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Vitamin D is a fat-soluble vitamin that regulates calcium homeostasis and is vital for bone health (1). While it can also be obtained from dietary sources or supplements, vitamin D3 (cholecalciferol) is synthesized in the human skin from 7-dehydrocholesterol upon exposure to ultraviolet-B (UVB) radiation from sunlight (see the separate article on Vitamin D and Skin Health). Vitamin D2 (ergocalciferol) is a vitamin D analog photosynthesized in plants, mushrooms, and yeasts; vitamin D2 is also sometimes used in vitamin D food fortification (2). When vitamin D3 in skin is inadequate due to insufficient exposure to UVB radiation, oral intake of vitamin D is necessary to meet vitamin D requirements.
Vitamin D metabolism
Cholecalciferol and ergocalciferol are biologically inactive precursors of vitamin D and must be converted to biologically active forms in the liver and kidneys. Indeed, following dietary intake or synthesis in the epidermis of skin after UVB exposure, both forms of vitamin D enter the circulation and are transported to the liver by the vitamin D-binding protein (and to a lesser extent by albumin). In hepatocytes (liver cells), vitamin D is hydroxylated to form 25-hydroxyvitamin D (calcidiol; calcifediol). Exposure to sunlight or dietary intake of vitamin D increases serum levels of 25-hydroxyvitamin D. 25-hydroxyvitamin D constitutes the major circulating form of vitamin D, and the sum of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 levels in serum is used as an indicator of vitamin D nutritional status (3). The renal 25-hydroxyvitamin D-1alpha-hydroxylase enzyme (also known as CYP27B1) eventually catalyzes a second hydroxylation that converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol). The production of 1,25-dihydroxyvitamin D in the kidneys is regulated by several factors, including serum phosphorus, calcium, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23), and 1,25-dihydroxyvitamin D itself. While the kidney is the main source of 1alpha-hydroxylase activity, extra-renal production of 1,25-dihydroxyvitamin D has also been demonstrated in a variety of tissues, including skin, parathyroid gland, breast, colon, prostate, as well as cells of the immune system and bone cells (2). Most of the physiological effects of vitamin D in the body are related to the activity of 1,25-dihydroxyvitamin D (4). Various forms of vitamin D are listed in the figure.
Mechanisms of action
Most, if not all, actions of vitamin D are mediated through a nuclear transcription factor known as the vitamin D receptor (VDR) (5). Upon entering the nucleus of a cell, 1,25-dihydroxyvitamin D binds to the VDR and recruits another nuclear receptor known as retinoic acid X receptor (RXR). In the presence of 1,25-dihydroxyvitamin D, the VDR/RXR complex binds small sequences of DNA known as vitamin D response elements (VDREs) and initiates a cascade of molecular interactions that modulate the transcription of specific genes. Thousands of VDREs have been identified throughout the genome, and VDR activation by 1,25-dihydroxyvitamin D is thought to directly and/or indirectly regulate 100 to 1,250 genes (6).
Maintenance of serum calcium levels within a narrow range is vital for normal functioning of the nervous system, as well as for bone growth and maintenance of bone density. Vitamin D is essential for the efficient utilization of calcium by the body (1). The parathyroid glands sense serum calcium levels and secrete parathyroid hormone (PTH) if calcium levels decrease below normal (diagram). Elevations in PTH stimulate the activity of the 25-hydroxyvitamin D3-1alpha-hydroxylase enzyme in the kidney, resulting in increased production of 1,25-dihydroxyvitamin D. Higher levels of 1,25-dihydroxyvitamin D result in VDR activation and changes in gene expression that normalize serum calcium by (1) increasing the intestinal absorption of dietary calcium, (2) increasing the reabsorption of calcium filtered by the kidneys, and (3) mobilizing calcium from bone when there is insufficient dietary calcium to maintain normal serum calcium levels (7).
The regulations of calcium and phosphorus homeostasis are closely related, and the calciotropic hormones PTH and 1,25-dihydroxyvitamin D can also control serum phosphorus. Specifically, 1,25-dihydroxyvitamin D increases intestinal phosphorus absorption by stimulating the expression of a sodium-phosphate cotransporter in the small intestine. While PTH increases urinary excretion of phosphorus by reducing reabsorption in the kidney, it is not yet clear whether 1,25-hydroxyvitamin D can directly regulate renal phosphorus transport. The phosphaturic hormone fibroblast growth factor 23 (FGF-23), secreted by osteoblasts (bone-forming cells), limits the production of 1,25-hydroxyvitamin D by inhibiting 25-hydroxyvitamin D-1alpha-hydroxylase (reviewed in 8).
Cells that are dividing rapidly are said to be proliferating. Differentiation results in the specialization of cells for specific functions. In general, differentiation of cells leads to a decrease in proliferation. While cellular proliferation is essential for growth and wound healing, uncontrolled proliferation of cells with certain mutations may lead to cancer. The active form of vitamin D, 1,25-dihydroxyvitamin D inhibits proliferation and stimulates the differentiation of cells through binding to the VDR (1).
Acting through the VDR, 1,25-dihydroxyvitamin D is a potent immune system modulator. The VDR is expressed by most cells of the immune system, including regulatory T cells and antigen-presenting cells, such as dendritic cells and macrophages (9). Under specific circumstances, monocytes, macrophages, and T cells can express the 25-hydroxyvitamin D3-1alpha-hydroxylase enzyme and produce 1,25-dihydroxyvitamin D, which acts locally to regulate the immune response (10, 11). There is considerable scientific evidence that 1,25-dihydroxyvitamin D has a variety of effects on immune system function, which may enhance innate immunity and inhibit the development of autoimmunity (12). Conversely, vitamin D deficiency may compromise the integrity of the immune system and lead to inappropriate immune responses (see Autoimmune diseases).
The VDR is expressed by insulin-secreting cells of the pancreas, and the results of animal studies suggest that 1,25-dihydroxyvitamin D plays a role in insulin secretion under conditions of increased insulin demand (13, 14). Cross-sectional and prospective studies suggest that insufficient vitamin D levels may have an adverse effect on insulin secretion and glucose tolerance in type 2 diabetes (noninsulin-dependent diabetes mellitus) (reviewed in 15).
The renin-angiotensin system plays an important role in the regulation of blood pressure (16). Renin is an enzyme that catalyzes the cleavage (splitting) of a small peptide (angiotensin I) from a larger protein (angiotensinogen) produced in the liver. Angiotensin-converting enzyme (ACE) catalyzes the cleavage of angiotensin I to form angiotensin II, a peptide that can increase blood pressure by inducing the constriction of small arteries and by increasing sodium and water retention. The rate of angiotensin II synthesis is dependent on renin (17). Research in mice lacking the gene encoding the VDR indicates that 1,25-dihydroxyvitamin D decreases the expression of the gene encoding renin through its interaction with the VDR (18). Since inappropriate activation of the renin-angiotensin system can contribute to the development of hypertension, achieving adequate vitamin D levels may be important for decreasing the risk of high blood pressure (see Hypertension).
In vitamin D deficiency, calcium absorption cannot be increased enough to satisfy the body’s calcium needs (4). Consequently, PTH production by the parathyroid glands is increased and calcium is mobilized from the skeleton to maintain normal serum calcium levels—a condition known as secondary hyperparathyroidism. Although it has long been known that severe vitamin D deficiency has serious consequences for bone health, research suggests that less obvious states of vitamin D deficiency are common and increase the risk of osteoporosis and various other health problems (see Disease Prevention).
Severe vitamin D deficiency
In infants and children, severe vitamin D deficiency results in the failure of bone to mineralize. The process of mineralization, which involves the production of crystals of calcium phosphate by bone-forming cells, determines the hardness and strength of bones. Vitamin D deficiency severely affects rapidly growing bones. The growth plates of bones continue to enlarge, but in the absence of adequate mineralization, weight-bearing limbs (arms and legs) become bowed. In infants, rickets may result in delayed closure of the fontanels (soft spots) in the skull, and the rib cage may become deformed due to the pulling action of the diaphragm. In severe cases, low serum calcium levels (hypocalcemia) may cause seizures. Although fortification of food has led to complacency regarding vitamin D deficiency, nutritional rickets is still being reported throughout the world (19, 20).
Although adult bones are no longer growing, they are in a constant state of turnover, or "remodeling." In adults with severe vitamin D deficiency, the collagenous bone matrix is preserved, but bone mineral is progressively lost, resulting in a softening of bones (osteomalacia), bone pain, and increased risk of osteoporosis (21).
Muscle weakness and pain
Vitamin D deficiency causes muscle weakness and pain in children and adults. Muscle pain and weakness were prominent symptoms of vitamin D deficiency in a study of Arab and Danish Muslim women living in Denmark (22). In a cross-sectional study of 150 consecutive patients referred to a clinic in Minnesota for the evaluation of persistent, nonspecific musculoskeletal pain, 93% had serum 25-hydroxyvitamin D levels equal to or below 20 ng/mL, with a mean concentration of 12.1 ng/mL, which is indicative of vitamin D insufficiency (23). Loss of muscle strength greatly contributes to increased risk of falling and bone fractures, especially in older people (24). In addition, long-term vitamin D insufficiency may be a contributing factor to osteoporosis in the elderly (see Osteoporosis).
