Coverage Policy Manual
Policy #: 2018006
Category: Laboratory
Initiated: February 2018
Last Review: January 2024
  Lab Test: Serum Vitamin D Levels
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, decrease in coagulation, and decrease in inflammatory markers (Shapses, 2011).  
 
Vitamin D Levels
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 2010 Institute of Medicine (IOM, 2010) report concluded that a level of 20 ng/mL is sufficient for most healthy adults. Some experts, such as the National Osteoporosis Foundation and the American Geriatrics Society, recommend a higher level (30 ng/mL) (Institute of Medicine, 2010).
 
Vitamin D deficiency, as defined by suboptimal serum levels, is common in the United States. In the National Health and Nutrition Examination Survey (NHANES) survey covering the period of 2000-2004, a total of 30% of individuals over the age of 12 had 25-hydroxyvitamin D levels less than 20 ng/mL (Yetley EA, 2008). 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 (NNMS) and the NHANES has indicated that the average consumption is below recommended levels of intake. Yetley (2008) estimated that average daily intake for U.S. adults ranged from 228 to 335 IU/d, depending on gender and ethnicity. This is below the average daily requirement, estimated by IOM (400 IU/d for healthy adults), and well below IOM’s required daily allowance, which was 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 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 (2010) IOM report concluded that 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. However, other conclusions on this point have differed. The Agency for Healthcare Research and Quality (AHRQ, 2011) systematic review on vitamin D and bone health concluded that “There is little evidence from existing trials that vitamin D above current reference intakes is harmful.” The Women’s Health Initiative (WHI) concluded that hypercalcemia and hypercalciuria in patients receiving calcium and vitamin D were not associated with adverse clinical events(Jackson et al, 2006).  The WHI did find a small increase in kidney stones for women aged 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, and these findings have led to the question of whether supplementation improves health outcomes (Holvik K et al, 2013; Cauley et al, 2010; Mithal et al, 2009; Cauley et al, 2008; Looker, 2008).  
 
For example, a relationship between vitamin D levels and overall mortality has been reported in most observational studies examining this relationship (Jia X, 2007; Visser et al, 2006) Mortality is lowest at vitamin D levels D 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.
 
Vitamin D Replacement
The IOM (2010) document recommended reference values for intake of vitamin D and serum levels, based on available literature and expert consensus.  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, 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.
 
On the other hand, excessive intake of vitamin D can have toxic effects. These 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 has the potential to exacerbate conditions such as calcium kidney stones and atherosclerotic vascular disease.
 
IOM defined 3 parameters of nutritional needs for vitamin D, on the assumption of minimal sun exposure. They 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 by age group are summarized below.
 
Institute of Medicine Recommendations for Vitamin D Dietary Intake (IOM, 2010)
 
1-3 years old--Minimum Average Requirement: 400.  Recommended Daily Allowance: 600. Upper Limit Intake: 2500
4-8 years old--Minimum Average Requirement: 400. Recommended Daily Allowance: 600. Upper Limit Intake: 3000
9-70 years old--Minimum Average Requirement: 400. Recommended Daily Allowance: 600. Upper Limit Intake: 4000
>70 years old--Minimum Average Requirement: 400. Recommended Daily Allowance: 800. Upper Limit Intake: 4000
 
(Values are expressed in IU per day (IU/d).  
 
 
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA) of 1988. Lab tests for vitamin D are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.
 
Coding
There are specific CPT codes for vitamin D testing:
 
82306 Vitamin D; 25 hydroxy, includes fraction(s), if performed
82652 Vitamin D; 1, 25 dihydroxy, includes fraction(s), if performed.
 
Policy/
Coverage:
EFFECTIVE JUNE 01, 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing vitamin D levels in patients with signs and/or symptoms of vitamin D deficiency or toxicity meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
Signs and/or symptoms of vitamin D deficiency may include:
    • A clinical diagnosis of an abnormality in bone health (eg, rickets, osteomalacia, osteoporosis)
    • Symptoms related to the clinical condition may be present, such as pain or low-impact fractures, but these symptoms are usually not indications for testing prior to a specific diagnosis.
    • Biochemical markers of bone health indicating an increased risk for vitamin D (e.g., unexplained abnormalities in serum calcium, phosphorous, 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.
 
