Can vitamin D supplementation improve childhood cardiometabolic statusdata from 2 randomized trials

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Editorial
Can vitamin D supplementation improve childhood cardiometabolic
status?—data from 2 randomized trials
Camilla T Damsgaard
Paediatric and International Nutrition, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Frederiksberg, Denmark
Vitamin D is important for calcium absorption and bone health
in adults as well as in children, and there is evidence that
(severe) vitamin D deficiency, typically defined as serum 25-
hydroxyvitamin D [25(OH)D] concentrations <25–30 nmol/L,
increases the risk of rickets in children (1, 2). In recent years
the vitamin has been intensively investigated and poor vitamin D
status been linked to a number of nonskeletal outcomes including
cardiovascular, respiratory, and even neurological diseases. With
>340 million children and adolescents being overweight or
obese and at risk of metabolic syndrome, type 2 diabetes, and
cardiovascular disease (3), there is an urgent need for prevention
strategies. Although the prevalence of vitamin D deficiency
depends strongly on the serum 25(OH)D cutoffs used to define it,
it is now widely recognized that vitamin D deficiency is common,
not only at northern latitudes during winter, but also in equatorial
regions of the world. In both adults and children, vitamin D status
has been inversely associated with overweight and cardiovascular
risk markers (4, 5). So is vitamin D the “magic bullet” we need
in order to prevent obesity, diabetes, and cardiovascular diseases
in childhood?
Because vitamin D is obtained both from diet (food and
supplements) and through sun exposure, we have to be careful
when interpreting the results of observational studies. Outdoor
physical activity, parents’ socioeconomic status, and a generally
healthy lifestyle all contribute positively to children’s vitamin D
status. Because these and other factors directly affect BMI and
cardiometabolic health, any associations with vitamin D status
and health outcomes could be confounded by these relations,
and the interpretation of such data can be difficult in case these
factors are not measured and taken into consideration. Reverse
causality is also very possible because children with obesity or
ill health can be less inclined to be physically active and/or be
sun-exposed. In order to overcome these and other shortcomings
of observational studies, clinical trials to evaluate the relation
between vitamin D status and health outcomes are critical to
advance our knowledge.
Recent large-scale randomized vitamin D supplementation
trials in adults have demonstrated no effects on cardiovascular
disease, type 2 diabetes, or cancer (6, 7). The trials were
notable for including participants with generally adequate
vitamin D status, wherein little additional benefit of vitamin
D supplementation might be expected. Among children and
adolescents, just over a dozen trials have been conducted, and
when combined in a recent meta-analysis (5) there was no
effect of vitamin D supplementation on markers of glucose
homeostasis, triacylglycerol, or HDL cholesterol but a small
increase in LDL cholesterol. Subgroup metaregression analysis
in participants with overweight or obesity, however, indicated that
HOMA-IR decreased slightly with higher serum concentrations
of 25(OH)D (5).
This issue of the Journal includes 2 new, moderately large,
randomized, double-blinded vitamin D trials in young and older
children that address this issue. Öhlund et al. (8) recruited 206
healthy 5–7-y-old children with various skin color and provided
200 mL/d of fortified milk with 10 or 25 μg/d vitamin D3. The
trial was performed at 2 sites in Sweden (63◦ and 55◦N) during
fall and winter, when 25(OH)D serum concentrations normally
show a decline at these latitudes. The doses of vitamin D studied
corresponded to 1 and 2.5 times the recommended intake in
the Nordic countries (9) and the United Kingdom (10), whereas
in the United States 15 μg/d is recommended for children (2).
The study had a low drop-out rate (8%), excellent self-reported
compliance (90%), and the children’s mean serum 25(OH)D
concentration, the study’s previously published primary outcome
(8), rose from ∼59 nmol/L to 84 nmol/L with the highest dose,
and was maintained in the control group, which received 2 μg/d
(8). In line with the results of the meta-analysis (5), Öhlund et
al. found no differences in blood pressure, nonfasting plasma
lipids, glucose homeostasis markers, or anthropometry between
the groups, but higher apoB with 10 and 25 μg/d, which has been
linked to cardiovascular risk in adults. It should be noted that
mean serum 25(OH)D concentrations were above the sufficiency
cutoff of 50 nmol/L (1, 2) in all groups at both baseline and
endpoint (8).
The second trial by Rajakumar et al. (11) involved 225 mainly
black, adolescent children with overweight or obesity living in
Pennsylvania (40◦N) who had serum 25(OH)D concentrations
<50 nmol/L. For 6 mo, participants received tablets with either 25
or 50μg/d (1000 or 2000 IU) vitamin D3 and were compared with
those receiving a lower dose of 15 μg/d (600 IU, which is close
to the highest dose provided in the Swedish study). A rather high
drop-out rate of 31% was noted. Compared with the lowest dose
of 15 μg/d, the 2 higher vitamin D doses did not affect the study’s
primary outcome, flow-mediated dilation, which is a measure
of endothelial function. Blood lipids, glucose homeostasis, and
inflammatory markers were similarly not different between the
The author reported no funding received for this study.
Address correspondence to CTD (e-mail: ctd@nexs.ku.dk).
First published online 0, 2020; doi: https://doi.org/10.1093/ajcn/nqaa021.
Am J Clin Nutr 2020;00:1–2. Printed in USA. Copyright © The Author(s) 2020. 1
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2 Editorial
treatment arms, whereas mean diastolic and systolic blood
pressure was lower in the 25 μg/d group compared with the
15 μg/d group. Over time there were significant if modest
increments in serum 25(OH)D concentrations, but little absolute
difference between groups at endpoint. Children who received
50 μg/d had a lower BMI (but not BMI z-score) at the end of the
trial compared with the 15 μg/d group; whether this was related
to the supplementation is unknown.
Taken together, where do these 2 trials leave us in evaluating
the role of vitamin D in childhood cardiovascular health?
Obviously the 2 trials differ in terms of participants’ age,
ethnic origin, weight status, baseline vitamin D status, the
supplementation regimen used as well as outcomes measured.
However, based on the data currently available, it seems that
vitamin D supplementation is not the “magic bullet” for the
early prevention of cardiovascular disease and type 2 diabetes
in children and adolescents. The findings concerning blood
lipid and blood pressure changes are of interest and deserve
follow-up in larger trials where children at risk of hypertension
or dyslipidemia could be enrolled, but careful attention to
nonbeneficial effects is warranted, especially at higher doses.
In addition, Mendelian randomization studies, in which genetic
variants associated with vitamin D status are related to disease,
might be helpful. Finally, well-designed studies investigating
the potential interaction of vitamin D with other nutrients such
as protein and calcium in relation to bone health as well as
nonskeletal outcomes are needed.
Author disclosures: The author reports no conflicts of interest.
References
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