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Bioavailability of Vitamin D-2 and D-3 in Healthy Volunteers, a Randomized Placebo-Controlled Trial

Authors:

Abstract

Background: The bioequivalence of the different forms of vitamin D, ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), has been questioned. Earlier studies have suggested that vitamin D2 is less biologically active than vitamin D3. Objective and design: In a parallel study, we tested the effects of supplementation with 50-μg/d doses of vitamin D2 or D3 or a placebo over a period of 8 weeks on 25(OH)D2, 25(OH)D3, their sum 25(OH)D (primary outcome variables), and PTH in healthy volunteers applying a double-blind, randomized study design. The study was conducted during the winter of 2012 in Halle (Saale), Germany, at latitude 51°47N, when UVB irradiation is virtually absent. Blood samples for the determinations of vitamin D status and PTH were collected at baseline and after 4 and 8 weeks of supplementation. Results: In the placebo group (n = 19), 25(OH)D3 decreased from 39.4 ± 14.2 to 31.1 ± 12.4 nmol/L after 8 weeks (P < .01). In the vitamin D3 group (n = 42), the concentrations of 25(OH)D3 increased from 41.5 ± 22.8 nmol/L at baseline to 88.0 ± 22.1 nmol/L after 8 weeks (P < .01). In the group receiving vitamin D2 (n = 46), the 25(OH)D2 concentrations increased significantly, whereas the 25(OH)D3 concentration fell from 36.4 ± 13.3 nmol/L at baseline to 16.6 ± 6.3 nmol/L after 8 weeks (P < .01). The total 25(OH)D was not different between the groups at baseline but differed significantly between the groups after 4 and 8 weeks (P < .001). Conclusions: Vitamin D3 increases the total 25(OH)D concentration more than vitamin D2. Vitamin D2 supplementation was associated with a decrease in 25(OH)D3, which can explain the different effect on total 25(OH)D.
Bioavailability of Vitamin D
2
and D
3
in Healthy
Volunteers, a Randomized Placebo-Controlled Trial
Ulrike Lehmann, Frank Hirche, Gabriele I. Stangl, Katja Hinz, Sabine Westphal,
and Jutta Dierkes
Institute of Agricultural and Nutritional Sciences (U.L., F.H., G.I.S.), Martin-Luther University Halle-
Wittenberg, 06110 Halle, Germany; Institute of Clinical Chemistry and Biochemistry (K.H., S.W.),
Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany; and Department of Clinical
Medicine (J.D.), University of Bergen, N-5020 Bergen, Norway
Background: The bioequivalence of the different forms of vitamin D, ergocalciferol (vitamin D
2
)
and cholecalciferol (vitamin D
3
), has been questioned. Earlier studies have suggested that vitamin
D
2
is less biologically active than vitamin D
3
.
Objective and Design: In a parallel study, we tested the effects of supplementation with 50-
g/d
doses of vitamin D
2
or D
3
or a placebo over a period of 8 weeks on 25(OH)D
2
, 25(OH)D
3
, their sum
25(OH)D (primary outcome variables), and PTH in healthy volunteers applying a double-blind,
randomized study design. The study was conducted during the winter of 2012 in Halle (Saale),
Germany, at latitude 51°47N, when UVB irradiation is virtually absent. Blood samples for the
determinations of vitamin D status and PTH were collected at baseline and after 4 and 8 weeks of
supplementation.
Results: In the placebo group (n 19), 25(OH)D
3
decreased from 39.4 14.2 to 31.1 12.4 nmol/L
after 8 weeks (P .01). In the vitamin D
3
group (n 42), the concentrations of 25(OH)D
3
increased
from 41.5 22.8 nmol/L at baseline to 88.0 22.1 nmol/L after 8 weeks (P .01). In the group
receiving vitamin D
2
(n 46), the 25(OH)D
2
concentrations increased significantly, whereas the
25(OH)D
3
concentration fell from 36.4 13.3 nmol/L at baseline to 16.6 6.3 nmol/L after 8 weeks
(P .01). The total 25(OH)D was not different between the groups at baseline but differed sig-
nificantly between the groups after 4 and 8 weeks (P .001).
Conclusions: Vitamin D
3
increases the total 25(OH)D concentration more than vitamin D
2
. Vitamin
D
2
supplementation was associated with a decrease in 25(OH)D
3
, which can explain the different
effect on total 25(OH)D. (J Clin Endocrinol Metab 98: 4339 4345, 2013)
V
itamin D exists in two different forms: ergocalciferol
(vitamin D
2
), which occurs in plants, mainly in
mushrooms; and cholecalciferol (vitamin D
3
), which oc
-
curs in animals and is also produced in human skin. Vi-
tamins D
2
and D
3
differ only in their side chains. The best
dietary sources of vitamin D are fatty fish and products
fortified with vitamin D (1, 2). It has been estimated that
most of the vitamin D
3
in humans is derived from endog
-
enous synthesis in the epidermis, which contains 7-dehy-
drocholesterol as a precursor for vitamin D
3
, after irradi
-
ation with UVB light at wavelengths of 290–330 nm (3).
Although vitamin D
2
is less frequently used in Europe, it
is the standard form of fortification and supplementation
outside Europe.
Thus, both forms can be found in human blood, as well
as the hydroxylated forms 25(OH)D
2
and 25(OH)D
3
.
It has been debated for many years whether the two
forms are bioequivalent. A number of studies have shown
that vitamin D
2
does not increase the serum total
25(OH)D concentrations to the same extent as vitamin D
3
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2013 by The Endocrine Society
Received December 21, 2012. Accepted August 18, 2013.
First Published Online September 3, 2013
Abbreviation: BMI, body mass index.
