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Vitamin D

Summaries of the latest research concerning vitamin D
By Hans R. Larsen MSc ChE


Vitamin D is a hugely important fat-soluble vitamin. Our main source is sunlight. It is estimated that at least 75 per cent of our supply comes from photochemical conversion of 7-dehydrocholesterol in the skin. This conversion occurs when we are exposed to the sun's UVB rays (290-320 nm wavelength). Vitamin D itself is biologically inactive, but is converted in the liver and kidneys to 1,25-dihydroxycholecalciferol [1,25(OH)2D3] which is a powerful hormone with many functions. Most foods contain very little vitamin D with the main sources being fish (liver), eggs, and fortified milk.

Lack of exposure to sunlight is the main cause of vitamin D deficiency. In recent years medical authorities have exhorted us to avoid the sun and apply sunscreen before we venture outside. This advice is aimed at reducing the astronomical increase in the incidence of skin cancer and melanoma. Recent research, however, has shown that relying on sunscreens to prevent skin cancer and melanoma is counterproductive. Research has also shown that regular use of sunscreens completely eliminates the body's synthesis of vitamin D and can lead to a serious vitamin D deficiency. Sun avoidance by itself leads to vitamin D deficiency. Windowpanes effectively screen out UVB rays(9). Clothing, whether it be a light cotton shirt or a heavy jogging suit, eliminates or seriously reduces the synthesis of vitamin D(10). Air pollution (ozone and sulfur dioxide) cuts out a large portion of the sunlight needed for vitamin D synthesis and many medications (anticonvulsants, steroids) also interfere with vitamin D formation. Vegetarians are at particular risk for vitamin D deficiency because of their high fiber intake and lack of dairy products in the diet. Health authorities have attempted to ensure that people get enough vitamin D through the diet by fortifying milk. This approach, however, is ineffective. Recent research studies have shown that the vitamin D content of milk is highly erractic and many of the samples tested in two recent surveys done in Canada and the United States contained no vitamin D at all.

The consequences of vitamin D deficiency are many and varied. Drs. Cedric and Frank Garland of the University of California suggested as early as 1980 that a lack of vitamin D could be a major cause of colon cancer. The Garland brothers found that the incidence of colon cancer was almost three times higher in New York than in New Mexico. They attributed this to a vitamin D deficiency caused by the relative lack of sunshine in the northern United States. Another survey carried out in Chicago reached the conclusion that men whose daily vitamin D intake was 150 IU or more had a 50 per cent lower risk of developing colon cancer than did men with a lower intake. Vitamin D deficiencies have also been implicated in the development of breast cancer, melanoma, ovarian cancer, prostate cancer, and of course, osteopenia, osteoporosis and hip fractures. Breast cancer rates in the northeastern part of the United States are almost twice as high as in the south and southwest. The incidence of ovarian cancer among women aged 45 to 54 years is five times higher in Indiana than in North Carolina. Researchers ascribe this difference to a vitamin D deficiency in northern states caused by a lack of sunlight. Osteoporosis affects about 24 million people in the United States alone and costs about 10 billion dollars a year to treat. One third of postmenopausal women suffer from osteoporosis and, as a result, experience a total of about 1.3 million bone fractures a year(19). Deficiencies in calcium and vitamin D intake have both been implicated in the development of osteoporosis. Recent research has shown that elderly people receiving a single, large, oral dose of vitamin D (100,000 IU) at the start of the winter had 20 per cent fewer bone fractures than a control group.

It is clear that vitamin D deficiency is widespread and can have serious, even fatal consequences. Regular, prudent, unprotected exposure to sunlight is the most effective way of maintaining an adequate vitamin D status. However, during the winter months, elderly people and people who spend most of their time indoors should supplement with vitamin D. A prominent vitamin D researcher, Dr. Reinhold Vieth of the University of Toronto, is convinced that vitamin D deficiency is widespread and that the current RDA (Recommended Daily Allowance) for vitamin D is totally inadequate. He points out that total-body sun exposure easily provides the equivalent of 10,000 IU of vitamin D a day and that this amount is what the human race originating in Africa was originally accustomed to. With our current, officially sanctioned phobia about sun exposure most people expose only their face and hands to the sun on a regular basis and as a result become woefully deficient. The use of sunscreens prevents the formation of any vitamin D at all and makes matters even worse. Dr. Vieth recommends a minimum vitamin D intake from supplements of 800-1000 IU/day and feels that a more optimum intake from sunlight and diet would be 4000 IU/day. He also states that numerous studies have shown that daily intakes as high as 10,000 IU are safe (in the absence of sunshine). Dr. Vieth also points out that the RDA for vitamin D (400 IU/day) used until 1997 was based on the amount of vitamin D found in a teaspoon of cod liver oil. The rationale being that one teaspoon of cod liver oil a day had been found over the years to protect children from rickets!



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CONTENTS

Vitamin D Deficiency and Supplementation

Vitamin D and Cancer
Vitamin D and Cardiovascular Disease
Vitamin D and Bone Health
Vitamin D: Odds and Ends

Vitamin D Deficiency and Supplementation

Vitamin D deficiency in southern Florida
MIAMI, FLORIDA. A vitamin D deficiency is widespread in northern latitudes and has been associated with an increased risk of osteoporosis and certain cancers, notably breast, colon and prostate. The main sources of vitamin D are sunlight exposure and supplementation with dietary sources playing a minor role. Since sunlight is capable of synthesizing large amounts of vitamin D, it has generally been assumed that people living in southern latitudes would be fairly immune to a vitamin D deficiency. Researchers at the University of Miami School of Medicine now dispute this assumption. Their study included 77 men and 135 women with an average age of 55 years (18-88 years). The participants completed food frequency and sun exposure questionnaires at the end of winter (March 2000) and at the end of summer (September 2000) and had blood samples drawn and tested for 25-hydroxyvitamin D [25(OH) D], 1,25-dihydroxyvitamin D, and parathyroid hormone (PTH). Vitamin D deficiency was defined as a blood level of 25(OH)D below 20 ng/mL (50 nmol/L); this is the point at which PTH levels begin to rise. The researchers found that 38% of men and 40% of women were deficient in vitamin D at the end of winter and that 10% of men and 28% of women were deficient at the end of summer. Actual average concentrations of 25(OH)D were 23.3 ng/mL (58.3 nmol/L) at end of winter and 26.8 ng/mL (67.0 nmol/L) at end of summer. A higher intake of supplemental vitamin D (800 IU/day or more) and greater sun exposure were associated with higher levels of 25(OH)D, but there was no association between 25(OH)D level and age. The researchers suggest that the higher than expected prevalence of vitamin D deficiency in southern Florida can be explained by sun avoidance and the use of sunscreens because of the heat and increased awareness of the risk of developing skin cancer.
Levis, S, et al. Vitamin D deficiency and seasonal variation in an adult south Florida population. Journal of Clinical Endocrinology & Metabolism, Vol. 90, March 2005, pp. 1557-62

