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Vitamin D and extraskeletal health

Vitamin D and extraskeletal health
Author:
Roger Bouillon, MD, PhD, FRCP
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Dec 2022. | This topic last updated: Nov 08, 2022.

INTRODUCTION — Vitamin D deficiency was originally discovered as the cause of rickets due to lack of exposure to sunshine or vitamin D-rich food. This disease is still endemic in major parts of the world [1]. Subsequently, several meta-analyses showed that supplementation with vitamin D and calcium decreased the risk of osteoporotic fractures in older adults. The details of the protocols and overall results of the studies are reviewed separately.

In addition to its role in calcium and bone homeostasis, vitamin D potentially regulates many other cellular functions. The vitamin D receptor (VDR) is nearly universally expressed in nucleated cells. Approximately 3 percent of the human/mouse genome is under the control of 1,25-dihydroxyvitamin D, the active form of vitamin D. Furthermore, at least 10 tissues outside the kidney express 1-alpha-hydroxylase (CYP27B1), the enzyme responsible for converting vitamin D to its active form, and therefore, the active hormone can be generated in an auto- or paracrine way. Thus, the spectrum of activity of the vitamin D endocrine system is much broader than calcium/bone homeostasis, and in this regard, the vitamin D-VDR system resembles that of other ligands of nuclear receptors, such as thyroid hormone [2-4].

This topic will review the "extraskeletal" effects of vitamin D (deficiency), especially its effect on muscle function, cancer, and on the immune, cardiovascular, and metabolic system. The skeletal manifestations, causes, and treatment of vitamin D deficiency are discussed elsewhere. (See "Epidemiology and etiology of osteomalacia" and "Calcium and vitamin D supplementation in osteoporosis" and "Causes of vitamin D deficiency and resistance" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

OPTIMAL VITAMIN D FOR EXTRASKELETAL HEALTH — There are a large number of epidemiologic data indicating that the risks of cancer and infectious, autoimmune, and cardiovascular diseases are higher when 25-hydroxyvitamin D (25[OH]D) levels are <20 ng/mL (50 nmol/L) and that risks decrease with higher 25(OH)D concentrations. However, there are no convincing randomized trial data that vitamin D supplements can decrease cancer risk or prognosis, decrease the risk or severity of infections or autoimmune diseases, or decrease cardiovascular risks or metabolic diseases [5-9]. In addition, there are no prospective studies to define optimal 25(OH)D levels for extraskeletal health. Thus, we do not suggest vitamin D supplementation above and beyond what is required for osteoporosis management. (See "Calcium and vitamin D supplementation in osteoporosis".)

MUSCLE FUNCTION

Muscle weakness — Observational studies suggest an association between poor vitamin D status (defined as <10 or <20 ng/mL [<25 or <50 nmol/L]) and muscle weakness in children and older individuals [10-14]. However, a causal relationship between vitamin D supplementation and improvement in muscle weakness has not been clearly demonstrated in randomized trials, and the optimal 25-hydroxyvitamin D (25[OH]D) concentration for muscle function is unknown. The greatest benefit of vitamin D supplementation on muscle strength is likely to occur in patients with baseline 25(OH)D levels below 10 ng/mL (25 nmol/L).

Observational evidence – There are several lines of evidence that suggest a relationship between vitamin D and muscle function [15]. Muscle from vitamin D receptor (VDR)-null mice shows clear developmental abnormalities as immature muscle genes and proteins survive in VDR-null, but not wild-type, adult muscle [4]. In addition, striated muscle fibers are smaller in VDR-null mice. Adult skeletal muscle, however, does not seems to express VDR protein when measured by highly specific antibodies [16], but VDR is expressed in muscle cell precursors or stem cells [4,15]. Children with hereditary vitamin D deficiency (ie, genetic CYP27B1 deficiency) who are deficient in the production of 1,25-dihydroxyvitamin D have profound muscle weakness, which vitamin D or 1,25-dihydroxyvitamin D therapy rapidly improves [4]. In addition, vitamin D supplementation improved muscle weakness and recovery of energy stores (maximal mitochondrial oxidative phosphorylation rate, as measured by in vivo magnetic resonance spectroscopy) after physical exercise in severely vitamin D-deficient, but otherwise, healthy adults [17].

Randomized trials – In systematic reviews of randomized trials comparing vitamin D supplementation (with or without calcium) with placebo or calcium alone in older adults (>60 years), the results are mixed [18-20]. In a meta-analysis of 29 trials, there was a small but significant improvement in global muscle strength with vitamin D supplementation [20]. However, the meta-analysis was limited by significant heterogeneity. In another systematic review, among four trials with patients with baseline serum 25(OH)D <10 ng/mL (25 nmol/L), three showed improvement in some aspects of muscle strength with vitamin D supplementation [19]. Few studies used proximal muscle strength (the most affected muscle function in clinical case reports) as a true endpoint, and few studies provided vitamin D supplementation in doses higher than 2000 international units per day.

In subsequent trials evaluating the effect of vitamin D supplementation on proximal muscle strength, there was little benefit, particularly at the highest doses (60,000 international units monthly). As examples:

In a trial from Norway, 251 healthy immigrant adults (from South Asia, Middle East, and Africa, mean age 36 to 39 years) with severe vitamin D deficiency (mean serum 25[OH]D 10.4 ng/mL [26 nmol/L]) were randomly assigned to vitamin D3 supplementation (1000 or 400 international units daily) or to placebo [21]. After 16 weeks, mean serum 25(OH)D levels improved in the active treatment groups (20.8 and 17.2 ng/mL [52 and 43 nmol/L] in the 1000 and 400 international unit dose groups, respectively). However, there were no differences in improvement in maximum jump height (a measure of proximal leg-muscle strength), chair-rising (proximal leg-muscle strength), or handgrip strength.

In another trial, 200 older postmenopausal women (mean age 78 years) with mean serum 25(OH)D of 19 ng/mL (47.5 nmol/L) were randomly assigned to 24,000 or 60,000 international units of vitamin D monthly or to 24,000 international units plus 300 mcg of calcifediol monthly [22]. After 12 months, achieved mean serum 25(OH)D levels were approximately 30, 40, and 45 ng/mL (75, 100, and 112 nmol/L), respectively. Improvement in lower extremity function did not differ among the three groups.

In a 2021 meta-analysis of 54 intervention studies, including 8747 individuals and excluding older studies that have been retracted due to falsifications, patients assigned to vitamin D compared with placebo performed worse on the timed get up and go test [23]. Other measures of muscle strength were not different between the two groups. Overall, there was not a beneficial effect of vitamin D on muscle health.

