Relationships of oxidative stress, HMGB1 and Irisin with bone mineral density during the first year of life: first results from the REMS-bone study

Introduction: The REMS-bone study (clinical trial: NCT06750523) aimed to evaluate bone status starting from intrauterine life and investigate factors that may affect bone mineral density (BMD) in infants. Experimental and clinical studies have suggested that oxidative stress (OS) and chronic inflammation affect BMD accrual. Perinatal life represents a developmental window that can influence future bone growth and quality. However, understanding of the role of OS remains insufficient. The aim of this substudy was to investigate the associations among cord serum OS markers, high mobility group box-1 (HMGB1) and irisin as markers of glucose/muscle metabolism and inflammation, and BMD z-scores during the first year of life. Methods: This prospective longitudinal study analyzed data from 44/65 healthy full-term AGA babies (25 males and 19 females). BMD z-scores were obtained from femoral neck and bone using new Radiofrequency Echographic Multi Spectrometry (REMS) technology at 48 hours after birth, 1, 3, 6 and 12 months of life. HMGB1 and irisin were assayed using ELISA kits and biochemical mediators involved in oxidative stress (total antioxidant capacity (TAC), advanced oxidation protein products (AOPP), 8‑hydroxy‑2′-deoxyguanosine (8OH-dG), superoxide dismutase (SOD), glutathione peroxidase (GPx), paraoxonase-1 (PON-1), advanced oxidation protein products (AOPP), 4-hydroxynonenal (4-HNE)). Correlation analyses and principal component analysis (PCA) were used to examine associations between cord serum biomarkers and longitudinal BMD outcomes. Results: Cord serum markers of oxidative stress showed significant associations with BMD during the first year of life. Correlation analysis showed an association between BMD z-score at birth and TAC (r: -0.309, p:0.047). At 1 month, BMD z-scores were positively associated with GPx activity (r:0.403, p:0.015). At 3 months, BMD z-score was associated with 4-HNE (r: -0.357, p:0.033). At 12 months, BMD z-score was associated with SOD activity (r:0.515, p:0.041). No significant associations were observed among HMGB1 or irisin levels and BMD z-scores or oxidative stress markers. PCA further underlined patterns of associations between proteins and oxidative stress markers and BMD z-scores during the 1st year of life, such as positive loadings of SOD activity and irisin and a negative loading for 4-HNE. Conclusions: These findings highlight the importance of the perinatal oxidative environment in the development of early bone mineral accrual. Enzymatic antioxidant defenses appear to favour neonatal bone health, whereas elevated total antioxidant capacity and irisin levels may reflect compensatory responses associated with a lower BMD.