Evaluating the relationship between glycemic control and bone fragility within the UK biobank: Observational and one-sample Mendelian randomization analyses

Aims/hypothesis This 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. Methods This 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. Results In 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/interpretation We 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project has received funding from the European Union's Horizon 2020 research and innovation program under the MARIE SKŁODOWSKA-CURIE grant agreement no. 860898. LO is funded by an Erasmus MC fellowship grant. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank had obtained ethics approval from the North West Multi-centre Research Ethics Committee which covers the UK (approval number: 11/NW/0382) and had obtained informed consent from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data generated or analyzed during this study are included in this published article [and its supplementary information files]. * List of abbreviations : (GWAS) : Genome-wide association study (LD) : linkage disequilibrium (type 2 diabetes) : type 2 diabetes (PRS) : polygenic risk scores (MR) : Mendelian randomization (SNP) : single nucleotide polymorphism (BMI) : body mass index (BMD) : Bone mineral density (DXA) : Dual X-ray absorptiometry.