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Evaluation, Treatment, and Prevention of Vitamin D
Evaluation, Treatment, and Prevention of Vitamin D
C l i n i c a l P r a c t i c e G u i d e l i n e
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 D2 or vitamin D3 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: 1911–1930, 2011)
ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: BMD, Bone mineral density; BMI, body mass index; CI, confidence interval;
Printed in U.S.A. I2, inconsistency; IOM, Institute of Medicine; MI, myocardial infarction; OHase, hydroxy-
Copyright © 2011 by The Endocrine Society lase; 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; OR, odds ratio;
doi: 10.1210/jc.2011-0385 Received February 14, 2011. Accepted May 18, 2011. RCT, randomized controlled trials; RDA, recommended dietary allowance; RR, relative risk.
First Published Online June 6, 2011
2.0 Recommended dietary intakes of vitamin D for vitamin D2 or vitamin D3, or with 50,000 IU of vitamin D2
patients at risk for vitamin D deficiency or vitamin D3 once weekly for 6 wk to achieve a blood level
2.1 We suggest that infants and children aged 0 –1 yr re- of 25(OH)D above 30 ng/ml, followed by maintenance
quire at least 400 IU/d (IU ⫽ 25 ng) of vitamin D and children therapy of 400-1000 IU/d (2|QQQQ).
1 yr and older require at least 600 IU/d to maximize bone 3.3 For children aged 1–18 yr who are vitamin D de-
health. Whether 400 and 600 IU/d for children aged 0 –1 yr ficient, we suggest treatment with 2000 IU/d of vitamin D2
and 1–18 yr, respectively, are enough to provide all the po- or vitamin D3 for at least 6 wk or with 50,000 IU of vi-
tential nonskeletal health benefits associated with vitamin D tamin D2 once a week for at least 6 wk to achieve a blood
to maximize bone health and muscle function is not known level of 25(OH)D above 30 ng/ml, followed by mainte-
at this time. However, to raise the blood level of 25(OH)D nance therapy of 600-1000 IU/d (2|QQQQ).
consistently above 30 ng/ml (75 nmol/liter) may require at 3.4 We suggest that all adults who are vitamin D defi-
to formulate evidence-based recommendations. The Task ingested is incorporated into chylomicrons, which are ab-
Force followed the approach recommended by the sorbed into the lymphatic system and enter the venous
GRADE group, an international group with expertise in blood. Vitamin D that comes from the skin or diet is bi-
development and implementation of evidence-based ologically inert and requires its first hydroxylation in the
guidelines (1). A detailed description of the grading liver by the vitamin D-25-hydroxylase (25-OHase) to
scheme has been published elsewhere (2). The Task Force 25(OH)D (3, 8). However, 25(OH)D requires a further
used the best available research evidence to develop some hydroxylation in the kidneys by the 25(OH)D-1␣-OHase
of the recommendations. The Task Force commissioned (CYP27B1) to form the biologically active form of vitamin
the conduct of two systemic reviews of the literature to D 1,25(OH)2D (3, 8). 1,25(OH)2D interacts with its vi-
inform its key recommendations. tamin D nuclear receptor, which is present in the small
The Task Force also used consistent language and intestine, kidneys, and other tissues (3, 8). 1,25(OH)2D
vitamin D deficiency and insufficiency worldwide. Vita- 10, 22, 23). Secondary hyperparathyroidism maintains
min D deficiency is common in Australia, the Middle East, serum calcium in the normal range at the expense of mo-
India, Africa, and South America (3, 26, 27). In the United bilizing calcium from the skeleton and increasing phos-
States, more than 50% of Hispanic and African-American phorus wasting in the kidneys. The PTH-mediated in-
adolescents in Boston (28) and 48% of white preadoles- crease in osteoclastic activity creates local foci of bone
cent girls in Maine had 25(OH)D below 20 ng/ml (29). In weakness and causes a generalized decrease in bone min-
addition, 42% of African-American girls and women aged eral density (BMD), resulting in osteopenia and osteopo-
15– 49 yr throughout the United States had a blood level rosis. Phosphaturia caused by secondary hyperparathy-
of 25(OH)D below 15 ng/ml at the end of the winter (30), roidism results in a low normal or low serum phosphorus
and 32% of healthy students and physicians at a Boston level. This results in an inadequate calcium-phosphorus
hospital had 25(OH)D below 20 ng/ml (31). Pregnant and product, causing a mineralization defect in the skeleton (3,
lactating women who take a prenatal vitamin and a cal-
there was an outbreak of vitamin D intoxication in young population screening for vitamin D deficiency in individ-
children, resulting in laws that forbade the fortification of uals who are not at risk (1|QQQQ).
foods with vitamin D. However, Sweden and Finland now
fortify milk, and many European countries add vitamin D 1.1 Evidence
to cereals, breads, and margarine (3). There is no evidence demonstrating benefits of screen-
Multivitamin preparations contain 400-1000 IU of vi- ing for vitamin D deficiency at a population level. Such
tamin D2 or vitamin D3, whereas pharmaceutical prepa- evidence would require demonstration of the feasibility
rations in the United States contain only vitamin D2 (Table and cost-effectiveness of such a screening strategy, as well
1) (3). 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.