Testing vitamin D levels in asymptomatic patients meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the following patient populations:
 
    • Individuals who have risk factors for vitamin D deficiency as manifested by one of the following:
        • Chronic kidney disease, stage 3
        • Cirrhosis/chronic liver disease
        • Malabsorption states
        • Osteomalacia
        • Osteoporosis
        • Rickets
        • Hypo- or hypercalcemia
        • Granulomatous diseases
        • Vitamin D deficiency, on replacement
        • Obstructive jaundice/biliary tract disease
        • Osteogenesis imperfecta
        • Osteosclerosis/osteopetrosis
        • Chronic use of anticonvulsant medication or corticosteroids
        • Parathyroid disorders
        • Osteopenia
 
    • Institutionalized patients (e.g., those 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)
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing vitamin D levels in asymptomatic patients does not meet member benefit certificate primary coverage criteria and is not covered when the above criteria are not met.
 
For members with contracts without primary coverage criteria, testing vitamin D levels in asymptomatic patients is considered not medically necessary. Services that are considered not medically necessary are specific contract exclusions in most member benefit certificates of coverage.
 
NOTE: 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 be indicated occasionally, such as in cases where, eg, supplementation has not been successful in restoring levels, continued or recurrent signs and symptoms may indicate ongoing deficiency, and/or inadequate absorption or noncompliance with replacement therapy is suspected.
Rationale:
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.   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.
 
Skeletal Health
Numerous systematic reviews and meta-analyses of RCTs have been published evaluating the impact of vitamin D supplementation on skeletal health outcomes (Leblanc, 2015; AHRQ, 2011; Avenell, 2009; Bischoff-Ferrari, 2009; Palmer, 2009).  Relevant health outcomes considered for this evidence review include fractures and falls. Studies that look at bone mineral density and/or other physiologic measures of bone health are not included.  
 
Among the trials included in the meta-analyses, few are large studies; most are small or moderate in size and limited by a small number of outcomes 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 participant with low serum vitamin D. Most studies excluded institutionalized patients but some included them. There is inconsistency in the results, especially for studies of fracture prevention, as evidenced by the relative large degree of heterogeneity among the studies.
 
An AHRQ (2011) review was completed in on the effectiveness and safety of vitamin D in relation to bone health. This review concluded that:
 
    • The evidence on reduction in fractures is 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.
    • The evidence on a benefit in fall risk is also inconsistent. The results showed benefit in a 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.
 
One systematic review of double-blind RCTs published in 2005 estimated the benefit of vitamin D supplementation on fracture risk and examined the dose-response relationship between vitamin D and outcomes(Bischoff-Ferrari et al, 2005). Based on meta-analysis of 5 RCTs that used high-dose vitamin D, this review 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.
 
One RCT published in 2010 (not included in most of the systematic reviews) reported results that are inconsistent with some of the previous trials and conclusions of meta-analyses (Sanders et al, 2010). In this trial, 2256 community-dwelling elderly individuals at high risk for falls were treated with high-dose vitamin D¾ 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=0.03) and a 26% increase in fractures (p=0.02). In addition, there was a temporal relationship to the increase in fall risk, with the risk greatest in the time 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 randomize 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 risk of falls. Therefore, the evidence does not convincingly demonstrate an improvement in skeletal health outcomes with vitamin D supplementation.
 
Cardiovascular Disease
A large number of trials report on the impact of vitamin D supplementation on cardiovascular events. A number of systematic reviews have examined the relationship between vitamin D and cardiovascular outcomes, including an AHRQ report in 2009 (Chung et al, 2009).
 
The AHRQ report concluded that:
    • 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 ascertainment of cardiovascular events.
 
