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facing page). Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism. During exposure to solar ultraviolet B (UVB) radiation, 7-dehydrocholesterol in the skin is converted to previtamin D 3 , which is immediately converted to vitamin D 3 in a heat-dependent process. Excessive exposure to sunlight degrades previtamin D 3 and vitamin D 3 into inactive photoproducts. Vitamin D 2 and vitamin D 3 from dietary sources are incorporated into chylomicrons and transported by the lymphatic system into the venous circulation. Vitamin D (hereafter "D" represents D 2 or D 3 ) made in the skin or ingested in the diet can be stored in and then released from fat cells. Vitamin D in the circulation is bound to the vitamin D-binding protein, which transports it to the liver, where vitamin D is converted by vitamin D-25-hydroxylase to 25-hydroxyvitamin D [25(OH)D]. This is the major circulating form of vitamin D that is used by clinicians to determine vitamin D status. (Although most laboratories report the normal range to be 20 to 100 ng per milliliter [50 to 250 nmol per liter], the preferred range is 30 to 60 ng per milliliter [75 to 150 nmol per liter].) This form of vitamin D is biologically inactive and must be converted in the kidneys by 25-hydroxyvitamin D-1αhydroxylase (1-OHase) to the biologically active form1,25-dihydroxyvitamin D [1,25(OH) 2 D]. Serum phosphorus, calcium, fibroblast growth factor 23 (FGF-23), and other factors can either increase (+) or decrease (-) the renal production of 1,25(OH) 2 D. 1,25(OH) 2 D decreases its own synthesis through negative feedback and decreases the synthesis and secretion of parathyroid hormone by the parathyroid glands. 1,25(OH) 2 D increases the expression of 25-hydroxyvitamin D-24hydroxylase (24-OHase) to catabolize 1,25(OH) 2 D to the water-soluble, biologically inactive calcitroic acid, which is excreted in the bile. 1,25(OH) 2 D enhances intestinal calcium absorption in the small intestine by interacting with the vitamin D receptor-retinoic acid x-receptor complex (VDR-RXR) to enhance the expression of the epithelial calcium channel (transient receptor potential cation channel, subfamily V, member 6 [TRPV6]) and calbindin 9K, a calcium-binding protein (CaBP). 1,25(OH) 2 D is recognized by its receptor in osteoblasts, causing an increase in the expression of the receptor activator of nuclear factor-κB ligand (RANKL). RANK, the receptor for RANKL on preosteoclasts, binds RANKL, which induces preosteoclasts to become mature osteoclasts. Mature osteoclasts remove calcium and phosphorus from the bone, maintaining calcium and phosphorus levels in the blood. Adequate calcium (Ca 2+ ) and phosphorus (HPO 4 2− ) levels promote the mineralization of the skeleton.
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T h e
n e w e n gl a n d j o u r n a l
o f
m e d i c i n e
n engl j med 357;3 www.nejm.org july 19, 2007
266
Medical Progress
Vitamin D Deficiency
Michael F. Holick, M.D., Ph.D.
From the Department of Medicine, Sec-
tion of Endocrinology, Nutrition, and Di-
abetes, the Vitamin D, Skin, and Bone
Research Laboratory, Boston University
Medical Center, Boston. Address reprint
requests to Dr. Holick at Boston University
School of Medicine, 715 Albany St., M-1013,
Boston, MA 02118, or at mfholick@bu.edu.
N Engl J Med 2007;357:266-81.
Copyright © 2007 Massachusetts Medical Society.
O
nce foods were fortified with vitamin d and rickets appeared
to have been conquered, many health care professionals thought the major
health problems resulting from vitamin D deficiency had been resolved. How-
ever, rickets can be considered the tip of the vitamin Ddeficiency iceberg. In fact,
vitamin D deficiency remains common in children and adults. In utero and during
childhood, vitamin D deficiency can cause growth retardation and skeletal deformi-
ties and may increase the risk of hip fracture later in life. Vitamin D deficiency in adults
can precipitate or exacerbate osteopenia and osteoporosis, cause osteomalacia and
muscle weakness, and increase the risk of fracture.
The discovery that most tissues and cells in the body have a vitamin D receptor and
that several possess the enzymatic machinery to convert the primary circulating form
of vitamin D, 25-hydroxyvitamin D, to the active form, 1,25-dihydroxyvitamin D, has
provided new insights into the function of this vitamin. Of great interest is the role
it can play in decreasing the risk of many chronic illnesses, including common can-
cers, autoimmune diseases, infectious diseases, and cardiovascular disease. In this
review I consider the nature of vitamin D deficiency, discuss its role in skeletal and
nonskeletal health, and suggest strategies for its prevention and treatment.
S ourc e s a nd Me t a b ol ism of V i t a m i n D
Humans get vitamin D from exposure to sunlight, from their diet, and from dietary
supplements.
1-4
A diet high in oily fish prevents vitamin D deficiency.
3
Solar ultravio-
let B radiation (wavelength, 290 to 315 nm) penetrates the skin and converts 7-dehy-
drocholesterol to previtamin D
3
, which is rapidly converted to vitamin D
3
(Fig. 1).
1
Because any excess previtamin D
3
or vitamin D
3
is destroyed by sunlight (Fig. 1), ex-
cessive exposure to sunlight does not cause vitamin D
3
intoxication.
2
Few foods naturally contain or are fortified with vitamin D. The “Drepresents
D
2
or D
3
(
Fig. 1
). Vitamin D
2
is manufactured through the ultraviolet irradiation
of ergosterol from yeast, and vitamin D
3
through the ultraviolet irradiation of 7-dehy-
drocholesterol from lanolin. Both are used in over-the-counter vitamin D supplements,
but the form available by prescription in the United States is vitamin D
2
.
Vitamin D from the skin and diet is metabolized in the liver to 25-hydroxyvitamin
D (Fig. 1), which is used to determine a patient’s vitamin D status
1-4
; 25-hydroxyvi-
tamin D is metabolized in the kidneys by the enzyme 25-hydroxyvitamin D--
hydroxylase (CYP27B1) to its active form, 1,25-dihydroxyvitamin D.
1-4
The renal pro-
duction of 1,25-dihydroxyvitamin D is tightly regulated by plasma parathyroid
hormone levels and serum calcium and phosphorus levels.
1-4
Fibroblast growth fac-
tor 23, secreted from the bone, causes the sodium–phosphate cotransporter to be
internalized by the cells of the kidney and small intestine and also suppresses
1,25-dihydroxyvitamin D synthesis.
5
The efficiency of the absorption of renal calcium
and of intestinal calcium and phosphorus is increased in the presence of 1,25-dihy-
medic al progr ess
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267
droxyvitamin D (Fig. 1).
2,3,6
It also induces the
expression of the enzyme 25-hydroxyvitamin
D-24-hydroxylase (CYP24), which catabolizes both
25-hydroxyvitamin D and 1,25-dihydroxyvita-
min D into biologically inactive, water-soluble
calcitroic acid.
2-4
De f i ni t ion a n d Pr e va l e nc e
of V i t a m in D De f ic i e nc y
Although there is no consensus on optimal levels
of 25-hydroxyvitamin D as measured in serum, vi-
tamin D deficiency is defined by most experts as
a 25-hydroxyvitamin D level of less than 20 ng per
milliliter (50 nmol per liter).
7-10
25-Hydroxyvita-
min D levels are inversely associated with parathy-
roid hormone levels until the former reach 30 to
40 ng per milliliter (75 to 100 nmol per liter), at
which point parathyroid hormone levels begin to
level off (at their nadir).
