Abstract
Objective. To relate hormonal, osteoimmune, and metabolic regulation of bone remodeling during the menopause transition to clinical evidence.
Material and methods. A narrative analysis covered publications identified through PubMed and journal and professional society websites: studies from 2020 – 2025 and pivotal research from 1998 – 2019. Evidence from the menopause transition, postmenopause, and experimental models was considered separately.
Main findings. Integrating mechanistic and clinical evidence identifies estrogen-dependent control of osteoclastogenesis, the RANKL/OPG axis, and Wnt/β-catenin-dependent bone formation as major regulatory nodes during the menopause transition. RANKL and sclerostin have clinically validated therapeutic relevance in postmenopausal osteoporosis, whereas ERβ-dependent mechanoadaptation and GPX4-dependent osteoblast protection, including its epigenetic regulation, remain predominantly experimental. Molecular regulators, bone turnover markers, and densitometric measures therefore represent distinct levels of assessment.
Conclusion. A hypothesis-driven combination of reproductive stage, clinical fracture risk, standardized DXA, PINP and β-CTX-I, and selected molecular markers is more informative than an indiscriminate broad panel. Longitudinal studies during the menopause transition should link cellular mechanisms to clinically meaningful skeletal outcomes.
Authors and affiliations
https://elibrary.ru/efqukt M.M. Khabibulina(1), S.D. Marchenko(2), G.N. Gildeeva(2), M.D. Shamilov(1(, N.O. Danilova2(2), Kh.A. Dubacheva(2),, A.A. Abasov(3)
1-Ural State Medical University, Ministry of Health of the Russian Federation, Repina St., 3, Yekaterinburg, 620028, Russian Federation;
2-I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of the Russian Federation,
Trubetskaya St., 8/2, Moscow 119991, Russian Federation; 3-Russian University of Medicine, Ministry of Health
of the Russian Federation, Dolgorukovskaya St., 4, Moscow 127006, Russian Federation
References
1. Lumsden M.A., Dekkers O.M., Faubion S.S., Lindén Hirschberg A., Jayasena C.N., Lambrinoudaki I., Louwers Y. et al. European society of endocrinology clinical practice guideline for evaluation and management of menopause and the perimenopause. Eur. J. Endocrinol. 2025; 193 (4): G49–G81. DOI: 10.1093/ejendo/lvaf206.
2. Greendale G.A., Sowers M., Han W., Huang M.-H., Finkelstein J.S., Crandall C.J., Lee J.S. et al. Bone mineral density loss in relation to the final menstrual period in a multiethnic cohort: results from the Study of Women’s Health Across the Nation (SWAN). J. Bone Miner Res. 2012; 27 (1): 111–8. DOI: 10.1002/jbmr.534.
3. Greendale G.A., Huang M., Cauley J.A., Liao D., Harlow S., Finkelstein J.S., Hans D. et al. Trabecular Bone Score Declines During the Menopause Transition: The Study of Women’s Health Across the Nation (SWAN). J. Clin. Endocrinol Metab. 2020; 105 (4): 1872–82. DOI: 10.1210/clinem/dgz056.
4. Gregson C.L., Armstrong D.J., Avgerinou C., Bowden J., Cooper C., Douglas L., Edwards J. et al. The 2024 UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos. 2025; 20 (1): 119. DOI: 10.1007/s11657-025-01588-3.
5. Nakamura T., Imai Y., Matsumoto T., Sato S., Takeuchi K., Igarashi K., Harada Y. et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell. 2007; 130 (5): 811–23. DOI: 10.1016/j.cell.2007.07.025.
6. Martin-Millan M., Almeida M., Ambrogini E., Han L., Zhao H., Weinstein R.S., Jilka R.L. et al. The estrogen receptor-alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol Endocrinol. 2010; 24 (2): 323–34. DOI: 10.1210/me.2009-0354.
7. Kim H.-N., Ponte F., Nookaew I., Ucer Ozgurel S., Marques-Carvalho A., Iyer S., Warren A. et al. Estrogens decrease osteoclast number by attenuating mitochondria oxidative phosphorylation and ATP production in early osteoclast precursors. Sci Rep. 2020; 10 (1): 11933. DOI: 10.1038/s41598-020-68890-7.