Vitamin D deficiency common in non-Western pregnant women
THE HAGUE, NETHERLANDS. Vitamin D deficiency during pregnancy is an important issue for the bone health of mother and child, and the range of other functions recently linked to this nutrient. Vitamin D is produced in the skin following exposure to sunlight or other ultraviolet light, but the skin pigment in persons with darker skin absorbs some of the rays and causes vitamin D deficiency to be more likely when living in northern countries. Researchers from the Municipal Health Service of The Hague gathered data on pregnant women from several ethnic backgrounds living in the Netherlands. Serum vitamin D was measured by midwives in 358 Western, Turkish, Moroccan, and other non-Western women during the 12th week of pregnancy. The Western women had a mean concentration of 52.7 nmol per liter. But concentrations in the other groups were significantly lower. Turkish women had a mean of 15.2, the Moroccan women 20.1, and the other non-Western women 26.3. Further analysis suggested that these differences were based on ethnicity rather than other factors that may be related to vitamin D status. More than 50 per cent of the women in all non-Western groups had a vitamin D deficiency, compared with 8 per cent of Western women, say the authors. They conclude that the prevalence of vitamin D deficiency in pregnant non-Western women in the Netherlands is very high, and urge health services to include vitamin D status screening as routine for all pregnant non-Western women.

In an editorial, experts from the Medical University of South Carolina point out that the definition if deficiency used in the study was conservative - 25-hydroxyvitamin D concentration of less than 25 nmol per liter - so the rate of deficiency may be underestimated. They would like to see pregnant women achieve at least 80 nmol per liter, and discuss the necessary vitamin D intake. An intake of 200 IU per day is way too low, they believe. Instead, to increase vitamin D to meaningful concentrations, a daily intake of 2000 IU may be required. The authors call for further studies to establish the true vitamin D requirement during pregnancy.
van der Meer, I. M. et al. High prevalence of vitamin D deficiency in pregnant non-Western women in The Hague, Netherlands. The American Journal of Clinical Nutrition, Vol. 84, August 2006, pp. 350-53
Hollis, B. W. & Wagner, C. L. Vitamin D deficiency during pregnancy: an ongoing epidemic. The American Journal of Clinical Nutrition, Vol. 84, August 2006, pp. 273

Vitamin D3 preferred over vitamin D2, say experts
WOLFVILLE, CANADA. The two major forms of vitamin D currently available in supplements are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Although considered very similar, emerging evidence suggests that vitamin D3 has greater bioefficacy. Unfortunately, vitamin D2 is still the predominant synthetic form used in North America. Drawing attention to this are experts from Acadia University, who explain that sunshine exposure and fish consumption provide vitamin D in the form of D3, and that repeatedly vitamin D3 has been found to be the "more potent form of vitamin D in all primate species, including humans" at raising serum 25(OH)D concentrations. The authors believe that vitamin D2 should no longer be considered equivalent to vitamin D3, and even that it should not be regarded as suitable for supplementation. Supporting their argument are several plausible biological explanations for this greater bioefficacy, due to the different metabolic pathways followed by the two forms of vitamin D. The authors write that vitamin D2 has a non-physiologic metabolism, that is, it works differently to the body's natural function. Vitamin D2 also has a shorter shelf-life. The poorer stability and greater impurities in vitamin D2 powders may lead to a higher risk of toxicity than with vitamin D3. Care should be taken to distinguish the form of vitamin D used in clinical studies, the authors state, especially as metabolism of vitamin D2 can become impaired in older people. In conclusion, they concede that vitamin D2, if given in high enough doses, can help prevent rickets, but state that the superiority of vitamin D3 is now well documented. "Continual application of vitamin D2 in clinical use, including in research trials, only serves to confound our understanding of optimal vitamin D dosing recommendations", they write.
Houghton, L. A. and Vieth, R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. The American Journal of Clinical Nutrition, Vol. 84, October 2006, pp. 694-97

Lack of vitamin D increases risk of nursing home admission
AMSTERDAM, NETHERLANDS. Vitamin D deficiency is common among older people, so researchers from Vrije University set out to investigate whether lower vitamin D levels increase the risk of nursing home admission or early death in a large group of independent, community-dwelling older men and women. They recruited 1,260 participants aged 65 years or above and measured their serum 25(OH)D concentrations as a marker for vitamin D status. In the group, 10.1 per cent were deficient (less than 25 nmol/L) and 36.7 per cent were "insufficient" (25 to 49.9 nmol/L). The individuals were followed from 1995/96 until 2003. During this time, 11.0 per cent were admitted to nursing homes, and 30.2 per cent died. These events were clearly linked to vitamin D status. Nursing home admission was 3.48 times more likely among those who were deficient and 2.77 times more likely among those who were insufficient, compared with individuals with high vitamin D status (75 nmol/L 25(OH)D or greater). Higher mortality was linked to lower 25(OH)D, but not significantly, so the authors conclude that lower serum 25(OH)D concentrations in older persons are associated with a greater risk of future nursing home admission and "may be" associated with mortality.

