![Fracture efficacy by achieved 25(OH)D levels. To convert nmol/liter to ng/ml, divide by 2.496. [Reproduced with permission from H. A. Bischoff-Ferrari et al. : JAMA 293:2257–2264, 2005 (51). © American Medical Association.]](https://www.researchgate.net/profile/David-Hanley-6/publication/51196545/figure/fig1/AS:305845427556356@1449930640288/Fracture-efficacy-by-achieved-25OHD-levels-To-convert-nmol-liter-to-ng-ml-divide-by_Q320.jpg)
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Evaluation, Treatment, and Prevention of Vitamin D
Deficiency: an Endocrine Society Clinical Practice
Guideline
Michael F. Holick, Neil C. Binkley, Heike A. Bischoff-Ferrari,
Catherine M. Gordon, David A. Hanley, Robert P. Heaney, M. Hassan Murad,
and Connie M. Weaver
Boston University School of Medicine (M.F.H.), Boston, Massachusetts 02118; University of Wisconsin
(N.C.B.), Madison, Wisconsin 53706; University Hospital Zurich (H.A.B.-F.), CH-8091 Zurich, Switzerland;
Children’s Hospital Boston (C.M.G.), Boston, Massachusetts 02115; University of Calgary Faculty of
Medicine (D.A.H.), Calgary, Alberta, Canada T2N 1N4; Creighton University (R.P.H.), Omaha, Nebraska
68178; Mayo Clinic (M.H.M.), Rochester, Minnesota 55905; and Purdue University (C.M.W.), West
Lafayette, Indiana 47907
Objective: The objective was to provide guidelines to clinicians for the evaluation, treatment, and pre-
vention of vitamin D deficiency with an emphasis on the care of patients who are at risk for deficiency.
Participants: The Task Force was composed of a Chair, six additional experts, and a methodologist.
The Task Force received no corporate funding or remuneration.
Consensus Process: Consensus was guided by systematic reviews of evidence and discussions during
several conference calls and e-mail communications. The draft prepared by the Task Force was
reviewed successively by The Endocrine Society’s Clinical Guidelines Subcommittee, Clinical Affairs
Core Committee, and cosponsoring associations, and it was posted on The Endocrine Society web
site for member review. At each stage of review, the Task Force received written comments and
incorporated needed changes.
Conclusions: Considering that vitamin D deficiency is very common in all age groups and that few foods
contain vitamin D, the Task Force recommended supplementation at suggested daily intake and tol-
erable upper limit levels, depending on age and clinical circumstances. The Task Force also suggested
the measurement of serum 25-hydroxyvitamin D level by a reliable assay as the initial diagnostic test
in patients at risk for deficiency. Treatment with either vitamin D
2
or vitamin D
3
was recommended for
deficient patients. At the present time, there is not sufficient evidence to recommend screening indi-
viduals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for
cardiovascular protection. (J Clin Endocrinol Metab 96: 0000–0000, 2011)
Summary of Recommendations
1.0 Diagnostic procedure
1.1 We recommend screening for vitamin D deficiency in
individuals at risk for deficiency. We do not recommend
population screening for vitamin D deficiency in individ-
uals who are not at risk (1|QQQQ).
1.2 We recommend using the serum circulating 25-hy-
droxyvitamin D [25(OH)D] level, measured by a reliable
assay, to evaluate vitamin D status in patients who are at
risk for vitamin D deficiency. Vitamin D deficiency is de-
fined as a 25(OH)D below 20 ng/ml (50 nmol/liter). We
recommend against using the serum 1,25-dihydroxyvita-
min D [1,25(OH)
2
D] assay for this purpose and are in
favor of using it only in monitoring certain conditions,
such as acquired and inherited disorders of vitamin D and
phosphate metabolism (1|QQQQ).
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2011 by The Endocrine Society
doi: 10.1210/jc.2011-0385 Received February 14, 2011. Accepted May 18, 2011.
Abbreviations: BMD, Bone mineral density; BMI, body mass index; CI, confidence interval;
I2, inconsistency; IOM, Institute of Medicine; MI, myocardial infarction; OHase, hydroxy-
lase; 1,25(OH)
2
D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; OR, odds ratio;
RCT, randomized controlled trials; RDA, recommended dietary allowance; RR, relative risk.
SPECIAL FEATURE
Clinical Practice Guideline
J Clin Endocrinol Metab, July 2011, 96(7):0000– 0000 jcem.endojournals.org 1
2.0 Recommended dietary intakes of vitamin D for
patients at risk for vitamin D deficiency
2.1 We suggest that infants and children aged 0–1 yr re-
quire at least 400 IU/d (IU ⫽25 ng) of vitamin D and children
1 yr and older require at least 600 IU/d to maximize bone
health. Whether 400 and 600 IU/d for children aged 0–1 yr
and 1–18 yr, respectively, are enough to provide all the po-
tential nonskeletal health benefits associated with vitamin D
to maximize bone health and muscle function is not known
at this time. However, to raise the blood level of 25(OH)D
consistently above 30 ng/ml (75 nmol/liter) may require at
least 1000 IU/d of vitamin D (2|QQQQ).
2.2 We suggest that adults aged 19–50 yr require at
least 600 IU/d of vitamin D to maximize bone health and
muscle function. It is unknown whether 600 IU/d is
enough to provide all the potential nonskeletal health ben-
efits associated with vitamin D. However, to raise the
blood level of 25(OH)D consistently above 30 ng/ml may
require at least 1500–2000 IU/d of vitamin D (2|QQQQ).
2.3 We suggest that all adults aged 50–70 and 70⫹yr
require at least 600 and 800 IU/d, respectively, of vitamin D.
Whether 600 and 800 IU/d of vitamin D are enough to pro-
vide all of the potential nonskeletal health benefits associated
with vitamin D is not known at this time. However, to raise
the blood level of 25(OH)D above 30 ng/ml may require at
least 1500 –2000 IU/d of supplemental vitamin D (2|QQQQ).
2.4 We suggest that pregnant and lactating women re-
quire at least 600 IU/d of vitamin D and recognize that at least
1500–2000 IU/d of vitamin D may be needed to maintain a
blood level of 25(OH)D above 30 ng/ml (2|QQQE).
2.5 We suggest that obese children and adults and chil-
dren and adults on anticonvulsant medications, glucocor-
ticoids, antifungals such as ketoconazole, and medications
for AIDS be given at least two to three times more vitamin
D for their age group to satisfy their body’s vitamin D
requirement (2|QQQQ).
2.6 We suggest that the maintenance tolerable upper lim-
its (UL) of vitamin D, which is not to be exceeded without
medical supervision, should be 1000 IU/d for infants up to 6
months, 1500 IU/d for infants from 6 months to 1 yr, at least
2500 IU/d for children aged 1–3 yr, 3000 IU/d for children aged
4 –8 yr, and 4000 IU/d for everyone over 8 yr. However, higher
levels of 2000 IU/d for children 0–1 yr, 4000 IU/d for children
1–18 yr, and 10,000 IU/d for children and adults 19 yr and older
may be needed to correct vitamin D deficiency (2|QQQQ).
3.0 Treatment and prevention strategies
3.1 We suggest using either vitamin D
2
or vitamin D
3
for the treatment and prevention of vitamin D deficiency
(2|QQQQ).
3.2 For infants and toddlers aged 0–1 yr who are vi-
tamin D deficient, we suggest treatment with 2000 IU/d of
vitamin D
2
or vitamin D
3
, or with 50,000 IU of vitamin D
2
or vitamin D
3
once weekly for 6 wk to achieve a blood level
of 25(OH)D above 30 ng/ml, followed by maintenance
therapy of 400-1000 IU/d (2|QQQQ).
3.3 For children aged 1–18 yr who are vitamin D de-
ficient, we suggest treatment with 2000 IU/d of vitamin D
2
or vitamin D
3
for at least 6 wk or with 50,000 IU of vi-
tamin D
2
once a week for at least 6 wk to achieve a blood
level of 25(OH)D above 30 ng/ml, followed by mainte-
nance therapy of 600-1000 IU/d (2|QQQQ).
3.4 We suggest that all adults who are vitamin D defi-
cient be treated with 50,000 IU of vitamin D
2
or vitamin
D
3
once a week for 8 wk or its equivalent of 6000 IU of
vitamin D
2
or vitamin D
3
daily to achieve a blood level of
25(OH)D above 30 ng/ml, followed by maintenance ther-
apy of 1500–2000 IU/d (2|QQQQ).
3.5 In obese patients, patients with malabsorption syn-
dromes, and patients on medications affecting vitamin D me-
tabolism, we suggest a higher dose (two to three times higher;
at least 6000–10,000 IU/d) of vitamin D to treat vitamin D
deficiency to maintain a 25(OH)D level above 30 ng/ml, fol-
lowed by maintenance therapy of 3000 –6000 IU/d (2|QQQQ).
3.6 In patients with extrarenal production of
1,25(OH)
2
D, we suggest serial monitoring of 25(OH)D
levels and serum calcium levels during treatment with vi-
tamin D to prevent hypercalcemia (2|QQQQ).
3.7 For patients with primary hyperparathyroidism
and vitamin D deficiency, we suggest treatment with vi-
tamin D as needed. Serum calcium levels should be mon-
itored (2|QQQQ).
4.0 Noncalcemic benefits of vitamin D
4.1 We recommend prescribing vitamin D supplemen-
tation for fall prevention. We do not recommend prescrib-
ing vitamin D supplementation beyond recommended
daily needs for the purpose of preventing cardiovascular
disease or death or improving quality of life (2|QQQQ).
Method of Development of Evidence-
Based Clinical Practice Guidelines
The Task Force commissioned the conduct of two systematic
reviews of the literature to inform its key recommendations.
