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Orthomolecular Medicine News Service, January 12, 2018

Top Twelve Vitamin D Papers for 2017

by William B. Grant, PhD

(OMNS Jan 12, 2018) While the importance of vitamin D for calcium absorption and metabolism and bone health was recognized about a century ago, its importance for non-skeletal effects has only been generally recognized and appreciated in this century. Most of the supporting evidence is either from observational studies related to serum 25-hydroxyvitamin D [25(OH)D] concentrations, including prospective studies, or studies of vitamin D mechanisms, with some of the evidence coming from clinical trials. Indirect support comes from the fact that skin pigmentation varies globally in response to prevailing solar ultraviolet-B (UVB) doses as modified by clouds and forest cover, and that nearly every cell in the body has vitamin D receptors. Most of the effects of vitamin D are mediated through the hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D, binding to a vitamin D receptor and affecting gene expression, upregulating some, downregulating others; the production of this metabolite in target tissues being regulated mainly through the availability of 25(OH)D in the circulation and by local production of the catabolic 24(OH)ase enzyme [Ganguly, 2017]. However, in order for the health systems to recommend higher serum 25(OH)D concentrations appropriate for non-skeletal effects, clinical trials are required. The year 2017 saw some progress along this front.

Vitamin D reduces the risk of acute lung infections

In February, a meta-analysis of results of clinical trials found that vitamin D supplementation reduced the risk of acute respiratory tract infections, especially if baseline 25(OH)D concentration was low < 20 ng/ml (50 nmol/l) [Martineau, 2017].

Vitamin D reduces risk for cancer

A clinical trial involving post-menopausal women given 2000 IU/d vitamin D3 plus 1500 mg/d calcium or a placebo found that based on intention to treat (i.e. ignoring whether the vitamin D was actually taken by participants), the reduction in cancer incidence rate was almost significant (P=0.06) [Lappe, 2017]. A peer in the field commented that this rejection of benefit was a mistake and clinical journals should foster more responsible interpretation of research, Indeed, when cancer incidence rates were analyzed in terms of 25(OH)D concentrations, it was found that achieved serum 25(OH)D concentration between 45 and 85 ng/ml was associated with significantly reduced incidence of cancer. Since the mean baseline 25(OH)D concentration was 33 ng/ml and remained at that value for the control group, this finding was due to vitamin D3 plus calcium supplementation. However, since this analysis was not included in the trial protocol, JAMA relegated it to an online supplement, which was not widely read. This type of bias against correct scientific reporting of positive benefits of vitamin and mineral supplements is widespread in clinical journals.

Vitamin D reduces behavioural abnormalities of the autistic children

A vitamin D clinical trial was conducted on children with autism in China [Feng, 2017]. At baseline, the mean 25(OH)D concentration for those with autism was 21 ng/ml while that for controls was 25 ng/ml. After vitamin D3 treatment (150,000 IU/m by injection plus 400 IU/d orally for three months) significant improvements were observed for behavioural abnormalities of the autistic children (apart from the sensory subscale).

Vitamin D reverses hypertension

Another vitamin D clinical trial found that high-dose vitamin D3 significantly reduced blood pressure for those who had hypertension [Mirhosseini, 2017]. At baseline, the mean 25(OH)D concentration of the 8155 participants was 87 ± 37 nmol/l (35 ± 15 ng/ml) and they were taking 1600 ± 2500 IU/d vitamin D3. At the end of one year after increasing the vitamin D3 intake to 5200 ± 4300 IU/d, the mean 25(OH)D concentration was 113 ± 39 nmol/l (45 ng/ml) while the controls, who did not change vitamin D3 intake, 25(OH)D concentrations were relatively unchanged. For the 480 hypertensives who increased their vitamin D3 intake, the mean systolic blood pressure dropped from 156 mm to 138 mm and the mean diastolic blood pressure dropped from 96 mm to 84 mm, both independent of whether they were taking blood pressure medication. As a result, 71% of those hypertensive at baseline were no longer hypertensive at the end of the trial. There was no significant reduction in blood pressure for non-hypertensives.

Vitamin D reduces arterial stiffness in African Americans

A clinical trial involving overweight African Americans with vitamin D deficiency ( < 20 ng/ml) supplemented with 600, 2000, or 4000 IU/d vitamin D3 for 16 weeks found that 4000 IU/d was associated with 10% reduction in carotid-femoral pulse wave velocity (PWV) and an 8% reduction in carotid-radial PWV [Raed, 2017]. The 2000 IU/d dose was nearly as effective for carotid-radial PWV but not carotid-femoral PWV. The results of this trial are very important for several reasons. First, it is one of the few vitamin D clinical trials to show that vitamin D supplementation has an impact on physiological factors relevant to cardiovascular disease risk. Second, African Americans have a high rate of death from cardiovascular disease. Third, it was performed on African Americans, which is important since I have learned in the past that they are reluctant to accept results of vitamin D trials on white Americans. One reason is that African Americans have a different calcium economy than white Americans since their mineral metabolism is adapted to life on a hot, dry continent, so they excrete less calcium in their urine and have higher bone mass density than white Americans even though they have much lower 25(OH)D concentrations.

