Medical Policy

Policy Num:      11.001.040
Policy Name:    Testing Serum Vitamin D Levels
Policy ID:          [11.001.040  [Ac / B / M+ / P-]  [2.04.135]

Last Review:    January 15, 2025
Next Review:    January 20, 2026
 

Related Policies: None

Testing Serum Vitamin D Levels

Summary

Description

Vitamin D, also known as calciferol, is a fat-soluble vitamin that has a variety of physiologic effects, most prominently in calcium homeostasis and bone metabolism. In addition to the role it plays in bone metabolism, other physiologic effects include inhibition of smooth muscle proliferation, regulation of the renin-angiotensin system, a decrease in coagulation, and a decrease in inflammatory markers.

Summary of Evidence

For individuals who are asymptomatic without conditions or risk factors for which vitamin D treatment is recommended who receive testing of vitamin D levels, the evidence includes no randomized controlled trials (RCTs) of clinical utility (ie, evidence that patient care including testing vitamin D levels versus care without testing vitamin D levels improves outcomes). Relevant outcomes are overall survival, test validity, symptoms, morbid events, and treatment-related morbidity. Indirect evidence of the potential utility of testing includes many RCTs and systematic reviews of vitamin D supplementation. There is a lack of standardized vitamin D testing strategies and cutoffs for vitamin D deficiency are not standardized or evidence-based. In addition, despite the large quantity of evidence, considerable uncertainty remains about the beneficial health effects of vitamin D supplementation. Many RCTs have included participants who were not vitamin D deficient at baseline and did not stratify results by baseline 25-hydroxyvitamin D level. Nonwhite race/ethnic groups are underrepresented in RCTs, but have an increased risk of vitamin D deficiency. For skeletal health, there may be a small effect of vitamin D supplementation on falls, but there does not appear to be an impact on reducing fractures for the general population. The effect on fracture reduction may be significant in elderly women, and with higher doses of vitamin D. However, high doses of vitamin D may be associated with safety concerns in patients at risk for falls. For patients with asthma, there may be a reduction in severe exacerbations with vitamin D supplementation, but there does not appear to be an effect on other asthma outcomes. For patients who are pregnant, vitamin D supplementation may improve certain maternal and fetal outcomes. For overall mortality, there is also no benefit to the general population. RCTs evaluating extraskeletal, cancer, cardiovascular, and multiple sclerosis outcomes have not reported a statistically significant benefit for vitamin D supplementation. Although vitamin D toxicity and adverse events appear to be rare, few data on risks have been reported. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to examine whether testing for vitamin D deficiency improves net health outcomes in asymptomatic patients.

Policy Statements

Testing vitamin D levels in individuals with signs and/or symptoms of vitamin D deficiency or toxicity (see Policy Guidelines section) may be considered medically necessary.

Testing vitamin D levels in asymptomatic individuals may be considered medically necessary in the following populations:

• Individuals who have risk factors for vitamin D deficiency (see Policy Guidelines section).

• Institutionalized individuals (see Policy Guidelines section).

Testing vitamin D levels in asymptomatic individuals is considered investigational when the above criteria are not met.

Policy Guidelines

Signs and symptoms of vitamin D deficiency are largely manifested by changes in bone health and biochemical markers associated with bone production and resorption. In most cases, a clinical diagnosis of an abnormality in bone health (eg, rickets, osteomalacia, osteoporosis) will lead to a decision to test vitamin D levels. Symptoms related to the clinical condition may be present (eg, pain, low-impact fractures), but these symptoms are usually not indications for testing prior to a specific diagnosis. Some biochemical markers of bone health may indicate an increased risk for vitamin D deficiency, and testing of vitamin D levels may, therefore, be appropriate. These biochemical markers include unexplained abnormalities in serum calcium, phosphorus, alkaline phosphatase, and/or parathyroid hormone.

Signs and symptoms of vitamin D toxicity (hypervitaminosis D) generally result from induced hypercalcemia. Acute intoxication can cause symptoms of confusion, anorexia, vomiting, weakness, polydipsia, and polyuria. Chronic intoxication can cause bone demineralization, kidney stones, and bone pain.

“Institutionalized” as used herein refers to individuals who reside at long-term facilities where some degree of medical care is provided. These circumstances and facilities can include long-term hospital stays, nursing homes, assisted living facilities, and similar environments.

There are no standardized lists of factors denoting high risk for vitamin D deficiency, and published lists of high-risk factors differ considerably. Certain factors tend to be present on most lists, however, and they may constitute a core set of factors for which there is general agreement that testing is indicated. The Endocrine Society guidelines form the basis for the following list of high-risk factors for vitamin D deficiency (see also Appendix 1):

• Chronic kidney disease stage ≥3;

• Cirrhosis and chronic liver disease;

• Malabsorption states;

• Osteomalacia;

• Osteoporosis;

• Rickets;

• Hypo- or hypercalcemia;

• Granulomatous diseases;

• Vitamin D deficiency, on replacement;

• Obstructive jaundice and biliary tract disease;

• Osteogenesis imperfecta;

• Osteosclerosis and osteopetrosis;

• Chronic use of anticonvulsant medications or corticosteroids;

• Parathyroid disorders;

• Osteopenia.

The need for repeat testing may vary by condition. A single test may be indicated for diagnostic purposes; a repeat test may be appropriate to determine whether supplementation has been successful in restoring normal serum levels. More than 1 repeat test may occasionally be indicated, such as in cases where supplementation has not been successful in restoring levels (another example might include an instance in which continued or recurrent signs and symptoms may indicate ongoing deficiency, and/or when inadequate absorption or noncompliance with replacement therapy is suspected).

