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Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III

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Magnesium plays an essential role in the synthesis and metab ABSTRACT: BACKGROUND: Magnesium plays an essential role in the synthesis and metabolism of vitamin D and magnesium supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-dependent vitamin-D-resistant rickets. We hypothesized that dietary magnesium alone, particularly its interaction with vitamin D intake, contributes to serum 25-hydroxyvitamin D (25(OH)D) levels, and the associations between serum 25(OH)D and risk of mortality may be modified by magnesium intake level. We tested these novel hypotheses utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2001 to 2006, a population-based cross-sectional study, and the NHANES III cohort, a population-based cohort study. Serum 25(OH)D was used to define vitamin D status. Mortality outcomes in the NHANES III cohort were determined by using probabilistic linkage with the National Death Index (NDI). High intake of total, dietary or supplemental magnesium was independently associated with significantly reduced risks of vitamin D deficiency and insufficiency respectively. Intake of magnesium significantly interacted with intake of vitamin D in relation to risk of both vitamin D deficiency and insufficiency. Additionally, the inverse association between total magnesium intake and vitamin D insufficiency primarily appeared among populations at high risk of vitamin insufficiency. Furthermore, the associations of serum 25(OH)D with mortality, particularly due to cardiovascular disease (CVD) and colorectal cancer, were modified by magnesium intake, and the inverse associations were primarily present among those with magnesium intake above the median. Our preliminary findings indicate it is possible that magnesium intake alone or its interaction with vitamin D intake may contribute to vitamin D status. The associations between serum 25(OH)D and risk of mortality may be modified by the intake level of magnesium. Future studies, including cohort studies and clinical trials, are necessary to confirm the findings.
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RES E AR C H A R T I C L E Open Access
Magnesium, vitamin D status and mortality:
results from US National Health and Nutrition
Examination Survey (NHANES) 2001 to 2006 and
NHANES III
Xinqing Deng
1
, Yiqing Song
2
, JoAnn E Manson
2,3
, Lisa B Signorello
3
, Shumin M Zhang
2
, Martha J Shrubsole
1
,
Reid M Ness
4
, Douglas L Seidner
4
and Qi Dai
1,5*
Abstract
Background: Magnesium plays an essential role in the synthesis and metabolism of vitamin D and magnesium
supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-
dependent vitamin-D-resistant rickets. We hypothesized that dietary magnesium alone, particularly its interaction
with vitamin D intake, contributes to serum 25-hydroxyvitamin D (25(OH)D) levels, and the associations between
serum 25(OH)D and risk of mortality may be modified by magnesium intake level.
Methods: We tested these novel hypotheses utilizing data from the National Health and Nutrition Examination
Survey (NHANES) 2001 to 2006, a population-based cross-sectional study, and the NHANES III cohort, a population-
based cohort study. Serum 25(OH)D was used to define vitamin D status. Mortality outcomes in the NHANES III
cohort were determined by using probabilistic linkage with the National Death Index (NDI).
Results: High intake of total, dietary or supplemental magnesium was independently associated with significantly
reduced risks of vitamin D deficiency and insufficiency respectively. Intake of magnesium significantly interacted
with intake of vitamin D in relation to risk of both vitamin D deficiency and insufficiency. Additionally, the inverse
association between total magnesium intake and vitamin D insufficiency primarily appeared among populations at
high risk of vitamin D insufficiency. Furthermore, the associations of serum 25(OH)D with mortality, particularly due
to cardiovascular disease (CVD) and colorectal cancer, were modified by magnesium intake, and the inverse
associations were primarily present among those with magnesium intake above the median.
Conclusions: Our preliminary findings indicate it is possible that magnesium intake alone or its interaction with
vitamin D intake may contribute to vitamin D status. The associations between serum 25(OH)D and risk of mortality
may be modified by the intake level of magnesium. Future studies, including cohort studies and clinical trials, are
necessary to confirm the findings.
Keywords: Magnesium intake, Serum 25-hydroxyvitamin D levels, Vitamin D insufficiency, Vitamin D deficiency,
Parathyroid hormone, Mortality, Colorectal cancer, Cardiovascular diseases
* Correspondence: qi.dai@vanderbilt.edu
1
Department of Medicine, Division of Epidemiology, Vanderbilt University
School of Medicine, Nashville, TN 37203, USA
5
Institute for Medicine and Public Health, Vanderbilt University Medical
Center, Nashville, TN 37203, USA
Full list of author information is available at the end of the article
© 2013 Deng et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Deng et al. BMC Medicine 2013, 11:187
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Background
Vitamin D deficiency cause s rickets among children and
osteomalacia in adults [1]. Many epidemiologic studies
suggest that low vitamin D status may also be associated
with risk of non-skeletal chronic diseases, such as, all-
cause mortality [2-4], type 2 diabetes [5-7], cardiovascu-
lar diseases (CVD) [8,9], and colorectal cancer [10-12].
However, findings have not been entirely consistent
[13-16]. Large-scale clinical trials of vitamin D supple-
mentation are ongoing [13,14,17]. Despite food fortifica-
tion and dietary supplementation, some studies have
observed that low vitamin D status is still relativ ely
common in the US [18] while a large portion of the
interperson variation in serum 25-hydroxyvitamin D
(25(OH)D) levels is unexplained [19,20].
Magnesium, the second most abundant intracellular
cation, plays a critical role in the synthesis and metabo-
lism of parathyroid hormone (PTH) and vitamin D
[21-23]. Previous studies have shown that the activities
of three major enzymes determining 25(OH)D level
[22-25] and vitamin D binding protein [23] are magne-
sium dependent (Figure 1). Magnesium deficien cy,
which leads to reduced 1,25(OH)
2
vitamin D and im-
paired PTH response [23], has been implicated in mag-
nesium-dependent vitamin-D-resistant rickets [21].
Magnesium supplementation substantially reversed the
resistance to vitamin D treatment [21]. Interestingly, a
study conduc ted among osteoporosis patients showed
much higher prevalence rates of magnesium deficiency
or insufficiency among people with insufficient 25(OH)D
than those with sufficie nt 25(OH)D [26]. Two small
clinical trials of magnesium-deficient patients [23,27]
found that magn esium infusion alone led to a non-
significant increase in 1,25(OH)
2
D and 25(OH)D [23]
whereas magnesium infusion plus oral vitamin D
substantially increased both serum 25(OH)D and 1,25
(OH)
2
D [27]. These findings suggest a potential inter-
action between vitamin D and magnesium treatments
Sunlight/Skin Synthesis
Dietary Sources
Vitamin D
3
/D
2
7-dehydrocholesterol
Previtamin D
3
Vitamin D
3
Natural sources:
UV exposed mushroom (Vitamin D
2
)
Fatty fish (Vitamin D
3
)
Supplements
Fortified foods
(Vitamin D
3
)
Binding to VDBP Non-VDBP carriers
Vitamin
D
3
/D
2
25(OH)D
25 - hydroxylase
25(OH)D
24, 25(OH)
2
D 1, 25(OH)
2
D
1, 24, 25(OH)
3
D
1-α hydroxylase
24 hydroxylase
24 hydroxylase
Slowly and
stable
Swiftly but not
sustained
Circulating 25(OH)D
Binding to VDBP
Liver
Kidney
Mg
Mg
UVB
radiation
1-α hydroxylase
Temperature
Mg
Mg
Mg
PTH synthesis
and secretion
Mg
Mg
Mg
Figure 1 Magnesium and metabolism of vitamin D. PTH, parathyroid hormone; UVB, ultraviolet B; VDBP, vitamin D binding protein.
Deng et al. BMC Medicine 2013, 11:187 Page 2 of 14
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and a possible moderate effect of magnesium on 25(OH)
D status.
We hypothesize that magnesium intake alone and par-
ticularly its interaction with vitamin D intake contribute
to serum 25(OH)D status and tested this novel hypothesis
utilizing data from the National Health and Nutrition
Examination Survey (NHANES) 2001 to 2006. Further-
more, previous studies reported that serum 25(OHD) con-
centrations were associated with reduced risks of total
mortality, particularly mortality due to colorectal cancer
[28] and CVD [4,29]. We hypothesize that the inverse as-
sociations between serum 25(OH)D and risk of mortality
are modified by intake level of magnesium and tested this
hypothesis using the NHANES III cohort.
Methods
Participants
The 2001 to 2006 NHANES and the NHANES III were
reviewed and approved by the National Center for
Health Statistics (NCHS) Institutional Review Board
(IRB) (Hyattsville, MD, USA). A detailed description of
the study design has been published elsewhere [30,31].
To investigate if dietary magnesium alone and its inter-
action with vitamin D intake contribute to serum 25
(OH)D levels, we utilized data from the NHANE S 2001
to 2006, which was conducted during years 2001 to 2006
by the NCHS of the Centers for Disease Control and
Prevention (CDC) (Atlanta, GA, USA). This is a nation-
ally representative and recent sample among the civilian,
non-institutionalized US population. Thus, the status of
serum 25(OH)D represents the current vitamin D status
of US population. Furthermore, serum PTH data are
available only in the NHANES conducted during 2003
to 2006. We limited our study population to 12257 par-
ticipants aged 20 years with serum 25(OH)D, reliable
dietary data, and negative for pregnancy test. However,
no follow-up of mortality outcomes were conducted for
NH ANES 2001 to 2006. The mortality outcomes have
been prospectively followed in the NHANES III cohort
for which baseline data and blood collection were
conducted during 1988 to 1994 among a nationally
representative sample of US adults. Included in the
NH ANES III cohort were those aged 17 years with 25
(OH)D measurements (n = 16819). The participants
were followed for mortality status from baseline until
December 31, 2006. Thus, we used the NHANES III
cohort to examine the modifying effects of magnesium
intake on the associations between serum 25(OH)D and
risk of mortality. Although the NHANES III cohort is
suitable for the investigation of the associations between
serum 25(OH)D and mortality outcomes, no serum
PTH data are available. NHANES III was approved by
the National Center for Health Statistics (NCHS) Insti-
tutional Review Board (IRB) an d documented consent
was obtained from participants. The NCHS IRB (before
2003)/and the NCHS Research Ethics Review Boar d
(ERB) (year 2003 and after) approved the NHANES
2001 to 2006 (protocol #98-12 for the NHANES 2001 to
2004 and protocol #2005-06 for the NHANES 2005 to
2006).
