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

Abstract 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 (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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded internally by Leumit Health Services. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was reviewed and approved by the Leumit Health Services Institutional Review Board (IRB). Ethical approval was granted, with a waiver of informed consent (LEU-0020-24). The LHS data were fully de-identified prior to access and analysis for this study. All LHS data were analyzed retrospectively and anonymously under IRB approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes This version includes expanded covariate matching and adjustment, addition of lagged analyses (6- and 12-month), clarification of model structures and reference categories, and improved figures and supplementary materials. Data Availability Access to the LHS data used in this study are restricted to researchers approved by the IRB. The TriNetX data used in this study is limited to members of the TriNetX network. - Abbreviations - aOR - adjusted Odds Ratio - BMI - Body Mass Index - BP - Blood pressure - CNS - Central nervous system - EHR - Electronic health records - HR - Hazard Ratio - ICD-9 - International Classification of Diseases, Ninth Revision - LHS - Leumit Health Services - OR - Odds Ratio - PO - Per os - PSM - Propensity score matching - SES - Socioeconomic status - SMD - Standardized Mean Difference