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration‒approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Vitamin D

Vitamin D, also known as calciferol, is a fat-soluble vitamin that has a variety of physiologic effects, most prominently in calcium homeostasis and bone metabolism. In addition to the role vitamin D plays in bone metabolism, other physiologic effects include inhibition of smooth muscle proliferation, regulation of the renin-angiotensin system, a decrease in coagulation, and a decrease in inflammatory markers.^1,

Vitamin D Replacement

The Institute of Medicine (now the National Academy of Medicine [NAM]) has recommended reference values for the intake of vitamin D and serum levels, based on available literature and expert consensus.^2, Recommended daily allowances are 600 IU/d for individuals between 1 and 70 years of age, and 800 IU/d for individuals older than 70 years.

Estimates of vitamin D requirements are complicated by the many other factors that affect serum levels. Sun exposure is the most prominent of factors that affect serum levels, and this is because individuals can meet their vitamin D needs entirely through adequate sun exposure. Other factors such as age, skin pigmentation, obesity, physical activity, and nutritional status also affect vitamin D levels and can result in variable dietary intake requirements to maintain adequate serum levels.

Excessive intake of vitamin D can be toxic. Toxic effects are usually due to hypercalcemia and may include confusion, weakness, polyuria, polydipsia, anorexia, and vomiting. In addition, high levels of vitamin D may promote calcium deposition and have the potential to exacerbate conditions such as calcium kidney stones and atherosclerotic vascular disease.

The Institute of Medicine defined 3 parameters of nutritional needs for vitamin D, on the assumption of minimal sun exposure. These parameters were the estimated average requirement, defined as the minimum intake required to maintain adequate levels; the recommended daily allowance, defined as the optimal dose for replacement therapy; and the upper-level intake, defined as the maximum daily dose to avoid toxicity. These recommendations are summarized in Table 1.

Table 1. Institute of Medicine Recommendations for Vitamin D Dietary Intake

regular status

The U.S. Food and Drug Administration (FDA) has cleared a number of immunoassays for in vitro diagnostic devices for the quantitative measurement of total 25-hydroxyvitamin D through the 510(k) process.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Lab tests for vitamin D are available under the auspices of CLIA. Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

Rationale

This evidence review was created in September 2015 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through October 15, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Vitamin D testing in patients with signs and/or symptoms of vitamin D toxicity

Signs and symptoms of vitamin D toxicity (hypervitaminosis D) generally result from induced hypercalcemia. Acute intoxication can cause symptoms of confusion, anorexia, vomiting, weakness, polydipsia, and polyuria. Chronic intoxication can cause bone demineralization, kidney stones, and bone pain.

The first measurable consequences of vitamin D toxicity are hypercalciuria and hypercalcemia, which have been observed only at 25(OH)D levels above 88 ng/mL (220 nmol/L) [73-75]. In 2010, the IOM defined the Safe Upper Limit for vitamin D as 4000 international units/day [33].

Many patients, especially older adults, take vitamin and mineral supplements that contain vitamin D. The patient may not be aware that these supplements contain vitamin D. It is important to inquire about additional dietary supplements that patients may be taking before prescribing extra vitamin D.

Testing vitamin D levels in patients with signs and/or symptoms of vitamin D toxicity  (see Policy Guidelines section) may be considered medically necessary.

Population Reference No. 2

Vitamin D testing in patients with signs and/or symptoms of vitamin D deficiency or at risk for vitamin D deficiency

Prevalence — The prevalence of vitamin D deficiency depends upon the definition used (<20 or <30 ng/mL [50 or 75 nmol/L]). In the National Health and Nutrition Examination Survey (NHANES) 2005 to 2006, 41.6 percent of adult participants (≥20 years) had 25-hydroxyvitamin D (25[OH]D) levels below 20 ng/mL (50 nmol/L) [36]. Multivariate analyses showed that being from a non-white race, not college educated, obese, having low high-density lipoprotein (HDL) cholesterol, poor health, and no daily milk consumption were significantly and independently associated with low vitamin D levels. In the 2000 to 2004 survey, over 70 percent of participants had levels <32 ng/mL (the proportion <30 ng/mL was not specified).

The prevalence of low vitamin D levels may be increasing globally [37-39]. In a review of vitamin D levels in different regions of the world, vitamin D levels below 30 ng/mL (75 nmol/L) were prevalent in every region studied, and low vitamin D levels (<10 ng/mL [25 nmol/L]) were more common in South Asia and the Middle East than in other regions [38]. Data from the NHANES in the United States showed a decrease in mean 25(OH)D concentrations from 30 to 24 ng/mL (75 to 60 nmol/L) between surveys in 1988 and 2004 and from 24 to 19.9 ng/mL (60 to 50 nmol/L) between 2004 and 2006 [37,40,41]. Although assay changes accounted for some of the decrease, other factors (changes in milk intake, use of sun protection, and body mass index [BMI]) also contributed to the decline in vitamin D levels [40].

Causes — There are several causes of vitamin D deficiency, including decreased intake or absorption, reduced sun exposure, increased hepatic catabolism, decreased endogenous synthesis (via decreased 25-hydroxylation in the liver or 1-hydroxylation in the kidney), or end-organ resistance to vitamin D. In patients with 1-alpha hydroxylase deficiency or end-organ resistance to vitamin D, the serum 25(OH)D is typically within the normal range, not reduced. This topic is reviewed in more detail separately.

Groups at high risk — Older persons confined indoors may have low serum 25(OH)D concentrations. Cutaneous production of vitamin D declines with age and in the northern latitudes [3]. In addition, dietary vitamin D intake is often low in older individuals. As an example, in a study of postmenopausal women living in France, mean daily vitamin D intake from food was 144.8 international units /day [42]. More than one-third of women consumed <100 units/day from food.

