Vitamin D Research: 2004-2009

Vitamin D Deficiency and Requirements

D3 dose dependence of serum 25-hydroxyvitamin D
In a letter commenting on a recent study[1] which attempted to establish the vitamin D requirements for free-living adults age greater than or equal to 65, Reinhold Vieth criticizes the extrapolations used and comments that empirical data on the topic already exists. If one examines the publications from Vieth's laboratory over the last decade which address the question of the connection between vitamin D intake and serum levels of 25(OH)D, it is clear that there is considerable inter-individual variation and that there is a distinct plateau effect that occurs within 3 months of initiation supplementation.[2- 4] Furthermore, the final 25(OH)D concentration is not significantly correlated with the initial value nor with body weight.[3] For example, supplementation for more than 6 months produced the following results in one study[4]

These results suggest that once one has their baseline 25(OH)D value, something everyone no matter what age should have, then it is only possible to roughly estimate the dose required to achieve, say, 50 to 70 ng/mL. If it is assumed that all the studies on toxicity are correct, then starting with 4000-5000 IU per day appears safe, and after a few months another blood test is indicated and the dose adjusted accordingly.

1. Cashman KD, Wallace JM, Horigan G et al. Estimation of the dietary requirement for vitamin D in free- living adults >=64 y of age. Am J Clin Nutr 2009 May 1;89(5):1366-74.
2. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999 May 1;69(5):842-56.
3. Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am J Clin Nutr 2001 February 1;73(2):288-94.
4. Vieth R, Kimball S, Hu A, Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the well-being of patients. Nutr J 2004 July 19;3:8.

New data from American Academy of Pediatrics on prevalence of vitamin D deficiency
Shocking new numbers just appeared from a new study which indicate that 61% of those between 1 and 21 years in the U.S. have vitamin D levels, as measured by 25-hydroxyvitamin D that are classified as insufficient (15-29 ng/mL), and 9% have levels so low as to be described as deficient (< 15 ng/mL). For non-Hispanic black individuals and Mexican Americans the prevalence of deficiency and insufficiency was even higher. For example, for non-Hispanic black girls 1-6, 7-12 and 13-21 years of age, 85%, 97% and 98% had levels < 30 ng/mL respectively. For levels < 15 ng/mL, the corresponding prevalence figures were 10%, 28% and 59%, i.e. more than half of the female adolescents in this ethnic group were outright deficient. In all groups, the problem became more severe with increasing age. One of the study authors, Dr. Michael Melamed from Albert Einstein College of Medicine, was quoted in the Washington Post (August 3, 2009) as saying "At first we couldn't believe the numbers. I think it's very worrisome". A study published in the same issue of Pediatrics found that low levels of vitamin D in U.S. adolescents were strongly associated with hypertension, hyperglycemia, and the metabolic syndrome, independent of adiposity. The distribution of 25-hydroxyvitamin D levels in the cohort was such that they used > 26 ng/mL as the threshold for the highest quartile, i.e. insufficiency was very common.

In late 2008, the American Academy of Pediatrics published guidance concerning recommended vitamin D supplementation in infants, children and adolescents. They abandoned the long-standing recommendation of 200 IU/day in favour of 400 IU/day. They recognized deficiency at a blood level < 20 ng/mL of 2-hydroxyvitamin D and insufficiently in the range of 20-32 ng/mL. Apparently on the basis of just one cited study which showed that 400 U/day of vitamin D would maintain levels above 20 ng/mL in exclusively breast fed infants, they recommend for infants, children and adolescents an intake of 400 IU/day. It is well known that 400 IU/day is totally inadequate for many adults and thus probably for adolescents if the goal is sufficiency or optimal levels, so presumably the recommendation is to avoid profound deficiency but not even eliminate insufficiency. The recommendation does not take into account age, skin color or latitude of residence. More importantly, it does not take into account seasonal variation. Also, they strongly support the recommendation advising decreasing sunlight exposure with protective clothing and sunscreens. However they recognize that 10-15 minutes of sun full-body sun exposure in the summer will generate 10,000- 20,000 IU. Readers of the paper are left to ponder the discrepancy between 400 IU/day and 20,000 IU/day.

The "optimum" blood levels quoted above, i.e. 50-70 ng/mL, which may still be too conservative, are clearly off the radar screen of experts in pediatrics and are so far above what is seen in infants, children and adolescents, that it is hard to be optimistic that optimum levels will be reached any time soon. The impact this will have not only general health but also the susceptibility to influenza will probably be significant. Finally, one wonders why the goal is sufficiency and not optimization of vitamin D levels and why the need for distinguishing between deficient and insufficient when both are highly undesirable.
Kumar J, Muntner P, Kaskel FJ, Hailpern SM, Melamed ML. Prevalence and Associations of 25-Hydroxyvitamin D Deficiency in US Children: NHANES 2001-2004. Pediatrics 2009 August 3;eds.

Institute of Medicine (US) ready to recommend new adequate intake and upper limits of vitamin D
The Institute of Medicine (IOM) has formed a committee to set recommendations regarding adequate intake of and upper limits for vitamin D. In The Vitamin D Newsletter, concerns are raised regarding the composition of the committee. The major problem pointed out is the noteworthy absence of scientists who have been leaders in the so-called vitamin D revolution. Nevertheless, the committee does appear to have diversified experience in vitamin D related areas, and one individual was involved with the Woman's Health Initiative study. The Vitamin D Newsletter points out that this large and expensive study was noteworthy for simply showing that "meaningless doses of vitamin D are meaningless". The newsletter also points out that a number of the most distinguished vitamin D investigators just published a paper critical of the IOM and the related Food and Nutrition Board. This paper will be discussed below. The criticism centered on recommendations regarding adequate intakes of vitamin D, the mandate of the new committee. And if past performance is any guide, the adequate levels of intake will be considerably lower if not vastly lower than currently recommended by the experts whose absence from the committee was noted.
National Academies. Committee Membership Information--Dietary Reference Intakes for Vitamin D and Calcium. http://www8.nationalacademies.org/cp/committeeview.aspx?key=49031 . 20-1-0009

Circulating vitamin D and 25-hydroxyvitamin D
An interesting and important question regarding vitamin D therapy is the conversion of vitamin D3 to 25-hydroxyvitamin D (25-OH D). A recent study has provided considerable insight. It was found that the concentration of 25-OH D in response to input vitamin D3 was biphasic, i.e. a rapid increase occurs at low vitamin D concentration and a slower response occurs at higher concentrations. Thus, if one starts with a low level of 25-OH D, almost all the input vitamin D was converted and there was little storage. Once the turning point is reached, the 25-OH D continues to rise, but now the level of vitamin D also increases, with the vitamin level increasing faster than the product molecule. This turning point is produced by an intake of roughly 2000 IU. Thus below the turning point, the 25-OH D product is the major storage molecule for vitamin D. Above this point, the conversion in the liver appears to saturate and the vitamin itself is stored, most likely in the fat. The authors postulate that the point where the conversion in the liver saturates may be considered optimal for health. Their results suggest a value of 35 ng/mL or 88 nmol/L. They point out that this value is close to that obtained in attempts to define the lower end of normal from the relationship of 25-OH D to calcium absorption and to serum parathyroid hormone concentrations (75-85 nmol/L). Parathyroid concentrations are inversely related to 25-OH D levels but level off at 75-100 nmol/L of serum 25-OH D.
Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr 2008 June;87(6):1738-42.

Vitamin D - The American Institute for Cancer Research position
In an online position statement bearing a copyright date of 2007, this cancer research institute stated a number of points which included:

• "Children between six months and five years could benefit from taking drops containing vitamins A, C and D, although children with good appetite who eat a wide variety of foods may not need them".

• "Older people should consider taking a vitamin D supplement, as should: people who rarely go outdoors; people who cover up all their skin when outdoors; those who don't eat meat or oily fish".

One would think that when a recommendation is put out for a world-wide audience, it would provide accurate and useful information. Missing from the above statement are (a) the fact that in the northern latitudes, and this includes a significant portion of the US, exposure to the sun from October to March is a non-issue since no vitamin D is generated. The AICR presumably does not think this is important information in spite of the fact that they mention being outdoors as a factor; (b) Food is a notoriously poor source of vitamin D unless one eats large amounts of oily fish. If we are to believe the current expert opinion that 2000 IU or more is needed in the winter in the northern latitudes, then food as a source is totally unrealistic, and certainly meat is also. 2000 IU/day from oily fish requires consuming about a pound per day. There are very few individuals who will eat a pound of salmon every day; (c) Why restrict the recommendations to older people. Is vitamin D deficiency, which is recognized to be widespread among all ages, to be ignored in favour of an age group where the problem is especially severe? (d) Given that this is such a critical issue - why do they not discuss supplement doses. Many who read this recommendation will look at their multivitamin bottle, see 400 IU and think all is OK when in fact this amount turns out to have almost no impact on achieving optimal vitamin D status; (e) they state clearly that children between six months and 5 years who have a "good appetite and eat a wide variety of foods" do not need vitamin D supplements but otherwise vitamin drops would be satisfactory. No mention is made of graduated dose per body weight and if children do not eat oily fish, about the only source left is fortified food which is generally inadequate, and simply eating a wide variety of food devoid of vitamin D has no bearing on the problem.

Editor's comment: This paper prompted an editorial in the same issue (pp. 649) with an author list that reads like a Who's Who in vitamin D research and nutritional epidemiology. They point out that 30-40 years ago, these same low levels of 25(OH)D were considered indicative of healthy white adults in the UK, a judgment based on levels that just prevented rickets, a crippling disease characterized by the softening and bending of bones. The authors of this editorial reiterate the position that the threshold for a desirable 25(OH)D level is 75 nmol/L. Statements indicating the merits of this threshold and as well the widespread prevalence of vitamin D deficiency have repeatedly appeared in the medical literature and in the media, but the authors point out that media reports also frequently repeat what they term outdated and misleading guidelines from such organizations as the Institute of Medicine, and the impression is frequently given that it is not wise to exceed the amounts recommended by accepted guidelines for daily intake, amounts that are in general inadequate to raise 25(OH)D levels to a minimum of 75 nmol/L. They also point out that a recent study of toxicity concluded that a safe upper limit for adults should be raised to 10,000 IU/day (Am J Clin Nutr, 2007;85:6-18), whereas the conventional guidelines for daily intake for those aged 51-70 is a mere 600 IU/day and the currently accepted safe upper limit is 2000 IU/day. Finally, they recommend that action be taken with regard to more food fortification and increasing the amounts of vitamin D in supplement products (such as multivitamins), actions they suggest that could well bring about "rapid and important reductions in morbidity" associated with the current state of affairs as regards low vitamin D status.

Vitamin D intakes in North America and Asia-Pacific countries insufficient
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. Journal of Steroid Biochemistry & Molecular Biology, Vol. 103, March 2007, pp. 626-30

Vitamin D3 should be used in preference to vitamin D2, say experts
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 Has time come for an increase in recommended vitamin D intakes?
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

Vitamin D deficiency in southern Florida
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 and Influenza

What is interesting is the total absence of any mention whatsoever in the print and TV media of the role that vitamin D plays in infectious diseases in general and influenza in particular. Lack of professional awareness may be due to the fact that the key literature is not in any of the very few high-profile journals (but nevertheless is in important peer-reviewed specialty journals). It may be due to the fact that a major source of medical information is the drug rep, and drug reps obviously do not discuss vitamin D or hand out appropriate reprints. Furthermore, the high levels of evidence "required" today combined with the general distaste for vitamin therapy may combine to encourage many professionals simply to dismiss vitamin D, thus ignoring both our evolution and a huge body of evidence related not just to the flu but to infectious diseases in general, heart disease, multiple sclerosis, diabetes and cancer. Whatever the reason, the general public is not being told about the one simple, cheap and potentially effective step they can take to reduce the risk of flu in themselves and their children. And in fact this information should have been provided months ago in order that vitamin D levels could be enhanced. Measurement of vitamin D status appears rare, although the two reports in the November issue of the Newsletter https://www.yourhealthbase.com/ihn_november2009.pdf suggest that when it is done and corrective measures taken, the dividends appear large in the context of influenza.

