REVIEWS OF THERAPEUTICS

Vitamin D Supplementation: What’s Known, What to Do,

and What’s Needed
Stuart T. Haines, Pharm.D., FCCP, and Sharon K. Park, Pharm.D.

The use of vitamin D supplements to prevent and treat a wide range of ill-
nesses has increased substantially over the last decade. Epidemiologic evi-
dence links vitamin D deficiency to autoimmune disease, cancer,
cardiovascular disease, depression, dementia, infectious diseases, musculo-
skeletal decline, and more. The Institute of Medicine published an exhaus-
tive report in 2010 that concluded that vitamin D supplementation for
indications other than musculoskeletal health was not adequately sup-
ported by evidence and that most North Americans receive sufficient vita-
min D from their diet and sun exposure. These conclusions are at odds
with some clinical practice guidelines; thus, we sought to summarize the
best available evidence regarding the benefits of vitamin D supplementa-
tion, to examine the potential risks, and to provide practical dosing
advice. The adequacy of vitamin D stores is determined by measuring the
25-hydroxyvitamin D serum concentrations. The demarcations between
deficiency (< 20 ng/ml), insufficiency (20–30 ng/ml), and optimal (30–
80 ng/ml) serum concentrations are controversial. Vitamin D in doses of
800–5000 IU/day improve musculoskeletal health (e.g., reduces the rate of
fractures and falls in older adults (aged  65 yrs). In patients with docu-
mented vitamin D deficiency, a cumulative dose of at least 600,000 IU
administered over several weeks appears to be necessary to replenish vita-
min D stores. Single large doses of 300,000–500,000 IU should be
avoided. Vitamin D supplementation should not be offered routinely to
other patient populations. Although results from some prospective clinical
trials are promising, most have not been robustly designed and executed.
The decision by young, otherwise healthy adults to take vitamin D in
doses of 2000 IU/day or lower is unlikely to cause harm. For patients who
are not at risk for developing vitamin D deficiency, sensible sun exposure
is an inexpensive and enjoyable way to maintain vitamin D stores.
Key Words: vitamin D, ergocalciferol, cholecalciferol, nutritional supple-
mentation.
(Pharmacotherapy 2012;32(4):354–382)

Likely Benefits of Vitamin D Supplementation

OUTLINE
Vitamin D and Disease
Vitamin D Metabolism and Physiologic Actions
Vitamin D Deficiency and Insufficiency
Prevention and Treatment of Bone Disease
Fall Prevention
Unproven Benefits of Vitamin D Supplementation
Prevention and Treatment of Cardiovascular Diseases
Hypertension
 VITAMIN D SUPPLEMENTATION Haines and Park
Heart Failure
Cardiovascular Morbidity and Mortality
Statin-Associated Myalgia
Prevention and Treatment of Endocrine Disorders
Diabetes Mellitus and Glycemia
Prevention and Treatment of Neurologic Diseases
Multiple Sclerosis
Depression
Cognitive Decline and Dementia
Prevention and Treatment of Respiratory Diseases
Asthma
Chronic Obstructive Pulmonary Disease
Over the last decade there has been consider-
able interest in vitamin D and the use of vita-
min D supplements to prevent or treat a
variety of ills.1 Claims in the media abound,
and the sales of vitamin D supplements have
increased 10-fold since 2001.2 Although vitamin
D supplementation has been used for several
decades to improve bone health in children
with rickets and adults with osteomalacia,
lengthy lists of potential indications for vitamin
D supplementation now appear in peer-
reviewed journals1, 3 and on reputable consumer
health information Web sites.4 Should clinicians
routinely recommend vitamin D supplementation
to their patients? To all patients or specific
patient populations? Or to only a select few with
a known deficiency?
The vitamin D story is unfolding rapidly, and
the enormous volume of scientific reports pub-
lished over the last few years has made it difficult
for clinicians to stay current. In late 2010, the
Institute of Medicine (IOM) published a report
that exhaustively reviewed the available evi-
dence.5 The authors concluded that most of the
science regarding the extraskeletal benefits of
vitamin D, with or without calcium, could not be
considered reliable and warned that intakes
greater than the recommended daily allowance
(600–800 IU) have not been shown to confer
From the Department of Pharmacy Practice and Science,
University of Maryland School of Pharmacy (Dr. Haines),
and the Department of Clinical and Administrative Sci-
ences, Notre Dame of Maryland University School of Phar-
macy (Dr. Park), Baltimore, Maryland.
For reprints, visit https://caesar.sheridan.com/reprints/
redir.php?pub=10089&acro=PHAR. For questions or com-
ments, contact Stuart T. Haines, Pharm.D., FCCP, Univer-
sity of Maryland School of Pharmacy, 20 North Pine Street,
4th Floor, Baltimore, MD 21201; e-mail: shaines@rx.umary-
land.edu.
355
Prevention and Treatment of Infectious Diseases
Tuberculosis
Upper Respiratory Tract Infections
Cancer
Cancer Prevention
Colorectal Cancer
Breast Cancer
Vitamin D Toxicity and Adverse Effects
Recommendations and Replacement Strategies
Future Directions
Conclusion
any health benefits, and in fact, they have been
linked to other health problems. Moreover, the
report asserts, that, with few exceptions, all
North Americans are receiving enough calcium
and vitamin D. Therefore, according to the IOM
report, the need for vitamin D supplementation,
beyond what is already obtained through a well-
balanced diet and periodic sun exposure, is
unnecessary for most individuals. These state-
ments seem at odds with the International Osteo-
porosis Foundation’s 2010 position statement
that contends that intakes of 2000 IU/day of vita-
min D may be needed in some older adults to
maintain bone health and a 2007 International
Consensus Workshop that concluded that 50%
of the adult population in North America and
Northern Europe have vitamin D serum concen-
trations less than 20 ng/ml (i.e., deficient).6, 7
Indeed, some authors believe that the IOM report
uses faulty logic, misinterprets some of the sci-
ence, and fails to provide sufficient guidance.8
Predictably, natural medicine advocates contend
that the IOM recommendations actually promote
vitamin D deficiency and protect the interests of
the pharmaceutical industry.9
The purpose of this review is to summarize
the best available evidence regarding the benefits
of vitamin D supplementation for some of its
most commonly purported uses, to examine the
potential risks of vitamin D supplementation, to
provide practical advice regarding dosing, and to
alert readers to ongoing clinical trials. A com-
prehensive literature search was conducted using
the PubMed and EMBASE databases for articles
published between January 2000 and June 2011
using the key words “vitamin D,” “ergocalcifer-
ol,” “cholecalciferol,” and “vitamin D supple-
mentation.” In addition, the bibliographies of
review articles and meta-analyses were screened.
Each article’s title and abstract were reviewed to
356 PHARMACOTHERAPY Volume 32, Number 4, 2012

determine if the manuscript related to either an

association between vitamin D serum concentra-
tions and the incidence of disease, or the use of
vitamin D supplementation for the prevention or
treatment of bone disease, cardiovascular dis-
ease, endocrine disorders, neurologic disease,
psychiatric disorders, respiratory diseases, infec-
tious diseases, or cancer. Articles were included
in the review if they were deemed by the
authors to have merit, with a strong emphasis
on prospective studies that examined the use of
vitamin D supplementation. Given that the num-
ber of potential references was large, only the
best available evidence related to each disease
state was included.

Vitamin D and Disease

Vitamin D Metabolism and Physiologic Actions

Vitamin D is not a vitamin but rather a steroid
hormone. The functionally inactive prehor-
mones, vitamin D2 (ergocalciferol) and vitamin
D3 (cholecalciferol), are converted to more
active forms through hepatic and renal metabo-
lism (Figure 1).10 Vitamin D2 is obtained
through dietary sources, primarily oily fish (e.g.,
mackerel, salmon, sardines, tuna) and fortified
dairy products. Vitamin D3 is synthesized in the
skin by ultraviolet B radiation from sunlight
(230–313 nm), which stimulates 7-dehydrocho-
lesterol in the keratinocytes. Both vitamin D2
and D3 undergo hydroxylation in the liver to
form the prohormone 25-hydroxyvitamin D (25
(OH)D or calcidiol) and are subsequently con-
verted to the active hormone 1,25-dihydroxyvi-
tamin D (1,25(OH)2D or calcitriol) in the
kidneys. Hydroxylation of vitamins D2 and D3 in Figure 1. Vitamin D metabolism and physiologic actions.
the liver and kidneys by 1a-hydroxylase Reprinted with permission from reference 10.
increases the polarity of the hormone and makes
it more water soluble. Serum concentrations of
25(OH)D are considered a good indicator of processes that affect cell proliferation, differenti-
vitamin D stores in the body.1, 11 The conver- ation, and death.5, 11 Functions at the cellular
sion of 25(OH)D to 1,25(OH)2D is tightly regu- and genomic level may explain the potential role
lated by the concentrations of plasma of vitamin D in disease states such as multiple
parathyroid hormone (PTH) as well as serum sclerosis, depression, tuberculosis, cardiovascular
calcium and phosphate.11, 12 disease, asthma, and cancer.
The primary physiologic function of vitamin
D is to regulate the absorption of calcium from
Vitamin D Deficiency and Insufficiency
the intestinal lumen, thereby maintaining suffi-
cient serum calcium concentrations to support The definitions of what constitutes vitamin D
bone building and maintenance. However, vita- deficiency and insufficiency as well as optimal
min D receptors are ubiquitous throughout the vitamin D status are not trivial. The decision to
body. Vitamin D also modulates immunity, cell initiate vitamin D supplementation and the
growth, and inflammation as well as genomic goals of therapy would be predicated on these
 VITAMIN D SUPPLEMENTATION Haines and Park
thresholds. Unfortunately, it is unclear what the
optimal 25(OH)D concentrations are, and con-
sensus is lacking about where the demarcations
between normal, insufficiency, and deficiency
should be. A patient’s vitamin D status is deter-
mined by measuring serum concentrations of the
prohormone 25(OH)D.13 Given its 2–3-week
half-life, 25(OH)D serum concentrations are a
good indicator of vitamin D stores and reflect
the amount of vitamin D derived from both die-
tary intake and sun exposure. Although 1,25
(OH)2D is the more biologically active form of
the hormone, serum concentrations of 1,25
(OH)2D are not useful for determining a
patient’s vitamin D status due to its relatively
short serum half-life (4–6 hrs). Furthermore,
1,25(OH)2D serum concentrations may be nor-
mal or elevated in patients with vitamin D defi-
ciencies due to the counterregulatory effects of
PTH.13 Although 25(OH)D serum concentration
is considered the best biomarker of vitamin D
status, whether it accurately predicts the risk of
disease is controversial.1, 5 The assays used to
measure 25(OH)D serum concentrations have
been prone to considerable performance prob-
lems with regard to accuracy and precision.
Recent reference standards for vitamin D testing
have led to significant improvements, but
research data from before 2009 should be
viewed with caution given the potential for mea-
surement variability.5
Historically, vitamin D deficiency was identi-
fied by the presence of rickets or osteomalacia.14
Bone disease in the context of vitamin D defi-
ciency is not typically seen until serum concen-
trations of 25(OH)D are less than 10 ng/ml.3 A
subtle insufficiency of vitamin D stores might
also lead to physiologic aberrations that, in turn,
might increase the risk of a variety of diseases
over time. Some authors have suggested that
functional measures of vitamin D status might
be a useful way to determine the adequacy of
vitamin D stores at the population level.1 Given
that PTH concentrations are elevated when there
is insufficient serum ionized calcium, suppres-
sion of PTH secretion in patients who consume
adequate dietary calcium has been proposed as a
marker for vitamin D status. Epidemiologic stud-
ies have shown that PTH levels reach a nadir
when 25(OH)D concentrations are 30–40 ng/
ml.13 Another way to determine the adequacy of
vitamin D stores is to examine bone health. An
autopsy series in 675 Northern European
patients found pathologic bone mineralization
357
defects in a substantial proportion of patients
with a 25(OH)D serum concentration less than
30 ng/ml but not in patients with serum concen-
trations above this threshold.15 Finally, the ade-
quacy of vitamin D stores could be determined
by examining the frequency of bone disease. A
meta-analysis of randomized controlled trials
demonstrated a significant relationship between
25(OH)D concentration and fracture risk.16, 17
No fracture benefit from vitamin D supplemen-
tation was observed in studies where the mean
25(OH)D concentration was less than 28 ng/ml.
Due to these results, some authors have postu-
lated that minimally adequate vitamin D stores
are not achieved until 25(OH)D concentrations
are greater than 30 ng/ml.1, 3, 12, 14, 18 However,
the authors of the recent IOM report correctly
point out that the 25(OH)D serum concentration
is not a validated surrogate measure for any
health outcome and contend that a concentra-
tion of 20 ng/ml or greater should be sufficient
for most (97.5%) of the population.5
The question of what is the optimal 25(OH)D
serum concentration is even more controversial.
Based on estimates of vitamin D synthesis
through daily sun exposure in primitive humans,
25(OH)D serum concentrations of 40–80 ng/ml
might be physiologically appropriate.8 Some
analyses have indicated that serum concentra-
tions of 36–48 ng/ml are necessary to prevent
cancer.19 Whether serum concentrations greater
than 30, 40, or even 50 mg/ml are needed to
maintain optimal health are merely hypotheses
until randomized controlled trials using 25(OH)
D concentrations to guide therapy have been
conducted. Unfortunately, such studies seem
unlikely.
The identification of patients who have vita-
min D deficiency or insufficiency is important in
order to make appropriate recommendations
regarding vitamin D replacement and dosing
strategy. Who should be screened and how often
is not clear.5 Several patient populations are at
relatively high risk for developing vitamin defi-
ciency, and obtaining a 25(OH)D serum concen-
tration to screen for a deficiency is
recommended by the Endocrine Society’s Clini-
cal Practice Guidelines (Table 1).14 Currently,
there are no recommendations regarding how
frequently to rescreen patients who have 25
(OH)D concentrations greater than 30 ng/ml,
but it seems reasonable to retest high-risk indi-
viduals every 5 years if they are not receiving
vitamin D supplementation.
358 PHARMACOTHERAPY Volume 32, Number 4, 2012
Table 1. Patient Populations at High Risk for Vitamin D Deficiency and Who Should Be Screened14
African-American or Hispanic descent
Obesity (body mass index > 30 kg/m2)
Older adults with history of bone fractures or falls
Bone diseases (osteoporosis, osteomalacia, rickets)
Chronic kidney disease
Hepatic failure
Chronic drug therapy (glucocorticoids, antiseizure drugs, azole antifungals, antiretroviral drugs, cholestyramine)
Malabsorption syndromes (cystic fibrosis, inflammatory bowel disease, Crohn’s disease, bariatric surgery, radiation enteritis)
Granuloma-forming disorders (sarcoidosis, tuberculosis, histoplasmosis, coccidiomycosis, beryliosis)
Likely Benefits of Vitamin D Supplementation
Prevention and Treatment of Bone Disease
The use of vitamin D supplementation to treat
bone disease was first described in case reports
in the 1920s. Children with rickets experienced
symptom improvements after prescribed sun
exposure and vitamin D supplementation.20
These early experiences led to the fortification
of food, particularly milk and other dairy prod-
ucts. Formal randomized controlled studies
regarding the benefits and risks of food fortifica-
tion or vitamin D supplementation for the pre-
vention and treatment of rickets or osteomalacia
have not been reported. Nonetheless, vitamin D
supplementation is recommended for infants and
children to prevent and treat rickets based on
accumulated medical experience.21
Although there is a correlation between vita-
min D serum concentrations and the occurrence
of osteoporosis and hip fracture, the data regard-
ing the use of vitamin D to improve bone min-
eral density (BMD) are far from conclusive. Few
studies have examined the effects of vitamin D
independent of calcium supplementation. In
children with very low 25(OH)D serum concen-
trations (< 15 ng/ml), supplementation with
vitamin D improved total body mineral content
and lumbar spine BMD.22 In late postmeno-
pausal women whose mean age ranged from 62–
70 years old and lived in northern latitudes (in
the United States and the Netherlands), vitamin
D supplementation in doses of 400–800 IU/day
prevented bone loss.23 The effects of vitamin D
on BMD appear to be in addition to the benefits
observed with calcium supplementation, at least
in older, postmenopausal women.23 However, in
early postmenopausal Australian women (mean
age 56 yrs) with a mean baseline vitamin D
serum concentration greater than 30 ng/ml and
daily sun exposure of approximately 115 min-
utes, supplementation with ergocalciferol
10,000 IU once/week plus calcium carbonate
1000 mg once/day taken for 2 years had no
effect on BMD compared with calcium supple-
mentation alone.24 These findings are consistent
with those of other studies in premenopausal
and early postmenopausal women who had nor-
mal baseline vitamin D stores.23 Despite these
observations, nearly all clinical practice guide-
lines recommend the use of vitamin D 400–
800 IU/day with calcium supplementation in
postmenopausal women to prevent bone loss or
treat osteoporosis.25 Furthermore, most clinical
trials that evaluate the benefits of antiresorptive
therapies for osteoporosis have required all
participants to take calcium and vitamin D
supplements.
With regard to the use of vitamin D to pre-
vent fractures, the data are generally positive,
with a few notable exceptions (Table 2). A
meta-analysis of randomized controlled trials
found that cholecalciferol given in high doses
(700–800 IU/day) with or without calcium sup-
plementation significantly reduced the risk of
hip fracture and nonvertebral fractures.16 How-
ever, results from two randomized controlled tri-
als included in the meta-analysis in which 3722
subjects received low doses (400 IU/day) of vita-
min D showed no effect on fracture risk; the
pooled relative risk (RR) for hip fracture was
1.15 (95% confidence interval [CI] 0.88–1.50),
and the pooled RR for any nonvertebral fracture
was 1.03 (95% CI 0.86–1.24). In contrast, very
high doses of vitamin D may be harmful.26, 27
An Australian study found that cholecalciferol
500,000 IU given as a single oral dose once/year
(in the autumn) increased the risk of fractures
compared with placebo.26 Similarly, a study con-
ducted in the United Kingdom using high-dose
intramuscular ergocalciferol once/year in elderly
men and women found an increased risk of hip
fracture.27 These seemingly conflicting data
Table 2. Summary of Studies of Vitamin D for the Prevention and Treatment of Fractures and Falls
Vitamin D Indication
and Patient Population
Fractures
Adult women and men
(n = 5572 from 3 RTCs)16
Nonvertebral fractures
Adult women and men
(n = 6098 from 5 RTCs)16
Fractures
Community-dwelling women,
aged > 70 yrs, in Australia
(n = 2258)26
Fractures
Community-dwelling adults,
aged > 75 yrs, in the United
Kingdom (n = 2258)27
Falls
Adult women and men, mean
age 60 yrs (n = 1237 from 5
RTCs)28
Falls
Adult women and men in
assisted-living facilities or
nursing homes in Australia,
mean age 83 yrs (n = 625)29
Falls
Community-dwelling adults,
mean age 71 yrs (n = 1237)30
Falls
Adult women and men, mean
age  65 yrs (n = 1921 from
7 RTCs)31
Duration
Study Design Study Treatment of Follow-up
Meta-analysis Cholecalciferol 700–800 IU/
day with or without
calcium supplementation
vs placebo
Meta-analysis Cholecalciferol 700–800 IU/
day with or without
calcium supplementation
vs placebo
RCT Single dose of cholecalciferol
500,000 IU vs placebo
every autumn
RCT Single dose of ergocalciferol
300,000 IU i.m. vs placebo
every autumn
Meta-analysis Various vitamin D products
and dosages vs calcium
supplementation alone
or placebo
RCT Ergocalciferol 10,000 IU/wk,
then 1000 IU/day vs
placebo
RCT Cholecalciferol 700 IU/day
+ calcium citrate malate
500 mg/day vs placebo
Meta-analysis Cholecalciferol or
ergocalciferol
700–1000 IU/day with or
without calcium vs
placebo
Major Findings Comments
2–5 yrs Risk of hip fracture reduced No benefit observed for
by 26% (pooled RR 0.74, cholecalciferol
95% CI 0.61–0.88) doses < 700 IU/day
in a separate analysis;
NNT = 45 to
prevent 1 hip fracture
2–5 yrs Risk of nonvertebral fractures No benefit observed for
reduced by 23% (pooled RR 0.77, cholecalciferol
95% CI 0.68–0.87) doses < 700 IU/day
in a separate analysis
3–5 yrs Increased risk of fractures in vitamin Relied on self-reports of
D group (4.9 vs 2.9 fractures/100 fracture but
patient-yrs; p=0.047) confirmed by
Post hoc analysis found temporal radiologic evidence
relationship between fracture events
and vitamin D administration
3 yrs Increased risk of hip fracture in Relied on self-reports of
vitamin D group (OR 1.49, 95% fracture but confirmed
CI 1.02–2.18, p=0.04) by medical record
No protective effect was observed review; 50% dropout
when stratified by sex, age, or rate
previous fracture
3 mo–3 yrs Risk of falls reduced by 22% NNT = 15 to
(corrected OR 0.78, 95% prevent 1 fall
CI 0.64–0.92)
2 yrs Risk of falls reduced by 27% Baseline 25(OH)D
(incident rate ratio 0.73; 95% level < 16 ng/ml in
CI 0.57–0.95) majority of patients
VITAMIN D SUPPLEMENTATION Haines and Park
3 yrs Reduced risk of falling in women Baseline 25(OH)D level
(OR 0.54, 95% CI 0.30–0.97) did not alter the
but not in men; effect most treatment effect
pronounced in less active women
(OR 0.35, 95% CI 0.15–0.81)
2–36 mo Risk of falls reduced by 19% NNT = 11 to prevent
(OR 0.81, 95% CI 0.71–0.92) 1 fall
Low-dose
(  400 IU/day) in a
separate analysis was
not effective (OR 1.10)
359
360 PHARMACOTHERAPY Volume 32, Number 4, 2012

