Importance: Low serum vitamin D levels have been associated with adverse clinical outcomes; identifying and treating deficiency may improve outcomes.

Objective: To review the evidence about screening for vitamin D deficiency in adults.

Data Sources: PubMed, EMBASE, the Cochrane Library, and trial registries through March 12, 2020; bibliographies from retrieved articles, outside experts, and surveillance of the literature through November 30, 2020.

Study Selection: Fair- or good-quality, English-language randomized clinical trials (RCTs) of screening with serum 25-hydroxyvitamin D (25[OH]D) compared with no screening, or treatment with vitamin D (with or without calcium) compared with placebo or no treatment conducted in nonpregnant adults; nonrandomized controlled intervention studies for harms only. Treatment was limited to studies enrolling or analyzing participants with low serum vitamin D levels.

Data Extraction and Synthesis: Two reviewers assessed titles/abstracts and full-text articles, extracted data, and assessed study quality; when at least 3 similar studies were available, meta-analyses were conducted.

Main Outcomes and Measures: Mortality, incident fractures, falls, diabetes, cardiovascular events, cancer, depression, physical functioning, and infection.

Results: Forty-six studies (N = 16,205) (77 publications) were included. No studies directly evaluated the health benefits or harms of screening. Among community-dwelling populations, treatment was not significantly associated with mortality (pooled absolute risk difference [ARD], 0.3% [95% CI, −0.6% to 1.1%]; 8 RCTs, n = 2006), any fractures (pooled ARD, −0.3% [95% CI, −2.1% to 1.6%]; 6 RCTs, n = 2186), incidence of diabetes (pooled ARD, 0.1% [95% CI, −1.3% to 1.6%]; 5 RCTs, n = 3356), incidence of cardiovascular disease (2 RCTs; hazard ratio, 1.00 [95% CI, 0.74 to 1.35] and 1.09 [95% CI, 0.68 to 1.76]), incidence of cancer (2 RCTs; hazard ratio, 0.97 [95% CI, 0.68 to 1.39] and 1.01 [95% CI, 0.65 to 1.58], or depression (3 RCTs, various measures reported). The pooled ARD for incidence of participants with 1 or more falls was −4.3% (95% CI, −11.6% to 2.9%; 6 RCTs). The evidence was mixed for the effect of treatment on physical functioning (2 RCTs) and limited for the effect on infection (1 RCT). The incidence of adverse events and kidney stones was similar between treatment and control groups.

Conclusions and Relevance: No studies evaluated the direct benefits or harms of screening for vitamin D deficiency. Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection.

Vitamin D has a variety of actions on calcium homeostasis, bone metabolism,and other cellular regulatory functions.^1-3 Vitamin D deficiency refers to serum levels of vitamin D (serum total hydroxyvitamin D, or 25[OH]D) that are inadequate to support bodily needs. Serum total 25(OH)D is currently considered the best marker of vitamin D status.^4,5 However, there is no consensus regarding the serum level of 25(OH)D that represents optimal health or deficiency.^1,5,6

The rationale for screening for vitamin D deficiency among asymptomatic adults is to identify low serum vitamin D levels that place persons at risk for deficiency and offer treatment before potential adverse clinical outcomes (falls, fractures, and other outcomes) occur. In 2014, the US Preventive Services Task Force (USPSTF) concluded that the evidence was insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in adults (I statement). This review was conducted for the USPSTF to inform an update of its 2014 recommendation.^7-9

Scope of the Review

The analytic framework and key questions (KQs) that guided the review are shown in Figure 1. Detailed methods, evidence tables, supplemental analyses, and contextual information are available in the full evidence report.¹⁰

Data Sources and Searches

PubMed, the Cochrane Library, and EMBASE were searched for English-language articles published from January 1, 2013, through March 12, 2020. ClinicalTrials.gov, Cochrane Register of Controlled Trials, and the World Health Organization International Clinical Trials Registry Platform were also searched. To supplement systematic electronic searches, reference lists of pertinent articles and studies suggested by reviewers were searched. Ongoing surveillance was conducted through article alerts and targeted searches of journals to identify major studies published in the interim that may affect the conclusions or understanding of the evidence and the related USPSTF recommendation. The last surveillance was conducted on November 30, 2020.

