Interest in the nonskeletal effects of vitamin D has been increasing since the discovery of vitamin D receptors and the 1α-hydroxylase enzyme in multiple tissues, including cells of the pancreas, immune system, macrophages, vascular endothelium, stomach, epidermis, colon, and placenta.6
In these tissues, 25(OH)D can be converted to 1,25(OH)2
D locally, without altering serum 1,25(OH)2
D concentrations. Through these paracrine effects, 1,25(OH)2
D influences the expression of genes in local tissues. However, the evidence for the nonskeletal benefits of vitamin D is not as strong as the evidence for the skeletal effects.
Lower Mortality Rate.
In a prospective observational study of adults older than 65 years participating in NHANES III, the risk of death was 45% lower in those with 25(OH)D values greater than 40 ng/mL compared with those with values less than 10 ng/mL (hazard ratio [HR], 0.55; 95% CI, 0.34-0.88).45
However, this may simply reflect the fact that people with underlying illness or immobility (who are more likely to die) tend to have lower 25(OH)D levels, in part as a result of having spent less time outdoors or of having less adequate nutrition. Because vitamin D is sequestered in adipose tissue, obesity is also associated with lower 25(OH)D levels. However, observational studies cannot prove whether low 25(OH)D status is the cause of greater mortality or just a marker of other underlying risk factors.
In contrast, a meta-analysis of 18 RCTs of vitamin D supplementation in postmenopausal women of advanced age, with dosages ranging from 300 to 2000 IU/d, reported a 7% lower risk of death in those receiving a vitamin D supplement (RR, 0.93; 95% CI, 0.87-0.99).46
This highlights the difference often found between RCTs and observational studies. The effect sizes found in observational studies are often attenuated or absent in RCTs.47
The situation with vitamin D is analogous to that of hormone replacement therapy (HRT) in postmenopausal women. The beneficial effects of HRT were demonstrated for multiple health outcomes in observational studies,48-50
but the WHI RCT in older postmenopausal women failed to confirm the beneficial effects of HRT on dementia and cardiovascular disease.51,52
In the observational trials, healthier women were more likely to use estrogen replacement and had fewer adverse health outcomes, indicating a “healthy user” bias. Only an RCT definitively demonstrated that the risks of first-time use of HRT outweighed the benefits in women older than 60 years.
Despite the slight reduction in mortality associated with vitamin D supplementation, the primary aim of the RCTs included in the meta-analysis was not to assess mortality. Not all trials of vitamin D reported mortality outcomes, so those trials could not be included in the meta-analysis. Trials that showed a mortality effect would be more likely to report this outcome, leading to a high likelihood of reporting bias that could render the slight mortality reduction statistically insignificant.
Lower Cardiovascular Mortality.
The reduced mortality in the aforementioned observational study mirrored in large part the reduced cardiovascular mortality in those with 25(OH)D values greater than 40 ng/mL compared with those with values less than 10 ng/mL (HR, 0.42; 95% CI, 0.21-0.85).45
In another observational cohort study, patients who had angiography and 25(OH)D measurements were followed up for 8 years. Those from the highest 25(OH)D quartile (median, 28 ng/mL) had a lower mortality (HR, 0.45; 95% CI, 0.32-0.64) than those from the lowest quartile (median, 8 ng/mL).53
Although these observational studies do not demonstrate that low 25(OH)D values accelerate cardiovascular mortality, low 25(OH)D concentrations were associated with serum markers of inflammation that are indicators of cardiac risk.
Recently, concern has been expressed that vitamin D could potentially accelerate vascular disease. In a study of African Americans with type 2 diabetes mellitus, 25(OH)D levels correlated with increased calcified plaque in the aorta and carotids, but not in the coronary arteries.54
Vascular disease associated with chronic kidney disease, especially that associated with very low bone turnover, may also be accelerated with supplementation with standard doses of vitamin D. Furthermore, concern has been raised recently that other disorders characterized by vascular inflammation, such as diabetes mellitus, rheumatoid arthritis, or systemic lupus erythematosus, may not benefit from standard recommended doses of vitamin D supplementation.
Vitamin D may affect other cardiovascular and metabolic disease risks. In an observational study of adolescents in NHANES III, those with the lowest 25(OH)D values (<15 ng/mL) had more than a 2-fold greater odds of having an elevated blood pressure compared with the group of adolescents with higher 25(OH)D levels (>26 ng/mL) (odds ratio [OR], 2.4; 95% CI, 1.3-4.2).55
The NHANES III data in adults indicated that those with 25(OH)D levels of less than 21 ng/mL had an increased risk of hypertension, diabetes, obesity, and high triglyceride levels—all metabolic manifestations associated with increased cardiovascular mortality.56
Although obesity is associated with lower serum 25(OH)D levels because of the sequestration of vitamin D in adipose tissue, it is likely not the consequence of low 25(OH)D levels. Additionally, the 25(OH)D level may be a marker of other factors associated with obesity, such as physical inactivity and reduced outdoor sun exposure.
