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.

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.

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.

1. Goldberg P, Fleming MC, Picard FH. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med Hypotheses 1986; 21:193-200.

2. Hayes CF, Cantorna MT, DeLuca HF. Vitamin D and multiple sclerosis. Proc Soc Exp Biol Med 1997; 216:21-27.

3. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 1980; 9:227-231.

4. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 2002; 94:1867-1875.

5. Hypponen F, Laara F, Reunanen A, et al. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358:1500-1503.

6.  Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998; 351:805-6.

7. Gloth FM, Gundberg CM, Hollis BW, Haddad HG, Tobin JD. Vitamin D deficiency in homebound elderly persons. JAMA1995; 274:1683-6.

8. Gloth FM, Tobin JD, Sherman SS, Hollis BW. Is the recommended daily allowance for vitamin D too low for the homebound elderly? Jam Geriatr Soc 1991; 39:137- 41.

9. Lips P, Duong T, Oleksik A, et al. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab 2001; 86:1212-21.

10.  Thomas KK, Lloyd-Jones DH, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998; 338:777- 83.

11. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med 2002; 112: 659-662.

12. Sullivan SS, Rosen CJ, Chen TC, Holick MF. Seasonal changes in serum 25(OH)D in adolescent girls in Maine. Proceedings of the American Society for Bone and Mineral Research Annual Meeting. Washington, DC: American Society for Bone and Mineral Research, 2003:S407.

13. Holick MF. Vitamin D deficiency in obesity and health consequences. Curr Opin Endocrinol Diabetes Obes 2006; 13:412-8.

14. Holick MF. Environmental factors that influence the cutaneous production of vitamin D. Am J Clin Nutr 1995; 61: 638S,-645S.

15. Holick MF. Photosynthesis of vitamin D in the skin: effect of environmental and life-style variables. Eed Proc 1987; 46:1876-1882.

16. Holick MF. Vitamin D and bone health. J Nutr 1996; 126:1159S-1164S.

17. Simpson RU, Thomas GA, Arnold AJ. Identification of 1,25-dihydroxyvitamin D3 receptors and activities in muscle. J Biol Chem 1985; 260:8882-8891.

18. Sorenson OH, Lund B, Saltin B, et al. Myopathy in bone loss of ageing: improvement by treating with 1 alpha-hydroxycholecalciferol and calcium. Clin Sci (Lond) 1979; 56:157-161.

19. Sattin RW, Lambert Huber DA, DeVito CA, et al. Risk factors for falls among elderly persons living in the community. N Engl J Med 1988; 319:1701-1707.

20. Rizzo JA, Friedkin R, Williams CS, et al. Healthcare utilization and costs in a Medicare population by fall status. Med Care 1998; 36:1174-1188.

21. Pfeifer M, Begerow B, Minne HW, et al. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res 2000; 15:1113-1118.

22. Bischoff HA, Stahelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res 2003; 18:343-351.

23. Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metab 2001; 86:3618-3628.

24. Dukas L, Bischoff HA, Lindpaintner LS, et al. Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily. J Am Geriatr Soc 2004; 52:230-236.

25. Graafmans WC, Ooms ME, Hofstee HM, et al. Falls in the elderly: a prospective study of risk factors and risk profiles. Am J Epidemiol 1996; 143:1129-1136.

26. Norman AW. Sunlight, season, skin pigmentation, vitamin D, Osteoporos Int 1999; 9: 461-8 and 25-hydroxyvitamin D: integral components of the vitamin

27. Holick MF. Vitamin D. A millennium perspective. J Cell Biochem. 2003; 88: 296-307

28. DeLuca HF. Overview of general physiologic features and 1437-43 functions of vitamin D. Am J Clin Nutr 2004; 80 (6 Suppl.).

29. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004; 79:362-71.

30. Tangpricha V, Koutkia P, Rieke SM, Chen TC, Perez AA, Holick MF. Fortification of orange juice with vitamin D: a novel approach to enhance vitamin D nutritional health. Am J Clin Nutr 2003; 77:1478-83.

31. Welsh J, Wietzke JA, Zinser GM, Byrne B, Smith K, Narvaez CJ. Vitamin D-3 receptor as a target for breast cancer prevention. J Nutr 2003; 133:2425-33S.

32. Trang HM, Cole DE, Rubin LA, Pierratos A, Siu S, Vieth R. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr 1998; 68:854-8.

33. Colston KW, Hansen CM. Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer. Endocr Relat Cancer 2002; 9:45-59.

34. Pawley N, Bishop NJ. Prenatal and infant predictors of bone health: the influence of vitamin D. Am J Clin Nutr 2004; 80:1748S-1751S.

