Elevated IGF-1 levels are associated with accelerated bone age advancement during growth hormone therapy in children: a multicenter cohort study.

BACKGROUND: Elevated insulin-like growth factor-1 (IGF-1) levels are associated with earlier pubertal onset and accelerated bone maturation. However, the effect of IGF-1 increases during growth hormone (GH) therapy on bone age (BA) advancement across different etiologies of short stature remains unclear. METHODS: This multicenter observational study included 1,944 children with idiopathic growth hormone deficiency (IGHD), idiopathic short stature (ISS), or small for gestational age (SGA) enrolled in the LG Growth Study registry between 2020 and 2024. IGF-1 standard deviation score (SDS), auxological parameters, GH dose, and BA were assessed during GH therapy. BA advancement was defined as the first occurrence of a BA-to-chronological age ratio (BA/CA) >1 during follow-up. Cox proportional hazards regression models were used to evaluate the association between IGF-1 SDS and BA advancement, with additional multivariable adjustment for potential clinical confounders. Additional subgroup analyses according to age, sex, diagnosis, and GHD severity were performed. A sensitivity analysis using BA/CA >1.2 was also conducted. RESULTS: Each 1-unit increase in IGF-1 SDS was associated with a higher risk of BA advancement in the overall cohort (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.15-1.33, p<0.001), with consistent associations in males and females. Compared with IGHD, children with ISS (HR 1.63, 95% CI 1.26-2.11) and SGA (HR 2.15, 95% CI 1.82-2.55) showed significantly increased risks of BA advancement. Additional analyses stratified by age, GHD severity, and pubertal initiation showed consistent findings. Sensitivity analysis using BA/CA >1.2 confirmed the association between IGF-1 SDS elevation and significant BA advancement. CONCLUSION: Increases in IGF-1 SDS during GH therapy are independently associated with accelerated bone maturation in children with short stature, particularly in those born SGA. These findings remained consistent across multiple subgroups and sensitivity analyses, supporting the importance of individualized GH dosing with careful monitoring of IGF-1 levels and skeletal maturation.