{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:02:37Z","timestamp":1789984957601,"version":"4.0.1"},"reference-count":130,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Aging and glycative stress are major, interrelated drivers of skeletal fragility, yet the extent to which they act through shared versus distinct biological pathways remains poorly defined, limiting integrated therapeutic strategies. This review compares the convergent and divergent mechanisms by which aging and glycative stress affect osteocytes, osteoblasts, and osteoclasts, extracellular matrix properties, and bone mechanotransduction. Both conditions converge on oxidative stress, mitochondrial dysfunction, chronic low-grade inflammation, cellular senescence, impaired autophagy, NLRP3 inflammasome activation, and ferroptosis, ultimately reducing osteocyte viability and disrupting RANKL\/OPG-mediated remodeling. They diverge in their primary drivers: Aging is characterized by hormonal decline, stem-cell exhaustion, and progressive loss of bone mass and microarchitecture, whereas glycative stress acts through AGE\u2013RAGE signaling and collagen cross-linking, compromising bone quality and mechanosensitivity while often preserving bone mineral density, explaining the disproportionate fracture risk seen in diabetes. Since current anabolic and anti-resorptive therapies do not specifically target AGE-related pathways, combined strategies incorporating senolytic, antiglycative, and mechanoprotective approaches\u2014alongside lifestyle interventions\u2014may be needed to more effectively reduce fracture risk in aged and diabetic populations.<\/jats:p>","DOI":"10.3390\/cells15181712","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bone Aging and Glycative Stress: Convergent and Divergent Mechanisms Driving Skeletal Deterioration"],"prefix":"10.3390","volume":"15","author":[{"given":"Salvador","family":"Pe\u00f1arrubia","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Hospital Universitario Fundaci\u00f3n Jim\u00e9nez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Mart\u00edn-Guerrero","sequence":"additional","affiliation":[{"name":"Bone Physiopathology Laboratory, Instituto de Medicina Molecular Aplicada (IMMA), School of Medicine, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28925 Alcorc\u00f3n, Spain"},{"name":"Department of Basic Medical Sciences, School of Medicine, Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorc\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-3141","authenticated-orcid":false,"given":"Arancha R.","family":"Gort\u00e1zar","sequence":"additional","affiliation":[{"name":"Bone Physiopathology Laboratory, Instituto de Medicina Molecular Aplicada (IMMA), School of Medicine, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28925 Alcorc\u00f3n, Spain"},{"name":"Department of Basic Medical Sciences, School of Medicine, Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorc\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2827-3364","authenticated-orcid":false,"given":"Juan A.","family":"Ardura","sequence":"additional","affiliation":[{"name":"Bone Physiopathology Laboratory, Instituto de Medicina Molecular Aplicada (IMMA), School of Medicine, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28925 Alcorc\u00f3n, Spain"},{"name":"Department of Basic Medical Sciences, School of Medicine, Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorc\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/s41413-022-00219-8","article-title":"Bone remodeling: An operational process ensuring survival and bone mechanical competence","volume":"10","author":"Bolamperti","year":"2022","journal-title":"Bone Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Barak, M.M. (2024). Cortical and Trabecular Bone Modeling and Implications for Bone Functional Adaptation in the Mammalian Tibia. Bioengineering, 11.","DOI":"10.3390\/bioengineering11050514"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.tem.2010.01.010","article-title":"What old means to bone","volume":"21","author":"Manolagas","year":"2010","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101608","DOI":"10.1016\/j.arr.2022.101608","article-title":"Osteocytes in bone aging: Advances, challenges, and future perspectives","volume":"77","author":"Cui","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1177\/0022034510377791","article-title":"Aging and Bone","volume":"89","author":"Boskey","year":"2010","journal-title":"J. Dent. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e138815","DOI":"10.1172\/jci.insight.138815","article-title":"Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence","volume":"5","author":"Kim","year":"2020","journal-title":"JCI Insight"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e93771","DOI":"10.1172\/jci.insight.93771","article-title":"Old age causes de novo intracortical bone remodeling and porosity in mice","volume":"2","author":"Piemontese","year":"2017","journal-title":"JCI Insight"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3978","DOI":"10.1016\/j.scib.2024.10.013","article-title":"Bone aging and extracellular vesicles","volume":"69","author":"Wang","year":"2024","journal-title":"Sci. Bull."