From Inflammation to Bone Loss: The Multifaceted Role of Neutrophils in Osteoporosis

Neutrophils, the most abundant innate immune cells, have recently emerged as central regulators in the pathogenesis and treatment of osteoporosis. Traditionally viewed as transient inflammatory responders, neutrophils are now recognized as dynamic mediators linking immune dysregulation, bone remodeling, and aging in the context of osteoimmunology. This review provides a comprehensive synthesis of their multifaceted roles in bone metabolism: promoting osteoclastogenesis via RANKL, ROS, and neutrophil extracellular traps (NETs), while concurrently inhibiting osteoblast activity through TGF-β1 and bone marrow-derived stress signals. We highlight the involvement of neutrophils in postmenopausal osteoporosis driven by estrogen deficiency and in senile osteoporosis associated with immune aging, with particular attention to pathogenic subsets such as TGF-β1⁺CCR5⁺ neutrophils. In addition, we examine the clinical relevance of neutrophil-related biomarkers, such as neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and citrullinated histone H3 (Cit-H3), for diagnosis and risk stratification, as well as emerging therapeutic strategies that target NETosis and CCR5 signaling or employ neutrophil-homing drug delivery systems. By elucidating these immune-bone interactions, neutrophils were found to be promising diagnostic biomarkers and immunotherapeutic targets in osteoporosis, paving the way for precision intervention.