Background: Osteoporotic vertebral fractures cause pain and disability, which result in heavy socioeconomic burden. However, the incidence and cost of vertebral fractures in China are unknown. We aimed to assess the incidence and cost of clinically recognized vertebral fractures among people aged 50 years and older in China from 2013 to 2017. Materials and Methods: This population-based cohort study was conducted by using Urban Employee Basic Medical Insurance (UEBMI) and Urban Resident Basic Medical Insurance (URBMI) data in China from 2013 to 2017, which covered more than 95% of the Chinese population in urban areas. Vertebral fractures were identified by the primary diagnosis (i.e., International Classification of Diseases code or text of diagnosis) in UEBMI and URBMI. The incidence and medical cost of these clinically recognized vertebral fractures in urban China were calculated. Results: A total of 271,981 vertebral fractures (186,428, 68.5% females and 85,553, 31.5% males) were identified, with a mean age of 70.26 years. The incidence of vertebral fractures among patients aged 50 years and over in China increased approximately 1.79-fold during the five years, from 85.21 per 100,000 person-years in 2013 to 152.13 per 100,000 person-years in 2017. Medical costs for vertebral fracture increased from US$92.74 million in 2013 to US$505.3 million in 2017. Annual costs per vertebral fracture case increased from US$3.54 thousand in 2013 to US$5.35 thousand in 2017. Conclusion: The dramatic increase in the incidence and cost of clinically recognized vertebral fracture among patients aged 50 and over in urban China implies that more attention should be given to the management of osteoporosis to prevent osteoporotic fractures.

Background: Breast invasive carcinoma (BRCA) is a malignant tumor with high morbidity and mortality, and the prognosis is still unsatisfactory. Both ferroptosis and cuproptosis are apoptosis-independent cell deaths caused by the imbalance of corresponding metal components in cells and can affect the proliferation rate of cancer cells. The aim in this study was to develop a prognostic model of cuproptosis/ferroptosis-related genes (CFRGs) to predict survival in BRCA patients.Methods: Transcriptomic and clinical data for breast cancer patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Cuproptosis and ferroptosis scores were determined for the BRCA samples from the TCGA cohort using Gene Set Variation Analysis (GSVA), followed by weighted gene coexpression network analysis (WGCNA) to screen out the CFRGs. The intersection of the differentially expressed genes grouped by high and low was determined using X-tile. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) were used in the TGCA cohort to identify the CFRG-related signature. In addition, the relationship between risk scores and immune infiltration levels was investigated using various algorithms, and model genes were analyzed in terms of single-cell sequencing. Finally, the expression of the signature genes was validated with quantitative real-time PCR (qRT‒PCR) and immunohistochemistry (IHC).Results: A total of 5 CFRGs (ANKRD52, HOXC10, KNOP1, SGPP1, TRIM45) were identified and were used to construct proportional hazards regression models. The high-risk groups in the training and validation sets had significantly worse survival rates. Tumor mutational burden (TMB) was positively correlated with the risk score. Conversely, Tumor Immune Dysfunction and Exclusion (TIDE) and tumor purity were inversely associated with risk scores. In addition, the infiltration degree of antitumor immune cells and the expression of immune checkpoints were lower in the high-risk group. In addition, risk scores and mTOR, Hif-1, ErbB, MAPK, PI3K/AKT, TGF-β and other pathway signals were correlated with progression.Conclusion: We can accurately predict the survival of patients through the constructed CFRG-related prognostic model. In addition, we can also predict patient immunotherapy and immune cell infiltration.

Tumor vessels play important roles in cancer development and angiogenesis has been characterized as an essential process for tumor cell tumor growth. Our previous studies found that a single-dose local intraosseous simvastatin injection rapidly and long-termly mobilized bone marrow-derived endothelial progenitor cells to peripheral blood, promoting angiogenesis and ameliorating ischemia injury. However, whether intraosseous injection of simvastatin participates in cancer progression and the role of angiogenesis enhancement in this process remain unknown. In this study, we found that intraosseous injection of simvastatin improves tumor vascular structure, along with increasing the percentage of pericyte coverage on tumor vessels, and reducing vascular permeability, tumor hypoxia and tumor necrosis. Further, we demonstrate that a single-dose local intraosseous simvastatin injection suppresses tumor growth, facilitates sensitivity of chemotherapy and prolongs survival in breast cancer-bearing mice. In addition, oral application, intravenous, subcutaneous and intraperitoneal injection of simvastatin do not show these effects. Taken together, these results demonstrate that intraosseous injection of simvastatin suppresses breast cancer with tumor vascular normalization, which might be a promising strategy for cancer treatment.

