Vitamin D: Benefits and Recent Changes in Dietary Recommendations

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1 Vitamin D: Benefits and Recent Changes in Dietary Recommendations Sandra Hrometz, RPh, PhD and Laura Tietz, PharmD This knowledge-based activity is targeted for all pharmacists and is acceptable for 1.0 hour (0.1 CEU) of continuing education credit. This course requires completion of the program evaluation and at least a 70 percent grade on the program assessment questions. ACPE Universal Activity Number H01-P Objectives Upon completion of this CE article, the reader will be able to: 1. Identify environmental and dietary sources of vitamin D 2. Recognize risk factors for vitamin D deficiency 3. Describe the physiologic roles of vitamin D 4. Initiate an appropriate vitamin D supplementation regimen based on current recommendations 5. Discuss the importance of carefully scrutinizing claims of vitamin D benefits Introduction Research within the past decade has shown that the physiological roles of vitamin D go beyond calcium homeostasis, skeletal development and bone metabolism. The discovery of vitamin D receptors and 1α-hydroxylase on a variety of extraskeletal tissues has prompted research on the effects of vitamin D on multiple physiological systems and processes. Vitamin D deficiency is widely known to be directly associated with skeletal diseases such as osteoporosis and rickets. However, vitamin D deficiency has also been linked to diabetes, cardiovascular disease, cognitive decline, and certain cancers. Due to the increasing prevalence and emerging evidence of consequences of vitamin D deficiency, it is becoming an important health concern. In the past two years, the recommended daily allowance (RDA) for vitamin D has been increased twice for infants, toddlers, adolescents, and adults. (1,2) Physiological Roles of Vitamin D Vitamin D synthesis involves multiple steps and is tightly regulated by negative feedback mechanisms. Vitamin D synthesis begins when ultraviolet B (UVB) rays convert 7-dehydrocholesterol (provitamin D 3 ) in the skin to vitamin D 3. Vitamin D 3 is also known as cholecalciferol. Cholecalciferol is converted to calcifidiol (also referred to as 25-hydroxycholecalciferol, 25(OH)D or 25-hydroxyvitamin D) in the liver by the enzyme 25-hydroxylase. Calcifidiol is transported to the kidney where it is converted to calcitriol (also referred to as 1,25 dihydroxycholecalciferol, 1,25-dihydroxyvitamin D, or 1,25(OH) 2 D) by the enzyme 1α-hydroxylase. Conversion of calcifidiol to calcitriol is tightly regulated by serum levels of calcium, phosphorus and parathyroid hormone (PTH). 25(OH)D, or calcifidiol, is the main circulating form of vitamin D and is used to determine vitamin D status due to its circulation half-life of two to three week. (3) However, calcitriol, or 1,25(OH) 2 D, is the most biologically active form of vitamin D. 1

2 Vitamin D increases plasma calcium levels via action on the small intestine, kidneys, and bone. In the presence of vitamin D, calcium (and phosphate) absorption is enhanced in the small intestine via transepithelial transport. (3,4) while renal excretion is decreased. (4) It is reported that when vitamin D is present, the body is able to absorb 30-40% of calcium and 80% of phosphorus ingested. (5) In a vitamin D deficient state, only 10-15% of dietary calcium and 60% of phosphorus is absorbed. (3) In bone, vitamin D has a paradoxical role in that it is capable of both enhancing and decreasing bone integrity, depending on the clinical situation. By enhancing oral calcium absorption and decreasing renal calcium excretion, vitamin D plays an important role in maintaining serum calcium and phosphorus for normal bone growth and mineralization. However, in situations of hypocalcemia, vitamin D has a protective role to maintain normal plasma calcium levels by stimulating bone resorption (break down). Lesser known actions of vitamin D include stimulation of insulin secretion and antiproliferative effects. These are some of the actions that have received recent attention in the medical community. Vitamin D Requirements Although there are no guidelines that clearly define appropriate plasma vitamin D levels, general consensus holds that an optimal range is one where PTH levels are minimized and calcium absorption is maximized. (6) Until 2010, separate agencies were determining the RDA for vitamin D in adults and children. This changed when the Institute of Medicine (IOM) published its report on the dietary reference intakes for calcium and vitamin D, as well as safe maximal doses for all age groups. (7) This report was based upon review of over 1000 studies and seems to be a consensus of multiple opinions that further increases in the RDA for vitamin D were warranted, even though the recommended