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Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Review Article
Page 6
Abstract
The recent discovery – from a meta-analysis of 18 randomized
controlled trials – that supplemental cholecalciferol (vitamin
D) significantly reduces all-cause mortality emphasizes the
medical, ethical, and legal implications of promptly diagnosing
and adequately treating vitamin D deficiency. Not only are
such deficiencies common, and probably the rule, vitamin D
deficiency is implicated in most of the diseases of civilization.
Vitamin D’s final metabolic product is a potent, pleiotropic, repair
and maintenance, seco-steroid hormone that targets more than
200 human genes in a wide variety of tissues, meaning it has
as many mechanisms of action as genes it targets. One of the
most important genes vitamin D up-regulates is for cathelicidin,
a naturally occurring broad-spectrum antibiotic. Natural vitamin
D levels, those found in humans living in a sun-rich environment,
are between 40-70 ng/mL, levels obtained by few modern
humans. Assessing serum 25-hydroxy-vitamin D (25(OH)D) is
the only way to make the diagnosis and to assure treatment
is adequate and safe. Three treatment modalities exist for
vitamin D deficiency: sunlight, artificial ultraviolet B (UVB)
radiation, and vitamin D supplementation. Treatment of vitamin
D deficiency in otherwise healthy patients with 2,000-7,000
IU vitamin D
3
per day should be sufficient to maintain year-
round 25(OH)D levels between 40-70 ng/mL. In those with
serious illnesses associated with vitamin D deficiency, such
as cancer, heart disease, multiple sclerosis, diabetes, autism,
and a host of other illnesses, doses should be sufficient to
maintain year-round 25(OH)D levels between 55-70 ng/
mL. Vitamin D-deficient patients with serious illness should
not only be supplemented more aggressively than the well,
they should have more frequent monitoring of serum 25(OH)
Use of Vitamin D
in Clinical Practice
John J. Cannell, MD and Bruce W. Hollis, PhD
D and serum calcium. Vitamin D should always be adjuvant
treatment in patients with serious illnesses and never replace
standard treatment. Theoretically, pharmacological doses
of vitamin D (2,000 IU/kg/day for three days) may produce
enough of the naturally occurring antibiotic cathelicidin to cure
common viral respiratory infections, such as influenza and
the common cold, but such a theory awaits further science.
(Altern Med Rev 2008;13(1):6-20)
Introduction
A recent meta-analysis of 18 randomized con-
trolled trials (RCT) found that cholecalciferol (vitamin
D) significantly reduced total mortality.
1
is discovery
is all the more remarkable because of the relatively low
doses of vitamin D used (mean dose 528 IU (13 mcg))
and because the finding persisted across a number of
subgroup analyses. In spite of the low doses used and
the short duration of the trials, vitamin D’s mortality re-
duction was seven percent.
2
Indeed, the recent discovery
that statins significantly increase 25-hydroxy-vitamin D
(25(OH)D) levels raise the possibility that some – or
all – of the mortality reduction of statins may be medi-
ated through increases in vitamin D levels.
3,4
Lappe et al recently reported the first RCT of
vitamin D in preventing internal cancers and found a
60-percent reduction in such cancers by increasing base-
line 25(OH)D levels from 29 ng/mL to 38 ng/mL with
1,100 IU (28 mcg) per day.
5
Baseline and treatment-
induced serum 25(OH)D levels were strong and inde-
pendent predictors of cancer risk. Lappe et al’s study
left open the possibility that higher doses and higher
John J. Cannell, MD – Director, Vitamin D Council
Correspondence address: 9100 San Gregorio Road, Atascadero, CA 93422
Email: jjcannell@gmail.com
Bruce W. Hollis, PhD – Professor of biochemistry, molecular biology, and
pediatrics, Medical University of South Carolina, Charleston, SC
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Review Article
Page 7
treatment-induced 25(OH)D levels might prevent even
more cancers. (Note that 25(OH)D levels are reported
in the literature as either ng/mL or nmol/L; 1.0 ng/mL
equals 2.5 nmol/L.)
Besides cancer, vitamin D deficiency is associ-
ated with cardiovascular disease, hypertension, stroke,
diabetes, multiple sclerosis, rheumatoid arthritis, in-
flammatory bowel disease, osteoporosis, periodontal
disease, macular degeneration, mental illness, propen-
sity to fall, and chronic pain.
6-10
A recent review pre-
sented considerable evidence that influenza epidemics,
and perhaps even the common cold, are brought on by
seasonal deficiencies in antimicrobial peptides (AMP),
such as cathelicidin, secondary to seasonal deficiencies
in vitamin D.
11
Results of an RCT support the theory,
finding 2,000 IU of vitamin D/day for one year virtu-
ally eliminated self-reported incidence of colds and in-
fluenza (Figure 1).
12
Even the current triple childhood
epidemics of autism
13
(Figure 2), asthma,
14
and type 1
diabetes,
15
all of which blossomed after sun-avoidance
advice became widespread, might be the tragic and
iatrogenic sequela of gestational or early childhood vi-
tamin D deficiencies brought on by medical advice to
avoid the sun.
Claims that vitamin D may help prevent such
a wide variety of diseases seem incredible until one re-
alizes vitamin D is not a vitamin; rather, it is the only
known substrate for a potent, pleiotropic, repair and
maintenance, seco-steroid hormone with a single endo-
crine function, but multiple autocrine functions. Previ-
ously, many practitioners thought vitamin D’s activity
was principally its endocrine function – the regulation
of serum calcium – and was thus mainly involved in
bone metabolism. Indeed, the classic endocrine func-
tion of vitamin D begins when the kidney hydroxylates
25(OH)D into 1,25(OH)
2
D, which then acts, both di-
rectly and indirectly, to maintain serum calcium.
However, in the last ten years, it has become
clear the vitamin D steroid hormone system includes
more than the classic endocrine pathway used to pre-
serve calcium economy.
16
e enzyme that further
hydroxylates 25(OH)D to 1,25(OH)
2
D (activated vi-
tamin D, the steroid hormone) is present in a wide va-
riety of human tissues other than kidney. 1,25(OH)
2
D
is autonomously made in tissues and directly affects
numerous cells via its autocrine, and presumed para-
crine, functions.
17
Most organs show evidence of end
organ responsiveness to 1,25(OH)
2
D.
18
Like all steroid
25
20
15
10
5
0
Winter Spring Summer
Placebo 800 IU/d 2000 IU/d
Autumn
Incidence of reported cold/influenza symptoms according to season. The placebo group
reported more cold/influenza symptoms in the winter. Only one subject had cold/influenza
symptoms while taking a higher dose of vitamin D (2000 IU/d).
Adapted from: Aloia JF, Li-Ng M. Epidemic influenza and vitamin D. Epidemiol Infect 2007;
135:1095-1096. Used with permission.
Figure 1. Incidence of Colds/Influenza After 2,000 IU Vitamin D Daily for One Year
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Vitamin D
Page 8
hormones, 1,25(OH)
2
D acts as a molecular switch, ac-
tivating more than 200 target genes, thereby regulating
gene expression. us, locally produced 1,25(OH)
2
D
exists in most tissues of the body, is under autonomous
autocrine control, and has as many mechanisms of ac-
tion as genes it targets. is explains why the same sub-
stance may have a role in preventing cancer, influenza,
autism, asthma, multiple sclerosis, and cardiovascular
disease, not just curing rickets and osteomalacia (Figure 3).
Such claims leave practitioners with under-
standable skepticism and multiple questions. Is vitamin
D a cure-all? When should I recommend vitamin D?
How much should I prescribe? What form of vitamin
D should I use? How much do children need? How
much do pregnant or breastfeeding women need? Is it
appropriate to use higher doses of vitamin D as adju-
vant treatment for any of the above diseases? How do I
interpret vitamin D blood tests and which tests should
I order? What is the risk of toxicity?
Another way to ask many of these questions
is, “What is an ideal 25(OH)D level?” Levels needed to
optimize intestinal calcium absorption (34 ng/mL)
19

are lower than those needed to optimize neuromuscular
performance (38 ng/mL).
20
Recent pooled meta-analy-
ses estimate 25(OH)D levels of 52 ng/mL are needed to
effect a 50-percent reduction in the incidence of breast
cancer.
21
Although some experts believe the lower limit
of adequate 25(OH)D levels is in the low 30s,
22,23
oth-
ers recommend a lower limit of 40 ng/mL;
24,25
there is
certainly no scientific consensus.
Ideal levels are unknown but are probably
close to levels present when the human genome evolved
in sub-equatorial Africa. Natural levels, such as those
found at the end of summer in 30 young men who
spent the summer working outdoors, were around 50
ng/mL;
26
however, these levels are obtained by only a
small fraction of people.
27
Furthermore, despite such
summertime levels, at the end of winter 25(OH)D
1
9
9
2
2
0
0
2
2
0
0
1
2
0
0
0
1
9
9
9
1
9
9
8
1
9
9
7
1
9
9
6
1
9
9
5
1
9
9
4
2
0
0
3
1
9
9
3
18000
6000
4000
2000
1000
800
600
400
200
15558
19048
22652
29057
34356
42493
54049
66015
79552
98532
118602
140920
0
N
u
m
b
e
r

o
f

C
h
i
l
d
r
e
n
Cases of Autism
U.S. School Years 1992-2003 - Ages 6-22
50 States, D.C., & Puerto Rico
Time trend of autism prevalence for the 50 states and Puerto Rico. (Reproduced with permission, Fighting
Autism, http://www.fightingautism.org/idea/autism.php, accessed 5/8/07)
Figure 2. Increased Prevalence of Autism: 1992-2003
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Review Article
Page 9
levels in 50 percent of these men dropped to less than
30 ng/mL, indicating a sun-induced level of 50 ng/mL
at the end of summer is inadequate to maintain such a
level during wintertime.
Another way to ask the “ideal 25(OH)D” ques-
tion involves understanding vitamin D’s unique phar-
macokinetics. Unlike any other steroid hormone system,
the substrate concentrations for the liver production of
25(OH)D are absolutely rate limiting. is means the
liver enzymes that initially hydroxylate vitamin D to
form 25(OH)D and the enzyme in tissue that generates
1,25(OH)
2
D operate below their Michaelis-Menten
constants throughout the full range of modern human
substrate concentrations; i.e., the reactions follow first-
order mass action kinetics.
28
e more vitamin D that is
ingested, the more is converted into 25(OH)D, and the
more is converted into 1,25(OH)
2
D in the tissues. e
reaction appears to be uncontrolled; an aberrant, totally
unique, and potentially dangerous situation for a steroid
hormone system. Imagine, for example, if cortisol, tes-
tosterone, progesterone, or estradiol levels were entirely
dependent on the intake of their substrate, cholesterol.
Hollis et al recently explained this conundrum
and concluded very few humans obtain enough vitamin
D even if they take several thousand units per day.
29