Study Selection

Two investigators independently reviewed titles, abstracts, and full-text articles using prespecified inclusion criteria for each KQ; disagreements about inclusion were resolved by discussion or by a third reviewer. For all KQs, randomized clinical trials (RCTs) conducted in nonpregnant adults were eligible for selection. For KQ1 and KQ2, studies that were conducted among participants not known to have vitamin D deficiency were eligible for selection. For KQ3 and KQ4, studies that either enrolled participants with known deficiency (defined as serum vitamin D level less than 30 ng/mL [to convert to nmol/L, multiply by 2.496]) or reported findings for a subgroup of participants with known deficiency were eligible, as were nested case-control studies within RCTs. For KQ1 and KQ2, studies that evaluated screening using total serum 25(OH)D were eligible, and for KQ3 and KQ4, studies that evaluated treatment with oral or injectable vitamin D₂ or vitamin D₃ of any dosage with or without concomitant calcium were eligible. For KQ1 and KQ3, studies reporting health outcomes, such as mortality, falls, fractures, incident disease (eg, diabetes, cancer, cardiovascular event, and others), and validated quality of life, and self-reported physical functioning measures were eligible; studies reporting only changes in serum vitamin D levels, intermediate physiologic outcomes (eg, bone mineral density, blood pressure), or physical fitness/muscle strength measures were not eligible. For KQ2 and KQ4, studies reporting harms from screening (eg, anxiety, labeling) or harms from treatment (eg, toxicity, nephrolithiasis, adverse events) were eligible; nonrandomized controlled intervention studies, cohort studies, and case-control studies were also eligible for selection.

English-language studies that met all study selection criteria, were fair or good methodological quality, and were conducted in countries categorized as very highly developed by the 2016 United Nations Human Development Index were included.¹¹ Studies included in the prior 2014 review for the USPSTF were reassessed against the study selection and methodological quality criteria for this update.

Data Extraction and Quality Assessment

For each included study, 1 reviewer abstracted relevant study characteristics (ie, population, intervention, comparator) and data for eligible outcomes into a structured form. A second reviewer checked all data for completeness and accuracy. Two senior reviewers independently assessed each study’s methodological quality using predefined criteria established by the USPSTF and others.¹² Disagreements in study quality ratings were resolved through discussion or with a third senior reviewer.

Data Synthesis and Analysis

Data were synthesized in tabular and narrative formats. When at least 3 similar studies were available, a quantitative synthesis was performed using random-effects models with the inverse-variance weighted method of DerSimonian and Laird in Stata version 16 (StataCorp) to generate pooled estimates of the absolute risk difference (ARD), the relative risk ratio (RR), the incidence rate difference, or the incidence rate ratio.¹³ Analyses were stratified based on study population (community dwelling vs institutionalized) when possible. For rare event outcomes, such as mortality, sensitivity analyses were also conducted using other estimators and models with and without continuity corrections to assess robustness of the main findings. Significance testing was based on the exclusion of the null value by the 95% confidence interval around the pooled estimate.

The strength of evidence was assessed based on the Agency for Healthcare Quality and Research Methods Guide for Effectiveness and Comparative Effectiveness Reviews, which specifies the assessment of study limitations, directness, consistency, precision, and reporting bias for each intervention comparison and major outcome of interest.¹⁴ Two senior reviewers independently developed initial strength-of-evidence assessments for each relevant outcome and comparison across the KQs; disagreements were resolved through discussion or input of a third senior reviewer.