Vitamin D insufficiency appears to be common among several other populations, including those who are:

●Dark skinned

●Obese

●Taking medications that accelerate the metabolism of vitamin D (such as phenytoin)

●Hospitalized on a general medical service

●Institutionalized

And those who have:

●Limited effective sun exposure due to protective clothing or consistent use of sun screens

●Osteoporosis

●Malabsorption, including inflammatory bowel disease and celiac disease

Candidates for 25(OH)D measurements — There are few data regarding screening for vitamin D deficiency in asymptomatic adults or during pregnancy [48-50]. Most experts agree that it is not necessary to perform broad-based screening of serum 25(OH)D levels in the general population or during pregnancy [35,48]. Normal-risk adults do not need assessment. In individuals who are in the high-risk groups described above, however, it is appropriate to measure serum 25(OH)D, to supplement with the amount estimated to be needed to reach the target 25(OH)D level, and then to remeasure three to four months later to verify that the target has been achieved.

We also typically measure vitamin D in pregnant women who are obese, wear protective clothing, have a history of malabsorption (celiac disease, inflammatory bowel disease), or have other risk factors for vitamin D deficiency.

Clinical manifestations — The clinical manifestations of vitamin D deficiency depend upon the severity and duration of the deficiency. The majority of patients with moderate to mild vitamin D deficiency (serum 25[OH]D between 15 and 20 ng/mL [37.5 to 50 nmol/L]) are asymptomatic. Serum calcium, phosphorus, and alkaline phosphatase are typically normal. Serum parathyroid hormone (PTH) levels have been reported to be elevated in as many as 40 and 51 percent of patients with serum 25(OH)D levels less than 20 and 10 ng/mL (50 and 25 nmol/L), respectively [51]. Patients with low vitamin D and secondary elevations in PTH are at increased risk for having accelerated bone loss, as evidenced by low bone mass on bone densitometry (dual-energy x-ray absorptiometry [DXA]) and fractures.

With prolonged, severe vitamin D deficiency, there is reduced intestinal absorption of calcium and phosphorus and hypocalcemia occurs, causing secondary hyperparathyroidism, which leads to phosphaturia, demineralization of bones, and when prolonged, osteomalacia in adults and rickets and osteomalacia in children. Associated symptoms may then include bone pain and tenderness, muscle weakness, fracture, and difficulty walking. Patients with nutritional osteomalacia, from either a gastrointestinal disorder or suboptimal nutrition and inadequate sun exposure, tend to have serum 25(OH)D levels <10 ng/mL (25 nmol/L). The clinical manifestations and biochemical findings of osteomalacia are reviewed in detail separately.

In addition to its role in calcium and bone homeostasis, vitamin D could potentially regulate many other cellular functions. However, there are insufficient data to confirm a causal relationship between vitamin D deficiency and the immune, cardiovascular, and metabolic systems. This topic is reviewed in detail elsewhere.

The majority of healthy adults with vitamin D deficiency (eg, serum 25-hydroxyvitamin D [25(OH)D] 10 to 20 ng/mL [25 to 50 nmol/L]) do not require any additional evaluation. Patients with serum 25(OH)D levels <10 ng/mL are at risk for developing osteomalacia. In such patients, we measure serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH), electrolytes, blood urea nitrogen (BUN), creatinine, and tissue transglutaminase antibodies (to assess for celiac disease). Radiographs are necessary in certain settings, such as the presence of bone pain.

Some UpToDate editors also measure similar tests in patients with serum 25(OH)D between 10 and 20 ng/mL (25 and 50 nmol/L), particularly if the level is 10 to 15 ng/mL and there is clinical concern for a secondary cause of vitamin D deficiency (eg, malabsorption, celiac disease).

We do not routinely assess bone mineral density in patients whose only risk factor is low serum vitamin D. Patients with low vitamin D require vitamin D supplementation regardless of the findings on bone mineral density. However, many patients have serum vitamin D levels assessed as part of an evaluation for known osteoporosis (diagnosed on bone mineral density or due to a fragility fracture). In such patients with severely low vitamin D levels (and particularly if the serum PTH is high), the need for osteoporosis therapy should be reevaluated after vitamin D repletion. In severely vitamin D deficient patients, there can be marked increases in bone mineral density after treatment of osteomalacia with calcium and vitamin D supplementation, such that treatment for "osteoporosis" is not necessary. Similarly, treatment of celiac disease with a gluten-free diet can result in significant improvement in bone mineral density. The treatment of osteomalacia is reviewed separately.

Testing vitamin D levels in patients with signs and/or symptoms of vitamin D deficiency (see Policy Guidelines section) may be considered medically necessary.

Population Reference No. 3

Vitamin D testing in patients asymptomatic without conditions or risk factors for which vitamin D treatment is recommended

Vitamin D deficiency is best assessed by measuring serum levels of 25-hydroxyvitamin D. However, there is no consensus on the minimum vitamin D level or on the optimal serum level for overall health. A 2011 Institute of Medicine (IOM) report concluded that a serum level of 20 ng/mL is sufficient for most healthy adults.^2, Some experts, such as the Bone Health and Osteoporosis Foundation (formerly the National Osteoporosis Foundation), have recommended a higher level (30 ng/mL) in some patient populations.^3,

Vitamin D deficiency, as defined by suboptimal serum levels, is common in the U.S. In the National Health and Nutrition Examination Survey covering the period of 2011 to 2014, 5% of patients aged 1 year and older were at risk of vitamin D deficiency (25-hydroxyvitamin D levels <12 ng/mL) and 18.3% of patients were at risk of vitamin D inadequacy (25-hydroxyvitamin D levels 12 to 19.6 ng/mL).^4, Vitamin D deficiency occurs most commonly as a result of inadequate dietary intake coupled with inadequate sun exposure. Evidence from the National Nutrition Monitoring System and the National Health and Nutrition Examination Survey has indicated that the average vitamin D consumption is below recommended levels of intake. Yetley (2008) estimated that the average daily intake for U.S. adults ranged from 228 to 335 IU/d, depending on gender and ethnicity.^5, This level is below the average daily requirement, estimated by IOM (400 IU/d for healthy adults), and well below IOM’s required daily allowance (estimated to be 600 IU for nonelderly adults and 800 IU for elderly adults).

