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Clinical Reviews


How much vitamin D should you recommend to your nonpregnant patients?

Two experts explain what’s known about vitamin D, review the guidance offered to clinicians by the Institute of Medicine, and offer concrete recommendations for vitamin D intake and supplementation

July 2011 · Vol. 23, No. 7

IN THIS ARTICLE

No question: Vitamin D plays a vital role in bone health. In recent years, the possibility that it plays a role in other aspects of health has prompted considerable speculation, fueled by both widespread media coverage and dissemination of conflicting information about the potential nonskeletal benefits of high-dose vitamin D supplementation. Controversy has emerged about:

  • the appropriate criteria for defining vitamin D deficiency
  • the extent to which vitamin D influences nonskeletal health conditions
  • the optimal level of vitamin D supplementation.

In 2010, the Institute of Medicine (IOM) released a report that provided recommendations for vitamin D intake, which were also summarized in a recent article for clinicians.1,2 The IOM report provided much-needed clinical guidance, but it has also fueled additional questions.

This article describes the IOM recommendations, explains what we know now about the effect of vitamin D on various health outcomes, and offers concrete recommendations on vitamin D measurement, intake, and supplementation.

INTEGRATING EVIDENCE AND EXPERIENCE:
How the Institute of Medicine formulated its recommendations

The Institute of Medicine (IOM) committee conducted a comprehensive review of the literature to date on the relationship between vitamin D (and calcium) intake and several health outcomes. In terms of skeletal health, the IOM committee concluded that a 25OHD level of at least 20 ng/mL is sufficient to meet the needs of at least 97.5% of the population. The vitamin D intake thought to be necessary to achieve this 25OHD level for at least 97.5% of the population was provided for different age groups (TABLE 2).

The Recommended Dietary Allowance (RDA) of vitamin D is 600 IU daily for all adults up to age 70 years, and 800 IU daily for adults older than 70 years. These values were based on an assumption of minimal sun exposure, due to wide variability in vitamin D synthesis from ultraviolet light, as well as the risk of skin cancer. The IOM concluded that there is no compelling evidence that a 25OHD level above 20 ng/mL or a vitamin D intake greater than 600 IU (800 IU for adults over 70) affords greater skeletal or nonskeletal benefits.

The IOM recommendations were based on the integration of bone health outcomes. The evidence supporting causal relationships between vitamin D insufficiency and nonskeletal outcomes such as cancer, cardiovascular disease, diabetes, impaired physical performance, autoimmune disorders, and other chronic diseases was found to be inconsistent and inconclusive.

The IOM report also noted the emergence of a “U”-shaped curve in regard to vitamin D and several health outcomes, which has fueled concern about attainment of a 25OHD level above 50 ng/mL. The IOM committee designated 4,000 IU daily as the tolerable upper intake but emphasized that research into long-term outcomes and safety at intakes above the RDA is limited. Therefore, this upper limit should not be interpreted as a target intake level.

How is vitamin D metabolized?

Vitamin D is produced endogenously in the skin in the form of vitamin D3 (cholecalciferol). It also can be ingested exogenously in the form of vitamin D3 or vitamin D2 (ergocalciferol). Cutaneous synthesis of vitamin D is stimulated by solar ultraviolet radiation.

Vitamin D2 and D3 are hydroxylated in the liver to form 25-hydroxyvitamin D (25OHD). Measurement of the serum 25OHD level is thought to be the most reliable indicator of vitamin D exposure.3 25OHD is hydroxylated again, primarily in the kidneys, to the most active form of vitamin D (1,25-dihydroxyvitamin D).

The adverse skeletal effects of severe vitamin D deficiency are well established; those effects include calcium malabsorption, secondary hyperparathyroidism, bone loss, and increased risk of fracture. In this setting, secondary hyperparathyroidism results from both decreased gastrointestinal calcium absorption and decreased suppression of parathyroid hormone (PTH) production by the parathyroid glands from vitamin D metabolites. Secondary hyperparathyroidism leads to increased bone resorption and bone loss. Rickets, osteomalacia, hypocalcemia, hypophosphatemia, muscle weakness, and bone pain are less common effects that can occur with severe vitamin D deficiency.