Risk factors for vitamin D deficiency
Both environmental factors and cultural practices result in variations in vitamin D status:
Assessing vitamin D nutritional status
Growing awareness that vitamin D insufficiency has serious health consequences beyond rickets and osteomalacia highlights the need for accurate assessment of vitamin D nutritional status. It is currently agreed that the measurement of total serum 25-hydroxyvitamin D concentration (1 ng/mL corresponding to 2.5 nmol/L) is the best indicator to evaluate vitamin D status. However, high-quality evidence is still needed to ensure that the current cutoff values are optimal to define states of insufficiency and deficiency (36). Although laboratory reference values for sufficient levels of vitamin D have been initially based on serum 25-hydroxyvitamin D levels from cohorts of healthy individuals, additional studies have suggested that health-based cutoff values aimed at preventing secondary hyperparathyroidism and bone loss should be considerably higher. Indeed, while it is considered that serum 25-hydroxyvitamin D concentrations less than 8-10 ng/mL (20-25 nmol/L) indicate severe deficiency associated with rickets and osteomalacia, several studies have observed that PTH levels (45, 46) and calcium absorption (47) were not optimized with serum 25-hydroxyvitamin D levels below 32 ng/mL (80 nmol/L).
Yet, more recent studies have failed to find threshold values of serum 25-hydroxyvitamin D concentrations in relation to PTH suppression and optimal calcium absorption. On the one hand, the recent cross-sectional analysis of 312,962 clinical samples did not find any evidence of threshold for PTH suppression in the well-fitted curve displaying the inverse association between paired measurements of serum PTH and 25-hydroxyvitamin D, even with 25-hydroxyvitamin D concentrations beyond 70 ng/mL (175 nmol/L) (48). This contradicted a recent analysis of the US National Health and Nutrition Examination Survey (NHANES 2003-2006) that estimated maximum PTH suppression for 25-hydroxyvitamin D concentrations of 40 ng/mL (100 nmol/L) and above (49). In addition, both studies identified evidence of mild hyperparathyroidism (serum PTH >65 pg/mL) in individuals with serum 25-hydroxyvitamin D levels well beyond 20 ng/mL (50 nmol/L), questioning the use of serum PTH as a sensible indicator of vitamin D insufficiency (48, 49). On the other hand, a recent randomized, placebo-controlled trial in postmenopausal women with vitamin D insufficiency (serum 25-hydroxyvitamin D <20 ng/mL) supplemented with daily vitamin D3 doses from 400 to 4,800 IU found little change (6%) in calcium absorption over a normal 25-hydroxyvitamin D concentration range of 20 to 66 ng/mL (50).
The current cutoffs proposed by the Institute of Medicine are as follows: deficiency as serum 25-hydroxyvitamin D values ≤12 ng/mL (30 nmol/L); insufficiency as serum 25-hydroxyvitamin D values of 12-19 ng/mL (30-49 nmol/L); and sufficiency as serum 25-hydroxyvitamin D values of 20-50 ng/mL (50-125 nmol/L) (51). The dietary reference intakes (EAR, RDA) set by the Institute of Medicine are based on achieving circulating 25-hydroxyvitamin D concentrations (20-50 ng/mL) that are adequate to maintain bone health and optimal calcium absorption (52). Yet, considering the potential role of circulating levels lower than 30 ng/mL in the burden of many chronic diseases (6), the US Endocrine Society has suggested to define cutoff values as follows: deficiency as serum 25-hydroxyvitamin D values ≤20 ng/mL (50 nmol/L); insufficiency as serum 25-hydroxyvitamin D values of 21-29 ng/mL (51-74 nmol/L); sufficiency as serum 25-hydroxyvitamin D values of 30-100 ng/mL (75-250 nmol/L) (36). Yet, this alternate target range is supported by some observational studies, but it is not based on data from randomized controlled trials (43) (see Disease Prevention). With these latter cutoff values, studies from across the world have estimated that hypovitaminosis D is widespread and that children and adults of all ages are equally at risk of insufficiency and deficiency (53). Data from supplementation studies indicate that vitamin D intakes of at least 800-1,000 IU/day are required by adults living in temperate latitudes to achieve serum 25-hydroxyvitamin D levels of at least 30 ng/mL (75 nmol/L) (36). Finally, total serum 25-hydroxyvitamin D concentrations may not always adequately reflect vitamin D bioavailability (35) and additional evidence is needed to improve the determination of vitamin D status in different ethnic populations.
In 2010, the Food and Nutrition Board (FNB) of the Institute of Medicine set a Recommended Dietary Allowance (RDA) based on the amount of vitamin D needed for bone health. While the RDA was increased from the adequate intake (AI) set in 1997, the optimal levels of recommended intakes and serum 25-hydroxyvitamin D to minimize hyperthyroidism and maximize bone health in the general population remain controversial (36). The RDA for vitamin D is listed in the table below by life stage and gender.
| Recommended Dietary Allowance
(RDA) for Vitamin D
Set by the Institute of Medicine
|Infants||0-6 months||10 mcg (400 IU) (AI)||10 mcg (400 IU) (AI)|
|Infants||6-12 months||10 mcg (400 IU) (AI)||10 mcg (400 IU) (AI)|
|Children||1-3 years||15 mcg (600 IU)||15 mcg (600 IU)|
|Children||4-8 years||15 mcg (600 IU)||15 mcg (600 IU)|
|Children||9-13 years||15 mcg (600 IU)||15 mcg (600 IU)|
|Adolescents||14-18 years||15 mcg (600 IU)||15 mcg (600 IU)|
|Adults||19-50 years||15 mcg (600 IU)||15 mcg (600 IU)|
|Adults||51-70 years||15 mcg (600 IU)||15 mcg (600 IU)|
|Adults||71 years and older||20 mcg (800 IU)||20 mcg (800 IU)|
|Pregnancy||all ages||-||15 mcg (600 IU)|
|Breast-feeding||all ages||-||15 mcg (600 IU)|
Although the causes of osteoporosis are multifactorial, vitamin D insufficiency can be an important etiological factor in older adults. Osteoporosis affects one-third of women aged 60-70 years and two-thirds of women aged 80 years and above (54). A multinational (18 different countries with latitudes ranging from 64 degrees north to 38 degrees south) survey of more than 2,600 postmenopausal women with osteoporosis revealed that 64% of subjects had 25-hydroxyvitamin D levels lower than 30 ng/mL (75 nmol/L) (55). In addition, in a recent case-control study that included 111 hip fracture patients and 73 controls (median age, 83 years) found low serum levels of both 25-hydroxyvitamin D and vitamin K were associated with an increased risk of hip fracture (56). Without sufficient vitamin D from sun exposure or dietary intake, intestinal calcium absorption can be significantly reduced. This increases PTH secretion by the parathyroid glands; sustained PTH elevation may result in increased bone resorption, which in turn may increase the risk of osteoporotic fracture (57).
A prospective cohort study that followed more than 72,000 postmenopausal women in the US for 18 years found that those who consumed at least 600 IU/day of vitamin D from diet and supplements had a 37% lower risk of osteoporotic hip fracture than women who consumed less than 140 IU/day of vitamin D (58). However, daily supplementation with 400 IU of vitamin D, in combination with 1,000 mg calcium, did not significantly reduce risk of hip fracture compared to a placebo in 36,282 postmenopausal women from the Women's Health Initiative trial (59), suggesting that there might be a threshold of vitamin D intake that is necessary to observe reductions in fracture risk. Yet, this study has been questioned for reasons that include poor adherence and the fact that participants were allowed to take additional vitamin D and calcium supplements that might have confounded the results. In addition, use of hormone replacement therapy fails to be considered in the study of the effect of vitamin D and calcium on skeletal health in postmenopausal women despite being a major confounding factor in this population (52, 60). Another trial, the Randomised Evaluation of Calcium Or vitamin D (RECORD) study, reported that oral supplemental vitamin D (800 IU/day) alone, or in combination with calcium (1,000 mg/day), did not prevent the occurrence of osteoporotic fractures in elderly adults who had already experienced a low-trauma, osteoporotic fracture (61). In this latter study as well, a number of limitations, including poor adherence and/or the fact that vitamin D supplementation did not raise serum 25-hydroxyvitamin D levels to a level that would protect against fractures, might explain the lack of an effect (62). Nevertheless, the US Preventive Services Task Force that conducted the meta-analysis of 11 randomized placebo-controlled trials, including 52,915 older people (of whom 69% were postmenopausal women), found that the supplementation of vitamin D (300-1,000 IU/day) and calcium (500-1,200 mg/day) for up to 7 years resulted in a 12% reduction in the risk of any new fracture (63). Another meta-analysis of 11 randomized, double-blind, placebo-controlled trials on the effect of vitamin D supplementation in 31,022 individuals (91% women) aged 65 years and over indicated that those with the highest vitamin D intake (792-2,000 IU/day) had a 30% lower risk of hip fracture and a 14% lower risk of any non-spine fracture (64). Finally, the latest meta-analysis of trials that examined the effect of combined vitamin D and calcium in preventing fractures in older men and postmenopausal women also concluded that the risk of new fractures, including hip fractures, was significantly reduced in those supplemented compared to controls (65). Interestingly, the three meta-analyses have found that the prevention of fractures by supplemental vitamin D and calcium was limited to institutionalized, older people. However, the risk of fracture was not significantly reduced by vitamin D in community-dwelling seniors (63-65).