35. Fuller KF. Low birth-weight infants: the continuing ethnic disparity and the interaction of biology and environment. Ethn Dis 2000; 10:432-445.

36. Bischoff-Ferrari HA, Conzelmann M, Dick W, et al. Effect of vitamin D on muscle strength and relevance in regard to osteoporosis prevention. Z Rheumatol 2003; 62:518-521.

37. Eriksen EF, Glerup H. Vitamin D deficiency and aging: implications for general health and osteoporosis. Biogerontology 2002; 3:73-77.

38. Holick MF. Vitamin D deficiency: what a pain it is. Mayo Clin Proc 2003; 78:1457-1459.

39. Holick MF. McCollum Award Lecture, 1994: vitamin D: new horizons for the 21st century. Am J Clin Nutr 1994; 60:619-30.

40. Brown EM, Pollak M, Seidman CE, et al. Calcium-ion-sensing cell surface receptors. N Engl J Med I995; 333:234-24O.

41. Hollick, MF. Vitamin D: Important for Prevention of Osteoporosis, Cardiovascular Heart Disease, Type 1 Diabetes, Autoimmune Diseases, and Some Cancers. Southern Medical Journal; 2005 9: 1024-1027.

42. Adami S, Giannini S, Bianchi G, Sinigaglia L, Di Munno O, Fiore CE, Minisola S, Rossini M. Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int. 2009 Feb;20(2):239-44.

43. Garland FC, Garland CF, Gorham ED, Young JR. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 1990; 19:614-622.

44. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation. Cancer 1992; 70: 2861-2869.

45. Lefkowitz ES, Garland CF Sunlight, vitamin D, and ovarian cancer mortality rates in US women. Int J Epidemiol 1994; 23:1133-1136.

46. Freedman DM, Dosemeci M, McGlynn K. Sunlight and mortality from breast, ovarian, colon, prostate, and non-melanoma skin cancer: a composite death certificate based case-control study. Occup Environ Med. 2002; 50:257-262.

47. Welsh J. Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr 2004; 80:1721- 4S.

48. Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Canfield AE. 1a,25- Dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res 2000; 87:214-20.

49. Colston KW, Berger U, Coombes RC. Possible role for vitamin D in controlling breast cancer cell proliferation. Lancet 1989; 1:188- 91.

50. Saez S, Falette N, Guillot C, Meggouh F, Lefebvre MF, Crepin M. William L. McGuire Memorial Symposium. 1,25(OH)2D3 modulation of mammary tumor cell growth in vitro and in vivo. Breast Cancer Res Treat 1993; 27: 69 – 81.

51. Sinotte M, Rousseau F, Ayotte P, Dewailly E, Diorio C, Giguère Y, Bérubé S, Brisson J. Vitamin D receptor polymorphisms (FokI, BsmI) and breast cancer risk: association replication in two case-control studies within French Canadian population. Cancer. 2008 Dec;15(4):975-983.

52. Nielsen L.R. and Mosekilde L. Vitamin D and breast cancer. Ugeskr. Laeg. 2007 169:14 (1299-1302).

53. Vitamin D intake and breast cancer risk in postmenopausal women: The Iowa Women's Health Study Robien K., Cutler G.J. and Lazovich D. Cancer Causes and Control 2007 18:7 (775-782).

54. Garland C.F., Gorham E.D., Mohr S.B., Grant W.B., Giovannucci E.L., Lipkin M., Newmark H., Holick M.F. and Garland F.C. Vitamin D and prevention of breast cancer: Pooled analysis. Journal of Steroid Biochemistry and Molecular Biology 2007 103:3-5 (708-711).

55. Li H., Stampfer M.J., Hollis J.B., Mucci L.A., Gaziano J.M., Hunter D., Giovannucci E.L. and Ma J A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS Med. 2007 4:3 (e103).

56. Ochs-Balcom HM, Cicek MS, Thompson CL, Tucker TC, Elston RC, J Plummer S, Casey G, Li L Association of vitamin D receptor gene variants, adiposity and colon cancer. Carcinogenesis. 2008 Sep;29(9):1788-93.

57. Do sunlight and vitamin D reduce the likelihood of colon cancer? Garland C.F. and Garland F.C. International Journal of Epidemiology 2006 35:2 (217-220).

58. Garland C.F., Mohr S.B., Gorham E.D., Grant W.B. and Garland F.C. Role of Ultraviolet B Irradiance and Vitamin D in Prevention of Ovarian Cancer. American Journal of Preventive Medicine 2006 31:6 (512-514)

59. Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500-3.

