Talk:Vitamin D/Archive 8

Mortality section skewed
The mortality section does not seem to have an appropriate balance between the benefit and harm aspects. It includes this bit:


 * ... However, both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging. The relationship between serum calcidiol level and all-cause mortality is parabolic, Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population.

Now, I've looked at the sources, and this treatment is just not a fair representation of what they say. The first ref should be thrown out, as it's a primary-source lecture, and pretty much duplicates that second anyway.

The second looks like an OK "mini-review" (find online pdf); the abstract notes "Clinical data suggest that vitamin D(3) insufficiency is associated with an increased risk of several CNS diseases, including multiple sclerosis, Alzheimer's and Parkinson's disease, seasonal affective disorder and schizophrenia. In line with this, recent animal and human studies suggest that vitamin D insufficiency is associated with abnormal development and functioning of the CNS." The paper shows a U-shaped response in Fig. 2 and the conclusion includes "A new model of aging is presented here (Fig. 2), in which both too high and too low activity of calcipherol hormone activity seems to enhance aging, whereas optimal concentrations appear to delay aging." This "new model" is a long way from solid support for our claim that "both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging." It's probably true, but unbalanced, in light of their observation that "Due to tight physiological regulation of hormonal forms of vitamin D3 by 24-hydroxylase, which is modulated by physiological concentrations of calcidiol, hypervitaminosis D3 is rare in humans (Lou et al., 2004)."

The third does not appear to be a review, but is about mouse models, and the abstract doesn't say anything useful, and I don't see a free version online, so I'd be interested in seeing a quote form it.

The last is a very comprehensive report, free online, which says on the referenced page, "Because the trials did not evaluate particularly high doses and as observational studies are subject to confounding, one cannot interpret conclusively whether or not this U-shaped relationship is real or causal. However, the data are clearly suggestive of a U-shaped or reverse-J-shaped risk curve between serum 25OHD level and all-cause mortality; increases in risk are suggested at thresholds in the range of 75 to 120 nmol/L for the white population, with lower levels for the black population." This is not a conclusion, but a summary of someone else's models that they slow a plot of in Fig. 6-3 (where the non-adjusted raw data show no hint of reverse J shape, but the "models" show a small, less than 10%, possible adverse effect). Their "increases in risk are suggested" summary of somebody's models turned into our "The relationship between serum calcidiol level and all-cause mortality is parabolic" and "Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population." These tentative model results certainly do not deserve this kind of prominence in wikipedia, especially compared to the other side of the curve, where a very clear harm from low levels of vitamin D is shown.

If our presentation makes it look like too much vitamin D is as bad as too little, when in reality too much is a problem that would seldom be encountered by anybody, while too little is pretty common and pretty clearly harmful, and we have to twist sources pretty badly to support that, then we're not doing a good job presenting what's known about vitamin D. Would anyone like to help work on this? Dicklyon (talk) 01:04, 5 February 2014 (UTC)

Updated edit to Cancer section of Vitamin D page
I propose replacing the two sentences now in this article about Cancer with all of the material below. of course it will be appropriately formatted.

As of February 4, 2014, there were 3342 references to journal articles with vitamin D and cancer in the title and/or abstract listed at pubmed.gov, starting in 1976. Of these references, over 300 also include ultraviolet (UV) or UVB in the title, abstract, and/or key words. The evidence that vitamin D reduces risk of cancer is from various types of studies. The evidence is discussed here in the order of the perceived quality of the studies for medical research. In addition, an alternative approach using Hill’s criteria for causality in a biological system will be discussed after reviewing the evidence according to the rules for medical studies.

Randomized controlled trials (RCTs)

As noted in many reviews, RCTs have not adequately demonstrated that vitamin D reduces the risk of cancer or increases survival after diagnosis [Pilz, 2013]. However, a meta-analyses of vitamin D3 supplementation found statistically significantly decreased cancer mortality (relative risk 0.88 (95% confidence interval 0.78 to 0.98); P = 0.02; I2 = 0%; 44,492 participants; 4 trials) [Bjelakovic, 2014; Zheng, 2013]. However, RCTs are but one aspect of research on vitamin D and cancer.

Observational studies

Observational studies of cancer incidence and mortality rates with respect to serum 25(OH)D levels have been reported for many types of cancer. There is a general consensus that prospective studies of colorectal cancer incidence rates with respect to serum 25(OH)D levels at time of enrollment in cohort studies demonstrate a beneficial effect of vitamin D in reducing risk of this cancer [IARC, 2008; Giovannucci, 2013]. There is less agreement regarding breast cancer since observational studies with short periods after blood draw for 25(OH)D measurements report significant inverse correlations while those with long intervals do not [Yin, 2010; Gandini, 2011].

Observational studies have found significantly lower mortality rates for high vs. low serum 25(OH)D levels near time of diagnosis for several types of cancer: breast, colorectal, gastric, lung, prostate cancer, chronic lymphocytic leukemia, lymphoma, melanoma, and non-Hodgkin’s lymphoma [Robsahm, 2013].

A meta-analysis of all-cancer incidence and mortality rates found significant inverse correlations with respect to serum 25(O)D levels for both incidence and mortality rates; however, the inverse correlation for mortality rates was limited to women, with no significant effect for men [Yin, 2013].

Ecological studies

Ecological studies based on geographical variation in cancer incidence and/or mortality rates with respect to indices of solar UVB doses and other cancer-risk modifying factors have provided very strong evidence that vitamin D reduces risk of many types of cancer. The UVB-vitamin D-cancer hypothesis was first proposed in 1980 by the brothers Cedric and Frank Garland after seeing the map of colon cancer mortality rates in the United States [Garland, 1980]. Rates were lowest in the southwest and highest in the northeast. Annual solar radiation doses and summertime solar UVB doses are highest in the southwest and lowest in the northeast. Since then, ecological studies from Australia, China, France, Japan, Nordic countries, Spain, and the United States have found strong inverse correlations between solar UVB doses and incidence or mortality rates for many types of cancer, with the strongest evidence found for breast, colon, esophageal, gastric, pancreatic, and rectal cancer (5-7 studies each), followed by bladder, gallbladder cancer and leukemia (4 each), endometrial, lung, ovarian, and prostate cancer (3 each), cervical, oral/pharyngeal, renal, thyroid cancer and Hodgkin’s lymphoma (2 each), and brain and vulvar cancer (1 each) [Grant, Anticancer Res. 2012; Moukayed, 2013].

Solar UVB is the primary source of vitamin D for most people [Hyppönen, 2007]. No factor other than vitamin D production has been proposed to explain the protective effect of UVB irradiance against cancer.

Properly conducted ecological studies should control for other cancer risk-modifying or confounding factors. All of the recent ecological studies evaluating the correlation between solar UVB and cancer incidence and/or mortality rates have included a number of other factors including alcohol consumption, dietary supply factors, smoking as well as other factors in some studies such as socioeconomic status and ethnic background [Grant, Anticancer Res., 2012].

Mechanisms

Identification of mechanisms whereby an agent affects the risk of disease is not included in the standard criteria for evaluating pharmaceutical drugs. However, doing so adds considerable strength to claiming a causal link between agent and outcome. The primary mechanisms whereby vitamin D reduces the risk of cancer include effects on cellular differentiation, proliferation and apoptosis and reductions in angiogenesis around tumors and metastasis. These and other cancer reducing mechanisms are discussed in recent reviews [Vuolo, 2012; Moukayed, 2013]. In addition, “alternative mechanisms include enhancing DNA repair, antioxidant protection and immunomodulation. In addition, other cell targets, such as the stromal cells, endothelial cells and cells of the immune system, may be regulated by 1,25(OH)2D and contribute to vitamin D-mediated cancer prevention.” [Fleet, 2012].

Hill’s criteria

A scientific way to evaluate whether an agent can be considered causally linked in a biological system is through application of Hill’s criteria for causality in a biological system. The criteria applicable for vitamin D and cancer include strength of association, consistent findings in different populations, temporality, biological gradient (dose-response relation), plausibility (e.g., mechanisms), experiment (e.g., RCT), and analogy. Not all criteria need be satisfied for causality to be claimed; however, the more that are, the better. Temporality is considered the only one that must be satisfied. Hill’s criteria have been found to be well satisfied for breast and colorectal cancer [Grant, 2009; Mohr, 2012] as well as cancer survival in general [Robsahm, 2013] and moderately well for several other types of cancer [Grant, 2009]. More recent studies such as those discussed here strengthen the case for several more types of cancer.

Reviews of vitamin D and cancer by agencies or groups

Since the study of the UVB-vitamin D-cancer hypothesis is still ongoing, it is worthwhile to see the level of support it has in major peer-reviewed journals and by agencies, organizations, and ad hoc review committees comprised of vitamin D experts. A chapter in the 3rd Edition of Vitamin D, the standard detailed reference on vitamin D, concluded “Extensive epidemiologic data exist to demonstrate a role for vitamin D status on incidence, progression, and mortality in cancers of the breast, colon, and prostate as well as in hematologic malignancies.” [Trump, 2011]. Data were considered not as extensive or as well characterized for many other types of cancer.

