Osteoporosis (OP) represents a systemic disease causing reduced bone mass and fragility fractures. Qigu Capsule (QGC), a traditional Chinese medicine, shows potential in alleviating human OP, but its precise mechanisms remain unclear, limiting clinical application.

The bioactive components of QGC were analyzed using high-performance liquid chromatography (HPLC). An ovariectomy (OVX)-provoked OP rat model was established to evaluate QGC's effects on bone mass, trabecular architecture, and mechanical strength using micro-CT, histological staining, and biomechanical testing. RNA-seq analysis of human OP-derived mesenchymal stem cell (MSC) samples was performed to identify oxidative stress (OxS)- and senescence-associated gene changes. OxS-induced MSC senescence was modeled in vitro using H₂O₂, and QGC's effects on MSC proliferation, migration, and osteogenic differentiation were assessed. Network pharmacology (NP) was deployed to predict the key mechanisms behind the QGC treatment of OP. Further mechanistic studies utilized pharmacological inhibitors and siRNA-mediated gene knockdown to confirm the involvement of critical signaling pathways.

HPLC-MS analysis identified 505 unique bioactive compounds in QGC. In vivo, QGC significantly improved BMD, enhanced trabecular microarchitecture, and restored mechanical properties in OVX rats. ELISA, histological, and immunohistochemical analyses confirmed that QGC primarily enhanced osteoblast activity. RNA-seq analysis of GEO datasets revealed upregulation of senescence and OxS markers (P53, CDKN1A, and INOS) in human OP-derived MSCs. Both in vivo and in vitro QGC alleviated OxS-induced MSC senescence, reduced reactive oxygen species (ROS) levels, suppressed senescence and OxS marker, and promoted MSC proliferation, migration, and osteogenic differentiation. Moreover, NP predicted HIF-1α signaling as critical in QGC's regulation of MSC function during OP. Mechanistic studies demonstrated that QGC activated the HIF-1α/AMPK axis, and inhibition of either HIF-1α or AMPK abolished its therapeutic effects.

QGC mitigates OxS-induced MSC senescence and promotes osteogenesis through the HIF-1α/AMPK axis, highlighting its mechanistic basis in treating OP. These findings show QGC's potential as a therapeutic agent, not only by promoting osteogenesis but also by complementing or serving as an alternative to current OP treatments, offering valuable prospects for enhanced clinical management.

Mesenchymal stem cells (MSCs), possessing multilineage potential, are capable of differentiating into osteoblasts and thus serve as suitable seed cells for bone regeneration. Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) gene encodes osteoprotegerin (OPG), which has a critical role in repressing osteoclast differentiation and has been reported to influence the adipogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs). Nevertheless, the impact of TNFRSF11B on the osteogenic differentiation of umbilical cord mesenchymal stem cells (UCMSCs) remains unclear. This study aimed to investigate the role of TNFRSF11B in the osteogenesis of UCMSCs and bone remodeling.

Differentially expressed genes (DEGs) were identified from the GEO database using R software. TNFRSF11B was transduced into UCMSCs by a lentiviral vector. Cell differentiation capacity was assessed by ALP staining, TRAP staining, and qRT-PCR assay. Proteomic analysis was performed to investigate the key proteins in TNFRSF11B-OE-UCMSCs that inhibit osteoclast differentiation.

We found that the TNFRSF11B gene was upregulated during osteogenic differentiation and downregulated during adipogenic differentiation of UCMSCs. UCMSCs overexpressing the TNFRSF11B gene were successfully generated via lentivirus transfection. However, neither the overexpression of TNFRSF11B nor treatment with exogenous OPG protein was sufficient to enhance the osteogenic potential of UCMSCs in vitro. Conditioned medium from TNFRSF11B-overexpressing UCMSCs significantly suppressed RANKL-induced osteoclast differentiation, while no significant effect was observed on osteoblast differentiation compared to the control group. Proteome analysis revealed that in the TNFRSF11B-OE-CM group, the expression of C1R, MDH1, and ACLY was significantly downregulated, while the expression of FETUB and METRNL was upregulated in the TNFRSF11B-OE-CM group, which was associated with the inhibition of osteoclast differentiation.

This study demonstrates that although TNFRSF11B overexpression does not promote osteogenesis in UCMSCs, it may participate in regulating bone remodeling by inhibiting osteoclast differentiation.

Aged individuals with type 2 diabetes (T2D) may suffer from complications of common comorbid conditions like osteoporosis or osteoarthritis. MGL3196 (MGL) is a therapeutic thyroid hormone receptor beta (TRβ) agonist that has been shown to rescue non-alcoholic steatohepatitis by enhancing lipid metabolism. In a previous study, we demonstrated that MGL treatment protected against high-fat diet (HFD)-induced adiposity but increased HFD-induced trabecular bone loss in male mice. In this study, we explored the impact of MGL treatment on adiposity, bone, and cartilage in aged-21-month-old C57BL/6J mice after a 12-week HFD regimen. Our results show that MGL reduced body weight as well as adverse effects caused by HFD adiposity, in male mice only. Aged HFD-fed male mice experienced cortical bone loss, in contrast to the trabecular bone loss observed in adult male mice. Notably, MGL treatment further exacerbated the cortical bone loss. Mechanical testing of tibias from aged male mice by 3-point bending revealed a reduced maximum load and tibia stiffness with HFD and MGL treatment. Transcriptome analyses for cortical bone formation regulators unveiled a decreased expression of Wnt16 and increased expression of the Wnt inhibitor, Sost, in the bones of HFD-fed male mice. Additionally, measurements of articular cartilage indicated that MGL treatment reduced articular cartilage degradation in both sexes, which was attributed to aging and a HFD. Our findings suggest tailored therapies are necessary to address the adverse effects of a HFD on fat, bone, and cartilage metabolism, specifically considering factors such as age and sex.

Osteoporosis, a common disorder, is characterized by a systemic reduction in bone mass and structural integrity, resulting in brittle bones. Reducing bone loss and enhancing bone density through oral administration of biopharmaceuticals provides significant advantages, including convenience and non-invasiveness for patients. However, challenges such as poor absorption and enzymatic degradation necessitate the development of innovative drug delivery systems. This research introduces a core-shell hydrogel system inspired by the natural architecture of Longan fruit, constructed from pectin and chitosan biopolymers, designed to create biocapsules and sustain the release of biodrugs. In this system, salmon calcitonin (sCT) was encapsulated within mesoporous silica nanoparticles (MSNs) and incorporated into the core of the beads. The synthesis of the core-shell hydrogel beads was carefully regulated by adjusting the immersion time and concentration of the crosslinker. The hydrogel beads demonstrated durability, with the pectin shell effectively preventing rapid degradation in the stomach, while the chitosan layer enhanced adhesion to the intestinal walls, safeguarded sCT, and enabled sustained drug release over an extended period of up to 30 h. Furthermore, biocompatibility tests indicated minimal cytotoxicity and hemolysis. Cellular uptake assays demonstrated that the core-shell beads effectively encapsulated sCT and ensured its prolonged release to CT-26 cells. This study presents a promising platform for oral sCT delivery, offering enhanced efficacy, patient compliance, and a potential replacement for injection-based therapies.