Forty-six studies (N = 16,205) from 77 publications were included (Figure 2). Twenty-seven studies of treatment benefits (KQ3)^15-59 and 36 studies evaluating the harms of treatment (KQ4)^{15-19,21-29,35,36,39-43,58-88} were identified. Study characteristics of included RCTs are described in Table 1. A list of full-text articles screened but excluded is provided in the JAMA Supplement.

Benefits of Screening

Key Question 1a. Does screening for vitamin D deficiency improve health outcomes?

Key Question 1b. Does screening efficacy vary among patient subpopulations at higher risk for vitamin D deficiency (eg, persons residing in institutions, persons with obesity, persons with low levels of sun exposure, or older adults) or vary by race/ethnicity?

No studies were identified.

Harms of Screening

Key Question 2. What are the harms of screening for vitamin D deficiency?

No studies were identified.

Benefits of Treatment

Key Question 3a. Does treatment of vitamin D deficiency with vitamin D improve health outcomes?

Key Question 3b. Does treatment efficacy vary among patient subpopulations at higher risk for vitamin D deficiency (eg, persons residing in institutions, persons with obesity, persons with low levels of sun exposure, or older adults) or vary by race/ethnicity?

Twenty-six RCTs^15-29,35-59 and 1 nested case-control study from the Women’s Health Initiative (WHI) Calcium and Vitamin D RCT^30-34 reported eligible outcomes. Nine RCTs were assessed as good quality,^{17,20,22,26,27,41,46,54,57} and the rest were assessed as fair quality. Detailed study characteristics, outcomes, and individual study methodological quality are described in eTables 1-7 and 13-17 in the JAMA Supplement.

Five studies were conducted exclusively or predominantly among populations in nursing homes or homes for the elderly (ie, “institutionalized” settings);^16,19,35,42 the rest were conducted exclusively or predominantly among community-dwelling populations. The mean age of included populations ranged from 36 to 85, but 54% were conducted among study populations with a mean age of 60 years or older. Twelve studies were conducted exclusively among female populations.^{16-19,21,22,26,30,39,42,52,58} The race/ethnicity of the studied populations included multiple races and ethnicities in 9 studies,^{15,21,22,26,30,46,53,54,57} was exclusively White in 1 study,⁵⁸ was mostly Latino in 1 study,²⁰ and was not reported in the remaining studies.

Nine studies^{17,18,21,22,35,36,43,52,57} enrolled participants with serum vitamin D levels less than 20 ng/mL, and 5 studies enrolled participants using thresholds between 20 and 30 ng/mL.^{15,20,26,41,51} Eight studies did not require participants to meet specific serum vitamin D–level criteria for enrollment, but the mean baseline serum vitamin D levels reported among the enrolled populations suggested that 90% or more of the enrolled participants had baseline serum levels less than 30 ng/mL.^{16,19,25,27,39,42,44,58} Five studies did not require participants to be vitamin D deficient for enrollment but reported results separately for the subgroup of participants with serum levels less than 20 ng/mL.^{30,37,46,53,54} Vitamin D assays used by studies varied.

All studies used vitamin D₃ as part of the active treatment intervention. Most studies used daily doses, which varied from as low as 400 IU to as high as 4000 IU. Two studies used a high initial loading dose, followed by lower monthly doses;^26,54 1 of these studies also titrated the dose to reach a target serum level of 30 ng/mL.²⁶ One study titrated the weekly dose to achieve a target serum level between 65 ng/mL and 90 ng/mL, resulting in an average weekly dose of 88,865 IU.²⁰ The rest of the studies used weekly, twice weekly, twice monthly, or monthly doses. Two studies used a no-intervention control group;^39,42 the rest used placebo controls. Four studies included various doses of oral calcium as part of the active treatment intervention.^18,19,39,42 Six studies provided calcium to both the active vitamin D treatment group and control group.^{16,21,22,43,51,52} Treatment duration ranged from 8 weeks to 7 years.