The progressive loss of bone mineral density (BMD) leading to osteopenia (pre-osteoporosis) and osteoporosis is commonly observed in older adults, especially the elderly. The results of a recent meta-analysis of 23 randomized controlled trials with more than 4,000 participants (mean age, 59 years) showed little evidence for an effect of vitamin D supplementation on BMD at any of the five skeletal sites examined, including lumbar spine, femoral neck, trochanter, forearm, and total body. A significant increase in BMD was reported only at the femoral neck (66). It was, however, suggested that individuals in this age group would have adequate levels of calcium and thus normal bone metabolism, explaining the lack of an effect of vitamin D in strengthening bone mass (67). Conversely, in older individuals, vitamin D supplementation is essential to correct and maintain adequate levels of serum 25-hydroxyvitamin D and to prevent secondary hyperparathyroidism and BMD loss (68).
Overall, the current evidence suggests that vitamin D3 supplements of at least 800 IU/day may be helpful in reducing bone loss and fracture rates in older adults. In order for vitamin D supplementation to be effective in preserving bone health, adequate dietary calcium (1,000 to 1,200 mg/day) should be consumed (see the article on Calcium) (69).
Ecological studies first suggested an association between Northern latitudes, vitamin D deficiency, and cancer incidence (70). Since the 1980s, several prospective cohort studies have examined the association of vitamin D intake or status and various types of cancer. A recent systematic review and meta-analysis of 16 prospective studies, including 137,567 subjects, reported an 11% reduction in total cancer incidence and a 17% reduction in cancer mortality with each 20 ng/mL (50 nmol/L) increase in circulating 25-hydroxyvitamin D levels. Yet, a sex-based subgroup analysis of eight studies found an inverse association between circulating vitamin D and cancer mortality in women, but not in men (71). In addition, increasing evidence suggests that a few variations in the gene coding for the vitamin D receptor (VDR) might influence individual vitamin D status and subsequently modify the susceptibility to site-specific cancers (72). Finally, many malignant tumors have been found to express the VDR, including breast, lung, skin (melanoma), colon, and bone (73), suggesting that they might be susceptible to the effects of vitamin D. Numerous experimental studies have demonstrated that biologically active forms of vitamin D, such as 1,25-dihydroxyvitamin D and its analogs, upon binding to the VDR, can control cell fate by inhibiting proliferation and/or inducing cell differentiation or death (apoptosis) of a number of cancerous cell types (74).
The geographic distribution of colon cancer mortality resembles the historical geographic distribution of rickets (75), providing circumstantial evidence that decreased sunlight exposure and diminished vitamin D nutritional status may be related to an increased risk of colon cancer. There is strong evidence from prospective cohort studies suggesting higher vitamin D intakes and serum 25-hydroxyvitamin D levels are associated with reductions in colorectal cancer risk (76-78). Interestingly, early studies found that serum 25-hydroxyvitamin D levels were inversely associated with the risk of potentially precancerous colorectal polyps (79) and indices of colonic epithelial cell proliferation (80), two biomarkers for colon cancer. A meta-analysis of four prospective studies and five case-control studies further demonstrated an inverse relationship between circulating vitamin D and incidence of colorectal adenoma (benign tumor that may transform to become malignant). The analysis identified a 27% risk reduction between top vs. bottom quantiles of serum 25-hydroxyvitamin D levels (81). However, a seven-year, randomized, double-blind, placebo-controlled trial in 36,282 postmenopausal women participating in the Women's Health Initiative study found that a combination of supplemental vitamin D (400 IU/day) and calcium (1,000 mg/day) did not lower incidence of colorectal cancer (82). Yet, a daily vitamin D dose of 400 IU may be too low to detect any effect on cancer incidence (83). In fact, a dose-response analysis based on five observational studies estimated that a serum 25-hydroxyvitamin D level equal to or above 33 ng/mL (compared to ≤12 ng/mL) was associated with a 50% lower risk of colorectal cancer; reaching this threshold generally requires a daily intake of 1,000-2,000 IU of oral vitamin D (84). Additional randomized clinical trials are needed to assess whether vitamin D supplementation could help prevent colorectal cancer. Finally, growing evidence suggests that adequate vitamin D status may be linked to better survival of colorectal cancer patients. A meta-analysis of five prospective studies found a 35% reduced risk of colorectal cancer-specific mortality in cancer patients with higher serum 25-hydroxyvitamin D levels. A dose-response analysis estimated that every 8 ng/mL increase in 25-hydroxyvitamin D level was associated with a 10% decrease in colorectal cancer mortality (85).
Together with ecological evidence that breast cancer mortality rises with increasing latitudes and decreasing sunlight exposure, the most current observational data support an association between vitamin D nutritional status and breast cancer (86). An early prospective study of women who participated in the first National Health and Nutrition Examination Survey (NHANES I) found that Caucasian women with adequate sunlight exposure and dietary vitamin D intake had a significantly reduced risk of breast cancer 20 years later (87). A 16-year study of more than 88,000 women observed that higher intakes of vitamin D were associated with significantly lower breast cancer risk in premenopausal women but not postmenopausal women (88). More recently, a meta-analysis of 11 case-control studies, including 7,550 breast cancer cases and 8,790 controls, found a significant reduction in the risk of breast cancer (39% lower risk) in women in the top vs. bottom quintiles of serum 25-hydroxyvitamin D levels (≥33 ng/mL vs. ≤13.6 ng/mL). A pooled, dose-response analysis found that women with a 25-hydroxyvitamin D level of 44 ng/mL (110 nmol/L) experienced a 50% lower risk of developing breast cancer compared to those with levels lower than 9.7 ng/mL (24 nmol/L) (89). While the current RDA of 600-800 IU/day of vitamin D may only raise serum 25-hydroxyvitamin D levels by 4-6 ng/mL, authors of one study estimated that 2,000 to 4,000 IU of vitamin D might be needed to achieve a level of 44 ng/mL (89). Of note, the current tolerable upper intake level (UL) for adults, set by the Food and Nutrition Board of the Institute of Medicine, is 4,000 IU/day (see Safety). A more recent meta-analysis of 14 observational studies (9,110 cases and 16,244 controls) reported an overall risk reduction of 16% when the highest quantile of serum 25-hydroxyvitamin D levels was compared to the lowest. This inverse association was statistically significant in postmenopausal women but not in premenopausal women (90). Further, increasing evidence suggests that specific genetic variations in the gene coding for the VDR may influence the risk of breast cancer (91). VDR expression in breast cancer samples from 82 postmenopausal women was recently correlated with favorable clinical prognostic indicators and significantly better survival (92).
A recent meta-analysis of studies conducted in patients in the early stage of breast cancer also identified associations between inadequate vitamin D status and increased risks of recurrence and death (93). Evidence from randomized controlled trials is currently too limited to conclude whether vitamin D supplementation may reduce breast cancer incidence (reviewed in 94).
Other types of cancer
Evidence associating vitamin D status with other types of cancer is currently limited. While incidence of prostate cancer appears to be inversely associated with the availability of sunlight, prospective studies have not generally found significant relationships between serum 25-hydroxyvitamin D levels and subsequent risk of developing prostate cancer (95, 96). However, a few studies suggested an increased risk of prostate cancer with higher circulating vitamin D levels. A nested case-control study of men (622 cases and 1,451 controls) from Scandinavia found a U-shaped relationship between serum 25-hydroxyvitamin D levels and prostate cancer risk. In that study, serum 25-hydroxyvitamin D concentrations of 7.6 ng/mL or lower, or 32 ng/mL or higher, were associated with increased prostate cancer risk (97). In another nested case-control study, the risk of aggressive disease was increased in prostate cancer patients with higher levels of serum 25-hydroxyvitamin D (98). Finally, in the few and often heterogeneous studies published to date, serum 25-hydroxyvitamin D levels were not associated with non-Hodgkin’s lymphoma (96), ovarian cancer (99), or skin cancers (100).