dosages were last increased in 2008 for infants, children and adolescents and 2009 for adults. Historical review of changes in vitamin D RDA. In 2009, the National Institute of Health s (NIH) Office of Dietary Supplements (ODS) recommendation for vitamin D intake in adults was 200 IU daily for individuals less than 50 years of age, 400 IU daily for those years of age and 600 IU in those over the age of 71. (8) Although updated in 2009, the recommendations were the same as those released in In 2009, the National Osteoporosis Foundation (NOF) endorsed even higher vitamin D RDA for adults: IU in adults up to age 50 and 800 1,000 IU in adults 50 years and above. (2) The 2010 recommended vitamin D doses published by the IOM are closer to the range suggested by the NOF than the NIH ODS. In 2003, an updated statement from the Academy of Pediatrics (AAP) regarding vitamin D intake recommended that all infants (beginning in the first two months after birth), children, and adolescents receive 200 IU of vitamin D daily to prevent rickets and vitamin D deficiency. (9) Guidelines were again updated by the AAP in 2008 to at least 400 IU of vitamin D per day (double the previous guidelines) in healthy infants beginning soon after birth (rather than two months of age), children, and adolescents to prevent rickets and vitamin D deficiency. (1) The report also recommended that solely breastfed infants as well as breastfed infants being supplemented with formula (mixed fed) receive 400 IU vitamin D supplements daily since it is extremely difficult to receive adequate amounts of vitamin D from breast milk. Since an infant s vitamin D levels depend on the 2

3 mother, it is estimated that the child may receive less than IU/L of vitamin D from breast milk compared to 400 IU/L provided by formula. (1) Lastly, any infant, child, or adolescent who is not receiving 400 IU of vitamin D daily through formula (one liter/day), vitamin D fortified milk (one liter/day), or vitamin D fortified foods should also receive an additional 400 IU vitamin D supplement daily. Due to concerns that the AAP s updated recommended dosing of vitamin D in infants was still not sufficient, a study was conducted to estimate the prevalence of infants who actually met the 2008 AAP criteria for vitamin D supplementation during their first year of life. Data was analyzed from the Infant Feeding Practices Study II (a national survey conducted between 2005 and 2007) to determine the extent of oral vitamin D supplementation, the average amount consumed at each feeding, and the average number of feedings per day or week. Regarding oral vitamin D supplementation, 5 13 % of infants in the breastfed group, 4 11 % in the mixed fed group, and 1 4 % in the formula fed group received oral supplementation. Based upon these reports, it was estimated that only 9-13 % of breastfed, 9 14 % of mixed fed, and % of formula fed infants would have met the 2008 AAP recommendations. With the disappointing results, the authors concluded that most infants will require oral vitamin D supplementation in order to consume at least 400 IU of vitamin D per day. (10) Another study of 380 healthy infants and toddlers in Massachusetts found that only 2 % of solely breastfed infants received vitamin D supplements. The authors estimated a 10-fold increased risk of vitamin D deficiency in breastfed compared to formula fed infants. (11) In addition to recommending daily doses of calcium and vitamin D, the IOM s report also supplied values for tolerable upper intake levels (UL). For our purposes, we are only presenting and commenting on the vitamin D portion of the report (Table 1). (7) These recommendations apply to all adults, irrespective of whether they are male, female, pregnant or breastfeeding. Table 1: Institute of Medicine 2010 recommendations for vitamin D (7) Age RDA (IU/day) UL (IU/day) 0 6 months months years years years > 70 years Vitamin D deficiency Definition. The lab value used to define normal vitamin D levels determines the incidence of deficiency. There is not a central authority to determine cut-off values for defining vitamin D sufficiency, insufficiency and deficiency. Therefore, there is variability between agencies and the literature. Part of the discrepancy has to do with whether or not recommendations were based upon preventing disease such as rickets or promoting bone health. 3