Blood sample collection and measures of serum 25(OH)D
Over 88% of the 2001 to 2006 NHANES participants
and about 90% of the NH ANES III participants donated
a spot blood sample. Measurements of serum 25(OH)D
were performed at the NCH, CDC, Atlanta, GA using a
radioimmunoassay (RIA) kit (Diasorin Inc., Stillwater
MN, USA) [32] and the coefficients of variations (CV)
were 13% to 19% in the NHANES III and 10% to 13% in
the NHANES 2001 to 2006 [29]. Serum PTH concentra-
tions were measured using the ECL/Origen electroche-
miluminescent process (Elecsys 1010 system, Roche
Diagnostics, Indianapolis, IN, USA) and CV was less
than 10%. Data were available only for the NHANES
2003 to 2006.
Outcomes
We have utilized the cut-off points as defined in the re-
cently issued Institute of Medicine (IOM) report to de-
fine vitamin D deficiency and insufficiency [33]. We
classified the participants in the NHANES 2001 to 2006
into the following three categories: (1) participants who
had IOM recommended vitamin D level (serum 25(OH)
D 20 ng/ml (50 nmol/l)); (2) participants who had
insufficient vitamin D (serum 25(OH)D 12 ng/ml
(30 nmol/l) but below 20 ng/ml (50 nmol/l)); and (3)
participants who had vitamin D deficiency (serum 25
(OH)D <12 ng/ml (30 nmol/l)). In addition to Institute
of Medicines recommendation, the other reason we
used 20 ng/ml as the cut-off point is that the median
value of serum 25(OH)D for the NHANES 2001 to 2006
was 21.0 ng/mg, which is very close to 20 ng/ml.
In the NHANES III cohort, mortality outcomes were
determined by using probabilistic linkage with the Na-
tional Death Index (NDI). For mortality due to CVD or
colorectal cancer, participants who died of other diseases
or were not known deceased, were censored at the date
of death or December 31, 2006, whichever was earlier.
Nutrient intake assessments
Daily dietary intake data were obtained from 24-h diet-
ary recalls and 30-day supplement interviews, which are
described in detail elsewhere [34]. Only one 24-h recall
was conducted in NHANES III and from 2001 to 2002.
To keep intake information consistent through the study
period only the first dietary recall for all subjects was
utilized in the present analysis. Only dietary recall data
with a status of reliable were used in the analysis.
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Supplemental doses and intakes of magnesium, vitamin
D, and calcium were obtained from the response to a
dietary supplement questionnaire.
Statistical analysis
We performed statistical analyses using PROC Survey in
SAS 9.2 software (SAS Institute, Cary, NC, USA) to esti-
mate variance after incorporating the weights for the
sample popula tion in NHANES.
Covariates were compared among three groups with
differing vitamin D status (Table 1). Any covariate that
significantly differed among groups was considered as a
potential confounding factor. In particular, those con-
founders that altered the estimate of association by 10% or
more were retained in the final models (see footnotes to
Tables 2 and 3). Other factors, such as use of phosphorus,
potassium, and retinol, did not materially alter the risk es-
timates. Multivariate adjusted odds ratios (ORs) and 95%
confidence intervals (CIs) for vitamin D deficiency and in-
sufficiency were calculated. Stratified analyses by potential
effect modifiers and tests for multiplicative interactions
using the Wald test were conducted.
Hazard ratios (HR) were estimated in Cox propor-
tional hazard regression models to examine whether the
associations between serum 25(OH)D and risk of mor-
tality differed by intake level of total magnesium, using
the data from the NHANES III cohort. The same cut-off
points for serum 25(OH)D were used as those in the
published report [28]. We adjusted for the same
confounding factors as we did for vitamin D deficiency
and insufficiency analyses. All reported P values were
two-sided. P values of <0.05 were considered statistically
significant in all analyses.
In Table 4, we present the associations between serum
25(OH)D and risk of mortality within two strata (<2 64
mg/day and 264 mg/day) of magnesium intake. How-
ever, this is only for data presen tation purpose. In statis-
tical modeling, we have used continuous variables for
both serum 25(OH)D and intakes of magnesium in the
tests for interactions between serum 25(OH)D and in-
takes of magnesium in relation to total mortality, mor-
tality due to cardiovascular disease and mor tality due to
colorectal cancer. We chose 264 mg/day as the cut-off
point presented in Table 4 based on both statistical
power consideration and biological support. We have a
limited sample size for colorectal cancer mortality
outcome. By using a median magnesium intake of 264
mg/day, we could maximize the sample size, and, thus,
the power to detect association between vitamin D levels
and mortality outcomes in both strata. Furthermore, 264
mg/day is very close to the 265 mg/day, the estimated
average requirement s (EAR) for women and so it gave
us the opportunity to evaluate the relationship to the
EAR [35].
Results
Selected demographic characteristics and potential
confounding factors by the three categories of serum 25
(OH)D status are shown in Table 1. Compared to the
Estimate Average Requirements (EAR, intake levels for
vitamin D (400 IU/day) and magnesium (330 mg/day)
recommended by the US Food and Nutrition Board of
the Institute of Medicine), the vitamin D normal group
generally met the recommended intake levels for both
vitamin D and magnesium whereas the average intake
levels of these nutrients were significantly lower in the
vitamin D-insufficient group and much lower among the
vitamin D-deficient group.
After adjusting for confounding factors, the ORs (95%
CI) for vitamin D deficiency and insufficiency were 0.10
(0.06 to 0.17) and 0.37 (0.27 to 0.51) comparing the
highest quartile intake of total vitamin D versus the low-
est (P
trend
<0.001) (Table 2). The corresponding ORs
(95% CI) were 0.34 (0.21 to 0.56) and 0.62 (0.46 to 0.82)
for total magnesium intake (P
trend
<0.001), respectively.
In addition, we found that both dietary and supplemen-
tal intakes of vitamin D and magnesium were signifi-
cantly inversely associated with risks of vitamin D
deficiency and insufficiency.
In stratif ied analyses by intake of vitamin D and other
factors related to vitamin D status (Table 3), we found
intake of magnesium significantly interacted with intake
of vitamin D in relation to both vitamin D deficiency
(P
interaction
, <0.001) and insufficiency (P
interaction
, <0.001).
The inverse association between magnesium intake and
risk of vitamin D deficiency only appeared significant
among those older than 50 years or with serum PTH
level being in the highest or lowest tertile category.
Meanwhile, the inverse associations between magnesium
intake and risk of vitamin D insufficiency were statisti-
cally significant only among people at high risk of
vitamin D insufficiency, such as those whose samples
were collected during winter (at southern latitude), those
with vitamin D intake below the median, women, non-
Hispanic Blacks, obese individuals or those with the
PTH levels in the highest tertile.
As reported previously, high levels of serum 25(OH)D
were associated with a reduced risk of mortality due to
all-cause CVD [4,29,36], and colorectal cancer [28]. We
found that the inverse associations for higher serum 25
(OH)D with risks of total mortality and mortality due to
CVD were only statistically significant among those with
magnesium intake above the median (Table 4). Although
the test for interaction was not statistically significant
for total mortality, it was statistically significant for mor-
tality due to CVD (P
interaction
, 0.03). Sample size was
small for mortality due to colorectal cancer. None of the
associations, including the main association, were statis-
tically significant. However, the association pattern in
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Table 1 Selected characteristics of the study participants by serum 25(OH)D levels, National Health and Nutrition
Examination Survey (NHANES) 2001 to 2006
Characters
a
Normal, n = 6962 Insufficiency, n = 3620 Deficiency, n = 1575 P value
b
Serum 25(OH)D (ng/ml), mean (SE) 28.5 (0.2) 16.1 (0.2) 8.8 (0.1) <0.001
Age (years), mean (SE) 47.0 (0.4) 46.7 (0.4) 46.2 (0.6) <0.001
Male, n (%) 3711 (51.2) 1833 (47.7) 696 (38.4) <0.001
Body mass index (kg/m
2
), mean (SE) 27.3 (0.1) 29.6 (0.2) 31.5 (0.4) <0.001
Month of blood collection, n (%)
1 November to 30 April (winter) 2,688 (34.4) 1,980 (50.7) 999 (57.6) <0.001
1 May to 31 October (summer) 4,274 (65.6) 1,640 (49.3) 676 (42.4)
Education, n (%)
Less than high school 1,694 (14.8) 1,194 (21.8) 621 (28.5) <0.001
High school 1,729 (25.3) 872 (26.3) 384 (25.4)
Greater than high school 3,535 (59.9) 1,550 (51.9) 667 (46.1)
Race/ethnicity, n (%)
Non-Hispanic Caucasian 4,812 (84.5) 1,390 (59.5) 316 (33.9) <0.001
Non-Hispanic Black 558 (3.5) 965 (17.0) 906 (44.8)
Hispanic 1,394 (8.6) 1,091 (16.5) 394 (14.1)
Others 198 (3.4) 174 (7.1) 59 (7.1)
Family poverty income ratio, n (%)
<1 929 (9.7) 661 (15.6) 358 (20.0) <0.001
1 to 4 4,181 (61.5) 2,230 (63.6) 1,031 (65.7)
5 1,507 (28.8) 516 (20.8) 181 (14.3)
Smoker, n (%)
Non-smoker 3,407 (49.5) 1,856 (50.0) 869 (50.0) <0.001
Former smoker 1,914 (24.8) 833 (21.0) 303 (16.3)
Current smoker 1,637 (25.7) 926 (29.0) 500 (33.8)
Alcohol user, n (%)
Non-drinker 784 (15.0) 555 (21.5) 293 (24.2) <0.001
Former drinker 559 (10.3) 382 (14.3) 187 (14.1)
Current drinker 3,139 (74.8) 1,452 (64.2) 639 (61.7)
Physical activity during the day, n (%)
Sit and not walk about very much 1,512 (21.2) 960 (27.0) 541 (32.9) <0.001
Walk a lot 3,584 (50.4) 1,904 (50.5) 857 (49.2)
Light work 1,276 (20.5) 497 (15.2) 202 (13.9)
Heavy work 582 (8.0) 254 (7.3) 73 (4.0)
Leisure time physical activity
(Metabolic equivalent/h/week), mean (SE)
1,292.4 (52.2) 788.5 (55.6) 674.2 (53.1) <0.001
Users of supplement containing vitamin D (%) 3,258 (47.2) 1,018 (30.4) 202 (12.5) <0.001
Users of supplement containing Ca (%) 3,860 (57.1) 1,380 (42.6) 351 (22.3) <0.001
Users of supplement containing Mg (%) 3,040 (45.1) 1,072 (32.0) 235 (14.9) <0.001
Energy-adjusted nutrient intakes
c
, mean (SE)
Protein (g/day) 82.0 (0.5) 80.1 (0.7) 77.8 (1.3) <0.01
Carbohydrate (g/day) 258.5 (1.4) 262.4 (1.7) 261.6 (2.9) 0.135
Fat (g/day) 80.7 (0.5) 80.3 (0.6) 81.2 (0.9) 0.93
Calcium (mg/day) 929.0 (8.4) 805.2 (9.1) 690.3 (13.6) <0.001
Magnesium (mg/day) 293.1 (2.2) 266.6 (2.9) 252.4 (4.2) <0.001
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stratified analysis (P
interaction
, 0.15) was very similar to
that for total mortality and mortality due to CVD.
