Research Trends in Immunomodulatory Therapy for Postmenopausal Osteoporosis: A Bibliometric Analysis

Abstract

This bibliometric analysis investigates the research trends in immunomodulatory therapies for postmenopausal osteoporosis from 2000 to 2024. Utilizing 950 articles retrieved from the Web of Science Core Collection, we employed CiteSpace, VOSviewer, and R-based Bibliometrix to analyze publication dynamics, collaborative networks, and thematic evolution. Key findings include: (1) a steady rise in annual publications, peaking at 82 articles in 2024, with China (265 articles) and the United States (173 articles) as leading contributors. (2) Research hotspots centered on the RANKL/RANK/OPG pathway, T-cell-mediated inflammation (e.g., Th17/IL-17 axis), and emerging topics such as gut microbiota-bone axis and mesenchymal stem cell differentiation. (3) Clinical strategies prioritized denosumab (anti-RANKL) and IL-17 inhibitors, though long-term safety requires validation. (4) Institutional collaboration spanned continents, with Emory University, Harvard University, and Sichuan University as pivotal hubs. Keyword bursts revealed a shift from foundational mechanisms (e.g., TNF-α/IL-6 signaling) to translational topics like gene editing and precision medicine. Limitations include database bias (exclusive reliance on Web of Science) and undifferentiated clinical versus preclinical studies analysis. This study underscores the transformative potential of immunotherapies in osteoporosis management while advocating for multidisciplinary integration, expanded data sources, and rigorous clinical validation to address existing gaps.

Keywords

bibliometric analysis / immunomodulation / osteoimmunology / postmenopausal osteoporosis

References

[1] J. Berdah, “Promoting a Healthy Lifestyle for Preventing Osteoporosis: The Role of the Gynaecologist,” Gynécologie, Obstétrique & Fertilité 35 (2007): 785-790.

[2] T. Miyamoto, “Mechanism Underlying Post-Menopausal Osteoporosis: HIF1α Is Required for Osteoclast Activation by Estrogen Deficiency,” Keio Journal of Medicine 64 (2015): 44-47.

[3] P. Chavassieux and P. J. Meunier, “Mechanisms of Bone Loss in Osteoporosis,” La Revue du Praticien 45 (1995): 1083-1088.

[4] C. Christiansen, “The Strategy for the Treatment of Osteoporosis,” Osteoporosis International 7 (1997): 147-149.

[5] J. A. Kanis, E. V. McCloskey, D. de Takats, J. Bernard, and D. M. Zhang, “Treatment of Osteoporosis With Vitamin D,” Osteoporosis International 7 (1997): 140-146.

[6] M. D. Stone and D. J. Hosking, “Treatment of Osteoporosis: Current and Future,” Annals of the Rheumatic Diseases 50 (1991): 663-665.

[7] L. Sapra, C. Saini, S. Sharma, et al., “Targeting the Osteoclastogenic Cytokine IL-9 as a Novel Immunotherapeutic Strategy in Mitigating Inflammatory Bone Loss in Post-Menopausal Osteoporosis,” JBMR Plus 8 (2024): ziae120.

[8] C. E. Bogado, J. A. Boailchuk, M. B. Zanchetta, F. E. Massari, and J. R. Zanchetta, “Denosumab: An Update,” Drugs of Today 47 (2011): 605-613.

[9] B. Ren, X. Ren, L. Wang, et al., “A Bibliometric Research Based on Hotspots and Frontier Trends of Denosumab,” Frontiers in Pharmacology 13 (2022): 929223.

[10] E. Hernlund, A. Svedbom, M. Ivergård, et al., “Osteoporosis in the European Union: Medical Management, Epidemiology and Economic Burden. A Report Prepared in Collaboration With the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA),” Archives of Osteoporosis 8 (2013): 136.

[11] J. Rho, M. Takami, and Y. Choi, “Osteoimmunology: Interactions of the Immune and Skeletal Systems,” Molecules and Cells 17 (2004): 1-9.

[12] R. Baron and M. Kneissel, “WNT Signaling in Bone Homeostasis and Disease: From Human Mutations to Treatments,” Nature Medicine 19 (2013): 179-192.

[13] J. Li, W. T. P. Ho, C. Liu, et al., “The Role of Gut Microbiota in Bone Homeostasis,” Bone 10 (2021): 51-59.

[14] Y. Liu, J. Wu, Y. Zhu, and J. Han, “Therapeutic Application of Mesenchymal Stem Cells in Bone and Joint Diseases,” Clinical and Experimental Medicine 14 (2014): 13-24.

[15] B. L. Riggs, S. Khosla, and L. R. Melton, “Sex Steroids and the Construction and Conservation of the Adult Skeleton,” Endocrine Reviews 23 (2002): 279-302.

[16] S. Khosla, “Minireview: The OPG/RANKL/RANK System,” Endocrinology 142 (2001): 5050-5055.

[17] L. C. Hofbauer and M. Schoppet, “Clinical Implications of the Osteoprotegerin/RANKL/RANK System for Bone and Vascular Diseases,” JAMA 292 (2004): 490-495.

