by William B. Grant, PhD
Research on the effects of vitamin D continued at a strong pace in 2019 with 4541 publications with vitamin D in the title or abstract listed at pubmed.gov for 2019, up from less than 1500 per year prior to 2004.  Here I highlight some of the important advances in the understanding of vitamin D's effects on human health in 2019.
The most impactful article in 2019 was the widely reported VITamin D and OmegA-3 TriaL (VITAL) at Brigham and Women's Hospital, an affiliate of Harvard Medical School.  Briefly, VITAL was a clinical trial to assess the effects of vitamin D and omega-3 fatty acids on the risk of cancer, cardiovascular disease (CVD), and a number of other health outcomes. Over 25,000 participants were enrolled, including over 5000 blacks. Half were randomly selected to take 2000 IU/d vitamin D3 and half to take one gram of marine omega-3 fatty acid, and the others to take placebos. Male participants were 50 years or older, female participants were 55 years or older. Participants were permitted to take up to 600 IU/d vitamin D3 (800 IU/d if over 70 years). The trial ran a median of 5.3 years. Mean baseline 25-hydroxyvitamin D [25(OH)D] concentrations for those who provided values were over 30 ng/ml (75 nmol/l). The article was published in the New England Journal of Medicine, which mandated that only the principle outcome for each supplement could be presented in the abstract. For the entire group, neither vitamin D3 nor omega-3 fatty acids reduced the risk of cancer or CVD. However, in the secondary analyses, vitamin D3 supplementation reduced the risk of overall cancer incidence for those with BMI < 25 kg/m and for blacks, as well as overall cancer mortality rates for the entire group after the first one and two years.  Unfortunately, nearly all of the press coverage ignored the secondary findings; a meta-analysis of 21 randomized clinical trials was included (including 83,291 patients, of whom 41,669 received vitamin D and 41,622 received placebos), found no effect of vitamin D supplementation on major adverse CVD events or all-cause mortality.  However, few participants in the trials had 25(OH)D concentrations below 10 ng/ml, and it is possible that vitamin D supplementation of deficiency could have reduced the risk of CVD events.
A recent article reviewed the potential beneficial effects of vitamin D on coronary artery disease.  It mentioned that vitamin D concentrations have been found inversely correlated with essential hypertension and that vitamin D may decrease vascular inflammation and atherosclerosis.
A thorough review of the role of vitamin D and peripheral arterial disease (PAD) formation was published.  Topics discussed include: abdominal aortic aneurysm (pathologically characterized by progressive degeneration of the arterial wall structure by chronic inflammation and extracellular matrix remodeling which leads to irreversible dilatation and eventual rupture resulting in death); vitamin D status and mechanisms relevant in PAD formation: Insufficient levels of vitamin D may affect the vasculature via the classic mechanism of promoting changes in the calcium-phosphate metabolism, or via effects on the renin-angiotensin-aldosterone system and regulation of nitric oxide concentration; atherosclerosis, inflammation, arterial stiffness and calcification, and angiogenesis; vitamin D and the genome; vitamin D and the epigenome; histone modifications; and DNA methylation. While the author concludes that the role of vitamin D in PAD formation is not fully understood, the article provides a textbook discussion of what is known and an overall optimistic view that its role will eventually be understood.
An observational study conducted with 135 patients with chronic heart failure (CHF) in China found that 25(OH)D concentrations were significantly lower in patients with CHF (11 ng/ml vs. 21 ng/ml).  However, the lower concentrations for those with CHF could be due to reverse causality, i.e., caused by having CHF. However, the study also found that Heterozygous and minor allele for FokI and TaqI polymorphisms were significantly higher in heart failure patients when compared to healthy controls. Since this was based on a small number of patients, further studies are warranted.
The second most important vitamin D clinical trial with results reported in 2019 was the Vitamin D and Type 2 Diabetes (D2d) study.  This trial enrolled 2423 participants with at least two glycemic criteria for pre-diabetes and randomized half to take 4000 IU/d vitamin D3 while the other half took placebos. During a median follow-up period of 2.5 years, 293 participants in the treatment group developed diabetes, compared to 323 in the placebo group. There was a non-significant 12% reduction in the treatment group. Again, this was the only result given in the abstract. However, the secondary analyses found significant reductions from vitamin D treatment for several groups including those with BMI < 30 kg/m2, those not taking calcium supplements, males, aged > 60.9 years, and non-Hispanics.  Some of these secondary findings could have been expected while others may form the basis for further research.
