Prevention of urinary tract infections with vitamin D supplementation 20,000 IU per week for five years. Results from an RCT including 511 subjects

Abstract

Background:
In observational studies vitamin D deficiency is associated with increased risk of infections, whereas the effect of vitamin D supplementation in randomized controlled trials is non-conclusive.

Methods:
Five hundred and eleven subjects with prediabetes were randomized to vitamin D3 (20,000 IU per week) versus placebo for five years. Every sixth month, a questionnaire on respiratory tract infections (RTI) (common cold, bronchitis, influenza) and urinary tract infection (UTI) was filled in.

Results:
Mean baseline serum 25-hydroxyvitamin D (25(OH)D) level was 60 nmol/L. Two hundred and fifty-six subjects received vitamin D and 255 placebo. One hundred and sixteen subjects in the vitamin D and 111 in the placebo group completed the five-year study. Eighteen subjects in the vitamin D group and 34 subjects in the placebo group reported UTI during the study (p < 0.02), whereas no significant differences were seen for RTI. The effect on UTI was most pronounced in males. The effect of vitamin D on UTI was unrelated to baseline serum 25(OH)D level.

Conclusion:
Supplementation with vitamin D might prevent UTI, but confirmatory studies are needed.

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Infectious Diseases
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Prevention of urinary tract infections with vitamin
D supplementation 20,000 IU per week for five
years. Results from an RCT including 511 subjects
Rolf Jorde, Stina T. Sollid, Johan Svartberg, Ragnar M. Joakimsen, Guri
Grimnes & Moira Y. S. Hutchinson
To cite this article: Rolf Jorde, Stina T. Sollid, Johan Svartberg, Ragnar M. Joakimsen, Guri
Grimnes & Moira Y. S. Hutchinson (2016) Prevention of urinary tract infections with vitamin D
supplementation 20,000 IU per week for five years. Results from an RCT including 511 subjects,
Infectious Diseases, 48:11-12, 823-828, DOI: 10.1080/23744235.2016.1201853
To link to this article: https://doi.org/10.1080/23744235.2016.1201853
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ORIGINAL ARTICLE
Prevention of urinary tract infections with vitamin D supplementation 20,000 IU
per week for five years. Results from an RCT including 511 subjects
Rolf Jorde
a,b
,Stina T. Sollid
a,b
,Johan Svartberg
a,b
,Ragnar M. Joakimsen
a,b
,Guri Grimnes
a,b
and
Moira Y. S. Hutchinson
c
a
Department of Clinical Medicine, Tromsø Endocrine Research Group, UiT The Arctic University of Norway, Tromsø, Norway;
b
Division of
Internal Medicine, University Hospital of North Norway, Tromsø, Norway;
c
Division of Head and Motion, Department of Rheumatology,
Nordland Hospital, Bodø, Norway
ABSTRACT
Background: In observational studies vitamin D deficiency is associated with increased risk of infec-
tions, whereas the effect of vitamin D supplementation in randomized controlled trials is non-
conclusive.
Methods: Five hundred and eleven subjects with prediabetes were randomized to vitamin D
3
(20,000IU per week) versus placebo for five years. Every sixth month, a questionnaire on respiratory
tract infections (RTI) (common cold, bronchitis, influenza) and urinary tract infection (UTI) was filled in.
Results: Mean baseline serum 25-hydroxyvitamin D (25(OH)D) level was 60 nmol/L. Two hundred and
fifty-six subjects received vitamin D and 255 placebo. One hundred and sixteen subjects in the vitamin
D and 111 in the placebo group completed the five-year study. Eighteen subjects in the vitamin D
group and 34 subjects in the placebo group reported UTI during the study (p<0.02), whereas no sig-
nificant differences were seen for RTI. The effect on UTI was most pronounced in males. The effect of
vitamin D on UTI was unrelated to baseline serum 25(OH)D level.
