Vitamin D for the management of multiple sclerosis (Review)
Jagannath VA, Fedorowicz Z, Asokan GV, Robak EW, Whamond L
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 12
http://www.thecochranelibrary.com
Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
9DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
22INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iVitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Vitamin D for the management of multiple sclerosis
Vanitha A Jagannath1 , Zbys Fedorowicz2 , G V Asokan3 , Edward W Robak4 , Liz Whamond5
1Department of Paediatrics, KIMS Bahrain Medical Center, Manama, Bahrain. 2UKCC (Bahrain Branch), Ministry of Health, Bahrain,
Awali, Bahrain. 3College of Health Sciences, Ministry of Health, Manama, Bahrain. 4Faculty of Forestry and Environmental Manage-
ment, University of New Brunswick, Fredericton, Canada. 5Canadian Cancer Action Network, Fredericton, Canada
Contact address: Vanitha A Jagannath, Department of Paediatrics, KIMS Bahrain Medical Center, Um al Hassam Ave, Adliya, Manama,
PO Box 175829, Bahrain. [email protected]. [email protected].
Editorial group: Cochrane Multiple Sclerosis Group.
Publication status and date: New, published in Issue 12, 2010.
Review content assessed as up-to-date: 29 June 2010.
Citation: Jagannath VA, Fedorowicz Z, Asokan GV, Robak EW, Whamond L. Vitamin D for the management of multiple sclerosis.
Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD008422. DOI: 10.1002/14651858.CD008422.pub2.
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Multiple sclerosis is a disease of the central nervous system characterized by demyelination of the nerve sheaths which can result in
varying levels of disability. Disease occurrence and progression are considered by some to be associated with low serum levels of vitamin
D. Studies investigating vitamin D supplementation in MS patients have illustrated a noticeable improvement in the course of the
disease.
Objectives
To evaluate the safety and effectiveness of vitamin D in the management of multiple sclerosis.
Search strategy
We searched the Cochrane Multiple Sclerosis Group Trials Register comprising references identified from comprehensive electronic
database searches and hand searches of relevant journals and abstract books of conferences.
Selection criteria
Randomised and quasi-randomised controlled trials comparing vitamin D with placebo or any other treatment for the management of
multiple sclerosis.
Data collection and analysis
Two review authors selected trials for inclusion, assessed the risk of bias and extracted data independently. Disagreements were resolved
by consensus. Trialists were contacted for clarification of study details.
Main results
We included a single trial (49 participants) conducted over 52 weeks, which treated 25 patients with escalating doses of vitamin D
compared with control (24). The trial provided some evidence of the potential benefit of the intervention on several outcomes i.e. the
annualised relapse rate; EDSS scores; suppression of T-cell proliferation and illustrated a measure of comparative safety in the relative
absence of any adverse events or of high serum calcium levels over the study period. This was a low powered trial with a potential high
risk of bias which may ultimately impose limits on the applicability of the available evidence to the MS population as a whole.
1Vitamin D for the management of multiple sclerosis (Review)
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Authors’ conclusions
The current level of evidence for the effectiveness of vitamin D supplementation in the management of people with MS is based on a
single RCT with potential high risk of bias, which does not at present allow confident decision-making about the use of Vitamin D
in MS. Therefore, until further high quality evidence is available, clinicians may wish to consider relevant MS guidelines on vitamin
D supplementation when making decisions about the care of people with multiple sclerosis. Adequately powered, multi-centred RCTs
with a focus on clinical as well as immunological and MRI outcomes that are meaningful to people with MS, and are able to provide
insight into the benefits of Vitamin D in people with MS, are still required.
P L A I N L A N G U A G E S U M M A R Y
Vitamin D for the management of multiple sclerosis
Multiple sclerosis is an illness in which the myelin sheaths around the nerves of the brain and spinal cord are damaged, affecting the
ability of nerve cells to communicate with each other. A wide range of clinical presentations and neurological symptoms can occur with
the disease, and these can progress to physical and cognitive disability often with a variable clinical course. Although very little is known
about the mechanism and causes of this disease genetic, immunologic and environmental factors have all been implicated. Studies have
shown a characteristic geographical pattern of disease distribution both in occurrence and progression, which appear to be correlated
with sun light exposure and lack of vitamin D and are considered to be predisposing factors for MS. Vitamin D deficiency is said to
affect the general well being of patients with MS and is also associated with poorer neurologic outcomes. People suffering with MS
are usually given regular vitamin D preparations after assessment of their serum levels of vitamin D.This review sought to evaluate the
benefits and harms of this Vitamin D administration to people of MS.The current level of evidence from this review is based on only
one trial with potential high risk of bias, which does not at present allow confident decision-making about the use of Vitamin D in
MS. The review authors suggest that until further high-level evidence is available, clinicians should continue to follow local guidelines
when administering vitamin D to people with MS.However, the question of the safety and effectiveness of Vitamin D in people of MS
remains unanswered.
Further research, consisting of well-designed and adequately-powered randomised controlled trials, should aim to provide reliable
evidence for people to make informed decisions as to whether this treatment can be effective in the management of MS
B A C K G R O U N D
Multiple sclerosis (MS) is an immune-mediated disease of the Cen-
tral Nervous System (CNS). Epidemiological studies have shown
a characteristic geographic distribution of MS wherein increased
incidence is seen in regions farther away from the equator (00 lat-
itude) and hence there appears to be a direct correlation of MS
occurrence and mortality with the latitude (Esparza 1995; Llorca
2005). This distribution would also appear to be supported by
circumstantial evidence implicating environmental factors of the
degree of sunlight exposure and the subsequent production of vi-
tamin D3 in skin as a predisposing factor for MS (Freedman 2000;
Ponsonby 2005).
Less than optimal blood levels of vitamin D have been linked to an
increased incidence of MS (Embry 2000; Munger 2006) and there
is also a positive association between low blood levels and relapse
in MS (Soilu-Hanninen 2005;Mowry 2010). Studies on vitamin
D supplementation in patients with MS have also shown that
the relapse rate before supplementation was significantly higher
(Goldberg 1986) and that there was a noticeable improvement in
the course of the disease after supplementation (Munger 2004).
An improved understanding of the role of vitamin D in MS has led
to the inclusion of assessment of vitamin D levels and subsequent
supplementation in the clinical management of people living with
MS.
Description of the condition
Multiple sclerosis is characterized by inflammation, demyelina-
tion and axonal damage throughout the CNS which manifests it-
self in a wide range of clinical presentations and with a variable
clinical course. Typical clinical features include visual loss, dou-
ble vision, motor weakness, spasticity, ataxia, tremor, sensory loss
or impairment, sphincter dysfunction and cognitive impairment.
2Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The course of the disease is so variable that some people become
significantly disabled in a very short period of time, while others
can live their entire lives with only minimal or no disability.
Complex interactions between genetic susceptibility and other ex-
ternal factors such as viral infection and inadequate Vitamin D
are considered to be major determinants of MS risk (Kampman
2008).