Hollis et al studied the pharmacokinetics of the parent
compound, vitamin D, and its first metabolic product,
25(OH)D, in two groups; Hawaiians with significant
sun exposure and lactating women receiving 6,400
IU of supplemental vitamin D per day. ey found
25(OH)D levels had to exceed a minimum of 40 ng/
mL, and often 50 ng/mL, to begin to detect the parent
compound in the blood and begin to normalize the ki-
netics of 25(OH)D production. In other words, when
25(OH)D levels > 40 ng/mL were achieved, the parent
compound began to be detectable in the blood, the re-
actions became saturable and controlled (like other ste-
roid hormone systems), and thus levels above 40 ng/mL
appear to represent the lower limit of “normal” 25(OH)
D levels.
is implies virtually everyone has a chronic
25(OH)D substrate deficiency, at least in the winter,
and the absence of the parent vitamin D compound
(cholecalciferol) in the blood means all available vitamin
D is used for metabolic needs and none of it is stored.
Figure 3. Autocrine and Endocrine Functions of Vitamin D
Vitamin D
Liver
25(OH)D
Kidney
Most tissues
in the body
1, 25(OH)
2
D
Maintain
calcium
economy Prevent and/or treat:
Viral respiratory disease
Cancer, Osteoporosis
Heart disease, Multiple sclerosis
Diabetes, Hypertension
Milk,
Orange Juice,
Salmon,
or Supplements
Previtamin D
Skin
1, 25(OH)
2
D
Autocrine Endocrine
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Vitamin D
Page 10
Because of this, most individuals have chronic substrate
starvation, functional vitamin D deficiency, and thus,
perhaps, higher risk for the “diseases of civilization.”
e ideal 25(OH)D level continues to be de-
bated in scientific circles and consensus awaits further
science. However, do we wait for science to complete its
work with highly seasonal 25(OH)D levels (Figure 4)
that reflect sunlight deprivation, levels where vitamin D
steroid pharmacokinetics are aberrant, or is it safer to
wait with levels normally achieved by humans in a sun-
rich environment, levels where vitamin D’s kinetics are
normalized (>40 ng/mL)?
Once a practitioner is comfortable with ideal
25(OH)D levels being above 40 ng/mL, the answers to
the questions posed above become fairly simple. Healthy
humans should be supplemented with enough vitamin
D or exposed to enough ultraviolet B (UVB) radiation
to achieve natural 25(OH)D levels (40-70 ng/mL)
year-round, whether they are infants, children, pregnant
women, lactating women, healthy young adults, or the
elderly.
What role vitamin D has in treating – rather
than preventing – disease is largely unknown, but given
vitamin D’s genetic mechanism of action, it may have a
significant role. For example, vitamin D reduces cellular
proliferation, induces differentiation, induces apoptosis,
and prevents angioneogenesis, each a laudable goal in
cancer treatment. A simple risk-versus-benefit analysis
suggests patients with a potentially fatal cancer (see
below) may think it wise to maintain 25(OH)D lev-
els in the high end of natural ranges (55-70 ng/mL),
ranges that assure vitamin D’s kinetics are normalized.
While the RCTs needed to clarify vitamin D’s role in
the treatment of disease are being conducted, a strong
case already exists for adequately diagnosing and ag-
gressively treating vitamin D deficiency.
22,25,30
S
e
p
t
J
u
l
y
J
u
n
e
M
a
y
A
p
r
M
a
r
F
e
b
J
a
n
D
e
c
N
o
v
A
u
g
O
c
t
34
30
28
24
20
16
12
8
4
0
S
e
p
t
M
a
r
F
e
b
J
a
n
D
e
c
N
o
v
O
c
t
Geometric mean monthly variations in serum 25-hydroxyvitamin D [25)OH)D] concentration in men (blue, n=3723) and
women (orange, n=3712) in a 1958 British (England, Scotland, and Wales) birth cohort at age 45. Adapted from: Hypponen
E, Power C. Hypovitaminosis D in British adults at age 45y: nationwide cohort study of dietary and lifestyle predictors. Am J
Clin Nutr 2007;85:860-868. Used with permission.
Figure 4. Seasonal Serum Levels of 25-hydroxyvitamin D
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Review Article
Page 11
Incidence of Vitamin D Deficiency
Adult vitamin D deficiency is the rule rather
than the exception in industrialized nations.
31-33
A high
number of otherwise healthy children and adolescents
are also vitamin D deficient.
34,35
Rickets, a disease of
the industrial revolution, is being diagnosed more fre-
quently,
36
especially in breast-fed infants.
37
Alarmingly,
given mounting animal data that gestational vitamin D
deficiency causes subtle but irreversible brain damage in
mammalian offspring,
38,39
severe deficiencies are com-
mon in newborn infants and pregnant women, espe-
cially African-Americans.
40
A population-based study
of 2,972 U.S. women of childbearing age found 42 per-
cent of African-American women had 25(OH)D levels
below 15 ng/mL, and 12 percent had levels below 10
ng/mL.
41
Furthermore, the definition of vitamin D defi-
ciency changes almost yearly as research shows the low
end of ideal 25(OH)D ranges are higher than were pre-
viously thought. e aforementioned prevalence stud-
ies used outdated reference values for low-end 25(OH)
D ranges and therefore underestimate the incidence of
vitamin D deficiency. Obviously, the higher the low end
of the 25(OH)D cutoff point, the higher the percentage
of the population defined as deficient. Only 10 percent
of the subjects in any of the above studies had 25(OH)
D levels > 40 ng/mL.
Vitamin D Metabolism and Physiology
Perhaps because the term “vitamin D” contains
the word “vitamin,” most people wrongly assume they
can obtain adequate amounts by eating a healthy diet.
e natural diets most humans consume, however, con-
tain minimal vitamin D, unless those diets are rich in
wild-caught fatty fish, sun-dried Shitake mushrooms,
or wild reindeer meat. Small amounts of vitamin D are
contained in fortified foods, such as fortified milk, some
orange juices, and cereals, but such sources are minor
contributors to vitamin D stores. Traditionally, the hu-
man vitamin D system began in the skin, not in the
mouth.
Vitamin D normally enters the circulation after
UVB from sunlight strikes 7-dehydro-cholesterol in the
skin, converting it to vitamin D
3
or cholecalciferol (vita-
min D). When taken by mouth, the body metabolizes
vitamin D similarly to that generated in the skin. No
matter how it arrives in the circulation, the liver read-
ily hydroxylates vitamin D to 25(OH)D, the circulat-
ing form of vitamin D. Hundreds of tissues in the body
use 25(OH)D as a substrate to make the end-product,
1,25(OH)
2
D, known as activated vitamin D, a pleiotro-
pic seco-steroid. If enough 25(OH)D substrate is avail-
able, multiple tissues are free to autonomously produce
and locally regulate the amount of steroid needed for
any particular disease state.
e skin’s manufacture of vitamin D is ex-
traordinarily rapid and remarkably robust; production
after only a few minutes of sunlight easily exceeds di-
etary sources by an order of magnitude. Incidental sun
exposure, not dietary intake, is the principal source of
vitamin D stores and is a function of skin surface area
exposed.
42,43
For example, when fair-skinned people
sunbathe in the summer (one, full-body, minimal ery-
themal dose of UVB), they produce about 20,000 IU
of vitamin D in 30 minutes,
44
the equivalent of drinking
200 glasses of milk (100 IU/8 oz. glass) or taking 50
standard multivitamins (400 IU/tablet) to obtain the
same amount orally.
e fact that 20,000 IU vitamin D can be
produced in the skin in 30 minutes of sun exposure,
combined with vitamin D’s basic genomic mechanism
of action, raises profound questions. Why did nature
develop a system that delivers huge quantities of a ste-
roid precursor after only brief periods of sun exposure?
Would natural selection evolve such a system if the re-
markably high input that system achieved were unim-
portant? As humans evolved in a sun-rich environment
(sub-equatorial Africa), is modern sunlight deprivation
– and the resultant routinely low levels of this repair-
and-maintenance steroid in tissues – a possible com-
mon cause of the diseases of civilization?
Factors Affecting Vitamin D Levels
Factors that can affect UVB exposure, and thus
the skin’s production of vitamin D, include latitude, sea-
son of the year, time of day, air pollution, cloud cover,
melanin content of the skin, use of sunblock, age, and
the extent of clothing covering the body. When the sun
is low on the horizon, ozone, clouds, and particulate air
pollution deflect UVB radiation away from the earth’s
surface. erefore, cutaneous vitamin D production is
effectively absent early and late in the day and for the
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Vitamin D
Page 12
entire day during several wintertime months at latitudes
above 35 degrees, and impaired anytime the skies are
polluted or cloudy.
us, vitamin D deficiency is more common
the further poleward the population. For example, Bos-
ton, Massachusetts (latitude 42 degrees), has a four-
month “vitamin D winter” centered around the winter
solstice, when insufficient UVB penetrates the atmo-
sphere to trigger skin production. is becomes an even
longer period when the fall and late winter months are
included, when sufficient UVB only penetrates around
solar noon. In northern Europe and Canada, the “vita-
min D winter” can extend for six months. Furthermore,
properly applied sunblock, common window glass in
homes and cars, and clothing all effectively block UVB
radiation – even in the summer. ose who avoid sun-
light – at any latitude – are at risk of vitamin D defi-
ciency any time of the year. For example, a surprisingly
high incidence of vitamin D deficiency exists in Miami,
Florida, despite its sunny weather and subtropical lati-
tude.
45
African-Americans, the elderly, and the obese
face added risk. Because melanin in the skin acts as an
effective and ever-present sunscreen, dark-skinned peo-
ple need much longer UVB exposure times to generate
the same 25(OH)D stores as fair-skinned individuals.
46

e elderly make much less vitamin D than 20-year-
olds after exposure to the same amount of sunlight.
47

