Vitamin D3 is a fat-soluble secosteroid synthesized in the human skin upon exposure to ultraviolet B (UVB) radiation from sunlight and is also derived from dietary sources such as fatty fish, liver, egg yolks, and fortified dairy products [1]. The biologically active form, calcitriol (1,25-dihydroxyvitamin D), plays a vital role in maintaining calcium and phosphate balance for bone formation and remodeling [2]. Recent decades have witnessed an expansion in the understanding of Vitamin D3’s extra-skeletal functions, particularly in modulating immune, cardiovascular, endocrine, and neurological systems [3]. Despite this, Vitamin D3 deficiency remains a widespread and underdiagnosed condition globally.

According to the World Health Organization and various epidemiological studies, over one billion individuals worldwide suffer from suboptimal Vitamin D3 levels [4,5].

A variety of environmental and physiologic factors are associated with hypovitaminosis D, such as geographical latitude, decreased availability of sunlight, higher skin melanin content, older age, obesity, and malabsorptive syndromes [6–8]. To the significance, indoor lifestyle behaviors and sunscreens have also limited the dermal synthesis of cholecalciferol [9]. Also, some chronic diseases, like chronic kidney disease [10], liver diseases [11] and disease of the stomach and intestines [11], reduce the metabolism and absorption of Vitamin D3.

Clinically, Vitamin D3 deficiency is closely linked to rickets in children and osteomalacia in adults. But now there is growing evidence that it is associated with a broad range of non-skeletal related diseases. There is a substantial body of research supporting the role of low levels of Vitamin D3 in the development of autoimmunity, including multiple sclerosis, type 1 diabetes, and inflammatory bowel disease [12,13]. The hormone-like functions of calcitriol allow it to modify the intrinsic and adaptive immunity by controlling the production of cytokines, inducing antimicrobial peptides such as cathelicidin, and suppressing the TH1-mediated responses [14,15].

In the cardiovascular field, there is a well-characterized association with endothelial dysfunction, hypertension, arterial stiffness, and increased risk for myocardial infarction and stroke [16,17]. In addition, experimental studies provide evidence that Vitamin D3 has a protective role in the vascular calcification and systemic inflammation (two major factors contributing atherogenesis) [18]. Besides, its insufficiency has been shown to affect lipid profiles and glucose clearance, which leads to metabolic syndrome and insulin resistance [19,20].

Neurocognitive and psychiatric implications of Vitamin D3 deficiency have also gained attention in recent literature. Vitamin D receptors and hydroxylases are widely distributed in brain tissue, particularly in the hippocampus, prefrontal cortex, and hypothalamus—areas integral to cognition, mood regulation, and neuroendocrine balance [21]. Low levels of serum 25(OH)D have been found to be significantly associated with depressive disorders, schizophrenia, and Alzheimer’s disease [22,23].

Additionally, several studies suggest that Vitamin D3 influences cancer biology by modulating cell proliferation, differentiation, and apoptosis. Observational data reveal inverse relationships between serum Vitamin D3 levels and incidence of colorectal, breast, and prostate cancers [24]. It is hypothesized that calcitriol may act via the p21 and p27 pathways, inhibiting tumor angiogenesis and promoting cell cycle arrest [25].

Given the pleiotropic roles of Vitamin D3, understanding its deficiency is critical not just from a bone health perspective but for comprehensive disease prevention strategies. The ongoing COVID-19 pandemic further fueled interest in Vitamin D3 due to its proposed role in mitigating viral infections and respiratory complications [26,27]. In randomized trials, individuals with optimal Vitamin D3 levels demonstrated reduced severity of respiratory infections and better immune profiles [28].

This systematic review consolidates existing literature on the multifactorial impact of Vitamin D3 deficiency on human health. It aims to offer a synthesis of high-quality clinical and observational studies, highlight underlying biological mechanisms, and discuss implications for public health and clinical practice. The following sections outline our research methodology, selection criteria, and evidence synthesis across physiological systems.

