Bone aging: a paradigm of multiscale degeneration and targeted rejuvenation

Abstract

Bone aging is not merely a process of bone mass loss but rather a multi-level, networked degenerative phenomenon spanning molecular, cellular, tissue, and system levels. With the accelerating pace of global population aging, bone degenerative diseases have emerged as a major public health challenge. Consequently, there is an urgent need to elucidate the underlying mechanisms from an integrated perspective and to develop innovative intervention strategies. This review systematically synthesizes the comprehensive landscape of bone aging. At the macroscopic level, bone aging is characterized by declines in bone mass, microstructure, and biomechanical properties, ultimately leading to increased fragility. At the microscopic level, its pathogenesis involves dysfunction across multiple layers. Molecular mechanisms include genetic and epigenetic alterations, oxidative stress, the senescence-associated secretory phenotype, and dysregulation of key signaling pathways. Cellular level changes involve telomere attrition, mitochondrial and endoplasmic reticulum dysfunction, impaired proteostasis, altered nutrient sensing, and cellular senescence. At the microenvironmental and systemic levels, contributing factors include chronic inflammation, hormonal changes, and extracellular matrix remodeling. Correspondingly, intervention strategies include non-pharmacological approaches, such as dietary optimization, physical activity, and avoidance of alcohol and tobacco, as well as pharmacological therapies, including antiresorptive agents, anabolic bone-forming drugs, and senolytics. Emerging therapeutic avenues include regenerative medicine, gene therapy, and tissue engineering. Future research should focus on constructing a multi-omics-integrated bone aging atlas, developing bone organoids and computational models, establishing multimodal risk assessment systems, advancing precision therapies that target aging-related pathways, and promoting prevention-centered public health strategies. This review aims to provide a systematic framework for understanding the complex pathophysiology of bone aging and to provide key insights and directions for future interdisciplinary collaborations, translational research, and clinical interventions.

References

[1] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos. Int., 2006, 17: 1726-1733.

[2] Welc SS, Brotto M, White KE, Bonewald LF. Aging: a struggle for beneficial to overcome negative factors made by muscle and bone. Mech. Ageing Dev., 2025, 224: 112039.

[3] Barkaoui A, Ben Kahla R, Merzouki T, Hambli R. Age and gender effects on bone mass density variation: finite elements simulation. Biomech. Model Mechanobiol., 2017, 16: 521-535.

[4] Riggs BL, et al.Differential changes in bone mineral density of the appendicular and axial skeleton with aging: relationship to spinal osteoporosis. J. Clin. Investig., 1981, 67: 328-335.

[5] Cui J, Shibata Y, Zhu T, Zhou J, Zhang J. Osteocytes in bone aging: advances, challenges, and future perspectives. Ageing Res. Rev., 2022, 77: 101608.

[6] Augat P, Schorlemmer S. The role of cortical bone and its microstructure in bone strength. Age Ageing, 2006, 35: ii27-ii31.

[7] Seeman E, Delmas PD. Bone quality-the material and structural basis of bone strength and fragility. N. Engl. J. Med., 2006, 354: 2250-2261.

[8] Chartier SR, Mitchell SAT, Majuta LA, Mantyh PW. The changing sensory and sympathetic innervation of the young, adult and aging mouse femur. Neuroscience, 2018, 387: 178-190.

[9] Feingold M, Nelson DA, Parfitt AM. Composite index of skeletal mass: principal components analysis of regional bone mineral densities. J. Bone Miner. Res., 1992, 7: 89-96.

[10] Seeman E. Pathogenesis of bone fragility in women and men. Lancet, 2002, 359: 1841-1850.

[11] Seeman E. Age- and menopause-related bone loss compromise cortical and trabecular microstructure. J. Gerontol. A Biol. Sci. Med Sci., 2013, 68: 1218-1225.

[12] Mosekilde L, Mosekilde L, Danielsen CC. Biomechanical competence of vertebral trabecular bone in relation to ash density and age in normal individuals. Bone, 1987, 8: 79-85.

[13] Martin B. Aging and strength of bone as a structural material. Calcif. Tissue Int., 1993, 53: S34-S40.

[14] Boskey AL, Coleman R. Aging and bone. J. Dent. Res., 2010, 89: 1333-1348.

[15] Ballhause, T. M. et al. Spatio-temporal characterization of compositional and cellular properties in the murine fracture callus. Acta Biomater.206, 150–159 (2025).

[16] Yu YE, Hu YJ, Zhou B, Wang J, Guo XE. Microstructure determines apparent-level mechanics despite tissue-level anisotropy and heterogeneity of individual plates and rods in normal human trabecular bone. J. Bone Miner. Res., 2021, 36: 1796-1807.

[17] Koehne T, et al.Trends in trabecular architecture and bone mineral density distribution in 152 individuals aged 30-90 years. Bone, 2014, 66: 31-38.

[18] Saito, M. & Marumo, K. Collagen Cross-links as a determinant of bone quality. In Osteoporosis in Orthopedics: Assessment and Therapeutic Options (eds Shimada, Y. & Miyakoshi, N.) 35–54. https://doi.org/10.1007/978-4-431-55778-4_3 (Springer Japan, 2016)

[19] Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos. Int., 2010, 21: 195-214.

[20] Casella G, et al.Transcriptome signature of cellular senescence. Nucleic Acids Res., 2019, 47: 7294-7305.

[21] Purcell M, Kruger A, Tainsky MA. Gene expression profiling of replicative and induced senescence. Cell Cycle, 2014, 13: 3927-3937.