Discussion
Consistent with our hypothesis, we observed that high
intake of total, dietary or supplemental magnesium was
independently and significantly associated with reduced
risks of both vitamin D deficiency and insufficiency. Fur-
thermore, intake of magnesium significantly interacted
with intakes of vitamin D in relation to both vitamin D
deficiency and insufficiency. In the NHANES III cohort,
a population-based prospective study, we found the in-
verse associations of serum 25(OH)D with mortality,
particularly mortality due to CVD and colorectal cancer,
were modified by magnesium intake, and the inverse as-
sociations were primari ly present among those with
magnesium intake above the median. In addition, we
found the inverse association between magnesium intake
and risk of vitamin D deficiency primarily occurred in
those who had the highest or the lowest tertile of PTH
level; while the inverse association between total magne-
sium intake and vitamin D insufficiency primarily
appeared among populations at high risk of vitamin D
insufficiency. To the best of our knowledge, this is the
first study to examine the interaction between vitamin D
and magnesium in association to mortality; and this is
the first study to suggest a potential independent contri-
bution of total magnesium intake and its interaction
with vitamin D intake to vitamin D status in the general
population.
Under normal physiologic conditions, 25(OH)D is de-
rived primarily from endogenous synthesis via exposure
of skin to sunlight because few natural foods contain
vitamin D except by fortification or supplementation
(see Figure 1). Vitamin D
3
or D
2
is transferred to the
liver via vitamin D binding protein (VDBP) and
converted to 25(OH)D by 25-hydroxylase and subse-
quently carried to the kidney by VDBP and converted to
1,25(OH)
2
Dby1α-hydroxylase enzyme. Both 25(OH)D
and 1,25(OH)
2
D can be converted by 24-hydroxylase to
the 24,25(OH)
2
D or 1,24,25(OH)
3
D, respectively [37].
Therefore, 25(OH)D levels are primarily determined by
VDBP, 25-hydroxylase, 1α-hydroxylase and 24-hydroxy-
lase activity, a fact that has recently been substantiated
by a genome-wide association study [38]. Based on pre-
vious in vitro studies, magnesium status regulates both
1α-hydroxylase and 24-hydroxylase activity [22,24].
Previous studies indicated both VDBP [23] and 25-
hydroxylase [25,39] might also be magnesium depen-
dent. Therefore, magnesium would be expected to play
an important role in 25(OH)D metabolism.
A previous clinical study found that parenteral magne-
sium treatment without vitamin D replacement in 23
magnesium-deficient patients led to a 12% rise in 25
(OH)D and 30% increase in 1,25(OH)
2
D, but both
changes were not statistically significant [23]. In a subse-
quent study of five magnesium-deficient patients, intra-
muscular treatment with magnesium alone also did not
significantly increase 25(OH)D, but magn esium infusion
together with pharmacological dose of 25(OH)D sub-
stantially increased both 25(OH)D and 1,25(OH)
2
D
among patients with magnesium deficiency. One inter-
pretation is that magnesium treatment does not affect
25(OH)D status [23,27]. However, we postulate that
several factors may have contributed to the insignificant
increase in 25(OH)D status. First, the subjects participat-
ing in these studies had low concentrations of 25(OH)D
and 1,25(OH)
2
Daswellaspre-vitaminD
3
and vitamin D
3
as a result of limited sunlight exposure, underlying disease
and/or lack of oral supplementation. Therefore, concen-
trations of 25(OH)D and 1,25(OH)
2
D did not substantially
increase during short-term magnesium repletion because
pre-vitamin D3 was not available in sufficient amounts.
Second, there was a modest increase in the conversion of
25(OH)D to 1,25(OH)
2
D and, thus, a reduction in 25(OH)
D level was expected due to this conversion [22]. Finally,
the sample size in these two studies was very small par-
ticularly if the direct effect of magnesium treatment on
vitamin D status is only moderate.
We found that high magnesium intake was also associ-
ated with a reduced risk of vitamin D deficiency or in-
sufficiency. We believe that this observation is the result
of the interaction between various metabolic pathways
that regulate 25(OH)D levels. Previous studies have
shown that endogenously synthesized vitamin D
3
is
transferred almost completely by VDBP to liver and this
Table 1 Selected characteristics of the study participants by serum 25(OH)D levels, National Health and Nutrition
Examination Survey (NHANES) 2001 to 2006 (Continued)
Vitamin D (IU/day) 196 (8.0) 160 (8.0) 116 (8.0) <0.001
Total calcium (mg/day)
d
1,168.8 (12.6) 935.4 (12.3) 748.5 (15.9) <0.001
Total magnesium (mg/day)
d
344.2 (3.5) 297.3 (3.2) 262.4 (4.4) <0.001
Total vitamin D (IU/day)
d
376 (8.0) 276 (8.0) 152 (8.0) <0.001
a
Values are present as weighted means (SE) and unweighted frequencies (weighted percentages, %).
b
Rao-Scott χ
2
test for categorical data and analysis of variance (ANOVA) test for continuous variables.
c
Values are energy-adjusted means (SE).
d
Total calcium, magnesium and vitamin D intake from foods and supplements.
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Table 2 Multivariate-adjusted odds ratios (95% CIs)
a
for associations between total intakes of vitamin D and
magnesium and risk of vitamin D deficiency and insufficiency, National Health and Nutrition Examination Survey
(NHANES) 2001 to 2006
Nutrient intakes Controls,
N
Deficiency Insufficiency
N OR (95% CI) N OR (95% CI)
Total vitamin D intake (IU/day)
Q1 <114 1,741 1,005 1.00 1,450 1.00
Q2 114 to 307 1,740 446 0.55 (0.40 to 0.75) 1,086 0.75 (0.62 to 0.91)
Q3 308 to 539 1,741 152 0.22 (0.15 to 0.34) 665 0.55 (0.44 to 0.69)
Q4 540 1,740 72 0.10 (0.06 to 0.17) 419 0.37 (0.27 to 0.51)
P for trend <0.001 <0.001
Dietary vitamin D intake (IU/day)
Q1 <57.8 1,741 764 1.00 1,183 1.00
Q2 57.8 to 137 1,740 468 0.71 (0.55 to 0.91) 997 0.86 (0.71 to 1.05)
Q3 138 to 261 1,741 279 0.54 (0.40 to 0.72) 807 0.72 (0.59 to 0.88)
Q4 262 1,740 164 0.29 (0.20 to 0.41) 633 0.69 (0.56 to 0.86)
P for trend <0.001 <0.001
Supplemental vitamin D intake (IU/day)
Non-user 3,704 1,473 1.00 2,602 1.00
1 to 239 809 93 0.32 (0.20 to 0.50) 377 0.84 (0.68 to 1.03)
240 to 399 331 19 0.29 (0.13 to 0.64) 109 0.57 (0.38 to 0.87)
400 2,118 90 0.19 (0.11 to 0.33) 532 0.40 (0.29 to 0.53)
P for trend <0.001 <0.001
Total magnesium intake (mg/day)
Q1 <225 1,749 876 1.00 1,362 1.00
Q2 225 to 310 1,733 392 0.67 (0.50 to 0.90) 907 0.78 (0.61 to 1.00)
Q3 311 to 419 1,737 245 0.43 (0.30 to 0.63) 758 0.73 (0.59 to 0.89)
Q4 420 1,743 162 0.34 (0.21 to 0.56) 593 0.62 (0.46 to 0.82)
P for trend <0.001 <0.001
Dietary magnesium intake (mg/day)
Q1 <195 1,754 726 1.00 1,255 1.00
Q2 195 to 268 1,732 432 0.75 (0.58 to 0.97) 893 0.75 (0.62 to 0.90)
Q3 269 to 363 1,741 297 0.68 (0.47 to 0.99) 777 0.69 (0.55 to 0.87)
Q4 364 1,735 220 0.43 (0.26 to 0.70) 695 0.61 (0.45 to 0.83)
P for trend 0.002 0.002
Supplemental magnesium intake (mg/day)
Non-user 3,922 1,440 1.00 2,548 1.00
1 to 49 669 109 0.53 (0.34 to 0.81) 334 1.14 (0.91 to 1.43)
50 to 99 506 43 0.35 (0.17 to 0.71) 205 0.80 (0.53 to 1.22)
100 1,865 83 0.30 (0.17 to 0.52) 533 0.68 (0.52 to 0.88)
P for trend <0.001 0.008
a
Survey logistic regression models used to estimate odds ratios and 95% confidence intervals. Models adjusted for age, sex, body mass index (BMI), educational
attainment, race, household income, smoking status, alcohol use, physical activity, month of blood collection, dietary intakes of total energy and total calcium
intake. Models were also adjusted for total intake of vitamin D or magnesium mutually.