A pooled analysis of participant-level data from 17 cohorts, comprising 5706 colorectal cancer case participants and 7107 control participants with a wide range of circulating 25(OH)D concentrations was reported.  Those with 25(OH)D < 12 ng/ml had a 31% higher risk of colorectal cancer than those with 25(OH)D between 30 and 38 ng/ml. Interestingly for each 10 ng/ml increase in 25(OH)D concentration, risk was decreased by 19% for women but only 7% for men.
Two articles strengthened the support for vitamin D in reducing risk of dementia and Alzheimer's disease (AD). One article was a meta-analysis of seven prospective cohort studies and one retrospective cohort study (total n = 28,354) involving 1953 cases of dementia and 1607 cases of AD.  "The pooled HRs of dementia and AD were 1.09 (95% CI: 0.95, 1.24) and 1.19 (95% CI: 0.96, 1.41) for vitamin D insufficiency (10-20 ng/ml), and 1.33 (95% CI: 1.08, 1.58) and 1.31 (95% CI: 0.98, 1.65) for deficiency (<10 ng/ml), respectively. The lower risk of dementia was observed at serum 25(OH)D of ~25 ng/ml, whereas the risk of AD decreased continuously along with the increases of serum 25(OH)D up to ~35 ng/ml." The other article reported results of a Mendelian randomization study of genetically-determed 25(OH)D concentrations from large-scale vitamin D genome-wide association study (GWAS) with associated data on AD.  One data set, the AD GWAS data set included 21,982 cases of AD and 41,944 cognitively normal controls. The six genes considered in this set were associated with a significant 38% reduced risk of AD. The other data set, Biobank UK, with 314,278 participants, based the findings on parental AD, and found a non-significant 12% reduced risk of AD.
Chronic obstructive pulmonary disease (COPD), which includes emphysema, is an important disease, especially among smokers. It is estimated that over 16 million in the U.S. have COPD. A recent meta-analysis found that vitamin D supplementation reduced the overall rate of moderate/severe COPD exacerbations for those with baseline 25(OH)D concentrations below 10 ng/ml, but did not reduce them for participants with higher baseline 25(OH)D concentrations. 
There is continued interest in the importance of vitamin D during pregnancy. A meta-analysis of 54 observational studies found that mothers with VDD (<12 ng/ml) had offspring with lower birth weight [mean difference (MD) -88 g; 95% CI -120, -56 g], head circumference (MD -0.19 cm; 95% CI -0.32, -0.06 cm) and a higher risk of small for gestational age (SGA) infants and preterm birth (PTB) (OR 1.59; 95% CI 1.24, 2.03) compared to mothers with concentrations =12 ng/ml. ) Vitamin D insufficiency (<20 ng/ml) was associated with a higher risk of SGA and PTB (OR 1.43; 95% CI 1.08, 1.91 and OR 1.28; 95% CI 1.08, 1.52, respectively). Concentrations of 25(OH)D =30 ng/ml were not found to be associated with birth weight, SGA or PTB. Offspring of vitamin D-insufficient mothers had lower scores in mental (MD -1.1 points; 95% CI -1.8, -0.4 cm).
A second article reported a review and meta-analysis of 25(OH)D concentrations in maternal blood in pregnancy or newborn blood at birth and neurodevelopmental outcomes.  "Comparing the highest vs. the lowest category of prenatal 25(OH)D levels, the pooled beta coefficients were 0.95 (95% CI -0.03, 1.93; p = 0.05) for cognition, and 0.88 (95% CI -0.18, 1.93; p = 0.10) for psychomotor development. The pooled relative risk for [attention deficit hyperactivity disorder] ADHD was 0.72 (95% CI, 0.59, 0.89; p = 0.002), and the pooled odds ratio for autism-related traits was 0.42 (95% CI, 0.25, 0.71; p = 0.001). There was little evidence for protective effects of high prenatal 25(OH)D for language development and behavior difficulties." A case-control study conducted in Finland involving 1067 ADHD cases found that lowest vs. highest maternal 25(OH)D concentration was associated with a significant 53% increased risk of ADHD. 
Another article reviewed the evidence regarding the role of vitamin D in inflammatory bowel disease.  The authors reported "VD prevents the inflammatory process such as negatively interfering with the release of Interleukin (IL)-1, IL-6, and Tumour Necrosis Factor-a; enhancing the function of the intestinal epithelial barrier; decreasing the occurrence of apoptosis; stimulating Toll-Like Receptor-4; inducing the production of an antimicrobial peptide in Paneth cells. Furthermore, deficiency of VD is related to the severity of the symptoms and increased the risk of cancer and surgery. In conclusion, VD shows a potential role in the management of IBD, the supplementation is inexpensive, safe, and leads to improvement of the quality of life"; related to that finding, a trial of vitamin D supplementation on 20 adults examined the effects on gut microbiota given 600, 4000 or 10,000 IU/d vitamin D3.  Increased serum 25(OH)D was associated with increases in beneficial bacteria and decreases in pathogenic bacteria and the increases in bacteria associated with decreased inflammatory bowel disease activity observed after vitamin D3 supplementation were dose dependent.
