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Prevention of recurrent benign paroxysmal positional vertigo with vitamin D

supplementation: a meta-analysis

Article  in  Journal of Neurology · August 2020

DOI: 10.1007/s00415-020-09952-8

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Journal of Neurology
https://doi.org/10.1007/s00415-020-09952-8

REVIEW

Prevention of recurrent benign paroxysmal positional vertigo

with vitamin D supplementation: a meta‑analysis
Seong‑Hae Jeong1 · Sun‑Uk Lee2 · Ji‑Soo Kim3,4 

Received: 28 April 2020 / Revised: 24 May 2020 / Accepted: 26 May 2020

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Research Background  Vitamin D insufficiency/deficiency is known to be related to occurrences and recurrences of benign
paroxysmal positional vertigo (BPPV). However, the efficacy of vitamin D supplementation in reducing recurrences of BPPV
remains to be established. We performed a meta-analysis to determine the therapeutic effects of vitamin D supplementation,
with or without calcium, for preventing recurrences of BPPV.
Methods  We searched the PubMed, the Embase, the Web of Science and the reference lists of the articles. We included
randomized or non-randomized trials that determined the efficacy of supplementing vitamin D or related compounds, alone
or with calcium, in comparison to placebo or no intervention in preventing recurrences of BPPV. The primary outcome was
the number of patients with BPPV recurrences. Data were collected and pooled using a weighted relative risk (RR) with
corresponding 95% CIs, where possible, by adopting the fixed-effect or random-effect model according to the heterogeneity
among the studies. The between-study heterogeneity was tested using the χ2 test and the I2 statistic, and funnel plots were
used to evaluate any publication bias.
Results  We included five trials (four non-randomized trials and one randomized controlled trial) with a total of 1250 par-
ticipants. The analyses showed a significant preventive effect on the recurrences of BPPV (RR = 0.37; 95% CI = 0.18–0.76;
p = 0.007 with the random-effects model) with supplementation of vitamin D. Although a considerable heterogeneity was
detected among the studies, the sensitivity analyses showed the reliability and stability of our results.
Conclusions  Vitamin D supplementation provides a benefit for secondary prevention of BPPV. Supplementation of vitamin
D should be considered in patients with frequent attacks of BPPV, especially when serum vitamin D is subnormal.

Keywords  Vitamin D · Vertigo · BPPV · Prevention · Calcium

Introduction

Human vestibular dysfunction is a common clinical prob-

Electronic supplementary material  The online version of this
article (https​://doi.org/10.1007/s0041​5-020-09952​-8) contains
supplementary material, which is available to authorized users.
* Ji‑Soo Kim
jisookim@snu.ac.kr
1
Department of Neurology, Chungnam National University
Hospital, Chungnam National University School
of Medicine, Daejeon, Korea
2
Department of Neurology, Korea University Medical Center,
Seoul, Republic of Korea
3
Department of Neurology, Seoul National University College
of Medicine, 300 Gumi‑dong, Bundang‑gu, Seongnam‑si,
Gyeonggi‑do, Seoul 463‑707, Korea
4
Dizziness Center, Seoul National University Bundang
Hospital, Seongnam, Korea
lem. Among the vestibular disorders, benign paroxysmal
positional vertigo (BPPV) is the most common cause of
recurrent vertigo [1]. Although benign, the unexpected
occurrence could make the patients debilitated [2]. The
link between vitamin D and BPPV was first described in
2013 [3]. Since then, several studies across the globe have
reported a higher prevalence of vitamin D deficiency in
patients with BPPV than in general population [4–10]. A
possible explanation for this is low sunshine exposure result-
ing from immobilization due to vertigo [11]. However, a
previous study showed no difference in the serum vitamin
D level between the controls and 397 community residents
who had a history of vertigo/dizziness or imbalance dur-
ing the preceding year [3]. This indicates that decreased