[22] Hernandez-Segura A, et al.Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol., 2017, 27: 2652-2660.e4.

[23] Kim Y-M, et al.Implications of time-series gene expression profiles of replicative senescence. Aging Cell, 2013, 12: 622-634.

[24] Jochems F, et al.The Cancer SENESCopedia: a delineation of cancer cell senescence. Cell Rep., 2021, 36109441

[25] de Boer J, et al.Premature aging in mice deficient in DNA repair and transcription. Science, 2002, 296: 1276-1279.

[26] Rasheed N, Wang X, Niu Q-T, Yeh J, Li B. Atm-deficient mice: an osteoporosis model with defective osteoblast differentiation and increased osteoclastogenesis. Hum. Mol. Genet., 2006, 15: 1938-1948.

[27] Ruzankina Y, et al.Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell, 2007, 1: 113-126.

[28] Chen Q, et al.DNA damage drives accelerated bone aging via an NF-κB-dependent mechanism. J. Bone Miner. Res., 2013, 28: 1214-1228.

[29] Chandra A, et al.Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis. FASEB J., 2018, 32: 52-62.

[30] Rivadeneira F, et al.Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat. Genet., 2009, 41: 1199-1206.

[31] Wehmeyer C, et al.Sclerostin inhibition promotes TNF-dependent inflammatory joint destruction. Sci. Transl. Med., 2016, 8: 330ra35.

[32] Sims A-M, et al.Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. J. Bone Miner. Res., 2008, 23: 499-506.

[33] Saul D, et al.A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nat. Commun., 2022, 134827

[34] Chandra A, et al.Bone marrow adiposity in models of radiation- and aging-related bone loss is dependent on cellular senescence. J. Bone Miner. Res., 2022, 37: 997-1011.

[35] Fuggle NR, Laskou F, Harvey NC, Dennison EM. A review of epigenetics and its association with ageing of muscle and bone. Maturitas, 2022, 165: 12-17.

[36] Soerensen M, Figeac F, Christensen K, Kassem M. Epigenetic clocks as biomarkers for bone aging: evidence from a twin study. Aging Cell, 2025, 24: e70204.

[37] Alshammari RA, et al.Integrative epigenomic and targeted protein analysis in MRONJ: correlating DNA methylation with bone biomarkers. Int. J. Mol. Sci., 2025, 26: 11208.

[38] Reppe S, et al.Distinct DNA methylation profiles in bone and blood of osteoporotic and healthy postmenopausal women. Epigenetics, 2017, 12: 674-687.

[39] Voisin S, et al.An epigenetic clock for human skeletal muscle. J. Cachexia Sarcopenia Muscle, 2020, 11: 887-898.

[40] Lin Q, et al.Delivery of miR-29a/29c-3p by serum exosomes promotes osteogenesis through TET3-dependent Sox9 demethylation and PI3K/Akt activation. J. Nanobiotechnol., 2025, 23751

[41] Cheng K, et al.MicroRNA-874-3p is a potential contributor to primary hyperparathyroidism-induced osteoporosis. Clin. Interv. Aging, 2025, 20: 2079-2089.

[42] Huang B, et al.KDM3A and KDM4C regulate mesenchymal stromal cell senescence and bone aging via condensin-mediated heterochromatin reorganization. iScience, 2019, 21: 375-390.

[43] Wu L, et al.Integrative analysis reveals synergistic regulation of Sp7 by BRD9 and Wnt/β-catenin signaling during osteogenic differentiation. Commun. Biol., 2025, 9: 23.

[44] Liu F, et al.S-sulfhydration of SIRT3 combats BMSC senescence and ameliorates osteoporosis via stabilizing heterochromatic and mitochondrial homeostasis. Pharm. Res., 2023, 192106788

[45] Li M, et al.Genistein mitigates senescence of bone marrow mesenchymal stem cells via ERRα-mediated mitochondrial biogenesis and mitophagy in ovariectomized rats. Redox Biol., 2023, 61102649

[46] Sun Y, et al.Macrophage-osteoclast associations: origin, polarization, and subgroups. Front. Immunol., 2021, 12: 778078.

[47] Gao J, et al.SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress. Cell Death Differ., 2018, 25: 229-240.

[48] Zhu C, et al.Autophagy in bone remodeling: a regulator of oxidative stress. Front. Endocrinol., 2022, 13898634

[49] Zahan O-M, Serban O, Gherman C, Fodor D. The evaluation of oxidative stress in osteoarthritis. Med. Pharm. Rep., 2020, 93: 12-22.

[50] Li J, et al.Pyrroloquinoline quinone alleviates natural aging-related osteoporosis via a novel MCM3-Keap1-Nrf2 axis-mediated stress response and Fbn1 upregulation. Aging Cell, 2023, 22e13912

[51] Yuan H, et al.Ganoderic acid D prevents oxidative stress-induced senescence by targeting 14-3-3ε to activate CaM/CaMKII/NRF2 signaling pathway in mesenchymal stem cells. Aging Cell, 2022, 21e13686

[52] Sun K, et al.The role of the sirtuin family in cartilage and osteoarthritis: molecular mechanisms and therapeutic targets. Arthritis Res. Ther., 2022, 24: 286.