Reduced Risk of Diabetes Mellitus.
A meta-analysis of 5 observational studies of vitamin D supplementation in childhood reported a nearly 30% reduction in the risk of type 1 diabetes in children who had ever received vitamin D supplements (OR, 0.71; 95% CI, 0.60-0.84).57
Unfortunately, most studies had no information about vitamin D dosage or adherence. Because these were observational studies, and vitamin D was not randomly assigned to children, it is possible that characteristics of families who provided supplemental vitamin D to their children contributed to the decreased risk of type 1 diabetes in children receiving supplements.
Vitamin D receptors are present in pancreatic β cells, and vitamin D may augment insulin secretion and insulin sensitivity. Adolescents in NHANES III with serum 25(OH)D levels of less than 15 ng/mL were more likely to have elevated blood glucose levels than those with the highest 25(OH)D values (>26 ng/mL) (OR, 2.5; 95% CI, 1.0-6.4).55
The observational Nurses Health Study found that vitamin D supplementation and calcium supplementation were both associated with a reduction in risk of type 2 diabetes.58
Current data related to vitamin D and the risk of type 2 diabetes are limited by inadequate adjustment for confounding variables, post hoc analyses, and inability to identify the separate effects of calcium and vitamin D.59
Because milk is the major source of both vitamin D and calcium in the diet, it is difficult to identify the independent effects of dietary calcium and vitamin D on the basis of intake or 25(OH)D levels. Skim milk intake is also inversely associated with obesity, which could account for an association between the intake of dietary calcium and vitamin D and a reduced risk of type 2 diabetes.
Reduced Risk of Cancer.
Vitamin D is known to promote cellular differentiation, inhibit cellular proliferation, and reduce the growth of certain tumors in laboratory animals. A meta-analysis of case-control studies of those with and without colon cancer found that, for each 20 ng/mL increase in serum 25(OH)D levels, the odds of colon cancer were reduced by more than 40% (OR, 0.57; 95% CI, 0.43-0.76).60
Other studies have shown that dietary calcium intake is also associated with reduced colon cancer risk and adenoma formation.61,62
Because milk intake is a major determinant of serum 25(OH)D levels, it is difficult to separate the effect of vitamin D from that of calcium intake.
In the case of colon cancer, one large RCT was performed to evaluate the effect of combined supplementation with calcium and vitamin D on the risk of colon cancer. In the WHI trial, supplementation with calcium and vitamin D had no significant effect on the risk of colorectal cancer during 8 years of follow-up.63
Several limitations of this study may have contributed to this lack of effect. Colorectal cancer is a long latency disease, and 8 years may not have been sufficient time to observe the effect of calcium and vitamin D. Another criticism is that the relatively low dose of 400 IU of vitamin D may have not been protective or sufficient to increase serum 25(OH)D levels adequately. Concentrations of 25(OH)D were measured at baseline but not during follow-up. Declining adherence over time would have further reduced the effective doses of calcium and vitamin D.
Breast cancer has also been associated with vitamin D insufficiency. A meta-analysis combining 7 observational studies reported a lower risk of breast cancer among women in the highest compared with the lowest quartile of 25(OH) D values (OR, 0.55; 95% CI, 0.38-0.80).64
As with colon cancer, calcium intake was also associated with a reduced risk of breast cancer. Because obesity is associated with an increased risk of breast cancer and low 25(OH)D levels, it is a confounding factor in the association between breast cancer risk and vitamin D.
As with colon cancer, the WHI RCT of a combined regimen of calcium and vitamin D showed no benefit of supplementation on the risk of breast cancer, again highlighting the different conclusions of observational studies and RCTs.65
The limitations of the breast cancer study are similar to those of the study focused on colon cancer. This study demonstrated the potential confounding effects of physical activity and obesity. Baseline 25(OH)D levels were greater among women with lower body mass index and more recreational physical activity. When controlling for body mass index and physical activity, serum 25(OH)D concentration was not associated with breast cancer risk.
In a meta-analysis of 11 observational studies, prostate cancer was not associated with serum 25(OH)D levels.66
The evidence regarding an association between pancreatic cancer and 25(OH)D levels is conflicting.67
A multinational cohort study found no protective association between greater 25(OH)D values and gastric, esophageal, endometrial, ovarian, kidney, non-Hodgkin lymphoma, and pancreatic cancers.68
Drake et al69
recently showed that event-free survival and overall survival were reduced in vitamin D–insufficient patients newly diagnosed as having diffuse large B-cell lymphoma and T-cell lymphoma during 34.8 months of follow-up.
To date, studies have not shown impressive effects of vitamin D treatment on malignancies.70
Reduced Risk of Multiple Sclerosis.