The H1N1 virus appears to be particularly dangerous for children, young people and pregnant women. Thus the question, what is known about the role of vitamin D in respiratory infections in newborns and children? The answer appears to be quite a lot. A recent review of the vitamin D connection with pediatric infections and immune function makes a number of important observations.[1]

1. Several recent epidemiologic studies have observed the association between inadequate vitamin D concentrations and hospitalization and/or respiratory infection among children.
2. Children who have contracted TB typically have inadequate vitamin D stores.
3. Vitamin D deficiency manifest by rickets is strongly correlated with respiratory diseases.
4. Subclinical vitamin D deficiency was associated with acute lower respiratory tract infections (ALRIs) in children without rickets admitted to a private hospital in India.
5. A study found that newborns with acute lower respiratory infections had lower serum 25- hydroxyvitamin D levels than healthy controls. Infants with ALRIs spent an average of eight days in the neonatal ICU.
6. In contrast to data from adults, infections observed in children with inadequate vitamin D stores were more frequently of viral origin.
7. Susceptibility to infections in children appears before the overt manifestations of nutritional rickets are apparent.
8. Vitamin D insufficiency among pregnant women places newborns at greater risk for vitamin D deficiency which is dependent on and correlated with maternal 25-hydroxyvitamin D levels with the neonates exhibiting lower levels than the mother. Those born to marginally vitamin D sufficient women will still be at risk of significant deficiency, and those born to women who are deficient will almost certainly be deficient if not severely deficient themselves.

A study just published supports this general view. Twenty-five newborns with ALRIs who were admitted to a neonatal ICU were compared with 15 health newborns of the same age who acted as controls. The mean 25-hydroxyvitamin D (25(OH)D) levels were significantly lower in the ALRI group than the control group and as well, so were the levels of the mothers in the case group as compared to the control mothers. It was concluded that this strong correlation between vitamin D status and ALRIs shows that adequate vitamin D supplementation should be emphasized during pregnancy and especially in the winter months.[2]

In this connection, it is of interest that in 2008 the American Academy of Pediatrics changed their 2005 recommendation regarding vitamin D from 200 IU/day to 400 IU/day with supplementation to begin in the first few days after birth and continue through childhood and adolescence. The consensus committee involved in these recommendations also acknowledged the possibility that studies might indicate the merits of higher doses (1000-4000IU/day). It is clear that there is a critical need for clinical data that directly connects maternal and neonatal 25(OH)D levels and the risk of infectious diseases, including influenza and ALRIs.[1]

The connection between serum 25-hydroxyvitamin D levels and adolescent and adult upper respiratory tract infections based on a study published in the February 25th issue of the Journal of the American Medical Association[3] was briefly reviewed in the April, 2009 issue of the Newsletter. Contrary to the impressive results reported in this large study, recently a small randomized trial running only 12 weeks found no benefit from 2000 IU/day of vitamin D3 as regards the incidence of upper respiratory infections in adults. But this study was limited by short duration, the relatively high baseline levels of 25(OH)D, the lack of optimum power because of the small sample size and the limited number of self-reported cases and the fact that the subjects were not taking vitamin D before the influenza season started. Furthermore, this was not a trial to determine the impact of supplementation on a vitamin D deficient population. It would be unfortunate if this study was used to discredit vitamin D in the context of influenza or respiratory infections.[4]

1. Walker VP, Modlin RL. The Vitamin D Connection to Pediatric Infections and Immune Function. Pediatr Res Vol. 65, Pt 2, May 2009, pp. 106R-113R
2. Karatekin G, Kaya A, Salihoglu O, Balci H, Nuhoglu A. Association of subclinical vitamin D deficiency in newborns with acute lower respiratory infection and their mothers. Eur J Clin Nutr 2007 November 21;63(4):473-7.
3. Shaneyfelt TM, Centor RM. Reassessment of Clinical Practice Guidelines: Go Gently Into That Good Night. JAMA 2009 February 25;301(8):868-9.
4. Li-Ng M, Aloia JF, Pollack S et al. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect 2009 October;137(10):1396- 404.

H1N1 influenza and vitamin D
Readers may recall an earlier discussion of a landmark paper on vitamin D and influenza, which, among other things, attributed the seasonal and latitude variation to population vitamin D status. With this in mind, it my have struck some readers as odd that on TV and in the print media, the silence regarding the role that vitamin D might play in the prevention of an H1N1 infection has been profound. Mainstream focus is on vaccines and prescription anti-virals, period. While a whole issue could be easily be devoted to the subject of vitamin D and the flu, the extensive material on the website of the Vitamin D Council (http://www.vitamindcouncil.org/) does such a good job of providing an up-to-date to most of the important questions that instead readers are referred to this resource. This subject is well worth studying since it is not as simple a matter as one might suppose, even given the remarkable success of vitamin D supplementation in preventing flu and colds as seen in randomized and other intervention trials. In particular, attention is drawn to the article by Dr. J.J. Cannell, M.D., who is an internationally recognized vitamin D expert, coauthor of the paper mentioned above, and the Director of the Vitamin D Council. The title of the article is H1N1 Flu and Vitamin D and is listed currently among items on the home page. This may change so the URL is http://www.vitamindcouncil.org/newsletter/h1n1-flu-and-vitamin-d.shtml. Readers are also referred to the "Research" section under the research area subheading "Influenza" for an impressive set of links to the literature on vitamin D and influenza. Some of these links will yield full text and in particular the landmark paper Epidemic Influenza and Vitamin D and as well an equally important paper On the Epidemiology of Influenza. Dr. Cannell is the lead author in these papers, and both are co-authored by experts in either vitamin D or epidemiology. Attention is also directed to the paper on cod liver oil and vitamin A toxicity and the adverse impact on vitamin D efficacy which is also available in full text.

To your editor, it appears we have reached the point where all readers and their family members who do not know their current 25-hydroxy-vitamin D level should have the blood test. One of the reasons is that while the current recommendation of Cannell and many others is 4000-5000 IU of D3 per day, for some individuals this will not bring the serum level up optimum. Opinions vary on what is optimum, but start at 50-70 ng/mL (divide numbers in nmol/L by 2.5 to get ng/mL). This is not a simple matter because of the seasonal variation, and the goal should be to remain within or the above-optimum range throughout the year. Thus the result of the blood test must be considered in the light of when the sample was drawn. In general, the seasonal increase starts strongly in early spring, but this depends on the latitude. See the Vitamin D Council website for a discussion of optimum levels, deficiency seasonal variation and related topics. Also, it is important that one get the right blood test. The test for 1,25 dihydroxy-vitamin D is the wrong test and tells one next to nothing, but it is sometimes ordered by mistake or out of ignorance. Finally, the so-called reference ranges or "normal" values that come with laboratory reports should be ignored. In Canada, one of the major testing laboratory companies gives sufficiency as 30-100 ng/mL and toxicity as > 100 ng/mL. The former is misleading since 30 ng/mL is considerably below the threshold for optimum, and the toxicity level, according to modern opinion, is too conservative.

Finally, according to the July 27, 2009 Toronto Globe and Mail, the Public Health Agency of Canada is sponsoring a study of the 25-hydroxy-vitamin D levels in individuals diagnosed with H1N1. The goal is to determine if there is an association between the severity of the disease and the vitamin D status. The outcome and the resultant recommendation should prove interesting for a number of reasons. Furthermore, the medical scientists involved should have a wide range of 25-hydroxy-vitamin D levels with which to work, given that severe vitamin D deficiency is widespread, increasing, and acquiring the vitamin from sun exposure, which of course is what we evolved to do, is under constant attack from the dermatology community. Witness the latest campaign against getting just a suntan.

Association between vitamin D and influenza confirmed
A group of investigators have used the Third National Health and Nutrition Examination Survey database and examined the association between 25-hydroxyvitamin D (25(OH)D) blood levels and upper respiratory tract infections (URTI). Records of almost 19,000 participants 12 years and older were searched. Compared to individuals with 25(OH)D greater than or equal to 30 ng/mL, those with levels < 10 ng/mL and between 10 and < 30 ng/mL had increased risk of URTIs of 24% and 36%. For individuals with asthma or chronic obstructive pulmonary disease, those with low vitamin D levels were at much higher risk. Individuals with asthma and 25(OH)D levels < 10 were at 5.67 times the risk of URTIs compared to those with levels greater than or equal to 30 ng/mL and the same comparison for those with chronic obstructive pulmonary disease had a 2.26 times enhanced risk.
Cannell JJ, Zasloff M, Garland CF, Scragg R, Giovannucci E. On the epidemiology of influenza. Virol J, Vol. 5, Feb. 25, 2008, p.29

Vitamin D and influenza
A short report presenting a post hoc analysis of the incidence of influenza and common colds has recently been published. The data was derived from a prospective double blind trial of supplemental vitamin D for the prevention of bone disease in 208 African-American postmenopausal women of approximately 60 years of age. The dose was 800 IU per day in the first two years and 2000 IU per day in the third, with half given a placebo. Twenty-six women taking the placebo reported at least on cold or influenza compared to 7 taking 800 IU and only one taking 2000 IU per day.[1]

Editor's comments: It seems the following quote from a paper that discusses the pros and cons of sun exposure is appropriate: "Although diseases caused by excessive UVR [ultraviolet radiation] exposure are extremely common, they tend to occur in older age groups (due to the long lag between exposure and tumor development or a requirement for cumulative exposure) and be relatively benign, thus incurring a relatively low burden of disease in spite of their high prevalence".[2] The reader can contrast this observation with the serious nature of the diseases impacted by vitamin D and should reflect on the fact that aside from malignant melanoma, the skin cancers associated with sun exposure rarely metastasize and are generally cured by local treatment in the doctors office, which is something that most certainly can not be said for breast cancer or colorectal cancer!

1. Grant WB, Garland CF. The role of vitamin D3 in preventing infections. Age Ageing 2008 January 1;37(1):121-a.
2. Lucas RM, Ponsonby AL. Considering the potential benefits as well as adverse effects of sun exposure: can all the potential benefits be provided by oral vitamin D supplementation? Prog Biophys Mol Biol 2006 September;92(1):140-9.

Vitamin D, sun exposure and seasonal flu - Is there a connection?
While classified as a review article, this paper might better be considered a wake-up call. The authors 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 degrees to 40 degrees 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 degrees (the so-called temperate zones) and no seasonal variation in the tropical zones (0-29 degrees 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, 2006, 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 degrees 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 degrees latitude!

