Evaluating the relationship between glycemic control and bone fragility within the UK biobank: Observational and one-sample Mendelian randomization analyses
Authors: Ghatan Samuel , Koromani Fjorda , Trajanoska Katerina , van Velsen Evert F.S. , Kavousi Maryam , Zillikens M Carola. , Medina-Gomez Carolina , Oei Ling , Rivadeneira Fernando 
Published: December 2023

AbstractAims/hypothesisThis study aimed to: (1) examine the relationship between glycemic control, bone mineral density estimated from heel ultrasound (eBMD) and fracture risk in individuals with type 1 and type 2 diabetes and (2) perform a one-sample Mendelian randomization study to explore potential linear and non-linear associations between glycemic control, eBMD, and fractures.MethodsThis study comprised 452,131 individuals from the UK Biobank with glycated hemoglobin A1C (HbA1c) and eBMD levels. At baseline, 4,078 participants were diagnosed with type 1 diabetes and 23,682 with type 2 diabetes. HbA1c was used to classify patients into “adequately-” (ACD; n=17,078; HbA1c < 7.0%/53mmol/mol) and “inadequately-” (ICD; n=10,682; HbA1c ≥ 7.0%/53mmol/mol) controlled diabetes. The association between glycemic control (continuous and categorical) and eBMD was tested using linear regression, while fracture risk was estimated in Cox regression models, both controlling for covariates. Mendelian randomization (MR) was used to evaluate linear and non-linear causal relationships between HbA1c levels, fracture risk, and eBMD.ResultsIn individuals with type 1 diabetes, a 1% unit (11mmol/mol) increase in HbA1c levels was associated with a 12% increase in fracture risk (HR: 1.12, 95% CI [1.05-1.19]). Individuals with type 1 diabetes had lower eBMD in both the ICD (beta = −0.08, 95% CI [−0.11, −0.04]) and ACD (beta = −0.05, 95% CI [-0.11,0.01]) groups, as compared to subjects without diabetes. Fracture risk was highest in individuals with type 1 diabetes and ICD (HR 2.84, 95%CI [2.53, 3.19]), followed by those with ACD (HR 2.26, 95%CI [1.91, 2.69]). Individuals with type 2 diabetes had higher eBMD in both ICD (beta=0.12SD, 95%CI [0.10, 0.14]) and ACD (beta=0.07SD, 95%CI [0.05, 0.08]) groups. Significant evidence for a non-linear association between HbA1c and fracture risk was observed (F-test ANOVA p-value = 0.002) in individuals with type 2 diabetes, with risk being increased at both low and high levels of HbA1c. Fracture risk between the type 2 diabetes ACD and ICD groups was not significantly different (HR: 0.97, 95%CI [0.91-1.16]), despite increased BMD. In MR analyses genetically predicted higher HbA1c levels were not significantly associated with fracture risk (Causal Risk Ratio: 1.04, 95%CI [0.95-1.14]). However, disease stratified analyses were underpowered. We did observe evidence of a non-linear causal association with eBMD (quadratic test P-value = 0.0002), indicating U-shaped relationship between HbA1c and eBMD.Conclusion/interpretationWe obtained evidence that lower HbA1c levels will reduce fracture risk in patients with type 1 diabetes. In individuals with type 2 diabetes, lowering HbA1c levels can mitigate the risk of fractures up to a threshold, beyond which the risk may begin to rise once more. MR analyses demonstrated a causal relationship between genetically predicted HbA1c levels and eBMD, but not fracture risk.