[18] J. Pfeilschifter, R. Koditz, M. Pfohl, and H. Schatz, “Changes in Proinflammatory Cytokine Activity After Menopause,” Endocrine Reviews 23 (2002): 90-119.

[19] M. Gnant, B. Mlineritsch, W. Schippinger, et al., “Endocrine Therapy Plus Zoledronic Acid in Premenopausal Breast Cancer,” New England Journal of Medicine 360 (2009): 679-691.

[20] S. Khosla, M. J. Oursler, and D. G. Monroe, “Estrogen and the Skeleton,” Trends in Endocrinology and Metabolism 23 (2012): 576-581.

[21] A. M. Tyagi, K. Srivastava, M. N. Mansoori, R. Trivedi, N. Chattopadhyay, and D. Singh, “Estrogen Deficiency Induces the Differentiation of IL-17 Secreting Th17 Cells: A New Candidate in the Pathogenesis of Osteoporosis,” PLoS One 7 (2012): e44552.

[22] J. Y. Li, B. Chassaing, A. M. Tyagi, et al., “Sex Steroid Deficiency-Associated Bone Loss Is Microbiota Dependent and Prevented by Probiotics,” Journal of Clinical Investigation 126 (2016): 2049-2063.

[23] R. A. Britton, R. Irwin, D. Quach, et al., “Probiotic L. reuteri Treatment Prevents Bone Loss in a Menopausal Ovariectomized Mouse Model,” Journal of Cellular Physiology 229 (2014): 1822-1830.

[24] S. C. Manolagas, C. A. O'Brien, and M. Almeida, “The Role of Estrogen and Androgen Receptors in Bone Health and Disease,” Nature Reviews. Endocrinology 9 (2013): 699-712.

[25] V. Fischer and M. Haffner-Luntzer, “Interaction Between Bone and Immune Cells: Implications for Postmenopausal Osteoporosis,” Seminars in Cell & Developmental Biology 123 (2022): 14-21.

[26] D. Wu, A. Cline-Smith, E. Shashkova, A. Perla, A. Katyal, and R. Aurora, “T-Cell Mediated Inflammation in Postmenopausal Osteoporosis,” Frontiers in Immunology 12 (2021): 687551.

[27] T. Wang and C. He, “TNF-α and IL-6: The Link Between Immune and Bone System,” Current Drug Targets 21 (2020): 213-227.

[28] Y. Saxena, S. Routh, and A. Mukhopadhaya, “Immunoporosis: Role of Innate Immune Cells in Osteoporosis,” Frontiers in Immunology 12 (2021): 687037.

[29] P. Chotiyarnwong and E. V. McCloskey, “Pathogenesis of Glucocorticoid-Induced Osteoporosis and Options for Treatment,” Nature Reviews. Endocrinology 16 (2020): 437-447.

[30] M. C. Erlandsson, E. Gömöri, M. Taube, and H. Carlsten, “Effects of Raloxifene, a Selective Estrogen Receptor Modulator, on Thymus, T Cell Reactivity, and Inflammation in Mice,” Cellular Immunology 205 (2000): 103-109.

[31] R. Flores, S. Döhrmann, C. Schaal, A. Hakkim, V. Nizet, and R. Corriden, “The Selective Estrogen Receptor Modulator Raloxifene Inhibits Neutrophil Extracellular Trap Formation,” Frontiers in Immunology 7 (2016): 566.

[32] D. Flegar, A. Sucur, A. Markotic, N. Kovacic, and D. Grcevic, “Osteoporosis in the View of Osteoimmunology: Common Feature Underlined by Different Pathogenic Mechanisms,” Periodicum Biologorum 117 (2015): 35-43.

[33] J. J. Stepan, H. Hruskova, and M. Kverka, “Update on Menopausal Hormone Therapy for Fracture Prevention,” Current Osteoporosis Reports 17 (2019): 465-473.

[34] Y. H. Gao, Y. Gao, W.-P. Qian, et al., “Estrogen Prevents Bone Loss Through Transforming Growth Factor β Signaling in T Cells,” Proceedings of the National Academy of Sciences of the United States of America 101 (2004): 16618-16623.

[35] K. C. Wu and D. M. Black, “A Perspective on Postmenopausal Bone Loss With Aging,” Journal of Bone and Mineral Research 37 (2022): 171-172.

[36] S. Roux and P. Orcel, “Bone Loss—Factors That Regulate Osteoclast Differentiation: An Update,” Arthritis Research 2 (2000): 451-456.

[37] M. M. McDonald, W. H. Khoo, P. Y. Ng, et al., “Osteoclasts Recycle via Osteomorphs During RANKL-Stimulated Bone Resorption,” Cell 184 (2021): 1330-1347.e13.

[38] E. M. Lewiecki, “Denosumab—An Emerging Treatment for Postmenopausal Osteoporosis,” Expert Opinion on Biological Therapy 10 (2010): 467-476.

[39] P. Makras and A. D. Anastasilakis, “Questions and Facts Regarding Denosumab Discontinuation Among Postmenopausal Women,” Expert Opinion on Drug Safety 20 (2021): 499-501.

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2025 The Author(s). Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.