In an accompanying editorial, a nutrition expert from Creighton University, Omaha, Nebraska writes that insufficient nutrition may contribute to chronic disease, but that true causal connections between specific nutrients and disorders are hard to establish, as most chronic diseases have a range of causes and take several years to develop. Vitamin D is one such nutrient. The present study makes biological sense, he writes, because low vitamin D can impair lower-extremity function, so can increase the risk of falls. He recommends that physicians assess and correct vitamin D status in their elderly patients, or even that a global intervention is considered, given the high rate of deficiency. The author suggests fortification of food, but this would probably require more solid proof than currently available. At the moment, "a substantial potential for reduction in the burden of chronic disease hangs in the balance", he concludes.
Visser, M. et al. Low serum concentrations of 25-hydroxyvitamin D in older persons and the risk of nursing home admission. The American Journal of Clinical Nutrition, Vol. 84, September 2006, pp. 616-22
Heaney, R. P. Nutrition, chronic disease, and the problem of proof. The American Journal of Clinical Nutrition, Vol. 84, September 2006, pp. 471-72

Has time come for an increase in recommended vitamin D intakes?
BOSTON, MASSACHUSETTS. Higher recommended daily intakes of vitamin D should be set in order to improve public health, say researchers following a review of the evidence to date. Current daily recommended intakes in the US are 200 IU for younger adults and 600 IU for older adults. The team, based at Harvard School of Public Health, concluded that vitamin D intakes above current recommendations are linked to better health outcomes. They set out to determine the optimal serum concentrations of 25-hydroxyvitamin D (25(OH)D), the circulating reservoir of vitamin D for bone mineral density, lower extremity function (muscle strength), dental health, and risk of falls, fractures, and colorectal cancer. This approach contrasts with the usual focus on a 25(OH)D concentration that maximally suppresses serum parathyroid hormone (PTH), which promotes bone loss. The review took data from randomized controlled trials and prospective and cross-sectional studies. It found that optimum serum levels begin at 75 nmol per liter, and the greatest benefit is between 90 and 100 nmol per liter - levels which cannot easily be achieved on the present recommended intakes. The authors therefore state that an increase in the current recommended intake of vitamin D may be warranted. They propose that the recommended intake should be raised to 1000 IU per day for all adults. This would bring at least half of the population up to a serum level of 75 nmol per liter, and so benefit bone health in younger adults and all studied outcomes in older adults, they believe. Such a target was supported by several experts at a recent conference on the role of vitamin D in cancer prevention. But it would require vitamin D supplementation for a large majority of the population. However, the authors say this is a simple, highly affordable, and well-tolerated strategy which should become a public health priority to combat several common and costly chronic diseases.
Bischoff-Ferrari, H. A. et al. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. The American Journal of Clinical Nutrition, Vol. 84, July 1, 2006, pp. 18-28

Evidence for widespread vitamin D deficiency
LONDON, UK. A paper just published in the American Journal of Clinical Nutrition adds to the evidence that vitamin D deficiency in the temperate zones is widespread. The researchers measured 25-hydroxyvitamin D levels (25(OH) D), the now well-accepted marker for vitamin D status, in 7437 British white-skinned individuals of age 45. The prevalence of vitamin D deficiency was greatest in the winter and spring when 25(OH)D levels of <25, <40, and <75 nmol/L were found in 15.5%, 46.6% and 87.1% of the subjects, respectively. The equivalent numbers for summer and fall were 3.2%, 15.4% and 60.9% respectively. As the authors point out, the threshold for optimal bone health is = 75 nmol/L (>80 nmol/L has also been proposed) and thus the prevalence of vitamin D deficiency is, in their words, "alarmingly high" and they suggest that this situation requires action at a population level rather than a risk group level. The threshold is based on achieving optimal bone mineral density and calcium absorption. A study of the monthly changes revealed a smooth variation with a minimum mean 25(OH)D level in February and a maximum in September, a variation which of course clearly reflects sun exposure. This was also beautifully illustrated by the variation from north to south in Great Britain which was maintained throughout the seasons. Men tended to have slightly higher levels than women throughout the year, but the differences were small. Also, the expected variations with supplements and oily fish intake were observed. The authors conclude that since vitamin D deficiency is also implicated in the development of various types of cancer, cardiovascular diseases, and diabetes the high rates of deficiency suggest immediate action is needed.
Hypponen, E. et al. Hypovitaminosis D in British Adults at Age 45 y: Nationwide Cohort Study of Dietary and Lifestyle Predictors. American Journal of Clinical Nutrition, 2007, Vol. 85, pp.860-8.

Vitamin D intakes in North America and Asia-Pacific countries insufficient
SASKATOON, CANADA. This study from Canada, New Zealand and the U.S. presents essentially the same picture as the British study discussed above. In the U.S. there have been only minor changes in vitamin D intake from foods and supplements over the periods 1988-94 and 1999-2000. The amounts based on national surveys range from about 200 to 400 IU/day with most clustered between 200 and 300 IU/day. The figures they present for Canada for intakes from food and supplements range from 350 to 730 IU/day. with the latter figure applying mainly to older adults with osteoporosis and presumably taking heavier doses via supplements. In New Zealand, the prevalence of vitamin D deficiency as determined by 25(OH)D levels ranges from 43% to 79% of the population, and this is using 50 nmol/L as a cut-off. They conclude that the mean requirement for vitamin D needed in the absence of ultraviolet exposure cannot be reached except by aggressive supplementation.
Whiting, S. J. et al. Vitamin D Intakes in North America and Asia-Pacific Countries Are Not Sufficient to Prevent Vitamin D Insufficiency. Steroid Biochemistry & Molecular Biology, 2007, e-published ahead of print.

Vitamin D deficiency in pregnant women
PITTSBURGH, PA. Bodnar et al have just reported a study in the Journal of Nutrition concerning the vitamin D status of pregnant black and white women and their newborn children living in the Northern U.S. All the subjects resided in Pittsburgh, PA (latitude 40 degree N) where the sun provides only negligible vitamin D generation in the winter. Vitamin D deficiency was defined as < 37.5, insufficiency as 37.5-80, and sufficiency as > 80 nmol/L of 25-hydroxyvitamin D. For newborns the assay was done on cord blood. At the time of delivery, deficiency and insufficiency occurred in 29.2% and 54.1 % of black women and 45.6% and 46.8% of black newborns, respectively. For white women and their babies, the comparable figures were 5% and 42.1% at delivery and 9.7% and 56.4% for newborns. The results were similar at < 22 weeks gestation. This study also looked at seasonal variation adjusted for body weight and preconceptional multivitamin use. Black women had smaller increases in 25-hydroxyvitamin D from spring to summer than white women (changes of 13.2 vs. 27.6 nmol/L). The authors conclude that both black and white pregnant women and their babies residing in the northern U.S. are at high risk of vitamin D insufficiency. Data collected on vitamin D intake from prenatal vitamin use suggested that the above prevalence of deficiency or insufficiency persisted even when the mothers were compliant with regard to taking prenatal vitamins. This is a significant problem, according to the authors, since in utero and early-life vitamin D deficiency is associated with skeletal problems, type 1 diabetes, schizophrenia, autoimmune diseases, cancer, and heart disease, and that high dose supplementation is needed to improve maternal and neonatal vitamin D status.
Bodnar et al. High Prevalence of Vitamin D Insufficiency in Black and White Women Residing in the Northern United States and Their Neonates. The Journal of Nutrition, 2007, Vol. 137, pp.447-52.