Another trial examined the dose-dependent 25(OH)D alteration in broad gene expression involving 30 participants. During the six-month trial with 600, 4000 or 10,000 IU/d vitamin D3, there was a dose-dependent 25(OH)D alteration in broad gene expression with 162, 320 and 1289 genes up- or down-regulated in their white blood cells, respectively. 
Carlbeg reviewed the different aspects of how vitamin D interacts with the human genome, focusing on nutritional epigenomics in context of immune responses.  Vitamin D can influence the epigenome in multiple ways including increasing vitamin D receptor binding, affecting a group of vitamin D target genes, and changing histone modification and chromatin accessibility. Thus, individuals respond differently to increases in 25(OH)D. As a result, the individual's molecular response to vitamin D requires personalized supplementation with vitamin D3 in order to obtain optimized clinical benefits in the prevention of osteoporosis, sarcopenia, autoimmune diseases, and different types of cancer.
While many assume that ergocalciferol (vitamin D2) may be equivalent to cholecalciferol (vitamin D3), and that vitamin D2 is a form of vitamin D that physicians can readily prescribe, there is increasing evidence that the health effects of vitamin D2 can be negative. A meta-analysis of mortality rates resulting from vitamin D supplementation found that vitamin D3 supplementation was associated with a 5% reduction [risk ratio = 0.95 (95% confidence interval (CI), 0.90, 100)] in all-cause mortality rate while vitamin D2 supplementation was associated with a 3% increased mortality rate [risk ratio = 1.03 (95% CI, 0.98, 1.09)].  High-dose vitamin D3 is readily available through the Internet and some pharmacies and is much less expensive than vitamin D2.
Many people have low 25(OH)D concentrations. An article presented a model analysis of reducing the prevalence of vitamin D deficiency (VDD) in England and Wales based on vitamin D fortification of wheat flour and providing free vitamin D supplements to all groups at risk of VDD. VDD was defined as <12 ng/ml for children and <20 ng/ml for adults.  Wheat flour would be fortified at the rate of 400 IU vitamin D per 100 g of flour. The analysis was conducted for a period of 90 years with a total population of 250 million, with a suitable discount rate for costs and benefits. The combined fortification plus supplementation program was estimated to cost £1.81 per VDD case prevented and £9.50 per quality-adjusted life-year increase. Supplementation alone was estimated to cost £22.50 per VDD case prevented and £135.00 per quality-adjusted life-year increase.
A very interesting analysis of trends in research on vitamin D was developed based on high-frequency Medical Subject Headings (MeSH) terms. 
The main findings are presented in Table 1. As can be seen, the emphasis has shifted from musculoskeletal diseases, neoplasms to endocrine and metabolic system diseases. Among endocrine and metabolic system diseases for 2015-8, the rankings are diabetes (50%), obesity (25), thyroid diseases (9%), polycystic ovary syndrome, and others. Among neoplasms for 2015-8, the order was breast (24%), colorectal (20%), skin (10%), prostate (9%), leukemia, lung, uterine, ovarian, thyroid, bone, pancreatic, esophageal, and others.
Table 1. Distribution of vitamin D research publications based on a search of MeSH terms
|Endocrine, metabolic system diseases||11||18|
|Circulation system diseases||7|
|Digestive system diseases||5|
|Respiratory tract diseases||4|
Overall, 2019 was a good year for vitamin D research. Two major clinical trial results were reported that found significant beneficial effects for vitamin D supplementation according to secondary analyses of subgroups for who a beneficial effect of vitamin D would be expected
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:
https://www.facebook.com/Evidas-902724609761886/ (European Vitamin D Association)
The author wishes to acknowledge contributions from Barbara J. Boucher, MD and Henry Lahore.
Disclosure: the author receives funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR, USA).