[53] Zhou Z, et al.Protective effect of SIRT1 activator on the knee with osteoarthritis. Front. Physiol., 2021, 12661852

[54] Zhang J, Yu H, Man M-Q, Hu L. Aging in the dermis: fibroblast senescence and its significance. Aging Cell, 2024, 23e14054

[55] Jha SK, et al.Cellular senescence in lung cancer: molecular mechanisms and therapeutic interventions. Ageing Res. Rev., 2024, 97102315

[56] Fang C-L, Liu B, Wan M. Bone-SASP’ in skeletal aging. Calcif. Tissue Int., 2023, 113: 68-82.

[57] Farr JN, et al.Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res., 2016, 31: 1920-1929.

[58] Chandra A, et al.Targeted reduction of senescent cell burden alleviates focal radiotherapy-related bone loss. J. Bone Miner. Res., 2020, 35: 1119-1131.

[59] Hennrich ML, et al.Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline. Nat. Commun., 2018, 94004

[60] Farr JN, et al.Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med., 2017, 23: 1072-1079.

[61] Lee J, et al.Cabozantinib, an anti-aging agent, prevents bone loss in estrogen-deficient mice by suppressing senescence-associated secretory phenotype factors. Int. J. Mol. Sci., 2025, 26: 7123.

[62] Farr JN, et al.Effects of age and estrogen on skeletal gene expression in humans as assessed by RNA sequencing. PLoS One, 2015, 10: e0138347.

[63] Movérare-Skrtic S, et al.Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nat. Med., 2014, 20: 1279-1288.

[64] Yu B, et al.Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-κB. Nat. Med., 2014, 20: 1009-1017.

[65] Cosman F, et al.Romosozumab treatment in postmenopausal women with osteoporosis. N. Engl. J. Med., 2016, 375: 1532-1543.

[66] Bai J, et al.Gαi1/3 regulates Wnt/β-Catenin signaling to promote osteogenesis and bone formation. J. Bone Miner. Res., 2025, 41: 46-59.

[67] Song J, et al.FOXO-regulated OSER1 reduces oxidative stress and extends lifespan in multiple species. Nat. Commun., 2024, 157144

[68] Wang G, et al.Roburic acid attenuates osteoclastogenesis and bone resorption by targeting RANKL-induced intracellular signaling pathways. J. Cell Physiol., 2022, 237: 1790-1803.

[69] Lorthongpanich C, et al.YAP as a key regulator of adipo-osteogenic differentiation in human MSCs. Stem Cell Res. Ther., 2019, 10: 402.

[70] Sladitschek-Martens HL, et al.YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING. Nature, 2022, 607: 790-798.

[71] Li Z, Lin J, Wu J, Suo J, Wang Z. The Hippo signalling pathway in bone homeostasis: under the regulation of mechanics and aging. Cell Prolif., 2024, 57e13652

[72] Coffin JD, Homer-Bouthiette C, Hurley MM. Fibroblast growth factor 2 and its receptors in bone biology and disease. J. Endocr. Soc., 2018, 2: 657-671.

[73] Kir S, et al.FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science, 2011, 331: 1621-1624.

[74] Zhao Y-X, et al.Association between bile acid metabolism and bone mineral density in postmenopausal women. Clinics, 2020, 75e1486

[75] Bär L, et al.Insulin suppresses the production of fibroblast growth factor 23 (FGF23). Proc. Natl. Acad. Sci. USA, 2018, 115: 5804-5809.

[76] Rupp T, et al.High FGF23 levels are associated with impaired trabecular bone microarchitecture in patients with osteoporosis. Osteoporos. Int., 2019, 30: 1655-1662.

[77] Wu Y-T, et al.Lower serum fibroblast growth factor 21 levels are associated with normal lumbar spine bone mineral density in hemodialysis patients. Int. J. Environ. Res. Public Health, 2020, 17: 1938.

[78] Hu W, et al.Fibroblast growth factor 21 is associated with bone mineral density, but not with bone turnover markers and fractures in chinese postmenopausal women. J. Clin. Densitom., 2019, 22: 179-184.

[79] Valdes AM, et al.Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis. Osteoporos. Int., 2007, 18: 1203-1210.

[80] Bekaert S, et al.Telomere length versus hormonal and bone mineral status in healthy elderly men. Mech. Ageing Dev., 2005, 126: 1115-1122.

[81] Sanders JL, et al.Leukocyte telomere length is not associated with BMD, osteoporosis, or fracture in older adults: results from the health, aging and body composition study. J. Bone Miner. Res., 2009, 24: 1531-1536.

[82] Tang NLS, et al.The effect of telomere length, a marker of biological aging, on bone mineral density in elderly population. Osteoporos. Int., 2010, 21: 89-97.

[83] Kirk B, et al.Leukocyte telomere length is associated with MRI-thigh fat-free muscle volume: data from 16 356 UK Biobank adults. J. Cachexia Sarcopenia Muscle, 2024, 15: 1157-1166.

[84] Kalyan S, et al.Premature spinal bone loss in women living with HIV is associated with shorter leukocyte telomere length. Int. J. Environ. Res. Public Health, 2018, 15: 1018.

[85] Kirk B, Kuo C-L, Xiang M, Duque G. Associations between leukocyte telomere length and osteosarcopenia in 20,400 adults aged 60 years and over: data from the UK Biobank. Bone, 2022, 161: 116425.

[86] Pignolo RJ, et al.Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis. Aging Cell, 2008, 7: 23-31.

[87] Guerrero-López R, et al.Premature ageing of lung alveoli and bone marrow cells from Terc deficient mice with different telomere lengths. Sci. Rep., 2025, 156102

[88] von Zglinicki T, Saretzki G, Döcke W, Lotze C. Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence?. Exp. Cell Res., 1995, 220: 186-193.