ORIGINAL ARTICLE
Endocrine Care
doi: 10.1210/jc.2012-4287 J Clin Endocrinol Metab, November 2013, 98(11):43394345 jcem.endojournals.org 4339
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(4 6), but this finding has also been questioned by other
investigators (7, 8). Because fortification or supplemen-
tation with vitamin D is currently the subject of much
discussion owing to the widespread occurrence of vitamin
D deficiency in nearly all populations investigated (9–19),
it is important to know which form is more effective in
supplementation and fortification. Although some studies
have already shown that serum 25(OH)D
3
is lowered after
the administration of vitamin D
2
, either these studies lack
sufficient statistical power (5, 20) and a control group (21)
and they measured only total 25(OH)D (6, 7), or they were
conducted in specific population groups (eg, elderly) (21,
22). Furthermore, it seems that the route of administration
(bolus vs daily) may affect the comparison of both vitamin
D forms. A recent meta-analysis showed that there was no
significant difference in total 25(OH)D after daily admin-
istration of either vitamin D
2
or vitamin D
3
(1). In this
meta-analysis, studies using 1000 –1600 IU of vitamin D
2
or vitamin D
3
were included, but it was also estimated that
larger, more robust trials are required that further address
this issue.
We therefore conducted a bioavailability study in
healthy volunteers who received a placebo—50
g/d of
vitamin D
2
or 50
g/d of vitamin D
3
(2000 IU/d). The aim
was to investigate the effects of this high dose on the se-
rum levels of the hydroxylated forms 25(OH)D
2
and
25(OH)D
3
and on their sum total 25(OH)D. In addition,
we investigated PTH concentrations, which are regarded
as a functional parameter of vitamin D status (23). The
measurability of 25(OH)D
3
serum or plasma levels is su
-
perior to that of 1,25(OH)
2
D
3
, owing to the much lower
concentrations of 1,25(OH)
2
D
3
and its shorter half-life
compared with 25(OH)D
3
(24). The PTH concentra
-
tions are higher in the presence of vitamin D deficiency
and decline upon supplementation with vitamin D; they
can therefore be used as a functional parameter of vi-
tamin D metabolism.
Furthermore, due to the inclusion of a placebo group,
we were able to monitor the decrease of 25(OH)D
3
and
total 25(OH)D in healthy subjects during wintertime at
latitude 51°North.
Subjects and Methods
Design
The trial was conducted as a double-blind, randomized study
in parallel groups during January, February, and March 2012,
when virtually no UVB irradiation is measurable in Halle and the
surrounding region. Study visits were scheduled at baseline and
after 4 and 8 weeks. The subjects were randomized (stratified for
body mass index [BMI] as determined during the screening visit)
to receive vitamin D
2
(50
g/d; n 46), vitamin D
3
(50
g/d; n
42), or placebo (n 19).
The supplements were manufactured commercially (Zein-
Pharma) and were outwardly indistinguishable from one an-
other. The tablets were tested for their vitamin D content after
the study by a liquid chromatography, tandem mass spectrom-
etry method in four separate runs, and the content was found to
be 54 12
g for vitamin D
2
and 48 6
g for vitamin D
3
per
tablet.
The participants were issued containers of tablets at baseline
and after 4 weeks and were instructedto take one tablet orally per
day and to return any remaining tablets at 4 and 8 weeks. The
containers were numbered by an investigator with no involve-
ment in the trial. All investigators were unaware of the order of
numbering. The participants were enrolled by the physician in-
volved in the trial but were assigned to the intervention by an-
other investigator. Compliance, which was checked by counting
the returned tablets, was 97%. During each study visit, a venous
blood sample was collected for determination of 25(OH)D
2
,
25(OH)D
3
, their sum 25(OH)D, PTH, and serum calcium. The
samples were frozen at 80°C until the time of analysis. The
study protocol had been evaluated and approved by the Ethics
Committee of the Medical Faculty at the Martin-Luther-Univer-
sity Halle-Wittenberg, and each participant gave his or her writ-
ten, informed consent before the start of the study. The study was
registered at clinicaltrails.gov (NCT01503216).
Subjects
Participants were recruited through newspaper advertise-
ments, personal contacts, and information in public institutions.
During a screening in the autumn (about 2 mo before the start of
the study), the participants answered a self-administered ques-
tionnaire on their medical history, weight, height, lifestyle
(smoking, use of sun blocker-containing cosmetics), and dietary
habits relating to food rich in vitamin D. The exclusion criteria
were: use of vitamin D and calcium supplements, history of
chronic illness and elevated serum creatinine (in females, 1.1
mg/dL; in males, 1.3 mg/dL), elevated serum calcium, preg-
nancy or lactation, and vacations in areas with abundant UVB
irradiation in the course of the study.
A total of 119 subjects had been recruited for the intervention
study (age range, 19 67 y), were finally included in the study,
and were randomized by a computer-generated randomization
list to the intervention groups with the BMI as the stratification
criterion. Participants were randomized into three groups ac-
cording to their BMI: normal weight (BMI below 25 kg/m
2
),
overweight (25–30 kg/m
2
), and obese (above 30 kg/m
2
). Before
the start of the intervention, seven subjects (placebo group, n
1; vitamin D
2
group, n 3; vitamin D
3
group, n 3) dropped
out. During the study period, five subjects (vitamin D
2
group,
n 1; vitamin D
3
group, n 4) dropped out for personal rea
-
sons. During each visit, the participants were interviewed about
any adverse effect. In addition, the calcium concentration in se-
rum was measured in serum obtained at each visit.
After completion of the study, all subjects, including those in
the control group, were informed about their vitamin D status
and offered vitamin D supplements.
Analytical methods
Serum concentrations of total 25(OH)D, 25(OH)D
3
, and
25(OH)D
2
were determined by liquid chromatography coupled
with mass spectrometry (MassChrom 25-OH Vitamin D
3
/D
2
reagent kit for liquid chromatography, tandem mass spectrom-
4340 Lehmann et al Bioavailability of Vitamin D2 and D3 J Clin Endocrinol Metab, November 2013, 98(11):43394345
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etry analysis; Chromsystems Instruments and Chemicals GmbH)
on an API 2000 system (Applied Biosystems). The coefficient of
variation for the determination of 25(OH)D
2
was 3.1% at a
concentration of 44.8 nmol/L;
for 25(OH)D
3
, it was 5.3% at a concentration of 42.8 nmol/L.
Total 25(OH)D was calculated as the sum of 25(OH)D
2
and
25(OH)D
3
. The detection limit for both 25(OH)D
2
and
25(OH)D
3
was 2.5 nmol/L, and the limit of quantification was
7.5 nmol/L. However, the measured levels were used for the
calculation of total 25(OH)D as the sum of 25(OH)D
2
and
25(OH)D
3
, even in subjects with 25(OH)D
2
levels below the
limit of quantification.