suggest that there is a dose–response curve

Randomly allocated to
whereby relatively low doses of vitamin D pro-

Relied on self-reports
(118 homes); staff
vide little protection, daily supplementation with

treatment group;
group by facility
Comments

was blinded to

relied on staff
moderate doses reduces fracture risk, and very

to report falls
large bolus doses have a harmful effect.

of falls
Fall Prevention

RCT = randomized controlled trial; 25(OH)D = 25-hydroxyvitamin D; RR = relative risk; CI = confidence interval; NNT = number needed to treat; OR = odds ratio.
One of the most common uses of vitamin D
supplementation over the last decade has been to
prevent falls in those at highest risk, particularly
vitamin D–treated patients had
Frequency of falls was similar in

elderly patients with a history of falling (Table 2).

Given that falls are a contributing factor to many
Risk of falls increased 15%
Major Findings

at least 1 fall vs 43% in

the two groups: 44% of

bone fractures in older adults, reductions in frac-

CI 1.02–1.30, p=0.03)

ture rates may be attributable, at least in part, to

the control group

reductions in falls. A meta-analysis of five ran-

(RR 1.15, 95%

domized controlled trials that enrolled older

adults and used a variety of vitamin D products
and dosing regimens found a 22% reduction in
the risk of falls compared with calcium supple-
mentation alone or placebo.28 Since the publica-
tion of this meta-analysis, additional studies have
confirmed these findings.29, 30 A follow-up meta-
of Follow-up
Duration

analysis that included 10 randomized controlled

3–5 yrs
10 mo

trials again found that vitamin D 700–1000 IU/

day had a positive effect on the risk of falling.31
The benefits were particularly evident in those
Single dose of cholecalciferol

who achieved a 25(OH)D serum concentration

Ergocalciferol 100,000 IU

greater than 24 ng/ml; these patients experienced

500,000 IU vs placebo
every 3 mo vs control
(no supplementation)
Study Treatment

a 23% reduction in fall risk (RR 0.77, 95% CI

0.65–0.90). These data, similar to the findings
from the bone fracture studies, suggest that there
every autumn

is a dose-response relationship with vitamin D

supplementation and a threshold vitamin D con-
centration necessary to positively affect musculo-
skeletal health.
It should be noted that two large community-
RCT (cluster design)

based clinical trials failed to demonstrate a bene-

fit with high-dose vitamin D supplementation
Study Design

with regard to falls.26, 32 In a British study,

elderly residents in residential care homes were
randomized to receive high-dose ergocalciferol
every 3 months or no intervention.32 After a
RCT

mean follow-up of 10 months, the percentage of

patients in each group who experienced at least
homes in England, mean age

one fall was similar (44% in the vitamin D group

aged > 70 yrs, in Australia

vs 43% in the control group). The staff at the

Adults in residential care

facilities were blinded to the study’s primary

and Patient Population

85 yrs (n = 3717)32
Table 2. (continued)

Vitamin D Indication

outcome but were relied on to report the occur-

dwelling women,

rence of falls. The second study, conducted in

(n = 2258)26

Australia, showed a detrimental effect on fall

Community-

risk with very high-dose cholecaliferol.26

Mirroring the findings in fracture studies, the
risk of falls appears to decrease with doses of at
Falls

Falls

least 700 IU/day, but very high doses given

 VITAMIN D SUPPLEMENTATION Haines and Park
sporadically (e.g., quarterly or annually) appear
to have little or potentially a negative effect on
musculoskeletal health. The biologic explanation
for these findings can only be speculated, but
upregulation of enzymatic pathways responsible
for vitamin D metabolism may protect against
vitamin D intoxication and hypercalcemia but
diminish effectiveness when megadoses of vita-
min D are given.33
Unproven Benefits of Vitamin D
Supplementation
Prevention and Treatment of Cardiovascular
Diseases
Hypertension
Physiologically, vitamin D has indirect regula-
tory control over intracellular calcium as well as
the renin-angiotensin-aldosterone system (RAAS),
which, together, influence smooth muscle
vascular tone.34 Thus, there has been consider-
able interest in the use of vitamin D supplemen-
tation to prevent and treat high blood pressure.
There are more than 30 epidemiologic studies
assessing the relationship between vitamin D
serum concentrations and blood pressure.35
Early cross-sectional studies from the 1980s
found an association between low 25(OH)D
serum concentrations and blood pressure control
in patients with hypertension.35 Subsequently,
cross-sectional data from the National Health
and Nutrition Examination Survey III (NHANES
III) found that higher vitamin D intake mitigated
age-related increases in systolic blood pressure.36
In contrast, other cross-sectional studies, includ-
ing a Dutch study in older adults as well as a
large Norwegian study, found no association
between vitamin D intake and blood pressure
after accounting for physical activity, body
weight, and smoking status.37, 38
Findings from prospective cohort studies have
also been inconsistent. Analyses of the Nurses
Health Study I and the Health Professionals Fol-
low-up Study found that the risk of new-onset
hypertension was significantly greater in those
with 25(OH)D serum concentrations less than
15 ng/ml.39 A prospective, nested case-control
study in 1484 patients found that premenopau-
sal women (mean age 43 yrs) enrolled in the
Nurses Health Study II who had a 25(OH)D
serum concentration less than 21 ng/ml had a
66% greater risk (odds ratio [OR] 1.66, 95% CI
1.11–2.48) of developing high blood pressure
361
over 7 years of follow-up compared with
matched subjects whose 25(OH)D serum con-
centrations were greater than 32.3 ng/ml.40
However, these findings are not consistent with
those of another study, which did not find a dif-
ference in the rates of incident hypertension
among 1268 normotensive, middle-aged Norwe-
gians (mean age 56 yrs) who had 25(OH)D
serum concentrations less than 16.6 ng/ml ver-
sus greater than 25.1 ng/ml at baseline and were
followed for 14 years (RR 1.10, 95% CI 0.77–
1.57).41
Several prospective, randomized controlled tri-
als have examined the relationship of vitamin D
supplementation, with or without calcium sup-
plementation, and blood pressure (Table 3). The
largest of these studies is the Women’s Health Ini-
tiative (WHI), a study designed to examine the
benefit of calcium and vitamin D supplementa-
tion to prevent osteoporosis-related fractures.42
Although the WHI found no effect from calcium
plus vitamin D supplementation on the self-
reported incidence of hypertension in the overall
study population of 36,282 patients, a subgroup
analysis found a higher risk of incident hyperten-
sion among African-American women who took
supplementation when compared to those who
took placebo. (RR 1.22, 95% CI 1.0–1.4).42
A meta-analysis of 10 randomized controlled
trials that examined the effects of vitamin D sup-
plementation, with or without calcium, on blood
pressure and incident hypertension found a very
modest and nonsignificant improvement in sys-
tolic and diastolic blood pressure with supple-
mentation.43 No benefit was seen in studies in
which vitamin D was taken alone. A higher dose
(  1000 IU/day) of vitamin D, compared with
lower doses, had no effect on systolic blood
pressure but a small effect on diastolic blood
pressure (weighted mean difference 1.5 mm
Hg, p=0.039).
Heart Failure
Given the prevalence of vitamin D deficiency
and insufficiency in the general population, it is
not surprising that patients with heart failure
commonly have vitamin D deficiency as well.44
In one study, patients with heart failure had 25
(OH)D serum concentrations 34% lower than
age- and sex-matched controls.45 Vitamin D defi-
ciency may accelerate disease progression
through multiple mechanisms. Vitamin D has
some regulatory effects on the RAAS, and
deficiency is associated with increased RAAS
 362

Table 3. Summary of Studies of Vitamin D for the Prevention and Treatment of Cardiovascular Diseases
Vitamin D Indication and Duration of
Patient Population Study Design Study Treatment Follow-up Major Findings Comments
Blood Pressure RCT Cholecalciferol 400 IU/ 7 yrs No differences between groups in Subanalysis of the Women’s
Community-dwelling women, day + elemental mean change in SBP (0.22 mm Health Initiative; primary
aged 50–70 yrs, enrolled in calcium 1000 mg/day Hg, 95% CI 0.05–0.49 mm outcome of study was hip
the Women’s Health vs placebo Hg) and DBP (0.11 mm Hg, fracture
Initiative (n = 36,282)41 95% CI 0.04–0.27 mm Hg)