Falls — Vitamin D supplementation in community-dwelling adults does not reduce the risk of falls. High intermittent doses of vitamin D (eg, 500,000 international units annually) should be avoided as such dosing may transiently increase the risk of falls [24]. This may also apply to doses of vitamin D (eg, 60,000 international units monthly) that increase serum levels above 50 ng/mL (125 nmol/L) [22]. Vitamin D for falls prevention is reviewed in detail separately. (See "Falls: Prevention in community-dwelling older persons", section on 'Vitamin D supplementation'.)

CANCER

Risk of cancer — There is extensive literature on vitamin D, cell proliferation, and cancer. In vitro studies have shown that the active hormone or its analogs can decrease cell proliferation, and a very large number of genes are coherently activated or inactivated to generate this effect [4,25]. In a review of eight Mendelian randomization studies of genetic polymorphisms associated with serum 25-hydroxyvitamin D (25[OH]D), seven of eight studies did not show an association between genetically low serum 25(OH)D concentrations and total or organ-specific cancer incidence [9]. One study, however, found an association between genetically low 25(OH)D levels and risk of ovarian cancer [26]. In some studies, polymorphisms in the VDR gene have been associated with cancer risk and cancer outcomes [9,27].

Several observational studies have evaluated the relationship between serum vitamin D levels and cancer. Although some suggest an association between vitamin D deficiency and cancer, other studies have shown an elevated risk of some cancers (eg, pancreatic) at higher 25(OH)D levels (relative risk [RR] 2.12, 95% CI 1.23-3.64 for levels ≥40 versus 20 to 30 ng/mL [≥100 versus 50 to 75 nmol/L]) [28-31].

Colon cancer – The World Health Organization (WHO) working group identified an association between vitamin D deficiency and risk of colon cancer [5]. This finding is supported by the results of an analysis of participant-level data from 17 cohorts (5706 colorectal cancer cases and 7107 controls) [32]. Compared with 25(OH)D levels of 20 to <25 ng/mL (50 to <62.5 nmol/L), a 25(OH)D level of <12 ng/mL (30 nmol/L) was associated with a higher risk of colorectal cancer (RR 1.31, 95% CI 1.05-1.62), whereas 25(OH)D levels ≥30 ng/mL (75 nmol/L) were associated with a lower risk (RRs 0.81, 95% CI 0.67-0.99 and 0.73, 95% CI 0.59-0.91, for levels of 30 to <35 ng/mL [75 to <87.5 nmol/L] and 35 to <40 ng/mL [87.5 to <100 nmol/L], respectively). These vitamin D levels (30 to 40 ng/mL [75 to 100 nmol/L]) are within the accepted range for optimizing skeletal health. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Serum 25-hydroxyvitamin D'.)

Breast cancer – Observational studies examining the relationship between vitamin D and breast cancer report inconsistent results. A meta-analysis of prospective studies examining the relationship between serum 25(OH)D concentrations and breast cancer risk showed a significant inverse association in post- but not premenopausal women [33]. The risk of postmenopausal breast cancer decreased with 25(OH)D levels between 27 and <35 ng/mL (67 to 87 nmol/L), with no further reduction for levels above 35 ng/mL. (See "Factors that modify breast cancer risk in women", section on 'Calcium/vitamin D'.)

Prostate cancer – A relationship between serum 25(OH)D levels and prostate cancer incidence has not been consistently found [6,34]. In observational studies, higher (highest compared with lowest quartiles or quintiles) serum 25(OH)D levels have been associated with both an increased [35] and reduced [36] risk of more aggressive disease. (See "Risk factors for prostate cancer", section on 'Calcium and vitamin D'.)

Prevention — The current evidence is insufficient to support large-dose vitamin D supplementation for the purpose of cancer prevention. However, patients with overt vitamin D deficiency (serum 25[OH]D <20 ng/mL [50 nmol/L]) should receive vitamin D supplementation to treat the deficiency. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Dosing'.)

The majority of vitamin D intervention trials do not show a reduction in cancer risk [37-46]. However, these trials have been carried out predominantly in adults without vitamin D deficiency. In a meta-analysis of 18 randomized trials in predominantly older, community-dwelling women, vitamin D supplementation had no effect on the incidence of cancer [41]. Trials published after the meta-analysis show similar results. As examples:

In one trial, 2303 healthy postmenopausal women (mean baseline 25[OH]D 32.8 ng/mL [81.9 nmol/L]) were randomly assigned to 2000 international units vitamin D3 and 1500 mg of calcium daily or identical placebos [42]. After four years, the proportion of patients in each group with newly diagnosed cancer did not significantly differ (3.89 and 5.58 percent, respectively, hazard ratio [HR] 0.70, 95% CI 0.47-1.02). An analysis by cancer site showed no difference in the incidence of breast cancer between the two groups; there were too few cancers at other sites to analyze.

In a larger trial, 25,871 men ≥50 and women ≥55 years of age (mean serum 25[OH]D 30 ng/mL [77 nmol/L]) were randomly assigned in a two-by-two factorial design to 2000 international units of vitamin D3 and 1 g omega-3 fatty acids or to placebo [43]. After a median follow-up of 5.3 years, invasive cancer developed in a similar proportion of patients in the vitamin D and placebo groups (6.1 versus 6.4 percent with placebo, HR 0.96, 95% CI 0.88-1.06). In a prespecified subgroup analysis of patients with serum 25(OH)D <20 ng/mL (50 nmol/L), the results were similar. There was also no difference between the vitamin D and placebo groups in the incidence of breast, prostate, or colorectal cancer.

In a post hoc analysis of a third trial, 5110 individuals 50 to 84 years of age (mean serum 25[OH]D 25.3 ng/mL [63 nmol/L]) were randomly assigned to vitamin D3 supplementation (initial dose 200,000 international units followed by 100,000 international units monthly) or placebo [44]. After a median follow-up of 3.3 years, there was no difference in the incidence of invasive or in situ cancers (6.5 versus 6.4 percent in the placebo group [HR 1.01, 95% CI 0.81-1.25]).

Treatment — Current evidence is insufficient to support large-dose vitamin D supplementation to treat cancer. However, patients with overt vitamin D deficiency (serum 25[OH]D <20 ng/mL [50 nmol/L]) should receive vitamin D supplementation to treat the deficiency. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Dosing'.)

Preliminary findings from randomized trials evaluating vitamin D supplementation in patients with digestive tract or colorectal cancer show the following:

In a trial evaluating vitamin D (2000 international units daily) or placebo in 417 Japanese patients with stages I to III digestive tract cancers (colorectal, gastric, esophageal) and a median follow-up of 3.5 years, there was no difference in overall or relapse-free survival at five years [47].