[89] Lavhale MP, Mandlik SK, Shinde VM, Mandlik DS. Nrf2 signaling in bone health: unlocking new avenues for osteoporosis management. Inflammopharmacology, 2025, 33: 6419-6455.

[90] Deng Y, et al.SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch. Bone Res., 2025, 13: 36.

[91] Zeng X, et al.Matrix stiffness promotes DRP1-mediated myofibroblast senescence to drive silica-induced pulmonary fibrosis. Aging Cell, 2025, 24e70275

[92] Liu J, Zhang X, Hou H, Ouyang J, Dai J. Advances in osteoblast and mitochondrial dynamics and their transfer in osteoporosis. J. Cell Mol. Med., 2024, 28e70299

[93] Cai W, et al.STING regulates aging-related osteoporosis by mediating the Hk2-Vdac1 mitochondrial axis. Free Radic. Biol. Med., 2024, 225: 1-14.

[94] Volodarsky M, et al.A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. Hum. Mutat., 2013, 34: 582-586.

[95] Cabral WA, et al.Absence of the ER cation channel TMEM38B/TRIC-B disrupts intracellular calcium homeostasis and dysregulates collagen synthesis in recessive osteogenesis imperfecta. PLoS Genet., 2016, 12: e1006156.

[96] Webb EA, et al.Phenotypic spectrum in osteogenesis imperfecta due to mutations in TMEM38B: unraveling a complex cellular defect. J. Clin. Endocrinol. Metab., 2017, 102: 2019-2028.

[97] Zhong M, Wu Z, Chen Z, Ren Q, Zhou J. Advances in the interaction between endoplasmic reticulum stress and osteoporosis. Biomed. Pharmacother., 2023, 165: 115134.

[98] Son H-E, Kim E-J, Jang W-G. Curcumin induces osteoblast differentiation through mild-endoplasmic reticulum stress-mediated such as BMP2 on osteoblast cells. Life Sci., 2018, 193: 34-39.

[99] Suzuki R, et al.Intracellular accumulation of advanced glycation end products induces osteoblast apoptosis via endoplasmic reticulum stress. J. Bone Miner. Res., 2020, 35: 1992-2003.

[100] Zhu T, Yuan L-Q. Complex relationship between proton pump inhibitor use and bone health. Am. J. Gastroenterol., 2017, 112: 651.

[101] Tao Z-S, Ma T, Yang M. Cyclosporine a inhibits bone regeneration and induces bone loss in a rat model. Int. Immunopharmacol., 2024, 132: 111951.

[102] Chen X, et al.Palmitic acid induces lipid droplet accumulation and senescence in nucleus pulposus cells via ER-stress pathway. Commun. Biol., 2024, 7: 539.

[103] Chalil S, et al.Increased endoplasmic reticulum stress in mouse osteocytes with aging alters Cox-2 response to mechanical stimuli. Calcif. Tissue Int., 2015, 96: 123-128.

[104] Zheng B, et al.S1P regulates intervertebral disc aging by mediating endoplasmic reticulum-mitochondrial calcium ion homeostasis. JCI Insight, 2024, 9e177789

[105] Yin M, Zheng X, Shi L. Targeting p38 MAPK: a potential bridge between ER stress and age-related bone loss. Cell Signal, 2025, 127: 111549.

[106] Zheng J, Gao Y, Lin H, Yuan C, KeqianzhiEnhanced autophagy suppresses inflammation-mediated bone loss through ROCK1 signaling in bone marrow mesenchymal stem cells. Cells Dev., 2021, 167: 203687.

[107] Hayashi C, et al.miR-1260b inhibits periodontal bone loss by targeting ATF6β-mediated regulation of ER stress. Front. Cell Dev. Biol., 2022, 101061216

[108] Zhang Y, et al.CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress. Sci. Rep., 2016, 637827

[109] Wang B, Dong Y, Tian Z, Chen Y, Dong S. The role of dendritic cells derived osteoclasts in bone destruction diseases. Genes Dis., 2021, 8: 401-411.

[110] van der Kraan AGJ, et al.HSP90 inhibitors enhance differentiation and MITF (microphthalmia transcription factor) activity in osteoclast progenitors. Biochem. J., 2013, 451: 235-244.

[111] Zhou J, Fujiwara T, Ye S, Li X, Zhao H. Ubiquitin E3 ligase LNX2 is critical for osteoclastogenesis in vitro by regulating M-CSF/RANKL signaling and Notch2. Calcif. Tissue Int, 2015, 96: 465-475.

[112] Lee K, et al.Blocking of the ubiquitin-proteasome system prevents inflammation-induced bone loss by accelerating M-CSF receptor c-Fms degradation in osteoclast differentiation. Int. J. Mol. Sci., 2017, 18: 2054.

[113] Li M, et al.Gasdermin D maintains bone mass by rewiring the endo-lysosomal pathway of osteoclastic bone resorption. Dev. Cell, 2022, 57: 2365-2380.e8.

[114] Li Y, Su J, Sun W, Cai L, Deng Z. AMP-activated protein kinase stimulates osteoblast differentiation and mineralization through autophagy induction. Int. J. Mol. Med., 2018, 41: 2535-2544.

[115] Wang J, et al.The role of autophagy in bone metabolism and clinical significance. Autophagy, 2023, 19: 2409-2427.

[116] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell, 2023, 186: 243-278.

[117] Zhang X, et al.Local delivery of insulin/IGF-1 for bone regeneration: carriers, strategies, and effects. Nanotheranostics, 2020, 4: 242-255.