Conclusion: Supplementation with vitamin D might prevent UTI, but confirmatory studies are needed.
ARTICLE HISTORY
Received 13 April 2016
Revised 6 June 2016
Accepted 9 June 2016
Published online 29 June
2016
KEYWORDS
Diabetes; respiratory
infection; urinary tract
infection; vitamin D
Introduction
Vitamin D is vital for the calcium metabolism, and severe vita-
min D deficiency leads to rickets in children and osteomalacia
in adults. Vitamin D is produced in the skin upon UV expos-
ure or obtained from the diet where fatty fish is the main
source. For its activation, vitamin D is hydoxylated in the liver
to 25-hydroxyvitamin D (25(OH)D), which is used as a marker
of a subject’s vitamin D status, and then in the kidneys (and
some peripheral tissues) to the active form 1,25-dihydroxyvi-
tamin D (1,25(OH)
2
D).[1] The active form binds to the nuclear
vitamin D receptor (VDR) which is located in tissues through-
out the body, including immune cells,[2,3] and regulates tran-
scription of hundreds of genes, including genes for
antimicrobial peptides and cytokines.[4,5] Vitamin D is there-
fore likely to be important for more than bone health.
Thus, from observational studies there are a number of
indications for an association between vitamin D deficiency
and infectious diseases like tuberculosis, respiratory tract
infections (RTI), influenza and sepsis.[6] As an example, non-
pandemic influenza occurs mostly in temperate climates in
the winter season when the serum 25(OH)D levels are low [7];
influenza pandemics are associated with solar activity cycles
[8]; and even the mortality rates during influenza pandemics
appear related to the level of solar radiation.[9] However,
randomized controlled trials (RCT) with vitamin D supplemen-
tation for treatment and/or prevention of infections have so
far not given conclusive results.[6]
We have recently performed a five-year intervention study
with vitamin D in subjects with prediabetes for the preven-
tion of progression to T2DM. As part of the study the subjects
were asked every sixth month for upper respiratory infections
(common cold, bronchitis, influenza) and urinary tract infec-
tions (UTI) since the last visit. We therefore had the opportun-
ity to evaluate the effect of supplementation with vitamin D
on these infections.
Materials and methods
Study design
The design of the study has been described in detail
before.[10,11] In short, subjects with prediabetes (impaired
fasting glucose (IFG) (serum glucose 6.0–6.9 mmol/L) and/or
impaired glucose tolerance (IGT) (fasting serum glucose
<7.0 mmol/L and 2-h value 7.8–11.0 mmol/L at oral glucose
tolerance test (OGTT) with 75 g glucose) were included.
Subjects with primary hyperparathyroidism, granulomatous
disease, history of urolithiasis, cancer diagnosed in the past
five years, unstable angina pectoris, myocardial infarction or
stroke in the past year were excluded. Pregnant or lactating
women, or women of fertile age with no use of contracep-
tion, were not included.
All visits were performed at the Clinical Research Unit at the
University Hospital of North Norway. At the first visit, a brief
CONTACT Rolf Jorde rolf.jorde@unn.no Division of Internal Medicine, University Hospital of North Norway, NO-9038 Tromsø, Norway
ß2016 Society for Scandinavian Journal of Infectious Diseases
INFECTIOUS DISEASES, 2016
VOL. 48, NO. 11-12, 823–828
http://dx.doi.org/10.1080/23744235.2016.1201853
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clinical examination was performed, and questionnaires on
medical history including infections, medication and vitamin D
supplementation were filled in. Height and weight were meas-
ured wearing light clothing. Fasting blood samples had been
collected at the OGTT, and supplementary non-fasting blood
samples were drawn at this visit. The subjects were then
randomized (non-stratified) in a 1:1 ratio to one capsule vitamin
D (cholecalciferol 20,000 IU (Dekristol; Mibe, Jena, Germany))
per week or an identical looking placebo capsule containing
arachis oil (Hasco-Lek, Wroclaw, Poland). New medication was
supplied every sixth month and unused capsules returned and
counted. The subjects were not allowed to take vitamin D sup-
plements (including cod liver oil) exceeding 400 IU per day.
