Keywords: Vitamin D deficiency, Vitamin D treatment, mortality, Chronic diseases

Background:

Vitamin D deficiency is prevalent, consistently associated with increased morbidity and all-cause mortality. However, confounding by sunlight exposure and healthy-behavior factors has persistently obscured its causal role and limited the adoption of routine supplementation guidelines.

Research questions:

To evaluate the independent contribution of severe vitamin D deficiency to chronic disease and mortality risks, and to quantify the benefits of prescribed vitamin D supplementation, independent of baseline status and confounders.

Method:

A large-scale, longitudinal matched-cohort analysis using electronic health-record data from two distinct healthcare organizations: Leumit Health Services (LHS) in Israel and the US-based TriNetX Research Network. The study included over 468,500 adults with >1.67 million Vitamin D measurements. We compared severely deficient individuals to those with sufficient levels (>30 ng/mL) using matched pairs. To isolate the effect of the intervention, we employed advanced time-dependent Cox proportional-hazards models that incorporated monthly pharmacy-dispensed vitamin D supplementation, effectively controlling for seasonality and baseline serum levels.

Results:

Severe vitamin D deficiency was independently associated with a significantly increased risk of all-cause mortality, cardiovascular events, end-stage renal disease, and diabetic complications in both cohorts. Supplementation was associated with a dose-dependent, independent reduction in mortality and most complications (e.g., HR = 0.69 [0.65–0.73] for >10 ng/mL serum-equivalent). The one-year number needed to treat to prevent one death declined markedly with age and severity, reaching approximately 10–15 in older adults (>70) with very low baseline levels, demonstrating a high-impact preventive benefit in this high-risk group.

Conclusions:

By using a time-dependent modeling approach that leverages pharmacy dispensing records, we provide strong observational evidence supporting a causal link between severe vitamin D deficiency and adverse clinical outcomes. The low NNT in vulnerable populations shifts the focus from population-wide screening to targeted therapeutic intervention. Severe vitamin D deficiency may be a highly modifiable, clinically significant risk factor and may offer a substantial mortality reduction.

Points for discussion:

Strength and weaknesses of the study, is it time for a prospective study on Vit D supplementation