Insulin-dependent diabetes mellitus (type 1 diabetes mellitus), multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) are examples of autoimmune diseases. Autoimmune diseases occur when the body mounts an immune response against its own tissue, rather than a foreign pathogen. In type 1 diabetes mellitus, insulin-producing beta-cells of the pancreas are the target of an inappropriate immune response. In MS, the targets are the myelin-producing cells of the central nervous system, and in RA, the targets are the collagen-producing cells of the joints (101). SLE is characterized by the presence of a large spectrum of autoantibodies resulting in potential damage to multiple tissues (102). Autoimmune responses are mediated by immune cells called T cells. The biologically active form of vitamin D, 1,25-dihydroxyvitamin D, has been found to modulate T cell responses, such that the autoimmune responses are diminished. Ecological studies have found that the prevalence of autoimmune diseases (particularly for MS (103)) increases as latitude increases, suggesting that lower exposure to UVB radiation and associated decreases in skin vitamin D synthesis may play a role in the pathology of these diseases. Results of several prospective cohort studies also suggest that adequate vitamin D status at different ages (including in utero, early childhood, and during adolescence) could possibly decrease the risk of autoimmune diseases.
Lower levels of circulating vitamin D have been reported in patients newly diagnosed with type 1 diabetes compared to age- and sex-matched non-diabetic subjects (104, 105). A greater prevalence of vitamin D insufficiency and deficiency has also been observed in pre-diabetic children who developed multiple islet autoantibodies (antibodies against insulin-secreting pancreatic cells) compared to autoantibody-negative children. However, a prospective study that followed the cohort of pre-diabetic children found that their vitamin D status, defined as either insufficient, deficient, or sufficient, was not associated with rate of progression to type 1 diabetes after 5 or 10 years of follow up (106). An earlier prospective cohort study of children born in Finland during the year 1966 and followed for 30 years found that children supplemented with vitamin D during the first year of life had an 88% lower risk of developing type 1 diabetes compared to those receiving no supplementation. Moreover, children suspected of having had rickets (severe vitamin D deficiency) during the first year of life showed a significantly higher risk of developing type 1 diabetes (107). Thus, vitamin D supplementation appears protective against type 1 diabetes onset, and sub-optimal vitamin D status in infancy may have long-term effects on immune responses later in life.
There are also limited data suggesting maternal vitamin D insufficiency during pregnancy may influence the risk of type 1 diabetes in offspring. In a recent case-control study, the risk of childhood onset of type 1 diabetes was more than two-fold greater in children whose mothers had serum 25-hydroxyvitamin D levels below 21.6 ng/mL (54 nmol/L) during the last trimester of pregnancy compared to children born from women with serum 25-hydroxyvitamin D above 35.6 ng/mL (89 nmol/L) (108). Other case-control studies have found that vitamin D supplementation during pregnancy was associated with a lower risk of their children developing diabetes-related autoantibodies (109, 110). However, a larger study conducted in mothers of children at increased genetic risk for diabetes reported no association between the appearance of islet autoantibodies and/or diabetes onset in offspring in the first year of life and maternal vitamin D intake during pregnancy (111). Another case-control study failed to observe a relationship between serum 25-dihydroxyvitamin D during early pregnancy and type 1 diabetes diagnosis in offspring (112). Large prospective studies are needed to establish whether maternal vitamin D status during pregnancy can influence the risk of type 1 diabetes in offspring.
Finally, the relationship of polymorphisms in vitamin D metabolism-related genes and type 1 diabetes is currently under investigation. It has been proposed that specific polymorphisms in genes, such as CYP27B1 (coding for 25-hydroxyvitamin D3-1alpha-hydroxylase) and VDR, may be functionally relevant to the action of vitamin D and may thus affect disease susceptibility. In a study conducted in 8,517 children and adolescents with type 1 diabetes and 7,320 control subjects, polymorphisms in genes involved in cholesterol synthesis and vitamin D hydroxylation were linked to circulating vitamin D levels and diabetic status (25).
Low levels of sun exposure and vitamin D deficiency appear to be associated with the development of multiple sclerosis (MS). Poor vitamin D status may compromise the function of specific immune cells critical in the regulation of various immune responses and help trigger autoimmunity in MS (113). Several observational studies suggest vitamin D sufficiency is associated with a decreased MS risk. A retrospective study of levels of ambient UV radiation and cases of MS conducted in Australia revealed that MS incidence in offspring was inversely correlated to maternal exposure to UV during early pregnancy (114). Sun exposure was also used as a surrogate marker for vitamin D exposure in a recent case-control study that included 1,660 MS patients and 3,050 controls. The authors found that infrequent outdoor activities and the use of sunscreen during early childhood and adolescence were associated with a significant increase in risk of developing MS later in life (115). In a cross-sectional study, sun exposure and intake of cod liver oil (rich in vitamin D) during childhood were linked to later symptom onset among veterans with relapsing MS (116). Additionally, a case-control study in US military personnel, including 257 cases of diagnosed MS, found that Caucasian subjects in the highest quintile of serum 25-hydroxyvitamin D (>39.6 ng/mL) had a 62% lower risk of developing MS compared to the lowest quintile (<25.3 ng/mL) (117). Further, in two large cohorts of over 187,000 US women followed for at least 10 years, vitamin D supplement use (≥400 IU/day) was associated with a 41% reduction in the risk of developing MS (118).
However, two recent clinical trials have failed to demonstrate any benefit of vitamin D supplementation, alone or in combination with interferon beta treatment, with respect to relapse rates and disability-related symptoms in MS patients (119, 120). Yet, in a multicenter study conducted in patients newly diagnosed with a clinically isolated syndrome (CIS) and treated with interferon beta, vitamin D status was predictive of MS disease activity and progression. Higher serum 25-hydroxyvitamin D levels (≥20 ng/mL or 50 nmol/L) in the first year following CIS diagnosis predicted a longer time to MS diagnosis, lower number of new lesions, and lower changes in lesion and brain volume during the subsequent four years of follow-up (121).
Vitamin D deficiency may also be implicated in the etiology and/or progression of rheumatoid arthritis (RA), although evidence is mainly from animal studies. The absence of vitamin D receptors (VDR) in genetically modified mice has been linked to higher levels of inflammation and increased susceptibility to autoimmunity (122). When transgenic mice that spontaneously develop inflammatory arthritis are also deficient in VDR, they develop a more aggressive form of chronic arthritis (123). Also, specific polymorphisms in the VDR gene have been linked to an increased susceptibility to RA in certain populations, although how these genetic variants influence vitamin D functionality is not fully understood (124-126). The current data, however, point to a role for vitamin D in modulating the inflammatory process that underlies many chronic diseases, including RA. Several cross-sectional studies in individuals with moderate-to-high levels of inflammation have reported either no association or an inverse association between circulating 25-dihydroxyvitamin D and markers of inflammation. Nonetheless, there is a lack of intervention trials to show whether vitamin D supplementation could limit inflammation and reduce disease risk (including RA) in subjects with high inflammation levels (127).
At this time, it remains unclear whether the prevalence of vitamin D deficiency is linked to RA incidence. In a large cohort study of nearly 30,000 postmenopausal US women, subjects with the highest total vitamin D intakes (≥467.7 IU/day) had a 33% lower risk of developing RA after 11 years of follow-up than those with the lowest intakes (<221.4 IU/day) (128). Yet, more recent analyses of two large cohorts of nearly 200,000 US women followed for several decades found no association between reported vitamin D dietary intakes (using food frequency questionnaires) during adolescence or adulthood and incidence of RA later in life (129, 130). Moreover, several studies that explored the relationship between circulating vitamin D and disease activity in RA patients have reported mixed results (reviewed in 131). Finally, there is a dearth of studies exploring the effect of vitamin D supplementation on disease activity in arthritis subjects. A small randomized, double-blind, placebo-controlled study in 22 RA patients failed to demonstrate improvements in disease activity and inflammation level in subjects supplemented with calcium (1,500 mg/day) and high doses of vitamin D2 (ergocalciferol; averaging over 4,500 IU/day) for a year compared to placebo (132). Since this study has several limitations, including small sample size, additional research is warranted.
More prevalent and severe in non-Caucasian populations (Hispanics, African descendants, and Asians) (133), systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous clinical manifestations. The disease can potentially affect most tissues and organs, including skin (skin rash and photosensitivity), kidneys (nephritis), and joints (arthritis). There is evidence of a role for vitamin D in the prevention of SLE in animal models (134). Interestingly, a recent meta-analysis of 11 case-control studies found that specific VDR polymorphisms were linked to SLE in Asians particularly (135). However, the functional relevance of such genetic variants is not known (136). Analyses of two large prospective cohort studies of nearly 200,000 US women failed to show an association between dietary vitamin D intake (measured by food frequency questionnaire) during the adolescence or adulthood and incidence of SLE later in life (129, 130). Yet, a sub-optimum vitamin D status is commonly observed in subjects with SLE, and this is partly explained by the lack of sunlight exposure, which tends to aggravate disease symptoms (137, 138). Serum concentrations of 25-hydroxyvitamin D were inversely correlated with measures of disease activity in a cohort of 378 patients with SLE (139). The correction of vitamin D insufficiency with high levels of vitamin D3 (100,000 IU/week for one month followed by 100,000 IU/month for six months) in 20 subjects with SLE was linked to a reduction in signs of immune imbalance and in levels of autoantibodies typically detected in SLE, suggesting a therapeutic value for vitamin D in disease treatment (140). Another prospective study conducted in 52 vitamin D-deficient patients with cutaneous lupus erythematosus (a type of lupus with skin disorders only) reported a reduction in disease severity in the group supplemented with vitamin D3 (1,400 IU/day initially, followed by 800 IU/day) and calcium for a year compared to untreated patients (141). Supplementation with vitamin D3 (200 IU/day for one year) was also able to reduce the level of inflammatory cytokines in a randomized, placebo-controlled study conducted in 267 patients with SLE (142). The safety and efficacy of oral vitamin D supplementation in SLE are currently being investigated in clinical trials (143).