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Table 3 Odds ratios (95% CI)
a
for vitamin D deficiency and insufficiency stratified by the median of vitamin D intake or
season, National Health and Nutrition Examination Survey (NHANES) 2001 to 2006
Magnesium intake, mg/day Controls,
N
Deficiency Insufficiency
N OR (95% CI) N OR (95% CI)
Vitamin D intake <308 (IU/day)
Q1 <225 1,359 834 1.00 1,218 1.00
Q2 225 to 310 940 328 0.79 (0.58 to 1.07) 650 0.89 (0.69 to 1.15)
Q3 311 to 419 697 184 0.64 (0.46 to 0.91) 426 0.78 (0.63 to 1.08)
Q4 420 485 105 0.58 (0.35 to 0.97) 242 0.71 (0.47 to 1.07)
P for trend 0.01 <0.05
Vitamin D intake 308 (IU/day)
Q1 <225 390 42 1.00 144 1.00
Q2 225 to 310 793 64 1.09 (0.47 to 2.55) 257 0.94 (0.62 to 1.42)
Q3 311 to 419 1,040 61 0.76 (0.30 to 1.88) 332 1.19 (0.80 to 1.77)
Q4 420 1,258 57 0.71 (0.24 to 2.11) 351 0.96 (0.60 to 1.55)
P for trend 0.97 0.67
P for interaction <0.001 <0.001
Non-vitamin D supplement user
Q1 <225 1,292 812 1.00 1,160 1.00
Q2 225 to 310 958 332 0.81 (0.57 to 1.14) 651 0.91 (0.70 to 1.18)
Q3 311 to 419 793 205 0.59 (0.40 to 0.88) 462 0.80 (0.63 to 1.02)
Q4 420 661 124 0.60 (0.35 to 1.00) 329 0.81 (0.55 to 1.19)
P for trend 0.02 0.18
Vitamin D supplement user
Q1 <225 457 64 1.00 202 1.00
Q2 225 to 310 775 60 1.23 (0.59 to 2.56) 256 0.80 (0.53 to 1.20)
Q3 311 to 419 944 40 1.05 (0.41 to 1.68) 296 0.96 (0.65 to 1.41)
Q4 420 1,082 38 0.91 (0.35 to 2.36) 264 0.73 (0.49 to 1.10)
P for trend 0.56 0.40
P for interaction 0.47 0.37
Winter and Southern latitude
Q1 <225 664 493 1.00 726 1.00
Q2 225 to 310 691 239 0.63 (0.47 to 0.85) 495 0.73 (0.57 to 0.92)
Q3 311 to 419 653 156 0.49 (0.30 to 0.78) 422 0.89 (0.74 to 1.07)
Q4 420 680 111 0.54 (0.28 to 1.02) 337 0.57 (0.41 to 0.78)
P for trend 0.03 <0.01
Summer and Northern latitude
Q1 <225 1,085 383 1.00 636 1.00
Q2 225 to 310 1,042 153 0.95 (0.64 to 1.41) 412 0.91 (0.66 to 1.26)
Q3 311 to 419 1,084 89 0.61 (0.43 to 0.86) 336 0.73 (0.56 to 0.96)
Q4 420 1,063 51 0.33 (0.20 to 0.55) 256 0.85 (0.61 to 1.19)
P for trend 0.001 0.35
P for interaction 0.55 0.21
Age <50 (years)
Q1 <225 862 465 1.00 726 1.00
Q2 225 to 310 821 209 0.74 (0.49 to 1.11) 495 0.83 (0.60 to 1.16)
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Table 3 Odds ratios (95% CI)
a
for vitamin D deficiency and insufficiency stratified by the median of vitamin D intake or
season, National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 (Continued)
Q3 311 to 419 831 150 0.63 (0.35 to 1.13) 422 0.84 (0.62 to 1.13)
Q4 420 892 110 0.67 (0.32 to 1.42) 337 0.73 (0.50 to 1.08)
P for trend 0.26 0.15
Age 50 (years)
Q1 <225 1,085 383 1.00 636 1.00
Q2 225 to 310 1,042 153 0.85 (0.50 to 1.37) 412 0.86 (0.63 to 1.16)
Q3 311 to 419 1,084 89 0.43 (0.24 to 0.77) 336 0.79 (0.57 to 1.10)
Q4 420 1,063 51 0.24 (0.11 to 0.49) 256 0.71 (0.46 to 1.10)
P for trend <0.01 0.81
P for interaction 0.07 0.41
Male
Q1 <225 712 283 1.00 519 1.00
Q2 225 to 310 854 164 0.64 (0.41 to 1.00) 466 1.12 (0.78 to 1.61)
Q3 311 to 419 995 143 0.39 (0.21 to 0.74) 439 0.90 (0.65 to 1.26)
Q4 420 1,150 106 0.33 (0.16 to 0.69) 409 0.95 (0.59 to 1.52)
P for trend 0.001 0.54
Female
Q1 <225 1,037 593 1.00 843 1.00
Q2 225 to 310 879 228 0.85 (0.61 to 1.21) 441 0.71 (0.54 to 0.93)
Q3 311 to 419 742 102 0.63 (0.37 to 1.05) 319 0.83 (0.64 to 1.07)
Q4 420 593 56 0.47 (0.25 to 0.87) 184 0.60 (0.43 to 0.82)
P for trend 0.16 0.14
P for interaction 0.11 0.17
Non-Hispanic Black
Q1 <225 181 530 1.00 442 1.00
Q2 225 to 310 163 181 0.51 (0.34 to 0.76) 229 0.74 (0.53 to 1.03)
Q3 311 to 419 110 115 0.44 (0.26 to 0.74) 175 0.53 (0.33 to 0.88)
Q4 420 104 81 0.43 (0.27 to 0.68) 119 0.64 (0.39 to 1.04)
P for trend <0.001 <0.05
Non-Hispanic Caucasian and others
Q1 <225 1,568 346 1.00 920 1.00
Q2 225 to 310 1,570 212 0.91 (0.65 to 1.28) 678 0.86 (0.67 to 1.10)
Q3 311 to 419 1,627 130 0.66 (0.45 to 0.97) 583 0.87 (0.67 to 1.10)
Q4 420 1,639 81 0.52 (0.29 to 0.95) 474 0.76 (0.58 to 0.99)
P for trend <0.05 0.27
P for interaction 0.305 0.82
BMI <25 (kg/m
2
)
Q1 <225 631 172 1.00 336 1.00
Q2 225 to 310 611 90 1.04 (0.51 to 2.12) 339 0.92 (0.61 to 1.40)
Q3 311 to 419 606 58 0.84 (0.40 to 1.76) 189 1.00 (0.70 to 1.44)
Q4 420 608 41 0.51 (0.23 to 1.15) 162 0.77 (0.47 to 1.27)
P for trend 0.13 0.45
BMI 25 to <30 (kg/m
2
)
Q1 <225 605 232 1.00 448 1.00
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transport is slow, leading to a more sustained plasma
vitamin D
3,
compared to that from supplementation of
vitamin D, which is delivered to the liver by non-VDBP
carriers in the plasma [40]. VDBP may also be an im-
portant determinant of serum 25(OH)D concentration,
particularly when dietary intake of vitamin D is low. In
the study by Rude et al., the concentration of VDBP was
lower among 11 magnesium-deficient patients and
significantly increased to normal after magnesium treat-
ment without vitamin D supplementation [23]. There-
fore, it is possible that an improvement in magnesium
status leads to an increase in VDBP synthesis and, in
turn, an elevated transport of vitamin D
3
to the liver and
25(OH)D to the kidney.
The critical roles of magnesium in the synthesis of
VDBP, PTH, 25(OH)D and 1,25(OH)
2
D may partially ex-
plain why the inverse associations between serum 25
(OH)D and risk of total mortality and mortality due to
colorectal cancer and CVD primarily existed among
those with magnesium intake above the median. High
magnesium may increase the availability of 1,25 (OH)2D
through activating the synthesis of 25(OH)D and 1,25
(OH)2D and increasing the transfer to target tissues by
elevating vitamin D binding protein (VDBP) (Figure 1).
Table 3 Odds ratios (95% CI)
a
for vitamin D deficiency and insufficiency stratified by the median of vitamin D intake or
season, National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 (Continued)
Q2 225 to 310 632 106 0.71 (0.43 to 1.15) 316 0.77 (0.51 to 1.17)
Q3 311 to 419 661 75 0.50 (0.29 to 0.86) 266 0.63 (0.50 to 0.79)
Q4 420 677 46 0.47 (0.22 to 1.01) 213 0.73 (0.48 to 1.13)
P for trend 0.02 0.06
BMI 30 (kg/m
2
)
Q1 <225 463 440 1.00 532 1.00
Q2 225 to 310 457 177 0.63 (0.35 to 1.14) 341 0.82 (0.63 to 1.06)
Q3 311 to 419 441 108 0.46 (0.24 to 0.88) 288 0.83 (0.59 to 1.15)
Q4 420 424 69 0.42 (0.19 to 0.96) 202 0.63 (0.44 to 0.91)
P for trend 0.02 0.02
P for interaction 0.23 0.13
PTH <32 (pg/ml)
Q1 <225 322 63 1.00 179 1.00
Q2 225 to 310 369 39 0.42 (0.18 to 1.02) 109 0.72 (0.42 to 1.24)
Q3 311 to 419 363 21 0.17 (0.07 to 0.43) 107 0.77 (0.47 to 1.28)
Q4 420 392 19 0.22 (0.07 to 0.73) 100 0.74 (0.38 to 1.42)
P for trend <0.01 0.46
PTH 32 to <46 (pg/ml)
Q1 <225 378 136 1.00 271 1.00
Q2 225 to 310 382 66 1.20 (0.66 to 2.21) 195 0.94 (0.73 to 1.22)
Q3 311 to 419 406 54 1.19 (0.53 to 2.66) 181 0.85 (0.59 to 1.23)
Q4 420 414 33 1.11 (0.36 to 3.42) 131 0.79 (0.55 to 1.15)
P for trend 0.85 0.24
PTH 46 (pg/ml)
Q1 <225 390 375 1.00 447 1.00
Q2 225 to 310 382 157 0.73 (0.48 to 1.10) 297 0.93 (0.68 to 1.28)
Q3 311 to 419 382 95 0.52 (0.28 to 0.95) 209 0.78 (0.60 to 1.01)
Q4 420 365 50 0.28 (0.14 to 0.53) 159 0.57 (0.35 to 0.92)
P for trend 0.01 0.41
P for interaction 0.73 0.53
Parathyroid hormone (PTH) laboratory results were only available from the NHANES 2003 to 2006.
a
Survey logistic regression models used to estimate odds ratios and 95% confidence intervals. Models were adjusted for age, sex, body mass index (BMI),
educational attainment, race, household income, smoking status, alcohol use, physical activity, month of blood collection, dietary intakes of total energy, total
intake of calcium and vitamin D.
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This explanation is also supported by the observation in
previous clinical studies that magnesium supplementa-
tion substantially reversed the resistance to vitamin D
treatment among magnesium-deficient patients [21].