In another systematic review published by Pittas et al (2010), 5 RCTs evaluating the impact of vitamin D supplementation on incident cardiovascular disease were reviewed. None of the 5 trials reported a significant reduction in cardiovascular outcomes in the vitamin D group. Combined analysis of these trials found a relative risk (RR) for cardiovascular outcomes of 1.08 (95% confidence interval [CI], 0.99 to 1.19) in the vitamin D group.
 
Wang et al (2008) also performed a systematic review on whether vitamin D and calcium prevent cardiovascular events.  There were 8 RCTs of vitamin D supplementation in the general population that 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 and calcium supplementation were included, there was no trend toward a benefit (RR=1.04; 95% CI, 0.92 to 1.18).
 
Elamin et al (2007) published a meta-analysis of cardiovascular outcomes in 2011.  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.
 
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, but 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. Recent research has highlighted a potential increase in cardiovascular outcomes associated with calcium supplementation (Bolland et al, 2010). Thus, if there are beneficial effects of vitamin D, they may be obscured or attenuated by 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.
 
Hypertension
A systematic review by Pittas et al (2010) included 10 intervention trials that evaluated the relationship between vitamin D and hypertension. Most did not report a decrease in incident hypertension associated with vitamin D supplementation. The largest trial with the longest follow-up was the WHI, which included over 36,000 patients (Margolis et al, 2008). The WHI study did not show a reduction in the incidence of hypertension in vitamin D?treated individuals. There was a small, nonsignificant decrease in systolic blood pressure for patients in the vitamin D group (-1.9 mmHg; 95% CI, -4.2 to 0.4 mm Hg) and no change in diastolic blood pressure (-0.1 mm Hg; 95% CI, -0.7 to 0.5).
 
Cancer
In 2014, a Cochrane systematic review and meta-analysis assessed the benefits and harms of vitamin D supplementation on prevention of cancer in adults (Bjelakovic, 2014).   Reviewers included 18 RCTs (50,623 participants) that compared vitamin D at any dose, duration, and route of administration to placebo or no intervention in healthy adults or diagnosed with a specific disease. Cancer occurred in 1927 (7.6%) of 25,275 participants assigned to receive vitamin D versus 1943 (7.7%) of 25,348 participants assigned to receive control interventions (RR=1.00; 95% CI, 0.94 to 1.06) based on GRADE moderate quality evidence. 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 to trials including participants with vitamin D levels of 20 ng/mL or greater at enrollment. Vitamin D3 combined with calcium was associated with increased nephrolithiasis (RR=1.17; 95% CI, 1.03 to 1.34).
 
The 2014 AHRQ report summarized the evidence on vitamin D supplementation and cancer outcomes (Quality AfHRa, 2014).  Based on a limited number of RCTs, the following conclusions were made:
 
    • One RCT reported no effect of vitamin D on overall cancer mortality in healthy postmenopausal women.
    • One RCT reported no effect of vitamin D on overall cancer mortality for elderly men or women.
 
The evidence on the association between vitamin D levels and cancer was reviewed by IOM,2 with the following conclusions:
    • There are a small number of studies that address this question and they show a lack of consistency in associations between vitamin D intake, or levels, and all cancer mortality
    • Most available RCTs do not have cancer as a prespecified primary outcome, thus the validity of the data is less than optimal.
    • Overall, the evidence is insufficient to form conclusions about the association of vitamin D with cancer.
 
In 2015, Baron et al published results of a 2×2 factorial RCT of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas.   The trial enrolled 2259 patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. Patients received treatment and continued follow-up for 3 to 5 years and the primary outcome was adenomas diagnosed through colonoscopy. Overall, 1301 (43%) of patients had 1 or more adenomas. Relative risks for recurrent adenomas were adjusted for age, clinical center, anticipated surveillance interval (3 or 5 years), sex, type of randomization, and number of baseline adenomas. The adjusted relative risk for recurrent adenomas was 0.99 (95% CI, 0.89 to 1.09) with vitamin D versus no vitamin D. The findings for advanced adenomas were similar. There were few serious adverse events, and hypercalcemia did not differ between vitamin D and no vitamin D.
 
