by William R. Ware, PhD and Hans R. Larsen, MSc ChE
Vitamin D, the so-called sunshine vitamin, is in fact not really a vitamin but a hormone which the body can make using sunlight. Historically, vitamin-D deficiency was associated with the childhood disease of rickets characterized by severe growth retardation and the bending or bowing of the legs. Today, research on the role of vitamin D metabolites in health and illness has gone well beyond their role in calcium homeostasis and bone health. They are implicated in cancer prevention, hypertension, rheumatoid arthritis, multiple sclerosis, and early-onset diabetes (type 1). Humans acquire vitamin D from the action of sunlight and from food. The skin contains a cholesterol derivative, 7-dehydrocholesterol (provitamin D), which ultraviolet light (UVB, 290-315 nm) converts to vitamin D which is then either stored in body fat or converted in the liver to 25-hydroxyvitamin D, which we will denote as 25(OH)D. Vitamin D from dietary sources is also converted in the liver to 25(OH)D. Circulating 25(OH)D is converted, mostly in the kidney, to another derivative, 1,25(OH)2D, also called calcitriol, or vitamin D hormone, which regulates serum calcium and phosphorus levels by controlling the intestinal efficiency of absorption. Many tissues and cells in the body have receptors for vitamin D hormone, and it has been recognized for at least two decades that this hormone is a potent inhibitor of cellular proliferation and an inducer of cell maturation. This may have very important implications in connection with the incidence and progression of cancer. Vitamin D hormone receptors are known to exist, for example, in breast, prostate and colon tissue.
There are two forms of vitamin D, D2 and D3. Vitamin D3 is also called cholecalciferol, whereas vitamin D2 is called calciferol or ergocalciferol. The same conversion is used for both to convert from grams to International Units (IU), i.e. 100 IU = 2.5 micrograms (µg). The two forms are thought to have different biological activity, with D3 having between 1.7 and 2 times the conversion efficiency to 25(OH)D for approximately equivalent amounts. However, this area remains uncertain and it is common practice not to differentiate between the two forms. Vitamin D2 is not a natural component of human biochemistry but can be manufactured, for example, by UV irradiation of a lipid extracted from yeast. Thus its existence in fortified food and therapeutic prescriptions is mainly for the sake of synthetic convenience. Supplements may contain either form, and sometimes this is not clear from the label. Typical supplement users probably consume 200-800 IU/d.
Fish are the primary natural food source of dietary vitamin D (the D3 form), with 100 grams of herring or salmon providing 1000 IU or 640 IU respectively. A teaspoon of cod liver oil provides about 400 IU, an egg only about 100 IU. For those who consume only limited amounts of these foods, fortified foods and sunlight are the only sources. If one avoids fortified dairy or cereal products, and in addition minimizes exposure to the sun, deficiency becomes a real possibility. In addition, the fear of skin cancer has promoted the extensive use of sunscreens which essentially eliminates any solar vitamin D generation. A sunscreen SPF of 8 reduces vitamin D3 production by about 98%! To put these numbers in perspective, consider that an adult with white skin wearing a bathing suit generates about 10,000 IU of vitamin D3 in 15-30 minutes when exposed to the summer sun. This is 25-50 times what is in the typical multivitamin. Lengthy sun exposure does not produce toxic levels because vitamin D is also photolabile and as it builds up it is converted (also by UVB) to compounds that do not lead to bioactive metabolites. It may surprise some readers to learn that in the northern latitudes (>35°-40°N) the amount of UVB in sunlight is low to negligible in the winter months, except at higher altitudes, and contrary to popular belief, sunbathing in the winter in Boston or Edmonton does not generate significant Vitamin D. The same is true in latitudes below about 35°S. Even the sunny French Rivera and Spain have low levels of UVB in the winter.
To establish daily requirements and the prevalence of deficiency, it is desirable to have a marker, ideally a blood marker. The concentration of vitamin D3 in the blood turns out to be uninformative. The consensus today is that the serum concentration of the metabolite 25(OH)D is the most informative measure of the vitamin status and should be used to define deficiency, sufficiency and perhaps toxicity. There is growing evidence that levels of 25(OH)D in the range of 75-100 nM may be required for optimum health.
|Vitamin D – Deficiency and Requirements|
|Vitamin D and Influenza|
|Vitamin D and Cardiovascular Disease|
|Vitamin D and Geriatric Care|
|Vitamin D and Alzheimer’s/Dementia|
|Vitamin D and Breast Cancer|
|Vitamin D and Colorectal Cancer|
|Vitamin D and Prostate Cancer|
|Vitamin D and Cancer - General|
|Vitamin D and Depression|
|Vitamin D and Autism|
|Vitamin D and Multiple Sclerosis|
|Vitamin D and Pregnancy|
|Vitamin D - Odds and Ends|
D3 dose dependence of serum 25-hydroxyvitamin D
The ± values represent one standard deviation and illustrate the inter-individual variation in a group totaling 64 individuals, but based on an earlier study, the final numbers were probably reached within 3 months. Data from the above table was derived from a study involving individuals much younger than the nursing home cohort discussed above whose initial levels were much lower but 5000 IU brought the levels to about 50 ng/mL, again with considerable inter-individual variation, and the plateau was reached within 6 months.