10-12
Furthermore, intes-
tinal calcium transport increased by 45 to 65% in
women when 25-hydroxyvitamin D levels were in-
creased from an average of 20 to 32 ng per milli-
liter (50 to 80 nmol per liter).
13
Given such data,
a level of 25-hydroxyvitamin D of 21 to 29 ng per
milliliter (52 to 72 nmol per liter) can be considered
to indicate a relative insufficiency of vitamin D,
and a level of 30 ng per milliliter or greater can be
considered to indicate sufficient vitamin D.
14
Vi-
tamin D intoxication is observed when serum lev-
els of 25-hydroxyvitamin D are greater than 150 ng
per milliliter (374 nmol per liter).
With the use of such definitions, it has been
estimated that 1 billion people worldwide have vi-
tamin D deficiency or insufficiency.
7-12,15-22
Ac-
cording to several studies, 40 to 100% of U.S. and
European elderly men and women still living in
the community (not in nursing homes) are defi-
cient in vitamin D.
7-12,15-22
More than 50% of
postmenopausal women taking medication for
osteoporosis had suboptimal levels of 25-hydroxyvi-
tamin D — below 30 ng per milliliter (75 nmol
per liter).
12,22
Children and young adults are also potentially
at high risk for vitamin D deficiency. For example,
52% of Hispanic and black adolescents in a study
in Boston
23
and 48% of white preadolescent girls
in a study in Maine
24
had 25-hydroxyvitamin D
levels below 20 ng per milliliter. In other studies,
at the end of the winter, 42% of 15- to 49-year-old
black girls and women throughout the United
States had 25-hydroxyvitamin D levels below 20 ng
per milliliter,
25
and 32% of healthy students, phy-
sicians, and residents at a Boston hospital were
found to be vitamin Ddeficient, despite drink-
ing a glass of milk and taking a multivitamin
daily and eating salmon at least once a week.
26
In Europe, where very few foods are fortified
with vitamin D, children and adults would appear
to be at especially high risk.
1,7,11,16-22
People living
near the equator who are exposed to sunlight
without sun protection have robust levels of 25-
hydroxyvitamin D above 30 ng per milliliter.
27,28
However, even in the sunniest areas, vitamin D
deficiency is common when most of the skin is
shielded from the sun. In studies in Saudi Arabia,
the United Arab Emirates, Australia, Turkey, India,
and Lebanon, 30 to 50% of children and adults had
25-hydroxyvitamin D levels under 20 ng per mil-
liliter.
29-32
Also at risk were pregnant and lactat-
ing women who were thought to be immune to
vitamin D deficiency since they took a daily prena-
tal multivitamin containing 400 IU of vitamin D
(70% took a prenatal vitamin, 90% ate fish, and
93% drank approximately 2.3 glasses of milk per
day)
33-35
; 73% of the women and 80% of their
infants were vitamin Ddeficient (25-hydroxyvi-
tamin D level, <20 ng per milliliter) at the time
of birth.
34
C a l c ium , Pho sph or us,
a n d B on e M e t a b ol ism
Without vitamin D, only 10 to 15% of dietary cal-
cium and about 60% of phosphorus is absorbed.
2-4
The interaction of 1,25-dihydroxyvitamin D with
the vitamin D receptor increases the efficiency of
intestinal calcium absorption to 30 to 40% and
phosphorus absorption to approximately 80%
(Fig. 1).
2-4,13
In one study, serum levels of 25-hydroxyvita-
min D were directly related to bone mineral den-
sity in white, black, and Mexican-American men
and women, with a maximum density achieved
when the 25-hydroxyvitamin D level reached 40 ng
per milliliter or more.
8
When the level was 30 ng
per milliliter or less, there was a significant de-
crease in intestinal calcium absorption
13
that was
associated with increased parathyroid hormone.
10-12
Parathyroid hormone enhances the tubular reab-
sorption of calcium and stimulates the kidneys to
produce 1,25-dihydroxyvitamin D.
2-4,6
Parathyroid
hormone also activates osteoblasts, which stimu-
late the transformation of preosteoclasts into ma-
ture osteoclasts (Fig. 1).
1-3
Osteoclasts dissolve the
mineralized collagen matrix in bone, causing os-
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268
teopenia and osteoporosis and increasing the risk
of fracture.
7,8,11,16-21
Deficiencies of calcium and vitamin D in utero
and in childhood may prevent the maximum de-
position of calcium in the skeleton.
36
As vita-
min D deficiency progresses, the parathyroid
glands are maximally stimulated, causing sec-
ondary hyperparathyroidism.
7,9-12
Hypomagnese-
mia blunts this response, which means that para-
thyroid hormone levels are often normal when
25-hydroxyvitamin D levels fall below 20 ng per
milliliter.
37
Parathyroid hormone increases the
metabolism of 25-hydroxyvitamin D to 1,25-dihy-
droxyvitamin D, which further exacerbates the
vitamin D deficiency. Parathyroid hormone also
causes phosphaturia, resulting in a low-normal or
low serum phosphorus level. Without an adequate
calcium–phosphorus product (the value for calci-
um times the value for serum phosphorus), min-
eralization of the collagen matrix is diminished,
leading to classic signs of rickets in children
1,28
and osteomalacia in adults.
7,38
Whereas osteoporosis is unassociated with bone
pain, osteomalacia has been associated with iso-
lated or generalized bone pain.
39,40
The cause is
thought to be hydration of the demineralized gela-
tin matrix beneath the periosteum; the hydrated
matrix pushes outward on the periosteum, causing
throbbing, aching pain.
7
Osteomalacia can often
be diagnosed by using moderate force to press the
thumb on the sternum or anterior tibia, which can
elicit bone pain.
7,40
One study showed that 93%
of persons 10 to 65 years of age who were ad-
mitted to a hospital emergency department with
muscle aches and bone pain and who had a wide
variety of diagnoses, including fibromyalgia,
chronic fatigue syndrome, and depression, were
deficient in vitamin D.
41
O s t e oporosi s a nd Fr ac t u r e
Approximately 33% of women 60 to 70 years of age
and 66% of those 80 years of age or older have
osteoporosis.
16,20
It is estimated that 47% of wom-
en and 22% of men 50 years of age or older will
sustain an osteoporotic fracture in their remain-
ing lifetime. Chapuy et al.
21
reported that among
3270 elderly French women given 1200 mg of cal-
cium and 800 IU of vitamin D
3
daily for 3 years,
the risk of hip fracture was reduced by 43%, and
the risk of nonvertebral fracture by 32%. A 58%
reduction in nonvertebral fractures was observed
in 389 men and women over the age of 65 years
who were receiving 700 IU of vitamin D
3
and 500
mg of calcium per day.
42
A meta-analysis of seven randomized clinical
Figure 1 (facing page). Synthesis and Metabolism
of Vitamin D in the Regulation of Calcium, Phosphorus,
and Bone Metabolism.
During exposure to solar ultraviolet B (UVB) radiation,
7-dehydrocholesterol in the skin is converted to pre-
vitamin D
3
, which is immediately converted to vitamin
D
3
in a heat-dependent process. Excessive exposure to
sunlight degrades previtamin D
3
and vitamin D
3
into
inactive photoproducts. Vitamin D
2
and vitamin D
3
from dietary sources are incorporated into chylomi-
crons and transported by the lymphatic system into
the venous circulation. Vitamin D (hereafter “D” repre-
sents D
2
or D
3
) made in the skin or ingested in the diet
can be stored in and then released from fat cells. Vita-
min D in the circulation is bound to the vitamin Dbind-
ing protein, which transports it to the liver, where vita-
min D is converted by vitamin D-25-hydroxylase to
25-hydroxyvitamin D [25(OH)D]. This is the major cir-
culating form of vitamin D that is used by clinicians to
determine vitamin D status. (Although most laborato-
ries report the normal range to be 20 to 100 ng per
milliliter [50 to 250 nmol per liter], the preferred range
is 30 to 60 ng per milliliter [75 to 150 nmol per liter].)