The Task Force used consistent language and geographical
descriptions of both the strength of recommendation and the
quality of evidence using the recommendations of the Grad-
ing of Recommendations, Assessment, Development, and
Evaluation (GRADE) system.
The Clinical Guidelines Subcommittee of The Endo-
crine Society deemed vitamin D deficiency a priority area
in need of practice guidelines and appointed a Task Force
2Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000
to formulate evidence-based recommendations. The Task
Force followed the approach recommended by the
GRADE group, an international group with expertise in
development and implementation of evidence-based
guidelines (1). A detailed description of the grading
scheme has been published elsewhere (2). The Task Force
used the best available research evidence to develop some
of the recommendations. The Task Force commissioned
the conduct of two systemic reviews of the literature to
inform its key recommendations.
The Task Force also used consistent language and
graphical descriptions of both the strength of a recom-
mendation and the quality of evidence. In terms of the
strength of the recommendation, strong recommenda-
tions use the phrase “we recommend” and the number 1,
and weak recommendations use the phrase “we suggest”
and the number 2. Cross-filled circles indicate the quality
of the evidence, such that QEEE denotes very low quality
evidence; QQEE, low quality; QQQE, moderate quality;
and QQQQ, high quality. The Task Force has confidence
that persons who receive care according to the strong rec-
ommendations will derive, on average, more good than
harm. Weak recommendations require more careful con-
sideration of the person’s circumstances, values, and pref-
erences to determine the best course of action. Linked to
each recommendation is a description of the evidence and
the values that panelists considered in making the recom-
mendation; in some instances, there are remarks, a section
in which panelists offer technical suggestions for testing
conditions, dosing, and monitoring. These technical com-
ments reflect the best available evidence applied to a typ-
ical person being treated. Often this evidence comes from
the unsystematic observations of the panelists and their
values and preferences; therefore, these remarks should be
considered suggestions.
Vitamin D Photobiology, Metabolism,
Physiology, and Biological Functions
Vitamin D is unique among hormones because it can be
made in the skin from exposure to sunlight (3–7). Vitamin
D comes in two forms. Vitamin D
2
is obtained from the UV
irradiation of the yeast sterol ergosterol and is found nat-
urally in sun-exposed mushrooms. Vitamin D
3
is synthe-
sized in the skin and is present in oil-rich fish such as
salmon, mackerel, and herring; commercially available vi-
tamin D
3
is synthesized from the cholesterol precursor
7-dehydrocholesterol naturally present in the skin or ob-
tained from lanolin (3). Both vitamin D
2
and vitamin D
3
are used for food fortification and in vitamin D supple-
ments. Vitamin D (D represents D
2
,orD
3
, or both) that is
ingested is incorporated into chylomicrons, which are ab-
sorbed into the lymphatic system and enter the venous
blood. Vitamin D that comes from the skin or diet is bi-
ologically inert and requires its first hydroxylation in the
liver by the vitamin D-25-hydroxylase (25-OHase) to
25(OH)D (3, 8). However, 25(OH)D requires a further
hydroxylation in the kidneys by the 25(OH)D-1
␣
-OHase
(CYP27B1) to form the biologically active form of vitamin
D 1,25(OH)
2
D (3, 8). 1,25(OH)
2
D interacts with its vi-
tamin D nuclear receptor, which is present in the small
intestine, kidneys, and other tissues (3, 8). 1,25(OH)
2
D
stimulates intestinal calcium absorption (9). Without vi-
tamin D, only 10 to 15% of dietary calcium and about
60% of phosphorus are absorbed. Vitamin D sufficiency
enhances calcium and phosphorus absorption by 30–
40% and 80%, respectively (3, 10). 1,25(OH)
2
D interacts
with its vitamin D receptor in the osteoblast to stimulate
the expression of receptor activator of nuclear factor
B
ligand; this, in turn, interacts with receptor activator of
nuclear factor
B to induce immature monocytes to be-
come mature osteoclasts, which dissolve the matrix and
mobilize calcium and other minerals from the skeleton. In
the kidney, 1,25(OH)
2
D stimulates calcium reabsorption
from the glomerular filtrate (3, 11).
The vitamin D receptor is present in most tissues and
cells in the body (3, 12). 1,25(OH)
2
D has a wide range of
biological actions, including inhibiting cellular prolifera-
tion and inducing terminal differentiation, inhibiting an-
giogenesis, stimulating insulin production, inhibiting
renin production, and stimulating macrophage cathelici-
din production (3, 12–14). In addition, 1,25(OH)
2
D stim-
ulates its own destruction by enhancing the expression of
the 25-hydroxyvitamin D-24-OHase (CYP24R) to metab-
olize 25(OH)D and 1,25(OH)
2
D into water-soluble inac-
tive forms. There are several tissues and cells that possess
1-OHase activity (3, 7, 12, 13). The local production of
1,25(OH)
2
D may be responsible for regulating up to 200
genes (15) that may facilitate many of the pleiotropic health
benefits that have been reported for vitamin D (3–7, 12).
Prevalence of Vitamin D Deficiency
Vitamin D deficiency has been historically defined and
recently recommended by the Institute of Medicine (IOM)
as a 25(OH)D of less than 20 ng/ml. Vitamin D insuffi-
ciency has been defined as a 25(OH)D of 21–29 ng/ml (3,
10, 16–20). In accordance with these definitions, it has
been estimated that 20–100% of U.S., Canadian, and Eu-
ropean elderly men and women still living in the commu-
nity are vitamin D deficient (3, 21–25). Children and
young and middle-aged adults are at equally high risk for
J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000 jcem.endojournals.org 3
vitamin D deficiency and insufficiency worldwide. Vita-
min D deficiency is common in Australia, the Middle East,
India, Africa, and South America (3, 26, 27). In the United
States, more than 50% of Hispanic and African-American
adolescents in Boston (28) and 48% of white preadoles-
cent girls in Maine had 25(OH)D below 20 ng/ml (29). In
addition, 42% of African-American girls and women aged
15–49 yr throughout the United States had a blood level
of 25(OH)D below 15 ng/ml at the end of the winter (30),
and 32% of healthy students and physicians at a Boston
hospital had 25(OH)D below 20 ng/ml (31). Pregnant and
lactating women who take a prenatal vitamin and a cal-
cium supplement with vitamin D remain at high risk for
vitamin D deficiency (32–34).
Causes of Vitamin D Deficiency
The major source of vitamin D for children and adults is
exposure to natural sunlight (3, 7, 35–37). Very few foods
naturally contain or are fortified with vitamin D. Thus, the
major cause of vitamin D deficiency is inadequate expo-
sure to sunlight (5–7, 38). Wearing a sunscreen with a sun
protection factor of 30 reduces vitamin D synthesis in the
skin by more than 95% (39). People with a naturally dark
skin tone have natural sun protection and require at least
three to five times longer exposure to make the same
amount of vitamin D as a person with a white skin tone
(40, 41). There is an inverse association of serum
25(OH)D and body mass index (BMI) greater than 30
kg/m
2
, and thus, obesity is associated with vitamin D de-
ficiency (42). There are several other causes for vitamin D
deficiency (3, 38). Patients with one of the fat malabsorp-
tion syndromes and bariatric patients are often unable to
absorb the fat-soluble vitamin D, and patients with ne-
phrotic syndrome lose 25(OH)D bound to the vitamin
D-binding protein in the urine (3). Patients on a wide va-
riety of medications, including anticonvulsants and med-
ications to treat AIDS/HIV, are at risk because these drugs
enhance the catabolism of 25(OH)D and 1,25(OH)
2
D
(43). Patients with chronic granuloma-forming disorders,
some lymphomas, and primary hyperparathyroidism who
have increased metabolism of 25(OH)D to 1,25(OH)
2
D
are also at high risk for vitamin D deficiency (44, 45).
Consequences of Vitamin D Deficiency
Vitamin D deficiency results in abnormalities in calcium,
phosphorus, and bone metabolism. Specifically, vitamin
D deficiency causes a decrease in the efficiency of intestinal
calcium and phosphorus absorption of dietary calcium
and phosphorus, resulting in an increase in PTH levels (3,
10, 22, 23). Secondary hyperparathyroidism maintains
serum calcium in the normal range at the expense of mo-
bilizing calcium from the skeleton and increasing phos-
phorus wasting in the kidneys. The PTH-mediated in-
crease in osteoclastic activity creates local foci of bone
weakness and causes a generalized decrease in bone min-
eral density (BMD), resulting in osteopenia and osteopo-
rosis. Phosphaturia caused by secondary hyperparathy-
roidism results in a low normal or low serum phosphorus
level. This results in an inadequate calcium-phosphorus
product, causing a mineralization defect in the skeleton (3,
46). In young children who have little mineral in their
skeleton, this defect results in a variety of skeletal defor-
mities classically known as rickets (24, 47). In adults, the
epiphyseal plates are closed, and there is enough mineral
in the skeleton to prevent skeletal deformities so that this
mineralization defect, known as an osteomalacia, often
goes undetected. However, osteomalacia causes a decrease in
BMD and is associated with isolated or generalized aches and
pains in bones and muscles (48, 49). Vitamin D deficiency
also causes muscle weakness; affected children have diffi-
culty standing and walking (47, 50), whereas the elderly have
increasing sway and more frequent falls (51, 52), thereby
increasing their risk of fracture.
Sources of Vitamin D
A major source of vitamin D for most humans comes from
exposure of the skin to sunlight typically between 1000 h
and 1500 h in the spring, summer, and fall (3–5, 7). Vi-
tamin D produced in the skin may last at least twice as long
in the blood compared with ingested vitamin D (53).
