Background: Previous studies have shown inconsistent results for associations between vitamin D and risk of stroke. We gathered the existing published articles and conducted this meta-analysis with the aim to explore the association between vitamin D and risk of stroke. Methods: We searched for articles exploring the association between vitamin D and risk of stroke and published before April 2021 in the following databases: PubMed, Web of Science, MEDLINE, EMBASE, and Google Scholar. All statistical analyses were made using STATA 12.0 software. Q test and I2 were applied to examine heterogeneities between studies. Results: For the association between serum levels of 25(OH) vitamin D and risks of stroke, the present analysis included 20 cohort studies (including 213,276 participants) and a case-control analysis (including 13,642 participants). Additionally, the analysis included 15 studies (including 41,146 participants given vitamin D supplementation and 41,163 participants given placebo) to evaluate the influence of vitamin D supplementation on risk of stroke. Higher circulating levels of 25(OH) vitamin D were associated with a reduced risk of stroke (odds ratio/relative risk = 0.78, 95% confidence interval [CI]: 0.70–0.86, I2 = 41.5%, p = 0.025). However, the present analysis showed that vitamin D supplementation did not influence the risk of stroke (hazard ratio = 1.05, 95% CI: 0.96–1.14, I2 = 2.3%, p = 0.425). Conclusions: Our analysis indicated that lower circulating level of vitamin D was associated with an elevated risk of stroke, but extra supplement of vitamin D failed to show benefit in decreasing the risk of stroke. Further research and study are also needed to show the role of vitamin D in relation to stroke.

Vitamin D is a micronutrient that plays a crucial role in maintaining mineral and bone metabolism [1]. We can obtain vitamin D not only from diet and supplement use but also from biosynthesis in the skin under the influence of ultraviolet light [2]. Vitamin D can stimulate the intestinal absorption of calcium and phosphorus and is the precursor of 1,25-dihydroxycholecalciferol (calcitriol) which can regulate the secretion of parathyroid hormone [3, 4]. In addition, the deficiency of vitamin D has been found to be associated with an increased risk of diabetes mellitus, inflammatory bowel disease, cardiovascular disease, and certain cancers [5, 6]. Various factors are associated with the decreased level of vitamin D in vivo, such as poor diet intake, low physical activity, smoking, decreased sun exposure, and living at a high latitude area [7]. Although vitamin D can be acquired from outside supplement and synthesized at the skin under sunlight exposure, vitamin D deficiency is still becoming a global problem. According to published data, at least half of the Spanish population is vitamin D deficient [8]. Vitamin D deficiency occurs in 30–90% of the population in Middle East countries, even in 40% in the USA [9, 10].

Stroke, a cerebrovascular disorder, is a leading cause of long-term disability and death globally [11]. Stroke affects >795,000 cases per year in the USA [12]. Moreover, the prevalence of stroke in China was up to 1,114.8/100,000 people according to a nationwide population-based study of 480,687 adults [13]. And, the incidence of ischemic stroke in young adults has increased greatly, which may be a huge challenge for health-care systems [14].

However, the association between the serum concentration of vitamin D and stroke risk is still unclear. The study conducted by Leung et al. [15] proved that low vitamin D level is a risk factor for stroke, whereas the result from Guo et al. [16] showed no association with low vitamin D level and an increased risk of stroke [15, 16]. Besides, the recent result of a randomized controlled trial on the association between vitamin D supplements and prevention of cardiovascular disease showed that supplementation of vitamin D may not decrease the risk of cardiovascular disease including stroke (stroke: hazard ratio [HR] = 0.95, 95% confidence interval [CI]: 0.76–1.20) [17]. Therefore, we gathered the existing published articles and conducted this meta-analysis with the aim to explore the association between vitamin D and risk of stroke.

Based on the PRISMA guideline [18], we made a meta-analysis to investigate the association between vitamin D and risk of stroke. The present study is a meta-analysis, and ethical approval and patient consent are not applicable.

