Published April 20, 2011 Hospital/Health System Vitamin D, the “Sunshine” Vitamin Manouchehr Saljoughian, PharmD, PhD Department of Pharmacy Services Alta Bates Summit Medical Center Berkeley, California US Pharm. 2011;36(4):HS-28-HS-32. The major role of vitamin D (calciferol) is to help the body absorb calcium and maintain bone density to prevent osteoporosis. But recent reports suggest new roles for this vitamin in protecting against certain chronic diseases such as diabetes, cardiovascular disease, cancer, and autoimmune disorders. This vitamin is available in two forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Ergocalciferol has a shorter shelf life compared to cholecalciferol and loses its potency faster.1 Vitamin D2 is manufactured by plants or fungus, and it can be acquired through fortified foods such as juices, milk, and cereals. Vitamin D3 is formed when the body is exposed to sunlight. This occurs mainly through the exposure of the skin to the sun's ultraviolet A (UVA) and ultraviolet B (UVB) rays. Vitamin D3 can also be obtained by consuming animal products. The biologically active form of vitamin D or calcitriol (Rocaltrol) is used to treat and prevent low levels of calcium in the blood of patients whose kidneys or parathyroid glands are not working normally.2 Recently, there has been extensive research and concern about the level of vitamin D in United States citizens. This stems from increasing reports of vitamin D deficiency and the fact that an estimated 10 million Americans over age 50 years are diagnosed with osteoporosis.3 This is because vitamin D is not abundant in our usual food sources, so we get most of the vitamin from sun exposure and taking multivitamins. The problem is that the sun is not a reliable source for everyone.3 Many factors, such as the season, time of day, geography, latitude, level of air pollution, color of skin, and age, may decrease the skin's ability to produce enough vitamin D. Further, the form of vitamin D found in most multivitamins is vitamin D2, which does not deliver the same amount of the vitamin to the body as the more desirable D3 form. In this short review, we look into the benefits of this vitamin, the issues that cause vitamin D deficiency, and how to resolve these problems.3 Vitamin D Sources Vitamin D is the only vitamin that also has hormonal properties. After vitamin D (D3) is made by the skin or acquired through food or supplements, the kidney and liver change it into a hormone. As a hormone, it controls calcium absorption to help the body build strong bones and teeth and maintain muscle strength. Vitamin D and calcium deficiency results in the breakdown of bones' ability to supply calcium to the rest of the body. This impacts the skeletal structure and results in bone loss. In addition, it has been revealed that vitamin D deficiency is linked to poor muscle strength and other chronic conditions, such as cardiovascular disease and some forms of cancer.4 Many people living in the southeastern U.S. can get enough vitamin D by taking about 10 to 15 minutes of sun exposure on their arms and face a few times a week--as long as they do not use sunscreen. Sunscreens block some of the UV rays necessary to make the vitamin. It is therefore important to remember that not all sun exposure is the same, and that many factors help determine how much sun we absorb. In general, the farther away we are from the equator, the less efficient the vitamin D production is. Dark-skinned people have low levels of vitamin D. Dark pigment in the skin reduces the skin's ability to synthesize vitamin D from sunlight. As a result, darker-skinned people need 5 to 10 times as much sun exposure to synthesize the same amount of vitamin D as lighterskinned people. Sensible sun exposure to arms and legs for short periods of time will not increase the risk of serious skin cancer such as melanoma.5 Vitamin D Requirements Until 1997, the recommended intake of vitamin D was 200 IU (international units) for those up to age 50 years; 400 IU for people 51-70; and 600 IU for those older than 70. Requirements increase with age because older skin produces less vitamin D. Additional reports have been published since that time documenting the effectiveness of higher levels of vitamin D.6 According to the Institute of Medicine Dietary Reference Intakes, the safe upper limit for vitamin D is 2,000 IU for children, adults, and pregnant and lactating