Vitamin D refers to several forms of fat-soluble vitamins found in fortified milk and cereals, egg yolks, and fish. The two forms utilized in humans are ergocalciferol (D2) and cholecalciferol (D3). Sunlight can promote the synthesis of D3 in the skin. Vitamin D maintains serum calcium and phosphorus levels by regulating their absorption and excretion, and is important for bone formation. Other biologic functions include its role as an antiproliferative agent ⁽¹⁾, and as a pro-differentiation hormone ⁽²⁾ with anti-inflammatory and immunoregulatory properties ⁽³⁾. Low levels of vitamin D are associated with a greater risk of mortality ⁽¹³⁾, may affect cardiovascular health ⁽¹⁴⁾, and increase the risk for development of multiple sclerosis in women ⁽⁷⁴⁾, but a large study found no association between lower levels and cognitive function ⁽¹⁵⁾. However, deficiency during pregnancy may affect neurocognitive development in newborns ⁽⁷⁵⁾. Deficiency can also cause rickets or other bone disorders, and may be a risk factor for extraskeletal diseases ⁽⁴⁵⁾. Lower D levels may occur due to time of year or living in northern climates ⁽⁹⁾; in non-Caucasian race ⁽⁴⁶⁾ or obese individuals ⁽⁴⁷⁾; with chronic use of steroids or anticonvulsants; or with diseases such as autoimmune disorders ⁽³⁾, cystic fibrosis ⁽⁴⁸⁾, kidney disease, and cancer ^{(46) (48) (49)}.

Although some studies suggest vitamin D improves bone mineral density and prevents fractures in the elderly ^(4) (5) and in postmenopausal women ⁽⁶⁾, it did not lower risk of fractures in midlife and older adults ⁽¹⁰⁸⁾, in hemodialysis patients ⁽¹²¹⁾ or improve lower extremity function and was associated with an increased fall risk in older adults ⁽⁶⁴⁾. Safety concerns also arose with doses of 1000 IU/d or higher in older persons who had elevated fall risk and low serum D levels ⁽⁹⁹⁾ but conflicting findings do not support such concerns ⁽¹¹³⁾. Data are also conflicting for primary fracture prevention in other populations ^{(7) (8) (9)} and a meta-analysis did not find benefit for preventing fractures or falls, or for bone mineral density ⁽¹⁰⁰⁾. 

In healthy adults, D3 also does not appear to decrease fall risk ⁽¹⁰¹⁾ and high-dose supplementation did not benefit bone health ⁽⁹²⁾, with 4000 or 10,000 IU compared with 400 IU resulting in greater bone mineral density loss in healthy vitamin D-sufficient women, but not men ⁽⁹³⁾. Supplementation did not affect the rate of frailty change or incidence over time in healthy community-dwelling older adults ⁽¹⁰⁹⁾, and US Preventive Services Task Force reports also found no associations between supplementation and reduced falls or fracture incidence in this subset ^(79) (80). Another study failed to find associations between vitamin D status and chronic pain ⁽⁸⁸⁾.

Findings on whether vitamin D protects against cardiovascular (CV) risk factors have varied across populations and regimens. In a Women’s Health Initiative sub-study, calcium plus vitamin D and hormone therapy had a greater effect than either intervention alone or placebo ⁽⁶⁷⁾, but vitamin D did not improve CV risk factors or physical function in large long-term trials of older adults ^(68) (110) or reduce all-cause mortality in older adults who are vitamin D-replete ⁽¹¹¹⁾. Meta-analyses also found no effect on vascular function markers ⁽⁸¹⁾ nor reduction in CV disease endpoints ⁽⁹⁴⁾. Yet in another placebo-controlled trial, supplementation benefited diabetic patients with coronary artery disease who were vitamin D-deficient ⁽⁶⁹⁾. In addition, a single large dose of vitamin D2 improved endothelial function in type-2 diabetic patients ⁽¹¹⁾. In non-dialysis patients with chronic kidney disease, D3 was more effective than D2 in raising serum D levels ⁽⁷⁰⁾. Dietary vitamin D intake was shown to be inversely associated with mortality from stroke ⁽⁷⁶⁾, but supplementation was not associated with reduced all-cause mortality in critically ill patients ⁽¹⁰²⁾, and did not reduce risk of atrial fibrillation ⁽¹⁰³⁾.

In other trials, vitamin D did not significantly reduce upper respiratory tract infections (URTIs) in healthy adults ⁽¹⁶⁾, or infections/antibiotic use in the elderly ⁽¹⁷⁾. However, it may protect against influenza ⁽⁷⁸⁾ and reduce wheezing in some infants ⁽⁸²⁾. Vitamin D was not helpful for mild psoriasis ⁽⁸³⁾ or seasonal affective disorder ^(18) (19). Supplementation may reduce relapse risk in Crohn’s disease ⁽¹²⁾, and D3 plus calcium may have a small effect on postmenopausal weight gain ⁽¹⁰⁾. A single oral high-dose of D3 significantly improved fatigue in healthy persons who were vitamin D-deficient ⁽⁷²⁾. Supplementation may also reduce the size of uterine fibroids ⁽¹²²⁾ and improve sexual function in women with sexual dysfunction and vitamin D deficiency ⁽⁸⁹⁾, but long-term supplementation did not prevent erectile dysfunction in older men ⁽¹²³⁾ nor depression in healthy adults ⁽⁹⁶⁾. In small studies, higher serum levels of vitamin D were associated with increased beneficial gut bacteria and decreased pathogenic bacteria ⁽⁹⁵⁾ and supplementation improved liver fibrogenic factors in patients with metabolic dysfunction-associated steatotic liver disease  ⁽¹²⁴⁾ and metabolic parameters in women with subclinical hypothyroidism ⁽¹²⁵⁾ although a large trial did not find overall reduction in incidence of  hypothyroidism  ⁽¹²⁶⁾.