In a trial evaluating high-dose (8000 international units daily) or standard (400 international units daily) vitamin D during active chemotherapy in 139 patients with advanced or metastatic colorectal cancer, the group receiving high-dose vitamin D experienced a statistically nonsignificant two-month increase in median PFS [48]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Issues related to vitamin D'.)

Larger phase III trials are needed to evaluate these preliminary findings. Vitamin D and cancer mortality are discussed below. (See 'Mortality' below.)

IMMUNE SYSTEM — The causal link between poor vitamin D status and autoimmune diseases or infections in humans remains unclear. Vitamin D has major effects on nearly all cells of the immune system. Antigen-presenting cells, such as dendritic cells, macrophages, and T and B cells, express the vitamin D receptor (VDR). Thus, the VDR-vitamin D endocrine system can modulate most aspects of the acquired and innate immune system (and even mast cells) when challenged by extreme deficiency or exposure to high 1,25-dihydroxyvitamin D (or its analogs). Although vitamin D reduces activation of the acquired immune system, it activates the innate immune system, particularly monocytes and macrophages.

Autoimmunity — The active form of vitamin D, 1,25-dihydroxyvitamin D, is an inhibitor of dendritic cell maturation and functions as an immune modulator, reducing activation of the acquired immune system. Therefore, vitamin D deficiency could theoretically increase the risk of autoimmune diseases, which has been reported in animal models [49].

Observational studies in humans suggest an association between vitamin D deficiency and type 1 diabetes, multiple sclerosis, and inflammatory bowel disease [50-53]. Type 1 diabetes is reviewed below. (See 'Type 1 diabetes' below.)

In the vitamin D and omega 3 (VITAL) trial, 25,871 participants (mean age 67 years with mean baseline 25-hydroxyvitamin D [25(OH)D] of approximately 30 ng/mL) were randomly assigned to vitamin D (2000 international units per day) or placebo [54]. After a median follow-up of 5.7 years, the cumulative incidence of autoimmune disease (particularly rheumatoid arthritis and polymyalgia rheumatica) was lower in the treatment group (0.95 versus 1.2 percent, hazard ratio [HR] 0.78, 95% 0.61-0.99).

This study has important implications as no other strategies have proven preventive efficacy for autoimmune diseases. Whether vitamin D supplementation would also have effects on major autoimmune diseases starting at a much younger age (type 1 diabetes mellitus and multiple sclerosis) has to be explored by appropriate studies including much younger subjects than in the VITAL trial.

Multiple sclerosis — In a large, prospective case-control study involving over seven million United States military personnel, White American recruits with 25(OH)D levels below 20 ng/mL (50 nmol/L) had approximately a twofold increased risk for later development of multiple sclerosis [50]. Three independent Mendelian randomization studies confirmed a causal link between genetically low lifetime serum 25(OH)D (based on four different polymorphisms) and the later risk of multiple sclerosis (two studies in adult-onset and one in childhood-onset multiple sclerosis) [9,52,55,56].

Asthma — It remains unclear whether vitamin D supplementation has a role in asthma prevention. There are conflicting reports on the association between vitamin D status and allergic diseases. In some reports, vitamin D deficiency (in pregnant women, children, or adolescents) has been associated with increased as well as with decreased frequency of allergic diseases such as asthma or eczema [4,57,58]. Randomized trials examining the effect of vitamin D supplementation on asthma outcomes are inconclusive.

Examples of trials showing no benefit:

In a randomized trial of vitamin D supplementation in adults with asthma (baseline mean 25[OH]D 19 ng/mL), there was no improvement in corticosteroid responsiveness or a reduction in the treatment failure rate [59].

In a trial of vitamin D (4000 international units/day) or placebo in 192 children with asthma (baseline mean 25[OH]D 22.6 ng/mL), there was no difference in the time to a severe asthma exacerbation (mean 240 versus 253 days with placebo, adjusted HR 1.13, 95% CI 0.69-1.85) [60].

Examples of trials showing some benefit:

In one trial, asthma patients (aged 10 to 50 years) with mean 25(OH)D of 24 ng/mL were randomly assigned to vitamin D versus no supplementation [61]. After 24 weeks, patients who received vitamin D supplementation had a significantly better forced expiratory volume in one second (FEV1).

In another trial evaluating vitamin D supplementation or placebo in 300 Black infants who were born preterm, supplementation with vitamin D reduced the risk of recurrent wheezing by 12 months of age (31.1 versus 41.8 percent of infants assigned to placebo) [62].

Two trials examining vitamin D supplementation during pregnancy found a reduction in wheezing in children, but the results did not reach statistical significance:

In one trial, 623 pregnant women were randomly assigned to receive 2800 or 400 international units of vitamin D, starting at 24 weeks gestation [63]. Persistent wheezing at three years of age developed in 16 and 20 percent, respectively (HR 0.75, 95% CI 0.51-1.10).

In a second trial, 876 pregnant women were randomly assigned to 4400 or 400 international units of vitamin D, starting at 10 to 18 weeks of gestation [64]. Asthma or recurrent wheezing at three years of age developed in 24.3 and 30.4 percent, respectively (HR 0.8, 95% CI 0.6-1.0). In a subsequent analysis, there was no difference between the two groups in the incidence of asthma or recurrent wheeze at six years of age [65].

The point estimates (HRs 0.75 and 0.8) and the lower bounds of the confidence intervals for the HRs are similar and suggest a clinically important benefit [66]. However, the small number of events reduced the precision of the analyses to detect a statistically significant clinical effect of prenatal vitamin D on the incidence of recurrent wheezing in early childhood. Given the small reduction in absolute risk with supplementation, vitamin D insufficiency would explain only a small proportion of the asthma incidence in young children. Larger trials with longer-term follow-up are needed.

Vitamin D supplementation during pregnancy is reviewed in more detail separately. (See "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Calcium and vitamin D' and "Complementary, alternative, and integrative therapies for asthma", section on 'Dietary changes and supplements' and "Risk factors for asthma", section on 'Maternal diet during pregnancy'.)

Infection — A causal relationship between vitamin D and infection has not been firmly established, and vitamin D supplementation for the case of prevention of infection alone is not warranted.

Although vitamin D reduces activation of the acquired immune system, it activates the innate immune system, particularly monocytes and macrophages. Exposure of monocytes and/or macrophages to bacterial infections upregulates VDR and 1-alpha-hydroxylase expression and, after 48 hours, increases the production of several natural defensins (at least in human monocytes) capable of decreasing the intracellular survival of such mycobacteria [2,67]. In addition, there is a hypothesis that common virologic infections have a marked seasonal variation because of the seasonal variation of the vitamin D status [68,69].

In view of the wide variety of infectious diseases, additional studies are needed to better define which target group might benefit from vitamin D supplementation. There are several ongoing randomized trials to clarify the possible beneficial effects of vitamin D supplementation on infectious diseases (see National Institutes of Health [NIH] and European clinical trial registers).