For the next five years, the subjects met every sixth month
and filled in questionnaires on infections. Adverse events were
specifically asked for. The questions regarding infections were:
have you the last six months had a common cold, and in
that case how many times?
have you the last six months had bronchitis, and in that
case how many times?
have you the last six months had influenza or influenza-
like illness (with fever), and in that case how many times?
have you the last six months had a UTI, and in that case
how many times?
If at the annual OGTT the fasting blood glucose was
>6.9 mmol/L and/or the 2-h value >11.0 mmol/L the subject
was considered to have T2DM, thus ending their participation
in the study, and thereafter retested (if necessary) and fol-
lowed by their general practitioner. Due to the inclusion of
HbA
1c
(alone or in combination with glucose criteria) as a
diagnostic criterion for diabetes in the WHO report from
2011,[12] and the acceptance of this in Norway the year later,
it was also implemented in the present study from November
2012. Thus, if HbA
1c
alone was 6.5%, the subject was
retested with new HbA
1c
measurement and if still 6.5%
diagnosed as T2DM and ending their participation in the
study. Also, if diagnosed elsewhere with T2DM between visits
in the study, participation was ended.
Subjects who developed persistent hypercalcemia (serum
calcium >2.55 mmol/L), and subjects who developed renal
stones, or symptoms compatible with renal stones, were also
excluded. In the initial protocol, subjects who during the
study were diagnosed with cancer, coronary infarction,
unstable angina pectoris, or stroke, were to be excluded from
the study. From October 2011, this was changed to exclusion
of subjects who during the study developed serious disease
making it difficult or impossible to attend scheduled visits. As
part of the safety monitoring, serum calcium was measured
at each of the six-month visit.
Biochemical analyses including serum 25(OH)D were ana-
lyzed as previously described.[11]
Statistical analyses
Normal distribution was evaluated with visual inspection of
histograms and by kurtosis and skewness. Comparisons
between the two groups at baseline and during the study
were performed with Student’s t-test or chi-square tests.
Occurrence of RTI or UTI in the two groups was evaluated
with Cox regression with gender and age as covariates.
p<0.05 (two-tailed) was considered statically significant.
Data are presented as mean ± SD for normally distributed val-
ues and as median (5th, 95th percentiles) for serum parathy-
roid hormone (PTH) that had a non-normal distribution. All
statistical analyses were performed using IBM SPSS version 22
software (SPSS INC, Chicago, IL).
The power calculation of the study was made for the main
endpoint (development of T2DM),[11] and a separate power
calculation for the infection questionnaire was not made.
Ethics
All subjects gave written informed consent. The study was
approved by the Regional Committee for Medical and Health
Research Ethics (REK NORD 81/2007) and by the Norwegian
Medicines Agency (2007-002167-27). The trial is registered at
ClinicalTrial.gov (NCT00685594).
Results
Five hundred and eleven subjects were included in the study;
256 were randomized to vitamin D and 255 to placebo. Their
baseline characteristics are shown in Table 1. The baseline
serum 25(OH)D levels were 59.9 ± 21.9nmol/L in the vitamin
D group and 61.1 ± 21.2nmol/L in the placebo group. During
the intervention period, the mean serum 25(OH)D level in the
vitamin D group increased to 110 nmol/L after 1 year and
thereafter gradually to 122 nmol/L at the end of the study;
whereas the levels remained stable in the placebo group.
After 1 year median serum PTH decreased by 0.5 pmol/L in
the vitamin D group, whereas there was an increase of
0.2 pmol/L in the placebo group (p<0.001). A similar differ-
ence in serum PTH persisted throughout the study. The com-
pliance rate was between 95 and 99% at all visits in both
groups.