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1093\/gerona\/glq074","article-title":"Does Accumulation of Advanced Glycation End Products Contribute to the Aging Phenotype?","volume":"65A","author":"Semba","year":"2010","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Twarda-Clapa, A., Olczak, A., Bia\u0142kowska, A.M., and Kozio\u0142kiewicz, M. (2022). Advanced Glycation End-Products (AGEs): Formation, Chemistry, Classification, Receptors, and Diseases Related to AGEs. Cells, 11.","DOI":"10.3390\/cells11081312"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e22710","DOI":"10.1002\/jbt.22710","article-title":"Advanced glycation end products and their adverse effects: The role of autophagy","volume":"35","author":"Sruthi","year":"2021","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"G\u00f3mez, O., Perini-Villanueva, G., Yuste, A., Rodr\u00edguez-Navarro, J.A., Poch, E., and Bejarano, E. (2021). Autophagy and Glycative Stress: A Bittersweet Relationship in Neurodegeneration. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.790479"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.1016\/j.bbadis.2018.08.036","article-title":"Mechanistic targeting of advanced glycation end-products in age-related diseases","volume":"1864","author":"Rowan","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"ziae110","DOI":"10.1093\/jbmrpl\/ziae110","article-title":"In vivo glycation\u2014Interplay between oxidant and carbonyl stress in bone","volume":"8","author":"Sroga","year":"2024","journal-title":"JBMR Plus"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.redox.2013.12.016","article-title":"Role of advanced glycation end products in cellular signaling","volume":"2","author":"Ott","year":"2014","journal-title":"Redox Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s10522-019-09808-3","article-title":"The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging","volume":"20","author":"Teissier","year":"2019","journal-title":"Biogerontology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"116880","DOI":"10.1016\/j.bone.2023.116880","article-title":"Advanced glycation and glycoxidation end products in bone","volume":"176","author":"Wang","year":"2023","journal-title":"Bone"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chao, C.-T., and Lin, S.-H. (2021). Uremic Toxins and Frailty in Patients with Chronic Kidney Disease: A Molecular Insight. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126270"},{"key":"ref_20","first-page":"927","article-title":"Inflammatory Bridges: Interconnections Between Alzheimer\u2019s Disease and Bone Health","volume":"17","author":"Li","year":"2025","journal-title":"Aging Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"bvae112","DOI":"10.1210\/jendso\/bvae112","article-title":"Bone Health in Patients with Type 2 Diabetes","volume":"8","author":"Forner","year":"2024","journal-title":"J. Endocr. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s11914-014-0214-3","article-title":"Collagen modifications in postmenopausal osteoporosis: Advanced glycation endproducts may affect bone volume, structure and quality","volume":"12","author":"Willett","year":"2014","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s00223-022-01007-6","article-title":"Increased Cortical Porosity, Reduced Cortical Thickness, and Reduced Trabecular and Cortical Microhardness of the Superolateral Femoral Neck Confer the Increased Hip Fracture Risk in Individuals with Type 2 Diabetes","volume":"111","author":"Cirovic","year":"2022","journal-title":"Calcif. Tissue Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1002\/jbmr.2892","article-title":"Identification of Senescent Cells in the Bone Microenvironment","volume":"31","author":"Farr","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/s41574-021-00555-5","article-title":"Update on the pathogenesis and treatment of skeletal fragility in type 2 diabetes mellitus","volume":"17","author":"Khosla","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s11914-019-00499-w","article-title":"RAGE Signaling in Skeletal Biology","volume":"17","author":"Plotkin","year":"2019","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1210\/js.2019-00160","article-title":"Advanced Glycation End Products (AGEs), Receptor for AGEs, Diabetes, and Bone: Review of the Literature","volume":"3","author":"Asadipooya","year":"2019","journal-title":"J. Endocr. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/s41419-020-03059-8","article-title":"Osteocyte apoptosis: The roles and key molecular mechanisms in resorption-related bone diseases","volume":"11","author":"Ru","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s11914-020-00619-x","article-title":"Osteocyte Cellular Senescence","volume":"18","author":"Farr","year":"2020","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/nm.2452","article-title":"Evidence for osteocyte regulation of bone homeostasis through RANKL expression","volume":"17","author":"Nakashima","year":"2011","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s11914-016-0297-0","article-title":"The Role of Osteocytes in Age-Related Bone Loss","volume":"14","author":"Jilka","year":"2016","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.bone.2012.09.030","article-title":"Beyond gap junctions: Connexin43 and bone cell signaling","volume":"52","author":"Plotkin","year":"2013","journal-title":"Bone"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, G., Zhang, L., Lu, Z., Yang, B., Yang, H., Shang, P., Jiang, J.X., Wang, D., and Xu, H. (2022). Connexin 43 Channels in Osteocytes Are Necessary for Bone Mass and Skeletal Muscle Function in Aged Male Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113506"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1111\/acel.12586","article-title":"Disruption of the Cx43\/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging","volume":"16","author":"Davis","year":"2017","journal-title":"Aging Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.bbrc.2015.02.091","article-title":"Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells","volume":"461","author":"Tanaka","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.bone.2006.09.011","article-title":"Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways","volume":"40","author":"Alikhani","year":"2007","journal-title":"Bone"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.bone.2019.01.015","article-title":"Cellular senescence in bone","volume":"121","author":"Farr","year":"2019","journal-title":"Bone"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lawrence, M., Goyal, A., Pathak, S., and Ganguly, P. (2024). Cellular Senescence and Inflammaging in the Bone: Pathways, Genetics, Anti-Aging Strategies and Interventions. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137411"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00223-013-9774-y","article-title":"Osteocyte-Driven Bone Remodeling","volume":"94","author":"Bellido","year":"2013","journal-title":"Calcif. Tissue Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.1002\/jcp.30849","article-title":"PTH1R translocation to primary cilia in mechanically-stimulated ostecytes prevents osteoclast formation via regulation of CXCL5 and IL-6 secretion","volume":"237","author":"Ardura","year":"2022","journal-title":"J. Cell. Physiol."},{"key":"ref_41","first-page":"2417","article-title":"Consequences of Aging on Bone","volume":"15","author":"Zhang","year":"2023","journal-title":"Aging Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bone.2018.07.012","article-title":"Impact of aging on bone, marrow and their interactions","volume":"119","author":"Hoffman","year":"2019","journal-title":"Bone"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/jbmr.4485","article-title":"Hedgehog Signaling Controls Bone Homeostasis by Regulating Osteogenic\/Adipogenic Fate of Skeletal Stem\/Progenitor Cells in Mice","volume":"37","author":"Zhang","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e239","DOI":"10.3346\/jkms.2021.36.e239","article-title":"Effects of Advanced Glycation End Products on Differentiation and Function of Osteoblasts and Osteoclasts","volume":"36","author":"Park","year":"2021","journal-title":"J. Korean Med. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1038\/cdd.2015.168","article-title":"Fate decision of mesenchymal stem cells: Adipocytes or osteoblasts?","volume":"23","author":"Chen","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1084\/jem.20051947","article-title":"Regulation of osteoclast function and bone mass by RAGE","volume":"203","author":"Zhou","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_47","first-page":"e154888","article-title":"Cellular senescence and the skeleton: Pathophysiology and therapeutic implications","volume":"132","author":"Khosla","year":"2022","journal-title":"JCI Insight"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s11914-013-0135-6","article-title":"The Changing Balance Between Osteoblastogenesis and Adipogenesis in Aging and its Impact on Hematopoiesis","volume":"11","author":"Bethel","year":"2013","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41413-023-00283-8","article-title":"Loss of Notch signaling in skeletal stem cells enhances bone formation with aging","volume":"11","author":"Remark","year":"2023","journal-title":"Bone Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/nm.4385","article-title":"Targeting cellular senescence prevents age-related bone loss in mice","volume":"23","author":"Farr","year":"2017","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/s41586-021-03795-7","article-title":"Aged skeletal stem cells generate an inflammatory degenerative niche","volume":"597","author":"Ambrosi","year":"2021","journal-title":"Nature"},{"key":"ref_52","first-page":"99","article-title":"Expression and Role of Sonic Hedgehog in the Process of Fracture Healing with Aging","volume":"30","author":"Matsumoto","year":"2016","journal-title":"In Vivo"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"28189","DOI":"10.1074\/jbc.M115.669499","article-title":"Advanced