Body fat absorbs vitamin D, thus obesity is a major risk
factor for deficiency, with obese African-Americans at
an even higher risk.
48
Anyone who works indoors, lives
at higher latitudes, wears excessive clothing, regularly
uses sunblock, is dark-skinned, obese, aged, or who
consciously avoids the sun is at high risk for vitamin D
deficiency.
Diagnosis of Vitamin D Deficiency
In the absence of a metabolic bone disease such
as rickets, osteomalacia, or osteoporosis, most practitio-
ners assume vitamin D deficiency is asymptomatic, al-
though that may be changing. Complaints endemic to
every practitioner’s office, such as muscular weakness, a
feeling of heaviness in the legs, chronic musculoskeletal
pain, fatigue, or easy tiring may be symptoms of vitamin
D deficiency.
49
Such complaints are extremely common,
difficult to treat, and easy to dismiss, but they may indi-
cate symptomatic vitamin D deficiency.
Physical examination is usually unremarkable
but may reveal undue pain on sternal or tibial pressure
if deficiency is severe. e vast majority of cases appear
normal on exam, although frequent infections, autoim-
mune illness, diabetes, cancer, heart disease, major de-
pression, and a host of other “diseases of civilization”
may be warning signs that deficiency has been present
for many years.
22,25
e aged may be wheelchair-bound second-
ary to vitamin D deficiency-induced myopathy, yet they
typically recover mobility after treatment.
50
e recent
strong association of low mood and cognitive impair-
ment in the aged with vitamin D deficiency
51
suggests
depressed mood and/or impaired cognition may be pre-
senting symptoms. A blinded intervention trial found
4,000 IU vitamin D per day improved the mood of
endocrinology outpatients,
52
but there are no interven-
tional studies of its effects on cognition.
Even without physical signs or symptoms,
the physician should screen those at risk. Obtaining
and properly interpreting a serum 25(OH)D level is
the only way to make the diagnosis. A 25(OH)D level
should be obtained at least twice yearly on any patient
at risk, once in the early spring for the nadir and once
in the late summer for a peak level.
53
We recommend
25(OH)D levels be kept above 40 ng/mL year-round
(Figure 5).
It is crucial to remember that serum
1,25(OH)
2
D levels play no role in diagnosing vita-
min D deficiency. e kidney tightly controls serum
1,25(OH)
2
D levels, which are often normal or even
elevated in vitamin D deficiency. erefore, a patient
with normal or high 1,25(OH)
2
D serum levels but low
25(OH)D levels is vitamin D deficient despite high se-
rum levels of the active hormone. Practitioners who rely
on serum 1,25(OH)
2
D levels to make the diagnosis of
vitamin D deficiency will routinely miss it.
25
Treatment of Vitamin D Deficiency
ree options exist for treatment of vitamin D
deficiency: sunlight, artificial UVB light, and vitamin
D supplements. An exposure of 10-15 minutes of full-
body summer noon-day sun or artificial UVB radiation
(such as tanning beds) will input more than 10,000 IU
of vitamin D into the systemic circulation of most light-
skinned adults. One or two such exposures per week
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Review Article
Page 13
should maintain 25(OH)D levels in an ideal range, but
adequacy should be assured by 25(OH)D blood levels.
ose who choose UVB light for vitamin D repletion,
from either sunlight or artificial sources, should avoid
sunburn, which is associated with malignant melanoma.
Furthermore, they should understand that regular UV
exposure ages the skin and increases the risk of non-
melanoma skin cancers.
e treatment of choice for vitamin D deficien-
cy is vitamin D, cholecalciferol, also known as vitamin
D
3
. Oral vitamin D treatment is more challenging than
treatment with UVB light for several reasons. First, un-
expectedly high doses of vitamin D are usually needed
to achieve adequate serum 25(OH)D levels. One of the
problems with vitamin D terminology is the archaic
method used to express dose, international units or IU.
One thousand IU of vitamin D sounds like a lot; in fact,
it is only .025 mg or 25 micrograms; i.e., one mcg is 40
IU. Second, the amount of vitamin D needed varies with
body weight, body fat, age, skin color, season, latitude,
and sunning habits. ird, unlike sun exposure, toxicity
is possible with oral supplementation – although it is
extraordinarily rare.
Cholecalciferol is available over-the-counter
and via the Internet in 400, 1,000, 2,000 and (recently)
5,000, 10,000, and 50,000 IU capsules. Supplementa-
tion with 1,000 IU per day will usually result in about
a 10-ng/mL elevation of serum 25(OH)D when given
over 3-4 months. erefore, a normal weight, healthy
adult with an initial level of 10 ng/mL would gener-
ally require about 2,000 IU per day to achieve a level of
30 ng/mL in the absence of cutaneous UVB exposure.
However, its kinetics are not linear; 1,000 IU per day
will substantially raise low baseline levels but a similar
dose will not increase higher baseline levels by a simi-
lar increment (that is, 2,000 IU per day may not raise
30 ng/mL to 50 ng/mL). In the absence of significant
UVB exposure, input from diet and supplements of
approximately 1,000 IU (25 mcg) per day for every 15
kg of body weight may be needed; i.e., an obese 150-kg
adult may require up to 10,000 IU per day to achieve
a 25(OH)D level of 50 ng/mL. Patients with serious
diseases may need more if the metabolic clearance of
25(OH)D is increased (see below).
e only prescription vitamin D preparation
available in the United States is the vitamin D analogue
ergocalciferol (vitamin D
2
), available as 50,000 IU (1.25
mg) capsules. However, ergocalciferol is not human vi-
tamin D, it may be a weaker agonist, it is not normally
present in humans, and its consumption results in meta-
bolic by-products not normally found in humans.
54
It is
also less effective than cholecalciferol in raising 25(OH)
D levels.
55,56
Recently, 50,000 IU capsules of vitamin D
3

became available in retail outlets. Grey at al treated 21
vitamin D-deficient patients with 50,000 IU cholecal-
ciferol weekly for four weeks, then 50,000 IU monthly
for one year.
57
Blood levels rose from a mean of 11 ng/
mL at baseline to 30 ng/mL at six months and to 31 ng/
mL at one year, indicating monthly doses of 50,000 IU
of vitamin D
3
do not achieve natural 25(OH)D levels
and such levels do not continue to rise after six months
of such treatment. If such intermittent high doses of
cholecalciferol are used, maintenance requirements are
probably 50,000 IU every 1-2 weeks in most adults,
although such supplementation studies have not been
done.
Toxic > 150ng/mL
Excessive > 100ng/mL
Ideal > 40-70ng/mL
Deficient < 40ng/mL
70ng/mL
100ng/mL
150ng/mL
40ng/mL
0ng/mL
Author’s recommendations for serum
25(OH) vitamin D levels.
Figure 5. Ranges of Serum 25(OH)D
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Vitamin D
Page 14
Cod liver oil contains a variable amount of
vitamin D, but usually contains high amounts of vita-
min A. Consumption of pre-formed retinols, even in
amounts consumed in multivitamins, may be causing
low-grade, but widespread, bone toxicity.
58
Vitamin A
antagonizes the action of vitamin D,
59
and high retinol
intake thwarts vitamin D’s protective effect on distal
colorectal adenoma.
60
e authors do not recommend
cod liver oil.
Neither the regular consumption of officially
recommended amounts of vitamin D (e.g., 400 IU in a
multivitamin), nor the regular consumption of vitamin
D fortified foods (e.g., 100 IU per 8 oz. glass of milk),
effectively prevent vitamin D deficiency.
61,62
Further-
more, 2,000 IU/day for one year failed to achieve a 32
ng/mL target 25(OH)D concentration in 40 percent of
104 African-American women studied.
63
e admin-
istration of 4,000 IU/day for more than six months
to middle-age Canadian endocrinology outpatients
resulted in average 25(OH)D levels of 44 ng/mL and
produced no side effects other than improved mood.
52

Heaney estimates 3,000 IU/day is required to assure
that 97 percent of Americans obtain levels greater than
35 ng/mL.
23
Healthy adult men utilize up to 5,000 IU
of vitamin D per day, if it is available.
64
In general, the more a patient weighs, the more
vitamin D will be required, and large amounts of body
fat further increase requirements. Not only are baseline
25(OH)D levels lower in the obese, the obese require
higher doses of oral supplements or UV radiation than
lean individuals in order to obtain the same increases
in 25(OH)D blood levels.
65
Fat malabsorption syn-
dromes may increase oral requirements or necessitate
the use of ultraviolet radiation. Advancing age impairs
the skin’s ability to make vitamin D, so older persons
generally need higher supplemental doses than younger
ones. erefore, dark-skinned, large, obese, or older pa-
tients often require higher maintenance doses than fair-
skinned, small, thin, or younger ones. Loading doses
of 50,000 IU (1.25 mg) of cholecalciferol per day for a
week, or at the most two, are safe to use before begin-
ning maintenance therapy.
Cytochrome P-450 enzymes are responsible
for both the initial metabolism and subsequent catabo-
lism of vitamin D. erefore, drugs dependent on cy-
tochrome P-450 enzymes – and there are many – may
affect vitamin D metabolism. What clinically relevant
interactions these substances – including cardiac drugs,
erythromycins, psychotropics, and even grapefruit juice
– have on the metabolism of vitamin D is an area await-
ing further research. Of the research done on drug/vi-
tamin D interactions, anticonvulsants, corticosteroids,
cimetidine, anti-tuberculosis agents, theophylline, and
orlistat may lower 25(OH)D levels, while thiazide di-
uretics and statins increase 25(OH)D levels.
66,67
Pa-
tients on medications of any kind should have frequent
testing of 25(OH)D levels when being treated with
doses above 2,000 IU per day.
e authors recommend parents supplement
breast-fed infants with at least 800 IU of vitamin D
daily, while formula fed infants need 400 IU per day.
Infants and toddlers may be at extremely high risk of
deficiency during weaning. Around 12-18 months,
many stop drinking vitamin D-fortified infant formula
and begin consuming unfortified juices, which – inter-
estingly – is also the time many autistic children rapidly
deteriorate. Toddlers and young children who do not
get regular sun exposure should take 1,000-2,000 IU
daily year-round, depending on body weight, keeping
in mind that current Food and Nutrition Board recom-
mendations state doses up to 2,000 IU per day are safe
for children over the age of one. In the summer, children
who spend time in the sun without wearing sunblock
will need little or none. Parents can easily open 1,000
IU capsules containing powdered vitamin D and dis-
solve the contents in juice or food for easy delivery to
children and infants.
Vitamin D deficiency in pregnancy is an on-
going epidemic,
68
and animal evidence continues to
accumulate that maternal vitamin D deficiency perma-
nently injures fetal brains.
38,39,69
Pregnant women – or
women thinking of becoming pregnant – should have
25(OH)D levels checked every three months and be
adequately treated, often with 5,000 IU or more per
day, as outlined above.
70
Lactating women require even
more, up to 7,000 IU per day, to assure breast milk is
a rich source of vitamin D.
71
Infants being breast fed
by supplementing mothers will not require additional
supplementation, but will require adequate supplemen-
tation during and after weaning.
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Review Article
Page 15
Treatment of Disease
By far the most common reason to treat with
vitamin D is osteoporosis, but the dose needed remains
controversial because the lowest effective dose (800 IU/
day) is known, but the ideal dose is not.
72
Currently, vir-
tually all of the evidence that vitamin D is an effective
adjuvant for the treatment of other serious medical con-
ditions is anecdotal, implied by epidemiological studies,
from open trials, or inferred from vitamin D’s mecha-
nism of action. For example, there is an anecdotal report
that pharmacological doses of vitamin D are effective
in treating – not just preventing – viral respiratory in-
fections.
73
Doses of 2,000 IU/kg body weight for three
days (200,000 IU per day for three days for a 100-kg
adult) may seem excessive to those unfamiliar with vita-
min D’s pharmacology and toxicity. In fact, such doses
are common in many parts of the world simply to pre-
vent or treat vitamin D deficiency.
For example, single injections of 600,000 IU
(15 mg) vitamin D raised 25(OH)D levels from 2 ng/
mL to 22 ng/mL at two weeks and to 27 ng/mL at six
weeks in 10 elderly subjects, with no evidence of toxic-
ity.
74
Indeed, a single injection of 600,000 IU of vita-
min D is not only safe; such doses were recently recom-
mended in the autumn for the elderly, simply to prevent
wintertime vitamin D deficiency.
75
Likewise, there was
no evidence of toxicity in young men taking 50,000 IU
of vitamin D per day for six weeks (although such a dose
would become toxic if taken over a longer period).
76
In
32 severely vitamin D-deficient elderly patients, 50,000
IU/day for 10 days showed no evidence of toxicity and
only raised 25(OH)D levels by an average of 5 ng/mL
three months after administration. In no patient did
levels increase more than 11 ng/mL at three months.
77
Treatment of colds and influenza with phar-
macological doses of vitamin D may only be the tip of
the infectious disease iceberg. As Aloia and Li-Ng have
pointed out,
12
it is intriguing that vitamin D-sensitive
antimicrobial peptides (AMP) inhibit the HIV virus
and there is evidence that vitamin D plays a role in
HIV.
78
Invasive pneumococcal disease, meningococcal
disease, and group A streptococcal disease are more
common when vitamin D levels are lowest (winter)
79-81