A vitamin D conference attended by over 500 health practitioners in Warsaw, Poland in October 2012 resulted in a report that accepted observational study findings for vitamin D for breast and colorectal cancer. It also noted the two successful randomized controlled trials on cancer incidence along with the poor design of most randomized controlled trials to date [Pludowski, 2013]. Also, a major review of the health benefits of vitamin D noted the extensive results from ecological and observational studies for many types of cancer as well as results for many other types of disease [Hossein-Nezhad and Holick, 2013].

The Canadian Cancer Society has this statement posted at its website: “Vitamin D is needed for healthy bones and muscles, especially in children and the elderly. There is growing evidence that vitamin D may reduce the risk of some types of cancer, particularly colorectal and breast cancers. Experts are now concerned that many people are not getting enough vitamin D.” Read more: http://www.cancer.ca/en/prevention-and-screening/live-well/vitamin-d/?region=on#ixzz2rufVxsy7

References

Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470. [Epub ahead of print]

Fleet JC, Desmet M, Johnson R, Li Y. Vitamin D and cancer: a review of molecular mechanisms. Biochem J. 2012 Jan 1;441(1):61-76.

Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ, Mullie P, Autier P. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer. 2011 Mar 15;128(6):1414-24,

Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980 Sep;9(3):227-31.

Giovannucci E. Epidemiology of vitamin D and colorectal cancer. Anticancer Agents Med Chem. 2013;13(1):11-9.

Grant WB. Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res. 2012;32(1):223-36.

Grant WB. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill’s criteria for causality. Dermatoendocrinol. 2009;1(1):17-24.

Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965 May;58:295-300.

Hossein-Nezhad A, Holick MF. Vitamin D for health: A global perspective. Mayo Clin Proc. 2013 July;88(7):720-55.

Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr. 2007 Mar;85(3):860-8.

IARC Working Group Report 5: Vitamin D and Cancer. IARC, Lyon, France (Nov. 25, 2008) www.iarc.fr/en/publications/pdfs-online/wrk/wrk5/Report_VitD.pdf

Mohr SB, Gorham ED, Alcaraz JE, Kane CI, Macera CA, Parsons JE, Wingard DL, Garland CF. Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria? Dermatoendocrin. 2012;4(2):152-7.

Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023.

Pilz S, Kienreich K, Tomaschitz A, Ritz E, Lerchbaum E, Obermayer-Pietsch B, Matzi V, Lindenmann J, März W, Gandini S, Dekker JM. Vitamin D and cancer mortality: Systematic review of prospective epidemiological studies. Anticancer Agents Med Chem. 2013;13(1):107-17.

Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, Shoenfeld Y, Lerchbaum E, Llewellyn DJ, Kienreich K, Soni M. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality- a review of recent evidence. Autoimmun Rev. 2013 Aug;12(10):976-89.

Robsahm TE, Schwartz GG, Tretli S. The inverse relationship between 25-hydroxyvitamin D and cancer survival: Discussion of causation. Cancers. 2013, 5(4), 1439-1455.

Trump DL, Johnson CS. The anti-tumor effects of vitamin D in other cancers. Ch. 90 in Vitamin D, Third Edit. Feldman D, Pike JW, Adams JS (eds). 2011, 1763-73.

Vuolo L, Di Somma C, Faggiano A, Colao A. Vitamin d and cancer. Front Endocrinol (Lausanne). 2012;3:58.

Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: Serum vitamin D and breast cancer risk. Eur J Cancer. 2010 Aug;46(12):2196-2205.

Yin L, Mena JM, Chen T, Schöttker B, Arndt V, Brenner H. Circulating 25-hydroxyvitamin D serum concentration and total cancer incidence and mortality: a systematic review and meta-analysis. Prev Med. 2013 Dec;57(6):753-64.

Zheng Y, Zhu J, Zhou M, Cui L, Yao W, Liu Y. Meta-analysis of long-term vitamin d supplementation on overall mortality. PLoS One. 2013 Dec 3;8(12):e82109. Jag8452 (talk) 01:14, 5 February 2014 (UTC)


 * I think you're biting off too big a change, but I do a agree that a more comprehensive look at effects on cancer and other areas is warranted. The current coverage is way too thin, and quite imbalanced toward rejecting the possibility of much good effect.  Dicklyon (talk) 01:31, 5 February 2014 (UTC)
 * Thanks for your general support of updating the vitamin D page. Admittedly this posting is a large chunk of information. However, it seems warranted in order to give a comprehensive overview of the evidence from various approaches and types of studies. A couple of questions:


 * 1 - what would you suggest omitting or condensing?


 * 2 - would you rather see this a separate Wikipedia page: Vitamin D and Cancer?


 * Please note that after the information on vitamin D and cancer is posted, the evidence that vitamin D has benefits for other health outcomes such as cardiovascular disease, infections, diabetes, etc., will be prepared for review and posting.


 * For those of you who would like to read a recent open access review about vitamin D, here is one:


 * Wacker M, Holick MF. Vitamin D - effects on skeletal and extraskeletal health and the need for supplementation. Nutrients. 2013 Jan 10;5(1):111-48. http://www.mdpi.com/2072-6643/5/1/111. Jag8452 (talk) 02:41, 5 February 2014 (UTC)
 * Are you proposing adding this "As of February 4, 2014, there were 3342 references to journal articles with vitamin D and cancer in the title and/or abstract listed at pubmed.gov, starting in 1976. Of these references, over 300 also include ultraviolet (UV) or UVB in the title, abstract, and/or key words" While many of the refs above are good a bunch are a little old. I oppose adding it as is. Doc James  (talk · contribs · email) (if I write on your page reply on mine) 02:59, 5 February 2014 (UTC)
 * Additionally wording needs to be simplified and condense. Doc James  (talk · contribs · email) (if I write on your page reply on mine) 03:01, 5 February 2014 (UTC)
 * We are saying all that needs to be said about Cancer. I'd oppose any additions from lesser sources that aren't in line with the strong sources we are using. The above proposal looks to me like a big "howevering" of what reliable sources say. Alexbrn talk 08:05, 5 February 2014 (UTC)


 * With all due respect to Alexbrn, the three references for vitamin D and cancer in the existing article are not very strong. For example, Ref. 9 discusses vitamin D randomized controlled trials on healthy populations without much concern for serum 25-hydroxyvitamin D levels at baseline. A recent paper did find a reduced risk of cancer mortality rate with respect to vitamin D supplementation [Bjelakovic, 2014]. Ref. 24 is an editorial related to observational studies for rarer types of cancer. It was very negative based on the author’s review of the literature on vitamins A, B, and C. The paper associated with the editorial [Helzlsouer, 2010] had too few participants to see a beneficial effect of vitamin D. Ref. 25 is also based on randomized controlled trials in cancer patients. A recent observational study found significantly reduced mortality rates for those with higher serum 25-hydroxyvitamin D levels at time of cancer diagnosis [Robsahm, 2013].


 * These three papers associated with vitamin D and cancer suffer from representing one point of view in the middle of a rich and varied landscape, not a NPOV.


 * As I have been discussing, understanding the role of vitamin D and cancer should involve reviewing all types of studies: randomized controlled trials, observational studies, laboratory studies, and ecological studies. The question I am addressing is whether there is a relation between serum 25-hydroxyvitamin D level and risk of cancer incidence or mortality rate. There are hints that randomized controlled trials show that vitamin D reduces the risk of cancer, but such trials to date have not been well conducted; thus, it is important to look at other types of evidence. I do not consider this approach to be a “however” exercise but rather one that looks at types of studies that have a longer history and are more mature for examining the roles of solar UVB and vitamin D and cancer risk.


 * I will submit a shorter version of a vitamin D-cancer document for review on this Talk page soon.


 * Have you read WP:MEDRS? We need to summarize the best secondary sources, not attempt to be a secondary source ourselves. The new Cochrane review will be usable. Alexbrn talk 17:53, 6 February 2014 (UTC)


 * While Alex's statement that "We are saying all that needs to be said about Cancer" is clearly short-sighted and unhelpful, his point that we need to respect WP:MEDRS is true. Let's start by finding high-quality reviews of the state of knowledge about vitamin D, and make (hopefully brief) additions based on those; we should not attempt to synthesis a coherent story, just report findings.  It doesn't have to only be medical sources, though if it's about cancer it probably will be.  Non-medical research on how vitamin D works may also be useful.  Dicklyon (talk) 20:11, 6 February 2014 (UTC)


 * Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470. [Epub ahead of print]


 * Helzlsouer KJ. For the VDPP Steering Committee. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epi, 2010 172: 4-9.