Glycation End Products Affect Osteoblast Proliferation and Function by Modulating Autophagy Via the Receptor of Advanced Glycation End Products\/Raf Protein\/Mitogen-activated Protein Kinase\/Extracellular Signal-regulated Kinase Kinase\/Extracellular Signal-regulated Kinase (RAGE\/Raf\/MEK\/ERK) Pathway","volume":"290","author":"Meng","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e23871","DOI":"10.1096\/fj.202400790R","article-title":"Low bone turnover is associated with advanced glycation end-products, oxidative stress, and inflammation induced by type 2 diabetes mellitus","volume":"38","author":"Shi","year":"2024","journal-title":"FASEB J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"975872","DOI":"10.1155\/2014\/975872","article-title":"Advanced Glycation End Products Play Adverse Proinflammatory Activities in Osteoporosis","volume":"2014","author":"Sanguineti","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Maharajan, N., Ganesan, C.D., Moon, C., Jang, C.-H., Oh, W.-K., and Cho, G.-W. (2021). Licochalcone D Ameliorates Oxidative Stress-Induced Senescence via AMPK Activation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147324"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1007\/s00223-017-0243-x","article-title":"Advanced Glycation End Product 3 (AGE3) Increases Apoptosis and the Expression of Sclerostin by Stimulating TGF-\u03b2 Expression and Secretion in Osteocyte-Like MLO-Y4-A2 Cells","volume":"100","author":"Notsu","year":"2017","journal-title":"Calcif. Tissue Int."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Cavati, G., Pirrotta, F., Merlotti, D., Ceccarelli, E., Calabrese, M., Gennari, L., and Mingiano, C. (2023). Role of Advanced Glycation End-Products and Oxidative Stress in Type-2-Diabetes-Induced Bone Fragility and Implications on Fracture Risk Stratification. Antioxidants, 12.","DOI":"10.3390\/antiox12040928"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Zhu, C., Shen, S., Zhang, S., Huang, M., Zhang, L., and Chen, X. (2022). Autophagy in Bone Remodeling: A Regulator of Oxidative Stress. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.898634"},{"key":"ref_60","first-page":"751","article-title":"Molecular mechanisms in bone mechanotransduction","volume":"32","author":"Maycas","year":"2017","journal-title":"Histol. Histopathol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Choi, J.U.A., Kijas, A.W., Lauko, J., and Rowan, A.E. (2022). The Mechanosensory Role of Osteocytes and Implications for Bone Health and Disease States. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.770143"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41413-020-0099-y","article-title":"Molecular mechanosensors in osteocytes","volume":"8","author":"Qin","year":"2020","journal-title":"Bone Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/jre.70085","article-title":"The Role of Wnt Signaling in Age-Related Alveolar Bone Loss and Regeneration","volume":"61","author":"Sung","year":"2026","journal-title":"J. Periodontal Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.gene.2016.11.006","article-title":"Old age and the associated impairment of bones\u2019 adaptation to loading are associated with transcriptomic changes in cellular metabolism, cell-matrix interactions and the cell cycle","volume":"599","author":"Galea","year":"2017","journal-title":"Gene"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/j.bbrc.2005.12.107","article-title":"Disordered osteoclast formation in RAGE-deficient mouse establishes an essential role for RAGE in diabetes related bone loss","volume":"340","author":"Ding","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s11914-020-00645-9","article-title":"Connexin Gap Junctions and Hemichannels Link Oxidative Stress to Skeletal Physiology and Pathology","volume":"19","author":"Hua","year":"2021","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"117301","DOI":"10.1016\/j.bone.2024.117301","article-title":"AGEs (Advanced Glycation End-products) in bone come of age","volume":"190","author":"Vashishth","year":"2024","journal-title":"Bone"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3817","DOI":"10.1093\/nar\/gkac189","article-title":"Oxidative stress-CBP axis modulates MOB1 acetylation and activates the Hippo signaling pathway","volume":"50","author":"Jin","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1080\/03008207.2020.1712377","article-title":"Mechanosensitive Ca2+ signaling and coordination is diminished in osteocytes of aged mice during ex vivo tibial loading","volume":"61","author":"Morrell","year":"2020","journal-title":"Connect. Tissue Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1038\/s41467-024-45023-6","article-title":"Rescuing SERCA2 pump deficiency improves bone mechano-responsiveness in type 2 diabetes by shaping osteocyte calcium dynamics","volume":"15","author":"Shao","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"111786","DOI":"10.1016\/j.cellsig.2025.111786","article-title":"Mechanical stress overload promotes NF-\u03baB\/NLRP3-mediated osteoarthritis synovitis and fibrosis through Piezo1","volume":"132","author":"Yu","year":"2025","journal-title":"Cell. Signal."