Section Summary: Cancer
Many RCTs have been examined the effect of vitamin D supplementation on cancer outcomes although cancer was not the prespecified primary outcome in most. The current evidence suggests that vitamin D supplementation does not reduce the incidence of cancer.
 
ASTHMA
A 2015 meta-analysis of the effect of vitamin D supplementation plus asthma controller medication on acute asthma exacerbation and lung function was published (Luo, 2015).   Seven RCTs from 7 countries (total N=903 patients) published up to July 2015 were selected. Three studies included children and 4 included adults. Doses as well as routes and lengths of administration of vitamin D varied by study, as did asthma severity. Mean baseline 25-OH(D) levels ranged from 19 to 21 ng/mL. The pooled relative risk (vitamin D vs control) of asthma exacerbation was 0.66 (95% CI, 0.32 to 1.37). There was no effect of vitamin D on difference in mean in forced expiratory volume in 1 second) or Asthma Control Test score.
 
An RCT of prenatal supplementation in 881 pregnant women at high risk of having children with asthma was published in 2016 (Litonjua, 2016).  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. The proportion of infants with asthma or recurrent wheeze was 24% in the 4400 IU group versus 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 RCTs have been mixed 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 severity of asthma. The current evidence is insufficient to determine the effect of vitamin D supplementation on asthma outcomes.
 
MULTIPLE SCLEROSIS
Three systematic reviews have examined the effect of vitamin D supplementation in patients with multiple sclerosis (MS) (Pozuelo-Moyano, 2013; James, 2013; Jagannath, 2010).   Reviewers described 6 RCTs, all of which were small (n<100). Patient follow-up ranged from 6 months to 2 years, and 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
A number of meta-analyses of RCTs of vitamin D supplementation have examined the benefit of vitamin D supplementation on overall mortality (Leblanc, 2015; Chowdhury, 2014; Bjelakovic, 2011; Palmer, 2009a; Palmer, 2009b). The individual studies range in size from fewer than 100 to several thousand patients. No significant heterogeneity was reported for these included trials.
 
The most relevant information comes from the meta-analysis of patients with vitamin D deficiency (LeBlanc, 2015). This report included 11 total studies and reported a marginally significant reduction in overall mortality, with a confidence interval that approached 1.0. When subgroup analysis was performed, it appeared that most of the benefit was restricted to patients who were institutionalized, whereas in community-dwelling patients there was no reduction in mortality.
 
AHRQ performed 2 evidence reports on the health effects of vitamin D supplementation. The most recent report was published in 2014, and consisted of an update to the original 2007 report (Quality AfHRa, 2014). A quantitative synthesis of all the trials was not performed in the 2014 update. Rather they identified areas where the new trials might change previous conclusions. The main conclusions of this document on overall mortality were that the results of the available studies do not support a benefit on overall mortality associated with vitamin D supplementation. There were no important trials identified in the update that would potentially change this conclusion.
 
For meta-analyses that included RCTs that treated all patients with vitamin D, most analyses did not show a significant reduction in mortality. The single analysis that did show a significant reduction was the Chowdhury (2014) study that reported a marginally significant result for vitamin D3 supplementation but not for vitamin D2 supplementation.
 
Section Summary: Overall Mortality
Evidence from a number of systematic reviews and meta-analyses does not support a benefit on overall mortality for the general, noninstitutionalized population. Populations included in the studies varied by baseline vitamin D deficiency and administration of vitamin D.
 
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 vs care without testing vitamin D levels improves outcomes). Indirect evidence of potential utility of testing includes many RCTs and systematic reviews of vitamin D supplementation. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, symptoms, morbid events, and treatment-related morbidity. 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 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. For overall mortality, there is also no benefit for the general population. RCTs evaluating extraskeletal, asthma, and multiple sclerosis outcomes have not reported a 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 the effects of the technology on health outcomes.
 