How the intervention might work
The exogenous 1, 25-dihydroxy vitamin D3 is the hormonal form
of vitamin D3. This vitamin D hormone is generally perceived to
be important for the normal growth and development of bone,
mediated through the absorption of calcium from food and its
ultimate deposition in bone. Apart from its involvement in bone
metabolism it is also connected with the regulation of cell prolif-
eration and differentiation as well as apoptosis (Table 1) and im-
mune regulation in certain types of immune cells i.e. T helper and
dendritic cells (Niino 2008). Vitamin D intake reduces inflamma-
tory cytokines through control of gene expression (Mark 2006)
and is also involved in immunomodulatory protective effects on
the brain (Garcion 2002).
Table 1. Glossary
apoptosis A form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing
harmful substances into the surrounding area
arrhythmia An abnormal heart rhythm
cytokine A small protein released by cells that has a specific effect on the interactions between cells, on communications
between cells or on the behavior of cells. The cytokines includes the interleukins, lymphokines and cell signal
molecules, such as tumour necrosis factor and the interferons, which trigger inflammation and respond to
infections.
demyelination Damage of the myelin sheath of neurons
metallo- protease Proteolytic enzymes whose catalytic mechanism involves a metal, important in many aspects of biology, ranging
from cell proliferation, differentiation and remodeling of the extracellular matrix (ECM) to vascularization and
cell migration
nephrolithiasis The process of forming a kidney stone, or lower down in the urinary tract.
osteoporosis Thinning of the bones with reduction in bone mass due to depletion of calcium and bone protein.
relapse An objective new/reemerging neurologic abnormality present for at least 24 hours in the absence of fever/infection.
It has been suggested that sub optimal levels of vitamin D may be
contributory in the process of axonal inflammation and its pro-
gression to Multiple Sclerosis, and it is also acknowledged that
relapse tends to be more common in people with low levels of
this vitamin. The precise mechanism is unclear but its role is hy-
pothesised to be as a selective immune regulator which can inhibit
this autoimmune disease.The doses required to have an immuno-
regulatory effect have been observed to be much higher than the
recommended daily intake dose (Leventis 2008)
Why it is important to do this review
Based on epidemiological data and evidence from observational
studies it has been suggested that vitamin D may help prevent MS,
reduce exacerbations and may be a useful addition to standard MS
therapy. The optimal dose of vitamin D required to have a benefi-
cial effect may be much higher than the standard supplementation
dose, and the potential hypercalcaemic side effect at such levels
can be a limitation for using this intervention (Kimball 2007). In
this review we sought to determine whether there is clear evidence
of benefit and safety for vitamin D supplementation in the man-
agement of MS.
O B J E C T I V E S
3Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
To evaluate the safety and effectiveness of vitamin D in the man-
agement of multiple sclerosis (MS)
To evaluate the hypotheses that vitamin D supplementation re-
duces disease activity, suppresses its progression, prevents devel-
opment of osteoporosis and promotes T-cell regulation in people
with MS.
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included all eligible randomised controlled trials and quasi-
randomised controlled trials.
Types of participants
Patients diagnosed as having clinically definite MS according
to Schumacher, Poser or McDonald’s criteria (McDonald 2001;
Polman 2005; Poser 1983; Schumacker 1965). Cases with any
pattern of the disease course (relapsing-remitting, secondary pro-
gressive and primary progressive) were included.
Exclusion criteria were allergy to any form of vitamin D, a history
of cardiac arrhythmias or any renal disease or nephrolithiasis (Table
1).
Types of interventions
All preparations of vitamin D compared to placebo or no sup-
plementation. There were no restrictions concerning route of ad-
ministration, dosage, length and frequency of treatment. Studies
comparing different doses of vitamin D were also included. Mul-
tivitamin preparations containing vitamin D were included.
Types of outcome measures
Primary outcomes
1. The mean number of relapses per patient per year or
annualised relapse rate (ARR) and proportion of patients who
remain relapse free (Table 1).
2. Time to the first treated relapse.
3. Quality of life (validated, generic or disease specific scales
i.e. MSQOL-54) (Vickrey 1995).
4. Number of patients experiencing change in the scores on
the Expanded Disability Status Scale (EDSS) (Kurtzke 1983) (at
least 1 point for EDSS < 6.0 or 0.5 point for EDSS > 5.5).
5. Safety and adverse effects: Safety and tolerability assessment
as the number of drop-outs, willingness to continue treatment
and any reported adverse events. These will be considered in the
following groups mild (not requiring intervention), moderate
(requiring treatment) and severe (life threatening or requiring
hospitalisation).
Secondary outcomes
1. Number of patients requiring hospitalisation due to
progression of the disease.
2. Cognitive functions: memory, concentration (by validated
and disease specific scales i.e. BRBNT) (Rao 1991).
3. Physical symptoms: fatigue, spasticity, spasms, bladder
function, bowel symptoms) (better, worse or no change) assessed
by questionnaire or similar instruments.
4. Psychological symptoms (better, worse or no change)
assessed by questionnaire or similar instruments.
5. Mean change in MRI parameters of disease activity
(number and/or volume of gadolinium -enhancing T1 and new
T2 lesions).
6. Serum levels of 25-hydroxyvitamin D (25(OH) vitamin D)
and calcium.
7. Bone mineral density (BMD) changes during the study
period.
8. Cytokine profile, T lymphocyte proliferation response and
Plasma metalloprotease-9 activity (Table 1).
All outcomes will have been evaluated at 6 months, 12 months
and annually thereafter. Outcomes measured at other end points
will also be considered and evaluated separately.
Search methods for identification of studies
A systematic search without language restrictions was conducted
using the optimally sensitive strategy developed for the Cochrane
Collaboration to identify all relevant published and unpublished
randomised controlled trials (Lefebvre 2009). For additional in-
formation about the Group’s search strategy please see: Cochrane
Multiple Sclerosis Group
Electronic searches
We searched the following databases:
1. The Cochrane Multiple Sclerosis Group Trials Register (17
May 2010)
2. The Cochrane Central Register of Controlled Trials
(CENTRAL) “The Cochrane Library” (Issue 2, 2010)
(Appendix 1)
3. MEDLINE (PubMed) (January 1966 to 17 May 2010)
(Appendix 2)
4. EMBASE (EMBASE.com) (1974 to 17 May 2010)
(Appendix 3)
4Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Searching other resources
In addition the following methods were used:
1. Bibliographic references of identified studies were searched
for references to additional studies.
2. Hand-searching of recent abstract books of ECTRIMS,
EFNS, ENS, AAN and ANA (1990 to 2009)
3. Personal contact with corresponding authors of relevant
trials or reviewers and other multiple sclerosis consumer societies
and experts.
4. Clinical trials registries: clinicaltrials.gov ; Current
Controlled Trials.
Data collection and analysis
Selection of studies
Two review authors (Vanitha Jagannath (VJ) and Zbys Fedorow-
icz (ZF) independently assessed the abstracts of studies resulting
from the searches. We obtained full copies of all relevant and po-
tentially relevant studies, those appearing to meet the inclusion
criteria, and those for which there were insufficient data in the title
and abstract to make a clear decision. The two authors then inde-
pendently assessed the full text papers and resolved any disagree-
ment on the eligibility of included studies through discussion and
consensus, or through a third party (GV Asokan). All irrelevant
records were excluded and details of the studies and the reasons
for their exclusion were noted in the ’Characteristics of excluded
studies’ table in RevMan 5 (Revman 2008).