8. Cenci S., Weitzmann M.N., Roggia C., Namba N., Novack D., Woodring J., Pacifici R. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J. Clin. Invest. 2000; 106 (10): 1229–37. DOI: 10.1172/JCI11066.
9. Okamoto K. Crosstalk between bone and the immune system. J. Bone Miner Metab. 2024; 42 (4): 470–80. DOI: 10.1007/s00774-024-01539-x.
10. Lacey D.L., Timms E., Tan H.-L., Kelley M.J., Dunstan C.R., Burgess T., Elliott R. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998; 93 (2): 165–76. DOI: 10.1016/S0092-8674(00)81569-X.
11. Takayanagi H., Kim S., Koga T., Nishina H., Isshiki M., Yoshida H., Saiura A. et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002; 3 (6): 889–901. DOI: 10.1016/S1534-5807(02)00369-6.
12. Nakashima T., Hayashi M., Fukunaga T., Kurata K., Oh-Hora M., Feng J.Q., Bonewald L.F. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011; 17 (10): 1231–4. DOI: 10.1038/nm.2452.
13. Hu L., Chen W., Qian A., Li Y.-P. Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease. Bone Res. 2024; 12 (1): 39. DOI: 10.1038/s41413-024-00342-8.
14. Glass D.A. 2nd, Bialek P., Ahn J.D., Starbuck M., Patel M.S., Clevers H., Taketo M.M. et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 2005; 8 (5): 751–64. DOI: 10.1016/j.devcel.2005.02.017.
15. Li X., Zhang Y., Kang H., Liu W., Liu P., Zhang J., Harris S.E. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 2005; 280 (20): 19883–7. DOI: 10.1074/jbc.M413274200.
16. Robling A.G., Niziolek P.J., Baldridge L.A., Condon K.W., Allen M.R., Alam I., Mantila S.M. et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J. Biol. Chem. 2008; 283 (9): 5866–75. DOI: 10.1074/jbc.M705092200.
17. Almeida M., Han L., Martin-Millan M., O’Brien C.A., Manolagas S.C. Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription. J. Biol. Chem. 2007; 282 (37): 27298–305. DOI: 10.1074/jbc.M702811200.
18. Zhang Q.-Y., Gong H.-B., Jiang M.-Y., Jin F., Wang G., Yan C.-Y., Luo X. et al. Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis. Nat Commun. 2025; 16 (1): 758. DOI: 10.1038/s41467-025-55929-4.
19. Luo J., Li L., Shi W., Xu K., Shen Y., Dai B. Oxidative stress and inflammation: roles in osteoporosis. Front Immunol. 2025; 16: 1611932. DOI: 10.3389/fimmu.2025.1611932.
20. Wang X., Zhang C., Zhao G., Yang K., Tao L. Obesity and lipid metabolism in the development of osteoporosis (Review). Int J Mol Med. 2024; 54 (1): 61. DOI: 10.3892/ijmm.2024.5385.
21. Peacock M. Calcium metabolism in health and disease. Clin. J. Am. Soc Nephrol. 2010; 5 (1): 23–30. DOI: 10.2215/CJN.05910809.
22. Manolagas S.C., O’Brien C.A., Almeida M. The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol. 2013; 9 (12): 699–712. DOI: 10.1038/nrendo.2013.179.
23. Xie Y., Pan M., Zhang Z., Zhang L., Liu H., Wang X., Lu W.W. et al. Testosterone Delays Bone Microstructural Destruction via Osteoblast-Androgen Receptor-Mediated Upregulation of Tenascin-C. Adv Sci (Weinh). 2025; 12 (31): e01518. DOI: 10.1002/advs.202501518.
24. Davis S.R., Baber R., Panay N., Bitzer J., Perez S.C., Islam R.M., Kaunitz A.M. et al. Global Consensus Position Statement on the Use of Testosterone Therapy for Women. J. Clin Endocrinol Metab. 2019; 104 (10): 4660–6. DOI: 10.1210/jc.2019-01603.