The prevalence of osteoporosis (OP) on a global scale is significantly elevated that causes life threatening issues. The potential of groundbreaking biomolecular therapeutics in the field of OP is highly encouraging. The administration of biomolecular agents has the potential to mitigate the process of bone demineralization while concurrently augmenting the regenerative capacity of bone tissue, thereby facilitating a personalized therapeutic approach. Biomolecules-based therapies showed promising results in term of bone mass protection and restoration in OP.

We summarized the recent biomolecular therapies with notable progress in clinical, demonstrating the potential to transform illness management. These treatments frequently utilize different biomolecule based strategies. Biomolecular therapeutics has a targeted character, which results in heightened specificity and less off-target effects, ultimately leading to increased patient outcomes. These aspects have the capacity to greatly enhance the management of OP, thus resulting in a major enhancement in the quality of life encountered by individuals affected by this condition.

This study aimed to construct a miRNA-mRNA network in OF and explored the effect of the hsa-miR-32-3p/TNFSF11 axis on osteoclast function.

GSE70318 and GSE74209 datasets were used to filter the differentially expressed miRNAs in OF. Then, the targets of these miRNAs intersected with the disease genes of OF. The target genes were annotated using GO terms and KEGG pathway enrichment analysis. The network for miRNA-gene-top 30 GO terms/top 20 pathways was drawn. Sankey diagrams were drawn for Parathyroid hormone synthesis, secretion, and action pathway (hsa04928) and ossification (GO:0001503) related to osteoporotic fracture. The hsa-miR-32-3p/TNFSF11 axis was selected for expression and functional verification.

A total of 21 differentially expressed miRNAs in OF were obtained by analyzing GSE70318 and GSE74209 datasets. A total of 36 genes were related to OF among the miRNA-targets. The genes were enriched in GO terms and KEGG pathways related to OF. Parathyroid hormone synthesis, secretion, and action pathway (hsa04928) and ossification proposed that the hsa-miR-32-3p/TNFSF11 axis may be involved in OF. The expression level of hsa-miR-32-3p was decreased in patients with low bone mineral density (BMD) and fracture, while the expression level of TNFSF11 mRNA was increased. Hsa-miR-32-3p complementarily bound with TNFSF11. Hsa-miR-32-3p inhibited osteoclast activation, while TNFSF11 promoted osteoclast activation.

The miRNA-mRNA network in OF proposed the TNFSF11 as a downstream target of hsa-miR-32-3p. The hsa-miR-32-3p/TNFSF11 axis was involved in the regulation of osteoclast activity.

Not applicable.

Mesenchymal stem cells (MSCs), known for their ability to differentiate into osteoblasts, play a pivotal role in bone metabolism. In our previous investigations, we identified a novel long non-coding RNA (lncRNA) named MCP1 Regulatory Factor (MRF), which exhibits significant involvement in immune regulation of BMSCs. Moreover, we observed noticeable expression changes of MRF during the osteogenic differentiation of BMSCs. However, the exact role and underlying mechanism of MRF in the osteogenic differentiation of BMSCs remain elusive.

QRT-PCR analysis was employed to assess the expression levels of MRF. RNA interference and overexpression plasmids were utilized to modulate MRF expression, allowing for the observation of changes in the osteogenic differentiation capacity of BMSCs. Downstream pathways involved in the MRF-mediated regulation of BMSCs' osteogenic differentiation were predicted using transcriptome sequencing. The functionality of MRF in vivo was validated through a mouse tibial drilling defect model.

In patients with osteoporosis, there is a notable increase in the expression of MRF within BMSCs. During the osteogenic differentiation of BMSCs, the MRF expression progressively decreases. The knockdown of MRF significantly enhances the osteogenic differentiation of BMSCs, promoting an increased expression of bone-related proteins such as RUNX2, ALP, and COL1A1. Transcriptome sequencing and western blot indicated that cAMP/PKA/CREB signaling pathway was significantly activated after lncRNA-MRF knockdown. Moreover, in the mouse tibial drilling defect model, MRF knockdown significantly promotes ossification in vivo.

MRF modulates the cAMP/PKA/CREB signaling pathway via the follicle stimulating hormone receptor (FSHR), thereby influencing the ossification differentiation of BMSCs. Our research suggests that MRF may serve as a potential target for bone-related disorders.

Injectable hydrogels represent a highly promising approach for localized drug delivery systems (DDSs) in the management of bone-related conditions such as osteoporosis, osteonecrosis, osteoarthritis, osteomyelitis, and osteosarcoma. Their appeal lies in their biocompatibility, adjustable mechanical properties, and capacity to respond to external stimuli, including pH, temperature, light, redox potential, ionic strength, and enzymatic activity. These features enable enhanced targeted delivery of bioactive agents. This mini-review evaluates the synthesis of injectable hydrogels as well as recent advancements for treating a range of bone disorders, focusing on their mechanisms as localized and sustained DDSs for delivering drugs, nanoparticles, growth factors, and cells (e.g., stem cells). Moreover, it highlights their clinical studies for bone disease treatment. Additionally, it emphasizes the potential synergy between injectable hydrogels and hydrogel-based point-of-care technologies, which are anticipated to play a pivotal role in the future of bone disease therapies. Injectable hydrogels have the potential to transform bone disease treatment by facilitating precise, sustained, and minimally invasive therapeutic delivery. Nevertheless, significant challenges, including long-term biocompatibility, scalability, reproducibility, and precise regulation of drug release kinetics, must be addressed to unlock their clinical potential fully. Addressing these challenges will not only advance bone disease therapy but also open new avenues in regenerative medicine and personalized healthcare.

RNA binding Fox-1 homolog 2 (RBFOX2) is an RNA-binding protein that has been extensively studied in heart disease. Its downstream target, Jph2, has also been primarily investigated in relation to heart disease. However, their roles in osteoblast differentiation remain unexplored. This study aimed to investigate the regulatory role of RBFOX2 in osteoblast differentiation through its relationship with Jph2 in the MC3T3-E1 preosteoblast cell line.

The expression levels of RBFOX2, Jph2, and osteoblast differentiation markers (Dlx5 and Runx2) were analyzed using RT-PCR, qPCR, and Western blotting. Alkaline phosphatase (ALP) activity and extracellular matrix mineralization were evaluated using ALP and Alizarin Red S staining. Transient overexpression and siRNA-mediated knockdown were performed to assess the functional roles of RBFOX2 and Jph2 in osteoblast differentiation. Overexpression of RBFOX2 significantly increased Dlx5 and Runx2 expression at both mRNA and protein levels (p < 0.05) and enhanced mineralization in MC3T3-E1 cells. Conversely, knockdown of RBFOX2 or Jph2 resulted in decreased expression of these markers and reduced mineralization. Notably, RBFOX2 was found to upregulate Jph2, and this interaction promoted osteoblast differentiation via modulation of Dlx5 and Runx2.

These findings suggest that RBFOX2 regulates osteoblast differentiation through Jph2, making it a potential therapeutic target for bone diseases. Further studies are warranted to explore the detailed molecular mechanisms and clinical implications of this regulatory pathway.