Tuberculosis — There is an association between vitamin D deficiency and tuberculosis (TB) and a putative beneficial (historic) effect of ultraviolet B (UVB) exposure of such patients before antibiotic therapy became available [70]. However, vitamin D supplementation does not appear to improve clinical outcomes in patients with active TB nor prevent TB infection in children with vitamin D deficiency.

Treatment – A small-scale intervention study in India showed that vitamin D supplementation accelerated sputum clearance in patients with TB [71]. However, vitamin D supplementation compared with placebo did not improve clinical outcomes (including mortality) among 281 West African patients [72] or among 146 patients from London [73] who had active TB and were receiving antituberculosis treatment. In the latter trial, patients with a mean baseline 25(OH)D level of 8.4 ng/mL (21 nmol/L) were randomly assigned to vitamin D (100,000 international units [2.5 mg] every two weeks for two months) or placebo [73]. Although median time to sputum culture conversion was better in the vitamin D group (36 versus 43.5 days with placebo), the results were not statistically significant (HR 1.39, 95% CI 0.90-2.16).

Prevention – Vitamin D supplementation did not prevent latent or active TB disease in vitamin D-deficient children in Mongolia [74]. In this trial, 8851 children with a negative baseline interferon-gamma release assay (IGRA) for TB were randomly assigned to vitamin D supplementation (14,000 international units weekly) or placebo. The mean baseline 25(OH)D level was 11.9 ng/mL [30 nmol/L]). After three years, the percentage of children with a positive IGRA was similar (3.6 and 3.3 percent, adjusted risk ratio 1.1, 95% CI 0.87-1.38). TB disease was diagnosed in 21 and 25 children respectively (adjusted risk ratio 0.87, 95% CI 0.49-1.55). (See "Latent tuberculosis infection in children".)

Upper respiratory infection — There is insufficient evidence to support the use of high-dose vitamin D for the prevention of viral upper respiratory infections. Although a meta-analysis of trials suggested a small reduction in the occurrence of acute respiratory infection with vitamin D supplementation, subsequent trials have not reported a benefit [75-78].

In a meta-analysis of 37 trials (over 45,000 patients) evaluating the incidence of acute respiratory infection with vitamin D supplementation compared with placebo, there was a small reduction in the proportion of patients experiencing one acute respiratory tract infection in the vitamin D group (61.3 versus 62.3 percent with placebo, odds ratio [OR] 0.92, 95% CI 0.86-0.99) [79,80]. In a prespecified subgroup analysis, there was no significant effect of supplementation on risk of acute respiratory infection for any subgroup defined by baseline 25(OH)D level. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

In a separate trial, there was no difference in the number of overall laboratory-confirmed viral upper respiratory tract infections in healthy children aged 1 to 5 years receiving 2000 versus 400 international units of vitamin D daily [75]. The trial was not designed to determine whether vitamin D reduces upper respiratory infections in general.

In a trial from the United Kingdom, in which 6200 adults were randomly assigned to testing of serum 25(OH)D with daily low-dose (800 international units) or high-dose (3200 international units) vitamin D supplementation when the 25(OH)D concentration was <30 ng/mL (<75 nmol/L) versus no testing or supplementation, the occurrence of an acute respiratory illness during six months of follow-up was not different among the groups (5, 5.7, and 4.6 percent in the high-dose, low-dose, and no supplementation groups, respectively; OR 1.09, 95% CI 0.82-1.46 for high-dose versus no supplementation and 1.26, 95% CI 0.96-1.66 for low-dose versus no supplementation) [76]. In the testing group, the baseline mean serum 25(OH)D level was 15.8 ng/mL (39.7 mmol/L).

In a trial from Norway, in which 34,601 adults were randomly assigned to 5 mL of cod liver oil (400 international units [10 mcg] vitamin D) or placebo daily for six months, there was no difference in the proportion of participants reporting more than one acute respiratory infection (22.9 and 22.1 percent, respectively) [77]. Serum 25(OH)D was measured in a small subset of patients; 86.3 percent had a level ≥20 ng/mL [50 nmol/L]) prior to the study intervention.

COPD exacerbations — There is insufficient evidence to support the use of vitamin D for the prevention of acute COPD exacerbations.

In a meta-analysis of individual patient data from three trials in patients with COPD, vitamin D supplementation did not change the overall rate of moderate to severe COPD exacerbations [81]. In a prespecified subgroup analysis, there was a protective effect in patients with a baseline serum 25(OH)D level <10 ng/mL (<25 nmol/L; 1.2 versus 2.1 exacerbations per year in the placebo group, adjusted rate ratio 0.55, 95% CI 0.36-0.84). As the meta-analysis predominantly showed significant effects in patients with very severe vitamin D deficiency, who should be treated anyway because of risk of rickets or osteomalacia, vitamin D supplementation for the prevention of COPD exacerbation alone is not a proven indication. (See "COPD exacerbations: Prognosis, discharge planning, and prevention", section on 'Vitamin D supplementation'.)

COVID-19 — In patients with coronavirus disease 2019 (COVID-19), vitamin D supplementation may be necessary to meet the recommended intake or to treat deficiency; however, doses exceeding the upper level intake with the intention of improving COVID-19 outcomes are not advised [82]. It is reasonable for all individuals to take 15 to 25 mcg (600 to 1000 international units) of vitamin D daily.

There is growing interest in the role of vitamin D as a facilitator of the innate immune response during SARS-CoV-2 infection [83-85]. Serum 25(OH)D levels are reportedly lower in critically ill (intensive care unit [ICU]) patients with COVID-19 than in patients on the general medical unit [86]. Although small observational studies report an inverse association between mean vitamin D levels and COVID-19 cases [87,88], the association is confounded by common risk factors for both vitamin D deficiency and SARS-CoV-2 (eg, obesity). Larger observational studies report mixed findings. As examples:

In a large cohort study from the United Kingdom (UK) Biobank (348,598 participants, 499 with COVID-19), after adjustment for confounders, there was no association between 25(OH)D levels and risk of [89,90] or mortality from [91] COVID-19.

In a subsequent study of 489 individuals who had a 25(OH)D level measured within one year of testing for COVID-19, the risk of a positive COVID-19 test was higher in those who were likely vitamin D deficient (25[OH]D level <20 ng/mL without increase in supplementation) than in those who were not (estimated mean rate 21.6 versus 12.2 percent in the unlikely deficient groups, RR 1.77, 95% CI 1.12-2.81) [92].