Vitamin D and Cardiovascular Disease

Vitamin D and the JUPITER trial
As discussed in the February issue https://www.yourhealthbase.com/ihn194jn.pdf, in the JUPITER trial the statin rosuvastatin (Crestor) reduced non-fatal heart attacks (MIs) by about 50% in individuals with normal LDL cholesterol and quite elevated C-reactive protein (CRP).[1] This was a primary prevention trial of subjects free of symptomatic heart disease although a significant number of subjects had the characteristics of the metabolic syndrome. It now turns out that there may have been more going on than just the reduction of LDL and CRP. In a just published study by Yavuz et al,[2] rosuvastatin was found to dramatically increase levels of 25(OH)D. Doses of 10-20 mg per day of rosuvastatin caused the 25(OH)D levels to increase from a mean of 14.0 (3.7 - 67) to 36.3 (3.8 - 117) ng/mL. Thus many individuals who would be considered deficient or insufficient achieved sufficiency or even optimum levels under the statin treatment. If one looks at the inverse association between the relative risk of MI according to 25(OH)D levels, for less than or equal to 15 ng/mL vs. greater than or equal to 30 ng/mL, the relative risk of 2.42 was found in a recent prospective study of subjects free at baseline of cardiovascular disease.[3] In Jupiter the subjects quite probably experienced a similar increase in vitamin D status as Yavuz et al found since the dose was the same. In JUPITER the relative risk of an MI for no statin vs. statin therapy was about 2.2. Thus there arises the question, was JUPITER seriously confounded by changes in vitamin D status? The change in 25(OH)D was large enough to explain the entire effect! In addition, the benefit in terms of MI was larger in JUPITER than, for example, in studies with atorvastatin which causes a much smaller increase in vitamin D status.[4] While the decrease in the risk of an MI was attributed to the impact of rosuvastatin on LDL and CRP in the JUPITER trial, it seems clear that this may be only part of the story, and how big a part can be debated. The most recent subgroup analysis of the JUPITER trial did not discuss this potential confounder.[5]

The results of Yavuz et al are curious in that statins inhibit the synthesis of 7-dehydrocholesterol which is both the precursor of cholesterol and the compound upon which UV light acts to produce vitamin D3 in the skin which then yields the metabolite 25(OH)D. It was expected that statins would reduce the levels of vitamin D3, but this effect was looked for some time ago but never observed. Now it appears that statins in fact increase at least the metabolites of vitamin D3 including 25(OH)D. In an editorial concerning the paper by Yavuz and colleagues, David Grimes discusses the possibility that the effect of the statin on 25(OH)D levels may be due to an interference with some mechanism which reduces the consumption of this metabolite. He suggests a mechanism involving the anti- inflammatory action of statins. He concludes that the ability of statins to lower cholesterol may be their least important clinical effect and reminds readers of the Framingham result that a significant relationship between life expectancy and high serum cholesterol is seen only in young men.

1. Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med, Vol. 359, Nov. 20, 2008, pp. 2195-207
2. Yavuz B, Ertugrul DT, Cil H et al. Increased levels of 25 hydroxyvitamin D and 1,25-dihydroxyvitamin D after rosuvastatin treatment: a novel pleiotropic effect of statins? Cardiovasc Drugs Ther 2009 August;23(4):295-9.
3. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med 2008 June 9;168(11):1174-80.
4. Aloia JF, Li-Ng M, Pollack S. Statins and vitamin D. Am J Cardiol 2007 October 15;100(8):1329.
5. Ridker PM, Danielson E, Fonseca FA et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009 April 4;373(9670):1175-82.

Vitamin D and risk of developing hypertension
A study presented at a recent American Heart Association meeting found that low vitamin D status was associated with increased risk of developing hypertension. While the abstract is short on details, the study examined 559 women in 1992 with measurements of blood pressure and 25-hydroxyvitamin D. At that time, 5.5% with deficiencies had high blood pressure compared to 2.8% who were deemed to have normal D status. In 2007, more than 10% of the women with baseline vitamin D deficiencies had high blood pressure whereas only 3.7% with sufficient D levels were hypertensive.
Reuters, September 23, 2009

Vitamin D and heart attacks in men
A study published in the Archives of Internal Medicine described a 10-year study which was part of the Health Professionals Follow-up Study. Over 18,000 men were involved, aged 40-75 who were free of diagnosed cardiovascular disease at baseline when blood was collected. At the end of the follow-up, there were 454 fatal heart attacks (MIs) or fatal coronary heart disease. A comparison was then made with 900 controls matched for age, date of blood collection and smoking status. At issue in this particular study was the connection between vitamin D status as measured by serum levels of 25-hydroxyvitamin D (25-OH D), with deficiency defined as ? 15 ng/mL and sufficiency ? 30 ng/mL (to get nmol/L, multiply by 2.5). Men who were deficient were at a 2.45 fold increased risk of MI. Correction for family history of MI, body mass index, alcohol consumption, physical activity, history of type 2 diabetes, hypertension, omega-3 intake, cholesterol, and triglycerides reduced the risk only to 2 fold. Both results were statistically significant. Even men with intermediate 25-OH D levels were at elevated risk providing an indication of a graded risk associated with vitamin D status.
Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med 2008 June 9;168(11):1174-80.

Vitamin D and all-cause and cardiovascular mortality
In this study, over 3000 men and women, mean age 62, scheduled for coronary angiography at a single center provided blood samples from which their vitamin D status could be determined. During a follow-up of almost 8 years, 737 patients died, including 463 from cardiovascular causes. Those in the lower two 25-OH D quartiles (median 7.6 and 13.3 ng/mL) had a 2-fold higher all-cause mortality compared to patients in the highest quartile (median 24.4 ng/mL). This enhanced risk was independent of coronary artery disease, physical activity level, comorbidities and functionality. Low vitamin D status was correlated with inflammation markers (c-reactive protein and interleukin-6), oxidative burden, and cell adhesion. Vitamin D(25-0H D) levels were consistently higher in patients without significant coronary artery disease and low vitamin D status seemed to be an important mediator of mortality even in the absence of overt vascular disease.
Dobnig H, Pilz S, Scharnagl H et al. Independent association of low serum 25-hydroxyvitamin d and 1,25- dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med 2008 June 23;168(12):1340-9.

Vitamin D and hypertension
Calcium metabolism is known to influence blood pressure (BP) and thus vitamin D may play a role in BP regulation. In fact, a receptor is present in smooth muscle tissue for the metabolite of vitamin D downstream from 25-hydroxyvitamin D (25-OH)D, suggesting a potential role of vitamin D in the regulation of smooth muscle contraction and therefore blood pressure. In addition, blood pressure is known to show a summer-winter variation in the northern hemisphere where vitamin D production during the winter is low. A study related to this subject has recently reported[1] that made use of data from the Third National Health and Nutrition Examination Survey, a gold mine of data for investigators attempting to examine important health related questions. The researchers made use of both serum 25-hydroxyvitamin D data and blood pressure data for a total of over 7600 individuals, a cohort representing white and black men and women. Sixty-three percent were between 18 and 49 years of age and 53% were women. Black individuals constituted about half of the cohort. It was found that a statistically significant inverse association was observed between circulating 25-(OH)D levels and six categories of systolic blood pressure (SBP) ranging from normal (< 120 mm Hg through the various stages to serious hypertension (greater than or equal to 160 mm Hg). In white participants, the age- associated risk of elevated SBP was 20% less in those who had 25-(OH)D levels > 80 nmol/L compared to their deficient counterparts with levels < 50 nmol/L. The researchers found that in the cohort examined, if a cut-off for deficiency of < 80 mmol/L was used, 61% of whites and 92% of blacks were deficient. In fact, the analysis for the black segment of the cohort was limited because so few black individuals had sufficient levels of vitamin D by this definition.

These results are consistent with another recently reported study that used the same database. When participants were divided into 25(OH)D quintiles, the mean systolic BP was 3.0 mm Hg lower and the diastolic BP 1.6 mm Hg lower for participants in the highest vs. the lowest quintile (greater than to equal to 86 vs. less than or equal to 40 nmol/L. This result was adjusted for confounding. The inverse association was stronger in participants greater than or equal to 50 years of age compared to younger individuals.[2]

These studies looked at 25(OH)D levels at the time of blood pressure measurements. In a prospective study of middle-aged and older women with a follow-up of 10 years, the risk of developing hypertension was examined as a function of the dietary intake of dairy products, calcium and vitamin D, all of which were ascertained by a food frequency questionnaire. It was found that low- fat dairy products, calcium and vitamin D were each inversely associated with the risk of developing hypertension, an observation the authors suggest should prompt consideration of their potential roles in primary prevention both of hypertension and cardiovascular complications.[3]

These results suggest that supplementation with vitamin D should reduce BP, but intervention studies are very limited - one randomized, placebo-controlled study of 145 elderly women showed that 400 IU of vitamin D3 and 600 mg of calcium significantly reduced systolic BP by over 9% after 8 weeks, whereas 600 mg of calcium alone produced only a 4% reduction. Serum 25(OH)D levels increased by 72% in the calcium plus vitamin D group.[4] Also, a study that used UV light in a small group obtained a reduction in systolic BP of 6 mm Hg after 6 weeks which accompanied an average increase in serum 25(OH)D level from 50 to 152 nmol/L.[5]

1. Judd SE, Nanes MS, Ziegler TR, Wilson PW, Tangpricha V. Optimal vitamin D status attenuates the age- associated increase in systolic blood pressure in white Americans: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr 2008 January;87(1):136-41.
2. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am J Hypertens 2007 July;20(7):713-9.
3. Wang L, Manson JE, Buring JE, Lee IM, Sesso HD. Dietary Intake of Dairy Products, Calcium, and Vitamin D and the Risk of Hypertension in Middle-Aged and Older Women. Hypertension 2008 February 7;51:1-7.
4. Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a Short-Term Vitamin D3 and Calcium Supplementation on Blood Pressure and Parathyroid Hormone Levels in Elderly Women. J Clin Endocrinol Metab 2001 April 1;86(4):1633-7.
5. Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet 1998 August 29;352(9129):709-10.

Vitamin D and cardiovascular risk
Published research by Wang et al addresses this issue in a prospective study of over 1700 men and women with a mean age of 59 years. Vitamin D status was ascertained by the blood levels of the standard marker 25-hydroxyvitamin D (25-OHD). They examined the impact of a deficiency defined either as < 15 ng/mL (38 nmol/L) or < 10 ng/mL (25 nmol/L). For individuals with levels below 15 ng/mL, an increase of about 62% was found for the risk of a first cardiovascular event (stroke or heart attack). When just those with hypertension were examined, the risk more than doubled as compared to those with levels greater than 15 ng/mL. The authors take a conservative view that "experimental studies may be warranted to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease". This is consistent with the fact that their study did not examine the risk stratified by 25-OHD levels up to those being widely recommended for cancer protection, i.e. 1000 IU per day, which would put most people in the serum range of over 75 nmol/L.

Editor's comments: The position of the American Heart Association in response to the study by Wang et al is interesting (Public release 7 January 2008 quoted on www.eurekalert.org). "The American Heart Association recommends that healthy people get adequate nutrients by eating a variety of foods in moderation, rather than by taking supplements. Food sources of Vitamin D include milk, salmon, mackerel, sardines, cod liver oil and some fortified cereals. Vitamin or mineral supplements aren't a substitute for a balanced, nutritious diet that limits excess calories, saturated fat, trans fat, sodium and dietary cholesterol". To obtain about 1000 IU per day from food, the minimum amount being recommended, incidentally by organizations representing mainstream medicine, for cancer prevention, avoiding influenza, and for good health in general, would require eating per day approximately 1/2 pound of salmon, 3/4 pound of sardines or mackerel, or 7 packets of instant fortified oatmeal. However, two to three teaspoons of cod liver oil would indeed provide such levels. The AHA position also implies that supplemental vitamin D is different than that found in food, but they then have to explain why supplements raise the level of the same chemical in the blood, 25- OHD, which is the know metabolite of vitamin D from either sun exposure or food.
Wang TJ, Pencina MJ, Booth SL et al. Vitamin D Deficiency and Risk of Cardiovascular Disease. Circulation, Vol. 117,Jan. 29, 2008, pp. 503-11

Statins and vitamin D
Those who have read the review on cholesterol in the past three issues are aware that there is considerable evidence concerning the non-lipid lowering benefits of the statin class of drug. In a recent issue of the American Journal of Cardiology, Aloia et al[1] report another benefit. In a randomized study, statin users and non-users were given either 800 IU of vitamin D3 or a placebo. After three years the dose was increased to 2000 IU. The really interesting observation was that at baseline, statin users as compared to non-users had significantly higher 25-hydroxyvitamin D (25- OHD) levels. The effect of supplementation was to raise the 25-OHD levels in both the statin user and non-user groups. The statin users achieved higher levels because the started with higher levels. The authors comment that statin use has been reported to reduce hip fractures and improve hip bone mineral density and they suggest that this may be associated with higher levels of 25-OHD. The mechanism by which statins increase vitamin D levels is not clear.