Previous studies found PTH level was elevated when
serum 25(OH)D was under 20 ng/ml [41]. In the current
study, we found magnesium intake was associated with a
reduced risk of vitamin D insufficiency or deficiency
only among those in the highest or the lowest tertile of
PTH. This finding is possible because magnesium plays
an important role in PTH regulation. This finding is also
supported by observations made in a study of 30 women
with osteoporosis that were investigated for magnesium
deficiency using a magnes ium tolerance test [26]. The
subjects were divided into three groups: ten with vitamin
D insufficiency (low vitamin D and rais ed P TH); ten
with functional hypoparathyroidism (low vitamin D and
low/low normal PTH); and ten who were vitamin D
replete (norma l vitamin D and normal PTH). All ten
subjects with functional hypoparathyroidism were found
to be magnesium deficient; five magnesium-deficient
and five magnesium-insufficient patients were found in
the subjects with vitamin D insufficiency, and only one
magnesium-deficient and four magnesium-insufficient
patients were found in the vitamin D replete group.
Furthermore, intravenous magnesium infusion led to a
significant rise in PTH in the group with functional
hypoparathyroidism and a reduction in PTH in the sub-
jects with vitamin D insufficiency.
A number of previous studies have examined the asso-
ciations between magnesium intake with risk of stroke
[42,43] and coronary heart disease [43,44], however, the
results have been inconsistent in these previous studies.
Two meta-analyses of prospective studies found that
magnesium intake was related to a significantly reduced
risk of stroke [42,43]. However, the inverse association
Table 4 Hazard ratios (HRs)
a
and 95% CIs for total mortality in the National Health and Nutrition Examination Survey
(NHANES) III (1988 to 2006)
Magnesium intake (mg/day) Serum vitamin D level (ng/ml) P for trend
<20 20 to 31 32 to 39 40
Total mortality
Total Cases 1,274 1,547 558 324
HR (95% CI) 1.00 0.83 (0.74 to 0.94) 0.80 (0.69 to 0.93) 0.79 (0.66 to 0.93) <0.01
<264 Cases 848 786 249 143
HR (95% CI) 1.00 0.89 (0.74 to 1.08) 0.87 (0.69 to 1.08) 0.87 (0.64 to 1.20) 0.23
264 Cases 426 761 309 181
HR (95% CI) 1.00 0.77 (0.64 to 0.92) 0.73 (0.58 to 0.93) 0.70 (0.57 to 0.88) <0.01
P for interaction 0.96
Cardiovascular mortality
Total Cases 574 656 253 132
HR (95% CI) 1.00 0.73 (0.62 to 0.86) 0.77 (0.61 to 0.99) 0.73 (0.56 to 0.97) 0.04
<264 Cases 386 346 112 57
HR (95% CI) 1.00 0.83 (0.66 to 1.04) 0.88 (0.61 to 1.28) 0.91 (0.61 to 1.35) 0.45
264 Cases 188 310 141 75
HR (95% CI) 1.00 0.59 (0.44 to 0.80) 0.65 (0.44 to 0.95) 0.57 (0.38 to 0.87) <0.05
P for interaction 0.03
Colorectal cancer mortality
Total Cases 32 34 12 8
HR (95% CI) 1.00 0.84 (0.36 to 2.00) 0.80 (0.31 to 2.05) 0.50 (0.15 to 1.73) 0.31
<264 Cases 19 17 3 3
HR (95% CI) 1.00 1.17 (0.39 to 3.56) 0.79 (0.17 to 3.75) 0.85 (0.17 to 4.12) 0.73
264 Cases 13 17 9 5
HR (95% CI) 1.00 0.55 (0.16 to 1.85) 0.67 (0.17 to 2.64) 0.28 (0.03 to 2.25) 0.29
P for interaction 0.15
a
A Coxs proportional hazards model was performed with the SURVEYPHREG procedure to estimate odds ratios and 95% confidence intervals. Models were
adjusted for age, race, sex, BMI, education attainment, household income, smoking status, alcohol use, physical activity, month of blood collection, intakes of total
energy, phosphorus, calcium and magnesium.
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was weak (an 8% reduction in risk per 100 mg magne-
sium/day increment). Likewise, a previous meta-analysis
found that magnesium intake was non-significantly in-
versely associated with coronary heart disease with a
pooled RR (95% confidence intervals (CIs)) of 0.86 (0.67
to 1.10) for the highest intake versus the lowest intake
category [43]. In the current study, we found that the
HR (95% CIs) for risk of mortality due to cardiovascular
disease was 0.88 (0.61 to 1.26) for the highest quartile
intake of magnesium versus the lowest quartile intake,
which is very close to that in previous studies. Several
previous studies have also evaluated the associations be-
tween magnesium intake and risk of colorectal cancer
and results have also not been consistent [45 ]. A very re-
cent meta-analysis found that every 100 mg/day increa se
in magnesium intake was related to 12% reduced risk of
colorectal cancer (RR: 0.88; 95% CI 0.81 to 0.97). In the
current study, we found that the HR (95% CIs) for risk
of mortality due to colorectal cancer was 0.76 (0.15 to
3.86) for the highest quartile intake of magnesium versus
the lowest quartile intake, which is also consistent with
those from previous cohort studies. The significant inter-
action between serum vitamin D and magnesium intake in
relation to mortality for cardiovascular disease and colo-
rectal cancer may also explain some inconsistencies in
previous studies which examined the associations of mag-
nesium intake alone with risk of cardiovascular disease
and colorectal cancer.
A strength of our study is that it is based on
NH ANES, a popula tion-based study with nationally rep-
resentative samples. As with all prevalent casecontrol
studies, one concern is that the temporal sequence may
not be clear. However, it is unlikely that serum vitamin
D status led to high or low intake of magnesium or vita-
min D. Furthermore, the analysis of data from the
NH ANES III, a population-based prospective cohort,
provides additional indications that magnesium interacts
with vitamin D in relation to mortality. It is possible that
people who consumed a high level of magnesium may
also have a healthy lifestyle (for example, more physical
activity and higher proportion of dietary supplement
users). Supplement users may consume a high level of
vitamin D from supplements while outdoor physical ac-
tivity is related to an increa sing production of 25(OH)D
from sunlight exposure. We have adjusted for physical
activity and intake of vitamin D from both diet and sup-
plement in all analyses. Furthermore, we have conducted
stratified analyses by physical activity and use of supple-
ment. We found, unlike intake of magnesium, physical
activity and use of suppleme nts did not significantly or
marginally significantly modify the association between
serum 25(OH)D and mortality. Finally, although mul-
tiple 24-h dietary recalls are used as a gold standard
measure in nutritional epidemiologic studies, a one-time
24-h dietary recall may not capture long-term dietary
exposure. However, similar to dietary vitamin D and
supplemental vitamin D intake, we found both dietary
intake of magnesium (based on 24-h dietary recall) and
magnesium from supplementation intake (derived from
30-day supplement questionnaire) significantly contrib-
uted to serum vitamin D status. Moreover, total intake
of magnesium sign ificantly interacted with intake of vita-
min D in relation to both magnesium deficiency and in-
sufficiency while total intake of magnesium modified the
association between serum vitamin D and mortality.
Since inter-day variation in magnesium intake is ran-
dom, any residual inter-day variation may lead to non-
differential misclassification , which usually biases the
result to the null. Thus, the true associations of magne-
sium intake with vitamin D status risk may be stronger
than those we observed. Our findings are not only bio-
logically plausible, but also remarkably consistent , indi-
cating our findings may not be solely due to chance. In
the current study, we did not have data for other param-
eters of the vitamin D/PTH axis (that is, serum PTH
and 1,25-dihydroxyvitamin D), which may indeed be af-
fected by magnesium status. Future studies are warranted
to examine if low magnesium status using dietary and
body status of magnesium affected both PTH levels and
1,25-dihydroxyvitamin D because this could serve as one
mechanism for the observed interaction between serum
25(OH)D and magnesium intake on mortality.
Conclusions
Our preliminary findings indicate it is possible that
magnesium intake alone or its interaction with vitamin
D intake may contribute to vitamin D status. The associ-
ations between serum 25(OH)D and risk of mortality
may be modified by the intake level of magnesium. Fu-
ture studies, including cohort studies and clinical trials,
are ne cessary to confirm the findings.
Abbreviations
25(OH)D: 25-Hydroxyvitamin D; 95% CI: 95% confidence interval; HR: Hazard
ratio; IOM: Institute of Medicine; NDI: National death index; NHANES: National
Health and Nutrition Examination Survey; OR: Odds ratios; PTH: Parathyroid
hormone; UVB: Ultraviolet-B; VDBP: Vitamin D binding protein.
Competing interests
The authors declare that they have no competing interests.
Authors contributions
XD and QD designed the current study and drafted the manuscript. XD
carried out the statistical analysis. YS, JEM, LBS, MJS, RMN, DLS, and QD
contributed to study design, data interpretation, and the critical review of
the paper. All authors read and approved the final manuscript.
Acknowledgements
XD and QD were supported by R01 CA149633 (to QD) from the National
Cancer Institute and R01 AT004660 (to QD) from the National Center for
Complementary & Alternative Medicine and Office of Dietary Supplements,
Department of Health and Human Services and AICR #08A074-REV (to QD)
from the American Institute for Cancer Research, and Vanderbilt Institute for
Deng et al. BMC Medicine 2013, 11:187 Page 12 of 14
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Clinical and Translational Research grant support (UL1TR000011 from NCATS/
NIH). The funding sponsors had no role in study design, data collection,
statistical analysis and result interpretation, the writing of the report, and the
decision to submit for publication. We thank the investigators, the staff, and the
participants of NHANES for their valuable contribution. The content is solely the
responsibility of the authors and does not necessarily represent the official
views of the National Cancer Institute or the National Institutes of Health.
Author details
1
Department of Medicine, Division of Epidemiology, Vanderbilt University
School of Medicine, Nashville, TN 37203, USA.
2
Division of Preventive
Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston,
MA 02115, USA.
3
Department of Epidemiology, Harvard School of Public
Health, Boston, MA 02115, USA.
4
Department of Medicine, Division of
Gastroenterology, Vanderbilt School of Medicine, Nashville, TN 37232, USA.
5
Institute for Medicine and Public Health, Vanderbilt University Medical
Center, Nashville, TN 37203, USA.
