Osteoporosis is a systemic bone metabolic disease characterized by reduced bone mass and disrupted bone microstructure. Its pathogenesis is no longer viewed solely as a process of imbalance between bone formation and resorption. Recent advancements in bone immunology have revealed that bone immune dysregulation driven by chronic low-grade inflammation serves as an important pathological foundation for bone loss associated with aging, estrogen deficiency, and metabolic stress. In this context, inflammatory regulated cell death (RCD), which has high immunogenicity, is increasingly recognized as a key mechanism linking immune inflammation and bone remodeling disorders. Unlike apoptosis, which is relatively "silent" immunologically, inflammatory RCD forms such as pyroptosis and ferroptosis actively remodel the bone marrow immune microenvironment through the release of pro-inflammatory cytokines, reactive oxygen species, and damage-associated molecular patterns. This continuous amplification of osteoclastogenic signals and suppression of osteoblast function plays a structural role in the pathogenesis of osteoporosis. This review systematically integrates the molecular mechanisms and network interactions of pyroptosis, ferroptosis, and their interplay with other RCD forms such as apoptosis, autophagy, and PANoptosis, within the framework of "inflammatory cell death-bone immune regulation-osteoporosis." It emphasizes the pivotal role of NLRP3 inflammasome-mediated pyroptosis in amplifying bone immunity, as well as how ferroptosis driven by disturbances in iron homeostasis and lipid peroxidation selectively damages osteogenic lineage cells through metabolic oxidative stress, thereby reinforcing inflammatory responses. Furthermore, from the perspectives of shared signaling pathways, cell type specificity, and spatiotemporal dynamics, the review delves into the pathological mechanisms through which multiple RCD modes collaborate and reciprocally transform within the bone immune niche. It proposes that inflammatory bone loss results from the network coupling of various cell death programs under chronic inflammation, rather than being driven by a single pathway. Finally, the review summarizes and forecasts the potential translational medical value of targeting the inflammatory RCD-bone immune axis, discussing the feasibility of targeting key nodes such as the NLRP3 inflammasome, GPX4/Nrf2 antioxidant system, and PANoptosome for therapeutic interventions. It also highlights the potential of multi-target integrated strategies combining immune modulation, metabolic intervention, and targeted bone tissue delivery as promising approaches to overcoming current treatment bottlenecks in osteoporosis.