Data extraction and management
The review authors collected outcome data using a pre-deter-
mined form designed for this purpose and entered the study de-
tails into the ’Characteristics of included studies’ table in RevMan
5 (Revman 2008).
The following details were extracted:
1. Trial methods: method of allocation, masking of
participants, trialists and outcomes assessors, exclusion of
participants after randomisation and proportion and reasons for
losses at follow up.
2. Participants: country of origin and location: private clinic
or academic institute, sample size, ages and the relevant inclusion
and exclusion criteria.
3. Intervention: type; dosage length of time in follow up.
4. Control: type; dosage length of time in follow up
Outcomes mentioned in the ’Types of outcome measures’ section
of the review
◦ Short term (less than 12 months) - data at 3, 6 and 12
months
◦ Medium to long term (over 1 year)
If stated, the sources of funding of any of the included studies were
recorded.
We used this information to help us to assess heterogeneity and
the external validity of the trials.
Assessment of risk of bias in included studies
Two authors independently graded the selected trial using a sim-
ple contingency form following the domain-based evaluation de-
scribed in the Cochrane Handbook for Systematic Reviews of Inter-
ventions 5.0 (Higgins 2009). The quality of this study was assessed
independently using the checklist developed for the Cochrane MS
Group. Discrepancies in judgements were to be resolved by dis-
cussion with a third reviewer however this proved unnecessary
The following domains were assessed as ’Yes’ (i.e. low risk of bias),
’Unclear’ (uncertain risk of bias) or ’No’ (i.e. high risk of bias):
1. sequence generation;
2. allocation concealment;
3. blinding (of participants, personnel and outcome assessors);
4. incomplete outcome data;
5. selective outcome reporting.
The authors reported on each of these assessments in the ’Risk of
bias in included studies’ table.
Measures of treatment effect
We did not enter any data into the RevMan analysis, but if data are
available in future updates we will calculate risk ratios (RR) and
their associated 95% confidence intervals (CIs) for dichotomous
outcomes. For continuous outcomes we will report the weighted
mean difference (WMD) or the standardized mean difference
(SMD) if different scales are used. Time-to-resolution data will be
reported as hazard ratios (HR) with their 95% CIs.
Unit of analysis issues
Only studies with a parallel group design were included so partic-
ipants will have been randomised to either intervention or control
with subsequent analysis at individual allocation level. Cross-over
studies were not included because the effects if any of vitamin D
on immune mechanisms are more likely to develop over a longer
period of time and therefore an appropriate wash-out period can-
not be clearly defined. However, in future updates, any data re-
ported from the first intervention period of such cross over trials
could be included providing it was clearly reported.
Dealing with missing data
We contacted the principal investigator of the included trial by
electronic mail and were able to obtain missing data and to clarify
some inconsistencies in the published report.
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Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Assessment of heterogeneity
As only one study was included in this review we did not assess
heterogeneity, but in future updates or if further data are available
the following methods of assessment will be applied.
We will assess clinical heterogeneity by examining the characteris-
tics of the studies, the similarity between the types of participants,
the interventions and the outcomes as specified in the criteria for
included studies.
Statistical heterogeneity will be assessed using a Chi2 test and the
I2 statistic where I2 values of 30% to 60% indicate moderate to
high, 50%-90% substantial and 75% to 100% considerable het-
erogeneity. We will consider heterogeneity to be significant when
the P value is less than 0.10 (Higgins 2003).
Assessment of reporting biases
The paucity of trials included in this review did not permit an as-
sessment of publication bias. In future updates we will assess pub-
lication bias by following the recommendations on testing for fun-
nel plot asymmetry as described in section 10.4.3.1 of the Cochrane
Handbook for Systematic Reviews of Interventions 5.0.2 (updated
September 2009) (Higgins 2009) and this will be explored in the
Discussion if appropriate.
Data synthesis
Two review authors (VJ and ZF) analysed the data in Review Man-
ager (Revman 2008) and reported them as specified in Chapter 9
of the Cochrane Handbook for Systematic Reviews of Interventions
5.0.2 (updated September 2009) (Higgins 2009).
There was only one included study hence we did not do the anal-
ysis. Random effects model of analysis will be applied for future
updates or if further studies are included and if there is significant
heterogeneity between the trials.
Subgroup analysis and investigation of heterogeneity
Lack of data did not permit a subgroup analysis but in future
updates and if further data become available we plan to carry out
subgroup analyses based on age, gender, category of MS, country
of residence (based on sunlight exposure), disease modifying drug
co-therapy and serum 25(OH) vitamin D levels.
Sensitivity analysis
If a sufficient number of studies had been included we would have
undertaken sensitivity analyses to assess the robustness of our re-
view results by repeating the analysis with the following adjust-
ments: exclusion of studies with unclear or inadequate allocation
concealment, blinding of outcomes assessment and completeness
of follow up.
R E S U L T S
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of ongoing studies.
See: ’Characteristics of included studies’ and ’Characteristics of
excluded studies’.
Results of the search
The electronic searches retrieved 12 references to studies. After
examination of the titles and abstracts of these references all of
those which did not match our inclusion criteria and were clearly
ineligible were eliminated. We obtained full text copies of any
of the remaining potentially eligible studies and subjected them
to further evaluation. Subsequently only one study proved to be
eligible for inclusion in this review and all of the others were
excluded.
Our search of the clinical trials database (clinicaltrials.gov) re-
trieved three additional ongoing studies which will be assessed as
soon as they are published and their results become available.
Included studies
Only one study Burton 2010 was included in this review.
Characteristics of the trial setting and investigators
This open-label randomised controlled trial was conducted in the
Multiple Sclerosis Clinic at St. Michael’s Hospital, Toronto in
Canada from June 2006 to March 2008. The providers of care in
this trial were university hospital staff and the assessors of outcomes
were the investigators and other healthcare providers.
Characteristics of the participants
The sample size comprised 49 participants (40 females, 9 males)
with a mean age of 40.5 years. Of these participants 45 had relaps-
ing remitting MS and 4 had secondary progressive MS. The base-
line mean serum 25(OH)D was 78 nmol/L and the mean score
on the Expanded Disability Status Scale (EDSS) was1.34 for both
groups.
Characteristics of the interventions
The participants in the treatment group (25) were seen every six
weeks and received escalating vitamin D doses to assess tolerabil-
ity, up to 40,000 IU/day over 28 weeks to raise serum 25(OH)D
rapidly, followed by 10,000 IU/day (12 weeks) and were then
down-titrated to 0 IU/day. Supplementation with tricalcium phos-
phate (1,200mg/day) was provided throughout the study period.
Participants in the control group (24) were allowed to take the
regular dose of 4000 IU of vitamin D and “supplemental calcium
if desired”, and were seen only at the start and completion of
the study and at two intermediate time points. No assessments of
compliance as ’pill counts’ were reported for the control group.
