Accurate estimates of vitamin D deficiency prevalence are difficult due to the wide variety of cut points, populations, season of blood draw, and testing methods used in existing studies.1 A review of the National Health and Nutrition Examination Survey (NHANES) of 2001 to 2006 reported that approximately 32% of the U.S. population was vitamin D deficient, using the most widely accepted serum cut point. This reflects an approximate 5% increase in prevalence from the NHANES of 1988 to 1994.2
A wide variety of recommendations exist for daily vitamin D intake, screening, diagnosis, and treatment of vitamin D deficiency. Despite the lack of expert consensus, the NP's role is to provide safe, effective evaluation and treatment of vitamin D deficiency to promote positive health outcomes.
Physiology and importance of vitamin D
Vitamin D is considered both a fat-soluble vitamin and a hormone.3 Ergocalciferol (D2) is produced by irradiation of yeast and plant sterols, while cholecalciferol (D3) is found naturally in oily fish and synthesized through UV radiation of human skin or lanolin obtained from sheep's wool. When skin synthesis of vitamin D is inadequate, the vitamin must be obtained through diet or supplementation.4
Despite the method of introduction into the body, inactive 25-hydroxyvitamin D (25[OH]D) must be transformed by the liver and kidney into its biologically active form, 1,25-dihydroxycholecalciferol, (1,25[OH])2D), which controls calcium absorption and excretion, regulated in part by parathyroid hormone (PTH).5 The absorption of calcium and phosphorus is substantially decreased with insufficient levels of vitamin D.6 Bone health is maintained through this endocrine pathway and is the primary action of vitamin D.
However, vitamin D targets more than 200 genes, and its receptors have been identified in more than 30 body tissues or organs. Enzymatic conversion of inactive to active vitamin D also occurs at the tissue level independent of renal conversion.6-8 This autocrine conversion may be an important component of the varied actions of vitamin D. In addition to maintaining bone health, vitamin D also has a role in modulation of neuromuscular function and cell regulation, reduction of inflammation, insulin production by beta-islet cells, antimicrobial peptide expression in epithelial cells and macrophages, and regulation of growth and proliferation of vascular smooth muscle.5,7-11
Numerous studies have reported an association of inadequate vitamin D levels with all-cause mortality and cancer, cardiovascular disease, hypertension, diabetes mellitus, metabolic syndrome, infections, chronic lung disease, immunodeficiency, reduced neuropsychological functioning, and preeclampsia.12,13
Circulating serum 25(OH)D levels estimate the amount of vitamin D available to the body; however, little evidence demonstrates the direct association of 25(OH)D levels as a predictor of specific health outcomes.4 A systematic review of studies through April 2009 related to vitamin D and health outcomes concluded that the available evidence was inadequate or too inconsistent to reliably establish causality between inadequate vitamin D levels and negative outcomes related to disease processes other than bone health.13
An updated review, adding studies from 2009 to 2013, concurred with the initial findings in regard to lack of causality or clear dose-response relationships between intakes of vitamin D and health outcomes.12 However, the possibility of a U-shaped association was identified in that individuals with 25(OH)D concentrations lower or higher than a specified range experienced negative health outcomes related to both all-cause mortality and hypertension.12
Active 1,25(OH)2D is not a good indicator of vitamin D status due to its short half-life and close regulation by PTH, calcium, and phosphate.4,14 Experts agree that the serum concentration of total 25(OH)D is the best marker for vitamin D nutrients, and therefore, the best screening test for vitamin D deficiency.3,4,15 Serum 25(OH)D is reported in nanomoles per liter (nmol/L) or nanograms per milliliter (ng/mL), with 2.496 nmol/L equaling 1 ng/mL.4
In 2010, the National Institutes of Health Office of Dietary Supplements established the Vitamin D Standardization Program to address the lack of an internationally recognized standard for testing, which has complicated efforts to provide a reliable and consistent measure of the prevalence of vitamin D deficiency and health outcomes at specified 25(OH)D levels. Standardized lab measurements of 25(OH)D would make results accurate and comparable over time, location, and lab procedure.16
Insufficient evidence exists to assess the balance of benefits and harms of vitamin D deficiency screening in asymptomatic adults, and no national primary care organization recommends population-wide 25(OH)D screening.1 However, many expert organizations encourage an individualized risk assessment and subsequent testing in those at higher risk for deficiency (or whose symptoms or disease processes have been associated with vitamin D deficiency).6,17-24 The American Academy of Pediatrics (AAP) recommends screening for deficiency only in pediatric patients who exhibit signs of reduced bone mass and/or recurrent low-impact fractures.4,24
