Vitamin D deficiency occurs when people do not have an appropriate dietary intake or exposure to UVB rays. It is universally accepted that the circulating level of 25-hydroxyvitamin D should be used as an indicator of vitamin D status due to its ease of measurement, long half-life in circulation (approximately 2 or 3 weeks), and the correlation of its level with clinical disease states 1 11 12 . Although no consensus on an optimal level of 25-hydroxyvitamin D has been reached, vitamin D deficiency is defined by most experts as a level of less than 20 ng per millilitre (50 nmol per litre) 13 14 15 16 . A level of 25-hydroxyvitamin D of 21 to 29 ng per millilitre (52 to 72 nmol per litre) is considered as an insufficiency of vitamin D, and sufficient vitamin D should reach a level of 30 ng per millilitre or greater 17 .

In 1997, the Institute of Medicine of the US National Academy of Sciences recommended new adequate intakes for vitamin D as 200 IU for children and adults up to 50 years of age, 400 IU for adults 51 to 70 years of age, and 600 IU for adults 71 years of age or older 18 . However, a great number of studies revealed that without adequate sun exposure, children and adults require approximately 800 to 1000 IU per day 19 20 21 22 .

Vitamin D intoxication is extremely rare. Studies showed that doses of more than 50,000 IU per day, which raises 25-hydroxyvitamin D to more than 150 ng/ml, is associated with hypercalcemia and hyperphosphatemia 8 9 23 . Even doses of 10,000 IU of vitamin D3 per day for up to 5 months did not cause toxicity 24 . However, patients with chronic granulomatous disorders should be cautious with the dose of vitamin D since macrophage production of 1,25-dihydroxyvitamin D causes hypercalcemia and hyperphosphatemia 8 9 23 .

Several studies showed that 40 to 100% of U.S. and European elderly men and women still living in the community (not nursing homes) are deficient in vitamin D 13 14 15 . It has already become a largely unrecognized global epidemic. Vitamin D inadequacy can be seen in young adults as well as healthy children. For example, 48% of white preadolescent girls in a study in Maine 46 and 52% of Hispanic and black adolescents in a study in Boston are vitamin D deficient 47 . In Europe, where very few foods are fortified with vitamin D, children and adults would appear to be at especially high risk 48 49 50 . A study of middle aged British adults showed that 60% are vitamin D insufficient, and the number rose to 90% during winter and spring 51 .

As UVB exposure is not associated with vitamin D intoxication, the major concern of using UVB to boost vitamin D content is the erythema reaction, which is a result of cell irritation and destruction caused by ultraviolet radiation. In the UVB region, the wavelength range between 290 and 297 nm has the greatest erythema effect on the human body with a steep decrease above 297 nm. Therefore UVB tubes with spectral features of minimal irradiance from 290 to 297 nm should always be chosen to treat vitamin D deficiency.

The duration of exposure determines the dose of UVB one receives. The product of the UVB lamp power output (mW/cm²) and the duration of exposure is UVB radiation (mJ/cm²). Minimal erythema dose (MED) is defined as the minimum amount of UVB radiation that produces redness 24 hours after exposure. It is used when using UVB to treat psoriasis in order to minimize the potential for developing erythema. Therefore the radiation should not be more than one MED for safety considerations when treating vitamin D deficiency. Thus, a limit should be put on exposure time depending on power output.

It should be noted that MED varies with skin type (Table 2) and there are large variations in MED even within the same skin type 56 . According to the U.S. Food and Drug Administration and the American Academy of Dermatology, there are six skin-type categories: skin type I-VI. Generally the darker the skin, the harder it is for the skin to burn, thus the higher the value of MED which results in a longer exposure duration to achieve a certain value of MED.