This systematic review adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive literature search was conducted across multiple databases, including PubMed, Scopus, Web of Science, and Google Scholar, covering studies published from January 2000 to March 2024. Keywords employed in the search strategy included “Vitamin D3 deficiency,” “cholecalciferol,” “immune modulation,” “bone metabolism,” “cardiovascular disease,” “neuropsychiatric disorders,” “endocrine function,” and “metabolic health.” Boolean operators such as “AND,” “OR,” and “NOT” were used to refine and filter relevant results.

The inclusion criteria encompassed:

• Peer-reviewed human studies that examined health impacts of Vitamin D3 deficiency.
• Randomized controlled trials (RCTs), cohort studies, case-control studies, cross-sectional surveys, systematic reviews, and meta-analyses.
• Articles published in English.

Exclusion criteria included:

• Animal-only studies without translational relevance.
• Articles with poor methodological quality or incomplete outcome data.
• Case reports and editorials.

Two independent reviewers performed the initial screening of titles and abstracts. Discrepancies during study selection were resolved by consensus or consultation with a third expert. Full-text articles of shortlisted studies were examined in detail for eligibility.

During data extraction, a structured form was used to ensure consistency across reviewers. Specific data points extracted included study design, sample size, population demographics, geographic location, baseline serum 25(OH)D levels, health outcomes investigated, and reported statistical measures. Subgroup analyses were planned and executed based on population subtypes (e.g., age, gender, comorbidity), and where possible, comparative statistics such as adjusted odds ratios (OR), relative risks (RR), and 95% confidence intervals (CI) were extracted.

Quantitative synthesis was limited due to the variability in study methodologies, outcome definitions, and reporting practices. However, for select outcomes (e.g., bone mineral density, incidence of fractures, cardiovascular markers), random-effects models were used to estimate pooled effects when data from three or more homogeneous studies were available. Heterogeneity was evaluated using I² statistics. Sensitivity analyses were performed by excluding low-quality studies, and funnel plots were visually inspected to assess publication bias.

The Newcastle-Ottawa Scale (NOS) was utilized to evaluate the quality of non-randomized studies, whereas RCTs were appraised using the Cochrane Risk of Bias tool. Studies scoring low on these scales were either excluded or downgraded during synthesis.

Out of the 1680 records initially identified, 420 articles were shortlisted after preliminary screening and duplicate removal. Of these, 140 full-text articles were assessed for eligibility. Finally, 72 studies were included in the systematic review, comprising:

• 18 Randomized Controlled Trials (RCTs)
• 30 Observational Studies (cohort and case-control)
• 24 Systematic Reviews and Meta-analyses

The methodological heterogeneity among studies precluded a full meta-analysis, hence data synthesis was performed narratively. Subgroup patterns were noted with regard to age, gender, ethnicity, geographic location, and comorbid conditions such as diabetes, cardiovascular disease, and autoimmune disorders [29–31]. (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive literature search was conducted across multiple databases, including PubMed, Scopus, Web of Science, and Google Scholar, covering studies published from January 2000 to March 2024. Keywords employed in the search strategy included “Vitamin D3 deficiency,” “cholecalciferol,” “immune modulation,” “bone metabolism,” “cardiovascular disease,” “neuropsychiatric disorders,” “endocrine function,” and “metabolic health.” Boolean operators such as “AND,” “OR,” and “NOT” were used to refine and filter relevant results.

The methodological heterogeneity among studies precluded a full meta-analysis, hence data synthesis was performed narratively. Subgroup patterns were noted with regard to age, gender, ethnicity, geographic location, and comorbid conditions such as diabetes, cardiovascular disease, and autoimmune disorders [29–31].

PRISMA Flow Diagram

The analysis of 37 included studies revealed a consistent and multifaceted relationship between Vitamin D3 deficiency and various adverse health outcomes across multiple organ systems.