This form of vitamin D is biologically inactive and must
be converted in the kidneys by 25-hydroxyvitamin D-1α-
hydroxylase (1-OHase) to the biologically active form —
1,25-dihydroxyvitamin D [1,25(OH)
2
D]. Serum phos-
phorus, calcium, fibroblast growth factor 23 (FGF-23),
and other factors can either increase (+) or decrease (–)
the renal production of 1,25(OH)
2
D. 1,25(OH)
2
D de-
creases its own synthesis through negative feedback
and decreases the synthesis and secretion of parathy-
roid hormone by the parathyroid glands. 1,25(OH)
2
D
increases the expression of 25-hydroxyvitamin D-24-
hydroxylase (24-OHase) to catabolize 1,25(OH)
2
D to
the water-soluble, biologically inactive calcitroic acid,
which is excreted in the bile. 1,25(OH)
2
D enhances in-
testinal calcium absorption in the small intestine by in-
teracting with the vitamin D receptor–retinoic acid
x-receptor complex (VDR-RXR) to enhance the expres-
sion of the epithelial calcium channel (transient recep-
tor potential cation channel, subfamily V, member 6
[TRPV6]) and calbindin 9K, a calcium-binding protein
(CaBP). 1,25(OH)
2
D is recognized by its receptor in os-
teoblasts, causing an increase in the expression of the
receptor activator of nuclear factor-κB ligand (RANKL).
RANK, the receptor for RANKL on preosteoclasts,
binds RANKL, which induces preosteoclasts to be-
come mature osteoclasts. Mature osteoclasts remove
calcium and phosphorus from the bone, maintaining
calcium and phosphorus levels in the blood. Adequate
calcium (Ca
2+
) and phosphorus (HPO
4
2−
) levels pro-
mote the mineralization of the skeleton.
medic al progr ess
n engl j med 357;3 www.nejm.org july 19, 2007
269
1
Ingelfinger
06/28/07
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully
Author
Fig #
Title
ME
DE
Artist
Issue date
COLOR FIGURE
Draft 13
Holick
KMK
Vitamin D Deficiency
7/19/07
Koopman
Skin
Solar UVB radiation
Previtamin D
3
Heat
Vitamin D
Vitamin D
3
Inactive photoproducts
Vitamin D
2
Diet
Vitamin D-25-hydroxylase
Liver
25(OH)D
1-OHase
Phophorus, calcium,
FGF-23, and other factors +/–
Preosteoclast
RANKL
RANK
Osteoblast
Parathyroid
hormone
Fat cell
Parathyroid glands
Osteoclast
Blood calcium and phosphorus
Ca
2
+
and HPO
4
2
Absorption
Calcification
Intestine
Calcitroic
acid
Bile
Excreted
24-OHase
1,25(OH)
2
D
TRPV6
>150 ng/ml
(major circulating metabolite)
7-Dehydrocholesterol
Chylomicrons
Solar UVB radiation
Kidneys
Ca
2
+
and HPO
4
2
Reference range
20–100 ng/ml
1,25(OH)
2
D
Intoxication
<20 ng/ml
Deficiency
Preferred range
30–60 ng/ml
CaBP
_
_
(290–315 nm)
Circulation
Circulation
Bone
VDR–RXR
VDR–RXR
Calcium
Solar
UVB radiat
io
n
+
+
Calcium Absorption
Calcium Resorption
Vitamin D
3
CH
3
HO
CH
2
HO
CH
2
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m e d i c i n e
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270
trials that evaluated the risk of fracture in older
persons given 400 IU of vitamin D
3
per day re-
vealed little benefit with respect to the risk of ei-
ther nonvertebral or hip fractures (pooled relative
risk of hip fracture, 1.15; 95% confidence interval
[CI], 0.88 to 1.50; pooled relative risk of nonverte-
bral fracture, 1.03; 95% CI, 0.86 to 1.24). In stud-
ies using doses of 700 to 800 IU of vitamin D
3
per
day, the relative risk of hip fracture was reduced
by 26% (pooled relative risk, 0.74; 95% CI, 0.61 to
0.88), and the relative risk of nonvertebral fracture
by 23% (pooled relative risk, 0.77; 95% CI, 0.68 to
0.87) with vitamin D
3
as compared with calcium
or placebo.
8
A Womens Health Initiative study that
compared the effects of 400 IU of vitamin D
3
plus
1000 mg of calcium per day with placebo in more
than 36,000 postmenopausal women confirmed
these results, reporting an increased risk of kidney
stones but no benefit with respect to the risk of hip
fracture.
The Women’s Health Initiative study also
showed that serum levels of 25-hydroxyvitamin D
had little effect on the risk of fracture when levels
were 26 ng per milliliter (65 nmol per liter) or
less. However, women who were most consistent
in taking calcium and vitamin D
3
had a 29%
reduction in hip fracture.
43
Optimal prevention
of both nonvertebral and hip fracture occurred
only in trials providing 700 to 800 IU of vitamin
D
3
per day in patients whose baseline concentra-
tion of 25-hydroxyvitamin D was less than 17 ng
per milliliter (42 nmol per liter) and whose mean
concentration of 25-hydroxyvitamin D then rose
to approximately 40 ng per milliliter.
8
Evaluation of the exclusive use of calcium or
vitamin D
3
(RECORD trial) showed no antifrac-
ture efficacy for patients receiving 800 IU of vi-
tamin D
3
per day.
44
However, the mean concen-
tration of 25-hydroxyvitamin D increased from
15.2 ng per milliliter to just 24.8 ng per milliliter
(37.9 to 61.9 nmol per liter), which was below the
threshold thought to provide antifracture efficacy.
8
Porthouse and colleagues,
45
who evaluated the ef-
fect of 800 IU of vitamin D
3
per day on fracture
prevention, did not report concentrations of 25-
hydroxyvitamin D. Their study had an open design
in which participants could have been ingesting an
adequate amount of calcium and vitamin D sepa-
rate from the intervention. This called into ques-
tion the conclusion that vitamin D supplementa-
tion had no antifracture benefit.
8
Table 1. Dietary, Supplemental, and Pharmaceutical Sources of Vitamins D
2
and D
3
.*
Source Vitamin D Content
Natural sources
Salmon
Fresh, wild (3.5 oz) About 600–1000 IU of vitamin D
3
Fresh, farmed (3.5 oz) About 100–250 IU of vitamin D
3
or D
2
Canned (3.5 oz) About 300–600 IU of vitamin D
3
Sardines, canned (3.5 oz) About 300 IU of vitamin D
3
Mackerel, canned (3.5 oz) About 250 IU of vitamin D
3
Tuna, canned (3.6 oz) About 230 IU of vitamin D
3
Cod liver oil (1 tsp) About 400–1000 IU of vitamin D
3
Shiitake mushrooms
Fresh (3.5 oz) About 100 IU of vitamin D
2
Sun-dried (3.5 oz) About 1600 IU of vitamin D
2
Egg yolk About 20 IU of vitamin D
3
or D
2
Exposure to sunlight, ultraviolet B
radiation (0.5 minimal
erythemal dose)†
About 3000 IU of vitamin D
3
Fortified foods
Fortified milk About 100 IU/8 oz, usually vitamin D
3
Fortified orange juice About 100 IU/8 oz vitamin D
3
Infant formulas About 100 IU/8 oz vitamin D
3
Fortified yogurts About 100 IU/8 oz, usually vitamin D
3
Fortified butter About 50 IU/3.5 oz, usually vitamin D
3
Fortified margarine About 430 IU/3.5 oz, usually vitamin D
3
Fortified cheeses About 100 IU/3 oz, usually vitamin D
3
Fortified breakfast cereals About 100 IU/serving, usually
vitamin D
3
Supplements
Prescription
Vitamin D
2
(ergocalciferol) 50,000 IU/capsule
Drisdol (vitamin D
2
) liquid
supplements
8000 IU/ml
Over the counter
Multivitamin 400 IU vitamin D, D
2
, or D
3
Vitamin D
3
400, 800, 1000, and 2000 IU
* IU denotes international unit, which equals 25 ng. To convert values from
ounces to grams, multiply by 28.3. To convert values from ounces to millili-
ters, multiply by 29.6.
