Vitamin D supplementation as a potential cause of U-shaped associations between vitamin D levels and negative health outcomes: a decision tree analysis for risk of frailty

Background: A recent controversy in vitamin D research is a "U-shaped association", with elevated disease risks at both high and low 25-hydroxyvitamin D (25 (OH) D) levels. Methods: This is a cross-sectional study of 238 male nursing home veterans in Hawaii. Classification and regression tree (CART) analysis identified groups based on 25 (OH) D and vitamin D supplementation for frailty risk. Characteristics were examined and compared across the groups using logistic regression and receiver operating characteristic (ROC) curve analyses. Results: CART analysis identified three distinct groups: vitamin D supplement users (n = 86), non-users with low vitamin D (n = 55), and non-users with high vitamin D (n = 97). Supplement users were the most frail, but had high mean 25 (OH) D of 26.6 ng/mL, which was compatible with 27.1 ng/mL in non-users with high vitamin D, while mean 25 (OH) D of non-users with low vitamin D was 11.7 ng/mL. Supplement users and non-users with low vitamin D were significantly more likely to be frail (odds ratio (OR) = 9.90, 95% CI = 2.18-44.86, p = 0.003; OR = 4.28, 95% CI = 1.44-12. 68, p = 0.009, respectively), compared with non-users with low vitamin D. ROC curve analysis showed the three groups significantly predicted frailty (area under the curve = 0.73), with sensitivity of 64.4% and specificity of 76.7%, while 25 (OH) D did not predict frailty. Conclusions: In these nursing home veterans, vitamin D supplement users were the most frail but with high 25 (OH) D. This can potentially be a cause of U-shaped associations between vitamin D levels and negative health outcomes.