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Aging Research 2025
老龄化影响下骨质疏松性骨折的病理机制及其影响研究
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Abstract:
随着全球老龄化进程的加快，骨质疏松性骨折(OPF)已成为严重威胁老年人健康的公共卫生问题，特别是在绝经后女性和老年男性中，骨折发生率显著上升。本文系统地分析了骨质疏松性骨折的病理机制，重点探讨了破骨细胞与成骨细胞在骨折发生及愈合过程中的关键作用。破骨细胞过度激活和成骨细胞功能受损是导致骨折愈合延迟和骨质量下降的主要原因。衰老、氧化应激、炎症反应以及雌激素缺乏等因素通过多条信号通路共同影响破骨细胞和成骨细胞的功能。为有效治疗骨质疏松性骨折，本文总结了近年来针对破骨细胞和成骨细胞的最新治疗策略，包括靶向RANKL/RANK信号通路抑制破骨细胞活性、应用甲状旁腺激素类药物促进成骨细胞功能、以及基因治疗和纳米技术在骨折治疗中的潜力。综上所述，精准治疗策略有望加速骨折愈合、改善骨质量，并显著减轻骨质疏松性骨折对患者生活质量和社会经济负担的影响。
With the acceleration of global aging, osteoporotic fractures (OPF) have become a significant public health issue threatening the health of the elderly, especially with a marked increase in fracture incidence among postmenopausal women and elderly men. This article systematically analyzes the pathological mechanisms of osteoporotic fractures, focusing on the key roles of osteoclasts and osteoblasts in fracture occurrence and healing. Overactivation of osteoclasts and dysfunction of osteoblasts are the main causes of delayed fracture healing and bone quality deterioration. Aging, oxidative stress, inflammatory responses, and estrogen deficiency, among other factors, influence osteoclast and osteoblast functions through various signaling pathways. To effectively treat osteoporotic fractures, this article summarizes the latest therapeutic strategies targeting osteoclasts and osteoblasts, including inhibition of osteoclast activity via the RANKL/RANK signaling pathway, promotion of osteoblast function with parathyroid hormone (PTH) analogs, and the potential application of gene therapy and nanotechnology in fracture treatment. In conclusion, precision treatment strategies are expected to accelerate fracture healing, improve bone quality, and significantly reduce the impact of osteoporotic fractures on patients’ quality of life and the socioeconomic burden.
| [1] | Salari, N., Ghasemi, H., Mohammadi, L., Behzadi, M.H., Rabieenia, E., Shohaimi, S., et al. (2021) The Global Prevalence of Osteoporosis in the World: A Comprehensive Systematic Review and Meta-Analysis. Journal of Orthopaedic Surgery and Research, 16, Article No. 609. https://doi.org/10.1186/s13018-021-02772-0 |
| [2] | Weaver, C.M., Gordon, C.M., Janz, K.F., Kalkwarf, H.J., Lappe, J.M., Lewis, R., et al. (2016) The National Osteoporosis Foundation’s Position Statement on Peak Bone Mass Development and Lifestyle Factors: A Systematic Review and Implementation Recommendations. Osteoporosis International, 27, 1281-1386. https://doi.org/10.1007/s00198-015-3440-3 |
| [3] | Pinto, D., Alshahrani, M., Chapurlat, R., Chevalley, T., Dennison, E., Camargos, B.M., et al. (2022) The Global Approach to Rehabilitation Following an Osteoporotic Fragility Fracture: A Review of the Rehabilitation Working Group of the International Osteoporosis Foundation (IOF) Committee of Scientific Advisors. Osteoporosis International, 33, 527-540. https://doi.org/10.1007/s00198-021-06240-7 |
| [4] | Shevroja, E., Reginster, J., Lamy, O., Al-Daghri, N., Chandran, M., Demoux-Baiada, A., et al. (2023) Update on the Clinical Use of Trabecular Bone Score (TBS) in the Management of Osteoporosis: Results of an Expert Group Meeting Organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), and the International Osteoporosis Foundation (IOF) under the Auspices of WHO Collaborating Center for Epidemiology of Musculoskeletal Health and Aging. Osteoporosis International, 34, 1501-1529. https://doi.org/10.1007/s00198-023-06817-4 |
| [5] | Collaborators, G.B.D.M.D. (2022) Global, Regional, and National Burden of 12 Mental Disorders in 204 Countries and Territories, 1990-2019: A Systematic Analysis for the Global Burden of Disease Study 2019. The Lancet Psychiatry, 9, 137-150. http://doi.org/10.1016/S2215-0366(21)00395-3 |
| [6] | Long, G., Liu, C., Liang, T., Zhang, Z., Qin, Z. and Zhan, X. (2023) Predictors of Osteoporotic Fracture in Postmenopausal Women: A Meta-Analysis. Journal of Orthopaedic Surgery and Research, 18, Article No. 574. https://doi.org/10.1186/s13018-023-04051-6 |