4 Plasma vitamin D levels are expressed in the literature as either ng/ml or the universal units of nmol/l. Dividing the value expressed in nmol/l by provides the conversion to ng/ml. (1) As of 2009, the National Institute of Health s (NIH) Office of Dietary Supplements (ODS) considered a 25(OH)D plasma concentration of < 15 ng/ml (~37.4 nmol/l) to be inadequate and therefore concentrations > 15 ng/ml are recommended. (8) In their latest report, the IOM considered a vitamin D level of 20 ng/ml to be adequate for good bone health for most individuals. Although there is slight variability within references, most of the literature we reviewed considered a vitamin D level of ng/ml to be insufficient while a value of less than 20 ng/ml to be deficient. (12) Incidence. The National Health and Nutrition Examination Survey (NHANES) is a program conducted by the National Center for Health Statistics (NCHS), which is part of the Centers for Disease Control and Prevention (CDC). NHANES utilizes a combination of interviews and physical examinations to assess the health and nutritional status of adults and children in the U. S. Although it began in the early 1960s as a series of surveys, NHANES became a continuous program in 1999, which changes the focus of its measurements based on emerging health issues throughout the nation. Serum 25(OH)D levels were measured for the first time in the third NHANES (NHANES III) and a second time in NHANES In NHANES III, a nationally representative sample was obtained in two cycles between 1988 and 1994, whereas in NHANES , a nationally representative sample was collected each year. (13) A secondary analysis of NHANES III conducted by Zadshir and colleagues in 2005 reported that slightly more than 40% of adult ( > 18 years) men and 50% of adult women in the U.S. were vitamin D deficient (set at < 70 nmol/l or < 28 ng/ml). The prevalence of hypovitaminosis (< 28 ng/ml) was significantly higher among women and minority (African American and Hispanic) populations. (14) An analysis of NHANES determined that in the U.S., 9 % of those aged 1 to 21 studied were deficient (< 15 ng/ml) and 61 % were vitamin D insufficient (15 29 ng/ml). (15) Comparisons between the two NHANES surveys have sparked controversy due to changes in demographics and characteristics between the two populations as well as the 1998 reformulation of the radioimmunoassay (RIA) kits used to quantitate serum 25(OH)D levels. To assess whether the kit reformulation contributed to differences in serum 25(OH)D readings between NHANES III and NHANES , the CDC reanalyzed a subset of 150 banked serum samples from NHANES III with the updated RIA kit in It was determined an adjustment was needed to correct the original NHANES III serum levels. The correction factor for the quality control (QC) shift between the formulations was determined to be the following: NHANES III 25OHD 2004 assay pre-qc shift = ( * NHANES III 25OHD 2004 assay during-qc shift ) nmol/l. (Looker, et al., 2008) (13) Table 2 contains a portion of the original mean vitamin D levels (nmol/l) reported by Zadshir in The adjusted vitamin D values in the table were determined using the above correction factor equation, with the original values in parenthesis. (13,14) Since individual lab values are not available, the standard error of the mean cannot be determined for the adjusted values. Table 2 also includes a column of the vitamin D levels expressed as ng/ml. 4

5 Table 2: Adjusted vitamin D values from NHANES III (13,14) MEN WOMEN Group n Mean n Mean nmol/l ng/ml nmol/l ng/ml All (78.69) (31.53) (71.07) 31.1 (28.47) Age >60 Race/ethnicity White Black Hispanic (81.38) 84 (76.76) (75.41) (82.99) 56.5 (52.22) 74.53(68.31) (32.60) (30.75) (30.21) (33.25) (20.92) (27.37) (77.01) (67.55) (64.54) (75.95) (45.31) (56.69) (30.85) (27.06) (25.86) (30.43) (18.15) (22.71) With the conversions, the serum 25(OH)D levels are all slightly elevated compared to those initially reported from NHANES III. (14) With respect to characterization of vitamin D insufficiency (20-30 ng/ml) or deficiency (< 20 ng/ml), very little changed with the conversions according to our analysis. When looking at overall means, the average value for all men is still considered sufficient (> 30 ng/ml); however, the overall mean value for women has moved from the category of insufficient (previously ng/ml) to sufficient at 31.1 ng/ml. Nonetheless, the status of 25(OH)D level still falls within the original categories for the age and ethnicity breakdown (ie. the mean for hispanic and black women, as well as women aged 40 and above, remains insufficient). Likewise, the black and hispanic male populations are still categorized as insufficient while white men and those aged 18 and above are still deemed sufficient. The actual percentages of men and women with insufficient and deficient 25(OH)D levels cannot be determined due to our lack of individual 25(OH)D levels from the participants in NHANES III. However, based upon similarities between the mean values before and after the correction factor, it is plausible to expect them to be close to those numbers originally published. Zadshir and colleagues (14) have not published updated analyses of the statistics from their original publications