 * Robsahm TE, Schwartz GG, Tretli S. The inverse relationship between 25-hydroxyvitamin D and cancer survival: Discussion of causation. Cancers. 2013, 5(4), 1439-1455.       Jag8452 (talk) 17:17, 6 February 2014 (UTC)


 * it is too much text to comment on at once - would the OP please break this into separate sections for commenting? With respect to "As of February 4, 2014, there were 3342 references to journal articles with vitamin D and cancer in the title and/or abstract listed at pubmed.gov, starting in 1976. Of these references, over 300 also include ultraviolet (UV) or UVB in the title, abstract, and/or key words"  this is a) original research, and b) not meaningful in a health-related section.  Lots of things are studied, in vitro, in simple organisms, in higher organisms, in humans epidemeologically, interventionally, etc.  A sheer # of citations is not information that belongs in Wikipedia. Jytdog (talk) 20:49, 5 February 2014 (UTC)

new version
After considering all of the comments and perspectives, I have rewritten this proposed change. If the following is acceptable, I will post it to the Vitamin D article as a replacement for the two paragraphs in the Cancer section. I will, of course, format it properly."

Vitamin D and cancer
The evidence that vitamin D reduces risk of cancer is discussed here in the order of the strength of the evidence by type of study as well as analyzed applying a scientific approach (Hill’s [1965] criteria for causality in a biological system).

Ecological studies

Ecological studies based on geographical variation in cancer incidence and/or mortality rates with respect to indices of solar ultraviolet-B (UVB) doses and other cancer-risk modifying factors have provided strong evidence that vitamin D reduces risk of many types of cancer. Ecological studies from Australia, China, France, Japan, Nordic countries, Spain, and the United States [Garland, 2006] have found significant inverse correlations between solar UVB doses and incidence or mortality rates for many types of cancer, with the strongest evidence found for breast, colon, esophageal, gastric, pancreatic, and rectal cancer (5-7 studies each), followed by bladder, gallbladder cancer and leukemia (4 each), endometrial, lung, ovarian, and prostate cancer (3 each), cervical, oral/pharyngeal, renal, thyroid cancer and Hodgkin’s lymphoma (2 each), and brain and vulvar cancer (1 each) [Moukayed, 2013].

Mechanisms

The primary mechanisms whereby vitamin D reduces the risk of cancer are well known and include effects on cellular differentiation, proliferation and apoptosis and reductions in metastasis and angiogenesis around tumors [Moukayed, 2013].

Observational studies

Observational studies of cancer incidence and mortality rates with respect to serum 25-hydeoxyvitamin D [25(OH)D] levels have been reported for many types of cancer [Garland, 2006]. There is a general consensus that prospective studies with respect to 25(OH)D levels at time of enrollment in cohort studies reduce the risk of colorectal cancer [Giovannucci, 2013]. There is less agreement regarding breast cancer since observational studies with short periods after blood draw for 25(OH)D measurements report significant inverse correlations while those with long intervals do not [Chen, 2010; Grant, 2011].

Observational studies have found significantly lower mortality rates for high vs. low serum 25(OH)D levels near time of diagnosis for several types of cancer: breast, colorectal, gastric, lung, prostate cancer, chronic lymphocytic leukemia, lymphoma, melanoma, and non-Hodgkin’s lymphoma [Robsahm, 2013].

A meta-analysis of all-cancer incidence and mortality rates found significant inverse correlations with respect to serum 25(OH)D levels for both incidence and mortality rates; however, the inverse correlation for mortality rates was limited to women, with no significant effect for men [Yin, 2013].

Randomized controlled trials (RCTs)

RCTs have not adequately demonstrated that vitamin D reduces the risk of cancer [Bolland, 2014]. A meta-analyses of vitamin D3 supplementation found statistically significantly decreased cancer mortality (relative risk 0.88 (95% confidence interval 0.78 to 0.98); P = 0.02; 44,492 participants; 4 trials) [Bjelakovic, 2014].

Hill’s criteria

A scientific way to evaluate whether an agent can be considered causally linked in a biological system is through application of Hill’s criteria for causality in a biological system [Hill, 1965] (link to Wikipedia Hill’s criteria). The criteria applicable for vitamin D and cancer include strength of association, consistent findings in different populations, temporality, biological gradient (dose-response relation), plausibility (e.g., mechanisms), experiment (e.g., RCT), and analogy. Not all criteria need be satisfied for causality to be claimed; however, the more that are, the better. Hill’s criteria have been found to be well satisfied for breast and colorectal cancer and moderately well for several other types of cancer [Grant, 2009; Mohr, 2012] as well as survival for several types of cancer [Robsahm, 2013].

Reviews of vitamin D and cancer

Reviews of the role of vitamin D in general have accepted that vitamin D reduces risk of cancer [Holick, 2007; Holick, 2012].

References

(citation numbers at the end of references are from Scholar.google.com, but will be removed before posting on the Vitamin D page)



Jag8452 (talk) 03:10, 8 February 2014 (UTC)


 * Please read WP:MEDRS. We use secondary sources, not primary sources. Yobol (talk) 03:35, 8 February 2014 (UTC)
 * Most of the above appear to be high quality secondary sources. Boghog (talk) 08:19, 8 February 2014 (UTC)
 * Thanks for putting in the citation links. This will make it a lot easier for editors to review and comment on sources.  I had only checked one so far; it seemed like a secondary source, in that it reviewed evidence from many other sources.  I think the pushback we're likely to get is exactly what this proposed change is about:  getting beyond the limitation to secondary analyses of controlled studies.  As the Moukayed ref explains, there are reasons why such studies have a hard time coming up with significant results even when there are real effects, and lots of real effects are known via other methods.  Dicklyon (talk) 08:32, 8 February 2014 (UTC)
 * @Boghog: You are correct, apologies to Jag8452, most do appear to be secondary sources. Several of these studies still fail MEDRS (one is too old per WP:MEDDATE, several are not MEDLINE indexed), and overall the text doesn't make clear that observational studies are generally poorer studies compared to RCTs. There is a reason why evidence based medicine places a premium on RCTs, and the above's emphasis on observational studies goes against that. I think part of our problem is this article does a very poor job of distinguishing vitamin D as a treatment or prophylactic agent as a supplement in those without low viatmin D, vitamin D's molecular role in the pathophysiology of disease, and the role of vitamin D deficiency in diseases, and would argue that we need a significant reorganization of this article's health section.  As an aside, it is almost criminal that there is no discussion of the role of vitamin D in chronic kidney disease, something I shall rectify when I have time. Yobol (talk) 16:37, 8 February 2014 (UTC)


 * The Moukayed, 2013 source used to support the 1st and 2nd sections is not MEDRS-compliant. It is not a review - it is a primary source that investigates a hypothesis, and it has a WP:REDFLAG in that is from an "open access" publisher that has published a lot of nonsense.Jytdog (talk) 22:11, 8 February 2014 (UTC)


 * The statement in the Mechanisms section that "The primary mechanisms whereby vitamin D reduces the risk of cancer..." begs the question. There is no definitive evidence that taking Vitamin D reduces the risk of cancer. Jytdog (talk)


 * In the "Observational studies" section, the first sentence "Observational studies of cancer incidence and mortality rates with respect to serum 25-hydeoxyvitamin D [25(OH)D] levels have been reported for many types of cancer " makes no claim. I don't understand why it is here.  Also the sentence "There is a general consensus that prospective studies with respect to 25(OH)D levels at time of enrollment in cohort studies reduce the risk of colorectal cancer [Giovannucci, 2013]" makes no sense.  What are you trying to say?  Also the Robsahm source used here, like the Moukayed, 2013 source, is primary and published by the same open access publisher: WP:REDFLAG.  And this sentence contradicts itself "A meta-analysis of all-cancer incidence and mortality rates found significant inverse correlations with respect to serum 25(OH)D levels for both incidence and mortality rates; however, the inverse correlation for mortality rates was limited to women, with no significant effect for men"; significance for incidence and mortality is not the same and they shouldn't be lumped.Jytdog (talk) 22:11, 8 February 2014 (UTC)


 * In the RCT paragraph (which should be first, as you did in the first version) the word "adequately" is weasel-word-y (it simply "has not been demonstrated"), and the statement of the effectiveness of D3 is far broader than what the review found (D3 "seemed to decrease mortality in elderly people living independently or in institutional care")


 * The Hill's criteria paragraph is interesting.  However the Grant article is also published in an open access journal and is not listed as a review by Pubmed.  Same exact story with the Mohr article (same journal even).


 * We should not have a separate section on "Reviews" as everything we cite should be reviews. We don't need a source from 2007 on this issue either.  Finally, I want to talk about this sentence a bit: "Reviews of the role of vitamin D in general have accepted that vitamin D reduces risk of cancer".  This is not a useful sentence.  In general, as you have done here, there is no distinction made between correlations between disease incidence and Vitamin D deficiency, and the effect of taking Vitamin D supplements.  These are two separate things.  I know it seems logical to assume that if low Vitamin D correlates with a disease, that taking Vitamin D supplements will actually treat or prevent a disease, but this is a false assumption.  Yobol pointed this out too, I just wanted to underline it.  Jytdog (talk) 22:11, 8 February 2014 (UTC)

New version of Vitamin D and cancer
I thank the editors for additional comments on the proposed discussion of vitamin D and cancer. References from open access journals were omitted. Older references were omitted. However, one reference from 2008 was added since it is from a recognized agency, the International Center for Research on Cancer. The Hill’s criteria section was omitted. The order of the evidence was reversed with randomized controlled trials first, ecological trials last. If there are no further comments, this version will replace the current vitamin D cancer section.


