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http://jpp.sagepub.com/content/early/2011/10/08/0897190011421839The online version of this article can be found at:
DOI: 10.1177/0897190011421839
published online 10 October 2011Journal of Pharmacy PracticeNicole Marie Summerday, Sherrill J. Brown, Douglas R. Allington and Michael P. Rivey
Vitamin D and Multiple Sclerosis: Review of a Possible Association
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Review Article
Vitamin D and Multiple Sclerosis: Reviewof a Possible Association
Nicole Marie Summerday, PharmD1,2, Sherrill J. Brown, PharmD2,Douglas R. Allington, PharmD1,2, and Michael P. Rivey, MS1,2
AbstractThere has been growing interest in determining environmental risk factors that may play a role in the development or progressionof multiple sclerosis (MS). Epidemiological evidence and data from human and animal studies have shown an association betweenlow serum vitamin D levels and an increased incidence of MS and that supplementation with vitamin D may protect against MSdevelopment and/or disease relapses. The most appropriate vitamin D dosage for patients with MS is unclear, but investigatorshave proposed that serum vitamin D concentrations between 75 and 100 nmol/L (30-40 ng/mL) are optimal to achieve favorableclinical outcomes. Vitamin D supplemented in doses up to 3000 International Units (IU) daily may be necessary to achieve theselevels in many patients, and doses of 500 to 800 IU daily appear to be necessary to maintain desired serum vitamin D levels.Short-term supplementation with doses up to 40 000 IU daily has been found to be safe. However, larger and longer clinicalstudies are needed to assess whether a true relationship exists between serum vitamin D concentrations and MS and todetermine a safe and effective amount of vitamin D supplementation.
Keywordsmultiple sclerosis, vitamin D, recommended daily allowance (RDA), experimental autoimmune encephalomyelitis (EAE)
Introduction
Multiple sclerosis (MS) is a chronic neurodegenerative disorder
which appears to be associated with both genetic risk factors, as
well as, environmental triggers.1,2 The hallmark of MS is a pro-
gressive degeneration of the myelin sheaths surrounding the
patient’s neuronal axons resulting in musculoskeletal dysfunc-
tion which can result in pain, disability, and death. The exact
etiology of this process is unknown, although it is thought to
be an autoimmune response triggered in genetically susceptible
individuals by environmental factors such as smoking, previous
Epstein Barr infection, and low vitamin D levels.2 An increasing
interest in the prevention of MS has led to a growing body of evi-
dence evaluating possible environmental triggers. Vitamin D is a
well-established mediator of bone homeostasis and is now
thought to play a role in other health aspects. Serum vitamin
D levels may be associated with the risk of or course of various
autoimmune diseases, cardiovascular disease, and cancer.3
Overall the incidence of MS appears to be rapidly increas-
ing.4,5 In a study of US military veterans, the incidence of
MS determined in World War II and Korean War veterans was
significantly lower than in Vietnam veterans; the increased
incidence was more prominent in women and nonwhite male
veterans. The authors proposed that the rapid increase occurred
too quickly to be explained by genetic variation and was most
likely due to changes in environmental risk factors.4 Moreover,
a substantial increase in the incidence of MS has been observed
in various other regions of the world.5 The observed increase in
MS in different regions of the world is more consistent with
changes in environmental factors rather than genetic factors,
since population genetic drift typically affects disease charac-
teristics over a more prolonged time period.5 Ultraviolet B
(UVB) exposure and resultant changes in vitamin D levels are
possible environmental risk factors that have been investigated
to assess their relationship with the increased incidence of
MS.2-5 It is unclear whether these rapid increases are the result
of varying environmental factors or whether they are a reflec-
tion of changes in medical care which has led to increased
access to diagnostic procedures, neurologists, and an increased
public awareness of MS.5
Vitamin D Physiology
Vitamin D in humans is obtained from dietary sources, by sup-
plementation, and through exposure to sunlight. Vitamin D
1 Community Medical Center, Department of Pharmacy, Missoula, MT, USA2 Skaggs School of Pharmacy, Department of Pharmacy Practice, The University
of Montana, Missoula, MT, USA
Corresponding Author:
Nicole Marie Summerday, Skaggs School of Pharmacy, The University of
Montana, 32 Campus Drive 1522, Missoula, MT 59812, USA
Email: nsummerday@communitymed.org
Journal of Pharmacy Practice000(00) 1-10ª The Author(s) 2011Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/0897190011421839http://jpp.sagepub.com
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exists in 2 biologically inert forms as vitamin D2 (also known
as ergocalcifereol) and vitamin D3 (cholecalciferol). After
absorption from diet or the skin, vitamin D first undergoes
metabolism in the liver to 25-hydroxyvitamin D (25(OH)D,
calcidiol) that is composed of hydroxylated metabolites of both