Intact PTH was measured in the serum by an ELISA
(Biomerica Inc). Serum creatinine was determined spectropho-
tometrically (DiaSys Diagnostic Systems GmbH).
Statistical analyses
Statistical analyses were performed using PASW version 18.0
(SPSS Inc). All data are expressed in the form of means SD,
with P .05 as the significance threshold. The primary outcome
variables were the 25(OH)D
2
, 25(OH)D
3
, and total 25(OH)D
concentrations. These variables and PTH concentrations are pre-
sented in Table 2. Because changes in total 25(OH)D and PTH
tend to depend on the baseline level, we used repeated measure
analysis to analyze changes upon supplementation. We used the
generalized linear models repeated measures procedure in PASW
for this analysis. Total 25(OH)D and 25(OH)D
3
at baseline and
at 4 and 8 weeks were used as the within-subjects factor, and the
supplementation group was used as the between-subjects factor.
In addition, post hoc analyses by Scheffé were used to detect
differences between single groups. PTH was highly skewed and
was therefore analyzed by the nonparametric Kruskal-Wallis
test.
In addition, we calculated the absolute change and the per-
centage change in total 25(OH)D, 25(OH)D
3
, and PTH (8 wk
baseline) and compared these changes among groups by
ANOVA (Table 3).
According to a power calculation, 50 subjects per group
would be required to show a difference of 10 nmol/L in the mean
total 25(OH)D concentration after 8 weeks of supplementation
between the vitamin D
2
and D
3
groups (at an assumed standard
variation of 15 nmol/L for each group, at a power of 80%, and
a significance level of 0.05). Because it was the main aim to
compare vitamin D
2
with D
3
, the size of the placebo group was
only about half that of the vitamin D groups. Only subjects who
finished the study according to protocol were included into the
analyses.
Results
The characteristics of the subjects are presented in Table
1. The average total 25(OH)D concentration at baseline in
January was 40.2 18.0 nmol/L, indicating a high degree
of suboptimal vitamin D status in these healthy, young
volunteers, with no significant differences between the
groups. The total 25(OH)D concentration increased sig-
nificantly throughout the study in the groups supple-
mented with vitamin D
2
or vitamin D
3
and decreased sig
-
nificantly to 33.1 13.9 nmol/L after 4 weeks and to
32.1 12.8 nmol/L after 8 weeks in the placebo group.
After 4 and 8 weeks, the 25(OH)D concentrations differed
significantly between the groups (Table 2).
At baseline, the 25(OH)D
2
concentration was below
the limit of quantification (7.5 nmol/L) in all but two par-
ticipants. In neither the vitamin D
3
group nor the placebo
group did the average 25(OH)D
2
rise above the limit of
quantification in the course of the study. In the vitamin D
2
group, 25(OH)D
2
increased significantly to 39.6 11.7
nmol/L at 4 weeks and to 51.2 18.5 nmol/L at 8 weeks
(Table 2).
At baseline, there was no difference in the 25(OH)D
3
concentration between the groups. Although in the vitamin
D
3
group 25(OH)D
3
increased significantly after 4 and 8
weeks, it decreased significantly in the vitamin D
2
and pla
-
cebo groups. The decrease was more pronounced in the vi-
tamin D
2
group, and the difference from the placebo group
was significant at both 4 and 8 weeks (Table 2).
The increases (4-wk baseline, 8-wk baseline) in the spe-
cific hydroxylated forms of vitamin D [either 25(OH)D
2
or 25(OH)D
3
] were as follows: in the case of 25(OH)D
2
in
the vitamin D
2
group, 38.4 11.0 nmol/L after 4 weeks
and 50.0 18.0 nmol/L after 8 weeks; in the case of
25(OH)D
3
in the vitamin D
3
group, 34.2 17.2 nmol/L
after 4 weeks and 46.7 21 nmol/L after 8 weeks. The
increase was calculated from the baseline value in this
group, without taking the decrease in 25(OH)D
3
in the
placebo group into account. The increase was not signif-
icantly different at either 4 or 8 weeks.
Table 1. Characteristics of Study Participants at Baseline
Vitamin D
2
Group
Vitamin D
3
Group
Placebo Group P (ANOVA)
n464219
Age, y 33.2 12.4 35.6 13.5 31.6 9.3 .445
No. of males/females 15/31 16/26 8/11 .745
BMI, kg/m
2
23.7 3.8 24.0 4,2 23.7 4.9 .928
Systolic blood pressure, mm Hg 121 14 120 15 115 8 .201
Diastolic blood pressure, mm Hg 76 876 10 75 6 .894
Creatinine at screening, mg/dL 0.80 0.22 0.86 0.23 0.88 0.24 .298
Data are expressed as mean SD.
doi: 10.1210/jc.2012-4287 jcem.endojournals.org 4341
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The PTH concentrations were not significantly differ-
ent between the groups at baseline or after 4 and 8 weeks
(Table 2). PTH concentrations decreased significantly
during the course of the study in all groups.
The absolute and percentage differences in total
25(OH)D, 25(OH)D
3
, and 25(OH)D
2
between baseline
and 8 weeks were significant among the supplementa-
tion groups. Absolute or percentage differences in PTH
concentrations were not significant among the groups
(Table 3).
No adverse effects were reported by the participants.
Serum calcium did not exceed the normal range in any of
the participants (data not shown). The analysis for total
25(OH)D, the primary outcome variable, was repeated
with all randomized subjects included (intention-to-treat
analysis). This did not change the results (data not shown).