Vitamin D deficiency may occur less commonly for other reasons. Kidney or liver disease can cause deficiency as a result of the impaired conversion of inactive vitamin D to its active products. In rare situations, there is vitamin D resistance at the tissue level, which causes a functional vitamin D deficiency despite "adequate" serum levels.

The safe upper level for serum vitamin D is also not standardized. The IOM report concluded there is potential harm associated with levels greater than 50 ng/mL and recommended that serum levels be maintained in the 20 to 40 ng/mL range.^2, However, conclusions on this point have differed. A 2011 Agency for Healthcare Research and Quality systematic review of vitamin D and bone health concluded that “There is little evidence from existing trials that vitamin D above current reference intakes is harmful.”^6, The Women’s Health Initiative concluded that hypercalcemia and hypercalciuria in patients receiving calcium and vitamin D were not associated with adverse clinical events.^7, The Women’s Health Initiative did find a small increase in kidney stones for women ages 50 to 79 years who received vitamin D and calcium.

Associations of vitamin D levels with various aspects of health have been noted over the last several decades,^{8,9,10,11,12,} and these findings have led to the question of whether supplementation improves health outcomes. For example, a relation between vitamin D levels and overall mortality has been reported in most observational studies examining this association.^13,14, Mortality is lowest at vitamin D levels in the 25 to 40 nmol/L range. At lower levels of serum vitamin D, mortality increases steeply, and overall mortality in the lowest quintile was more than 3 times that in the middle quintiles. Theodoratou et al (2014) identified 107 systematic reviews of observational studies examining the association between vitamin D levels and more than 100 different outcomes.^15,

Clinical Context

The purpose of measuring vitamin D levels is to guide a treatment option that is an alternative to or an improvement on existing management in individuals who are asymptomatic without conditions or risk factors for which vitamin D supplementation is recommended.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who are asymptomatic without conditions or risk factors for which vitamin D supplement is recommended.

Interventions

The therapy being considered is testing of vitamin D levels.

Comparators

The following practice is currently being used to manage vitamin D deficiency: routine care without testing for vitamin D deficiency. Routine care may include recommendations for increased ultraviolet B exposure, dietary intake of vitamin D, or vitamin D supplementation in the absence of known vitamin D deficiency.

Outcomes

Relevant outcomes of interest are overall survival, test validity, symptoms, morbid events, and treatment-related morbidity.

The length of time needed to correct subclinical vitamin D deficiency and improve outcomes is unknown and likely varies for different clinical situations.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with preference for randomized controlled trials (RCTs);

• In the absence of such trials, comparative observational studies were sought, with preference for prospective studies.

• To assess longer term outcomes and adverse effects, single-arm studies that capture longer periods of follow up and/or larger populations were sought.

Studies with duplicative or overlapping populations were excluded.

Analytic Framework

Figure 1 summarizes the approach to this evidence review. The diagram demonstrates the framework for how vitamin D testing affects outcomes. Using this framework, the main question is whether testing individuals for vitamin D deficiency improves outcomes.

Figure 1. Analytic Framework

Based on this analytic framework, the most relevant studies for showing the clinical utility of vitamin D testing are trials that directly compare care including testing vitamin D levels against care without testing vitamin D levels. Should vitamin D screening in an asymptomatic, general population be shown to be effective, guidelines would then be needed to establish criteria for screening, screening intervals, and appropriate follow-up for positive tests. Indirect evidence of the utility of vitamin D testing would include evidence of the effectiveness of supplementation from trials testing supplementation to no supplementation in patients who are vitamin D deficient. Many of the existing RCTs, including the largest trial (Women’s Health Initiative), did not test vitamin D levels prior to treatment. Rather, they treated all patients enrolled regardless of vitamin D levels. Results of some of the main systematic reviews that take this approach will be reviewed, but this evidence is indirect and must be extrapolated from the treatment of all patients to the treatment of patients who are vitamin D deficient.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

There is no consensus on how to define vitamin D deficiency or inadequacy, and there is no accepted reference standard. Available cutoffs for deficiency are neither standardized nor based on rigorous scientific studies.^16, Therefore, despite the availability of many tests that measure total serum 25-hydroxyvitamin D (25(OH)D) levels, their sensitivities and specificities for detecting clinically important deficiency are currently unknown.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

No RCTs were found that evaluated clinical outcomes or harms in patients tested for vitamin D deficiency versus not tested for vitamin D deficiency. In the absence of direct evidence of the utility of testing, evidence of the effectiveness of vitamin D supplementation could indirectly support the utility of testing by identifying a group of patients in which baseline serum 25(OH)D is a predictor of supplement effect so that testing might be useful.

A large number of RCTs have evaluated the impact of vitamin D supplementation on outcomes. Theodoratou et al (2014) identified 87 meta-analyses of RCTs on vitamin D supplementation^15,; there were 21 meta-analyses on skeletal health, 7 on metabolic disease, 4 on pediatric outcomes, 3 on cardiovascular disease, 3 on pregnancy-related outcomes, and 18 on other outcomes. Because of the large literature base, this review of evidence will focus on the largest and most recent systematic reviews and meta-analyses of RCTs. Individual trials will be reviewed separately if they were not included in the meta-analyses or if particular features need highlighting. The evidence review includes use of vitamin D testing and supplementation in the following indications: skeletal health, cardiovascular disease, cancer, asthma, pregnancy, multiple sclerosis (MS), and overall mortality.

Review of Evidence

Skeletal Health

Systematic Reviews

Numerous systematic reviews and meta-analyses of RCTs have been published evaluating the impact of vitamin D supplementation on skeletal health outcomes. The relevant health outcomes considered for this evidence review include fractures and falls. Studies that looked at bone mineral density and/or other physiologic measures of bone health were not included. Table 2 summarizes the results of systematic reviews performing quantitative meta-analyses on the relevant outcomes.