forms. Subsequent metabolism occurs in the kidneys with
conversion to the active form 1,25-dihydroxyvitamin D
(1,25(OH)2D, calcitriol); this represents the classic metabolic
pathway for vitamin D. Activated vitamin D augments intest-
inal absorption of calcium and is regulated by parathyroid
hormone (PTH) and circulating levels of calcium and
phosphorus (Figure 1). A nonclassic, extra-renal vitamin D
metabolic pathway via cellular 1a-hydroxylase exists in
macrophages, neutrophils, and epithelial cells.6 Extra-renal
vitamin D hydroxylase expression is not regulated by PTH.7
The body is very efficient at producing vitamin D from sun-
light exposure. 7-dehydrocholesterol in the skin is converted
into pre-vitamin D3 on exposure to UVB radiation at wave-
lengths of 290 to 315 nm; pre-vitamin D3 is subsequently con-
verted into cholecaciferol.2,6,8-10 Exposure to bright sunlight
for 10 to 15 minutes can potentially generate 10 000 to
15 000 IU of vitamin D and exposing major portions of the
body, primarily the arms and legs, for as little as 5 to 30 min-
utes twice a week is sufficient to produce and maintain ade-
quate vitamin D serum levels in many individuals. However,
the amount of UVB exposure and subsequent vitamin D pro-
duction depends on the time of day of exposure, a person’s skin
pigmentation, clothing worn, use of sunscreen, latitude, and
season of the year.2,8,11,12
Quantifying sunlight exposure and the subsequent genera-
tion of vitamin D3 is often expressed as a minimal erythema
dose (MED). A single MED is based on a person wearing a
bathing suit exposed to sunlight of the proper UVB spectrum
for a time interval equivalent to 25% of the time required for
that person to develop a mild sunburn (a slight redness to the
skin).9 One MED produces approximately 6000 to -
10 000 IU of vitamin D3. It is estimated that most individuals
receive 90% to100% of their vitamin D from sunlight exposure.
However, during winter months at the 35th latitude in the
northern and southern hemispheres, sunlight exposure and
UVB penetration of the earth’s atmosphere is not sufficient for
individuals to generate sufficient quantities of vitamin D. Total
body stores of vitamin D at the end of the summer are critical
for most individuals to maintain adequate vitamin D serum
concentrations throughout the rest of the year.9
The other 10% of vitamin D is acquired through dietary
means. There are very few foods which are naturally rich in
vitamin D, but the best sources include fish, fish oil, mush-
rooms and foods that have been exposed to UVB radiation.8,11
Therefore, many dietary items such as milk, infant formulas,
orange juice, cheese, and various breakfast cereals have been
fortified with vitamin D2 or D3. Most fortified food items con-
tain between 40 and 100 IU of vitamin D per common serving
size, but the exact quantity of vitamin D provided is product
specific. Unfortunately, the food labeling system stipulates that
the vitamin content be given in percentage of recommended
daily intake (RDI) based upon a 2000-calorie diet and not in the
more recognizable International Unit (IU) designation.13
Because the majority of vitamin D is produced by UVB expo-
sure and supplementation through dietary means is difficult,
people who live in areas with decreased levels of UVB expo-
sure are at risk of depleting their vitamin D stores and develop-
ing a deficiency.8
Vitamin D supplements are commonly available over-the-
counter, but products containing higher concentrations are also
available by prescription (Table 1). Some evidence suggests
vitamin D2 is only 30% as efficient as vitamin D3 at increasing
serum levels of 25(OH)D,14 but other data have not supported a
difference between the 2 forms.15
Vitamin D Pathophysiology
Vitamin D is critical in the development, support, and mainte-
nance of human health. Rickets was once thought to be the sole
consequence of vitamin D deficiency. However, more recent
studies have demonstrated that vitamin D receptors (VDRs) are
located throughout the body, and vitamin D deficiency is linked
to cardiovascular disease,3 cancer,16 and numerous innate and
adaptive immunity diseases including MS. 1,25(OH)2D helps
regulate over 200 genes and is involved in cellular angiogen-
esis, differentiation, and apoptosis.12
Mystery still remains regarding the identity of the genetic
characteristics and environmental risk factors that predispose
individuals to acquiring MS. However, significant advances
in research have provided a clearer understanding of MS immu-
nology and the pathology that leads to myelin insult, plaque
formation, and impaired remyelination. The initial immunolo-
gical events require a foreign or self-antigen to be presented to
naive T cells (CD4þ and/or CD8þ).17 Activated T cells
Table 1. Vitamin D Fortified Foods and Supplements
Sample fortified foodsApproximatevitamin D content
Salmona(7 oz) 200-2000 IUCanned tunaa (7 oz) 450 IU
Canned sardinesa (7 oz) 500 IU
Canned mackerela
(7 oz)600 IU
Fortified fluid milkb 42 IU/100 gNonfat dry milkb 42 IU/100 g
Evaporated milkb 42 IU/100 gCalcium-fortified
juicesb100 IU/RACC
Supplements Prescriptionc Nonprescriptionc
Vitamin D2 50 000 IU/capsule;8000 IU/mL
400 IU in multivitamins
Vitamin D3 400, 800, 1000, and 2000IU
Abbreviations: RACC, reference amount customarily consumed.a Reference 9.b Reference 13.c Reference 47.