All-Cause Mortality

Twelve RCTs^{18,19,21,22,25-27,35,39,42-44} reported all-cause mortality outcomes over 4 months to 3 years; however, none evaluated mortality as a primary study aim. The pooled ARD comparing vitamin D treatment with control among studies conducted in community-dwelling populations was 0.3 percentage points (95% CI, −0.6% to 1.1%; 2006 participants; 8 RCTs; I² = 0%), and the pooled RR was 1.13 (95% CI, 0.39 to 3.28) (Figure 3). Because events were rare, sensitivity analyses were conducted using alternative pooling methods, and ARD estimates were stable. The findings from the WHI nested case-control study were consistent with the findings from the RCTs.^30,34

Fractures

Nine RCTs^{17,19,26,27,35,44,51,52,54} reported fracture outcomes over 12 weeks to 3.3 years; studies varied by type of fracture reported and ascertainment methods. The pooled ARD comparing vitamin D treatment with control among studies conducted in community-dwelling participants for incidence of fractures was −0.3 percentage points (95% CI, −2.1% to 1.6%; 2186 participants; 6 RCTs; I² = 13.0%), and the pooled RR was 0.84 (95% CI, 0.58 to 1.21) (Figure 4). Findings from the WHI nested case-control study were consistent with findings from the RCTs.³⁰ Four RCTs^19,35,44,52 reported the incidence of hip fracture, but only 1 was conducted among community-dwelling populations;⁵² only 1 hip fracture occurred, leading to an imprecise effect estimate.

Falls

Eleven RCTs reported fall outcomes over 1 to 3 years among either community-dwelling or institutionalized populations.^{16,19,26,27,39,46,51,52,54,57,58,89} Four RCTs reported the number of participants who experienced 1 or more falls,^19,27,54,57 1 RCT reported the number of participants who experienced 2 or more falls,⁸⁹ 2 RCTs reported the total number of falls experienced in each treatment group,^26,58 and 4 RCTs reported both outcomes.^16,39,51,52 The pooled ARD comparing vitamin D treatment with control for the incidence of participants with 1 or more falls among community-dwelling populations was −4.3 percentage points (95% CI, −11.6% to 2.9%; 2633 participants; 6 RCTs; I² = 70.1%), and the RR was 0.90 (95% CI, 0.75 to 1.08) (Figure 5). Heterogeneity was high, as indicated by the I² statistic.

The 2 studies observing a more than 10–percentage point absolute decrease in incidence were conducted by the same research team using similar methods and calcium controls;^51,52 findings were statistically significant in only 1 of the studies.⁵¹ The other 4 studies observed smaller effects ranging from a decrease of 4.6 percentage points to an increase of 3.1 percentage points; these findings were not statistically significant.^27,39,54,57 In the RCT reporting on the incidence of 2 or more falls, no significant difference was observed between vitamin D and placebo groups among participants with baseline vitamin D levels less than 12 ng/mL (adjusted odds ratio, 1.03 [95% CI, 0.59 to 1.79]) or for participants with baseline levels between 12 and 20 ng/mL (adjusted odds ratio, 1.13 [95% CI, 0.87 to 1.48]).^46,89

Vitamin D treatment was associated with fewer total falls compared with control in studies conducted among community-dwelling populations (incidence rate difference, 0.10 fewer falls per person-year [95% CI, −0.19 to −0.002]; 2838 person-years; 6 RCTs; I² = 76.9%; incidence rate ratio, 0.76 [95% CI, 0.57 to 0.94]) (Figure 6).

Other Morbidities

Studies also reported on the incidence of other morbidities, including diabetes, cardiovascular disease, cancer, depression, and infection, and on physical functioning. Five RCTs, all conducted among community-dwelling populations, reported on incident diabetes over 1 to 7 years, although ascertainment methods varied.^{20,31,37,53,58} The pooled ARD for incident diabetes was 0.1 percentage points (95% CI, −1.3% to 1.6%; 3356 participants; 5 RCTs; I² = 0%), and the pooled RR was 0.96 (95% CI, 0.80 to 1.15).