since the 2004 quality control study or the 2008 publication by Looker, et al. (13) Smaller but more recent studies in the U.S. have reported vitamin D deficiency in a significant percentage of the young population. Vitamin D levels were examined in adolescents aged 14 to 18 located in the southeastern U.S. The overall prevalence of vitamin D insufficiency (< 30 ng/ml) and deficiency (< 20 ng/ml) were 56.4 % and 28.8 %, respectively. Black subjects had significantly lower vitamin D levels than whites. (Dong, et al., 2010)(16) A 2004 study of healthy adolescents (11 to 18 years) in from Children s Hospital Boston in Massachusetts revealed that 24.1 % were vitamin D deficient (15 ng/ml or less) and 42 % were considered insufficient (vitamin D levels of 20 ng/ml or less). The participants were at the hospital for annual physical exams. (17) In 2008, another study on vitamin D levels was published using 380 healthy infants and toddlers (eight to 24 months of age) from Children s Hospital Boston in Massachusetts. The participants were undergoing a routine blood draw, which revealed vitamin D deficiency (less than 20 ng/ml) in 12.1 % of the participants. Forty percent of the participants had a vitamin D level below an accepted optimal threshold of 30 ng/ml. The study also noted that infants who were breastfeeding without vitamin D supplementation had significantly

6 lower vitamin D levels (mean [SD] of 16.7 [3.4] ng/ml) compared to formula fed infants (36.3 [0.9] ng/ml). This was reported to equate to a 10-fold increased risk of vitamin D deficiency in breastfed infants compared to formula fed infants. (11) Symptoms. Signs and symptoms of vitamin D deficiency are manifested as bone discomfort and muscle aches. Common areas affected include the lower back, pelvis, sternum, and lower extremities. These symptoms are sometimes misdiagnosed as fibromyalgia, chronic fatigue syndrome, or arthritis. (18) Risk Factors. Risk factors for vitamin D deficiency are listed in table 3. (19) In general, risk factors for vitamin D deficiency include situations of decreased production, decreased ingestion, decreased intestinal absorption and use of certain medications. Table 3: Risk factors for vitamin D deficiency (19) Age > 65 Infants exclusively breast fed with no supplementation Dark skin Low/no sunlight exposure Gastric bypass surgery Obesity Chronic kidney disease Diabetes Hyperparathyroidism Conditions that can affect fat absorption (sprue, cystic fibrosis, Crohn s disease) Medications that enhance vitamin D metabolism (phenytoin, phenobarbitol, carbamazepine, primidone) Medications that decrease vitamin D bioavailability (colestipol, cholestyramine, orlistat) Medications that decrease activation of vitamin D (corticosteroids) Sources of Vitamin D Vitamin D is obtained from exposure to sunlight, diet, and dietary supplements. (12) Vitamin D from these sources is biologically inert until it undergoes two hydroxylations to become 1,25(OH) 2 D. With respect to dermal vitamin D production, the number of UVB photons that are able to penetrate the epidermal layer determines the efficiency of vitamin D synthesis. Increased skin pigmentation and/application of sunscreen decreases absorption of UVB photons, causing diminished production of vitamin D by as much as %. (3,6) Body mass, cloud cover, latitude, and air pollution also affect the extent of solar UVB exposure and absorption. (20) It is reported that full-body sun exposure during summer months for minutes in lighter-pigmented adults can generate 10,000-20,000 IU of vitamin D in the body within 24 hours. Darker-skinned individuals require five to ten times more sun exposure to synthesize the same amount. During winter months, sunlight is insufficient at latitudes above 37 N to contribute to vitamin D synthesis in the skin. (6) The latitude of 37 N cuts right through the center of the U.S., from approximately San Francisco, California to Richmond, Virginia. Additionally, 6

7 elderly individuals have decreased vitamin D synthesis due to a reduction of 7- dehydrocholesterol in the skin. (12) Dietary sources of vitamin D include cod liver oil, oily fish (salmon, mackerel, tuna, and sardines), egg yolks, and foods fortified with vitamin D, including milk, cereal, yogurt, margarine, and orange juice. (6) Because there are few foods that are naturally high in vitamin D, it is difficult to obtain enough through diet to maintain appropriate levels within the body. Table 4 lists common exogenous sources of vitamin D. (8,12) Table 4: Sources of vitamin D (8,12) Source Fortified food Cereal Milk Orange Juice Yogurt Infant formulas (USA) Nonfortifed foods Beef liver Breast milk Cod liver oil Egg yolk (of an egg weighing 60 grams) Mackerel (canned) Margarine Salmon (canned) Salmon (fresh, farmed) Salmon (fresh, wild) Sardines (canned) Shiitake mushrooms, fresh Shiitake mushrooms, freeze dried Tuna (canned) Prescription supplements Ergocalciferol (Drisdol) Calcitriol (1,25-dihyroxyvitamin D [Rocaltrol]) Calcitriol (1,25-dihyroxyvitamin D [Calcijex]) Approximate amount of vitamin D 100 IU/serving 100 IU/8 oz 100 IU/8 oz IU/8 oz 100 IU/8 oz 46/3.5 oz 20 IU /L IU/ 5mL IU/capsule 20 IU 250 IU/3.5 oz 60 IU/tbsp 300 to 600 IU/3.5 oz 100 to 250 IU/3.5 oz 600 to 1,000 IU/3.5 oz 300 IU/3.5 oz 100 IU/3.5 oz 1600 IU/3.5 oz 230 IU/3.6 oz 50,000 IU/capsule; 8,000 IU/mL 0.25 mcg, 0.5 mcg/capsule; 1 mcg/ml oral solution 1 mcg/ml solution for injection The food sources of vitamin D are in the form of D 3, with the exception of egg yolk, which also contains D 2. In regards to the differences noted in amounts of vitamin D found in salmon, farmed salmon are fed a pellet diet, which may explain their lower vitamin D content compared to wild salmon. (21) Other Benefits: The identification of vitamin D receptors in more areas outside of the skeleton, kidneys and intestines has led to speculation of additional physiological effects. In the last few years, vitamin D has received favorable publicity for benefits outside of the 7

8 realm of calcium homeostasis and skeletal health. Although benefits have been touted for a variety of disease states and medical conditions, the strongest evidence is in the areas of cardiovascular disease, diabetes, cognitive decline, and colorectal cancer. It is easy to get excited about the prospects of this readily available, inexpensive vitamin. However, one must appreciate that vitamin D is actually a hormone. Although its actions are more complex than most other vitamins, it is available over-the-counter and perceived by the public as safe. Caution must be exercised concerning the therapeutic claims of vitamin D since most of the human studies are observational and typically report trends rather than therapeutic endpoints. Therefore, factors other than vitamin D status may be responsible for or contribute to the benefits suggested in the studies. Health claims associated with vitamin D must be carefully scrutinized. Most literature reports a link between deficiency of vitamin D to causing, worsening, or exacerbating a disease rather than use of vitamin D to prevent, or manage a disease. For example, when considering vitamin D deficiency as a risk factor for developing cardiovascular disease or diabetes, it must be considered that an individual with adequate vitamin D status may lead a healthier lifestyle in the form of increased outdoor activity (sun exposure) and/or a diet that consists of healthy foods such as fish. In such a scenario, the reported decreased risk of cardiovascular disease and diabetes may be due to exercise and healthy diet and not necessarily just to the increased vitamin D levels. Cardiovascular disease and diabetes. An analysis of NHANES III reported a significant inverse relationship between systolic blood pressure and serum vitamin D concentrations. (22) An NHANES analysis involving participants aged 1 to 21 reported that vitamin D deficiency (< 15 ng/ml) was associated with elevated PTH, higher systolic blood pressure, lower serum calcium, and lower high-density lipoprotein cholesterol compared to those participants with levels > 30 ng/ml. (15) The elevated systolic blood pressure and lower high-density lipoprotein are known risk factors for cardiovascular disease. Both studies adjusted for multiple logical variants such as age, gender, race, obesity, activity level, and income. A 2010 systematic review of vitamin D and calcium supplementation in the prevention of cardiovascular events concluded that vitamin D supplements at moderate to high doses may reduce cardiovascular disease risk. However, none of the reviewed studies were designed to specifically assess primary effects on cardiovascular outcomes. (23) Two articles report a significant decrease in the risk of developing type 1 diabetes in children who received vitamin D supplementation during the first year of life. These studies are a bit misleading due to inconsistencies in reporting doses and the use of vitamin D supplements alone versus cod liver oil. (24,25) Hyppönen and colleagues did not separate out participants based upon their source of vitamin D supplementation. The study data on vitamin D use was only collected during the first year of life; however, subjects were followed for 31 years. The study reported that vitamin D supplementation was associated with a decreased frequency of type 1 diabetes. (24) In another study, Stene and colleagues separated out subjects who received vitamin D from cod liver oil versus other supplements. Their results showed that children given cod liver oil had a significantly lower risk of type 1 diabetes; while children given vitamin D supplements did not. Cod liver oil, although a rich source of vitamin D, also contains the long chain fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The authors 8

