Cardiovascular Disease and Fracture Risk in People with Type 2 Diabetes: A Nationwide Matched Case-Control Study

To examine, among people with type 2 diabetes (T2D), whether cardiovascular disease (CVD) phenotypes and cardiovascular medications are associated with any fracture as the primary outcome and major osteoporotic fracture (MOF) as a secondary outcome. Nationwide registry-based matched case-control study in Denmark (2013-2021) among people with T2D. Cases were individuals with T2D who sustained an incident fracture (n = 12,390), and controls were fracture-free individuals with T2D matched 1:3 by age, sex, T2D onset date, and weighted Charlson Comorbidity Index (n = 37,170). The exposures were overall CVD, prespecified clinical CVD phenotypes (acute myocardial infarction (AMI), stroke, heart failure, atrial fibrillation/flutter (AFib/AFL), and atherosclerosis), subclinical CVD phenotypes (hypertension, hypercholesterolemia, and chronic kidney disease (CKD)), individual CVD subtypes, and cardiovascular medications. Any fracture was the primary outcome, and major osteoporotic fracture (MOF) was examined as a secondary outcome. Conditional logistic regression estimated overall and sex-stratified odds ratios (ORs) with 95% confidence intervals (CIs), and sex interactions were assessed. any fracture, overall CVD (OR 1.20; 95% CI 1.15-1.26), clinical (OR 1.15; 1.09-1.21), and subclinical CVD (OR 1.22; 1.17-1.28) were associated with higher odds. AFib/AFL, atherosclerosis, CKD, heart failure, hypercholesterolemia, hypertension, and stroke showed positive associations, whereas AMI was inversely associated. Higher fracture odds were observed with factor Xa inhibitors, nitrates, and antiplatelet agents. Sex-stratified analyses showed broadly similar associations for CVD phenotypes in men and women, with no consistent evidence of sex-specific differences. Associations were weaker and non-significant for major osteoporotic fractures. In T2D, CVD and selected cardiovascular medications are associated with higher odds of fracture, highlighting the importance of incorporating cardiovascular status into fracture risk assessment.