The American College of Obstetrics and Gynecology (ACOG) does not recommend routine screening of pregnant women. When deficiency is suspected, obtaining a 25(OH)D measurement is reasonable and should be interpreted in the context of the clinical presentation.18 The International Osteoporosis Foundation does not recommend routine vitamin D deficiency screening or monitoring of 25(OH)D in older adults before or during supplementation when dietary intake is within the recommended limits.22
Based primarily on bone health research and outcomes, the Institute of Medicine (IOM) determined that half of the general population would be vitamin D sufficient at 16 ng/mL, with almost all reaching sufficiency at 20 ng/mL4 (with no additional benefit above 20 ng/mL).7 Levels of 50 ng/mL or greater were not recommended due to preliminary data regarding potential negative outcomes.4
Many other experts support a definition of deficiency as less than 20 ng/mL and sufficiency as 30 ng/mL in order to ensure optimum bone health and possible nonskeletal benefits of vitamin D.6,21,25 The target 25(OH)D range would be 30 ng/mL to 50 ng/mL for most individuals, as no safety concerns have been demonstrated at these levels (see 25(OH)D cut points).23,25
Assessment of risk factors for deficiency
Although factors have been identified that increase an individual's risk of deficiency, vitamin D deficiency has been identified in most ethnic and socioeconomic populations.25,26 Vitamin D supplementation, rather than screening, is recommended for some at-risk individuals. To aid in the decision between serum 25(OH)D measurement or vitamin D supplementation without measurement, the NP should conduct an individualized assessment to identify specific risk factors for deficiency, and individuals in whom routine vitamin D supplementation is recommended.3,6,11
Vitamin D intake below the dietary reference intakes (DRIs) may predispose an individual of any age to deficiency. Intake may be impacted due to diets limited by food availability, choice, or medical restriction.4 Fatty fish contains the largest amount of dietary vitamin D yet is consumed infrequently by much of the U.S. population.27 Vitamin D-fortified foods can significantly increase 25(OH)D levels; however, NHANES 2011 to 2012 data revealed lower-than-DRIs of vitamin D for adult males (216 international units [IU]) and females (156 IU).28,29 For infants age 0 to 12 months, adequate intake of vitamin D is 400 IU; the DRI for individuals age 1 to 70 is 600 IU. A stronger association between total vitamin D intake and 25(OH)D levels was noted in postmenopausal women ages 50 to 79 who spent less rather than more daylight time outdoors in summer, suggesting that reduced dietary vitamin D intake is a stronger risk factor for those with limited sun exposure.30
Infants are at risk for vitamin D deficiency, particularly if they are partially or exclusively breastfed, as vitamin D only crosses into breast milk when the mother is taking approximately 6,000 IU of vitamin D daily.24 Risk of deficiency is reduced when the infant consumes at least 1 L of vitamin D-fortified formula or milk daily.24
An increased risk for vitamin D deficiency or reduced treatment effectiveness could be seen with inadequate magnesium intake. A high intake of dietary or supplemental magnesium was independently and significantly associated with reduced risks of vitamin D deficiency, as magnesium plays a critical role in the synthesis and metabolism of PTH and vitamin D.31
The DRI of vitamin D increases to 800 IU for adults over age 70 due to additional risk factors that occur during the aging process.4 Aging can decrease the skin's capacity to synthesize vitamin D in response to UV exposure. Participating in few outdoor activities, decreased appetite and food variation, and polypharmacy increase the risk of vitamin D deficiency, with institutionalized older adults at greatest risk.25 Falls, fall-related injuries, frailty, and osteoporosis should prompt assessment of vitamin D status in older adults.32
Geographic location and lifestyle
Limited or inadequate unprotected sun exposure increases the risk of vitamin D deficiency. Individuals living at latitudes above 33° N during winter months may be unable to adequately synthesize vitamin D or require a markedly increased amount of sun exposure for synthesis compared with summer months.6 Even at latitudes with adequate year-round sun exposure, 25(OH)D levels may decrease by one-third from the summer to winter season with peaks in August and troughs in February.4,33 UV exposure is influenced by weather, pollution, and ozone fluctuations and may vary between urban and suburban locations.25 Clothing (particularly darker fabrics and tighter weaves) and properly applied sunscreen can block UV exposure.25 Work patterns, extremely warm or cold climates, indoor hobbies, culturally mandated conservative dress, and skin cancer concerns may result in reduced amounts of individual sun exposure.