Osteoporosis, a prevalent bone disease, is characterized by the deterioration of bone tissue microstructure and imbalanced osteogenesis. The regulatory role of PPARγ m6A methylation mediated by METTL16 remains poorly elucidated. This study utilized advanced single-cell RNA sequencing (scRNA-seq) and Bulk RNA-seq techniques to explore how METTL16 influences the osteogenic differentiation of Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs) and its implication in osteoporosis. The research revealed that METTL16 enhances the suppression of osteogenic differentiation in BMSCs, while PPARγ is associated with BMSC ferroptosis. Mechanistically, METTL16 facilitates the m6A modification of PPARγ transcription, thereby promoting ferroptosis in BMSCs and impeding their osteogenic differentiation. The in vivo animal experiments confirmed the pivotal role of the METTL16-PPARγ axis in osteoporosis development in mice. These findings suggest that the regulation of PPARγ m6A methylation by METTL16, leading to ferroptosis, is a critical mechanism impacting BMSC osteogenic differentiation and the pathogenesis of osteoporosis.

The etiology of osteoporosis is rooted in the disruption of the intricate equilibrium between bone formation and bone resorption processes. Nevertheless, the conventional anti-osteoporotic medications and hormonal therapeutic regimens currently employed in clinical practice are associated with a multitude of adverse effects, thereby constraining their overall therapeutic efficacy and potential. Recently, nanomaterials have emerged as a promising alternative due to their minimal side effects, efficient drug delivery, and ability to enhance bone formation, aiding in restoring bone balance. This review delves into the fundamental principles of bone remodeling and the bone microenvironment, as well as current clinical treatment approaches for osteoporosis. It subsequently explores the research status of nanomaterial-based drug delivery systems for osteoporosis treatment, encompassing inorganic nanomaterials, organic nanomaterials, cell-mimicking carriers and exosomes mimics and emerging therapies targeting the osteoporosis microenvironment. Finally, the review discusses the potential of nanomedicine in treating osteoporosis and outlines the future trajectory of this burgeoning field. The aim is to provide a comprehensive reference for the application of nanomaterial-based drug delivery strategies in osteoporosis therapy, thereby fostering further advancements and innovations in this critical area of medical research.

Osteoporosis (OP) is a common systemic metabolic bone disease characterized by the decrease in bone mass and hyperactivity of osteoclasts. ACT001 is approved as an orphan drug by FDA and has shown multiple protective effects against tissue injury. However, its role in prevention of osteoclast differentiation and the underlying mechanisms have not been elucidated. Herein, we show that ACT001 inhibited RANKL-induced osteoclast differentiation and F-actin ring formation through suppressing the expression of Nfatc1, TRAP, Ctsk, Dc-stamp without obvious cytotoxicity in vitro. ACT001 restrained the phosphorylation of NF-κB and the activation of NLRP3 inflammasome, thereby decreased the expression of pyroptosis-related protein. (GSDMD, caspase-1, IL-1β, IL-18). Consistent with ACT001, the NLRP3 inflammasome inhibitor MCC950 treatment also suppressed the osteoclastogenesis through inhibiting the transcriptional activation of Nfatc1. Furthermore, ACT001 protected ovariectomy-induced bone loss in mice, reduced the number of osteoclasts, downregulated the expression of NLRP3 and IL-1β. These data indicate that ACT001 can reduce RANKL-induced osteoclast differentiation through suppressing the NF-κB/NLRP3 pathway, and attenuate the bone loss induced by estrogen-deficiency, suggesting its therapeutic potential for bone homeostasis maintenance and osteoporosis treatment.

The regulation of bone metabolic microenvironment imbalances in diseases such as osteoporosis, bone defects, infections, and tumors remains a significant challenge in orthopedics. Therefore, it has become urgent to develop biomaterials with effective bone metabolic microenvironmental regulatory functions. Zeolites, as advanced biomedical materials, possess distinctive physicochemical properties such as multi-level pore structures, adjustable frameworks, easily modifiable surfaces, and excellent adsorption capabilities. These advantageous characteristics give zeolites broad application prospects in regulating the bone metabolic microenvironment. Therefore, this paper first classifies zeolites used to regulate the bone metabolic microenvironment based on their topological structures and compositional frameworks. Subsequently, it provides a detailed description of modification strategies for zeolite materials aimed at regulating this microenvironment. Next, a comprehensive summary was provided on the preparation strategies for zeolite materials aimed at regulating the bone metabolic microenvironment. Additionally, the paper focuses on the specific applications of zeolite materials in conditions of bone metabolic imbalance, such as osteoporosis, bone defects, orthopedic infections, and bone tumors, highlighting their potential in enhancing osteogenic microenvironments, controlling infections, and treating bone tumors. Finally, it outlines the prospects and challenges associated with the application of zeolites in regulating the bone metabolic microenvironment. This review comprehensively summarizes zeolites used for bone metabolic regulation, aiming to provide guidance for future research and application development.

Ferroptosis, a form of iron-dependent cell death, plays a pivotal role in age-related diseases; yet, its impact on cellular senescence and healthspan in mammals remains largely unexplored. This study identifies ferroptosis as a key regulator of cellular senescence, showing that its inhibition can significantly delay aging and extend healthspan across multiple species. During cellular senescence, ferroptosis is progressively exacerbated, marked by increased lipid peroxidation, oxidative stress, and diminished glutathione peroxidase 4 (GPX4) levels. Ferroptosis inducers such as Erastin and RSL3 accelerate senescence; while, inhibitors such as liproxstatin-1 (Lip-1) and ferrostatin-1 (Fer-1) effectively mitigate both chemically and replicatively induced senescence. In vivo, Fer-1 extends lifespan and healthspan in Caenorhabditis elegans, enhances motor function, preserves tissue integrity, and mitigates cognitive decline in both prematurely and naturally aged mice. These effects are attributed to Fer-1's upregulation of GPX4 and inhibition of ferroptosis. Notably, long-term Fer-1 treatment (over 6 months) does not adversely affect body weight or induce aging-related tissue damage but rejuvenates hematological parameters. These findings establish ferroptosis as a critical player in aging dynamics and highlight its inhibition as a promising strategy to extend healthspan and lifespan, providing valuable insights for translational approaches to combat aging and age-related decline.

Bone loss is common with aging, particularly due to reduced sex hormones, as seen in menopause. While physical training is a known non-pharmacological therapy for osteopenia and sarcopenia, few studies compare resistance and aerobic protocols, especially with systemic inflammatory markers. This study evaluated the effects of aerobic and resistance training on physical performance, femoral trabecular bone quality (micro-computed tomography), serum inflammatory markers (IL-1β, IL-6, TNF-α, IL-10) and gastrocnemius muscle area in ovariectomized (OVX) female mice.

Sixty-four c57bl/6 mice were divided into OVX and SHAM groups and subjected to sedentary, resistance (climbing) or aerobic (treadmill) protocols for 8 weeks.