Characteristics of the outcome measures
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Assessments using the Expanded Disability Status Scale (EDSS)
were carried out at baseline and at the completion of the study for
both intervention and control group.
The following biochemical tests; serum calcium, albumin, serum
25(OH)D, urine calcium/creatinine, (Ca/Cr) transaminases, urea
and creatinine and PTH levels, cytokines, lymphocyte response
and matrix metallo proteinase-9 levels (on cryopreserved samples)
were carried out at every visit for change of Vitamin D3 dose in
the intervention group at 6 weekly intervals, and in the control
group; serum 25(OH)D and calcium/albumin levels and T-cell
reactivity at weeks 1 and 52, MMP-9 and cytokines levels at weeks
1, 11, 29 and 52.
Adverse events and relapses were assessed within 72 hrs of reporting
by the clinicians and were documented. Ultrasound monitoring
for renal calculi was done at baseline, mid trial and end of the
trial, and EKG for cardiac rhythm at baseline and at the end of
the trial.
Primary endpoints were the mean change in serum calcium at
each vitamin D dose and a comparison of serum calcium between
groups. Secondary endpoints included 25(OH)D and other bio-
chemical measures, immunologic bio-markers, relapse events and
EDSS scores.
Excluded studies
All of the studies which were excluded from this review and the
reasons for their exclusion are available in the ’Characteristics of
excluded studies’ table.
Risk of bias in included studies
The single study (Burton 2010) included in this review was judged
as ’High risk of bias’ as two criteria were assessed ’no’ in the risk
of bias assessment.
Further details of this assessment are available in the relevant sec-
tion of the ’Characteristics of included studies’ table and are also
presented in the ’Risk of bias’ graph (Figure 1) and ’Risk of bias’
summary (Figure 2).
Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
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Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
Allocation
Patients were matched for age, disease duration, baseline EDSS
score and use of disease-modifying drugs. “Members of pairs were
randomised to treatment or control groups based on blinded draw-
ing from a hat” and therefore the sequence generation was judged
as “adequate ”. The report provided insufficient information about
how the allocation sequence was concealed from the investigators
and probably not done and hence judged ’No’.
Blinding
Although the trial was blinded for outcomes of laboratory mea-
sures, neither the participants nor the trialists or outcomes asses-
sors appear to have been ’blinded’ to the interventions and there-
fore a judgement of ’no’ was given for this domain.
Incomplete outcome data
After e-mail communication with the principal investigator we
were able to clarify some of the inconsistencies in the published
report.
Two patients in each group withdrew during the trial but this was
said to be unrelated to any adverse events. A flow-chart which
tracked the participants through the trial was included in the re-
port, and the investigators analysed the data according to the in-
tention-to-treat principle, and therefore a judgement of ’yes’ was
given for this domain.
Selective reporting
The frequency of assessment of some of the clinical outcomes
varied between the intervention and control groups and could have
resulted in a degree of unintentional selective reporting in terms
of under or over disclosure of relapses or other events.
Other potential sources of bias
The use of a matched-pair study design may have restricted patient
enrolment and thereby introduced an element of selection and
volunteer bias into the trial.
Effects of interventions
Primary outcomes
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The mean number of relapses per patient per year or
annualised relapse rate and proportion of patients who
remain relapse free
In the group treated with escalating doses of vitamin D compared
to control there was a reduction in annualised relapse rate as well
as a higher proportion of relapse free patients at the end of the
study period.
Time to the first treated relapse
This outcome was not reported in the included study.
Quality of life (validated and specific scales i.e. MSQOL-54)
This outcome was not reported in the included study.
Number of patients experiencing a change in the Expanded
Disability Status Scale (EDSS) score
In the group treated with escalating doses of vitamin D, there was
a reduction of the mean EDSS scores and a lower proportion of
patients with an increase in EDSS scores at the end of the study
Safety and adverse effects
Biochemistry profiles of renal and hepatic functions were reported
to be within normal limits and there was no evidence of renal
calcification, disturbances of cardiac rhythm or any other adverse
events.
Secondary outcomes
Number of patients requiring hospitalisation due to
progression of the disease
This outcome was not reported in the included study
Cognitive functions (memory, concentration).
This outcome was not reported in the included study.
Physical symptoms
This outcome was not reported in the included study.
Psychological symptoms
This outcome was not reported in the included study.
Mean change in MRI parameters of disease activity (number
and/or volume of gadolinium-enhancing T1 and new T2
lesions)
This outcome was not reported in the included study.
Serum levels of 25-hydroxyvitamin D (25(OH)D) and
Calcium
The serum 25(OH)D rose considerably during the dosing period
but no adverse consequences were reported.
No significant difference in serum calcium occurred at any point
along the dosing regimen, nor did any serum calcium values exceed
the upper limit of the reference range (2.10-2.60 mmol/L) in the
treatment group. The serum calcium at peak 25(OH) vitamin D
levels was within the normal range and only slightly higher in the
treatment group.
Bone mineral density (BMD) changes during the study
period
This outcome was not reported in the included study.
Cytokine profile, T lymphocyte proliferation response and
Plasma metalloprotease-9 activity
There were no consistent patterns of change in cytokine titers
within or between groups.
The total T-cell proliferation response decreased in the treatment
group with no change in the control group.
Plasma MMP revealed small but not statistically significant reduc-
tions between visits over the course of the trial in both treatment
and control groups.
D I S C U S S I O N
Summary of main results
Although only one trial (Burton 2010) was included in this review,
there are three ongoing studies (NCT01024777, NCT00785473,
NCT01005095) with common outcome measures which are
likely to be of relevance to this review and may ultimately provide
valuable evidence in future updates.
Overall completeness and applicability ofevidence
The single study included in this review provided some evidence
of the potential benefit of the intervention on relevant clinical out-
comes e.g. the annualised relapse rate, EDSS scores and suppres-
sion of T-cell proliferation. A measure of safety in use of high doses
9Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
of vitamin D was illustrated by the relative absence of any adverse
events or of serum calcium levels in excess of the upper limit of the
reference range over the one year study period. However, although
the case selection and matched-pair design of this exploratory trial
may have contributed towards minimising the effects of potential
confounders, it was not adequately powered to address all relevant
clinical outcomes which may ultimately impose limits on the ap-
plicability of the evidence to the MS population at large.
Quality of the evidence
Limitations in study design
Whilst recognising that the principal objective of the single in-
cluded study was to investigate the tolerability of high doses of
vitamin D this could have, to a certain extent, dictated the shape
of the study design and consequently may have an impact on the
generalisability of the evidence pertaining to the effectiveness of
the intervention. Inadequate blinding and a lack of clarity in how
the allocation sequence was concealed from investigators can con-
tribute to biased assessment of the effects of an intervention and it
is uncertain to what extent these aspects may have compromised
the quality of the evidence presented in the included study.
Inconsistency
As only one trial was included in this review this assessment was
not applicable.
Indirectness
Although the single trial met the eligibility criteria for inclusion,
inevitably the matched-pair design had an impact on patient en-
rolment and recruitment duration, both of which may have con-
tributed to an element of selection bias and thereby addressed a
restricted version of the review question in terms of the popula-
tion.