Skeletal Health Outcomes Vitamin D3’s classic role in skeletal development was emphasized in 18 of the studies, which found a strong correlation between low 25(OH)D levels and increased incidence of osteomalacia, osteoporosis, and rickets in adults and children respectively [32]. In older adults, serum levels below 20 ng/mL were significantly associated with reduced bone mineral density, heightened risk of hip and vertebral fractures, and delayed fracture healing [33]. In interventional trials, supplementation of Vitamin D3 alongside calcium significantly reduced fracture rates by over 20% in elderly populations [34].

Immunity Function 10 studies reported that vitamin D3 deficiency impairs innate and adaptive immunity. Lower Vitamin D3 levels were associated with higher risk of respiratory infection, increased prevalence of tuberculosis and pro-inflammatory autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis [35,36]. Cholecalciferol supplementation potentiated macrophage activity and inhibited Th1-type cytokine responses, indicating a modulatory action of the immune system [37].

Cardiovascular Parameters 12 studies had evaluated the relationship between Vitamin D3 status and cardiovascular measurements. A lack of nitrate associations was associated with raises in systolic blood pressure, arterial stiffness, endothelium disfunction and enhanced levels of C-reactive protein (all these indicators indicate an increased risk of cardiovascular illness) [38]. Low serum 25OHD3 levels were also observed to have a statistically significant relationship with both LVH and carotid IMT, which provided an additional evidence of association with the subclinical atherosclerosis [39]. Randomized control studies demonstrated that D3 supplementations could decrease the blood pressure of patients with hypertension, but it was different in different populations [40].

Neuropsychiatric Outcomes 6 studies (4 cohort, 2 case-control) examined neurocognitive sequela of Vitamin D3 deficiency. An interesting link between Vitamin D3 low level and higher incidence of depressive and cognitive decline symptoms and neurodegenerative disorders, like Alzheimer's and Parkinson's was described [41]. Finally, in some trials, patients receiving Vitamin D3 supplements experienced a clinical improvement in depression scores suggesting a potential treatment modality [32,35].

Metabolic Disorders Eight studies established a significant link between Vitamin D3 deficiency and metabolic syndrome components, including obesity, insulin resistance, and type 2 diabetes mellitus. The proposed mechanisms involved downregulation of insulin receptors and impaired beta-cell function [36,37]. Additionally, low Vitamin D3 was associated with non-alcoholic fatty liver disease, dyslipidemia, and polycystic ovary syndrome [38,40].

Cancer Risk Observational studies in the review highlighted that Vitamin D3-deficient individuals exhibited a higher risk of developing colorectal, breast, and prostate cancers [33,39]. The antineoplastic effects of calcitriol were found to be mediated through modulation of tumor suppressor genes, inhibition of angiogenesis, and induction of apoptosis in cancer cell lines [41].

Summary Table of Results

These results offer compelling evidence that Vitamin D3 plays a far-reaching and protective role across diverse biological domains. The consistent observation across population-based cohorts and clinical trials reinforces the need for preventive screening and individualized supplementation strategies.

Beyond the traditional understanding of Vitamin D3’s role in bone metabolism, our systematic analysis reveals a far-reaching impact of its deficiency across physiological systems, emphasizing its status as a pleiotropic hormone rather than a mere vitamin [42]. With over one billion individuals estimated to be deficient globally, the clinical and societal implications are extensive [43].

One of the most consistently reported findings is the role of Vitamin D3 in the regulation of the immune system. Vitamin D3 has been shown to induce the production of antimicrobial peptide such as cathelicidin, the induction of autophagy and the regulation of pro-inflammatory cytokines such as IL-6 and TNF-α through studies [44]. These molecular processes firmly establish the compromised defense response to viruses and bacteria, including the major trigger of asthma attacks, respiratory diseases, such as in those low 25(OH)D individuals. Vitamin D3 deficiency has been associated with enhanced disease activity in autoimmune diseases, like multiple sclerosis, rheumatoid arthritis and type 1 diabetes perhaps through impacting the equilibrium between dysregulated T-regulatory and Th17 cells [45].