and all three bacteria are sensitive to AMP,
82-84
raising
the possibility that pharmacological doses of vitamin
D would be an effective adjuvant treatment. In fact, the
dramatically increased production of AMPs by vitamin
D and the broad spectrum of action of AMP make it
reasonable to hypothesize that pharmacological doses
of vitamin D are effective adjuvants in treating a large
number of infections.
In a recent report, 12 patients in active phases
of multiple sclerosis were treated with progressively in-
creasing weekly doses of vitamin D
3
(the equivalent of
starting with 4,000 IU per day and increasing to 40,000
IU per day) and calcium.
85
Mean serum concentrations
of 25(OH)D initially were 31 ng/mL and rose to a
mean of 154 ng/mL at the end of 28 weeks, with no
abnormalities in serum or urine calcium detected in the
12 subjects. e number of MS lesions per patient on
brain scan decreased from an initial mean of 1.75 at the
beginning to a mean of 0.83 (p=0.03) at the end of the
study. However, doses of 40,000 IU per day may cause
toxicity if given for longer periods; certainly, such doses
flirt with toxicity. Doses of 10,000 IU per day may well
have achieved the same result without the risk of toxic-
ity.
Both epidemiological evidence and vitamin D’s
mechanism of action suggest it may have a treatment ef-
fect in early cancer. For example, a study of recurrence-
free survival in early-stage, non-small-cell lung cancer
patients found those with the highest vitamin D input
had double the five-year recurrence-free survival and
much better overall survival than those with the low-
est.
86
is strongly implies a vitamin D treatment effect,
i.e., untreated vitamin D deficiency in non-small-cell
lung cancer patients is a risk factor for early death.
Season of diagnosis has a survival effect on
numerous cancers; i.e., cancer patients live longer if the
diagnosis is made in the summer rather than the win-
ter.
87,88
Although no one has proven vitamin D causes
this summer-season treatment effect, vitamin D’s anti-
cancer mechanism of action is basic to all cancers. us,
it is reasonable to hypothesize a general cancer treat-
ment effect, at least in cancer’s early stages, when aber-
rant cells are more likely to retain both the vitamin D
receptor and the enzyme needed to activate vitamin D.
Practitioners who treat type-2 diabetic or hy-
pertensive patients with physiological doses of vitamin
D should be prepared for the possibility of either hypo-
glycemia or hypotension, especially after several months
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Vitamin D
Page 16
of treatment. eoretically, such doses of vitamin D
should eventually lower both blood sugar and blood
pressure, although blood sugars may worsen for several
weeks after initiation or increase of vitamin D. Should
either hypoglycemia or hypotension occur, the diabetic
and/or hypertensive medication should be lowered, not
the vitamin D.
Although modern science knows little or noth-
ing about the metabolic clearance of vitamin D in differ-
ent disease states, it is reasonable to predict that vitamin
D is cleared more rapidly in some disease states. For ex-
ample, patients with diabetes, HIV, or cancer may rap-
idly use 25(OH)D as substrate to make large amounts
of 1,25(OH)
2
D to fight their disease. erefore, a pa-
tient with cancer may require significantly higher doses
of vitamin D to maintain 25(OH)D levels of 55-70 ng/
mL than a healthy adult of similar weight and body fat.
Practitioners should supplement such patients (assum-
ing they are not hypercalcemic) to high natural levels,
even if it means taking 10,000 IU or more per day.
Frequent monitoring of 25(OH)D and calcium levels
should guide dosing in patients with cancer and other
serious illnesses, and such treatment should be adjunc-
tive and never take the place of standard treatment.
e authors believe that those who claim the
lack of RCTs showing vitamin D’s effectiveness as adju-
vant cancer treatment means it should never be so used
miss an important point. For example, recent studies
show a high incidence of vitamin D deficiency in pa-
tients undergoing treatment for cancer.
89
Even at the
end of summer, 48 percent of cancer patients in Boston
had levels less than 20 ng/mL.
89
In another study, 72
percent of 60 cancer patients had 25(OH)D levels less
than 30 ng/mL, and virtually none had natural levels.
90

A 1998 study of inpatients at Massachusetts General
Hospital found 57 percent had 25(OH)D levels less
than 15 ng/mL.
91
us, the question should not be, “Should can-
cer (or multiple sclerosis, septic, cardiac, HIV, or hepa-
titis B) patients be treated with vitamin D?” e better
question is, “Should practitioners routinely screen and
aggressively treat vitamin D deficiency in patients with
serious or potentially fatal illnesses, or should such pa-
tients combat their disease vitamin D deficient?” As ref-
erenced above, the vast majority of such patients prob-
ably expire severely vitamin D deficient.
Vitamin D Toxicity
Vitamin D toxicity is exceedingly rare and few
practitioners ever see it,
92
although that could change
with the recent availability of 50,000 IU capsules. Tox-
icity is secondary to the unbridled effects of hypercal-
cemia. In chronic toxicity, first urine calcium and then
serum calcium will begin to gradually increase when
25(OH)D levels exceed some level above 150 ng/mL.
Such levels must be associated with hypercalcemia in
order to indict vitamin D. Chronic vitamin D toxicity
results when hypercalcemia goes undetected and calci-
fies internal organs, especially the kidneys. In order to
produce hypercalcemia, most adults would have to take
in excess of 10,000 IU per day for many months or even
years. Most patients with vitamin D toxicity recover
fully by simply stopping the vitamin D and practicing
strict sun-avoidance.
Credible evidence of vitamin D toxicity in
those chronically consuming 10,000 IU of supplemen-
tal cholecalciferol daily is absent in the literature. In fact,
the literature contains few cases of cholecalciferol toxic-
ity from supplement use; virtually all the reported cases
of hypercalcemia are from faulty industrial production,
labeling errors, dosing errors, and patients treated medi-
cally with pharmacological doses of ergocalciferol.
e current Adequate Intakes and Upper Lim-
its are for medically unsupervised intake by adults and
children, set by the Institute of Medicine’s Food and
Nutrition Board (FNB) in 1997, and do not apply to
medically supervised treatment. Surprisingly, the FNB
says Adequate Intake is the same 200 IU/day for the
smallest infant as it is for the largest pregnant woman.
Likewise, the FNB’s Upper Limit for both one-year-old
children and forty-year-old adults is 2,000 IU/day, a
limit based on old and faulty literature.
93
e current
official recommendations are illogical; for example, how
can 200 IU/day be the adequate intake for both a 3-kg
infant and a 60-kg pregnant woman, and 2,000 IU/day
be the Upper Limit for both a 10-kg child and a 150-kg
adult?
Although a 2,000-IU Upper Limit is prob-
ably appropriate for infants and young children, such a
limit in older children, adolescents, and adults has the
effect of both limiting effective treatment of vitamin D
deficiency and impairing dose-appropriate interven-
tional research. However, the current 2,000-IU per day
Upper Limit does not impair a practitioner’s ability to
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Review Article
Page 17
treat vitamin D deficiency with higher doses just as the
comparable Upper Limit for calcium does not impair
the practitioner’s ability to treat hypocalcemia with cal-
cium doses above the Upper Limit once hypocalcemia is
properly diagnosed.
Practitioners who use doses above 2,000 IU
per day should periodically monitor serum 25(OH)D
levels, especially if patients are on other medications.
Periodic monitoring will also educate the practitio-
ner not only to the safety of supplementation, but to
the surprisingly high oral dose required to achieve and
maintain adequate serum 25(OH)D levels, especially in
the fall and winter.
Absolute and Relative Contraindications
to Treatment
e only absolute contraindication to vitamin
D supplementation is vitamin D toxicity or allergy to
vitamin D, although no reports in the literature were
found of acute allergic reactions to vitamin D supple-
ments. Contraindications to sunlight or artificial UV
radiation include a number of dermatological condi-
tions (porphyrias, xeroderma pigmentosum, albinism),
as well as various photosensitizers (sulfonamides, phe-
nothiazines, tetracyclines, psoralens). Previous skin
cancers, especially cutaneous melanoma, are contra-
indications to excessive UV exposure, although a recent
study found reduced mortality in melanoma patients
who continued exposure to sunlight.
94
Nevertheless,
oral treatment is recommended for patients who have
had any type of skin cancer.
Although the liver initially metabolizes vitamin
D, liver disease is not a contraindication to treatment of
deficiency. e liver conserves the ability to hydroxylate
vitamin D despite advanced liver disease.
95
A recent
study of patients with advanced noncholestatic chronic
liver disease recommended treatment of concomitant
vitamin D deficiency after finding serum 25(OH)D
levels of less than 10 ng/mL predicted coagulopathy,
hyperbilirubinemia, hypoalbuminemia, anemia, and
thrombocytopenia.
96
Vitamin D hypersensitivity syndromes – often
confused with vitamin D toxicity – occur when extra-
renal tissues produce 1,25(OH)
2
D in an unregulated
manner, causing hypercalcemia.
97
ese syndromes
are diagnosed by measuring serum calcium (elevated),
25(OH)D (normal or low), and 1,25(OH)
2
D (elevat-
ed). Vitamin D hypersensitivity syndromes can occur in
some of the granulomatous diseases (especially sarcoi-
dosis and tuberculosis), and in some cancers (especially
non-Hodgkin’s lymphoma and oat cell carcinoma of the
lung). Such conditions may be unmasked by vitamin D
treatment; for example, sarcoidosis may become clini-
cally evident after summer sun exposure.
erefore, hypercalcemia is a relative contra-
indication to vitamin D, sunlight, and artificial UVB ra-
diation. e practitioner should carefully evaluate any
hypercalcemic patient for the cause of hypercalcemia.
Once the cause is clear, should the practitioner decide
to treat concomitant vitamin D deficiency – despite the
hypercalcemia – it should only be if the hypercalcemia is
mild to moderate (<12 mg/dL) and should proceed cau-
tiously, with frequent monitoring of clinical condition,
urine and serum calcium, 25(OH)D, and 1,25(OH)
2
D.
Vitamin D, especially in large doses, could theoretically
precipitate a worsening clinical course in such patients.
Summary
Vitamin D deficiency is endemic and is asso-
ciated with numerous diseases. Understanding vitamin
D’s physiology and having a high index of suspicion are
keys to determining the diagnosis. Serum 25(OH)D
levels less than 40 ng/mL are seldom found in those liv-
ing in a sun-rich environment and such levels are need-
ed to assure normalization of the pharmacokinetics of
vitamin D. Treatment with sunlight or artificial UVB
radiation is simple but increases the risk of non-mela-
noma skin cancers and ages the skin. Sunburn increases
the risk of malignant melanoma. Adequate oral supple-
mentation will require doses that might make a prac-
titioner initially uncomfortable, as physiological doses
of vitamin D, in the absence of sun exposure, probably
range between 400 IU/day for premature infants to
10,000 IU/day for the morbidly obese.
Treatment of vitamin D deficiency in other-
wise healthy patients must be individualized due to the
numerous factors affecting 25(OH)D levels, and doses
should be adequate to maintain serum 25(OH)D levels
between 40-70 ng/mL. Patients with chronic diseases
associated with vitamin D deficiency, especially internal
Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 1 March 2008
Alternative Medicine Review Volume 13, Number 1 2008
Vitamin D
Page 18
cancers, should be supplemented with doses adequate to
maintain 25(OH)D levels in the higher normal range,
55-70 ng/mL. Caution is required in any patient with
hypercalcemia. e use of short-term pharmacological
doses of vitamin D as treatment for the common cold or
flu – 2,000 IU/kg/day for several days – while theoreti-
cally promising, awaits further study.
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Yanoff LB, Parikh SJ, Spitalnik A, et al. e prevalence of 48.
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Erkal MZ, Wilde J, Bilgin Y, et al. High prevalence of 49.
vitamin D deficiency, secondary hyperparathyroidism
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Gloth FM 3rd, Lindsay JM, Zelesnick LB, Greenough WB 50.
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Wilkins CH, Sheline YI, Roe CM, et al. Vitamin D 51.
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Vieth R, Kimball S, Hu A, Walfish PG. Randomized 52.
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responses and the wellbeing of patients. Nutr J 2004;3:8.
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Houghton LA, Vieth R. e case against ergocalciferol 54.
(vitamin D2) as a vitamin supplement. Am J Clin Nutr
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vitamin D3 increases serum 25-hydroxyvitamin D
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in patients with primary hyperparathyroidism and
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2005;90:2122-2126.
Penniston KL, Tanumihardjo SA. e acute and 58.
chronic toxic effects of vitamin A. Am J Clin Nutr
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Rohde CM, DeLuca HF. All-trans retinoic acid 59.
antagonizes the action of calciferol and its active
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Oh K, Willett WC, Wu K, et al. Calcium and vitamin D 60.
intakes in relation to risk of distal colorectal adenoma in
women. Am J Epidemiol 2007;165:1178-1186.
Vieth R, Cole DE, Hawker GA, et al. Wintertime vitamin 61.
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pregnancy: an ongoing epidemic. Am J Clin Nutr
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requirements during pregnancy and lactation. Am J Clin
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lactation: high-dose maternal supplementation as therapy
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intramuscular injection of a megadose of cholecalciferol for
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its major metabolites: serum levels after graded oral dosing
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Wu F, Staykova T, Horne A, et al. Efficacy of an oral, 77.
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Zhou W, Suk R, Liu G, et al. Vitamin D is associated 86.
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diagnosis is a predictor of cancer survival. Sun-induced
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Cancer 2006;56:143-148.
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periodontal disease. osteoporosis. functions. are brought on by seasonal deficiencies in antimicrobial peptides (AMP). Incidence of Colds/Influenza After 2. Indeed. However. propensity to fall. 1. No Reprint Without Written Permission. the steroid hormone) is present in a wide variety of human tissues other than kidney. repair and maintenance.25(OH)2D is autonomously made in tissues and directly affects numerous cells via its autocrine.25(OH)2D (activated vitamin D.25(OH)2D. many practitioners thought vitamin D’s activity was principally its endocrine function – the regulation of serum calcium – and was thus mainly involved in bone metabolism.000 IU of vitamin D/day for one year virtually eliminated self-reported incidence of colds and influenza (Figure 1). Epidemic influenza and vitamin D. Placebo 800 IU/d 2000 IU/d Adapted from: Aloia JF. Inc. Number 1 2008 Review Article treatment-induced 25(OH)D levels might prevent even more cancers.14 and type 1 diabetes. finding 2. rheumatoid arthritis. All Rights Reserved.12 Even the current triple childhood epidemics of autism13 (Figure 2). might be the tragic and iatrogenic sequela of gestational or early childhood vitamin D deficiencies brought on by medical advice to avoid the sun. Used with permission. Epidemiol Infect 2007.15 all of which blossomed after sun-avoidance advice became widespread. 1. mental illness. Page 7 Copyright © 2008 Thorne Research.Alternative Medicine Review Volume 13. macular degeneration.25(OH)2D. Number 1 March 2008 . (Note that 25(OH)D levels are reported in the literature as either ng/mL or nmol/L. hypertension. 135:1095-1096. asthma. The placebo group reported more cold/influenza symptoms in the winter.18 Like all steroid Figure 1. Alternative Medicine Review Volume 13. stroke. in the last ten years. Li-Ng M. diabetes.16 hydroxylates 25(OH)D to 1.000 IU Vitamin D Daily for One Year 25 20 15 10 5 0 Winter Spring Summer Autumn Incidence of reported cold/influenza symptoms according to season. Previously. and chronic pain. it is the only known substrate for a potent. pleiotropic. but multiple autocrine functions. it has become clear the vitamin D steroid hormone system includes more than the classic endocrine pathway used to pree enzyme that further serve calcium economy. Claims that vitamin D may help prevent such a wide variety of diseases seem incredible until one realizes vitamin D is not a vitamin. such as cathelicidin.0 ng/mL equals 2.5 nmol/L.11 Results of an RCT support the theory. rather. which then acts.) Besides cancer. secondary to seasonal deficiencies in vitamin D. Only one subject had cold/influenza symptoms while taking a higher dose of vitamin D (2000 IU/d). to maintain serum calcium. seco-steroid hormone with a single endocrine function.17 Most organs show evidence of end organ responsiveness to 1. and presumed paracrine.6-10 A recent review presented considerable evidence that influenza epidemics. vitamin D deficiency is associated with cardiovascular disease. inflammatory bowel disease. both directly and indirectly. multiple sclerosis. and perhaps even the common cold. the classic endocrine function of vitamin D begins when the kidney hydroxylates 25(OH)D into 1.