Practice Guidelines and Position Statements
 
Endocrine Society
In 2011, the Endocrine Society published clinical practice guidelines for the evaluation, treatment and prevention of vitamin D deficiency (Holick et al, 2011). The following recommendations were made regarding testing vitamin D levels:
 
    • 25(OH)D [25-hydroxyvitamin D] serum level testing is recommended to evaluate vitamin D status only in patients who are at risk of deficiency. The guideline does not recommend screening of individuals who are not at risk of vitamin D deficiency.
    • 1,25(OH)2D [1,25-dihydroxyvitamin D] testing is not recommended to evaluate vitamin D status. However, the guideline does recommend monitoring calcitriol levels in certain conditions.
 
American College of Obstetrics and Gynecology
The American College of Obstetrics and Gynecology issued guidelines on the testing of vitamin D levels and vitamin D supplementation in pregnant women (American College of Obstetrics and Gynecology Committee on Obstetric Practice, 2011). The following recommendation was made about 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 25-OH-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.”
 
American Academy of Family Physicians
In 2014, the American Academy of Family Physicians concluded that the current evidence was insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency (Physicians AA oF, 2014).  
 
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force (USPSTF) published a recommendation in 2014 and associated guidelines in 2015 on vitamin D screening (USPSTF, 2014).  USPSTF concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic individuals (grade I [insufficient evidence]).
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below.
 
Ongoing
    • NCT02805907 - Efficacy of Calcifediol Supplementation in Asthma Control in Asthmatic Patients With Vitamin D Deficiency (ACViD); planned enrollment 100; completion date Jan 2017
    • NCT02750293 - The Effect of Vitamin D Supplementation on Cardiovascular Risk Factors in Subjects With Low Serum 25-hydroxyvitamin D Levels; planned enrollment 600; completion date Sept 2017
    • NCT01169259 - Vitamin D and Omega-3 Trial (VITAL); planned enrollment 25,874; completion date Dec 2017
    • NCT02424552 - EVITA Trial: Effect of VItamin D as add-on Therapy for Vitamin D Insufficient Patients With Severe Asthma: a Randomized, Double-blind, Placebo-controlled Trial;  planned enrollment 160; completion date Mar 2018
    • NCT02422784 A Double-Blind, Randomized, Control Study to Examine the Effects of Vitamin Fortification on Vitamin D Metabolite Profiles and Status in Vitamin D Insufficient Individuals. Planned Enrollment: 65. Completion Date:Jun 2018.
    • NCT01490502 - A Randomized Controlled Trial of Vitamin D Supplementation in Multiple Sclerosis; planned enrollment 172; completion date Mar 2019
    • NCT00920621 - Randomized Trial: Maternal Vitamin D Supplementation to Prevent Childhood Asthma (VDAART); planned enrollment 870; completion date Jun 2019
    • NCT02166333 - Vitamin D Supplements to Prevent Falls in Older Adults: A Dose-Response Trial; planned enrollment 1200; completion date Dec 2019
 
Unpublished
    • NCT01153568 - Vitamin D and Osteoporosis Prevention in Elderly African American Women (NIHD); planned enrollment 260; completion date Oct 2016.
NCT010520151 – Clinical Trial of Vitamin D3 to reduce Cancer Risk in Postmenopausal Women (CAPS);  planned enrollment 2303; completion date Aug 2015 (completed)
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
American Academy of Family Physicians
The American Academy of Family Physicians concluded that the current evidence was insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency (AAFP, 2018).
 
 In 2018, key recommendations for practice concluded that there was insufficient information to recommend screening the general population for vitamin D deficiency and that treating asymptomatic individuals with identified deficiency has not been shown to improve health (LeFevre, 2018).
 
2020 Update
A literature search was conducted through June 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
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) (Herrick, 2019). 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
 
Systematic reviews have evaluated the effect of vitamin D supplementation on prevention of cancer. Both systematic reviews by Keum et al and Bjelakovic et al found that vitamin D supplementation did not reduce cancer incidence compared to placebo or no intervention; however, total cancer mortality was reduced (Keum, 2019; Bjelakovic, 2014).
 