There is no clear evidence that vitamin D supplementation reduces the risk or severity of COVID-19 [87,93-95]. In an earlier pilot study from Spain, 76 hospitalized patients with COVID-19 and acute respiratory infection were randomly assigned to oral calcifediol (0.532 mg, followed by 0.266 mg on day 3 and 7 of hospitalization, and then weekly) or to no supplementation [96]. All patients received standard care for COVID-19. Fewer patients assigned to calcifediol required ICU admission (2 versus 50 percent). Despite randomization, more patients in the unsupplemented group had diabetes (19 versus 6 percent) and hypertension (58 versus 24 percent), known risk factors for severe COVID-19, which may have confounded the results of the study.

Subsequent large trials have not shown a benefit of vitamin D supplementation on COVID-19 outcomes. As examples:

In a randomized trial from Brazil evaluating a single dose of vitamin D3 (200,000 international units) versus placebo in 240 moderately ill patients hospitalized with COVID-19 (mean baseline 25[OH]D 20.9 ng/mL [52 nmol/L]), there was no difference in hospital length of stay (median seven days in both groups) [97]. There were also no significant differences in the secondary outcomes, including in-hospital mortality (7.6 versus 5.1 percent, mean difference 2.5 percent, 95% CI -4.1 to 9.2 percent), admission to the ICU (16 versus 21.2 percent, mean difference -5.2 percent, 95% CI -15.1 to 4.7 percent), or need for mechanical ventilation (7.6 versus 14.4 percent, mean difference -6.8 percent, 95% CI -15.1 to 1.2 percent).

In a trial from Norway, in which 34,601 adults were randomly assigned to 5 mL of cod liver oil (400 international units [10 mcg] vitamin D) or placebo daily for six months, there was no difference in the incidence (1.31 and 1.32 percent) or severity of COVID-19 [77]. Approximately 35 percent of participants in each group received ≥1 dose of a COVID-19 vaccine during the study. Serum 25(OH)D was measured in a small subset of patients; 86.3 percent had a level ≥20 ng/mL [50 nmol/L]) prior to the study intervention.

In a trial from the United Kingdom, 6200 adults were randomly assigned to testing of serum 25(OH)D followed by daily low-dose (800 international units) or high-dose (3200 international units) vitamin D supplementation when the 25(OH)D concentration was <30 ng/mL (<75 nmol/L) versus no testing or supplementation [76]. In the testing group, the mean serum 25(OH)D level was 15.8 ng/mL (39.7 mmol/L). During six months of follow-up, there was no difference in the incidence or severity of COVID-19 (secondary endpoints). A positive test for COVID-19 was reported in 3, 3.6, and 2.6 percent of participants in the high-dose, low-dose, and no supplementation groups, respectively (OR 1.13, 95% CI 0.78-1.63 for high-dose versus no supplementation and 1.39, 95% CI 0.98-1.97 for low-dose versus no supplementation). The majority of participants (89.1 percent) received at least one dose of a COVID-19 vaccine during the study.

CARDIOVASCULAR SYSTEM — Although observational studies show an association between low vitamin D status and risk of hypertension and cardiovascular events [98], most randomized trials have not shown a cardiovascular benefit of vitamin D supplementation. The causal nature of any association between vitamin D and cardiovascular disease and whether the association differs across patient populations (eg, different sexes and racial/ethnic groups, chronic kidney disease, diabetes) remain uncertain [99,100].

Hypertension — Overall, there does not appear to be a beneficial clinical effect of vitamin D supplementation on blood pressure. It is unclear if specific ethnic groups are more likely to benefit from vitamin D supplementation.

There is geographic and racial variation in blood pressure, with risk of hypertension increasing from south to north in the Northern hemisphere. One proposed explanation for the association with latitude is that exposure to sunlight may be protective, either because of an effect of ultraviolet B (UVB) radiation or of vitamin D [101]. In animal studies, 1,25-dihydroxyvitamin D has been shown to regulate the renin-angiotensin system. Vitamin D receptor (VDR)-null mice or mice with inborn deficiency of the 1-alpha-hydroxylase gene develop high renin hypertension and cardiac hypertrophy [4,102]. Moreover, vascular endothelial and smooth muscle cells respond to exposure to 1,25-dihydroxyvitamin D with a "favorable cardioprotective" gene response. This corresponds well with reduced thrombogenesis and increased fibrinolysis as observed in vivo [2,4].

Observational studies are consistent with these preclinical data. In normotensive and hypertensive individuals, there is an inverse association between 25-hydroxyvitamin D (25[OH]D) concentration and blood pressure [103-106]. However, the link between vitamin D status and hypertension is complicated by a strong negative association between body mass index (BMI), a well-known risk factor for hypertension, and 25(OH)D. A 2015 meta-analyses of 46 intervention trials did not show a benefit of vitamin D supplementation on systolic or diastolic blood pressure [107]. The results were similar when the analysis was derived from trial-level (46 trials) or individual patient (27 trials) data. Prespecified subgroup analysis (by baseline blood pressure, baseline 25[OH]D, type and dose of vitamin D supplementation, presence or absence of diabetes) did not show any factors predictive of a response. In a trial in 283 Black adults (approximately 50 percent with hypertension), which was not included in the meta-analysis, vitamin D supplementation significantly decreased systolic blood pressure (-1.4 mmHg for each additional 1000 units/day of cholecalciferol) but did not affect the diastolic pressure [108].

Cardiovascular events — Although low serum 25(OH)D levels have been associated with an increased risk of cardiovascular disease in some studies, there is no evidence that vitamin D supplementation improves cardiovascular outcomes.

The link between vitamin D and cardiovascular disease involves a much broader spectrum of cardiovascular risks beyond its association with hypertension [98,109]. In a meta-analysis of 19 prospective studies (65,994 patients), there was an inverse relationship between serum 25(OH)D levels (ranging from 8 to 24 ng/mL [20 to 60 nmol/L]) and risk of cardiovascular disease (relative risk [RR] 1.03, 95% CI 1.00-1.60, per 10 ng/mL [25 nmol/L] decrement in serum 25[OH]D) [110]. Examples of individual studies include the following:

In the Framingham Offspring Study, participants who had a 25(OH)D <15 ng/mL (37.5 nmol/L) were more likely to have their first cardiovascular event during 5.4 years (mean) of observation than those with values ≥15 ng/mL (hazard ratio [HR] 1.62, 95% CI 1.11-2.36) [111].

In the National Health and Nutrition Examination Survey (NHANES) 2001 to 2004, the prevalence of coronary heart disease (angina, myocardial infarction) was more common in adults with 25(OH)D levels <20 ng/mL compared with ≥30 ng/mL (odds ratio [OR] adjusted for age, race, and sex 1.49, 95% CI 1.17-1.91) [112,113]. Adjusting for other risk factors (BMI, chronic kidney disease, hypertension, diabetes mellitus, smoking, use of vitamin D supplements) attenuated the association (OR 1.24, 95% CI 0.95-1.62). The prevalence of heart failure and peripheral arterial diseases was also higher among those with 25(OH)D values <20 ng/mL (ORs 2.10 and 1.82, respectively) with similar attenuation after adjustment for other risk factors.