| [7] | Gurban, C.V., et al. (2019) Bone Turnover Markers in Postmenopausal Osteoporosis and Their Correlation with Bone Mineral Density and Menopause Duration. Romanian Journal of Morphology and Embryology, 60, 1127-1135. |
| [8] | Luo, F., Chen, T., Chen, S., Bai, D. and Li, X. (2025) Regulation of Osteoclast-Mediated Bone Resorption by Lipids. Bone, 193, Article ID: 117423. https://doi.org/10.1016/j.bone.2025.117423 |
| [9] | Guo, J., Huang, X., Dou, L., Yan, M., Shen, T., Tang, W., et al. (2022) Aging and Aging-Related Diseases: From Molecular Mechanisms to Interventions and Treatments. Signal Transduction and Targeted Therapy, 7, Article No. 391. https://doi.org/10.1038/s41392-022-01251-0 |
| [10] | Wang, L., Chen, L. and Chen, K. (2023) Hormone-Related and Drug-Induced Osteoporosis: A Cellular and Molecular Overview. International Journal of Molecular Sciences, 24, Article No. 5814. https://doi.org/10.3390/ijms24065814 |
| [11] | Cheng, C., Chen, L. and Chen, K. (2022) Osteoporosis Due to Hormone Imbalance: An Overview of the Effects of Estrogen Deficiency and Glucocorticoid Overuse on Bone Turnover. International Journal of Molecular Sciences, 23, Article No. 1376. https://doi.org/10.3390/ijms23031376 |
| [12] | Sun, X., Xie, Z., Hu, B., Zhang, B., Ma, Y., Pan, X., et al. (2020) The Nrf2 Activator RTA-408 Attenuates Osteoclastogenesis by Inhibiting STING Dependent NF-κB Signaling. Redox Biology, 28, Article ID: 101309. https://doi.org/10.1016/j.redox.2019.101309 |
| [13] | Wang, Y., Li, X., Zhou, S., Li, J., Zhu, Y., Wang, Q., et al. (2022) MCU Inhibitor Ruthenium Red Alleviates the Osteoclastogenesis and Ovariectomized Osteoporosis via Suppressing RANKL-Induced ROS Production and Nfatc1 Activation through P38 MAPK Signaling Pathway. Oxidative Medicine and Cellular Longevity, 2022, Article ID: 7727006. https://doi.org/10.1155/2022/7727006 |
| [14] | Fu, L., Wu, W., Sun, X. and Zhang, P. (2020) Glucocorticoids Enhanced Osteoclast Autophagy through the PI3K/Akt/mTOR Signaling Pathway. Calcified Tissue International, 107, 60-71. https://doi.org/10.1007/s00223-020-00687-2 |
| [15] | Meirow, Y., Jovanovic, M., Zur, Y., Habib, J., Colombo, D.F., Twaik, N., et al. (2022) Specific Inflammatory Osteoclast Precursors Induced during Chronic Inflammation Give Rise to Highly Active Osteoclasts Associated with Inflammatory Bone Loss. Bone Research, 10, Article No. 36. https://doi.org/10.1038/s41413-022-00206-z |
| [16] | Pajarinen, J., Lin, T., Gibon, E., Kohno, Y., Maruyama, M., Nathan, K., et al. (2019) Mesenchymal Stem Cell-Macrophage Crosstalk and Bone Healing. Biomaterials, 196, 80-89. https://doi.org/10.1016/j.biomaterials.2017.12.025 |
| [17] | Goodnough, L.H. and Goodman, S.B. (2022) Relationship of Aging, Inflammation, and Skeletal Stem Cells and Their Effects on Fracture Repair. Current Osteoporosis Reports, 20, 320-325. https://doi.org/10.1007/s11914-022-00742-x |
| [18] | Wu, J., Cai, P., Lu, Z., Zhang, Z., He, X., Zhu, B., et al. (2020) Identification of Potential Specific Biomarkers and Key Signaling Pathways between Osteogenic and Adipogenic Differentiation of hBMSCs for Osteoporosis Therapy. Journal of Orthopaedic Surgery and Research, 15, Article No. 437. https://doi.org/10.1186/s13018-020-01965-3 |
| [19] | Yoshida, G., Kawabata, T., Takamatsu, H., Saita, S., Nakamura, S., Nishikawa, K., et al. (2022) Degradation of the NOTCH Intracellular Domain by Elevated Autophagy in Osteoblasts Promotes Osteoblast Differentiation and Alleviates Osteoporosis. Autophagy, 18, 2323-2332. https://doi.org/10.1080/15548627.2021.2017587 |
| [20] | Wang, Z., Wu, J., Li, L., Wang, K., Wu, X., Chen, H., et al. (2023) Eicosapentaenoic Acid Supplementation Modulates the Osteoblast/Osteoclast Balance in Inflammatory Environments and Protects against Estrogen Deficiency-Induced Bone Loss in Mice. Clinical Nutrition, 42, 1715-1727. https://doi.org/10.1016/j.clnu.2023.07.022 |