2 Journal of Pharmacy Practice 000(00)
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Figure 1. Metabolic Pathways for Vitamin D
Summerday et al 3
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ultimately cause expanded immunological responses that
involve macrophages, antimyelin protein antibodies, numerous
interleukins (ILs), and cytokines.18-20 Vitamin D actions have
the potential to modify responses at multiple steps along this
inflammatory cascade.
Vitamin D not only serves a primary function of regulating
serum calcium to protect and maintain bone health, but
1,25(OH)2D also acts as a sterol hormone integral to essential
immune system functions. Naive or quiescent CD4 T cells
express low concentrations of VDRs that increase 5-fold after
activation.21 Vitamin D actions result in reduced IL-2, IL-5,
and gamma-interferon (g-IFN) secretion by CD4 T cells,
enhancing proliferation of transforming growth factor (TGF),
IL-4, and IL-10, ultimately shifting immune responses from a
T-helper 1 (Th1) to T-helper 2 (Th2) dominance.22 MS is typi-
cally described as a Th1-dominant autoimmune disease.23
Dendritic cells present antigens to T cells initiating or perpe-
tuating critical steps in the immunological cascade responsible
for reactions to foreign and self antigens. Reduction in dendri-
tic cell differentiation and secretion of IL-12 after administra-
tion of vitamin D has been shown during in vitro
experiments.24 1,25 (OH)2D demonstrates pleotrophic actions
by enhancing bacteriocidal actions of macrophages, as well
as, by repressing antigen-presenting expressions of macro-
phage and dendritic cells, potentially reducing immune-
mediated diseases such as MS. Vitamin D suppresses granulo-
cyte macrophage colony-stimulating factor (GM-CSF) by
binding to VDR in the DNA element responsible for the
gene-encoding GM-CSF. Vitamin D has also been shown to
inhibit the antigen-presenting capacity of macrophages to lym-
phocytes by restricting major histocompatibility complex
(MHC) II expression on cell surfaces.25
Activated dendritic cells and macrophages produce 1a-
hydroxylase, an enzyme which is responsible for converting
vitamin D3 into its metabolically active form. Immune cell
1a-hydroxylase is primarily regulated by IFN-g and other
immune factors.26 Vitamin D influence on cellular, enzyme,
and cytokine functions of the immune system serves as the phy-
siological basis for understanding its potential role in the acqui-
sition and modulation of MS and its clinical course.
Vitamin D Recommendations
Vitamin D is a fat-soluble vitamin with an approximate 2-
month half-life for its elimination from total body stores.27
Given the efficiency of vitamin D generation via sunlight expo-
sure and most individuals’ access to vitamin D fortified foods, a
considerable time of sun avoidance or inadequate vitamin D
supplementation would seem to be required to deplete vitamin
D stores. It is perhaps this efficient storage and utilization
mechanism that has minimized vigilance regarding vitamin
D’s role in health and disease over the years.
25-Hydroxyvitamin D3 is the major form of circulating vita-
min D but measurement of total serum 25(OH)D is the pre-
ferred test to assess vitamin D body stores. Although
25(OH)D is a precursor to the physiologically active metabolite
1,25(OH)2D, the conversion is regulated by factors including
calcium homeostasis. A long serum half-life of approximately
15 days also makes 25(OH)D the preferred vitamin D metabo-
lite for testing.28
Setting standards which represent optimal vitamin D levels in
adults has been difficult and historic normal values have recently
undergone scrutiny and debate. Vitamin D deficiency has com-
monly been attributed to levels less than 50 to 62 nmol/L (20 to
25 ng/mL), vitamin D insufficiency to levels from 52 to
72 nmol/L (20 to 29 ng/mL), and adequate or optimal vitamin
D to 62 to 200 nmol/L (25 to 80 ng/mL). Vitamin D levels of
200 to 374 nmol/L (80 to 150 ng/mL) have served as a numeric
breakpoint for toxicity.12 Even at these historically low serum
level standards, the prevalence of vitamin D insufficiency in the
population has become a growing health concern.28
The previous recommendations for vitamin D intake pub-
lished by the Institute of Medicine’s Food and Nutrition Board
(FNB) in 1997 stated that the adequate intake (AI) for vitamin
D was 200 IU daily for people up to 50 years old, 400 IU for
people 51 to 70 years old, and 600 IU in people over age
70.11 The FNB listed 2000 IU daily as the tolerable upper limit
for people over 1 year old. These recommendations were based
on the level of vitamin D needed to maintain bone health and
prevent rickets. The FNB also did not recommend supplement-
ing vitamin D based on serum levels but considered a level over
37.5 nmol/L (15 ng/mL) necessary to maintain bone health.11
However, studies completed since 1997 suggest the recom-
mended AI was insufficient to maintain vitamin D levels pro-
posed as needed to impact chronic diseases like
cardiovascular disease, autoimmune diseases, and cancer.29
This was especially true in people who are not exposed to sun-
light year round.3,29 A panel of experts from 12 different fields
recently met to review the new data on vitamin D supplemen-
tation in patients with cardiovascular disease, autoimmune dis-
ease, and cancer and people at risk of musculoskeletal
disability.3 The goal of the meeting was to discuss and deter-
mine recommendations regarding major issues surrounding
vitamin D including the most appropriate amount of vitamin