When an adult wearing a bathing suit is exposed to one
minimal erythemal dose of UV radiation (a slight pinkness
to the skin 24 h after exposure), the amount of vitamin D
produced is equivalent to ingesting between 10,000 and
25,000 IU (5). A variety of factors reduce the skin’s produc-
tion of vitamin D
3
, including increased skin pigmentation,
aging, and the topical application of a sunscreen (3, 39, 40).
An alteration in the zenith angle of the sun caused by a change
in latitude, season of the year, or time of day dramatically
influences the skin’s production of vitamin D
3
(3, 5). Above
and below latitudes of approximately 33°, vitamin D
3
syn-
thesis in the skin is very low or absent during most of the
winter.
Few foods naturally contain vitamin D
2
or vitamin D
3
(Table 1).
In the United States and Canada, milk is fortified with
vitamin D, as are some bread products, orange juices, ce-
reals, yogurts, and cheeses (3). In Europe, most countries
do not fortify milk with vitamin D because in the 1950s,
4Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000
there was an outbreak of vitamin D intoxication in young
children, resulting in laws that forbade the fortification of
foods with vitamin D. However, Sweden and Finland now
fortify milk, and many European countries add vitamin D
to cereals, breads, and margarine (3).
Multivitamin preparations contain 400-1000 IU of vi-
tamin D
2
or vitamin D
3
, whereas pharmaceutical prepa-
rations in the United States contain only vitamin D
2
(Table
1) (3).
1.0 Diagnostic Procedure
Recommendation
1.1 We recommend screening for vitamin D deficiency
in individuals at risk for deficiency. We do not recommend
population screening for vitamin D deficiency in individ-
uals who are not at risk (1|QQQQ).
1.1 Evidence
There is no evidence demonstrating benefits of screen-
ing for vitamin D deficiency at a population level. Such
evidence would require demonstration of the feasibility
and cost-effectiveness of such a screening strategy, as well
as benefits in terms of important health outcomes. In the
absence of this evidence, it is premature to recommend
screening at large at this time.
Currently, 25(OH)D measurement is reasonable in
groups of people at high risk for vitamin D deficiency and
in whom a prompt response to optimization of vitamin D
status could be expected (Table 2) (3, 25, 52, 54–56).
TABLE 1. Sources of vitamin D
2
and vitamin D
3
Source Vitamin D content
Natural sources
Cod liver oil ⬃400–1,000 IU/teaspoon vitamin D
3
Salmon, fresh wild caught ⬃600–1,000 IU/3.5 oz vitamin D
3
Salmon, fresh farmed ⬃100–250 IU/3.5 oz vitamin D
3
, vitamin D
2
Salmon, canned ⬃300– 600 IU/3.5 oz vitamin D
3
Sardines, canned ⬃300 IU/3.5 oz vitamin D
3
Mackerel, canned ⬃250 IU/3.5 oz vitamin D
3
Tuna, canned 236 IU/3.5 oz vitamin D
3
Shiitake mushrooms, fresh ⬃100 IU/3.5 oz vitamin D
2
Shiitake mushrooms, sun-dried ⬃1,600 IU/3.5 oz vitamin D
2
Egg yolk ⬃20 IU/yolk vitamin D
3
or D
2
Sunlight/UVB radiation ⬃20,000 IU equivalent to exposure to 1 minimal erythemal dose (MED) in a bathing
suit. Thus, exposure of arms and legs to 0.5 MED is equivalent to ingesting
⬃3,000 IU vitamin D
3
.
Fortified foods
Fortified milk 100 IU/8 oz, usually vitamin D
3
Fortified orange juice 100 IU/8 oz vitamin D
3
Infant formulas 100 IU/8 oz vitamin D
3
Fortified yogurts 100 IU/8 oz, usually vitamin D
3
Fortified butter 56 IU/3.5 oz, usually vitamin D
3
Fortified margarine 429 IU/3.5 oz, usually vitamin D
3
Fortified cheeses 100 IU/3 oz, usually vitamin D
3
Fortified breakfast cereals ⬃100 IU/serving, usually vitamin D
3
Pharmaceutical sources in the United States
Vitamin D
2
(ergocalciferol) 50,000 IU/capsule
Drisdol (vitamin D
2
) liquid 8,000 IU/cc
Supplemental sources
Multivitamin 400, 500, 1,000 IU vitamin D
3
or vitamin D
2
Vitamin D
3
400, 800, 1,000, 2,000, 5,000, 10,000, and 50,000 IU
IU ⫽25 ng. 关Reproduced with permission from M. F. Holick: N Engl J Med 357:266–281, 2007 (3). © Massachusetts Medical Society.兴
J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000 jcem.endojournals.org 5
Recommendation
1.2 We recommend using the serum circulating
25(OH)D level, measured by a reliable assay, to evaluate
vitamin D status in patients who are at risk for vitamin D
deficiency. Vitamin D deficiency is defined as a 25(OH)D
below 20 ng/ml (50 nmol/liter). We recommend against
using the serum 1,25(OH)
2
D assay for this purpose and
are in favor of using it only in monitoring certain condi-
tions, such as acquired and inherited disorders of vitamin
D and phosphate metabolism (1|QQQQ).
1.2 Evidence
25(OH)D is the major circulating form of vitamin D,
with a circulating half-life of 2–3 wk, and it is the best
indicator to monitor for vitamin D status (3, 8, 25, 54, 56).
The circulating half-life of 1,25(OH)
2
D is approximately
4 h. It circulates at 1000 times lower concentration than
25(OH)D, and the blood level is tightly regulated by
serum levels of PTH, calcium, and phosphate. Serum
1,25(OH)
2
D does not reflect vitamin D reserves, and mea-
surement of 1,25(OH)
2
D is not useful for monitoring the
vitamin D status of patients. Serum 1,25(OH)
2
Disfre
-
quently either normal or even elevated in those with vita-
min D deficiency, due to secondary hyperparathyroidism.
Thus, 1,25(OH)
2
D measurement does not reflect vitamin
D status. Measurement of 1,25(OH)
2
D is useful in ac-
quired and inherited disorders in the metabolism of
25(OH)D and phosphate, including chronic kidney dis-
ease, hereditary phosphate-losing disorders, oncogenic
osteomalacia, pseudovitamin D-deficiency rickets, vita-
min D-resistant rickets, as well as chronic granuloma-
forming disorders such as sarcoidosis and some lympho-
mas (3, 11, 50, 57, 58).
1.2 Remarks
All clinical assays, including 25(OH)D measurements,
are subject to variability. Such variability confounds at-
tempts to define a single “cut point” value as indicating
low vitamin D status. Multiple methodologies for
25(OH)D measurement exist, including RIA, HPLC, and
liquid chromatography tandem mass spectroscopy (3, 54,
59). For clinical care, it appears that all current method-
ologies are adequate if one targets a 25(OH)D value higher
than current cut points; for example, a value of 40 ng/ml
is without toxicity and virtually ensures that the individ-
ual’s “true” value is greater than 30 ng/ml. A clinical ap-
proach of targeting a higher 25(OH)D value seems pru-
dent in that improving vitamin D status should reduce
multiple adverse consequences of vitamin D deficiency at
extremely low cost with minimal toxicity risk. Finally, the
comparability of 25(OH)D results seems likely to improve
as uniform standards available through the National In-
stitute of Standards and Technology become widely
implemented.
Suggested 25(OH)D levels
Vitamin D deficiency in children and adults is a clinical
syndrome caused by a low circulating level of 25(OH)D
(3, 10, 25, 47, 50). The blood level of 25(OH)D that is
defined as vitamin D deficiency remains somewhat con-
troversial. A provocative study in adults who received
50,000 IU of vitamin D
2
once a week for 8 wk along with
calcium supplementation demonstrated a significant re-
duction in their PTH levels when their 25(OH)D was be-
low 20 ng/ml (16). Several, but not all, studies have re-
ported that PTH levels are inversely associated with
25(OH)D and begin to plateau in adults who have blood
levels of 25(OH)D between 30 and 40 ng/ml (20–22, 60);
these findings are consistent with the threshold for hip and
nonvertebral fracture prevention from a recent meta-anal-
ysis of double-blind randomized controlled trials (RCT)
with oral vitamin D (56). When postmenopausal women
who had an average blood level of 25(OH)D of 20 ng/ml
increased their level to 32 ng/ml, they increased the effi-
ciency of intestinal calcium absorption by 45–65% (17).
Thus, based on these and other studies, it has been sug-
gested that vitamin D deficiency be defined as a 25(OH)D
below 20 ng/ml, insufficiency as a 25(OH)D of 21–29
ng/ml, and sufficiency as a 25(OH)D of 30 –100 ng/ml (3).
TABLE 2. Indications for 25(OH)D measurement
(candidates for screening)
Rickets
Osteomalacia
Osteoporosis
Chronic kidney disease
Hepatic failure
Malabsorption syndromes
Cystic fibrosis
Inflammatory bowel disease
Crohn’s disease
Bariatric surgery
Radiation enteritis
Hyperparathyroidism
Medications
Antiseizure medications
Glucocorticoids
AIDS medications
Antifungals, e.g. ketoconazole
Cholestyramine
African-American and Hispanic children and adults
Pregnant and lactating women
Older adults with history of falls
Older adults with history of nontraumatic fractures
Obese children and adults (BMI ⬎30 kg/m
2
)
Granuloma-forming disorders
Sarcoidosis
Tuberculosis
Histoplasmosis
Coccidiomycosis
Berylliosis
Some lymphomas
6Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000
The IOM report (20) also concluded, based in part on the
PTH data, that vitamin D deficiency was defined as
25(OH)D below 20 ng/ml. They dismissed the calcium
absorption study by Heaney et al. (17) as being a single
study that did not directly measure calcium absorption
and noted studies such as Hansen et al. (18), which showed
no increase in intestinal calcium absorption across a broad
range of serum 25(OH)D levels. However, the Heaney et
al. (17) study was strengthened by the fact that they in-
vestigated a change in intestinal calcium absorption in the
same women who had a blood level of 25(OH)D of ap-
proximately 20 ng/ml that was raised to an average of 32
ng/ml. The normalization of PTH at certain levels of
25(OH)D indirectly implies that these values can be sug-
gested to define deficiency and insufficiency and indirectly
informs treatment decisions. Studies of vitamin D replace-
ment and treatment showing changes in patient-important
outcomes (61) at certain levels of 25(OH)D are needed and
would provide higher quality evidence that would lead to
stronger recommendations.