[118] Dixit M, Poudel SB, Yakar S. Effects of GH/IGF axis on bone and cartilage. Mol. Cell Endocrinol., 2021, 519: 111052.

[119] Li D, et al.Dynamic control of mTORC1 facilitates bone healing in mice. Bone, 2025, 190117285

[120] Hiraiwa M, et al.mTORC1 activation in osteoclasts prevents bone loss in a mouse model of osteoporosis. Front. Pharm., 2019, 10: 684.

[121] Liu Q, Liu C, Yang Y, Yang H, Chen J. Osteocyte-intrinsic mTORC1 signaling restrains trabecular bone accrual in mice. J. Cell Biochem., 2018, 119: 8743-8749.

[122] Liu J-Y, et al.AMPK, a hub for the microenvironmental regulation of bone homeostasis and diseases. J. Cell Physiol., 2024, 239e31393

[123] Park S-G, et al.The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling. Commun. Biol., 2024, 7: 1644.

[124] Zhang T, et al.Sirtuins mediate mitochondrial quality control mechanisms: a novel therapeutic target for osteoporosis. Front. Endocrinol., 2023, 141281213

[125] Zhao H, Yu F, Wu W. New perspectives on postmenopausal osteoporosis: mechanisms and potential therapeutic strategies of sirtuins and oxidative stress. Antioxidants, 2025, 14: 605.

[126] Zou Z, et al.Endothelin-1/endothelin B receptor signalling mediates Prx1+ skeletal stem cells senescence: a driver of osteoporotic bone loss. J. Orthop. Transl., 2026, 57101048

[127] Liu Y, et al.Chk2 deletion rescues bone loss and cellular senescence induced by Bmi1 deficiency via regulation of Cyp1a1. J. Orthop. Transl., 2025, 52: 360-375

[128] Yang C, et al.The senolytic agent ABT263 ameliorates osteoporosis caused by active vitamin D insufficiency through selective clearance of senescent skeletal cells. J. Orthop. Transl., 2024, 49: 107-118

[129] Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol., 2007, 8: 729-740.

[130] Xu Z, Teixeira MT. The many types of heterogeneity in replicative senescence. Yeast, 2019, 36: 637-648.

[131] Toussaint O, et al.Stress-induced premature senescence. essence of life, evolution, stress, and aging. Ann. N.Y. Acad. Sci., 2000, 908: 85-98.

[132] Wang H, et al.Osteoclasts and osteoarthritis: novel intervention targets and therapeutic potentials during aging. Aging Cell, 2024, 23e14092

[133] Saeed H, Iqtedar M. Bone marrow stromal cell (BMSC) and skeletal aging: role of telomerase enzyme. Pak. J. Pharm. Sci., 2014, 27: 321-333.

[134] Kumar N, Saraber P, Ding Z, Kusumbe AP. Diversity of vascular niches in bones and joints during homeostasis, ageing, and diseases. Front. Immunol., 2021, 12: 798211.

[135] Peng Y, Wu S, Li Y, Crane JL. Type H blood vessels in bone modeling and remodeling. Theranostics, 2020, 10: 426-436.

[136] Liang T-Z, et al.Targeting the central and peripheral nervous system to regulate bone homeostasis: mechanisms and potential therapies. Mil. Med. Res., 2025, 12: 13.

[137] Liu M, et al.Molecular mechanisms and therapeutic implications of the sympathetic nervous system in bone-related disorders: a brain-bone axis perspective. Bone Res., 2025, 13: 98.

[138] Zhang H, et al.The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies. Bone Res., 2023, 11: 15.

[139] Reya T, et al.A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature, 2003, 423: 409-414.

[140] Mistry JJ, et al.ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection. Proc. Natl. Acad. Sci. USA, 2019, 116: 24610-24619.

[141] Wang J, et al.Bcl11a maintains hematopoietic stem cell function but accelerates inflammation-driven exhaustion during aging. Sci. Immunol., 2025, 10eadr2041

[142] Koh BI, et al.Adult skull bone marrow is an expanding and resilient haematopoietic reservoir. Nature, 2024, 636: 172-181.

[143] Tao H, et al.Urolithin A suppresses RANKL-induced osteoclastogenesis and postmenopausal osteoporosis by, suppresses inflammation and downstream NF-κB activated pyroptosis pathways. Pharm. Res., 2021, 174105967

[144] Liu R-X, et al.Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling. Bone Res., 2023, 11: 56.

[145] Chen L, et al.Cross-sectional studies of the causal link between asthma and osteoporosis: insights from Mendelian randomization and bioinformatics analysis. Osteoporos. Int., 2024, 35: 1007-1017.

[146] Ambrosi TH, et al.Aged skeletal stem cells generate an inflammatory degenerative niche. Nature, 2021, 597: 256-262.

[147] Yin C, et al.Senescent fibroblasts drive FAP/OLN imbalance through mTOR signaling to exacerbate inflammation and bone resorption in periodontitis. Adv. Sci., 2025, 12e2409398

[148] Blacher E, et al.Aging disrupts circadian gene regulation and function in macrophages. Nat. Immunol., 2022, 23: 229-236.

[149] Widjaja AA, et al.Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature, 2024, 632: 157-165.

[150] Critchlow AJ, Hiam D, Williams R, Scott D, Lamon S. The role of estrogen in female skeletal muscle aging: a systematic review. Maturitas, 2023, 178: 107844.