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2. Barbalho, S. M., R. A. Goulart and R. G. Gasparini (2019). "Associations between inflammatory bowel diseases and vitamin D." Crit Rev Food Sci Nutr 59(8): 1347-1356. https://www.ncbi.nlm.nih.gov/pubmed/29236523
3. Barbarawi, M., B. Kheiri, Y. Zayed, O. Barbarawi et al. (2019). "Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis." JAMA Cardiol. https://www.ncbi.nlm.nih.gov/pubmed/31215980
4. Carlberg, C. (2019). "Nutrigenomics of Vitamin D." Nutrients 11(3): 676. https://www.mdpi.com/2072-6643/11/3/676
5. Charoenngam, N., A. Shirvani, T. A. Kalajian, A. Song et al. (2020). "The Effect of Various Doses of Oral Vitamin D3 Supplementation on Gut Microbiota in Healthy Adults: A Randomized, Double-blinded, Dose-response Study." Anticancer Res 40(1): 551-556. https://www.ncbi.nlm.nih.gov/pubmed/31892611
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7. Grant, W. B. and B. J. Boucher (2019). "Why Secondary Analyses in Vitamin D Clinical Trials Are Important and How to Improve Vitamin D Clinical Trial Outcome Analyses-A Comment on "Extra-Skeletal Effects of Vitamin D, Nutrients 2019, 11, 1460"." Nutrients 11(9): 2182. https://www.mdpi.com/2072-6643/11/9/2182
8. Hao, Y. and Y. Chen (2019). "Vitamin D levels and vitamin D receptor variants are associated with chronic heart failure in Chinese patients." J Clin Lab Anal 33(4): e22847. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30714636/
9. Jayedi, A., A. Rashidy-Pour and S. Shab-Bidar (2019). "Vitamin D status and risk of dementia and Alzheimer's disease: A meta-analysis of dose-response." Nutr Neurosci 22(11): 750-759. https://www.ncbi.nlm.nih.gov/pubmed/29447107
10. Jolliffe, D. A., L. Greenberg, R. L. Hooper, C. Mathyssen, R. et al. (2019). "Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials." Thorax 74(4): 337-345. https://thorax.bmj.com/content/thoraxjnl/74/4/337.full.pdf
11. Krishna, S. M. (2019). "Vitamin D as A Protector of Arterial Health: Potential Role in Peripheral Arterial Disease Formation." Int J Mol Sci 20(19): E4907. http://www.mdpi.com/resolver?pii=ijms20194907
12. Legarth, C., D. Grimm, M. Kruger, M. Infanger and M. Wehland (2020). "Potential Beneficial Effects of Vitamin D in Coronary Artery Disease." Nutrients 12(99): 22. http://www.mdpi.com/resolver?pii=nu12010099
13. Manson, J. E., N. R. Cook, I. M. Lee, W. Christen et al. (2019). "Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease." N Engl J Med 380(1): 33-44. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30415629/
14. McCullough, M. L., E. S. Zoltick, S. J. Weinstein, V. Fedirko et al. (2019). "Circulating Vitamin D and Colorectal Cancer Risk: An International Pooling Project of 17 Cohorts." J Natl Cancer Inst 111(2): 158-169. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29912394/
15. Pittas, A. G., B. Dawson-Hughes, P. Sheehan, J. H. Ware et al. (2019). "Vitamin D Supplementation and Prevention of Type 2 Diabetes." N Engl J Med 381(6): 520-530. https://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1127&context=veterans
16. Shirvani, A., T. A. Kalajian, A. Song, R. Allen et al. (2020). "Variable Genomic and Metabolomic Responses to Varying Doses of Vitamin D Supplementation." Anticancer Res 40(1): 535-543. https://www.ncbi.nlm.nih.gov/pubmed/31892609
17. Sucksdorff, M., A. S. Brown, R. Chudal, H. M. Surcel et al. (2019). "Maternal Vitamin D Levels and the Risk of Offspring Attention-Deficit/Hyperactivity Disorder." J Am Acad Child Adolesc Psychiatry. https://www.ncbi.nlm.nih.gov/pubmed/31863882
18. Tous, M., M. Villalobos, L. Iglesias, S. Fernandez-Barres and V. Arija (2019). "Vitamin D status during pregnancy and offspring outcomes: a systematic review and meta-analysis of observational studies." Eur J Clin Nutr. https://www.ncbi.nlm.nih.gov/pubmed/30683894
19. Wang, L., Y. Qiao, H. Zhang, Y. Zhang,et al. (2019). "Circulating Vitamin D Levels and Alzheimer's Disease: A Mendelian Randomization Study in the IGAP and UK Biobank." J Alzheimers Dis. https://www.ncbi.nlm.nih.gov/pubmed/31815694
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21. Zhang, Y., F. Fang, J. Tang, L. Jia et al. (2019). "Association between vitamin D supplementation and mortality: systematic review and meta-analysis." BMJ 366: l4673. http://www.bmj.com/cgi/pmidlookup?view=long&pmid=31405892
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