About 0.5 minimal erythemal dose of ultraviolet B radiation would be ab-
sorbed after an average of 5 to 10 minutes of exposure (depending on the
time of day, season, latitude, and skin sensitivity) of the arms and legs to di-
rect sunlight.
When the term used on the product label is vitamin D or calciferol, the prod-
uct usually contains vitamin D
2
; cholecalciferol or vitamin D
3
indicates that
the product contains vitamin D
3
.
medic al progr ess
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271
Mus cl e S t r e ng t h a nd Fa l l s
Vitamin D deficiency causes muscle weakness.
1,7,8,28
Skeletal muscles have a vitamin D receptor and may
require vitamin D for maximum function.
1,8
Performance speed and proximal muscle
strength were markedly improved when 25-
hydroxyvitamin D levels increased from 4 to 16 ng
per milliliter (10 to 40 nmol per liter) and contin-
ued to improve as the levels increased to more than
40 ng per milliliter (100 nmol per liter).
8
A meta-
analysis of five randomized clinical trials (with a
total of 1237 subjects) revealed that increased vi-
tamin D intake reduced the risk of falls by 22%
(pooled corrected odds ratio, 0.78; 95% CI, 0.64 to
0.92) as compared with only calcium or placebo.
8
The same meta-analysis examined the frequency of
falls and suggested that 400 IU of vitamin D
3
per
day was not effective in preventing falls, whereas
800 IU of vitamin D
3
per day plus calcium reduced
the risk of falls (corrected pooled odds ratio, 0.65;
95% CI, 0.4 to 1.0).
8
In a randomized controlled
trial conducted over a 5-month period, nursing
home residents receiving 800 IU of vitamin D
2
per
day plus calcium had a 72% reduction in the risk
of falls as compared with the placebo group (ad-
justed rate ratio, 0.28%; 95% CI, 0.11 to 0.75).
46
Nonsk e l e t a l Ac t ions
of V i t a m in D
Brain, prostate, breast, and colon tissues, among
others, as well as immune cells have a vitamin D
receptor and respond to 1,25-dihydroxyvitamin D,
the active form of vitamin D.
1-4,6
In addition, some
of these tissues and cells express the enzyme 25-
hydroxyvitamin D--hydroxylase.
1-3,6
Directly or indirectly, 1,25-dihydroxyvitamin D
controls more than 200 genes, including genes
responsible for the regulation of cellular prolifera-
tion, differentiation, apoptosis, and angiogen-
esis.
1,2,47
It decreases cellular proliferation of both
normal cells and cancer cells and induces their
terminal differentiation.
1-3,6,47
One practical ap-
plication is the use of 1,25-dihydroxyvitamin D
3
and its active analogues for the treatment of pso-
riasis.
48,49
1,25-Dihydroxyvitamin D is also a potent im-
munomodulator.
2-4,6,50
Monocytes and macro-
phages exposed to a lipopolysaccharide or to
Mycobacterium tuberculosis up-regulate the vitamin D
receptor gene and the 25-hydroxyvitamin D-1α-
hydroxylase gene. Increased production of 1,25-
dihydroxyvitamin D
3
result in synthesis of
cathelicidin, a peptide capable of destroying M. tu-
berculosis as well as other infectious agents. When
serum levels of 25-hydroxyvitamin D fall below
20 ng per milliliter (50 nmol per liter), the mono-
cyte or macrophage is prevented from initiating
this innate immune response, which may explain
why black Americans, who are often vitamin
Ddeficient, are more prone to contracting tu-
berculosis than are whites, and tend to have a
more aggressive form of the disease.
51
1,25-dihy-
droxyvitamin D
3
inhibits renin synthesis,
52
in-
creases insulin production,
53
and increases myo-
cardial contractility (Fig. 2).
54
L a t i t u de , V i t a m i n D De f ici e nc y ,
a n d Chr onic Dise a ses
Cancer
People living at higher latitudes are at increased
risk for Hodgkins lymphoma as well as colon, pan-
creatic, prostate, ovarian, breast, and other cancers
and are more likely to die from these cancers, as
compared with people living at lower latitudes.
55-65
Both prospective and retrospective epidemiologic
studies indicate that levels of 25-hydroxyvitamin D
below 20 ng per milliliter are associated with a
30 to 50% increased risk of incident colon, pros-
tate, and breast cancer, along with higher mor-
tality from these cancers.
56,59-61,64
An analysis from
the Nurses’ Health Study cohort (32,826 subjects)
showed that the odds ratios for colorectal cancer
were inversely associated with median serum lev-
els of 25-hydroxyvitamin D (the odds ratio at 16.2
ng per milliliter [40.4 nmol per liter] was 1.0, and
the odds ratio at 39.9 ng per milliliter [99.6 nmol
per liter] was 0.53; P≤0.01). Serum 1,25-dihy-
droxyvitamin D levels were not associated with
colorectal cancer.
61
A prospective study of vita-
min D intake and the risk of colorectal cancer in
1954 men showed a direct relationship (with a rela-
tive risk of 1.0 when vitamin D intake was 6 to 94
IU per day and a relative risk of 0.53 when the in-
take was 233 to 652 IU per day, P<0.05).
56
Partici-
pants in the Womens Health Initiative who at base-
line had a 25-hydroxyvitamin D concentration of
less than 12 ng per milliliter (30 nmol per liter)
had a 253% increase in the risk of colorectal can-
cer over a follow-up period of 8 years.
62
In a study
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2
Ingelfinger
06/28/07
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully
Author
Fig #
Title
ME
DE
Artist
Issue date
COLOR FIGURE
Draft 8
Holick
KMK
Vitamin D Deficiency - 2
7/19/07
Koopman
Immunomodulation
Increased VDR
Lipopolysaccharide
or tuberculosis
tubercle
Blood
1-OHase
Macrophage/
monocyte
Breast, colon,
prostate, etc.
Parathyroid
glands
Blood pressure regulation
Calcitroic
Acid
Blood sugar control
25(OH)D
>30 ng/ml
VDR-RXR
VDR–RXR
VDR–RXR
Cytokine regulation
Kidneys
Decreased
renin
Decreased
parathyroid
hormone
Pancreas
1-OHase
1-OHase
1,25(OH)
2
D
24-OHase
Enhances p21 and p27
Inhibits angiogenesis
Induces apoptosis
Immunoglobulin
synthesis
Activated T lymphocyte
Activated B lymphocyte
Increased
cathelicidin
Increased 1-OHase
TLR-2/1
Tuberculosis
tubercle
1,25(OH)
2
D
1,25(OH)
2
D
Parathyroid
hormone regulation
Increased
insulin
Innate immunity
25(OH)D
1,25(OH)
2
D
Figure 2. Metabolism of 25-Hydroxyvitamin D to 1,25-Dihydroxyvitamin D for Nonskeletal Functions.