60. Anastassios G. Pittas, Joseph Lau, Frank B. Hu, and Bess Dawson-Hughes REVIEW: The Role of Vitamin D and Calcium in Type 2 Diabetes. A Systematic Review and Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism 92(6):2017–2029.

61. Holick MF. Diabetes and the vitamin d connection Curr Diab Rep. 2008;8:393-8

62. Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358(9292):1500-3.

63. Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004; 79(5):820-5.

64. Norman AW, Frankel JB, Heldt AM, Grodsky GM. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science 1980; 209:823-5.

65. Luong K, Nguyen LT, Nguyen DN. The role of vitamin D in protecting type 1 diabetes mellitus. Diabetes Metab Res Rev 2005; 21:338-46.

66. DeLuca, H.F. and Cantorna, M.T. Vitamin D: its role and uses in immunology. FASEB J. 2001; 15: 2579-2585.

67. Lemire, J. 1,25-Dihydroxyvitamin D3-a hormone with immunomodulatory properties. Z. Rheumatol. 2000; 59 (Suppl 1): 24–27.

68. Hein, G. and Oelzner, P. Vitamin D metabolites in rheumatoid arthritis: findings – hypotheses – consequences. Z. Rheumatol. 2000; 59(Suppl 1), 28-32.

69. Cannell JJ, Vieth R, Umhau JC et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006; 134: 1129-40.

70. Aloia JF, et al. A randomized controlled trial of vitamin D3 supplementation in African American women. Archives of Internal Medicine 2005; 165: 1618–1623.

71. Zasloff M: Inducing endogenous antimicrobial peptides to battle infections. Proc Natl Acad Sci USA 2006, 103:8913-4.

72. Schauber J, Dorschner RA, Coda AB, Büchau AS, Liu PT, Kiken D, Helfrich YR, Kang S, Elalieh HZ, Steinmeyer A, Zügel U, Bikle DD, Modlin RL, Gallo RL: Injury Enhances TLR2 Function and Antimicrobial Peptide Expression Through a Vitamin D Dependent Mechanism. J Clin Invest 2007, 117:803-811.

73. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis. Arthritis Rheum 2004; 50:72–7.

74. Munger KL, Zhang SM, O’Reilly E, Hernan MA, Olek MJ, Willett WC, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004; 62:60-5.

75. Ponsonby AL, Lucas RM, van der Mei IA. UVR, vitamin D and three autoimmune diseases—multiple sclerosis, type 1 diabetes, rheumatoid arthritis. Photochem Photobiol 2005; 81:1267-75.

76. Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr 2005; 94:483-92.

77. Zittermann A, Schleithoff SS, Tenderich G, Berthold HK, Korfer R, Stehle P. Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol 2003; 41:105-12.

78. Vieth R, Kimball S. Vitamin D in congestive heart failure. Am J Clin Nutr 2006; 83:731-2.

79. Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab 2001; 86:1633-7.

80. Van den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq L, Bouillon R. Bone turnover in prolonged critical illness: effect of vitamin D. J Clin Endocrinol Metab 2003; 88:4623-32.

81. Zittermann A, Schleithoff SS, Koerfer R. Vitamin D insufficiency in congestive heart failure: why and what to do about it? Heart Fail Rev 2006; 11:25-33.

82. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-Hydroxyvitamin D and Risk of Myocardial Infarction in MenArch Intern Med. 2008; 168:1174-1180.

83. Przybelski RJ and Binkley NC. Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Archives of Biochemistry and Biophysics. 2007; 460: 202–205.

84. Embry, A.F., Snowden, L.R., and Vieth, R. Vit-D and seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann. Neurol. 2000; 48: 271–272.

85. Auer, D.P., Schmann, E.M., Kumpfel, T., Gossl, C., and Trenkwalder, C. Seasonal fluctuations of gondolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann. Neurol. 2000; 47: 276–277.

86. Kurtzke, J.F. Geography in multiple sclerosis. J. Neurol. 1977; 215: 1–26.

87. Hernan, M.A., Olek, M.J., and Ascherio, A. Geographic variation of MS incidence in two prospective studies of US women. Neurology 1999; 53:1711–1718.

88. McLeod, J.G., Hammond, S.R., and Hallpike, J.F. Epidemiology of multiple sclerosis in Australia. With NSW and SA survey results. Med. J. Aust. 1994; 160: 117–122.

89. Kragt et al Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women. Mult Scler. 2008 August.

90. Soilu-Häet al. A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis. J. Neurol. Neurosurg. Psychiatr. 2008; 79:152-157.

91. Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts R. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis Mult Scler. 2008 Jul 24. [Epub ahead of print].