Received: 29 December 2012 Accepted: 24 July 2013
Published: 27 August 2013
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doi:10.1186/1741-7015-11-187
Cite this article as: Deng et al.: Magnesium, vitamin D status and
mortality: results from US National Health and Nutrition Examination
Survey (NHANES) 2001 to 2006 and NHANES III. BMC Medicine
2013 11:187.
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... Further, all enzymes used for the metabolism of Vit D seem to require magnesium, which acts as a co-factor in the enzymatic reactions of the liver and kidneys (24). Magnesium intake alone or its interaction with Vit D intake may contribute to Vit D status (25,26). The enzymatic activation of 25-hydroxylase in the liver and 1α-hydroxylase in the kidneys is a process that requires magnesium. ...
... Although the current study is a cross-sectional analysis, our finding is consistent with that in a 2013 prospective cohort study in which the inverse associations between serum Vit D concentrations and risk of mortality due to cardiovascular disease only appeared in those with higher intakes of magnesium, but not in those with lower intakes of magnesium (25). ...
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Background Previous clinical studies and randomized controlled trials have revealed that low serum vitamin D levels are associated with the risk of developing insulin resistance. Magnesium has been reported to be a protective factor for insulin resistance, and magnesium has been considered an important co-factor for vitamin D activation. However, the effect of dietary magnesium intake on the relationship between vitamin D and the risk of developing insulin resistance has not been comprehensively investigated. Therefore, we designed this cross-sectional analysis to assess whether dietary magnesium intake modifies the association of vitamin D and insulin resistance. Methods A total of 4,878 participants (male: 48.2%) from 4 consecutive cycles of the National Health and Nutrition Examination Survey (2007–2014) were included in this study after a rigorous screening process. Participants were stratified by their dietary magnesium intake into low-intake (<267 mg/day) and high-intake (≥267 mg/day) groups. We assessed differences between serum vitamin D levels and the risk of developing insulin resistance (interaction test), using a weighted multivariate logistic regression to analyze differences between participants with low and high magnesium intake levels. Results There was a negative association between vitamin D and insulin resistance in the US adult population [OR: 0.93 (0.88–0.98)], P < 0.001. Dietary magnesium intake strengthened the association ( P for interaction < 0.001). In the low dietary magnesium intake group, vitamin D was negatively associated with the insulin resistance [OR: 0.94 (0.90–0.98)]; in the high dietary magnesium intake group, vitamin D was negatively associated with insulin resistance [OR: 0.92 (0.88–0.96)]. Conclusion Among adults in the United States, we found an independent association between vitamin D level and insulin resistance, and this association was modified according to different levels of magnesium intake.
... Mg is required for the binding of vitamin D to its transport protein as well as hepatic and renal hydroxylation. Mg deficiency leads to 1,25(OH) 2 D reduction and an impaired PTH response [37,38]. The cause-effect relationship between serum PTH level and Mg concentration seems to be complex. ...
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Magnesium (Mg) is an essential nutrient for maintaining vital physiological functions. It is involved in many fundamental processes, and Mg deficiency is often correlated with negative health outcomes. On the one hand, most western civilizations consume less than the recommended daily allowance of Mg. On the other hand, a growing body of evidence has indicated that chronic hypomagnesemia may be implicated in the pathogenesis of various metabolic disorders such as overweight and obesity, insulin resistance (IR) and type 2 diabetes mellitus (T2DM), hypertension (HTN), changes in lipid metabolism, and low-grade inflammation. High Mg intake with diet and/or supplementation seems to prevent chronic metabolic complications. The protective action of Mg may include limiting the adipose tissue accumulation, improving glucose and insulin metabolism, enhancing endothelium-dependent vasodilation, normalizing lipid profile, and attenuating inflammatory processes. Thus, it currently seems that Mg plays an important role in developing metabolic disorders associated with obesity, although more randomized controlled trials (RCTs) evaluating Mg supplementation strategies are needed. This work represents a review and synthesis of recent data on the role of Mg in the pathogenesis of metabolic disorders.
... Serum 25(OH)D concentrations were measured at the National Center for Environmental Health, CDC, Atlanta, Georgia, USA, using a radioimmunoassay kit (Diasorin, Stillwater, Minnesota, USA) and the coefficients of variations were 13%-19% in the NHANES III. 28 VD deficiency was defined as serum 25(OH)D concentrations <20 ng/ mL. 14 Measures of H. pylori CagA antibody H. pylori CagA antibody was measured on participants 20 years or older from phase I of NHANES III by an immunoglobulin G enzyme-linked immunosorbent assay (Wampole Laboratories, Cranbury, New Jersey, USA) with sensitivity and specificity of 96%. ...
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Objective To assess the association of serum vitamin D (VD) levels and Helicobacter pylori ( H. pylori ) cytotoxic-associated gene A (CagA) seropositivity, and further explore potential effect modifiers in this association. Design Cross-sectional study. Setting Data from phase I of the National Health and Nutrition Examination Survey (NHANES III, 1988–1991) led by the Center for Disease Control and Prevention. Participants A total of 3512 US adults (≥20 years) with both serum VD levels and H. pylori CagA antibody data from NHANES III were included in the analysis. Methods VD deficiency was defined as serum 25(OH)D concentrations<20 ng/mL. Logistic regression models were used to assess the association of serum VD levels and H. pylori CagA seropositivity (VD –Hp CagA+), and stratification analyses were used to explore potential effect modifiers. Results There was no significant association of VD– Hp CagA+ in the general population. But serum 25(OH)D concentrations were associated with H. pylori CagA+ in non-Hispanic whites (adjusted OR=1.02, 95% CI: 1.00 to 1.03), other races/ethnicities (adjusted OR=1.08, 95% CI: 1.01 to 1.06), populations born in other countries (adjusted OR=1.09, 95% CI: 1.04 to 1.15) or occasional drinkers (adjusted OR=0.93, 95% CI: 0.88 to 0.99). VD deficiency was associated with H. pylori CagA+ in non-Hispanic whites (adjusted OR=0.69, 95% CI: 0.53 to 0.92), populations born in other countries (adjusted OR=0.47, 95% CI: 0.25 to 0.89), non-drinkers (adjusted OR=0.80, 95% CI: 0.65 to 0.99), occasional drinkers (adjusted OR=2.53, 95% CI: 1.06 to 6.05), population with first quartile level of serum ferritin (adjusted OR=0.70, 95% CI: 0.51 to 0.96) or fourth quartile level of serum folate (adjusted OR=0.63, 95% CI: 0.46 to 0.87). Conclusions Racial/ethnic differences and different serum ferritin or serum folate levels may be effect modifiers for the association of VD– Hp CagA+.
... With our current detailed knowledge about vitamin D metabolism, central cofactors (e.g., magnesium [69]), the influence of SNPs according to (epi)genetic studies [39], and worldwide experience of several thousands of patients treated with the CP from 2012 onwards with daily doses up to 340,000 IU [70], we are able to develop an individualized vitamin D3 treatment for autoimmune patients by the careful planning and determination of reliable mechanisms for regular laboratory controls. Based on our findings, hypercalcemia does not appear to be a first line risk of high-dose vitamin D3 therapy. ...
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Background: In 2013, the group of Cicero Coimbra, Brazil, reported the clinical efficacy of high doses of vitamin D3 in patients suffering from autoimmune skin disorders ("Coimbra protocol", CP). However, hypercalcemia and the subsequent impaired renal function may be major concerns raised against this protocol. Methods: We report for the first time for a broad spectrum of autoimmune diseases in 319 patients (mean age (±SD) 43.3 ± 14.6 years, 65.5% female, 34.5% male) safety data for high doses of orally applied vitamin D3 (treatment period: up to 3.5 years) accompanied by a strict low-calcium diet and regular daily fluid intake of at least 2.5 L. Results: Mean vitamin D3 dose was 35,291 ± 21,791 IU per day. The measurement of more than 6100 single relevant laboratory parameters showed all mean values (±SD) within the normal range for total serum calcium (2.4 ± 0.1 mmol/L), serum creatinine (0.8 ± 0.2 mg/dL), serum creatinine associated estimated GFR (92.5 ± 17.3 mL/min), serum cystatin C (0.88 ± 0.19 mg/L), serum TSH (1.8 ± 1 mIU/L), and for 24 h urinary calcium secretion (6.9 ± 3.3 mmol/24 h). We found a very weak relationship between the dosage of oral vitamin D3 and the subsequent calcium levels, both in serum and in urinary excretion over 24 h, respectively. Conclusions: Our data show the reliable safety of the CP in autoimmune patients under appropriate supervision by experienced physicians.
... Can Magnesium, as an activator of Vit D and a regulator of pancreatic β-cell functionality, affect the association between serums Vit D levels and pancreatic β-cells? There have been few similar reports in the existing literature (8,31,32). Hence, clinical research concerning the effect of Magnesium intake on the association of serums Vit D levels with the risk of pancreatic β-cell impairment is necessary. In this study, we hypothesize that Magnesium intake can affect such association. ...
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Background Some studies have shown that, the circulating vitamin D (Vit D) concentration in the body exerts a crucial role in regulating the pancreatic β-cell function. Meanwhile, the role of magnesium is important in the synthesis of Vit D, since it is an essential element for activating Vit D. Nevertheless, there remains insufficient studies concerning whether dietary Magnesium intake influences the association between Vit D and risk of pancreatic β-cell dysfunction. Hence, this cross-sectional study aimed to assess the effect of Magnesium intake alterations on the association between serum Vit D levels and the risk of pancreatic β-cell dysfunction.Methods This large-scale cross-sectional study involves four cycles of National Health and Nutrition Examination Survey (NHANES) (2007–2014), with totally 4,878 participants. Groups were divided depending on the median daily intake of Magnesium, namely, the low intake group (Magnesium intake <267 Magnesium/d) and the high intake group (Magnesium intake ≥ 267 Magnesium/d). By constructing multiple multivariate linear and logistics regression models, the associations between serum Vit D levels and HOMA-β, as well as between serum Vit D levels and the risk of pancreatic β-cell dysfunction were explored at different Magnesium intakes.ResultsIn this cross-sectional study, the serum Vit D level is independently correlated with the HOMA-β index [β: 0.65 (0.40–0.90)] and the risk of pancreatic β-cell dysfunction [OR: 0.95 (0.92–0.98)]. Moreover, such correlations are affected by different dietary Magnesium intakes (P for interaction < 0.001).Conclusion According to the results of this study, the dietary Magnesium intake influences the associations of serum Vit D levels with HOMA-β index and pancreatic β-cell dysfunction. Besides, the finding requires validation through more RCT or cohort studies.