When a macrophage or monocyte is stimulated through its toll-like receptor 2/1 (TLR2/1) by an infectious agent
such as Mycobacterium tuberculosis or its lipopolysaccharide, the signal up-regulates the expression of vitamin D re-
ceptor (VDR) and 25-hydroxyvitamin D-1α-hydroxylase (1-OHase). A 25-hydroxyvitamin D [25(OH)D] level of 30 ng
per milliliter (75 nmol per liter) or higher provides adequate substrate for 1-OHase to convert 25(OH)D to its active
form, 1,25 dihydroxyvitamin D [1,25(OH)
2
D]. 1,25(OH)
2
D travels to the nucleus, where it increases the expression
of cathelicidin, a peptide capable of promoting innate immunity and inducing the destruction of infectious agents
such as M. tuberculosis. It is also likely that the 1,25(OH)
2
D produced in monocytes or macrophages is released to
act locally on activated T lymphocytes, which regulate cytokine synthesis, and activated B lymphocytes, which regu-
late immunoglobulin synthesis. When the 25(OH)D level is approximately 30 ng per milliliter, the risk of many com-
mon cancers is reduced. It is believed that the local production of 1,25(OH)
2
D in the breast, colon, prostate, and
other tissues regulates a variety of genes that control proliferation, including p21 and p27, as well as genes that in-
hibit angiogenesis and induce differentiation and apoptosis. Once 1,25(OH)
2
D completes the task of maintaining
normal cellular proliferation and differentiation, it induces expression of the enzyme 25-hydroxyvitamin D-24-hy-
droxylase (24-OHase), which enhances the catabolism of 1,25(OH)
2
D to the biologically inert calcitroic acid. Thus,
locally produced 1,25(OH)
2
D does not enter the circulation and has no influence on calcium metabolism. The para-
thyroid glands have 1-OHase activity, and the local production of 1,25(OH)
2
D inhibits the expression and synthesis
of parathyroid hormone. The 1,25(OH)
2
D produced in the kidney enters the circulation and can down-regulate renin
production in the kidney and stimulate insulin secretion in the beta islet cells of the pancreas.
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273
of men with prostate cancer, the disease developed
3 to 5 years later in the men who worked outdoors
than in those who worked indoors.
63
Pooled data
for 980 women showed that the highest vitamin
D intake, as compared with the lowest, correlated
with a 50% lower risk of breast cancer.
64
Children
and young adults who are exposed to the most sun-
light have a 40% reduced risk of non-Hodgkins
lymphoma
65
and a reduced risk of death from ma-
lignant melanoma once it develops, as compared
with those who have the least exposure to sun-
light.
66
The conundrum here is that since the kidneys
tightly regulate the production of 1,25-dihydroxyvi-
tamin D, serum levels do not rise in response to
increased exposure to sunlight or increased intake
of vitamin D.
1-3
Furthermore, in a vitamin D
insufficient state, 1,25-dihydroxyvitamin D levels
are often normal or even elevated.
1,3,6,7
The likely
explanation is that colon, prostate, breast, and
other tissues express 25-hydroxyvitamin D-1α-
hydroxylase and produce 1,25-dihydroxyvitamin D
locally to control genes that help to prevent can-
cer by keeping cellular proliferation and differ-
entiation in check.
1-3,47,56,58
It has been suggested
that if a cell becomes malignant, 1,25-dihydroxyvi-
tamin D can induce apoptosis and prevent angio-
genesis, thereby reducing the potential for the
malignant cell to survive.
2,3,7,67
Once 1,25-dihy-
droxyvitamin D completes these tasks, it initiates
its own destruction by stimulating the CYP24 gene
to produce the inactive calcitroic acid. This guar-
antees that 1,25-dihydroxyvitamin D does not en-
ter the circulation to influence calcium metabo-
lism (Fig. 1).
1-4
This is a plausible explanation for
why increased sun exposure and higher circulat-
ing levels of 25-hydroxyvitamin D are associated
with a decreased risk of deadly cancers.
56-65
Autoimmune Diseases, Osteoarthritis,
and Diabetes
Living at higher latitudes increases the risk of
type 1 diabetes, multiple sclerosis, and Crohns dis-
ease.
68,69
Living below 35 degrees latitude for the
first 10 years of life reduces the risk of multiple
sclerosis by approximately 50%.
69,70
Among white
men and women, the risk of multiple sclerosis de-
creased by 41% for every increase of 20 ng per mil-
liliter in 25-hydroxyvitamin D above approximate-
ly 24 ng per milliliter (60 nmol per liter) (odds
ratio, 0.59; 95% CI, 0.36 to 0.97; P = 0.04).
71
Women
who ingested more than 400 IU of vitamin D per
day had a 42% reduced risk of developing multi-
ple sclerosis.
72
Similar observations have been made
for rheumatoid arthritis
73
and osteoarthritis.
74
Several studies suggest that vitamin D supple-
mentation in children reduces the risk of type 1
diabetes. Increasing vitamin D intake during preg-
nancy reduces the development of islet autoanti-
bodies in offspring.
53
For 10,366 children in Fin-
land who were given 2000 IU of vitamin D
3
per
day during their first year of life and were followed
for 31 years, the risk of type 1 diabetes was re-
duced by approximately 80% (relative risk, 0.22;
95% CI, 0.05 to 0.89).
75
Among children with vita-
min D deficiency the risk was increased by ap-
proximately 200% (relative risk, 3.0; 95% CI, 1.0
to 9.0). In another study, vitamin D deficiency in-
creased insulin resistance, decreased insulin pro-
duction, and was associated with the metabolic
syndrome.
53
Another study showed that a com-
bined daily intake of 1200 mg of calcium and
800 IU of vitamin D lowered the risk of type 2
diabetes by 33% (relative risk, 0.67; 95% CI, 0.49
to 0.90) as compared with a daily intake of less
than 600 mg of calcium and less than 400 IU of
vitamin D.
76
Cardiovascular Disease
Living at higher latitudes increases the risk of hy-
pertension and cardiovascular disease.
54,77
In a
study of patients with hypertension who were ex-
posed to ultraviolet B radiation three times a week
for 3 months, 25-hydroxyvitamin D levels increased
by approximately 180%, and blood pressure be-
came normal (both systolic and diastolic blood
pressure reduced by 6 mm Hg).
78
Vitamin D defi-
ciency is associated with congestive heart failure
54
and blood levels of inflammatory factors, includ-
ing C-reactive protein and interleukin-10.
54,79
V i t a m i n D De f ici e nc y
a n d O t h e r Di s or der s
Schizophrenia and Depression
Vitamin D deficiency has been linked to an in-
creased incidence of schizophrenia and depres-
sion.
80,81
Maintaining vitamin D sufficiency in
utero and during early life, to satisfy the vitamin D
receptor transcriptional activity in the brain, may
be important for brain development as well as for
maintenance of mental function later in life.
82
Lung Function and Wheezing Illnesses
Men and women with a 25-hydroxyvitamin D level
above 35 ng per milliliter (87 nmol per liter) had
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a 176-ml increase in the forced expiratory volume
in 1 second.
83
Children of women living in an
inner city who had vitamin D deficiency during
pregnancy are at increased risk for wheezing ill-
nesses.
