Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline

Abstract

Objective:

The objective was to provide guidelines to clinicians for the evaluation, treatment, and prevention 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 tolerable 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 individuals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for cardiovascular protection.

Issue Section:

 Special featuresSpecial Features - Clinical Practice Guideline

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 individuals who are not at risk (1|⊕⊕⊕⊕).

1.2 We recommend using the serum circulating 25-hydroxyvitamin 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 defined as a 25(OH)D below 20 ng/ml (50 nmol/liter), and vitamin D insufficiency as a 25(OH)D of 21–29 ng/ml (525–725 nmol/liter). We recommend against using the serum 1,25-dihydroxyvitamin D [1,25(OH)₂D] 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|⊕⊕⊕⊕).

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 require 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 potential 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|⊕⊕⊕⊕).

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 benefits 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|⊕⊕⊕⊕).

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 provide 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|⊕⊕⊕⊕).

2.4 We suggest that pregnant and lactating women require 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|⊕⊕⊕○).

2.5 We suggest that obese children and adults and children and adults on anticonvulsant medications, glucocorticoids, 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|⊕⊕⊕⊕).

2.6 We suggest that the maintenance tolerable upper limits (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|⊕⊕⊕⊕).

3.0 Treatment and prevention strategies

3.1 We suggest using either vitamin D₂ or vitamin D₃ for the treatment and prevention of vitamin D deficiency (2|⊕⊕⊕⊕).

3.2 For infants and toddlers aged 0–1 yr who are vitamin D deficient, we suggest treatment with 2000 IU/d of vitamin D₂ or vitamin D₃, or with 50,000 IU of vitamin D₂ or vitamin D₃ 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|⊕⊕⊕⊕).

3.3 For children aged 1–18 yr who are vitamin D deficient, we suggest treatment with 2000 IU/d of vitamin D₂ or vitamin D₃ for at least 6 wk or with 50,000 IU of vitamin D₂ once a week for at least 6 wk to achieve a blood level of 25(OH)D above 30 ng/ml, followed by maintenance therapy of 600-1000 IU/d (2|⊕⊕⊕⊕).

3.4 We suggest that all adults who are vitamin D deficient be treated with 50,000 IU of vitamin D₂ or vitamin D₃ once a week for 8 wk or its equivalent of 6000 IU of vitamin D₂ or vitamin D₃ daily to achieve a blood level of 25(OH)D above 30 ng/ml, followed by maintenance therapy of 1500–2000 IU/d (2|⊕⊕⊕⊕).

3.5 In obese patients, patients with malabsorption syndromes, 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 3000–6000 IU/d (2|⊕⊕⊕⊕).

3.6 In patients with extrarenal production of 1,25(OH)₂D, we suggest serial monitoring of 25(OH)D levels and serum calcium levels during treatment with vitamin D to prevent hypercalcemia (2|⊕⊕⊕⊕).

3.7 For patients with primary hyperparathyroidism and vitamin D deficiency, we suggest treatment with vitamin D as needed. Serum calcium levels should be monitored (2|⊕⊕⊕⊕).

4.0 Noncalcemic benefits of vitamin D

4.1 We recommend prescribing vitamin D supplementation for fall prevention. We do not recommend prescribing vitamin D supplementation beyond recommended daily needs for the purpose of preventing cardiovascular disease or death or improving quality of life (2|⊕⊕⊕⊕).

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 Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system.

The Clinical Guidelines Subcommittee of The Endocrine Society deemed vitamin D deficiency a priority area in need of practice guidelines and appointed a Task Force 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 recommendation and the quality of evidence. In terms of the strength of the recommendation, strong recommendations 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 ⊕○○○ denotes very low quality evidence; ⊕⊕○○, low quality; ⊕⊕⊕○, moderate quality; and ⊕⊕⊕⊕, high quality. The Task Force has confidence that persons who receive care according to the strong recommendations will derive, on average, more good than harm. Weak recommendations require more careful consideration of the person's circumstances, values, and preferences 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 recommendation; in some instances, there are remarks, a section in which panelists offer technical suggestions for testing conditions, dosing, and monitoring. These technical comments reflect the best available evidence applied to a typical 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 D₂ is obtained from the UV irradiation of the yeast sterol ergosterol and is found naturally in sun-exposed mushrooms. Vitamin D₃ is synthesized in the skin and is present in oil-rich fish such as salmon, mackerel, and herring; commercially available vitamin D₃ is synthesized from the cholesterol precursor 7-dehydrocholesterol naturally present in the skin or obtained from lanolin (3). Both vitamin D₂ and vitamin D₃ are used for food fortification and in vitamin D supplements. Vitamin D (D represents D₂, or D₃, or both) that is ingested is incorporated into chylomicrons, which are absorbed into the lymphatic system and enter the venous blood. Vitamin D that comes from the skin or diet is biologically 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-1α-OHase (CYP27B1) to form the biologically active form of vitamin D 1,25(OH)₂D (3, 8). 1,25(OH)₂D interacts with its vitamin D nuclear receptor, which is present in the small intestine, kidneys, and other tissues (3, 8). 1,25(OH)₂D stimulates intestinal calcium absorption (9). Without vitamin 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)₂D interacts with its vitamin D receptor in the osteoblast to stimulate the expression of receptor activator of nuclear factor κB ligand; this, in turn, interacts with receptor activator of nuclear factor κB to induce immature monocytes to become mature osteoclasts, which dissolve the matrix and mobilize calcium and other minerals from the skeleton. In the kidney, 1,25(OH)₂D 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)₂D has a wide range of biological actions, including inhibiting cellular proliferation and inducing terminal differentiation, inhibiting angiogenesis, stimulating insulin production, inhibiting renin production, and stimulating macrophage cathelicidin production (3, 12–14). In addition, 1,25(OH)₂D stimulates its own destruction by enhancing the expression of the 25-hydroxyvitamin D-24-OHase (CYP24R) to metabolize 25(OH)D and 1,25(OH)₂D into water-soluble inactive forms. There are several tissues and cells that possess 1-OHase activity (3, 7, 12, 13). The local production of 1,25(OH)₂D 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 insufficiency 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 European elderly men and women still living in the community are vitamin D deficient (3, 21–25). Children and young and middle-aged adults are at equally high risk for vitamin D deficiency and insufficiency worldwide. Vitamin 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 preadolescent 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 calcium 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 exposure 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/m², and thus, obesity is associated with vitamin D deficiency (42). There are several other causes for vitamin D deficiency (3, 38). Patients with one of the fat malabsorption syndromes and bariatric patients are often unable to absorb the fat-soluble vitamin D, and patients with nephrotic syndrome lose 25(OH)D bound to the vitamin D-binding protein in the urine (3). Patients on a wide variety of medications, including anticonvulsants and medications to treat AIDS/HIV, are at risk because these drugs enhance the catabolism of 25(OH)D and 1,25(OH)₂D (43). Patients with chronic granuloma-forming disorders, some lymphomas, and primary hyperparathyroidism who have increased metabolism of 25(OH)D to 1,25(OH)₂D 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 mobilizing calcium from the skeleton and increasing phosphorus wasting in the kidneys. The PTH-mediated increase in osteoclastic activity creates local foci of bone weakness and causes a generalized decrease in bone mineral density (BMD), resulting in osteopenia and osteoporosis. Phosphaturia caused by secondary hyperparathyroidism 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 deformities 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 difficulty 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). Vitamin 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 production of vitamin D₃, 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 D₃ (3, 5). Above and below latitudes of approximately 33°, vitamin D₃ synthesis in the skin is very low or absent during most of the winter.