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Vitamin D - Summary of Research

Vitamin D’s role in calcium absorption and bone health is well known. However research over the past twenty years has suggested that vitamin D is also important for reducing the risk of multiple sclerosis1,2, breast, prostate and colon cancers3-5, type 1 diabetes and depression6. Vitamin D deficiency is not rare; on the contrary it has a very high prevalence and is even recognized as a major health problem for older adults7-10.

In a recent study on outpatients, 41% of healthy adults, 49 to 83 years of age were found to be vitamin D deficient throughout the year7. Students and young adults are also at risk for vitamin D deficiency, especially those who work inside or who always wear sun protection. In a study conducted at the Boston Medical Center, it was observed that 32% of students and doctors 18 to 29 years of age were vitamin D deficient at the end of the winter11. Surprisingly, nowadays even teenagers and young children are at risk. Sullivan et al.12 observed that 48% of Caucasian girls aged 9 to 13 years were vitamin D deficient at the end of winter and 17% were still vitamin D deficient at the end of summer due to sunscreen and sun protection.

Sources and metabolism of vitamin D 
Sunlight is the primary source of vitamin D26, 27. Exposure of the skin to UVB from sunlight leads to cutaneous synthesis of cholecalciferol (vitamin D) from its precursors28. A very small number of foods naturally contain vitamin D: oily fish such as salmon, mackerel, and sardines, irradiated mushrooms, egg yolks (although they are high in cholesterol and the amounts are low and highly variable), cod liver oil and fortified foods such as milk (100 IU per 8-ounce serving), orange juice (100 IU per 8-ounce serving) and some breads and cereals20, 30.

There are two naturally occurring forms of vitamin D: cholecalciferol (vitamin D3) from animal sources and ergocalciferol (vitamin D2) from plant sources31. Recent studies in humans have provided evidence that vitamin D3 is more efficient than vitamin D2 in increasing serum 25-hydroxyvitamin D [25(OH)D], the precursor of the biologically active form of vitamin D, 1,25(OH)D32. The pro-hormone vitamin D, in the form of vitamin D2 or D3, is first metabolized to 25(OH)D in the liver and then further metabolized to 1,25 dihydroxyvitamin D [1,25(OH)2D] by 1-α-hydroxylase in the kidneys and other target tissues33.

Populations at risk
Individuals who have darkly pigmented skin, those who are obese and the elderly have an increased risk of vitamin D deficiency. Skin pigmentation (melanin) evolved over time as an effective natural sunscreen because it efficiently absorbs UVB photons. It follows that people with increased skin melanin pigmentation require longer exposures to sunlight to make the same amount of vitamin D3. Thus it is very likely that individuals with darkly pigmented skin are vitamin D deficient.

Those who are obese are also much more likely to be vitamin D deficient. Vitamin D is irreversibly sequestered in the fat pool, especially if body mass index exceeds 30. Obese persons also do very little outdoor activity meaning they acquire very little vitamin D from the sun13.

Elderly persons metabolize vitamin D less efficiently and also on average spend less time outdoors14-16. A person 70 years of age makes less than 25% vitamin D3 when exposed to the same amount of sunlight as a 20 year old.

Bone health and development
One of the primary roles of vitamin D is the regulation of calcium/phosphorus absorption and metabolism for bone health. This role becomes more important during pregnancy and lactation as bones are developing rapidly during this period. Furthermore, insufficient vitamin D intake during infancy can result in biochemical disturbances, reduced bone mineralization, slower growth, bone deformities, and increased risk of fracture, all of which make up the symptoms of rickets34. Studies also suggest that vitamin D deficiency could also lead to low birth weight35.

Adult bone metabolism
In adults, vitamin D maintains bone mineral density and prevents osteoporosis36. Vitamin D also maintains muscle strength and a deficiency in vitamin D can lead to osteomalacia, associated with muscle and bone pain37, 38.

Vitamin D is involved in calcium and phosphorus metabolism and maintains serum calcium concentrations within the physiologically acceptable range, by increasing intestinal calcium absorption. In a vitamin D deficient state, the intestine absorbs 10-15% of dietary calcium39, 29 where as when there is a sufficient level of vitamin D, 30% of calcium is absorbed from the diet.