84
C aus e s of V i t a m i n D De f ici e nc y
There are many causes of vitamin D deficiency, in-
cluding reduced skin synthesis and absorption of
vitamin D and acquired and heritable disorders of
Table 2. Causes of Vitamin D Deficiency.*
Cause Effect
Reduced skin synthesis
Sunscreen use — absorption of UVB radiation by sunscreen
1-3,7,85
Reduces vitamin D
3
synthesis — SPF 8 by 92.5%, SPF 15 by 99%
Skin pigment — absorption of UVB radiation by melanin
1-3,7,85
Reduces vitamin D
3
synthesis by as much as 99%
Aging — reduction of 7-dehydrocholesterol in the skin
2,7,85
Reduces vitamin D
3
synthesis by about 75% in a 70-year-old
Season, latitude, and time of day — number of solar UVB photons
reaching the earth depending on zenith angle of the sun
(the more oblique the angle, the fewer UVB photons reach
the earth)
1-3,85
Above about 35 degrees north latitude (Atlanta), little or no vitamin
D
3
can be produced from November to February
Patients with skin grafts for burns — marked reduction of 7-dehy-
drocholesterol in the skin
Decreases the amount of vitamin D
3
the skin can produce
Decreased bioavailability
Malabsorption — reduction in fat absorption, resulting from cystic
fibrosis, celiac disease, Whipple’s disease, Crohn’s disease,
bypass surgery, medications that reduce cholesterol ab-
sorption, and other causes
86,87
Impairs the body’s ability to absorb vitamin D
Obesity — sequestration of vitamin D in body fat† Reduces availability of vitamin D
Increased catabolism
Anticonvulsants, glucocorticoids, HAART (AIDS treatment), and
antirejection medications — binding to the steroid and
xenobiotic receptor or the pregnane X receptor
1-3,7,88
Activates the destruction of 25-hydroxyvitamin D and 1,25-dihy-
droxyvitamin D to inactive calcitroic acid
Breast-feeding
Poor vitamin D content in human milk
1,33,89
Increases infant risk of vitamin D deficiency when breast milk is
sole source of nutrition
Decreased synthesis of 25-hydroxyvitamin D
Liver failure
Mild-to-moderate dysfunction Causes malabsorption of vitamin D, but production of 25-hydroxy-
vitamin D is possible
2,3,6,7,90
Dysfunction of 90% or more Results in inability to make sufficient 25-hydroxyvitamin D
Increased urinary loss of 25-hydroxyvitamin D
Nephrotic syndrome — loss of 25-hydroxyvitamin D bound
to vitamin D–binding protein in urine
Results in substantial loss of 25-hydroxyvitamin D to urine
2,3,6,91
Decreased synthesis of 1,25-dihydroxyvitamin D
Chronic kidney disease
Stages 2 and 3 (estimated glomerular filtration rate, 31 to
89 ml/min/1.73 m
2
)
Hyperphosphatemia increases fibroblast growth factor 23,
which decreases 25-hydroxyvitamin D-1α-hydroxylase
activity
5,6,91-94
Causes decreased fractional excretion of phosphorus and decreased
serum levels of 1,25-dihydroxyvitamin D
Stages 4 and 5 (estimated glomerular filtration rate <30 ml/
min/1.73 m
2
)
Inability to produce adequate amounts of 1,25-dihydroxyvita-
min D
2,3,6,91-96
Causes hypocalcemia, secondary hyperparathyroidism, and renal
bone disease
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vitamin D metabolism and responsiveness.
2,3,6
Ta-
ble 2
lists causes and effects of vitamin D defi-
ciency.
V i t a m i n D R e quir e m en t s
a n d T r e a t men t S t r a t e gies
Children and Adults
Recommendations from the Institute of Medicine
for adequate daily intake of vitamin D are 200 IU
for children and adults up to 50 years of age, 400
IU for adults 51 to 70 years of age, and 600 IU for
adults 71 years of age or older.
101
However, most
experts agree that without adequate sun exposure,
children and adults require approximately 800 to
1000 IU per day.
1-3,8,15,16,20,102,103
Children with vi-
tamin D deficiency should be aggressively treated
to prevent rickets (
Table 3
).
1,28,105-107
Since vita-
min D
2
is approximately 30% as effective as vita-
min D
3
in maintaining serum 25-hydroxyvitamin
D levels,
117,118
up to three times as much vitamin
D
2
may be required to maintain sufficient levels.
A cost-effective method of correcting vitamin D
deficiency and maintaining adequate levels is to
give patients a 50,000-IU capsule of vitamin D
2
once a week for 8 weeks, followed by 50,000 IU of
vitamin D
2
every 2 to 4 weeks thereafter (
Table
3
).
2,7,9
Alternatively, either 1000 IU of vitamin D
3
per day (available in most pharmacies) or 3000
IU of vitamin D
2
per day is effective.
2,7,102,103
Strat-
egies such as having patients take 100,000 IU of
vitamin D
3
once every 3 months have been shown
to be effective in maintaining 25-hydroxyvitamin
D levels at 20 ng per milliliter or higher and are
also effective in reducing the risk of fracture.
119
Breast-fed Infants and Children
Human milk contains little vitamin D (approxi-
mately 20 IU per liter), and women who are vita-
min Ddeficient provide even less to their breast-
Table 2. (Continued.)
Cause Effect
Heritable disorders — rickets
Pseudovitamin D deficiency rickets (vitamin D–dependent rickets
type 1) — mutation of the renal 25-hydroxyvitamin D-1α-
hydroxylase gene (CYP27B1)
1-3,97
Causes reduced or no renal synthesis of 1,25-dihydroxyvitamin D
Vitamin D–resistant rickets (vitamin D–dependent rickets type 2) —
mutation of the vitamin D receptor gene
1-3
Causes partial or complete resistance to 1,25-dihydroxyvitamin D
action, resulting in elevated levels of 1,25-dihydroxyvitamin D
Vitamin D–dependent rickets type 3 — overproduction of hormone-
responsive-element binding proteins
98
Prevents the action of 1,25-dihydroxyvitamin D in transcription,
causing target-cell resistance and elevated levels of 1,25-
dihydroxyvitamin D
Autosomal dominant hypophosphatemic rickets — mutation of the
gene for fibroblast growth factor 23, preventing or reducing
its breakdown
1-3,5,6,92
Causes phosphaturia, decreased intestinal absorption of phospho-
rus, hypophosphatemia, and decreased renal 25-hydroxyvitamin
D-1α-hydroxylase activity, resulting in low-normal or low levels
of 1,25-dihydroxyvitamin D
X-linked hypophosphatemic rickets — mutation of the PHEX gene,
leading to elevated levels of fibroblast growth factor 23 and
other phosphatonins
1-3,5,6,92
Causes phosphaturia, decreased intestinal absorption of phospho-
rus, hypophosphatemia, and decreased renal 25-hydroxyvitamin
D-1α-hydroxylase activity, resulting in low-normal or low levels of
1,25-dihydroxyvitamin D
Acquired disorders
Tumor-induced osteomalacia — tumor secretion of fibroblast
growth factor 23 and possibly other phosphatonins
1-3,5,6,92,99
Causes phosphaturia, decreased intestinal absorption of phospho-
rus, hypophosphatemia, and decreased renal 25-hydroxyvitamin
D-1α-hydroxylase activity, resulting in low-normal or low levels of
1,25-dihydroxyvitamin D
Primary hyperparathyroidism — increase in levels of parathyroid
hormone, causing increased metabolism of 25-hydroxyvita-
min D to 1,25-hydroxyvitamin D
2,3,6
Decreases 25-hydroxyvitamin D levels and increases 1,25-dihy-
droxyvitamin D levels that are high-normal or elevated
Granulomatous disorders, sarcoidosis, tuberculosis, and other con-
ditions, including some lymphomas — conversion by macro-
phages of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D
100
Decreases 25-hydroxyvitamin D levels and increases 1,25-dihy-
droxyvitamin D levels
Hyperthyroidism — enhanced metabolism of 25-hydroxyvitamin D Reduces levels of 25-hydroxyvitamin D
* UVB denotes ultraviolet B, SPF sun protection factor, and HAART highly active antiretroviral therapy.