women. Some experts have suggested increasing the recommended amount to more than 2,000 IU (up to 5,000 IU) daily. However, since vitamin D is a fat-soluble vitamin that is stored in the body, there is some concern it can be harmful in large doses. Each 10,000 IU of vitamin D equals 250 mcg (or 1 mcg vitamin D = 40 IU). Taking a daily vitamin D3 supplement of 1,000 IU or obtaining safe amounts of sun exposure to maintain proper blood levels of vitamin D may reduce the risk of many chronic diseases. Good dietary sources are milk, yogurt, margarines, cereals, catfish, sardines, salmon, tuna, and egg yolks. It is difficult to get enough vitamin D through the diet unless a person enjoys dairy products and fish. It makes sense to try to limit one's exposure to sunlight if a daily vitamin D supplement is taken. It is unlikely one will get too much vitamin D in the diet unless an overdose of cod liver oil is ingested.6,7 Although it is believed that the current “normal” range for vitamin D is 20 to 55 ng/mL of blood, this level is much too low. It may be sufficient to prevent rickets or osteomalacia, but it is not adequate for optimal health. The ideal range for optimal health is 50 to 80 ng/mL.7 It is believed that vitamin D overdose may lead to calcification of soft tissues in the body; therefore, it is best that the vitamin D dose to be individualized based on blood-test results. Chemistry Vitamin D is a generic term and indicates a molecule with a steroidal structure that has four rings of A, B, C, and D with differing side chain structures (FIGURE 1). The A, B, C, and D ring structure is derived from the parent compound cholesterol. Technically, vitamin D is classified as a secosteroid. Seco-steroids are those in which one of the rings has been broken; in vitamin D, the 9,10 carbon-carbon bond of ring B is broken. Asymmetric centers are designated by using the R, S notation; the configuration of the double bonds is notated E for trans and Z for cis. Thus, the chemical name of vitamin D2 is 9,10-seco(5Z,7E)-5,7,10(19)cholestatriene-3-beta-ol, and the official name of vitamin D3 is 9,10-seco(5Z,7E)-5,7,10(19), 22-ergostatetraene-3-beta-ol. Vitamin D3 can be produced photochemically by the action of sunlight or UV light from the precursor sterol 7-dehydrocholesterol, which is present in the skin of most higher animals. The conjugated double-bond system in the molecule allows the absorption of light at certain wavelengths in the UV range; this can readily be provided in most geographical locations by natural sunlight (or UVB). Absorption initiates a complex series of transformations that ultimately result in the appearance of vitamin D3. Thus, it is important to appreciate that vitamin D3 can be endogenously produced and that as long as the animal (or human) has access on a regular basis to sunlight, there is no dietary requirement for this vitamin.8 Mode of Action Vitamin D or calciferol is converted to the biologically active form of vitamin D or calcitriol in the kidneys before it is released into the circulation. Calcitriol is transferred to many different organs by binding to vitamin D-binding protein, a carrier protein in the plasma. Calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of most cells. The binding of calcitriol to the VDR allows the VDR to modulate the gene expression of transport proteins, which are involved in calcium/phosphorus absorption in the intestine. The vitamin D receptor is expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breasts. Activation of the vitamin D receptor in the intestinal, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood and to the maintenance of bone content. Vitamin D is involved in a number of other biological processes. It increases expression of the tyrosine hydroxylase gene in adrenal medullary cells. Vitamin D is also involved in the biosynthesis of neurotrophic factors, the synthesis of nitric oxide synthase, and the increase in the glutathione level (endogenous antioxidant). In addition, Vitamin D affects the immune system, and VDRs are expressed in several white blood cells, including monocytes and activated T and B cells.9 Vitamin D Deficiency and Supplementation Vitamin D deficiency results in impaired bone mineralization and leads to bone-softening diseases such as rickets and osteomalacia. Rickets is caused by vitamin D deficiency and either calcium or phosphorus deficiency as well, and it results in