Hypertension
Adults with hypertension
(10 RCTs)42
Heart failure
Adults with heart failure,
mean age 58 yrs, in
Germany (n = 123)46
Heart failure
Adults with heart failure,
aged > 70 yrs, in Scotland
(n = 105)47
Statin-induced myalgia
Patients with statin-induced
myalgia and 25(OH)D
levels < 24 ng/ml, followed
in a lipid clinic in Australia
(n = 8)50
Meta-analysis Various vitamin D
products and dosages
with or without
calcium vs placebo
RCT Cholecalciferol 2000 IU/
day vs placebo for
9 mo; all patients
received calcium
supplementation
RCT Ergocalciferol
100,000 IU at baseline
and repeated at
10 wks vs placebo
Case series Cholecalciferol
1000–10,000 IU/day
and discontinuation of
statin therapy
5 wks–7 yrs No net change between groups in
weighted mean SBP ( 1.9 mm
Hg, 95% CI 4.2–0.4 mm Hg)
or DBP ( 0.1 mm Hg, 95%
CI 0.7–0.5 mm Hg)
15 mo No differences in mortality: 7
deaths in vitamin D group vs 6
deaths in placebo group
No differences in LVEF, SBP,
or DBP
20 wks No differences between groups in
6-min walk test, time up and go
test, or daily physical activity
levels
Health-related quality of life
worse in vitamin D group
6 mo Resolution of muscle symptoms in
majority; 6 of the 8 patients
agreed to statin rechallenge,
and 4 of the 6 were able to
tolerate a statin for > 6 mo
Results were similar when the
Women’s Health Initiative was
excluded from the analysis
Baseline 25(OH)D level was very
low (< 15 ng/ml);
improvements in IL-10 and
TNF-a levels were noted in the
vitamin D group; high dropout
rate
B-type naturetic peptide improved
in the vitamin D group ( 22 vs
78 pg/ml, p=0.04)
No control group; potential for
strong placebo effect
PHARMACOTHERAPY Volume 32, Number 4, 2012

Statin-induced mylagia Case series Ergocalciferol 12 wks Resolution of muscle symptoms No control group; potential for
Patients with statin-induced 50,000 IU/ in majority (93%) strong placebo effect
myalgia and 25(OH)D wk 9 12 wks while
levels < 32 ng/ml, followed continuing statin
in a lipid clinic in Ohio therapy
(n = 38)55
RCT = randomized controlled trial; SBP = systolic blood pressure; CI = confidence interval; DBP = diastolic blood pressure; LVEF = left ventricular ejection fraction; 25(OH)D = 25-hydroxyvi-
tamin D; IL-10 = interleukin-10; TNF-a = tumor necrosis factor-a.
 VITAMIN D SUPPLEMENTATION Haines and Park
activity.44 Moreover, vitamin D supplementation
may improve muscle function and reduce car-
diac remodeling.
Relatively few prospective clinical trials have
examined the potential benefits of vitamin D
supplementation in patients with heart failure
(Table 3). In one small study of 123 patients,
investigators examined the effects of cholecalcif-
erol 2000 IU/day versus placebo on mortality
and several relevant disease markers, including
left ventricular ejection fraction, and biochemi-
cal variables, such as serum naturetic peptide
levels.46 There was no difference in mortality
(seven deaths in the vitamin D group vs six
deaths in the placebo group) or in any markers
of disease after 15 months of follow-up. The
only potential benefit of vitamin D supplementa-
tion observed in this study were changes in the
serum concentrations of the inflammatory mark-
ers interleukin-10 and tumor necrosis factor-a,
which demonstrated significant improvements
compared with placebo.
A second randomized, placebo-controlled trial
conducted in 105 elderly patients with heart fail-
ure and documented vitamin D deficiency failed
to demonstrate any improvement in functional
capacity or health-related quality of life after
patients received ergocalciferol 100,000 IU at
baseline and 10 weeks later.47 No improvements
with vitamin D supplementation relative to pla-
cebo were noted in the 6-minute walk test, time
up and go test, or daily physical activity. Of
some surprise, there was a slight worsening in
health-related quality of life with vitamin D sup-
plementation relative to placebo (p=0.03 at
20 wks). Mortality and hospitalization rate were
similar between the two groups. Therefore, high-
dose vitamin D supplementation failed to pro-
vide any discernable short-term benefit to
elderly patients with heart failure and docu-
mented vitamin D deficiency.
Cardiovascular Morbidity and Mortality
An analysis of the NHANES III found that
vitamin D insufficiency was associated with an
increased risk of all-cause mortality, largely dri-
ven by increases in cardiovascular- and cancer-
related deaths.48 Further analysis of this data set
limited to older adults (aged > 65 yrs) found
that cardiovascular-related mortality was signifi-
cantly higher (adjusted hazard ratio [HR] 2.36,
95% CI 1.17–4.75) in patients with 25(OH)D
serum concentrations less than 10 ng/ml com-
pared with patients with vitamin D concentra-
363
tions greater than 40 ng/ml.49 However, despite
attempts to adjust for differences between
groups, these findings may simply reflect the
underlying health status of the two groups. Indi-
viduals who have low vitamin D stores are more
likely to have underlying cardiovascular disease,
be less physically active, and spend less time
outdoors. Therefore, randomized controlled tri-
als are needed to determine the potential bene-
fits of vitamin D supplementation on mortality
and cardiovascular outcomes.
Four randomized controlled trials of fair-to-
good quality have reported the effect of vitamin
D supplementation on cardiovascular event rates
and mortality.43 None of these studies found a
statistically significant effect on cardiovascular
mortality or cardiovascular event rates including
myocardial infarction and stroke. It should be
noted that these studies were not designed to
examine the effects of vitamin D supplementa-
tion on cardiovascular events and that three of
the studies used vitamin D in combination with
calcium supplementation. The largest of these
studies, the WHI, found that vitamin D plus cal-
cium supplementation resulted in a small, but
nonsignificant, increase in the composite of car-
diovascular disease–related death, nonfatal myo-
cardial infarction, and need for revascularization
procedure (RR 1.08, 95% CI 0.99–1.19).42
Statin-Induced Myalgia
Perhaps one of the most promising uses of
vitamin D supplementation is for the prevention
and treatment of statin-induced myalgia, a well-
known adverse effect of 3-hydroxy-3-methylglut-
aryl coenzyme A (HMG-CoA) reductase inhibi-
tors (statins) that affects more than 10% of
patients who take these drugs.50, 51 Vitamin D
receptors are found on the surface of skeletal
muscle cells as well as in their nuclei. Stimula-
tion of these nuclear receptors increases muscle
cell proliferation and differentiation. A defi-
ciency in vitamin D can result in muscle weak-
ness and generalized pain.50, 52 Therefore, an
interplay between statin therapy and vitamin D
deficiency may predispose patients to develop
muscle symptoms.
Some studies, but not all, have found a rela-
tionship between 25(OH)D concentrations and
the occurrence of statin-induced myalgias. In a
case series of 99 patients referred to and man-
aged in a lipid clinic in Oregon, vitamin D defi-
ciency (< 20 ng/ml) was found in 32% of
patients and myalgia was reported by 38%.53
364 PHARMACOTHERAPY Volume 32, Number 4, 2012
Among those patients with 25(OH)D serum con-
centrations less than 20 ng/ml, 62.1% reported
muscle pain. In contrast, only 17.6% of those
who had a 25(OH)D serum concentration
greater than 30 ng/ml complained of myalgia
(p < 0.01). Thus, low 25(OH)D serum concen-
trations were associated with a 4-fold increase in
the incidence of myalgia. These findings are not
consistent with a post hoc analysis of the Treat
to New Target (TNT) study.53 A subset of 1509
patients who participated in the TNT study had
25(OH)D serum concentrations measured at
baseline and 1 year after randomization to ator-
vastatin 80 or 10 mg once/day. Vitamin D defi-
ciency (< 30 ng/ml) was common and was
observed in 49% of patients at baseline and in
56% at 1 year. However, the percentage of
patients with vitamin D deficiency who were
experiencing muscle pain was not different than
the percentage of patients with normal vitamin
D stores, at both baseline (8.3% vs 12%) and
1 year (11% vs 9.7%).
In one small case series, 11 patients who dis-
continued statin therapy due to severe muscle
pain were screened for vitamin D deficiency
(Table 3).50 Eight of the 11 patients were dis-
covered to have 25(OH)D serum concentrations
of less than 24 ng/ml. Six patients with vitamin
D deficiency agreed to a statin rechallenge after
completing 3 months of vitamin D supplementa-
tion. Four of the six patients were able to toler-
ate statin therapy for at least 6 months using a
statin dosage that achieved their lipid level goal.
Finally, in a large case series of 621 consecu-
tive patients referred to a lipid management
clinic, investigators examined the relationship
between vitamin D status and myalgia as well as
the reversibility of symptoms with vitamin D
supplementation.55 At baseline, the mean ± SD
25(OH)D serum concentration in 128 patients
(20.6% of the cohort) with muscle symptoms was
28.6 ± 13.2 ng/ml compared with 34.2 ± 13.8 ng/
ml in 493 asymptomatic patients (p < 0.001). A
cohort of 38 symptomatic patients with vitamin D
deficiency were treated with ergocalciferol
50,000 IU once/week for 12 weeks. Despite
continuing statin therapy, the majority of the
patients (93% [35 patients]) experienced resolu-
tion of their muscle symptoms. These data sug-
gest that statin-induced myopathy may be
reversible in some patients who have a vitamin
D deficiency. However, because pain is particu-
larly responsive to placebo, a randomized,
blinded, placebo-controlled study is needed to
validate these findings.
Prevention and Treatment of Endocrine
Disorders
Diabetes Mellitus and Glycemia
Several longitudinal epidemiologic studies
have found higher vitamin D intake to be asso-
ciated with a reduced risk of new-onset diabe-
tes mellitus.43 The mechanisms by which
vitamin D might lead to improvements in glu-
cose metabolism is a bit unclear, but it is plau-
sible that patients who take supplements are
more health conscious, exercise more often,
maintain their weight, and eat healthier diets.
Indeed, most prospective studies have failed to
demonstrate any benefits from vitamin D sup-
plementation on either the onset of type 2 dia-
betes or glycemic control.43 An analysis of data
from 33,951 patients in the WHI study found
that supplementation with cholecalciferol
400 IU/day plus calcium carbonate 1000 mg
once/day had no effect on the risk of develop-
ing type 2 diabetes over the 7-year study (HR
1.01, 95% CI 0.94–1.10).56 Similarly, a German
study of obese men and women with low 25
(OH)D serum concentrations (< 12 ng/ml) who
were otherwise healthy found that vitamin D sup-
plementation had no effect on fasting plasma glu-
cose levels or hemoglobin A1c compared with
placebo (Table 4).57 Furthermore, a small Norwe-
gian study in patients with type 2 diabetes found
no benefits in terms of glycemia with high-dose
vitamin D supplementation.58 In contrast, an Ira-
nian study found that a vitamin D–fortified
yogurt drink significantly improved glycemic con-
trol in patients with type 2 diabetes.59 Significant
reductions in waist circumference, body mass
index, and insulin resistance (measured by
homeostasis model assessment of insulin resis-
tance [HOMA-IR]) were also observed in the
vitamin D supplement group compared with
the plain yogurt group, suggesting that perhaps
changes in caloric intake or lifestyle behaviors
may have influenced the results. Although these
results are promising, they must be replicated
in a robust clinical trial that controls for poten-
tial confounding variables.
Prevention and Treatment of Neurologic
Diseases
Multiple Sclerosis
Epidemiologic studies suggest that vitamin D
deficiency may be a modifiable, environmental
Table 4. Summary of Studies on the Effects of Vitamin D on Blood Glucose Level
Vitamin D Indication and Study Duration of
Patient Population Design Study Treatment Follow-up Major Findings Comments
Obesity RCT Cholecalciferol 3332 IU/ 12 mo No differences between groups in Similar weight loss in
Obese adults (body mass day vs placebo fasting plasma glucose levels (net both groups
index > 27 kg/m2) with 25 difference 1.2 mg/dl, p=0.39) or
(OH)D levels < 12 ng/ml, A1C (net difference 0.0%, p=0.96)
but otherwise healthy, in
Germany (n = 200) 57

Type 2 diabetes mellitus
Adults with type 2 diabetes
and baseline A1C 7–9.5%,
receiving stable antidiabetic
drug regimens, in Norway
(n = 32)58
RCT Cholecalciferol 6 mo No differences between groups in More dropouts in
40,000 IU/wk vs placebo fasting plasma glucose levels (net vitamin D group
difference 10.8 mg/dl, p=0.43),
A1C (net difference 0.0%,
p=0.90), or C-peptide
concentrations (net difference
73 pmol/L, p=0.27)

Type 2 diabetes mellitus
Adults with type 2 diabetes in
Iran (n = 90)59
RCT Yogurt drink containing
cholecalciferol 500 IU +
calcium b.i.d. vs
unfortified plain
yogurt drink
12 wks Fasting plasma glucose levels
decreased 10–13 mg/dl with
vitamin D–fortified yogurt drink
but not with plain yogurt drink
(increased 16 mg/dl; p=0.01,
p=0.01 analyzed by 2-factor
ANOVA)
Unusually large increase
in fasting plasma
glucose levels and
A1C in control group
VITAMIN D SUPPLEMENTATION Haines and Park

A1C decreased by 0.4–0.5% with

vitamin D–fortified drink but not
with plain yogurt drink (increased
1.2%; p=0.001 analyzed by 2-
factor ANOVA)
25(OH)D = 25-hydroxyvitamin D; RCT = randomized controlled trial; A1C = hemoglobin A1c; ANOVA = analysis of variance.
365
366 PHARMACOTHERAPY Volume 32, Number 4, 2012
risk factor for multiple sclerosis.10, 60 The inci-
dence of multiple sclerosis increases with lati-
tude and is inversely related to low vitamin D
concentrations. Moreover, the prevalence of
multiple sclerosis decreases in populations living
in high latitudes but where the consumption of
vitamin D–rich fatty fish is high.61 In a prospec-
tive, case-control study, investigators examined
the relationship between vitamin D level status
and the incidence of multiple sclerosis in 7 mil-
lion United States military personnel from 1992–
2004.60 The study revealed that high circulating
25(OH)D serum concentrations (> 39.7 ng/ml)
were significantly associated with a reduced risk
of multiple sclerosis in Caucasians (OR 0.38,
95% CI 0.19–0.75, p=0.006). However, this
association was not significant in African-Ameri-
cans and Hispanics, possibly due to the smaller
number of cases and lower serum concentrations
of 25(OH)D in these subgroups.
The immunomodulatory effects of vitamin D
supplementation in patients with multiple scle-
rosis were investigated in a randomized, double-
blind trial in which vitamin D supplementation
significantly increased serum transforming
growth factor-b1 (TGF-b1) concentrations
(Table 5).62 This growth factor appears to be an
important immunomodulatory factor in multiple
sclerosis, and vitamin D supplementation led to
increased TGF-b1 production and inhibition of
multiple sclerosis–like symptoms in mice.63 To
date, only one randomized controlled trial has
investigated the efficacy and tolerability of high-
dose vitamin D on clinical outcomes in patients
with multiple sclerosis.64 In this open-label, pro-
spective, 52-week, dose-escalation trial, 49
patients with multiple sclerosis were randomized
to receive high-dose vitamin D or usual care.
The majority (45 patients) had relapsing remit-
ting multiple sclerosis, but four patients had sec-
ondary progressive multiple sclerosis. The mean
baseline score on the Expanded Disability Status
Scale (EDSS) was 1.34 in both groups. The treat-
ment group had significantly fewer patients hav-
ing an increase in the EDSS score and a
significant reduction in T-cell reactivity and pro-
liferation. These effects were most pronounced
in patients with a 25(OH)D serum concentration
of 40 ng/ml or greater at 52 weeks (end of
study). High-dose vitamin D supplementation
was well tolerated, and the mean peak 25(OH)D
concentration reached 172 ng/ml. These results
need to be interpreted with caution; the study
was not blinded and did not assess treatment
adherence.
Overall, the results of these studies indicate
that vitamin D may have immunomodulatory
effects in patients with multiple sclerosis, but
many questions remain unanswered. A clear
understanding regarding the basic mechanisms
that modulate these protective effects, the genetic
variations that modify the response to vitamin D,
and whether vitamin D supplementation can pre-
vent multiple sclerosis or alter disease progres-
sion is unknown. Larger, well-designed studies
are needed to determine an appropriate dose and
duration for vitamin D supplementation in
patients with multiple sclerosis.
Depression
The discovery of vitamin D receptors in the
central nervous system has led to speculation
that vitamin D may affect mood and the
development of major depressive disorder.65
Epidemiologic and observational studies have
demonstrated an association between low levels
of vitamin D and the occurrence of depressive
symptoms, particularly during winter months
and in northern latitudes where sunlight expo-
sure is less frequent.66 One survey of 2070 rel-
atively healthy elderly participants in the
United Kingdom demonstrated that depressive
symptoms were associated with vitamin D defi-
ciency (< 10 ng/ml) (OR 1.79, 95% CI 1.28–
2.49).67 In a prospective study that followed
7358 patients with cardiovascular disease but
no history of depression for up to 6.8 years,
low (16–30 ng/ml) and very low (  15 ng/ml)
vitamin D concentrations were associated with
incident depression (HR 2.15, 95% CI 1.10–
4.21, and HR 2.70, 95% CI 1.35–5.40, respec-
tively).68
A Norwegian study investigated the effects of
high-dose vitamin D supplementation on depres-
sive symptoms in 334 obese adults (body mass
index 28.0–47.0 kg/m2).69 In this double-blind,
controlled trial, subjects with 25(OH)D serum
concentrations of less than 16 ng/ml at baseline
had significantly higher total Beck Depression
Inventory (BDI) scores than those with concen-
trations of 16 ng/ml or greater (Table 5). Both
groups who received vitamin D supplementation
had significant improvements in their total BDI
scores compared with baseline. However, the
study was limited by a high dropout rate, and
improvements in the BDI scores were observed
only in the per-protocol analysis.
Investigations regarding the association
between seasonal affective disorder and vitamin
Table 5. Summary of Studies of Vitamin D for the Prevention and Treatment of Neurologic and Psychiatric Disorders
Vitamin D Indication and Study Duration of
Patient Population Design Study Treatment Follow-up Major Findings Comments
Multiple sclerosis RCT Vitamin D 1000 IU/ 6 mo Significant increase in TGF-b1 No difference between groups
Adults with confirmed daya + calcium 800 mg/day vs (from 230 ± 21 to 295 ± 40 pg/ in TNF-a, IFN-c, or IL-13
diagnosis of multiple calcium 800 mg/day ml) in vitamin D group levels
sclerosis in the United States
(n = 39)62