During the study, 50 subjects in the vitamin D group and
45 subjects in the placebo group dropped out or were
excluded due to illness; and 103 subjects in the vitamin D
group and 112 in the placebo group developed T2DM. The
study flow including the number of subjects who attended
the annual visits is shown in Figure 1. Regarding the main
endpoint, development of T2DM, or the secondary endpoints
(changes in measures of glucose metabolism and insulin
resistance, serum lipids and blood pressure) there were no
statistically significant differences between the two
groups.[10,11]
No significant differences in adverse events were recorded
as described in detail previously.[11] Regarding calcium-spe-
cific adverse events, two subjects in the vitamin D group and
one subject in the placebo group developed renal stones and
were excluded; one subject in the vitamin D group was
excluded after a serum calcium of 2.64 mmol/L after six
months with a retest value of 2.63 mmol/L (later testing
showed normal serum calcium and PTH values), and two
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subjects in the vitamin D group and one in the placebo
group had single serum calcium values in the range
2.56–2.61 mmol/L that normalized at second testing, and thus
continued in the study.
Infections
At baseline, there were not any statistically significant differ-
ences between the groups regarding infections the previous
six months, although there were considerably more subjects
in the placebo than the vitamin D group who had experi-
enced one or more UTI (20 subjects versus 10) (Table 1).
During the five-year intervention, a total number of 141
UTI events were recorded, 44 (18 incident and 26 recurrent)
in the vitamin D group and 97 (34 incident and 63 recurrent)
in the placebo group. The numbers of subjects who experi-
enced one or more events with RTI or UTI are shown in
Table 2. A statistically significant difference between the two
groups was only seen for UTI, with less UTI in the vitamin D
group. This difference was significant when evaluating sub-
jects who experienced at least one UTI during the study
period (18 in the vitamin D group vs. 34 in the placebo
group, p¼0.018, Pearson’s chi-square test); when also consid-
ering total number of UTI events (p¼0.025, chi-square test,
linear-by-linear association), and when analyzing with Cox
regression for first UTI event after inclusion in the study (HR
0.51; 95% CI 0.29–0.90, age and gender as covariates,
p¼0.021) (Figure 2). The difference regarding UTI was statis-
tically significant in men (3 in the vitamin D group vs. 11 in
the placebo group) (HR 0.26; 95% CI 0.07–0.93, p¼0.038)
(Figure 3), but did not reach statistical significance in women
(15 in the vitamin D group vs. 23 in the placebo group) (HR
0.64; 95% CI 0.33–1.23, p¼0.18).
Although not statistically significant, there were more sub-
jects with prior UTI in the placebo than the vitamin D group
(20 subjects vs. 10 subjects). Since there is a high relapse rate
for UTI, the lower rate of UTI in the vitamin D group during
the study could therefore be due to this baseline difference.
However, during the intervention, 7 of these 10 subjects in
the vitamin D group and 7 of these 20 subjects in the
placebo group had a recurrence during the study. Exclusion
of these 30 subjects in the Cox regression therefore increased,
and not diminished, the difference between the two groups
regarding first UTI (HR 0.38; 95% CI 0.19–0.76), p¼0.006).
Effect of baseline serum 25(OH)D
Baseline serum 25(OH)D levels did not differ significantly
between those with or without an infection the previous six
months (Table 3), nor was the baseline serum 25(OH)D level a
significant predictor of infections during the intervention
study in neither study group (data not shown).
In the group of subjects with serum 25(OH)D above 50
mnol/L at baseline (167 in the vitamin D group and 170 in
the placebo groups) the effect of vitamin D supplementation
regarding first UTI during the study was still significant (HR
0.49; 95% CI 0.25–0.96, p¼0.038). However, in the group of
subjects with baseline serum 25(OH)D below 50 nmol/L (88
subjects in the vitamin D group and the 85 in the placebo
group), the effect did not reach statistical significance
(HR 0.53; 95% CI 0.17–1.64, p¼0.27).