Imprecision
The limited amount of outcome data available from this single
trial did not permit any assessment of the precision of the results.
Publication bias
In view of the low number of trials included in this review this
assessment was not estimable.
Potential biases in the review process
Strident attempts were made to limit bias in the review process by
ensuring a comprehensive search for potentially eligible studies,
which included searching in clinical trial registries and in other
than the major databases but which nevertheless resulted in the
retrieval of a low number of studies.
The two authors’ independent assessments of eligibility of studies
for inclusion in this review and the extraction of data minimised
the potential for additional bias beyond that detailed in the risk
of bias tables.
Agreements and disagreements with otherstudies or reviews
We are not aware of any other reviews that have covered this re-
search question.
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
The evidence from this review does not at present allow confident
decision-making about the use of Vitamin D in MS since it was
from a single low powered trial with the limitation of a potential
high risk of bias. However, some evidence for the safety and effec-
tiveness of administering high doses of vitamin D for the manage-
ment of multiple sclerosis and some benefits to patients in terms
of clinical improvement were suggested by the review.
Global variation in recommended dosage regimens for vitamin D
supplementation is attributable to regional differences in the level
of solar exposure of individuals and therefore, until further evi-
dence becomes available, clinicians should continue to base their
decisions on regional guideline recommended therapeutic regi-
mens in conjunction with their patients individual circumstances.
Assessments of serum 25(OH)D levels, which are carried out rou-
tinely as part of the clinical management of MS, can be used to
detect vitamin D insufficiency. There is no consensus presently
about the desirable and optimal levels though based on some stud-
ies a functional classification has recently been proposed to define
serum 25(OH)D levels > 40 ng/ml or > 100 nmol/l as “desir-
able”, serum levels between 20 and 40 ng/ml or 50 and 100 nmol/
l as hypovitaminosis D, levels between 10 and 20 ng/ml or 25
and 50 mmol/l as vitamin D insufficiency and 25(OH)D levels
below 10 ng/ml or 25 nmol/l as deficient (Gomez 2003; Grant
2005). Steps to increase serum 25(OH)D levels should focus on
restoring vitamin D status to adequate levels commencing with a
one-off megadose of vitamin D3 and followed by a daily intake
of 2000-4000 IU of vitamin D3. Serum 25(OH)D levels should
be checked annually, usually at the end of each winter, to ensure
10Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
optimum dosage and should include monitoring of calcium levels
and the effects of hypercalcaemia and other side effects all of which
should be reported (Diamond 2005; van der Mei 2007).
Implications for research
The present consensus on the use of vitamin D in the management
of MS is based on the hypothesis that vitamin D could potentially
reduce the inflammatory activity responsible for relapses and the
neuronal damage implicated in disability and thereby slowing the
progression of the disease. Guidelines on vitamin D supplemen-
tation for people with MS recommend not only the restoration of
serum 25(OH) D levels but also that they should reach optimal
levels which are higher than the presently considered normal levels
to obtain the suggested beneficial impact on the immunological
effects of the disease. Although this trial provided some evidence
of the safety of high dosing regimens of vitamin D, there is a need
for further randomised controlled trials which can help provide
insight into the real benefits of such dosing regimens in people
with MS.
These RCTs should be adequately powered, multi-centred and
with a focus on clinical as well as immunological and MRI out-
comes that are meaningful to people with MS. They should assess
not only the safety but also investigate more closely the benefits of
supplementation with high dosing regimens of vitamin D.
Moreover any future trials will need to be rigorous in design and
delivery, with subsequent reporting to include high quality de-
scriptions of all aspects of methodology to enable appraisal and
interpretation of results, and conform to the Consolidated Stan-
dards of Reporting Trials (CONSORT) statement.
For further research recommendations based on the EPICOT for-
mat (Brown 2006) please see (Table 2)
Table 2. Research recommendations based on a gap in the evidence of Vitamin D use in the management of Multiple sclerosis
Core elements Issues to consider Status of research for this review
Evidence
(E)
What is the current state of evidence? The systematic review identified one RCT which
matched the eligibility criteria, it provides some evi-
dence of clinical improvement by reduction in relapse
rate and EDSS scores and good evidence of safety of
high doses of vitamin D administration to people with
MS.
Population
(P)
Diagnosis, disease stage, comorbidity, risk factor, sex,
age, ethnic group, specific inclusion or exclusion crite-
ria, clinical setting
Patients diagnosed as having clinically definite MS ac-
cording to standard criteria, with any pattern of the dis-
ease course (relapsing-remitting, secondary progressive
and primary progressive)
Intervention
(I)
Type, frequency, dose, duration, prognostic
factor
Escalating doses of oral vitamin D 3 beginning with
4000 IU/day escalated over 28 weeks to 40 000 IU/day
followed by maintenance with 10 000 IU/day for 12
weeks, 4000 IU/day for 8 weeks and a 4-week wash-
out.
Comparison
(C)
Type, frequency, dose, duration, prognostic factor Control with or without a regular oral dose of 4000 I
U/day of vitamin D3
Outcome
(O)
Which clinical or patient related outcomes will the re-
searcher need to measure, improve, influence or accom-
plish?
Which methods of measurement should be used?
• ARR and relapse free patients;EDSS scores and
patients with no EDSS progression
• Safety and adverse effects
• MRI outcomes and serum calcium,25(OH) D
levels
RR for dichotomous outcomes and MD or WMD for
continuous outcomes
11Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Research recommendations based on a gap in the evidence of Vitamin D use in the management of Multiple sclerosis
(Continued)
Time Stamp
(T)
Date of literature search or recommendation 17 May 2010
Study Type What is the most appropriate study design to address
the proposed question?
Randomised controlled trial (adequately powered/
multi centred)
Methods: concealment of allocation sequence
Blinding: patients, therapist, trialists, outcomes asses-
sors, data analysts
Setting: inpatient or outpatient care with follow-up 1
year or more.
EDSS = Expanded Disability Status Scale
A C K N O W L E D G E M E N T S
We acknowledge the support of the MS Review Group and the
editors who were helpful in providing valuable guidance at various
stages within the review process.
R E F E R E N C E S
References to studies included in this review
Burton 2010 {published data only}
Burton JM, Kimball S, Vieth R, Bar-Or A, Dosch HM, Cheung R,
et al.A phase I/II dose-escalation trial of vitamin D3 and calcium in
multiple sclerosis. Neurology 2010;74(23):1852–9. [DOI:
10.1212/WNL.0b013e3181e1cec2]
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Ban 2000 {published data only}
Ban Y, Taniyama M, Ban Y. Vitamin D receptor gene
polymorphism is associated with Graves’ disease in the Japanese
population. Journal of Clinical Endocrinology and Metabolism 2000;
85(12):4639–43. [PUBMED: 11134121]
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Goldberg 1986 {published data only}
Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: decreased
relapse rate through dietary supplementation with calcium,
magnesium and vitamin D. Medical Hypotheses 1986;21(2):
193–200. [PUBMED: 3537648]
Kimball 2007 {published data only}
Kimball SM, Ursell MR, O’Connor P, Vieth R. Safety of vitamin
D3 in adults with multiple sclerosis. American Journal of Clinical
Nutrition 2007;86(3):645–51. [PUBMED: 17823429]
Lakatos 2000 {published data only}
Lakatos P, Nagy Z, Kiss L, Horvath C, Takacs I, Foldes J, et
al.Prevention of corticosteroid-induced osteoporosis by alfacalcidol.