Search Strategy and Selection Criteria

C.S. and H.X. searched for articles published before April 2021 and in English in the following databases: PubMed, Web of Science, MEDLINE, EMBASE, and Google Scholar. The following search terms were used: (“vitamin D” OR “cholecalciferol” OR “25-hydroxyvitamin D” OR “ergocalciferol”) AND (“stroke” OR “cerebrovascular disease” OR “cerebrovascular accident” OR “brain vascular accident” OR “cerebral infarction” OR “cerebral hemorrhage” OR “apoplexy”). Eight hundred eighty-seven studies were included after excluding duplicates. We excluded studies which did not explore vitamin D and the risk of stroke. We excluded secondary processing articles (meta-analyses and reviews), meeting abstracts, and guidelines. Additionally, case studies were excluded from the analysis. We excluded 793 articles after reading the titles and abstracts. After that, 94 full-text articles were assessed for eligibility. For the association between low circulating levels of vitamin D and risk of stroke, we only included case-control and cohort studies, reporting relative risk (RR) or odds ratio (OR) and 95% CI associated with vitamin D and the risk of stroke in the analysis. Thirty-two studies were excluded because of this exclusion criterion. For the effect of vitamin D supplementation on risk of stroke, we only included studies with randomized clinical trial design investigating the influence of vitamin D supplementation on risk of stroke. Twenty-six studies were excluded because of this exclusion criterion. Finally, 36 studies were included in the present study. All the abstracts and full texts were read independently by 2 researchers (C.S. and H.X.). When inconsistencies in the study selection appeared, the articles were discussed and decided by 3 authors (C.S., H.X., and K.Z.).

Data Extraction and Analysis

Two reviewers (C.S. and B.J.) independently used an Excel file to abstract the following data: author, publication year, study type, study location, numbers of participants, subgroups, information of included participants (age and gender), numbers of current smokers, BMI of participants, numbers of statin users, numbers of participants with hypertension, numbers of participants with diabetes, endpoint, follow-up time, cases of stroke, adjustment, mean serum levels of 25-hydroxy (OH) vitamin D, vitamin D type and dosage, and results. STATA 12.0 software was used to compute these results. When a factor of interest was reported by ≥2 studies in a consistent manner, these were combined in a meta-analysis: first for all studies together (considering OR from case-control studies to be estimates of RR) to generate a pooled effect size and 95% CI and second separately for case-control and cohort studies. For the association between low circulating levels of vitamin D and risk of stroke, we computed the multivariate ORs or RRs and 95% CIs, comparing the lowest and highest category of vitamin D levels. Regarding the influence of vitamin D supplementation on risk of stroke, we computed the multivariate ORs or RRs and 95% CIs. Regarding the influence of vitamin D supplementation on risk of stroke, we computed the multivariate HRs and 95% CIs. Q test and I2 were used to explore heterogeneities between studies. When the heterogeneity was low (p value for Q test >0.05), fixed-effects models were conducted as pooling methods. Inversely, random-effects models were used as pooling methods with invariably high heterogeneity (p value for Q test ≤0.05). Additionally, we used subgroup analyses and meta-regression analyses to explore the source of heterogeneity. Subgroup analyses for different races were conducted for studies which provided information of association between vitamin D and risk of stroke in specific races. Sensitivity analysis was conducted to evaluate the stabilization of the analysis. We used Begg’s test, Egger’s test, and funnel plot to assess publication bias. Quality appraisal was made using the Cochrane Risk of Bias Tool. Data were analyzed using Review Manager 5.3.

Study Selection and Characteristics

Figure 1 shows the selection procedures and results. Online suppl. Tables 1 and 2 (for all online suppl. material, see www.karger.com/doi/10.1159/000517584) show the characteristics of 36 finally included studies. For the association between serum levels of 25(OH) vitamin D and risks of stroke, the present analysis included 20 cohort studies [15, 16, 19-36] (including 213,276 participants) and a case-control analysis (including 13,642 participants). Additionally, the analysis included 15 studies [17, 37-50] (including 41,146 participants given vitamin D supplementation and 41,163 participants given placebo) to evaluate the influence of vitamin D supplementation on risk of stroke.

Fig. 1.

Flow of information through the different phases of a meta-analysis. RR, relative risk; OR, odds ratio; RCT, randomized controlled trial.

Fig. 1.

Flow of information through the different phases of a meta-analysis. RR, relative risk; OR, odds ratio; RCT, randomized controlled trial.