Training reduced body mass (p < 0.001) in trained animals compared to sedentary. Bone quality was higher in trained groups versus sedentary. OVX increased TNF-α, but training did not alter it. IL-1β levels were higher in climbing than treadmill groups, and IL-6 increased with OVX and aerobic training (p < 0.001). IL-10 was elevated in the SHAM and climbing groups (p < 0.01). Gastrocnemius muscle area increased in both trained groups (p < 0.001) with no differences between modalities.

Aerobic and resistance training improved bone quality and muscle area in OVX mice, with climbing training uniquely linked to increased IL-10 levels.

This study aimed to identify key genes related to focal adhesions (FA) and cells involved in osteoblast (OS) and adipocyte (AD) differentiation in osteoporosis. A mouse model of disuse osteoporosis was made by hindlimbs unloading (HLU)/Tail - suspension. Micro - CT and histological analysis were done, and differentially expressed genes (DEGs) from GSE100930 were analyzed. Soft clustering on GSE80614 OS/AD samples found FA - related candidate genes. protein-protein interaction (PPI) network and cytoHubba's Degree algorithm identified key FA - genes, validated by quantitative polymerase chain reaction (qPCR). Key OS/AD - associated cells were identified by single - cell analysis. The mouse model showed decreased bone density, microstructure damage, increased marrow adiposity, and altered gene expression. Key FA - related genes for osteogenesis (ITGB3, LAMC1, COL6A3, ITGA8, PDGFRB) and adipogenesis (ITGB3, ITGA4, LAMB1, ITGA8, LAMA4) were found and validated. Key cells (chondrocyte, adipocyte, and osteoblast progenitors) are involved in specific pathways, with osteoblast progenitors having stronger interactions. Pseudotime analysis implies differentiation from chondrocyte progenitors to adipocyte, then osteoblast progenitors. This study provides new insights for disuse osteoporosis research.

Osteoporosis, particularly postmenopausal osteoporosis, is a significant global health challenge with limited treatment options due to severe side effects associated with the long-term use of conventional therapies. Therefore, this study aims to provide a potentially novel therapeutic approach by examining olive oil's effects on bone mineral density (BMD), biochemical markers, biomechanical properties, and histopathological changes in an ovariectomized (OVX) rat model.

In this study, Twenty-four 6-month-old female Wistar rats were randomly allocated into four equal groups (n = 6 rats, for each group): control group, rats given 1mL/100g olive oil, ovariectomized rats (OVX-group), and OVX rats treated with olive oil. The femoral bone mineral density (BMD), biochemical parameters, biomechanical properties, and histopathological features were studied.

After 3 months of extra virgin olive oil treatment, there were significant improvements in the different estimated parameters. This was demonstrated by preventing the changes in bone remodeling and BMD, improving the hormonal changes, oxidant/antioxidant imbalance, and abnormal levels of pro-inflammatory cytokines associated with OVX-induced osteoporosis. In addition, there was a marked improvement in the histological architecture of the cancellous and cortical bone appearance.

Olive oil dietary intake effectively reduces the impact of osteoporosis induced by ovariectomy in rats, suggesting a potentially feasible treatment option for postmenopausal osteoporosis that benefits bone architecture without any detrimental side effects on women's health.

Our study aims to assess alendronate-related adverse events (AEs) from the US FDA adverse event reporting system database.

The AE data associated with alendronate between the first quarter of 2004 and the first quarter of 2024 were selected. Various signal quantification methods, including the ROR, PRR, BCPNN, and EBGM, were applied for analysis.

In 34,943 reports where alendronate was the primary suspected drug for the AE, 24 affected system organ classes and 1046 significant preferred terms were identified in this study. Several significant AEs beyond drug instructions with strong signals were determined, including low turnover osteopathy, fracture delayed union, fracture nonunion, loss of anatomical alignment after fracture reduction, fracture malunion, periprosthetic fracture, carotid bruit, oral fibroma, traumatic occlusion, and phlebolith. The median time to onset of alendronate-related AEs was 306 days (interquartile range [IQR] 12-1,461 days), and the majority of cases occurred 2 years later (18.80%) and within 30 days (14.49%).

The current study detected multiple potential new AE signals for alendronate, and more clinical research is required to further validate our results and clarify their associations.

Osteoporosis (OP) is a common disease in the elderly, characterized by decreased bone strength, reduced bone density, and increased fracture risk. There are two clinical types of osteoporosis: primary osteoporosis and secondary osteoporosis. The most common form is postmenopausal osteoporosis, which is caused by decreased estrogen production after menopause. Secondary osteoporosis, on the other hand, occurs when certain medications, diabetes, or nutritional deficiencies lead to a decrease in bone density. Ferroptosis, a new iron-dependent programmed cell death process, is critical in regulating the development of osteoporosis, but the underlying molecular mechanisms are complex. In the pathologic process of osteoporosis, several studies have found that ferroptosis may occur in osteocytes, osteoblasts, and osteoclasts, cell types closely related to bone metabolism. The imbalance of iron homeostasis in osteoblasts and excessive iron accumulation can promote lipid peroxidation through the Fenton reaction, which induces ferroptosis in osteoblasts and affects their role in regulating bone metabolism. Ferroptosis in osteoblasts inhibits bone formation and reduces the amount of new bone production. Osteoclast-associated ferroptosis abnormalities, on the other hand, may alter the homeostasis of bone resorption. In this paper, we start from the molecular mechanism of ferroptosis, and introduce the ways in which ferroptosis affects the physiological and pathological processes of the body. After that, the effects of ferroptosis on osteoblasts and osteoclasts will be discussed separately to elucidate the molecular mechanism between ferroptosis and osteoporosis, which will provide a new breakthrough for the prevention and treatment of osteoporosis and a more effective and better idea for the treatment strategy of osteoporosis.

The incidence of type 2 diabetes mellitus (T2DM) complicated with osteoporosis (OP) (T2DM-OP) is growing. Dapagliflozin and metformin are commonly prescribed to manage glycemic levels in T2DM patients. We investigated the clinical efficacy of combining dapagliflozin with metformin in elderly patients with T2DM-OP. Totally 144 T2DM-OP patients were prospectively enrolled and allocated into two groups: the Metformin and Dapagliflozin + Metformin groups. Each group received treatment for 12 months. Fasting peripheral blood samples were collected before and after 12 months of treatment. Glycemic parameters and bone metabolic parameters were measured using oral glucose tolerance test, automatic biochemical analyzers, or liquid chromatography. Bone mineral density (BMD) changes at lumbar vertebrae (L1-4), femoral neck (FN) and total hip (TH) were assessed using dual-energy X-ray bone mineral densitometry. Pain severity was evaluated using the visual analog scale (VAS). The total effective rate, fracture incidence, and adverse reaction rate were also evaluated. After 12 months, both groups showed improvements in glycemic parameters, bone metabolic parameters, and BMD at L1-4, FN, and TH, and reductions in VAS scores. The Dapagliflozin + Metformin group exhibited more significant improvements. The overall effective rate was higher and fracture incidence, was lower in Dapagliflozin + Metformin group, with comparable rates of adverse reactions and safety profiles between the two groups. Taken together, treatment with a combination of dapagliflozin and metformin led to improvements in blood glucose levels, bone metabolism, and BMD in elderly patients with T2DM-OP, demonstrating superior efficacy and safety compared to metformin monotherapy.