In addition to increasing the efficiency of calcium and phosphorus absorption from the intestine and increasing renal re-absorption, vitamin D also plays an important regulatory role in skeletal metabolism. When intestinal calcium absorption decreases, there is a subsequent decrease in ionized calcium in the blood. Calcium sensors in the parathyroid glands respond to low levels of calcium by increasing the production of parathyroid hormone (PTH)40. PTH then induces the conversion of pre-osteoclasts into mature osteoclasts and these mature osteoclasts dissolve bone matrix to release calcium into the extracellular space.

Bone is the largest source of calcium used for maintaining serum levels, thus with low levels of vitamin D, more bone is needed for adequate calcium levels and there is therefore an increased risk for fracture, lower bone mineral density and osteoporosis41. Vitamin D levels are also involved in the treatment of postmenopausal osteoporosis. The effect of vitamin D repletion on the prevention of bone re-absorption was assessed in 1515 postmenopausal women who were being treated with anti-resorbing medication. When tested at a later date, women who remained vitamin D deficient had a significantly lower change in annualized spine and hip/bone mineral density (BMD) when compared to women whose vitamin D levels had been repleted. It was concluded that optimal vitamin D repletion seems to be necessary to maximize the response to anti-resorbers in terms of both BMD changes and anti-fracture efficacy. 42

Vitamin D and muscle strength
Vitamin D appears to have a direct effect on muscle strength and is thought to maintain function of type II muscle fibers17. Treatment with the active metabolite 1-alpha-hydroxyvitamin D for three months directly increases both the relative number and size of type II muscle fibers18.

These physiologic changes may lead to improvements in muscular functioning and therefore could reduce risk of falling and fractures in the elderly. Vitamin D’s protection against fracture risk in the elderly has been attributed to changes in bone mineral density, however; vitamin D may also directly improve muscle strength thereby reducing fracture risk through fall prevention19. Falls are the single most common cause of injury mortality in the elderly and account for 40% of all nursing home admissions20. A recent meta-analysis reviewed the effect of vitamin D on elderly individuals (mean age 70) for two months to three years. Vitamin D and number of falls showed consistency of effect21-25 and corrected pooled results indicated that vitamin D treatment reduced the risk of falling by 22% compared with placebo or calcium treatment alone.

Anticarinogenic properties
Vitamin D levels have been linked with the prevention of several forms of cancer. Studies have shown that vitamin D helps prevent breast, colorectal, ovarian and prostate cancers43-46. Experimental studies have shown that 1,25(OH)2D can inhibit the growth and expansion of cancer cells proliferation, induces cancer cell death, and inhibits the transfer from dormant to malignant tumor cells47-50.

Studies have shown that an inverse correlation exists between breast cancer mortality and sun exposure/dietary vitamin D intake. In a recent study, two vitamin D receptor (VDR) gene single nucleotide polymorphisms were associated with breast cancer risk lending support the idea that vitamin D, through its signaling pathway, can affect breast cancer risk51. In clinical studies an impaired vitamin D status is associated with a 20 to 30% increase in breast cancer incidence and a 10 to 20% increase in mortality52. In another study, the association between vitamin D intake and breast cancer risk among women in a large prospective cohort was assessed. This study, known as the Iowa Women’s health study assessed questionnaire results about diet and supplements use in 34,321 postmenopausal women. Subsequently, information regarding breast cancer incidence from 1986 to 2004 was gathered. Adjusted relative risks for breast cancer were calculated for dietary, supplemental and total vitamin D intake among all women. They found that a vitamin D intake of greater than 800 IU per day was associated with a decrease in risk of breast cancer among postmenopausal women53. Individuals with serum 25(OH)D levels of approximately 52 ng/mL (4000 IU vitamin D per day) had a 50% lower risk of breast cancer than those with serum levels less than 13 ng/mL54.

Vitamin D has also been linked to prostate cancer prevention. In a recent study, 14,916 men initially free of diagnosed cancer were re-assessed 18 years later. One thousand and sixty-six men were identified with incident prostate cancer and the relationship between pre-diagnostic plasma levels of 25(OH)D and 1,25(OH)2D with total and aggressive disease was explored. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in 25(OH)D (less than 20 ng/mL) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels (less than 32 ng/mL). Men whose levels for both 25(OH)D and 1,25(OH)2D were below the median level had a significantly increased risk of aggressive prostate cancer55

It has also been proposed that vitamin D provides protection against colon cancer. Genetic variation at the VDR locus, in particular Cdx-2 and FokI SNPs, may influence colon cancer risk56. This hypothesis is strengthened by inspection of the geographic distribution of colon cancer deaths in the USA. Analysis reveals that colon cancer mortality rates are highest in places where populations were exposed to the least amounts of natural light (major cities and rural areas at high latitudes)57.

