Spermidine mitigates glucocorticoid-induced bone osteoporosis by targeting oxidative stress and RANKL/OPG pathway.

Glucocorticoid-induced osteoporosis (GIOP) is one of the most prevalent types of osteoporosis. This disorder is linked to a high disability and morbidity rate, highlighting the critical need for better preventative and treatment techniques. Spermidine (SPD), a naturally occurring polyamine, modulates critical biological activities, including cell proliferation, autophagy, aging, oxidative stress, and inflammation, and has bone-protective properties. The present study investigated whether SPD could attenuate bone loss in a GIOP rat model. Four groups were created: control, SPD (20 mg/kg), dexamethasone (DEX) (7 mg/kg intramuscularly injected once a week for 5 weeks), and DEX + SPD. DEX administration significantly disrupted bone homeostasis, as evidenced by decreased osteocalcin levels, elevated C-telopeptide of type I collagen (CTX-1), upregulated receptor activator of nuclear factor kappa-β ligand (RANKL) expression, downregulated runt-related transcription factor 2 (RUNX2) and osteoprotegerin (OPG) expression, elevated oxidative stress (increased malondialdehyde and depleted reduced glutathione), and heightened pro-inflammatory cytokines. These biochemical alterations were accompanied by significant deterioration in bone morphometric parameters. Spermidine co-administration markedly attenuated these changes, restoring redox balance, suppressing inflammatory mediators, modulating the RANKL/OPG axis, and partially preserving bone microarchitecture. These findings indicate that SPD shows beneficial effects in safeguarding against GIOP in a rat model, providing a foundation for further preclinical and clinical investigations.