Table 2. Vitamin D Metabolites in Healthy Volunteers Receiving Supplementation With Vitamin D
2
, Vitamin D
3
,or
Placebo for 8 Weeks
Vitamin D
2
Group
Vitamin D
3
Group
Placebo Group P (ANOVA)
n464219
Total 25(OH)D
Baseline, nmol/L 37.6 13.3 43.7 23.3 40.7 14.5 .292
4 wk, nmol/L 59.9 15.2
a
77.1 23.5
b
33.1 13.9 .001
8 wk, nmol/L 67.8 20.1
a
89.2 22.1
b
32.1 12.8 .001
Repeated measure analysis .001
25(OH)D
3
Baseline, nmol/L 36.4 13.3 41.5 22.8 39.4 14.2 .409
4 wk, nmol/L 20.3 8.1
a
75.7 23.2
b
31.1 13.9 .001
8 wk, nmol/L 16.6 6.3
a
88.0 22.1
b
31.1 12.4 .001
Repeated measure analysis .001
25(OH)D
2
Baseline, nmol/L 7.5
c
7.5 7.5 .110
4 wk, nmol/L 39.6 11.7
a
7.5 7.5 .001
8 wk, nmol/L 51.2 18.5
a
7.5 7.5 .001
Repeated measure analysis .001
PTH
Baseline, ng/mL 69.8 45.2 59.3 22.6 79.4 49.2 .334
4 wk, ng/mL 63.0 33.2 49.1 19.5 65.0 40.0 .086
8 wk, ng/mL 56.8 26.5 40.3 19.5 60.8 38.1 .007
Repeated measure analysis .651
Data are shown as mean SD. Differences between the groups at the various time points of the study were tested by one-way ANOVA with post
hoc Scheffé comparison. The overall effect of supplementation was tested by an ANOVA with repeated measurement (PASW procedure GLM
repeated measure). Due to the high degree of skewness, the Kruskal-Wallis test was used for testing differences in PTH between groups.
a
Significantly different at P .01 from vitamin D
3
group and placebo.
b
Significantly different at P .01 from vitamin D
2
group and placebo.
c
Values for 25(OH)D
2
at baseline and in the vitamin D
3
and placebo groups in the course of the study are only provided for those levels exceeding
the limit of detection (2.5 nmol/L).
Table 3. Absolute and Percentage Changes in Total 25(OH)D, 25(OH)D
3
, 25(OH)D
2
(Absolute Change Only), and
PTH at 8 Weeks Compared to Baseline
Vitamin
D
2
Group
Vitamin
D
3
Group
Placebo
Group P (ANOVA)
n 464219
Total 25(OH)D at 8 wk (to baseline), nmol/L 30.2 20.1
c
45.5 21.7
a
8.6 7.3 .001
% Total 25(OH)D at 8 wk (of baseline) 200 97%
a
259 149%
a
79 16% .001
25(OH)D
3
at 8 wk (to baseline), nmol/L
19.8 9.6
c
46.5 21.3
b
8.3 6.1 .001
% 25(OH)D
3
at 8 wk (of baseline)
47 14% 280 183%
b
79 15% .001
25(OH)D
2
at 8 wk (to baseline), nmol/L
43.7 18.5
d
7.5 7.5 .001
PTH at 8 wk (to baseline), ng/mL 13.0 35.4 19.0 29.4 18.6 35.1 .658
% PTH at 8 wk (of baseline) 95 47% 80 58% 82 38% .354
Data are shown as mean SD. Significance was tested by ANOVA, followed by a post hoc Scheffé comparison.
a
Significantly different from placebo group.
b
Significantly different from vitamin D
2
and placebo groups.
c
Significantly different from vitamin D
3
and placebo groups.
d
Significantly different from vitamin D
2
and vitamin D
3
groups.
4342 Lehmann et al Bioavailability of Vitamin D2 and D3 J Clin Endocrinol Metab, November 2013, 98(11):4339 4345
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Discussion
Our major finding is that vitamin D
3
increased 25(OH)D
more effectively than vitamin D
2
. By measuring the spe
-
cific hydroxylated forms, we have been able to show that
the underlying reason for this difference is a substantial
decrease in 25(OH)D
3
in subjects receiving vitamin D
2
.
This had not been demonstrated earlier with sufficient
statistical power. We have also been able to show that
hydroxylation of vitamin D
2
was similar to hydroxyla
-
tion of vitamin D
3
because the increase in the specific
hydroxylated forms [25(OH)D
2
and 25(OH)D
3
] was
similar in the two groups (compare the absolute differ-
ences in Table 3).
Vitamins D
2
and D
3
have been compared earlier in a
number of studies that differed in their design, supplement
dosage, frequency of supplementation, use of the delivery
method, and selection of participants and also in their
conclusion regarding the bioequivalence of the two forms
of the vitamin (4 8, 20–22, 25, 26). A recent meta-anal-
ysis that included seven of these studies (48, 21, 22)
concluded that the change in 25(OH)D was significantly
greater after supplementation with vitamin D
3
than after
one with vitamin D
2
, although the effect was largely due
to the studies that used a bolus dose; it was not significant
in studies with daily supplementation (1). However, for
the latter analysis, only six studies (6 8, 21, 22) with a
total number of 248 participants were available. Our
study with 42 and 46 participants in the vitamin D
3
and D
2
groups, respectively, would have changed the result of this
analysis, yielding a significant effect in favor of vitamin D
3
compared to vitamin D
2
also with daily supplementation
(the analysis using present data in addition to those of
Tripkovic et al [1] was made using Review Manager 5.2;
data not shown).
The most interesting result of our study, however, is
the decrease in 25(OH)D
3
after supplementation with
vitamin D
2
. This was already evident after 4 weeks, and
the decrease was significantly different from the sea-
sonal decrease observed in the placebo group. A de-
crease in 25(OH)D
3
after supplementation with vitamin
D
2
was reported earlier by Glendenning et al (22) in
elderly hip fracture patients receiving 1000 IU/d for a
period of 3 months, and also by Armas et al (26), who
studied single doses of 50 000 IU of D
2
and D
3
in healthy
men with a follow-up period of 28 days. Interestingly,
both groups of authors did not discuss these findings
specifically. This was also observed by Binkley et al (21)
after administration of 1600 IU daily for a period of 12
months. It is surprising that this effect was observed in
only a few studies, although it should be pointed out
that only studies using methods capable of distinguish-
ing between 25(OH)D
2
and 25(OH)D
3
would be able to
show this effect. The use of immunoassays will therefore
not make it possible to observe the effect. The biological
reason behind this finding remains to be elucidated.
It has been suggested that an increased catabolism of
25(OH)D takes place due to supplementation with vita-
min D
2
(5). Heaney et al (5) studied, groups of 16 and 17
subjects who received 50 000 IU once weekly for 12
weeks, and a significantly higher AUC
25(OH)D
was ob
-
served after 84 days for vitamin D
3
. Interestingly, vitamins
D
3
and D
2
were also measured in the fat tissue of two
participants, and a decrease in vitamin D
3
in fat tissue after
supplementation with vitamin D
2
was observed. Because
the authors measured vitamin D
2
in fat biopsies from only
two participants, however, this finding did not reach sta-
tistical significance.
