Metabolic Phenotyping of Nutritional Rickets in Bangladeshi Children

Background/Objectives: Nutritional rickets is a childhood bone disorder leading to skeletal deformities and life-long disabilities. Early-stage diagnosis remains challenging due to the limited availability of non-invasive tools. This study explores metabolic variation associated with the active disease stages and with etiological factors, such as nutritional deficiencies and biochemical alterations. Methods: Untargeted ¹H NMR spectroscopy-based metabolomics were performed on urine and plasma samples collected from Bangladeshi children with radiologically active rickets (AR; n = 24; aged 2.98 ± 1.19 years), inactive rickets (IR; n = 36; aged 3.39 ± 1.87 years), and healthy matched controls (n = 58; aged 3.58 ± 1.59 years). This analysis also integrated corresponding clinical biochemistry and dietary intake data previously collected from the cohort. Results: Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) identified the 24 h urinary excretion of 13 metabolites to vary with AR, including those previously associated with bone metabolism such as β-aminoisobutyrate, N-methylnicotinamide, taurine and hypoxanthine. Biochemically, AR was strongly characterized by increased plasma alkaline phosphatase and decreased iFGF23. The multi-block integration of metabolomic, biochemical, and nutritional data achieved an 18.6% classification error rate. Children with IR exhibited metabolic profiles similar to healthy controls, aligning with their clinical resolution. Conclusions: Active nutritional rickets presents a distinct metabolic profile, highlighting novel biologically relevant metabolites. These exploratory signals provide insights into the physiological impact of the disease and warrant further targeted investigation to assess their potential for informing early non-invasive detection and preventive interventions. In the long term, such tools are vital to prevent irreversible skeletal damage and to help mitigate lifelong physical disability and the resulting social vulnerability for affected children.