It is worth noting that women of color are at increased risk of vitamin D deficiency as a result of greater skin pigmentation.3 Obesity is also a risk factor for vitamin D deficiency.3 Additional risk factors for vitamin D insufficiency are listed in TABLE 1.

TABLE 1

Risk factors for vitamin D insufficiency

Obesity

Dark skin pigmentation

Decreased sun exposure

  • Lack of outdoor activity
  • Institutionalization
  • Wearing of protective clothing
  • Regular, conscientious use of sunscreen

Low dietary intake of vitamin D

Malabsorption of ingested vitamin D

Increased hepatic degradation of 25-hydroxyvitamin D

  • Use of anticonvulsant medications
  • Antituberculous therapy

Decreased hepatic hydroxylation of vitamin D (occurs only with severe hepatic disease)

Impaired renal hydroxylation of vitamin D (renal insufficiency)

Osteoporosis or osteopenia

How should vitamin D insufficiency be defined?

Biochemical criteria for defining vitamin D insufficiency vary. That makes it difficult to estimate the prevalence of vitamin D insufficiency.

Severe vitamin D deficiency is commonly defined as a serum 25OHD level below 10 ng/mL.3 Vitamin D insufficiency has been variably defined as a serum 25OHD level below 20 to 32 ng/mL,3,4 and the lower limit of normal in most clinical laboratories is now typically 30 to 32 ng/mL. Many patients become concerned when their serum 25OHD level is flagged as “low” on a laboratory report, and it’s likely that you are called on from time to time to interpret and make recommendations about the appropriate response to this “abnormal” finding.

The broad definition of vitamin D insufficiency stems, in part, from the assessment of a wide range of outcomes. Measures that have been used include fracture risk, calcium absorptive capacity, and the serum concentration of PTH. In regard to calcium absorption, most studies suggest that maximal dietary calcium absorption occurs when the 25OHD level reaches 20 ng/mL, although some studies suggest a higher threshold.1,3

The optimal level of 25OHD for PTH suppression remains unclear. Several studies have suggested that the PTH level increases when the 25OHD concentration falls below 30 ng/mL,4,5 although this threshold has varied substantially across studies.6

How prevalent is vitamin D insufficiency?

Estimates of the prevalence of vitamin D insufficiency vary by the criteria used to define the condition. A recent report using data from the National Health and Nutrition Examination Survey (NHANES) estimated that approximately 30% of US adults 20 years of age or older have a 25OHD level below 20 ng/mL, and more than 70% of this age group has a 25OHD level below 32 ng/mL.7

The IOM committee noted that several reports have most likely overestimated the prevalence of vitamin D insufficiency through the use of 25OHD cut points higher than 20 ng/mL.

The data on vitamin D insufficiency and skeletal health

Many studies have examined the relationship between vitamin D supplementation or the 25OHD level and fracture risk, and conflicting results have emerged. Many trials have examined the combination of calcium and vitamin D supplementation, the effects of which are tightly interwoven, confounding interpretation.

Interpretation of large observational studies is further confounded by the inability to attribute association to causation. In the Women’s Health Initiative (WHI) study of calcium with vitamin D, treatment of healthy postmenopausal women with 1,000 mg of calcium and 400 IU of vitamin D daily led to improved bone density at the hip but no statistically significant reduction in hip fracture.8 However, a reduced risk of hip fracture was demonstrated in secondary analyses among women who adhered to treatment and among women 60 years or older. Meta-analyses of clinical trials have reported that treatment with varying doses of vitamin D (more than 400 IU daily) reduces the risk of vertebral,9 nonvertebral,10 and hip fractures.10

Several studies have examined the relationship between the 25OHD level and fracture risk, with inconsistent findings:

  • A nested case-control study from the WHI found that the risk of hip fracture was significantly increased among postmenopausal women who had a 25OHD level of 19 ng/mL or lower.11
  • A 2009 report from the Agency for Healthcare Research and Quality (AHRQ) concluded that the association between the 25OHD level and the risk of fracture was inconsistent.12

After a comprehensive review of the available research, the IOM committee concluded that a serum 25OHD level of 20 ng/mL would meet the needs for bone health for at least 97.5% of the US and Canadian populations.