It has also been suggested that one reason for the lower
increase in 25(OH)D after vitamin D
2
in comparison with
supplementation with D
3
was due to impaired hydroxy
-
lation at C25 (atom of the vitamin D molecule) (27). We
have shown that at least the increases in the specific hy-
droxylation products [either 25(OH)D
2
or 25(OH)D
3
]
were similar. However, we cannot exclude the possibility
that vitamin D
2
impairs hydroxylation of vitamin D
3
,
which is also present in the circulation. Because the de-
crease in 25(OH)D
3
exceeded the observed decrease in the
placebo group, this is a likely explanation. The problem
should be investigated further.
Other explanations include an increased catabolism of
the 25(OH)D
2
molecule due to a lower degree of binding
to the vitamin D binding protein (28). Our data do not
support an increased catabolism of 25(OH)D
2
, although
they cannot exclude it.
Because we did not measure any other metabolite
[24,25(OH)
2
D metabolites, 1,24,25(OH)
3
D metabo
-
lites], we can only speculate about differences in the 24-
hydroxylation step between 25(OH)D
2
and 25(OH)D
3
.
Further studies should include these metabolites to obtain
a deeper insight into the competitive nature of the two
forms of vitamin D.
Our study has several strengths and also some limita-
tions. The strengths of the present study include its large
sample size, which allowed us to detect small differences
between vitamin D
2
and D
3
treatments that earlier studies
had been unable to show. Another important strength is
the measurement of both 25(OH)D
2
and 25(OH)D
3
in
this study. Measurements of the specific hydroxylated
forms of vitamin D enabled us to show the effect of vitamin
D
2
on the 25(OH)D
3
levels. In addition, due to the inclu
-
sion of the placebo group, we were able to monitor the
decrease in total 25(OH)D concentrations within healthy
subjects living at the approximate latitude 51°North. We
doi: 10.1210/jc.2012-4287 jcem.endojournals.org 4343
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observed a strong decrease from January to February and
no further decrease from February to March.
One limitation of our study was that we did not mea-
sure the active forms, 1,25(OH)
2
D
2
and 1,25(OH)
2
D
3
,or
other metabolites. In addition, we did not obtain a dose-
response curve after a single dose, and we did not determine
the catabolic products 24,25(OH)
2
D, 24,25(OH)
2
D
3
,or
24,25(OH)
2
D
2
. Measurement of these metabolites would
provide valuable insights into the metabolism of vitamin
D
3
in the presence of vitamin D
2
. We also studied only one
dose, and the level of 50
g/d is beyond current recom-
mendations and fortification levels.
In future studies, the effect of lower doses of vitamin D
that are closer to the recommended daily amounts should
be investigated. In light of the decrease in 25(OH)D
3
by
vitamin D
2
, the effect of vitamin D
2
supplementation on
disease outcomes, eg, bone health and fractures, should be
carefully analyzed. Indeed, the effect of vitamin D
2
on falls
was found to be lower than that of vitamin D
3
in recent
meta-analyses (29, 30).
PTH and vitamin D are both involved in bone metabolism
(31) and show an inverse correlation. PTH secretion is directly
modulated (23) and suppressed by 25(OH)D concentrations
(31). Leventis and Kiely (32) demonstrated that vitamin D
3
af
-
fected PTH concentration more than vitamin D
2
, a finding that
is not supported by our data. However, our study was not de-
signed to demonstrate an effect of vitamin D supplementation
on PTH concentrations as the primary outcome. To demon-
strate such an effect, we had to include even more subjects due
to the largevariation inPTH concentrations.Therefore, wemay
have missed an effect of vitamin D supplementation on PTH
concentrations. This is in line with a number of other studies (8,
21, 22).
In conclusion, we have shown that vitamin D
3
is more
effective in raising the vitamin D status than vitamin D
2
and that vitamin D
2
supplementation causes a decrease in
25(OH)D
3
. These findings question the usefulness of vi
-
tamin D
2
supplements. Instead, vitamin D
3
should be used
for supplementation and fortification purposes.
Acknowledgments
Address all correspondence and requests for reprints to: Jutta
Dierkes, PhD, Department of Clinical Medicine, P.O. Box 7804,
N-5020 Bergen, Norway. E-mail: jutta.dierkes@med.uib.no.
This work was supported by Grant 0315668A from the Ger-
man Ministry of Education and Research.
Author contributions: J.D. and G.I.S. designed the research.
U.L., K.H., S.W., and F.H. conducted the study. J.D. and U.L.
analyzed the data and wrote the paper. J.D. has primary respon-
sibility for the final content. All authors read and approved the
final manuscript. None of the authors declared any financial or
personal relationships with other persons or organizations that
could have an inappropriate influence on this work. The funding
agency had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Registered at clinicaltrials.gov with identifier NCT01503216.
Disclosure Summary: The authors have nothing to disclose.
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... In Europe, the prevalence of insufficient vitamin D concentrations is even higher and is estimated to be 40.4% [9]. The intake of vitamin D supplements is one option to combat vitamin D deficiency [32,33,39]. However, vitamin D supplements are not widely used, at least in Germany, and therefore are not suitable to improve vitamin D status in large populations [24]. ...
... New food sources of vitamin D could be a more efficient strategy to prevent vitamin D insufficiency. The exposure of foods such as yeast, edible mushrooms or milk to UVB light is a promising approach to increase the vitamin D concentrations in foods and diets [25,29,32,44]. Nowadays, UVB-exposed foods are commercially available and considered to be safe (EFSA Panel on Nutrition, Novel Foods and Food Allergens [14][15][16]. ...
... Firstly, the efficiency of a vitamin D 2 to increase the serum concentrations of 25(OH)D has been shown to be lower than that of vitamin D 3 (reviewed in [43]). A few studies which distinguished between the 25(OH)D 2 and 25(OH)D 3 concentrations found a marked reduction of 25(OH)D 3 in vitamin D 2 treated groups that was stronger than in groups that received no vitamin D [3,7,18,32]. Although both isoforms of vitamin D are considered equally in the treatment of rickets [36], Lehman et al. found substantially lower levels of 25(OH)D in the group supplemented with vitamin D 2 Table 5 Concentrations of fatty acids, lipids, and tocopherol in plasma Data are presented as means ± SD. ...
