Inverse association between high-density lipoprotein cholesterol and bone mineral density in patients with diabetes results from a nationally representative survey

Diabetes mellitus substantially increases the risk of osteoporosis and fractures, but the mechanisms remain unclear. Dyslipidemia, particularly the role of high-density lipoprotein (HDL), may influence bone mineral density (BMD), yet evidence in diabetic patients is limited. This study aimed to explore the association between HDL and BMD in US adults with diabetes using a nationally representative dataset. We analyzed data from 5 National Health and Nutrition Examination Survey cycles (2005-2018). A total of 5014 diabetic participants with available HDL and dual-energy X-ray absorptiometry (DXA)-measured BMD were included. Weighted multivariable linear regression models, smooth curve fitting, and 2-piecewise linear regression were employed to examine linear and nonlinear associations. Subgroup and sensitivity analyses were also conducted to assess robustness. Among 5014 participants (mean age 40.1 ± 31.2 years; 50.8% male), mean femoral neck and lumbar spine BMD were 0.81 and 1.03 g/cm2, respectively, with a mean HDL of 48.9 mg/dL. Higher HDL levels were inversely associated with BMD at both the femoral neck (β = -0.0011, 95% CI: -0.0015 to -0.0007) and lumbar spine (β = -0.0012, 95% CI: -0.0018 to -0.0007) after full adjustment. Participants in the highest HDL quartile had significantly lower BMD compared with those in the lowest quartile (femoral neck: -0.0294 g/cm2; lumbar spine: -0.0378 g/cm2). Smooth curve fitting indicated nonlinear, negative associations. Subgroup analyses revealed stronger inverse associations in men, participants with hypertension, those <60 years at the femoral neck, and those ≥60 years at the lumbar spine. Sensitivity analyses confirmed the robustness of the results. Higher HDL levels were consistently and independently associated with lower BMD in US adults with diabetes. These findings challenge the traditional view of HDL as universally protective, suggesting that in the diabetic context, elevated HDL may exert detrimental effects on bone health. Further longitudinal and mechanistic studies are warranted to clarify causal pathways and guide osteoporosis prevention strategies in this high-risk population.