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.
New data from American Academy of Pediatrics on prevalence of vitamin D
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
Institute of Medicine (US) ready to recommend new adequate intake and upper
limits of vitamin D
Circulating vitamin D and 25-hydroxyvitamin D
Vitamin D – The American Institute for Cancer Research position
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.
Incidentally, the title of the recommendation is “Don’t Use Supplements to Protect Against Cancer.” It
is abstracted from an “Expert Report.”
Evidence for widespread vitamin D deficiency
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 insufficent
Vitamin D3 should be used in preference to vitamin D2, say experts
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.
Has time come for an increase in recommended vitamin D intakes?
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.
Vitamin D deficiency in southern Florida
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
that 10% of men and 28% of women were deficient at the end of summer. Actual average
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
higher intake of supplemental vitamin D (800 IU/day or more) and greater sun exposure were
higher levels of 25(OH)D, but there was no association between 25(OH)D level and age. The
suggest that the higher than expected prevalence of vitamin D deficiency in southern Florida can be
by sun avoidance and the use of sunscreens because of the heat and increased awareness of the
developing skin cancer.
H1N1 virus and role of vitamin D
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 http://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.
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.
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.
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 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.
H1N1 influenza and vitamin D
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
Vitamin D and influenza
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.”
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
Vitamin D, sun exposure and seasonal flu – Is there a connection?
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° to 40° 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° (the so-called temperate zones) and no seasonal variation in the tropical zones (0-29° 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.
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° 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° latitude!
Vitamin D and the JUPITER trial
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.
Vitamin D and risk of developing hypertension
Vitamin D and heart attacks in men
Vitamin D and all-cause and cardiovascular mortality
Vitamin D and hypertension
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.
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.
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. 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.
Vitamin D and cardiovascular risk
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.
Statins and vitamin D
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. 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.
Vitamin D and cardiovascular risk
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
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.
Benefits of high-dose vitamin D in nursing homes
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
http://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.
Vitamin D, aging and telomere length
Vitamin D and risk of macular degeneration
Vitamin D and nursing home falls
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
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.
Supplementary vitamin D may prevent fractures
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
They believe that a compelling case has been made for general vitamin D supplementation in older
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
vitamin D and the interaction between the two nutrients.
Vitamin D and cognitive impairment
Curcumin, vitamin D and Alzheimer’s disease
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.
Vitamin D and cognitive impairment
Vitamin D and breast cancer
Vitamin D and risk of premenopausal breast cancer
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, 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.
More evidence of vitamin D’s impact on breast cancer
Vitamin D and breast cancer
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.
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
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.
Vitamin D and colorectal adenoma
Vitamin D and colorectal cancer
Vitamin D and colorectal cancer prevention – A pooled analysis
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
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 mortality
It is possible that the mechanism providing this benefit may involve a transcription factor called Stat3 which in active in malignant prostate cancer. 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. 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.
Vitamin D and prostate cancer
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 . In another study, increased sun exposure decreased prostate cancer mortality  . 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 , 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.
View of vitamin D from Geneva
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.
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
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
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
Evidence points to vitamin D for cancer prevention
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
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 ½ 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 symptoms of depression
These results are consistent with a large study of over 1200 individuals, aged 65 to 95 years, published earlier this year. 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, 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.
Vitamin D and depression in overweight and obese individuals
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.
Autism and vitamin D
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.
Childhood sun exposure 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.
Are high doses of vitamin D safe in treatment of MS?
Vitamin D and multiple sclerosis
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
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
Vitamin D deficiency in pregnant women
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
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.
Vitamin D in pregnancy protects children’s bones
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.
Vitamin D for chronic back pain or failed back surgery
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.
Vitamin A and cod liver oil interfere with action of vitamin D
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
Impact of vitamin D deficiency on adolescent health
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
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.
Fish a poor source of vitamin D
Vitamin D’s protective effect on bones unravelled
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.
Disagreement over health benefit from tanning beds
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.
Sun exposure: Both harmful and beneficial
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.
Vitamin D may protect against gingivitis
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
Vitamin D helps prevent gum 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.