[151] Deltourbe LG, et al.Steroid hormone levels vary with sex, aging, lifestyle, and genetics. Sci. Adv., 2025, 11eadu6094

[152] Hage C, Salvatori R. Growth hormone and aging. Endocrinol. Metab. Clin. North Am., 2023, 52: 245-257.

[153] Bobillier A, et al.Association of vitamin D and parathyroid hormone status with the aging-related decline of bone microarchitecture in older men: the prospective Structure of Aging Men’s Bones (STRAMBO) study. J. Bone Min. Res., 2022, 37: 1903-1914.

[154] Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet, 2014, 383: 146-155.

[155] Pondel M. Calcitonin and calcitonin receptors: bone and beyond. Int. J. Exp. Pathol., 2000, 81: 405-422.

[156] Martin CS, Cooper MS, Hardy RS. Endogenous glucocorticoid metabolism in bone: friend or foe. Front Endocrinol, 2021, 12: 733611.

[157] Zhu S, et al.Endocrine regulation on bone by thyroid. Front Endocrinol, 2022, 13873820

[158] Upadhyay J, Farr OM, Mantzoros CS. The role of leptin in regulating bone metabolism. Metabolism, 2015, 64: 105-113.

[159] Naot D, Musson DS, Cornish J. The activity of adiponectin in bone. Calcif. Tissue Int., 2017, 100: 486-499.

[160] Rahmati M, Nalesso G, Mobasheri A, Mozafari M. Aging and osteoarthritis: central role of the extracellular matrix. Ageing Res. Rev., 2017, 40: 20-30.

[161] Nyström A. The intertwined aging, the extracellular matrix, and fibrosis. Am. J. Physiol. Cell Physiol., 2024, 326: C645-C646.

[162] Zhang L, Zhou J, Kong W. Extracellular matrix in vascular homeostasis and disease. Nat. Rev. Cardiol., 2025, 22: 333-353.

[163] Yi J, et al.Elastin-derived extracellular matrix fragments drive aging through innate immune activation. Nat. Aging, 2025, 5: 2380-2398.

[164] Boaru DL, et al.Extracellular matrix dysregulation in aging, calcification, and cancer diseases: insights into cellular senescence, inflammation, and novel therapeutic strategies. Int. J. Biol. Sci., 2025, 21: 6808-6881.

[165] Garg K, Boppart MD. Influence of exercise and aging on extracellular matrix composition in the skeletal muscle stem cell niche. J. Appl. Physiol., 2016, 121: 1053-1058.

[166] Guvatova ZG, Borisov PV, Alekseev AA, Moskalev AA. Age-related changes in extracellular matrix. Biochemistry, 2022, 87: 1535-1551.

[167] Bab I, Smoum R, Bradshaw H, Mechoulam R. Skeletal lipidomics: regulation of bone metabolism by fatty acid amide family. Br. J. Pharm., 2011, 163: 1441-1446.

[168] Khazai N, Judd SE, Tangpricha V. Calcium and vitamin D: skeletal and extraskeletal health. Curr. Rheumatol. Rep., 2008, 10: 110-117.

[169] Massé O, et al.Calcium, vitamin D, or combined supplementation to prevent fractures and falls: systematic review and meta-analysis. BMJ, 2026, 393: e088050.

[170] Aaseth JO, Finnes TE, Askim M, Alexander J. The importance of vitamin K and the combination of vitamins K and D for calcium metabolism and bone health: a review. Nutrients, 2024, 16: 2420.

[171] Rizzoli R, Chevalley T. Nutrition and osteoporosis prevention. Curr. Osteoporos. Rep., 2024, 22: 515-522.

[172] Zhang J, et al.Feeding blueberry diets in early life prevent senescence of osteoblasts and bone loss in ovariectomized adult female rats. PLoS One, 2011, 6: e24486.

[173] Li T, Wu S-M, Xu Z-Y, Ou-Yang S. Rabbiteye blueberry prevents osteoporosis in ovariectomized rats. J. Orthop. Surg. Res, 2014, 9: 56.

[174] Damani JJ, De Souza MJ, VanEvery HL, Strock NCA, Rogers CJ. The role of prunes in modulating inflammatory pathways to improve bone health in postmenopausal women. Adv. Nutr., 2022, 13: 1476-1492.

[175] Damani JJ, et al.Prune Consumption attenuates proinflammatory cytokine secretion and alters monocyte activation in postmenopausal women: secondary outcome analysis of a 12-mo randomized controlled trial: the Prune study. J. Nutr., 2024, 154: 1699-1710.

[176] Hooshmand S, et al.The effect of two doses of dried plum on bone density and bone biomarkers in osteopenic postmenopausal women: a randomized, controlled trial. Osteoporos. Int., 2016, 27: 2271-2279.

[177] Smith BJ, et al.Montmorency tart cherry protects against age-related bone loss in female C57BL/6 mice and demonstrates some anabolic effects. Eur. J. Nutr., 2019, 58: 3035-3046.

[178] Dodier T, et al.U.S. Montmorency tart cherry juice decreases bone resorption in women aged 65-80 Years. Nutrients, 2021, 13: 544.

[179] Adedigba P, et al.Dietary tart cherry and fructooligosaccharides promote bone health via the gut microbiota and increased bone formation. Nutrients, 2025, 17: 2829.

[180] Shimizu S, et al.Effect of anthocyanin-rich bilberry extract on bone metabolism in ovariectomized rats. Biomed. Rep., 2018, 8: 198-204.

[181] Perna S, et al.Berries derived polyphenols and bone health: a systematic review. Nutrients, 2025, 17: 3440.