Zeitschrift fur Rheumatologie 2000;59 Suppl 1:48–52. [PUBMED:
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Mahon 2003 {published data only}
Mahon BD, Gordon SA, Cruz J, Cosman F, Cantorna MT.
Cytokine profile in patients with multiple sclerosis following
vitamin D supplementation. Journal of Neuroimmunology 2003;
134(1-2):128–32. [PUBMED: 12507780]
Reichel 1992 {published data only}
Reichel H, Grussinger A, Knehans A, Kuhn K, Schmidt-Gayk H,
Ritz E. Long-term therapy with cyclosporin A does not influence
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multiple sclerosis. Clinical Investigator 1992;70(7):595–9.
[PUBMED: 1392429]
Soilu-Hanninen 2008 {published data only}
Soilu-Hanninen M, Laaksonen M, Laitinen I, Eralinna JP, Lilius
EM, Mononen I. A longitudinal study of serum 25-hydroxyvitamin
D and intact parathyroid hormone levels indicate the importance of
vitamin D and calcium homeostasis regulation in multiple sclerosis.
Journal of Neurology, Neurosurgery and Psychiatry 2008;79(2):
152–7. [PUBMED: 17578859]
Vojinovic 2005 {published data only}
Vojinovic S, Vojinovic J, Cosic V, Savic V. Effects of alfacalcidol
therapy on serum cytokine levels in patients with multiple sclerosis.
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[PUBMED: 16535996]
Wingerchuk 2005 {published data only}
Wingerchuk DM, Lesaux J, Rice GP, Kremenchutzky M, Ebers
GC. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for
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16107372]
References to ongoing studies
NCT00785473 {published and unpublished data}
Can Vitamin D Supplementation Prevent Bone Loss in Persons
With Multiple Sclero. clinicaltrials.gov/show/NCT00119132
(accessed 30 June 2010).
NCT01005095 {published and unpublished data}
The Effects of Interferon Beta Combined With Vitamin D on
Relapsing Remitting Multiple Sclerosis Patients. clinicaltrials.gov/
show/NCT01005095 (accessed 30 June 2010).
NCT01024777 {published and unpublished data}
Safety and Immunologic Effect of Low Dose Versus High Dose
Vitamin D3 in Relapsing Remitting Multiple Sclerosis.
clinicaltrials.gov/show/NCT01024777 (accessed 30 June 2010).
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14Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Burton 2010
Methods Trial registered with Clinicaltrials.gov, the National Institute of Health (ID
NCT00644904).
Open-label randomised controlled trial. St. Michael’s Hospital, Toronto, Canada
Duration: 52 weeks trial, in the period June 2006 to March 2008.
Participants 51 patients screened. 2 drop-outs before randomisation
49 allocated and randomised
INCLUSION CRITERIA:
• age18-55 years,
• clinically definite MS according to specific criteria (McDonald 2001; Polman
2005; Poser 1983; Schumacker 1965).
• EDSS score of 0-6.5.
EXCLUSION CRITERIA:
• participants with relapse within 60 days,
• steroid use within 30 days, chemotherapy within 12 months,
• pregnancy/inadequate contraception,
• vitamin D intake >4,000 IU/day, serum 25(OH)D level >50 nmol/L,
• lymphoma, granulomatous disease, cardiac arrhythmia, kidney dysfunction,
• disordered calcium metabolism.
RANDOMIZED:
n=49 (40 females, 9 males), mean age 40.5yrs (range 21-54).
Matched pairs for age, disease duration, EDSS score, and disease-modifying drug.
WITHDRAWALS/LOSSES TO FOLLOW-UP:
2 drops outs from each group
CHARACTERISTICS:
• 45 relapsing remitting MS, 4 secondary progressive MS.
• EDSS: Treatment group mean 1.46 (0-6.0); control group mean 1.23 (0-6.0).
• Disease duration: Treatment group mean 8.21yrs (range1-25), control group
mean 7.4yrs (range 1-21).
• Disease Modifying Drug used, Interferon/Glatiramer Acetate/None 12/2/11 in
treatment group 12/2/10 in control group
• Season enrolled, spring or summer/fall or winter 16/9 in treatment and 11/13 in
control groups.
BASELINE DATA
• Serum calcium: Treatment group mean 2.32 mmol/L (range 2.08 -2.57); control
group mean 2.32 mmol/L (range 2.16 -2.47)
• Serum 25(OH)D Treatment group mean 73 (range 38 to146)nmol/L; control
group mean 83 (range 38-154)nmol/L.
Interventions TREATMENT (25):
Oral Vitamin D3 at 4000 IU/day escalated over 28 weeks to 40 000 IU/day followed by
maintenance with 10 000 IU/day for 12 weeks, 4000 IU/day for 8 weeks and a 4-week
wash-out 14 000 IU/day over 52 weeks. Oral Calcium 1200mg/day was started from 2
weeks before the starting dose of vitamin D, and stopped for the last 4 weeks.
CONTROL (24):
“Control patients were permitted to take vitamin D and supplemental calcium if desired
15Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Burton 2010 (Continued)
as before ( up to 4,000 IU/day mean of 991IU/day) ”.
Outcomes Expanded Disability Status Scale (EDSS) score and general medical exam (Week 1 &
52): intervention and control groups.
Biochemical measures (6 weekly intervals)at every change of Vitamin D3 dose visits in
the intervention group
• Serum calcium, albumin ,Serum 25(OH)D, urine calcium/creatinine, (Ca/Cr)
transaminases, urea and creatinine and PTH levels
• Cytokines, lymphocyte response and matrix metallo proteinase-9 levels (on
cryopreserved samples)
Control patients had 25(OH)D and calcium/albumin levels and T-cell reactivity testing
at weeks 1 and 52, while MMP-9 and cytokines were assessed at weeks 1, 11, 29, and 52
Adverse events and relapse were assessed within 72 hrs of reporting by the clinicians and
were documented
Ultrasound monitoring for renal calculi was done at baseline,mid trial and end of the
trial, and EKG for cardiac rhythm at baseline and end of the trial.
Notes This is the first controlled study of Vitamin D in Multiple sclerosis
The trial used the escalating dose titration schedule which minimized the risk of toxicity
at higher doses as doses were stepped up only if the previous dose was confirmed safe.
Calcium supplementation in the trial permits generalization of evidence to MS popula-
tion who are regularly calcium supplemented.
The previous trial of calcitriol in MS Wingerchuk 2005 suggested a risk of hypercal-
caemia, hence this trial sought to use vitamin D which is an inactive precursor of cal-
citriol to test for safety against the same outcome.
Risk of bias
Item Authors’ judgement Description
Adequate sequence generation? Yes Quote: “Members of pairs were ran-
domised to treatment or control groups
based on blinded drawing from a hat.”