Close modal

Meta-Analysis Results

The analysis indicated that higher circulating levels of 25(OH) vitamin D were associated with a reduced risk of stroke with a random effects model (OR/RR = 0.78, 95% CI: 0.70–0.86, I2 = 41.5%, p = 0.025, Fig. 2). In addition, subgroup analysis showed that higher circulating levels of 25(OH) vitamin D might be associated with a reduced risk of stroke in both white and Asian participants but not in black participants (white: OR/RR = 0.81, 95% CI: 0.72–0.90; Asian: OR/RR = 0.63, 95% CI: 0.49–0.80; black: OR/RR = 0.70, 95% CI: 0.41–1.19; Fig. 3). Subgroup analysis showed that higher circulating levels of 25(OH) vitamin D might be related to a reduced risk of stroke in cohort studies (RR = 0.78, 95% CI: 0.70–0.86; Fig. 4). Meta-regression analysis showed that age and gender were not responsible for heterogeneity across studies (age: p = 0.218; gender: p = 0.711). Sensitivity analysis showed no changes in direction of effect when any 1 study was excluded in the meta-analysis (online suppl. Fig. 1a). No significant risk of publication bias was shown for the meta-analysis by Begg’s test, Egger’s test, and funnel plot (Begg’s test: p = 0.319; Egger’s test: p = 0.165; online suppl. Table 2a).

Fig. 2.

Forest plots of the association between circulating levels of 25-hydroxy vitamin D and risk of stroke. CI, confidence interval; OR, odds ratio; RR, relative risk.

Fig. 2.

Forest plots of the association between circulating levels of 25-hydroxy vitamin D and risk of stroke. CI, confidence interval; OR, odds ratio; RR, relative risk.

Close modal
Fig. 3.

Subgroup analysis regarding association between circulating levels of 25-hydroxy vitamin D and risk of stroke in Caucasian and Asian participants. CI, confidence interval; OR, odds ratio; RR, relative risk.

Fig. 3.

Subgroup analysis regarding association between circulating levels of 25-hydroxy vitamin D and risk of stroke in Caucasian and Asian participants. CI, confidence interval; OR, odds ratio; RR, relative risk.

Close modal
Fig. 4.

Subgroup analysis regarding association between circulating levels of 25-hydroxy vitamin D and risk of stroke in cohort and case-control studies. CI, confidence interval; OR, odds ratio; RR, relative risk.

Fig. 4.

Subgroup analysis regarding association between circulating levels of 25-hydroxy vitamin D and risk of stroke in cohort and case-control studies. CI, confidence interval; OR, odds ratio; RR, relative risk.

Close modal

However, the present analysis showed that vitamin D supplementation did not influence the risk of stroke with a fixed-effects model (HR = 1.05, 95% CI: 0.96–1.14, I2 = 2.3%, p = 0.425, Fig. 5). In addition, subgroup analysis showed no significant influence of vitamin D supplementation on risk of stroke in both white and Asian participants (white: HR = 1.00, 95% CI: 0.88–1.14; Asian: HR = 1.50, 95% CI: 0.78–2.88; Fig. 6). Meta-regression analysis showed that age, gender, percentage of current smoker, BMI, percentage of statin users, percentage of participants with hypertension, percentage of participants with diabetes, and baseline levels of 25(OH) vitamin D were not responsible for heterogeneity across studies (age: p = 0.573, gender: p = 0.926, percentage of current smoker: p = 0.688, BMI: p = 0.482, percentage of statin users: p = 0.510, percentage of participants with hypertension: p = 0.507, percentage of participants with diabetes: p = 0.842, and baseline levels of 25(OH) vitamin D: p = 0.917). Sensitivity analysis showed no changes in direction of effect when any 1 study was excluded in the meta-analysis (online suppl. Fig. 1b). No significant risk of publication bias was shown for the meta-analysis by Begg’s test, Egger’s test, and funnel plot (Begg’s test: p = 0.921; Egger’s test: p = 0.609; online suppl. Table 2b).

Fig. 5.

Forest plots of the effect of vitamin D supplementation on risk of stroke. CI, confidence interval; HR, hazard ratio.

Fig. 5.

Forest plots of the effect of vitamin D supplementation on risk of stroke. CI, confidence interval; HR, hazard ratio.

Close modal
Fig. 6.

Subgroup analysis regarding the effect of vitamin D supplementation on risk of stroke in Caucasian and Asian participants. CI, confidence interval; HR, hazard ratio.

Fig. 6.