Approximately 33% of women aged between 60 to 70 and 66% of those over 80 have osteoporosis 13 . The link between vitamin D deficiency and osteoporosis has been well established especially in the elderly. Vitamin D deficiency is associated with the marked suppression in intestinal Ca absorption and the impairment of Ca balance, which results in low bone mineral content and density. Reduced bone mineral density (BMD) increases the risk of fractures, which significantly contributes to morbidity and mortality of older persons 65 66 . Hip fracture is expected to be more prevalent worldwide with the increase in aging of the population, and the consequences are severe: 50% of older persons have permanent functional disabilities, 15% to 25% require long-term nursing home care, and 10% to 20% die within 1 year.

The efficacy of vitamin D as a prevention of fracture has been demonstrated by a number of studies. Trials using 700 to 800 IU/d oral vitamin D with or without calcium supplementation found a significant 26% reduction in risk of sustaining a hip fracture and a significant 23% reduction in risk of sustaining any non-vertebral fracture versus calcium or placebo 67 . Also, a 3-year French study of 3270 elderly women (mean age 84 years) living in care home, where vitamin D deficiency is prevalent, indicates that calcium (1200 mg daily) and vitamin D (800 IU daily) can reduce the probability of hip and all non-vertebral fractures by 43% and 32%, respectively, compared with placebo 68 69 . Conversely, a Dutch study of 2578 healthy elderly women treated with a high calcium intake, daily supplementation with vitamin D 400 IU over 3.5 years showed no effect on the risk of hip fracture 70 . Therefore, whether 400 IU vitamin D is enough to prevent fracture in healthy elderly subjects with normal BMD needs further investigation.

Muscle weakness is also a prominent feature of vitamin D deficiency. Patients with nonspecific muscle weakness, muscle aches and pains have also been found with vitamin D inadequacy 71 72 . Impaired muscle function is known to cause an increased number of falls which can lead to hip fractures. The incidence of falls go up substantially in those older than 70 years of age, and over 90% of hip factures resulted from a fall. It has been established that skeletal muscle tissue contains vitamin D receptor and may require vitamin D to realize maximum function 23 73 .

It has been reported that increased vitamin D levels can improve muscle performance, and thus reduce the incidence of fall. In a 5-month randomized controlled trial, elderly people in a nursing home received 800 IU of vitamin D2 plus calcium daily, exhibited a 72% reduction in the risk of falls as compared with the placebo group 74 . Long-term intake of 700 IU vitamin D plus 500 mg of calcium in 246 community-dwelling older women also showed a beneficial reduction falls: the odds of falling declined by 46% compared with the placebo group 74 . However, the results from one trial suggested that 400 IU vitamin per day may not be clinical effective in preventing falls in the elderly 75 .

Millions of people are affected by hypertension worldwide. Growing evidence in recent years suggests that vitamin D has an important association with blood pressure. Animal experiments implicate 1,25-dihydroxyvitamin D in inhibiting renin expression in the juxtaglomerular apparatus and blocks proliferation of vascular smooth muscle cells (VSMC), which could influence systemic blood pressure 76 77 78 79 . Studies showed that Afro-Americans have a significantly higher prevalence of diastolic hypertension 80 and have lower 25-hydroxyvitamin D levels 81 compared with white Americans.

Reduced blood pressure has been found in people taking oral supplementation of vitamin D. In humans, skin exposure to UVB, which is the major source of vitamin D formation, has been linked with lower blood pressure 82 83 84 . An 8-week single intervention study of 148 vitamin D deficient elderly women demonstrated a 9% decrease in systolic blood pressure with supplemental vitamin D (800 IU) plus calcium (1200 mg) compared with calcium alone 85 . In another study, patients with hypertension were exposed to UVB radiation three times a week for 3 months. Results showed that 25-hydroxyvitamin D levels increased by approximately 180%, and both systolic and diastolic blood pressure reduced by 6 mm Hg 84 . In contrast, a large prospective study of men and women found no association between intake of vitamin D from diet and supplements and hypertension incidents 86 . This difference may be attributed to the fact that the large observational study included subjects from the general public while other studies recruited hypertension patients. Thus the original vitamin D levels could have certain impacts on treatment effect.