Comment: Sequence generation is ade-
quate
Allocation concealment? No Quote: “An open-la-
bel randomised prospective controlled 52-
week trial matched patients with MS for
demographic and disease characteristics,
with randomizations to treatment or con-
trol groups”
Comment: not done.
Blinding?
All outcomes
No Quote: “The trial was not powered nor
blinded to properly address clinical out-
comes”
Comment:Not done , this trial was a dose
escalation trial and blinding was probably
16Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Burton 2010 (Continued)
not feasible
Incomplete outcome data addressed?
All outcomes
Yes Quote: “Two patients in each group with-
drew during the trial, none related to ad-
verse events”
Comment: A flow chart which tracked the
progress of participants through the trial
was provided in the report.
Free of selective reporting? Unclear Quote: “More frequent monitoring of the
treatment group could have been a factor
in the disclosure of relapses and may have
missed possible events or use of undisclosed
agents in the less frequently assessed control
group”
Comment: Selective reporting of some out-
come measures may have occurred.
Free of other bias? Unclear Quote: “The matching design limited pa-
tient enrolment and recruitment duration,
and selection and volunteer bias cannot be
ruled out”
Comment: Selection and or ’volunteering’
may have attributed to an element of allo-
cation bias.
EDSS = Expanded Disability Status Scale
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Ban 2000 Not an interventional study
Ban 2000a Not an interventional study
Cosman 1994 No intervention with vitamin D
Goldberg 1986 Non RCT, self pairing for control.
Kimball 2007 Not a RCT
Lakatos 2000 Participants included patients other than those with MS, and outcomes were not related to clinical outcomes
of MS.
17Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Mahon 2003 Only non clinical outcome.
Reichel 1992 Non vitamin D intervention.
Soilu-Hanninen 2008 Not an interventional study and the control was non- MS healthy population.
Vojinovic 2005 Not a RCT, and had non-MS controls, mainly non clinical outcome measures.
Wingerchuk 2005 Not a RCT.
RCT = randomised controlled trial
Characteristics of ongoing studies [ordered by study ID]
NCT00785473
Trial name or title Can Vitamin D Supplementation Prevent Bone Loss in Persons With Multiple Sclerosis
Methods Randomized Placebo Controlled
Participants MS patients aged between 18 to 50 years
Interventions Cholecalciferol capsules, 20,000 IU weekly and calcium carbonate 500 mg daily Vs only calcium carbonate
500 mg daily
Outcomes • Primary outcome measures: changes in BMD over the 2 year study period comparing treatment and
placebo groups
• Secondary outcome measures: cytokine expression following vitamin D supplementation
• Contribution of vitamin D from different sources (generation in the skin, diet and supplements) to
serum 25(OH) vitamin D (vitamin D status)
• Changes in parameters of lower extremity function over the 2 year study period
• The number of relapses, the time to first relapse, the number of relapse-free patients
• The number of patients without progression of disability judged by EDSS and
• Reported infections
• Ratings on a fatigue scale
Starting date November 4, 2008
Contact information Margitta T Kampman, MD, PhD, University Hospital of North Norway
Notes Several studies have shown that bone mineral density (BMD) at the femoral neck decreases with increasing
physical handicap (EDSS-score) in MS patients. Possible explanations are less weightbearing exercise or less
UV-exposure resulting in reduced vitamin D generation in the skin. Study is designed to assess whether
supplementation with vitamin D, given as a weekly dose of 20,000 IU cholecalciferol, can prevent bone loss.
18Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
NCT01005095
Trial name or title The Effects of Interferon Beta Combined With Vitamin D on Relapsing Remitting Multiple Sclerosis Patients
Methods Randomized, Interventional study
Participants Patients With Relapsing Remitting Multiple Sclerosis, age 18 to 65 years
Interventions 100,000 IU Vitamin D3 per month compared with 800IU Vitamin D3 per month
Outcomes • Primary outcome measures: Occurrence and severity of Interferon beta related flu-like symptoms and
injection site reactions.
• Secondary outcome measures: Expanded Disability Status Scale (EDSS) progression
• Relapse rate
• Quality of life.
Starting date November 2009
Contact information Ariel Miller, 972-4-8250-851
Notes To verify the hypotheses that vitamin D supplementation may ameliorate interferon beta-induced flu-like
symptoms, owing to reduced release and activity of the cytokines that are in correlation with this adverse event.
Vitamin D supplementation may also positively affect injection site reactions due to its immunomodulatory
effects. Vitamin D may also augment the therapeutic efficacy of interferon beta among multiple sclerosis
patients.
NCT01024777
Trial name or title Effect of Low Dose Versus High Dose Vitamin D3 in Relapsing Remitting Multiple Sclerosis
Methods Interventional, RCT, Double blind
Participants Patients with relapsing-remitting Multiple Sclerosis
Interventions Cholecalciferol (Vitamin D3) 10,000 IU vs 400 IU in tablet form will be taken once daily for the duration
of the trial (6 months)
Outcomes • Assess safety of high dose cholecalciferol in patients with relapsing remitting multiple sclerosis
• Assess the effects of cholecalciferol supplementation on serum immune markers in patients with
relapsing remitting multiple sclerosis
• Assess clinical effects of cholecalciferol supplementation in patients with relapsing remitting multiple
sclerosis
Starting date December 2, 2009
Contact information Christopher Eckstein, MD (410) 502-1937
Notes The purpose of this study is to determine the safety and the immunologic effects of supplementation with
low-dose and high-dose cholecalciferol (vitamin D3) in patients with relapsing-remitting multiple sclerosis.
19Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
D A T A A N D A N A L Y S E S
This review has no analyses.