Skin pigmentation and race
Even with adequate UV exposure, darker skin pigmentation and greater amounts of melanin, regardless of ethnicity, reduce the efficiency of dermal vitamin D synthesis, increasing the risk of deficiency. Lighter skin is significantly more efficient at vitamin D synthesis than darker skin.25,35 Hispanics and Black Americans have shown twice the prevalence of vitamin D deficiency as White Americans, and the deficiency is typically more severe.2 However, in community-dwelling adults, vitamin D-binding protein was shown to be lower in Black Americans than in White Americans, which resulted in similar concentrations of bioavailable 25(OH)D and no evidence of overt deficiency.34,36 This may explain why Black Americans traditionally have higher bone mineral density and lower risk of fragility fracture despite the increased prevalence of lower 25(OH)D levels.
Weight and adiposity
Obese individuals are approximately twice as likely to have vitamin D deficiency than individuals of normal weight.26 This may be due to differences in lifestyle, poor vitamin D absorption, or sequestration of vitamin D in adipose tissue reducing bioavailability for use by the body.4 Dilution and consideration of total body weight rather than body mass index (BMI) as a plausible explanation for lower levels is also being researched.37
Medications and disease processes
Reduced fat absorption due to intake of olestra, medications (such as bile acid sequestrants, orlistat), supplements (such as high-dose vitamin A), or disease processes (such as cystic fibrosis, celiac disease, Crohn disease, gastric bypass surgery) can limit absorption of vitamin D.14 The catabolic effect of anticonvulsants, glucocorticoids, antiretroviral therapy, and antirejection medications on vitamin D may lower 25(OH)D levels.25 In contrast, granulomatous disorders (sarcoidosis, tuberculosis) increase the risk of hypercalciuria and hypercalcemia at 25(OH)D levels over 30 ng/mL.25
The IOM recommends that individuals obtain the set DRIs for vitamin D, while other expert organizations (such as the Endocrine Society) recommend higher daily vitamin D intake for all individuals.4,6 Neither specifies whether the recommended vitamin D intake should be from dietary supplements or other sources, such as food or UV exposure. The organizations discussed below have made specific recommendations for or against routine supplementation in populations or for specific disease processes.
Rather than screen for deficiency, the AAP recommends that all infants consuming less than 1 L of vitamin D-fortified formula or milk daily be supplemented with 400 IU of vitamin D per day beginning in the first few days of life.24 Supplementation may cease when consumption of fortified formula or milk is at least 1 L daily. ACOG does not recommend vitamin D supplementation in pregnant women beyond what is contained in prenatal vitamins. Routine supplementation for the prevention of preterm birth or preeclampsia is also not recommended.18
The American Geriatric Society recommends supplementation with at least 1,000 IU of vitamin D as well as calcium in community-dwelling and institutionalized adults with a minimum 25(OH)D goal of 30 ng/mL.22 The International Osteoporosis Foundation and National Osteoporosis Foundation also recommend supplementation of 800 to 1,000 IU for older adults.11,23 The daily vitamin D intake from all sources (sunlight, diet, supplementation) for frail older adults should equal 4,000 IU.22,32 In addition, the Endocrine Society guidelines recommend routine vitamin D supplementation for fall prevention but not cardiovascular disease prevention.6
Treatment of deficiency
Because the exact serum level at which vitamin D deficiency occurs is difficult to define, the entire clinical presentation, including symptoms, disease processes, 25(OH)D levels, and deficiency risk factors, should be considered before initiating treatment for deficiency.38
The majority of circulating 25(OH)D is obtained through skin synthesis.4 UV exposure from the sun, a UVB lamp, or tanning bed on bare arms and legs that produces a slight pinkness to the skin 24 hours after exposure (minimal erythemal dose) can generate up to 20,000 IU of vitamin D.25,39 Diverse variables influence the amount of exposure required by an individual to synthesize vitamin D. A free app (http://dminder.ontometrics.com) is available to assist the user with sensible sun exposure and adequate vitamin D synthesis. Although UV exposure is a viable option for individuals who are unresponsive to or unwilling to undergo oral vitamin D supplementation, the provider must have a thorough discussion of risks, including skin cancer concerns, with the patient.