Subgroup analysis regarding the effect of vitamin D supplementation on risk of stroke in Caucasian and Asian participants. CI, confidence interval; HR, hazard ratio.

Close modal

The risk of bias graph is shown in online suppl. Figure 3. Details of the risk of bias summary can be found in online suppl. Figure 4.

In our analysis, we included published studies regarding the association of vitamin D status with stroke risk. And, our result demonstrated a modest association between low levels of serum 25(OH) vitamin D and an increased risk of stroke in both Asian and white population but not in black population.

Our result was consistent with several previous meta-analyses. Zhou et al. [51] found the similar effect of vitamin D on the risk of ischemic stroke based on 19 studies (the pooled RR was 1.62, 95% CI: 1.34–1.96). Wang et al. [52] reported that the pooled RR was 1.64 (95% CI: 1.27–2.10) by comparing the lowest to highest levels of circulating 25(OH) vitamin D. The analogous result of different studies indicated that the status of low circulating 25(OH) vitamin D may be a risk factor for stroke event. The present study showed a significant association between low levels of serum 25(OH) vitamin D and an increased risk of stroke in both Asian and white population but not in black population. Low serum 25(OH) vitamin D levels are much more common in black population compared to white population. Previous studies provided evidence to suggest that blacks have adapted a relative resistance to the adverse effects of 25(OH) vitamin D deficiency. In spite of their low 25(OH) vitamin D levels, blacks have lower rates of fractures because of a skeletal resistance to the actions of parathyroid hormone [53, 54]. According to an analysis including black and white participants of the Third National Health and Nutrition Examination Survey (NHANES), lower 25(OH) vitamin D levels were associated with higher risk of fatal stroke in white but not in black participants [29].

Meanwhile, we also noticed that supplementation with vitamin D may be of no use to decrease the risk of stroke. This finding was in accord with the recent published result of the vitamin D and omega-3 trial (VITAL) [17]. The analysis did not demonstrate a significant effect of vitamin D on the decreased risk of major cardiovascular events. Due to the insufficient clinical evidence regarding the effect of vitamin D on the prevention of stroke, vitamin D could not be recommended for the prevention of stroke.

Experimental studies have shown that vitamin D deficiency in mice by knockout of the vitamin D receptor or 25-OHD-1α-hydroxylase (CYP27B1) gene can develop cardiac hypertrophy, high renin hypertension, lipotoxic cardiomyopathy amplification, and increased thrombogenicity and aortic calcification, which may be the potential mechanism of low vitamin D levels on increased risk of stroke [55-57]. However, we should notice that results from intervention studies may not support vitamin D supplementation in the prevention of stroke. The result differences between intervention and observational studies may suggest that low vitamin D is just a signal of ill health [58]. Considering that there are few studies exploring the role of vitamin D deficiency on stroke, more studies are warranted to derive a definite effect of vitamin D on stroke occurrence.

In addition, our analysis is subject to a few limitations. First, we compared the lowest and highest category of vitamin D levels, but the classification criteria of included studies are various. For example, the vitamin levels of samples were divided into 2 groups [22, 24], 3 groups [25, 59], 4 groups [30, 36], and even 5 groups [15, 21]. Thus, subgroup analysis comparing risk of stroke in patients across different vitamin D levels could not be conducted. In addition, studies in other fields suggest that there may be differences in outcomes between the dosages of supplementation. However, due to the various classification criteria of supplementation dosages, the study did not perform subgroup analysis for different supplementation dosages. Second, the duration of observational studies ranges from 3 to 5 years; however, the vitamin D detection of samples may be once or twice per year. A single measure may not represent the long-term vitamin D levels of samples. Third, the dose of vitamin D supplementation was different in included studies, which may influence the function of vitamin D on the prevention of stroke.

In conclusion, our analysis suggests that lower circulating level of vitamin D was associated with an elevated risk of stroke, but extra supplement of vitamin D failed to show benefit in decreasing the risk of stroke. Further research and study are also needed to show the role of vitamin D in relation to stroke.

The present study is a meta-analysis. Thus, statement of ethics from the ethical review board is not applicable.

The authors declare no conflicts of interest.

The study was supported by the Zhenjiang Key Research and Development Program (Social Development) (SH2019032).

Cen Su participated in research design, writing of the manuscript, and performance of the research and data analysis. Haiping Xia and Kangren Zhao participated in the performance of the research and data analysis. Biao Jin participated in research design and data analysis.