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Vitamin D and Cancer

Vitamin D and the risk of pancreatic cancer
CHICAGO, IL. While there do not appear to be geographic studies suggesting sunlight protects against pancreatic cancer, scientists from Harvard Medical School and Northwestern University Medical School have recently reported on a very large study involving two cohorts that addresses the role of vitamin D. This study made use of data from the Health Professionals Follow-up Study and the Nurses Health Study. Food-frequency questionnaires which included questions regarding supplementation were employed to determine the total oral intake of vitamin D and examine its relationship to the risk of developing pancreatic cancer. Controlling for confounding by UV exposure was accomplished by taking into account the location of residence. Multivitamin intake as well as intakes of calcium and retinol were also taken into account in the final, pooled multivariate analysis. It was found that when the lowest category of total vitamin D intake was used as the reference point (< 150 IU/day), the relative risks for pancreatic cancer were 0.78 for 150-299 IU/day, 0.57 for 300-450 IU/day, 0.56 for 450-599 IU/day and 0.59 for = 600 IU/day. All but the first result were statistically significant, Supplement use ranged from 8-11% in the < 150 IU/day group to 94-94% in the =600 IU/day, a result that confirms that it is difficult to achieve higher levels of intake from food alone. The authors conclude that this study points to the potential role for vitamin D in the prevention of pancreatic cancer. They also point out that because there is no effective screening available for this cancer, identifying modifiable risk factors is essential for developing preventive strategies.
Skinner, H.G. et al. Vitamin D Intake and the Risk for Pancreatic Cancer in Two Cohort Studies. Cancer Epidemiology, Biomarkers and Prevention, 2006, Vol. 15, No. 9, pp. 1688-95

Vitamin D and breast and ovarian cancer
LONDON, UK. Exposure to solar ultraviolet B radiation (UVB) has been found to correlate with age-adjusted incidence of ovarian cancer in a study involving 175 countries and based on data from 2002. Not only was an inverse relationship found, but when the correlation with stratospheric ozone, which reduces UBV, was examined, a positive association was found consistent. These results are consistent with earlier studies that found a north-south gradient for age-adjusted mortality rates for ovarian cancer. In another recent study, serum levels of the vitamin D metabolite, 25-hydroxyvitamin D, were measured prospectively in 279 Caucasian women with invasive breast cancer, 204 of which had early stage cancer and 75 of which had locally advanced or metastatic disease. Patients with early stage disease had significantly higher circulating levels of 25-hydroxyvitamin D than those with advanced disease. The authors suggest that these results lend weight to the hypothesis that the growth of breast cancer in vivo is inhibited by vitamin D.
Garland, C.F. et al. Role of Ultraviolet B Irradiance and Vitamin D in Prevention of Ovarian Cancer. American Journal of Preventive Medicine., 2006y, Vol 31, No. 6,pp. 512-14.
Palmieri, C. Serum 25-Hydroxyvitamin D Levels in Early and Advanced Breast Cancer. Journal of Clinical Pathology, 2006, published on line ahead of print.

Vitamin D and colorectal cancer
BUFFALO, NY. In early 2006, the Woman's Health Initiative investigators reported on a study of supplementation with calcium plus vitamin D and the risk of colorectal cancer. The results for calcium plus vitamin D showed no effect. The study received considerable media attention and many physicians who read the abstract or heard about it on the news probably concluded that this was another study to add to their list where supplements failed the test of modern evidence-based medicine. Also, medial attention may have discouraged women from taking the supplements. It was quickly pointed out by two experts in this field, Michael Holick from Boston University and Edward Giovannucci from Harvard, in separate letters to the editor of the New England Journal of Medicine that the vitamin D intervention dose used was inadequate (400 IU), and the duration of the follow-up too short. It was also pointed out that at the start of the study the subjects in the placebo and intervention groups had an intake of about 400 IU per day, half of which was from supplements, and throughout the study both groups were allowed to continue taking any amounts of vitamin D they wanted, but the treatment group got an extra 400 IU. However, buried in the text was a small sub-group analysis where serum levels of 25-hydroxyvitamin D, a vitamin D status marker, were found to be inversely related to the risk of CRC. When serum levels of < 12 ng/L were compared with = 23 ng/L, the risk of CRC was increased by a factor of 2.5. This statistically significant result was not mentioned in the abstract. As will become clear from what follows, this result was important.
Wactawski-WendeJ. et al. Calcium Plus Vitamin D Supplementation and the Risk of Colorectal Cancer. New England Journal of Medicine, 2006, Vol. 354, No. 7,pp. 684-96.
Holick, M. New England Journal of Medicine, 2007, Vol 354, No 21, pp. 2287. Giovannucci, E. ibid pp. 2287

Vitamin D and colorectal cancer prevention - A pooled analysis
LAJOLLA, CA. The Woman's Health Initiative study suffered from a design where a supplement was tested by adding it to the normal intake of both the placebo and intervention groups, and only a minute fraction of the participants had their serum 25-hydroxyvitam D levels measured. Gorham et al have just published a study where they pooled five studies, all of which were based on 25-hydroxyvitamin D levels rather than merely estimates of oral intake. When they compared the risk of CRC for serum levels of = 12 ng/mL with levels = 33 ng/mL, they found a 50% lower risk of colorectal cancer, and in addition, there was a highly significant trend of decreasing risk with increasing level of this vitamin D marker. The authors conclude their paper with a brief discussion of vitamin D intake and 25-hydroxyvitamin D levels. Based on a median population level of 20 ng/mL, they estimate that it would require supplementation of 1000 IU/day to raise the levels to 33 ng/mL, but this would be less than optimal because half the population would still be below this level. If instead, the intake was 2000 IU/day, they estimate levels of 46 ng/mL, a level that should produce substantial protection from colorectal cancer. The studies in this pooled analysis were all done on white-skinned individuals. Persons with dark skin are much more susceptible to vitamin D deficiency and the authors point out that for these individuals, higher levels might be required. They cite a number of studies that demonstrate that 2000 IU/day is safe and is well below the intakes where adverse effects might begin to appear. The authors also discuss the potential synergistic action of vitamin D and calcium in the context of CRC prevention. Finally, the authors comment that the time period required for an increase in vitamin D status to reduce the risk of CRC is unknown, but could require = 10 years.
Gorham, E. D. et al. Optimal Vitamin D Status for Colorectal Cancer Prevention. A Quantitative Meta Analysis. American Journal of Preventive Medicine, 2007, Vol. 33, No. 3, pp. 210-16.