Multiple sclerosis
Adults with multiple sclerosis,
aged 18–55 yrs, with EDSS
scores of 0–6.5, in Toronto,
Canada (n = 49)64
RCT Cholecalciferol 40,000 IU/day +
calcium 1200 mg/day for
28 wks followed by
cholecalciferol 10,000 IU/day +
calcium 1200 mg/day for
12 wks vs cholecalciferol
4000 IU/day with or without
calcium
52 wks Nonsignificant reduction in
relapse rate from previous year
(41% vs 17%) and mean EDSS
scores ( 0.23 vs + 0.30) in the
high-dose vitamin D group;
fewer patients had increased
EDSS scores in the high-dose
vitamin D group (8% vs 37.5%,
p=0.019)
No adverse events were noted
with high levels of serum 25
(OH)D (mean 172 ng/ml);
study was not blinded;
treatment adherence was not
assessed

Decreased T-cell proliferation

was noted in the high-dose
vitamin D group (p=0.002)

Depression RCT Cholecalciferol 40,000 IU/wk + 52 wks Patients with serum 25(OH)D High dropout rates in all
Overweight or obese adults in calcium 500 mg/day vs levels < 16 ng/ml had higher groups (23–25%); BDI
Norway (n = 334)69 cholecalciferol 20,000 IU/wk + BDI scores than those with improvements seen only in
calcium 500 mg/day vs placebo levels  16 ng/ml (6.0 vs per-protocol analysis
4.5, p<0.05); significant
improvement in total BDI
scores in both cholecalciferol
VITAMIN D SUPPLEMENTATION Haines and Park

groups (p<0.01)

Seasonal affective disorder RCT Vitamin D 100,000 IU/daya vs 1 mo Significant improvement in Difficult to determine effects in
Adults with seasonal affective phototherapy daily symptom scoresb in vitamin D phototherapy group due to
disorder (n = 15)71 group (p<0.05) small sample size
RCT = randomized controlled trial; TGF-b1 = transforming growth factor-b1; TNF-a = tumor necrosis factor-a; IFN-c = interferon-c; IL-13 = interleukin-13; EDSS = Expanded Disability Sta-
tus Scale; 25(OH)D = 25-hydroxyvitamin D; BDI = Beck Depression Inventory.
a
Form of vitamin D not specified.
b
The Hamilton Depression Rating Scale; the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder (SIGH-SAD); and the SAD-8 Depression Scale
were used to assess symptoms.
367
368 PHARMACOTHERAPY Volume 32, Number 4, 2012
D began almost 2 decades ago, but most of these
studies were limited by small sample size and
short duration.70 One small study compared
vitamin D supplementation with phototherapy
and found that the vitamin D–treated group had
significant improvements in depression scale
scores (p<0.05), whereas those who received
phototherapy did not.71 However, the study may
not have been sufficiently powered to detect
improvements in the phototherapy group. Irre-
spective of group assignment, there was a signifi-
cant correlation between increased 25(OH)D
concentrations and improvements in depression
scale scores (r2=0.26, p=0.05).
Cognitive Decline and Dementia
Vitamin D deficiency is prevalent among
older adults, and several population-based stud-
ies have found an association between vitamin
D deficiency and dementia.65 A Japanese study
found that elderly women with Alzheimer’s dis-
ease were more likely to have vitamin D defi-
ciency and a lower intake of vitamin D from
dietary sources than women in a control group
without Alzheimer’s disease.72 In a cross-sec-
tional study conducted in Washington State,
investigators assessed the association between
vitamin D deficiency and cognitive status of 80
older patients (> 60 yrs) with or without mild
Alzheimer’s disease and found that vitamin D
deficiency was associated with a lower perfor-
mance on the Short Blessed Test (p=0.044)
and higher scores on the Clinical Dementia
Rating (p=0.047).73 In a large community-based
study in which 3313 European men underwent
a battery of cognitive functions tests, low 25
(OH)D serum concentrations (  15 ng/ml)
were significantly associated with slower psy-
chomotor processing speed as measured by the
Digit Symbol Substitution Test (b per 4 ng/ml
change in 25(OH)D level = 0.152, 95% CI
0.051–0.253).74 In addition, another cross-sec-
tional study found that vitamin D deficiency
(  20 ng/ml) was associated with more than
twice the odds of all-cause dementia (OR 2.3,
95% CI 1.2–4.2) and Alzheimer’s disease (OR
2.5, 95% CI 1.1–6.1) in 318 elderly subjects
who were receiving home care services.75
However, not all studies have shown a consis-
tent association between vitamin D status and
cognitive decline. An analysis of NHANES III
found no association between 25(OH)D serum
concentrations and neurocognitive perfor-
mance.76 Indeed, contrary to the investigators’
hypothesis, those with the highest 25(OH)D
serum concentrations performed the poorest on
the learning and memory tests. Similarly, the
prospective Osteoporotic Fractures in Men
(MrOS) study, which enrolled 1604 elderly men,
failed to find an association between low 25
(OH)D serum concentrations and cognitive
decline based on the results of Mini-Mental State
Examination and Trail-Making B test after
4.6 years of follow-up.77
To our knowledge, vitamin D supplementa-
tion has not been evaluated prospectively for
either the treatment or prevention of dementia.
Therefore, although vitamin D supplementation
might be appropriate in older adults at high
risk for fractures and falls, there is no evidence
that it will slow the progression of cognitive
decline.
Prevention and Treatment of Respiratory
Diseases
Asthma
The immunomodulatory effects of vitamin D in
the setting of asthma have been explored in sev-
eral in vitro and in vivo studies.78 The pulmonary
epithelia contains high levels of 1a-hydroxylase
that converts 25(OH)D to 1,25(OH)2D. More-
over, vitamin D appears to modulate the response
to infection by reducing inflammation and pro-
moting the release of immunomodulatory cyto-
kines from T cells.79 Polymorphisms in the genes
that code for vitamin D receptors have also been
linked to asthma.80
Vitamin D insufficiency was correlated with
lower pulmonary function test results, including
the forced expiratory volume in 1 second
(FEV1) and forced vital capacity in an analysis
of NHANES III data set.81 These findings were
confirmed in a prospective study that investi-
gated the relationship between 25(OH)D serum
concentrations and lung function, airway hy-
perresponsiveness, and response to inhaled
glucocorticoids in 54 adults with asthma.82 Vita-
min D concentrations were strongly correlated
with lung function (covariate adjusted r=0.8,
p=0.02). Moreover, patients with low vitamin D
stores (< 30 ng/ml) had increased airway
hyperresponsiveness (p=0.01) when given a
methacholine challenge and reduced glucocorti-
coid response (p=0.02). In a community-based
study that followed 1024 children with asthma
for 4 years, children with vitamin D insuffi-
ciency were more likely to have an acute asthma
 VITAMIN D SUPPLEMENTATION Haines and Park 369

exacerbation that required an emergency depart-

Immune-modulatory effects are

A decrease in serum 25(OH)D

greater likelihood of asthma

exacerbation (OR 8.6, 95%
ment visit or hospitalization.83

possible with vitamin D

level from baseline was

associated with 8 times
Several epidemiologic and observational stud-
ies have investigated the association between

Comments
vitamin D supplementation and the risk of

supplementation
developing asthma. Retrospective studies have

CI 2.1–34.6)
found that vitamin D supplementation during
pregnancy or early infancy reduced the risk of
asthma in childhood.78 A major limitation of
these studies is that vitamin D supplementation

RCT = randomized controlled trial; FEV1 = forced expiratory volume in 1 second; 25(OH)D = 25-hydroxyvitamin D; OR = odds ratio; CI = confidence interval.
was determined by questionnaires; therefore,
recall bias may have influenced the results.

No difference in asthma symptom

In a randomized, double-blind, placebo-con-

score or FEV1 among groups;

steroid treatment suppressed

combination group (17% vs

immunotherapy; vitamin D
trolled study conducted in Poland, investigators

attenuated the suppressive

Proportion of children with

significantly lower in the

asthma exacerbation was
examined the immunomodulatory effects of pred-

Major Findings
nisone with or without vitamin D supplementa-
tion versus placebo in 48 asthmatic children who

effects of steroids
effects of specific

46%, p=0.029)
later received allergen-specific immunotherapy
(Table 6).84 When compared with allergen-spe-
cific immunotherapy alone (i.e., those who
received placebo), pretreatment with prednisone
appeared to blunt the immunologic response to
Table 6. Summary of Studies of Vitamin D for the Prevention and Treatment of Respiratory Diseases
the allergen-specific immunotherapy. However,
coadministration of vitamin D appeared to pre- Duration of
vent the attenuating effects of prednisone, sug-
Follow-up

gesting that vitamin D may have some 12 mo

6 mo
immunomodulatory properties.
In a subsequent study conducted by the same
investigators, 48 children with newly diagnosed

budesonide 800 lg dry-powder

asthma and who were allergic to dust mites
placebo before allergen-specific

were randomly assigned to receive a budesonide

Single oral dose of prednisone
0.5–1 mg/kg vs predisone +
cholecalciferol 1000 IU vs

dry-powder inhaler alone

inhaler plus cholecalciferol or budesonide inha-
Study Treatment

Cholecalciferol 500 IU +

ler alone (Table 6).85 Treatment allocation was inhaler vs budesonide

blinded. After 6 months of treatment, the
immunotherapy

proportion of patients with an acute asthma

exacerbation was significantly lower among
those who received concurrent vitamin D
supplementation. Furthermore, regardless of
treatment assignment, children with a decrease
in 25(OH)D serum concentrations compared
with baseline were 8 times more likely to expe-
rience an asthma exacerbation than children
Design
Study

RCT

RCT

with stable or increased vitamin D concentra-

tions, and asthma exacerbations were preceded
by symptoms of an acute respiratory tract
newly diagnosed asthma and