2.0 Recommended Dietary Intakes of
Vitamin D for Patients at Risk for Vitamin
D Deficiency
Several recent studies have suggested that the recom-
mended dietary allowances (RDA) of the IOM (20) may be
inadequate, especially for patients who have underlying
conditions or are receiving medications that put them at
risk for vitamin D deficiency. The studies were reviewed,
and Table 3 summarizes what the present RDA recom-
mendations are and what we believe should be the rec-
ommended dietary intakes, especially for patients who are
at risk based on the most current literature. These recom-
mendations are often based on lower quality evidence (ex-
pert opinion, consensus, inference from basic science ex-
periments, noncomparative or comparative observational
studies); therefore, they should be considered as sugges-
tions for patient care.
Recommendation
2.1 We suggest that infants and children aged 0–1 yr
require at least 400 IU/d (IU ⫽25 ng) of vitamin D, and
TABLE 3. Vitamin D intakes recommended by the IOM and the Endocrine Practice Guidelines Committee
Life stage
group
IOM recommendations
Committee recommendations
for patients at risk for
vitamin D deficiency
AI EAR RDA UL Daily requirement UL
Infants
0 to 6 months 400 IU (10
g) 1,000 IU (25
g) 400–1,000 IU 2,000 IU
6 to 12 months 400 IU (10
g) 1,500 IU (38
g) 400–1,000 IU 2,000 IU
Children
1–3 yr 400 IU (10
g) 600 IU (15
g) 2,500 IU (63
g) 600–1,000 IU 4,000 IU
4– 8 yr 400 IU (10
g) 600 IU (15
g) 3,000 IU (75
g) 600–1,000 IU 4,000 IU
Males
9–13 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 600–1,000 IU 4,000 IU
14–18 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 600–1,000 IU 4,000 IU
19–30 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
31–50 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
51–70 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
⬎70 yr 400 IU (10
g) 800 IU (20
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
Females
9–13 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 600–1,000 IU 4,000 IU
14–18 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 600–1,000 IU 4,000 IU
19–30 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
31–50 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
51–70 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
⬎70 yr 400 IU (10
g) 800 IU (20
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
Pregnancy
14–18 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 600–1,000 IU 4,000 IU
19–30 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
31–50 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
Lactation
a
14–18 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 600–1,000 IU 4,000 IU
19–30 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
31–50 yr 400 IU (10
g) 600 IU (15
g) 4,000 IU (100
g) 1,500–2,000 IU 10,000 IU
AI, Adequate intake; EAR, estimated average requirement; UL, tolerable upper intake level.
a
Mother’s requirement, 4,000– 6,000 IU/d (mother’s intake for infant’s requirement if infant is not receiving 400 IU/d).
J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000 jcem.endojournals.org 7
children 1 yr and older require at least 600 IU/d to max-
imize bone health. Whether 400 and 600 IU/d for children
0 –1 yr and 1–18 yr, respectively, are enough to provide all
the potential nonskeletal health benefits associated with
vitamin D is not known at this time. However, to raise the
blood level of 25(OH)D consistently above 30 ng/ml may
require at least 1000 IU/d of vitamin D (2|QQQQ).
2.1 Evidence
Birth to 18 yr
Risk factors for vitamin D deficiency and rickets in an
infant include breast-feeding without vitamin D supple-
mentation, dark skin pigmentation, and maternal vitamin
D deficiency (38, 50, 62–68). In utero, the fetus is wholly
dependent on the mother for vitamin D. The 25(OH)D
passes from the placenta into the blood stream of the fetus.
Because the half-life for 25(OH)D is approximately 2–3
wk, the infant can remain vitamin D sufficient for several
weeks after birth, as long as the mother was vitamin D
sufficient. However, most pregnant women are vitamin D
deficient or insufficient (33–35). In a study of 40 mother-
infant pairs, Lee et al. (33) reported that 76% of mothers
and 81% of newborns had a 25(OH)D below 20 ng/ml at
the time of birth, despite the fact that during pregnancy,
the mothers ingested about 600 IU/d of vitamin D from a
prenatal supplement and consumption of two glasses of
milk.
Infants depend on either sunlight exposure or dietary
vitamin D to meet their requirement from birth. Human
breast milk and unfortified cow’s milk have very little vi-
tamin D (32). Thus, infants who are fed only human breast
milk are prone to developing vitamin D deficiency, espe-
cially during the winter when neither they nor their moth-
ers can obtain vitamin D from sunlight. Conservative es-
timates suggest that to maintain serum 25(OH)D
concentrations above 20 ng/ml, an infant in the Midwest
fed human milk must be exposed to sunlight in the summer
about 30 min/wk while wearing just a diaper (69, 70).
Human milk and colostrum contain low amounts of
vitamin D, on average 15.9 ⫾8.6 IU/liter (32). There is a
direct relationship between vitamin D intake and vitamin
D content in human milk. However, even when women
were consuming between 600 and 700 IU/d of vitamin D,
the vitamin D content in their milk was only between 5 and
136 IU/liter (71). Preliminary data suggest that only after
lactating women were given 4000– 6000 IU/d of vitamin
D was enough vitamin D transferred in breast milk to
satisfy her infant’s requirement (32).
Vitamin D intakes between 340 and 600 IU/d have been
reported to have the maximum effect on linear growth of
infants (72, 73). When Chinese infants were given 100,
200, or 400 IU/d of vitamin D, none demonstrated any
evidence of rickets (74). This observation is consistent
with what Jeans (75) observed in 1950, and it was the basis
for recommending that children only need 200 IU/d of
vitamin D. However, Markestad and Elzouki (76) re-
ported that Norwegian infants fed formula containing
300 IU/d obtained blood levels of 25(OH)D above 11 ng/
ml, which at the time was considered the lower limit of
normal. However, the IOM report says that the blood level
should be at least 20 ng/ml, which implies that consuming
even 300 IU/d is not adequate for infants (20, 47, 77).
Pediatric health care providers need to be aware of the
deleterious effects of rickets on growth and bone devel-
opment, including potential effects on bone density and
development of peak bone mass (78). Musculoskeletal
signs of rickets are well-described (47, 50, 66, 79, 80).
The American Academy of Pediatrics and the Canadian
Pediatric Association (77) both recommended 400 IU/d.
The IOM (20) recommended that the adequate intake and
RDA for children 0 –1 and 1–18 yr should be 400 and 600
IU/d, respectively. Whether 400 and 600 IU/d for these
children is enough to provide all the health benefits asso-
ciated with vitamin D is not known at this time.
Infants who received at least 2000 IU/d of vitamin D
during the first year of life in Finland reduced their risk of
developing type 1 diabetes in the ensuing 31 yr by 88%,
without any reports of toxicity (81). Japanese children
who received 1200 IU/d of vitamin D from December
through March compared with placebo reduced their risk
of influenza A by 42% (82). African-American normo-
tensive children (16.3 ⫾1.4 yr) who received 2000 IU/d
compared with 400 IU/d for 16 wk in a randomized con-
trolled trial had significantly higher serum 25(OH)D levels
(36 ⫾14 vs. 24 ⫾7 ng/ml) and significantly lower arterial
wall stiffness (83).
In the past, children of all races obtained most of their
vitamin D from exposure to sunlight and drinking vitamin
D-fortified milk, and therefore, they did not need to take
a vitamin D supplement (3, 84). However, children are
spending more time indoors now, and when they go out-
side, they often wear sun protection that limits their ability
to make vitamin D in their skin. Children and adolescents
are also drinking less vitamin D-fortified milk (28, 29,
85–90). There are reports that children of all ages are at
high risk for vitamin D deficiency and insufficiency and its
insidious health consequences (91–93), but with the cutoff
of 20 ng/ml set by the IOM (20), the prevalence of vitamin
D deficiency should be reevaluated. There are no data on
how much vitamin D is required to prevent vitamin D
deficiency in children aged 1–9 yr. A few studies have
shown that during the pubertal years, children maintained
a serum 25(OH)D above 11 ng/ml with dietary vitamin D
intakes of 2.5–10
g/d (100– 400 IU/d) (94). When in-
8Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000
takes were less than 2.5
g/d, Turkish children aged 12–17
yr had 25(OH)D levels consistent with vitamin D defi-
ciency, i.e. below 11 ng/ml (95). A 2008 study by Maalouf
et al. (91) suggests that this age group needs 2000 IU/d
vitamin D to maintain a blood level above 30 ng/ml. An-
other study, by El-Hajj Fuleihan (96), provides an insight
into the vitamin D requirement for children aged 10 –17 yr
(who were presumably exposed to an adequate amount of
sun-mediated vitamin D because they lived in Lebanon)
who ingested weekly doses of either 1,400 or 14,000 IU
vitamin D
3
for 1 yr. Those who received 1400 IU/wk in-
creased their blood level of 25(OH)D from 14 ⫾8to17⫾
6 ng/ml, whereas the children who received 14,000 IU/wk
for 1 yr increased their blood levels from 14 ⫾8to38⫾
31 ng/ml. No signs of intoxication (hypercalcemia) were
noted in the group receiving 14,000 IU/wk, although three
subjects had a high 25(OH)D at the end of the study (103,
161, and 195 ng/ml) (96).