Vitamin D and colorectal cancer - A multiethnic study
HONOLULU, HI. A prospective cohort study (follow-up study) conducted by researchers at the University of Southern California and the University of Hawaii examined the relationship between vitamin D intake and colorectal cancer (CRC) in five ethnic groups: African Americans, Native Hawaiians, Japanese Americans, Latinos, and Whites. Vitamin D intake was ascertained from a food and supplement questionnaire and follow-up was for an average of 7.3 years. Vitamin D intake ranged from< 85 to = 600 IU/day for men and < 70 to = 500 IU/day for women when the intake was stratified into quintiles (five groups). For men with the highest total intake (= 600 IU/day compared to the lowest intake, the risk of CRC was approximately cut in half. While this result was statistically significant, for women the smaller protective effect was not. For calcium intake, a significant protective effect was observed for both men and women.
Park, S-Y. et al. Calcium and Vitamin D intake and the Risk of Colorectal Cancer: The Multiethnic Cohort Study. American Journal of Epidemiology, 2007, electronically published ahead of print, Jan. 10.

Evidence points to vitamin D for cancer prevention
SAN DIEGO, CALIFORNIA. Many lives could be saved each year through higher vitamin D consumption, suggests a review of the scientific evidence. The review of 63 observational studies on vitamin D and cancer risk concluded that 1,000 international units (IU), or 25 micrograms, of vitamin D3 every day lowers the risk of developing colon cancer by half, and the risk of breast and ovarian cancer by 30 per cent. Vitamin D3 is found in eggs, organ meats, animal fat, cod liver oil and fish. It is equivalent to the form of vitamin D formed in skin from sunlight.

The review team, from the University of California in San Diego, is now demanding public health campaigns to increase vitamin D intake. They believe it is a cheap and easy way to prevent countless deaths. The authors report that early detection of breast cancer using mammography reduces mortality rates by approximately 20 per cent. But use of vitamin D might prevent this cancer in the first place. The review concludes that the high prevalence of vitamin D deficiency, combined with the discovery of increased risks of certain types of cancer in those who are deficient, suggest that vitamin D deficiency may account for several thousand premature deaths from colon, breast, ovarian and other cancers annually. It also found that people living in the northeastern United States are at an increased risk of vitamin D deficiency, as are individuals with higher skin pigmentation because this reduces the skin's ability to synthesize vitamin D. Researcher Cedric F. Garland pointed out that a preponderance of evidence, from the best observational studies the medical world has to offer, gathered over 25 years, has led to the conclusion that public health action is needed. We now have proof that the incidence of colon, breast, and ovarian cancer can be reduced dramatically by increasing the public's intake of vitamin D, he believes.
Garland, C.F. et al. The Role of Vitamin D in Cancer Prevention. The American Journal of Public Health. Published online December 2005, in print February 2006

Editor's comment: Foods, including fortified milk, are generally very poor sources of vitamin D. Therefore, if you reside in northern climes, are housebound, use sunscreens, or generally do not get at least a hour of unprotected sunlight exposure every day, it is necessary to supplement with at least 1000 IU/day of vitamin D3 (cholecalciferol). Vitamin D2 (ergocalciferol) should not be used since it is synthetic and can be toxic.

Sun exposure and lymphoma
STOCKHOLM, SWEDEN. It has been suggested that ultraviolet (UV) radiation exposure may be partly responsible for the increasing rate of malignant lymphoma. Certain studies have provided supporting evidence of an association, but it is still far from clear. Researchers from the Karolinska Institutet set out to investigate the link. They conducted a population-based, case-control study in Denmark and Sweden, taking detailed information on history of sun exposure and other risk factors for lymphoma from 3,740 lymphoma patients and a similar number of healthy people. The patients' conditions included non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and Hodgkin's lymphoma. Results showed that exposure to UV radiation were related to non-Hodgkin's lymphoma, but not in the direction that was expected. It appeared to decrease, rather than increase, the risk. The authors describe the association as consistent and statistically significant. High ratings on various measures of UV light exposure such as sunbathing, sunburn and holidays abroad by the age of 20 reduced non-Hodgkin's lymphoma risk by 30-40 per cent. Moreover, risk dropped as exposure level increased. Increased UV exposure was linked less strongly to a decreased risk of Hodgkin's lymphoma. Previous skin cancer increased the risk of malignant lymphoma, as expected from earlier studies, so the researchers suggest that the link between skin cancer and malignant lymphoma is probably not due to UV exposure. They add that further evidence is needed before we can be certain that UV exposure is protective against lymphomas. Knowledge of the mechanism behind the effect is also necessary.

In an editorial accompanying the study, experts from the International Epidemiology Institute write that vitamin D may be a central mediator in the relationship between UV exposure and cancer. They support the call for further research, given the major potential consequences for public health.
Ekstrom Smedby, K. et al. Ultraviolet radiation exposure and risk of malignant lymphomas. Journal of the National Cancer Institute, Vol. 97, February 2005, pp. 199-209
Egan, K.M., Sosman, J.A. and Blot, W.J. Sunlight and reduced risk of cancer: Is the real story vitamin D? Journal of the National Cancer Institute, Vol. 97, February 2005, pp. 161-163

Hope for thrombosis benefit of vitamin D for cancer patients
EDMONTON, CA. Thrombosis in cancer patients may be prevented by taking a form of vitamin D, suggests a clinical trial of 250 patients with advanced prostate cancer. Alongside treatment with the chemotherapy drug Docetaxel, half of the patients were given high-dose calcitriol - a naturally-occurring hormone and the biologically active form of vitamin D. The remainder took a placebo. The study set out to examine the effects of calcitriol on PSA levels, but the researchers discovered that those on calcitriol had a "significant reduction in both venous and arterial thromboses" compared with the placebo group. This reduction of thrombosis (clots in blood vessels) was not anticipated; say the researchers from Oregon Health and Science University, USA. They explain that thrombosis affects between 15 and 20 per cent of cancer patients, and can be serious. This finding offers an avenue of investigation that could result in a new class of anticoagulants, which could in turn, significantly improve outcomes for cancer patients.
Venner, P.M. et al. Reduced thromboembolic events with DN-101 (high-dose calcitriol) treatment of androgen-independent prostate cancer: Hypothesis for a new class of anticoagulants. Journal of Clinical Oncology, 2006 American Society of Clinical Oncology (ASCO) Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: Abstract number 4505