Two RCTs conducted among community-dwelling populations reported the effect of vitamin D treatment on the incidence of cardiovascular disease and cancer among subgroups of participants with serum levels less than 20 ng/mL at baseline.^46,53 No statistically significant differences in cardiovascular events (subgroup n = 2000; hazard ratio [HR], 1.09 [95% CI, 0.68 to 1.76] over 5.3 years⁴⁶ and subgroup n = 1270; HR, 1.00 [95% CI, 0.74 to 1.53] over 3.3 years^54,55) or incident invasive cancer (HR, 1.01 [95% CI, 0.65 to 1.58]⁹⁰ and HR, 0.97 [95% CI, 0.68 to 1.39]⁴⁶) were observed in either trial. No statistically significant associations were observed between vitamin D treatment and incident breast or colorectal cancer over 7 years in the WHI nested case-control study among participants with low serum vitamin D levels at baseline.^32,33

Three RCTs^36,41 (subgroup n = 1328,^46,91 n = 243,³⁹ and n = 408³⁴) reported on depression outcomes over 5.3 years, 16 weeks, and 26 weeks, respectively, and found no statistically significant differences between treatment and control as measured by various validated depression symptom rating scales. Two RCTs (n = 230²⁴ and n = 100¹³) reported measures of physical functioning (eg, fibromyalgia impact questionnaire at 8 weeks,¹³ modified Stanford Health Assessment Questionnaire²⁴ at 1 year); findings were mixed. One RCT³⁷ (subgroup n = 173) reported on incident urinary tract infection over 5 years of follow-up (HR, 0.53 [95% CI, 0.17 to 1.64]).

Variation in Benefits by Subgroup

One of the RCTs conducted in institutional settings reported mortality (1 participant), but this was not reported by group, so it could not be included in the quantitative synthesis.³⁵ Among the 3 RCTs conducted among institutionalized populations, an absolute risk decrease ranging from 2.2 to 5.6 percentage points was observed; however, no individual study estimates were precise enough to exclude the null effect (Figure 3). When pooled, the ARD was −2.8 percentage points (95% CI, −5.5% to −0.2%; 3409 participants; I² = 0%). The RR was 0.86 (95% CI, 0.74 to 0.99). Data were limited for evaluating effects among other subgroups, but for mortality, fractures, and falls, no differences between men and women or among studies using lower thresholds to define deficiency (eg, <20 ng/mL) for enrollment or calcium cointerventions were observed.

Only 1 study reported benefits of vitamin D treatment stratified by race or ethnicity.^22,23 In this study, no mortality events occurred among either the White or African American populations enrolled. With the exception of 1 study conducted primarily among a Latino population,²⁰ the studies reporting the race or ethnicity of the enrolled population were conducted among exclusively or majority White populations. Thus, the ability to determine the influence of race/ethnicity on benefit outcomes was limited.

Harms of Treatment

Key Question 4a. What are the harms of treatment of vitamin D deficiency with vitamin D?

Key Question 4b. Do harms vary among patient subpopulations at higher risk for vitamin D deficiency (eg, persons residing in institutions, persons with obesity, persons with low levels of sun exposure, or older adults) or vary by race/ethnicity?

Thirty-six RCTs^{15-19,21-29,35,36,39-43,58-88} reported on harms of treatment; 16 of these were also included for KQ3. Nine of the studies were assessed as good quality;^{17,22,26,27,41,63,74,77,84} the rest were assessed as fair quality. See the JAMA Supplement for additional study characteristics (eTables 1-3) and individual study quality ratings (eTables 15 and 16).