Osteoporosis is related to changes in vertebral bone marrow tissues, which can be detected by MRI. A novel MRI scoring method based on routine T1 and T2 sequences has been developed and demonstrated capabilities in detecting osteoporosis and discriminating vertebral fractures. The scoring method may provide an alternative tool other than BMD measurement for broad, opportunistic use in clinics.

As a routinely used radiation-free modality at the spine, magnetic resonance imaging (MRI) is promising to assess osteoporosis because it can detect age- or osteoporosis-related changes in bone marrow tissues. Here, we proposed a new MRI scoring method using the patient's low-back subcutaneous fat and cerebrospinal fluid as reference controls on routine T1 and T2 sequences, respectively, to indicate proton-rich changes in vertebrae for assessing osteoporosis and vertebral fractures.

The study included 60 female patients (64.1 ± 15.9 years) who underwent both MRI and quantitative computed tomography (QCT) at spine. T1-based F-scoresc.fat and T2-based W-scorecs.fluid were defined as the median signal intensity (SI) from L1 to L5 over their reference controls. QCT-measured vertebral BMD was used for defining osteoporosis. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performances of the new scores for osteoporosis and vertebral fractures, which were also compared with L1-L5 signal-to-noise ratio (SNRL1-L5) or SNR-based vertebral bone quality (VBQ) score.

The F-scoresc.fat and W-scorecs.fluid increased significantly by 25.3% and 22%, respectively, in patients with osteoporosis compared to non-osteoporosis. Age was also found to be significantly different between non-osteoporosis and osteoporosis (49.92 and 74.03 years, p < .001). ROC analysis indicated that F-scoresc.fat had a greater AUC value (0.85, p < .001) than VBQ score (0.77) and SNRL1-L5 (0.71) when being used to detect osteoporosis. For separating vertebral fractures from non-fractures, F-scoresc.fat resulted in the largest AUC value of 0.81 (p < .001), compared to W-scorecs.fluid (0.74), VBQ (0.72), and SNRL1-L5 (0.75).

A new MRI scoring method based on routine T1 and T2 sequences has been developed and demonstrated improved abilities in detecting osteoporosis and discriminating vertebral fractures over VBQ and SNR.

Osteoporosis is a complex multifactorial bone disease with a strong genetic component. Among the various genes implicated in the progression of osteoporosis, those encoding G-protein-coupled receptors (GPCRs) play a crucial role in its pathogenesis. This superfamily of membrane receptors regulates myriad of cellular events including physiological and pathological processes in bone tissue. Beta-2-adrenergic receptor (a member of the GPCR superfamily) mediates cues from sympathetic nervous system to the bone tissue being expressed on both types of bone cells osteoblasts and osteoclasts. While the impact of this receptor typically investigated using animal models, the human gene ADRB2 coding beta-2-adrenergic receptor harbors numerous non-synonymous single-nucleotide polymorphisms (SNPs) that alter the activity of the receptor. One of the most prevalent SNP is c.46G > A; however, its impact on bone homeostasis has only been explored in epidemiological studies with results showing considerable variability. In this study, we generated for the first time induced pluripotent stem cells (iPSCs) line from the patient with osteoporosis carrying c.46G > A in ADRB2. This new cell line exhibits hallmarks of pluripotency, normal karyotype, and ability to differentiate into three-germ layers. Furthermore, we conducted a comparative analysis of ADRB2 expression between newly obtained iPSCs and those derived from healthy donors. This comparison extended to mesenchymal stem cells (iMSCs) derived from these iPSC lines, assessing both basal and osteogenic conditions at the mRNA and protein levels. Our findings revealed that iMSCs from an osteoporotic patient with the c.46G > A in ADRB2 exhibited decreased ADRB2 expression, which correlated with a diminished potential for osteogenic differentiation. Newly obtained iPSCs line represents a promising cell source for in vitro osteoporosis model and offers the possibility to study in-depth the specific impact of c.46G > A in ADRB2 on osteoporosis pathogenesis.

Osteoporosis is a complex disease that is affected by a variety of factors, including genetic and epigenetic influences. While DNA markers for osteoporosis have been identified, they do not fully explain the hereditary basis of the disease. Epigenetic factors, such as small microRNAs (miRNAs), may provide a missing link in understanding the molecular mechanisms underlying osteoporosis. miRNAs are a class of non-coding RNAs that play a role in the epigenetic regulation of gene expression. They are known to be involved in various biological processes, including bone formation and remodelling. Differential expression of miRNAs has been linked to the pathological decrease in bone mineral density associated with osteoporosis. It has been shown that an abnormal miRNA expression pattern leads to a decrease in osteoblast activity and an increase in osteoclast activity. Further research into the role of miRNAs in osteoporosis may help to better understand this disease and identify potential therapeutic targets for treatment. Based on these assumptions, the study of miRNA expression patterns in osteoblasts, osteoclasts, and their precursors under normal and osteoporotic conditions is a rapidly growing field of scientific research. Although the results of this research are still incomplete and sometimes contradictory, they require additional scientific analysis to better understand the complex mechanisms involved. The purpose of this paper is to review the current research on miRNAs specifically expressed in osteoblasts and osteoclasts under both normal and pathological conditions. We will also discuss the potential applications of these miRNAs as biomarkers for osteoporosis diagnosis and as targets for osteoporosis treatment.

Osteoporosis results from a disruption in skeletal homeostasis caused by an imbalance between bone resorption and bone formation. Conventional treatments, such as pharmaceutical drugs and hormone replacement therapy, often yield suboptimal results and are frequently associated with side effects. Recently, biomaterial-based approaches have gained attention as promising alternatives for managing osteoporosis. This review summarizes the current advancements in 3D-printed biomaterials designed for osteoporosis treatment. The benefits of biomaterial-based approaches compared to traditional systemic drug therapies are discussed. These 3D-printed materials can be broadly categorized based on their functionalities, including promoting osteogenesis, reducing inflammation, exhibiting antioxidant properties, and inhibiting osteoclast activity. 3D printing has the advantages of speed, precision, personalization, etc. It is able to satisfy the requirements of irregular geometry, differentiated composition, and multilayered structure of articular osteochondral scaffolds with boundary layer structure. The limitations of existing biomaterials are critically analyzed and future directions for biomaterial-based therapies are considered.

Osteoporosis is a metabolic skeletal disease characterized by low bone mass and strength, and increased risk for fragility fractures. It is a major health issue in aging populations, due to fracture-associated increased disability and mortality. Antiresorptive treatments are first line choices in most of the cases.

Bone homeostasis is complicated, and multiple factors can compromise skeletal health. Bone turnover is a continuous process regulated by the coupled activities of bone cells that preserves skeletal strength and integrity. Imbalance between bone resorption and formation leads to bone loss and increased susceptibility to fractures. Antiresorptives prevent bone loss and reduce fracture risk, by targeting osteoclastogenesis and osteoclast function and survival. Their major drawback is the coupling of osteoclast and osteoblast activity, due to which any reduction in bone resorption is followed by suppression of bone formation.

