Bone Aging and Glycative Stress: Convergent and Divergent Mechanisms Driving Skeletal Deterioration

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–RAGE 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—alongside lifestyle interventions—may be needed to more effectively reduce fracture risk in aged and diabetic populations.