9 speculate that the preventative effects of cod liver oil on type 1 diabetes were more likely to be related to the DHA and EPA content rather than vitamin D. (25) Potential links between diabetes mellitus and vitamin D deficiency were reported in a 2004 study where participants with hypovitaminosis D (< 20 ng/ml) exhibited decreased pancreatic beta cell function and increased insulin sensitivity compared to those with 25(OH)D concentrations >20 ng/ml. The clinical relevance of the findings are of question since there is not a published follow-up study, so whether the subjects with hypovitaminosis suffered from future diabetes is unknown. (26) Cognitive decline. In a cross-sectional study of 225 outpatients diagnosed as likely having Alzheimer s disease, scores on their mini-mental state examination (MMSE) and vitamin D levels were analyzed. They found that sufficient serum vitamin D levels were associated with significantly higher MMSE scores compared to subjects with insufficient vitamin D levels. However, this study was a static measurement and although there was a trend, a cause and effect relationship between vitamin D deficiency and cognitive decline could not be made. The authors also acknowledged that cognitive decline may cause vitamin D deficiency due to malnutrition and behavioral changes that could limit outdoor/sunlight exposure. (27) A 2010 prospective, observational study of 858 elderly individuals (> 65 years) found a link between low vitamin D levels and cognitive decline over a six year period. Cognitive decline was assessed using the MMSE (at baseline, after 3 years, and after 6 years). Individuals with severe vitamin D deficiency (levels < 25 nmol/l or 10 ng/ml) at baseline declined by 0.3 MMSE points more per year more than those with sufficient vitamin D levels (> 75 nmol/l or 30 ng/ml). The increase in rate of decline was statically significant. (28) Cancer. Vitamin D is anticipated to have a protective role since it is a nuclear transcription factor that regulates cell growth, differentiation and apoptosis. Vitamin D has been shown to stimulate expression of the cell cycle inhibitors p21 and p27. (29) In light of this finding, vitamin D supplementation has been studied in humans with various cancers, since cancer involves uninhibited cell growth. Cancers most commonly studied include colorectal, breast, and prostate. There have been some promising reports regarding colorectal cancer and vitamin D; however, studies in breast and prostate cancer have not yielded consistent results. A recent review of the literature on vitamin D and colorectal cancer since 1980 found a high and consistent association between better vitamin D status and lower colorectal cancer risk. (30) Garland and colleagues reported a projected decrease in the risk of breast cancer based upon observational studies. They reported that a serum vitamin D level of 50 ng/ml would be associated with a 50 % lower incidence of breast cancer compared to a baseline of < 10 ng/ml. Maintaining a serum level of 50 ng/ml would require a daily vitamin D dose of 4000 IU, which is the newly defined upper limit of the IOM recommendation. (7) The authors report that an alternative would be to combine moderate sun exposure to an oral vitamin D dose of 2000 IU per day. (31) 9

10 Vitamin D products The vitamin D found in dietary supplements is either in the form of vitamin D 2 (ergocalciferol) or vitamin D 3 (cholecalciferol). (8) Vitamin D 2 is produced from irradiation of the yeast and plant sterol ergosterol and vitamin D 3 is obtained from oily fish and synthesis in the skin. (18) Over-the-counter ergocalciferol (vitamin D 2 ) products contain 8,000 IU per ml (Calciferol Drops, Drisdol Drops ). The vitamin D 2 prescription product (Drisdol ) contains 50,000 IU per capsule. All other vitamin D supplements contain cholecalciferol (vitamin D 3 ). Multivitamins contain 200 IU (children) and 400 IU (adult) of vitamin D 3 per serving. Supplements containing only vitamin D are available in liquid, tablet and capsule form. Available strengths range from 400 5,000 IU per ml per ml or tablet/capsule. (32,33) Ddrops is a specific product that provides an entire dose of vitamin D in one drop. Available strengths of Ddrops are 400, 600, 1,000 and 2,000 IU per drop. Although both vitamin D 2 and vitamin D 3 are effective in raising serum 25(OH)D levels, evidence has shown that vitamin D 3 is three times more effective than vitamin D 2 in its ability to increase serum 25(OH)D concentrations and to maintain higher levels for a longer period of time. (8) Most individuals can benefit from supplements containing either form of