Four studies were conducted among institutionalized populations,^16,19,35,42 2 were conducted among mixed community-dwelling and institutionalized populations,^43,66 and the rest were conducted exclusively in community-dwelling populations. Four studies exclusively enrolled Black participants.^60,61,74,82 Three studies evaluated vitamin D₂ as a 2000 IU daily dose,⁶⁹ a 50,000 IU weekly dose,⁶³ or a single 100,000 IU dose.⁷¹ The rest of the studies evaluated various daily, weekly, monthly, or single doses of vitamin D₃. In the studies using daily doses, the doses ranged from as low as 400 IU to as high as 4000 IU, and the studies using weekly doses ranged from 20,000 IU to 50,000 IU. Nine studies provided calcium to both the active vitamin D treatment group and the control group.^{16,21,22,43,60,61,65,74,84} The rest of the included studies did not include any calcium as part of the active or control intervention. The duration of the intervention ranged from a single, 1-time dose to 3 years; however, the duration of intervention was less than 6 months in 22 of the 36 studies.

No studies specified adverse events as primary outcomes. With 1 exception,³⁹ primary outcomes included laboratory (eg, serum vitamin D level), imaging (eg, bone mineral density), or physical strength (eg, grip strength) measures. Seven studies collected data on adverse events at study visits,^{16,43,65,67,72,77,86} 2 used follow-up telephone calls,^25,63 1 used a toll-free call-in line available to participants to report adverse events,⁸⁴ and 1 used multiple methods.⁴¹ Fourteen studies did not report how adverse events were ascertained.^{15,17,18,35,36,58,60,68-71,73,82,88} Consistent definitions for total and serious adverse events were not used across studies.

Total Adverse Events

Twenty-four studies (n = 3938) reported overall adverse events.^{15-18,25,35,41,43,58,60,63,65,67-73,77,82,84,86,88} The incidence of adverse events varied by study, ranging from 0% to 92% across the treatment and control groups. However, within any given study, the incidence of adverse events was generally similar between treatment and control groups. Seven studies reported no adverse events.^{15,35,60,70,71,73,82} However, 1 of the studies that reported no adverse events did in fact note adverse effects (eg, nausea) and discontinuations from the study.³⁵ Of the 14 studies reporting total adverse events by group, only 3 conducted statistical significance testing, and all reported no significant differences between groups.^18,77,86 Although many studies did not list the specific adverse events experienced by participants, those that did reported the following types of adverse events: abdominal discomfort, gastrointestinal issues, fatigue, musculoskeletal symptoms, nontoxic goiter, light-headedness, severe headaches, nausea, rash/hives, weakness, numbness, constipation, and itching.^{16,35,60,63,65,72,86}

Serious Adverse Events

Sixteen RCTs (n = 3912) reported serious adverse events.^{17,18,21,22,27,36,43,58,60,61,63,68,72,78,84,88} The incidence of serious adverse events ranged from 0% to 29.4% across the groups within the studies; the incidence appeared similar between treatment and control groups, although formal statistical significance testing was not conducted in any study. Seven studies (n = 1702) reported 0 serious adverse events overall.^{17,36,60,63,72,84,88} Five studies (n = 1341) reported serious adverse events, but authors indicated that these were most likely unrelated to the study medication.^{21,22,27,58,61}

Kidney Stones

Ten RCTs (n = 2120) reported on kidney stones.^{19,21,22,25,26,43,61,65,66,88} In all but 1 of those studies, the incidence of kidney stones was reported in 0% of both the active treatment and control groups. In the study reporting more than 0 events, 1 participant in the lower-dose vitamin D group (800 IU daily) reported a kidney stone; no kidney stones were reported in the placebo group or in the higher-dose vitamin D group (50,000 IU twice monthly).²⁶ This study did not use calcium as part of the active treatment or control intervention.

Other Harms

Discontinuations due to adverse events and various other specific harms are detailed in the eResults and eTables 10 and 12 in the JAMA Supplement.

Variation in Harms by Subgroup

Data were too limited to evaluate differences in harms by subgroups of participants.