Discussion
In the present study, we have found supplementation with
vitamin D to significantly reduce the occurrence and number
of UTI during a five-year intervention study, whereas no effect
was seen on RTI.
To our knowledge, this is the first RCT reporting effect of
vitamin D on UTI. However, there are several observational
reports linking vitamin D deficiency to UTI. Thus, in a case–
control study by van der Starre et al., adult subjects with UTI
Table 1. Baseline characteristics in the two study groups.
Vitamin D group
(n¼256)
Placebo group
(n¼255)
Male sex, n(%) 161 (62.9) 153 (60.0)
Age (years) 62.3 ± 8.1 61.9 ± 9.2
BMI (kg/m
2
) 30.1 ± 4.1 29.8 ± 4.4
Current smokers, n(%) 59 (23.0) 47 (18.3)
Vitamin D supplement use
a
87 (34.0) 92 (36.1)
Serum 25(OH)D (nmol/L) 59.9 ± 21.9 61.1 ± 21.2
Serum calcium (mmol/L) 2.31 ± 0.08 2.31 ± 0.08
Serum PTH (pmol/L) 5.5 (3.4, 9.7) 5.2 (3.1, 9.6)
Serum creatinine (lmol/L) 69.7 ± 13.6 69.5 ± 13.9
HbA
1c
(%) 5.98 ± 0.28 5.97 ± 0.34
Infections last six months
Common cold (yes/no) 99/157 100/155
Bronchitis (yes/no) 7/249 13/242
Influenza (yes/no) 58/198 43/212
UTI (yes/no) 10/246 20/255
a
Including cod liver oil.
BMI: body mass index; 25(OH)D: 25-hydroxyvitamin D; PTH: parathyroid hor-
mone; HbA
1c
: hemoglobin A1c; UTI: urinary tract infection.
Figure 1. Flow chart of the study.
INFECTIOUS DISEASES 825
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had 28% lower serum 25(OH)D levels than controls [13]; in
children with UTI Tekin et al. found the serum 25(OH)D levels
to be approximately half those in the controls,[14] and a simi-
lar observation was made by Nesir et al. in premenopausl
women [15]; Vaughan et al. found vitamin D deficiency to be
associated with lower urinary tract symptoms in a cohort of
2387 men in the 2005–2006 NHANES [16]; Caretta et al. found
low serum 25(OH)D levels to be associated with urinary tract
symptoms and benign prostate hypertrophy in male subjects
with T2DM [17]; and finally, Kwon et al. found vitamin D defi-
ciency to be an independent risk factor for UTI after renal
transplantation.[18]
There could be several mechanisms for a protective effect
of vitamin D on UTI. It has been shown that vitamin D can
induce production and secretion of the antimicrobial peptide
cathelicidin by bladder epithelial cells [19,20]; vitamin D is
important for innate immunity in defending against bacterial
infections by increasing the neutrophilic motility and
phagocytic function [21]; vitamin D supplementation could
alter the chemical composition of the urine by increasing the
urinary calcium excretion [22]; vitamin D has a direct effect
on muscle function and could contribute to pelvic floor func-
tion and bladder emptying, particularly in women [23]; and in
Table 2. Number of subjects according to number of events with common cold, bronchitis, influenza-like illness or urinary tract infection during the five-year study
period.
Number of subjects
Common cold Bronchitis Influenza-like illness Urinary tract infection
Number of events Vitamin D Placebo Vitamin D Placebo Vitamin D Placebo Vitamin D Placebo
0 71 73 223 224 137 158 238 221
1 5255 161968549 15
2 38 37 11 8 28 18 3 5
3 2224 329152 3
4 2119 1277 5
51710 4231
61211 11
711711 1
848121
911
10 2 3 1
>10 5 7 2
P vs. placebo (chi-square test) ns ns ns 0.025
Figure 3. Cumulative probability of urinary tract infection (UTI) based on Cox
regression with age as covariate in the 161 men in the vitamin D group and the
153 men in the placebo group.