infection. Although the predicted FEV1 and

Children aged 6–12 yrs, with

Children aged 5–18 yrs, with

stable asthma and allergy to

asthma therapy assessment questionnaire scores

allergy to dust mites, in
Vitamin D Indication and

improved in both groups, asthma therapy

dust mites, in Poland

assessment questionnaire scores improved more

Poland (n=48)85
Patient Population

rapidly in those who received vitamin D supple-

mentation. The authors speculated that vitamin
(n = 48)84

D supplementation may enhance the innate

immune response to viral and bacterial patho-
Asthma

Asthma

gens, thereby reducing the risk of asthma

exacerbations.
370 PHARMACOTHERAPY Volume 32, Number 4, 2012
Chronic Obstructive Pulmonary Disease
Epidemiologic and animal studies have dem-
onstrated that vitamin D may play a role in the
progression of obstructive respiratory disease.85, 86
Genetic variations in the vitamin D binding pro-
tein may place patients at risk for developing
chronic obstructive pulmonary disease.86, 88 In a
study of 414 heavy smokers, 25(OH)D serum
concentrations were strongly correlated with the
severity of chronic obstructive pulmonary dis-
ease symptoms and FEV1 (r=0.28, p<0.0001).88
A similar study found a correlation between
increased 25(OH)D levels and increased FEV1
(r=0.504, p<0.001), maximal aerobic capacity
(r=0.247, p<0.05), and transfer factor of the
lung for carbon monoxide in a single breath
(r=0.496, p<0.001) in 79 men with stable
chronic obstructive pulmonary disease.89 The
authors speculated that vitamin D supplementa-
tion might lead to improvements in exercise
capacity due to its effects on muscle mass and
function rather than addressing airflow limita-
tions. To date, no randomized controlled trials
have been published regarding the potential ben-
efits of vitamin D supplementation in patients
with chronic obstructive pulmonary disease.
Prevention and Treatment of Infectious Diseases
Tuberculosis
Tuberculosis infection often coincides with
nutritional deficiencies, and vitamin D insuffi-
ciency has been linked to impaired immune
function and an increased risk of active tubercu-
losis.90 Indeed, high-dose vitamin D supplemen-
tation was frequently used in the preantibiotic
era.91 In a randomized, double-blind, controlled
study conducted in Indonesia, investigators
examined the effect of adjunctive vitamin D sup-
plementation in 67 adults with smear-positive
pulmonary tuberculosis who received treatment
from a university-affiliated pulmonary clinic
(Table 7).92 Patients who were assigned to the
vitamin D group were more likely to experience
sputum conversion (p=0.002) as well as
improvements on radiologic examination.
In a trial conducted in the United Kingdom,
131 healthy adults who had been exposed to
contacts with active tuberculosis were randomly
assigned to receive ergocalciferol or placebo
(Table 7).93 The antimycobacterial immune
response was determined using the bacille Cal-
mette-Guerin (BCG)-lux assay. In ergocalciferol-
treated subjects, mean 25(OH)D serum concen-
trations increased significantly, from 14.7 ng/ml
at baseline to 28.3 ng/ml (p<0.001) at the
6-week follow-up visit. Moreover, vitamin D
supplementation significantly increased the
BCG-lux response and mean 24-hour lumines-
cence ratio. These results are not consistent with
a study conducted in tuberculosis clinics in
West Africa.94 Patients older than 15 years with
pulmonary tuberculosis were assigned randomly
to receive cholecalciferol or placebo. The
TBscore, a validated measure that counts signs,
symptoms, and anthropometry, was used to
judge the severity of illness at each follow-up
visit. At study conclusion, the TBscore, the rate
of sputum conversion, and mortality did not dif-
fer between the two treatment groups. However,
a major limitation of the study is the significant
and similar increases in 25(OH)D serum concen-
trations observed in both study groups.
In a multicenter, controlled clinical trial con-
ducted in the United Kingdom, investigators ran-
domized 126 adults with sputum smear–positive
pulmonary tuberculosis to receive either cholecal-
ciferol or placebo after starting standard antitu-
bercular treatment.95 The primary end point was
time from initiation of antitubercular treatment to
sputum culture conversion. Patients were geno-
typed for TaqI and FokI vitamin D receptor poly-
morphisms. At 56 days, the mean 25(OH)D
serum concentration had increased to 42.3 ng/ml
in the vitamin D group but remained low in the
control group (9.5 ng/ml, p<0.001). However,
there was no significant difference between
groups in the median time to sputum conversion.
The TaqI genotype had a significant effect on spu-
tum culture conversion (p=0.03), and patients
with the homozygous tt genotype experienced sig-
nificantly more rapid sputum culture conversion
(HR 8.09, 95% CI 1.36–48.01, p=0.02). Only 10%
of the study subjects had the tt genotype. FokI
vitamin D receptor polymorphisms had no effect
on the time to serum culture conversion.
Upper Respiratory Tract Infections
Epidemiologic studies have demonstrated
strong associations between seasonal variations in
vitamin D levels and the incidence of upper respi-
ratory tract infection (URTI) and influenza.91 A
secondary analysis of the NHANES III data set
found a strong inverse relationship between 25
(OH)D serum concentrations and recent URTIs in
18,883 subjects who were 12 years or older.96
Recent URTIs were significantly more common
Table 7. Summary of Studies of Vitamin D for the Prevention and Treatment of Infectious Diseases
Vitamin D Indication and
Patient Population
Tuberculosis
Smear-positive patients, aged
15–59 yrs, in Jakarta,
Indonesia (n = 67)92
Tuberculosis
Healthy adults, aged > 17 yrs,
in London, United Kingdom
(n = 131)93
Tuberculosis
Patients aged > 15 yrs in
Guinea-Bissau (n = 281)94
Tuberculosis
Patients aged > 18 yrs with
newly diagnosed tuberculosis
in London, United Kingdom
(n = 126)95
URTI
Postmenopausal
African-American women
(n = 208)97
URTI
Women with osteoporotic
fractures enrolled in the
RECORD trial in England
and Scotland (n = 3444)98
URTI
Ambulatory adults, aged
18–80 yrs, in Long Island,
NY, during winter season
(n = 148) 99
Duration of
Study Design Study Treatment Follow-Up
RCT Vitamin D 0.25 mg/daya vs
placebo; both groups
received 6 wks of
antitubercular treatment
RCT Single dose of ergocalciferol
100,000 IU vs placebo
RCT Cholecalciferol 100,000 IU vs
placebo at baseline, fifth mo,
and eighth mo; both groups
received antitubercular
treatment
RCT Cholecalciferol 100,000 IU vs
placebo after antitubercular
treatment
RCT (post hoc Cholecalciferol 800 IU vs
analysis) placebo
RCT Cholecalciferol 800 IU/day
(preplanned with or without calcium
analysis) 1000 mg/day vs placebo
RCT Cholecalciferol 2000 IU/day vs
placebo for 6–12 wks
Major Findings
8 wks Vitamin D group had higher sputum
conversion (100% vs 76.7%,
p=0.002) and improvement by
radiologic examination (87.5% vs
65%, p=not reported)
6 wks Vitamin D group had significant
increase in BCG-lux response and
24-hr luminescence ratio (i.e.,
antimycobacterial immunity)
(p=0.03)
12 mo No difference between groups in
mortality, TBscore,b or rate of
sputum conversion
56 days No difference between groups in
mean time to sputum culture
conversion (36.0 days for vitamin D
group vs 43.5 days for placebo
group); TaqI genotype affected
sputum culture conversion
(p=0.03) but FokI genotype
did not
3 yrs Number of episodes of URTI
symptoms significantly reduced in
vitamin D group (8 vs 26,
p<0.002)
18 mo No differences between groups in
infection rate (17.2% for vitamin D
group vs 18.8% for placebo group,
adjusted OR 0.90, 95% CI 0.76–
1.07, p=0.23) or antibiotic use
(6.4% for vitamin D group vs 7.5%
for placebo group, adjusted OR
0.84, 95% CI 0.64–1.09, p=0.18)
in the previous wk
3 mo No difference between groups in
frequency, severity, or duration of
URTI symptoms
Comments
Only 36 patients received
radiologic examination
Subjects had been exposed to
contacts with active
tuberculosis;
antimycobacterial immunity
test was assessed in vitro
36% of patients had HIV
coinfection; both groups had
similar increases in serum 25
(OH)D levels
75 patients had profound
deficiencies in 25(OH)D
levels
Retrospective analysis; study
designed to assess bone loss
Preplanned analysis was
designed to assess rate of
secondary fractures; assessed
VITAMIN D SUPPLEMENTATION Haines and Park
by self-administered
questionnaire at study
month 18
Assessed by self- administered
biweekly questionnaire
371
 372

Table 7. (continued)

Vitamin D Indication and Duration of

Patient Population Study Design Study Treatment Follow-Up Major Findings Comments
URTI RCT Cholecalciferol 400 IU/day vs 6 mo No difference between groups in High dropout rates in vitamin
Healthy men, aged 18–28 yrs, placebo for 6 mo URTI symptoms and number of D (n = 21) and placebo
in Finland (n = 164)100 days absent from work (n = 39) groups
Influenza A prevention RCT Cholecalciferol 1200 IU/day vs 17 wks Vitamin D group had significant No differences between groups
Schoolchildren aged 6–15 yrs placebo reduction in the incidence of in the incidence of influenza
in Japan during winter influenza (RR 0.58, 95% CI 0.34– B, hospitalizations, or
months (n = 334)101 0.99, p=0.04) and significantly number of days absent from
fewer asthma attacks (RR 0.17, school
95% CI 0.04–0.73, p=0.006)
Pneumonia RCT Single dose of cholecalciferol 90 d No difference between groups in Nonsignificant difference
Infants aged 1–36 mo in 100,000 IU vs placebo; both number of days to recovery between groups in time to
Kabul, Afghanistan groups received standard (4.74 days for vitamin D group vs first repeat episode of
(n = 453) 102 antibiotic treatment 4.98 days for placebo group); pneumonia (72 days for
significantly lower risk of a repeat vitamin D group vs 59 days
episode of pneumonia in vitamin D for placebo group)
group (45% vs 58%; RR = 0.78,
95% CI 0.64–0.94, p=0.01)
RCT = randomized controlled trial; BCG-lux = bacille Calmette-Guerin–lux assay; CI = confidence interval; HIV = human immunodeficiency virus; 25(OH)D = 25-hydroxyvitamin D;
URTI = upper respiratory tract infection; RECORD = Randomized Evaluation of Calcium and/or vitamin D; OR = odds ratio; RR = relative risk.
a
Form of vitamin D not specified; equivalent to 10,000 IU.
b
PHARMACOTHERAPY Volume 32, Number 4, 2012

TBscore is a validated measure that counts signs, symptoms, and anthropometry, and was used to judge the severity of illness at each follow-up visit.
 VITAMIN D SUPPLEMENTATION Haines and Park
among subjects with a 25(OH)D serum concen-
tration of less than 10 ng/ml compared with sub-
jects who had normal vitamin D stores (24% vs
17%; OR 1.24, 95% CI 1.07–1.43). Moreover, this
association was strongest among individuals with
asthma (OR 5.67) or chronic obstructive pulmo-
nary disease (OR 2.26).
Although epidemiologic studies suggest that
vitamin D supplementation might be useful, ret-
rospective studies in adults who have taken vita-
min D supplements have not shown a consistent
benefit (Table 7). A post hoc analysis of a ran-
domized, placebo-controlled trial investigating
vitamin D supplementation to prevent bone loss
in postmenopausal African-American women
suggested that long-term use may reduce the
occurrence of URTI.97 Significantly fewer sub-
jects randomized to vitamin D experienced URTI
symptoms over the 3-year study. These results
are in contrast to a preplanned analysis of the
Randomized Evaluation of Calcium and/or Vita-
min D (RECORD) trial that examined the rate of
self-reported infections and antibiotic use among
patients.98 After a median of 18 months after
randomization, 3444 women (55% of RECORD
study patients) completed a questionnaire
regarding incident infections and antibiotic use
in the previous week. There was no difference in
infection rates or antibiotic use between the vita-
min D and placebo groups.
Prospective trials examining vitamin D supple-
mentation to prevent or mitigate URTI symp-
toms in adults have failed to demonstrate any
benefits (Table 7). In a study conducted during
the winter season on Long Island, New York,
adults given cholecalciferol experienced no ben-
efit from vitamin D supplementation with regard
to URTI symptoms.99 It is possible that vitamin
D supplementation failed because treatment was
initiated during the winter months. However, a
study conducted in Finland in which young men
were randomized to daily cholecalciferol or pla-
cebo for 6 months starting in the autumn also
failed to demonstrate any benefits with regard to
URTI symptoms from vitamin D supplementa-
tion.100 The study may have been underpowered
due to a large number of dropouts.
Unlike the prospective trials conducted in
adults, studies in children have been consistently
positive (Table 7). A Japanese study investigated
the benefits of vitamin D supplementation for
prevention of influenza A in school-age chil-
dren.101 The diagnosis of influenza A was con-
firmed by a rapid influenza diagnostic test, and
parents were asked to complete a daily log that
373
inquired about absences from school, hospital
and clinic visits, asthma attacks, and a variety of
symptoms. Vitamin D supplementation signifi-
cantly reduced the incidence of influenza A.
Moreover, children with a previous diagnosis of
asthma who received vitamin D supplementation
were far less likely to experience an asthma
attack during the study. In a study conducted in
Afghanistan, investigators examined the potential
benefits of high-dose vitamin D supplementation
in infants on the rate of recovery and recurrence
of pneumonia.102 The infants received follow-up
care within 10 days of hospital discharge and
every 14 days thereafter for a total of 90 days. A
similar number of children in the vitamin D and
placebo groups (20 and 18, respectively) were
lost to follow-up. The risk of a repeat episode of
pneumonia within the 90-day follow-up period
was significantly lower in the vitamin D group.
Cancer
Cancer Prevention
One randomized, double-blind, controlled
study has demonstrated a possible benefit from
vitamin D supplementation on the development
of cancer (Table 8).103 A total of 1179 healthy
postmenopausal women older than 55 years of
age were selected randomly from rural Nebraska
and randomized to receive elemental calcium
1400–1500 mg/day (alone), calcium plus chole-
calciferol 1000 IU/day, or placebo. The investiga-
tors assessed adherence and 25(OH)D serum
concentrations. This 4-year study found that the
rate of incident cancers was lower in women who
took both calcium and vitamin D compared with
placebo (2.9% vs 6.9%, p<0.03), and this benefit
was most pronounced after the first 12 months of
supplementation (RR 0.232, 95% CI 0.09–0.60,
p<0.005). However, the sample size did not allow
for any analysis regarding the benefits of vitamin
D supplementation to prevent specific cancers. In
a logistic regression analysis, supplementation and
25(OH)D serum concentration were both inde-
pendent predictors of cancer risk. If these study
results can be replicated in other populations, cal-
cium plus vitamin D supplements should be con-
sidered, along with lifestyle modification, an
important strategy to prevent cancer in adults.
Colorectal Cancer
Colorectal cancer is the second leading cause
of cancer-related death in the United States and
 374

Table 8. Summary of Studies of Vitamin D for the Prevention and Treatment of Cancer
Vitamin D Indication and Duration of
Patient Population Study Design Study Treatment Follow-up Major Findings Comments
Cancer prevention RCT Cholecalciferol 1000 IU/day + 4 yrs Incident cancer lowest in Cancer was a secondary end point of
Healthy, community-dwelling, calcium 1400–1500 mg/day vitamin D + calcium group this study; supplementation and 25
postmenopausal women in vs calcium 1400–1500 mg/ (2.9% vs 6.9% in placebo (OH)D concentrations both
Nebraska (n = 1179)103 day alone vs placebo group, p<0.03); effect most predicted cancer risk
profound after 1 yr of
supplementation (RR 0.232,
95% CI 0.09–0.60,
p<0.005)
Colorectal cancer RCT Cholecalciferol 800 IU/day vs 6 mo Significantly increased Changes in biomarkers may not
Adults aged 30–75 yrs with elemental calcium 2 g/day vs expression of Bax, p21, and translate to risk reduction of
pathology-confirmed polyps both cholecalciferol + CaR in calcium and vitamin colon cancer
in the United States calcium vs placebo D groups; no significant
(n = 92)108–110 differences among groups in
Bcl-2, MIB-1, hTERT, or 8-OH-dG
Colorectal cancer RCT Cholecalciferol 400 IU/day + 7 yrs No difference in incidence of Trial period may not have been
Postmenopausal women aged calcium 1000 mg/day vs colorectal cancer in vitamin D long enough to detect colorectal
50–79 yrs from the Women’s placebo group (168 patients) vs cancer; vitamin D dose was low
Health Initiative trial placebo group (154 patients);
(n = 36,282)111 both groups had similar
tumor characteristics
Breast cancer Prospective Dietary and supplemental 15 yrs Reduction in breast cancer Self-reported vitamin D intake; did
Postmenopausal women aged cohort vitamin D intake  800 IU/ incidence in high–vitamin D not assess sun exposure
55–69 yrs in Iowa day vs 401–799 IU/day intake group during first
(n = 34,321)113 vs < 400 IU/day 5 yrs of study (RR 0.66;
95% CI 0.46–0.94)
Breast cancer Prospective Dietary and supplemental 8.5 yrs No association between Self-reported vitamin D intake;
Women aged 40–70 yrs in cohort vitamin D intake vitamin D intake and breast 62% had vitamin D
Norway (n = 179,338)114 cancer risk intake < 400 IU/day
Breast cancer Phase II Cholecalciferol 100,000 IU/ 4 mo Pain scores similar vs baseline; Single arm, unblinded study;
PHARMACOTHERAPY Volume 32, Number 4, 2012