In systematic reviews and meta-analyses, however, there was no effect of supplementation on cardiovascular outcomes, including myocardial infarction and stroke [114-117]. The meta-analyses also did not show a significant effect of vitamin D supplementation on cardiovascular risk factors (lipids, glucose, blood pressure) [115]. Trials published after the meta-analysis show similar results:

In one trial, 25,871 men ≥50 and women ≥55 years of age (mean serum 25[OH]D 30 ng/mL [77 nmol/L]) were randomly assigned in a two-by-two factorial design to 2000 international units of vitamin D3 and 1 g omega-3 fatty acids or to placebo [43]. After a median follow-up of 5.3 years, the primary cardiovascular endpoint (composite of myocardial infarction, stroke, or cardiovascular death) developed in a similar proportion of patients in the vitamin D and placebo groups (3.1 versus 3.2 percent, respectively, HR 0.97, 95% CI 0.85-1.12).

In another trial, 5110 adults 50 to 84 years of age (mean serum 25[OH]D 25.3 ng/mL [63 nmol/L]) were randomly assigned to vitamin D3 supplementation (initial dose 200,000 international units followed by 100,000 international units monthly) or placebo [118]. After a median follow-up of 3.3 years, the primary outcome (the number of patients with incident cardiovascular disease and death) occurred in a similar proportion of patients (11.8 versus 11.5 percent in the placebo group, HR 1.02, 95% CI 0.87-1.20). In a prespecified subgroup analysis of patients with vitamin D deficiency (baseline serum 25[OH]D <20 ng/mL [50 nmol/L]), there was also no difference in the primary outcome.

In patients with chronic kidney disease (estimated glomerular filtration rate [eGFR] 15 to 60 mL/min/1.73 m2), a randomized trial of an active vitamin D preparation (oral paricalcitol) versus placebo also showed no difference in left ventricular mass index or improvement in measures of diastolic dysfunction between the two groups [119]. Cardiovascular mortality is reviewed below. (See 'Mortality' below.)

DIABETES — There are a number of reasons to link type 1 and type 2 diabetes with vitamin D status [120]. For type 1 diabetes, the link is largely mediated by the effects of vitamin D on the immune system (see 'Autoimmunity' above). For type 2 diabetes, the potential mechanisms include improving both beta cell activity as well as insulin sensitivity [121].

Type 1 diabetes — Some [122,123], but not all [124], observational studies in humans suggest an association between vitamin D deficiency and type 1 diabetes. In a case-control study of 720 children with type 1 diabetes compared with 2610 age-matched children without diabetes, there was an association between type 1 diabetes and key genetic polymorphisms linked to vitamin D deficiency, lending support to the possibility of an association between vitamin D deficiency and type 1 diabetes [51]. (See 'Genes and vitamin D status' below.)

Several observational studies, mainly case-control studies, showed that vitamin D supplementation in early infancy reduced the subsequent risk of type 1 diabetes by approximately 30 percent [121,125,126]. However, there are no randomized trials evaluating the effect of vitamin D supplementation on the incidence of type 1 diabetes in childhood.

Type 2 diabetes and metabolic syndrome — Vitamin D status is lower in individuals with obesity and with type 2 diabetes, but the causality of this relationship is unknown. In nearly all human studies, obesity is associated with low 25(OH)D concentrations [127]. A large genetic study of more than 40,000 individuals showed that higher body mass index (BMI; and the genes that predispose for obesity) decreases serum 25(OH)D levels, whereas lower 25(OH)D levels (or the genes that are associated with reduced serum concentration of 25[OH]D) have, at most, very small effects on obesity [128]. (See "Type 2 diabetes mellitus: Prevalence and risk factors", section on 'Vitamin D deficiency'.)

In several cross-sectional and prospective cohort studies, type 2 diabetes and conditions known to be part of the metabolic syndrome were associated with a poor vitamin D status [114,129-136]. As an example, a meta-analysis of 21 prospective studies showed an inverse relationship between circulating 25(OH)D levels and the risk of type 2 diabetes (relative risk [RR] 0.62, 95% CI 0.54-0.70, for patients with the highest versus lowest category of 25[OH]D levels) [137].

However, the existing intervention studies are either negative or showed only limited beneficial effects [7,138-141]. In a meta-analysis of 23 trials evaluating the effect of vitamin D supplementation on glycemia, there was no effect of supplementation on glycemia (19 trials) or measures of insulin resistance (12 trials) [142]. However, a trial in severely vitamin D-deficient South Asian women living in New Zealand revealed a modest improvement of their insulin sensitivity after six months of vitamin D supplementation [143]. (See "Prevention of type 2 diabetes mellitus", section on 'Pharmacologic therapy'.)

NEUROPSYCHIATRIC FUNCTION — The vitamin D receptor (VDR) and the 1-alpha-hydroxylase enzyme that converts vitamin D to its active form are expressed in the human brain [144]. Through its effects on neuronal proliferation, differentiation, migration, and apoptosis, vitamin D may play an important role in brain development [145,146]. In addition, it has been proposed that prenatal vitamin D deficiency may increase the risk of neuropsychiatric disorders, such as schizophrenia [147]. There are inconsistent small effects of vitamin D deficiency on postnatal brain function [148]. Low levels of 25-hydroxyvitamin D (25[OH]D) are frequently found in patients with depression or Alzheimer disease [149-151], and a meta-analysis of observational studies showed lower Mini-Mental State Examination scores in patients with lower serum vitamin D concentrations (25[OH]D <20 versus ≥20 ng/mL [<50 versus ≥50 nmol/L]) [150]. (See "Risk factors for cognitive decline and dementia", section on 'Vitamin D deficiency'.)

There are few trials evaluating the effects of vitamin D supplementation on neuropsychiatric symptoms. In a meta-analysis of six trials evaluating vitamin D supplementation compared with placebo in adults with a diagnosis of depression or at risk for depression, there was no significant effect of vitamin D supplementation on depression symptoms [152]. The meta-analysis was limited by heterogeneity of study results and the overall low quality of the included trials. Thus, the causal nature of the association between vitamin D and neuropsychiatric function remains uncertain. Vitamin D deficiency in this population may be a consequence of their limited mobility and sun exposure.

PREGNANCY OUTCOMES — Poor vitamin D status in the perinatal period may have short-term (eg, preeclampsia) or long-term consequences (in the offspring) on bone, the immune system (autoimmune diseases, allergy), and general health, but the precise threshold for optimal vitamin D status during pregnancy, lactation, or in the neonate is not well defined. Recommendations for vitamin D supplementation during pregnancy are reviewed separately. (See "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Calcium and vitamin D'.)