Among the trials included in the meta-analyses, few were large studies; most were small or moderate in size and limited by a small number of outcome events. Doses of vitamin D varied widely from 400 to 4800 IU/d; treatment and follow-up durations varied from 2 months to 7 years. Some studies limited enrollment to participants with low serum vitamin D. Most studies excluded institutionalized patients, but some included them. There was inconsistency in the results, especially for studies of fracture prevention, as evidenced by the relatively large degree of heterogeneity among studies.

Table 2. Systematic Reviews Assessing the Impact of Vitamin D Supplementation on Skeletal Health

Cranney et al (2011) conducted a review for the Agency for Healthcare Research and Quality (AHRQ) on the effectiveness and safety of vitamin D in relation to bone health.^6, Reviewers concluded that:

• The evidence on the reduction in fractures was inconsistent. The combined results of trials using vitamin D₃ with calcium were consistent with a benefit on fractures, although the benefit was primarily found in the subgroup of elderly institutionalized women, which was a subgroup not included in this review.

• The evidence on a benefit in fall risk was also inconsistent. The results showed benefit in subgroups of postmenopausal women and in trials that used vitamin D in combination with calcium. There was a reduction in fall risk with vitamin D when 6 trials that adequately ascertained falls were combined.

A meta-analysis of double-blind RCTs by Bischoff-Ferrari et al (2005) estimated the benefit of vitamin D supplementation on fracture risk and examined the dose-response relation between vitamin D and outcomes.^23, Based on a meta-analysis of 5 RCTs that used high-dose vitamin D, reviewers concluded that supplementation at 700 to 800 IU/d reduced the incidence of hip fractures by 26%, and reduced any non-vertebral fracture by 23%. In this same review, based on the results of 2 RCTs, lower doses of vitamin D at 400 IU/d did not significantly reduce the fracture risk.

Similarly, a meta-analysis of RCTs by Tan et al (2024) examined the dose-response relationship between vitamin D supplementation and falls in elderly individuals.^18, The study found that when compared to Vitamin D supplementation at a dose of 800 to 1000 IU/day, the following doses significantly increased the risk of falls: ≤500 IU/d (relative risk [RR]=1.2; 95% confidence interval [CI], 1.02 to 1.45), 1100 to 1900 IU/d (RR=1.22; 95% CI, 1.04 to 1.47), and ≥2000 IU/d (RR=1.23; 95% CI, 1.06 to 1.45).

Randomized Controlled Trials

The STURDY Collaborative Research Group (Appel et al 2021) was a large (N=688) RCT evaluating 4 doses of vitamin D in individuals at least 70 years of age at elevated fall risk and a serum vitamin D level of 25 to 72.5 nmol/L.^24, The primary outcome was time to first fall or death over 2 years. The primary outcome during the confirmatory stage was not significantly different between those receiving the control dose of vitamin D (200 IU/day) and those receiving what was considered the optimal dose of 1000 IU/day. Doses of 1000 IU/day or greater were associated with safety concerns. The study is limited by the use of vitamin D 200 IU/day as a control group rather than use of a placebo.

An RCT not included in most of the systematic reviews (Sanders et al [2010]^25,) reported results inconsistent with some of the previous trials and conclusions of meta-analyses. In this trial, 2256 community-dwelling elderly individuals at high-risk for falls were treated with high-dose vitamin D 500,000 IU orally once per year for 3 to 5 years. There was a 15% increase in falls for the group treated with vitamin D (p=.03) and a 26% increase in fractures (p=.02). In addition, there was a temporal relation to the increase in fall risk, with the greatest risk in the period immediately after vitamin D administration. It is unclear whether the specific regimen used in this study (eg, high-dose vitamin D once/year) was responsible for the different results seen in this study compared with prior research.

Section Summary: Skeletal Health

Numerous RCTs and meta-analyses of RCTs have been published on the effect of vitamin D supplementation on skeletal health. The most direct evidence consists of trials that selected patients for vitamin D deficiency and randomized patients to vitamin D or placebo. A meta-analysis of these trials showed no reduction in fractures and an uncertain reduction in falls. In meta-analyses that treated all patients regardless of vitamin D levels, there are inconsistent findings on the effect of supplementation on fractures and falls. There is some evidence that subgroups (eg, elderly women) may benefit from supplementation and that higher doses may provide a benefit whereas lower doses do not; however, very high doses may increase the risk of falls. Therefore, the evidence does not convincingly demonstrate an improvement in skeletal health outcomes with vitamin D supplementation.

Cardiovascular Disease

Systematic Reviews

A large number of trials have reported on the impact of vitamin D supplementation on cardiovascular events. A number of systematic reviews have examined the relation between vitamin D and cardiovascular outcomes.

Elamin et al (2011) published a systematic review and meta-analysis evaluating cardiovascular outcomes.^26, It included 51 trials that used various forms of vitamin D with or without calcium. There was minimal heterogeneity among the studies. Combined analysis showed no significant impact on cardiovascular death (RR=0.96; 95% CI, 0.93 to 1.0), myocardial infarction (RR=1.02; 95% CI, 0.93 to 1.13), or stroke (RR=1.05; 95% CI, 0.88 to 1.25). No significant effects were found on the physiologic outcomes of lipids, glucose, or blood pressure.

A systematic review by Pittas et al (2010) assessed 5 RCTs evaluating the impact of vitamin D supplementation on incident cardiovascular disease.^27, None of the 5 trials reported a significant reduction in cardiovascular outcomes in the vitamin D group. A combined analysis of these trials found a RR for cardiovascular outcomes of 1.08 (95% CI, 0.99 to 1.19) in the vitamin D group.