impaired growth and deformity of the long bones. The dietary risk factors for rickets include abstaining from animal foods. Vitamin D deficiency remains the chief cause of rickets among young infants in most countries. An increase in the proportion of animal protein in the 20th-century American diet coupled with increased consumption of milk fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases. Osteomalacia, or adult rickets, is a bone-thinning disorder characterized by proximal muscle weakness and bone fragility. Osteomalacia is believed to contribute to chronic musculoskeletal pain, but there is no persuasive evidence of lower vitamin D status in chronic pain sufferers. Recent observational studies indicate that low levels of vitamin D are associated with peripheral vascular disease, certain cancers, multiple sclerosis, rheumatoid arthritis, juvenile diabetes, Parkinson's disease, and Alzheimer's disease. It is not yet clear, however, that vitamin D supplementation will reduce the risks of these diseases.9 Populations who may be at a high risk for vitamin D deficiencies include the elderly, obese individuals, exclusively breastfed infants, and those who have limited sun exposure. Individuals who have fat malabsorption syndromes (e.g., cystic fibrosis) or inflammatory bowel disease (e.g., Crohn's disease) are at risk too. Are Tanning Beds a Substitute for Sunshine? There is limited documentation that certain indoor tanning lamps effectively produce vitamin D, and the diversity of such devices has not been extensively surveyed. As a result, indoor tanning is not an advisable source of vitamin D3. The reason lies in the characteristics of UV light rays and how they affect the body. Both the sun and tanning beds emit two types of UV light rays, UVA and UVB. The skin absorbs both types, but in different ways. UVA rays have longer wavelengths that penetrate into the deepest layers of the skin, whereas UVB-ray wavelengths are short and only reach the surface layers of skin. Both types of rays contribute to the health risks associated with excessive sun exposure. However, UVB rays also trigger the synthesis of the vitamin D precursor in the skin, and thus are solely responsible for the healthy benefits of sunshine. Because overexposure to UVB rays quickly causes sunburn, tanning salons are also interested in UVA rays to generate a golden brown skin. As a result, most tanning salons calibrate their tanning beds to emit mainly UVA rays. Generally, 15 to 20 minutes of sunshine a day, several times per week, provides sufficient UVB absorption for most people to optimize their vitamin D levels. Anyone unsure of the amount of sunshine needed can get his/her vitamin D levels tested (25 [OH] D test) and consider supplementing vitamin D3 intake. Although it is claimed that vitamin D can be made by UVB exposure from indoor tanning units, the results are comparably variable. Indoor tanning offers some advantages, such as privacy; environmental conditions for practical full body exposure, which lowers the requisite exposure per skin surface area; and device timers, which limit the potential of overexposure. Nevertheless, guidance and precautionary measures for optimal use of tanning sources for vitamin D benefits are required.10 REFERENCES 1. Bell TD, Demay MB, Burnett-Bowie SA. The biology and pathology of vitamin D control in bone. J Cell Biochem. 2010;111(1):7-13. 2. Bouillon, R. Genetic and environmental determinants of vitamin D status. Lancet. 2010;376:148-149. 3. Schoenmakers I, Goldberg GR, Prentice A. Abundant sunshine and vitamin D deficiency. Br J Nutr. 2008;99(6):1171-1173. 4. Ingraham BA, Bragdon B, Nohe A. Molecular basis of the potential of vitamin D to prevent cancer. Curr Med Res Opin. 2008;24(1):139-149. 5. Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab. 2010;95(2):471-478. 6. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152(5):315-323. 7. Lips P. Worldwide status of vitamin D nutrition. J Steroid Biochem Mol Biol. 2010;121(1-2):297-300. 8. Zhu G-D, Okamura WH. Synthesis of vitamin D (calciferol). Chem Rev. 1995;95:1877-1952. 9. Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health: a review. Altern Med Rev. 2005;10(2):94-111. 10. Sayre RM , Dowdy JC, Shepherd JG. Variability of pre-vitamin D3 effectiveness of UV appliances for skin tanning. J Steroid Biochem Mol Biol. 2010;121:331-333. To comment on this article, contact rdavidson@uspharmacist.com.