[182] New SA, et al.Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health?. Am. J. Clin. Nutr., 2000, 71: 142-151.

[183] Langsetmo L, et al.Dietary patterns and incident low-trauma fractures in postmenopausal women and men aged ≥50 y: a population-based cohort study. Am. J. Clin. Nutr., 2011, 93: 192-199.

[184] Rizzoli R, Chevalley T. Bone health: biology and nutrition. Curr. Opin. Clin. Nutr. Metab. Care, 2024, 27: 24-30.

[185] LeBoff MS, Bischoff-Ferrari HA. The effects of vitamin D supplementation on musculoskeletal health: The VITAL and DO-health trials. J. Gerontol. A Biol. Sci. Med. Sci., 2023, 78: 73-78.

[186] Mullath Ullas A, Boamah J, Hussain A, Myrtziou I, Kanakis I. Impact of dietary patterns on skeletal health: a systematic review and meta-analysis of bone mineral density, fracture, bone turnover markers, and nutritional status. Nutrients, 2025, 17: 3845.

[187] Willems HME, van den Heuvel EGHM, Schoemaker RJW, Klein-Nulend J, Bakker AD. Diet and exercise: a match made in bone. Curr. Osteoporos. Rep., 2017, 15: 555-563.

[188] Shojaa M, et al.Effects of dynamic resistance exercise on bone mineral density in postmenopausal women: a systematic review and meta-analysis with special emphasis on exercise parameters. Osteoporos. Int., 2020, 31: 1427-1444.

[189] Mello JB, et al.Exercise in school physical education increase bone mineral content and density: systematic review and meta-analysis. Eur. J. Sport Sci., 2022, 22: 1618-1629.

[190] Wilson DJ. Osteoporosis and sport. Eur. J. Radiol., 2019, 110: 169-174.

[191] Di Lorito C, et al.Exercise interventions for older adults: a systematic review of meta-analyses. J. Sport Health Sci., 2021, 10: 29-47.

[192] Kemmler W, Shojaa M, Kohl M, von Stengel S. Effects of different types of exercise on bone mineral density in postmenopausal women: a systematic review and meta-analysis. Calcif. Tissue Int., 2020, 107: 409-439.

[193] Zhu T-R, et al.Effectiveness of exercise prescription variables to reduce fall risk among older adults: a meta-analysis. Eur. Rev. Aging Phys. Act., 2025, 227

[194] Zitzmann A-L, et al.The effect of different training frequency on bone mineral density in older adults. A comparative systematic review and meta-analysis. Bone, 2022, 154116230

[195] Balaji SM. Effect of smoking on implant-bone interface. Indian J. Dent. Res., 2019, 30: 3.

[196] Truntzer J, Vopat B, Feldstein M, Matityahu A. Smoking cessation and bone healing: optimal cessation timing. Eur. J. Orthop. Surg. Traumatol., 2015, 25: 211-215.

[197] Shin M, et al.Impact of heavy alcohol consumption on cortical bone mechanical properties in male rhesus macaques. Bone, 2024, 181117041

[198] Sampson HW. Alcohol’s harmful effects on bone. Alcohol Health Res. World, 1998, 22: 190-194.

[199] Cheraghi Z, et al.The effect of alcohol on osteoporosis: a systematic review and meta-analysis. Drug Alcohol Depend., 2019, 197: 197-202.

[200] Khiyali Z, Rashedi V, Tavacol Z, Dehghan A, Bijani M. Smoking, alcohol consumption, drug abuse, and osteoporosis among older adults: a cross-sectional study on PERSIAN cohort study in Fasa. BMC Geriatr., 2024, 24: 80.

[201] Aibar-Almazán A, et al.Current status of the diagnosis and management of osteoporosis. Int. J. Mol. Sci., 2022, 23: 9465.

[202] Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society. Menopause28, 973–997 (2021).

[203] Ayers C, et al.Effectiveness and safety of treatments to prevent fractures in people with low bone mass or primary osteoporosis: a living systematic review and network meta-analysis for the American College of Physicians. Ann. Intern. Med., 2023, 176: 182-195.

[204] Curtis JR, et al.Comparative effectiveness of denosumab vs alendronate among postmenopausal women with osteoporosis. J. Bone Miner. Res., 2024, 39: 826-834.

[205] Nakafero G, et al.Fragility fracture, atypical femoral fracture, and osteonecrosis of jaw after bisphosphonate prescription for three and five years, based on primary and secondary care data in England: nested case-control and cohort studies. BMJ Med., 2026, 5: e002085.

[206] Kendler DL, Cosman F, Stad RK, Ferrari S. Denosumab in the treatment of osteoporosis: 10 years later: a narrative review. Adv. Ther., 2022, 39: 58-74.

[207] Kumar S, et al.Denosumab discontinuation in the clinic: implications of rebound bone turnover and emerging strategies to prevent bone loss and fractures. J. Bone Miner. Res., 2025, 40: 1017-1034.

[208] Degboé Y, Couture G. Strategies for denosumab discontinuation in postmenopausal osteoporosis. Jt. Bone Spine, 2026, 93: 105954.

[209] Menéndez JQ, García Tellado Á, Pardo Lleidas J, Hernández Hernández JL. Hypercalcemia after denosumab discontinuation in patients with osteoporosis: a systematic review and case report. Osteoporos. Int., 2026, 37: 637-642.

[210] Shogry FF, et al.The rise and fall of raloxifene use for osteoporosis, 1999-2022. Osteoporos. Int., 2025, 36: 1277-1286.

