Vitamin D Deficiency

Vitamin D (VD), due to its hormonal action, plays a crucial role in calcium homeostasis and bone metabolism, and its deficiency has been associated with musculoskeletal disorders such as osteoporosis, fractures, and osteomalacia, as well as a growing attention of chronic conditions and certain cancers. Despite its physiological relevance and widespread prevalence, particularly among older individuals, patients with chronic diseases, institutionalized populations and pregnant or lactating women, clinical approaches to diagnosing and managing vitamin D deficiency (VDD) remain heterogeneous across guidelines and healthcare settings. This reflects a lack of consensus regarding the benefits and limitations of universal versus selective screening, the definition of adequate serum concentrations, and the clinical indications for supplementation across different patient profiles. This narrative review explores key controversies in the clinical management of VDD, including current perspectives on screening strategies and target populations, indications for empirical supplementation, criteria for biochemical monitoring, and therapeutic goals in bone-related outcomes. In particular, the review discusses the rationale for adopting a 30 ng/mL (75 nmol/L) threshold for adequate serum 25(OH) concentrations in skeletal health, the role of vitamin D and calcium in osteoporosis treatment, and the pharmacological advantages of cholecalciferol compared to other vitamin D compounds. Through a synthesis of available evidence and expert consensus, the review aims to support clinical decision-making in the prevention and treatment of VDD and to identify areas that require further clarification or research. This review aims to support evidence-based clinical decision-making.

Vitamin D, a fat-soluble secosteroid traditionally recognized for skeletal health, exerts pleiotropic effects on cardiovascular physiology and disease. Circulating 25-hydroxyvitamin D [25(OH)D], the principal biomarker of vitamin D status, is frequently suboptimal worldwide, particularly in older adults, individuals with darker skin pigmentation, and populations at higher latitudes. Observational studies consistently associate low 25(OH)D concentrations with increased risk of hypertension, atherosclerosis, myocardial infarction, heart failure, arrhythmias, stroke, and cardiovascular mortality. Mechanistic investigations have revealed that vitamin D modulates cardiomyocyte calcium handling, endothelial function, vascular smooth muscle proliferation, inflammation, oxidative stress, and renin-angiotensin-aldosterone system activity, establishing biologically plausible links to cardiovascular outcomes. Despite these associations, large randomized trials of vitamin D supplementation have failed to demonstrate reductions in major cardiovascular events, likely due to heterogeneity in baseline status, dosing regimens, intervention timing, genetic variability, and underlying comorbidities. Vitamin D may function more effectively as a biomarker of cardiovascular risk rather than a universal therapeutic agent, with deficiency reflecting systemic vulnerability rather than acting as a dominant causal factor. Emerging evidence supports precision approaches targeting individuals with severe deficiency, high renin activity, early endothelial dysfunction, or specific genetic profiles, potentially in combination with lifestyle or pharmacologic interventions. Future research should focus on defining optimal dosing strategies, intervention timing, and mechanistic biomarkers to identify subpopulations most likely to benefit, integrating vitamin D therapy into multifaceted cardiovascular prevention frameworks. This systematic review synthesizes molecular, observational, and clinical trial evidence, critically evaluating the current understanding of vitamin D in cardiovascular medicine and highlighting opportunities for targeted, personalized interventions. Vitamin D represents a complex, context-dependent modulator of cardiovascular health, offering both prognostic insight and potential therapeutic value when appropriately applied.

PURPOSE OF REVIEW: Vitamin D is a pleiotropic hormone with an established role in skeletal integrity and broader actions in immune regulation, inflammation, cellular proliferation, and energy homeostasis. Despite decades of research, its extra-skeletal effects remain controversial, largely due to discordant findings across observational studies, Mendelian randomization studies (MRS), and randomized controlled trials (RCTs). Unlike many prior reviews, this state-of-the-art review synthesizes triangulated evidence across these study designs to clarify outcome-specific causal relationships and ongoing controversies. RECENT FINDINGS: Triangulated evidence provides strong and consistent support for a causal role of vitamin D in skeletal health, particularly in the prevention and treatment of rickets and osteomalacia, and in fracture risk reduction among vitamin D–deficient and older populations. For selected extra-skeletal outcomes, modest and threshold-dependent benefits are observed, including reductions in cancer mortality, protection against autoimmune disorders, most convincingly multiple sclerosis, and decreased risk of acute respiratory infections, including COVID-19, primarily in individuals with low baseline 25(OH)D concentrations. In contrast, associations with cardiovascular disease, metabolic disorders, obesity, and most neuropsychiatric outcomes are not consistently supported by genetic or interventional evidence, suggesting limited or non-causal effects. Across outcomes, evidence indicates a non-linear relationship between vitamin D status and health, with increased risk concentrated at low 25-hydroxyvitamin D concentrations and limited benefit beyond sufficiency. All-cause mortality shows a modest, threshold-dependent association, with supplementation benefits largely confined to deficient or older populations. Key challenges include assay variability, non-linear dose–response relationships, and RCT designs that frequently enroll vitamin D–replete populations, resulting in substantial methodological heterogeneity and limiting causal inference. Overall, the presented triangulated model may reconcile longstanding inconsistencies by reframing vitamin D as a context-dependent determinant of health. These findings argue against indiscriminate population-wide supplementation and support targeted strategies focused on the identification and correction of deficiency. Vitamin D should be regarded neither as a universal panacea nor as a trivial supplement, but as a context-dependent hormone whose clinical value lies in outcome-specific correction of deficiency.