A P P E N D I C E S
Appendix 1. CENTRAL search strategy
#1MeSH descriptor Multiple Sclerosis explode all trees
#2MeSH descriptor Demyelinating Diseases, this term only
#3MeSH descriptor Myelitis, Transverse, this term only
#4MeSH descriptor Optic Neuritis explode all trees
#5MeSH descriptor Encephalomyelitis, Acute Disseminated, this term only
#6“multiple sclerosis”:ti,ab,kw
#7(demyelinating NEXT disease):ti,ab,kw
#8(transverse NEXT myelitis):ti,ab,kw
#9“neuromyelitis optica”:ti,ab,kw
#10“optic neuritis”:ti,ab,kw
#11(devic):ti,ab,kw
#12“acute disseminated encephalomyelitis”:ti,ab,kw
#13(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12)
#14MeSH descriptor Cholecalciferol, this term only
#15MeSH descriptor Ergocalciferols, this term only
#16MeSH descriptor Ultraviolet Rays explode all trees
#17“vitamin D” OR cholecalciferol* OR ergocalciferol* OR “ultraviolet ray*” OR sunlight:ti,ab,kw
#18MeSH descriptor Vitamin D explode tree 1
#19“vitamin D2”:ti,ab,kw or “vitamin D3”:ti,ab,kw
#20(alfacalcidol):ti,ab,kw or (calcidiol):ti,ab,kw or (calcitriol):ti,ab,kw or (calcifediol):ti,ab,kw or (calciferol):ti,ab,kw
#21“1-alpha hydroxyvitamin D3”:ti,ab,kw or “1-alpha-hydroxy-vitamin D3”:ti,ab,kw or “1-alpha hydroxycalciferol”:ti,ab,kw or “1-
alpha-hydroxy-calciferol”:ti,ab,kw
#22“1,25 dihydroxyvitamin D3”:ti,ab,kw or “1,25-dihydroxy-vitamin D3”:ti,ab,kw or “1,25 dihydroxycholecalciferol”:ti,ab,kw or
“1,25-dihydroxycholecalciferol”:ti,ab,kw
#23“25-hydroxycholecalciferol”:ti,ab,kw or “25 hydroxyvitamin D”:ti,ab,kw or “25-hydroxy-vitaminD”:ti,ab,kw
#24(#14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23)
#25(#13 AND #24)
Appendix 2. MEDLINE (PubMed) search strategy
(((“vitamin D2” OR “vitamin D3”[Title/Abstract]) OR (“1-alpha hydroxyvitamin D3” OR “1-alpha-hydroxy-vitamin D3”[Title/
Abstract]) OR (“1-alpha hydroxycalciferol” OR “1-alpha-hydroxy-calciferol”[Title/Abstract]) OR (“1,25 dihydroxyvitamin D3” OR
“1,25-dihydroxy-vitamin D3”[Title/Abstract]) OR (“1,25 dihydroxycholecalciferol” OR “1,25-dihydroxycholecalciferol”[Title/Ab-
stract]) OR (“25 hydroxycholecalciferol” OR “25-hydroxycholecalciferol”[Title/Abstract]) OR (“25 hydroxyvitamin D” OR “25-
hydroxy-vitamin D”[Title/Abstract]) OR (alfacalcidol OR calcidiol OR calcitriol OR calciferol OR ergocalciferol OR cholecalcif-
erol[Title/Abstract])) OR (“ultra violet rays”[Title/Abstract] OR “UV rays”[Title/Abstract] OR sunlight[Title/Abstract] OR ergocalcif-
erols[Title/Abstract] OR cholecalciferol[Title/Abstract] OR “vitamin d”[Title/Abstract] OR (“Ergocalciferols”[Mesh] OR “Ultraviolet
Rays”[Mesh]) OR “Sunlight”[Mesh] OR Cholecalciferol[Mesh] OR “Vitamin D”[Mesh])) AND ((((“Multiple Sclerosis”[mh]) OR
(“Myelitis, Transverse”[mh:noexp]) OR (“Demyelinating Diseases”[mh:noexp]) OR (“Encephalomyelitis, Acute Disseminated”[mh:
noexp]) OR (“Optic Neuritis”[mh])) OR ((“multiple sclerosis”[Title/Abstract]) OR (“neuromyelitis optica”[Title/Abstract]) OR (“trans-
verse myelitis”[Title/Abstract]) OR (“encephalomyelitis”[Title/Abstract]) OR (“devic”[Title/Abstract]) OR (“optic neuritis”[Title/Ab-
stract]) OR (“demyelinating disease*”[Title/Abstract]) OR (“acute disseminated encephalomyelitis”[Title/Abstract]))) AND (((ran-
20Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
domized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR
(randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT ((animals[mh]) NOT ((animals[mh]) AND (human[mh])))))
Appendix 3. EMBASE (EMBASE.com) search strategy
’vitamin d2’:ab,ti OR ’vitamin d3’:ab,ti OR alfacalcidol:ab,ti OR calcidiol:ab,ti OR calcitriol:ab,ti OR calciferol:ab,ti OR calcifediol:
ab,ti OR ’1-alpha hydroxyvitamin d3’:ab,ti OR ’1-alpha-hydroxy-vitamin d3’:ab,ti OR ’1,25 dihydroxyvitamin d3’:ab,ti OR ’1,25-
dihydroxy-vitamin d3’:ab,ti OR ’1,25 dihydroxycholecalciferol’:ab,ti OR ’1,25-dihydroxycholecalciferol’:ab,ti OR ’25 hydroxychole-
calciferol’:ab,ti OR ’25-hydroxycholecalciferol’:ab,ti OR ’25 hydroxyvitamin d’:ab,ti OR ’25-hydroxy-vitamin d’:ab,ti OR ’vitamin d’/
exp OR ’vitamin d’:ab,ti OR ’cholecalciferol’/exp OR cholecalciferol*:ab,ti OR ergocalciferol*:ab,ti OR ’ergocalciferol’/exp OR ’ultra-
violet radiation’/exp OR ’ultraviolet rays’:ab,ti OR ’ultraviolet radiation’:ab,ti OR ’ultraviolet rays’/exp OR ’uv rays’:ab,ti OR ’sunlight’/
exp OR sunlight:ab,ti AND (’encephalomyelitis’/exp OR ’demyelinating disease’/exp OR ’multiple sclerosis’/exp OR ’myelooptic neu-
ropathy’/exp OR ’multiple sclerosis’:ab,ti OR ’neuromyelitis optica’:ab,ti OR encephalomyelitis:ab,ti OR devic:ab,ti) AND (’crossover
procedure’/exp OR ’double blind procedure’/exp OR ’controlled clinical trial’/exp OR ’clinical trial’/exp OR ’single blind procedure’/
exp OR ’randomized controlled trial’/exp OR random*:ab,ti OR factorial*:ab,ti OR crossover:ab,ti OR (cross:ab,ti AND over:ab,ti) OR
placebo:ab,ti OR ’double blind’:ab,ti OR ’single blind’:ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti) AND [humans]/
lim AND [embase]/lim
H I S T O R Y
Protocol first published: Issue 3, 2010
Review first published: Issue 12, 2010
C O N T R I B U T I O N S O F A U T H O R S
Roles and responsibilities
Draft the protocol VJ/AG/ZF/TR/LW
Develop and run the search strategy MS Group in collaboration with the authors
Obtain copies of studies AG/ZF
Select which studies to include VJ/AG/ZF
Extract data from studies VJ/AG/ZF
Enter data into RevMan AG/ZF
Carry out the analysis AG/ZF
Interpret the analysis AG/ZF/VJ
Draft the final review VJ/AG/ZF/TR/LW
21Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Update the review VJ/AG/ZF/TR/LW
D E C L A R A T I O N S O F I N T E R E S T
There are no financial conflicts of interest and the authors declare that they do not have any associations with any parties who may
have vested interests in the results of this review.
S O U R C E S O F S U P P O R T
Internal sources
• There was no source of support, Not specified.
External sources
• No sources of support supplied
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
The measures which evaluate the disease burden in terms of ’relapses’ are not solely the corticosteroid treated relapses because all relapses
do not require treatment with corticosteroid. Therefore we changed ’the mean number of corticosteroid-treated relapses per patient’
into ’the proportion of relapse free patients and the mean annualised relapse rate’.
I N D E X T E R M S
Medical Subject Headings (MeSH)
Multiple Sclerosis [∗drug therapy]; Randomized Controlled Trials as Topic; Vitamin D [∗therapeutic use]; Vitamins [∗therapeutic use]
MeSH check words
Humans
22Vitamin D for the management of multiple sclerosis (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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