverse effects are areas worth discussing.

Association between dietary selenium intake and the prevalence of osteoporosis and its role in the treatment of glucocorticoid-induced osteoporosis

BackgroundLong-term glucocorticoid therapy may lead to osteoporosis (OP). Selenium (Se) is an essential microelement for human health and bone health. This study evaluated the association between dietary Se intake and the prevalence of OP and further explored the potential therapeutic effect of Se on glucocorticoid-induced OP (GIOP) in vivo and in vitro.MethodsData were collected from a population-based cross-sectional study conducted in our hospital. OP is diagnosed based on bone mineral density (BMD) measurements using compact radiographic absorptiometry. Dietary Se intake was assessed using a semi-quantitative food frequency questionnaire. The association between dietary Se intake and OP prevalence was analyzed by multivariable logistic regression. In animal experiments, male Sprague–Dawley rats were intramuscularly injected with dexamethasone (1 mg/kg) daily to induce GIOP, while different doses of Se were supplemented in rat drinking water for 60 d. BMD and biomechanical parameters of rat femur were measured. The histopathological changes of the femur were observed by HE staining, the number of osteoclasts was observed by TRAP staining, and OCN positive expression was detected by immunohistochemical staining. OPG, RANKL, Runx2, and BMP2 in rat femur were detected by Western blot. Bone turnover markers and oxidative stress markers were measured using commercial kits. MC3T3-E1 cells were induced to osteogenic differentiation, stimulated with DXM (100 μM), and/or treated with Se at different doses. Cell proliferation and apoptosis were assessed by CCK-8 and flow cytometry. ALP activity was detected by ALP staining and cell mineralization was observed by alizarin red staining.ResultsParticipants with lower dietary Se intake had higher OP prevalence. Se supplementation improved BMD, biomechanical parameters, and histopathological changes of the femur in GIOP rats. Se supplementation also suppressed DXM-induced changes in bone turnover- and oxidative stress-related markers. Under DXM conditions, Se treatment induced MC3T3-E1 cell proliferation, ALP activity, and mineralization.ConclusionLower Dietary Se intake is associated with OP prevalence. Moreover, Se takes a position in bone protection and anti-oxidative stress in GIOP models. Therefore, Se may be a complementary potential treatment for GIOP.

Agomelatine alleviates steroid-induced osteoporosis by targeting SIRT1/RANKL/FOXO1/OPG signalling in rats.

One of the major contributors to secondary osteoporosis is long-term glucocorticoid usage. Clinically used antidepressant agomelatine also has anti-inflammatory properties. Our research aimed to inspect the probable defensive effect of agomelatine against steroid-promoted osteoporosis. There were four groups of rats; group I had saline as a negative control; rats of group II had dexamethasone (0.6 mg/kg, s.c.), twice weekly for 12 weeks; rats of group III had agomelatine (40 mg/kg/day, orally), as a positive control, daily for 12 weeks; and rats of group IV had dexamethasone + agomelatine in the same previous doses combined for 12 weeks. Finally, biochemical as well as histopathological changes were evaluated and dexamethasone treatment caused osteoporosis, as evidenced by discontinuous thin cancellous bone trabeculae, minor fissures and fractures, irregular eroded endosteal surface with elevated alkaline phosphate, tartarate resistant acid phosphate (TRACP) and osteocalcin levels. Osteoprotegerin (OPG), calcium, and phosphorus levels decreased with disturbed receptor activator of nuclear factor κ B ligand (RANKL), forkhead box O1 (FOXO1), and silent information regulator 1 (SIRT1)protein expression. However, treatment with agomelatine restored the normal levels of biochemical parameters to a great extent, supported by SIRT activation with an improvement in histopathological changes. Here, we concluded that agomelatine ameliorates steroid-induced osteoporosis through a SIRT1/RANKL/FOXO1/OPG-dependent pathway.

In vivo and in vitro action mechanism of treatment of glucocorticoid-induced osteoporosis by regulation of osteoprotegerin/receptor activator of nuclear factor-κB pathways by denshensu.

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.

Gamma-aminobutyric acid (GABA)-mediated bone formation and its implications for anti-osteoporosis strategies: Exploring the relation between GABA and GABA receptors

Osteoporosis is a significant global health concern, linked to reduced bone density and an increased fracture risk, with effective treatments still lacking. This study explored the potential of gamma-aminobutyric acid (GABA) and its receptors as a novel approach to promote osteogenesis and address osteoporosis. GABA concentrations up to 10 mM were well-tolerated by MC3T3-E1 preosteoblast, stimulating osteoblast differentiation and mineralization in a concentration- and time-dependent manner. In vivo experiments with zebrafish larvae demonstrated the ability of GABA to improve vertebral formation and enhanced bone density, indicating the potential therapeutic value for osteoporosis. Notably, GABA countered the adverse effects of prednisolone on vertebral formation, bone density, and osteogenic gene expression in zebrafish larvae, suggesting a promising therapeutic solution to counteract corticosteroid-induced osteoporosis. Moreover, our study highlighted the involvement of GABA receptors in mediating the observed osteogenic effects. By using GABAA, GABAB, and GABAC receptor antagonists, we demonstrated that blocking these receptors attenuated GABA-induced osteoblast differentiation and vertebral formation in both MC3T3-E1 cells and zebrafish larvae, underscoring the importance of GABA receptor interactions in promoting bone formation. In conclusion, these findings underscore the osteogenic potential of GABA and its ability to mitigate the detrimental effects of corticosteroids on bone health. Targeting GABA and its receptors could be a promising strategy for the development of novel therapeutic interventions to address osteoporosis. However, further investigations are warranted to fully elucidate the underlying molecular mechanism of GABA and its clinical applications in treating osteoporosis.

