Vitamin D Deficiency, Supplementation, and Risk of Mortality and Chronic Disease: Evidence from Matched Cohorts in Israel and the US

Vitamin D deficiency is common worldwide and has been linked to excess morbidity and mortality, yet its causal role remains debated. We analyzed electronic health-record data from two large healthcare networks: Leumit Health Services (LHS) in Israel and the US-based TriNetX Research Network.

We examined more than 1.67 million serum 25-hydroxyvitamin D [25(OH)D] measurements from over 468,500 adults in LHS (2009-2020). In longitudinal matched-cohort analyses, we compared 13,352 severely deficient individuals (<10 ng/mL) to 12,352 with sufficient levels (>30 ng/mL) in LHS and validated findings in 223,000 matched pairs in TriNetX.

Severe deficiency was associated with increased risks of all-cause mortality, diabetes, diabetic retinopathy, myocardial infarction, cerebrovascular accident, dementia, dialysis, and foot/toe amputation, while skin malignancy showed an inverse association consistent with lower UV exposure.

To test modifiability, we fitted time-dependent Cox models in LHS incorporating monthly pharmacy-dispensed vitamin D supplementation. Supplementation was independently associated with dose-dependent risk reductions for mortality and most complications, but did not affect skin-malignancy risk, indicating supplementation effect is unlikely to be confounded by sun-exposure or other health-behavior factors.

These findings suggest severe vitamin D deficiency is a modifiable, clinically important risk factor, providing a strong rationale for evaluating targeted supplementation strategies in deficient populations.