An AHRQ report by Chung et al (2009) concluded that^28,:

• The evidence on the impact of vitamin D on cardiovascular outcomes is inconsistent, and conclusions are difficult to make because of the marked heterogeneity of the evidence.

• The RCTs that have evaluated the impact of vitamin D on cardiovascular outcomes use cardiovascular events as a secondary outcome, not as a prespecified primary outcome.

• These analyses have been hampered by low numbers of cardiovascular events and imperfect methods for the ascertainment of cardiovascular events.

Wang et al (2008) also performed a systematic review of whether vitamin D and calcium prevent cardiovascular events.^29, Eight RCTs of vitamin D supplementation in the general population evaluated cardiovascular outcomes as a secondary outcome. A combined analysis of studies that used high-dose vitamin D supplementation (≥1000 IU/d) found a 10% reduction in cardiovascular events, but this reduction was not statistically significant (RR=0.90; 95% CI, 0.77 to 1.05). When studies that combined vitamin D plus calcium supplementation were included, there was no trend toward a benefit (RR=1.04; 95% CI, 0.92 to 1.18).

A systematic review by Pittas et al (2010) included 10 intervention trials that evaluated the relation between vitamin D and hypertension.^27, Most did not report a decrease in incident hypertension associated with vitamin D supplementation.

A systematic review by Su et al (2021) assessed 36 studies that included cohort studies, RCTs, and case-control analyses for the association between serum levels of vitamin D and risk of stroke. ^30, Lower levels of serum vitamin D were associated with an elevated risk of stroke in both Asian and White populations, however, vitamin D supplementation did not show benefit in decreasing the risk of stroke. In a meta-analysis limited to RCTs, Fu et al (2022) had similar findings; vitamin D did not reduce stroke risk compared with placebo (RR=1.02; 95% CI, 0.93 to 1.13; p=.65).^31,

Section Summary: Cardiovascular Disease

The available evidence does not support a benefit of vitamin D supplementation on cardiovascular events. Numerous RCTs have assessed this outcome; however, in most studies, it is a secondary outcome with a limited number of events, thus limiting the power to detect a difference. Furthermore, it is difficult to separate the impact of vitamin D from the impact of calcium in many of these studies. It is common to use vitamin D and calcium supplementation together. Research has also highlighted a potential increase in cardiovascular outcomes associated with calcium supplementation.^32, Thus, if there are beneficial effects of vitamin D, they may be obscured or attenuated by the concomitant administration of calcium supplements. Another possibility is that vitamin D and calcium act synergistically, promoting either a greater protective effect against cardiovascular disease or an increase in cardiovascular risk.

Cancer

Systematic Reviews

Systematic reviews have evaluated the effect of vitamin D supplementation on the prevention of cancer. Table 3 contains characteristics of 2 systematic reviews, and Table 4 summarizes the results of the meta-analyses performed in the reviews. The individual RCTs included in the systematic reviews are listed in Table 5. Both systematic reviews by Keum et al (2019) and Bjelakovic et al (2014) found that vitamin D supplementation did not reduce cancer incidence compared to placebo or no intervention; however, total cancer mortality was reduced. ^33,34, In the systematic review by Bjelakovic et al, there was no substantial difference in the effect of vitamin D on cancer in subgroup analyses of trials only including participants with vitamin D levels less than 20 ng/mL at enrollment compared with trials including participants with vitamin D levels of 20 ng/mL or greater at enrollment. Notably, most included studies were not designed to assess cancer incidence or mortality. The authors of the systematic review by Bjelakovic et al (2014) noted that the estimates that were significantly different were at high risk of type I error due to sample size and potential attrition bias.

Table 3. Characteristics of Systematic Reviews Assessing Vitamin D and Cancer

Table 4. Results of Systematic Reviews Assessing Vitamin D and Cancer

Table 5. Comparison of Randomized Controlled Trials Included in the Systematic Reviews

Section Summary: Cancer

Systematic reviews of many RCTs have examined the effect of vitamin D supplementation on cancer outcomes, although cancer was not the prespecified primary outcome in most RCTs. The current evidence does not demonstrate that vitamin D supplementation reduces the incidence of cancer.

Asthma

Systematic Reviews

Several systematic reviews of vitamin D supplementation for the prevention of asthma exacerbations have been published. Four recent reviews are summarized in Tables 6 and 7. Twenty-six unique RCTs were included in these systematic reviews (see Table 8). Reviews by Williamson et al (2023), Liu et al (2022),^59,and Jolliffe et al (2017)^60, concluded that the RCTs were generally at low risk of bias. The RCTs included children and adults, as well as variable doses of vitamin D, routes and lengths of administration, and variable levels of asthma severity. The RCTs also included patients with variable baseline 25(OH)D levels and patients were not generally selected by baseline 25(OH)D.

The most recent Cochrane systematic review evaluating vitamin D for asthma management by Williamson et al (2023)^61,, failed to find improved outcomes with vitamin D use, reversing conclusions of a 2016 Cochrane review by Martineau et al (2016).^62, The Jolliffe et al (2017) review found that vitamin D supplementation reduced the rate (or proportion) of asthma exacerbations requiring treatment with systemic corticosteroids, while Liu et al (2022) found vitamin D supplementation to reduce overall asthma exacerbations. The review by Luo et al (2015)^63, found that vitamin D had no effect on Asthma Control Test (ACT) scores, forced expiratory volume in 1-second (FEV1) outcomes, or rates of adverse events. Liu et al (2022) found no benefit to vitamin D supplementation on ACT scores, FEV1, or Fractional Exhaled Nitric Oxide (FENO).^59, The review by Jolliffe et al (2017) used individual participant data and was, therefore, able to test for patient-level subgroup effects. For the outcome of “rate of asthma exacerbations treated with systemic corticosteroids,” the protective effect of vitamin D was larger in patients with a baseline 25(OH)D levels of less than 25 nmol/L (rate ratio=0.33; 95% CI, 0.11 to 0.98) compared with patients who had higher a baseline 25(OH)D levels (rate ratio=0.77; 95% CI, 0.58 to 1.03). However, the subgroup by treatment group interaction was not statistically significant (p=.25).