Vitamin D and breast cancer
SAN DIEGO, CA. A report has just appeared in the Journal of Steroid Biochemistry & Molecular Biology by Garland et al that addresses the issue of vitamin D and breast cancer risk with a pooled analysis of studies that determined the vitamin D status from serum 25-hydroxyvitamin D (25(OH)D) levels. The list of authors includes both well-known vitamin D experts and nutritional epidemiologists. The authors were only able to find two studies that met their requirements for inclusion in their pooled analysis, but together they involved 1760 individuals. Both studies covered a wide range of 25(OH)D levels and exhibited a high level of inverse correlation between breast cancer risk and the serum level of this vitamin D marker. When pooled analysis was carried out, the odds ratios for the lowest to highest quintile of 25(OH)D levels were 1.00, 0.90, 0.70, 0.70 and 0.50, i.e. the highest vitamin D status provided a 50% reduction in risk. The authors present a graph of risk (odds ratio) against serum 25(OH)D levels with an amazing correlation coefficient of 0.94 (a statistical measure of the goodness of fit to the model, in this case a straight line, and 1.00 represents a perfect fit), a correlation coefficient that would please those trained in the physical sciences and in fact a correlation very rarely seen in plots presented in the medical literature.

The authors discuss the level of intake that would accomplish the 50% level of risk reduction. If a person were to start at a serum level of 24 nmol/L (10 ng/mL) it would require supplementation of 4000 IU/day to achieve the required level of 120 nmol/L. This exceeds the current upper limit of 2000 IU/day. However, as they point out, a proposal has been made to raise this limit to 4000 IU/day. As discussed in this Newsletter, levels of 24 nmol/L are not uncommon among US women in the winter months. An alternative they explore is to take 2000 IU/day orally and make up the balance by judicious sun exposure. They estimate that 12 minutes of sun exposure for 50% of the skin would produce the missing 2000 IU. However, this would not happen in the northern latitudes in the winter months. The authors hammer home their point regarding the importance of vitamin D by calculating that, based on their data, an intake of 4000 IU of vitamin D per day would, in the U.S., prevent over 100,000 cases of breast cancer per year. Intake of 2000 IU/day was estimated to prevent 66,000 cases. In this paper, vitamin D refers to vitamin D3.
Garland, C. F. et al. Vitamin D and the Prevention of Breast Cancer; Pooled Analysis. Journal of Steroid Biochemistry & Molecular Biology, 2007, Vol. 103, pp. 708-711.

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Vitamin D and Cardiovascular Disease

Vitamin D and congestive heart failure
BONN, GERMANY. New research suggests that congestive heart failure (CHF) may be partly caused by raised levels of pro-inflammatory cytokines - proteins released by cells that direct the actions of other cells including tumor necrosis factor alpha and interleukin 6. CHF is a chronic condition involving loss of pumping power by the heart. Patients experience shortness of breath and fatigue because the inefficient blood flow limits oxygen delivery to tissues and organs.

Laboratory-based research indicates that vitamin D has the ability to suppress pro-inflammatory cytokines and increase anti-inflammatory cytokines, so a team from the University of Bonn examined the effect on CHF patients of supplementation with vitamin D. They analyzed data on 93 patients, half of whom received 50 micrograms/day (2000 IU/day) vitamin D3 and 500mg calcium. The remaining half received calcium alone, with a placebo. Survival to 15 months did not vary between the groups, neither did left ventricular function, however, participants on vitamin D3 showed significant increases in levels of 25-hydroxyvitamin D, parathyroid hormone, interleukin 10, and tumor necrosis factor alpha, after nine months. Specifically, 25-Hydroxyvitamin D (the biologically active form of vitamin D) was significantly increased in the vitamin D group compared with the control group. In the vitamin D group, levels of parathyroid hormone were significantly reduced following supplementation. This is beneficial, as parathyroid hormone removes calcium from the bones and other body stores. Furthermore, levels of the anti-inflammatory cytokine interleukin 10 went up after vitamin D supplementation. The pro-inflammatory cytokine tumor necrosis factor alpha was found to have increased in the control group, whereas it stabilized in the vitamin D group. The team concludes that vitamin D3 may prove a useful anti-inflammatory agent for CHF patients. They add that a problem with the vitamin D/parathyroid hormone/calcium axis may contribute to the worsening of CHF.

In an editorial, experts from the University of Toronto point out that a nutritional intervention for CHF would be extremely valuable. They write that the study suggests a protective effect for vitamin D on the heart and on the atherosclerosis (hardening of the arteries) that may trigger CHF.
Schleithoff, S. S. et al Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. American Journal of Clinical Nutrition, Vol. 83, April 2006, pp. 754-59
Vieth, R. and Kimball, S. Vitamin D in congestive heart failure. American Journal of Clinical Nutrition, Vol. 83, April 2006, pp. 731-32

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Vitamin D and Bone Health

Vitamin D in pregnancy protects children's bones
SOUTHAMPTON, UNITED KINGDOM. Giving pregnant women vitamin D could mean their babies grow stronger bones in later life and will therefore be at lower risk of sustaining bone fractures, a new study suggests. The study found that the mothers of children with weaker bones were lacking in vitamin D while they were pregnant. Vitamin D is needed for bone development during childhood, yet women of childbearing age are often deficient.