23 others recommend a lower limit of 40 ng/mL. http://www.21 Although some experts believe the lower limit of adequate 25(OH)D levels is in the low 30s. No Reprint Without Written Permission. locally produced 1. influenza. were around 50 ng/mL. 1.20 Recent pooled meta-analyses estimate 25(OH)D levels of 52 ng/mL are needed to effect a 50-percent reduction in the incidence of breast cancer. at the end of winter 25(OH)D 2003 Page 8 Copyright © 2008 Thorne Research.25 there is certainly no scientific consensus. us.Ages 6-22 50 States. Such claims leave practitioners with understandable skepticism and multiple questions. D. Alternative Medicine Review Volume 13. & Puerto Rico 140920 118602 1994 1995 1996 1997 1998 1999 2000 2001 2002 Time trend of autism prevalence for the 50 states and Puerto Rico.S. and has as many mechanisms of action as genes it targets.27 Furthermore. Ideal levels are unknown but are probably close to levels present when the human genome evolved in sub-equatorial Africa. “What is an ideal 25(OH)D level?” Levels needed to optimize intestinal calcium absorption (34 ng/mL)19 are lower than those needed to optimize neuromuscular performance (38 ng/mL).25(OH)2D exists in most tissues of the body. asthma. autism. not just curing rickets and osteomalacia (Figure 3).26 however. Increased Prevalence of Autism: 1992-2003 18000 6000 4000 Number of Children 2000 1000 800 600 54049 400 200 0 15558 19048 1992 1993 22652 29057 34356 42493 66015 79552 98532 Cases of Autism U.org/idea/autism. such as those found at the end of summer in 30 young men who spent the summer working outdoors. accessed 5/8/07) hormones. Natural levels.Alternative Medicine Review Volume 13.24.25(OH)2D acts as a molecular switch. Number 1 March 2008 . is under autonomous autocrine control. Is vitamin D a cure-all? When should I recommend vitamin D? How much should I prescribe? What form of vitamin D should I use? How much do children need? How much do pregnant or breastfeeding women need? Is it appropriate to use higher doses of vitamin D as adjuvant treatment for any of the above diseases? How do I interpret vitamin D blood tests and which tests should I order? What is the risk of toxicity? Another way to ask many of these questions is. thereby regulating gene expression. is explains why the same substance may have a role in preventing cancer. Inc. (Reproduced with permission. Fighting Autism. and cardiovascular disease. Number 1 2008 Vitamin D Figure 2. activating more than 200 target genes. despite such summertime levels..C.fightingautism. multiple sclerosis. School Years 1992-2003 .php. these levels are obtained by only a small fraction of people.22. All Rights Reserved.

and often 50 ng/mL. Number 1 March 2008 . 25(OH)2D Prevent and/or treat: Viral respiratory disease Cancer. and thus levels above 40 ng/mL appear to represent the lower limit of “normal” 25(OH) D levels. progesterone. the reactions follow firstorder mass action kinetics. Multiple sclerosis Diabetes. Orange Juice. Salmon. the parent compound began to be detectable in the blood. In other words. Hypertension Maintain calcium economy levels in 50 percent of these men dropped to less than 30 ng/mL. Inc. to begin to detect the parent compound in the blood and begin to normalize the kinetics of 25(OH)D production. Page 9 Copyright © 2008 Thorne Research. testosterone. and the absence of the parent vitamin D compound (cholecalciferol) in the blood means all available vitamin D is used for metabolic needs and none of it is stored. and the more is converted into 1. vitamin D. Autocrine and Endocrine Functions of Vitamin D Previtamin D Skin Milk.25(OH)2D operate below their Michaelis-Menten constants throughout the full range of modern human substrate concentrations. Number 1 2008 Review Article Figure 3.Alternative Medicine Review Volume 13. in two groups. or estradiol levels were entirely dependent on the intake of their substrate.28 e more vitamin D that is ingested. Alternative Medicine Review Volume 13. 25(OH)2D Kidney Endocrine 1..29 Hollis et al studied the pharmacokinetics of the parent compound.e.25(OH)2D in the tissues. the reactions became saturable and controlled (like other steroid hormone systems). the more is converted into 25(OH)D.400 IU of supplemental vitamin D per day. Imagine. 25(OH)D. Hawaiians with significant sun exposure and lactating women receiving 6. i. All Rights Reserved. ey found 25(OH)D levels had to exceed a minimum of 40 ng/ mL. or Supplements Vitamin D Liver 25(OH)D Autocrine Most tissues in the body 1. is means the liver enzymes that initially hydroxylate vitamin D to form 25(OH)D and the enzyme in tissue that generates 1. Osteoporosis Heart disease. at least in the winter. and potentially dangerous situation for a steroid hormone system. is implies virtually everyone has a chronic 25(OH)D substrate deficiency. an aberrant. Another way to ask the “ideal 25(OH)D” question involves understanding vitamin D’s unique pharmacokinetics. and its first metabolic product. when 25(OH)D levels > 40 ng/mL were achieved. totally unique. Hollis et al recently explained this conundrum and concluded very few humans obtain enough vitamin D even if they take several thousand units per day. e reaction appears to be uncontrolled. cholesterol. Unlike any other steroid hormone system. if cortisol. the substrate concentrations for the liver production of 25(OH)D are absolutely rate limiting. No Reprint Without Written Permission. indicating a sun-induced level of 50 ng/mL at the end of summer is inadequate to maintain such a level during wintertime. for example.

30 Page 10 Copyright © 2008 Thorne Research. do we wait for science to complete its work with highly seasonal 25(OH)D levels (Figure 4) that reflect sunlight deprivation. levels where vitamin D’s kinetics are normalized (>40 ng/mL)? Once a practitioner is comfortable with ideal 25(OH)D levels being above 40 ng/mL. n=3723) and women (orange. Scotland. Inc. pregnant women. each a laudable goal in cancer treatment. Healthy humans should be supplemented with enough vitamin D or exposed to enough ultraviolet B (UVB) radiation to achieve natural 25(OH)D levels (40-70 ng/mL) year-round. and W Am J Clin Nutr Because of this. What role vitamin D has in treating – rather than preventing – disease is largely unknown. and prevents angioneogenesis. No Reprint Without Written Permission. However. or the elderly. or is it safer to wait with levels normally achieved by humans in a sunrich environment. lactating women. Number 1 March 2008 Mar . it may have a significant role. higher risk for the “diseases of civilization. healthy young adults. children. functional vitamin D deficiency.Alternative Medicine Review Volume 13. induces apoptosis.” e ideal 25(OH)D level continues to be debated in scientific circles and consensus awaits further science. a strong case already exists for adequately diagnosing and aggressively treating vitamin D deficiency. While the RCTs needed to clarify vitamin D’s role in the treatment of disease are being conducted. n=3712) in a 1958 British (England. Seasonal Serum Levels of 25-hydroxyvitamin D 34 30 28 24 20 16 12 8 4 0 Oct Aug Jan Oct Sept Sept Nov Dec July Nov Dec Feb Jan June May Feb Mar Apr Geometric mean monthly variations in serum 25-hydroxyvitamin D [25)OH)D] concentration in men (blue. All Rights Reserved. levels where vitamin D steroid pharmacokinetics are aberrant. and thus. induces differentiation. most individuals have chronic substrate starvation. For example.25. Alternative Medicine Review Volume 13. A simple risk-versus-benefit analysis suggests patients with a potentially fatal cancer (see below) may think it wise to maintain 25(OH)D levels in the high end of natural ranges (55-70 ng/mL). the answers to the questions posed above become fairly simple. vitamin D reduces cellular proliferation. perhaps. Number 1 2008 Vitamin D Figure 4. ranges that assure vitamin D’s kinetics are normalized. but given vitamin D’s genetic mechanism of action. whether they are infants.22.