D supplementation, optimal serum vitamin D levels, the upper
tolerable intake of vitamin D, and a logical frequency of vita-
min D monitoring in people with the above listed diseases.3
Consequently, the FNB published updated guidelines in
2010; recommendations were established using the recom-
mended daily allowance (RDA) rather than the AI.30 The cur-
rent RDA was calculated assuming that people do not get a
substantial amount of unprotected sunlight exposure because
of the increased risk of skin cancer. Without substantial sun-
light exposure, the FNB now recommends 200 IU daily for
infants up to age 6 months, 400 IU daily for infants between the
ages of 6 and 12 months, 600 IU daily for people between the
ages of 1 and 70 years old, and 800 IU daily for individuals
over the age of 70 years. The FNB also increased the tolerable
upper limit of vitamin D intake from 2000 IU daily to 4000 IU
daily for individuals over age 8.30
The international panel also agreed that baseline testing of
vitamin D levels was appropriate in all cases except individuals
4 Journal of Pharmacy Practice 000(00)
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assumed to be deficient such as those with dark skin or who
were constantly veiled preventing sun exposure.3 After base-
line testing, a serum vitamin D reevaluation was recommended
after at least 3 months of vitamin D supplementation, with sub-
sequent follow-up at the provider’s discretion in patients found
to be deficient. The panel agreed that supplementation with
2000 IU of vitamin D daily was safe in most people but that
higher doses may be required in people with low vitamin D lev-
els to raise serum levels into the normal range. Daily, weekly,
or monthly dosing strategies are preferred since administration
of a single large dose (500 000 IU) of vitamin D on an annual
basis has been found to result in adverse effects.3
The normal serum range of vitamin D was determined to be
between 75 and 110 nmol/L (30-44 ng/mL) for optimal clinical
outcomes and an upper safe limit of 250 nmol/L (100 ng/mL)
was established. As a guideline to supplementation, 1000 IU
daily was estimated to cause a 25 nmol/L (10 ng/mL) increase
in the serum vitamin D level, subject to individual variability.
After serum levels have been corrected, 800 IU daily was deter-
mined to be a typically sufficient maintenance dose. The panel
also felt that it was important that vitamin D levels be main-
tained year-round.3
A study in Omaha, Nebraska, located at 41.2� North lati-
tude, evaluated how much vitamin D supplementation was nec-
essary to maintain baseline postsummer vitamin D levels in 67
healthy men.31 The average baseline serum vitamin D level in
these men was approximately 70 nmol/L (28 ng/mL). The men
were randomly assigned to receive doses of vitamin D ranging
from none to 10 000 IU daily. Overall, the subjects metaboli-
cally used approximately 3800 IU of vitamin D daily, with
approximately 80% of the vitamin D supplied by tissue stores
created during summer sun exposure. The study evaluated
doses as high as 10 000 IU/daily over 20 weeks with no ele-
vated serum calcium levels detected. The highest serum vita-
min D levels achieved were between 160 nmol/L (64 ng/mL)
and 220 nmol/L (88 ng/mL) and were found in the group that
received 10 000 IU daily. After analyzing the changes in serum
vitamin D over a period of 2 winters, the authors calculated that
subjects needed 500 IU daily to maintain a serum vitamin D
level of approximately 70 nmol/L (28 ng/mL), which could
be provided from tissue stores or diet. Based on their observa-
tions, the authors hypothesized that individuals without good
tissue stores of vitamin D would likely need a higher intake
of vitamin D to correct a deficiency from inadequate dietary
intake or sunlight exposure and to meet physiological
demands.31
A study evaluating vitamin D levels along with PTH levels
in 1163 ambulatory subjects with an average age of 60 found
that 40.8% of study subjects had deficient vitamin D levels
defined as less than or equal to 50 nmol/L (20 ng/mL) at base-
line, and that 79.8% of subjects had vitamin D levels below
75 nmol/L (30 ng/mL), which was considered to represent the
upper limit for vitamin D insufficiency and a concentration that
is insufficient to normalize the PTH levels.32
The authors of the study then followed 104 consecutive
patients from the overall group, most of whom had vitamin D
deficiency or metabolic bone disease. The subgroup was
followed to evaluate the effect of vitamin D supplementation
on serum vitamin D levels. At baseline, the subgroup had an
average serum vitamin D level of 45.2 nmol/L (18.1 ng/mL);
only 10.2% of patients had serum vitamin D levels greater than
75 nmol/L (30 ng/mL) and 79.9% had serum levels greater than
25 nmol/L (10 ng/mL). After 3 months of supplementation, the
number of patients with vitamin D levels greater than 75 (30
ng/mL) and 25 nmol/L (10 ng/mL) increased to 12.5% and
96.1%, respectively. The authors concluded that a daily dose
of 1500 to 3000 IU daily was necessary to cause a significant
increase in serum vitamin D levels.32
Based on the above data, a daily dose of 500 IU to 800 IU is
recommended to maintain optimal serum vitamin D levels of
75 to 110 nmol/L (30-44 ng/mL) and doses of 1500 to 3000
IU/daily may be needed to significantly increase serum vitamin
D levels. Serum levels greater than 250 nmol/L (100 ng/mL)
exceed the agreed upon upper limit.3,29,31 However, long-
term effects of supplementation at these dosages have not yet
been determined in large randomized controlled studies.