In pediatric trials, vitamin D did not influence growth, body composition, or pubertal development ⁽¹¹⁴⁾, and did not prevent viral URTIs ⁽⁷¹⁾ or tuberculosis ⁽¹¹⁵⁾. 

Vitamin D has also been examined for its anticancer potential. In animal models, dietary vitamin D3 exerted chemopreventive effects against breast cancer equivalent to those elicited by calcitriol without causing hypercalcemia ⁽²⁰⁾. In humans, vitamin D from sunlight exposure and dietary intake may have protective effects against breast cancer ^(21) (22), and insufficiency among breast cancer patients is high ⁽²³⁾. In postmenopausal women not on estrogen therapy, vitamin D and calcium supplementation may reduce colorectal cancer incidence ^(24) (25). In women with grade 1 cervical intraepithelial neoplasia, long-term supplementation resulted in regression and improved metabolic status ⁽⁶⁶⁾. However, in a large trial of healthy postmenopausal women with mean vitamin D levels above those of the US population, taking vitamin D3 plus calcium did not lower cancer risk after 4 years of supplementation ⁽⁷³⁾, and vitamin D supplementation did not prevent aromatase-induced arthralgia ⁽⁹⁷⁾ or affect cognition when combined with calcium, protein and a multicomponent exercise training in men treated with ADT for prostate cancer ⁽¹¹²⁾. In addition, even though pooled analyses found associations between higher serum D levels and lower risks of breast and colon cancers ^(85) (86), other analyses have not found preventive effects against cancer with high-dose supplementation ⁽⁸⁷⁾, and contributing factors such as better diet and lifestyle habits may also be at play.

In older patients with diffuse large B-cell lymphoma, supplementation normalized vitamin D levels and enhanced efficacy of rituximab ⁽²⁷⁾. Active vitamin D compounds may also decrease incidence of post-transplant malignancy among kidney transplant recipients ⁽²⁸⁾.

Other data reveal that vitamin D deficiency is highly prevalent in advanced pancreatic cancer ⁽⁴²⁾ and colorectal cancer (CRC) patients ⁽⁴³⁾, and that CRC patients with higher blood 25(OH)D concentrations have better survival ⁽⁸⁴⁾. A meta-analysis of vitamin D supplementation on CRC survival outcomes also suggests clinically meaningful benefit ⁽¹⁰⁴⁾. In patients with metastatic CRC, addition of high-dose vitamin D3 to chemotherapy resulted in statistically insignificant progression-free survival but improved supportive hazard ratio ⁽⁹⁰⁾. Increased vitamin D intake reduced CRC risk ^{(29) (31) (32) (33)}, but had no effect on colorectal adenomas ⁽⁶⁵⁾. Data on benefits to reduce skin cancer risk ^(38) (105) and advanced cancers ⁽¹⁰⁶⁾ are mixed. Vitamin D did not have a protective effect against non-Hodgkin lymphoma ⁽³⁴⁾, ovarian ⁽³⁵⁾, kidney ⁽³⁶⁾, endometrial ⁽³⁷⁾, esophageal or gastric ⁽³⁹⁾ cancers, may significantly increase risk of pancreatic ⁽⁴⁰⁾ or aggressive prostate cancer ⁽⁴¹⁾, and did not improve relapse-free survival in patients with digestive tract cancers ⁽⁹¹⁾ although conflicting findings in p53 immunoreactive subset ⁽¹¹⁶⁾ and in those with elevated serum levels of soluble CD40 ligand  ⁽¹²⁷⁾ suggest otherwise. Data from meta-analyses, however, are conflicting on whether vitamin D supplementation can reduce cancer incidence or mortality ^{(44) (77) (94)}.

In pediatric patients with solid tumors, findings showed a possible correlation between higher pretreatment serum vitamin D levels and improved overall and relapse-free survival ⁽¹²⁸⁾.

Oral supplementation has been shown to be the safest way to increase vitamin D levels ⁽⁵¹⁾, although debate continues on how this may translate to optimizing vitamin D status ⁽⁴⁵⁾. The Institute of Medicine recommends a Daily Dietary Allowance of vitamin D at 600 IU/day with the Upper Level Intake at 4,000 IU/day for bone health ⁽⁵⁰⁾, although safety concerns have been noted with higher doses in some populations ⁽⁹⁹⁾. Also, combined vitamin D and calcium supplementation has been associated with increased kidney stone incidence ^(7) (80). Therefore, patients should consult with their physicians if a deficiency is suspected to assess the amount of vitamin D needed for health maintenance and to avoid side effects.