Finally, vitamin D has also been shown to reduce the risk of ovarian cancer. A north to south gradient in mortality rates of ovarian cancer exists in the USA (after age adjustments). The highest rates of death occur in the Northeast areas and the lowest mortality rates are in the South through Southwest areas of the United States. This lends to the hypothesis that lower levels of solar radiation are associated with a higher risk of ovarian cancer. Indeed, a recent study which looked at the association of solar ultraviolet B and incidence of ovarian cancer in 175 countries found that solar UVB irradiance is inversely associated with incidence rates of ovarian cancer58.

Protection from diabetes
In a recent meta-analysis, done to assess the role of vitamin D in type 2 diabetes, several observational studies showed a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalence of type 2 diabetes or metabolic syndrome. There was also an inverse association with incidence of type 2 diabetes or metabolic syndrome with intake of vitamin D. Regular doses of vitamin D daily early in life have been projected to reduce diabetes incidence by 80% over the next 30 years59 and clinical trials with vitamin D and/or calcium supplementation have suggested that vitamin D and calcium have a role in the prevention of type 2 diabetes in populations at high risk. Vitamin D and calcium insufficiency may negatively influence glycemia, whereas combined supplementation with both nutrients may be beneficial in optimizing glucose metabolism for the prevention of diabetes60. The active metabolite of vitamin D, 1,25-Dihydroxyvitamin D, is a potent immunomodulator that enhances the production and secretion of several hormones, including insulin. Furthermore, glycemic control and insulin resistance are improved when vitamin D deficiency is corrected61. A longitudinal study that began in 1966 administered 2000 IU of vitamin D to children and revealed there was an 80% reduction in the development of type 1 diabetes throughout the following thirty years in those children given vitamin D62. In another study, increasing vitamin D levels from 25 to 75 nmol/l led to a 60% improvement in insulin sensitivity63,64. Finally, low vitamin D levels have been shown to have a negative effect on beta cell function65.

Improved immune system and protection from influenza
Vitamin D plays an important role in the regulation of immune system function and limits the over-production of lymphocytes and the cytokine cascades66. Over activity of T-helper cell mobilization can lead to an attack of the body’s own cells. Vitamin D suppresses T-helper cell over activity, and therefore plays an important role in the prevention of autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, scleroderma and graft rejection67,68. However, perhaps of even greater importance, is vitamin D’s dramatic ability to stimulate the expression of potent anti-microbial peptides. Vitamin D stimulates the anti-microbes which exist in neutrophils, monocytes, natural killer cells and in epithelial cells lining the respiratory system. Thus, vitamin D plays a major role in protecting the lung from infection.

Influenza is one of several respiratory viruses that show a distinct increase in infection during winter months. Influenza in North America and Europe, for example generally reaches epidemic peaks during December to March69. These are the months during which the UVB irradiance and serum levels of 25-hydroxyvitamin D3 are lowest in the population. A recent randomized controlled trial presented evidence that vitamin D provides a dramatic preventative effect against influenza and colds70. In a post-hoc analysis of their original three-year study, it was discovered that 104 post-menopausal African American women given vitamin D were three times less likely to report cold and flu symptoms than 104 placebo controls. A low dose (800 IU per day) reduced reported incidence of cold or flu, and abolished the seasonality of cold and flu reports. A higher dose (2000 IU per day), given during the last year of the trial, eliminated all reports of colds or flu.

Vitamin D has been deemed the "antibiotic vitamin"71 due primarily to its robust effects on innate immunity, the part of the immune system that responds rapidly to microorganisms using a genetically encoded effector that is ready to attack an antigen before the body has ever encountered that particular antigen. Furthermore, vitamin D appears to enhance the local capacity of the epithelium to produce endogenous antibiotics while it dampens parts of the adaptive immune response, like the signs and symptoms of acute inflammation72.

Cardiovascular disease
Vitamin D was shown to inhibit vascular smooth-muscle proliferation, suppress vascular calcification, down-regulate pro-inflammatory cytokines and up-regulate anti-inflammatory cytokines. Vitamin D acts as a negative endocrine regulator of the renin-angiotensin system76 and researchers now believe that vitamin D deficiency could contribute to congestive heart failure77,78.