This review is an updated report regarding screening for vitamin D deficiency in adults. However, no studies were identified that evaluated screening for vitamin D deficiency; thus, this evidence report was limited to an evaluation of the benefits and harms of vitamin D treatment among participants at risk for deficiency based on low serum vitamin D levels. Compared with the 2014 review for the USPSTF on this topic,^8,9 23 new RCTs were added, and 4 RCTs were excluded. Table 2 summarizes the evidence by KQ and provides an assessment of the strength of evidence.

For benefits of treatment (KQ3) among community-dwelling populations, the strength of evidence was assessed as moderate for no benefit for mortality, any fractures, incident diabetes, cardiovascular disease, and incident cancer. For these outcomes, the strength of evidence was downgraded for study limitations or imprecision. The strength of evidence was assessed as low for no benefit for hip fractures and depression because of study limitations and imprecision. The strength of evidence for incidence of falls was assessed as low for no benefit; it was downgraded because of inconsistency between the various fall measures (incidence vs total falls) and for imprecision in effect estimates. The strength of evidence for physical functioning and infection was assessed as insufficient because of inconsistency, imprecision, and study limitations. For harms of treatment (KQ4), the strength of evidence was assessed as low for no harm for total adverse events, serious adverse events, discontinuations due to adverse events, kidney stones, and other harms. The strength of evidence was downgraded for these outcomes because of imprecision and study limitations. Although studies were consistent in demonstrating no difference in harms between active treatment and control groups, the absolute incidence of reported adverse events varied vastly across studies, likely because of different approaches to defining and ascertaining these outcomes across the studies.

Despite a reasonable number of studies reporting falls outcomes, the body of evidence demonstrated mixed findings. Among the studies reporting the incidence of 1 or more falls, a numerical but not statistically significant decrease (pooled ARD, −4.3%) was observed among community-dwelling populations. The most recent good-quality trial reported the incidence of 2 or more falls among subgroups of participants with low vitamin D levels and also found no significant association, although effect estimates were imprecise. Among the studies reporting total number of falls, a small but statistically significant decrease (−0.1 falls per person-year) in the total number of falls was observed. Estimates for both types of outcomes were inconsistent and imprecise. Some studies reported both outcomes, but others reported only 1 of these outcomes, raising the possibility of selective outcome reporting. One hypothesis to explain the difference between these 2 outcomes is that although vitamin D may not prevent a first fall, it may have some benefit in preventing repeat falls.

A related systematic review on behalf of the USPSTF recommendation for fall prevention in community-dwelling populations at increased risk of falls found mixed findings for vitamin D interventions.⁹² There was also evidence of possible harms from high-dose vitamin D in such populations, resulting in a recommendation against vitamin D supplementation in community-dwelling adults 65 years or older.^92,93 The falls prevention review excluded studies conducted among vitamin D–deficient populations; thus, additional evidence specifically in vitamin D–deficient populations is needed to be able to draw definitive conclusions about the effect of screening for vitamin D deficiency on falls among community-dwelling adults.

Findings regarding benefits of treatment in this review are not directly comparable with those from other reviews of vitamin D supplementation because this review was focused specifically on persons with low vitamin D levels (ie, less than 20 or 30 ng/mL) and other differences in study selection criteria. Despite these differences, the findings from this review are largely consistent with those from other reviews conducted in broader populations with respect to most outcomes.

Limitations

This evidence review had several limitations. First, no available evidence that directly evaluated the health benefits and harms of screening (KQ1 and KQ2) was identified. Second, studies selected for this review included some conducted in institutionalized settings. However, the synthesis and strength of evidence assessment focused mainly on community-dwelling populations because USPSTF recommendations are for clinical preventive services in or referred from primary care settings. Studies focused on populations with a specific clinical condition to evaluate the treatment of vitamin D deficiency for the alleviation of specific symptoms or issues associated with that condition were not included. Third, the comparative benefits or harms of various vitamin D doses, formulations, or durations of treatment were not assessed. Fourth, this review included studies that enrolled participants based on 25(OH)D levels that used various assays and that may not have been standardized according to current criteria from the Vitamin D Standardization Program.⁹⁴ Fifth, for the trials enrolling participants unselected with respect to vitamin D status, only findings from the vitamin D–deficient subgroups were reported. Findings from the overall population were not included, but these may be eligible to be included in the next update of a related review of vitamin D supplementation conducted on behalf of the USPSTF.⁹⁵

No studies evaluated the direct benefit or harms of screening for vitamin D deficiency. Among asymptomatic,community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D (with or without calcium) has no effect on mortality or incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection.