Vitamin D lowers risk of preterm birth

Observational studies are still providing useful information on the benefits of vitamin D. For example, a field trial of preterm birth with respect to 25(OH)D concentration shortly before delivery was conducted on 1064 consecutive deliveries from September 2015 to December 2016 at the Medical University of South Carolina. The race/ethnicity composition of the cohort was 488 white, 395 African American, 117 Hispanic, 19 Asian/Pacific Islander, and 39 multiple/other. It found gestational age rising with increasing 25(OH)D [McDonnell, 2017], similar to the trend found in the Hollis and Wagner et al. trial cohort. Women with 25(OH)D ≥ 40 ng/ml had a 62% lower risk of preterm birth compared to those < 20 ng/ml (OR=0.38, 95% confidence interval: 0.23-0.63, p < 0.0001). Risk reduction was consistent for both white and non-white women, suggesting that increasing vitamin D status may decrease the disparity in preterm birth rates between ethnic groups.

Serum vitamin D is correlated with lower heart disease, cancer, and mortality

An observational study involving 26,916 individuals from a European consortium from six northern European countries with a median follow-up time of 10.5 years found significant inverse correlations between baseline serum 25(OH)D concentration and all-cause, cancer, and cardiovascular disease mortality rates [Gaksch, 2017]. The all-cause mortality rate hazard ratio (HR) increased from 1.0 at 80 nmol/l to 2.8 at 5 nmol/l. There was no significant increase in mortality rate for 25(OH)D concentration >100 nmol/L. While the authors stated that there was no significant linear association between 25(OH)D and cancer mortality, careful inspection of their data indicates otherwise. When the adjusted hazard ratios (HRs) for Model 4 of Table 4 were recalculated assuming that the value for 25(OH)D concentration >100 nmol should be set to 1.00 by multiplying all values by 1/0.79 = 1.26, and then the HRs and the 95% confidence intervals (CIs) plotted vs. 25(OH)D concentration for each of the six categories, the linear fit to the lower 95% CI rose above 1.0 near 90 nmol/l. Only one lower CI for 25(OH)D below 90 nmol/l fell below 1.0, that for the lowest 25(OH)D category. This type of bias against benefits from vitamins in reporting results is widespread in clinical journals.

Vitamin D status predicted by patient questionnaire

One of the issues regarding vitamin D is the cost of 25(OH)D assays. In several countries, limitations on physicians ordering 25(OH)D assays have been imposed. One way around this problem is to develop a questionnaire to categorize vitamin D status into broad classifications, < 25 nmol/l (10 ng/ml), 25-50 nmol/l, or 50-75 nmol/l. Such a questionnaire was recently developed and tested for older adults [Annweiler, 2017]. The questionnaire has 16 questions in nine categories: age, gender, general condition, nutrition, vision, mood, cognition, gait and falls, and osteoporosis. The agreement between physicians' and patients' responses was excellent for six of the questions, substantial for two, moderate for two, fair for three, and poor for three. The classification of vitamin D status was almost perfect. While this questionnaire was developed for elderly people, similar questionnaires could be developed for other populations.

Sales of high-dose vitamin D supplements rising rapidly in the U.S.

One measure of success in educating the public of the health benefits of vitamin D is the increasing trend towards taking vitamin D supplements. A paper published in JAMA reported that the use of ≥ 1000 IU vitamin D supplements among adults rose from 0.4% in 2003-2004 to 18.2% in 2013-2014 [Rooney, 2017]. In addition, use of >4000 IU vitamin D supplements rose to 3.9% for non-Hispanic whites, 2.0% for non-Hispanic blacks, 1.8% for Hispanics, and 3.3% for Asian Americans. The authors expressed concern regarding the "high" doses, which really are not very high, considering that one can make up to 20,000 IU/d in the sun and that toxic effects are rare below 40,000 IU/d. The concern regarding possible adverse health effects of high 25(OH)D concentrations (>40 ng/ml) has largely abated because the concerns were raised by observational studies in which some with high concentrations were placed in the wrong 25(OH)D category since they had only recently started taking vitamin D.