Calcium and vitamin D supplementation result in a 9.3% decrease in systolic blood pressure, a 5.4% decrease in heart rate79 and substantially reduces C-reactive protein levels in critically ill patients80. The dose necessary to prevent cardiovascular ailments is unknown, but 2000 - 4000 IU of vitamin D3 has been suggested81. Research also suggests that plasma 25[OH]D concentrations are associated with risk of coronary heart disease. In a recent study, men deficient in 25(OH)D were at increased risk for myocardial infarction compared with those considered to be sufficient in 25(OH)D. Low levels of 25(OH)D were associated with a higher risk of myocardial infarction even after controlling for factors known to be associated with coronary artery disease82.

Disorders of the brain and cognition
Vitamin D receptors can be found all throughout the body and are also present in the brain which suggests they are involved in neural behavior. Indeed, a retrospective review of older adults found a positive correlation between score on the mini-mental state examination and serum vitamin D levels which suggests that vitamin D promotes cognitive abilities in the elderly83. In another study vitamin D deficiency was associated with low mood and with impairment on two of four measures of cognitive performance.

Multiple sclerosis
There is evidence of correlation between frequency of multiple sclerosis (MS) lesions, seasonality84,85 and geographic latitude86,87. Studies also suggest that there is a latitude gradient for risk of developing MS. For example, in Australia, the risk of MS in temperate Tasmania is fivefold that of the much sunnier Queensland88,89. Living at a latitude higher than 37 degrees, where there is less UV exposure increases the risk of developing multiple sclerosis by more than 100%.

Studies also suggest that month of birth and risk of MS is clearly associated, more so in familial cases, implying an interaction exists between genes and environment which is related to latitude90. In light of these discoveries, it was hypothesized that vitamin D provides a protective effect and reduces ones risk of MS. Kraght et al., 2008 found that high serum levels of vitamin D decreased the risk of MS91. An inverse relationship exists between serum vitamin D and MS clinical activity92 and high serum levels of vitamin D decrease the relapse rate in MS diseased patients93. Taking a multivitamin with 400 IU of vitamin D is able to reduce the risk of MS by as much as 40%74,75.

The risk of osteoporosis is high in patients with MS and vitamin D supplementation is often recommended in the early stages of the disease94.

Mood and well-being
Vitamin D levels are related to positive mood and well-being and serum concentrations of vitamin D have been shown to be significantly lower in patients with unipolar and bipolar depression95. In a randomized study, eight subjects with seasonal affective disorder received vitamin D supplementation and seven subjects received phototherapy. Vitamin D, but not phototherapy was associated with improvement in depression measures96. Four-hundred and forty-one subjects were given the Beck Depression Inventory (BDI) and scores were related to vitamin D levels. Subjects with serum 25(OH)D levels <40 nmol/l scored significantly higher (more depressive traits) than those with serum 25(OH)D levels > or = 40 nmol/l; vitamin D supplementation for a year significantly improvement depression scores97. Finally, Lansdowne and Provost98 randomized 44 healthy subjects to vitamin D3 supplementation over five days in late winter, and reported that vitamin D3 was associated with improved positive effect, in conjunction with reduced negative effect.

Autism
The research suggesting autism could be linked to vitamin D is not direct but rather is inferred and circumstantial. An increase in autism over the last two decades corresponds with advice to avoid the sun. In rats, severe vitamin D deficiency during gestation leads to abnormalities similar to those found in autism such enlarged ventricles99. Children with rickets (from very low vitamin D) are likely to be hypotonic, display decreased activity, and have developmental motor delays before treatment100. Hypotonia is also common in children with autism101, as is decreased activity102 and developmental motor delays103. Children with vitamin D deficiency have several autistic markers104, autism is more common in areas where the population receives lower doses of UVB105, and autism is more common in dark-skinned persons106.

Chronic pain
A number of studies have suggested a link between low levels of vitamin D and higher incidence of chronic pain107-109. The relationship between latitude/season of the year and pain offer circumstantial evidence that vitamin D could be involved. Vitamin D has been associated with several types of pain: headaches, abdominal pain, knee pain and back pain; but the evidence is not yet entirely convincing110-112. Six selected cases have demonstrated improvement/resolution of chronic back pain after vitamin D repletion in a Canadian family practice setting113.