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e2023999118","DOI":"10.1073\/pnas.2023999118","article-title":"Disrupted osteocyte connectivity and pericellular fluid flow in bone with aging and defective TGF-\u03b2 signaling","volume":"118","author":"Schurman","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13018-019-1163-4","article-title":"Ageing characteristics of bone indicated by transcriptomic and exosomal proteomic analysis of cortical bone cells","volume":"14","author":"Zhang","year":"2019","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e49631","DOI":"10.7554\/eLife.49631","article-title":"Stimulation of Piezo1 by mechanical signals promotes bone anabolism","volume":"8","author":"Li","year":"2019","journal-title":"eLife"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.bone.2013.05.003","article-title":"Age-related bone deterioration is diminished by disrupted collagen sensing in integrin \u03b12\u03b21 deficient mice","volume":"56","author":"Stange","year":"2013","journal-title":"Bone"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1002\/jbmr.2439","article-title":"Role of the Parathyroid Hormone Type 1 Receptor (PTH1R) as a Mechanosensor in Osteocyte Survival","volume":"30","author":"Maycas","year":"2014","journal-title":"J. Bone Miner. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"7356","DOI":"10.1002\/jcp.29636","article-title":"Primary cilia mediate parathyroid hormone receptor type 1 osteogenic actions in osteocytes and osteoblasts via Gli activation","volume":"235","author":"Alonso","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e70067","DOI":"10.1002\/jcp.70067","article-title":"Caveolin-1 Regulates Parathyroid Hormone (PTH)-Related Protein (PTHrP) Actions on PTH Receptor Type 1 in Bone Cells","volume":"240","author":"Bellido","year":"2025","journal-title":"J. Cell. Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.molmed.2023.04.001","article-title":"Primary cilia shape hallmarks of health and aging","volume":"29","author":"Silva","year":"2023","journal-title":"Trends Mol. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"25501","DOI":"10.1074\/jbc.M702231200","article-title":"A Novel Ligand-independent Function of the Estrogen Receptor Is Essential for Osteocyte and Osteoblast Mechanotransduction","volume":"282","author":"Aguirre","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_81","first-page":"1771","article-title":"Is interaction between age-dependent decline in mechanical stimulation and osteocyte\u2013estrogen receptor levels the culprit for postmenopausal-impaired bone formation?","volume":"24","author":"Livshits","year":"2012","journal-title":"Osteoporos. Int."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"116485","DOI":"10.1016\/j.bone.2022.116485","article-title":"Causative or associative: A critical review of the role of advanced glycation end-products in bone fragility","volume":"163","author":"Willett","year":"2022","journal-title":"Bone"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3611","DOI":"10.1002\/jcp.25829","article-title":"High glucose alters the secretome of mechanically stimulated osteocyte-like cells affecting osteoclast precursor recruitment and differentiation","volume":"232","author":"Maycas","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1038\/s41598-018-38154-6","article-title":"Metabolomics reveals citric acid secretion in mechanically\u2013stimulated osteocytes is inhibited by high glucose","volume":"9","author":"Obeso","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"jcs230425","DOI":"10.1242\/jcs.230425","article-title":"YAP\/TAZ functions and their regulation at a glance","volume":"133","author":"Pocaterra","year":"2020","journal-title":"J. Cell Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"111813","DOI":"10.4239\/wjd.v16.i10.111813","article-title":"Diabetic bone fragility through advanced glycation end product-collagen axis: Mechanisms and therapy of sodium glucose cotransporter 2 inhibitors","volume":"16","author":"Li","year":"2025","journal-title":"World J. Diabetes"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3598","DOI":"10.1002\/jcp.25828","article-title":"Advanced glycation end products (AGE) potentiates cell death in p53 negative cells via upregulaion of NF-kappa B and impairment of autophagy","volume":"232","author":"Verma","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Zuo, L., Prather, E.R., Stetskiv, M., Garrison, D.E., Meade, J.R., Peace, T.I., and Zhou, T. (2019). Inflammaging and oxidative stress in human diseases: From molecular mechanisms to novel treatments. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184472"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"8580","DOI":"10.1038\/s41598-022-12206-4","article-title":"D-galactose-induced aging aggravates obesity-induced bone dyshomeostasis","volume":"12","author":"Imerb","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1161\/CIRCULATIONAHA.122.060860","article-title":"NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload","volume":"147","author":"Higashikuni","year":"2023","journal-title":"Circulation"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"103804","DOI":"10.1016\/j.redox.2025.103804","article-title":"Nrf2\/Nlrp3 signaling in aging BMSCs: Traf6 intervention as a novel approach to osteoporosis treatment","volume":"86","author":"Li","year":"2025","journal-title":"Redox Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e13912","DOI":"10.1111\/acel.13912","article-title":"Pyrroloquinoline quinone alleviates natural aging-related osteoporosis via a novel MCM3-Keap1-Nrf2 axis-mediated stress response and Fbn1 upregulation","volume":"22","author":"Li","year":"2023","journal-title":"Aging Cell"},{"key":"ref_93","first-page":"849","article-title":"Metabolic Rewiring and Post-Translational Modifications: Unlocking the Mechanisms of Bone Turnover in Osteoporosis","volume":"17","author":"Li","year":"2025","journal-title":"Aging Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e70090","DOI":"10.1002\/jcb.70090","article-title":"Hyperglycemia Leads to BMSC Impaired Osteogenesis, Enhanced Adipogenesis, and Altered Metabolism","volume":"127","author":"Shirazi","year":"2026","journal-title":"J. Cell. Biochem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e13657","DOI":"10.1111\/cpr.13657","article-title":"Osteocyte ferroptosis induced by ATF3\/TFR1 contributes to cortical bone loss during ageing","volume":"57","author":"Yin","year":"2024","journal-title":"Cell Prolif."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/s41420-025-02655-x","article-title":"Hallmarks and mechanisms of cellular senescence in aging and disease","volume":"11","author":"Ajoolabady","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/s41419-022-05089-w","article-title":"Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells contributing to osteoarthritis progression","volume":"13","author":"Fonseca","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"E6301","DOI":"10.1073\/pnas.1515386112","article-title":"JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age","volume":"112","author":"Xu","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41514-021-00058-7","article-title":"A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging","volume":"7","author":"Kim","year":"2021","journal-title":"npj Aging Mech. Dis."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.bone.2019.01.018","article-title":"Sirtuins and FoxOs in osteoporosis and osteoarthritis","volume":"121","author":"Almeida","year":"2019","journal-title":"Bone"},{"key":"ref_101","first-page":"1868","article-title":"Epigenetic Dysregulation and Osteocyte Senescence: Convergent Drivers of Osteosarcopenia in Aging Bone and Muscle","volume":"17","author":"Nusrat","year":"2025","journal-title":"Aging Dis."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"111503","DOI":"10.1016\/j.biopha.2021.111503","article-title":"Glycyrrhizin mitigates inflammatory bone loss and promotes expression of senescence-protective sirtuins in an aging mouse model of periprosthetic osteolysis","volume":"138","author":"Yamada","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12964-024-02025-7","article-title":"Role of sirtuins in obesity and osteoporosis: Molecular mechanisms and therapeutic targets","volume":"23","author":"Du","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.cmet.2016.09.013","article-title":"Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice","volume":"24","author":"Mills","year":"2016","journal-title":"Cell Metab."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.bonr.2015.09.003","article-title":"The role of the P2X7 receptor on bone loss in a mouse model of inflammation-mediated osteoporosis","volume":"7","author":"Kvist","year":"2017","journal-title":"Bone Rep."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1080\/15548627.2023.2186112","article-title":"The role of autophagy in bone metabolism and clinical significance","volume":"19","author":"Wang","year":"2023","journal-title":"Autophagy"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1513\/pats.200909-102JS","article-title":"Chaperone-Mediated Autophagy","volume":"7","author":"Bejarano","year":"2010","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"9913","DOI":"10.2147\/DDDT.S554555","article-title":"The Critical Role of Autophagy in the Pathogenesis of Diabetic Osteoporosis: Mechanisms and Therapeutic Measures","volume":"19","author":"Hou","year":"2025","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e10077","DOI":"10.1002\/jbm4.10077","article-title":"Glucocorticoid-Induced Autophagy Protects Osteocytes Against Oxidative Stress Through Activation of MAPK\/ERK Signaling","volume":"3","author":"Kar","year":"2018","journal-title":"JBMR Plus"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s00418-014-1194-1","article-title":"Decreased activity of osteocyte autophagy with aging may contribute to the bone loss in senile