Multiple Sclerosis: Effects of Location andUVB Exposure
A unifying aspect of a possible association of vitamin D home-
ostasis and MS centers on the proven impact of geographic
location on each. There is a well-established geographic gradi-
ent in MS cases, with a lower incidence found in equatorial
countries and an increasing prevalence of the disease that cor-
relates with increasing distance from the equator.4,5,33 The
highest risk areas are located in areas of the world with lower
sunlight exposure including the northern parts of the United
States, Northern Europe, Canada, Southeastern Australia, and
Southern New Zealand.4,5 Nevertheless, the importance of
genetic predisposition to MS must be acknowledged, as
demonstrated by a high prevalence of the disease in Israel, a
country that is relatively close to the equator.4 A study evaluat-
ing geographic location and MS risk in military veterans from
1964 through 1990 found a significantly higher risk ratio for
veterans from the northern third of the United States compared
to those from the southern third of the United States.4 Simi-
larly, a study using the 1981 census data from Queensland Aus-
tralia confirmed a significantly decreased incidence of MS in
tropical Northern Queensland compared with Southern
Queensland. Each study showed an increasing prevalence of
MS with increasing distance from the equator.33
A logical argument to explain the MS disease gradient
would be to associate it with the decreasing UVB exposure that
occurs with increasing distance from the equator.34 Latitudes
greater than 40� north receive insufficient UVB radiation dur-
ing 4 to 6 months of the year to fuel any significant vitamin D
conversion in the skin.10,11 A geospatial model of the United
States and Canada evaluated the correlation between the ultra-
violet index and MS incidence. Areas with the highest ultravio-
let index had the lowest incidence of MS, and conversely, areas
Summerday et al 5
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with the lowest ultraviolet index had the highest MS
incidence.34
The mortality of MS and skin cancer patients with varying
occupational and residential UVB exposure was evaluated using
patient death certificates from 24 states, which were collected
and cataloged35 by the National Cancer Institute, the National
Institute for Occupational Safety and Health, and the National
Center for Health Statistics between 1984 and 1995. The data-
base coded for occupation, cause of death, state of birth, and
state of death. Patients with nonmelanoma skin cancer (n ¼6565) and MS (n ¼ 5701) were included and compared to con-
trol cases that died from other causes (n ¼ 153 502). MS and
nonmelanoma skin cancer patients were matched on a 1:1 basis
with an age, sex, race, and socioeconomically matched control
case. Adjusted data demonstrated that low residential sunlight
exposure was associated with an odds ratio (OR) of 1.0 of dying
from MS, while high residential sunlight exposure was associ-
ated with a decreased OR of 0.53 of dying from MS. Conversely,
low residential sunlight exposure was associated with an OR of
1.0 of dying from skin cancer, while high residential sun expo-
sure was associated with an increased OR of 1.24 of dying from
skin cancer. This trend was also seen with occupational sunlight
exposure. Strictly indoor occupations had an OR of 1.9 of dying
from MS, while strictly outdoor occupations have a decreased
OR of 0.74 of dying from MS. Conversely, high occupational
sunlight exposure was associated with an increased OR of
1.21 of dying from skin cancer compared to an OR of 1.0 for
strictly indoor occupations.36
The possible protective effects of UVB on MS could be
attributed to either a direct protective effect of the UVB expo-
sure on the disease or an indirect effect of maintenance of ade-
quate vitamin D stores. Regardless, the increasing concern
about skin damage from excessive sun exposure encourages
more people to take an active role in protecting their skin
against damaging UV radiation. Consistent use of sunscreen
and protective clothing and the avoidance of midday sun
decreases UVB exposure and helps prevent skin damage; how-
ever, these measures also decrease potential vitamin D
synthesis.8,10,31,37
There is evidence from animal data that UVB radiation has
potential immunomodulatory effects which could impact the
development or progression of MS. A study was conducted
in female mice with experimental autoimmune encephalomye-
litis (EAE), the animal model of MS.37 One group received
only pretreatment with UV radiation, another group received
UV radiation every third day, and a third group received UV
radiation every other day. Mice receiving UV radiation treat-
ment either every other day or every third day had a signifi-
cantly slowed progression of EAE when compared to mice
receiving only pretreatment. Every other day UV exposure led
to a significant delay in symptom onset and decreased peak
severity of symptoms. Both every other day and every third day
UV radiation treatments significantly decreased the cumulative
disease index of EAE.37
Overall, it appears that UVB exposure may confer some pro-
tection against MS, but increases in skin cancer risk likely limit
this approach as a plausible treatment or prevention avenue.