Data could be obtained by emailing the corresponding author.

1.
Urena-Torres
P
,
Souberbielle
JC
.
Pharmacologic role of vitamin D natural products
.
Curr Vasc Pharmacol
.
2014
;
12
(
2
):
278
85
. .
2.
Skaaby
T
,
Thuesen
BH
,
Linneberg
A
.
Vitamin D, cardiovascular disease and risk factors
.
Adv Exp Med Biol
.
2017
;
996
:
221
30
. .
3.
de La Puente-Yagüe
M
,
Cuadrado-Cenzual
MA
,
Ciudad-Cabañas
MJ
,
Hernández-Cabria
M
,
Collado-Yurrita
L
.
Vitamin D: and its role in breast cancer
.
Kaohsiung J Med Sci
.
2018
;
34
(
8
):
423
7
. .
4.
Chesdachai
S
,
Tangpricha
V
.
Treatment of vitamin D deficiency in cystic fibrosis
.
J Steroid Biochem Mol Biol
.
2016
;
164
:
36
9
. .
5.
Mondul
AM
,
Weinstein
SJ
,
Layne
TM
,
Albanes
D
.
Vitamin D and cancer risk and mortality: state of the science, gaps, and challenges
.
Epidemiol Rev
.
2017
;
39
(
1
):
28
48
. .
6.
Trump
DL
,
Aragon-Ching
JB
.
Vitamin D in prostate cancer
.
Asian J Androl
.
2018 May
;
20
(
3
):
244
52
. .
7.
Holick
MF
.
The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention
.
Rev Endocr Metab Disord
.
2017
;
18
(
2
):
153
65
. .
8.
Rodríguez-Rodríguez
E
,
Aparicio Vizuete
A
,
Sánchez-Rodríguez
P
,
Lorenzo Mora
AM
,
López-Sobaler
AM
,
Ortega
RM
. (
Vitamin D deficiency in Spanish population. Importance of egg on nutritional improvement
).
Nutr Hosp
.
2019
;
36
:
3
7
.
9.
Lips
P
,
Cashman
KD
,
Lamberg-Allardt
C
,
Bischoff-Ferrari
HA
,
Obermayer-Pietsch
B
,
Bianchi
ML
,
Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society
.
Eur J Endocrinol
.
2019
;
180
:
P23
54
.
10.
Parva
NR
,
Tadepalli
S
,
Singh
P
,
Qian
A
,
Joshi
R
,
Kandala
H
,
Prevalence of Vitamin D deficiency and associated risk factors in the US population (2011–2012)
.
Cureus
.
2018
;
10
(
6
):
e2741
. .
11.
Caprio
FZ
,
Sorond
FA
.
Cerebrovascular disease: primary and secondary stroke prevention
.
Med Clin North Am
.
2019
;
103
(
2
):
295
308
. .
12.
Barthels
D
,
Das
H
.
Current advances in ischemic stroke research and therapies
.
Biochim Biophys Acta Mol Basis Dis
.
2020
;
1866
(
4
):
165260
. .
13.
Wang
W
,
Jiang
B
,
Sun
H
,
Ru
X
,
Sun
D
,
Wang
L
,
Prevalence, incidence, and mortality of stroke in China: results from a nationwide population-based survey of 480,687 adults
.
Circulation
.
2017
;
135
:
759
71
.
14.
Ekker
MS
,
Boot
EM
,
Singhal
AB
,
Tan
KS
,
Debette
S
,
Tuladhar
AM
,
Epidemiology, aetiology, and management of ischaemic stroke in young adults
.
Lancet Neurol
.
2018
;
17
(
9
):
790
801
. .
15.
Leung
RY
,
Han
Y
,
Sing
CW
,
Cheung
BM
,
Wong
IC
,
Tan
KC
,
Serum 25-hydroxyvitamin D and the risk of stroke in Hong Kong Chinese
.
Thromb Haemost
.
2017
;
117
(
1
):
158
63
. .
16.
Guo
J
,
Cockcroft
JR
,
Elwood
PC
,
Pickering
JE
,
Lovegrove
JA
,
Givens
DI
.
Vitamin D intake and risk of CVD and all-cause mortality: evidence from the caerphilly prospective cohort study
.
Public Health Nutr
.
2017
;
20
(
15
):
2744
53
. .
17.
Manson
JE
,
Cook
NR
,
Lee
IM
,
Christen
W
,
Bassuk
SS
,
Mora
S
,
Vitamin D supplements and prevention of cancer and cardiovascular disease