During the last couple of decades significant progress has been made in understanding of the genetic and molecular basis of osteoporosis. Critical pathways and key molecules that mediate regulation of bone resorption have been identified. These factors may underpin novel therapeutic avenues for osteoporosis, but their potential for translation into clinical applications is yet to be tested.

Primary osteoporosis (POP) is a common metabolic bone disorder that has a devastating effect on their quality of life in patients. Acupuncture, a traditional Chinese therapy, has been used to treat osteoporosis for over 2000 years. This study aimed to determine the efficacy of acupuncture in treating POP compared to conventional medicine or placebo.

We searched for potentially relevant studies in PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, China Biology Medicine disc, Wanfang database and ClinicalTrials.gov up to December 20, 2024. Randomized controlled trials investigating treatment of POP for which acupuncture was administered as a stand-alone treatment or combined with conventional medicine compared to conventional medicine or placebo, were included. The outcomes included bone mineral density (BMD), visual analogue scale (VAS) scores, clinical effectiveness rate, estradiol (E2), Oswestry Disability Index (ODI), and levels of serum alkaline phosphatase (ALP). Data were synthesized using a random-effects meta-analysis model, and the observed heterogeneity was investigated using subgroup analyses. Study quality was appraised using the Cochrane RoB 2 tools, and the quality of the aggregated evidence was evaluated using the GRADE guidelines. Publication bias was assessed by funnel plots and validated by Egger's test.

Forty eligible articles with 2654 participants were identified. Compared to the control group, acupuncture effectively increased the BMD (MD 0.04 [0.03-0.06], P < 0.001, I2 = 92%), clinical efficacy (RR 1.24 [1.14-1.34], P < 0.001, I2 = 81%), and levels of E2 (SMD 0.30 [0.09-0.52], P = 0.006, I2 = 0%), and reduced the VAS scores (SMD - 1.79 [- 2.29 to - 1.29], P < 0.001, I2 = 95%). Data on ODI and ALP were insufficient for meta-analysis.

The current evidence suggests that the efficacy of acupuncture in improving the symptoms of POP are encouraging for its use in clinical practice as a physical intervention for patients with POP. However, since the included patients were all from China, there was a risk of sample bias, high-quality multicenter studies in different countries or regions should be conducted in the future.

Facial bone density, including the jawbone, declines earlier than that of the lumbar spine and calcaneus. Calcium maltobionate is reported to mitigate bone resorption and maintain bone density of the lumbar spine in post-menopausal women, but its effects on facial bone density remain understudied. Therefore, this study compared variations in facial bone mineral density with variations in calcaneal bone mineral density and bone resorption markers among healthy women, examining differences between pre- and post-menopause and the effects of continuous calcium maltobionate intake.

This randomized, double-blind, placebo-controlled, parallel-group trial involved 48 healthy Japanese women aged 30-69 years, divided into two groups. The test food group received tablets containing calcium maltobionate, while the placebo group received tablets containing a maltose and calcium carbonate mixture for 24 weeks. Calcaneal and facial bone densities were measured pre- and post-intervention in both groups.

Post-intervention calcaneal bone mineral density and bone resorption marker deoxypyridinoline (DPD) showed no statistical difference between groups in pre-menopausal women. However, in post-menopausal women, the test food group exhibited significantly higher calcaneal bone density and lower DPD levels compared with the placebo group. Facial bone mineral density increased significantly in the test food group compared with the placebo group in post-menopausal participants, with similar trends observed in pre-menopausal participants.

Facial bone mineral density could serve as a useful indicator for monitoring bone health from middle age onward. Moreover, continuous calcium maltobionate intake appears to mitigate bone density decline in pre- and post-menopausal women, contributing to osteoporosis prevention (UMIN-CTR ID: 000046391).

Raw protein materials are beneficial for human health, so they are being increasingly used in health foods. In recent years, there has been more and more research on and applications of raw protein materials, but few teams have conducted a detailed review of the application status of raw protein materials in China's health foods, the basis for their compliance and use, and the research on their health care functions. Therefore, this review evaluates the application of animal and plant proteins in China's health foods, the impact of animal and plant proteins on human health, and future research recommendations for animal and plant proteins. This review analyzes and discusses the data on approved health foods that have been verified to contain raw protein materials (mainly including the number of protein health foods approved over the years, the classification of raw protein materials and types of relevant regulations, the analysis of the frequency of use of raw protein materials, and the functions of approved health foods). Through this process, the application of raw protein materials in health foods in China is systematically reviewed. In short, through data analysis, this study found that in 1996~2024, a total of 1142 health foods containing raw protein materials were approved in China, which are mainly divided into animal proteins, vegetable proteins, microbial proteins, and peptide raw materials, and peptide raw materials comprise the majority. The compliance applications of these ingredients are mainly related to China's five categories of food regulations. The results show the following for health foods containing raw protein materials: in terms of the dosage form, they are mainly solid preparations; according to their functional claims, they mainly help to enhance immunity, help improve bone density, help improve skin moisture, and relieve physical fatigue; and in the application of raw materials, it is found that the use of raw materials such as casein phosphopeptide, soybean protein isolate, whey protein, collagen, spirulina, and other raw materials in products is relatively high. Finally, based on these studies, this paper discusses suggestions for raw protein materials in the future development of health food in China and also discusses the limitations of the current research in this review.

Diabetic osteoporosis (DOP), a complication associated with diabetes mellitus (DM), is a metabolic bone disorder characterized by a reduction in bone mass per unit volume, impaired bone tissue microarchitecture, heightened bone fragility, and increased susceptibility to fractures. Individuals with diabetes exhibit a significantly greater incidence of osteoporosis and related fractures than those without diabetes. These fractures present a significant challenge in terms of the healing process and can result in severe consequences, including fatalities. MicroRNAs (miRNAs), a class of noncoding RNAs, play a pivotal role in numerous human diseases and are implicated in the pathogenesis of DOP. This review initially elucidates the essential role of miRNAs in the pathogenesis of DOP. Next, we emphasize the potential significance of miRNAs as valuable biomarkers for diagnosing DOP and predicting DOP-related fractures. Furthermore, we explore the involvement of miRNAs in managing DOP through various pathways, including conventional pharmaceutical interventions and exercise therapy. Importantly, miRNAs exhibit potential as targeted therapeutic agents for effectively treating DOP. Finally, we highlight the use of novel materials and exosomes for miRNA delivery, which has significant advantages in the treatment of DOP and overcomes the limitations associated with miRNA delivery.

Alveolar bone quality is essential for the maxillofacial integrity and function, and depends on alveolar bone mineralization. This study aims to investigate the in vivo changes in alveolar bone mineralization, from the perspective of mineral deposition and crystal transition in postnatal rats.

Nine postnatal time points of Wistar rats, ranging from day 1 to 56, were set to obtain the maxillary alveolar bone samples. Each time point consisted of ninety rats, with 45 females and 45 males. Macromorphology of alveolar bone was reconducted by Micro-Computed Tomography and the mineral content was quantified via Thermogravimetric analysis, Scanning Electron Microscope, High-Resolution Transmission Electron Microscopy and vibrational spectroscopy. Furthermore, the crystallinity and composition were characterized by vibrational spectroscopy, X-ray Diffraction, X-ray Photoelectron Spectroscopy and Selected Area Electron Diffraction.