1.0 Diagnostic Procedure
Currently, 25(OH)D measurement is reasonable in
Recommendation groups of people at high risk for vitamin D deficiency and
1.1 We recommend screening for vitamin D deficiency in whom a prompt response to optimization of vitamin D
in individuals at risk for deficiency. We do not recommend status could be expected (Table 2) (3, 25, 52, 54 –56).
1916 Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):1911–1930
TABLE 2. Indications for 25(OH)D measurement D status. Measurement of 1,25(OH)2D is useful in ac-
(candidates for screening) quired and inherited disorders in the metabolism of
25(OH)D and phosphate, including chronic kidney dis-
Rickets ease, hereditary phosphate-losing disorders, oncogenic
Osteomalacia
Osteoporosis osteomalacia, pseudovitamin D-deficiency rickets, vita-
Chronic kidney disease min D-resistant rickets, as well as chronic granuloma-
Hepatic failure
Malabsorption syndromes forming disorders such as sarcoidosis and some lympho-
Cystic fibrosis mas (3, 11, 50, 57, 58).
Inflammatory bowel disease
Crohn’s disease
Bariatric surgery 1.2 Remarks
Radiation enteritis All clinical assays, including 25(OH)D measurements,
Hyperparathyroidism
TABLE 3. Vitamin D intakes recommended by the IOM and the Endocrine Practice Guidelines Committee
Committee recommendations
for patients at risk for
Life stage IOM recommendations vitamin D deficiency
group 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
Lactationa
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).
1918 Holick et al. Guidelines on Vitamin D Deficiency J Clin Endocrinol Metab, July 2011, 96(7):1911–1930
children 1 yr and older require at least 600 IU/d to max- evidence of rickets (74). This observation is consistent
imize bone health. Whether 400 and 600 IU/d for children with what Jeans (75) observed in 1950, and it was the basis
0 –1 yr and 1–18 yr, respectively, are enough to provide all for recommending that children only need 200 IU/d of
the potential nonskeletal health benefits associated with vitamin D. However, Markestad and Elzouki (76) re-
vitamin D is not known at this time. However, to raise the ported that Norwegian infants fed formula containing
blood level of 25(OH)D consistently above 30 ng/ml may 300 IU/d obtained blood levels of 25(OH)D above 11 ng/
require at least 1000 IU/d of vitamin D (2|QQQQ). ml, which at the time was considered the lower limit of
normal. However, the IOM report says that the blood level
2.1 Evidence should be at least 20 ng/ml, which implies that consuming
Birth to 18 yr even 300 IU/d is not adequate for infants (20, 47, 77).
Risk factors for vitamin D deficiency and rickets in an Pediatric health care providers need to be aware of the
takes were less than 2.5 g/d, Turkish children aged 12–17 Very few studies have evaluated this age group’s vita-
yr had 25(OH)D levels consistent with vitamin D defi- min D requirement. However, in the large Third National
ciency, i.e. below 11 ng/ml (95). A 2008 study by Maalouf Health and Nutrition Examination Survey (NHANES III)
et al. (91) suggests that this age group needs 2000 IU/d population-based study, a threshold for optimal 25(OH)D and
vitamin D to maintain a blood level above 30 ng/ml. An- hip bone density has been addressed among 13,432
other study, by El-Hajj Fuleihan (96), provides an insight younger (20 – 49 yr) and older (50⫹ yr) individuals with
into the vitamin D requirement for children aged 10 –17 yr different ethnic and racial background (98). Compared
(who were presumably exposed to an adequate amount of with the lowest quintile of 25(OH)D, the highest quintile
sun-mediated vitamin D because they lived in Lebanon) had higher mean bone density by 4.1% in younger whites
who ingested weekly doses of either 1,400 or 14,000 IU (test for trend; P ⬍ 0.0001), by 1.8% in younger Mexican-
vitamin D3 for 1 yr. Those who received 1400 IU/wk in- Americans (P ⫽ 0.004), and by 1.2% in younger blacks
creased their blood level of 25(OH)D from 14 ⫾ 8 to 17 ⫾
clothing and sunscreen over sun-exposed areas and de- supplements of 400-1000 IU/d, they had a significant re-
creased consumption of vitamin D-fortified milk increases duction in bone resorption. In a randomized, placebo-
the risk for vitamin D deficiency (3, 31, 39, 103). In ad- controlled trial of elderly French women, those given cal-
dition, age decreases the capacity of the skin to produce cium and 800 IU/d of vitamin D had significantly fewer
vitamin D3 (3). Although it has been suggested that aging vertebral and nonvertebral fractures (113). A similar ob-
may decrease the ability of the intestine to absorb dietary servation was made in free-living men and women aged 65
vitamin D, studies have revealed that aging does not alter yr and older who received 500 mg of calcium and 700 IU/d
the absorption of physiological or pharmacological doses of vitamin D (114).