If enough 25(OH)D substrate is available. the higher the percentage of the population defined as deficient. production after only a few minutes of sunlight easily exceeds dietary sources by an order of magnitude.S. raises profound questions. sun-dried Shitake mushrooms.38.42. glass) or taking 50 standard multivitamins (400 IU/tablet) to obtain the same amount orally. Number 1 2008 Review Article Incidence of Vitamin D Deficiency matter how it arrives in the circulation. a pleiotropic seco-steroid. e skin’s manufacture of vitamin D is extraordinarily rapid and remarkably robust. a disease of the industrial revolution.36 especially in breast-fed infants. Inc. the higher the low end of the 25(OH)D cutoff point.000 IU of vitamin D in 30 minutes. especially African-Americans. and cereals. they produce about 20. unless those diets are rich in wild-caught fatty fish. cutaneous vitamin D production is effectively absent early and late in the day and for the Factors Affecting Vitamin D Levels Page 11 Copyright © 2008 Thorne Research. Obviously. Hundreds of tissues in the body use 25(OH)D as a substrate to make the end-product. is being diagnosed more frequently. contain minimal vitamin D. clouds. women of childbearing age found 42 percent of African-American women had 25(OH)D levels below 15 ng/mL. Number 1 March 2008 . is modern sunlight deprivation – and the resultant routinely low levels of this repairand-maintenance steroid in tissues – a possible common cause of the diseases of civilization? Adult vitamin D deficiency is the rule rather than the exception in industrialized nations. No Vitamin D Metabolism and Physiology Factors that can affect UVB exposure. and the extent of clothing covering the body. When the sun is low on the horizon. and 12 percent had levels below 10 ng/mL. time of day.000 IU vitamin D can be produced in the skin in 30 minutes of sun exposure. the liver readily hydroxylates vitamin D to 25(OH)D. e aforementioned prevalence studies used outdated reference values for low-end 25(OH) D ranges and therefore underestimate the incidence of vitamin D deficiency. full-body. age. cloud cover. All Rights Reserved. Incidental sun exposure. the body metabolizes vitamin D similarly to that generated in the skin. known as activated vitamin D. the circulating form of vitamin D.44 the equivalent of drinking 200 glasses of milk (100 IU/8 oz. or wild reindeer meat.35 Rickets. Only 10 percent of the subjects in any of the above studies had 25(OH) D levels > 40 ng/mL. erefore. the human vitamin D system began in the skin. the definition of vitamin D deficiency changes almost yearly as research shows the low end of ideal 25(OH)D ranges are higher than were previously thought. No Reprint Without Written Permission. Traditionally. use of sunblock. however. and thus the skin’s production of vitamin D.” most people wrongly assume they can obtain adequate amounts by eating a healthy diet. such as fortified milk.25(OH)2D. multiple tissues are free to autonomously produce and locally regulate the amount of steroid needed for any particular disease state. given mounting animal data that gestational vitamin D deficiency causes subtle but irreversible brain damage in mammalian offspring. Vitamin D normally enters the circulation after UVB from sunlight strikes 7-dehydro-cholesterol in the skin.40 A population-based study of 2. but such sources are minor contributors to vitamin D stores.Alternative Medicine Review Volume 13. not dietary intake. e natural diets most humans consume. minimal erythemal dose of UVB). some orange juices. converting it to vitamin D3 or cholecalciferol (vitamin D). when fair-skinned people sunbathe in the summer (one. melanin content of the skin. not in the mouth. Small amounts of vitamin D are contained in fortified foods. 1. Why did nature develop a system that delivers huge quantities of a steroid precursor after only brief periods of sun exposure? Would natural selection evolve such a system if the remarkably high input that system achieved were unimportant? As humans evolved in a sun-rich environment (sub-equatorial Africa). include latitude. When taken by mouth. is the principal source of vitamin D stores and is a function of skin surface area exposed. Alternative Medicine Review Volume 13. Perhaps because the term “vitamin D” contains the word “vitamin.39 severe deficiencies are common in newborn infants and pregnant women. and particulate air pollution deflect UVB radiation away from the earth’s surface.31-33 A high number of otherwise healthy children and adolescents are also vitamin D deficient. combined with vitamin D’s basic genomic mechanism of action. season of the year.43 For example.34.37 Alarmingly. e fact that 20.41 Furthermore. air pollution.972 U. ozone.

diabetes. is dark-skinned. Massachusetts (latitude 42 degrees). ose who avoid sunlight – at any latitude – are at risk of vitamin D deficiency any time of the year. Furthermore. Complaints endemic to every practitioner’s office. when insufficient UVB penetrates the atmosphere to trigger skin production.53 We recommend 25(OH)D levels be kept above 40 ng/mL year-round (Figure 5). common window glass in homes and cars. Obtaining and properly interpreting a serum 25(OH)D level is the only way to make the diagnosis.48 Anyone who works indoors. major depression.50 e recent strong association of low mood and cognitive impairment in the aged with vitamin D deficiency51 suggests depressed mood and/or impaired cognition may be presenting symptoms. although frequent infections. such as muscular weakness. dark-skinned people need much longer UVB exposure times to generate the same 25(OH)D stores as fair-skinned individuals. e vast majority of cases appear normal on exam. a feeling of heaviness in the legs. and a host of other “diseases of civilization” may be warning signs that deficiency has been present for many years.46 e elderly make much less vitamin D than 20-yearolds after exposure to the same amount of sunlight. cancer. In northern Europe and Canada. properly applied sunblock.Alternative Medicine Review Volume 13. difficult to treat.49 Such complaints are extremely common. Boston. Because melanin in the skin acts as an effective and ever-present sunscreen. e kidney tightly controls serum 1. although that may be changing. aged. with obese African-Americans at an even higher risk.000 IU of vitamin D into the systemic circulation of most lightskinned adults.25(OH)2D levels play no role in diagnosing vitamin D deficiency.25 In the absence of a metabolic bone disease such as rickets.22. a surprisingly high incidence of vitamin D deficiency exists in Miami. or who consciously avoids the sun is at high risk for vitamin D deficiency. the physician should screen those at risk. It is crucial to remember that serum 1. Physical examination is usually unremarkable but may reveal undue pain on sternal or tibial pressure if deficiency is severe. and clothing all effectively block UVB radiation – even in the summer. and impaired anytime the skies are polluted or cloudy. but they may indicate symptomatic vitamin D deficiency. For example.25(OH)2D levels to make the diagnosis of vitamin D deficiency will routinely miss it. when sufficient UVB only penetrates around solar noon. most practitioners assume vitamin D deficiency is asymptomatic. Even without physical signs or symptoms. and easy to dismiss. No Reprint Without Written Permission. once in the early spring for the nadir and once in the late summer for a peak level. regularly uses sunblock. lives at higher latitudes. autoimmune illness. and the obese face added risk. artificial UVB light. Number 1 2008 Vitamin D entire day during several wintertime months at latitudes above 35 degrees. vitamin D deficiency is more common the further poleward the population. is becomes an even longer period when the fall and late winter months are included.25 e aged may be wheelchair-bound secondary to vitamin D deficiency-induced myopathy.25(OH)2D serum levels but low 25(OH)D levels is vitamin D deficient despite high serum levels of the active hormone. or osteoporosis. wears excessive clothing.45 African-Americans. Practitioners who rely on serum 1. us. the “vitamin D winter” can extend for six months. thus obesity is a major risk factor for deficiency.52 but there are no interventional studies of its effects on cognition. or easy tiring may be symptoms of vitamin D deficiency. a patient with normal or high 1. A 25(OH)D level should be obtained at least twice yearly on any patient at risk. despite its sunny weather and subtropical latitude. yet they typically recover mobility after treatment. and vitamin D supplements. Diagnosis of Vitamin D Deficiency ree options exist for treatment of vitamin D deficiency: sunlight. erefore. Alternative Medicine Review Volume 13. An exposure of 10-15 minutes of fullbody summer noon-day sun or artificial UVB radiation (such as tanning beds) will input more than 10. One or two such exposures per week Treatment of Vitamin D Deficiency Page 12 Copyright © 2008 Thorne Research. which are often normal or even elevated in vitamin D deficiency.47 Body fat absorbs vitamin D.000 IU vitamin D per day improved the mood of endocrinology outpatients. chronic musculoskeletal pain. obese. Florida. has a fourmonth “vitamin D winter” centered around the winter solstice.25(OH)2D levels. osteomalacia. All Rights Reserved. Inc. Number 1 March 2008 . heart disease. A blinded intervention trial found 4. For example. the elderly. fatigue.

Alternative Medicine Review Volume 13. 10. Second.000. body fat. Inc. Number 1 2008 Review Article Cholecalciferol is available over-the-counter and via the Internet in 400. First. maintenance requirements are probably 50. Grey at al treated 21 vitamin D-deficient patients with 50. No Reprint Without Written Permission. an obese 150-kg adult may require up to 10. ose who choose UVB light for vitamin D repletion. Supplementation with 1. 1. Excessive > 100ng/mL should maintain 25(OH)D levels in an ideal range. and its consumption results in metabolic by-products not normally found in humans. However. 2.25 mg) capsules.000 IU per day will substantially raise low baseline levels but a similar dose will not increase higher baseline levels by a similar increment (that is.. 50. international units or IU. If such intermittent high doses of cholecalciferol are used. a normal weight.000 IU of vitamin D3 do not achieve natural 25(OH)D levels and such levels do not continue to rise after six months of such treatment. Ranges of Serum 25(OH)D Toxic > 150ng/mL 150ng/mL 100ng/mL 70ng/mL Ideal > 40-70ng/mL 40ng/mL Deficient < 40ng/mL 0ng/mL Author’s recommendations for serum 25(OH) vitamin D levels. 1.57 Blood levels rose from a mean of 11 ng/ mL at baseline to 30 ng/mL at six months and to 31 ng/ mL at one year. the amount of vitamin D needed varies with body weight. ird.000 IU per day will usually result in about a 10-ng/mL elevation of serum 25(OH)D when given over 3-4 months. Oral vitamin D treatment is more challenging than treatment with UVB light for several reasons.000 and (recently) 5.000 IU per day to achieve a level of 30 ng/mL in the absence of cutaneous UVB exposure.000 IU (25 mcg) per day for every 15 kg of body weight may be needed. One thousand IU of vitamin D sounds like a lot. i. they should understand that regular UV exposure ages the skin and increases the risk of nonmelanoma skin cancers.000 IU monthly for one year.000 IU cholecalciferol weekly for four weeks. toxicity is possible with oral supplementation – although it is extraordinarily rare. and 50.000 IU (1. e only prescription vitamin D preparation available in the United States is the vitamin D analogue ergocalciferol (vitamin D2). Number 1 March 2008 . erefore. ergocalciferol is not human vitamin D.Alternative Medicine Review Volume 13.e. it is only . unexpectedly high doses of vitamin D are usually needed to achieve adequate serum 25(OH)D levels. it may be a weaker agonist. indicating monthly doses of 50.025 mg or 25 micrograms. although such supplementation studies have not been done.54 It is also less effective than cholecalciferol in raising 25(OH) D levels. cholecalciferol. latitude. its kinetics are not linear. unlike sun exposure. Patients with serious diseases may need more if the metabolic clearance of 25(OH)D is increased (see below). All Rights Reserved. but adequacy should be assured by 25(OH)D blood levels. available as 50.000.000 IU every 1-2 weeks in most adults. Page 13 Copyright © 2008 Thorne Research.000 IU per day to achieve a 25(OH)D level of 50 ng/mL.. season. e treatment of choice for vitamin D deficiency is vitamin D. one mcg is 40 IU. from either sunlight or artificial sources. which is associated with malignant melanoma. input from diet and supplements of approximately 1. In the absence of significant UVB exposure. However.000 IU per day may not raise 30 ng/mL to 50 ng/mL). Furthermore.000 IU capsules. and sunning habits.56 Recently. Figure 5. it is not normally present in humans. also known as vitamin D3. i.000 IU capsules of vitamin D3 became available in retail outlets. 2. then 50. should avoid sunburn.55. skin color. healthy adult with an initial level of 10 ng/mL would generally require about 2.e. age. One of the problems with vitamin D terminology is the archaic method used to express dose.000. in fact.