13
Vol.:(0123456789)

serum vitamin D level in patients with BPPV is not due to
immobilization from vertigo but a contributing factor for
occurrences of BPPV [3]. Since the first case–control study
on BPPV and a serum level of vitamin D, a large body of
clinical evidences and a recent clinical trial have suggested
an association of decreased serum vitamin D with occur-
rences/recurrences of BPPV [4–10, 12–20]. A clinical ques-
tion which is yet to be answered is whether supplementation
of vitamin D reduces the recurrences of BPPV. This study
aimed to determine the efficacy of vitamin D supplementa-
tion with or without calcium in reducing the recurrences of
BPPV using a meta-analysis.
Methods
Study selection
This meta-analysis was performed in accordance with the
Preferred Reporting Items for Systemic Review and Meta-
analysis (PRISMA). The relevant available literature was
searched at the PubMed, the Embase, and the Web of Sci-
ence from inception to February 2020. The search terms
were presented in the supplementary table. The language
was restricted to English. We also reviewed the reference
lists of the articles obtained to identify other potentially rel-
evant literature.
Inclusion criteria
We included all the studies that determined the efficacy of
supplementing vitamin D or related compounds, alone or
with calcium, in comparison to placebo or no intervention in
preventing recurrences of BPPV. All studies had to provide
enough information about recurrences of BPPV. If differ-
ent publications based on the same study participants were
available, the most recent one was included.
Data extraction and quality assessment
For each study, the following data were independently
extracted by two reviewers: name of the first author, year
of publication, location of the study, study design, number
of participants, mean age, number of patients with vitamin
D management, vitamin D types and doses, the recurrence
of BPPV, and duration of follow-up. Any disagreement
was resolved through discussion by the reviewers (SHJ and
SUL). Moreover, the Review of Bias Assessment tool for
Non-randomized Study (RoBANS) was used to perform
the quality assessment of nonrandomized studies [21]. In
addition, a Cochrane risk of bias tool was used for the ran-
domized trials.
13
Journal of Neurology
Statistical analyses
Statistical analyses were performed using the Cochrane
Review Manager (RevMan, version 5.3) software. The
weighted relative risk (RR) with corresponding 95% con-
fidence intervals (CIs) was used to evaluate the treatment
effects in terms of BPPV recurrences using the fixed- and
random-effects models, and p < 0.05 was considered sta-
tistically significant. The between-study heterogeneity
was tested using the χ 2 test and the I2 statistic, whereby
I2 > 50% referred to a substantial heterogeneity among the
studies. Sensitively analyses were also conducted, and the
influence of a single study in the pooled effect was deter-
mined by removing one study at a time. Due to the limited
number of studies, a funnel plot was unavailable to assess
for reporting bias.
Results
Study selection
The selection process for inclusion of studies in this meta-
analysis is summarized in Fig. 1. A total of 655 poten-
tially relevant studies were initially identified via database
searches. After excluding duplicated studies, we retrieved
629 articles. Of these, we evaluated the titles and abstracts
and identified 18 studies for further assessment and full-
text review. Then, 14 studies were excluded since they did
not measure the serum vitamin D or compare the treatment
effects, or provided insufficient data about BPPV recur-
rences or control groups. Finally, four non-randomized
studies and one randomized controlled trial were included
for this meta-analysis [12, 13, 18, 20, 22].
Characteristics of the studies and quality
assessment
The publishing year of the studies included for this meta-
analysis ranged from 2013 to 2020. Of the 1114 partici-
pants with BPPV, 505 received vitamin D supplementa-
tion with or without calcium. Studies were conducted in
several regions including Saudi Arabia, Iran, Portugal,
Italy and South Korea [12, 13, 18, 20, 22]. We identified
four non-randomized studies that had adopted a high-dose
vitamin ­D3 (cholecalciferol) supplementation with a range
of 35,000–50,000 IU/week for 1–2 months. In contrast, a
standard dose of vitamin D ­ 3 (800 IU/d) with calcium car-
bonate was administered in a recent randomized controlled
trial. Details of the included studies are shown in Table 1.
Journal of Neurology
Fig. 1  A flow diagram for the selection of studies
BPPV recurrences
All five studies analyzed the recurrences of BPPV. As
shown in Fig. 2, all studies showed a significant decrease in
BPPV recurrences after supplementation of vitamin D with
both the fixed- (Fig. 2a, RR = 0.68; 95% CI = 0.59 to 0.78;
p < 0.0001) and random-effects models (Fig. 2b, RR = 0.37;
95% CI = 0.18 to 0.76; p = 0.007).
Sensitivity analysis
Sensitivity analyses were conducted using a leave-one-out
analysis. The results showed that none of the exclusions
altered the results of the previous analyses, indicating the
good reliability and stability of the results of this meta-anal-
ysis. Significant heterogeneity was noted among the studies
(I2 = 88%; p < 0.001), and this heterogeneity was decreased
after exclusion of a randomized trial with a relatively large
sample size (I2 = 43%).
13


13
Table 1  Clinical characteristics of included studies
First author Year Location Design Age Number of Number Recurrence of Recurrence of Duration Vitamin D dosage and schedule
treatments of con- BPPV in treat- BPPV in control (month)
trols ment group

