Top 20 Vitamin D Papers for 2013

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FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, January 16, 2014
Top 20 Vitamin D Papers for 2013 by William B. Grant, PhD
(OMNS Jan 16, 2014) There were 3774 papers published in 2013 with vitamin D in the title or
abstract according to pubmed.gov, up from 3099 in 2012. Among the top 20 vitamin D papers
chosen to highlight for 2013 were 11 reviews, five observational studies, one geographical ecological
study, one trial, one laboratory study, and one analysis of data from published results. The papers
were chosen in part by the number of times they have been cited in other works as reported by
Scholar.Google.com and in part based on expert opinion by vitamin D researchers. The fact that twothirds of the papers were reviews is an indication of the relative maturity of the field. However, as
noted in the discussion, the weak link in the vitamin D story is the limited number of randomized
controlled trials (RCTs) reporting beneficial effects of vitamin D. As discussed in the paper by
Heaney [2013], the primary reason for this result is that vitamin D RCTs have been poorly designed
and conducted in general; researchers have generally designed vitamin D RCTs based on the
pharmaceutical drug model, which assumes no other source of the agent and a linear dose-response
relation. These conditions are not satisfied for vitamin D. As a result, many of the trials enrolled
people who had relatively high serum 25-hydroxyvitamin D [25(OH)D] levels and gave them too little
vitamin D to produce a beneficial effect.
Especially Important Original Studies
A randomized controlled trial with 400 or 2000 IU/d vitamin D3 found that gene expression in white
blood cells was affected by vitamin D [Hossein-nezhad et al., 2013]. There was some improvement in
291 genes and significant improvement in 66 genes. In addition, 17 vitamin D-regulated genes were
found with new candidate vitamin D response elements "which have been shown to be important for
transcriptional regulation, immune function, response to stress and DNA repair". This study provides
strong support for the role of vitamin D in affecting risk of cancer, autoimmune disorders and
cardiovascular disease.
An observational study found that serum 25(OH)D levels below 30 nmol/l (12 ng/ml) were associated
with 1.0-1.6 additional cases of spontaneous preterm birth before 35 weeks' gestation per 100 births
for nonwhite mothers compared to levels above 75 nmol/l (30 ng/ml) [Bodnar, 2014]. Placental
inflammatory lesions played a role in this relation. It was not understood why there was no relation
between serum 25(OH)D level and risk of premature birth for white mothers. This paper adds to the
literature on the beneficial role of higher serum 25(OH)D levels during pregnancy.