population","volume":"142","author":"Chen","year":"2014","journal-title":"Histochem. Cell Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1016\/j.molcel.2024.07.020","article-title":"OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response","volume":"84","author":"Liang","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.neuron.2024.09.015","article-title":"Autophagy, aging, and age-related neurodegeneration","volume":"113","author":"Palmer","year":"2025","journal-title":"Neuron"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e18626","DOI":"10.7717\/peerj.18626","article-title":"Ferroptosis and its implications in bone-related diseases","volume":"12","author":"Wang","year":"2024","journal-title":"PeerJ"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1186\/s12967-024-05191-x","article-title":"Type 2 diabetic mellitus related osteoporosis: Focusing on ferroptosis","volume":"22","author":"Chen","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/s41584-025-01287-w","article-title":"Parathyroid hormone receptor agonists in the management of osteoporosis","volume":"21","author":"Fuggle","year":"2025","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e12755","DOI":"10.1111\/cpr.12755","article-title":"Parathyroid hormone ameliorates temporomandibular joint osteoarthritic-like changes related to age","volume":"53","author":"Cui","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1016\/S0140-6736(17)31613-6","article-title":"Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: A randomised, open-label, phase 3 trial","volume":"390","author":"Langdahl","year":"2017","journal-title":"Lancet"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"40676","DOI":"10.1038\/s41598-025-19835-5","article-title":"Analysis of the efficacy and safety of denosumab in the treatment of patients with osteoporotic vertebral compression fractures after PVP","volume":"15","author":"Jiang","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1007\/s00223-016-0211-x","article-title":"Bazedoxifene Ameliorates Homocysteine-Induced Apoptosis and Accumulation of Advanced Glycation End Products by Reducing Oxidative Stress in MC3T3-E1 Cells","volume":"100","author":"Kanazawa","year":"2016","journal-title":"Calcif. Tissue Int."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1002\/jbmr.3925","article-title":"Effect of Advanced Glycation End-Products (AGE) Lowering Drug ALT-711 on Biochemical, Vascular, and Bone Parameters in a Rat Model of CKD-MBD","volume":"35","author":"Chen","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1038\/s41598-018-20000-4","article-title":"Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype","volume":"8","author":"Wiley","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Chandra, A., and Rajawat, J. (2021). Skeletal Aging and Osteoporosis: Mechanisms and Therapeutics. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073553"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Li, Y., Huang, Z., Pan, S., Feng, Y., He, H., Cheng, S., Wang, L., Wang, L., and Pathak, J.L. (2023). Resveratrol Alleviates Diabetic Periodontitis-Induced Alveolar Osteocyte Ferroptosis Possibly via Regulation of SLC7A11\/GPX4. Nutrients, 15.","DOI":"10.3390\/nu15092115"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"111035","DOI":"10.1016\/j.jbiomech.2022.111035","article-title":"Moderate aerobic exercise on bone quality changes associated with aging and oxidative stress in BALB\/c mice","volume":"135","year":"2022","journal-title":"J. Biomech."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.jada.2010.03.018","article-title":"Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet","volume":"110","author":"Uribarri","year":"2010","journal-title":"J. Am. Diet. Assoc."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"965","DOI":"10.3233\/JAD-140720","article-title":"Observational and Ecological Studies of Dietary Advanced Glycation End Products in National Diets and Alzheimer\u2019s Disease Incidence and Prevalence","volume":"45","author":"Perrone","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/s41591-023-02235-5","article-title":"Optimal dietary patterns for prevention of chronic disease","volume":"29","author":"Wang","year":"2023","journal-title":"Nat. Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.2337\/dc19-2331","article-title":"Intrahepatic Fat and Postprandial Glycemia Increase After Consumption of a Diet Enriched in Saturated Fat Compared With Free Sugars","volume":"43","author":"Parry","year":"2020","journal-title":"Diabetes Care"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"101260","DOI":"10.1016\/j.preteyeres.2024.101260","article-title":"Glycative stress as a cause of macular degeneration","volume":"101","author":"Bejarano","year":"2024","journal-title":"Prog. Retin. Eye Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1712\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:21:50Z","timestamp":1789982510000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1712"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":130,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15181712"],"URL":"https:\/\/doi.org\/10.3390\/cells15181712","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]}}}