Hyperglycaemia, diabetes and risk of fragility fractures: observational and Mendelian randomisation studies.

AIMS/HYPOTHESIS: Fragility fractures may be a complication of diabetes, partly caused by chronic hyperglycaemia. We hypothesised that: (1) individuals with hyperglycaemia and diabetes have increased risk of fragility fracture; (2) hyperglycaemia is causally associated with increased risk of fragility fracture; and (3) diabetes and fragility fracture jointly associate with the highest risk of all-cause mortality.

METHODS: In total, 117,054 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study (the Copenhagen studies) and 390,374 individuals from UK Biobank were included for observational and one-sample Mendelian randomisation (MR) analyses. Fragility fractures were defined as fractures at the hip, spine and arm (humerus/wrist), collected from national health registries. Summary data for fasting glucose and HbA1c concentrations from 196,743 individuals in the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) were combined with data on fragility fractures from the Copenhagen studies in two-sample MR analyses.

RESULTS: Higher fasting and non-fasting glucose and HbA1c concentrations were associated with higher risk of any fragility fracture (p<0.001). Individuals with vs without diabetes had HRs for fragility fracture of 1.50 (95% CI 1.19, 1.88) in type 1 diabetes and 1.22 (1.13, 1.32) in type 2 diabetes. One-sample MR supported a causal association between high non-fasting glucose concentrations and increased risk of arm fracture in the Copenhagen studies and UK Biobank combined (RR 1.41 [1.11, 1.79], p=0.004), with similar results for fasting glucose and HbA1c in two-sample MR analyses (ORs 1.50 [1.03, 2.18], p=0.03; and 2.79 [1.12, 6.93], p=0.03, respectively). The corresponding MR estimates for any fragility fracture were 1.18 (1.00, 1.41), p=0.06; 1.36 (0.89, 2.09), p=0.15; and 2.47 (0.95, 6.43), p=0.06, respectively. At age 80 years, cumulative death was 27% in individuals with fragility fracture only, 54% in those with diabetes only, 67% in individuals with both conditions and 17% in those with neither.

CONCLUSIONS/INTERPRETATION: Hyperglycaemia and diabetes are risk factors for fragility fracture and one- and two-sample MR analyses supported a causal effect of hyperglycaemia on arm fractures. Diabetes and previous fragility fracture jointly conferred the highest risk of death in the general population.