Vitamin D supplementation during pregnancy probably reduces risk of pre-eclampsia (moderate-certainty evidence), gestational diabetes (moderate-certainty evidence), severe postpartum hemorrhage (low-certainty evidence), and low birthweight in infants (moderate-certainty evidence) (Palacios, 2019). 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.
 
The U.S. Preventive Services Task Force published a recommendation in 2014 and associated guidelines in 2015 on vitamin D screening (USPSTF, 2014; LeFevre, 2015). 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]). In the 2020 draft of the updated evidence review, the final recommendation upholds the same conclusion; however, the final version is not yet published (USPSTF, 2020).
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A systematic review by Su et al 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 (Su, 2021). 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.
 
Andujar-Espinosa published an RCT assessing the efficacy of vitamin D supplementation in adult asthmatic patients (Andujar-Espinosa, 2021). Adult asthmatic patients who had serum 25-OH(D) levels <30 ng/mL were randomized to receive either 16,000 IU (n=56) or placebo (n=56) weekly along with their regular asthma treatments for a period of 6 months. The primary outcome was the degree of asthma control as defined by the ACT scores, self-administered by patients. There was a significant difference between the 2 study groups, with clinical improvement seen in the vitamin D supplementation group compared to placebo (difference of 3.66 (95% CI, 0.89 to 5.43); p<.001) as measured using ACT scores.
 
The American Geriatrics Society issued a consensus statement in 2014 on vitamin D for prevention of falls and their consequences (Judge, 2014). The workgroup concluded that a serum 25-hydroxyvitamin D level of 30 ng/mL should be a minimum goal to achieve in older adults who are at higher risk of falls or injuries and would not require practitioners to measure serum vitamin D concentrations in the absence of underlying conditions (e.g. hypercalcemia).
 
The National Osteoporosis Society issued a patient management clinical guideline for vitamin D and bone health in 2014. It recommended that serum 25-hydroxyvitamin D levels should be measured to estimate vitamin D status in certain clinical scenarios such as: bone diseases that may improve with vitamin D treatment; bone diseases, prior to specific treatment where correcting vitamin D deficiency is appropriate; and musculoskeletal symptoms that could be due to vitamin D deficiency.
 
The U.S. Preventive Services Task Force published an updated recommendation and associated evidence report and systematic review in 2021 on vitamin D screening (Krist, 2021; Kohwati, 2021). 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]).
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
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 (Food and Nutrition Board Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D, 2011). 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 (LeBoff, 2022).
 
The STURDY Collaborative Research Group 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 (Appel, 2021). 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.
 
A systematic review by Su et al 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 (Su, 2021). 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 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) (Fu, 2022).
 
Several systematic reviews of vitamin D supplementation for the prevention of asthma exacerbations have been published. Reviews by Liu et al, Jolliffe et al, and Martineau et al concluded that the RCTs were generally at low risk of bias (Liu, 2022; Jolliffe, 2017; Martineau, 2016). 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 Jolliffe et al and Martineau et al reviews found that vitamin D supplementation reduced the rate (or proportion) of asthma exacerbations requiring treatment with systemic corticosteroids, while Liu et al found vitamin D supplementation to reduce overall asthma exacerbations. The reviews by Martineau et al and Luo et al 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 (Martineau, 2016; Luo, 2015). Liu et al found no benefit to vitamin D supplementation on ACT scores, FEV1, or Fractional Exhaled Nitric Oxide (FENO) (Liu, 2022). The review by Jolliffe et al 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).
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
0038UVitamin D, 25 hydroxy D2 and D3, by LC MS/MS, serum microsample, quantitative
82306Vitamin D; 25 hydroxy, includes fraction(s), if performed
82652Vitamin D; 1, 25 dihydroxy, includes fraction(s), if performed
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