Disinformation Playbook

There is a Disinformation Playbook used for decades by corporations to delay government action on matters of great public interest that would adversely affect their income and profit. Some of the well-known examples involve the sugar industry, tobacco, oil and gas, and the National Football League. The Union of Concerned Scientists outlined the five pillars of the Playbook http://www.ucsusa.org/our-work/center-science-and-democracy/disinformation-playbook#.WiA5wlWnFpg

The five elements are:

1. The Fake
Conduct counterfeit science and try to pass it off as legitimate research

2. The Blitz
Harass scientists who speak out with results or views inconvenient for industry

3. The Diversion
Manufacture uncertainty about science where little or none exists

4. The Screen
Buy credibility through alliances with academia or professional societies

5. The Fix
Manipulate government officials or processes to inappropriately influence policy

Big Pharma bias in vitamin D research

I have evaluated how Big Pharma follows the Disinformation Playbook regarding vitamin D but will not go into detail here. However, I would like to point to one recent example, a paper published in the Lancet, Diabetes and Endocrinology in December [Autier, 2017]. He and his colleagues work at the International Prevention Research Institute, Lyon, France. Their partners include many Big Pharma corporations including AstraZeneca, Bayer Schering Pharma, Eli Lilly and Company, Merck Serono, and Pfizer Limited (http://www.i-pri.org/about/partners/). Despite the fact that Big Pharma opposes vitamin D since it reduces the risk of many types of disease and, therefore income and profits for Big Pharma, the journal did not require the authors to mention those partners in the manuscript. The second half of their abstract summed up their findings:

Although vitamin D doses were greater than those assessed in the past, we found no new evidence that supplementation could have an effect on most non-skeletal conditions, including cardiovascular disease, adiposity, glucose metabolism, mood disorders, muscular function, tuberculosis, and colorectal adenomas, or on maternal and perinatal conditions. ..... There remains little evidence to suggest that vitamin D supplementation has an effect on most conditions, including chronic inflammation, despite use of increased doses of vitamin D, strengthening the hypothesis that low vitamin D status is a consequence of ill health, rather than its cause. (...) We identified many meta-analyses of suboptimal quality, which is of concern.

Overlooked in the paper was that vitamin D clinical trials have generally been based on the guidelines appropriate for pharmaceutical drugs. Two widely-made critical assumptions for such trials are that the only source of the agent is in the trial and that there is a linear dose-response relationship, are not valid for vitamin D trials. A third assumption, that vitamin D clinical trials should be based on measurements of 25(OH)D concentrations at baseline and during the trial, and that the 25(OH)D concentration-health outcome relationship should be used to guide participant selection and vitamin D dose -- will tend to bias the results. Some of the papers discussed in the present document point the way towards proper vitamin D clinical trials.

Latest perspectives on optimal dose of vitamin D

Michael Holick published another review of vitamin D that addressed some of the current controversies [Holick, 2017]. The abstract:

Vitamin D deficiency and insufficiency is a global health issue that afflicts more than one billion children and adults worldwide. The consequences of vitamin D deficiency cannot be under estimated. There has been an association of vitamin D deficiency with a myriad of acute and chronic illnesses including preeclampsia, childhood dental caries, periodontitis, autoimmune disorders, infectious diseases, cardiovascular disease, deadly cancers, type 2 diabetes and neurological disorders. This review is to put into perspective the controversy surrounding the definition for vitamin D deficiency and insufficiency as well as providing guidance for how to treat and prevent vitamin D deficiency.

Holick explains the current thinking about vitamin D dosing, including reasons why some studies of vitamin D have incorrectly concluded that 20 ng/ml are sufficient. The consensus among vitamin D researchers, especially in the United States, is that optimal 25(OH)D concentrations are above 30 ng/ml (75 nmol/l) and most likely in the range of 40-60 ng/ml (100-150 nmol/l). In addition, if one is diagnosed with a disease for which vitamin D is beneficial, one should aim for 40-60 ng/ml. Taking 2000-4000 IU/d vitamin D3 on a regular basis can help maintain healthy concentrations; the dose can be increased to 5,000-10,000 IU/d when sick. Note that since vitamin D contains 40 IU per microgram, 2000 IU is only 50 micrograms. Taking magnesium helps convert vitamin D to 25(OH)D, and taking calcium helps balance the effects of magnesium.

Conclusion

Overall, 2017 was a good year for vitamin D research. It appears that there is now a widespread understanding of how vitamin D clinical trials should be conducted. Unfortunately, several major vitamin D clinical trials will be completed and report results in the next year or two that were not so carefully designed and conducted.