Editor's comment: As discussed above, vitamin D levels appear to also have cardio protective benefits. Thus there is another non-lipid lowering effect that could be related to the benefits of statins in secondary prevention of CHD. This brings to mind the recent announcement from Merck/Schering-Plough that ezetimibe (Zetia) when added to simvastatin had no added benefit as measured by the progression of carotid atherosclerosis even though the LDL reduction after 2 years was 58% vs. 41% for simvastatin alone. Zetia is a non-statin drug that lowers cholesterol by interfering with absorption from the gut. Great surprise and disappointment was voiced by the experts, but it may be that the most important message is that Zetia did not provide the non-lipid lowering benefits associated with statins, further reinforcing the notion that lipid lowering is a side effect and that statins are effective mainly because they have other actions which are dose dependent just as is lipid lowering.[2] This vitamin D result seems to further weaken the hypothesis that the causal association between cholesterol and heart disease is proven by the fact that lowering serum levels reduces incidents in individuals at high risk or with preexisting CHD.

1. Aloia JF, Li-Ng M, Pollack S. Statins and vitamin D. Am J Cardiol 2007; 100: 1329.
2. www.theheart.org, 01/08/2008. WEBMED . 1-8-2008.

Vitamin D and cardiovascular risk
A national survey designed to estimate the prevalence of common chronic conditions and associated risk factors was conducted in the US between 1988 and 1994 (NHANES III). It provided a database which is constantly mined for information about specific questions. A study based on this data was recently published which addresses the question of the association between vitamin D status and the prevalence of risk factors for cardiovascular disease (CVD) using the vitamin D serum marker 25- hydroxyvitamin D. Data for over 15,000 adult participants were available. When individuals with 25- hydroxyvitamin D levels less than 52 nmol/L were compared with those with levels equal to or greater than 92 nmol/L, it was found that those in the low-level group had significantly higher probabilities of have hypertension, abnormal blood glucose, history of diabetes, obesity, and high triglycerides. However, for two prominent risk factors, high total cholesterol or non-HDL cholesterol, no correlations were found. The authors claim that to the best of their knowledge this is the first study to demonstrate significant association between low vitamin D status and CVD risk factors in a nationally representative sample. In addition, they pointed out that favorable trends for the risk factors for obesity, diabetes and hypertension may well continue to increase at levels greater than 92 nmol/L conferring additional health benefits. In addition, their results were regarded as consistent with the established literature that suggests a role for vitamin D in promoting insulin sensitivity and preventing diabetes. They also present plausible biological mechanisms for some of the observed dependencies on vitamin D.
Martins, D. et al. Prevalence of Cardiovascular Risk Factors and the Serum Levels of 25-Hydrfoxyvitamin D in the United States. Archives on Internal Medicine, 2007, Vol. 167, June 11, pp. 1159-1165.

Editor's comments: It is clear that there is a relationship between vitamin D status and a wide variety of disorders. This must be in part due to the role vitamin D plays in a very large number of cellular processes. In addition, as indicated in an article reviewed above, humans tolerate very large doses of vitamin D without any apparent ill effects. Also, a recent paper that presented negative results of an intervention study regarding vitamin D and cardiovascular events (Circulation, 2007;115:846-54) will not be reviewed simply because the doses used for vitamin D were so small (400 IU/day) that it is not surprising no effect was seen.

Vitamin D holds promise for treatment and prevention of heart failure
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

Vitamin D and Geriatric Care

This study illustrates that simple supplementation is all that is necessary to correct potentially dangerous vitamin D deficiencies, not only in nursing home residents, but also in the general public where similar deficiencies as seen above are widespread. It also highlights the impossibility of achieving adequate levels using small doses such as 400-800 IU/day, the amounts typically found in multivitamins, or even eating oily fish which typically contain 200-400 IU per serving. Capsules containing 5000 IU of vitamin D3 are readily available at https://www.yourhealthbase.com/vitamins/vitamin16.htm and in health food stores. The current recommendation for optimum health is typically a 25(OH)D level of 50-70 ng/mL. One can only hope that sometime in the future, the failure to measure this vitamin D metabolite during physical examinations or when a patient presents with practically any complaint will be considered malpractice. There is probably no other micronutrient where deficiency is so strongly related to such a multiplicity of disorders and there is probably no micronutrient so underappreciated.
Mocanu V, Stitt PA, Costan AR et al. Long-term effects of giving nursing home residents bread fortified with 125 micrograms (5000 IU) vitamin D(3) per daily serving. Am J Clin Nutr 2009 April;89(4):1132-7.

Vitamin D, aging and telomere length
Telomeres are the ends of chromosomes and they undergo shortening with each replication. Telomere shortening has been associated with chronic inflammation, autoimmune diseases such as arthritis, smoking, lupus, oxidative stress in general, and recently telomere shortening has been found to be a risk factor for coronary heart disease. Thus telomere shortening has been regarded as a marker for age related diseases and conditions associated with increasing burden of oxidative stress and inflammation. A recent study has found that higher vitamin D concentrations, which the authors point out are easily obtained through supplementation, are associated with longer telomeres and that this underscores the potentially beneficial effects of this hormone on aging and age-related diseases.
Richards JB, Valdes AM, Gardner JP et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am J Clin Nutr 2007 November;86(5):1420-5.

Vitamin D and risk of macular degeneration
Macular degeneration is far from uncommon in aging populations and has a huge impact on the quality of life since the resultant impaired vision generally makes it difficult to read, and as the disease progresses, dangerous to drive. Parekh et al have recently examined the association between age- related macular degeneration (AMD) and vitamin D status by mining data from a large U.S. government database (NHANES II). Over 11,000 individuals aged 40 and older were involved. Vitamin D status was determined by 25 hydroxyvitamin D serum levels. The risk reduction for early onset AMD among participants in the highest vs. the lowest fifths of serum vitamin D status was a statistically significant 36%. Dietary intakes of vitamin D from either fish or milk were also significant either for early or advanced AMD. For individuals who did not consume milk daily, the reduced risk associated with taking vitamin D through supplements vs. no supplements was 33%. When the risk of early AMD was studied according to serum 25 hydroxyvitamin D levels, the trend with increasing level was highly significant with a 40% reduction at levels > 78 nmol/L, a level around the currently suggested but unofficial minimum level for optimum health.
Parekh, N. Association Between Vitamin D and Age-related Macular Degeneration in the Third National Health and Nutrition Examination Survey, 1988 through 1994. Archives of Ophthalmology, 2007, Vol. 125, pp. 661-9

Vitamin D and nursing home falls
Fall-related fractures and injury represent a serious problem affecting the quality of life of elderly nursing home residents. In a just-published paper by Broe et al in the Journal of the American Geriatric Society, a randomized dose study was reported which investigated the role of vitamin D in the risk of nursing home falls. Supplement doses ranged from 200 to 800 IU/day. Participants in the 800 IU group (mean total intake 1026 IU, range 800-1200) had a 72% lower rate ratio of falls than those given a placebo and no significant differences were observed between the placebo and supplement groups at any of the lower doses (600, 400, and 200 IU/day). This threshold for effectiveness was associated with a serum 25-hydroxyvitamin D mean level of about 75 nmol/L. Those taking the standard multivitamin given regularly in the residence studied received 400 IU and 57% of the participants had levels below 50 nmol/L. The authors discuss the possibility that vitamin D supplementation provided both muscle and bone benefits which accounted for the decrease in falls for those above the threshold intake for benefit.
Broe, K. E. et al. A Higher Dose of Vitamin D Reduces the Risk of Falls in Nursing Home Residents: A Randomized Multiple Dose Study. Journal of the American Geriatric Society, 2007, Vol. 55, pp. 234-9

Editor's comment: Readers with parents or friends confined to nursing homes should be concerned about the problem of vitamin D deficiency. While a blood test would settle the question of deficiency (if judged against standards such as > 75 nmol/L of 25-hydroxyvitamin D) a simpler expedient would be to attempt to implement supplementation at level such as used in this study or perhaps even higher. As discussed in other issues of the Newsletter, with the elderly and especially those confined to nursing homes, several thousand IU/d may be necessary to eliminate deficiency.

Lack of vitamin D increases risk of nursing home admission
Vitamin D deficiency is common among older people, so researchers from Vrije University in Holland 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

Supplementary vitamin D may prevent fractures
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 and Alzheimer's/Dementia

Curcumin, vitamin D and Alzheimer's disease
The prevalence of Alzheimer's disease (AD) in the U.S. in the population over 71 years of age is about 10% whereas in India, for the population over 65 it is just over 1%.[1,2] The global prevalence is predicted to double every 20 years. One hypothesis concerning this huge geographical difference is that in India the spice turmeric (curcumin) is much more widely and heavily used for seasoning in India than in the U.S. This suggestion is supported by a recent study which found that 1-alpha 25- dihydroxyvitamin D (1,25D), also called vitamin D hormone, and compounds in curcumin interact to stimulate the clearance of amyloid-beta mediated by macrophages in patients with AD.[3] Amyloid- beta appears to be the main component of amyloid plaques in brain tissue, is implicated in the pathology of AD and is currently a therapeutic target for plaque prevention and regression.

It is important to recognize that vitamin D hormone is distinct from the metabolite 25-hydroxyvitamin D in that the former is tightly regulated and rather insensitive to an individual's vitamin D status or intake from sun or supplements. Thus while there are dozens of reasons for maintaining a high level of 25- hydroxyvitamin D, in the context of the synergism under discussion, manipulating the concentration of curcuminoids derived from curcumin appears to be indicated. Thus increasing the intake of curcumin while maintaining high vitamin D status may have very beneficial effects on the incidence and progression of AD. Randomized intervention trials would be very informative. However, it is not required to consume foods heavily seasoned with turmeric since curcumin is available as a supplement, and some vendors provide a highly bioavailable preparation. Curcumin is also thought to play a preventive or therapeutic role in cancer, diabetes, cardiovascular disease, arthritis and inflammatory disorders such as irritable bowel syndrome.[4]

1. Plassman BL, Langa KM, Fisher GG et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 2007;29(1-2):125-32.
2. ] Kalaria RN, Maestre GE, Arizaga R et al. Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol 2008 September;7(9):812-26.
3. ] Masoumi A, Goldenson B, Ghirmai S et al. 1alpha,25-dihydroxyvitamin D_{3} Interacts with Curcuminoids to Stimulate Amyloid-beta Clearance by Macrophages of Alzheimer's Disease Patients. J Alzheimers Dis, Vol. 17, July 2009, pp. 703-17
4. Pari L, Tewas D, Eckel J. Role of curcumin in health and disease. Arch Physiol Biochem 2008 April;114(2):127-49.

Vitamin D and cognitive impairment
The aim of this study was to examine the association between vitamin D status as measured by 25- hydroxyvitamin D (25(OH)D) levels and the presence of cognitive impairment in a large population- based sample of elderly adults, living independently and in institutions who were 65 years of age or older. A total of 1766 individuals participated (708 men and 1058 women) who were evaluated for cognitive status and had valid serum 25(OH)D data. Cognitive impairment was quantified by a mental test score. The risk of cognitive impairment increased as the vitamin D status decreased. The ranges of the four 25(OH)D quartiles were 8-30, 31-44, 45-65 and 66-170 nmol/L (to get ng/mL, divide by 2.5). Compared to the highest quartile, the increased risk of cognitive impairment was 10%, 40% and 130% for decreasing quartiles, respectively. These results were adjusted for age, gender, education, ethnicity, season of testing, and additional risk factors for cognitive impairment. This study underscores the importance of having a high vitamin D status. According to the vitamin D experts, a good level to aim for is to be above 125 nmol/L (50 mg/dL). According to the newsletter of the Vitamin D Council, it is important to be aware that sometimes the wrong vitamin D test is ordered. It is for 1,25-dihydroxyvitamin D and does not directly indicate the 25(OH)D levels. Readers are encouraged to ask for copies of the lab reports and check the test and the units and judge for themselves if they are deficient.
Llewellyn DJ, Langa K, Lang I. Serum 25-Hydroxyvitamin D Concentration and Cognitive Impairment. J Geriatr Psychiatry Neurol, Vol. 22, Sept. 2009, pp. 188-95

Vitamin D and Breast Cancer

1. Chlebowski RT, Johnson KC, Kooperberg C et al. Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer. J Natl Cancer Inst 2008 November 19;100(22):1581-91.
2. Speers C, Brown P. Breast Cancer Prevention Using Calcium and Vitamin D: A Bright Future? J Natl Cancer Inst 2008 November 19;100(22):1562-4.