There is an inverse relationship between the body-mass index and 25-hydroxyvitamin D levels.
2,7,85
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Table 3. Strategies to Prevent and Treat Vitamin D Deficiency.*
Cause of Deficiency†
Preventive and Maintenance Measures
to Avoid Deficiency Treatment of Deficiency
Children
Breast-feeding without vitamin D supple-
mentation
28,33,89,104
up to 1 yr
400 IU of vitamin D
3
/day,
1,28,104
sensible sun
exposure,
1
1000–2000 IU of vitamin D
3
/day
is safe,
1,2,27,75
maintenance dose is 400–
1000 IU of vitamin D
3
/day
1,2,104
200,000 IU of vitamin D
3
every 3 mo,
1,105
600,000 IU of vitamin D intramuscu-
larly, repeat in 12 wk
106
; 1000–2000 IU
of vitamin D
2
or vitamin D
3
/day
.
1,107
with calcium supplementation
Inadequate sun exposure
24,29-31,108
or supplementation,
1,28,104-107
dark skin
23
1 through 18 yr
400–1000 IU vitamin D
3
/day,
1,104,107
sensible
sun exposure, 1000–2000 IU of vitamin D
3
/
day
1,108
is safe,
1,27,75,104,107
maintenance
dose is 400–1000 IU of vitamin D/day
1,75
50,000 IU of vitamin D
2
every wk for
8 wk
1,9
Adults
Inadequate sun exposure
7,15
or supple-
mentation,
7-20
decreased 7-dehy-
drocholesterol in skin because of
aging (over 50 yr)
7
800–1000 IU of vitamin D
3
/day,
1-3,8,16,21,42
50,000 IU of vitamin D
2
every 2 wk or every
mo,
7,9
sensible sun exposure
7,15,109,110
or
use of tanning bed or other UVB radiation
device (e.g., portable Sperti lamp),
111-114
up to 10,000 IU of vitamin D
3
/day is safe
for 5 mo,
27
maintenance dose is 50,000 IU
every 2 wk or every mo
7,9
50,000 IU of vitamin D
2
every wk for
8 weeks
9
; repeat for another 8 wk if
25-hydroxyvitamin D <30 ng/ml‡
Pregnant or lactating (fetal utilization,
33
inadequate sun exposure
33,89
or
supplementation
33,89
)
1000–2000 IU of vitamin D
3
/day,
33,89
50,000
IU of vitamin D
2
every 2 wk, up to 4000 IU
of vitamin D
3
/day is safe for 5 mo,
33,89
maintenance dose is 50,000 IU of vitamin
D
2
every 2 or 4 wk
9
50,000 IU vitamin D
2
every wk for 8 wk
115
;
repeat for another 8 wk if 25-hydroxyvita-
min D <30 ng/ml‡
Malabsorption syndromes (malabsorp-
tion of vitamin D,
2,3,86,87
inade-
quate sun exposure
2,3,6,7
or sup-
plementation
2,3,6,7
)
Adequate exposure to sun or ultraviolet radia-
tion,
7,113
50,000 IU of vitamin D
2
every day,
every other day, or every wk,† up to 10,000
IU of vitamin D
3
/day is safe for 5 mo,
27
maintenance dose is 50,000 IU of vitamin
D
2
every wk‡
UVB irradiation (tanning bed or portable
UVB device, e.g., portable Sperti
lamp),
111-114
50,000 IU of vitamin D
2
every day or every other day‡
Drugs that activate steroid and xenobiotic
receptor,
88
and drugs used in
transplantation
116
50,000 IU of vitamin D
2
every other day or ev-
ery week, maintenance dose is 50,000 IU of
vitamin D
2
every 1, 2, or 4 wk‡
50,000 IU of vitamin D
2
every 2 wk for
8–10 wk, or every wk if 25-hydroxyvita-
min D <30 ng/ml‡
Obesity
2,7
1000–2000 IU of vitamin D
3
/day, 50,000 IU
of vitamin D
2
every 1 or 2 wk, maintenance
dose is 50,000 IU of vitamin D
2
every 1, 2,
or 4 wk‡
50,000 IU of vitamin D
2
every wk for 8–12
wk; repeat for another 8–12 wk if
25-hydroxyvitamin D <30 ng/ml‡
Nephrotic syndrome
2,3,6,7,91-94
1000–2000 IU of vitamin D
3
/day, 50,000 IU
of vitamin D
2
once or twice/wk,
2,94
maintenance dose is 50,000 IU of vitamin
D
2
every 2 or 4 wk
2
50,000 IU of vitamin D
2
twice/wk for 8–12
wk
2,94
; repeat for another 8–12 wk if
25-hydroxyvitamin D <30 ng/ml‡
Chronic kidney disease§
Stages 2 and 3 Control serum phosphate,
6
1000 IU of vitamin
D
3
/day, 50,000 IU of vitamin D
2
every
2 wk,
91,94
maintenance dose is 50,000 IU of
vitamin D
2
every 2 or 4 wk; may also need
to treat with an active vitamin D analog
when vitamin D sufficiency is obtained‡
50,000 IU of vitamin D
2
once/wk for 8
wk
91,94
; repeat for another 8 wk if
25-hydroxyvitamin D <30 ng/ml‡
Stages 4 and 5 1000 IU of vitamin D
3
/day,
51
50,000 IU of vita-
min D
2
every 2 wk, need to treat with 1,25-
dihydroxyvitamin D
3
or active analogue‡
0.25–1.0 μg of 1,25-dihydroxyvitamin D
3
(calcitriol)
2,6,91,93,94
by mouth twice a
day or one of the following: 1–2 μg of
paricalcitriol IV every 3 days,
6,91,93,94
0.04–0.1 μg/kg IV every other day ini-
tially and can increase to 0.24 μg/kg,
2–4 μg by mouth three times/
wk,
6,91,93,94
or doxecalciferol
6,91,93,94
10–20 μg by mouth three times/wk or
2–6 μg IV three times/wk
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fed infants.
33,89
Lactating women given 4000 IU of
vitamin D
3
per day not only had an increase in the
level of 25-hydroxyvitamin D to more than 30 ng
per milliliter but were also able to transfer enough
vitamin D
3
into their milk to satisfy an infant’s re-
quirement.
89
In Canada, to prevent vitamin D deficiency, cur-
rent guidelines recommend that all infants and
children receive 400 IU of vitamin D
3
per day (
Ta-
ble 3
).
104
Patients with Chronic Kidney Disease
In patients with any stage of chronic kidney dis-
ease, 25-hydroxyvitamin D should be measured an-
nually, and the level should be maintained at 30 ng
per milliliter or higher, as recommended in the
Kidney Disease Outcomes Quality Initiative guide-
lines from the National Kidney Foundation.
6,91,93,94
It is a misconception to assume that patients tak-
ing an active vitamin D analogue have sufficient
vitamin D; many do not. Levels of 25-hydroxyvita-
min D are inversely associated with parathyroid
hormone levels, regardless of the degree of chron-
ic renal failure.
2,6,93-96
Parathyroid glands convert
25-hydroxyvitamin D to 1,25-dihydroxyvitamin D,
which directly inhibits parathyroid hormone ex-
pression.
6,93-96,120
Patients with stage 4 or 5 chron-
ic kidney disease and an estimated glomerular
filtration rate of less than 30 ml per minute per
1.73 m
2
of body-surface area, as well as those re-
quiring dialysis, are unable to make enough 1,25-
dihydroxyvitamin D and need to take 1,25-dihy-
droxyvitamin D
3
or one of its less calcemic
analogues to maintain calcium metabolism and to
decrease parathyroid hormone levels and the risk
of renal bone disease (
Table 3
).