Vitamin D2 is the only oral prescription high-dose (50,000 IU) supplement available in the United States, although high-dose (25,000 to 50,000 IU) D3 is easily found online without a prescription. D3 is also available over the counter in a wide range of lower dosages. Both D2 and D3 are efficacious for supplementation and deficiency treatment, but a recent meta-analysis demonstrated a significantly greater response from vitamin D3 over D2 when given as an oral or I.M. bolus dose, but a nonsignificant greater effect with daily supplementation.25,40
Deficiency treatment principles
Generally, vitamin D3 is recommended over D2 when possible, and dosing frequency should be based on patient preference and adherence—but no interval greater than once monthly. Cumulative vitamin D dosage was identified as more predictive of achieving serum 25(OH)D levels of 30 ng/mL than was dosing schedule, but large annual bolus doses are not recommended.6,19,41,42
A number of patient variables will impact treatment effectiveness. Dosing regimens (D2) that have demonstrated the ability to replete vitamin D to a level of 20 ng/mL or greater in varied adult populations include 50,000 IU three times weekly for 6 weeks, 50,000 to 100,000 IU weekly, and regimens administering over 600,000 IU for a mean time of 60 ± 40 days.41,43 The odds of not attaining sufficiency (30 ng/mL or greater) were increased in patients with a BMI of 30 kg/m2 and receiving less than 50,000 IU per week.41 Larger doses of vitamin D are traditionally required for supplementation or repletion of deficiency in individuals with a higher BMI.6,36
Vitamin D dosing individualized by body weight is a promising area for future research.37 Serum 25(OH)D measurements may be repeated after 3 to 4 months of treatment and every 6 months in individuals who require monitoring.11,25,43
Supplementation after repletion
When educating patients about vitamin D intake, identify why, if necessary, the dosage is above the DRIs to avoid confusion or inadvertent cessation of supplementation. Barring a change in circumstances that caused the initial vitamin D deficiency, individuals will likely need daily vitamin D supplementation after repletion. An individualized approach should be taken, with identification of risk factors and targeted questions related to lifestyle and preference. Vitamin D supplementation may be administered daily, weekly, monthly, or possibly every 4 months to maintain adequate serum 25(OH)D levels.22,25
Daily supplementation doses over 1,000 IU should be avoided unless warranted by patient circumstances or condition.4 A range of 1,000 IU to 2,550 IU vitamin D daily has demonstrated effectiveness in maintaining a year-round 25(OH)D level of at least 30 ng/mL.25,44 Individuals with higher sun exposure may require less, while obese individuals and older adults may require higher daily supplementation doses. Periodic monitoring of serum 25(OH)D and calcium levels in individuals requiring doses above 2,000 IU daily will allow safe supplementation.4,6
More vitamin D studies have demonstrated the detrimental effects of deficiency than reported toxicity. No vitamin D toxicity from sun exposure has ever been recorded. Inappropriate intake may result in toxicity with manifestations, which may include serum 25(OH)D greater than 150 ng/mL, hypercalcemia, anorexia, weight loss, polyuria, and cardiac dysrhythmias.14 Chronic vitamin D toxicity can lead to internal organ calcification and failure. Cessation of vitamin D supplementation and sun avoidance typically returns levels to normal. Until clearer evidence identifies the serum 25(OH)D level at which optimal outcomes occur, maintaining vitamin D levels between 30 ng/mL and 50 ng/mL should provide the benefit of vitamin D while limiting the risk of potential harm.
The lack of expert consensus on evaluation and treatment of vitamin D status could lead NPs to avoid the subject altogether. Though inconsistent evidence exists regarding vitamin D deficiency and the causality of many chronic disease processes, it is clear that the functions of vitamin D impact more than just bone health. By understanding basic vitamin D concepts and varied recommendations, the NP has the tools and the responsibility to provide safe, individualized, effective, evaluation, and treatment of each patient's vitamin D status to promote positive health outcomes.
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