Thus, evidence from human epidemiological studies suggests that while it cannot yet be concluded that vitamin D supplementation is beneficial in prevention or treatment of autoimmune disease, it is reasonable to assume that correcting vitamin D insufficiency and maintaining sufficient levels could possibly help decrease disease risk (144).
Hypertension is a well-known risk factor for cardiovascular diseases (CVD) (145). The results of observational and clinical studies suggest a role for vitamin D in lowering blood pressure, which may be partly explained by the fact that 1,25-dihydroxyvitamin D inhibits renin synthesis (see Function). Thus, vitamin D deficiency and subsequent up-regulation of the renin-angiotensin system may contribute to high blood pressure and CVD risk. It has also been suggested that elevated PTH levels may increase the risk of hypertension and CVD (6). Yet, in a recent prospective study of 3,002 individuals (aged 59 years at baseline), the incidence of hypertension, which affected 41% of participants during the nine-year follow-up period, was not higher in those with serum 25-hydroxyvitamin D levels lower than 20 ng/mL and was only marginally associated with elevated PTH levels (146). Nevertheless, a meta-analysis of seven prospective studies, including a total of 48,633 participants with nearly 5,000 incident hypertension cases, found a 30% lower risk of hypertension in those in the top vs. bottom tertiles of serum 25-hydroxyvitamin D levels. The dose-response analysis estimated that every 10 ng/mL increase in serum 25-hydroxyvitamin D level was associated with a 12% lower risk of hypertension (147). Another meta-analysis of 4 prospective and 14 cross-sectional studies also reported an inverse relationship between circulating 25-hydroxyvitamin D and hypertension (148).
Vascular endothelium dysfunction, which contributes to an increased risk of cardiovascular disease (CVD), is common in patients with chronic kidney disease (CKD) (149). In CKD patients, abnormal endothelial function is associated with low values of flow-mediated dilation (FMD) of the brachial artery, a surrogate marker of vascular health. In a recent study conducted in subjects with mild-to-moderate CKD, serum 25-hydroxyvitamin D levels were positively associated with FMD values, suggesting a link between sub-optimal vitamin D status and endothelial dysfunction (150). In a preliminary intervention study, 26 patients with moderate CKD and vitamin D insufficiency/deficiency were supplemented twice with 300,000 IU of vitamin D3 (at weeks 1 and 8) and followed for a total of 16 weeks. Vitamin D supplementation nearly doubled serum 25-hydroxyvitamin D levels and decreased PTH levels by 68.5%; improved vitamin D status was accompanied by increased FMD values and reduced levels of endothelial dysfunction markers (151).
To date, the many epidemiological studies investigating the relationship between vitamin D and outcomes of CVD have provided mixed results (reviewed in 152). Intervention trials in people with impaired kidney function or in the general population are too limited to assess the efficacy of vitamin D therapy in CVD prevention. Data on the effect of calcium and/or vitamin D supplementation on cardiovascular events were recently collected from 11 randomized controlled studies and combined in a meta-analysis. No effect of vitamin D was reported for major cardiovascular events, including myocardial infarction (heart attack) and stroke. Subgroup analysis suggested an increased risk of cardiovascular events with calcium and/or vitamin D supplementation in men but not in women. However, caution is advised with the interpretation of the results since the trials were initially designed to evaluate the effect of vitamin D (and calcium) on bone health, and cardiovascular outcomes were not primary endpoints (153). Two large, randomized controlled trials exploring the effect of vitamin D supplementation on CVD risk are currently under way: the ViDA (Vitamin D Assessment) in New Zealand and the VITAL (Vitamin D and Omega-3 Trial) in the US (154).
People with metabolic syndrome are at increased risk for type 2 diabetes (noninsulin-dependent diabetes mellitus) and cardiovascular disease (CVD). Metabolic syndrome refers to several metabolic disorders, including dyslipidemia, hypertension, insulin resistance, and obesity. A recent study found that the prevalence of type 2 diabetes was associated with suboptimal levels of serum 25-hydroxyvitamin D (<30 ng/mL) in 1,801 patients with metabolic syndrome. During an eight-year follow-up period, lower risks of all-cause mortality (72% lower risk) and CVD-specific mortality (64% lower risk) were reported in individuals with serum 25-hydroxyvitamin D levels over 30 ng/mL (75 nmol/L) when compared to those with levels below 10 ng/mL (25 nmol/L) (155).
In healthy people, vitamin D sufficiency is positively correlated with insulin sensitivity and adequate pancreatic beta-cell function. Conversely, vitamin D deficiency might affect glucose homeostasis and cause impaired glucose tolerance and insulin resistance (156). In a cross-sectional study conducted in 12,719 adults, of whom 4,057 had prediabetes (i.e., an increased risk of developing type 2 diabetes), the prevalence of prediabetes was associated with lower levels of serum 25-hydroxyvitamin D (≤32.4 ng/mL). Subjects with the lowest levels of serum 25-hydroxyvitamin D (≤17.7 ng/mL) were more likely to be current smokers, obese, and have hypertension (157). Vitamin D insufficiency in high-risk individuals may accelerate the progression to overt diabetes. In a prospective study of 2,378 middle-aged men and women followed for 8 to 10 years, the risk for progression to type 2 diabetes from prediabetes was 62% lower in women and 60% lower in men in the highest compared to the lowest quartile of circulating vitamin D (>28.4 ng/mL vs. <18.5 ng/mL). A dose-response analysis measured an average 23% reduction in the risk of progression to type 2 diabetes for every 4 ng/mL (10 nmol/L) increment in serum 25-hydroxyvitamin D concentration (158). A recent review and meta-analysis of 18 prospective studies, including over 210,000 participants followed for a median period of 10 years, found that individuals in the top third of vitamin D levels (reported as either circulating vitamin D or dietary intakes) had lower risks of developing type 2 diabetes (19% lower risk) and metabolic syndrome (14% lower risk) compared to those in the bottom third (159). Currently, limited evidence suggests that vitamin D supplementation may improve insulin sensitivity in individuals with glucose intolerance or manifest type 2 diabetes (160, 161). There is a need for well-designed clinical trials to examine whether maintaining adequate vitamin D levels can prevent adverse metabolic outcomes in healthy and at-risk individuals.
Cognitive impairment and Alzheimer's disease
Alzheimer's disease (AD) is the most common form of dementia, characterized by the presence of extra-neuronal beta-amyloid plaques and intra-neuronal Tau protein aggregates (known as neurofibrillary tangles) in the brain. Mechanistic models currently investigated in animal research suggest that vitamin D deficiency or disorders of vitamin D metabolism and/or the disruption of the vitamin D-VDR pathway in the cerebral regions of the cortex and hippocampus may be involved in the degeneration of neurons and loss of cognitive functions (162). Experimental evidence supporting a role for vitamin D in calcium channel regulation, neuroprotection, and immunomodulation in the central nervous system also implies that low vitamin D status may precede or contribute to cognitive dysfunction with age (163).
In humans, poor vitamin D dietary intakes and low serum 25-hydroxyvitamin D levels have been linked to cognitive decline and degenerative brain disease in the elderly. Several observational studies have found an association between low serum 25-hydroxyvitamin D levels and mild cognitive impairment in older adults (164-166). The cross-sectional and longitudinal analysis of two prospective studies, which included 1,604 men (167) and 6,257 women (168) aged 65 and over, reported a 60% greater odds of cognitive impairment at baseline and a 58% increased risk of cognitive decline during a four-year follow-up period in women, but not in men, with lower levels of circulating 25-hydroxyvitamin D (<10 ng/mL vs. ≥30 ng/mL). In a large French cohort study on osteoporosis and hip fractures in postmenopausal women, impairments in global cognitive performance, assessed with the Pfeiffer Short Portable Mental State Questionnaire (SPMSQ), were associated with lower dietary intakes of vitamin D (<1,400 IU/week vs. ≥1,400 IU/week) in 5,596 elderly women (mean age 80.5 years) (165). A seven-year follow-up study of a subgroup of 498 women indicated that the risk of Alzheimer's disease (but not other types of dementia) was 77% lower in those in the highest vs. the lowest quintiles of vitamin D dietary intakes at baseline (169). Yet, systematic reviews and meta-analyses of observational studies have given mixed results regarding the association of vitamin D status with cognitive performance and AD (170-173).