The progressive increase of mineral deposition was accompanied by substantial growth in alveolar bone mass and volume in postnatal rats. Whereas the mineral percentage initially decreased and then increased, reaching a nadir on postnatal day 14 (P14) when tooth eruption was first observed. Besides, localized mineralization was initiated by the formation of amorphous precursors and then converted into mineral crystals, while there was no statistically significant change in the average crystallinity of the bone during growth.

Mineralization of alveolar bone is ongoing throughout the early growth in postnatal rats. Mineral deposition increases with age, whereas the crystallinity remains stable within a certain range. Besides, the mineral percentage reaches its lowest point on P14, which may be attributed to tooth eruption.

As the population aging progresses, age-related osteoporosis has become one of the most common and severe chronic degenerative diseases. Due to insufficient understanding of its complex pathomechanisms, current clinical treatments often suffer from many negative effects. Type H vessels play critical role in bone remodeling owing to their specialized function in coupling angiogenesis and osteogenesis. Increasing evidences have shown a close association between the age-related decline of type H vessels and bone loss. However, the underlying mechanisms whereby the regression of type H vessels with aging remain largely unknown.

Col2-Cre ERT /Foxo1 flox/flox mice and FOXO1 inhibitor (AS1842856) treated adult (6 months) and middle aged (10 months) mice were utilized for evaluating the variations in bone volume, bone microarchitecture and type H vessels through micro-CT scanning analysis, histological staining and immunofluorescence staining. In vitro tube-forming and scratch assays were applied to evaluate the angiogenic capacity of human umbilical vein endothelial cells (HUVECs) exposed to AS1842856 or conditioned culture milieu of Human Brain Vascular Pericytes (HBVPs). The expression of pericyte marker proteins, myofibroblast-related proteins and genes in inhibitors-stimulated HBVPs were detected via western blot analysis and Reverse transcription-quantitative PCR (RT-qPCR). Furthermore, perivascular myofibroblastic-like transformation was confirmed in AS1842856-treated animal models through immunofluorescence staining. We also constructed Adipoq-Cre/Foxo1 flox/flox conditional knockout mice and measured their bone mass and type H vessels by micro-CT and immunofluorescence staining. Mechanistic experiments in vitro were conducted via detection of mTOR signalling expression in HBVPs with pharmacological intervention (AS1842856 and rapamycin), genetic knockdown of Foxo1, or FOXO1-overexpression plasmid treatment, verified by RT-qPCR, western blot analysis and cellular immunofluorescence staining. In vivo validation was conducted on Adipoq-Cre/Foxo1 flox/flox mice using immunofluorescence staining. Finally, alterations in osteo-morphology and type H vessels were verified in AS1842856-treated and rapamycin-treated aged mouse models.

This study identified FOXO1 in pericytes as key components for the formation of type H vessels. We found that FOXO1 expression in pericytes decreases with aging, and pharmacological blocking with AS1842856 promoted type H vessels degeneration and increased bone loss in adult and middle-aged mice, while rapamycin prevented the above pathology in middle-aged mice. We further showed that the loss of FOXO1 in Adipoq + pericytes led to degeneration of type H vessels and bone loss in mice. Mechanistically, the inhibition of FOXO1 by AS1842856 or knockdown of Foxo1 by siRNAs activated mTOR signaling, thereby resulting in the myofibroblastic transformation of pericytes. Furthermore, blocking mTOR signaling by rapamycin rescued the above effects in vitro and in vivo.

Our findings uncover a hitherto unknown role of FOXO1 in maintaining the phenotype and function of pericytes, thereby promoting formation of type H vessels. This suggests that targeting the FOXO1-mTOR pathway in pericytes could be a potential therapeutic approach to overcome the regression of type H vessels and bone degeneration with aging.

Our research uncovers a previously unidentified role of FOXO1 in preserving pericyte characteristics and promoting the development of type H vessels. Future translational research targeting the FOXO1-mTOR pathway in pericytes may provide new strategies for the prevention and treatment of age-related osteoporosis in the clinic.

This comprehensive review examines the relationship between osteoarthritis (OA) and osteoporosis (OP), two common disorders in the elderly. OA involves joint cartilage degeneration and pain, while OP leads to fractures due to reduced bone mass. Despite different pathologies, both conditions share risk factors such as age and genetics. Studies reveal mixed results: some show higher bone mineral density (BMD) in OA patients, suggesting an inverse relationship, while others find no significant link. Proposed mechanisms include mechanical loading, bone remodeling, and inflammation. Clinical strategies focus on maintaining bone health in OA and monitoring joint health in OP, with treatments like bisphosphonates and exercise. Understanding these interactions is crucial for developing integrated treatments to improve patient outcomes and quality of life. Further research is needed to clarify these complex mechanisms.

Osteoporosis is a systemic disease with complex etiology and high prevalence, resulting in a huge economic burden. For a long time, the search for new therapeutic pharmaceuticals has never stopped. Bone loss is related to the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. In recent years, the role of immunity and inflammation in the development of osteoporosis has studied well. For example, various cytokines, chemokines and endocrine factors regulate osteoclastogenesis via activating different macrophage subtypes, including pro-inflammatory M1 and anti-inflammatory M2. Bilobalide (Bil), an active Ginkgo biloba ingredient, has garnered great interest because of its anti-oxidant and anti-inflammatory activities. In this study, we found that Bil can attenuate osteoclast generation induced by receptor activator of nuclear factor- kappa B ligand (RANKL) through upregulating the sirtuin 3 (SIRT3) and negatively regulating NF-κB signaling. Furthermore, Bil promotes M2 polarization of macrophages in a dose-dependent manner. In vivo studies provided evidence that Bil improves bone density in osteoporosis mice models. Based on the above results, we have reason to believe that Bil has potential therapeutic value in osteoclast-mediated bone loss and offers an effective option for long-term osteoporosis management.

Natural products that inhibit osteoclast differentiation are promising therapeutic and preventive agents for osteoporosis. Conventionally, identifying osteoclast differentiation involves visual inspection of the microscope images of stained osteoclasts. In this study, a supervised machine learning model was developed to classify bright-field microscope images of osteoclasts without staining. The model was used to screen a compound library, and osteoclast differentiation inhibitors were identified, demonstrating the validity of our method. Next, an in-house library of fungal extracts was screened, and pinolidoxin was revealed as an inhibitor of osteoclast differentiation. Our machine learning method enabled accurate, objective, and high-throughput evaluation of osteoclast differentiation and efficient screening of the inhibitors from natural product extracts. This study represents the first machine learning classification developed to evaluate the inhibitory activity of natural products in osteoclast differentiation.

Bone-destructive diseases including rheumatoid arthritis (RA), osteoporosis, and bone metastases, are increasingly prevalent and worrisome due to the over-activated of osteoclasts. Chongrenside D (CGD) is a furostanol saponin extracted from Smilax china L, which has been demonstrated to have anti-inflammatory properties in our previous research. However, its effect on rheumatoid arthritis, especially on osteoclast differentiation and bone destruction has not yet been investigated.