Talaat 2016 Saudi Arabia Cohort 28–70 28 65 4 28 18 Loading dose for 1 month, 50,000 IU
oral vitamin D3, 3 times/week,
followed by maintenance dose,
50,000 IU oral vitamin D3, once
every 2 weeks plus Calcium citrate
600 mg tablets twice daily
Sheikhzadeh 2016 Iran Case–Control 36–59 27 27 4 26 6 50,000 IU cholecalciferol weekly for 2
months to raise serum 25-OHD up to
30 ng/ml or higher
de Sousa 2019 Portugal Comparative before–after study 52–82 5 5 0 5 12 eight oral drops per day if there was
deficiency (ensuing 5000 IU of vita-
min D per day) and only one pill per
month (assuring 800 IU of vitamin
D per day) if there was only insuf-
ficiency
Califano 2019 Italy Comparative before–after study 36–85 68 68 13 28 12 Cholecalciferol (vitamin D3) per os,
from 10,000 to 50,000 IU, weekly, in
relation to the laboratory data, with
the overall limit of 600,000 IU in a
year
Jeong 2020 South Korea Randomized-Controlled trial 28–94 445 512 168 239 12 Vitamin D 400 IU and 500 mg of cal-
cium carbonate twice a day
Journal of Neurology
Journal of Neurology
Fig. 2  Forest plot comparison of vitamin D supplementation in preventing recurrences of benign paroxysmal positional vertigo using the fixed-
(a) and random-effects (b) models
Discussion
In the present study, we demonstrated the effectiveness of
vitamin D supplementation with/without calcium in the sec-
ondary prevention of BPPV. The results showed an efficacy
for both standard and high-dose vitamin D supplementation.
Hence, for patients with recurrent attacks of BPPV, vitamin
D supplementation would be an appealing option.
The beneficial effect of vitamin D therapy in BPPV may
be attributed to the direct effect of vitamin D on the vestibu-
lar system or the indirect effect of vitamin D on the musculo-
skeletal system. BPPV is believed to be caused by detached
otoconia with a size up to 30 μm and a density of calcite at
2.71 in humans [23]. Otoconia are bio-crystals anchored to
the macular sensory epithelium of the utricle and saccule
in the inner ear for motion sensing and balance. Disloca-
tion, degeneration and ectopic calcification of the otoconia
may result in displacement of utricular otoconia into the
semicircular canals. Migration of the dislodged otoconia into
the semicircular canals gives rise to abnormal sensations of
dizziness and loss of balance during head motion, a con-
dition referred to as BPPV [24–27]. Normal generation of
otoconia requires a complex temporal and spatial control of
developmental and biochemical formation based on matrix
vesicle mineralization [28]. During these processes, vitamin
D could influence the dynamic turnover of otoconia via the
calcium metabolism.
Dynamic calcium turnover in the otoconia
Otoconia are the complex of calcium carbonate ­(CaCO3)
biominerals in the vertebrate utricle and saccule, and are
embedded in a fibrous extracellular matrix (gelatinous mem-
brane) [28]. Human otoconia are subject to demineraliza-
tion and to alteration in the structure and composition from
aging, diseases, and exposure to common pharmaceutical
agents. For example, streptomycin especially interferes with
calcium uptake into the otoconia [29, 30], and the otoconia
in Guinea pigs begin to recover 4 weeks after the last injec-
tion of streptomycin into the utricle and after 6 weeks into
the saccule with an increasing number of small otoconia
[30, 31]. It has been indicated, therefore, that the recovery
of calcium uptake as well as otoconial regeneration may play
an important role for the recovery from the loss of otoconia
after various insults. These dynamic changes may be closely
related to the dynamics of calcium turnover in the otoconia.
Low calcium in the endolymph
The endolymph of the inner ear represents a unique extracel-
lular ionic milieu. The ­Ca2+ concentration of the vestibular
endolymph (~ 250 μM) is lower than that of the perilymph
(~ 1 mM). This plays a critical role in sensory transduction
­ a2+ absorption system
through the hair cells [32]. Thus, a C
should be present in the inner ear epithelial cells to maintain
13