Nevertheless, the prevalence of vitamin D insufficiency/deficiency ranges between 70% and 90% in older adults, and correcting low levels of serum 25-hydroxyvitamin D may help improve cognitive processes, in particular executive functions (174). In a small non-randomized controlled study in an outpatient clinic, global cognitive function was assessed at baseline and after 16 months in 20 patients supplemented with 800 IU/day (or 100,000 IU/month) of vitamin D and in 24 control subjects. The supplementation of outpatients with vitamin D resulted in the correction of low vitamin D status (average serum 25-hydroxyvitamin D levels at baseline and at 16 months: 16.8 ng/mL to 30 ng/mL) and was associated with a significantly improved scoring in cognition tests compared to the non-supplemented group (175). In a small randomized, placebo-controlled clinical trial in 32 mild-to-moderate AD patients receiving nasal insulin, high doses of vitamin D2 supplementation for eight weeks (up to 36,000 IU/day) did not significantly improve cognitive performance compared to low doses (1,000 IU/day) (176). More research is needed to investigate a causal relationship between vitamin D repletion and potential long-term cognitive benefits in older adults. Further, it is of great importance to evaluate whether correcting vitamin D deficiency in cognitively impaired subjects can improve the impact of anti-dementia therapy (177).
Parkinson's disease (PD) has been associated with a high prevalence of vitamin D insufficiency among patients, especially those with greater mobility problems (178). A case-control study of 296 outpatients with a mean age of 65 years indicated that 55% of PD subjects had serum 25-hydroxyvitamin D levels equal to or lower than 30 ng/mL compared to 41.2% and 36.4% of AD and healthy individuals, respectively (179). In another study, vitamin D insufficiency (serum 25-hydroxyvitamin D <30 ng/mL) was found in up to 69% of patients with early, non-disabling PD (180). The association between vitamin D status and risk of incident PD was assessed in a prospective study conducted among 3,173 men and women aged 50-79 years and free of PD at baseline. The results showed that individuals in the highest quartile of serum 25-hydroxyvitamin D had a 67% lower risk of PD compared to those in the lowest quartile (181). In a randomized, double-blind, placebo-controlled study, 112 PD patients (mean age, 72 years) on standard PD treatment were supplemented with 1,200 IU/day of vitamin D or a placebo for 12 months. Vitamin D supplementation more than doubled the levels of serum 25-hydroxyvitamin D (from mean of 22.5 ng/mL to 41.7 ng/mL) in supplemented subjects and limited the progression of PD, as indicated by a greater proportion of patients who showed no worsening (as assessed by the Hoehn and Yahr stage and the United Parkinson Disease Rating Scale part II) in the supplemented group compared to the placebo group (182). It is not known whether vitamin D insufficiency has a role in the pathogenesis of the disease, but the repletion of vitamin D may provide health benefits that go beyond the prevention and/or the treatment of PD. For example, vitamin D deficiency may contribute to the increased risk of osteoporosis and bone fracture in individuals with neurologic disorders, including PD and multiple sclerosis (183-185). Interestingly, sunlight exposure was found to be associated with improved vitamin D status, higher bone mineral density of the second metacarpal bone, and lower incidence of hip fracture in a prospective study conducted in 324 elderly people with PD (186).
A recent systematic review and meta-analysis of 31 observational studies on maternal vitamin D status and pregnancy outcomes indicated that vitamin D insufficiency may be associated with gestational diabetes mellitus, preeclampsia, and bacterial vaginosis in pregnant women. Low maternal serum vitamin D during pregnancy was also linked to an increased risk for small-for-gestational age infants and low-birth-weight infants, but not for Cesarean section (187). However, the number of intervention trials is currently too limited to draw conclusions as to whether vitamin D supplementation during pregnancy might reduce the incidence of the above-mentioned adverse outcomes (188, 189). In addition, a few observational studies have given rather weak evidence in support of a relationship between maternal vitamin D sufficiency during pregnancy and incidence of respiratory conditions and allergies in children (190, 191). A recent randomized controlled trial found that the supplementation of 108 pregnant women in the third trimester (at week 27 of gestation until delivery) with either 800 IU/day or a bolus dose of 200,000 IU of vitamin D3 did not decrease the risk of wheezing, allergic rhinitis, food allergy diagnosis, lower respiratory tract infections, and eczema in offspring at three years of age, compared to placebo (N=50) (192). In a cohort of 378 mother-child pairs, high serum 25-hydroxyvitamin D levels measured during in the 34th week of pregnancy were associated with an increase in food allergy of the child during the first two years of life, suggesting that the safety of vitamin D supplementation during pregnancy needs to be carefully evaluated (193).
Since vitamin D insufficiency has been linked to autoimmunity (see Autoimmune diseases), it has also been proposed that poor maternal vitamin D status during pregnancy may contribute to an increased risk of autoimmune diabetes (insulin-dependent type 1 diabetes mellitus) in the offspring. Yet, the results of a study of 3,723 children at high genetic risk for type 1 diabetes and followed for a mean 4.3 year-period found that maternal intake of vitamin D (from food and/or supplements) during the third trimester of pregnancy (assessed through food frequency questionnaires) was not associated with advanced beta-cell autoimmunity or clinical diabetes (111). In a nested case-control study, there was no difference in mean serum level of 25-hydroxyvitamin D during the first trimester of pregnancy between 343 mothers of children with type 1 diabetes and 343 control mothers. No association was found between serum vitamin D levels and the age of onset of diabetes in children (112).
Gestational diabetes mellitus
Abnormal hyperglycemia due to pancreatic beta-cell dysfunction characterizes the onset of gestational diabetes mellitus (GDM) in pregnant women without known type 2 diabetes mellitus. This condition is associated with serious adverse maternal outcomes, including preeclampsia, high risk of Cesarean delivery, and life-long increased risk of developing metabolic syndrome and type 2 diabetes mellitus. GDM may also contribute to increased risks of fetal macrosomia (excessive birth weight), neonatal hypoglycemia, infant respiratory distress, and increased life-long risk for obesity, glucose intolerance, type 2 diabetes mellitus, and cardiovascular disease in the offspring (reviewed in 194). A recent prospective study conducted in 655 pregnant women found that the mean serum 25-hydroxyvitamin D level during the first trimester of pregnancy was significantly lower in 54 women who developed incident GDM compared to the rest of the cohort (23 ng/mL vs. 25.4 ng/mL). After multiple adjustments for confounding factors of vitamin D status and GDM risk (including prior history of type 2 diabetes and GDM, and overweight/obesity), the study found each 7.5 ng/mL decrease in serum 25-hydroxyvitamin D level during early pregnancy was associated with a 48% higher risk of developing GDM (195). There was also a significant association between low level of serum 25-hydroxyvitamin D (<29.4 ng/mL) during the second trimester of pregnancy and incidence of GDM in a nested case-control study in 118 women with GDM and 219 matched control subjects (196). A meta-analysis of earlier observational studies (three cross-sectional, two case-control, and two nested case-control studies), including 2,146 participants of whom 433 had GDM, also confirmed that maternal vitamin D level during pregnancy was inversely related to the risk of developing GDM, despite evidence of bias amongst studies, such as the use of different methods for serum 25-hydroxyvitamin D measurement, measures done in different trimesters, and different criteria to assess GDM (197).
Further, evidence for the role of vitamin D in glucose regulation during pregnancy was recently reported in a small randomized, double-blind, placebo-controlled trial in 54 pregnant women diagnosed with GDM. The supplementation with 50,000 IU of vitamin D3 twice during a six-week period (at day 1 and day 21) resulted in significantly lower fasting plasma glucose and serum insulin concentration, reduced insulin resistance, and improved insulin sensitivity compared to placebo (198). This suggests that vitamin D deficiency may adversely affect glucose tolerance during pregnancy and contribute to the onset of GDM. Yet, the potential benefits of vitamin D supplementation in the prevention of glucose intolerance and GDM during pregnancy have not been assessed. Of note, a multi-centered, randomized, controlled trial is ongoing in Europe to evaluate the effects of vitamin D and lifestyle interventions (healthy eating and physical activity) on the metabolic status of pregnant women at risk of GDM (inclusion criteria: pre-pregnancy BMI ≥ 29 kg/m2) (199).