We evaluated the toxicity of CGD on the cell we used, RANKL-induced osteoclast formation, bone resorption activity, and osteoclast-specific genes or protein expression using bone marrow-derived monocytes (BMMs) -derived osteoclasts. Furthermore, the protective function of CGD on the paws of osteolytic mice was carried out using micro-CT, H&E, TRAP staining, as well as real-time PCR, and western blotting. Inflammatory cytokine levels were conducted through ELISA assay. The relative signaling pathways were investigated using western blotting, immunofluorescence microscopy and real-time PCR.

CGD notably inhibited RANKL-induced osteoclast formation, and suppressed the expression of osteoclast markers and actin ring formation, thus attenuating its bone resorption activity. For in vivo work, CGD protected against joint bone destruction induced by LPS, increased trabecular number and thickness, and reduced trabecular separation. CGD also inhibited the levels of inflammatory cytokines IL-6and TNF-α, improved the integrity of joint bones and decreased TRAP-positive staining area. The mechanistic study indicated that CGD down-regulated MMP9 and FAK-Src signaling, which were crucial for the resorption function of osteoclasts. CGD also inhibited MAPK pathway-mediated cell differentiation and survival, finally resulting in weak osteoclastogenesis.

CGD exerts a significant anti-osteolytic activity both in vitro and in vivo by inhibiting RANKL-induced osteoclastogenesis and function. Consequently, our study indicated that CGD may have a potential therapeutic role in the precaution of osteolytic bone disease.

Angiogenesis-osteogenesis coupling is critical for proper functioning and maintaining the health of bones. Any disruption in this coupling, associated with aging and disease, might lead to loss of bone mass. Osteoporosis (OP) is a debilitating bone metabolic disorder that affects the microarchitecture of bones, gradually leading to fracture. Computational analysis revealed that normal angiogenesis is disrupted during the progression of OP, especially postmenopausal osteoporosis (PMOP). The genes associated with OP and PMOP were retrieved from the DisGeNET database. Hub gene analysis and molecular pathway enrichment were performed via the Cytoscape plugins STRING, MCODE, CytoHubba, ClueGO and the web-based tool Enrichr. Twenty-eight (28) hub genes were identified, eight of which were transcription factors (HIF1A, JUN, TP53, ESR1, MYC, PPARG, RUNX2 and SOX9). Analysis of SNPs associated with hub genes via the gnomAD, I-Mutant2.0, MUpro, ConSurf and COACH servers revealed the substitution F201L in IL6 as the most deleterious. The IL6 protein was modeled in the SWISS-MODEL server and the substitution was analyzed via the YASARA FoldX plugin. A positive ΔΔG (1.936) of the F201L mutant indicates that the mutated structure is less stable than the wild-type structure is. Thirteen hub genes, including IL6 and the enriched molecular pathways were found to be profoundly involved in angiogenesis/endothelial function and immune signaling. Mechanical loading of bones through weight-bearing exercises can activate osteoblasts via mechanotransduction leading to increased bone formation. The present study suggests proper mechanical loading of bone as a preventive strategy for PMOP, by which angiogenesis and the immune status of the bone can be maintained. This in silico analysis could be used to understand the molecular etiology of OP and to develop novel therapeutic approaches.

A single-center, randomized, open, 2-period, self-crossover, single-dose trial was conducted to evaluate the bioequivalence of the test (T) and reference (R) preparations in healthy adult female subjects under fasting conditions. Seventy-six subjects were enrolled in the study, and subjects were randomly divided into 2 groups at a 1:1 ratio and were administered once per period, with a 4-day washout period. In each period, plasma drug concentrations, blood calcium changes, and antibodies were determined for pharmacokinetics, pharmacodynamics, and immunogenicity analysis, respectively, and adverse events were recorded for safety analysis. The 90% confidence intervals for the geometric mean ratios (T:R) of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the last measurable concentration, and area under the plasma concentration-time curve from time 0 to infinity were within the predefined bioequivalence criterion of 80%-125%, indicating bioequivalence between the T and R preparations under fasting conditions. Comparable serum calcium levels demonstrated pharmacodynamics similarity, and no differences were found in immunogenicity profiles. Additionally, the incidence of adverse reactions to the T preparation was 18.4% lower than that of the R preparation (31.6%). This study confirmed the bioequivalence of the T and R preparations under fasting conditions, along with comparable immunogenicity profiles and good safety.

The pathological mechanism of osteoporosis (OP) involves increased bone resorption mediated by osteoclasts and decreased bone formation mediated by osteoblasts, leading to an imbalance in bone homeostasis. Identifying key molecules in osteoclast-mediated OP progression is crucial for the prevention and treatment of OP.

Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed on the OP patient datasets from the GEO database. The results were intersected with the differential expression results from the osteoclast differentiation dataset to identify key genes. These key genes were then subjected to disease relevance analysis, and consensus clustering was performed on OP patient samples based on their expression profiles. The subgroups were analyzed for differences, followed by GO, KEGG, GSEA, and GSVA analyses, and immune infiltration. Finally, osteoclast differentiation model was constructed. After validating the success of the model using TRAP and F-actin staining, the differential expression of key genes was validated in vitro via Western blot.

CTRL, ARHGEF5, PPAP2C, VSIG2, and PBLD were identified as key genes. These genes exhibited strong disease relevance (AUC > 0.9). Functional enrichment results also indicated their close association with OP and osteoclast differentiation. In vitro differential expression validation showed that during osteoclast differentiation, CTRL was downregulated, while ARHGEF5, PPAP2C, VSIG2, and PBLD were upregulated, with all differences being statistically significant (P < 0.05).

Currently, there are no studies on the effects of these five genes on osteoclast differentiation. Therefore, it is meaningful to design in vivo and in vitro perturbation experiments to observe the impact of each gene on osteoclast differentiation and OP progression.

CTRL, ARHGEF5, PPAP2C, VSIG2, and PBLD show high potential as molecular targets for basic and clinical research in osteoclast-mediated OP.

The treatment of bone defects remains a great clinical challenge. With the development of science and technology, bone tissue engineering technology has emerged, which can mimic the structure and function of natural bone tissues and create solutions for repairing or replacing human bone tissues based on biocompatible materials, cells and bioactive factors. Hydrogels are favoured by researchers due to their high water content, degradability and good biocompatibility. This paper describes the hydrogel sources, roles and applications. According to the different types of stimuli, hydrogels are classified into three categories: physical, chemical and biochemical responses, and the applications of different stimuli-responsive hydrogels in bone tissue engineering are summarised. Stimuli-responsive hydrogels can form a semi-solid with good adhesion based on different physiological environments, which can carry a variety of bone-enhancing bioactive factors, drugs and cells, and have a long retention time in the local area, which is conducive to a long period of controlled release; they can also form a scaffold for constructing tissue repair, which can jointly promote the repair of bone injury sites. However, it also has many defects, such as poor biocompatibility, immunogenicity and mechanical stability. Further studies are still needed in the future to facilitate its clinical translation.