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 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

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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)

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Funding

The author(s) received no financial support for the research, author-

ship, and/or publication of this article.

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