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Purpose This study investigated whether UVB-exposed wheat germ oil (WGO) is capable to improving the vitamin D status in healthy volunteers. Methods A randomized controlled human-intervention trial in parallel design was conducted in Jena (Germany) between February and April. Ultimately, 46 healthy males and females with low mean 25-hydroxyvitamin D (25(OH)D) levels (34.9 ± 10.6 nmol/L) were randomized into three groups receiving either no WGO oil (control, n = 14), 10 g non-exposed WGO per day (– UVB WGO, n = 16) or 10 g WGO, which was exposed for 10 min to ultraviolet B-light (UVB, intensity 500–630 µW/cm ² ) and provided 23.7 µg vitamin D (22.9 µg vitamin D 2 and 0.89 µg vitamin D 3 ) (+ UVB WGO, n = 16) for 6 weeks. Blood was obtained at baseline, after 3 and 6 weeks and analyzed for serum vitamin D-metabolite concentrations via LC–MS/MS. Results Participants who received the UVB-exposed WGO were characterized by an increase of circulating 25(OH)D 2 after 3 and 6 weeks of intervention. However, the 25(OH)D 3 concentrations decreased in the + UVB WGO group, while they increased in the control groups. Finally, the total 25(OH)D concentration (25(OH)D 2 + 25(OH)D 3 ) in the + UVB WGO group was lower than that of the non-WGO receiving control group after 6 weeks of treatment. In contrast, circulating vitamin D (vitamin D 2 + vitamin D 3 ) was higher in the + UVB WGO group than in the control group receiving no WGO. Conclusion UVB-exposed WGO containing 23.7 µg vitamin D can increase 25(OH)D 2 levels but do no improve total serum levels of 25(OH)D of vitamin D-insufficient subjects. Trial registration ClinicalTrials.gov: NCT03499327 (registered, April 13, 2018).
... The body's vitamin D needs are provided either through nutrition or directly through the skin. [1] Although it can be taken into the body through nutrients, as in most vitamins, it is known that vitamin D is mainly produced in the skin through ultraviolet radiation. The main function of vitamin D in the body is known as the absorption of calcium and phosphorus, which promotes bone growth. ...
... Vitamin D 2 , also known as ergocalciferol, is found in plants, while vitamin D 3 , also known as cholecalciferol, is found in animals and is also produced in human skin. [1] Normally, vitamins are the nutrients that cannot be produced in the body, so they must be taken through food. However, the form of vitamin D 2 is not sufficient for human metabolism. ...
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... The efficiency of 25-hydroxylation could be different for vitamins D 2 and D 3 . In humans, supplementation of vitamin D 3 yielded higher concentrations of total 25-hydroxylated derivatives than supplementation of the identical amount vitamin D 2 (Heaney et al. 2011;Lehmann et al. 2013). One reason for this might be that supplementation of vitamin D 2 leads to a substantial decrease of the concentration of 25(OH)D 3 (Lehmann et al. 2013). ...
... In humans, supplementation of vitamin D 3 yielded higher concentrations of total 25-hydroxylated derivatives than supplementation of the identical amount vitamin D 2 (Heaney et al. 2011;Lehmann et al. 2013). One reason for this might be that supplementation of vitamin D 2 leads to a substantial decrease of the concentration of 25(OH)D 3 (Lehmann et al. 2013). Moreover, it has been suggested that a lower concentration of total 25(OH)D in plasma after supplementation of vitamin D 2 in comparison to vitamin D 3 could be due to the shorter half-life of 25(OH)D 2 in contrast to 25(OH)D 3 (Heaney et al. 2011). ...
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... In spite of the continued controversy regarding the relative effectiveness of vitamin D2 and D3 on raising serum levels of 25(OH)D [32,33], vitamin D2 has been used for more than 50 years for the treatment and prevention of vitamin D deficiency [25]. 25(OH)D2, one of the intermediates of the most bioactive vitamin D metabolites (1,25(OH) 2D), was found not to be bound as tightly to vitamin D binding protein (DBP) as 25(OH)D3 [34], leading to a higher free level of 25(OH)D2 compared to that of 25(OH) D3 [35]. ...
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... Bescos Garcia et al., 40 Ducher et al., 42 Kim et al., 46 Lovell et al., 47 Pollock et al., 49 D 3 (cholecalciferol), which may be more effective in restoring vitamin D levels than combined vitamin D 3 /D 2 (ergocalciferol) therapy, 77 since vitamin D 3 has a superior bioavailability compared to vitamin D 2 as a result of stronger association with vitamin D binding protein. 78,79 Regarding the dosage and timing of administration, current evidence suggests that 2000e6000 IU of supplemental vitamin D 3 can be consumed daily, 9 a continuous consumption of <2000 IU may lead to sufficiency in vitamin D concentrations during spring and summer, and maintain sufficiency throughout the wintertime. 70 However, as we believe the increased vitamin D utilisation in athletes may play a significant role in vitamin D deficiency, the administration of vitamin D supplementation to athletes who have a low basal vitamin D level would be too simplistic. ...
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... The best characterized mediator of ultraviolet radiation (UVR)-dependent effects is vitamin D (vitD), which is generated from its precursor 7-dehydrocholesterole (7-DHC) in the skin, further metabolized in the liver and kidney, and that exerts its function in its active form 1-α,25-dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ], also known as calcitriol (5). Precursors of active vitD can also be found in food in the form of ergocalciferol (or vitamin D 2 ), which is, however, of little relevance for total serum vitD levels (6). For MS, low vitD levels have been shown to be associated with disease risk (7,8) and Mendelian randomization studies hint toward a causal role for vitD (9,10). ...
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... Many supplements are in the form of vitamin D3 and only high-dose, prescription vitamin D formulation is available for vitamin D2 in the United States [33]. In Europe, vitamin D2 is less frequently used for fortification and supplementation [38]. By searching for product information on the internet, the majority of vitamin D supplements on the China market are for vitamin D3. ...