The suggestion that vitamin D supplementation could represent
an alternative treatment avenue has greater practical applica-
tion, if serum levels sufficient to suppress MS symptoms can
be reached without inducing hypercalcemia.
Vitamin D and MS
Observational studies have shown that vitamin D levels are sig-
nificantly lower in MS patients compared to healthy control
subjects and that increased serum vitamin D levels and the
presence of vitamin D supplementation are associated with a
decreased risk of developing MS.35,38,39 A study evaluating
vitamin D levels and bone mass densities in patients with MS
found that, compared to the control population, MS patients
had a significantly lower mean serum vitamin D level (43.2
vs 107.6 nmol/L [17.3 vs 43.1 ng/mL]; P < .001), and that
61% of MS patients had vitamin D insufficiency, defined as
a vitamin D level less than 50 nmol/L (20 ng/mL).38 An evalua-
tion of vitamin D levels using serum samples obtained from a
repository at the US Department of Defense found that higher
serum levels of vitamin D correlated with a decreased risk of
MS, with the lowest risk in persons with concentrations of
100 nmol/L (40 ng/mL) or higher.35
The Nurses’ Health Study did not evaluate serum vitamin D
levels but found that women who supplemented with at least
400 IU of vitamin D daily had a significantly lower incidence
of MS than those who took less than 400 IU daily (Relative
Risk ¼ 0.59; P ¼ .006) and that women in the top quintile for
vitamin D intake (between 641 and 742 IU/d) had a 40% lower
incidence of MS compared to the quintile with the lowest
vitamin D intake (Relative Risk ¼ 0.67; P ¼ .03).39
The above data raise the question of whether low vitamin D
levels increase the risk of developing MS or whether early MS
pathology decreases vitamin D levels. MS symptoms, which
are often exacerbated by heat, may lead to sun avoidance and
a drop in vitamin D levels before other symptoms become evi-
dent. In contrast, low vitamin D levels that precede MS devel-
opment could possibly be an environmental risk factor rather
than a consequence of MS symptoms. The Vietnam veterans
study by Munger et al35 evaluated the temporal relationship
between the development of MS symptoms and low vitamin
D levels. Using veterans’ serum samples stored in the US
Department of Defense respository, vitamin D levels were not
found to significantly change from baseline during the years
preceding MS symptom development (P ¼ .42). However, a
significant decrease in vitamin D levels occurred after patients
became symptomatic for MS (P ¼ .02). The authors concluded
that the presymptomatic low vitamin D levels were more likely
an environmental risk factor and that the additional drop in
vitamin D levels after diagnosis was probably due to sun
avoidance.35
A Finnish study evaluated vitamin D levels at the time of
diagnosis in 33 newly diagnosed MS patients. Vitamin D levels
did not differ between MS patients and patients without MS
during winter months (50 vs 57 nmol/L [20 vs 22.8 ng/mL];
6 Journal of Pharmacy Practice 000(00)
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P ¼ .202). However, the newly diagnosed MS patients had sig-
nificantly lower vitamin D levels compared to control patients
during summer months (58 vs 85 nmol/L [23.2 vs 34.1 ng/mL];
P ¼ .022).40
Vitamin D levels also have been found to vary in patients
with relapsing-remitting MS in concordance with exacerba-
tions.41 In a study of 132 Hispanic patients, vitamin D levels
were significantly lower during MS exacerbations compared
to periods of remission. Mean vitamin D levels during remis-
sion were 118.25 nmol/L (47.0 + 9.0 ng/mL) compared to a
mean vitamin D level of 96.25 nmol/L (38.5 + 5.6 ng/mL) dur-
ing exacerbations. Overall, mean vitamin D levels in both
patient groups were still lower than the healthy control vitamin
D level of 153 nmol/L (61.2 + 5.6 ng/mL).41
In summary, results of the studies suggest that MS patients
have a higher incidence of low serum vitamin D levels, and that
higher serum vitamin D levels may confer some protection
against MS.35,38,39 A goal serum vitamin D level of at least
100 nmol/L (40 ng/mL) is suggested to decrease the incidence
of MS development in patients with genetic risk factors.35
Additional studies have shown that vitamin D levels vary in
concordance with MS exacerbations, suggesting that vitamin
D supplementation may help decrease the number of
relapses.41
Vitamin D Treatment for MS
The immunomodulatory effects of vitamin D are now being
investigated as a potential treatment of MS. Animal data are
available that suggest vitamin D may have a direct effect to
suppress or slow the progression of MS. In mice, vitamin D
treatment reduced central nervous system (CNS) inflammation
and inhibited EAE symptoms without inducing hypercalce-
mia.1 In the previously discussed animal study, the effects of
UVB exposure on vitamin D synthesis and EAE severity in
mice were compared to vitamin D supplementation alone and
placebo.37 In the UV radiation treatment groups, there was a
transient increase in vitamin D level, but serum calcium levels
did not differ significantly from the control group. Vitamin D
treatment also significantly decreased EAE symptoms; how-
ever, the effects were only seen at doses that induced severe
hypercalcemia. The doses of vitamin D used in this study were
approximately 100, 400, 2000, 4000, and 42 000 IU/kg daily.