92. Willer, C.J., Dyment, D.A., Sadovnick, A.D., Rothwell, P.M., Murray, J., Ebers, G.C., and the Canadian Collaborative Study Group. Timing of birth and risk of multiple sclerosis: population based study. BMJ 2005; 330: 120.

93. Schwarze, S. and Leweling, H. Multiple sclerosis and nutrition. Mult. Scler. 2005; 11: 24–32.

94. Garcion, E., Sindji, L., Nataf, S., Brachet, P., Darcy, F., and Montero-Menei, C.N. Treatment of experimental autoimmune encephalomyelitis in rat by 1,25-dihydroxyvitamin D3 leads to early effects within the central nervous system. Acta Neuropathol. (Berl.) 2003; 105: 438–448.

95. Pasco JA, Henry MJ, Nicholson GC, Sanders KM, Kotowicz MA. Vitamin D status of women in the Geelong osteoporosis study: association with diet and casual exposure to sunlight. Med J Aust 2001; 175(8):401–5.

96. Gloth 3rd FM, Alam W, Hollis B. Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder. J Nutr Health Aging 1999; 3(1):5–7.

97. Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K.Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. 2008;264:599-609.

98. Lansdowne AT, Provost SC. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology (Berl) 1998; 135(4):319–23.

99. Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F. Vitamin D3 and brain development. Neuroscience 2003;118(3):641–53.

100. Pettifor JM. Vitamin D deficiency and nutritional rickets in children. In: Feldman D, Pike JW, Glorieux FH, editors. Vitamin D. San Diego: Elsevier; 2005.

101. Ming X, Brimacombe M, Wagner GC. Prevalence of motor impairment in autism spectrum disorders. Brain Dev 2007 Apr 27; [Epub ahead of print].

102. Zwaigenbaum L, Bryson S, Rogers T, Roberts W, Brian J, Szatmari P. Behavioral manifestations of autism in the first year of life. Int J Dev Neurosci 2005;23(2–3):143–52.

103. Provost B, Lopez BR, Heimerl S. A comparison of motor delays in young children: autism spectrum disorder, developmental delay, and developmental concerns. J Autism Dev Disord 2007;37(2):321–8.

104. Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders–autism and developmental disabilities monitoring network, 14 sites, United States, 2002. MMWR Surveill Summ 2007;56:12–28.

105. Croen LA, Grether JK, Hoogstrate J, Selvin S. The changing prevalence of autism in California. J Autism Dev Disord 2002;32(3):207–15.

106. Gillberg C, Schaumann H, Gillberg IC. Autism in immigrants: children born in Sweden to mothers born in Uganda. J Intellect Disabil Res 1995;39(Pt 2):141–4.

107. Atherton K, Berry DJ, Parsons T, Macfarlane GJ, Power C, Hypponen E. Vitamin D and chronic widespread pain in a white middle-aged British population: evidence from a cross-sectional population survey. Ann Rheum Dis 2008 Aug 12. [Epub ahead of print].

108. Benson J, Wilson A, Stocks N, Moulding N. Muscle pain as an indicator of vitamin D deficiency in an urban Australian Aboriginal population. Med J Aust 2006;185:76–7. 2003;78:1463–70.

109. Lotfi A, Abdel-Nasser AM, Hamdy A, Omran AA, El-Rehany MA. Hypovitaminosis D in female patients with chronic low back pain. Clin Rheumatol 2007;26:1895–901.

110. Mitsikostas DD, Tsaklakidou D, Athanasiadis N, Thomas A. The prevalence of headache in Greece. Correlations to latitude and climatological factors. Headache 1996;36:168–73.

111. Saps M, Blank C, Khan S, Seshadri R, Marshall B, Bass L, et al. Seasonal variation in the presentation of abdominal pain. J Pediatr Gastroenterol Nutr 2008;46:279–84.

112. Zeng QY, Chen R, Xiao ZY, Huang SB, Liu Y, Xu JC, et al. Low prevalence of knee and back pain in southeast China; the Shantou COPCORD study. J Rheumatol 2004;31:2439–43.

113. Schwalfenberg G. Improvement of chronic back pain or failed back surgery with vitamin d repletion: a case series. J Am Board Fam Med. 2009;22:69-74.

114. Grove O, Halver B. Relief of osteoporotic backache with fluoride, calcium, and calciferol. Acta Med Scand 1981;209:469–71.

115. Al Faraj S, Al Mutairi K. Vitamin D deficiency and chronic low back pain in Saudi Arabia. Spine 2003;28:177–9.1994;27:209–17.

116. Gloth 3rd FM, Lindsay JM, Zelesnick LB, Greenough 3rd WB. Can vitamin D deficiency produce an unusual pain syndrome? Arch Intern Med 1991;151:1662–4.