... Previous studies have shown that the enzymes that synthesize and metabolize vitamin D depend on magnesium (12). Recent observational studies have shown that magnesium and vitamin D have a significant interaction, and the inverse association between serum vitamin D and risk of mortality due to cardiovascular disease and colorectal cancer is present only when the intake of magnesium is above the median (13). However, limited clinical studies have assessed the effect of magnesium intake on vitamin D and BP (12,14). ...
Article
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Introduction Although the association between blood pressure and vitamin D has been well studied, the effects of dietary magnesium intake on this relationship are still unclear. Thus, this study aimed to determine the effects of dietary magnesium intake on the association between vitamin D and blood pressure. Methods The present study analyzed data from the continuous the National Health and Nutrition Examination Survey (NHANES) 2007–2014. We included 8,799 participants aged 20 years or older. Multivariable linear regression was performed to assess the association between vitamin D and systolic blood pressure (SBP) and diastolic blood pressure (DBP). Dietary magnesium intake was stratified by low magnesium intake (<299 mg/d) and high magnesium intake (≥299 mg/d). Effect modification by dietary magnesium intake was assessed through interaction tests between vitamin D and SBP in the multivariable linear regression. Results In this cross-sectional study, we found that vitamin D was negatively related to SBP, but not to DBP. The relationship between vitamin D and SBP was different in the low and high magnesium intake group (β: −0.25 95%Cl: −0.4~0.07 vs β: −0.32 95%Cl: −0.52~-0.12). Furthermore, magnesium intake significantly modified the negative relationship between vitamin D and SBP in most of the models. Conclusion Our research showed that magnesium and vitamin D have an interactive effect in reducing SBP, which may have great importance for clinical medication.
... In infected persons, MNDs contribute to the emergence of more virulent strains and, with dysfunction of the immune response, may contribute to the morbidity of COVID-19 infection (70). Additionally, vitamin D deficiency worsens the clinical outcome of patients with COVID-19 (71), while Mg could help in absorption, synthesis, and function of vitamin D in the body, and a Mg deficiency negatively affects vitamin D status (72)(73)(74)(75). This implies that the high Mg supply from Malawian maize could contribute in fighting against the burden of COVID-19 disease in the population. ...
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Maize is a major staple and plays an essential role in food and nutrition security in Sub-Saharan Africa (SSA). Conservation agriculture (CA), a climate-smart agriculture practise based on minimum soil disturbance, crop residue retention, and crop diversification, has been widely advocated but without extensive research on the impact it may have on maize nutrient composition, and food and nutrition security. This study assessed the grain yield, macro- and micronutrient mineral content, and nutrient yield of eight maize varieties grown in Malawi, and how these are affected by CA practises over two seasons. The minerals were analysed by inductively coupled plasma (ICP) coupled to optical emission spectroscopy (OES) and to mass spectroscopy (MS). Grain yield and Se content differed among the varieties, while C, N, Fe, K, Mg, Mn, P, and Zn were similar. The local variety Kanjerenjere showed lowest grain and nutrient yields. The open-pollinated varieties (OPVs) concentrated more minerals than the F1 hybrids, but the latter showed higher yields for both grain and nutrients. Typical consumption of the eight maize varieties could fully meet the protein and Mg dietary reference intake (DRIs) of Malawian children (1–3 years), as well as Mg and Mn needs of adult women (19–50 years), but their contribution to dietary requirements was low for Fe (39–41%) and K (13–21%). The trials showed that CA increased grain yield (1.2- to 1.8-fold) and Se content (1.1- to 1.7-fold), but that it had no effect on C, K, Mg, P, and Zn, and that N (1.1- to 1.2-fold), Mn (1.1- to 1.8-fold), and Fe (1.3- to 3.4-fold) were reduced. The high increase in grain yield under CA treatments resulted in increased yields of protein and Se, no effect on the yields of K, Mg, Mn, P, Zn, and reduced Fe yield. Conservation agriculture could contribute in reducing the risk of Se deficiency in Malawian women and children but exacerbates the risk of Fe deficiency. A combination of strategies will be needed to mitigate some of the foreseen effects of climate change on agriculture, and food and nutrition security, and improve nutrient intake.
... Diet status (Table 1) was assessed using modified Gallup Diet Questionnaire with 6 questions ( Table 1). The total score was 42 and again the higher score denoted the worst diet pattern [32][33][34][35][36]. Physical activity ( Table 1] was inquired based on a modified question from Brunel lifestyle physical activity questionnaire [37]. ...
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Objective To study the relationship of self-rated wellness/health and lifestyle in patients with rheumatoid arthritis. Methods Self-rated wellness/health, demographics, smoking, mood, sleep, physical activity, diet, symptoms/signs, body mass index and laboratory findings in 142 patients with rheumatoid arthritis were collected in the current cross-sectional study. Multivariable generalized additive model (GAM) was employed to study the association of self-rated wellness/health score and lifestyle factors. Results Female/male ratio was 116/26 and the mean (SD) age of sample was 52 (13) years. Mean (SD) self-rated wellness/health score out of 10 was 7.2 (1.63). Mean (SD) number of tender joints and swollen joints were 4.42 (4.55) and 4.00 (4.26), respectively. The mean sleep score was 29.5 out of 70. Patients went to bed more than one hour earlier during the weekdays compared to weekends (22:45 vs. 23:52 PM, respectively, p < 0.0001). They also woke up more than one hour earlier during the weekdays compared to the weekends (6:08 vs. 7:20 AM, respectively, p < 0.0001). Their nap duration during weekdays was about half an hour shorter than the nap duration on weekends (19.75 vs. 48.02 minutes, respectively, p < 0.0001). The mean mood and diet scores were 18.5/35 and 22.5/42, respectively. By backward elimination in multivariable regression model (GAM), disease duration, mood, sleep quality, weekdays sleep characteristics (sleep duration, time to go to bed, wake-up time, time to fall asleep and nap duration), and sleep duration on weekends remained in the final model (R ² = 0.225, p = 0.01). Sleep quality, nap duration on weekdays, night sleep duration on weekends and mood status were the significant variables associated with self-rated wellness/health score. Conclusion In patients with rheumatoid arthritis, the low self-rated wellness/health score was associated with the low sleep quality, long sleep duration on weekends, and long nap duration on weekdays.
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Background: Diabetes mellitus of type II (T2DM) has a link to bone resorption, as seen by the great level of most osteoclastic activity indicators. As a result, the mineral density of bones is not reduced in individuals with non-insulin-managed T2DM, and this type does not seem to contribute to osteoporosis. This study aims to evaluate the bone metabolism biochemical markers in T2DM patients. Materials and Methods: A total of 120 blood samples were divided into (70) patients (with quite equal numbers of both females and males), and (50) normal cases as controls (also with quite equal numbers of both females and males), the ages were between 30 and 65 years old. During the period between February and August 2020, patients were admitted to Ballad and Salah Aldeen General Hospitals. The samples that were undertaken were (blood sugar, albumin, total calcium, corrected calcium, parathyroid hormone and phosphorus). Results: In male DM patients, there were high significant differences (P≤0.01) in (blood sugar, parathyroid hormone, total calcium, and corrected calcium), but non-significant differences (P≥0.05) in phosphorus. On contrary, in female DM patients, there was high noticeable difference (P≤0.01) in blood sugar, and a considerable difference (P≤0.05) only in albumin, but non-significant differences (P≥0.05) in parathyroid hormone, total calcium, and corrected calcium. Conclusion: The current findings concluded that hyperglycemia combined with an insulin deficiency can result in a hypoparathyriod status with PTH downregulation.
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This draft clinical practice guideline for the diagnosis, treatment and prevention of vitamin D deficiency is an update from a previous 2016 document. An analysis of the relevant literature data was carried out, with particular attention to meta-­analyzes, randomized clinical trials and systematic reviews published over the past 5 years. The updated recommendations were discussed and revised by the leading endocrinologists of the Russian Federation, who have expert status in this issue. The classification of 25(OH)D levels has been revised (in particular, the target range of 25(OH)D values has been specified), recommendations have been developed for screening of the disorders associated with vitamin D deficiency. The concept of vitamin D-associated toxicity and recommendations for its diagnosis and prevention have been introduced. Also, indications for the assessment of other vitamin D metabolites besides 25(OH)D, the main marker of vitamin D status, have been indicated. The section regarding treatment of vitamin D deficiency has been expanded and corrected. The major additions concerned the replenishment of the vitamin D deficiency and insufficiency in certain categories of patients (particularly, in the presence of the chronic kidney disease and autoimmune diseases, as well as in pregnant women) and monitoring of the effectiveness and safety of the therapy. The indications for prescribing active metabolites of vitamin D have been adjusted. Recommendations for the prevention of vitamin D deficiency in the general population have also been revised, taking into account large randomized clinical trials, meta-analyzes and systematic reviews of recent years. This publication is an expanded version of the federal guidelines.
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Evidence continues to mount that vitamin D reduces the risk and mortality rates of many types of disease. However, evidence from prospective cohort studies is sometimes weaker than that from case-control and ecological studies. A suggested reason for this discrepancy is that, because serum levels of 25-hydroxyvitamin D [25(OH)D] change over time, a single 25(OH)D concentration measurement taken at study enrollment does not reliably indicate 25(OH)D concentration related to the health outcome. To evaluate this suggestion further, this paper plots results from 12 prospective cohort studies of all-cause mortality rate vs. follow-up time. The regression fit to the hazard ratio per 20-nmol/l increase in serum 25(OH)D concentration vs. time increased from 0.82 (95% CI, 0.67-1.02) for 6 y to 0.96 (95% CI, 0.90-1.01) for 14 y. The value extrapolated for zero follow-up time was 0.72 (95% CI, 0.50-1.03), giving a hazard ratio reduction 3.5 times higher than the standard result from the meta-analysis [0.92 (95% CI, 0.89-0.95)]. Using the example of the Vitamin D Pooling Project of Rarer Cancers, this paper also discusses follow-up time's effect in interpreting prospective cohort studies of cancer outcome. This paper recommends that meta-analyses of prospective cohort studies account for follow-up time and, if possible, that studies measure serum 25(OH)D concentration every 2-4 y.