Children aged 9–18 yr have a rapid growth spurt char-
acterized by a marked increase in their requirement of
calcium and phosphorus to maximize skeletal mineraliza-
tion. During puberty, the metabolism of 25(OH)D to
1,25(OH)
2
D increases. In turn, the increased blood levels
of 1,25(OH)
2
D enhance the efficiency of the intestine to
absorb dietary calcium and phosphorus to satisfy the
growing skeleton’s requirement for these minerals during
its rapid growth phase. However, although production of
1,25(OH)
2
D is increased, there is no scientific evidence to
date demonstrating an increased requirement for vitamin
D in this age group, possibly because circulating concen-
trations of 1,25(OH)
2
D are approximately 500-1000
times lower than those of 25(OH)D (i.e. 15–60 pg/ml vs.
20–100 ng/ml, respectively) (97).
Recommendation
2.2 We suggest that adults aged 19–50 yr require at
least 600 IU/d of vitamin D to maximize bone health and
muscle function. It is unknown whether 600 IU/d is
enough to provide all the potential nonskeletal health ben-
efits associated with vitamin D. However, to raise the
blood level of 25(OH)D consistently above 30 ng/ml may
require at least 1500–2000 IU/d of vitamin D (2|QQQQ).
2.2 Evidence
Ages 19–50 yr
This age group is at risk for vitamin D deficiency be-
cause of decreased outdoor activities and aggressive sun
protection. Available data have not sufficiently explored
the relationship between total vitamin D intake per se and
health outcomes, nor have data shown that a dose-re-
sponse relationship between vitamin D intake and bone
health is lacking (20).
Very few studies have evaluated this age group’s vita-
min D requirement. However, in the large Third National
Health and Nutrition Examination Survey (NHANES III)
population-based study, a threshold for optimal 25(OH)D and
hip bone density has been addressed among 13,432
younger (20– 49 yr) and older (50⫹yr) individuals with
different ethnic and racial background (98). Compared
with the lowest quintile of 25(OH)D, the highest quintile
had higher mean bone density by 4.1% in younger whites
(test for trend; P⬍0.0001), by 1.8% in younger Mexican-
Americans (P⫽0.004), and by 1.2% in younger blacks
(P⫽0.08). In the regression plots, higher serum 25(OH)D
levels were associated with higher BMD throughout the ref-
erence range of 10 to 38 ng/ml in all subgroups. In younger
whites and younger Mexican-Americans, higher 25(OH)D
was associated with higher BMD, even beyond 40 ng/ml. An
evaluation of 67 white and 70 black premenopausal women
ingesting 138 ⫾84 and 145 ⫾73 IU/d, respectively, revealed
that serum 25(OH)D levels were in the insufficient or defi-
cient range (circulating concentrations of 21.4 ⫾4 and
18.3 ⫾5 ng/ml, respectively) (99).
During the winter months (November through May) in
Omaha, Nebraska, 6% of young women aged 25–35 yr
(n ⫽52) maintained serum concentrations of 25(OH)D
above 20 ng/ml but below 30 ng/ml when estimated daily
vitamin D intake was between 131 and 135 IU/d (100).
Healthy adults aged 18– 84 yr who received 1000 IU/d
vitamin D
3
for 3 months during the winter increased their
25(OH)D from 19.6 ⫾11.1 to 28.9 ⫾7.7 ng/ml (101).
A dose-ranging study reported that men who received
10,000 IU/d of vitamin D
3
for 5 months did not experience
any alteration in either serum calcium or urinary calcium
excretion (127). Adults older than 18 yr who received
50,000 IU vitamin D
2
every 2 wk (which is equivalent to
3000 IU/d) for up to 6 yr had a normal serum calcium and
no evidence of toxicity (102).
Recommendation
2.3 We suggest that all adults aged 50–70 and 70⫹yr
require at least 600 and 800 IU/d, respectively, of vitamin
D to maximize bone health and muscle function. Whether
600 and 800 IU/d of vitamin D are enough to provide all of
the potential nonskeletal health benefits associated with vi-
tamin D is not known at this time. However, to raise the
blood level of 25(OH)D above 30 ng/ml may require at least
1500–2000 IU/d of supplemental vitamin D (2|QQQQ).
2.3 Evidence
Men and women older than 51 yr depend on sunlight
for most of their vitamin D requirement. Increased use of
clothing and sunscreen over sun-exposed areas and de-
creased consumption of vitamin D-fortified milk increases
J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000 jcem.endojournals.org 9
the risk for vitamin D deficiency (3, 31, 39, 103). In ad-
dition, age decreases the capacity of the skin to produce
vitamin D
3
(3). Although it has been suggested that aging
may decrease the ability of the intestine to absorb dietary
vitamin D, studies have revealed that aging does not alter
the absorption of physiological or pharmacological doses
of vitamin D (101, 104–106).
The IOM report (20) suggests that 25(OH)D levels
need to be at least 20 ng/ml to maintain skeletal health.
Prior estimates have ranged from as little as 12 to as high
as 40 ng/ml (107). Recently, Priemel et al. (108) examined
675 iliac crest biopsies from male and female German
adults (401 males, mean age, 58.2 yr; and 270 females,
mean age, 68.2 yr) for structural histomorphometric pa-
rameters including osteoid indices. They reported that al-
though they could not establish a minimum 25(OH)D
level that was inevitably associated with mineralization de-
fects, they did not find pathological accumulation of osteoid
in any patients with circulating 25(OH)D above 30 ng/ml.
They concluded that in conjunction with sufficient calcium
intake, the dose of vitamin D supplementation should ensure
that circulating levels of 25(OH)D reach a minimum thresh-
old of 30 ng/ml to maintain skeletal health. In contrast, the
IOM (20) concluded from the same study that a level of
25(OH)D of 20 ng/ml was adequate to prevent osteomalacia
in at least 97.5% of the population and therefore recom-
mended a threshold of 20 ng/ml to maintain skeletal health
in 97.5% of the adult population.
Many studies have evaluated the influence of dietary
vitamin D supplementation on serum 25(OH)D, PTH,
and bone health as measured by BMD and fracture risks
in older men and women. Several randomized, double-
blind clinical trials of senior men and women who had an
intake of 400 IU/d showed insufficient 25(OH)D levels
(25, 55, 80, 109–112). When men and women received
supplements of 400-1000 IU/d, they had a significant re-
duction in bone resorption. In a randomized, placebo-
controlled trial of elderly French women, those given cal-
cium and 800 IU/d of vitamin D had significantly fewer
vertebral and nonvertebral fractures (113). A similar ob-
servation was made in free-living men and women aged 65
yr and older who received 500 mg of calcium and 700 IU/d
of vitamin D (114).
A threshold for optimal 25(OH)D and hip BMD has been
addressed among 13,432 individuals studied in the
NHANES III, including both younger (20– 49 yr) and older
(⬎50 yr) individuals with different ethnic and racial back-
grounds (98). In the regression plots, higher hip BMD was
associated with higher serum 25(OH)D levels throughout
the reference range of 9–37 ng/ml in all subgroups.
A 2005 meta-analysis of high-quality primary preven-
tion RCT of vitamin D and fracture risk consistently found
that antifracture efficacy of vitamin D increases with a
higher achieved level of 25(OH)D (Fig. 1) (51). Antifrac-
ture efficacy started at 25(OH)D levels of at least 30 ng/ml.
This level was reached only in trials that gave 700– 800
IU/d vitamin D
3
(high-quality trials with oral vitamin D
2
were not available at the time).
The most up-to-date meta-analysis focused on antifrac-
ture efficacy from high-quality double-blind RCT (55).
The higher received dose (treatment doseⴱadherence) of
482–770 IU/d vitamin D reduced nonvertebral fractures
in community-dwelling (⫺29%) and institutionalized
(⫺15%) older individuals, and its effect was independent
of additional calcium supplementation (⫺21% with ad-
ditional calcium supplementation; ⫺21% for the main
effect of vitamin D). As with the 2005 meta-analysis, an-
tifracture efficacy started at 25(OH)D levels of at least 30
ng/ml (75 nmol/liter).
Muscle weakness is a prominent feature of the clinical
syndrome of severe vitamin D deficiency. Clinical findings
in vitamin D-deficiency myopathy include proximal mus-
cle weakness, diffuse muscle pain, and gait impairments
such as a waddling way of walking (115, 116).
Double-blind RCT demonstrated that 800
IU/d vitamin D
3
resulted in a 4–11% gain in
lower extremity strength or function (80, 117),
an up to 28% improvement in body sway (117,
118), and an up to 72% reduction in the rate of
falling (119) in adults older than 65 yr after 5
months of treatment.
Several systematic reviews and meta-analy-
ses have demonstrated a reduction in falls as-
sociated with interventions to raise 25(OH)D
levels. Murad et al. (120) demonstrated that
such interventions were associated with statis-
tically significant reduction in the risk of falls
[odds ratio (OR) ⫽0.84; 95% confidence in-
terval (CI), 0.76– 0.93; inconsistency (I
2
)⫽
FIG. 1. Fracture efficacy by achieved 25(OH)D levels. To convert nmol/liter to ng/ml,
divide by 2.496. [Reproduced with permission from H. A. Bischoff-Ferrari et al.:
JAMA 293:2257–2264, 2005 (51). © American Medical Association.]