Vitamin D and risk of premenopausal breast cancer
A German study just published in the International Journal of Cancer appears to be the first to use serum 25-hydroxyvitamin D (25-(OH)D) in a study of breast cancer risk in premenopausal women.[1] For premenopausal risk, earlier studies assessed dietary intake only, and food, even with a simple multivitamin, is a notoriously poor source of this essential vitamin. In this case-control study, the age range was 30 to 49 with the majority of subjects between 40 and 49 years. Extensive data was collected to allow adjustment for confounding by all the recognized risk factors. It was found that the risk of diagnosed breast cancer was reduced by 41% for women with plasma 25-(OH)D levels between 45 and 60 nmol/L and 55% when the level was greater than or equal to 60 nmol/L. The reference was < 30 nmol/L and while there was a 32% risk reduction between 30 and 45 nmol/L, this result did not achieve statistical significance. However, the trend over the entire 25-(OH)D range was highly significant. Some evidence of a threshold was seen at 50 nmol/L. The association was stronger for women diagnosed with progesterone receptor negative tumors.

Considerable evidence suggests that 25-(OH)D levels > 75 nmol/L are required for optimal health. In addition, vitamin D deficiency is widespread even at latitudes where there is sunlight-induced synthesis during the winter months. Thus appropriate supplement doses and safe upper limits of vitamin D3 constitute an important question. In a recent paper by Aloia et al in the American Journal of Clinical Nutrition,[2] it was concluded that a dose of 3800 IU/day was appropriate for individuals above a threshold serum level of 55 nmol/L and 5000 IU/day for those below that threshold. These intakes of supplemental D3 provided 25-(OH)D serum levels in the range of 75-220 nmol/L. The authors cite a number of studies which indicated that these are safe levels of intake and serum levels.

1. Abbas S, Chang-Claude J, Linseisen J. Plasma 25-hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study. Int J Cancer, Vol. 124, Jan. 1, 2009, pp. 250-55
2. Aloia JF, Patel M, DiMaano R et al. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr 2008 June 1;87(6):1952-8.

More evidence of vitamin D's impact on breast cancer
A recent study from Stanford University, Wake Forest University and the University of Southern California has examined the connection between sun exposure and breast cancer. The study involved Hispanic, African-American, and non-Hispanic white women aged 35-79. A sun exposure index was created based on skin reflectance of light. In addition, tissue samples were obtained for genetic typing. A high sun exposure index based on reflectometry was associated with a reduced risk of advanced breast cancer among women with light skin pigmentation with a risk reduction of 49% that was statistically significant. The association did not depend on the vitamin D receptor gene variations. No protection was found for women with medium or dark skin pigmentation, nor was localized breast cancer associated with either sun exposure or gene types. The author concludes that this study supports the hypothesis that sunlight exposure reduces the risk of advanced breast cancer among women with light skin pigmentation.
John EM, Schwartz GG, Koo J, Wang W, Ingles SA. Sun exposure, vitamin D receptor gene polymorphisms, and breast cancer risk in a multiethnic population. Am J Epidemiol 2007 December 15;166(12):1409-19.

Vitamin D and breast cancer
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.

Editor's comment: A preliminary report of this analysis was presented in the Research Review concerning the primary prevention of breast cancer which appeared starting in the October 2006 issue of the Newsletter. The reductions in risk seem very impressive. No doubt Big Pharma would love to have a patent drug that would accomplish this result. But 1000 IU capsules of vitamin D3 are widely available in health food stores, drugstores and online. It is noteworthy how little summer sun exposure, albeit to a significant skin area, that is necessary to generate the equivalent of 2000 IU of vitamin D. Working outside or sunbathing in the summer can quickly generate 10,000 or more IU of vitamin D, but the body as a mechanism for limiting the effect of prolonged exposure so toxicity is never a problem. After all, if one believes modern theories, our human biochemistry goes back virtually unchanged to times when our distant ancestors were exposed to intense tropical sunlight daily throughout the year. The real issues here are the winter months in the temperate zone and the modern tendency to severely limit sun exposure at all times with clothing, hats and sun screen and as well, for some, severely limited sun exposure due to lifestyle or disability. The net result is discussed in this Newsletter where papers are presented which deal with the near epidemic level of vitamin D deficiency. Because mainstream medicine tends to identify deficiency of vitamin D with rickets which is rare today (but still seen), if one judges by the conservative guidelines, it is concluded that all is well, especially since there is some food fortification. Including a 25(OH)D measurement along with the normal blood tests in a routine physical would be an extraordinary event, probably not covered by many insurance plans and government health care programs, and some physicians may not even be aware of the strong variation of vitamin D status from summer to winter in the northern latitudes. Also interpreting the results might be a problem if the laboratory reference range is used rather than what one finds in the modern literature. One Canadian medical laboratory a couple of years ago was giving 25-100 nmol/L as the reference range and > 250 nmol/L as potentially toxic, so 25 nmol/L is viewed as OK (divide by 2.4 to get mg/dL). Finally, the paper by Garland et al is not in the public domain. Even doctors cannot read it unless they subscribe (highly unlikely at $400 a year for a very highly specialized publication) or have privileges at a medical library, something generally restricted to academic physicians, other academics (like your Editor) and researchers. In fact, many physicians will probably never hear about this paper. Drug company reps will certainly not be promoting vitamin D during their frequent visits to doctor's offices!

Vitamin D, breast and ovarian cancer
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., 2006, Vol 31, No. 6,pp. 512-14.
Palmieri, C. Serum 25-Hydroxyvitamin D Levels in Early and Advanced Breast Cancer. Journal of Clinical Pathology, Vol. 59, December 2006, pp. 1334-36

Vitamin D and Colorectal Cancer

Vitamin D and colorectal cancer
In early 2006, the Women'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 greater than or equal to 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
The above 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 less than or equal to 12 ng/mL with levels greater than or equal to 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 greater than or equal to 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.

Editor's comment: A blood test for 25-hydroxy vitamin D is available from most diagnostic labs and can be ordered by a physician. For residents in the temperate zone, the result will vary from summer to winter and will also depend on the amount of sun exposure in the summer and during winter vacations "in the sun" and of course on the level of supplementation. The result should be compared with the recent literature, not with the range given on the laboratory printout. Optimum levels, as discussed above and in recent issues of this Newsletter, appear to be in the range of 40-50 ng/mL (approximately 100-125 nmol/L).

Vitamin D and colorectal cancer - A multiethnic study
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 greater than or equal to 600 IU/day for men and < 70 to greater than or equal to 500 IU/day for women when the intake was stratified into quintiles (five groups). For men with the highest total intake (greater than or equal to 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, Vol. 165, Apr. 1, 2007, pp. 784-93

Editor's Comment: This study did not measure serum 25-hyderoxyvitamin D levels nor was any attempt made to examine potential confounding from sun exposure, which in the areas in question is an important source of vitamin D all year. Thus the intake from food and supplements is on top of that generated by the sun, which confound the results. The need to correlate CRC incidence and actual vitamin D status obtained from 25-hydroxyvitamin D levels seems obvious. It also seems clear that once this is done, vitamin D emerges as very significant for primary protection against CRC, but only if the total intake from food, supplements and sunlight results in levels of the metabolite 25- hydroxyvitamin D well in excess of 30 ng/mL and that supplementation of 1000-2000 IU/day is thus indicated. When the study of Gorham et al is compared with the studies that found no or small benefit, of which only two of the most recent are discussed, it is clear that there is a strong dose dependence and that intake from food, a poor source, and from low levels of supplementation such as is recommended by various guidelines (e.g. 400 IU/day) does not for most individuals raise their vitamin D status to a protective level in this context. For those who wish to make a case for the position that vitamin D does not reduce the risk of CRC, there are ample studies published in high- profile journals and the opportunity for citation bias is great. However, it appears that now enough is known to allow one to dismiss these negative studies on the grounds that the intake of vitamin D was insufficient, the results confounded, or the study design flawed. When overall vitamin D status is examined rather than estimated from food and supplement intake, a quite different picture emerges - one of dramatic benefit. Thus Gorham and colleagues are to be commended for their meta analysis which brought together five such studies and provided the statistical power to yield convincing evidence and as well, guidance as to indicated supplement levels.

Vitamin D and Prostate Cancer

It is possible that the mechanism providing this benefit may involve a transcription factor called Stat3 which in active in malignant prostate cancer.[3] Grant has pointed out that vitamin D has been found to inhibit the action of Stat3 and increase cancer cell death and invasion and metastasis.[4] It is also possible that the metabolite of 25(OH)D, 1,25-dihydroxyvitamin D is involved since it is known that prostate cancer cells contain the required enzyme to convert 25(OH)D to this metabolite. Grant points out that making sure that those diagnosed with prostate cancer have high 25(OH)D levels may be important for this reason.

1. Ahn J, Peters U, Albanes D et al. Serum Vitamin D Concentration and Prostate Cancer Risk: A Nested Case- Control Study. J Natl Cancer Inst 2008 June 4;100(11):796-804.
2. Tretli S, Hernes E, Berg JP, Hestvik UE, Robsahm TE. Association between serum 25(OH)D and death from prostate cancer. Br J Cancer, Vol. 100, Feb. 10, 2009, pp. 450-54
3. Abdulghani J, Gu L, Dagvadorj A et al. Stat3 Promotes Metastatic Progression of Prostate Cancer. Am J Pathol 2008 June 1;172(6):1717-28.
4. Grant WB. Vitamin D May Reduce Prostate Cancer Metastasis by Several Mechanisms Including Blocking Stat3. Am J Pathol 2008 November 1;173(5):1589-90.

Vitamin D and prostate cancer
Recent studies have provided strong evidence for a significant and large inverse association between the vitamin D serum marker 25-hydroxyvitamin D [25(OH)D] and both breast and colorectal cancer. It is therefore surprising that such a direct and evidentially easily observed relationship is not seen with prostate cancer. Epidemiological data is far from meager and yet has been characterized by inconsistencies and results that lacked statistical significance. Also, a metabolite of 25(OH)D, namely 1,25dihydroxyvitamin D [1,25(OH)D] has been strongly implicated as an inhibitor of the development of prostate cancer to the extent that safe ways of getting this metabolite into the prostate are currently under investigation. While 1,25(OH)D is made by an enzyme mediated reaction from 25(OH)D, the serum levels of the former are rather tightly controlled. However, 1,25(OH)D can also be made from its precursor within the cells of various organs. Thus one has a complex situation. The reader is referred to the Research Report on vitamin D that appeared in IHN for more detail (issues 147 and 148, May and June 2004).

A recently reported study attempts to address the issue of the role of vitamin D in prostate cancer using data from the Physicians Health Study, including serum levels of both 25(OH)D and 1,25(OH)D. This study found that a large proportion of US men had suboptimal vitamin D status, especially during the winter/spring season, An inverse association between 1,25(OH)D alone or together with 25(OH)D and aggressive prostate cancer was found which provided evidence that both of these metabolites may play a role in preventing the progression of prostate cancer, especially among older men. However, the results were not as compelling and seemingly straightforward as those presented in this Newsletter for breast and colorectal cancer.