For further information on vitamin D, the interested reader is urged to search for papers at pubmed.gov and scholar.google.com as well as visit the websites of the major vitamin D advocacy organizations:

http://vitamindsociety.org/
http://www.sunarc.org/
https://grassrootshealth.net/
https://purenorth.ca/vitamin-d-your-health/
https://www.facebook.com/Evidas-902724609761886/
https://www.vitamindcouncil.org/
https://www.vitamindwiki.com/VitaminDWiki

References

Annweiler C, Kabeshova A, Callens A, Paty ML, Duval GT, Holick MF. Self-administered Vitamin D Status Predictor: Older adults are able to use a self-questionnaire for evaluating their vitamin D status.PLoS One. 2017 Nov 1;12(11):e0186578. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186578

Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, Pizot C, Boniol M. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials.Lancet Diabetes Endocrinol. 2017 Dec;5(12):986-1004 https://www.ncbi.nlm.nih.gov/pubmed/29102433

Feng J, Shan L, Du L, Wang B, Li H, Wang W, Wang T, Dong H, Yue X, Xu Z, Staal WG, Jia F. Clinical improvement following vitamin D3 supplementation in Autism Spectrum Disorder.Nutr Neurosci. 2017 Jun;20(5):284-90. https://www.ncbi.nlm.nih.gov/pubmed/26783092

Ganguly A, Tamblyn JA, Finn-Sell S, Chan SY, Westwood M, Gupta J, Kilby M, Gross SR, Hewison M. Vitamin D, the placenta and early pregnancy: effects on trophoblast function.J Endocrinol. 2017 Nov 6. pii: JOE-17-0491. doi: 10.1530/JOE-17-0491. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29109081

Gaksch M, Jorde R, Grimnes G, Joakimsen R, Schirmer H, Wilsgaard T, Mathiesen EB, Njolstad I, Lochen ML, M„rz W, Kleber ME, Tomaschitz A, Gr�bler M, Eiriksdottir G, Gudmundsson EF, Harris TB, Cotch MF, Aspelund T, Gudnason V, Rutters F, Beulens JW, van 't Riet E, Nijpels G, Dekker JM, Grove-Laugesen D, Rejnmark L, Busch MA, Mensink GB, Scheidt-Nave C, Thamm M, Swart KM, Brouwer IA, Lips P, van Schoor NM, Sempos CT, Durazo-Arvizu RA, Skrab kov  Z, Dowling KG, Cashman KD, Kiely M, Pilz S. Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium.PLoS One. 2017 Feb 16;12(2):e0170791. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170791

Holick MF. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention.Rev Endocr Metab Disord. 2017 Jun;18(2):153-65. https://www.ncbi.nlm.nih.gov/pubmed/28516265

Lappe J, Watson P, Travers-Gustafson D, Recker R, Garland C, Gorham E, Baggerly K, McDonnell SL. Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial.JAMA. 2017 Mar 28;317(12):1234-43. https://jamanetwork.com/journals/jama/fullarticle/2613159 https://www.ncbi.nlm.nih.gov/pubmed/?term=28350929

Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, Goodall EC, Grant CC, Griffiths CJ, Janssens W, Laaksi I, Manaseki-Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, Simpson S Jr, Stelmach I, Kumar GT, Urashima M, Camargo CA Jr. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.BMJ. 2017 Feb 15;356:i6583. http://www.bmj.com/content/356/bmj.i6583.long

McDonnell SL, Baggerly KA, Baggerly CA, Aliano JL, French CB, Baggerly LL, Ebeling MD, Rittenberg CS, Goodier CG, Mateus Ni¤o JF, Wineland RJ, Newman RB, Hollis BW, Wagner CL. Maternal 25(OH)D concentrations ò40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center.PLoS One. 2017 Jul 24;12(7):e0180483. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180483

Mirhosseini N, Vatanparast H, Kimball SM. The Association between Serum 25(OH)D Status and Blood Pressure in Participants of a Community-Based Program Taking Vitamin D Supplements.Nutrients. 2017 Nov 14;9(11). pii: E1244. http://www.mdpi.com/2072-6643/9/11/1244

Raed A, Bhagatwala J, Zhu H, Pollock NK, Parikh SJ, Huang Y, Havens R, Kotak I, Guo DH, Dong Y. Dose responses of vitamin D3 supplementation on arterial stiffness in overweight African Americans with vitamin D deficiency: A placebo controlled randomized trial.PLoS One. 2017 Dec 7;12(12):e0188424. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188424

Rooney MR, Harnack L, Michos ED, Ogilvie RP, Sempos CT, Lutsey PL. Trends in Use of High-Dose Vitamin D Supplements Exceeding 1000 or 4000 International Units Daily, 1999-2014.JAMA. 2017 Jun 20;317(23):2448-2450 https://www.ncbi.nlm.nih.gov/pubmed/28632857

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