 * What is the point of omitting "open access" journal references? Is it a problem that they don't charge readers to read the papers?  Dicklyon (talk) 02:18, 14 February 2014 (UTC)
 * please don't ask questions that assume bad faith.Jytdog (talk) 02:26, 14 February 2014 (UTC)
 * I don't understand. I assume he removed it for some good-faith reason; the reason I proposed was perhaps half-kidding, but isn't this what open access means?  Dicklyon (talk) 02:33, 14 February 2014 (UTC)
 * there are some open access journals that are seen as OK, but many are what we call "predatory" and will publish any kind of crap. (not sure if you know, but open access journals make money by charging authors, not by subscription. hence anybody can access them. the downside of this, is that it incentivizes the journal to accept whatever is submitted... if they don't publish they don't get paid)  open access is, today, a red flag with respect to quality.   there have been some extensive conversations at the Talk page of MEDRS about excluding them; here is one.  so if you are working on contested content it is best to avoid them. Jytdog (talk) 02:46, 14 February 2014 (UTC)
 * Yes, I'm aware of the "author pays" model, and the potential for abuse; yet it is becoming a very popular and successful model for other good reasons. As the discussion you linked shows, open access is pretty orthogonal to the problem.  So I guess the question then is what journals have been excluded, and by what criteria?  Not, I hope, because they're open access, which is not itself any kind of red flag, right?  Dicklyon (talk) 03:26, 14 February 2014 (UTC)

Vitamin D and cancer
The evidence that vitamin D reduces risk of cancer is discussed here in the order of the perceived strength of the evidence by type of study.

Randomized controlled trials (RCTs)

RCTs have not adequately demonstrated that vitamin D reduces the risk of cancer [Bolland, 2014]. A meta-analyses of vitamin D3 supplementation found statistically significantly decreased cancer mortality (12% reduction (95% confidence interval, 2%-22%); P = 0.02; 44,492 participants; 4 trials) [Bjelakovic, 2014]. Reasons that there have been few successful vitamin D RCTs reported for cancer incidence rates include that generally low vitamin D doses were used, vitamin D was combined with calcium, and little effort was made to enroll people with low serum 25(OH)D levels at baseline [Heaney, 2014]. The VITAL study underway overcomes some of the problems of RCTs and has enrolled a large number of people, but the results will not be available until at least 2017 [Manson, 2012].

Observational studies

Prospective observational studies of cancer incidence and mortality rates with respect to serum 25-hydeoxyvitamin D [25(OH)D] levels have been reported for many types of cancer. The serum 25(OH)D level-cancer incidence relation changes rapidly for 25(OH)D levels below 20 ng/ml (50 nmol/l) then more slowly to levels around 40 ng/ml (100 nmol/l) [Grant, 2010]. The International Agency for Research on Cancer (IARC) of the World Health Organization convened a panel to review the evidence for the UVB-vitamin D-cancer hypothesis. They concluded that “Observational studies provide evidence of a decreased risk of colorectal cancer associated with higher serum 25-hydroxyvitamin D. This evidence is supported by a decrease in colonic adenoma with higher serum 25-hydroxyvitamin D [IARC, p.216]. There is less agreement regarding breast cancer since observational studies with short periods between blood draw for 25(OH)D measurements and cancer incidence report significant inverse correlations while those with long intervals do not [Chen, 2010; Grant, 2011]. There is very little evidence that higher serum 25(OH)D levels are associated with risk of prostate cancer [IARC, 2008; Grant, 2010; Gilbert, 2012], although more aggressive prostate cancer is associated with lower serum 25(OH)D levels [Gilbert, 2012].

A meta-analysis of all-cancer incidence and mortality rates with respect to serum 25(OH)D levels found significant inverse correlations for both incidence and mortality rates; however, the inverse correlation for mortality rates was limited to women, with no significant effect for men [Yin, 2013].

A recent review of the role of vitamin D at a vitamin D conference in Warsaw, Poland attended by 550 health professionals accepted the hypothesis that vitamin D reduces risk of cancer based primarily on evidence from observational studies [Pludowski, 2013].

Mechanisms

The primary mechanisms whereby vitamin D reduces the risk of cancer are well known and include effects on cellular differentiation, proliferation and survival, modulation of growth factor actions, anti-inflammatory effects, inhibition of angiogenesis, and inhibition of invasion and metastasis [Krishnan, 2011a; Krishnan, 2011b; Fleet, 2012]. The mechanisms are driven by the hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D, which can control gene expression by binding to the vitamin D receptor. The first three mechanisms help reduce the risk of cancer from DNA damage, while the others reduce the growth of the tumors and the spread of tumors into the surrounding tissues. Organs in which cancer is developing convert circulating 25(OH)D to 1,25-dihydroxyvitamin D [Krishnan, 2011b], which is why serum 25(OH)D levels are important.

Ecological studies

Ecological studies based on geographical variation in cancer incidence and/or mortality rates with respect to indices of solar ultraviolet-B (UVB) doses and other cancer-risk modifying factors have provided strong evidence that vitamin D reduces risk of many types of cancer. Ecological studies from Australia, China, France, Japan, Nordic countries, Spain, and the United States [Grant, 2012] have found significant inverse correlations between solar UVB doses and incidence or mortality rates for many types of cancer, with the strongest evidence found for breast, colon, esophageal, gastric, pancreatic, and rectal cancer, followed by bladder, gallbladder cancer and leukemia, endometrial, lung, ovarian, and prostate cancer, cervical, oral/pharyngeal, renal, thyroid cancer and Hodgkin’s lymphoma, and brain and vulvar cancer [Grant, 2012]. Such ecological studies consider other cancer risk-modifying factors. The ecological studies are supported by prospective observational studies. The IARC concluded that overall, case control and cohort studies of individual sun exposure “identified a protective effect of sun exposure on the risk of colon, breast, and prostate cancer.” [IARC, 2008, p. 166]. More recently, UV doses where people lived in several U.S. states was associated with significantly increased melanoma risk, and decreased risk of bladder, colon, kidney, lung (squamous cell), prostate cancer and non-Hodgkin's lymphoma [Lin, 2012].

References

Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470. [Epub ahead of print]

Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes & Endocrinology, Early Online Publication 24 January 2014. doi:10.1016/S2213-8587(13)70212-2. http://download.thelancet.com/pdfs/journals/landia/PIIS2213858713702122.pdf

Chen P, Hu P, Xie D, Qin Y, Wang F, Wang H. Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Breast Cancer Res Treat. 2010 Jun;121(2):469-77,

Fleet JC, Desmet M, Johnson R, Li Y. Vitamin D and cancer: a review of molecular mechanisms. Biochem J. 2012 Jan 1;441(1):61-76.

Gilbert R, Metcalfe C, Fraser WD, Donovan J, Hamdy F, Neal DE, Lane JA, Martin RM. Associations of circulating 25-hydroxyvitamin D with prostate cancer diagnosis, stage and grade. Int J Cancer. 2012 Sep 1;131(5):1187-96.

Grant WB. Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res. 2012;32(1):223-36.

Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines. Dermatoendocrinol. 2011;3(3):199-204,

Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B, 2010;101(2):130–6.

Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014 Jan;72(1):48-54.

IARC Working Group Report 5: Vitamin D and Cancer. IARC, Lyon, France (Nov. 25, 2008) http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk5/Report_VitD.pdf

Krishnan AV, Feldman D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol. 2011a, Feb 10;51:311-36.

Krishnan AV, Feldman D. Vitamin D and prostate cancer. Ch. 86 in Vitamin D, Third Edit. Feldman D, Pike JW, Adams JS (eds). 2011b, 1675-709.

Lin SW, Wheeler DC, Park Y, Cahoon EK, Hollenbeck AR, Freedman DM, Abnet CC. Prospective study of ultraviolet radiation exposure and risk of cancer in the U.S. Int J Cancer. 2012 Sep 15;131(6):E1015-23.

Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, Zaharris E, Macfadyen JG, Danielson E, Lin J, Zhang SM, Buring JE. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012 Jan;33(1):159-71.

Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, Shoenfeld Y, Lerchbaum E, Llewellyn DJ, Kienreich K, Soni M. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality- a review of recent evidence. Autoimmun Rev. 2013 Aug;12(10):976-89.