These results are surprising because of several recent studies that connect sun exposure to reduced risk of prostate cancer. In one 528 prostate cancer patients and 442 basal cell carcinoma cases (a UV induced cancer) were examined for a correlation between cancer and sun exposure. Both groups were measured the same way as regards sun exposure. For those with the highest sun exposure, the risk of basal cell carcinoma was the highest, and for those with prostate cancer it was the lowest [1]. In another study, increased sun exposure decreased prostate cancer mortality [2] . In a study that looked at geographical distributions of UV intensity and prostate cancer mortality in the US, the expected variation with latitude was observed [3], i.e. those living in the higher latitudes had higher risk. Why this is not reflected in a more dramatic correlation between serum 25(OH)D and prostate cancer is not clear.

1. Rukin NJ et al., 2007. A comparison of sunlight exposure in men with prostate cancer and basal cell carcinoma. Br.J Cancer. 96(3):523-528.
2. Colli JL, Colli A, 2006. International comparisons of prostate cancer mortality rates with dietary practices and sunlight levels. Urol Oncol. 24(3):184-194.
3. Schwartz GG, Hanchette CL, 2006. UV, latitude, and spatial trends in prostate cancer mortality: all sunlight is not the same (United States). Cancer Causes Control. 17(8):1091-1101.

Vitamin D and Cancer - General

In order to provide significant data, a randomized clinical trial with total cancer incidence and as well, various types of cancer as endpoints, would require a very large study group and to have much meaning would have to be conducted over a period of many years. One would hope that a number of endpoints not related to cancer would also be tracked. Given the extensive data supporting the notion that high vitamin D levels are critical to good health, perhaps the tens if not hundreds of million dollars might be spent on something more important within the context of the WHO mandate. At least some organizations are not waiting. The Canadian Cancer Society is recommending population-wide use of vitamin D and has taken the position that white individuals should take 1000 IU daily during the fall and winter and that dark-skinned individuals should do this year-around. As discussed many times in this Newsletter, even 1000 IU per day may be insufficient.

Vitamin D and cancer mortality in the U.S.A.
A prospective follow-up study has just been reported which involved almost 17,000 participants from the Third National Health and Nutrition Examination Survey. Vitamin D status was determined by blood levels of 25-hydroxyvitamin D, the standard serum marker and cancer related mortality was ascertained from national death registers. The principal findings were (a) total cancer mortality was not associated with baseline vitamin D status. The range of 25(OH)D ran from < 50 to greater than or equal to 100 nmol/L; (b) colorectal cancer mortality was significantly lower for individuals with 25(OH)D levels greater than or equal to 80 nmol/L with a risk reduction of 72% when the reference comparison was with those with levels lower than 50 nmol/L. The authors list as limitations the fact that the study lacked the power to detect associations between cancer sites for which there were insufficient deaths, and it relied on a single measurement of vitamin D status.
Freedman, D. M. et al. Prospective study of Serum Vitamin D and Cancer Mortality in the United States. Journal of the National Cancer Institute, 2007, Vol. 99, No. 21, pp.1594-602.

Editor's comments: Readers should compare this study with that reported in the November issue of International Health News which involved a much larger group of participants and obtained significant evidence regarding mortality. If one is trying to establish the association between vitamin D status and some endpoint, what does one use as a 25(OH)D value, an average over the year, a peak value or just a more or less random value? In this study it is not possible to determine how close the values used were to either a maximum or minimum or average value. Furthermore, the subjects resided in both the southern latitudes and northern latitudes which could have accentuated the departures of single measurements from something more representative like an annual average. In addition, when only one measurement is made this opens up the possibility of the value being highly uncharacteristic of even the average for some individuals. Finally, for the breast cancer part of the study, only two ranges of 25(OH)D were used, less than 62.5 and greater than or equal to 62.5 nmol/L. In the low status group, there were 20 deaths from breast cancer whereas in the higher status group, the number was 8, resulting in a significant relative risk reduction of 72%. But these are very low numbers of events which highlights one of the serious problems with this study. In addition, an endpoint that would have been of great interest is site-specific incidence rather than mortality, given the rather long period cancers require to run their course and lead to death. The design of course precluded such analysis. The results for colorectal cancer are impressive. Ralph Moss in Cancer Decisions, December 2 issue, calculates that preventing 72% of deaths from this cancer would translate into 37,570 lives saved each year, roughly the seating capacity of Fenway Park in Boston. But the numbers that would be really interesting would relate to the relative risk for various cancers, both for incidence and mortality, if levels of 25(OH)D were maintained roughly constant at some high value throughout the year, say > 90 or > 100 nmol/L with a combination of supplementation and sun exposure. Considering the small number of cancer cases observed in a cohort of almost 18,000 individuals, it may be a long time before statistically significant data becomes available in what would have to be a long-term intervention study with frequent vitamin D status assessment. Given this, some may find it attractive to simply play it safe and take levels of supplementation that will assure such levels. This matter has been discussed in previous newsletters.

Vitamin D status and overall cancer risk
The first randomized controlled trial with an endpoint of cancer of all types and an intervention sufficient to raise serum 25-hydroxyvitamin D levels to > 80 nmol/L has just been reported. This was a 4-year double-blind study of 1179 healthy postmenopausal women aged > 55 years in rural Nebraska. Subjects were randomized to receive 1400-1500 mg of calcium alone, or calcium plus 1100 IU of vitamin D3 per day or a placebo. The decrease in relative risk of cancer in the Ca + D group was about 60%. as compared to the placebo group. For cancers diagnosed after 12 months, the reduction in relative risk in the Ca + D group increased to about 77%. In terms of absolute risk reduction, in the period from year 2 to 4, approximately 98% of the D + Ca group remained cancer free whereas this was only true for 93% of the placebo group. The serum level of 25-hydroxyvitamin D was a significant independent predictor of cancer risk. The specific cancers monitored included breast, colon, lung, lymph (leukemia, myeloma), uterus with all others lumped in one "other" category. The authors point out that these results highlight the importance of promoting optimum vitamin D status and emphasize the importance of achieving and maintaining a high serum 25-hydroxyvitamin D level.
Lappe, J. M. et al. Vitamin D and Calcium Supplementation Reduces Cancer Risk: Results of a Randomized Trial. American Journal of Clinical Nutrition, 2007, Vol. 85, pp. 1586-91

Editor's comments: At baseline the mean 25-hydroxyvitamin D level in this cohort was about 72 nmol/L. At 12 months supplementation with 1100 IU/day of vitamin D3 raised mean serum levels to 96 nmol/L. It is this change that produced the large risk reductions in all cause cancer in the study of Lappe et al, and it must be admitted that these risk reductions, when added to those already reported in this Newsletter specifically for breast and colorectal cancer, are dramatic and compelling. As has been pointed out a number of times in this Newsletter, a routine blood test is available for this vitamin D metabolite. It is a pity that it is not part of the commonly ordered blood tests at periodic physical exams. It can be argued that it might be one of the most important health parameters to measure both in the spring and fall, and that by now, considerable data exists on optimum levels, information which incidentally is not contained on the clinical laboratory printouts which describe the "normal" range. Achieving optimum levels appears as simple as picking up a bottle of vitamin D3 from the drug store and taking enough to bring the serum level up to 95-100 ng/mol. If Vitamin D3 was a prescription drug, it can almost be guaranteed that it would be aggressively and no doubt successfully marketed by the patent holder(s), in doctors' offices and on prime time TV. The simplicity of vitamin D supplementation as compared to other approaches to cancer prevention is striking and the accumulated data compelling.

Vitamin D and risk of pancreatic cancer
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 greater than or equal to 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 greater than or equal to 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

Editor's comment: These results show a leveling off of effectiveness above about 400 IU/day, which is currently the U.S. Recommended Daily Allowance. Many multivitamin preparations contain this amount. Thus the indicated preventive action is simple and inexpensive. This is a serious matter since pancreatic cancer is the fourth-leading cause of cancer death in the U.S. There is also a recent study (Cancer Research, 2006;66:10213, commentary pp.9802) that found higher vitamin D status was associated with increased risk of pancreatic cancer, but this study was restricted to smokers and will not be discussed.

Hope for thrombosis benefit of vitamin D for cancer patients
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

Evidence points to vitamin D for cancer prevention
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, Vol. 96, February 2006, pp. 252-61

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 half-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.

Vitamin D and Depression

These results are consistent with a large study of over 1200 individuals, aged 65 to 95 years, published earlier this year.[2] This study found a significant association between depression status and 25(OH)D levels in both persons with minor depression and major depressive disorders. Approximately half of the subjects had 25(OH)D levels below 50 nmol/L.

In an editorial accompanying this second study,[3] it was suggested that the time has come for clinical trials on the antidepressant effects of vitamin D. The author cites two small trials, one with low levels of supplementation and one with UV light. Both indicated positive effects. To these should be added the above-discussed trial which also indicated positive results from intervention. While some would consider this enough evidence to try vitamin D therapy, others would demand a large intervention trial using significant amounts of vitamin D and careful monitoring of 25(OH)D levels. As the author points out, vitamin D is likely to be one of the most cost-effective treatments in psychiatry and one with negligible side effects. Thus the need for a large trial.

1. Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med 2008 December;264(6):599-609.
2. Hoogendijk WJG, Lips P, Dik MG, Deeg DJH, Beekman ATF, Penninx BWJH. Depression Is Associated With Decreased 25-Hydroxyvitamin D and Increased Parathyroid Hormone Levels in Older Adults. Arch Gen Psychiatry 2008 May 1;65(5):508-12.
3. Young SN. Has the time come for clinical trials on the antidepressant effect of vitamin D? J Psychiatry Neurosci 2009 January;34(1):3.

Vitamin D and depression in overweight and obese individuals
In clinical studies, low serum levels of 25-hydroxyvitamin D (25-(OH)D), which is the storage form of vitamin D in the body, have been associated with reduced anxiety, depression and reduced cognitive function. Vitamin D has been implicated with what is called seasonal affective disorder, a condition characterized by depression-like symptoms during the winter months. In addition, there is an association between obesity and depression. A study has just been published that investigated the connection between vitamin D levels and depression in obese subjects. The study group consisted of 159 males and 282 females with an age range of 20 to 70 years. At the start of the study, they were given a standard test to evaluate the extent of depression. They were then randomized into three groups - one received two capsules (20,000 IU each) of vitamin D3 per week, the second group one capsule of D3 and one of a placebo, and finally the third group received two placebos. Subjects with 25-(OH)D levels < 40 nmol/L at baseline exhibited significantly higher levels of depression than those with levels greater than or equal to 40 nmol/L. After one year, in the both vitamin D groups but not in the placebo group where was a significant improvement in depression scores. No hypocalcaemia was observed. In the group receiving 40,000 IU/week, mean 25-(OH)D levels went from 55 to 112 nmol/L whereas for the group receiving 20,000 IU/week, the change was from 52 to 88 nmol/L. These large doses are not a misprint! The placebo group started at 52 and ended at 50 nmol/L.

These results are interesting for two reasons. The supplementation with vitamin D appeared to ameliorate symptoms of depression in this obese cohort suggesting a possible causal relationship. In addition, what might appear to be huge doses, when given once a week, are not out of line with those discussed above when converted to daily doses. In addition, this dose protocol produced serum levels of 25-(OH)D that are considered safe.