Table 6. Characteristics of Systematic Reviews Assessing Vitamin D and Asthma

Table 7. Results of Systematic Reviews Assessing Vitamin D and Asthma

Table 8. Comparison of Randomized Controlled Trials Included in the Systematic Reviews

Randomized Controlled Trials

An RCT of prenatal supplementation in 881 pregnant women at high-risk of having children with asthma was published in 2016.^90, Women between gestational ages of 10 and 18 weeks were randomized to daily vitamin D 4000 IU plus a multivitamin containing vitamin D 400 IU (4400 IU group) or daily placebo vitamin D plus a multivitamin containing vitamin D 400 IU (400 IU group). Coprimary outcomes were (1) parental report of physician-diagnosed asthma or recurrent wheezing through 3 years of age and (2) third-trimester maternal 25-OH(D) levels. Analysis of infant outcomes included 806 infants, 218 of whom developed asthma by age 3 years. The proportion of infants with asthma or recurrent wheeze was 24% in the 4400 IU group vs 30% in the 400 IU group (difference= -6%; 95% CI, -30% to 18%). There were no differences in the proportion of infants experiencing eczema or lower respiratory tract infections.

Section Summary: Asthma

Results of systematic reviews have reported mixed findings with respect to the effect of vitamin D supplementation on asthma outcomes. Populations included in studies varied by baseline vitamin D deficiency levels, administration of vitamin D, and the severity of asthma. In general, patients were not selected based on a low baseline 25(OH)D level. While there is some evidence that vitamin D supplementation reduces the rate of asthma exacerbations, it is unclear if baseline 25(OH)D level is related to treatment benefit. The current evidence is insufficient to determine the effect of vitamin D supplementation on asthma outcomes.

Pregnancy

Systematic Reviews

A 2019 and updated 2024 Cochrane review of studies examining the role of vitamin D supplementation in pregnancy are summarized in Table 9 and Table 10. The individual studies included in the reviews are listed in Table 11. In the 2019 review, Vitamin D supplementation during pregnancy was found to probably reduce the risk of pre-eclampsia (moderate-certainty evidence), gestational diabetes (moderate-certainty evidence), severe postpartum hemorrhage (low-certainty evidence), and low birth weight in infants (moderate-certainty evidence).^91, However, not all studies measured baseline 25(OH)D levels and analyses based on initial 25(OH)D concentrations were not performed. Most studies were considered to have a low-moderate risk of bias. In the 2024 update, a trustworthy assessment tool removed most of the studies that were previously included in the 2019 review.^92, In the updated analyses, the evidence was very uncertain about Vitamin D supplementation for the outcome of pre-eclampsia (very low certainty evidence), gestational diabetes (very low certainty evidence), and pre-term birth (very low certainty evidence). However, the authors found that supplementation with Vitamin D during pregnancy may reduce the risk of severe postpartum hemorrhage (low-certainty evidence) and low birth weight (low-certainty evidence). The risk of bias was high for blinding in 4 studies and for attrition in 4 studies. Additionally, not all studies measured baseline 25(OH)D levels.

Table 9. Characteristics of Systematic Review Assessing Vitamin D and Pregnancy

Table 10. Results of Systematic Review Assessing Vitamin D and Pregnancy

Table 11. Randomized Controlled Trials Included in the Systematic Review

Section Summary: Pregnancy

A 2019 systematic review found vitamin D supplementation in pregnancy reduced the risk of pre-eclampsia, gestational diabetes, low birthweight, and possibly severe postpartum hemorrhage; however, the significance of baseline 25(OH)D levels was not defined. An 2024 update of this review excluded less reputable studies, and found that Vitamin D during pregnancy may reduce the risk of severe postpartum hemorrhage and low birth weight.

Multiple Sclerosis

Three systematic reviews have examined the effect of vitamin D supplementation in patients with MS.^116,117,118, Reviewers described 6 RCTs, all of which were small (N<100). Patient follow-up ranged from 6 months to 2 years, and the dosing and administration of vitamin D varied. None of the trials reported improvement in MS relapse rates; most trials showed no effect of vitamin D on any of the surrogate or clinical outcomes. Only 1 trial reported improvement in magnetic resonance imaging of lesions in the vitamin D supplementation group. The evidence for vitamin D supplementation in MS is poor.

Overall Mortality

Systematic Reviews

A number of meta-analyses of RCTs of vitamin D supplementation have examined the benefit of vitamin D supplementation on overall mortality. Table 12 summarizes the most recent meta-analyses. The individual studies ranged in size from fewer than 100 to several thousand patients. No significant heterogeneity was reported for these trials.

The most relevant information comes from a meta-analysis of patients with vitamin D deficiency by LeBlanc et al (2015).^119, This report included 11 studies and found a marginally significant reduction in overall mortality, with a CI that approached 1.0. When the subgroup analysis was performed, it became apparent that most of the benefit was specific to institutionalized patients whereas, in community-dwelling patients, the data revealed no reduction in mortality.

The AHRQ report by Newberry et al (2014),^120, assessing the health effects of vitamin D supplementation, updated the original 2007 report. A quantitative synthesis of all trials was not performed in the 2014 update. Rather reviewers identified areas where the new trials might change previous conclusions. Their main conclusions were that the results did not support a benefit on overall mortality associated with vitamin D supplementation. No important trials identified in the update would potentially change this conclusion.

