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

Samuel Ghatan; Fjorda Koromani; Katerina Trajanoska; Evert F S van Velsen; Maryam Kavousi; M Carola Zillikens; Carolina Medina-Gomez; Ling Oei; Fernando Rivadeneira

doi:10.1093/jbmrpl/ziae126

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

JBMR Plus. 2024 Oct 17;8(11):ziae126. doi: 10.1093/jbmrpl/ziae126. eCollection 2024 Nov.

Authors

Samuel Ghatan¹, Fjorda Koromani¹, Katerina Trajanoska², Evert F S van Velsen¹, Maryam Kavousi³, M Carola Zillikens¹, Carolina Medina-Gomez¹, Ling Oei¹, Fernando Rivadeneira¹

Affiliations

¹ Department of Internal Medicine, Erasmus Medical Center, 3015 GD, Rotterdam, The Netherlands.
² Canada Excellence Research Chair in Genomic Medicine, Victor Philip Dahdaleh Institute of Genomic Medicine, Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, QC H3G 2M1, Montreal, QC, Canada.
³ Department of Epidemiology, Erasmus Medical Center, 3015 GD, Rotterdam, The Netherlands.

Abstract

We aimed to: (1) examine the relationship between glycemic control, BMD estimated from heel ultrasound (eBMD) and fracture risk in individuals with type 1 (T1D) and type 2 diabetes (T2D) and (2) perform a one-sample Mendelian randomization (MR) study to explore potential causal associations between glycemic control, eBMD, and fractures. This study comprised 452 131 individuals from the UK Biobank with glycated hemoglobin A1C (HbA_1c) and eBMD levels. At baseline, 4078 participants were diagnosed with T1D and 23 682 with T2D. HbA_1c was used to classify patients into "adequately-" (ACD; n = 17 078; HbA_1c < 7.0%/53 mmol/mol) and "inadequately-" (ICD; n = 10 682; HbA_1c ≥ 7.0%/53 mmol/mol) controlled diabetes. In individuals with T1D, a 1% unit (11 mmol/mol) increase in HbA_1c levels was associated with a 12% increase in fracture risk (HR: 1.12, 95% CI [1.05-1.19]). Fracture risk was highest in individuals with T1D 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]), as compared to subjects without diabetes. Evidence for a non-linear association between HbA_1c and fracture risk was observed (F-test ANOVA p-value = 0.002) in individuals with T2D, with risk being increased at both low and high levels of HbA_1c. Fracture risk between the T2D 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 HbA_1c levels were not significantly associated with fracture risk (causal risk ratio: 1.04, 95%CI [0.95-1.14]). We did observe evidence of a non-linear causal association with eBMD (quadratic test p-value = 0.0002), indicating U-shaped relationship between HbA_1c and eBMD. We obtained evidence that lower HbA_1c levels will reduce fracture risk in patients with T1D. In individuals with T2D, lowering HbA_1c levels can mitigate the risk of fractures up to a threshold, beyond which the risk may begin to rise again.

Keywords: BMD; HbA1c; Mendelian randomization; fractures; glycemic control; type 1 diabetes; type 2 diabetes.