of vitamin D (101, 104 –106). A threshold for optimal 25(OH)D and hip BMD has been
The IOM report (20) suggests that 25(OH)D levels addressed among 13,432 individuals studied in the
need to be at least 20 ng/ml to maintain skeletal health. NHANES III, including both younger (20 – 49 yr) and older
Prior estimates have ranged from as little as 12 to as high (⬎50 yr) individuals with different ethnic and racial back-
tically significant reduction in the risk of falls [odds ratio maintain a blood level of 25(OH)D above 30 ng/ml
(OR) ⫽ 0.84; 95% confidence interval (CI), 0.76 – 0.93; (2|QQQE).
inconsistency (I2) ⫽ 61%; 23 studies). This effect was
more prominent in patients who were vitamin D deficient 2.4 Evidence
at baseline. Results of other reviews were consistent. A Pregnancy and lactation
meta-analysis of only five high-quality double-blind RCT During the first and second trimesters, the fetus is de-
(n ⫽ 1237) found that vitamin D reduced the falling risk veloping most of its organ systems and laying down the
by 22% (pooled corrected OR ⫽ 0.78; 95% CI, 0.64 – collagen matrix for its skeleton. During the last trimester,
0.92) compared with calcium or placebo (116). For two
the fetus begins to calcify the skeleton, thereby increasing
trials with a total of 259 subjects using 800 IU/d of vitamin
maternal demand for calcium. This demand is met by in-
D3 over 2 to 3 months (117, 121), the corrected pooled OR
creased production of 1,25(OH)2D by the mother’s kid-
3.0 Treatment and Prevention Strategies vitamin D intoxication were seen with any of the three
regimens studied.
Recommendation Children with rickets have been successfully treated
3.1 We suggest using either vitamin D2 or vitamin D3 with 600,000 IU of vitamin D either orally or im once a
for the treatment and prevention of vitamin D deficiency year (47, 50). In the United States, there are two pharma-
(2|QQQQ). ceutical formulations of vitamin D. For the pediatric pop-
ulation, vitamin D2 is available in a liquid form at a con-
3.1 Evidence
centration of 8000 IU/ml, and for older children and
Some (47, 101, 128) but not all (129 –131) studies have adults, a gelatin capsule containing 50,000 IU of vitamin
shown that both vitamin D2 and vitamin D3 are effective D2 is available.
in maintaining serum 25(OH)D levels. Two meta-analyses
of double-blind RCT suggested reduction in falls and non-
25(OH)D above 30 ng/ml, followed by maintenance ther- unregulated fashion (3, 44). This results in an increase in
apy of 1500 –2000 IU/d (2|QQQQ). the efficiency of intestinal calcium absorption and mobi-
lization of calcium from the skeleton that can cause hy-
3.4 Evidence percalciuria and hypercalcemia. These patients may re-
A dose of 50,000 IU of vitamin D2 once a week for 8 wk quire vitamin D treatment to raise their blood level of
is often effective in correcting vitamin D deficiency in 25(OH)D to approximately 20 –30 ng/ml to prevent vita-
adults (3, 16). Patients who do not show an increase in min D-deficiency metabolic bone disease while mitigating
their blood level of 25(OH)D should be worked up for hypercalciuria and hypercalcemia.
celiac disease or occult cystic fibrosis, assuming that they The 25(OH)D levels need to be carefully monitored for
were compliant with treatment. To prevent recurrence of these patients. Hypercalciuria and hypercalcemia are usu-
vitamin D deficiency, 50,000 IU of vitamin D2 once every ally observed when the 25(OH)D is above 30 ng/ml (44).
other week was effective in maintaining blood levels of
overall risk of all cancers by more than 60%. This was as- Nevertheless, in making recommendations, the panel
sociated with an increase in mean serum 25(OH)D levels placed the highest value on preserving musculoskeletal
from 29 –39 ng/ml. Several observational studies have re- health and preventing childhood rickets and adult bone
ported that colon cancer risk became progressively lower as disease, and less value on vitamin D cost and potential for
serum 25(OH)D increased up to 30 –32 ng/ml. However, toxicity. Vitamin D supplementation/treatment is likely
because population values above 30 –32 ng/ml are uncom- inexpensive and would be cost-effective, particularly in
mon, most observational studies do not extend much beyond treating entities such as osteoporosis, rickets, and osteo-
this level of repletion, and thus, observational data are largely malacia. Cost and resource utilization in other preventive
silent about the optimal 25(OH)D levels. indications are less known. Ample evidence provided the
Several studies found associations between 25(OH)D panel with a high level of confidence that toxicity of vi-
levels and hypertension, coronary artery calcification, as tamin D at the recommended dosages is quite unlikely. The
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