vitamin D since their liver and kidneys are able to convert vitamin D 2 and D 3 to calcitriol. However, patients with moderate to severe chronic renal failure cannot convert precursors to calcitriol and must take calcitriol directly. Calcitriol is only available with a prescription. Calcitriol products include Rocaltrol (oral) and Calcijex (injection). Toxicity. Signs of vitamin D toxicity include hypercalcemia, hyperphosphatemia and potentially impaired renal function. Early symptoms include fatigue, headache, metallic taste, dry mouth, nausea, vomiting, constipation, and muscle pain. Later symptoms include dehydration, anorexia, anemia, arrhythmias, mild metabolic acidosis, and hypertension. In extreme cases, hypervitaminosis can lead to calcification of soft tissues and even more rare incidents of mental retardation have been reported. (18,34) Most side effects of vitamin D supplementation are associated with excessive doses, as vitamin D supplementation can result in hypervitaminosis D. Due to the high likelihood and danger of concomitant hypercalcemia, if hypervitaminosis D does occur, both vitamin D and calcium supplementation should be discontinued immediately. Additionally, supportive measures such as a low calcium diet and fluid replacement to reduce serum calcium concentration should be utilized. (34) Conclusion Mounting evidence in recent years has led to significant changes in how vitamin D is viewed by health care professionals. Although the role of vitamin D in the management of osteoporosis and overall bone health is well known, the physiologic importance of vitamin D has recently expanded to include disease management of conditions such as cardiovascular disease, diabetes mellitus, cognitive decline, and cancer. Given the continual attention that vitamin D has received for a diverse number of diseases and with the public s tendency to self-medicate, it is imperative that health care professionals are aware of changes in vitamin D recommendations. Additionally, any updates must be properly communicated to patients. Likewise, it is important that health care professionals stay current and continue to scrutinize the literature in order to provide 10

11 the best education to the public. Most reports of vitamin D use for disease treatment and prevention are observational studies which can suggest associations but do not establish cause and effect. Ideally, randomized controlled trials are needed to unequivocally determine the benefits of vitamin D in the treatment and prevention of disease. References 1). Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008;122: ). National Osteoporosis Foundation Available from URL (accessed December 2010) 3). Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest 2006;116: ). Hadley, ME. Hormonal Control of Calcium Homeostasis. In: Endocrinology. 5 th ed. Prentice-Hall, Inc, Upper Saddle River, NJ. 2000: ). Heaney RP, Dowell MS, Hale CA, Bendich A. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr. 2003; 22: ). Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81(3): ). IOM (Institute of Medicine) Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academics Press. Institute of Medicine Web site: Accessed December 30, ). Dietary Supplement Fact Sheet: Vitamin D. Office of Dietary Supplements. National Institutes of Health. Bethesda, Maryland. 13 Nov 2009 [accessed 12 November 2010]. Available from: URL: 9). Gartner LW, Greer FR. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics 2003;111: ). Perrine CG, Sharma AJ, Jefferds MED, Serdula MK, Scanlon KS. Adherence to vitamin D recommendations among US infants. Pediatrics 2010;125: ). Gordon CM, Feldman HA, Sinclair L, Williams AF, Kelinman PK, Perez-Rosselo J, Cox JE. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med 2008; 162(6): ). Holick MF. Vitamin D deficiency. N Engl J Med 2007;357: ). Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF, Yetley EA. Serum 25- hydroxyvitamin D status of the US population: compared with Am J Clin Nutr 2008; 88: ). Zadshir A, Tareen N, Pan D, Norris K, Martins D. The prevalence of hypobitaminosis D among US adults: data from NHANES III. Ethn Dis 2005; 51(5):97-101). 15). Kumar J, Muntner P, Kaskel FJ, Hailpern SM, Melamed ML. Prevalence and associations of 25-hydroxyvitamin D deficiency in US children: NHANES Pediatrics 2009;124:e362-e ). Dong Y, Pollock N, Stallmann-Jorgensen IS, Gutin B, Lan L, Chen TC, Keeton D, Petty K, Holick MF,Zhu H. Low 25-hydroxyvitamin D levels in adolescents: race, season, adiposity, physical activity, and fitness. Pediatrics 2010; 125: ). Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 2004; 158(6): ). Bordelon P, Ghetu M, Langan R. Recognition and management of vitamin D deficiency. Am Fam Physician. 2009;80(8):

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