TABLE 2

Calcium and vitamin D dietary reference intakes for adults, by life stage

Life stage (gender)

Calcium

Vitamin D

RDA (mg/d)

Tolerable upper intake level (mg/d)*

RDA (IU/d)

Serum 25OHD level (ng/mL) (corresponding to the RDA)

Tolerable upper intake level (IU/d)*

19–50 yr (male and female)

1,000

2,500

600

20

4,000

51–70 yr (male)

1,000

2,000

600

20

4,000

51–70 yr (female)

1,200

2,000

600

20

4,000

71+ yr (male and female)

1,200

2,000

800

20

4,000

Adapted from: Ross AC, Manson JE, Abrams SA, et al. J Clin Endocrinol Metab. 2011;96(1):53–58.
RDA = Recommended Dietary Allowance, 25OHD=25-hydroxyvitamin D
* The tolerable upper intake level is the threshold above which is a risk of adverse events. The upper intake level is not intended to be a target intake. There is no consistent evidence of greater benefit at intake levels above the RDA. The serum 25OHD level corresponding to the upper intake level is 50 ng/mL.
Measures of the serum 25OHD level corresponding to the RDA and covering the requirements of at least 97.5% of the population.

The data on vitamin D insufficiency and nonskeletal outcomes

Many observational studies have reported relationships between vitamin D insufficiency and myriad nonskeletal health outcomes, particularly cardiovascular disease, cancer, diabetes, and autoimmune disorders.3 However, well-designed randomized clinical trials that examine nonskeletal outcomes as primary pre-specified outcomes are lacking.13 Such studies will be essential to elucidate the relationship between vitamin D insufficiency and nonskeletal chronic diseases. The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing large-scale, randomized clinical trial designed to evaluate the role of supplementation with 2,000 IU of vitamin D3 daily in the primary prevention of cancer and cardiovascular disease.14

Key points about vitamin D

  • Vitamin D plays a vital role in bone health
  • The Institute of Medicine released a 2010 report that provided public health recommendations for vitamin D intake based on bone health outcomes
  • Many observational studies have reported a relationship between vitamin D insufficiency and adverse nonskeletal health outcomes, including cardiovascular disease, cancer, diabetes, and autoimmune disorders, but evidence from randomized clinical trials on the potential nonskeletal benefits of vitamin D is sparse
  • Excessive vitamin D intake should be avoided because of the potential for harm and the lack of evidence from well-designed clinical trials that vitamin D intake beyond the recommended amount affords greater skeletal or nonskeletal health benefits
  • Among women who have an increased risk of vitamin D insufficiency or bone loss, 25OHD concentration should be measured and vitamin D supplementation should be provided as necessary to achieve the target 25OHD level

What we recommend for treatment

The IOM report provided the medical community with evidence-based recommendations for vitamin D intake at the population level, based on a public health perspective.1,2 However, the public health guideline model must be distinguished from the medical model, in which shared clinical decision-making between physician and patient occurs on an individual level and is informed by individual clinical risk factors. The public health recommendations detailed in the IOM report are not intended to replace or interfere with clinical judgment or preclude individualized clinical decision-making.

The debate over optimal levels of vitamin D supplementation for individual patients who have osteoporosis or other health conditions continues.15 Here, we provide general guidelines for treatment, based on the evidence available to date.


Clear benefits of vitamin D in bone health notwithstanding, advise your patients to avoid excessive intake because it can cause harm. See “More is not necessarily better”.

Recommendations for healthy adult nonpregnant women

Vitamin D intake: We recommend a daily vitamin D intake of 600 IU for healthy nonpregnant women up to age 70 years (and 800  IU daily for women older than 70 years) who are at average risk of vitamin D insufficiency and bone loss, consistent with the IOM recommendations. The IOM guidelines assume minimal to no sun exposure.

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