and large amounts of body fat further increase requirements. e authors recommend parents supplement breast-fed infants with at least 800 IU of vitamin D daily.68 and animal evidence continues to accumulate that maternal vitamin D deficiency permanently injures fetal brains..000 IU of vitamin D per day. the more vitamin D will be required. erefore.000 IU per day are safe for children over the age of one.67 Patients on medications of any kind should have frequent testing of 25(OH)D levels when being treated with doses above 2.Alternative Medicine Review Volume 13.000 IU/day for more than six months to middle-age Canadian endocrinology outpatients resulted in average 25(OH)D levels of 44 ng/mL and produced no side effects other than improved mood.62 Furthermore.64 In general. Alternative Medicine Review Volume 13.23 Healthy adult men utilize up to 5. theophylline.000 IU or more per day. Page 14 Copyright © 2008 Thorne Research.000 IU per day. thin. but usually contains high amounts of vitamin A.66. Vitamin D deficiency in pregnancy is an ongoing epidemic.38. corticosteroids. glass of milk).39. large. Infants and toddlers may be at extremely high risk of deficiency during weaning. even in amounts consumed in multivitamins. Number 1 March 2008 . Number 1 2008 Vitamin D Cod liver oil contains a variable amount of vitamin D. erefore.000 IU capsules containing powdered vitamin D and dissolve the contents in juice or food for easy delivery to children and infants. up to 7.69 Pregnant women – or women thinking of becoming pregnant – should have 25(OH)D levels checked every three months and be adequately treated. cimetidine. obese.52 Heaney estimates 3. but widespread.g. if it is available. but will require adequate supplementation during and after weaning. or younger ones. 2.000-2. the obese require higher doses of oral supplements or UV radiation than lean individuals in order to obtain the same increases in 25(OH)D blood levels. Not only are baseline 25(OH)D levels lower in the obese. as outlined above. All Rights Reserved. often with 5. Loading doses of 50. erythromycins.g. the more a patient weighs. psychotropics. Around 12-18 months.63 e administration of 4. or at the most two. so older persons generally need higher supplemental doses than younger ones. dark-skinned. effectively prevent vitamin D deficiency. Advancing age impairs the skin’s ability to make vitamin D. 400 IU in a multivitamin).71 Infants being breast fed by supplementing mothers will not require additional supplementation. anti-tuberculosis agents. to assure breast milk is a rich source of vitamin D. Consumption of pre-formed retinols. Cytochrome P-450 enzymes are responsible for both the initial metabolism and subsequent catabolism of vitamin D. while formula fed infants need 400 IU per day. anticonvulsants. Neither the regular consumption of officially recommended amounts of vitamin D (e. Of the research done on drug/vitamin D interactions. or older patients often require higher maintenance doses than fairskinned. children who spend time in the sun without wearing sunblock will need little or none.. may be causing low-grade. Parents can easily open 1.59 and high retinol intake thwarts vitamin D’s protective effect on distal colorectal adenoma.000 IU daily year-round. small.58 Vitamin A antagonizes the action of vitamin D. while thiazide diuretics and statins increase 25(OH)D levels. 100 IU per 8 oz. Inc. bone toxicity. No Reprint Without Written Permission.70 Lactating women require even more. nor the regular consumption of vitamin D fortified foods (e.000 IU/day is required to assure that 97 percent of Americans obtain levels greater than 35 ng/mL.65 Fat malabsorption syndromes may increase oral requirements or necessitate the use of ultraviolet radiation. many stop drinking vitamin D-fortified infant formula and begin consuming unfortified juices.61. Toddlers and young children who do not get regular sun exposure should take 1. which – interestingly – is also the time many autistic children rapidly deteriorate. drugs dependent on cytochrome P-450 enzymes – and there are many – may affect vitamin D metabolism.000 IU/day for one year failed to achieve a 32 ng/mL target 25(OH)D concentration in 40 percent of 104 African-American women studied.25 mg) of cholecalciferol per day for a week. In the summer. keeping in mind that current Food and Nutrition Board recommendations state doses up to 2. are safe to use before beginning maintenance therapy. and orlistat may lower 25(OH)D levels.60 e authors do not recommend cod liver oil. depending on body weight.000 IU per day. and even grapefruit juice – have on the metabolism of vitamin D is an area awaiting further research.000 IU (1. What clinically relevant interactions these substances – including cardiac drugs.

such doses flirt with toxicity. it is reasonable to hypothesize a general cancer treatment effect. there is an anecdotal report that pharmacological doses of vitamin D are effective in treating – not just preventing – viral respiratory infections.000 IU of vitamin D is not only safe. meningococcal disease. but the ideal dose is not. non-small-cell lung cancer patients found those with the highest vitamin D input had double the five-year recurrence-free survival and much better overall survival than those with the lowest. 12 patients in active phases of multiple sclerosis were treated with progressively increasing weekly doses of vitamin D3 (the equivalent of starting with 4.88 Although no one has proven vitamin D causes this summer-season treatment effect. simply to prevent wintertime vitamin D deficiency. Practitioners who treat type-2 diabetic or hypertensive patients with physiological doses of vitamin D should be prepared for the possibility of either hypoglycemia or hypotension. there was no evidence of toxicity in young men taking 50. For example. i. untreated vitamin D deficiency in non-small-cell lung cancer patients is a risk factor for early death. Number 1 2008 Review Article Treatment of Disease dramatically increased production of AMPs by vitamin D and the broad spectrum of action of AMP make it reasonable to hypothesize that pharmacological doses of vitamin D are effective adjuvants in treating a large number of infections.03) at the end of the study. or inferred from vitamin D’s mechanism of action.e. a study of recurrencefree survival in early-stage.77 Treatment of colds and influenza with pharmacological doses of vitamin D may only be the tip of the infectious disease iceberg. from open trials..82-84 raising the possibility that pharmacological doses of vitamin D would be an effective adjuvant treatment. i. when aberrant cells are more likely to retain both the vitamin D receptor and the enzyme needed to activate vitamin D.000 IU per day) and calcium.000 IU per day may cause toxicity if given for longer periods.86 is strongly implies a vitamin D treatment effect.000 IU per day may well have achieved the same result without the risk of toxicity.74 Indeed.12 it is intriguing that vitamin D-sensitive antimicrobial peptides (AMP) inhibit the HIV virus and there is evidence that vitamin D plays a role in HIV.000 IU per day and increasing to 40. certainly. especially after several months By far the most common reason to treat with vitamin D is osteoporosis. For example.Alternative Medicine Review Volume 13. and group A streptococcal disease are more common when vitamin D levels are lowest (winter)79-81 and all three bacteria are sensitive to AMP.. doses of 40. Doses of 10.87. 50. with no evidence of toxicity.83 (p=0. implied by epidemiological studies. cancer patients live longer if the diagnosis is made in the summer rather than the winter.000 IU (15 mg) vitamin D raised 25(OH)D levels from 2 ng/ mL to 22 ng/mL at two weeks and to 27 ng/mL at six weeks in 10 elderly subjects.75 at the beginning to a mean of 0.78 Invasive pneumococcal disease.85 Mean serum concentrations of 25(OH)D initially were 31 ng/mL and rose to a mean of 154 ng/mL at the end of 28 weeks. but the dose needed remains controversial because the lowest effective dose (800 IU/ day) is known. the Page 15 Copyright © 2008 Thorne Research. single injections of 600.000 IU/day for 10 days showed no evidence of toxicity and only raised 25(OH)D levels by an average of 5 ng/mL three months after administration. a single injection of 600. In no patient did levels increase more than 11 ng/mL at three months. As Aloia and Li-Ng have pointed out. vitamin D’s anticancer mechanism of action is basic to all cancers. For example. Season of diagnosis has a survival effect on numerous cancers. In fact.000 IU per day for three days for a 100-kg adult) may seem excessive to those unfamiliar with vitamin D’s pharmacology and toxicity. In a recent report.000 IU/kg body weight for three days (200. such doses were recently recommended in the autumn for the elderly. e number of MS lesions per patient on brain scan decreased from an initial mean of 1. Both epidemiological evidence and vitamin D’s mechanism of action suggest it may have a treatment effect in early cancer.e. Alternative Medicine Review Volume 13.76 In 32 severely vitamin D-deficient elderly patients. virtually all of the evidence that vitamin D is an effective adjuvant for the treatment of other serious medical conditions is anecdotal.72 Currently.000 IU of vitamin D per day for six weeks (although such a dose would become toxic if taken over a longer period).73 Doses of 2. Inc. with no abnormalities in serum or urine calcium detected in the 12 subjects. Number 1 March 2008 . In fact. However. us. No Reprint Without Written Permission. such doses are common in many parts of the world simply to prevent or treat vitamin D deficiency. All Rights Reserved. at least in cancer’s early stages.75 Likewise.