The lowest dose which suppressed symptoms was 2000 IU/
kg daily, but this dose also resulted in hypercalcemia. It is
unknown whether a more moderate dose between 400 and
2000 IU/kg daily would have yielded disease-modifying results
without inducing toxicity.37
A pilot study examined the efficacy of 19-nor-1,25-
dihydroxyvitamin D2, a vitamin D analogue, in 11 patients with
relapsing remitting MS.42 After treatment with an average dose
of 4 mcg for 6 months, there was no difference in clinical
symptoms or magnetic resonance imaging (MRI) lesions com-
pared to the 6 months prior to the study. However, this uncon-
trolled study was too small to make definitive conclusions on
the effectiveness of 19-nor-1,25-dihydroxyvitamin D2.42
Another small open-label pilot study evaluated the safety of
oral 1,25(OH)2D (calcitriol) in 15 patients with relapsing-
remitting MS.43 Each patient received 100 IU (2.5 mcg) of
1,25(OH)2D daily for 48 weeks, and dietary calcium intake was
restricted to 800 mg daily. Patients were evaluated every 8
weeks with clinical and laboratory examinations, and MRIs
were performed to track disability, disease progression, and side
effects. There were 2 cases of symptomatic hypercalcemia,
which were attributed to dietary indiscretions. There was also
a small decrease in clinical exacerbations, but the small study
size and low calcitriol dose limit this study’s clinical findings.43
The effect of vitamin D supplementation in combination
with calcium and magnesium on MS relapses was evaluated
in 16 patients. The patients received 10 mg/kg magnesium,
16 mg/kg calcium, and 5000 IU vitamin D daily for 11 to 24
months. Compared to the expected number of exacerbations
based on patient histories, treatment significantly reduced the
number of MS exacerbations (14 actual vs 32 expected; P <
.005). Results of this study suggested that vitamin D supple-
mentation may be helpful in MS patients, but it was unclear
whether the results were due to the vitamin combination or one
of the individual ingredients.44
A phase I/II dose-escalating trial evaluated the safety of treat-
ing MS with larger vitamin D doses.45 Twenty-five patients with
MS formed the active treatment group and were matched with 24
control patients with MS. The treatment arm received 1200 mg
of calcium daily and escalating doses of vitamin D starting at
4000 IU daily titrated up to a maximum of 40 000 IU daily; the
control group was allowed to take up to 4000 IU daily of vitamin
D. The main focus of this study was to evaluate vitamin D safety
since the study was not sufficiently powered to look at clinical
improvement in MS. The patients were monitored for signs of
calcium toxicity including kidney stones, serum calcium levels,
and basic laboratory and metabolic markers. At baseline, the
mean vitamin D level for all patients was 78 nmol/L (31.25
ng/mL) and was not different between the groups.45 Vitamin
D levels rose to a maximum of 413 nmol/L (40 ng/mL), well
above the upper limit of 250 nmol/L (100 ng/mL),10 and many
patients had vitamin D serum levels above the recommended
upper limit for more than 18 weeks.45
No cases of hypercalcemia were reported, and no cases of
kidney stones or disturbances in cardiac rhythm were
detected.45 There was a significantly (P ¼ .009) decreased pro-
portion of patients experiencing MS relapses in the treatment
group (16% compared to the placebo group [37%] during the
study); however, the study was too small to determine whether
this result is clinically significant or merely coincidental. There
was also a significant (P ¼ .002) decrease in the number of
patients in the treatment group with positive T-cell prolifera-
tion assays after 52 weeks; there was no change in the control
group. A vitamin D level of 100 nmol/L (40 ng/mL) or greater
was determined to be the most effective at decreasing T-cell
proliferation, and the authors proposed this serum level as a
tentative serum goal for patients with MS. The authors also
found that short-term treatment with up to 40 000 IU daily did
not result in toxicity.45
Summerday et al 7
at UNIV OF MONTANA on November 30, 2011jpp.sagepub.comDownloaded from
Animal studies have shown a correlation between UV expo-
sure and MS, and both animal and human studies have shown a
correlation between MS and vitamin D.37,43-45 Treatment in
MS patients with high doses of vitamin D ranging from 100
to 40 000 IU of vitamin D has been associated with a decrease
in MS disease markers and a decreased relapse rate; however,
available studies were too small to evaluate clinical improve-
ment. Treatment with these large doses of vitamin D appears
to be safe over a short period of time, if calcium intake and
serum calcium levels are monitored.37,43-45 Larger, longer trials
are still needed to demonstrate that supplementation with large
doses of vitamin D is clinically beneficial to patients with MS.