117. Ginde AA, Mansbach JM, Camargo CA Jr. Vitamin D, respiratory infections, and asthma. Curr Allergy Asthma Rep. 2009;9:81-7.

118. Brehm JM, Celedon JC, Soto-Quiros ME, Avila L, Hunninghake GM, Forno E, Laskey D, Sylvia JS, Hollis BW, Weiss ST, Litonjua AA. Serum Vitamin D Levels and Markers of Severity of Childhood Asthma in Costa Rica. Am J Respir Crit Care Med. 2009 Jan 29. [Epub ahead of print]

119. Compston JE, Vedi S, Ledger JE, Webb A, Gazet JC, Pilkington TR 1981 Vitamin D status and bone histomorphometry in gross obesity. Am J Clin Nutr 34:2359 –2363 .

120. Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S 1985 Evidence for alteration of the vitamin D-endocrine system in obese subjects. J Clin Invest 76:370 –373.

121. Arunabh S, Pollack S, Yeh J, Aloia JF 2003 Body fat content and 25-hydroxy vitamin D levels in healthy women. J Clin Endocrinol Metab 88:157–161.

122. Parikh SJ, Edelman M, Uwaifo GI, Freedman RJ, Semega-Janneh M, Reynolds J, Yanovski JA 2004 The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab 89:1196 –1199.

123.  Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF 2000 Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 72:690 – 693.

124. 25. Kamycheva E, Joakimsen RM, Jorde R 2003 Intakes of calcium and vitamin d predict body mass index in the population of Northern Norway. J Nutr 133:102–106.

125. Buffington C, Walker B, Cowan Jr GS, Scruggs D 1993 Vitamin D deficiency in the morbidly obese. Obes Surg 3:421– 424.

126. Kong J, Li YC 2006 Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells. Am J Physiol Endocrinol Metab 290: E916 –E924.

127. Kremer R, Campbell PP, Reinhardt T, Gilsanz V.Vitamin d status and its relationship to body fat, final height, and peak bone mass in young women. J Clin Endocrinol Metab. 2009;94:67-73.

128. Braff M H, Bardan A, Nizet V, Gallo R L. Cutaneous defense mechanisms by antimicrobial peptides. J Invest Dermatol 2005: 125: 9–13.

129. Schauber J, Gallo R L. Expanding the roles of antimicrobial peptides in skin: alarming and arming keratinocytes. J Invest Dermatol 2007: 127: 510–512.

130. Ong P Y, Ohtake T, Brandt C et al. Endogenous antimicrobial pep- tides and skin infections in atopic dermatitis. N Engl J Med 2002: 347: 1151–1160.

131. Wang T-T, Nestel F, Bourdeau V et al. Cutting edge: 1,25-di- hydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004: 173: 2909–2912.

132. Hata TR, Kotol P, Jackson M, Nguyen M, Paik A, Udall D, Kanada K, Yamasaki K, Alexandrescu D, Gallo RL Administration of oral vitamin D induces cathelicidin production in atopic individuals. J Allergy Clin Immunol. 2008 Oct;122(4):829-31.

133. Weiland SK, Hu¨ sing A, Strachan DP et al. Climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children. Occup Environ Med 2004; 61:609–15.

134. Perez A, Raab R, Chkn TC, Turner A & Holick MF. Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis. British journal of dermatology 1996-.: 134: 107(1-11)78.

135. Ramesh et al. A new role for vitamin D: cholecalciferol promotes dermal wound strength and reepithelization. Indian J Exp Biol. 1993;31:778-9.

136. Gamady A, Koren R, Ron D, Liberman UA, Ravid A. Vitamin D enhances mitogenesis mediated by keratinocyte growth factor receptor in keratinocytes. J Cell Biochem. 2003 Jun 1;89(3):440-9.

137. National Academy of Sciences, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes: for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press 1997; 38–144.

138. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999; 69:842–856.

139. Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am J Clin Nutr 2001; 73:288-294.

140. Heaney RP, Davies KM, Chen TC, et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003; 77:204-210.

141. Food and Nutrition Board and National Research Council. Recommended dietary allowances. 7th ed. Washington, DC: National Academy Press; 1968.

142. Expert Group on Vitamins and Minerals. Safe upper levels for vitamins and minerals. Great Britain: Food Standards Agency; 2003.

143. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999; 69:842–56.

144. Barger-Lux MJ, Heaney RP. Effects of above average summer sun exposure on serum 25-hydroxyvitamin d and calcium absorption. J Clin Endocrinol Metab. 2002; 87:4952-6.