.
N Engl J Med
.
2019
;
380
(
1
):
33
44
. .
18.
Moher
D
,
Liberati
A
,
Tetzlaff
J
,
Altman
DG
.
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
.
PLoS Med
.
2009
;
6
(
7
):
b2535
. .
19.
Berghout
BP
,
Fani
L
,
Heshmatollah
A
,
Koudstaal
PJ
,
Ikram
MA
,
Zillikens
MC
,
Vitamin D status and risk of stroke: the rotterdam study
.
Stroke
.
2019
;
50
(
9
):
2293
8
. .
20.
Judd
SE
,
Morgan
CJ
,
Panwar
B
,
Howard
VJ
,
Wadley
VG
,
Jenny
NS
,
Vitamin D deficiency and incident stroke risk in community-living black and white adults
.
Int J Stroke
.
2016
;
11
(
1
):
93
102
. .
21.
Schneider
AL
,
Lutsey
PL
,
Selvin
E
,
Mosley
TH
,
Sharrett
AR
,
Carson
KA
,
Vitamin D, vitamin D binding protein gene polymorphisms, race and risk of incident stroke: the atherosclerosis risk in communities (ARIC) study
.
Eur J Neurol
.
2015
;
22
(
8
):
1220
7
. .
22.
Leu Agelii
M
,
Lehtinen-Jacks
S
,
Zetterberg
H
,
Sundh
V
,
Björkelund
C
,
Lissner
L
.
Low vitamin D status in relation to cardiovascular disease and mortality in Swedish women – effect of extended follow-up
.
Nutr Metab Cardiovasc Dis
.
2017
;
27
(
12
):
1143
51
. .
23.
Kojima
G
,
Bell
C
,
Abbott
RD
,
Launer
L
,
Chen
R
,
Motonaga
H
,
Low dietary vitamin D predicts 34-year incident stroke: the Honolulu heart program
.
Stroke
.
2012
;
43
(
8
):
2163
7
. .
24.
Bolland
MJ
,
Bacon
CJ
,
Horne
AM
,
Mason
BH
,
Ames
RW
,
Wang
TK
,
Vitamin D insufficiency and health outcomes over 5 year in older women
.
Am J Clin Nutr
.
2010
;
91
(
1
):
82
9
. .
25.
Kühn
T
,
Kaaks
R
,
Teucher
B
,
Hirche
F
,
Dierkes
J
,
Weikert
C
,
Plasma 25-hydroxyvitamin D and its genetic determinants in relation to incident myocardial infarction and stroke in the European prospective investigation into cancer and nutrition (EPIC)-Germany study
.
PLoS One
.
2013
;
8
(
7
):
e69080
. .
26.
Schierbeck
LL
,
Rejnmark
L
,
Tofteng
CL
,
Stilgren
L
,
Eiken
P
,
Mosekilde
L
,
Vitamin D deficiency in postmenopausal, healthy women predicts increased cardiovascular events: a 16-year follow-up study
.
Eur J Endocrinol
.
2012
;
167
(
4
):
553
60
. .
27.
Marniemi
J
,
Alanen
E
,
Impivaara
O
,
Seppänen
R
,
Hakala
P
,
Rajala
T
,
Dietary and serum vitamins and minerals as predictors of myocardial infarction and stroke in elderly subjects
.
Nutr Metab Cardiovasc Dis
.
2005
;
15
(
3
):
188
97
. .
28.
Zittermann
A
,
Morshuis
M
,
Kuhn
J
,
Pilz
S
,
Ernst
JB
,
Oezpeker
C
,
Vitamin D metabolites and fibroblast growth factor-23 in patients with left ventricular assist device implants: association with stroke and mortality risk
.
Eur J Nutr
.
2016
;
55
(
1
):
305
13
. .
29.
Michos
ED
,
Reis
JP
,
Post
WS
,
Lutsey
PL
,
Gottesman
RF
,
Mosley
TH
,
25-Hydroxyvitamin D deficiency is associated with fatal stroke among whites but not blacks: The NHANES-III linked mortality files
.
Nutrition
.
2012
;
28
(
4
):
367
71
. .
30.
Skaaby
T
,
Husemoen
LL
,
Pisinger
C
,
Jørgensen
T
,
Thuesen
BH
,
Fenger
M
,
Vitamin D status and incident cardiovascular disease and all-cause mortality: a general population study
.
Endocrine