Catalpol ameliorates dexamethasone-induced osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via the activation of PKD1 promoter

ObjectiveTo investigate the effects of CA on glucocorticoid-induced osteoporosis (GIOP) and lucubrate the underlying mechanism of CA via the activation of polycystic kidney disease-1(PKD1) in bone marrow mesenchymal stem cells (BMSCs). MethodsIn vivo, a GIOP model in mice treated with dexamethasone (Dex) was established. Biomechanical, micro-CT, immunofluorescence staining of OCN, ALP and PKD1 and others were severally determined. qRT-PCR and Western blot methods were adopted to elucidate the particular mechanisms of CA on GIOP. In addition, BMSCs cultured in vitro were also induced by Dex to verify the effects of CA. Finally, siRNA and luciferase activity assays were performed to confirm the mechanisms. ResultsWe found that CA could restore the destroyed bone microarchitecture and increase the bone mass in GIOP mice. CA could also upregulate PKD1 protein expression, reduce oxidative stress, and promote mRNA expression of bone formation-associated markers in GIOP mice. Furthermore, it was also observed that CA reduced oxidative stress and promoted osteogenic differentiation in Dex-induced BMSCs. Mechanically, CA could promote protein expression via increasing the activity of PKD1 promoter. ConclusionThis study provides important evidences for CA in the further clinical treatment of GIOP, reveals the activation of PKD1 promoter as the underlying mechanism.

Association of sarcopenia and vitamin D deficiency withglucocorticoid-induced osteoporosis in Chinese patients with rheumatoid arthritis.

The study aimed to explore the association of sarcopenia and vitamin D deficiency with glucocorticoid-induced osteoporosis (GIOP) in Chinese patients with rheumatoid arthritis (RA). Skeletal muscle mass, serum 25(OH)D levels, and bone mineral density (BMD) were assessed. The prevalence of OP, sarcopenia, and vitamin D deficiency in RA patients was significantly higher than in controls (all P < 0.001). The percentage of GC use was 56.9%, and the prevalence of GIOP was 38.1% in 480 RA patients. The prevalence of OP in RA patients without sarcopenia was lower than that in RA patients with sarcopenia (P < 0.05). In RA patients with and without GC, the prevalence of OP in patients without sarcopenia was significantly lower than that in patients with sarcopenia (P < 0.001 and P < 0.05). Female sex (OR = 54.737; 95% CI: 7.103-421.809; P < 0.0001), age (OR = 1.078; 95% CI: 1.048-1.110; P < 0.0001), sarcopenia, and vitamin D deficiency (OR = 2.250; 95% CI: 1.246-64.065; P = 0.007) were risk factors for GIOP in RA patients. GIOP is associated with sarcopenia and vitamin D deficiency and is widespread among Chinese patients with RA. Key points ·Percentage of using GC and the prevalence of OP were all high in Chinese patients with RA. ·GIOP was widely existed in Chinese RA patients, which was associated with sarcoprnia and vitamin D deficiency.

Disturbed bone marrow adiposity in patients with Cushing's syndrome and glucocorticoid- and postmenopausal- induced osteoporosis.

Skeletal stem/progenitor cells (SSPCs) in the bone marrow can differentiate into osteoblasts or adipocytes in response to microenvironmental signalling input, including hormonal signalling. Glucocorticoids (GC) are corticosteroid hormones that promote adipogenic differentiation and are endogenously increased in patients with Cushing´s syndrome (CS). Here, we investigate bone marrow adiposity changes in response to endogenous or exogenous GC increases. For that, we characterize bone biopsies from patients with CS and post-menopausal women with glucocorticoid-induced osteoporosis (GC-O), compared to age-matched controls, including postmenopausal osteoporotic patients (PM-O). Transiliac crest bone biopsies from CS patients and healthy controls, and from postmenopausal women with GC-O and matched controls were analysed; an additional cohort included biopsies from women with PM-O. Plastic-embedded biopsies were sectioned for histomorphometric characterization and quantification of adipocytes. The fraction of adipocyte area per tissue (Ad.Ar/T.Ar) and marrow area (Ad.Ar/Ma.Ar), mean adipocyte profile area (Ad.Pf.Ar) and adipocyte profile density (N.Ad.Pf/Ma.Ar) were determined and correlated to steroid levels. Furthermore, the spatial distribution of adipocytes in relation to trabecular bone was characterized and correlations between bone marrow adiposity and bone remodeling parameters investigated. Biopsies from patients with CS and GC-O presented increased Ad.Ar/Ma.Ar, along with adipocyte hypertrophy and hyperplasia. In patients with CS, both Ad.Ar/Ma.Ar and Ad.Pf.Ar significantly correlated with serum cortisol levels. Spatial distribution analyses revealed that, in CS, the increase in Ad.Ar/Ma.Ar near to trabecular bone (<100 µm) was mediated by both adipocyte hypertrophy and hyperplasia, while N.Ad.Pf/Ma.Ar further into the marrow (>100 µm) remained unchanged. In contrast, patients with GC-O only presented increased Ad.Ar/Ma.Ar and mean Ad.Pf.Ar>100 µm from trabecular bone surface, highlighting the differential effect of increased endogenous steroid accumulation. Finally, the Ad.Ar/Ma.Ar and Ad.Ar/T.Ar correlated with the canopy coverage above remodeling events. Increased cortisol production in patients with CS induces increased bone marrow adiposity, primarily mediated by adipocyte hypertrophy. This adiposity is particularly evident near trabecular bone surfaces, where hyperplasia also occurs. The differential pattern of adiposity in patients with CS and GC-O highlights that bone marrow adipocytes and their progenitors may respond differently in these two GC-mediated bone diseases.