Vrieling et al. [2013] conducted a prospective cohort study in Germany including 2,177 incident
stage I-IV postmenopausal breast cancer patients aged 50-74 years. Lower concentrations of
25(OH)D were significantly associated with an 86% higher risk of overall mortality and a 76% higher
risk of distant disease in stage I-IIIa but not in stage IIIb-IV breast cancer patients. This study adds
to the evidence that vitamin D plays an important role in cancer and all-cause survival.
A laboratory study identified several genes associated with triple negative/basal-like breast cancer
that are regulated by vitamin D receptors [Laporta and Welsh, epub], thereby providing additional
evidence that vitamin D can be useful in reducing risk of and treating breast cancer.
A pair of papers published in the open-access journal Dermato-Endocrinology discussed the evidence
that solar ultraviolet-B irradiance and vitamin D reduce the risk of autism. In one, the prevalence of
autism by state for those aged 6 to 17 years was found inversely correlated with summertime solar
UVB doses [Grant and Cannell, 2013]. Rates for African Americans were higher than for European
Americans. The variation with respect to solar UVB doses is similar to that reported previously for
many types of internal cancer and dental caries in the United States. Summertime solar UVB doses
in the United States are highest in the Southwest, lowest in the Northeast due to a combination of
factors involving surface elevation, aerosol and cloud levels, and stratospheric ozone amounts. In the
second paper, the evidence supporting the role of vitamin D in reducing the risk of autism and
treating those with autism was presented and discussed. The mechanisms seem to include effects on
reducing DNA mutations, anti-inflammation and antiautoimmune effects, and upregulating
glutathione [Cannell and Grant, 2013]. It is not clear from either study what the relative
contributions of maternal and infant serum 25(OH)D levels might be. These two papers add to the
understanding of the roles of solar UVB and vitamin D in reducing risk of autism and could lead to a
reduction in the epidemic of autism.
One of the roles of vitamin D is the reduction of inflammation. In a study of morbidly obese women,
serum 25(OH)D levels were found inversely correlated with several indicators of inflammation
including high-sensitive C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-? (TNF-?)
after accounting for confounding factors including body mass index (BMI) [Bellia et al., 2013]. This
study adds to the literature connecting low serum 25(OH)D level to increased risk of inflammation.
This is important since inflammation is an important risk factor for many chronic diseases.
Another paper analyzed data from 21 adult cohort studies involving 42,000 participants with
information on BMI, serum 25(OH)D levels, and genes related to BMI and 25(OH)D. The analysis
found that each 1 kg/m(2) increase in BMI was associated with a 4.2% lower serum 25(OH)D level
[Vimaleswaran, 2013]. The authors were also able to conclude that changes in serum 25(OH)D level
would not affect BMI.
One of the concerns regarding taking vitamin D supplements is the possible risk of developing
kidney stones. An analysis of data on 2000 participants of the GrassrootsHealth.net vitamin D testing
program followed for an average of 19 months found no statistically significant association between
serum 25-hydroxyvitamin D and kidney stones (P?=?0.42) in the range of 20-100 ng/ml. However,
higher BMI was associated with an increased risk [Nguyen et al., 2013].
Comprehensive Reviews of the Health Benefits of Vitamin D
Pludowski et al. [2013] reviewed the evidence of health benefits of vitamin D as one of the outcomes
of a vitamin D conference attended by over 500 people in Warsaw, Poland in October 2012. The
evidence reviewed was primarily from observational studies. They found "Adequate vitamin D status
seems to be protective against musculoskeletal disorders (muscle weakness, falls, fractures),

infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes
mellitus, several types of cancer, neurocognitive dysfunction and mental illness, and other diseases,
as well as infertility and adverse pregnancy and birth outcomes. Vitamin D deficiency/insufficiency is
associated with all-cause mortality." This paper provided the basis for recommending serum
25(OH)D levels of at least 30 ng/ml (75 nmol/l) for Central and Eastern Europe.
Hossein-nezhad and Holick [2013] reviewed the effects of vitamin D on the risk of chronic illnesses,
including some cancers, autoimmune diseases, infectious diseases, type 2 diabetes mellitus,
neurocognitive disorders, and mortality. The authors recommend a serum 25(OH)D level of at least
30 ng/ml. This paper has open access.
The paper by Haussler et al. [2013] summarizes the molecular mechanisms of vitamin D, with
primary emphasis on the classical functions of vitamin D on intestinal calcium and phosphate
absorption and effects on skeletal and calcium homeostasis, but also discussion of how the active
form of vitamin D, 1,25-dihydroxyvitamin D, affects gene expression and, thus risk of chronic
diseases such as cancer, cardiovascular disease, and type 2 diabetes mellitus.
The paper by Palacios and Gonzalez [2013] presents an overview of what is known about serum
25(OH)D levels globally. Six maps are presented with data on vitamin D status (percent of
population <30 nmol/l, <50 nmol/l, <75 nmol/l) by country for infants, children, adolescents, adults,
pregnant or lactating women, and elders. The quality of the data (representative or individual
studies) is also indicated. For pregnant or lactating women for example, values for <50 nmol/l range
from 20% in Spain to 96% in India. For elders, values for <50 nmol/l are generally >50% for
European countries, but are 36% for China and 91% for India.
The Actions of Vitamin D
The effects of vitamin D on gene expression are controlled by the action of the hormonal metabolite
of vitamin D, 1,25-dihydroxyvitamin D on vitamin D receptors (VDRs). A paper by Carlberg and
Campbell [2013] reviews the actions of the VDR in comparison with those of other transcription
factors in order to better understand the role of vitamin D on gene expression.
The Role of Vitamin D for Specific Health Outcomes
The paper by Song et al. [2013] presents a meta-analysis of 21 prospective studies of type 2 diabetes
mellitus incidence with respect to serum 25(OH)D level at time of enrollment in the studies. The
studies involved a total of 76,220 participants and 4,996 incident type 2 diabetes cases. The second
order fit to the data went from a relative risk of 1.00 at 35 nmol/l (14 ng/ml) to 0.45 at 150 nmol/l
(60 ng/ml). This analysis provides strong support for the role of vitamin D in reducing the risk of
type 2 diabetes mellitus.
Girgis and colleagues [2013] published a comprehensive review of the role of vitamin D on skeletal
muscle. It has 51 pages and 390 references. It should be the standard reference on the topic for
years.
A paper by DeLuca et al. [2013] reviewed the evidence from 225 papers for the role of vitamin D in
reducing risk of nervous system diseases: Alzheimer's disease, amyotrophic lateral sclerosis, autism,
multiple sclerosis, Parkinson's disease, and schizophrenia. The strongest evidence is for multiple
sclerosis. They note that evidence from many types of studies finds that vitamin D plays a crucial
role in cellular proliferation and differentiation, neurotrophism, neuroprotection, neurotransmission,
and neuroplasticity. Given the importance and devastation of neurological diseases, more research