Background: Rapid bone loss after fracture elevates the risk of subsequent fractures, but the mechanisms remain unclear. IL-6, a key cytokine involved in fracture healing, is markedly upregulated during the immune response after fracture; however, its role in systemic skeletal deterioration remains poorly defined. Methods: In this study, we employed label-free proteomics to identify candidate mediators in vertebral samples following fracture. Next, osteocyte siRNA knockdown and Stattic (STAT3 phosphorylation inhibitor) inhibition were used to investigate IL-6 related signaling pathways. Subsequently, indirect co-cultures of osteocyte with osteoclast or osteoblast were used to evaluate the effects of the IL-6 pathway on bone resorption and formation. Furthermore, fractured mice were treated with MR16-1 (monoclonal anti-mouse IL-6 receptor antibody) or Stattic. Then, trabecular and cortical bone in vertebrae and femur were evaluated at 4, 14, and 28 days post-fracture, including histological analysis of p-STAT3⁺ osteocyte, RANKL expression, and bone formation/resorption markers. Results: : In vitro, IL-6 dose-dependently elevated RANKL and p-STAT3 levels in osteocyte and promoted osteoclast activity in co-culture. These effects were suppressed by Stattic and replicated by STAT3 knockdown. In contrast, co-culture of osteocyte with osteoblast exhibited no significant alterations in osteogenic marker expression upon IL-6 exposure, suggesting negligible effects on osteoblast activity. In vivo, MR16-1 reduced trabecular bone loss in the vertebrae and femur after fracture. It also diminished p-STAT3⁺ osteocyte, reduced RANKL expression, and suppressed osteoclast activity without impairing osteoblastogenesis. And Stattic produced a comparable reduction in systemic bone loss and osteoclast overactivation. Conclusion: This study demonstrates that IL-6 drives osteoclast-mediated bone resorption via STAT3-dependent RANKL induction in osteocyte, thereby aggravating post-fracture systemic bone loss. And the findings highlight that modulating the IL-6/STAT3/RANKL axis and targeting osteocyte function may offer a promising therapeutic approach for preventing bone loss and minimizing the risk of fracture recurrence.

Background: Patients with osteoporosis experience increased fracture risk and decreased quality of life, which pose significant health burdens and financial challenges. Despite established links between immune cell phenotypes and inflammatory cytokines and osteoporosis, the exact mechanism involved remains unclear, and further understanding is needed for effective prevention and treatment. Methods: Here, we performed a two-sample Mendelian randomization (MR) study to estimate the causal effects between 731 immune cell types, 91 and 41 inflammatory factors (which may have some overlap), and 5 types of osteoporosis. In subsequent mediation MR analysis, we assessed whether these inflammatory cytokines mediate the causal relationship between immune cell phenotypes and osteoporosis. Additionally, colo- calization analysis was performed using Bayesian colocalization. Single-cell transcriptomic analysis was performed using datasets from osteoporosis patients available in the Gene Expression Omnibus (GEO) database. Subsequently, single-cell sequencing analysis was performed, including dimensionality reduction, clustering, and pathway enrichment, to investigate the underlying mechanisms. Finally, to confirm the critical role of IgD⁺CD24⁺ B cells and IL-17C in osteoporosis, we established vivo dexamethasone-induced osteoporosis model. Micro-CT was used to assess the effectiveness of model establishment. Flow cytometry was performed to determine the proportion of IgD⁺CD24⁺ B cells within lymphocytes in the blood. ELISA and Western blotting were used to measure IL-17C levels in serum and bone tissue. Immunohistochemistry was conducted to evaluate the expression of IL-17C in bone tissue. Results: This study found that 32 immune cell phenotypes and 38 inflammatory cytokines were significantly associated with osteoporosis. Mediation analysis indicated that IgD+ CD24+ B cells exacerbated the risk of osteoporosis by influencing the levels of interleukin-17C (IL-17C). The mediated effect was 0.07837, accounting for 15.5% of the total effect. Single-cell transcriptome analysis supported that IgD+ CD24+ B cells play a key role in musculoskeletal-related pathways in osteoporosis patients. Additionally, we have demonstrated the significant involvement of IgD⁺CD24⁺ B cells and IL-17C in the osteoporosis disease model. Conclusion: Inflammatory cytokines play a crucial role in the pathogenesis of immunity-related osteoporosis. In particular, IgD+ CD24+ B cell %lymphocyte increase the risk of osteoporosis by modulating the levels of interleukin-17C. Our results provide evidence to support the link between immunity and osteoporosis and offer new therapeutic strategies for targeting inflammatory pathways in immune-mediated osteoporosis.