Yin L, Mena JM, Chen T, Schöttker B, Arndt V, Brenner H. Circulating 25-hydroxyvitamin D serum concentration and total cancer incidence and mortality: a systematic review and meta-analysis. Prev Med. 2013 Dec;57(6):753-64. Jag8452 (talk)

Discussion
I think the phase "evidence that vitamin D reduces risk of cancer" in the opening sentence is not quite right. The evidence mostly shows that low vitamin D increases risk of cancer. If there is some "normal" level with a "normal" risk of cancer, then more vitamin D may not significantly reduce that risk. I think that's what the controlled trials basically show. The point of the other information is that the controlled trials aren't looking at the low end of the spectrum, which is the only place where any significant effect is likely. It's not like a drug where there's a zero baseline, and a dose response curve. Dicklyon (talk) 03:32, 14 February 2014 (UTC)
 * No evidence does not "show that low vit D increases risk of cancer" Evidence shows an association.
 * This could be the same as the situation were the number of bars in a town is directly and closely associated with the number of churches. This does not necessarily mean that churches cause people to bring at bars. Or that bars cause people to go to church. There is a third factor called "the size of the town"
 * The same could be true with vit D. Maybe a factor that causes death also causes low vit D levels. Changing vit D will thus have no affect. Homocystein anyone? Doc James  (talk · contribs · email) (if I write on your page reply on mine) 04:15, 14 February 2014 (UTC)
 * Good point. We  should not interpret correlation as causation.  I haven't read the evidence enough to know what it shows, but my impression from the mechanisms and other stuff I've seen is that there is some support at least for a causal connection.  If the sources only support that "low vitamin D is associated with an increase in cancer risk", we should say only that.  Dicklyon (talk) 04:40, 14 February 2014 (UTC)

In biological systems, Hill’s criteria for causality can be used to evaluate ALL of the evidence. As demonstrated by the findings from ecological and observational studies, there is considerable evidence that vitamin D or more precisely, serum 25(OH)D levels, have a significant and generally consistent relation with respect to several types of cancer, and the mechanisms whereby vitamin D affects the initiation and progression and metastasis of cancer are well known. The fact that vitamin D randomized controlled trials have provided only weak evidence to date is due to the design and conduct of such studies. Thus, this section should be added to what is proposed for the vitamin D cancer description. There are several ways to evaluate whether Hill’s criteria for vitamin D and cancer are valid scientifically. One way is that there is a page on it at Wikipedia. A second is that one of the papers, Grant, 2009, has been cited 43 times according to the Web of Science and more than 98 times according to http://scholar.google.com/.

I agree that “low serum 25(OH)D level is associated with an increase in cancer risk” is an accurate statement.

A scientific way to evaluate whether an agent can be considered causally linked in a biological system is through application of Hill’s criteria for causality in a biological system. The criteria applicable for vitamin D and cancer include strength of association, consistent findings in different populations, temporality, biological gradient (dose-response relation), plausibility (e.g., mechanisms), experiment (e.g., RCT), and analogy. Not all criteria need be satisfied for causality to be claimed; however, the more that are, the better. Hill’s criteria have been found to be well satisfied for breast and colorectal cancer and moderately well for several other types of cancer [Grant, 2009; Mohr, 2012] as well as survival for several types of cancer [Robsahm, 2013].

Grant WB. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill’s criteria for causality. Dermatoendocrinol. 2009;1(1):17-24.

Mohr SB, Gorham ED, Alcaraz JE, Kane CI, Macera CA, Parsons JE, Wingard DL, Garland CF. Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria? Dermatoendocrin. 2012;4(2):152-7.

Robsahm TE, Schwartz GG, Tretli S. The inverse relationship between 25-hydroxyvitamin D and cancer survival: Discussion of causation. Cancers. 2013, 5(4), 1439-1455. Jag8452 (talk) 15:42, 14 February 2014 (UTC)
 * The journal Cancers does not have an impact factor yet. The other journal also started in 2009. Unable to find an impact factor either. Not the type of sources we should be using to refute / contradict the Lancet / BMJ / JAMA / USPSTF / Cochrane.  Doc James  (talk · contribs · email) (if I write on your page reply on mine) 16:03, 14 February 2014 (UTC)
 * Discussing "the existence of this wikipedia article" as evidence for anything is a) a violation of Wikipedia's sourcing policy (wikipedia cannot be a source for itself) and b) pure OR. Let's not go there. I have already noted that the Robshahm article is from an open source journal (MDPI is an especially problematic open access publisher) and Dermatoendocrinology is not MEDLINE indexed. Jytdog (talk) 16:23, 14 February 2014 (UTC)
 * Whether or not a journal is open source does not say much about quality. Doc James  (talk · contribs · email) (if I write on your page reply on mine) 16:33, 14 February 2014 (UTC)
 * I agree that being open source is not a definitive "no", it is just a flag. As you said it doesn't have an impact factor and as I think you noted before, it is not medline indexed. Jytdog (talk) 16:53, 14 February 2014 (UTC)
 * I agree the sources are not that good. Just for different reasons. Doc James  (talk · contribs · email) (if I write on your page reply on mine) 17:00, 14 February 2014 (UTC)
 * Dermato-Endocrinology is indexed at pubmed.gov. Its H-index is 15 at the Web of Science (checked it this afternoon). It is also indexed at SCOPUS (a European index similar to pubmed.gov). It is open access but it is also peer reviewed. The reason it does not have an index factor is that when the journal started in 2009, the publisher omitted the doi identification when submitting the information to Pubmed, SCOPUS, etc.


 * As of Feb. 14, 2014, there were 412 citations to 58 papers published in 2009, of which 49 were cited. That is 8.4 citations per paper cited, or 7.1 citations per paper published. I do not have the impact factor. While the Web of Science requires a subscription and can be accessed through university libraries, Scholar.Google.com has open access. If you go there and search “dermato-endocrinology 2009” you can judge for yourself the quality of the papers published in this journal.


 * DE is published by Landis Bioscience. Landis Bioscience publishes 43 journals, of which only DE is open access. It had four other open access journals but they seem to have had only one year of publication each.


 * Here are the editors; Michael Holick has 413 entries on vitamin D at pubmed.gov dating back to 1970. Thus, the quality of the journal is high.


 * Editor-in-Chief


 * Jorg Reichrath; Universitätsklinikum des Saarlandes; Homburg, DE


 * Associate Editors


 * Kenneth R. Feingold; University of California, San Francisco; San Francisco, CA, US


 * Michael F. Holick; Boston University Medical Center; Boston, MA, US


 * Christos C. Zouboulis; Dessau Medical Center; Dessau, DE Jag8452 (talk) 15:04, 15 February 2014 (UTC)

Sure still do not think they are suitable for attempting to refute the Lancet and the BMJ. Doc James (talk · contribs · email) (if I write on your page reply on mine) 15:13, 15 February 2014 (UTC)
 * We should not be using articles from non MEDLINE Indexed journals to refute higher quality sources. Yobol (talk) 03:34, 16 February 2014 (UTC)

Comment: I thank the editors for comments on how to report the evidence that vitamin D reduces the risk of cancer. This latest version divides the evidence into three sections: epidemiology, mechanisms, and treatment. The epidemiology is strong for colorectal cancer and some other types of cancer. The mechanisms are well understood. These findings should be considered scientific evidence of the role of vitamin D in reducing the risk of cancer. A caveat is added that further research is required before recommending supplementing with vitamin D3 to reduce the risk of cancer. All references included are thought to be in MEDLINE except the Bolland et al. paper.

Vitamin D and cancer
The evidence that vitamin D reduces risk of cancer is discussed in terms of three types of studies: epidemiology, mechanisms, and treatment. There is mounting evidence from observational and ecological studies that cancer incidence and/or mortality rates are inversely correlated with serum 25-hydroxyvitamin D [25(OH)D] levels and/or solar ultraviolet-B doses. The mechanisms whereby vitamin D reduces the incidence, progression and metastasis of cancer are well understood. There is limited evidence from randomized controlled trials that vitamin D3 supplementation reduces cancer mortality rates. Thus, further research is required before recommending supplementing with vitamin D3 to reduce the risk of cancer.

Epidemiology

Observational studies

Prospective observational studies of cancer incidence and mortality rates with respect to serum 25(OH)D levels have been reported for many types of cancer. The serum 25(OH)D level-cancer incidence relation changes rapidly for 25(OH)D levels below 20 ng/ml (50 nmol/l) then more slowly to levels around 40 ng/ml (100 nmol/l) [Grant, 2010]. “Mixed-effects dose-response meta-analyses showed that each 10-nmol/L increase in blood 25-(OH)D concentration was associated with a 6% (95% CI, 3% to 9%) reduced risk for colorectal cancer but no statistically significant dose-response relationships for prostate and breast cancer” [Chung, 2011]. There is very little evidence that higher serum 25(OH)D levels are associated with risk of prostate cancer [Grant, 2010; Gilbert, 2012], although aggressive prostate cancer is associated with lower serum 25(OH)D levels [Gilbert, 2012].