on the role of vitamin D in reducing risk of these diseases is warranted.

A Skeptical Viewpoint
One paper that has gotten considerable publicity is one calling into question the health benefits of
vitamin D. Autier and colleagues published a paper comparing vitamin D randomized controlled
trials to prospective studies based on health outcomes with respect to serum[25(OH)D levels [Autier
et al., 2013]. While they found reasonable evidence from the observational studies that higher serum
25(OH)D levels were correlated with lower disease and mortality rates, they noted that few
randomized controlled trials (RCTs) agreed with the observational studies. They also noted that
inflammation is an important aspect of many diseases, but that RCTs have not shown that vitamin D
can reduce inflammation. They proposed "the hypothesis that variations in 25(OH)D concentrations
would essentially be a result, and not a cause, of ill health." As noted with respect to the paper by
Bellia et al. [2013], there is evidence that serum 25(OH)D levels are inversely correlated with
markers of inflammation. The vitamin D RCTs conducted to date have for the most part been poorly
designed and conducted as pointed out by Heaney [2014]. Vitamin D RCTs have mostly been done
using the pharmaceutical drug model, paying limited attention to other sources of vitamin D, not
seeking to enroll people with low serum 25(OH)D levels, supplement them with sufficient vitamin D
to raise their levels to those that have significant impact on health outcome, and also measure serum
25(OH)D levels later in the study. The proper way to examine causality with respect to vitamin D is
to apply Hill's criteria for causality in a biological system [Hill, 1965]. These criteria appropriate for
vitamin D include strength of association, consistent findings in different populations, temporality,
biological gradient, plausibility (e.g., mechanisms), coherence, experiment (e.g., RCT), and analogy.
Not all criteria need be satisfied, but the more that are, the stronger the case. A number of health
outcomes have been found to satisfy Hill's criteria for causality for vitamin D including many types of
cancer. Unfortunately, the paper by Autier and colleagues will likely dissuade many from
recommending vitamin D in their practice or using it personally.
To learn more:
For further information on vitamin D, the interested reader is directed to these websites:
http://www.Grassrootshealth.net, http://www.VitaminDCouncil.org, and
http://www.VitaminDWiki.com.
Dr. William Grant directs the Sunlight, Nutrition and Health Research Center
http://www.sunarc.org/ . This paper was reviewed by:
Carole A. Baggerly, Director, http://www.Grassrootshealth.net
Barbara J Boucher. MD, FRCP, Centre for Diabetes, Blizard Institute, Bart's & The London School of
Medicine & Dentistry, Queen Mary University of London, London, UK.

Michael F. Holick, MD, PhD, Department of Medicine, Section of Endocrinology, Nutrition, and
Diabetes, and the Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical
Center, Boston.
Henry Lahore, Director, http://www.vitaminDwiki.com
Pawel Pludowski, MD, Department of Biochemistry, Radioimmunology and Experimental Medicine,
The Children's Memorial Health Institute, Warsaw, Poland
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