10 Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000
61%; 23 studies). This effect was more prominent in pa-
tients who were vitamin D deficient at baseline. Results of
other reviews were consistent. A meta-analysis of only five
high-quality double-blind RCT (n ⫽1237) found that
vitamin D reduced the falling risk by 22% (pooled cor-
rected OR ⫽0.78; 95% CI, 0.64– 0.92) compared with
calcium or placebo (116). For two trials with a total of 259
subjects using 800 IU/d of vitamin D
3
over 2 to 3 months
(117, 121), the corrected pooled OR was 0.65 (95% CI,
0.40- 1.00) (116), whereas 400 IU/d was insufficient to
reduce falls (122). The importance of dose of supplemen-
tal vitamin D in minimizing risk of falls was confirmed by
a multidose double-blind RCT among 124 nursing home
residents receiving 200, 400, 600, or 800 IU/d vitamin D
or placebo over 5 months (119) and by a 2009 meta-anal-
ysis (52). Participants receiving 800 IU/d had a 72% lower
rate of falls than those taking placebo or a lower dose of
vitamin D (rate ratio ⫽0.28; 95% CI, 0.11–0.75).
In the 2009 meta-analysis for supplemental vitamin D,
eight high-quality RCT (n ⫽2426) were identified, and
heterogeneity was observed for dose of vitamin D (low
dose, ⬍700 IU/d, vs. higher dose, 700 to 1000 IU/d; P⫽
0.02) and achieved 25(OH)D level (⬍24 ng/ml vs. 24 ng/
ml; P⫽0.005). Higher dose supplemental vitamin D re-
duced fall risk by 19% [pooled relative risk (RR) ⫽0.81;
95% CI, 0.71–0.92; n ⫽1921 from seven trials). Falls
were not reduced by low-dose supplemental vitamin D
(pooled RR ⫽1.10; 95% CI, 0.89–1.35 from two trials)
or by achieved serum 25(OH)D concentrations below 24
ng/ml (pooled RR ⫽1.35; 95% CI, 0.98–1.84). At the
higher dose of vitamin D, the meta-analysis documented a
38% reduction in the risk of falling with treatment dura-
tion of 2 to 5 months and a sustained effect of 17% fall
reduction with treatment duration of 12 to 36 months
(52). Most recently, the IOM did a very thorough review
on the effect of vitamin D on fall prevention (20). Their
synopsis is that the evidence of vitamin D on fall preven-
tion is inconsistent, which is in contrast to the 2010 as-
sessment by the International Osteoporosis Foundation
and the 2011 assessment of the Agency for Healthcare
Research and Quality for the U.S. Preventive Services Task
Force (123), both of which identified vitamin D as an
effective intervention to prevent falling in older adults.
Recommendation
2.4 We suggest that pregnant and lactating women re-
quire at least 600 IU/d of vitamin D and recognize that at
least 1500–2000 IU/d of vitamin D may be needed to
maintain a blood level of 25(OH)D above 30 ng/ml
(2|QQQE).
2.4 Evidence
Pregnancy and lactation
During the first and second trimesters, the fetus is de-
veloping most of its organ systems and laying down the
collagen matrix for its skeleton. During the last trimester,
the fetus begins to calcify the skeleton, thereby increasing
maternal demand for calcium. This demand is met by in-
creased production of 1,25(OH)
2
D by the mother’s kid-
neys and placenta. Circulating concentrations of
1,25(OH)
2
D gradually increase during the first and sec-
ond trimesters, owing to an increase in vitamin D-binding
protein concentrations in the maternal circulation. How-
ever, the free levels of 1,25(OH)
2
D, which are responsible
for enhancing intestinal calcium absorption, are only in-
creased during the third trimester. Pregnant women are at
high risk for vitamin D deficiency, which increases the risk
of preeclampsia (34) and cesarean section (124). Daily
doses of 600 IU do not prevent vitamin D deficiency in preg-
nant women (34, 124). Their daily regimen should at least
include a prenatal vitamin containing 400 IU vitamin D with
a supplement that contains at least 1000 IU vitamin D.
During lactation, the mother needs to increase the ef-
ficiency of dietary absorption of calcium to ensure ade-
quate calcium content in her milk. The metabolism of
25(OH)D to 1,25(OH)
2
D is enhanced in response to this
new demand. However, because circulating concentra-
tions of 1,25(OH)
2
D are 500-1000 times less than
25(OH)D, the increased metabolism probably does not
significantly alter the daily requirement for vitamin D. To
satisfy their requirement to maintain a 25(OH)D above 30
ng/ml, lactating women should take at least a multivitamin
containing 400 IU vitamin D along with at least 1000 IU
vitamin D supplement every day. To satisfy the require-
ments of an infant who is fed only breast milk, the mother
requires 4000 to 6000 IU/d to transfer enough vitamin D
into her milk (32). Thus, at a minimum, lactating women
may need to take 1400–1500 IU/d, and to satisfy their
infant’s requirement, they may need 4000– 6000 IU/d if
they choose not to give the infant a vitamin D supplement.
Recommendation
2.5 We suggest that obese children and adults and chil-
dren and adults on anticonvulsant medications, glucocor-
ticoids, antifungals such as ketoconazole, and medications
for AIDS be given at least two to three times more vitamin
D for their age group to satisfy their body’s vitamin D
requirement (2|QQQQ).
2.5 Evidence
Obesity and medications
Obese adults (BMI ⬎30 kg/m
2
) are at high risk for
vitamin D deficiency because the body fat sequesters the
J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000 jcem.endojournals.org 11
fat-soluble vitamin. When obese and nonobese adults
were exposed to simulated sunlight or received an oral
dose of 50,000 IU of vitamin D
2
, they were able to raise
their blood levels of vitamin D by no more than 50%
compared with nonobese adults. Patients on multiple an-
ticonvulsant medications, glucocorticoids, or AIDS treat-
ment are at increased risk for vitamin D deficiency because
these medications increase the catabolism of 25(OH)D (3,
42, 43).
Recommendation
2.6 We suggest that the maintenance tolerable UL of
vitamin D, which is not to be exceeded without medical
supervision, should be 1000 IU/d for infants up to 6
months, 1500 IU/d for infants from 6 months to 1 yr, at
least 2500 IU/d for children aged 1–3 yr, 3000 IU/d for
children aged 4– 8 yr, and 4000 IU/d for everyone over 8
yr. However, higher levels of 2000 IU/d for children 0–1
yr, 4000 IU/d for children 1–18 yr, and 10,000 IU/d for
children and adults 19 yr and older may be needed to
correct vitamin D deficiency (2|QQQQ).
2.6 Evidence
Vitamin D is a fat-soluble vitamin and is stored in the
body’s fat. Thus, there is concern about the potential tox-
icity of vitamin D. Bariatric patients who were found to
have vitamin D in their fat (4–320 ng/g) showed no sig-
nificant change in their serum 25(OH)D levels 3, 6, and 12
months after surgery (125). Limited human data (125,
126) show relatively low levels of vitamin D storage in fat
at prevailing inputs. Neonates who were given at least
2000/d IU of vitamin D for 1 yr in Finland not only did not
experience any untoward side effect but also had the ben-
efit of reducing their risk of developing type 1 diabetes by
88% in later life (81).
Preteen and teen girls who received an equivalent of
2000 IU/d of vitamin D for 1 yr showed improvement in
muscle mass without any untoward side effects (96). A
dose-ranging study reported that 10,000 IU/d of vitamin
D
3
for 5 months in men did not alter either urinary calcium
excretion or their serum calcium (127). A 6-yr study of
men and women aged 18– 84 yr who received an equiv-
alent of 3000 IU/d of vitamin D
2
reported no change in
serum calcium levels or increased risk of kidney stones
(102). However, long-term dose-ranging studies in chil-
dren are lacking.
Based on all of the available literature, the panel con-
cluded that vitamin D toxicity is a rare event caused by
inadvertent or intentional ingestion of excessively high
amounts of vitamin D. Although it is not known what the
safe upper value for 25(OH)D is for avoiding hypercalce-
mia, most studies in children and adults have suggested
that the blood levels need to be above 150 ng/ml before
there is any concern. Therefore, an UL of 100 ng/ml pro-
vides a safety margin in reducing risk of hypercalcemia (3,
96). The IOM report (20) recommended that the tolerable
UL for vitamin D should be 1000 IU/d for children 0– 6
months, 1500 IU/d for children 6 months to 1 yr, 2500
IU/d for children 1–3 yr, and 3000 IU/d for children 4– 8
yr. For children 9 yr and older and all adults, they recom-
mend that the UL be 4000 IU/d. These recommendations
were based on a variety of observations dating back to the
1940s. They also recognized that high intakes of calcium
along with high intakes of vitamin D exacerbate the risk
for hypercalcemia. Hyppo¨nen et al. (81) observed that
children during their first year of life received 2000 IU/d of
vitamin D without any untoward toxicity. To prevent
rickets, children during their first year of life received as
much as 250,000 IU of vitamin D as a single im injection
without any reported toxicity. Therefore, it is reasonable
for the UL to be 2000 IU/d for children 0–1 yr of age.
Toddlers who received 2000 IU/d of vitamin D for 6 wk
raised their blood level from 17 to 36 ng/ml without any
reported toxicity (47). Although no long-term studies have
examined these higher doses of vitamin D on serum cal-
cium levels, there are no reported cases of vitamin D in-
toxication in the literature to suggest that intakes of up to
4000 IU/d of vitamin D cause hypercalcemia. In healthy
adults, 5 months of ingesting 10,000 IU/d of vitamin D
neither caused hypercalcemia nor increased urinary cal-
cium excretion, which is the most sensitive indicator for
potential vitamin D intoxication (127). Therefore, a UL of
10,000 IU/d of vitamin D for adults is reasonable.