Acute respiratory infections
More than 200 viruses are responsible for causing familiar infections of the upper respiratory tract (URT), known as the common cold, resulting in symptoms of nasal congestion and discharge, cough, sore throat, and sneezing (200). The analysis of cross-sectional data from 18,883 participants (aged 12 years and older) of the Third US National Health and Nutrition Examination Survey (NHANES III) reported an inverse relationship between serum 25-hydroxyvitamin D levels and recent (self-reported) URT infection (URTI). Compared to levels of circulating vitamin D equal to and above 30 ng/mL, the risk of URTI was 24% higher in individuals with levels between 10 and 29 ng/mL and 36% higher in those with levels below 10 ng/mL (201). A subgroup analysis indicated that low levels of serum 25-hydroxyvitamin D in subjects with asthma and chronic obstructive pulmonary disease (COPD) was linked to a greater susceptibility to URTI when compared to people without pulmonary disease. In a randomized, double-blind, placebo-controlled trial conducted in 322 healthy adults (aged 18 years and over), monthly doses of vitamin D3—200,000 IU for the first 2 months and 100,000 IU for the following 16 months—significantly raised the mean serum 25-hydroxyvitamin D level (from 29 ng/mL to 48 ng/mL) in the intervention group but did not decrease the occurrence of URTI compared to placebo (202). Interestingly, the pooled analysis of these data with that of 10 additional trials suggested that large bolus doses of vitamin D may be significantly less effective than daily supplementation with lower doses in the prevention of URTI (203). The meta-analysis also reported an overall protective effect of vitamin D3 with a 36% reduction in URTI risk.
However, in a recent, multicenter, four-arm clinical trial in 2,259 subjects (aged 45-75 years) with a history of colorectal adenoma, daily vitamin D3 supplementation of 1,000 IU did not reduce the number or the duration of URTI episodes during winter and the rest of the year, even among participants with the lowest serum 25-hydroxyvitamin D levels at baseline (204). In addition, the post-hoc analysis of data from a randomized, placebo-controlled trial in 644 individuals (aged 60-84 years) found that monthly supplementation with 30,000 IU or 60,000 IU of vitamin D3 for a maximum period of one year did not significantly decrease the rate of antibiotic prescriptions for bacterial airway infections. The stratified analysis, however, found that doses of 60,000 IU/month reduced the risk of using antibiotics in participants aged 70 and older by 47% (205). Finally, compared to placebo, the supplementation of pregnant women with vitamin D3 (with 2,000 IU/day) for 3 months until birth followed by the supplementation of their infants (800 IU/day) from birth to age 6 months significantly reduced the number of acute respiratory infections after the intervention period, in children aged 6-18 months (206). The results of two ongoing large randomized clinical trials—the ViDA (Vitamin D Assessment) and the VITAL (Vitamin D and Omega-3 Trial)—examining the prevention of infectious diseases (as a secondary outcome) may provide more definitive evidence of an effect of vitamin D on the risk of airway infections (207).
Atopic dermatitis or eczema is particularly prevalent in industrialized countries, affecting 10%-20% of children and 1%-3% of adults. Atopic dermatitis is a chronic inflammatory skin disorder characterized by dry and pruritus (itchy) areas of the skin in affected subjects. Local skin inflammation and immune dysfunction can damage the epidermal barrier and increase the susceptibility to skin infections and atopic reactions in affected individuals. The disease is often associated with other atopic diseases, including food allergies, asthma, and allergic rhinitis (208). Although the etiology of the disease is not fully elucidated, vitamin D deficiency may contribute to the onset and/or the severity of the disease (209). It has thus been suggested that vitamin D may be an effective adjunct tool in disease management through regulating local inflammatory reactions and stimulating antimicrobial activities in the skin. Moreover, the beneficial effect of phototherapy observed in specific cases of atopic dermatitis may be partly mediated by the action of vitamin D (208). In a small randomized, double-blind, placebo-controlled study in 45 patients with atopic dermatitis and low vitamin D status (70% of subjects had serum 25-hydroxyvitamin D levels <20 ng/mL), daily administration of 1,600 IU of oral vitamin D3, alone or together with 600 IU of vitamin E, for a period of 60 days significantly reduced the extent and intensity of eczema, as assessed by the SCORAD (SCORing Atopic Dermatitis) score (210). Vitamin D3 (1,600 IU/day for 60 days) also improved vitamin D status and reduced disease severity in 53 patients with atopic dermatitis in another small randomized trial (211). Larger trials are needed to strengthen these preliminary findings and determine the most appropriate and effective supplementation regimen. Of note, topical treatment of psoriasis with vitamin D analogs has been approved by the US Food and Drug Administration (FDA) and may be effective in the management of other skin disorders (212).
Inflammatory bowel diseases
Several ill-defined environmental and genetic factors are thought to contribute to the development of the inappropriate immune response to the intestinal microbiota that causes ulcerative colitis (UC) and Crohn's disease (CD). While specific VDR polymorphisms may be linked to an increased susceptibility to developing UC and CD (213), higher vitamin D intakes and predicted circulating levels were found to be associated with a reduced incidence of UC and CD in a large cohort of 72,719 women (214). Two recent studies have investigated whether vitamin D3 could benefit patients with CD, possibly through reducing intestinal inflammation. In one multicenter, double-blind, placebo-controlled study, the relapse rate in CD patients in remission after one year of treatment was significantly lower in those supplemented daily with 1,200 IU of vitamin D3 and 1,200 mg of calcium compared to those who received calcium alone (13% vs. 29%) (215). In a second pilot study, incremental daily doses of vitamin D3, from 1,000 IU up to 5,000 IU, were administrated over a 24-week period to 18 CD patients in order to achieve circulating 25-hydroxyvitamin D levels above 40 ng/mL. Although half of the patients failed to achieve 40 ng/mL, the mean 25-hydroxyvitamin D level was raised to 45 ng/mL (from a baseline mean of 16 ng/mL), and the overall improvement in vitamin D status was associated with a significant decrease in disease severity as assessed by Crohn’s Disease Activity (CDAI) scores (216). Additional studies are needed to confirm the therapeutic efficacy of vitamin D in inflammatory bowel diseases.
The prospective analysis of 41,504 electronic medical records in the Intermountain Heart Collaborative study found that only one-third of patients had adequate serum 25-hydroxyvitamin D levels (>30 ng/mL); vitamin D insufficiency (serum 25-hydroxyvitamin D levels ≤30 ng/mL) was associated with increased prevalence and incidence of many cardiovascular conditions, including hypertension, coronary artery disease, heart failure, and stroke (217). Sub-optimal vitamin D status has also been linked to arterial stiffness and vascular endothelial dysfunction—strong determinants of incident hypertension and adverse cardiovascular outcomes (218).
Several intervention studies have evaluated the effect of vitamin D supplementation on high blood pressure. An early controlled clinical trial in 18 men and women with untreated mild hypertension living in the Netherlands found that exposure to UVB radiation three times weekly for six weeks during the winter increased serum 25-hydroxyvitamin D levels by 162%, lowered PTH levels by 15%, and decreased 24-hour ambulatory systolic and diastolic blood pressure measurements by an average of 6 mm Hg (219). A recent meta-analysis of 16 randomized controlled trials involving 1,879 participants, either healthy or with pre-existing cardiometabolic conditions (including hypertension), found no significant reduction in systolic and diastolic blood pressures with vitamin D supplementation (800-8,571 IU/day for five weeks to one year). However, a subgroup analysis of six trials found a significant reduction of 1.31 mm Hg in diastolic blood pressure in individuals with pre-existing conditions. While improvements in blood pressure may be expected in cases of vitamin D insufficiency/deficiency, the authors noted that sub-optimal vitamin D levels in participants were not exclusively observed in those with cardiometabolic conditions (220).
Conditions that decrease vitamin D synthesis in the skin, such as having dark-colored skin, living in temperate latitudes, and aging, are associated with increased prevalence of hypertension (221), suggesting that vitamin D may reduce blood pressure levels in selected groups of individuals. In the above-mentioned meta-analysis, one four-arm, double-blind, placebo-controlled clinical trial was conducted in 283 African Americans randomized to receive daily vitamin D supplements of 1,000 IU, 2,000 IU, or 4,000 IU for a period of three months. Systolic blood pressure was decreased by 0.66 mm Hg with 1,000 IU/day, 3.4 mm Hg with 2,000 IU/day, and by 4 mm Hg with 4,000 IU/day while it increased by 1.7 mm Hg in the placebo group when compared to baseline. A significant reduction of 0.2 mm Hg in systolic blood pressure was detected per 1 ng/mL incremental increase in 25-hydroxyvitamin D level (222). However, another randomized, placebo-controlled study in 150 elderly participants (mean age, 77 years) showed that supplementation with 100,000 IU of vitamin D every three months for one year did not significantly lower blood pressure compared to placebo (223). Further research is needed to determine whether vitamin D supplementation is helpful in the prevention or management of hypertension.