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Background: Vitamin D deficiency is prevalent globally and there is lack of evidence as to how 25(OH)D2 contributes to vitamin D status. The aim of this study was to describe vitamin D status and to assess the role of vitamin D2, a dietary vitamin D source, against the vitamin D status of children aged 3-5 years in China. Methods: Data were extracted from the Chinese National Nutrition and Health Surveillance (CNNHS) in 2013. The concentration of serum 25(OH)D2 and 25(OH)D3 was measured by using LC-MS/MS. Results: A total of 1435 subjects were enrolled and serum 25(OH)D were analyzed. The prevalence of total serum 25(OH)D < 30 nmol/L was 8.9%. Serum 25(OH)D2 was detected in 10.9% of the studied children. After adjusting for confounding factors, total 25(OH)D concentration was 8.48 nmol/L lower and odds ratio of vitamin D deficiency was 4.20 times (OR (95%CI): 4.20 (1.64, 10.77)) in children without 25(OH)D2 than those with 25(OH)D2 detected. Conclusions: Vitamin D deficiency was common among children aged 3-5 years in China. Vitamin D2 may play a role in preventing vitamin D deficiency in Chinese children aged 3-5 years.
Article
Background : The role of vitamin D in depression has been gaining increased research interest. However, little is known about the independent associations of serum 25-hydroxyvitamin D3 (25(OH)D3) and D2 (25(OH)D2) with depressive symptoms. The goal of this study was to examine the metabolites of vitamin D and their associations with depression. Methods : This study was conducted in US females using data from the National Health and Nutrition Examination Survey 2011–2014. Depressive symptoms were assessed using a nine-item Patient Health Questionnaire, and serum 25(OH)D3 and 25(OH)D2 levels were measured using liquid chromatography-tandem mass spectrometry. Linear regression and generalized additive models were applied to evaluate the associations between 25(OH)D3, 25(OH)D2 and depression. Results : A negative association between serum 25(OH)D3 and depressive symptoms was observed in the fully adjusted model. This association was also found among widowed, divorced, separated, and never-married individuals. The association between 25(OH)D2 and depressive symptoms was not statistically significant, but the dose-response analysis revealed an inverted U-shaped relationship between them with an inflection point at 56.2 nmol/L. To the left of the inflection point, we detected a positive association between 25(OH)D2 and depressive symptoms, whereas a negative association was observed to the right of the inflection point. Limitations : The study used a cross-sectional approach, so causation cannot be determined. Conclusions : Our study shows an inverse linear association between serum 25(OH)D3 and depressive symptoms in US females. The association between 25(OH)D2 and depression follows an inverted U-shaped curve with the inflection point at 56.2 nmol/L.
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Vitamin D insufficiency affects almost 50% of the population worldwide. An estimated 1 billion people worldwide, across all ethnicities and age groups, have a vitamin D deficiency (VDD). This pandemic of hypovitaminosis D can mainly be attributed to lifestyle (for example, reduced outdoor activities) and environmental (for example, air pollution) factors that reduce exposure to sunlight, which is required for ultraviolet-B (UVB)-induced vitamin D production in the skin. High prevalence of vitamin D insufficiency is a particularly important public health issue because hypovitaminosis D is an independent risk factor for total mortality in the general population. Current studies suggest that we may need more vitamin D than presently recommended to prevent chronic disease. As the number of people with VDD continues to increase, the importance of this hormone in overall health and the prevention of chronic diseases are at the forefront of research. VDD is very common in all age groups. As few foods contain vitamin D, guidelines recommended supplementation at suggested daily intake and tolerable upper limit levels. It is also suggested to measure the serum 25-hydroxyvitamin D level as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D2 or vitamin D3 is recommended for deficient patients. A meta-analysis published in 2007 showed that vitamin D supplementation was associated with significantly reduced mortality. In this review, we will summarize the mechanisms that are presumed to underlie the relationship between vitamin D and understand its biology and clinical implications.
Article
BACKGROUND: Antifracture efficacy with supplemental vitamin D has been questioned by recent trials. METHODS: We performed a meta-analysis on the efficacy of oral supplemental vitamin D in preventing nonvertebral and hip fractures among older individuals (> or =65 years). We included 12 double-blind randomized controlled trials (RCTs) for nonvertebral fractures (n = 42 279) and 8 RCTs for hip fractures (n = 40 886) comparing oral vitamin D, with or without calcium, with calcium or placebo. To incorporate adherence to treatment, we multiplied the dose by the percentage of adherence to estimate the mean received dose (dose x adherence) for each trial. RESULTS: The pooled relative risk (RR) was 0.86 (95% confidence interval [CI], 0.77-0.96) for prevention of nonvertebral fractures and 0.91 (95% CI, 0.78-1.05) for the prevention of hip fractures, but with significant heterogeneity for both end points. Including all trials, antifracture efficacy increased significantly with a higher dose and higher achieved blood 25-hydroxyvitamin D levels for both end points. Consistently, pooling trials with a higher received dose of more than 400 IU/d resolved heterogeneity. For the higher dose, the pooled RR was 0.80 (95% CI, 0.72-0.89; n = 33 265 subjects from 9 trials) for nonvertebral fractures and 0.82 (95% CI, 0.69-0.97; n = 31 872 subjects from 5 trials) for hip fractures. The higher dose reduced nonvertebral fractures in community-dwelling individuals (-29%) and institutionalized older individuals (-15%), and its effect was independent of additional calcium supplementation. CONCLUSION: Nonvertebral fracture prevention with vitamin D is dose dependent, and a higher dose should reduce fractures by at least 20% for individuals aged 65 years or older.
Article
This article appears in The Journal of Clinical Endocrinology & Metabolism, published December 22, 2010, 10.1210/jc.2010-2230
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25-Hydroxylation of vitamin D2 and D3 was studied in subcellular fractions from human liver, using a technique based on isotope dilution-mass spectrometry. The mitochondrial fraction fortified with isocitrate catalysed 25-hydroxylation of vitamin D3 at a rate of about 10 pmol/mg protein xmin. Under the same conditions, the rate of 25-hydroxylation of vitamin D2 was less than 2 pmol/mg protein × min. Crude microsomes fortified with NADPH catalysed 25-hydroxylation of vitamin D3 to a very low extent, and this activity was not linear with the amount of microsomal protein. A higher rate of conversion was obtained with a partially purified cytochrome P-450 fraction in the presence of NADPH-cytochrome P-450 reductase and NADPH. This fraction also catalysed 25-hydroxylation of 1α-hydroxyvitamin D3 and 5β-cholestane-3α, 7α, 12α-triol. 25-Hydroxylation of vitamin D2 could not be detected, neither with crude microsomes, nor with the microsomal cytochrome P-450 fraction. Since the assay for 25-hydroxyvitamin D2 was less sensitive than that for 25-hydroxyvitamin D3, these experiments do not rule out the presence of some 25-hydroxylase activity towards vitamin D2 in the microsomes. The results are discussed in relation to previous work in which a lower toxicity has been reported for vitamin D2 than for vitamin D3 in some mammalian species.