Multiple sclerosis (MS) is an autoimmune disease in which the body's immune system attacks myelin, a key substance that serves as a nerve insulator and helps in the transmission of nerve signals. It has been long recognised that MS is more common in temperate climates than the tropics 87 88 , and annual and winter hours of sunlight have been proved to have the strongest negative correlation with the prevalence of MS 89 90 . One explanation is that the increase of vitamin D results from sunlight exerting a protective effect 91 92 93 . Studies also found that individuals with MS tend to have insufficient vitamin D levels 71 94 95 96 97 .

However, only a few reports are available on the use of vitamin D in treating MS patients. One study (6 months) of the cytokine profile in MS patients with vitamin D (1000 IU/day) and calcium (800 mg/day) showed that 25-hydroxyvitamin D significantly increased from 42.5 ± 15 to 70 ± 20 nmol/l. Also vitamin D supplementation significantly increase serum transforming growth factor (TGF)-β1, which has been shown to be an important anti-inflammatory cytokine in animal models of MS 98 . The increased TGF-β1 suggests that vitamin D supplementation could potentially improve the symptoms of MS patients. Nonetheless, more studies are needed to establish vitamin D's efficacy in alleviating MS.

Apart from improving MS patients' health conditions, vitamin D has also been shown to have effects in preventing MS. One study revealed that women who used supplemental vitamin D (> 400 IU/day) had a 40% lower risk of MS than women who did not use vitamin D 99 . Another report among 7 million US military personnel reported that risk of MS decreased with increasing 25-hydroxyvitamin D which provided an evidence of vitamin D's protective role in MS developing 100 .

As explained above, certain conditions cause malabsorption, which results in vitamin D deficiency. Low BMD can be frequently found in these conditions. Thus vitamin D supplementation is required to boost vitamin D sera levels. For example, Cystic fibrosis (CF) patients have inefficient vitamin D absorption due to pancreatic exocrine insufficiency. It is reported that 95% of a treated cohort of CF patients required 1800 IU (45 μg/d or 0.13 mmol) of ergocalciferol (vitamin D2) daily to achieve a 25OHD concentration above 25 ng/ml 101 . Vitamin D deficiency is prevalent in Crohn's Disease (CD). CD is an inflammatory bowel disease which often leads to osteopenia and osteoporosis due to malabsorption of vitamin D. One study conducted on 154 CD patients for 76 days showed that daily calcium (500 mg) and vitamin D (400 IU) supplementation was associated with an increase in bone mineral density 102 .

With the re-arrival of widespread vitamin D deficiency, the re-emergence of rickets, a scourge from the ninetieth century was inevitable. In a recent review, the deficiency rates found in countries where extreme sunlight levels are readily available but people are covered or avoid sunlight and do not have access to vitamin D-fortified foods 23 . Insufficient levels of vitamin D in breastfeeding mothers can, often unknowingly, lead to deficiencies in children. It is suggested that a supplement level of 400IU/d for infants as practiced in Canada is optimal 23 .

The first study indicating that sunlight exposure may lower the risk of cancer was first made almost seven decades ago 103 . Garland and Garland were the first to propose that vitamin D deficiency may contribute to a higher risk of colon cancer mortality since vitamin D is formed in the skin through solar UVB radiation. More recently, the discovery of increased risks of certain types of cancer in those who are vitamin D deficient, suggests that vitamin D deficiency may account for thousands of premature deaths from colon 104 , breast 105 106 , ovarian 107 , and prostate cancer 108 every year.

Vitamin D is one of the most potent hormones for regulating cell growth. It was discovered that many cell types contain vitamin D receptors. These receptors can be activated by 1,25(OH)2 D, and induce differentiation into normally functioning cells, and inhibit proliferation, invasiveness, angiogenesis, and metastatic potential. In tumor models such as cancers of the lung 109 110 111 , colon 112 , kidney 113 , breast 114 , and prostate 115 , vitamin D played a role in activity against metastasis 116 117 118 119 120 .