000 IU/day be the Upper Limit for both a 10-kg child and a 150-kg adult? Although a 2. HIV. the vast majority of such patients probably expire severely vitamin D deficient. or hepatitis B) patients be treated with vitamin D?” e better question is. Should either hypoglycemia or hypotension occur. “Should cancer (or multiple sclerosis. dosing errors.000 IU per day for many months or even years. Inc. the FNB’s Upper Limit for both one-year-old children and forty-year-old adults is 2. a patient with cancer may require significantly higher doses of vitamin D to maintain 25(OH)D levels of 55-70 ng/ mL than a healthy adult of similar weight and body fat. 48 percent of cancer patients in Boston had levels less than 20 ng/mL. For example. and do not apply to medically supervised treatment. patients with diabetes. the current 2. In order to produce hypercalcemia.000-IU Upper Limit is probably appropriate for infants and young children. and such treatment should be adjunctive and never take the place of standard treatment. and 2. or cancer may rapidly use 25(OH)D as substrate to make large amounts of 1. such a limit in older children. Vitamin D toxicity is exceedingly rare and few practitioners ever see it. and virtually none had natural levels. the diabetic and/or hypertensive medication should be lowered. a limit based on old and faulty literature.91 us. erefore. virtually all the reported cases of hypercalcemia are from faulty industrial production.89 Even at the end of summer. and adults has the effect of both limiting effective treatment of vitamin D deficiency and impairing dose-appropriate interventional research. how can 200 IU/day be the adequate intake for both a 3-kg infant and a 60-kg pregnant woman. “Should practitioners routinely screen and aggressively treat vitamin D deficiency in patients with serious or potentially fatal illnesses. Although modern science knows little or nothing about the metabolic clearance of vitamin D in different disease states. 72 percent of 60 cancer patients had 25(OH)D levels less than 30 ng/mL. the literature contains few cases of cholecalciferol toxicity from supplement use.92 although that could change with the recent availability of 50.Alternative Medicine Review Volume 13.89 In another study. Credible evidence of vitamin D toxicity in those chronically consuming 10. Number 1 March 2008 .93 e current official recommendations are illogical. most adults would have to take in excess of 10.000 IU or more per day. or should such patients combat their disease vitamin D deficient?” As referenced above. although blood sugars may worsen for several weeks after initiation or increase of vitamin D. e authors believe that those who claim the lack of RCTs showing vitamin D’s effectiveness as adjuvant cancer treatment means it should never be so used miss an important point. Frequent monitoring of 25(OH)D and calcium levels should guide dosing in patients with cancer and other serious illnesses. e current Adequate Intakes and Upper Limits are for medically unsupervised intake by adults and children. cardiac. it is reasonable to predict that vitamin D is cleared more rapidly in some disease states. for example. All Rights Reserved. especially the kidneys. In fact. Surprisingly. and patients treated medically with pharmacological doses of ergocalciferol. HIV. labeling errors. No Reprint Without Written Permission. However.000 IU capsules. For example. adolescents.000-IU per day Upper Limit does not impair a practitioner’s ability to Page 16 Vitamin D Toxicity Copyright © 2008 Thorne Research. Alternative Medicine Review Volume 13. Chronic vitamin D toxicity results when hypercalcemia goes undetected and calcifies internal organs. set by the Institute of Medicine’s Food and Nutrition Board (FNB) in 1997. Most patients with vitamin D toxicity recover fully by simply stopping the vitamin D and practicing strict sun-avoidance. eoretically. septic. even if it means taking 10. not the vitamin D. Such levels must be associated with hypercalcemia in order to indict vitamin D. the FNB says Adequate Intake is the same 200 IU/day for the smallest infant as it is for the largest pregnant woman.000 IU of supplemental cholecalciferol daily is absent in the literature. Likewise.25(OH)2D to fight their disease. Practitioners should supplement such patients (assuming they are not hypercalcemic) to high natural levels. In chronic toxicity. recent studies show a high incidence of vitamin D deficiency in patients undergoing treatment for cancer.90 A 1998 study of inpatients at Massachusetts General Hospital found 57 percent had 25(OH)D levels less than 15 ng/mL. such doses of vitamin D should eventually lower both blood sugar and blood pressure. Toxicity is secondary to the unbridled effects of hypercalcemia.000 IU/day. Number 1 2008 Vitamin D of treatment. first urine calcium and then serum calcium will begin to gradually increase when 25(OH)D levels exceed some level above 150 ng/mL. the question should not be.

25(OH)D. Treatment with sunlight or artificial UVB radiation is simple but increases the risk of non-melanoma skin cancers and ages the skin. and 1. and in some cancers (especially non-Hodgkin’s lymphoma and oat cell carcinoma of the lung). No Reprint Without Written Permission. liver disease is not a contraindication to treatment of deficiency. but to the surprisingly high oral dose required to achieve and maintain adequate serum 25(OH)D levels. Vitamin D. as physiological doses of vitamin D. especially if patients are on other medications. Although the liver initially metabolizes vitamin D.Alternative Medicine Review Volume 13. phenothiazines. sunlight. e practitioner should carefully evaluate any hypercalcemic patient for the cause of hypercalcemia. are contraindications to excessive UV exposure. Understanding vitamin D’s physiology and having a high index of suspicion are keys to determining the diagnosis. Practitioners who use doses above 2. Adequate oral supplementation will require doses that might make a practitioner initially uncomfortable. Such conditions may be unmasked by vitamin D treatment. anemia. hyperbilirubinemia.94 Nevertheless. Once the cause is clear. with frequent monitoring of clinical condition. especially in the fall and winter. Treatment of vitamin D deficiency in otherwise healthy patients must be individualized due to the numerous factors affecting 25(OH)D levels. All Rights Reserved. xeroderma pigmentosum. sarcoidosis may become clinically evident after summer sun exposure. although a recent study found reduced mortality in melanoma patients who continued exposure to sunlight.000 IU/day for the morbidly obese.000 IU per day should periodically monitor serum 25(OH)D levels. Number 1 March 2008 . as well as various photosensitizers (sulfonamides. especially in large doses. Serum 25(OH)D levels less than 40 ng/mL are seldom found in those living in a sun-rich environment and such levels are needed to assure normalization of the pharmacokinetics of vitamin D. Sunburn increases the risk of malignant melanoma. and artificial UVB radiation. Contraindications to sunlight or artificial UV radiation include a number of dermatological conditions (porphyrias.96 Vitamin D hypersensitivity syndromes – often confused with vitamin D toxicity – occur when extrarenal tissues produce 1. Inc. especially cutaneous melanoma. especially internal Summary Page 17 Copyright © 2008 Thorne Research. albinism).95 A recent study of patients with advanced noncholestatic chronic liver disease recommended treatment of concomitant vitamin D deficiency after finding serum 25(OH)D levels of less than 10 ng/mL predicted coagulopathy. in the absence of sun exposure.25(OH)2D in an unregulated ese syndromes manner.25(OH)2D (elevated). are diagnosed by measuring serum calcium (elevated). probably range between 400 IU/day for premature infants to 10. and 1. erefore. and doses should be adequate to maintain serum 25(OH)D levels between 40-70 ng/mL.97 Absolute and Relative Contraindications to Treatment Vitamin D deficiency is endemic and is associated with numerous diseases. Patients with chronic diseases associated with vitamin D deficiency. 25(OH)D (normal or low). although no reports in the literature were found of acute allergic reactions to vitamin D supplements. Vitamin D hypersensitivity syndromes can occur in some of the granulomatous diseases (especially sarcoidosis and tuberculosis). Alternative Medicine Review Volume 13. hypoalbuminemia. Previous skin cancers. causing hypercalcemia. Number 1 2008 Review Article treat vitamin D deficiency with higher doses just as the comparable Upper Limit for calcium does not impair the practitioner’s ability to treat hypocalcemia with calcium doses above the Upper Limit once hypocalcemia is properly diagnosed.25(OH)2D. tetracyclines. Periodic monitoring will also educate the practitioner not only to the safety of supplementation. hypercalcemia is a relative contraindication to vitamin D. urine and serum calcium. could theoretically precipitate a worsening clinical course in such patients. for example. psoralens). should the practitioner decide to treat concomitant vitamin D deficiency – despite the hypercalcemia – it should only be if the hypercalcemia is mild to moderate (<12 mg/dL) and should proceed cautiously. and thrombocytopenia. oral treatment is recommended for patients who have had any type of skin cancer. e liver conserves the ability to hydroxylate vitamin D despite advanced liver disease. e only absolute contraindication to vitamin D supplementation is vitamin D toxicity or allergy to vitamin D.

84:18-28. total mortality: a meta-analysis of randomized controlled trials. Dietrich T. Caution is required in any patient with hypercalcemia. What is the optimal vitamin D status for health? Prog Biophys Mol Biol 2006. Binkley NC. et al.78:912-919. et al. 2005:995-1015. Cannell JJ. including fortification strategies. Dowell MS. Heaney RP. Peterlik M. Autier P. Am J Cardiol 2007. Page 18 Copyright © 2008 Thorne Research. Hale CA. Cannell JJ. et al. Vitamin D insufficiency in a population of healthy western Canadians. Peterlik M. Reunanen A. et al. Perez-Castrillon JL. J Steroid Biochem Mol Biol 2005. Laara E. Allan JA. Maamer M. Travers-Gustafson D. Slatopolsky E. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D.120:1031-1035.81:353-373. 31. Chapuy MC. Vieth R.103:631-634. Briel M. 7. Bischoff-Ferrari HA. 8. Vitamin D. Number 1 2008 Vitamin D cancers. Vega G. Am J Clin Nutr 2003. Gandini S. Med Hypotheses 2007.103:708-711. Vitamin D.289:F8-F28. 17. Diagnosis and treatment of vitamin D deficiency. 30. CMAJ 2002. et al. 55-70 ng/mL. 18. J Steroid Biochem Mol Biol 2007. 35. e vitamin D requirement in health and disease. Heaney RP. 32. Pike JW. Epidemic influenza and vitamin D. Gordon CM. In: Feldman D. Are national vitamin D guidelines sufficient to maintain adequate blood levels in children? Can J Public Health 2005. Drezner MK. 22. Eur J Clin Invest 2005. Am J Physiol Renal Physiol 2005. e use of short-term pharmacological doses of vitamin D as treatment for the common cold or flu – 2.97:13-19. Autism and vitamin D. J Am Coll Nutr 2003. 13. Vitamin D deficiency. Outila TA. Heaney RP. Epidemiol Infect 2006. 23. 33. Karkkainen MU.35:290-304. Barger-Lux MJ.9:107-118. et al. Am J Clin Nutr 2004. Gorham ED. et al. Willett WC. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.85:1586-1591. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. author reply 1097-1098.103:635-641.92:26-32. Vitamin D and calcium deficits predispose for multiple chronic diseases. et al. 19. 12. Hypponen E. Lips P. Giovannucci E. Prevalence of vitamin D insufficiency in an adult normal population.135:1095-1096.166:1517-1524. CA: Elsevier. Li-Ng M.87:4952-4956. Anticancer Res 2006. Arch Intern Med 2007. 6. High prevalence of vitamin D inadequacy and implications for health. 29. 20. Davies KM. should be supplemented with doses adequate to maintain 25(OH)D levels in the higher normal range. Expert Opin Pharmacother 2008.92:4-8. Am J Clin Nutr 2006. Martz P. Aloia JF. Cross HS. Sunlight and vitamin D for bone health and prevention of autoimmune diseases. Am J Clin Nutr 2004. Lancet 2001. Cannell JJ. Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and calcium absorption. J Clin Endocrinol Metab 2002. 5. No Reprint Without Written Permission.80:1678S-1688S. Number 1 March 2008 . Circulating vitamin D3 and 25-hydroxyvitamin D in humans: an important tool to define adequate nutritional vitamin D status.96:443-449. 34. Arch Intern Med 2005. 11. References 1. Prevalence of vitamin D deficiency among healthy adolescents. Orav EJ.167:1730-1737. Lamberg-Allardt CJ. Cross HS. Mohr SB. Weiss ST. Am J Clin Nutr 2007. Is vitamin D deficiency to blame for the asthma epidemic? J Allergy Clin Immunol 2007. Vitamin D physiology. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 2003. Dysfunction of the vitamin D endocrine system as common cause for multiple malignant and other chronic diseases. Dusso AS. Glorieux FH. Long-latency deficiency disease: insights from calcium and vitamin D. Heaney RP: e case for improving vitamin D status. Prog Biophys Mol Biol 2006. Oct 24 [Epub ahead of print] Litonjua AA. Am J Cardiol 2007. and cardiovascular disease. 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