Figure 2. Cumulative probability of urinary tract infection (UTI) based on Cox
regression with age and gender as covariates in the 256 subjects in the vitamin
D group and the 255 subjects in the placebo group.
Table 3. Baseline serum 25(OH)D levels in subjects with or without infection
last six months before baseline.
Subjects with infection
last six months
Subjects without infection
last six months
N
Serum 25(OH)D
(nmol/L) N
Serum 25(OH)D
(nmol/L)
Common cold 199 59.1 ± 21.0 312 61.4 ± 21.9
Bronchitis 20 52.9 ± 16.6 491 60.8 ± 21.7
Influenza 101 59.9 ± 20.8 410 60.6 ± 21.8
UTI 30 62.9 ± 24.1 481 60.3 ± 21.4
All infections 250 59.8 ± 21.8 261 61.2 ± 21.3
25(OH)D: 25-hydroxyvitamin D; UTI: urinary tract infection.
826 R. JORDE ET AL.
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men, vitamin D appears to be a regulator of prostatic cell
growth, could influence the development of benign prostatic
hyperplasia (BPH), and thereby reduce the likelihood of
UTI.[24]
The effect of vitamin D on BPH is supported by an
observational study where subjects with the highest quintile
of vitamin D intake had a 18% reduced risk of developing
BPH compared to those in the lowest quintile [25]; and
also from an RCT where the vitamin D
3
analog BXL628 was
able to arrest prostate growth in subjects with moderate
BPH.[26] In our study this is of particular interest since the
effect of the vitamin D supplementation was particularly
evident in men.
We did not observe any effect of vitamin D on the occur-
rence of RTI. This is in line with the conclusion in the recent
review by Kearns et al. that included 13 RCTs with vitamin D
for prevention of RTI.[6] Only two of those studies found a
positive effect of vitamin D, whereas the other found no
change in the incidence or severity of RTI or influenza
symptoms.
Our study has two main weaknesses: we used question-
naires with self-reported occurrence of infections without
any bacteriological, virological or serological verification,
and the effect on infections was not a primary endpoint. It
is also remarkable that the effect of vitamin D supplemen-
tation was not related to baseline serum 25(OH)D levels.
Thus, the protective effect of vitamin D was significant not
only in all subjects analyzed together, but also in those
with baseline serum 25(OH)D above 50 nmol/L, a level that
many consider as sufficient at least for bone health.[27]If
our result is not a chance finding, this may indicate that
the threshold for vitamin D effects is different for the urin-
ary tract than for the skeleton.
Our study also have some strengths: the study was per-
formed according to strict RCT rules, the questionnaire was
administered and checked by highly trained nurses, we
included a large number of subjects, and we gave sufficient
vitamin D doses for a long period of time.
In conclusion, there is an abundance of observational stud-
ies regarding vitamin D and health effect, and for almost
every disease examined, high serum 25(OH)D levels appear
beneficial. However, RCTs with vitamin D supplementation
have been disappointing.[28] In view of this, our result with a
positive effect of vitamin D on UTI should be viewed with
caution and more RCTs are clearly needed. In particular, the
unexpected effect in subjects apparently vitamin D sufficient
needs confirmation.
Acknowledgements
The superb assistance from the staff at the Clinical Research Unit (and
in particular Aslaug Jakobsen) and the Department of Medical
Biochemistry at the University Hospital of North Norway is gratefully
acknowledged.
Disclosure statement
The authors do not have a commercial or other association that might
pose a conflict of interest.
Funding information
The study was supported by grants from the Novo Nordisk foundation
(grant number R195-A16126), the North Norway Regional Health
Authorities (grant number 6856/SFP1029-12), UiT The Arctic University of
Norway, the Norwegian Diabetes Association, and the Research Council of
Norway (grant number 184766).
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