25. Хабибулина М.М., Шамилов М.Д., Елистратов Д.Г. Эффективная фармакотерапия остеопороза в перименопаузе. Врач. 2024; 35 (11): 38–40. [Khabibulina M.M., Shamilov M.D., Elistratov D.G. Effective pharmacotherapy of osteoporosis in perimenopause. Vrach. 2024; 35 (11): 38–40. DOI: 10.29296/25877305-2024-11-07 (in Russian)].
26. Cummings S.R., San Martin J., McClung M.R., Siris E.S., Eastell R., Reid I.R., Delmas P. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 2009; 361 (8): 756–65. DOI: 10.1056/NEJMoa0809493.
27. Cummings S.R., Ferrari S., Eastell R., Gilchrist N., Jensen J.-E.B., McClung M., Roux C. et al. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J. Bone Miner Res. 2018; 33 (2): 190–8. DOI: 10.1002/jbmr.3337.
28. Cosman F., Crittenden D.B., Adachi J.D., Binkley N., Czerwinski E., Ferrari S., Hofbauer L.C. et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N. Engl. J. Med. 2016; 375 (16): 1532–43. DOI: 10.1056/NEJMoa1607948.
29. Saag K.G., Petersen J., Brandi M.L., Karaplis A.C., Lorentzon M., Thomas T., Maddox J. et al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N. Engl. J. Med. 2017; 377 (15): 1417–27. DOI: 10.1056/NEJMoa1708322.
30. Cauley J.A., Robbins J., Chen Z., Cummings S.R., Jackson R.D., LaCroix A.Z., LeBoff M. et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA. 2003; 290 (13): 1729–38. DOI: 10.1001/jama.290.13.1729.
31. Bhattoa H.P., Vasikaran S., Trifonidi I., Kapoula G., Lombardi G., Jørgensen N.R., Pikner R. et al. Update on the role of bone turnover markers in the diagnosis and management of osteoporosis: a consensus paper from The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), International Osteoporosis Foundation (IOF), and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Osteoporos Int. 2025; 36 (4): 579–608. DOI: 10.1007/s00198-025-07422-3.
32. Chi G., Qiu L., Ma J., Wu W., Zhang Y. The association of osteoprotegerin and RANKL with osteoporosis: a systematic review with meta-analysis. J. Orthop Surg Res. 2023; 18 (1): 839. DOI: 10.1186/s13018-023-04179-5.
33. International Society for Clinical Densitometry. Official Adult Positions. 2023. Available at: https://iscd.org/official-positions-2023/ (accessed 10.10.2026).
34. Xu X., Yang H., Bullock W.A., Main R.P. Osteocyte Estrogen Receptor β (Ot-ERβ) Regulates Bone Turnover and Skeletal Adaptive Response to Mechanical Loading Differently in Male and Female Growing and Adult Mice. J. Bone Miner Res. 2023; 38 (1): 186–97. DOI: 10.1002/jbmr.4731.
35. Ruan B., Dong J., Wei F., Huang Z., Yang B., Zhang L. et al. DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis. Bone Res. 2024; 12: 68. DOI: 10.1038/s41413-024-00365-1.
36. Slart R.H.J.A., Punda M., Ali D.S., Bazzocchi A., Bock O., Camacho P. et al. Updated practice guideline for dual-energy X-ray absorptiometry (DXA). Eur. J. Nucl. Med. Mol. Imaging. 2025; 52 (2): 539–63. DOI: 10.1007/s00259-024-06912-6.
37. Поликлиническая терапия: учебник. Под ред. И.Л. Давыдкина, Ю.В. Щукина. 2-е изд., перераб. и доп. Москва: ГЭОТАР-Медиа, 2020; 840. ISBN: 978-5-9704-5545-6. [Outpatient Therapy: a textbook. Edited by I.L. Davydkin, Yu.V. Shchukin. 2nd ed., revised and supplemented. Moscow: GEOTAR-Media, 2020; 840. ISBN: 978-5-9704-5545-6 (in Russian)].