A meta-analysis of all-cancer incidence and mortality rates with respect to serum 25(OH)D levels found significant inverse correlations for both incidence and mortality rates; however, the inverse correlation for mortality rates was limited to women, with no significant effect for men [Yin, 2013].

A recent review of the role of vitamin D at a vitamin D conference in Warsaw, Poland attended by 550 health professionals accepted the hypothesis that vitamin D reduces risk of cancer based primarily on evidence from observational studies [Pludowski, 2013]. See, also, [Hossein-Nezhad, 2013] for a review of the evidence that vitamin D reduces risk of cancer.

Ecological studies

Ecological studies based on geographical variation in cancer incidence and/or mortality rates with respect to indices of solar ultraviolet-B (UVB) doses and other cancer-risk modifying factors have provided strong evidence that vitamin D reduces risk of many types of cancer. Ecological studies from Australia, China, France, Japan, Nordic countries, Spain, and the United States [Grant, 2012] have found significant inverse correlations between solar UVB doses and incidence or mortality rates for many types of cancer, with the strongest evidence found for breast, colon, esophageal, gastric, pancreatic, and rectal cancer, followed by bladder, gallbladder cancer and leukemia, endometrial, lung, ovarian, and prostate cancer, cervical, oral/pharyngeal, renal, thyroid cancer and Hodgkin’s lymphoma, and brain and vulvar cancer [Grant, 2012]. Such ecological studies consider other cancer risk-modifying factors. The ecological studies are supported by prospective observational studies. The IARC concluded that overall, case control and cohort studies of individual sun exposure “identified a protective effect of sun exposure on the risk of colon, breast, and prostate cancer.” [IARC, 2008, p. 166]. More recently, UV doses where people lived in several U.S. states was associated with significantly increased melanoma risk, and decreased risk of bladder, colon, kidney, lung (squamous cell), prostate cancer and non-Hodgkin's lymphoma [Lin, 2012].

Mechanisms

The primary mechanisms whereby vitamin D reduces the risk of cancer are well known and include effects on cellular differentiation, proliferation and survival, modulation of growth factor actions, anti-inflammatory effects, inhibition of angiogenesis, and inhibition of invasion and metastasis [Krishnan, 2011; Krishnan, 2011; Fleet, 2012]. The mechanisms are driven by the hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D, which can control gene expression by binding to the vitamin D receptor. The first three mechanisms help reduce the risk of cancer from DNA damage, while the others reduce the growth of the tumors and the spread of tumors into the surrounding tissues. Organs in which cancer is developing convert circulating 25(OH)D to 1,25-dihydroxyvitamin D [Krishnan, 2011], which is why serum 25(OH)D levels are important. (This Krishnan is the book chapter)

Treatment

RCTs have not adequately demonstrated that vitamin D reduces the risk of cancer [Bolland, 2014]. A meta-analyses of vitamin D3 supplementation found statistically significantly decreased cancer mortality (12% reduction (95% confidence interval, 2%-22%); P = 0.02; 44,492 participants; 4 trials) [Bjelakovic, 2014]. Reasons that there have been few successful vitamin D RCTs reported for cancer incidence rates include that generally low vitamin D doses were used, vitamin D was combined with calcium, and little effort was made to enroll people with low serum 25(OH)D levels at baseline [Heaney, 2014]. The VITAL study underway overcomes some of the problems of RCTs and has enrolled a large number of people, but the results will not be available until at least 2017 [Manson, 2012].

References

Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470. [Epub ahead of print]

Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes & Endocrinology, Early Online Publication 24 January 2014. doi:10.1016/S2213-8587(13)70212-2. http://download.thelancet.com/pdfs/journals/landia/PIIS2213858713702122.pdf

Chen P, Hu P, Xie D, Qin Y, Wang F, Wang H. Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Breast Cancer Res Treat. 2010 Jun;121(2):469-77,

Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011 Dec 20;155(12):827-38.

Fleet JC, Desmet M, Johnson R, Li Y. Vitamin D and cancer: a review of molecular mechanisms. Biochem J. 2012 Jan 1;441(1):61-76.

Gilbert R, Metcalfe C, Fraser WD, Donovan J, Hamdy F, Neal DE, Lane JA, Martin RM. Associations of circulating 25-hydroxyvitamin D with prostate cancer diagnosis, stage and grade. Int J Cancer. 2012 Sep 1;131(5):1187-96.

Grant WB. Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res. 2012;32(1):223-36.

Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines. Dermatoendocrinol. 2011;3(3):199-204,

Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B, 2010;101(2):130–6.

Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014 Jan;72(1):48-54.

Hossein-Nezhad A, Holick MF. Vitamin D for health: A global perspective. Mayo Clin Proc. 2013 July;88(7):720-55.

IARC Working Group Report 5: Vitamin D and Cancer. IARC, Lyon, France (Nov. 25, 2008) http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk5/Report_VitD.pdf

Krishnan AV, Feldman D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol. 2011a, Feb 10;51:311-36.

Krishnan AV, Feldman D. Vitamin D and prostate cancer. Ch. 86 in Vitamin D, Third Edit. Feldman D, Pike JW, Adams JS (eds). 2011b, 1675-709.

Lin SW, Wheeler DC, Park Y, Cahoon EK, Hollenbeck AR, Freedman DM, Abnet CC. Prospective study of ultraviolet radiation exposure and risk of cancer in the U.S. Int J Cancer. 2012 Sep 15;131(6):E1015-23.

Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, Zaharris E, Macfadyen JG, Danielson E, Lin J, Zhang SM, Buring JE. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012 Jan;33(1):159-71.

Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, Shoenfeld Y, Lerchbaum E, Llewellyn DJ, Kienreich K, Soni M. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality- a review of recent evidence. Autoimmun Rev. 2013 Aug;12(10):976-89.

Yin L, Mena JM, Chen T, Schöttker B, Arndt V, Brenner H. Circulating 25-hydroxyvitamin D serum concentration and total cancer incidence and mortality: a systematic review and meta-analysis. Prev Med. 2013 Dec;57(6):753-64. Jag8452 (talk) 01:25, 20 February 2014 (UTC)
 * This line here "The primary mechanisms whereby vitamin D reduces the risk of cancer are well known" is refuted by the fact that vit D supplementation does not reduce cancer. Doc James  (talk · contribs · email) (if I write on your page reply on mine) 02:28, 20 February 2014 (UTC)


 * Regarding the mechanisms, David Feldman is a highly respected vitamin D researcher. He has edited three editions of Vitamin D.


 * Krishnan AV, Feldman D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol. 2011 Feb 10;51:311-36.


 * Krishnan AV, Feldman D. Vitamin D and prostate cancer. Ch. 86 in Vitamin D, Third Edit. Feldman D, Pike JW, Adams JS (eds). 2011, 1675-709.


 * Vitamin D supplementation was found to reduce the risk of cancer mortality rates in the meta-analysis by the Cochrane review:


 * Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470. [Epub ahead of print]


 * The mechanisms are also supported by the observational and ecological studies.


 * The problem with the randomized controls of vitamin D for cancer are several including too little vitamin D as well as being given to populations with relatively high serum 25(OH)D levels.


 * Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014 Jan;72(1):48-54. Jag8452 (talk) 20:44, 20 February 2014 (UTC)
 * Hum, yes this is good. "Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I(2) = 0%; 44,492 participants; 4 trials). "  Doc James  (talk · contribs · email) (if I write on your page reply on mine) 20:54, 20 February 2014 (UTC)


 * User:Jag8452 you missed the point of DocJames statement. We "know" lots of things in vitro and even in model animals that don't work the same way in humans. What does the sentence: "The primary mechanisms whereby vitamin D reduces the risk of cancer are well known." mean?  You could mean:
 * If a human takes X mg/kg of vitamin D supplement every day, his or her risk of getting Y cancer (Y being some specific kind of cancer) is reduced by Z% (this is a statement about an actual therapeutic intervention - actual people taking actual supplements and seeing an effect)
 * Humans with levels of vitamin D below/above X have a Z% increased risk of getting Y cancer (this is more of a diagnostic screening claim) (this too involves measuring vitamin D levels in people and being able to quantify risk of getting a disease based on known thresholds)
 * Statements of the above, where "human" is replaced with some model animal
 * Cell signaling pathways through which vitamin D interacts with (some proliferation or anti-proliferative transduction pathway(s) or proteins related to cancer or cancer prevention) are well understood. (this is all about biology and has no direct mapping onto actual human health or disease or onto human phenotype)
 * So...which kind of statement are you making? I don't know either.  We have mentioned this problem with clarity before...  Jytdog (talk) 20:59, 20 February 2014 (UTC)


 * The quality of the evidence however is not the best per "Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted." Have added a line. Doc James  (talk · contribs · email) (if I write on your page reply on mine) 21:01, 20 February 2014 (UTC)


 * nice - pulling the newest cochrane review out of the pile! Thanks User:Jag8452 for bringing that super valuable source to the table. Jytdog (talk) 21:04, 20 February 2014 (UTC)
 * Regarding the mechanisms, this statement comes closest to the meaning intended:


 * Cell signaling pathways through which vitamin D interacts with (some proliferation or anti-proliferative transduction pathway(s) or proteins related to cancer or cancer prevention) are well understood. (this is all about biology and has no direct mapping onto actual human health or disease or onto human phenotype)


 * This is about biology. However, it does also play into human health, but does not in and of itself justify treatment. As to the discussion of vitamin D at Wikipedia, there appear to be several sections including Effects and Mechanism of Action. So, how about if the mechanisms for vitamin D in reducing risk of cancer is placed under the Mechanism of Action heading?


