Metabolic factors associated with incident fracture among older adults with type 2 diabetes mellitus: a nested case–control study

Summary Older adults with type 2 diabetes mellitus have an increased risk of fracture despite a paradoxically higher average bone mineral density. This study identified additional markers of fracture risk in this at-risk population. Non-esterified fatty acids and the amino acids glutamine/glutamate and asparagine/aspartate were associated with incident fractures. Purpose Type 2 diabetes mellitus (T2D) is associated with an increased risk of fracture despite a paradoxically higher bone mineral density. Additional markers of fracture risk are needed to identify at-risk individuals. Method The MURDOCK study is an ongoing study, initiated in 2007, of residents in central North Carolina. At enrollment, participants completed health questionnaires and provided biospecimen samples. In this nested case–control analysis, incident fractures among adults with T2D, age ≥ 50 years, were identified by self-report and electronic medical record query. Fracture cases were matched 1:2 by age, gender, race/ethnicity, and BMI to those without incident fracture. Stored sera were analyzed for conventional metabolites and targeted metabolomics (amino acids and acylcarnitines). The association between incident fracture and metabolic profile was assessed using conditional logistic regression, controlled for multiple confounders including tobacco and alcohol use, medical comorbidities, and medications. Results 107 incident fractures were identified with 210 matched controls. Targeted metabolomics analysis included 2 amino acid factors, consisting of: 1) the branched chain amino acids, phenylalanine and tyrosine; and 2) glutamine/glutamate, asparagine/aspartate, arginine, and serine [E/QD/NRS]. After controlling for multiple risk factors, E/QD/NRS was significantly associated with incident fracture (OR 2.50, 95% CI: 1.36–4.63). Non-esterified fatty acids were associated with lower odds of fracture (OR 0.17, 95% CI: 0.03–0.87). There were no associations with fracture among other conventional metabolites, acylcarnitine factors, nor the other amino acid factors. Conclusion Our results indicate novel biomarkers, and suggest potential mechanisms, of fracture risk among older adults with T2D.