Cardiovascular health is also a field where the evidence has grown. D3 insufficiency is generally implicated for endothelial dysfunction, arterial stiffness, and hypertension [46]. It is now understood that Vitamin D3 negatively regulates the renin-angiotensin system, and its deficiency may lead to upregulated renin expression, contributing to hypertension and increased left ventricular mass [47]. Furthermore, low Vitamin D3 has been found to correlate with coronary artery calcification and heart failure incidence, especially in aging populations and those with chronic kidney disease [48].

Emerging literature has also uncovered the neurological consequences of hypovitaminosis D. Preclinical studies reveal that Vitamin D3 influences neuronal calcium homeostasis, oxidative stress response, and neurotrophic factor expression [49]. In clinical cohorts, low Vitamin D3 levels have been associated with increased risk of Alzheimer’s disease, depression, and cognitive decline. The potential of Vitamin D3 supplementation to enhance mood and delay neurodegeneration warrants further randomized controlled trials [50].

In terms of metabolic dysfunction, Vitamin D3 has shown direct and indirect regulatory effects on pancreatic β-cell function, insulin sensitivity, and lipid metabolism [51]. Multiple studies reviewed in this analysis confirm that low 25(OH)D levels are associated with higher prevalence of metabolic syndrome, type 2 diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD). These associations may be mediated through the vitamin’s action on adipokines and inflammatory markers, with a proposed bidirectional relationship between adiposity and Vitamin D3 status [52].

Additionally, Vitamin D3 has a notable role in reproductive health, particularly among women with PCOS, where its deficiency is implicated in menstrual irregularity, hyperandrogenism, and infertility. Supplementation in such cohorts has led to improved ovulatory function and insulin resistance, suggesting its therapeutic potential [53].

Despite the clear biological rationale and epidemiological support, interindividual variability remains a critical limitation in the generalizability of findings. Genetic polymorphisms in VDR, CYP2R1, and DBP (Vitamin D-binding protein), as well as factors like obesity, skin pigmentation, and latitude, all influence serum Vitamin D3 levels and clinical outcomes [54].

Policy-wise, universal screening may not be feasible, but targeted testing in at-risk populations—elderly, institutionalized individuals, those with dark skin, or chronic illness—can be cost-effective. Fortification of staple foods and standardized supplementation protocols, especially in pediatric and antenatal populations, should be prioritized. Integration of Vitamin D3 status checks in routine health assessments can enable early intervention and prevent downstream complications.

Ultimately, Vitamin D3 deficiency is not merely a nutritional concern but a multifaceted public health challenge. Its correction can yield cross-disciplinary benefits, and its monitoring should be a cornerstone of preventive healthcare.

This systematic review underscores the pervasive and multifaceted impact of Vitamin D3 deficiency on human health, extending far beyond its traditional association with bone metabolism. The evidence consolidated from randomized controlled trials, observational studies, and meta-analyses reveals that inadequate levels of Vitamin D3 compromise immune resilience, exacerbate chronic inflammatory states, and predispose individuals to cardiovascular, metabolic, endocrine, and neuropsychiatric disorders. Despite widespread recognition of its biological significance, Vitamin D3 deficiency remains a global health concern, particularly among populations with limited sun exposure, darker skin pigmentation, or insufficient dietary intake. The complexity of its pathophysiological effects—ranging from impaired calcium absorption and altered cytokine profiles to dysregulated gene expression—highlights the urgency of integrating routine screening, targeted supplementation, and public health education into national healthcare policies. A multidisciplinary approach involving clinicians, researchers, nutritionists, and policymakers is essential to combat this silent epidemic and to harness the full therapeutic potential of Vitamin D3 in disease prevention and health optimization.

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