Vitamin D Requirements in MS:
Variations in vitamin D levels and the response to vitamin D
supplementation between males and females may warrant dif-
ferent recommendations for males and females with MS. A
study evaluating the serum vitamin D levels in MS patients
found a significantly greater mean serum vitamin D level in
women of 79.1 + 45.4 nmol/L (31.7 + 18.2 ng/mL) compared
to men with 50.2 + 15.3 nmol/L (20.1 + 6.1 ng/mL), an inter-
esting finding since females have a greater risk of developing
MS.4
A murine study of EAE and vitamin D supplementation
evaluated whether the effects of vitamin D supplementation
varied first between intact male and female mice and then
whether removal of the testes or ovarian tissue affected vitamin
D response.46 Intact female mice that were fed 25 IU (1 mcg)
daily of vitamin D had a significantly lower EAE incidence,
EAE severity, and cumulative disease index compared to intact
control females not given vitamin D, treated females that had
undergone ovariectomy, and all 3 groups of male mice (control,
treated, and treated after testes removal). In addition, pathology
cultures taken from the intact female treatment group showed
little sign of acute illness at 22 days compared to the other
groups which had developed both lesions and inflammatory
cell infiltrates in their CNS.46
Since it appeared that increased vitamin D supplementation
was needed in the other laboratory groups, vitamin D at a dose
of 5 mcg/d was administered to the male mice to determine
whether larger doses of vitamin D would confer EAE protec-
tion. However, the larger dose led to increased calcium levels
and weight loss indicating vitamin D toxicity while failing to
improve EAE symptoms.10,46 Since results of the study showed
vitamin D supplementation was only effective in intact female
mice, it was proposed that the positive response could be influ-
enced by estrogen levels. The authors hypothesized that estro-
gen could prevent CNS metabolism and help maintain levels of
vitamin D, resulting in a lessening of the inflammatory process
and subsequent damage in the CNS.46
Other subgroups of people with varying vitamin D levels are
people with darker skin tones. Studies have shown that individ-
uals with more melanin do not have serum vitamin D levels as
great as people with low levels of melanin in their skin.35
Results of the previously described US Vietnam veterans study
showed that both black and Hispanic people on average had
significantly lower serum vitamin D levels when compared to
white people (P < .001); no serum sample from any black indi-
vidual contained a vitamin D level greater than 100 nmol/L (40
mcg/mL). No significant relationship between vitamin D levels
and MS risk was found in the black study group, but this group
may have been too small to detect a relationship. Nevertheless,
despite the lower serum vitamin D levels, the black study group
was found to have a lower risk of developing MS compared to
the white study group.35 The observed differences suggest a
genetic variation in MS risk as well as vitamin D synthesis and
requirements that are dependent on race.
Conclusions
Current vitamin D RDA recommendations are too recent to
assess any potential impact on MS. In order to meet the new
recommendations, vitamin D supplementation will likely be
required for many people who spend the winter months at lati-
tudes greater than 42�N.10 Vitamin D levels of 100 nmol/L (40
ng/mL) or greater appear to confer some protection against MS
in people who have genetic risk factors.10,35 This protection
appears to be better documented in white people,35 and it is
possible that vitamin D supplementation is more effective in
females than in males.46
Doses of 1500 to 3000 IU daily appear to be necessary to meet
physiological demands which are estimated at 3800 IU daily in
healthy males,10,31 and doses as high as 40 000 IU of vitamin D
daily have been used over a short period of time without toxi-
city.45 In patients with adequate vitamin D stores, a dose of
500 to 800 IU daily appears to be adequate to maintain adequate
vitamin D levels; however, if a person does not have good tissue
vitamin D stores due to chronic use of sunscreen and protective
clothing, a strictly indoor occupation, or living very far from the
equator, a higher dose of vitamin D may initially be necessary to
increase serum vitamin D levels.31,36
In addition, people with MS using vitamin D for its anti-
inflammatory effects may need higher doses. Vitamin D should
be titrated in these patients to serum levels greater than
100 nmol/L (40 ng/mL) based on the association of this level
with a decreased MS incidence 10,45 Patients should be moni-
tored for signs of toxicity (hypercalcemia, kidney stones, and
weight loss) because, while some studies found that up to
40 000 IU of vitamin D daily could be taken safely, other stud-
ies found toxicity at doses as low as 100 IU 1,25(OH)2D (cal-
citriol) daily.43,45 Calcium intake may need to be monitored
and potentially restricted to prevent hypercalcemia. The new
recommendations for vitamin D still need to be evaluated in
large long-term clinical studies to determine whether a vitamin
D concentration of 100 nmol/L (40 mcg/mL) is sufficient to
confer protection against MS and if higher vitamin D doses are
safe for long-term supplementation.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
8 Journal of Pharmacy Practice 000(00)
at UNIV OF MONTANA on November 30, 2011jpp.sagepub.comDownloaded from
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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