.
2013
;
43
(
3
):
618
25
. .
31.
Afzal
S
,
Nordestgaard
BG
.
Vitamin D, hypertension, and ischemic stroke in 116,655 individuals from the general population: a genetic study
.
Hypertension
.
2017
.
32.
Perna
L
,
Schöttker
B
,
Holleczek
B
,
Brenner
H
.
Serum 25-hydroxyvitamin D and incidence of fatal and nonfatal cardiovascular events: a prospective study with repeated measurements
.
J Clin Endocrinol Metab
.
2013
;
98
(
12
):
4908
15
. .
33.
Welles
CC
,
Whooley
MA
,
Karumanchi
SA
,
Hod
T
,
Thadhani
R
,
Berg
AH
,
Vitamin D deficiency and cardiovascular events in patients with coronary heart disease: data from the heart and soul study
.
Am J Epidemiol
.
2014
;
179
(
11
):
1279
87
. .
34.
Anderson
JL
,
May
HT
,
Horne
BD
,
Bair
TL
,
Hall
NL
,
Carlquist
JF
,
Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population
.
Am J Cardiol
.
2010
;
106
(
7
):
963
8
. .
35.
Sheerah
HA
,
Eshak
ES
,
Cui
R
,
Imano
H
,
Iso
H
,
Tamakoshi
A
.
Relationship between dietary vitamin D and deaths from stroke and coronary heart disease: the japan collaborative cohort study
.
Stroke
.
2018
;
49
(
2
):
454
7
. .
36.
Drechsler
C
,
Pilz
S
,
Obermayer-Pietsch
B
,
Verduijn
M
,
Tomaschitz
A
,
Krane
V
,
Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients
.
Eur Heart J
.
2010
;
31
(
18
):
2253
61
. .
37.
Gallagher
JC
,
Fowler
SE
,
Detter
JR
,
Sherman
SS
.
Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss
.
J Clin Endocrinol Metab
.
2001
;
86
(
8
):
3618
28
. .
38.
Trivedi
DP
,
Doll
R
,
Khaw
KT
.
Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial
.
BMJ
.
2003
;
326
(
7387
):
469
. .
39.
Brazier
M
,
Grados
F
,
Kamel
S
,
Mathieu
M
,
Morel
A
,
Maamer
M
,
Clinical and laboratory safety of one year’s use of a combination calcium + vitamin D tablet in ambulatory elderly women with vitamin D insufficiency: results of a multicenter, randomized, double-blind, placebo-controlled study
.
Clin Ther
.
2005
;
27
(
12
):
1885
93
. .
40.
Grant
AM
,
Avenell
A
,
Campbell
MK
,
McDonald
AM
,
MacLennan
GS
,
McPherson
GC
,
Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (randomised evaluation of calcium or vitamin D, RECORD): a randomised placebo-controlled trial
.
The Lancet
.
2005
;
365
(
9471
):
1621
8
. .
41.
Jackson
RD
,
LaCroix
AZ
,
Gass
M
,
Wallace
RB
,
Robbins
J
,
Lewis
CE
,
Calcium plus vitamin D supplementation and the risk of fractures
.
N Engl J Med
.
2006
;
354
(
7
):
669
83
. .
42.
Berggren
M
,
Stenvall
M
,
Olofsson
B
,
Gustafson
Y
.
Evaluation of a fall-prevention program in older people after femoral neck fracture: a one-year follow-up
.
Osteoporos Int
.
2008
;
19
(
6
):
801
9
. .
43.
Prince
RL
,
Austin
N
,
Devine
A
,
Dick
IM
,
Bruce
D
,
Zhu
K
.
Effects of ergocalciferol added to calcium on the risk of falls in elderly high-risk women
.
Arch Intern Med
.
2008
;
168
(
1
):
103
8
. .
44.
Zhu
K
,
Devine
A
,
Dick
IM
,
Wilson
SG
,
Prince
RL
.
Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five-year randomized controlled trial
.
J Clin Endocrinol Metab
.
2008
;
93
(
3
):
743
9
. .
45.
Witham