Hence, vitamin D supplementation should not be a ma-
jor concern except in certain populations who may be
more sensitive to it. Patients who have chronic granuloma-
forming disorders including sarcoidosis or tuberculosis,
or chronic fungal infections, and some patients with
lymphoma have activated macrophages that produce
1,25(OH)
2
D in an unregulated fashion (3, 44). These pa-
tients exhibit an increase in the efficiency of intestinal cal-
cium absorption and mobilization of calcium from the
skeleton that can cause hypercalciuria and hypercalcemia.
Thus, their 25(OH)D and calcium levels should be mon-
itored carefully. Hypercalciuria and hypercalcemia are
usually observed only in patients with granuloma-forming
disorders when the 25(OH)D is above 30 ng/ml (44).
3.0 Treatment and Prevention Strategies
Recommendation
3.1 We suggest using either vitamin D
2
or vitamin D
3
for the treatment and prevention of vitamin D deficiency
(2|QQQQ).
12 Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000
3.1 Evidence
Some (47, 101, 128) but not all (129 –131) studies have
shown that both vitamin D
2
and vitamin D
3
are effective
in maintaining serum 25(OH)D levels. Two meta-analyses
of double-blind RCT suggested reduction in falls and non-
vertebral fractures with vitamin D
2
compared with vita-
min D
3
(52, 56).
Several studies using vitamin D
2
and vitamin D
3
as an
intervention have recorded changes in serum 25(OH)D
after up to 6 yr of treatment (47, 96, 102), and dose-
ranging studies extending out to 5 months of continuous
therapy produced data with respect to the steady-state
inputs needed to produce and sustain a specified level of
25(OH)D (127). Results of these studies converge on a rate
of rise in serum 25(OH)D at approximately 0.4 ng/ml/
g/d, which means that ingesting 100 IU/d of vitamin D
increases serum 25(OH)D by less than 1 ng/ml approxi-
mately (101, 127). For example, a typical patient with a
serum 25(OH)D level of 15 ng/ml would require an ad-
ditional daily input of about 1500 IU of vitamin D
2
or
vitamin D
3
to reach and sustain a level of 30 ng/ml. Most
of these studies have been conducted in adults. Similar
changes in 25(OH)D have been observed in children (47,
96); two to three times as much vitamin D, however, is
required to achieve this same increase in serum 25(OH)D
levels in patients who are obese (3, 38, 42).
Vitamin D can be taken on an empty stomach or with
a meal. It does not require dietary fat for absorption. Vi-
tamin D given three times a year, once a week, or once a
day can be effective in maintaining serum 25(OH)D levels
in both children and adults (23, 47, 61, 96, 102).
Recommendation
3.2 For infants and toddlers aged 0–1 yr who are vi-
tamin D deficient, we suggest treatment with 2000 IU/d of
vitamin D
2
or vitamin D
3
, or with 50,000 IU of vitamin D
2
or vitamin D
3
once weekly for 6 wk to achieve a blood level
of 25(OH)D above 30 ng/ml followed by maintenance
therapy of 400-1000 IU/d (2|QQQQ).
3.2 Evidence
Vitamin D-deficient infants and toddlers who received
either 2000 IU of vitamin D
2
or vitamin D
3
daily or 50,000
IU of vitamin D
2
weekly for 6 wk demonstrated equivalent
increases in their serum 25(OH)D levels (47). No signs of
vitamin D intoxication were seen with any of the three
regimens studied.
Children with rickets have been successfully treated
with 600,000 IU of vitamin D either orally or im once a
year (47, 50). In the United States, there are two pharma-
ceutical formulations of vitamin D. For the pediatric pop-
ulation, vitamin D
2
is available in a liquid form at a con-
centration of 8000 IU/ml, and for older children and
adults, a gelatin capsule containing 50,000 IU of vitamin
D
2
is available.
Recommendation
3.3 For children aged 1–18 yr who are vitamin D de-
ficient, we suggest treatment with 2000 IU/d of vitamin D
2
or vitamin D
3
for at least 6 wk or with 50,000 IU of vi-
tamin D
2
once a week for at least 6 wk to achieve a blood
level of 25(OH)D above 30 ng/ml followed by mainte-
nance therapy of 600-1000 IU/d (2|QQQQ).
3.3 Evidence
Children of all ages are at risk for vitamin D deficiency
and insufficiency (3, 29, 47, 77, 84–90), with the caveat
that at present we do not know optimal serum 25(OH)D
levels for any functional outcome. Vitamin D-deficient
infants and toddlers who received either 2000 IU of vita-
min D
2
or vitamin D
3
daily or 50,000 IU of vitamin D
2
weekly for 6 wk demonstrated equivalent increases in their
serum 25(OH)D levels (47). There are sparse data to guide
pediatric clinicians in the treatment of young children with
vitamin D deficiency. One study showed that infants with
vitamin D deficiency who receive doses of ergocalciferol
exceeding 300,000 IU as a one-time dose were at high risk
for hypercalcemia (132). Therefore, most pediatric pro-
viders use lower dose daily or weekly regimens. Caution
also needs to be shown in children with Williams syn-
drome or other conditions predisposing to hypercalcemia
(133).
Some studies indicate that children who receive adult
doses of vitamin D experience changes in 25(OH)D sim-
ilar to those seen in adults (47, 96). In accordance with the
findings of Maalouf et al. (91), this age group needs 2000
IU/d vitamin D to maintain a blood level above 30 ng/ml.
Children who received 1400 IU/wk increased their blood
level of 25(OH)D from 14 ⫾9to17⫾6 ng/ml, whereas
children who received 14,000 IU/wk for 1 yr increased
their blood levels from 14 ⫾8to38⫾31 ng/ml.
Recommendation
3.4 We suggest that all adults who are vitamin D defi-
cient be treated with 50,000 IU of vitamin D
2
or vitamin
D
3
once a week for 8 wk or its equivalent of 6000 IU/d of
vitamin D
2
or vitamin D
3
to achieve a blood level of
25(OH)D above 30 ng/ml, followed by maintenance ther-
apy of 1500–2000 IU/d (2|QQQQ).
3.4 Evidence
A dose of 50,000 IU of vitamin D
2
once a week for 8 wk
is often effective in correcting vitamin D deficiency in
adults (3, 16). Patients who do not show an increase in
J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000 jcem.endojournals.org 13
their blood level of 25(OH)D should be worked up for
celiac disease or occult cystic fibrosis, assuming that they
were compliant with treatment. To prevent recurrence of
vitamin D deficiency, 50,000 IU of vitamin D
2
once every
other week was effective in maintaining blood levels of
25(OH)D between 35 and 50 ng/ml without any unto-
ward toxicity (102). Obese adults need at least two to three
times more vitamin D to treat and prevent vitamin D de-
ficiency (38, 42).
Alternative strategies for nursing home residents include
50,000 IU of vitamin D
2
three times per week for 1 month
(134) or 100,000 IU of vitamin D every 4 months (61).
Recommendation
3.5 In obese patients, patients with malabsorption syn-
dromes, and patients on medications affecting vitamin D
metabolism, we suggest a higher dose (two to three times
higher; at least 6000–10,000 IU/d) of vitamin D to treat
vitamin D deficiency to maintain a 25(OH)D level above
30 ng/ml, followed by maintenance therapy of at least
3000– 6000 IU/d (2|QQQQ).
3.5 Evidence
Obese adults need at least two to three times more vitamin
D (at least 6000–10,000 IU/d) to treat and prevent vitamin
D deficiency (42, 135). Patients receiving anticonvulsant
medications, glucocorticoids, and a wide variety of other
medications that enhance the activation of the steroid xeno-
biotic receptor that results in the destruction of 25(OH)D
and 1,25(OH)
2
D often require at least two to three times
more vitamin D (at least 6000–10,000 IU/d) to treat and
prevent vitamin D deficiency (3, 43). In both groups, the
serum 25(OH)D level should be monitored and vitamin D
dosage adjusted to achieve a 25(OH)D level above 30 ng/ml.
Recommendation
3.6 In patients with extrarenal production of
1,25(OH)
2
D, we suggest serial monitoring of 25(OH)D
levels and serum calcium levels during treatment with vi-
tamin D to prevent hypercalcemia (2|QQQQ).
3.6 Evidence
Patients who suffer from chronic granuloma-forming
disorders including sarcoidosis, tuberculosis, and chronic
fungal infections and some patients with lymphoma have
activated macrophages that produce 1,25(OH)
2
Dinan
unregulated fashion (3, 44). This results in an increase in
the efficiency of intestinal calcium absorption and mobi-
lization of calcium from the skeleton that can cause hy-
percalciuria and hypercalcemia. These patients may re-
quire vitamin D treatment to raise their blood level of
25(OH)D to approximately 20–30 ng/ml to prevent vita-
min D-deficiency metabolic bone disease while mitigating
hypercalciuria and hypercalcemia.
The 25(OH)D levels need to be carefully monitored for
these patients. Hypercalciuria and hypercalcemia are usu-
ally observed when the 25(OH)D is above 30 ng/ml (44).
Recommendation
3.7 For patients with primary hyperparathyroidism
and vitamin D deficiency, we suggest treatment with vi-
tamin D as needed. Serum calcium levels should be mon-
itored (2|QQQQ).
3.7 Evidence
Patients with primary hyperparathyroidism and hyper-
calcemia are often vitamin D deficient. It is important to
correct their vitamin D deficiency and maintain suffi-
ciency. Most patients will not increase their serum calcium
level, and serum PTH may even decrease (45). Their serum
calcium should be monitored.