Women with breast cancer day + calcium 1000 mg/day significant reduction high-dose vitamin D was well
and bone metastases in for 4 mo in number of pain sites tolerated
Canada (n = 40)118 (p=0.01)
Breast cancer RCT, nested Cholecalciferol 400 IU/day + 7 yrs No difference between groups Vitamin D dose was low
Postmenopausal women aged case-control calcium 1000 mg/day vs in incident breast cancer; no
50–79 yrs from the Women’s placebo association between breast
Health Initiative trial cancer risk and serum 25
(n = 2134)115 (OH)D concentrations
RCT = randomized controlled trial; RR = relative risk; CI = confidence interval; 25(OH)D = 25-hydroxyvitamin D; Bax = apoptosis promoter; p21 = marker of cell differentiation; CaR = cal-
cium receptor; MIB-1 = marker of short-term proliferation; hTERT = marker of long-term proliferation; 8-OH-dG = marker of oxidative DNA damage.
 VITAMIN D SUPPLEMENTATION Haines and Park 375

has been associated with several environmental Breast Cancer

factors including poor dietary intake of vitamin
Geographic differences in the incidence of
D.104 Similar to the general population, vitamin
breast cancer have led to speculation that sun-
D deficiency is very common among patients
light exposure and vitamin D status may influ-
with colorectal cancer.105 Fifty percent of
ence breast cancer risk.112 Several investigations
patients with stage IV colorectal cancer had
have examined the potential role of vitamin D in
overt vitamin D deficiency (< 20 ng/ml) in one
breast cancer prevention. The Iowa Women’s
case series.105 Vitamin D may play a role in
Health Study was a large prospective cohort
preventing colorectal cancer by reducing the
study that examined the relationships among
proliferation of epithelial cells in the intestinal
diet, lifestyle behaviors, and the occurrence of
mucosa.104 Epidemiologic studies suggest an
cancer (Table 8).113 Postmenopausal women
association between vitamin D status and colo-
completed five questionnaires between 1986 and
rectal cancer. A meta-analysis of observational
2004 regarding diet and supplement use.
studies, including nine studies with a total of
Women who maintained a high vitamin D intake
2630 colorectal cancer cases, found a significant
(  800 IU/day) were less likely to develop
inverse relationship between 25(OH)D serum
breast cancer during the first 5 years of the fol-
levels (10–42 ng/ml) and the occurrence of
low-up compared with women who consumed
colorectal cancer.106 The authors estimated that
less than 400 IU/day. To date, the largest study
the RR of colorectal cancer would decrease
to investigate the relationship between vitamin
by 15% for each 10-ng/ml increase in serum
D intake and risk of breast cancer is the Norwe-
25(OH)D (RR 0.85, 95% CI 0.79–0.91,
gian Women and Cancer Study.114 In this popu-
p=0.004). A systematic review examining ultra-
lation-based cohort study, survey questionnaires
violet B light exposure in 16 studies, serum
were sent to a random sample of women. Inci-
vitamin D concentrations in 14 studies, and
dent breast cancer was determined using the
vitamin D intake from food sources or supple-
National Cancer Registry of Norway. The study
ments in 21 studies also found significant inverse
found no significant association between vitamin
relationships with the occurrence of colorectal
D status and breast cancer risk; however, 62% of
cancer.107
the women had an intake below the recom-
Several small, randomized controlled trials
mended 400 IU/day. A meta-analysis of observa-
have examined the potential chemoprotective
tional studies found a significant inverse
properties of vitamin D using various biomar-
relationship between 25(OH)D levels and the
kers (Table 8).108–110 However, the effects of
risk of breast cancer (RR 0.89, 95% CI 0.81–
vitamin D on the biomarkers do not necessarily
0.98, p<0.001); however, when the analysis was
translate to a risk reduction for colorectal can-
limited to only prospective studies, the
cer. The largest, randomized, double-blind, pla-
relationship disappeared (RR 0.97, 95% CI
cebo-controlled trial investigating the effect of
0.92–1.03).105 Finally, the WHI study failed to
vitamin D supplementation on colorectal cancer
demonstrate any benefits in terms of incident
was conducted by the WHI investigators.110 Risk
invasive breast cancer with calcium plus vitamin
factors for colorectal cancer were collected at
D versus placebo.115 However, the relatively low
baseline, and standardized, blinded assessments
dose of vitamin D in this study may not have
for colorectal cancer events were performed dur-
been sufficient to provide a protective effect.
ing the 7-year follow-up. The incidence of inva-
Vitamin D status does not appear to influence
sive colorectal cancer was not different between
the recurrence of breast cancer in women who
the calcium plus vitamin D and placebo groups.
have been treated for breast cancer. In a nested
However, a nested case-control analysis of the
case-control study using matched pairs from the
population revealed a significant relationship
Women’s Healthy Eating and Living (WHEL)
between lower baseline 25(OH)D serum concen-
study, there was no significant association
trations and the risk of colorectal cancer
between low 25(OH)D serum concentrations
(p=0.02). The authors acknowledged that the
and breast cancer recurrence among women
study may not have been of sufficient duration,
treated for early-stage breast cancer.116 In
given the long latency associated with the
another nested case-control study involving
development of colorectal cancer. In addition,
postmenopausal women who were participating
the dose of vitamin D supplementation was rela-
in the Cancer Prevention Study–II Nutrition
tively low and may have had limited effect on
Cohort, there was no association between 25
vitamin D stores.
376 PHARMACOTHERAPY Volume 32, Number 4, 2012

(OH)D serum concentrations and breast cancer Table 9. Vitamin D Products Available in the United
risk.117 States
To date, none of the prospective interventional Vitamin Dosage Cost/
studies have demonstrated a benefit from vitamin D Form Form Strength Montha
D supplementation in women with breast cancer. Ergocalciferol Capsule 50,000 IUb $$
A small, unblinded, single-arm, phase II study (vitamin D2)
Solution 8000 IU/ml $$
examined the palliative benefits and tolerability Cholecalciferol Tablet, 400 IU $
of high-dose vitamin D plus calcium supplemen- (vitamin D3) chewable
tation in patients with breast cancer and bone tablet, or
metastases (Table 8).118 There was no benefit in capsule 1000 IU $
terms of pain based on Brief Pain Inventory 2000 IU $
Capsule 5000 IU $
scores or daily morphine equivalent analgesia 10,000 IU $$
use. However, there was a significant reduction 50,000 IU $
in the number of pain sites (p=0.01). Drops 400 IU/drop $$
1000 IU/drop $$
2000 IU/drop $$
Vitamin D Toxicity and Adverse Effects Solution 400 IU/ml $$
5000 IU/ml $$
Most vitamin D supplements and fortified foods Spray 1000 IU/spray $$
do not pose a risk of toxicity unless taken inappro- 5000 IU/spray $$
priately.12 Physiologic mechanisms limit the forma- $ =  $20/mo; $$ = > $20/mo.119
a
tion and metabolism of vitamin D (Figure 1); Cost/month is based on daily administration
for doses  5000 IU and weekly administration for
therefore, the potential for vitamin D toxicity due doses > 5000 IU.
solely to sun exposure is highly unlikely. Conse- b
Available by prescription only.
quently, unless intentionally ingested in very large
doses, vitamin D toxicity is rare. Nonetheless, at
25(OH)D serum concentrations greater than in doses of 1000, 10,000, and 50,000 IU/day
150 ng/ml, vitamin D toxicity has been reported were given to 38 healthy men.122 A significant
and is most commonly manifested as hypercalce- dose-dependent increase in 25(OH)D serum
mia and hypophosphatemia.12 Nonspecific signs concentration was observed, and those taking
and symptoms such as nausea, vomiting, anorexia, 50,000 IU/day had a mean 25(OH)D serum con-
weight loss, cardiac arrhythmias, polyuria, and kid- centration greater than 250 ng/ml at the end of
ney stones may occur if the patient develops signif- the 8-week treatment period. None of the sub-
icant electrolyte abnormalities. jects had significant increases in serum calcium
The tolerable upper intake level, the highest levels or experienced symptomatic adverse
recommended daily intake established by the events. A long-term, 5-year trial that enrolled 43
IOM for vitamin D in adults, is 4000 IU/day.5 In patients with osteoporosis used high-dose vita-
children, the tolerable upper intake level min D supplementation.123 All patients were
increases progressively from 1000 IU/day in treated with ergocalciferol 18,000 IU/day,
infants (aged 0–6 mo) to 4000 IU/day in chil- sodium fluoride 60 mg/day, and calcium phos-
dren aged 9 years or older. A daily intake below phate 6 g/day. There was no evidence of hyper-
this limit is unlikely to pose a risk of harm, but calcemia or hypercalciuria, despite concurrent
intakes above this limit may increase the risk of calcium supplementation. However, this study
hypercalcemia. Most supplements provide less used ergocalciferol, which is metabolized and
than 4000 IU/dose of either ergocalciferol or cleared from the body more rapidly than chole-
cholecalciferol; however, some nonprescription calciferol. Doses up to 4000 IU/day in lactating
formulations contain as much as 50,000 IU/dose women were found to be safe and effective at
of cholecaliferol and can be easily obtained from increasing the vitamin D serum concentrations in
various sources (Table 9).119 the mother and infant without inducing hyper-
Published safety studies for vitamin D supple- calcemia or symptomatic adverse events.124
mentation have reported no significant adverse Intermittent (e.g., weekly, monthly, or quarterly)
events from cholecalciferol dosed up to doses as high as 100,000 IU have not been asso-
50,000 IU/day and from ergocalciferol up to ciated with adverse events.26, 120, 121 Single
18,000 IU/day.120, 121 In a study conducted at megadoses (300,000–500,000 IU) appear to be
northern latitudes and during the winter months well tolerated but have been associated with an
when sun exposure was limited, cholecalciferol increased risk of fracture in two studies.26, 27
 VITAMIN D SUPPLEMENTATION Haines and Park 377

Although high-dose vitamin D supplementa-
tion appears to be safe, numerous reports of acci-
dental or ill-informed consumption of very large
doses of vitamin D have been published.120 Many of
the patients in these reports developed hypercal-
cemia with significant symptoms. Doses con-
sumed in these reports were typically greater
than 50,000 IU/day, and the patients often had
underlying comorbidities that predisposed them
to develop vitamin D toxicity and hypercalcemia.
It should also be noted that the concurrent use
of calcium 1000 mg/day and vitamin D 400 IU/
day in supplements by postmenopausal women
was associated with a 17% increase in the risk of
kidney stones over 7 years in the WHI study.125
In addition, patients with chronic granulomatous
disorders warrant close monitoring of 25(OH)D
serum concentrations to prevent overproduction
of 1,25(OH)2D by macrophages.12
Recommendations and Replacement Strategies
Although vitamin D supplementation shows
some promise in preventing and treating several
diseases, the data regarding its benefits beyond
its use for fall prevention and osteoporosis can
only be characterized as tentative (Table 10).
Thus, the available data support the recommen-
dations of the IOM report. Sufficient data simply
do not yet exist for health care professionals to
routinely recommend the use of vitamin D sup-
plements to healthy patients younger than
65 years or for the treatment of any disease state
other than musculoskeletal indications. Sensible
sun exposure (15–20 min/day) is probably suffi-
cient to maintain adequate vitamin D stores in
most adults. For young adults (aged 18–65 yrs),
the decision to take vitamin D supplements,
either as part of a multivitamin or a separate
dosage form, appears to be safe in doses less
than 4000 IU/day. A patient can be reassured
that a personal decision to take vitamin D sup-
plements in low-to-moderate doses for general
health maintenance purposes, while of unproven
benefit, is safe. Given that cutaneous production
of vitamin D diminishes with age and the high
prevalence of vitamin D insufficiency in older
adults (aged  65 yrs), routine supplementa-
tion seems reasonable in this population. For
those whose 25(OH)D serum concentrations are