For meta-analyses including RCTs that treated all patients with vitamin D, most analyses have not shown a significant reduction in mortality. The single analysis that did show a significant reduction was that by Chowdhury et al (2014), who reported a marginally significant result for vitamin D₃ supplementation but not for vitamin D₂ supplementation.^121,

Table 12. Results of Systematic Reviews of Randomized Controlled Trials Assessing the Impact of Vitamin D Supplementation on Mortality

Section Summary: Overall Mortality

Evidence from a number of systematic reviews and meta-analyses does not support a benefit of vitamin D supplementation on overall mortality for the general, noninstitutionalized population. Populations included in the studies varied by baseline vitamin D deficiency and administration of vitamin D.

For individuals who are asymptomatic without conditions or risk factors for which vitamin D treatment is recommended who receive testing of vitamin D levels, the evidence includes no randomized controlled trials (RCTs) of clinical utility (ie, evidence that patient care including testing vitamin D levels versus care without testing vitamin D levels improves outcomes). Relevant outcomes are overall survival, test validity, symptoms, morbid events, and treatment-related morbidity. Indirect evidence of the potential utility of testing includes many RCTs and systematic reviews of vitamin D supplementation. There is a lack of standardized vitamin D testing strategies and cutoffs for vitamin D deficiency are not standardized or evidence-based. In addition, despite the large quantity of evidence, considerable uncertainty remains about the beneficial health effects of vitamin D supplementation. Many RCTs have included participants who were not vitamin D deficient at baseline and did not stratify results by baseline 25-hydroxyvitamin D level. Nonwhite race/ethnic groups are underrepresented in RCTs, but have an increased risk of vitamin D deficiency. For skeletal health, there may be a small effect of vitamin D supplementation on falls, but there does not appear to be an impact on reducing fractures for the general population. The effect on fracture reduction may be significant in elderly women, and with higher doses of vitamin D. However, high doses of vitamin D may be associated with safety concerns in patients at risk for falls. For patients with asthma, there may be a reduction in severe exacerbations with vitamin D supplementation, but there does not appear to be an effect on other asthma outcomes. For patients who are pregnant, vitamin D supplementation may improve certain maternal and fetal outcomes. For overall mortality, there is also no benefit to the general population. RCTs evaluating extraskeletal, cancer, cardiovascular, and multiple sclerosis outcomes have not reported a statistically significant benefit for vitamin D supplementation. Although vitamin D toxicity and adverse events appear to be rare, few data on risks have been reported. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Obstetrics and Gynecology

The American College of Obstetrics and Gynecology (2011, reaffirmed 2024 ) issued a committee opinion on the testing of vitamin D levels and vitamin D supplementation in pregnant women.^124, The following recommendation was made concerning testing vitamin D levels:

“At this time there is insufficient evidence to support a recommendation for screening all pregnant women for vitamin D deficiency. For pregnant women thought to be at increased risk of vitamin D deficiency, maternal serum 25-hydroxyvitamin D levels can be considered and should be interpreted in the context of the individual clinical circumstance. When vitamin D deficiency is identified during pregnancy, most experts agree that 1,000-2,000 international units per day of vitamin D is safe.”

Bone Health and Osteoporosis Foundation

The Bone Health and Osteoporosis Foundation updated recommendations for the prevention and treatment of osteoporosis in 2021.^3, They recommended monitoring serum 25-hydroxy vitamin D levels in postmenopausal women and men 50 years of age and older, and vitamin D supplementation as necessary to maintain levels between 30 and 50 ng/mL.

Endocrine Society

In 2024 , the Endocrine Society published clinical practice guidelines on Vitamin D for the prevention of disease.^125, The 2024 guideline updates and replaces a 2011 Endocrine Society guideline on the evaluation, treatment, and prevention of vitamin D deficiency.The 2024 guideline suggests against routine testing vitamin D levels in the following populations who do not otherwise have established indications for 25(OH)D testing (eg, hypocalcemia):

• General adult population younger than age 50 years, aged 50 to 74 years, and aged 75 years and older
• Pregnant individuals
• Healthy adults
• Adults with dark complexion
• Adults with obesity

For these populations, the guideline notes that: "25(OH)D levels that provide outcome-specific benefits have not been established in clinical trials."

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force published an updated recommendation^126, and associated evidence report and systematic review in 2021^127, on vitamin D screening. The Task Force concluded that the current evidence was insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic individuals (grade I [insufficient evidence]).

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing or unpublished trials that might influence this review are listed in Table 13.

Table 13. Summary of Key Trials

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36. Grady D, Halloran B, Cummings S, et al. 1,25-Dihydroxyvitamin D3 and muscle strength in the elderly: a randomized controlled trial. J Clin Endocrinol Metab. Nov 1991; 73(5): 1111-7. PMID 1939527
37. Komulainen M, Kröger H, Tuppurainen MT, et al. Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population-based 5-year randomized trial. J Clin Endocrinol Metab. Feb 1999; 84(2): 546-52. PMID 10022414
38. Gallagher JC, Fowler SE, Detter JR, et al. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metab. Aug 2001; 86(8): 3618-28. PMID 11502787
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44. Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. Jun 2007; 85(6): 1586-91. PMID 17556697
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61. Williamson A, Martineau AR, Sheikh A, et al. Vitamin D for the management of asthma. Cochrane Database Syst Rev. Feb 06 2023; 2(2): CD011511. PMID 36744416
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64. Ramos-Martínez E, López-Vancell MR, Fernández de Córdova-Aguirre JC, et al. Reduction of respiratory infections in asthma patients supplemented with vitamin D is related to increased serum IL-10 and IFNγ levels and cathelicidin expression. Cytokine. Aug 2018; 108: 239-246. PMID 29402723
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66. Jerzynska J, Stelmach W, Rychlik B, et al. The clinical effect of vitamin D supplementation combined with grass-specific sublingual immunotherapy in children with allergic rhinitis. Allergy Asthma Proc. 2016; 37(2): 105-14. PMID 26932169
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