Abstract
<title>Abstract</title> <p>Background Vitamin D supplementation is widely prescribed for conditions beyond skeletal health, yet the optimal dosage for extra-skeletal outcomes such as cardiovascular events, cancer, respiratory illness, and autoimmune disease remains contested. Conflicting results from large-scale randomised controlled trials (RCTs), including VITamin D and OmegA-3 TriaL (VITAL) and D-Health, have left clinicians without clear dose response guidance. We describe a protocol for a systematic review that will evaluate the comparative effectiveness of different vitamin D dosages on critical clinical outcomes in adults. Methods This review is prospectively registered with PROSPERO (CRD420251011893) and the Clinical Trials Registry of India (CTRI/2025/09/094241) and approved by a seventeen-member institute’s ethics committee for academic research project (ECARP/2025/109). We will search Embase, Ovid MEDLINE, CINAHL, Cochrane CENTRAL, Scopus, Web of Science, ClinicalTrials.gov, and CTRI for RCTs comparing different vitamin D dosages in adults aged 18 years or older. Two reviewers will independently screen records, extract data, and assess risk of bias using the Cochrane RoB 2.0 tool. Random effects metanalysis will pool binary outcomes as risk ratios and continuous outcomes as mean differences with 95% confidence intervals. Heterogeneity will be quantified using I², τ², and prediction intervals. Certainty of evidence will be graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Discussion This protocol establishes a transparent, pre-registered plan for synthesising trial evidence on vitamin D dose-response relationships across extra-skeletal outcomes. The completed review aims to inform supplementation guidelines and identify persisting evidence gaps for future trials. Systematic review registration: PROSPERO (CRD420251011893)</p>