Neutrophil extracellular traps in osteoporosis: mechanistic links to bone remodeling imbalance and therapeutic perspectives.

<h4>Background</h4>Osteoporosis (OP) is increasingly recognized as a disorder driven not only by endocrine and metabolic abnormalities but also by chronic low-grade inflammation and aging-related immune dysregulation. Neutrophil extracellular traps (NETs), web-like extracellular DNA-protein structures released by activated neutrophils, can act as structural inflammatory scaffolds that sustain sterile inflammation, oxidative injury, and microenvironmental imbalance. However, the mechanistic contribution and translational significance of NETs in osteoporosis remain incompletely integrated.<h4>Objective</h4>This review aims to summarize the current evidence linking NET formation to bone remodeling imbalance in osteoporosis, with particular emphasis on osteoclast activation, osteoblast dysfunction, inflammaging(definition), oxidative stress, ferroptosis, metabolic reprogramming, and potential NET-targeted therapeutic strategies.<h4>Methods</h4>We reviewed recent studies concerning NET biology, osteoimmunology, inflammaging, and inflammation-associated osteoporosis. Based on these findings, we constructed an integrated "NETs-inflammation-bone remodeling imbalance" framework to explain how persistent NET accumulation may promote osteoclastogenesis, impair osteogenic differentiation, amplify inflammatory feedback loops, and reshape the bone microenvironment. We also discussed the potential clinical relevance of neutrophil-related inflammatory indicators and NET-specific biomarkers.<h4>Conclusion</h4>Persistent NET formation and insufficient NET clearance under inflammaging conditions may contribute to a self-sustaining inflammatory-oxidative network in the bone microenvironment. NET-derived extracellular DNA, histones, neutrophil elastase, myeloperoxidase, and citrullinated proteins may activate pattern-recognition receptor pathways, including TLR4/NF-κB and potentially TLR9- and TLR2-related signaling, thereby enhancing RANKL-mediated osteoclastogenesis and suppressing osteoblast differentiation and survival. In parallel, NETs may amplify oxidative stress, disturb iron homeostasis, promote ferroptosis susceptibility, and induce metabolic reprogramming, collectively shifting bone remodeling toward bone resorption. Targeting NET formation, promoting NET degradation, or blocking NET-related inflammatory and oxidative signaling may provide new therapeutic opportunities for inflammation-driven osteoporosis. Nevertheless, the NETs-ferroptosis-metabolic reprogramming axis in osteoporosis should currently be regarded as a promising mechanistic framework that requires further experimental and clinical validation.