[211] Muñoz-Torres M, Alonso G, Raya MP. Calcitonin therapy in osteoporosis. Treat. Endocrinol., 2004, 3: 117-132.

[212] Luo Y, Liang M, Gao Y, Wang X, Li Y. Clinical indicators for perimenopausal hormone replacement therapy: an evidence-based narrative review. Niger. J. Clin. Pract., 2026, 29: 373-381.

[213] Lorentzon M, et al.Menopausal hormone therapy reduces the risk of fracture regardless of falls risk or baseline FRAX probability—results from the Women’s Health Initiative hormone therapy trials. Osteoporos. Int., 2022, 33: 2297-2305.

[214] Teriparatide. in Drugs and Lactation Database (LactMed®) (National Institute of Child Health and Human Development, 2006).

[215] Vahle JL, et al.Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol. Pathol., 2002, 30: 312-321.

[216] Gilsenan A, et al.Teriparatide did not increase adult osteosarcoma incidence in a 15-year US postmarketing surveillance study. J. Bone Miner. Res., 2021, 36: 244-251.

[217] Barnett, M., Riley, L. J., Casipit, C. & Azmaiparashvili, Z. Boxed in: should the black box warning for osteosarcoma be retired for good? Endocr. Abstr.110, (2025).

[218] Miller PD, et al.Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. JAMA, 2016, 316: 722-733.

[219] Wu D, Li L, Wen Z, Wang G. Romosozumab in osteoporosis: yesterday, today and tomorrow. J. Transl. Med., 2023, 21668

[220] Maruyama H, et al.Cardiovascular risk of romosozumab vs. teriparatide: a cohort study using Japan’s National Claims Database. Clin. Pharm. Ther., 2026, 119: 721-728.

[221] Cheng S-H, Chu W, Chou W-H, Chu W-C, Kang Y-N. Cardiovascular safety of romosozumab compared to commonly used anti-osteoporosis medications in postmenopausal osteoporosis: a systematic review and network meta-analysis of randomized controlled trials. Drug Saf., 2025, 48: 7-23.

[222] Nayak S, Greenspan SL. A systematic review and meta-analysis of sequential treatment strategies for osteoporosis. Osteoporos. Int., 2026, 37: 1-13.

[223] Cipolloni V, et al.The anabolic-first strategy in osteoporosis: a systematic review and meta-analysis of fracture outcomes in patients at very high fracture risk. Medicines, 2026, 62: 687.

[224] Reid IR, Billington EO. Drug therapy for osteoporosis in older adults. Lancet, 2022, 399: 1080-1092.

[225] Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J. Intern. Med., 2020, 288: 518-536.

[226] Ansari MM, Ghosh M, Lee D-S, Son Y-O. Senolytic therapeutics: an emerging treatment modality for osteoarthritis. Ageing Res. Rev., 2024, 96: 102275.

[227] Zhu Y, et al.The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell, 2015, 14: 644-658.

[228] Farr JN, et al.Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial. Nat. Med., 2024, 30: 2605-2612.

[229] Houssaini A, et al.mTOR pathway activation drives lung cell senescence and emphysema. JCI Insight, 2018, 3e9320393203

[230] Yousefzadeh MJ, et al.Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018, 36: 18-28.

[231] Lin C, et al.Engineering a targeted and safe bone anabolic gene therapy to treat osteoporosis in alveolar bone loss. Mol. Ther., 2024, 32: 3080-3100.

[232] Ocarino de NM, et al.Intra-bone marrow injection of mesenchymal stem cells improves the femur bone mass of osteoporotic female rats. Connect Tissue Res., 2010, 51: 426-433.

[233] Cao C, et al.Bone marrow mesenchymal stem cells slow intervertebral disc degeneration through the NF-κB pathway. Spine J., 2015, 15: 530-538.

[234] Kostecka A, et al.Adipose-derived mesenchymal stromal cells in clinical trials: insights from single-cell studies. Life Sci., 2024, 351122761

[235] Evans, C. H., Ghivizzani, S. C. & Robbins, P. D. Orthopaedic gene therapy: twenty-five years on. JBJS Rev.9 (2021).

[236] Oh W-T, et al.WNT-modulating gene silencers as a gene therapy for osteoporosis, bone fracture, and critical-sized bone defects. Mol. Ther., 2023, 31: 435-453.

[237] Serrano DR, et al.Exosome-based drug delivery: a next-generation platform for cancer, infection, neurological and immunological diseases, gene therapy and regenerative medicine. Pharmaceutics, 2025, 17: 1336.

[238] Jakob F, et al.Bone tissue engineering in osteoporosis. Maturitas, 2013, 75: 118-124.

[239] de Moraes VAF, Moreira FM, Dos Santos Santinoni C, de Souza Batista VE, Mori GG. Would exosome therapy be effective for bone regeneration? Systematic review and meta-analysis. Calcif. Tissue Int., 2025, 116: 127.

[240] Zhang Q, et al.Tissue engineering and regenerative medicine therapies for cell senescence in bone and cartilage. Tissue Eng. Part. B. Rev., 2020, 26: 64-78.

Funding

National Key Research and Development Program of China (2024YFB3814700) National Natural Science Foundation of China (82372450)

China Postdoctoral Science Foundation General Fund (2025M782894) Natural Science Foundation of Beijing Municipality (L256033)

Natural Science Foundation of Beijing Municipality (L234062) National Natural Science Foundation of China (82402828)

Natural Science Foundation of Beijing Municipality (L254010)

Rights & permissions

The Author(s)