A team at the MRC Epidemiology Resource Center, Southampton General Hospital gathered data on 198 children born in 1991 and 1992 and compared it against the vitamin D status of their mothers, assessed by a blood test in late pregnancy. Nearly half the women (49 per cent) had insufficient vitamin D at this point. When the children reached nine years of age, the researchers measured their body size and bone mass and found that children whose mothers were lacking in vitamin D had weaker bones and a higher fracture risk. The authors explain that these findings provide evidence that maternal vitamin D status during pregnancy influences the bone growth of the offspring, and their risk of osteoporosis in later life. Maternal vitamin D levels have not previously been measured in relation to children's bone mass. The results add to a large body of evidence suggesting that development within the womb and during the time shortly after birth contributes to bone mineral accrual and thereby osteoporosis risk. The findings also point to preventive strategies which now require evaluation in randomized controlled trials, say the authors. Vitamin D supplementation of pregnant women, especially during winter months, could lead to long-lasting reductions in the risk of bone fracture in their children. Vitamin D is crucial for the absorption of calcium which is central to the formation of healthy bones. Levels can be improved though diet (oily fish and eggs), supplementation, and sunlight, which enables the body to make vitamin D in the skin.
Javaid, M.K. et al. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet, Vol. 367, January 2006, pp.36-43

Supplementary vitamin D may prevent fractures
BOSTON, MASSACHUSETTS. Bone fractures in older people are a significant cause of mortality and ill-health, with rates set to increase with the aging population. Hip fractures are particularly widespread, and lead to permanent disability in approximately 50 per cent of patients. One prevention strategy, which has been suggested, is supplementing with vitamin D. It has been examined in several studies and a team from Harvard School of Public Health has analyzed the findings so far. They used rigid rules to select 14 reliable studies of oral vitamin D supplement (using cholecalciferol [vitamin D3]) against placebo on hip and non-vertebral fractures in people over 60 years of age. In total, this included 9,294 participants in hip fracture studies and 9,820 in studies of non-vertebral fractures. The average age of participants was 79 years, and two-thirds were female. The trials using low-dose (400 IU/d) and higher-dose vitamin D (700-800 IU/d) were analyzed separately. The higher dose lowered hip fracture risk by 26 per cent and overall non-vertebral fracture by 23 per cent. No benefit was found for the lower dose. Results suggest that for every 45 people taking the higher dose, one hip fracture could be avoided, and for every 27 people one non-vertebral fracture could be avoided. The duration of supplementation did not alter fracture rates, possibly due to the rapid effects of vitamin D found previously. The mechanisms which lie behind the benefit may be reductions in bone loss and increases in muscle strength and balance, all of which reduce fall risk. However, calcium was also given in many of the trials and may have influenced fracture rates. The authors conclude that vitamin D at 700-800 IU per day should reduce fracture rates by about a quarter. They believe that a compelling case has been made for general vitamin D supplementation in older people. They also conclude that the currently recommended daily intake of 400 IU is inadequate to prevent fractures. A high intake of calcium may also be necessary and should be investigated further, as should even higher doses of vitamin D and the interaction between the two nutrients.
Bischoff-Ferrari, H.A. et al. Fracture Prevention with Vitamin D Supplementation A Meta-analysis of Randomized Controlled Trials. Journal of the American Medical Association, Vol. 293, May 2005, pp. 2257-2264

Vitamin D's protective effect on bones confirmed
OBU, JAPAN. The importance of vitamin D for the prevention of osteoporosis is well recognized, especially in the elderly population, in whom vitamin D deficiency is common. Researchers have now discovered one of the ways in which vitamin D keeps bones strong, and they may be close to developing targeted drugs for osteoporosis. A team at Japan's National Center for Geriatrics and Gerontology discovered that treating rats with the active form of vitamin D (1,25-dihydroxyvitamin D3) inhibited bone resorption and prevented bone loss. They found that this is due to vitamin D inhibiting the production of a protein called c-Fos, which is important in the formation of osteoclasts - specialized cells which oversee breakdown and resorption of bone. Therefore, when c-Fos is inhibited by vitamin D, osteoclast development and activity is suppressed and the natural bone loss through ageing is slowed. The study involved mice with severe osteoporosis, some of which had their ovaries removed to imitate human osteoporosis more closely, as the condition is much more common in postmenopausal women with less estrogen. The team also used these mice to look for other agents, similar to vitamin D, which might suppress c-Fos. A compound known as DD281 was identified, and shown to prevent bone loss even more effectively than natural vitamin D. The authors explain that vitamin D is routinely prescribed for the treatment of osteoporosis, but little has been known about how it regulates bone cell function. They state that this study clarifies how vitamin D helps limit bone resorption in conditions such as osteoporosis. Further trials are needed using DD281 for the treatment of osteoporosis and other bone diseases associated with excessive bone resorption, they believe, due to the compound's potent antiresorptive action.
Takasu, H. et al. C-Fos protein as a target of anti-osteoclastogenic action of vitamin D, and synthesis of new analogs. The Journal of Clinical Investigation, Vol. 116, February 2006, pp. 528-535. http://www.jci.org/cgi/content/full/116/2/528

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Vitamin D: Odds and Ends

Vitamin D and multiple sclerosis
BOSTON, MASS. It is estimated that 350,000 individuals in the U.S. and 2 million worldwide are afflicted with multiple sclerosis (MS). This terrible disease is more common in young adults. One high profile victim well known to classical music fans was the famous cellist Jacqueline Dupre, for whom the disease proved fatal by the time she was in her early 40s, long after she was forced to stop performing. A study reported in the December 20th Journal of the American Medical Association found high circulating levels of vitamin D associated with a lower risk of MS. The authors point out that a striking feature of MS is a multifold increase in incidence with increasing latitude both north and south of the equator. Such a geographic variation points to vitamin D as a potential factor. Because food provides little vitamin D, most people must obtain this vitamin through the action of ultraviolet (UV) sunlight on the skin which generates vitamin D from cholesterol by a photochemical process. In the temperate latitudes (>40 degree N) there is a huge seasonal variation in sunlight-generated vitamin D because during the winter months there is little or no ultraviolet radiation of the necessary wavelength. Thus seasonal vitamin D deficiency is not only common but almost the norm for those living in the temperate zones, and this includes a significant percentage of the world's population. Also, dark-skinned individuals generate lower levels of vitamin D from the same sunlight exposure due to the blocking of UV by skin pigments.

The study in question made use of a unique source of data from more than 7 million blood samples left over from routine blood tests which were stored by the U.S. military. Military personnel generally provide one sample at entry and on average, one every two years thereafter. This allowed a prospective nested case control study that related vitamin D status to the risk of MS. Controls were randomly selected and 2 controls were matched to each MS case by age, race/ethnicity, and dates of sample collection. The metabolite 25-hydroxyvitamin D was used as a measure of vitamin D status. In addition, information was collected on latitude of place of residence at time of entry into the military in order to account for variability caused by sunlight exposure. Among white skinned individuals, when the lowest quintile (fifth) of serum 25-hydroxy vitamin D was compared with the highest (>99.2 nmol/L), a statistically significant 62% reduction in MS risk was observed, and there was a 41% decrease in risk for every 50 nmol/L increase in this serum marker. This inverse association between 25-hydroxyvitamin D levels and MS was particularly strong in individuals where the vitamin D status was measured before the age of 20. No protective effect was observed among blacks or Hispanics. but in this cohort, black skinned individuals had much lower levels of the serum marker.