Grove et al.114 assessed backache in postmenopausal women. When 50,000 IU of the vitamin D metabolite calciferol was administered twice weekly there was a significantly better improvement in ‘pain-mobility score’ compared to placebo. Al Faraj and Al Mutairi115 published a case series that assessed chronic low back pain without obvious cause in 360 people. Vitamin D (5000 10,000 IU per day) led to a disappearance of low back pain in 341 of the 360 participants. Goth et al.116 looked at unusual pain resistant to analgesics but in only five people. Pain was resolved five to seven days after supplementation. Unfortunately there is a striking contrast in treatment effects between randomized, double blind trials and those with open designs making it difficult to conclude whether vitamin D is or is not beneficial to pain.

Asthma
As mentioned, vitamin D is important in host defenses against respiratory tract pathogens and studies suggest that vitamin D deficiency increases the risk of respiratory infections. New research suggests that this increased risk may contribute to incident wheezing and illness and may cause asthma exacerbations in both children and adults. Although unproven, the increased risk of respiratory infection could contribute to some cases of asthma. Vitamin D also modulates regulatory T-cell function and interleukin-10 production. This could increase the therapeutic response to glucocorticoids in steroid-resistant asthma117. Furthermore, Brehm et al 2009118 found that vitamin D insufficiency is frequent in asthmatic children and that lower vitamin D levels are associated with increased markers of allergy and asthma severity.

Obesity and body fat
Several studies have shown adult obesity to be inversely correlated with 25OHD levels119-125 and it has been suggested that adipogenesis may be inhibited by 1,25 dihydroxyvitamin D126. Vitamin D insufficiency is associated with increased body fat and decreased height in 90 adolescents females (age 16-22)127.

Skin health
Vitamin D has been shown to be beneficial in wound healing, atopic dermatitis (AD) and psoriasis. Cathelicidins were among the first families of antimicrobial peptide (AMPs) discovered on the skin. Cathelicidins have direct antimicrobial activity and will initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis128,129. Dysfunction of cathelicidin is relevant in the pathogenesis of several cutaneous diseases and could provide new treatment modalities in the management of infectious and inflammatory skin diseases including atopic dermatitis (where cathelicidin induction is suppressed) and psoriasis, where a cathelicidin peptide can convert self-DNA to a potent stimulus of an autoinflammatory cascade130. Recent work has identified vitamin D as a major factor involved in the regulation of cathelicidin expression131. To follow, when patients with atopic dermatitis were given 4000 IU per day oral vitamin D for 21 days, AD lesional skin showed a statistically significant increase in cathelicidin expression132. Providing further support to vitamin D’s modulation of AD; atopic dermatitis is more common at higher latitudes, places where vitamin D would be diminished133.

Oral vitamin D has also been assessed in psoriasis. When oral calcitriol was given to 85 psoriasis patients; 88% had some improvement in their disease and 26.5,36.2 & 25.3 had complete, moderate and slight improvement in their disease, respectively. The mean baseline psoriasis area severity index score (PASI) was reduced after oral calcitriol therapy134.

Vitamin D3 was evaluated for its actions on dermal wound healing in Wistar rats. Intraperitonial injectons of cholecalciferol at 5, 10, 15 IU/g body weight doses produced increases in wound breaking strength and promoted epithelization135. Furthermore in an in vitro study, 0.5 mM of 1,25(OH)2D3, the active metabolite of vitamin D modulated keratinocyte proliferation & increased wound healing136.  

The optimal dose of vitamin D
The current recommended daily allowance for vitamin D is 200 IU for children and adults under 50 years of age, 400 IU for adults aged 51 to 70 and 600 IU for those older than 70 years137. Recent evidence related to osteoporosis, as presented above, however, suggests that the current RDA is too low to maintain optimal vitamin D status. Vitamin D has a very low degree of toxicity. Hypercalcemia, the main toxic effect does not usually develop until serum 25-OH vitamin D levels are over 500 nmol/l (200 ng/mL) and is more common above 750 nmol/l (300 ng/mL)138. Single doses of vitamin D3 as high as 600 000 IU have been administered without producing hypercalcemia139,140. The current tolerable upper intake level (UL) for vitamin D is 50 mcg/d (2000 IU per day) in North America and Europe141 and in the United Kingdom a guidance level exists for vitamin D of 1000 IU per day142. However sun exposure to the skin safely provides vitamin D in an amount equivalent to an oral dose of 250 mcg/d143-144. Unfortunately, low and inappropriate upper intake values have hindered objective clinical research on vitamin D nutrition and have thus diminished our understanding of its role in disease prevention.

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