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SummaryThis review describes the vitamin D status in different regions of the world with the objective of understanding the scope of hypovitaminosis D and the factors related to its prevalence that may contribute to the pathogenesis of osteoporosis and fragility fractures. IntroductionVitamin D status has been linked to the pathogenesis of hip fractures as well as other skeletal and non-skeletal disorders. The purpose of this review is to provide a global perspective of vitamin D status across different regions of the world and to identify the common and significant determinants of hypovitaminosis D. MethodsSix regions of the world were reviewed—Asia, Europe, Middle East and Africa, Latin America, North America, and Oceania—through a survey of published literature. ResultsThe definition of vitamin D insufficiency and deficiency, as well as assay methodology for 25-hydroxyvitamin D or 25(OH)D, vary between studies. However, serum 25(OH)D levels below 75nmol/L are prevalent in every region studied whilst levels below 25nmol/L are most common in regions such as South Asia and the Middle East. Older age, female sex, higher latitude, winter season, darker skin pigmentation, less sunlight exposure, dietary habits, and absence of vitamin D fortification are the main factors that are significantly associated with lower 25(OH)D levels. ConclusionReports from across the world indicate that hypovitaminosis D is widespread and is re-emerging as a major health problem globally.
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To investigate the association between vitamin D status, assessed by plasma 25-hydroxyvitamin D, and risk of incident diabetes. Prospective observational study with a mean follow-up of 2.7 years in the Diabetes Prevention Program (DPP), a multicenter trial comparing different strategies for prevention of diabetes in patients with prediabetes. We assessed the association between plasma 25-hydroxyvitamin D, measured repeatedly during follow-up, and incident diabetes in the combined placebo (n = 1,022) and intensive lifestyle (n = 1,017) randomized arms of the DPP. Variables measured at multiple study time points (25-hydroxyvitamin D, BMI, and physical activity) entered the analyses as time-varying "lagged" covariates, as the mean of the previous and current visits at which diabetes status was assessed. After multivariate adjustment, including for the DPP intervention, participants in the highest tertile of 25-hydroxyvitamin D (median concentration, 30.1 ng/mL) had a hazard ratio of 0.72 (95% CI 0.56-0.90) for developing diabetes compared with participants in the lowest tertile (median concentration, 12.8 ng/mL). The association was in the same direction in placebo (0.70; 0.52-0.94) versus lifestyle arm (0.80; 0.54-1.17). Higher plasma 25-hydroxyvitamin D, assessed repeatedly, was associated with lower risk of incident diabetes in high-risk patients, after adjusting for lifestyle interventions (dietary changes, increased physical activity, and weight loss) known to decrease diabetes risk. Because of the observational nature of the study, the potential association between vitamin D and diabetes needs to be confirmed in intervention studies.
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We investigated the association between serum levels of 25-hydroxyvitamin D (25-OHD) and risk of death in Norwegian cancer patients. The study population was 658 patients with cancers of the breast (n = 251), colon (n = 52), lung (n = 210), and lymphoma (n = 145), obtained from JANUS, a population-based serum bank in Norway. Serum samples were collected within 90 days of cancer diagnosis and were analyzed for 25-OHD. Patients were diagnosed during 1984-2004 and were followed for death throughout 2008. We used Cox regression models to assess the relationship between serum 25-OHD and risk of death. Three hundred and ninety-nine patients died during follow-up, of whom 343 (86%) died from cancer. Adjusted for sex, age at diagnosis, and season of blood sampling, patients with 25-OHD levels below 46 nmol/L at diagnosis experienced shorter survival. Compared to patients in the lowest quartile of serum 25-OHD, the risk of cancer death among patients in the highest quartile was significantly reduced (HR 0.36 95% CI 0.27, 0.51). The estimated change in risk of cancer death was most pronounced between the first and the second quartile. The associations between 25-OHD levels and survival were observed for all four cancers. Higher circulating serum levels of 25-OHD were positively associated with the survival for cancers of the breast, colon, lung, and lymphoma.
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Data from laboratory studies, observational research, and/or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease (CVD), but primary prevention trials with adequate dosing in general populations (i.e., unselected for disease risk) are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a large randomized, double-blind, placebo-controlled, 2x2 factorial trial of vitamin D (in the form of vitamin D3 [cholecalciferol], 2000IU/day) and marine omega-3 fatty acid (Omacor® fish oil, eicosapentaenoic acid [EPA]+docosahexaenoic acid [DHA], 1g/day) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥50 and women aged ≥55. The mean treatment period will be 5years. Baseline blood samples will be collected in at least 16,000 participants, with follow-up blood collection in about 6000 participants. Yearly follow-up questionnaires will assess treatment compliance (plasma biomarker measures will also assess compliance in a random sample of participants), use of non-study drugs or supplements, occurrence of endpoints, and cancer and vascular risk factors. Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment, and deaths will be ascertained through national registries and other sources. Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance; hypertension; cognitive decline; depression; osteoporosis and fracture; physical disability and falls; asthma and other respiratory diseases; infections; and rheumatoid arthritis, systemic lupus erythematosus, thyroid diseases, and other autoimmune disorders.
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Objective: To provide a systematic review and meta-analysis of prospective, population-based cohort studies on the association of serum 25-hydroxyvitamin D (25(OH)D) and all-cause mortality. Methods: Relevant studies were identified by systematically searching Medline, EMBASE and ISI Web of Knowledge. Reported hazard ratios (HRs) for 25(OH)D categories were recalculated employing comprehensive trend estimation from summarized dose-response data and pooled in a random effects model meta-analysis. Results: Overall, 12 original studies were included in the review and meta-analysis comprising 32,142 mainly elderly study participants with measured 25(OH)D of whom 6921 died during follow-up. An inverse association between 25(OH)D levels and all-cause mortality was found in all but two studies that was statistically significant in several of the individual studies. In meta-analysis, 25(OH)D levels were significantly inversely associated with all-cause mortality with a pooled HR of 0.92 (95% confidence interval: 0.89-0.95) for a 20 nmol/l increase in 25(OH)D levels. Conclusion: In this meta-analysis of prospective, population-based cohort studies, a 20 nmol/l increase in 25(OH)D levels was associated with an 8% lower mortality in the general elderly population. This agrees with results from meta-analyses on randomized controlled trials that found a decrease in mortality with vitamin D3 supplementation of a comparable magnitude.
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Background: We investigated the relationship between dietary iron intake and mortality from cardiovascular disease (CVD) in a population-based sample of Japanese adults. Methods: The study cohort consisted of 58 615 healthy Japanese (23 083 men and 35 532 women), aged between 40 and 79 years, who had no history of stroke, coronary heart disease (CHD), or cancer at baseline. Dietary iron intake was assessed at baseline by a validated food frequency questionnaire administered between 1988 and 1990 as part of the Japan Collaborative Cohort (JACC) Study. Results: We documented 2690 (1343 men and 1347 women) deaths from CVD: 1227 (607 men and 620 women) deaths from total stroke, 651 from ischemic stroke (355 men and 296 women), 459 (196 men and 263 women) from hemorrhagic stroke, and 557 (311 men and 246 women) from CHD. Dietary intake of total iron was positively associated with mortality from total and ischemic stroke and total CVD in men. The multivariable hazard ratio for the highest versus the lowest quintile of total iron intake was 1.43 (95% CI, 1.02-2.00; P for trend = 0.009) for total stroke and 1.27 (1.01-1.58; 0.023) for total CVD in men. Dietary total iron intake was not associated with mortality from other endpoints in men, and was not associated with any endpoints in women. Conclusions: Dietary intake of total iron was positively associated with mortality from stroke and total CVD in Japanese men.
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Deficient 25-hydroxyvitamin D (25[OH]D) levels are associated with cardiovascular disease (CVD) events and mortality. 25(OH)D deficiency and stroke are more prevalent in blacks. We examined whether low 25(OH)D contributes to the excess risk of fatal stroke in blacks compared with whites. The Third National Health and Nutrition Examination Survey, a probability sample of U.S. civilians, measured 25(OH)D levels and CVD risk factors from 1988 through 1994. Vital status through December 2006 was obtained by a linkage with the National Death Index. In white and black adults without CVD reported at baseline (n = 7981), Cox regression models were fit to estimate hazard ratios (HR) for fatal stroke by 25(OH)D status and race. During a median of 14.1 y, there were 116 and 60 fatal strokes in whites and blacks, respectively. The risk of fatal stroke was greater in blacks compared with whites in models adjusted for socioeconomic status and CVD risk factors (HR 1.60, 95% confidence interval 1.01-2.53). Mean baseline 25(OH)D levels were significantly lower in blacks compared with whites (19.4 versus 30.8 ng/mL, respectively). In multivariable-adjusted models, deficient 25(OH)D levels lower than 15 ng/mL were associated with fatal stroke in whites (HR 2.13, 1.01-4.50) but not blacks (HR 0.93, 0.49-1.80). Vitamin D deficiency was associated with an increased risk of stroke death in whites but not in blacks. Although blacks had a higher rate of fatal stroke compared with whites, the low 25(OH)D levels in blacks were unrelated to stroke incidence. Therefore 25(OH)D levels did not explain this excess risk.
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Prospective studies of dietary magnesium intake in relation to risk of stroke have yielded inconsistent results. We conducted a dose-response meta-analysis to summarize the evidence regarding the association between magnesium intake and stroke risk. Relevant studies were identified by searching PubMed and EMBASE from January 1966 through September 2011 and reviewing reference lists of retrieved articles. We included prospective studies that reported RRs with 95% CIs of stroke for ≥3 categories of magnesium intake. Results from individual studies were combined by using a random-effects model. Seven prospective studies, with 6477 cases of stroke and 241,378 participants, were eligible for inclusion in the meta-analysis. We observed a modest but statistically significant inverse association between magnesium intake and risk of stroke. An intake increment of 100 mg Mg/d was associated with an 8% reduction in risk of total stroke (combined RR: 0.92; 95% CI: 0.88, 0.97), without heterogeneity among studies (P = 0.66, I(2) = 0%). Magnesium intake was inversely associated with risk of ischemic stroke (RR: 0.91; 95% CI: 0.87, 0.96) but not intracerebral hemorrhage (RR: 0.96; 95% CI: 0.84, 1.10) or subarachnoid hemorrhage (RR: 1.01; 95% CI: 0.90, 1.14). Dietary magnesium intake is inversely associated with risk of stroke, specifically ischemic stroke.