Ferroptosis in osteoporosis: core mechanisms, cell-specific effects in bone remodelling, and therapeutic perspectives

Abstract

Osteoporosis is an endocrine and metabolic bone disease driven by insufficient bone formation, enhanced bone resorption, and disrupted coupling of bone remodelling. Ferroptosis, characterised by iron-dependent membrane phospholipid peroxidation and failure of anti-lipid-peroxidation defences, is emerging as a mechanistic link between oestrogen deficiency, glucolipotoxicity, glucocorticoid exposure, ageing, iron overload, and dysfunction of bone-remodelling cells. This structured narrative review summarises iron homeostasis, lipid peroxidation, the System Xc − –GSH–GPX4 axis, ferritinophagy, mitochondrial metabolism, and non-GPX4-dependent defence systems, and compares the direction and strength of ferroptotic effects in osteoblasts, osteocytes, osteoclasts, and bone marrow mesenchymal stem cells. Current evidence indicates that ferroptosis in osteoblasts and bone marrow mesenchymal stem cells impairs osteogenic differentiation, matrix formation, and mineralisation; ferroptosis in osteocytes may further disrupt RANKL-related remodelling communication; whereas ferroptosis in osteoclasts may limit bone degradation under high-resorption conditions. This review further integrates the Nrf2, NOX4, Wnt/β-catenin, DNMT/GPX4, HIF-1α/NCOA4, FtMt/PINK1/Parkin, and metabolic regulatory pathways, compares dominant cellular targets across osteoporosis subtypes, and evaluates iron chelation, inhibition of lipid peroxidation, metabolic regulation, extracellular vesicles, epigenetic restoration, and selective induction of osteoclast ferroptosis. Overall, the therapeutic objective should not be uniform inhibition or induction of ferroptosis, but selective intervention according to cell identity, disease subtype, and bone-turnover status. Because the evidence remains predominantly preclinical, translation will require cell-specific models, standardised criteria for defining ferroptosis, and bone-targeted delivery.