Article
3-,9- and 15-year-old children were studied in autumn in order to evaluate their serum 25-hydroxy-vitamin D (25-OH-D) concentration and their vitamin D intake. The 25-OH-D was significantly lower in the 15-year-old than in the other children, but it was satisfactory in all groups as compared to the 25-OH-D of healthy, young adults. The mean dietary vitamin D intake as well as the mean total vitamin D intake including supplements was low in all groups of children. With a vitamin D intake as low as in this study, every house-bound child would be at risk of vitamin D deficiency.
Article
The development of chronic kidney disease (CKD) is accompanied by a progressive decrease in the ability to produce 1,25-dihydroxyvitamin D. Pharmacological replacement with active vitamin D therefore has been a cornerstone of secondary hyperparathyroidism therapy in the end-stage renal disease population treated by long-term dialysis. Recent evidence suggests that extrarenal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D may have significant biological roles beyond those traditionally ascribed to vitamin D. Furthermore, low 25-hydroxyvitamin D levels are common in patients with all stages of CKD. This article focuses on the role of nutritional vitamin D replacement in CKD and aims to review vitamin D biology and summarize the existing literature regarding nutritional vitamin D replacement in these populations. Based on the current state of the evidence, we provide suggestions for clinical practice and address areas of uncertainty that need further research.
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Currently, there is a lack of clarity in the literature as to whether there is a definitive difference between the effects of vitamins D2 and D3 in the raising of serum 25-hydroxyvitamin D [25(OH)D]. The objective of this article was to report a systematic review and meta-analysis of randomized controlled trials (RCTs) that have directly compared the effects of vitamin D2 and vitamin D3 on serum 25(OH)D concentrations in humans. The ISI Web of Knowledge (January 1966 to July 2011) database was searched electronically for all relevant studies in adults that directly compared vitamin D3 with vitamin D2. The Cochrane Clinical Trials Registry, International Standard Randomized Controlled Trials Number register, and clinicaltrials.gov were also searched for any unpublished trials. A meta-analysis of RCTs indicated that supplementation with vitamin D3 had a significant and positive effect in the raising of serum 25(OH)D concentrations compared with the effect of vitamin D2 (P = 0.001). When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a bolus dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation. This meta-analysis indicates that vitamin D3 is more efficacious at raising serum 25(OH)D concentrations than is vitamin D2, and thus vitamin D3) could potentially become the preferred choice for supplementation. However, additional research is required to examine the metabolic pathways involved in oral and intramuscular administration of vitamin D and the effects across age, sex, and ethnicity, which this review was unable to verify.
Article
To summarize recommendations from the 2011 US Institute of Medicine report (on vitamin D) and the new guideline from the US Endocrine Society with emphasis on treating and preventing vitamin D deficiency, including patients with inflammatory bowel disease and prior gastric bypass. The US Institute of Medicine Recommended Dietary Allowance of vitamin D is 400 IU per day for children younger than 1 year of age, 600 IU per day for children at least 1 year of age and adults up to 70 years, and 800 IU per day for older adults. The US Institute of Medicine concluded that serum 25-hydroxyvitamin D [25(OH)D] of 20 ng/ml or more will cover the requirements of 97.5% of the population. The US Endocrine Society's Clinical Practice Guideline suggested that 400-1000 IU per day may be needed for children aged less than 1 year, 600-1000 IU per day for children aged 1 year or more, and 1500-2000 IU per day for adults aged 19 years or more to maintain 25(OH)D above the optimal level of 30 ng/ml. Patients with inflammatory bowel disease even in a quiescent state and those with gastric bypass malabsorb vitamin D and need more vitamin D to sustain their vitamin D status. Difference in the recommendations from the US Institute of Medicine and the US Endocrine Society's Practice Guideline reflects different goals and views on current evidence. Significant gaps remain in the literature, and studies of vitamin D treatment assessing changes in outcomes at different 25(OH)D levels are needed.
Article
In recent years, a high prevalence of vitamin D deficiency among children and adolescents has been reported in countries with moderate climates. Those with an immigrant background living under these conditions are at especially high risk. To date, representative data in Germany is lacking. We analyzed 25-hydroxyvitamin D [25(OH)D] concentrations of 10,015 children and adolescents, aged 1-17 y, who participated in the German National Health Interview and Examination Survey for Children and Adolescents. The proportion of immigrants was 25.4%, corresponding well to their percentage of the population. Among 3- to 17-y-old participants, 29% of immigrant boys and 31% of immigrant girls had 25(OH)D concentrations <25 nmol/L (severe to moderate vitamin D deficiency) compared with 18% of nonimmigrant boys and 17% of nonimmigrant girls. Furthermore, 92% of immigrant boys and 94% of immigrant girls had 25(OH)D concentrations <75 nmol/L (levels above 75 nmol/L are defined as optimal regarding various health outcomes) compared with 87% of nonimmigrants. Boys with a Turkish or Arab-Islamic background had an increased risk of having 25(OH)D concentrations <25 nmol/L compared with nonimmigrants (odds ratio [OR] 2.3; [95% CI] 1.4-3.8 and OR 7.6; [95% CI] 3.0-19.1). The same was true for girls with a Turkish (OR 5.2; [95% CI] 2.9-9.6), Arab-Islamic (OR 5.9; [95% CI] 2.5-14.0), Asian (OR 6.7; [95% CI] 2.2-19.8), or African (OR 7.8; [95% CI] 1.5-40.8) background. Supplementation of vitamin D beyond infancy, especially in high-risk groups, or fortification of food should be considered.