The authors discuss the possibility of reducing the risk of MS by raising the circulating levels of 25-hydroxyvitamin D. They point out that almost half of white and two-thirds of black adults in the U.S. have 25-hydroxyvitamin D levels below 70 nmol/L and that according to recent evidence, the best levels are between 90 and 100 nmol/L. However, the authors appear reluctant to specify a supplement intake level and comment that a "several-fold increase in vitamin D intake among adolescents and young adults requires stronger evidence than provided by observational studies alone."
Munger, K.L. et al. Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis. Journal of the American Medical Association, 2006, Vol. 296, No. 23, pp. 2832-38.

Vitamin D may protect against gingivitis
BOSTON, MASSACHUSETTS. Vitamin D may reduce the risk of periodontal disease and tooth loss, but there is currently limited evidence of whether it could reduce chronic marginal gingivitis. A study based at Boston University investigated the link between body stores of vitamin D and gingivitis, a common inflammation of gum tissues due to bacterial plaque build-up. The study involved 6,700 non-smokers between 13 and 90 years of age taking part in the 3rd National Health and Nutrition Examination Survey. Participants gave blood samples, and vitamin D status in blood serum was measured with a radioimmunoassay kit. Levels ranged from 25 to 125 nanomols of 25-hydroxyvitaminD(25(OH)D) per liter (nmol/L). Study participants then underwent an assessment of their gums in which examiners used a periodontal probe to examine the health of the gums, as bleeding on probing is a typical symptom of gingivitis.

The researchers found a significant inverse association between serum vitamin D concentration and chronic gingivitis in all participants, meaning that the higher the vitamin D status of the individual, the less gingivitis they showed. Men and women in the highest fifth for vitamin D status were 20 per cent less likely to bleed on gingival probing than those in the lowest fifth. The link appeared to be linear, and was independent of age, sex, ethnicity, income, body mass index, diabetes, use of oral contraceptives and hormone replacement therapy. It was also unconnected to use of vitamin and mineral supplements. Although vitamin D is essential for bone growth, gingivitis is usually not related to the health of the jawbone, so the researchers conclude that vitamin D reduces vulnerability to gingivitis through an anti-inflammatory and immune system enhancing effect. They also believe that marginal gingivitis could be used to further study vitamin D's anti-inflammatory effects on the human body.
Dietrich, T. et al. Association between serum concentrations of 25-hydroxyvitamin D and gingival inflammation. American Journal of Clinical Nutrition, Vol. 82, Sept 2005, pp. 575-80

Vitamin D, sun exposure and seasonal flu
ATASCADERO, CA. The authors of this paper represent a wide range of expertise. Included are a highly respected expert in nutritional epidemiology from Harvard, well known investigators in the field of vitamin D research and an expert on atmospheric research. They advance the hypothesis that the remarkable and recurrent seasonality of epidemic influenza, i.e. its regular and predictable appearance each winter in each hemisphere, is related to vitamin D, or the lack of it, and that this is the source of the seasonal stimulus. Humans depend almost exclusively on sunlight as their source of vitamin D. It is probably not common knowledge among the general public that above a latitude of about 30 degree to 40 degree North or South the intensity of the required wavelengths of ultraviolet light (UV) is such that little or no vitamin D production in exposed skin occurs between October and April, and vitamin D deficiency has been repeatedly documented during the winter for individuals living in the higher latitudes.

The authors develop their case by reviewing the role vitamin D plays in immunology and how it dramatically stimulates the expression of potent anti-microbial peptides which exist in the various cellular components of the immune system and as well the in the epithelial cells lining the respiratory tract where these proteins play a significant role in protecting the lung from infection. They also discuss the ability of vitamin D to suppress excessive cytokine and chemokine production related to inflammation. There follows a large amount of evidence that directly supports their hypothesis, including the observation that UV radiation from either sunlight or artificial sources reduces the incidence of viral respiratory infections, as does cod liver oil, a source of vitamin D. Also, supplementation with vitamin D has been shown to reduce the incidence of respiratory infections in children and a vitamin D deficiency predisposes children to these infections. Finally, they show dramatic graphic evidence of the seasonal variation of influenza in both hemispheres for latitudes above 30 degree (the so-called temperate zones) and no seasonal variation in the tropical zones (0-29 degree latitude). The authors take the conservative position that it is premature to recommend vitamin D for either the prevention or treatment of viral respiratory infections, but they significantly qualify this position by saying that it is not too early to recommend that health-care providers aggressively diagnose and adequately treat vitamin D deficiency with a goal of achieving serum 25-hydroxy vitamin D (the easily measured metabolite found in blood) at summertime levels obtained by sun exposure (50 ng/mL which is equivalent to approximately 125 nmole/L). They point out that those with large amounts of melanin in their skin (dark-skinned), the obese and the aged may need up to 5000 IU per day to achieve such levels in the winter. They also point out that 3000 IU/day of vitamin D is the estimated requirement such that 97% of Americans obtain levels > 35 ng/mL.
J.J.Cannell et al, Epidemic Influenza and Vitamin D. Epidemiology and Infection, Vol. 134, No. 6, pp. 1129-40.

Editor's comment: This seems to be a very significant paper that may not receive the attention it deserves due to the somewhat specialized journal in which it was published. The case the authors make for their hypothesis seems quite strong and at the very least should prompt trials involving direct intervention with winter supplementation. Vitamin D researchers have for some time been suggesting doses of at least 1000 IU/day for individuals at risk of a deficiency, and the current U.S. government guideline gives 2000 IU/day as the safe upper limit. The authors of this paper suggests that even higher doses may be appropriate and safe for some, and they point out that even single injections of 600,000 IU have recently been recommended for the elderly to prevent vitamin D deficiency. In Europe, the 40 degree N latitude line runs near Madrid Spain, the heel of the Italy boot, and northern Greece. In North America, it runs near Reno, Denver, Columbus and Philadelphia, Obviously, a large number of individuals live above 40 degree N latitude!



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