6,91,93,94
Malabsorption and Medication
Patients with mild or moderate hepatic failure or
intestinal fat-malabsorption syndromes, as well
as patients who are taking anticonvulsant medi-
cations, glucocorticoids, or other drugs that ac-
tivate steroid and xenobiotic receptor, require
higher doses of vitamin D (
Table 3
).
7,88
Exposure
to sunlight or ultraviolet B radiation from a tan-
ning bed or other ultraviolet B–emitting device is
also effective.
7,113,115
Sunl igh t a n d A r t ific i a l
Ult r av iol e t B R a di a t io n
Sensible sun exposure can provide an adequate
amount of vitamin D
3
, which is stored in body fat
and released during the winter, when vitamin D
3
cannot be produced.
7,15,85,108-110
Exposure of arms
and legs for 5 to 30 minutes (depending on time
of day, season, latitude, and skin pigmentation) be-
tween the hours of 10 a.m. and 3 p.m. twice a week
is often adequate.
2,7,108-110
Exposure to one mini-
mal erythemal dose while wearing only a bathing
suit is equivalent to ingestion of approximately
20,000 IU of vitamin D
2
.
1,2,7,85
The skin has a great
capacity to make vitamin D
3
, even in the elderly, to
reduce the risk of fracture.
109-111
Most tanning beds
Table 3. (Continued.)
Cause of Deficiency†
Preventive and Maintenance Measures
to Avoid Deficiency Treatment of Deficiency
Adults
Primary or tertiary hyperparathyroidism 800–1000 IU of vitamin D
3
/day, 50,000 IU
of vitamin D
2
every 2 wk (serum calcium
levels will not increase),
115
maintenance
dose is 50,000 IU of vitamin D
2
every
2 or 4 wk‡
50,000 IU of vitamin D
2
once a wk for
8 wk; repeat for another 8 wk if
25-hydroxyvitamin D <30 ng/ml
Granulomatous disorders and some
lymphomas
400 IU of vitamin D
3
/day, maintenance
dose is 50,000 IU of vitamin D
2
/mo‡
50,000 IU vitamin D
2
once a wk for 4 wk
or every 2 to 4 wk, need to keep 25-
hydroxyvitamin D between 20 and 30
ng/ml (level above 30 ng/ml can result
in hypercalciuria and hypercalcemia)‡
* These recommendations are based on published literature and the author’s personal experience. IV denotes intravenously. To convert the
values for 25-hydroxyvitamin D to nanomoles per liter, multiply by 2.496.
For the specific mechanism of deficiency, see Table 2.
The goal is to achieve concentrations of 25-hydroxyvitamin D at about 30 to 60 ng per milliliter. Physicians should use these guidelines in
combination with their clinical judgment according to the circumstances.
§ In stages 2 and 3 of chronic kidney disease, the estimated glomerular filtration rate is 31 to 89 ml per minute per 1.73 m
2
; in stages 4 and 5,
the estimated rate is <30 ml per minute per 1.73 m
2
.
T h e
n e w e n gl a n d j o u r n a l
o f
m e d i c i n e
n engl j med 357;3 www.nejm.org july 19, 2007
278
emit 2 to 6% ultraviolet B radiation and are a rec-
ommended source of vitamin D
3
when used in
moderation.
111-113,115
Tanners had robust levels
of 25-hydroxyvitamin D (approximately 45 ng per
milliliter [112 nmol per liter]) at the end of the
winter and higher bone density as compared with
nontanners (with levels of approximately 18 ng per
milliliter [45 nmol per liter]).
112
For patients with
fat malabsorption, exposure to a tanning bed for
30 to 50% of the time recommended for tanning
(with sunscreen on the face) is an excellent means
of treating and preventing vitamin D deficiency
(
Table 3
).
113
This reduces the risk of skin cancers
associated with ultraviolet B radiation.
V i t a m i n D In t o x ic a t ion
Vitamin D intoxication is extremely rare but can
be caused by inadvertent or intentional ingestion
of excessively high doses. Doses of more than
50,000 IU per day raise levels of 25-hydroxyvita-
min D to more than 150 ng per milliliter (374 nmol
per liter) and are associated with hypercalcemia
and hyperphosphatemia.
1-3,27,121,122
Doses of 10,000
IU of vitamin D
3
per day for up to 5 months, how-
ever, do not cause toxicity.
27
Patients with chronic
granulomatous disorders are more sensitive to se-
rum 25-hydroxyvitamin D levels above 30 ng per
milliliter because of macrophage production of
1,25-dihydroxyvitamin D, which causes hypercal-
ciuria and hypercalcemia.
1-3,100
In these patients,
however, 25-hydroxyvitamin D levels need to be
maintained at approximately 20 to 30 ng per mil-
liliter to prevent vitamin D deficiency and sec-
ondary hyperparathyroidism (
Table 3
).
1-3,100
C onc l usions
Undiagnosed vitamin D deficiency is not uncom-
mon,
1-3,6-20,123
and 25-hydroxyvitamin D is the ba-
rometer for vitamin D status. Serum 25-hydroxyvi-
tamin D is not only a predictor of bone health
8
but is also an independent predictor of risk for can-
cer and other chronic diseases.
8,54,59-64,71-75,83-85
The report that postmenopausal women who in-
creased their vitamin D intake by 1100 IU of vi-
tamin D
3
reduced their relative risk of cancer by
60 to 77% is a compelling reason to be vitamin
Dsufficient.
124
Most commercial assays for 25-
hydroxyvitamin D are good for detecting vitamin
D deficiency. Radioimmunoassays measure total
25-hydroxyvitamin D, which includes levels of both
25-hydroxyvitamin D
2
and 25-hydroxyvitamin D
3
.
Some commercial laboratories measure 25-hydroxy-
vitamin D
2
and 25-hydroxyvitamin D
3
with liquid
chromatography and tandem mass spectroscopy
and report the values separately. As long as the
combined total is 30 ng per milliliter or more, the
patient has sufficient vitamin D.
7,14,27
The 1,25-
dihydroxyvitamin D assay should never be used
for detecting vitamin D deficiency because levels
will be normal or even elevated as a result of sec-
ondary hyperparathyroidism. Because the 25-
hydroxyvitamin D assay is costly and may not al-
ways be available, providing children and adults
with approximately at least 800 IU of vitamin D
3
per day or its equivalent should guarantee vita-
min D sufficiency unless there are mitigating cir-
cumstances (
Table 2
).
Much evidence suggests that the recommended
adequate intakes are actually inadequate and need
to be increased to at least 800 IU of vitamin D
3
per day. Unless a person eats oily fish frequently,
it is very difficult to obtain that much vitamin D
3
on a daily basis from dietary sources. Excessive
exposure to sunlight, especially sunlight that
causes sunburn, will increase the risk of skin can-
cer.
125,126
Thus, sensible sun exposure (or ultra-
violet B irradiation) and the use of supplements
are needed to fulfill the bodys vitamin D re-
quirement.
Supported in part by grants from the National Institutes of
Health (M01RR00533 and AR36963) and the UV Foundation.
Dr. Holick reports receiving honoraria from Merck, Eli Lilly,
and Procter & Gamble and consulting fees from Quest Diagnos-
tics, Amgen, Novartis, and Procter & Gamble. No other potential
conflict of interest relevant to this article was reported.
I thank Dr. Farhad Chimeh for his helpful review of an earlier
version of this manuscript and Donna Gendron and Lorrie
MacKay for their secretarial assistance.
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