 * The Effects section is largely limited to the effects of supplementation. What is missing is an Effects section on the effects of vitamin D produced by solar (or artificial) ultraviolet-B. Since most vitamin D comes from UVB irradiance, there should be an additional section on Effects related to UVB. Under this section the results of ecological and observational studies could be placed. There is a section Synthesis in the skin. Perhaps the Effects of vitamin D from UVB could be placed after that.


 * As stated earlier, RCTs are of two types: those for the healthy population with average 25(OH)D levels and those for populations with low 25(OH)D levels. This paper by Bolland points out that for those likely with low 25(OH)D levels, there is a beneficial effect on cancer risk of vitamin D plus calcium supplementation.


 * Bolland MJ1, Grey A, Gamble GD, Reid IR. Am J Clin Nutr. 2011 Oct;94(4):1144-9. doi: 10.3945/ajcn.111.015032. Epub 2011 Aug 31. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set.


 * Abstract


 * BACKGROUND:


 * Frequent use of personal, nonprotocol calcium supplements obscured an adverse effect of coadministered calcium and vitamin D (CaD) on cardiovascular risk in the Women's Health Initiative (WHI).


 * OBJECTIVE:


 * We investigated the effects of the use of personal calcium or vitamin D supplements on other outcomes in the WHI CaD Study (WHI CaD) by using the WHI limited-access clinical trials data set.


 * DESIGN:


 * The WHI CaD was a 7-y, randomized, placebo-controlled trial of CaD (1 g Ca/400 IU vitamin D daily) in 36,282 community-dwelling, postmenopausal women. The incidence of total cancer (excluding nonmelanoma skin cancers), breast and colorectal cancers, hip and total fracture, and mortality was assessed by using Cox proportional hazards models.


 * RESULTS:


 * In the WHI CaD, interactions between the use of either personal calcium or vitamin D supplements and CaD were found for total, breast, and colorectal cancers but not for fracture or mortality. In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD significantly decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26).


 * CONCLUSIONS:


 * For women in the WHI CaD who were not taking personal calcium or vitamin D supplements at randomization, CaD decreased the risk of total, breast, and colorectal cancers and did not change the risk of fractures or total mortality. The nonskeletal effects of CaD may be more important than the skeletal effects and should be considered when evaluating these supplements. The WHI CaD trial is registered at clinicaltrials.gov as NCT00000611.Jag8452 (talk) 22:27, 20 February 2014 (UTC)

Hi Jag8452, I get it that you are sincerely trying to improve the article, but please write more clearly. Please! Please stop writing things like "So, how about if the mechanisms for vitamin D in reducing risk of cancer is placed under the Mechanism of Action heading?" You have an idea locked into your head that there is a causal relationship - that somehow vitamin D reduces the risk of cancer. Given the publications we have today, this causation is not proven and there is no way that the MEDRS-rigorous editors are going let content into the article, that says that causation is proven. We don't know if low vitamin D just correlates with cancer, or if an absence of Vitamin D: allows cells to become cancerous; prevents apoptosis of cancer cells; promotes cancer proliferation/invasion/metastasis; or the opposite - if cancer depletes Vitamin D. We don't know if adding Vitamin D reverses whatever that process was (so far it appears not to). So really, we don't know there is causality and if there is causality we don't know if it rectifiable. So would you please stop saying that "vitamin D reduces risk of cancer"? (real question!)  I think you are going to find your proposals change if you would be so kind as to check that belief at the door.... 23:32, 20 February 2014 (UTC)
 * That said, it is an interesting question, whether this article should go deeper into the biological activity - down into the cellular level as Jag8452 says. I kind of like that.  btw I just changed the "Mechanism of action" section to "Biological activity", with Jag8452's question about where to put that, in mind. Jytdog (talk) 23:32, 20 February 2014 (UTC)

Added
Tb patients are deficient for Vitamin D.

Reference: Srinivasan A, Syal K, Banerjee D, Hota D, Gupta D, Kaul D & Chakrabarti A (2013) Low plasma levels of cholecalciferol and 13-cis-retinoic acid in tuberculosis: implications in host-based chemotherapy. Nutrition 29, 1245-1251 Kirtimaansyal (talk) 07:57, 5 February 2014 (UTC)
 * - not a WP:MEDRS. Alexbrn talk 08:00, 5 February 2014 (UTC)

@Alexbrn : Sorry, but i could not get, how it is not a reliable source. It is a human study with concrete evidences. It has been published in Nutrition journal (Elsevier) with 3.1 impact factor(implying good reputation in the field). And most importantly it is the latest and have been accepted by peer reviewed process. i am the co-author in this article and sure of its experiments as i have my self performed them. So please clearly indicate how it is not reliable. — Preceding unsigned comment added by Kirtimaansyal (talk • contribs) 14:53, 26 February 2014 (UTC)
 * Hi User:Kirtimaansya - I agree with Alexbrn. You are new here, I think, and there is a lot for you to learn about how we source content.  Responding first to the new information you disclosed:  you have a conflict of interest here.  This is your paper, and you benefit if it is included in Wikipedia and people talk about it.  You should not add citations of your own articles to Wikipedia.  See also WP:PROMOTION.  Secondly, please know that your personal authority does not matter here.  This is often shocking to people but it is true. Think about it - when you signed up for an account, you did not have to provide any proof that you are indeed Kirtimaan Syal.  None. You could be a 12 year old boy living in Mongolia, for all anybody here knows.  Wikipedia was built in such a way, that the authority in the outside world of any given editor, does not and cannot matter.  (editors can gain authority within Wikipedia in certain ways but that is a different story).  But here is how Wikipedia works.  First and foremost, hat we rely primarily on the secondary literature (ideally critical or systematic reviews) to generate content.  This is wikipedia policy, across the board.  The reason for this is that the primary literature is full of conflicting opinions and findings, and wikipedia editors are not allowed to conduct what we call "original research" or "syntheses" (please see WP:OR).  Sorting through the primary literature yourself, and picking this article or that one, is OR, and not allowed here.  We rely on experts in the field to summarize the consensus, and also to lay out the various sides in any given controversy - that is what happens in review articlesn (secondary sources).  Again this is foundational Wikipedia policy.  For health-related content, we have an even higher standard for sourcing, here: WP:MEDRS.  MEDRS explains clearly that we want to communicate to the public "medical knowledge" - not the latest hypotheses or cutting edge research findings.  We want to state the consensus.  Also we are not a newspaper - we don't "cover the story" as it unfolds.  We transmit medical and health related knowledge.  I am sure you aware that research in the biomedical field suffers from lack of replicability, which is another and really important reason why we don't cite primary sources - we wait to see if any given findings stand the test of time and replication - we find out whether they do in secondary sources.  Those are the main reasons why your paper is not acceptable to use as a source in Wikipedia. I hope you understand a bit more now how Wikipedia, "the encylopedia that anyone can edit", actually works, and how we are so often able to generate such high quality, reliable articles, when our policies are followed. (of course, we also have far too many crappy articles - we are always in need of editors who are 1)  competent in a given subject matter) and 2) competent in their understanding of how Wikipedia works (which I hope you will come to do).  In any case, I do hope you read WP:MEDRS - and please keep WP:COI in mind with respect to citing your own papers here.  In any case, welcome to Wikipedia! (there is some learning required, but once you are up and running, editing can be fun and rewarding, and you sometimes get to interact with great people) Jytdog (talk) 15:26, 26 February 2014 (UTC)


 * I really thank you Jytdog for investing so much time on me. Actually, i will not benefit in any way whether my article is discussed here or not. So there is no question of promotion. As I have some expertise on Vitamin D and tuberculosis. So I suggested that. And I got your point. In future i will not give primary source references alone. Thank you once again.Kirtimaansyal (talk) 17:53, 26 February 2014 (UTC)


 * thanks for receiving it so graciously. We very much need more experts (especially in health and medicine) so if you want to come in deeper you will be very welcome! (bw if you have some time please visit: WikiProject Medicine) best regards Jytdog (talk) 18:24, 26 February 2014 (UTC)


 * Thankyou Jytdog. I have already started looking into the WikiProject Medicine. I will certainly try to contribute in best possible way. Kirtimaansyal (talk) 06:42, 4 March 2014 (UTC)

Resuming the dialog
Greetings editors.