Finally, individuals who sit in front of a bright light for a short period each day during the winter to improve their mood and outlook might want to consider also taking sufficient vitamin D3 to bring their levels above 75 nmol/L. The lights employed for this purpose, while no doubt useful, are not UV sources and have no impact on vitamin D status.
Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med, Vol. 264, December 2008, pp. 599-609

Vitamin D and Autism

• The strong increase in autism over the last 20 years corresponds with increasing medical advice to avoid the sun. This would theoretically greatly lower vitamin D metabolite levels in developing brains.
• Animal data consistently shows that vitamin D deficiency during gestation dysregulates a large number of proteins involved in brain development and leads to rat pups with abnormalities similar to those found in autistic children.
• Children with the vitamin D deficiency disease rickets have several autistic markers that apparently disappear with high dose vitamin D therapy.
• Estrogens and testosterone have very different effects on the metabolism of vitamin D metabolites, difference which may explain the strong gender differences seen in the incidence of autism.
• The principal metabolite of vitamin D, calcitriol, down-regulates the production of inflammatory cytokines in the brain, cytokines that have been associated with autism.
• Autism is more prevalent in areas where there is reduced UV light penetration.
• Autism is more common in dark-skinned persons and severe maternal vitamin deficiency is very common in dark-skinned individuals.

Editor's comments: Thanks to one of the readers of this Newsletter, I was alerted to an interesting commentary by Dr. Cannell on this subject in the form a record of email exchanges with the mother of an autistic child (Google Cannell vitamin D newsletter June). This exchange discusses the improvement in the child's autistic symptoms with vitamin D supplementation. There is also an interesting discussion of genetic polymorphisms. But of even more interest, it would appear, is the point Dr. Cannell makes concerning the adverse influence on the benefits from vitamin D caused by vitamin A. In his advice to the mother, he makes a very strong point that all supplemental vitamin A including cod liver oil and vitamin A from multivitamin preparations must be eliminated if her son is to get maximum benefit from vitamin D therapy. He provides five references to back up this assertion, and it appears to be a significant and perhaps generally unrecognized issue. As a substitute, he recommends colored fruits and vegetables. When the exchange of emails ends, the dose which started at 5000 IU/day had been reduced to 2000 IU/day which appears to be the maintenance dose Cannell favours. The boy continued to show improvement in a number of areas including speech and various activities. His mother was also prompted by this experience to recall seasonal variations in behavior which correspond to seasonal variations in vitamin D status in the absence of supplements or intentional UV exposure. This exchange of emails should be of considerable interest to any parent of an autistic child. Hopefully Dr. Cannell's article in Medical Hypotheses will stimulate research into this interesting aspect of vitamin D. The 2008 Vitamin D Newsletter cited above also has an interesting and lengthy Q &A section on autism - see the sidebar "autism" link.

Vitamin D and Multiple Sclerosis

The authors point out that their study is consistent with the strong protective effect of sun exposure during childhood (6-15 years) found in a case-control study conducted in Tasmania. The protective effect (risk reduction) of averaging 2 or more hours per week of sun exposure compared to less than 2 hours was 69%. In addition, they mention a study where indoor and outdoor workers exhibited a dose-dependent protective effect of sun exposure on MS-related mortality. The present study is especially important because it eliminates questions about inheritable factors that might have influence these and other studies.

The mechanism involved in the protective effect is unknown, but MS is an autoimmune disease and exposure to sunlight could, according to the authors, produce protection by several immunosuppressive mechanisms. Or sunlight produced vitamin D could suppress the production of cytokines associated with MS activity. The authors also suggest that the fact that the protective effect was only seen in female twin pairs suggests that there may be a sex-specific vitamin D mediated immunomodulation as has been seen in animal studies.
Islam, T, et al. Childhood Sun Exposure Influences Risk of Multiple Sclerosis in Monozygotic Twins. Neurology, 2007, Vol. 69, pp. 381-88.

Are high doses of vitamin D safe in treatment of MS?
Kimball et al have recently reported on a study done in Toronto, Canada that addresses this question in the context of using very high doses of vitamin D for the treatment of multiple sclerosis (MS). During a 12-week period, 12 patients in an active phase of MS were given 1200 mg/day of calcium and progressively increasing doses of vitamin D3 which started at 28,000 IU and progressed to 280,000 IU. Mean serum 25-hydroxyvitamin D levels rose from 78 to 386 nmol/L. Adverse effects were sought by monitoring serum calcium levels, the urinary ratio of calcium to creatinine, liver enzymes, serum creatinine, electrolytes, serum protein, and parathyroid hormone. None were found. In particular, these huge doses of vitamin D caused neither elevated serum or urine calcium levels. The authors conclude that the data support the feasibility of pharmacologic doses of vitamin D for clinical research and as well provide objective evidence that vitamin D intake beyond the current upper limit of 2000 IU/day is safe by a large margin. They also point out that there is already evidence that daily doses of 4000 and 10,000 IU/day are safe. This so-called Phase I study concerned with the issue of safety and was not powered to detect changes in clinical outcomes in the patients involved.
Kimball, S.M. et al. Safety of Vitamin D3 in Adults with Multiple Sclerosis. American Journal of Clinical Nutrition, 2007, Vol. 86, pp. 645-51.

Vitamin D and multiple sclerosis
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 degrees) 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, L.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.

Editor's comment: It is not surprising that no recommendation is made regarding supplementation. Such recommendations are now generally made by representatives of mainstream medicine only on the basis of overwhelming and compelling data meeting the highest standards of randomized, controlled clinical studies. In many situations such studies will never be conducted for reasons too lengthy to enumerate. However, there are experts in the field of vitamin D research who are willing to publicly go on record as being in favor of the merits of raising the vitamin D status of the general public through supplementation and who point out that the U.S. official maximum intake considered to be safe is 2000 IU of a vitamin D3 supplement. Such supplementation would raise many individuals to a vitamin D status equivalent or better than 75-100 nmol/L, but some of these experts consider the 2000 IU limit to in fact be too low. In a paper that just appeared, Hathcock et al in fact recommend a revision of the upper limit to 10,000 IU/day (American journal of Clinical Nutrition, 2007; 85:6-18). Interested readers should also look at the paper by Reinhold Vieth (American journal of Clinical Nutrition, 1999;69:842-56). Both are available free at the journal website, www.ajcn.org. In general, the lower the starting level of 25-hydroxyvitamin D, the longer the time required to bring the levels up and the higher the dose, the faster the increase and the higher the achievable level.

Vitamin D and Pregnancy

Editor's comment: The skin color dependence of vitamin D status from spring to summer simply reflects the well-known effect of skin pigments in attenuating the photosynthesis of vitamin D by solar UV light. Also, in this study, white women were much heavier users of multivitamin supplements than black women. Nevertheless, even though white women on average regularly took a multivitamin both before conception and in the last 3 months of pregnancy (66.5% and 94.3%, respectively), vitamin D insufficiency was still observed, a result which reinforces the view held by vitamin D experts that the amount of vitamin D in commonly used multivitamin preparations is too low.

Vitamin D deficiency common in non-Western pregnant women
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 D in pregnancy protects children's bones
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

Vitamin D - Odds and Ends

Vitamin D for chronic back pain or failed back surgery
While ignored by advocates of evidence-based medicine, case studies constitute an important first step in the process of forming a hypothesis regarding some benefit or risk in medicine. In a report by Gerry Schwalfenberg from the University of Alberta published in the Journal of the American Board of Family Medicine, a case series was recently presented that relates to the connection between back pain and vitamin D. This study involves 4 patients who had chronic back pain for more than a year and 2 patients who had suffered for more than 3 years from failed back surgery. This study reports the vitamin D status prior to treatment, i.e. the 25(OH)D levels, the vitamin D dose used and the 25(OH)D levels after repletion. In two cases it was necessary to estimate the vitamin D status prior to treatment. Patient descriptions at baseline and the symptom improvements were given. Four of the six patients had complete resolution of pain. In one case, when vitamin D treatment was stopped for several months, pain returned only to disappear again on restarting treatment. Two of the cases showed some improvement with one patient able to use less pain medication. In the cases where initial vitamin D status was measured, most patients exhibited very low status. Patients were treated with 1000 to 5000 IU/day and measured 25(OH)D levels increased into the normal or optimal range for all but two patients.

In spite of the limitations inherent to this type of study, the results should encourage individuals with chronic back pain, a neurological complaint reported to be second only to headache, to become concerned about their vitamin D status, have a 25(OH)D measurement done, and consider following the suggestion of vitamin D experts to increase supplemental intake to at least 2000 IU/day.
Schwalfenberg, G. Improvement of chronic back pain or failed back surgery with vitamin D. Journal of the American Board of Family Medicine, Vol. 22, No. 1, 2009, pp. 69-74

Vitamin A and cod liver oil interfere with action of vitamin D
An important commentary on vitamin D has just appeared. The list of authors contains many well known vitamin D researchers and prominent nutritional epidemiologists. This commentary by Cannell et al focus on the unfavourable interaction between vitamin D and either vitamin A or cod liver oil, a major source of the latter and a minor source of the former. This is an important issue since some multivitamin preparations can contain large amounts of vitamin A if taken as directed. Also, in keeping with the notion growing in popularity that grandma was right all along, cod liver oil is staging a comeback.

Evidence of the potential role of vitamin A in interfering with the action of vitamin D was provided by a comparison between recent results and results from the 1930s regarding the effectiveness of cod liver oil in preventing and treating upper respiratory infections. Recent studies have provided only very weak evidence of effectiveness with some studies indicating no benefit.

Studies reported in the 1930s found much more dramatic and convincing effectiveness. The authors suggest that this is due to much less vitamin D in modern cod liver oil. This suggestion was supported by studies in the last two decades where enhancing the vitamin D status of children resulted in pronounced decrease in respiratory infections. They also suggest that the resultant imbalance between A and D in modern cod liver oil further exacerbates the effectiveness of vitamin D since vitamin A interferes with the action of vitamin D.

Vitamin A and D compete for each other's function. Retinoic acid antagonizes the action of vitamin D and as well its active metabolite. As an example, Cannell et al point out that in humans the vitamin A in a single serving of liver is sufficient to impair the intestinal calcium response associated with vitamin D. In one study cited, high levels of retinol intake also completely eliminated the protective effect of vitamin D on colorectal adenomas and furthermore, there is evidence that the highest intake of vitamin D from supplements correlated with a high intake of retinol of about 10,000 IU/day. Cannell et al go on to comment that consumption of preformed retinol, i.e. that found for example in multivitamins, may cause bone toxicity in individuals with inadequate vitamin D status. Women in the highest quintile of total vitamin A intake have a 1.5 times elevated risk of fracture of the hip and in addition, a recent Cochrane Review found that vitamin A supplements increased total mortality rates and appear to increase the risk or worsen the clinical course of acute lower respiratory tract infections in children with normal vitamin D status.

Cannell et al present evidence that the relative amounts of vitamin D and A differ in modern cod liver oil vs. that used decades ago. Modern cod liver oil typically contains 400 to 1200 IU of vitamin D but supra-physiological amounts of preformed retinol (4000 to 10,000 IU and in some samples, 30,000 IU) per tablespoon have been noted. They theorize that modern processing intended to improve odor removes vitamin D which is then added back in lower quantities. Also, the amount of vitamin D in modern cod liver oil appears to be on the decline. They cite one manufacturer who produces cod liver oil containing only 3-60 IU of vitamin D per tablespoon but it contains 3000-6000 IU of vitamin A. Some individuals increase their intake of multivitamins simply to increase the vitamin D intake, and in the process can consume enough vitamin A to destroy the effectiveness of the vitamin D. Anyone depending on a multivitamin for part or all of their vitamin D, reading the label is obviously essential and may be surprising.