| [21] | Daponte, V., Henke, K. and Drissi, H. (2024) Current Perspectives on the Multiple Roles of Osteoclasts: Mechanisms of Osteoclast-Osteoblast Communication and Potential Clinical Implications. eLife, 13, e95083. https://doi.org/10.7554/elife.95083 |
| [22] | Greco, T., Mascio, A., Comisi, C., Polichetti, C., Caravelli, S., Mosca, M., et al. (2023) RANKL-RANK-OPG Pathway in Charcot Diabetic Foot: Pathophysiology and Clinical-Therapeutic Implications. International Journal of Molecular Sciences, 24, Article No. 3014. https://doi.org/10.3390/ijms24033014 |
| [23] | Liu, Y., Liu, W., Yu, Z., Zhang, Y., Li, Y., Xie, D., et al. (2021) A Novel BRD4 Inhibitor Suppresses Osteoclastogenesis and Ovariectomized Osteoporosis by Blocking RANKL-Mediated MAPK and NF-κB Pathways. Cell Death & Disease, 12, Article No. 654. https://doi.org/10.1038/s41419-021-03939-7 |
| [24] | Xie, Y., Pan, M., Gao, Y., Zhang, L., Ge, W. and Tang, P. (2019) Dose-Dependent Roles of Aspirin and Other Non-Steroidal Anti-Inflammatory Drugs in Abnormal Bone Remodeling and Skeletal Regeneration. Cell & Bioscience, 9, Article No. 103. https://doi.org/10.1186/s13578-019-0369-9 |
| [25] | He, J., Zheng, L., Li, X., Huang, F., Hu, S., Chen, L., et al. (2023) Obacunone Targets Macrophage Migration Inhibitory Factor (MIF) to Impede Osteoclastogenesis and Alleviate Ovariectomy-Induced Bone Loss. Journal of Advanced Research, 53, 235-248. https://doi.org/10.1016/j.jare.2023.01.003 |
| [26] | Liu, X., Li, F., Dong, Z., Gu, C., Mao, D., Chen, J., et al. (2023) Metal-PolyDNA Nanoparticles Reconstruct Osteoporotic Microenvironment for Enhanced Osteoporosis Treatment. Science Advances, 9, eadf3329. https://doi.org/10.1126/sciadv.adf3329 |
| [27] | Yang, Y., Li, M., Zhou, B., Jiang, X., Zhang, D. and Luo, H. (2023) Graphene Oxide/Gallium Nanoderivative as a Multifunctional Modulator of Osteoblastogenesis and Osteoclastogenesis for the Synergistic Therapy of Implant-Related Bone Infection. Bioactive Materials, 25, 594-614. https://doi.org/10.1016/j.bioactmat.2022.07.015 |
| [28] | Dayanandan, A.P., Cho, W.J., Kang, H., Bello, A.B., Kim, B.J., Arai, Y., et al. (2023) Emerging Nano-Scale Delivery Systems for the Treatment of Osteoporosis. Biomaterials Research, 27, Article No. 68. https://doi.org/10.1186/s40824-023-00413-7 |
| [29] | Arthur Vithran, D.T., Essien, A.E., Rahmati, M., Opoku, M., Keon Yon, D., López Sánchez, G.F., et al. (2024) Teriparatide in Postmenopausal Osteoporosis: Uncovering Novel Insights into Efficacy and Safety Compared to Other Treatments—A Systematic Review and Meta-Analysis. EFORT Open Reviews, 9, 845-861. https://doi.org/10.1530/eor-23-0205 |
| [30] | Wang, Y., Hu, Y., Lan, S., Chen, Z., Zhang, Y., Guo, X., et al. (2023) A Recombinant Parathyroid Hormone‐Related Peptide Locally Applied in Osteoporotic Bone Defect. Advanced Science, 10, e2300516. https://doi.org/10.1002/advs.202300516 |
| [31] | Shen, G., Ren, H., Shang, Q., Zhao, W., Zhang, Z., Yu, X., et al. (2020) Foxf1 Knockdown Promotes BMSC Osteogenesis in Part by Activating the Wnt/β-Catenin Signalling Pathway and Prevents Ovariectomy-Induced Bone Loss. EBioMedicine, 52, 102626. https://doi.org/10.1016/j.ebiom.2020.102626 |
| [32] | Lowery, J.W. and Rosen, V. (2018) The BMP Pathway and Its Inhibitors in the Skeleton. Physiological Reviews, 98, 2431-2452. https://doi.org/10.1152/physrev.00028.2017 |
| [33] | Wu, Q., Wang, X., Jiang, F., Zhu, Z., Wen, J. and Jiang, X. (2020) Study of Sr-Ca-Si-Based Scaffolds for Bone Regeneration in Osteoporotic Models. International Journal of Oral Science, 12, Article No. 25. https://doi.org/10.1038/s41368-020-00094-1 |
| [34] | Wang, W., Xiong, Y., Zhao, R., Li, X. and Jia, W. (2022) A Novel Hierarchical Biofunctionalized 3D-Printed Porous Ti6Al4V Scaffold with Enhanced Osteoporotic Osseointegration through Osteoimmunomodulation. Journal of Nanobiotechnology, 20, Article No. 68. https://doi.org/10.1186/s12951-022-01277-0 |
| [35] | (2023) Summary for Patients: Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults. Annals of Internal Medicine, 176, I24. http://doi.org/10.7326/p22-0025 |