The protective relationship between sufficient vitamin D status and lower risk of cancer has been found in many studies. It has been reported that breast and colorectal cancer can be reduced by 50% with the concentration of 25-hydroxyvitamin D being >32 ng/mL 121 122 . A similar study of colorectal cancer found that a level of 34 ng/mL 25-hydroxyvitamin D can reduce the incidence by half, and 46 ng/mL can decrease it by two thirds 123 . A 4-year trial on postmenopausal women showed that 1100 IU/day vitamin D plus 1400-1500 mg/day calcium can substantially reduces all-cancer risk 121 .

RA is an autoimmune disorder of unknown etiology in which both genetic and nongenetic factors contribute to disease susceptibility 124 . The immunomodulatory effect of Vitamin D has received increasing attention in recent years. Studies showed that when confronted by an inappropriate and overly exuberant immune response, vitamin D may act in a paracrine manner to decrease T cell responsiveness through the inhibition of cellular proliferation and reduction in lymphokine production 125 126 127 128 . Therefore vitamin D has a beneficial effect as an immunosuppressant.

Vitamin D has shown its ability to suppress the development of autoimmunity in animal experiments. For example, murine models of human RA demonstrated that when treated with active vitamin D, both the incidence and severity of the disease in mice decreased 129 . However the association of vitamin D intake and RA incidence in humans has not been well studied. One study of 30,000 women aged 55 to 69 over 11 years observed an inverse association between greater intake of vitamin D and RA risk 130 . Interestingly, vitamin D from supplements showed a stronger influence in RA development than did dietary vitamin D. However, further studies are needed to establish the effect of vitamin D in the prevention of RA.

A diabetes epidemic has emerged during the 20^th century. The prevalence of diabetes for all age groups was estimated to be 2.8% in 2000, and this number will increase to 4.4% by 2030 131 . It has been reported as early as the 1980 s that vitamin D deficiency inhibits pancreatic secretion and turnover of insulin, resulting in impaired glucose tolerance 132 133 . An association was found between low UVB irradiance, indicating a low level of vitamin D, and high incidence of type 1 diabetes, whereas the incidence rate approached zero in regions with high UVB irradiance 134 135 136 137 .

A study of 83,779 women with no history of diabetes over 2-4 years showed that a combined daily intake of >1200 mg calcium and >800 IU vitamin D was associated with 33% lower risk of type 2 diabetes as compared with a daily intake of less than 600 mg of calcium and less than 400 IU of vitamin D 138 . Another study on 10,366 children in Finland over 31 years indicated that 2000 IU of vitamin D per day during their first year of life can reduce the risk of type 1 diabetes by approximately 80% 139 .

TB is a major global problem and responsible for 2 million deaths a year. It is estimated that one-third of the global population has latent TB infection 140 , which poses great potential risks of reactivation in the future. In fact, before antibiotics came in to use, high doses of vitamin D were widely used to treat active TB 141 . Cross-sectional studies showed that patients with TB have lower 25(OH)D levels in comparison with control subjects 142 143 . Recently, it was found that low vitamin D status resulting from a vegetarian diet is an independent risk factor for active TB in South Asians 144 .

Until now studies evaluating the effect of vitamin D on the body's immunity to mycobacteria, the family of bacteria that cause TB, are scanty. One study measuring 192 healthy adult TB contacts' showed that a single oral dose of 2.5 mg vitamin D significantly enhanced participants' whole blood ability to restrict functional whole blood (BCG-lux) luminescence in vitro 145 . It concluded that vitamin D enhances TB contacts' immunity to mycobacteria. However, the effect of vitamin D supplementation on TB incidence rates among deficient population with high rates of latent TB infection should be investigated to determine vitamin D's prevention effect in TB.