Congestive heart failure
Congestive heart failure (also called cardiac insufficiency) is characterized by increased heart rate and subsequent hypertrophy of the left heart ventricle. Cardiac insufficiency is associated with a reduced left ventricular ejection fraction (LVEF), assessed by echocardiography. Inhibitors of angiotensin-converting enzyme (ACE) (see Blood pressure regulation) are currently used as first-line therapy for patients with heart failure. Interestingly, in a recent cross-sectional study in healthy patients who underwent coronary angiography, insufficient serum 25-hydroxyvitamin D levels (defined as <30 ng/mL) were associated with poorer coronary flow rates (224). Results of vitamin D supplementation studies in those with cardiac insufficiency are only preliminary. In a 12-week randomized, double-blind, placebo-controlled study, daily supplementation with 1,200 IU of vitamin D in children with chronic congestive heart failure led to a significant increase in vitamin D status accompanied by an improved heart muscle performance (increased LVEF), as well as by lower levels of PTH and pro-inflammatory cytokines (225). In another randomized, double-blind, placebo-controlled trial in 64 elderly patients with heart failure, participants receiving 800 mg/day of calcium and 50,000 IU/week of vitamin D did not perform significantly better at physical performance tasks (used as proxy to assess aerobic capacity and skeletal muscle strength) compared to those supplemented with calcium only (226).
Solar ultraviolet-B radiation (UVB; wavelengths of 290 to 315 nanometers) stimulates the production of vitamin D3 in the epidermis of the skin (227). Sunlight exposure can provide most people with their entire vitamin D requirement. Children and young adults who spend a short time outside two or three times a week will generally synthesize all the vitamin D they need to prevent deficiency. One study reported that serum vitamin D concentrations following exposure to one minimal erythemal dose of simulated sunlight (the amount required to cause a slight pinkness of the skin) to the whole body was equivalent to ingesting approximately 10,000 to 25,000 IU of vitamin D (228). People with dark-colored skin synthesize markedly less vitamin D on exposure to sunlight than those with lighter complexion (33). Additionally, older adults have diminished capacity to synthesize vitamin D from sunlight exposure and frequently use sunscreen or protective clothing in order to prevent skin cancer and sun damage. The application of sunscreen with an SPF factor of 10 reduces production of vitamin D by 90% (29). In latitudes around 40 degrees north or 40 degrees south (Boston is 42 degrees north), there is insufficient UVB radiation available for vitamin D synthesis from November to early March. Ten degrees farther north or south (Edmonton, Canada), the "vitamin D winter" extends from mid-October to mid-March. It has been estimated that up to 15 minutes of daily sun exposure on the hands, arms, and face around 12 pm throughout the year at 25 degrees latitude (Miami, FL) and during the spring, summer, and fall at 42 degrees (Boston, MA) latitude may provide a light-skinned individual with 1,000 IU of vitamin D (229).
Vitamin D is found naturally in only a few foods, such as some fatty fish (mackerel, salmon, sardines), fish liver oils, and eggs from hens that have been fed vitamin D. In the US, milk and infant formula are fortified with vitamin D so that they contain 400 IU (10 mcg) per quart. However, other dairy products, such as cheese and yogurt, are not always fortified with vitamin D. Some cereals and breads are also fortified with vitamin D. Fruit juices fortified with vitamin D are also available in the US. Accurate estimates of average dietary intakes of vitamin D are difficult because of the high variability of the vitamin D content of fortified foods (230). The vitamin D content of some vitamin D-rich foods is listed in the table below in both international units (IU) and micrograms (mcg). For more information on the nutrient content of specific foods, search the USDA food composition database.
|Food||Serving||Vitamin D (IU)||Vitamin D (mcg)|
|Pink salmon, canned||3 ounces||465||11.6|
|Mackerel, canned||3 ounces||211||5.3|
|Sardines, canned||3 ounces||164||4.1|
|Quaker Nutrition for Women Instant Oatmeal||1 packet||154||3.9|
|Milk, low-fat, fortified with vitamin D||8 ounces||98||2.5|
|Orange juice, fortified with vitamin D||8 ounces||100||2.5|
|Cereal, fortified||1 serving (usually 1 cup)||40-50||1.0-1.3|
|Egg yolk||1 large||37||0.9|
Most vitamin D supplements available without a prescription contain cholecalciferol (vitamin D3). Multivitamin supplements generally provide 400-1,000 IU (10-25 mcg) of vitamin D2 or vitamin D3. Single ingredient vitamin D supplements may provide 400 to 50,000 IU of vitamin D3, but 400 IU is the most commonly available dose (54). Bolus doses of vitamin D2 (ergocalciferol) may not always be as effective as vitamin D3 in raising serum 25-hydroxyvitamin D levels; however, daily supplementation with vitamin D2 or vitamin D3 is equally effective (231). A number of calcium supplements may also provide vitamin D.
Vitamin D toxicity (hypervitaminosis D) has not been observed to result from sun exposure. The reason is that excessive sunlight exposure generates a number of biologically inert photoproducts from 7-dehydrocholesterol and cholecalciferol (3). Vitamin D toxicity induces abnormally high serum calcium levels (hypercalcemia), which could result in bone loss, kidney stones, and calcification of organs like the heart and kidneys if untreated over a long period of time. Hypercalcemia has been observed following daily doses of greater than 50,000 IU of vitamin D (232). Overall, research suggests that vitamin D toxicity is very unlikely in healthy people at intake levels lower than 10,000 IU/day (233-235). However, the Food and Nutrition Board of the Institute of Medicine conservatively set the tolerable upper intake level (UL) at 4,000 IU/day (100 mcg/day) for all adults (see table below). Certain medical conditions can increase the risk of hypercalcemia in response to vitamin D, including primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma (233). People with these conditions may develop hypercalcemia in response to any increase in vitamin D nutrition and should consult a qualified health care provider regarding any increase in vitamin D intake.
| Tolerable Upper
Intake Level (UL) for Vitamin D
Set by the Institute of Medicine
|Age Group||mcg/day (IU/day)|
|Infants 0-6 months||25 mcg (1,000 IU)|
|Infants 6-12 months||37.5 mcg (1,500 IU)|
|Children 1-3 years||62.5 mcg (2,500 IU)|
|Children 4-8 years||75 mcg (3,000 IU)|
|Children 9-13 years||100 mcg (4,000 IU)|
|Adolescents 14-18 years||100 mcg (4,000 IU)|
|Adults 19 years and older||100 mcg (4,000 IU)|
The following medications increase the metabolism of vitamin D and may decrease serum 25-hydroxyvitamin D levels: phenytoin (Dilantin), fosphenytoin (Cerebyx), phenobarbital (Luminal), carbamazepine (Tegretol), and rifampin (Rimactane) (6). The following medications should not be taken at the same time as vitamin D because they can decrease the intestinal absorption of vitamin D: cholestyramine (Questran), colestipol (Colestid), orlistat (Xenical), and mineral oil (236, 237). The oral anti-fungal medication, ketoconazole, inhibits the 25-hydroxyvitamin D3-1alpha-hydroxylase enzyme and has been found to reduce serum levels of 1,25-hydroxyvitamin D in healthy men (238). The Endocrine Society also recommends monitoring vitamin D status of patients on glucocorticoids and HIV treatment drugs because these medications increase the catabolism of 25-hydroxyvitamin D (36). The use of some cytostatic agents (cell growth inhibitors) may also increase the degradation of 25-hydroxyvitamin D and 1,25-hydroxyvitamin D in cancer patients under chemotherapy (6). The induction of hypercalcemia by toxic levels of vitamin D may precipitate cardiac arrhythmia in patients on digitalis (Digoxin) (239, 240).
The Linus Pauling Institute recommends that generally healthy adults take 2,000 IU (50 mcg) of supplemental vitamin D daily. Most multivitamins contain 400 IU of vitamin D, and single ingredient vitamin D supplements are available for additional supplementation. Sun exposure, diet, skin color, and body mass index (BMI) have variable, substantial impact on body vitamin D levels. To adjust for individual differences and ensure adequate body vitamin D status, the Linus Pauling Institute recommends aiming for a serum 25-hydroxyvitamin D level of at least 30 ng/mL (80 nmol/L). Observational studies suggest that serum 25-hydroxyvitamin D levels between 30 ng/mL and 60 ng/mL are associated with lower risks of adverse health outcomes, including cancers and autoimmune diseases.
Infants should have a daily intake of 400 to 1,000 IU (10 to 25 mcg) of vitamin D, and children and adolescents should have a daily intake of 600 to 1,000 IU (15 to 25 mcg) of vitamin D, consistent with the recommendations of The Endocrine Society (36). Given the average vitamin D content of breast milk, infant formula, and the diets of children and adolescents, supplementation may be necessary to meet these recommendations. The American Academy of Pediatrics currently suggests that all infants, children, and adolescents receive 400 IU of supplemental vitamin D daily (19).
Older adults (> 50 years)
Daily supplementation with 2,000 IU (50 mcg) of vitamin D is especially important for older adults because aging is associated with a reduced capacity to synthesize vitamin D in the skin upon sun exposure.
Written in March 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in July 2014 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in November 2014 by:
Adrian F. Gombart
Principal Investigator, Linus Pauling Institute
Associate Professor, Department of Biochemistry and Biophysics
Oregon State University
Copyright 2000-2014 Linus Pauling Institute
The Linus Pauling Institute Micronutrient Information Center provides scientific information on the health aspects of dietary factors and supplements, foods, and beverages for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional.
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