4.0 Noncalcemic Benefits of Vitamin D
Recommendation
4.1 We recommend prescribing vitamin D supplemen-
tation for fall prevention. We do not recommend prescrib-
ing vitamin D supplementation beyond recommended
daily needs for the purpose of preventing cardiovascular
disease or death or improving quality of life (2|QQQQ).
4.1 Evidence
Because most tissues and cells in the body have a vita-
min D receptor and 1,25(OH)
2
D influences the expression
levels along with other factors of up to one third of the
human genome, it is not at all unexpected that a numerous
of studies has demonstrated an association of vitamin D
deficiency with increased risk of more than a dozen can-
cers, including colon, prostate, breast, and pancreas; au-
toimmune diseases, including both type 1 and type 2 di-
abetes, rheumatoid arthritis, Crohn’s disease, and
multiple sclerosis; infectious diseases; and cardiovascular
disease. There are, however, very few RCT with a dosing
range adequate to provide level I evidence for the benefit
of vitamin D in reducing the risk of these chronic diseases
(20). In the cancer prevention study by Lappe et al. (136),
postmenopausal women who received 1100 IU of vitamin
D
3
daily along with calcium supplementation reduced their
overall risk of all cancers by more than 60%. This was as-
sociated with an increase in mean serum 25(OH)D levels
from 29–39 ng/ml. Several observational studies have re-
ported that colon cancer risk became progressively lower as
serum 25(OH)D increased up to 30–32 ng/ml. However,
because population values above 30–32 ng/ml are uncom-
14 Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000
mon, most observational studies do not extend much beyond
this level of repletion, and thus, observational data are largely
silent about the optimal 25(OH)D levels.
Several studies found associations between 25(OH)D
levels and hypertension, coronary artery calcification, as
well as prevalent and incident heart disease (137–140).
Prevalent myocardial infarction (MI) was found to be in-
versely associated with plasma 25(OH)D levels. The RR of
MI for subjects with levels at the median or above was 0.43
(95% CI, 0.27–0.69), compared with subjects below the
median. Similarly, individuals with levels below 15 ng/ml
had a multivariable-adjusted hazard ratio of 1.62 (95%
CI, 1.11–2.36) for incident cardiovascular events com-
pared with those with levels above 15 ng/ml (137). Fur-
thermore, although vitamin D deficiency is documented in
long-term stroke survivors and is associated with post-
stroke hip fractures, recent reports demonstrated low lev-
els of 25(OH)D in patients presenting with acute strokes,
suggesting that this deficiency had likely preceded the
stroke and may be a potential risk factor for it (141).
Therefore, two systematic reviews were conducted as
well as meta-analyses to summarize the best available re-
search evidence regarding the effect of vitamin D-raising
interventions on functional outcomes (falls, pain, quality
of life) and cardiovascular outcomes (death, stroke, MI,
cardiometabolic risk factors) (120, 142).
Vitamin D-raising interventions were associated with a
not significant and potentially trivial reduction in mortal-
ity that was consistent across studies (RR ⫽0.96; 95% CI,
0.93–1.00; P⫽0.08; I2 ⫽0%). There was no significant
effect on MI (RR ⫽1.02; 95% CI, 0.93–1.13; P⫽0.64;
I2 ⫽0%), stroke (RR ⫽1.05; 95% CI, 0.88–1.25; P⫽
0.59; I2 ⫽15%), lipid fractions, glucose, or blood pres-
sure; blood pressure results were inconsistent across stud-
ies, and the pooled estimates were trivial in absolute terms
(142). In terms of functional outcomes, there was a clear
reduction in the risk of falls as mentioned earlier, but no effect
on pain or quality of life. The evidence supporting the latter
outcomes was sparse, inconsistent, and of lower quality.
4.1 Values
The Task Force acknowledges the overall low-quality
evidence in this area (20) and the fact that many of their
recommendations are based on understanding of the bi-
ology of vitamin D pharmacokinetics, bone and minerals,
basic science experiments, and epidemiological studies.
Nevertheless, in making recommendations, the panel
placed the highest value on preserving musculoskeletal
health and preventing childhood rickets and adult bone
disease, and less value on vitamin D cost and potential for
toxicity. Vitamin D supplementation/treatment is likely
inexpensive and would be cost-effective, particularly in
treating entities such as osteoporosis, rickets, and osteo-
malacia. Cost and resource utilization in other preventive
indications are less known. Ample evidence provided the
panel with a high level of confidence that toxicity of vi-
tamin D at the recommended dosages is quite unlikely. The
Task Force also acknowledges that science is changing
rapidly in this field and that recommendations will likely
need to be revised as future evidence accumulates.
Future Directions
There needs to be an appreciation that unprotected sun
exposure is the major source of vitamin D for both chil-
dren and adults and that in the absence of sun exposure it
is difficult, if not impossible, to obtain an adequate
amount of vitamin D from dietary sources without sup-
plementation to satisfy the body’s requirement. Concerns
about melanoma and other types of skin cancer necessitate
avoidance of excessive exposure to midday sun. These ob-
servations strengthen the arguments for supplementation,
especially for people living above 33° latitude (143). All
available evidence suggests that children and adults
should maintain a blood level of 25(OH)D above 20 ng/ml
to prevent rickets and osteomalacia, respectively. How-
ever, to maximize vitamin D’s effect on calcium, bone, and
muscle metabolism, the 25(OH)D blood level should be
above 30 ng/ml. Numerous epidemiological studies have
suggested that a 25(OH)D blood level above 30 ng/ml may
have additional health benefits in reducing the risk of com-
mon cancers, autoimmune diseases, type 2 diabetes, car-
diovascular disease, and infectious diseases.
Few RCT have used an amount of vitamin D that raises
the blood level above 30 ng/ml, and thus there remains
appropriate skepticism about the potential noncalcemic
benefits of vitamin D for health. Concern was also raised
by the IOM report (20) that some studies have suggested
that all-cause mortality increased when blood levels of
25(OH)D were greater than approximately 50 ng/ml.
RCT that evaluate the effects of vitamin D doses in the
range of 2000–5000 IU/d on noncalcemic health out-
comes are desperately needed. There is no evidence that
there is a downside to increasing vitamin D intake in chil-
dren and adults, except for those who have a chronic gran-
uloma-forming disorder or lymphoma.
Acknowledgments
The members of the Task Force thank The Endocrine Society’s
Clinical Guidelines Subcommittee, Clinical Affairs Core Com-
mittee, and Council for their careful, critical review of earlier
versions of this manuscript and their helpful comments and sug-
J Clin Endocrinol Metab, July 2011, 96(7):0000 – 0000 jcem.endojournals.org 15
gestions. We also thank the leadership of the Canadian Society
of Endocrinology and the National Osteoporosis Foundation for
their review and comments. Finally we thank the many members
of The Endocrine Society who reviewed the draft version of this
manuscript when it was posted on the Society’s web site and who
sent a great number of additional comments and suggestions,
most of which were incorporated into the final version of the
manuscript.
Address all correspondence and requests for reprints to: The
Endocrine Society, 8401 Connecticut Avenue, Suite 900, Chevy
Chase, MD 20815. E-mail: govt-prof@endo-society.org, Tele-
phone: 301-941-0200. Address all commercial reprint requests
for orders 101 and more to: Walchli Tauber Group Inc. E-mail:
Karen.burkhardt@wt-group.com. Address all reprint requests
for orders for 100 or fewer to Society Services, Telephone: 301-
941-0210, E-mail: societyservices@endo-society.org, or Fax:
301-941-0257.
Cosponsoring Associations: Canadian Society of Endocrinol-
ogy and Metabolism and National Osteoporosis Foundation.
Financial Disclosures of the Task Force
Michael F. Holick, Ph.D., M.D. (chair)—Financial or
Business/Organizational Interests: Merck, Novartis,
Nichols-Quest Diagnostics, Bayer, Aventis, Warner
Chilcott, Amgen, UV Foundation, Mushroom Council
and Dairy Management, Inc.; Significant Financial Inter-
est or Leadership Position: none declared. Neil C. Binkley,
M.D.—Financial or Business/Organizational Interests:
American Society for Bone and Mineral Research, Inter-
national Society for Clinical Densitometry; Significant Fi-
nancial Interest or Leadership Position: none declared.
Heike A. Bischoff-Ferrari, M.D., Dr.P.H.—Financial or
Business/Organizational Interests: none declared; Signif-
icant Financial Interest or Leadership Position: none de-
clared. Catherine M. Gordon, M.D., M.Sc.—Financial or
Business/Organizational Interests: none declared; Signif-
icant Financial Interest or Leadership Position: Director,
Clinical Investigator Training Program (Harvard/MIT
with Pfizer/Merck). David A. Hanley, M.D., FRCPC—
Financial or Business/Organizational Interests: Canadian
Society of Endocrinology and Metabolism, Osteoporosis
Canada, International Society for Clinical Densitometry;
Advisory Boards: Amgen Canada, Merck Frosst Canada,
Eli Lilly Canada, Novartis Canada, Warner Chilcott Can-
ada; Significant Financial Interest or Leadership Position:
Past President of Canadian Society of Endocrinology and
Metabolism. Robert P. Heaney, M.D.—Financial or Busi-
ness/Organizational Interests: Merck, Procter & Gamble;
Significant Financial Interest or Leadership Position: none
declared. M. Hassan Murad, M.D.*—Financial or Busi-
ness/Organizational Interests: KER Unit (Mayo Clinic);
Significant Financial Interest or Leadership Position: none
declared. Connie M. Weaver, Ph.D.—Financial or Busi-
ness/Organizational Interests: Pharmavite; Significant Fi-
nancial Interest or Leadership Position: National Osteo-
porosis Foundation.
* Evidence-based reviews for this guideline were pre-
pared under contract with The Endocrine Society.
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