There are few data on timing of vitamin D supplementation. The earliest interventions made in published trials were in the late first trimester; initiation of therapy with vitamin D prior to conception has not been evaluated. Additional trials are needed to determine the optimal serum 25(OH)D level in pregnancy and whether vitamin D supplementation, particularly earlier in gestation, influences maternal and infant health outcomes.

In addition, more trials are needed to confirm the safety and efficacy of high-dose vitamin D supplementation in pregnant women with severe vitamin D deficiency. Severe and prolonged vitamin D deficiency can result in osteomalacia and, in pregnant women, cephalopelvic disproportion, necessitating cesarean delivery. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia", section on 'Pregnancy' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Pregnancy'.)

Birth and infancy outcomes – There are several observational studies suggesting an association between poor maternal vitamin D status and adverse pregnancy outcome [98,153-156]. As an example, in a meta-analysis of 31 studies, insufficient serum 25-hydroxyvitamin D (25[OH]D) concentrations were associated with a higher risk of gestational diabetes, preeclampsia, and small for gestational age infants [153]. However, the absence of a dose-response relationship between serum 25(OH)D and reported complications and the inclusion of studies that measured the 25(OH)D levels with variable precision raise significant doubt about the effects of vitamin D deficiency on the reported outcomes.

The growing number of trials examining the effects of vitamin D supplementation on pregnancy and birth outcomes show conflicting results [157-160], with some showing a reduction in risk of low birth weight or small for gestational age infants after vitamin D supplementation [157,159,160]. As examples:

In two meta-analyses of randomized trials (30 and 43 trials, respectively), prenatal vitamin D supplementation reduced the risk of low birth weight infants, but did not reduce the risk of preterm birth [159,160]. Most of the trials were of low methodological quality. Baseline serum 25(OH)D levels were not routinely reported, and supplementation was not initiated until 20 weeks of pregnancy or later.

In a 2018 meta-analysis of 24 trials (5405 participants) comparing vitamin D supplementation with placebo, no supplementation, or a different dose of vitamin D (usually 400 international units daily), vitamin D supplementation reduced the risk of small for gestational age (11.5 versus 17.1 percent, RR 0.72, 95% CI 0.52-0.99) [157]. The effect of supplementation on fetal or neonatal mortality (1.8 versus 2.2 percent, RR 0.72, 95% CI 0.47-1.11) and congenital anomalies (RR 0.94, 95% CI 0.61-1.43) was not significant. The dosing and types of vitamin D, as well as the timing of the intervention, varied among the trials. In a subgroup analysis, doses of ≤2000 international units daily were associated with reduced risk of small for gestational age and fetal or neonatal mortality, whereas doses >2000 international units daily were not.

In a subsequent trial, 1300 pregnant women from Bangladesh (mean 25 [OH]D 11 ng/mL [27.5 mmol/L]) were randomly assigned at 17 to 24 weeks gestation to weekly prenatal vitamin D supplementation (4200, 16,800, or 28,000 international units), pre- and postnatal vitamin D supplementation (28,000 international units weekly), or placebo [158]. At one year of age, there was no difference among the infants in length-for-age Z-score or in any other anthropometric outcome. The incidence of preterm birth, small for gestational age, or low birth weight did not differ among the groups. Whether these results are generalizable to other populations is uncertain.

Childhood outcomes – In a large, long-term prospective study (Avon Longitudinal Study of Parents and Children), which involved 3960 mother-and-offspring pairs mainly of White European origin, maternal 25(OH)D concentration was measured during pregnancy, and offspring underwent dual-energy x-ray absorptiometry (DXA) at age 9 to 10 years [161]. There was no significant association between maternal vitamin D status in pregnancy and offspring bone mineral content in late childhood. In contrast, a smaller cohort study (341 mother-and-offspring pairs) found that vitamin D deficiency during pregnancy was associated with lower bone mass in their children at 20 years of age [162].

In a secondary analysis of a randomized trial comparing high (2800 international units daily) versus standard (400 international units daily) dose vitamin D supplementation starting at week 24 of pregnancy, some parameters of bone mineralization were improved in the children (age 6 years) whose mothers received higher dose vitamin D [163]. The difference in the incidence of fractures (7 versus 11 percent) was not statically significant.

Vitamin D supplementation during pregnancy and risk of asthma in offspring is discussed in more detail above. (See 'Autoimmunity' above.)

MORTALITY — Large-scale epidemiologic data on predominantly White populations in North America and Europe suggest an association between low 25-hydroxyvitamin D (25[OH]D) levels (<20 ng/mL [50 nmol/L]) and high mortality risk. In some meta-analyses, there is a modest reduction in all-cause mortality with vitamin D supplementation (particularly in older, noncritically ill vitamin D-deficient patients) [164-166]. In subsequent trials in critically ill adults or in adults without vitamin D deficiency, there was no reduction in mortality with vitamin D supplementation [43,118,167]. (See "Nutrition support in critically ill patients: Parenteral nutrition", section on 'Therapeutic vitamin and mineral supplementation'.)

All-cause mortality – Some [164,168-175], but not all [176-178], epidemiologic studies suggest that low 25(OH)D levels (especially <10 to 20 ng/mL [25 to 50 nmol/L]) are associated with higher mortality. In some of these studies, the relationship between serum 25(OH)D and mortality was defined by a U- or reverse J-shaped curve, indicating higher mortality at very low (<20 ng/mL) and high (>30 to 50 ng/mL [75 to 125 nmol/L]) serum 25(OH)D concentrations [31,169,172]. In a meta-analysis of individual participant data from eight prospective European studies (approximately 27,000 participants) with a mean standardized serum 25(OH)D concentration of 21 ng/mL (54 nmol/L), there was an increase in all-cause mortality in individuals with vitamin D <20 ng/mL compared with 30 to 40 ng/mL (<50 nmol/L compared with 75 to 100 nmol/L), with the greatest risk occurring in those with the most severe deficiency (<12 ng/mL [30 nmol/L], hazard ratio [HR] 1.67, 95% CI 1.44-1.89) [179].

In an analysis of genetic polymorphisms associated with serum 25(OH)D in three large Danish cohort studies, genetically low 25(OH)D was associated with increased all-cause mortality [180]. Similarly, in a large cohort study from the United Kingdom that used 35 genetic variants to predict serum 25(OH)D levels in participants of White European ancestry, predicted 25(OH)D levels <20 ng/mL (50 nmol/L) were associated with an increased risk of all-cause mortality (odds ratio [OR] 1.25, 95% CI 1.16-1.35, for 25[OH]D level of 10 ng/mL [25 nmol/L] versus 20 ng/mL [50 nmol/L]) [181]. However, another smaller study did not find an association [9,182].