Here is my latest set of suggestions for the vitamin D page. Please review and let me know if the suggestions can be worked into the page and whether you would like to make the changes or have me do them.

In the text below, I am working with several different types of text. In the first section, I take excerpts from the existing Wikipedia article on Vitamin D, and bring additional points of view to bear on them and/or make my own comments on them. In the second section, I show excerpts from several articles, from Lancet, BMJ, etc., that illustrate important points that I believe are part of the growing consensus on the activity and uses of Vitamin D. [My comments in both sections are in brackets.]

COMMENTS ON EXISTING TEXT:

Cardiovascular disease


 * "Taking vitamin D supplements has no significant effect on the risk of stroke, cerebrovascular disease, cardial infarction or ischaemic heart disease.[9]"

[Note from reference cited below:]


 * “We searched MEDLINE and EMBASE from 1966 through February 2012 for prospective studies that assessed the association of 25(OH)-vitamin D concentrations with CVD risk. A total of 24 articles met our inclusion criteria, from which 19 independent studies with 6123 CVD cases in 65,994 participants were included for a meta-analysis. In a comparison of the lowest with the highest 25(OH)-vitamin D categories, the pooled relative risk was 1.52 (95% confidence interval, 1.30-1.77) for total CVD, 1.42 (95% confidence interval, 1.19-1.71) for CVD mortality, 1.38 (95% confidence interval, 1.21-1.57) for coronary heart disease, and 1.64 (95% confidence interval, 1.27-2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and were better controlled for season and confounding. We used a fractional polynomial spline regression analysis to assess the linearity of dose-response association between continuous 25(OH)-vitamin D and CVD risk. The CVD risk increased monotonically across decreasing 25(OH)-vitamin D below ≈60 nmol/L, with a relative risk of 1.03 (95% confidence interval, 1.00-1.06) per 25-nmol/L decrement in 25(OH)-vitamin D.”


 * Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: A meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012 Nov 1;5(6):819-29. http://www.ncbi.nlm.nih.gov/pubmed/23149428

Infectious disease


 * "In general, vitamin D functions to activate the innate and dampen the adaptive immune systems.[29] Vitamin D deficiency has been linked to increased risk of viral infections, including HIV and influenza.[30][31][32] Low levels of vitamin D appear to be a risk factor for tuberculosis,[33] and historically it was used as a treatment.[34][34"

[Note: Randomized controlled trials support this link:]


 * Aloia JF, Li-Ng M. Re: epidemic influenza and vitamin D. Epidemiol Infect. 2007 Oct;135(7):1095-6; author reply 1097-8. http://www.ncbi.nlm.nih.gov/pubmed/17352842


 * Camargo CA Jr, Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, Sumberzul N, Rich-Edwards JW. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012 Sep;130(3):e561-7. http://www.ncbi.nlm.nih.gov/pubmed/22908115


 * Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010 May;91(5):1255-60. http://www.ncbi.nlm.nih.gov/pubmed/20219962

[Since observational studies were cited for infectious diseases, they should be cited for other diseases as well!!]

Effects


 * "The effects of vitamin D supplementation on health are uncertain.[6] A 2013 review did not find any effect from supplementation on the rates of disease, other than a tentative decrease in mortality in the elderly.[14] Low vitamin D levels may result from disease rather than cause disease.[14]"


 * Reference 14:
 * Autier P, Boniol M, Pizot C, Mullie, P. Vitamin D status and ill health: a systematic review. Lancet Diabetes & Endocrinology. Jan. 2014;2(1):76-89.

[The April 2014 issue has many letters regarding this paper. See http://www.thelancet.com/journals/landia/issue/current. The idea that low vitamin D levels may result from disease state (in longitudinal studies) is not consistent with the fact that low 25(OH)D levels precede the disease.]

NEW PERSPECTIVES:


 * “It is now generally accepted that vitamin D deficiency is a worldwide health problem that affects not only musculoskeletal health but also a wide range of acute and chronic diseases. However, there remains cynicism about the lack of randomized controlled trials to support the association studies regarding the nonskeletal health benefits of vitamin D. This review was obtained by searching English-language studies published up to April 1, 2013, in PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials (search terms: vitamin D and supplementation) and focuses on recent challenges regarding the definition of vitamin D deficiency and how to achieve optimal serum 25-hydroxyvitamin D concentrations from dietary sources, supplements, and sun exposure. The effect of vitamin D on fetal programming epigenetics and gene regulation could potentially explain why vitamin D has been reported to have such wide-ranging health benefits throughout life. There is potentially a great upside to increasing the vitamin D status of children and adults worldwide for improving musculoskeletal health and reducing the risk of chronic illnesses, including some cancers, autoimmune diseases, infectious diseases, type 2 diabetes mellitus, neurocognitive disorders, and mortality.”


 * Hossein-Nezhad A, Holick MF. Vitamin D for health: A global perspective. Mayo Clin Proc. 2013 July;88(7):720-55. http://www.ncbi.nlm.nih.gov/pubmed/23790560

[Many of Holick’s earlier papers are referenced. This paper should be added, perhaps replacing one of his earlier papers.]


 * “The goal of this Consensus Statement is to help primary care practitioners achieve adequate vitamin D intake from all sources in their older patients, with the goal of reducing falls and fall-related injuries. The workgroup graded the quality of evidence and assigned an evidence level using established criteria. Based on the evidence for fall and fracture reduction in the clinical trials of older community-dwelling and institutionalized persons and meta-analyses, the workgroup concluded that a serum 25 hydroxyvitamin D (25(OH)D) concentration of 30 ng/mL (75 nmol/L) should be a minimum goal to achieve in older adults, particularly in frail adults, who are at higher risk of falls, injuries, and fractures. The workgroup concluded that the goal - to reduce fall injuries related to low vitamin D status - could be achieved safely and would not require practitioners to measure serum 25(OH)D concentrations in older adults in the absence of underlying conditions that increase the risk of hypercalcemia (e.g., advanced renal disease, certain malignancies, sarcoidosis).”


 * American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults. Recommendations abstracted from the American Geriatrics Society Consensus Statement on Vitamin D for Prevention of Falls and Their Consequences. J Am Geriatr Soc 2013 Dec 18. doi: 10.1111/jgs.12631. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/24350602


 * “Our findings suggest that vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. Future trials with similar designs are unlikely to alter these conclusions.”


 * Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes & Endocrinology, 2014 Apr;2(4):307-20. http://www.ncbi.nlm.nih.gov/pubmed/24703049


 * “RESULTS:


 * “In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods.


 * “CONCLUSIONS:


 * “Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.”


 * Chowdhury R, Kunutsor S, Vitezova A, Oliver-Williams C, Chowdhury S, Kiefte-de-Jong JC, Khan H, Baena CP, Prabhakaran D, Hoshen MB, Feldman BS, Pan A, Johnson L, Crowe F, Hu FB, Franco OH. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014 Apr 1;348:g1903. http://www.ncbi.nlm.nih.gov/pubmed/24690623


 * “RESULTS:


 * “107 systematic literature reviews and 74 meta-analyses of observational studies of plasma vitamin D concentrations and 87 meta-analyses of randomised controlled trials of vitamin D supplementation were identified. The relation between vitamin D and 137 outcomes has been explored, covering a wide range of skeletal, malignant, cardiovascular, autoimmune, infectious, metabolic, and other diseases. Ten outcomes were examined by both meta-analyses of observational studies and meta-analyses of randomised controlled trials, but the direction of the effect and level of statistical significance was concordant only for birth weight (maternal vitamin D status or supplementation). On the basis of the available evidence, an association between vitamin D concentrations and birth weight, dental caries in children, maternal vitamin D concentrations at term, and parathyroid hormone concentrations in patients with chronic kidney disease requiring dialysis is probable, but further studies and better designed trials are needed to draw firmer conclusions. In contrast to previous reports, evidence does not support the argument that vitamin D only supplementation increases bone mineral density or reduces the risk of fractures or falls in older people.


 * “CONCLUSIONS:


 * “Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.”


 * Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014 Apr 1;348:g2035. http://www.ncbi.nlm.nih.gov/pubmed/24690624

[The paper by Theodoratou et al. was a rather mechanical exercise of pouring results into the hopper and turning the handle. The problem with most vitamin D randomized controlled trials to date is that they were designed on the pharmaceutical drug model, i.e., the agent used in the trial is the only source and there is a linear dose-response relation. Neither assumption is correct for vitamin D due to other sources.]

[The proper way to design vitamin D randomized controlled trials is to start with the 25(OH)D level-health outcome relation, measure 25(OH)D levels in prospective participants, take only those with low 25(OH)D levels, give them sufficient vitamin D3 to raise their levels to the upper end of the quasi-linear region of the relation, then measure 25(OH)D levels again. Explained by Heaney [2014].]


 * Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014 Jan;72(1):48-54. http://www.ncbi.nlm.nih.gov/pubmed/24330136

Jag8452 (talk) 17:57, 11 April 2014 (UTC)