the low ­[Ca2+] in the vestibular endolymph. Previous reports
­ a2+ channels TRPV5 and TRPV6
showed that the epithelial C
(transient receptor potential type 5 and 6) are expressed in
the semicircular canal duct and are the important calcium-
binding proteins for maintenance of low ­[Ca2+] in the vestib-
ular endolymph. An experimental study also showed that the
expression of TRPV5 is regulated by 1,25-dihydroxyvitamin
­D3, likewise in other systems [33]. In addition, other calcium
transporters expressed in the semicircular canals, such as
calbindin-D9K and calbindin-D28K, are also up-regulated
after administration of 1,25-dihydroxyvitamin ­D3 [33].
Elemental composition of the otoconia
The otoconia have distinct central cores and peripheral zones
[34]. The core is predominantly organic with a lower level
of ­Ca2+, and the periphery is largely inorganic with a higher
­ a2+. The core, periphery and external surface of the
level of C
crystals all have inter-connecting fibrous materials with var-
ied diameters and organization [34]. These fibers are scaf-
folding protein for otoconia and are likely made up of the
inner ear-specific collagen called otolin-1 [35, 36]. A recent
study showed a higher level of serum otolin-1 in patients
with BPPV [37]; negatively correlated with T-score of bone
mineral density [38] and with serum 25(OH)-vitamin D in
those with an age > 70 [39]. These findings suggest that
vitamin D deficiency should be sought in old patients with
BPPV. In a recent study on prevention of BPPV with vita-
min D supplementation, the subgroup analysis also showed
an efficacy of vitamin D administration in old patients with
BPPV [20]. Gait and balance disorders are among the most
common causes of falls in older adults and often lead to
injury, disability, loss of independence, and limitations in
quality of life. These findings again emphasize that the
maintenance of serum vitamin D level is important in old
patients.
Existence of the vitamin D receptors
in the vestibular organs
The vitamin D endocrine system is essential for calcium
and bone homeostasis [40]. The active form of vitamin D,
dihydroxyvitamin ­D3 [1,25(OH)2D], is a seco-steroid that
binds to the nuclear vitamin D receptor (VDR) [41]. Studies
have also shown an existence and modulation of the VDR
in the vestibular organs [42]. The robust VDR expression in
the vestibular organs implies the important role of vitamin
D/VDR system in vestibular function [42]. Indeed, VDR-
deficient mice demonstrate vestibular dysfunctions [42].
These data also suggest that vitamin D is important for bal-
ance control.
13
Journal of Neurology
Clinical impacts of the study
According to our estimates, maintenance of serum vitamin D
level may provide up to 63% of risk reduction against recur-
rences of BPPV. Despite the favorable outcome of canalith
repositioning maneuvers, BPPV exerts adverse psychoso-
cial consequences that include reduced health-related qual-
ity of life and severe subjective impairments and avoidance
behavior in 70% of individuals with BPPV [43]. The adop-
tion of vitamin D supplementation in patients with BPPV
may improve the quality of life and socio-economic benefits
given the BPPV-related costs estimated in South Korea, the
USA and the United Kingdom [20]. A previous randomized
clinical trial showed a better outcome with vitamin D sup-
plementation in those older than 65, with canalolithiasis,
without previous ear disease and migraine, and with vascular
risk factors [20].
Limitations
Even with the positive results of vitamin D supplementa-
tion in reducing BPPV recurrences, several issues remain
to be addressed. First, we cannot exclude that our screening
criteria may have biased the effect estimates. Unfortunately,
most studies adopted a non-randomized study design, and
the information on the control group was insufficient. The
dosages of vitamin D administered were different among
the studies. Thus, the optimal dose of vitamin D supple-
mentation should be determined even though the sensitivity
analysis showed that the results remained unchanged even
when the analysis was restricted to those on the lower vs.
upper end of vitamin D dosage. The role of co-adminis-
tration of calcium should also be defined. We also need to
determine whether the changes in the serum level of vitamin
D after supplementation are predictive of future recurrences
of BPPV and what is a safe level. The biological mecha-
nisms by which the vitamin D may confer protection against
BPPV remain to be elucidated. Furthermore, future studies
are required to determine whether there are changes in the
biomarkers of BPPV, such as otolin-1, after long-term sup-
plementation of vitamin D or whether a short-term exposure
is enough to ward off BPPV attacks [37, 39]. In conclusion,
we need further studies adopting a larger number of patients
and longer duration of follow-ups to confirm the generaliz-
ability of these research findings in the population of more
diverse economic, medical, and social backgrounds.
Author contributions  SHJ acquired and analyzed the data, and drafted
the manuscript. SUL acquired and analyzed the data, and revised the
manuscript. JSK conceptualized and supervised the study, and revised
the manuscript.
Journal of Neurology
Funding  This study was supported by Basic Science Research
Program  through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Technology
(no. NRF-2016R1D1A1B04935568).
Data availability  The data that support the findings of this study are
available from the corresponding author, upon reasonable request.
Compliance with ethical standards  MAO.00000​00000​00116​7
Conflict of interest  The authors report no disclosure relevant to the
manuscript.
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