SEARCHNARRATIVE_REVIEWnutrition, vitamins

narrative_review·nutrition, vitamins, immunology, public health, epidemiology·PMC10295227

Physiological Basis for Using Vitamin D to Improve Health

Biomedicines · 1 author, 1 centre

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Vitamin D sufficiency improves metabolism, immune function, and overall health, while deficiency increases vulnerability to chronic diseases and infections. Maintaining serum 25(OH)D above 50 ng/mL is necessary for optimal immune function and reducing complications from infections and cancer. Vitamin D3 is the preferred supplement for deficiency, while calcifediol is indicated for emergencies and calcitriol for advanced renal failure or hypoparathyroidism.

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**Background:** Vitamin D is essential for life, with sufficiency improving metabolism, hormonal release, immune functions, and overall health. Deficiency increases vulnerability to type 2 diabetes, metabolic syndrome, cancer, obesity, and infections. The active enzyme CYP27B1 and vitamin D receptors (VDRs) are ubiquitously distributed, and calcitriol binding regulates over 1200 genes. Humans generate over 80% of vitamin D from sunlight, but behavioral changes have led to a global pandemic of deficiency. This review aims to clarify optimal serum 25(OH)D levels, proper use of vitamin D metabolites, and correct study design for RCTs.

**Methods:** This is a narrative review based on published evidence, over four decades of clinical experience, and over 50 peer-reviewed publications by the author. Data were gathered from literature searches on PubMed and the Library of Congress. The author personally conducted all searches, synthesized data, and generated figures. The manuscript focuses on physiological, clinical, and practical elements to help clinicians.

**Key Results:** The physiological range of 25(OH)D is 40-80 ng/mL. To mitigate infections, sepsis, and cancer, levels above 50 ng/mL are necessary. Vitamin D3 (cholecalciferol) should be used to correct deficiency, while calcifediol [25(OH)D] raises serum levels rapidly within one day and is the agent of choice in emergencies. Calcitriol is crucial for maintaining serum-ionized calcium in advanced renal failure and hypoparathyroidism but is ineffective for infections as it does not enter immune cells. Well-designed RCTs using proper doses in deficient subjects consistently show favorable outcomes, while poorly designed studies (e.g., VITAL, ViDA, D2d, VIOLET, EVITA) fail due to errors like allowing over-the-counter supplements, using infrequent doses, or not targeting deficient populations. Over 120 clinical studies on vitamin D and COVID-19 show strong associations, with a systematic review of six trials reporting a relative risk reduction of 0.60 (95% CI 0.40-0.92, p=0.02) for acute infection. For a healthy 70 kg adult, recommended doses are 5000 IU/day or 50,000 IU every tenth day; obese individuals require 2-4 times higher doses. Calcifediol dose is 0.5-1 mg orally (0.014 mg/kg) in emergencies.

**Clinical Implications:** Vitamin D3 supplements are safe, inexpensive, and should be used as long-term prophylaxis. Maintaining population sufficiency above 40 ng/mL (individuals above 50 ng/mL) is the most cost-effective way to reduce chronic diseases, infections, and healthcare costs. Healthcare workers should use body-weight-based dosing and avoid inappropriate use of expensive vitamin D analogs. Calcifediol is indicated for emergencies and hepatic failure, while calcitriol is restricted to renal failure and hypoparathyroidism. Proper vitamin D use can reduce hospitalizations, ICU admissions, and deaths from infections like COVID-19, and improve outcomes in metabolic and cardiovascular diseases and cancer.

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narrative_review

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nutrition

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ORIGINAL PAPER

PMC10295227

Physiological Basis for Using Vitamin D to Improve Health

Biomedicines

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ABSTRACT

Vitamin D is essential for life—its sufficiency improves metabolism, hormonal release, immune functions, and maintaining health. In contrast, vitamin D deficiency increases the vulnerability and severity of type 2 diabetes, metabolic syndrome, cancer, obesity, and infections. The active enzyme that generates vitamin D [calcitriol: 1,25(OH) 2 D], CYP27B1 (1α-hydroxylase), and calcitriol receptors (VDRs) are distributed ubiquitously in cells. Once calcitriol binds with VDRs, the complexes are translocated to the nucleus and interact with responsive elements, up- or down-regulating the expression of over 1200 genes and modulating many metabolic and physiological functions. The administration of vitamin D 3 or its correct metabolites at proper doses and frequency for extended periods will achieve the intended benefits. The same principle applies to designing and conducting RCTs. Different tissues have varied thresholds for 25(OH)D concentrations. To mitigate conditions such as infections/sepsis and cancer and reduce premature deaths, levels above 50 ng/mL are necessary. Cholecalciferol (D 3 ) (not its metabolites) should be used to correct vitamin D deficiency and raise serum 25(OH)D to the target concentration. Calcifediol [25(OH)D], in contrast, increases serum 25(OH)D concentrations rapidly and boosts the immune system in one day. Thus, it is the agent of choice in emergencies such as infections, for those in ICUs, and insufficient hepatic 25-hydroxylase (CYP2R1) activity. Calcitriol is crucial to maintaining serum-ionized calcium concentration in persons with advanced renal failure and hypoparathyroidism. Since administered calcitriol does not enter immune cells, it is ineffective in other conditions, like infections; it should not be used as vitamin D replacement therapy. Considering the high costs and higher incidence of adverse effects due to narrow therapeutic margins (ED50), 1α-vitamin D analogs, such as 1α-(OH)D and 1,25(OH) 2 D, should not be used for other conditions. Similarly, calcifediol costs 20 times more than D 3 : it should not be used as a routine vitamin D supplement for hypovitaminosis D, osteoporosis, or renal failure. Healthcare workers should resist accepting inappropriate promotions, such as calcifediol for chronic renal failure and calcitriol for osteoporosis or infections—there is no physiological rationale for doing so. Standard diets have too little vitamin D. Maintaining the population’s vitamin D sufficiency (above 40 ng/mL) (and individuals above 50 ng/mL) with vitamin D 3 supplements and/or daily sun exposure is the most cost-effective way to reduce chronic diseases and sepsis, overcome viral epidemics and pandemics like COVID-19, and reduce healthcare costs. Furthermore, vitamin D sufficiency improves overall health, reduces absenteeism, improves productivity, reduces the severity of chronic diseases such as metabolic and cardiovascular diseases and cancer, decreases all-cause mortality, and minimizes infection-related complications such as sepsis and COVID-19-related hospitalizations and deaths. Properly using vitamin D is the most cost-effective way to reduce chronic illnesses, infections, and healthcare costs; thus, it should be a part of routine clinical care.

CITATION EXPORT

Sunil J. Wimalawansa. Physiological Basis for Using Vitamin D to Improve Health. Biomedicines. (2024). https://doi.org/10.3390/biomedicines11061542

AUTHORS

1 · 1 CENTRES

Sunil J. Wimalawansa

Medicine, Endocrinology & Nutrition, Cardio Metabolic Institute, (Former) Rutgers University, North Brunswick, NJ 08901, USA; [email protected]

EDITOR / REVIEWER

Małgorzata Żychowska, Jędrzej Antosiewicz