In meta-analyses of randomized trials, vitamin D3 supplementation in older, noncritically ill vitamin D-deficient patients modestly reduced risk of mortality [164-166]. Subsequent trials do not show a mortality benefit for vitamin D supplementation. As examples:

In a trial of vitamin D supplementation (4000 international units daily for three years) compared with placebo in patients with advanced heart failure and baseline vitamin D levels <30 ng/dL (75 nmol/L), vitamin D supplementation did not reduce overall mortality (19.6 versus 17.9 percent with placebo, HR 1.09, 95% CI 0.69-1.71) [183].

In a placebo-controlled trial of early treatment with a single dose of vitamin D3 (540,000 international units orally or through a nasogastric tube) in critically ill, vitamin D-deficient adults (mean 25[OH]D 11.1 ng/mL [27.8 nmol/L]), there was no difference in 90-day mortality (23.5 versus 20.6 percent in the placebo group, mean difference 2.9 percentage points, 95% CI -2.1 to 7.9) [167]. By day three, vitamin D levels had improved substantially in the vitamin D group (46.9 versus 11.4 ng/mL in the placebo group [117 versus 28 nmol/L]).

In another trial, 21,315 Australian adults were randomly assigned to a monthly dose of 60,000 international units of vitamin D or placebo [184]. After a median follow-up of 5.7 years, the study did not show a benefit for overall mortality. The baseline serum 25(OH)D concentration revealed that most subjects were already vitamin D replete before the start of the study.

Cardiovascular mortality – In a prospective study using National Health and Nutrition Examination Survey (NHANES) data, there was an inverse association between 25(OH)D levels and all-cause and cardiovascular mortality with serum 25(OH)D levels <21 ng/mL (52 nmol/L) [185].

In randomized trials in patients without vitamin D deficiency, vitamin D supplementation does not appear to reduce cardiovascular mortality [43,118]. As examples,

In a trial evaluating vitamin D (2000 international units daily) or placebo in 25,871 men ≥50 and women ≥55 years of age (mean serum 25[OH]D 30 ng/mL [77 nmol/L]) with a median 5.3 years of follow-up, there was no significant difference in death from cardiovascular causes between the vitamin D and placebo groups (1.2 versus 1.1 percent, HR 1.11, 95% CI 0.88-1.40) [43].

In the Australian trial in which 21,315 adults were randomly assigned to a monthly dose of 60,000 international units of vitamin D or placebo, there was no benefit for cardiovascular mortality after a median follow-up of 5.7 years [184].

Cancer mortality – In a study using NHANES data, there was no association between serum 25(OH)D levels and overall cancer mortality [186]. In men, cancer mortality was significantly higher at the highest quintiles of 25(OH)D (relative risks [RRs] 1.66 and 1.85 for those with 25[OH]D levels of 32 to 40 and ≥40 ng/mL [80 to 100 and ≥100 nmol/L], respectively). When the risk for particular cancer sites was evaluated, there was a significant positive association between 25(OH)D levels and risk of mortality from lung cancer and an inverse association between 25(OH)D levels and colorectal cancer, which did not reach statistical significance. There was no relationship between 25(OH)D levels and cancer mortality in women. An association between higher baseline serum 25(OH)D concentrations and higher total cancer mortality among men, but not women, has also been reported in other prospective cohort studies [37,176,187], whereas meta-analyses of observational studies have suggested that higher serum 25(OH)D levels at the time of diagnosis were associated with reduced cancer mortality [27,188].

In a meta-analysis of five trials evaluating vitamin D supplementation and total cancer mortality, there was a modest reduction in cancer mortality in the vitamin D group (2.9 versus 3.4 percent, RR 0.87, 95% CI 0.79-0.96) [45]. The reduction was primarily driven by interventions with daily dosing rather than infrequent high doses. The meta-analysis was largely based on secondary analyses of large trials and therefore requires validation in appropriate trials before being translated in clinical practice.

In the largest trial in the meta-analysis, evaluating vitamin D (2000 international units daily) or placebo in 25,871 men ≥50 and women ≥55 years of age (mean serum 25[OH]D 30 ng/mL [77 nmol/L]) with a median 5.3 years of follow-up, the difference in cancer mortality (a prespecified secondary outcome) was not significant (1.2 versus 1.4 percent with placebo, HR 0.83, 95% CI 0.67-1.02) [43].

In a 2021 review of meta-analyses, vitamin D supplementation reduced cancer mortality (RR 0.84; 95% CI 0.74-0.95) [46].

GENES AND VITAMIN D STATUS — The large interindividual variation in 25(OH)D levels in normal individuals living in very comparable situations and the risk of adverse health outcomes associated with low serum 25(OH)D levels may be due, in part, to genetic factors.

Twin studies suggest a high degree of heritability of serum 25(OH)D levels [189]. Gene polymorphisms strongly associated with serum 25(OH) vitamin D have been identified [190]. In addition, a meta-analysis of cohort studies identified common polymorphisms in the vitamin D receptor (VDR) gene that significantly modified the association of serum 25(OH)D and major health outcomes [191].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitamin D deficiency".)

SUMMARY AND RECOMMENDATIONS

In addition to its role in calcium and bone homeostasis, vitamin D could potentially regulate many other cellular functions. (See 'Introduction' above and "Calcium and vitamin D supplementation in osteoporosis".)

A causal association between poor vitamin D status and nearly all major diseases (cancer, infections, autoimmune diseases, and cardiovascular and metabolic diseases) has not been established. (See 'Optimal vitamin D for extraskeletal health' above.)

Epidemiologic studies in predominantly White populations in North America and Europe suggest that low (especially <10 to 20 ng/mL [25 to 50 nmol/L]) compared with normal serum 25(OH)D levels are associated with higher mortality. In some meta-analyses, vitamin D3 supplementation in older, vitamin D-deficient patients modestly reduced risk of overall mortality. In subsequent trials in critically ill adults or in adults without vitamin D deficiency, there was no reduction in mortality with vitamin D supplementation. (See 'Mortality' above.)

Patients with vitamin D deficiency (serum 25[OH]D <12 ng/mL [30 nmol/L]) or insufficiency (12 to 20 ng/mL [30 to 50 nmol/L]) should receive vitamin D supplementation to treat the deficiency/insufficiency. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'.)

In patients without vitamin D deficiency or insufficiency, we suggest not administering vitamin D supplements above and beyond what is required for osteoporosis management (Grade 2C). (See "Calcium and vitamin D supplementation in osteoporosis".)

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Topic 13915 Version 61.0

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