Table 10. Vitamin D Supplementation: Potential Indications, Dosages, and Level of Evidence
Indication Recommended Dosage (Duration) Level of Evidence
General health
Age 18–65 yrs, no chronic illnesses Sensible sun exposure (indefinitely) D
Age  65 yrs, for bone health 800–2000 IU/day (indefinitely) A
Age  65 yrs, for fall prevention 800–5000 IU/day (indefinitely) A
Age < 18 yrs, no chronic illnesses 400 IU/day (until age 18) B
Vitamin D deficiency (< 20 ng/ml) 50,000 IU/wk (12 wks) or 50,000 IU 3 times/wk (6 wks) B
Cardiovascular disease
Hypertension 800–2000 IU/day (indefinitely) C
Heart failure 800–2000 IU/day (indefinitely) D
Atherosclerotic vascular disease 800–2000 IU/day (indefinitely) D
Statin-induced myopathy 5000 IU/day (12 wks) or 50,000 IU/wk (12 wks) C
Endocrine disorders
Diabetes mellitus 800–2000 IU/day (indefinitely) C
Neurologic disease
Multiple sclerosis 10,000 IU/day (1 yr) B
Depression 5000 IU/day (indefinitely) C
Dementia 800–2000 IU/day (indefinitely) D
Migraine headache 1200–2000 IU/day (indefinitely) D
Respiratory disease
Asthma 800–2000 IU/day (indefinitely) C
COPD 800–2000 IU/day (indefinitely) C
Infectious diseases
Tuberculosis 10,000 IU/day (6 wks) or 100,000 IU every 2 wks (42 days) B
Upper respiratory tract infections 800–2000 IU/day (indefinitely) B
Cancer
Cancer prevention 800–2000 IU/day (indefinitely) B
Colorectal cancer 800–2000 IU/day (indefinitely) D
Breast cancer 800–2000 IU/day (indefinitely) D
Levels of evidence are as follows: A = supported by multiple randomized controlled trials; B = supported by a single randomized controlled
trial, multiple uncontrolled studies, or multiple cohort studies; C = supported by a single cohort study or uncontrolled trial; D = epidemio-
logic association but no data to support supplementation.
378 PHARMACOTHERAPY Volume 32, Number 4, 2012
adequate (> 30 ng/ml), cholecalciferol 800–
2000 IU/day should maintain adequate vitamin
D stores.
In those patients who have a documented
vitamin D deficiency (< 20 ng/ml), a high-dose
replacement regimen may be necessary to replete
vitamin D stores. However, there are few data
regarding the best approach. One retrospective
case series suggested that a total vitamin D dose
of at least 600,000 IU is required to achieve vita-
min D sufficiency in most patients. This was
accomplished by taking ergocalciferol 50,000 IU
once/week for 12 weeks or 50,000 3 times/week
for 6 weeks.126
Two prospective studies have examined the
biochemical response to high-dose vitamin D
supplementation in patients with vitamin D defi-
ciency.127, 128 In a study conducted in the Uni-
ted Kingdom, patients who had a baseline 25
(OH)D serum concentration less than 16 ng/ml
were recruited from a rheumatology clinic.126
Fifty patients received a single, observed dose of
ergocalciferol 300,000 IU by intramuscular
injection, and 19 patients received oral cholecal-
ciferol 300,000 IU. Serum concentrations of 25
(OH)D were remeasured 6, 12, and 24 weeks
later. Patients who participated in this study
were relatively young (mean age < 55 yrs) and
80% female with very low 25(OH)D serum con-
centrations at baseline (mean < 12 ng/ml). Both
vitamin D regimens were well tolerated, and cal-
cium serum concentrations remained within nor-
mal limits in both cohorts over the entire study.
However, oral cholecalciferol produced a signifi-
cantly greater increase in 25(OH)D serum con-
centrations relative to baseline compared with
intramuscular ergocalciferol during the first
12 weeks (mean change 44.4 vs 2.8 ng/ml at
6 wks and 21.5 vs 4.9 ng/ml at 12 wks). The
majority of patients in the oral cholecalciferol
cohort were able to achieve and maintain a 25
(OH)D serum concentration of greater than
30 ng/ml at 12 weeks. At 24 weeks, 25(OH)D
serum concentrations had declined substantially
in both cohorts and nearly all patients had a
serum concentration less than 30 ng/ml. Based
on this relatively small study, it appears that a
large 300,000 IU oral dose of cholecalciferol is
able to achieve rapid repletion of vitamin D
stores in the majority of patients with severe
vitamin D deficiency, but that repeat doses
would likely be required every 3–6 months to
maintain adequate vitamin D stores.
In a double-blind, prospective study con-
ducted in the United States, community-dwelling
older adults (aged > 65 yrs) were randomized
into four blocks of 16 subjects each to receive
either ergocalciferol or cholecalciferol, 1600 IU
once/day or 50,000 IU once/month for 1 year.128
Subjects were instructed to avoid nonstudy vita-
min D supplement products and to use sun-
screen (sun protection factor  15) when sun
exposure of greater than 15 minutes was antici-
pated. Serum concentrations of 25(OH)D were
measured at baseline and at 1, 2, 3, 6, 9, and
12 months. Many of the subjects (39 of 63) who
completed the study had adequate vitamin D
stores (> 30 ng/ml) at baseline. Both vitamin D
products and regimens produced substantial
increases in 25(OH)D serum concentrations at
12 months compared with baseline measure-
ments. Greater increases were observed in those
subjects who were assigned to cholecalciferol
compared with ergocalciferol in both the daily
(mean change 9.2 vs 4.1 ng/ml, p=0.05) and
monthly (mean change 8.9 vs 3.6 ng/ml,
p=0.11) treatment groups. Daily vs monthly
administration of cholecalciferol achieved similar
mean 25(OH)D serum concentrations. The high-
est 25(OH)D serum concentration observed was
72.5 ng/ml in one patient assigned to the
monthly cholecalciferol group. None of the
patients developed hypercalcemia during the
study. Despite treatment with moderate doses of
vitamin D, repletion of vitamin D stores (>
30 ng/ml) was achieved in only 11 of 25 patients
who had vitamin D insufficiency (< 30 ng/ml) at
baseline. This study confirms that cholecalciferol
produces a superior response versus ergocalcifer-
ol when given in equivalent doses and suggests
that moderate doses (1000–2000 IU/day) would
not be sufficient to replete vitamin D stores in
the majority of patients with vitamin D insuffi-
ciency or overt deficiency.
Future Directions
Given the degree of uncertainty regarding the
benefits of vitamin D supplementation, more
research is clearly needed. Fortunately, the level
of interest in and funding for vitamin D research
have soared. A recent search (June 2011)
revealed there were more than 400 ongoing clini-
cal trials using vitamin D supplements registered
with ClinicalTrials.gov. Three ongoing National
Institutes of Health–funded studies merit close
observation. The Vitamin D Supplementation
in Older Women (VIDOS) Study129 led by investi-
gators from Creighton University and a study at
the University of Wisconsin130 are examining
 VITAMIN D SUPPLEMENTATION Haines and Park
the effects of cholecalciferol using various doses
and dosing strategies on 25(OH)D serum con-
centrations, bone mineral density, muscle
strength, and falls in women with baseline 25
(OH)D serum concentrations of 5–20 mg/ml129
and 16–25 ng/ml.130 The Vitamin D and Omega-
3 Trial (VITAL) is the first large, randomized,
placebo-controlled study examining the effects
of vitamin D and fish oil supplementation for pri-
mary prevention of cancer, heart disease, and
stroke in older, community-dwelling, healthy men
(aged  50 yrs) and women (aged  55 yrs).131
The study is powered to detect a 15–20% reduc-
tion in the rate of cancer and major cardiovascular
events; its enrollment goal is more than 20,000
subjects, including 5000 of African-American
descent. Subjects will be randomized in a 2 9 2
fashion to received marine omega-3 fatty acids
1 g once/day or cholecalciferol 2000 IU/day,
both, or neither and will be followed for a mean
of 5 years. The dosage of vitamin D selected for
this study should be sufficient to maintain 25
(OH)D serum concentrations greater than 30 ng/
ml in most subjects. Enrollment began in July
2010, and study completion is anticipated in
2016. Patients and health professionals who
wish to learn more about the VITAL study and
its enrollment procedures can visit the study
Web site (http://www.vitalstudy.org).
Conclusion
Epidemiologic studies have demonstrated a
strong association between vitamin D insuffi-
ciency and the development of a variety of dis-
eases. Whether low vitamin D intake and body
stores are a cause or merely a marker of illness
can only be determined, with certainty, through
randomized controlled trials. It is reasonable to
screen patients who are at high risk for vitamin D
deficiency (Table 1), particularly those with
chronic illnesses and limited sun exposure, and to
recommend supplementation with an oral high-
dose regimen for 6–12 weeks to replete vitamin D
stores in those individuals with a 25(OH)D serum
concentration less than 20 ng/ml (Table 10).
Once vitamin D stores have been replenished, a
maintenance dose of 800–2000 IU/day should be
recommended. Vitamin D supplements in doses
of 800–5000 IU/day appear to improve musculo-
skeletal health (e.g., fractures, falls, and statin-
associated myopathy) in older adults
(aged > 65 yrs), but megadoses of 300,000–
500,000 IU should be avoided. At this time, vita-
min D supplementation should not be routinely
379
offered to other patient populations. The results
of prospective clinical trials using vitamin D sup-
plementation for the prevention or treatment of
cardiovascular disease, diabetes, cancer, respira-
tory diseases, neurologic disorders, and infectious
disease have been far from compelling. Few of
these studies have been robustly designed and
executed. The decision by relatively young, other-
wise healthy individuals to take vitamin D supple-
ments in doses of 2000 IU/day or lower for the
prevention of cardiovascular disease and cancer is
not yet supported by the available data but it unli-
kely to cause harm. For most patients who are not
at risk for developing vitamin D deficiency, sensi-
ble sun exposure (15–20 min/day) is an inexpen-
sive and enjoyable way to maintain vitamin D
stores.
References
1. Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin
Proc 2011;86:50–60.
2. Kolata G. Report questions need for 2 diet supplements. The
New York Times, 30 November 2010; Inside Health: A1.
3. Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J
Med 2011;364:248–54.
4. MayoClinic.com 2011. Vitamin D. Available at: http://www.
mayoclinic.com/health/vitamin-d/NS_patient-vitamind. Accessed
June 17, 2011
5. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds.; Insti-
tute of Medicine (U.S.) Committee. Dietary reference intakes
for calcium and vitamin D. Washington DC: National Acade-
mies Press, 2011.
6. Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position
statement: vitamin D recommendations for older adults. Os-
teoporos Int 2010;21:1151–4.
7. Norman AW, Bouillon R, Whiting SJ, Vieth R, Lips P. 13th
Workshop consensus for vitamin D nutritional guidelines.
J Steroid Biochem Mol Biol 2007;103:204–5.
8. Heaney RP, Holick MF. Why the IOM recommendations for
vitamin D are deficient. J Bone Miner Res 2011;26:452–4.
9. Adams M. New vitamin D recommendations promote vitamin
D deficiency, protect cancer industry. NaturalNews.com 2010.
Available at: http://www.naturalnews.com/030598_vitamin_
D_Institute_of_Medicine.html. Accessed June 17, 2011.
10. Solomon AJ, Whitham RH. Multiple sclerosis and vitamin D:
a review and recommendations. Curr Neurol Neurosci Rep
2010;10:389–96.
11. Nussey S, Whitehead S, eds. Endocrinology: an integrated
approach. Oxford: BIOS Scientific Publishers, 2001.
12. Holick MF. Vitamin D deficiency. N Engl J Med
2007;357:266–81.
13. Holick MF. Vitamin D status: measurement, interpretation,
and clinical application. Ann Epidemiol 2009;19:73–8.
14. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evalua-
tion, treatment, and prevention of vitamin D deficiency: an
endocrine society clinical practice guideline. J Clin Endocri-
nol Metab 2011;96:911–30.
15. Priemel M, von Domarus C, Klatte TO, et al. Bone minerali-
zation defects and vitamin D deficiency: histomorphometric
analysis of iliac crest bone biopsies and circulating
25-hydroxyvitamin D in 675 patients. J Bone Miner Res
2010;25:305–12.
16. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E,
Dietrich T, Dawson-Hughes B. Fracture prevention with vita-
min D supplementation: a meta-analysis of randomized con-
trolled trials. JAMA 2005;293:2257–64.
380 PHARMACOTHERAPY Volume 32, Number 4, 2012
17. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention
of nonvertebral fractures with oral vitamin D and dose
dependency: a meta-analysis of randomized controlled trials.
Arch Intern Med 2009;169:551–61.
18. Bischoff-Ferrari HA. The 25-hydroxyvitamin D threshold
for better health. J Steroid Biochem Mol Biol 2007;103:
614–9.
19. Bischoff-Ferrari HA. Optimal serum 25-hydroxyvitamin D
levels for multiple health outcomes. Adv Exp Med Biol
2008;624:55–71.
20. Holick MF. Resurrection of vitamin D deficiency and rickets.
J Clin Invest 2006;116:2062–72.
21. Wagner CL, Greer FR; American Academy of Pediatrics Sec-
tion on Breastfeeding; American Academy of Pediatrics
Committee on Nutrition. Prevention of rickets and vitamin D
deficiency in infants, children, and adolescents. Pediatrics
2008;122:1142–52.
22. Winzenberg TM, Powell S, Shaw KA, Jones G. Vitamin D
supplementation for improving bone mineral density in chil-
dren. Cochrane Database Syst Rev 2010;10:CD006944.
23. Nakamura K, Iki M. Efficacy of optimization of vitamin D in
preventing osteoporosis and osteoporotic fractures: a system-
atic review. Environ Health Prev Med 2006;11:155–70.
24. Cooper L, Clifton-Bligh PB, Nery ML, et al. Vitamin D sup-
plementation and bone mineral density in early postmeno-
pausal women. Am J Clin Nutr 2003;77:1324–9.
25. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and
the future. Lancet 2011;377:1276–87.
26. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-
dose oral vitamin D and falls and fractures in older women: a
randomized controlled trial. JAMA 2010;303:1815–22.
27. Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Coo-
per C. Effect of annual intramuscular vitamin D on fracture
risk in elderly men and women – a population-based, ran-
domized, double-blind, placebo-controlled trial. Rheumatol-
ogy (Oxford) 2007;46:1852–7.
28. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al.
Effect of vitamin D on falls: a meta-analysis. JAMA
2004;291:1999–2006.
29. Flicker L, MacInnis RJ, Stein MS, et al. Should older peo-
ple in residential care receive vitamin D to prevent falls?
Results of a randomized trial. J Am Geriatr Soc
2005;53:1881–8.
30. Bischoff-Ferrari HA, Orav EJ, Dawson-Hughes B. Effect of
cholecalciferol plus calcium on falling in ambulatory older
men and women: a 3-year randomized controlled trial. Arch
Intern Med 2006;166:424–30.
31. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al.
Fall prevention with supplemental and active forms of vita-
min D: a meta-analysis of randomised controlled trials. BMJ
2009;339:b3692.
32. Law M, Withers H, Morris J, Anderson F. Vitamin D supple-
mentation and the prevention of fractures and falls: results of
a randomised trial in elderly people in residential accommo-
dation. Age Ageing 2006;35:482–6.
33. Dawson-Hughes B, Harris SS. High-dose vitamin D
supplementation: too much of a good thing? JAMA
2010;303:1861–2.
34. Vaidya A, Forman JP. Vitamin D and hypertension: current
evidence and future directions. Hypertension 2010;56:774–9.
35. Geleijnse JM. Vitamin D and the prevention of hypertension
and cardiovascular diseases: a review of the current evidence.
Am J Hypertens 2011;24:253–62.
36. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D,
ethnicity, and blood pressure in the Third National Health
and Nutrition Examination Survey. Am J Hypertens
2007;20:713–9.
37. Snijder MB, Lips P, Seidell JC, et al. Vitamin D status and
parathyroid hormone levels in relation to blood pressure: a
population-based study in older men and women. J Intern
Med 2007;261:558–65.
38. Jorde R, Bonaa KH. Calcium from dairy products, vitamin D
intake, and blood pressure: the Tromso Study. Am J Clin
Nutr 2000;71:1530–5.
39. Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hy-
droxyvitamin D levels and risk of incident hypertension.
Hypertension 2007;49:1063–9.
40. Forman JP, Curhan GC, Taylor EN. Plasma 25-hydroxyvita-
min D levels and risk of incident hypertension among young
women. Hypertension 2008;52:828–32.
41. Jorde R, Figenschau Y, Emaus N, Hutchinson M, Grimnes
