From the Vitamin D Paradox to Precision Nutrition: Targeted Supplementation, Assay Pitfalls, and Clinical Decision-Making.

PURPOSE OF REVIEW: Vitamin D is a pleiotropic secosteroid with established skeletal functions and proposed extraskeletal effects; however, its clinical application remains contentious. Despite extensive observational evidence linking low 25(OH)D concentrations to chronic diseases, randomized controlled trials (RCTs) have largely failed to confirm many of these associations. This review focuses on the practical clinical management of vitamin D, integrating determinants of vitamin D status, assay-related limitations, targeted testing, evidence-based supplementation, and decision-making within a precision-nutrition context.

RECENT FINDINGS: The discordance between observational and interventional evidence is partly explained by the inclusion of vitamin D-replete populations in major trials, background supplementation, non-linear dose-response relationships, and assay variability. For skeletal outcomes, clinically meaningful effects are mainly observed in deficiency, whereas selected benefits have been reported in specific populations, including mortality reduction in adults aged ≥ 75 years, a modest reduction in cancer mortality, and reduced progression to diabetes in adults with high-risk prediabetes. The 2024 Endocrine Society guideline recommends empiric supplementation for selected groups and discourages routine screening in healthy adults. Daily or weekly dosing is preferred to intermittent high-dose regimens, which may increase falls and fractures. Standardization initiatives have improved 25(OH)D measurement accuracy, but inter-method variability persists, complicating thresholds and cross-study comparisons. Genetic polymorphisms in GC, CYP2R1, CYP24A1, and VDR contribute to variability in supplementation response, although precision-nutrition approaches remain investigational. Vitamin D should be viewed as a context-dependent, threshold-driven nutrient rather than a universal preventive therapy. Clinically, priority should be given to preventing and correcting severe deficiency (< 12 ng/mL [< 30 nmol/L]), a threshold below which adverse skeletal outcomes are well documented. Supplementation should target evidence-based indications, and laboratory testing should be reserved for situations in which results inform management. Bridging evidence and practice requires trials in deficient populations, improved assay harmonization, and integration of individualized risk factors into clinical decision-making.