The incidence of multiple sclerosis increases with increasing latitude, corresponding with reduced ultraviolet B sun exposure and lower serum levels of 25(OH)D. A case-control study demonstrated that the odds of having multiple sclerosis were lower in the group with the highest 25(OH)D levels.71
However, the association was found only in white patients [OR, 0.59; 95% CI, 0.36-0.97 for a 20 ng/mL increase in 25(OH)D], not in African American patients. It is difficult to exclude the possibility that other confounding exposures associated with increasing latitude and greater indoor activity during winter months contribute to the risk of multiple sclerosis. Little evidence supports a therapeutic role for vitamin D in the treatment of multiple sclerosis.72
Reduced Risk of Allergy and Asthma.
Several lines of evidence demonstrate the effects of vitamin D on proinflammatory cytokines, regulatory T cells, and immune responses, with conflicting interpretation of the effects of vitamin D on allergic diseases.73,74
In a cross-sectional study of Costa Rican children, low 25(OH)D levels were associated with elevated IgE and eosinophil counts, as well as with increased asthma-related hospitalizations and use of anti-inflammatory medication.75
However, an association does not prove causation, and alternative explanations can account for this association. For example, children with more severe asthma may spend more time indoors and have less sun exposure.
Low maternal vitamin D intake in pregnancy has been associated with an increased likelihood of childhood wheezing at ages 3 and 5 years.76,77
In contrast, maternal 25(OH)D levels of greater than 30 ng/mL in pregnancy have been associated with childhood eczema at age 9 months and asthma at age 9 years.78
Vitamin D supplementation in infancy has been associated with increased atopy and allergic rhinitis in adulthood.79
Increasing 25(OH)D levels were associated with increasing risk of allergic rhinitis among adults in NHANES III.80
The conflicting data indicate the need for RCTs to demonstrate the effect of vitamin D on the prevention and control of allergic diseases.
Reduced Risk of Infection.
Vitamin D is required for the expression of cathelicidin by macrophages, which is involved in bacterial killing.81
A meta-analysis of 7 observational studies noted a reduced risk of active tuberculosis in those with the highest vs the lowest values of 25(OH)D (OR, 0.68; 95% CI, 0.43-0.93).82
However, an RCT in a West African population with baseline mean 25(OH)D values of 31 ng/mL showed no effect of 100,000 IU of supplemental vitamin D given at the beginning and at 3 and 8 months of tuberculosis treatment on the rate of sputum conversion or resolution of markers of clinical severity.83
However, this dose of vitamin D may have been insufficient because the increase in 25(OH)D concentration during treatment did not differ between the supplement and placebo groups.
In observational data from NHANES III, persons with 25(OH)D values lower than 10 ng/mL were more likely to have had a recent upper respiratory tract infection than those with higher 25(OH)D values in all 4 seasons of the year.84
This association was even stronger in those with asthma or chronic obstructive pulmonary disease. Whether this association is explained by the fact that people who remain indoors are more likely to catch colds remains unclear.
A case-control study reported that mean 25(OH)D values were lower in children with bronchiolitis or pneumonia admitted to the pediatric intensive care unit than in healthy control children or in children with pneumonia admitted to the general pediatric ward.85
Reduced Risk of Mental Illness.
A cohort of Finnish children who received supplemental vitamin D in their first year of life had a lower risk of developing schizophrenia.86
However, the significance of this association is unclear because it was unrelated to adherence to vitamin D supplementation, was only evident in males, and was not found with any other mental illness.
To examine the effect of vitamin D on depression, overweight and obese patients were randomized to receive 20,000 or 40,000 IU of vitamin D or placebo weekly for 1 year.87
At baseline, those with 25(OH)D concentrations lower than 16 ng/mL had greater Beck Depression Inventory scores, indicating that they were more depressed, than those with higher 25(OH)D levels. The 2 groups receiving vitamin D supplementation had significant improvement in their scores, whereas the placebo group did not.
Less Musculoskeletal Pain.
A small descriptive study reported that most patients (93%) with persistent musculoskeletal pain had 25(OH)D values of 20 ng/mL or less.88
In one RCT, patients with diffuse musculoskeletal pain or osteoarthritis and 25(OH)D values lower than 20 ng/mL were randomized to receive vitamin D or placebo for 3 months.89
Those given vitamin D had no improvement in their pain compared with baseline or compared with placebo-treated patients. In another double-blind RCT, primary care patients with 25(OH)D levels of 10 to 25 ng/mL were randomized to receive 50,000 IU of vitamin D or placebo weekly for 8 weeks.90
The treated group showed significantly greater improvement in fibromyalgia assessment scores than the placebo group. Patients with 25(OH)D values lower than 10 ng/mL were treated in an unblinded fashion with 50,000 IU of vitamin D weekly for 8 weeks but had no symptom improvement.
Reduced Risk of Renal Disease.
In a subgroup analysis of the NHANES III data set, low 25(OH)D values were associated with a greater risk of kidney failure in African American but not in white participants.91
However, the opposite trend was observed in whites.