The message seems clear. Vitamin D3 supplements and sun exposure in the summer represent the appropriate approach to maintaining healthy vitamin D status. Adequate amounts are virtually impossible to obtain from diet. The article by Cannell et al also contains strong criticism of the so- called Adequate Intakes and Upper Levels of Vitamin D set by the U.S. Institute of Medicine's Food and Nutrition board, especially as regards pregnant women and children. As indicated above, this board is now in the process of revising these recommendations. The new numbers will be interesting.
Cannell JJ, Vieth R, Willett W et al. Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic. Ann Otol Rhinol Laryngol 2008 November;117(11):864-70

Impact of vitamin D deficiency on adolescent health
A study reported at an American Heart Association Conference on Cardiovascular Disease Epidemiology and Prevention examined the association between the vitamin D status of over 3500 adolescents aged 12 to 19 as measured by a blood marker, and the incidence of a number of disorders. Data were obtained from the National Health and Nutrition Examination Survey. It was found that the group with the lowest levels of vitamin D had 2.36 times the likelihood of having high blood pressure, 2.54 times the likelihood of high blood sugar, and 3.99 times the likelihood of having metabolic syndrome. The presence of the metabolic syndrome increases the risk of future heart disease and type 2 diabetes.

These results are particularly disturbing since a number of studies have found a high prevalence of vitamin D deficiency in adolescents with the situation worsening in the winter. It seems clear that only supplementation will solve this problem which is aggravated by spending a large fraction of each day indoors, infrequently engaging in outdoor sports, using sunscreens, and following the conventional advice to avoid exposure to the sun. Percentages with low vitamin D status were as large as 50%. More evidence is published each month of not only the prevalence of profound deficiency but also its impact on the health of all age groups. It seems time for a general call for universal screening using 25-hydroxyvitamin D as the marker. When a deficiency is identified, the amounts of vitamin D in a multivitamin are inadequate to the point of being insignificant and the same can be said for food, even if fortified. Much higher intake is necessary and the success of the intervention should be measured by additional blood tests. Unfortunately, such an approach does not even appear to be under serious considered for adoption as standard practice.

Vitamin D supplementation and total mortality
There are those who believe that total or all-cause mortality is the only really important endpoint for studies of benefit. If an intervention does not cause one to live longer, why bother? However, this is not a universally shared belief and in addition, mortality studies generally must be both large and relatively long-term to yield statistically significant results. This problem can be overcome with a meta- analysis even if all or most of the included studies failed to achieve statistical significance. With the enlarged cohort obtained by combining studies, statistically significant results may be forthcoming. This is the case in the study by Autier and Gandini recently reported in the Archives of Internal Medicine. The researchers identified 18 trials for the analysis which included over 57,000 participants and a total of 4777 deaths from any cause. Daily vitamin D supplement doses ranged from 300 to 2000 IU. When the studies were stratified into two groups according to high vs. low statistical power, the nine with high power yielded a significant 8% reduction in mortality associated with vitamin D supplementation. The low power group failed to give statistical significant benefit, and for the nine high-powered studies, individually they all failed to achieve statistically significant evidence of benefit. Nevertheless, it was concluded that ordinary doses of vitamin D appeared to be associated with a decrease in mortality rates.

Only 8 studies reported 25-hydroxyvitamin D levels at baseline and during the study. In the intervention groups, 7 out of 8 studies found mean 25-hydroxyvitamin D levels below 50 nmol/L at baseline, levels that are considered by some to represent a deficiency. Supplementation brought the means up to where most were near or above 50 nmol/L but only 2 out of 8 studies achieved a mean value of over 100 nmol/L. This meta-analysis did not permit examining the question of the impact of dose on mortality. Nor were the results stratified by major causes of death. The authors also remark that the results based on this very large cohort indicate the absence of adverse effects from vitamin D supplementation at the doses involved, most of which were between 400 and 800 IU/day.

In an accompanying editorial, Edward Giovannucci from Harvard comments that the studies in question, which had a range of follow-up from 6 months to 7 years, may have underestimated the potential benefit from vitamin D supplementation since it was not possible to examine the impact of this vitamin on the incidence and development of a variety of diseases. He also points out that questions raised by the meta-analysis include the possibility of even a greater reduction of mortality if higher intakes of vitamin D were employed, if compliance was improved, if higher levels of 25- hydroxyvitamin D were achieved, and if the duration of supplementation were longer.
Autier, P. and Grandini, S. Vitamin D Supplementation and Total Mortality. Archives of Internal Medicine, 2007, Vol. 167, No. 16, pp. 1730-7.
Giovannucci, E. Can Vitamin D Reduce Mortality? Ibid, pp. 1709-10

Fish a poor source of vitamin D
At issue here is how to get adequate amounts of vitamin D if sunlight exposure is avoided or sunscreen protection heavily used or if an individual's place of residence is above 40 degrees latitude. One school of thought holds that the diet should be a major source of vitamin D. In a short paper recently published online in the Journal of Steroid Biochemistry and Molecular Biology, Lu et al examined the vitamin D content of several commonly consumed fish and the influence of preparation on the final vitamin D content. They found about 1000 IU of vitamin D3 in a 3.5 oz portion of wild salmon (a typical dinner portion) but farmed salmon had only 25% of this amount. Blue fish is very oily but had only about 280 IU per 3.5 oz portion. White fish such as cod and sole were very low in vitamin D, farmed trout and Ahi tuna came in at 388 and 404 IU per 3.5 oz portion respectively. When farmed salmon was baked, almost all the vitamin D survived, but frying in vegetable oil resulted in a 50% loss. The authors also point out that fortified milk frequently does not contain as much vitamin D as is stated on the label and that food tables are highly inaccurate sources of information about the vitamin D content of foods. The authors point out that most experts agree that 1000 IU is required in the absence of sunlight-generated vitamin D. These numbers suggest there is a real problem with the suggestion that individuals get all their vitamin D from food.
Lu, z. An Evaluation of the Vitamin D3 Content in Fish: Is the Vitamin D Content Adequate to Satisfy the Dietary Requirements for Vitamin D? Journal of Steroid Biochemistry and Molecular Biology, Vol. 103, March 2007, pp. 642-44

Vitamin D's protective effect on bones unravelled
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

Disagreement over health benefit from tanning beds
The benefits of vitamin D for bone health have been long known. Vitamin D is manufactured in the skin on exposure to ultraviolet (UV) rays in sunlight. In December 2004, the possibility that indoor tanning beds may improve a person's vitamin D status was raised by a study in the American Journal of Clinical Nutrition.

Vitamin D status was measured in 50 participants who regularly used a tanning bed, and 106 who did not. The researchers claimed to show that regular use of a tanning bed that emits UVB radiation is associated with a 90 per cent higher concentration of serum vitamin D, and thus may benefit bone health. It later emerged that some of the authors were linked with the US Indoor Tanning Association (ITA), a professional society representing the indoor tanning industry.

Now, experts from Brown University and the University of Minnesota take up the argument in a letter to the editor of the journal. They state their concerns over the original research suggesting that tanning beds may provide a medical benefit. Firstly they point out that the methods of recruitment into the study do not make the results applicable to the general population. Many relevant characteristics of the participants were not measured, they add, so could not be taken into account. People who visit tanning centers will not be able to tell whether they are under UVA or UVA/UVB lamps, or have a measurement of their exposure to radiation, they write. The study authors also fail to acknowledge the possible skin cancer-causing effects of artificial tanning lamps, or recognize that oral vitamin supplements are much safer and less expensive. If the readers were aware of the researchers' links to the commercial tanning industry, they may have reached a different conclusion, they write.

In a response published alongside the letter, one of the original researchers calls attention to the 'epidemic' of vitamin D deficiency in the US population, and states that vitamin D requirements cannot be met through diet alone. The researcher defends his study against criticisms of its methodology and conflicts of interest, and restates his belief that UVB-emitting lamps are very effective at producing vitamin D in the skin and increasing serum concentrations of the vitamin.
Tangpricha, V., et al. Tanning is associated with optimal vitamin D status (serum 25-hydroxyvitamin D concentration) and higher bone mineral density. American Journal of Clinical Nutrition, Vol. 80, December 2004, p. 1645-49
Weinstock, M. A., Lazovich, D. Tanning and vitamin D status. American Journal of Clinical Nutrition, Vol. 82, September 2005, p. 707
Holick, M. F. Reply to MA Weinstock and D Lazovich. American Journal of Clinical Nutrition, Vol. 82, September 2005, p. 707

Sun exposure: Both harmful and beneficial
UV radiation is a major risk factor for melanoma, a potentially deadly form of skin cancer. Rates of melanoma have increased over the past half-century, as has mortality from the disease, although they have risen less rapidly. Despite the confirmed causal link with sun exposure, recent studies suggest that UV radiation may also have a beneficial effect on melanoma survival. This is because areas with higher melanoma rates also have higher survival rates.

Researchers from the University of New Mexico investigated the possibility that increasing sun exposure increases melanoma survival as well as occurrence. They carried out a population-based study of 528 patients from the Connecticut Tumor Registry who had been diagnosed with melanoma in the late 1980s. Information was taken on sun exposure and history of skin awareness, suggesting early detection, and the participants were followed for five years. Increased levels of sun exposure - sunburn, high intermittent sun exposure, and solar elastosis (an indicator of sun damage) - and skin awareness were significantly linked to increased survival. Patients with solar elastosis had half the risk of death from melanoma as those without. Overall, the results could mean that sun exposure is protective or alternatively that early detection of melanoma is protective.

As found previously, further analysis showed that solar elastosis was independently linked to increased survival, so the authors conclude that sun exposure is indeed protective against death from melanoma. They suggest that the effect could be due to vitamin D production, or that sun exposure leads to less aggressive melanomas by increasing DNA repair functions which might reduce further mutational changes in the tumor.

Writing in an accompanying editorial, researchers from the International Epidemiology Institute encourage further work on the role of vitamin D in this area. They report that solar radiation is responsible for more cancers worldwide than any other single agent, but the idea that it may also be beneficial has long been considered. Commenting on the present study, they question whether the patients would have continued to spend time in the sun following diagnosis, so the results may not reflect continued sunlight exposure. The risks and benefits of sun exposure have to be weighed against many individual factors, they conclude.
Berwick, M. et al. Sun exposure and mortality from melanoma. Journal of the National Cancer Institute, Vol. 97, February 2005, pp. 195-199
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

Vitamin D may protect against gingivitis
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 helps prevent gum disease
Periodontal disease is the major cause of tooth loss in middle-aged and elderly people. It involves chronic inflammation of the gums and a gradual loss of tooth attachment. A team of researchers from Germany and the US now report that high body stores of vitamin D (high serum levels of 25- hydroxyvitamin D3) are associated with a reduced risk of periodontal disease. Their study involved 11,202 men and women over the age of 20 years who participated in the 3rd National Health and Nutrition Examination Survey. The researchers analyzed blood serum samples for 25-hydroxyvitamin D3 levels and also measured clinical tooth attachment levels in all participants. The clinical attachment level (AL) is measured with a periodontal probe as the distance between the cemento-enamel junction (roughly where the top of the gum meets the tooth) and the bottom of the pocket in which the tooth is encased. A higher AL level indicates greater loss of attachment and more pronounced periodontal disease.

The researchers found that a lower serum vitamin D concentration was associated with a higher AL in both men and women over the age of 50 years. Men with a vitamin D level equal to or less than 40.2 nmol/L had a 0.39 mm higher AL than did men with a vitamin D level of 85.6 nmol/L or greater. Women in the lowest vitamin D range had a 0.26 mm higher AL than did women with the highest vitamin D levels. The AL values were all adjusted for age, race, smoking, diabetes, calcium intake, body mass index, socioeconomic status, and extent of gum bleeding. No association between AL and vitamin D level was found for participants younger than 50 years of age.

The researchers postulate that vitamin D may favourably affect periodontal health through its beneficial effects on bone density or through its anti-inflammatory and immune system enhancing effects. As they found no association between AL and bone mass density, they conclude that vitamin D's known anti-inflammatory properties underlie its ability to prevent periodontal disease. They conclude that vitamin D is an important factor in oral health.
Dietrich, T, et al. Association between serum concentrations of 25-hydroxyvitamin D3 and periodontal disease in the US population. American Journal of Clinical Nutrition, Vol. 80, July 2004, pp. 108-13