G. Serum 25-hydroxyvitamin D levels are strongly related to
systolic blood pressure but do not predict future hyperten-
sion. Hypertension 2010;55:792–8.
42. Margolis KL, Ray RM, Van Horn L, et al. Effect of calcium
and vitamin D supplementation on blood pressure: the
Women’s Health Initiative Randomized Trial. Hypertension
2008;52:847–55.
43. Pittas AG, Chung M, Trikalinos T, et al. Systematic review:
vitamin D and cardiometabolic outcomes. Ann Intern Med
2010;152:307–14.
44. Zittermann A, Schleithoff SS, Koerfer R. Vitamin D insuffi-
ciency in congestive heart failure: why and what to do about
it? Heart Fail Rev 2006;11:25–33.
45. Zittermann A, Schleithoff SS, Tenderich G, Berthold HK,
Korfer R, Stehle P. Low vitamin D status: a contributing fac-
tor in the pathogenesis of congestive heart failure? J Am Coll
Cardiol 2003;41:105–12.
46. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK,
Stehle P, Koerfer R. Vitamin D supplementation improves
cytokine profiles in patients with congestive heart failure: a
double-blind, randomized, placebo-controlled trial. Am J Clin
Nutr 2006;83:754–9.
47. Witham MD, Crighton LJ, Gillespie ND, Struthers AD,
McMurdo ME. The effects of vitamin D supplementation on
physical function and quality of life in older patients with
heart failure: a randomized controlled trial. Circ Heart Fail
2010;3:195–201.
48. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvita-
min D levels and the risk of mortality in the general popula-
tion. Arch Intern Med 2008;168:1629–37.
49. Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr. Prospec-
tive study of serum 25-hydroxyvitamin D level, cardiovascu-
lar disease mortality, and all-cause mortality in older U.S.
adults. J Am Geriatr Soc 2009;57:1595–603.
50. Lee P, Greenfield JR, Campbell LV. Vitamin D insufficiency –
a novel mechanism of statin-induced myalgia? Clin Endo-
crinol (Oxf) 2009;71:154–5.
51. Gupta A, Thompson PD. The relationship of vitamin D defi-
ciency to statin myopathy. Atherosclerosis 2011;215:23–9.
52. Heidari B, Shirvani JS, Firouzjahi A, Heidari P, Hajian-Tilaki
KO. Association between nonspecific skeletal pain and vita-
min D deficiency. Int J Rheum Dis 2010;13:340–6.
53. Bittner V, Wenger NK, Waters DD, DeMicco DA, Messig M,
LaRosa JC. Vitamin D levels are not related to myalgias in
statin-treated patients with stable coronary disease. J Am Coll
Cardiol 2010;55:A177.E1659.
54. Duell PB, Conner WE. Vitamin D deficiency is associated
with myalgias in hyperlipidemic subjects taking statins. Cir-
culation 2011;118:S470.
55. Ahmed W, Khan N, Glueck CJ, et al. Low serum 25 (OH)
vitamin D levels (<32 ng/ml) are associated with reversible
myositis-myalgia in statin-treated patients. Transl Res
2009;153:11–6.
56. de Boer IH, Tinker LF, Connelly S, Curb JD; Womens Hlth
Initiative Investigato. Calcium plus vitamin D supplementa-
tion and the risk of incident diabetes in the women’s health
initiative. Diabetes Care 2008;31:701–7.
57. Zittermann A, Frisch S, Berthold HK, et al. Vitamin D sup-
plementation enhances the beneficial effects of weight loss on
cardiovascular disease risk markers. Am J Clin Nutr
2009;89:1321–7.
 VITAMIN D SUPPLEMENTATION Haines and Park
58. Jorde R, Figenschau Y. Supplementation with cholecalciferol
does not improve glycaemic control in diabetic subjects with
normal serum 25-hydroxyvitamin D levels. Eur J Nutr
2009;48:349–54.
59. Nikooyeh B, Neyestani TR, Farvid M, et al. Daily consump-
tion of vitamin D- or vitamin D + calcium-fortified yogurt
drink improved glycemic control in patients with type 2 dia-
betes: a randomized clinical trial. Am J Clin Nutr
2011;93:764–71.
60. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A.
Serum 25-hydroxyvitamin D levels and risk of multiple scle-
rosis. JAMA 2006;296:2832–8.
61. Ascherio A, Munger KL, Simon KC. Vitamin D and multiple
sclerosis. Lancet Neurol 2010;9:599–612.
62. Mahon BD, Gordon SA, Cruz J, Cosman F, Cantorna MT.
Cytokine profile in patients with multiple sclerosis following
vitamin D supplementation. J Neuroimmunol 2003;134:128–32.
63. Cantorna MT, Woodward WD, Hayes CE, DeLuca HF. 1,25-
dihydroxyvitamin D3 is a positive regulator for the two anti-
encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunol
1998;160:5314–9.
64. Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-esca-
lation trial of vitamin D3 and calcium in multiple sclerosis.
Neurology 2010;74:1852–9.
65. Nimitphong H, Holick MF. Vitamin D, neurocognitive func-
tioning and immunocompetence. Curr Opin Clin Nutr Metab
Care 2011;14:7–14.
66. Hoogendijk WJ, Lips P, Dik MG, Deeg DJ, Beekman AT,
Penninx BW. Depression is associated with decreased 25-hy-
droxyvitamin D and increased parathyroid hormone levels in
older adults. Arch Gen Psychiatry 2008;65:508–12.
67. Stewart R, Hirani V. Relationship between vitamin D levels
and depressive symptoms in older residents from a national
survey population. Psychosom Med 2010;72:608–12.
68. May HT, Bair TL, Lappe DL, et al. Association of vitamin D
levels with incident depression among a general cardiovascu-
lar population. Am Heart J 2010;159:1037–43.
69. Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K.
Effects of vitamin D supplementation on symptoms of depres-
sion in overweight and obese subjects: randomized double
blind trial. J Intern Med 2008;264:599–609.
70. Oren DA, Schulkin J, Rosenthal NE. 1,25 (OH)2 vitamin D3
levels in seasonal affective disorder: effects of light. Psycho-
pharmacology (Berl) 1994;116:515–6.
71. Gloth FM 3rd, Alam W, Hollis B. Vitamin D vs broad spec-
trum phototherapy in the treatment of seasonal affective dis-
order. J Nutr Health Aging 1999;3:5–7.
72. Sato Y, Asoh T, Oizumi K. High prevalence of vitamin D
deficiency and reduced bone mass in elderly women with
Alzheimer’s disease. Bone 1998;23:555–7.
73. Wilkins CH, Sheline YI, Roe CM, Birge SJ, Morris JC. Vita-
min D deficiency is associated with low mood and worse cog-
nitive performance in older adults. Am J Geriatr Psychiatry
2006;14:1032–40.
74. Lee DM, Tajar A, Ulubaev A, et al. Association between 25-
hydroxyvitamin D levels and cognitive performance in mid-
dle-aged and older European men. J Neurol Neurosurg Psy-
chiatry 2009;80:722–9.
75. Buell JS, Dawson-Hughes B, Scott TM, et al. 25-Hydroxyvita-
min D, dementia, and cerebrovascular pathology in elders
receiving home services. Neurology 2010;74:18–26.
76. McGrath J, Scragg R, Chant D, Eyles D, Burne T, Obradovic
D. No association between serum 25-hydroxyvitamin D3 level
and performance on psychometric tests in NHANES III. Neu-
roepidemiology 2007;29:49–54.
77. Slinin Y, Paudel ML, Taylor BC, et al. 25-Hydroxyvitamin D
levels and cognitive performance and decline in elderly men.
Neurology 2010;74:33–41.
78. Mak G, Hanania NA. Vitamin D and asthma. Curr Opin
Pulm Med 2011;17:1–5.
79. Chambers ES, Hawrylowicz CM. The impact of vitamin D
on regulatory T cells. Curr Allergy Asthma Rep 2011;11:
29–36.
381
80. Bosse Y, Lemire M, Poon AH, et al. Asthma and genes
encoding components of the vitamin D pathway. Respir Res
2009;10:98.
81. Black PN, Scragg R. Relationship between serum 25-hydrox-
yvitamin D and pulmonary function in the third national
health and nutrition examination survey. Chest 2005;128:
3792–8.
82. Sutherland ER, Goleva E, Jackson LP, Stevens AD, Leung
DY. Vitamin D levels, lung function, and steroid response in
adult asthma. Am J Respir Crit Care Med 2010;181:699–
704.
83. Brehm JM, Schuemann B, Fuhlbrigge AL, et al. Serum vita-
min D levels and severe asthma exacerbations in the Child-
hood Asthma Management Program study. J Allergy Clin
Immunol 2010;126:52.
84. Majak P, Rychlik B, Stelmach I. The effect of oral steroids
with and without vitamin D3 on early efficacy of immuno-
therapy in asthmatic children. Clin Exp Allergy 2009;39:
1830–41.
85. Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. Vita-
min D supplementation in children may prevent asthma exac-
erbation triggered by acute respiratory infection. J Allergy
Clin Immunol 2011;127:1294–6.
86. Gilbert CR, Arum SM, Smith CM. Vitamin D deficiency and
chronic lung disease. Can Respir J 2009;16:75–80.
87. Zosky GR, Berry LJ, Elliot JG, James AL, Gorman S, Hart
PH. Vitamin D deficiency causes deficits in lung function and
alters lung structure. Am J Respir Crit Care Med
2011;183:1336–43.
88. Janssens W, Bouillon R, Claes B, et al. Vitamin D deficiency
is highly prevalent in COPD and correlates with variants in
the vitamin D-binding gene. Thorax 2010;65:215–20.
89. Ferrari M, Schenk K, Papadopoulou C, Ferrari P, Dalle Car-
bonare L, Bertoldo F. Serum 25-hydroxy vitamin D and exer-
cise capacity in COPD. Thorax 2011;66:544–5.
90. Luong KV, Nguyen LT. Impact of vitamin D in the treatment
of tuberculosis. Am J Med Sci 2011;341:493–8.
91. Yamshchikov AV, Desai NS, Blumberg HM, Ziegler TR,
Tangpricha V. Vitamin D for treatment and prevention of
infectious diseases: a systematic review of randomized con-
trolled trials. Endocr Pract 2009;15:438–49.
92. Nursyam EW, Amin Z, Rumende CM. The effect of vitamin
D as supplementary treatment in patients with moderately
advanced pulmonary tuberculous lesion. Acta Med Indones
2006;38:3–5.
93. Martineau AR, Wilkinson RJ, Wilkinson KA, et al. A single
dose of vitamin D enhances immunity to mycobacteria. Am J
Respir Crit Care Med 2007;176:208–13.
94. Wejse C, Gomes VF, Rabna P, et al. Vitamin D as supple-
mentary treatment for tuberculosis: a double-blind, random-
ized, placebo-controlled trial. Am J Respir Crit Care Med
2009;179:843–50.
95. Martineau AR, Timms PM, Bothamley GH, et al. High-dose
vitamin D(3) during intensive-phase antimicrobial treatment
of pulmonary tuberculosis: a double-blind randomised con-
trolled trial. Lancet 2011;377:242–50.
96. Ginde AA, Mansbach JM, Camargo CA Jr. Association
between serum 25-hydroxyvitamin D level and upper respi-
ratory tract infection in the Third National Health and
Nutrition Examination Survey. Arch Intern Med 2009;169:
384–90.
97. Aloia JF, Li-Ng M. Epidemic influenza and vitamin D. Epi-
demiol Infect 2007;135:1095–6.
98. Avenell A, Cook JA, Maclennan GS, Macpherson GC. Vita-
min D supplementation to prevent infections: a sub-study of
a randomised placebo-controlled trial in older people. Age
Ageing 2007;36:574–7.
99. Li-Ng M, Aloia JF, Pollack S, et al. A randomized controlled
trial of vitamin D3 supplementation for the prevention of
symptomatic upper respiratory tract infections. Epidemiol
Infect 2009;137:1396–404.
100. Laaksi I, Ruohola JP, Mattila V, Auvinen A, Ylikomi T, Pi-
hlajamaki H. Vitamin D supplementation for the prevention
382 PHARMACOTHERAPY Volume 32, Number 4, 2012
of acute respiratory tract infection: a randomized, double-
blinded trial among young Finnish men. J Infect Dis
2010;202:809–14.
101. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y,
Ida H. Randomized trial of vitamin D supplementation to
prevent seasonal influenza A in schoolchildren. Am J Clin
Nutr 2010;91:1255–60.
102. Manaseki-Holland S, Qader G, Isaq Masher M, et al. Effects
of vitamin D supplementation to children diagnosed with
pneumonia in Kabul: a randomised controlled trial. Trop
Med Int Health 2010;15:1148–55.
103. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR,
Heaney RP. Vitamin D and calcium supplementation reduces
cancer risk: results of a randomized trial. Am J Clin Nutr
2007;85:1586–91.
104. Huncharek M, Muscat J, Kupelnick B. Colorectal cancer risk
and dietary intake of calcium, vitamin D, and dairy products:
a meta-analysis of 26,335 cases from 60 observational studies.
Nutr Cancer 2009;61:47–69.
105. Ng K, Sargent DJ, Goldberg RM, et al. Vitamin D status in
patients with stage IV colorectal cancer: findings from Inter-
group trial N9741. J Clin Oncol 2011;29:1599–606.
106. Gandini S, Boniol M, Haukka J, et al. Meta-analysis of obser-
vational studies of serum 25-hydroxyvitamin D levels and
colorectal, breast and prostate cancer and colorectal ade-
noma. Int J Cancer 2011;128:1414–24.
107. Rheem DS, Baylink DJ, Olafsson S, Jackson CS, Walter MH.
Prevention of colorectal cancer with vitamin D. Scand J Gas-
troenterol 2010;45:775–84.
108. Fedirko V, Bostick RM, Flanders WD, et al. Effects of vita-
min D and calcium on proliferation and differentiation in
normal colon mucosa: a randomized clinical trial. Cancer Ep-
idemiol Biomarkers Prev 2009;18:2933–41.
109. Fedirko V, Bostick RM, Long Q, et al. Effects of supplemen-
tal vitamin D and calcium on oxidative DNA damage marker
in normal colorectal mucosa: a randomized clinical trial.
Cancer Epidemiol Biomarkers Prev 2010;19:280–91.
110. Ahearn TU, McCullough ML, Flanders WD, et al. A ran-
domized clinical trial of the effects of supplemental calcium
and vitamin D3 on markers of their metabolism in normal
mucosa of colorectal adenoma patients. Cancer Res
2011;71:413–23.
111. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Cal-
cium plus vitamin D supplementation and the risk of colo-
rectal cancer. N Engl J Med 2006;354:684–96.
112. McKay JD, McCullough ML, Ziegler RG, et al. Vitamin D
receptor polymorphisms and breast cancer risk: results from
the National Cancer Institute Breast and Prostate Cancer
Cohort Consortium. Cancer Epidemiol Biomarkers Prev
2009;18:297–305.
113. Robien K, Cutler GJ, Lazovich D. Vitamin D intake and breast
cancer risk in postmenopausal women: the Iowa Women’s
Health Study. Cancer Causes Control 2007;18:775–82.
114. Edvardsen K, Veierod MB, Brustad M, Braaten T, Engelsen
O, Lund E. Vitamin D-effective solar UV radiation, dietary
vitamin D and breast cancer risk. Int J Cancer 2011;128:
1425–33.
115. Amir E, Simmons CE, Freedman OC, et al. A phase 2 trial
exploring the effects of high-dose (10,000 IU/day) vitamin D
(3) in breast cancer patients with bone metastases. Cancer
2010;116:284–91.
116. Jacobs ET, Thomson CA, Flatt SW, et al. Vitamin D and
breast cancer recurrence in the Women’s Healthy Eating and
Living (WHEL) Study. Am J Clin Nutr 2011;93:108–17.
117. McCullough ML, Stevens VL, Patel R, et al. Serum 25-hydrox-
yvitamin D concentrations and postmenopausal breast cancer
risk: a nested case control study in the Cancer Prevention
Study-II Nutrition Cohort. Breast Cancer Res 2009;11:R64.
118. Chlebowski RT, Johnson KC, Kooperberg C, et al. Calcium
plus vitamin D supplementation and the risk of breast can-
cer. J Natl Cancer Inst 2008;100:1581–91.
119. Drugstore.com. Ergocalciferol and cholecalciferol. Available
from www.drugstore.com. Accessed September 20, 2011.
120. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment
for vitamin D. Am J Clin Nutr 2007;85:6–18.
121. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J,
Giovannucci E, Willett WC. Benefit-risk assessment of vita-
min D supplementation. Osteoporos Int 2010;21:1121–32.
122. Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF.
Vitamin D and its major metabolites: serum levels after
graded oral dosing in healthy men. Osteoporos Int
1998;8:222–30.
123. Hasling C, Nielsen HE, Melsen F, Mosekilde L. Safety of
osteoporosis treatment with sodium fluoride, calcium phos-
phate and vitamin D. Miner Electrolyte Metab 1987;13:96–
103.
124. Basile LA, Taylor SN, Wagner CL, Horst RL, Hollis BW.
The effect of high-dose vitamin D supplementation on serum
vitamin D levels and milk calcium concentration in lactating
women and their infants. Breastfeed Med 2006;1:27–35.
125. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vita-
min D supplementation and the risk of fractures. N Engl J
Med 2006;354:669–83.
126. Pepper KJ, Judd SE, Nanes MS, Tangpricha V. Evaluation of
vitamin D repletion regimens to correct vitamin D status in
adults. Endocr Pract 2009;15:95–103.
127. Leventis P, Kiely PD. The tolerability and biochemical effects
of high-dose bolus vitamin D2 and D3 supplementation in
patients with vitamin D insufficiency. Scand J Rheumatol
2009;38:149–53.
128. Binkley N, Gemar D, Engelke J, et al. Evaluation of ergocal-
ciferol or cholecalciferol dosing, 1,600 IU daily or 50,000 IU
monthly in older adults. J Clin Endocrinol Metab
2011;96:981–8.
129. Vitamin D supplementation in older women (VIDOS). Clini-
cal Trials.Gov Identifier: NCT00472823. June 17, 2011;
2011:1.
130. Treatment of vitamin D insufficiency. Clinical Trial.Gov
Identifier: NCT00933244. 2010;2011:1.
131. Manson B, Buring J. The VITamin D and OmegA-3 TriaL:
rationale and design of a large randomized controlled trial of
vitamin D and marine omega-3 fatty acid supplements for the
primary prevention of cancer and cardiovascular disease.
Contemp Clin Trials 2012;33:159–7.