MD
,
Price
RJ
,
Struthers
AD
,
Donnan
PT
,
Messow
CM
,
Ford
I
,
Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial
.
JAMA Intern Med
.
2013
;
173
(
18
):
1672
9
. .
46.
Wang
AY
,
Fang
F
,
Chan
J
,
Wen
YY
,
Qing
S
,
Chan
IH
,
Effect of paricalcitol on left ventricular mass and function in CKD-the OPERA trial
.
J Am Soc Nephrol
.
2014
;
25
(
1
):
175
86
. .
47.
Baron
JA
,
Barry
EL
,
Mott
LA
,
Rees
JR
,
Sandler
RS
,
Snover
DC
,
A trial of calcium and vitamin D for the prevention of colorectal adenomas
.
N Engl J Med
.
2015
;
373
(
16
):
1519
30
. .
48.
Scragg
R
,
Stewart
AW
,
Waayer
D
,
Lawes
CMM
,
Toop
L
,
Sluyter
J
,
Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study: a randomized clinical trial
.
JAMA Cardiol
.
2017
;
2
(
6
):
608
16
. .
49.
Shoji
T
,
Shoji
T
,
Inaba
M
,
Fukagawa
M
,
Ando
R
,
Emoto
M
,
Effect of Oral alfacalcidol on clinical outcomes in patients without secondary hyperparathyroidism receiving maintenance hemodialysis: the J-DAVID randomized clinical trial
.
JAMA
.
2018
;
320
(
22
):
2325
34
. .
50.
Momosaki
R
,
Abo
M
,
Urashima
M
.
Vitamin D supplementation and post-stroke rehabilitation: a randomized, double-blind, placebo-controlled trial
.
Nutrients
.
2019
;
11
:
1295
.
51.
Zhou
R
,
Wang
M
,
Huang
H
,
Li
W
,
Hu
Y
,
Wu
T
.
Lower vitamin D status is associated with an increased risk of ischemic stroke: a systematic review and meta-analysis
.
Nutrients
.
2018
;
10
(
3
):
277
. .
52.
Wang
L
,
Song
Y
,
Manson
JE
,
Pilz
S
,
März
W
,
Michaëlsson
K
,
Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies
.
Circ Cardiovasc Qual Outcomes
.
2012
;
5
(
6
):
819
29
. .
53.
Gutiérrez
OM
,
Farwell
WR
,
Kermah
D
,
Taylor
EN
.
Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the national health and nutrition examination survey
.
Osteoporos Int
.
2011
;
22
(
6
):
1745
53
. .
54.
Harris
SS
.
Vitamin D and African Americans
.
J Nutr
.
2006
;
136
(
4
):
1126
9
. .
55.
Glenn
DJ
,
Cardema
MC
,
Gardner
DG
.
Amplification of lipotoxic cardiomyopathy in the VDR gene knockout mouse
.
J Steroid Biochem Mol Biol
.
2016
;
164
:
292
8
. .
56.
Bouillon
R
,
Carmeliet
G
,
Verlinden
L
,
van Etten
E
,
Verstuyf
A
,
Luderer
HF
,
Vitamin D and human health: lessons from vitamin D receptor null mice
.
Endocr Rev
.
2008
;
29
(
6
):
726
76
. .
57.
Schmidt
N
,
Brandsch
C
,
Kühne
H
,
Thiele
A
,
Hirche
F
,
Stangl
GI
.
Vitamin D receptor deficiency and low vitamin D diet stimulate aortic calcification and osteogenic key factor expression in mice
.
PLoS One
.
2012
;
7
(
4
):
e35316
. .
58.
Autier
P
,
Boniol
M
,
Pizot
C
,
Mullie
P
.
Vitamin D status and ill health: a systematic review
.
Lancet Diabetes Endocrinol
.
2014
;
2
(
1
):
76
89
. .
59.
Li
J
,
Lai
H
,
Yang
L
,
Zhu
H
,
Chen
S
,
Lai
S
.
Age and gender differences in the association between serum 25-hydroxyvitamin D and stroke in the general US population: the national health and nutrition examination survey, 2001–2006
.
J Stroke Cerebrovasc Dis
.
2017
;
26
(
11
):
2510
8
. .
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