Source: This article was first published online in the Journal of the American Medical Association on April 13, 2021 (JAMA. 2021;325(14):1443-1463. doi:10.1001/jama.2020.26498).

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was funded under contract HHSA-290-2015-00011-I, Task Order 11, from the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the US Preventive Services Task Force (USPSTF).

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings.

Additional Information: A draft version of the full evidence report underwent external peer review from 4 content experts (John Aloia, MD, New York University Winthrop Bone Mineral Research Center; JoAnn E. Manson, MD, MPH, DrPH, Harvard Medical School; Clifford Rosen, MD, Maine Medical Center Research Institute; and Christopher Sempos, PhD, Vitamin D Standardization Program LLC) and 4 individuals from 3 federal partner reviewers (2 from the National Institutes of Health, 1 from the Centers for Disease Control and Prevention). Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

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KQ indicates key question.

Size of each data marker indicates the weight of the study in the analysis. Weights are from random-effects analysis. To calculate the absolute risk difference in percentage points, multiply value by 100 (eg, 0.009 multiplied by 100 = 0.9 percentage points).

Size of each data marker indicates the weight of the study in the analysis. Weights are from random-effects analysis. To calculate the absolute risk difference in percentage points, multiply value by 100 (eg, 0.009 multiplied by 100 = 0.9 percentage points).

Size of each data marker indicates the weight of the study in the analysis. Weights are from random-effects analysis. To calculate the absolute risk difference in percentage points, multiply value by 100 (eg, 0.009 multiplied by 100 = 0.9 percentage points).

Size of each data marker indicates the weight of the study in the analysis. Weights are from random-effects analysis. To calculate the RD in percentage points, multiply value by 100 (eg, 0.009 multiplied by 100 = 0.9 percentage points).

Abbreviations: BEST-D, Biochemical Efficacy and Safety Trial of vitamin D; D2d, Vitamin D and Type 2 Diabetes; IQR, interquartile range; NR, not reported; OSTPRE-FPS, Osteoporosis Risk Factor and Prevention-Fracture Prevention Study; PODA, Physical Performance, Osteoporosis Prevention, and Vitamin D in Older African Americans; RCT, randomized clinical trial; ViDA New Zealand, Vitamin D Assessment Study; ViDA (US), Vitamin D, Diet, and Activity Study; VIDOS, Vitamin D Supplementation in Older Subjects; VITAL, VITamin D and OmegA-3 TriaL; Vitamin D &TT, Vitamin D and Testosterone Trial. SI conversion factor: To convert vitamin D levels to nmol/L, multiply by 2.496.
^a Calculated value.
^b Characteristic for the entire study population, not the subgroup that was vitamin D deficient.
^c Of those who completed the study.
^d Lips et al (1996)⁴⁴ included a majority of participants from institutionalized settings; thus, this study was considered an institutionalized setting in all stratified analyses. Lips et al (2010)⁴³ included a majority of participants who were community-dwelling participants; thus, this study was considered community-dwelling in all stratified analyses.

Abbreviations: ARD, absolute risk difference; CVD, cardiovascular disease; GI, gastrointestinal; HR, hazard ratio; IRD, incidence rate difference; KQ, key question; NR, not reported; OR, odds ratio; RCT, randomized clinical trial; RR, relative risk; ViDA (NZ), Vitamin D Assessment Study (New Zealand); VITAL, Vitamin D and Omega-3 Trial.
SI conversion factor: To convert vitamin D levels to nmol/L, multiply by 2.496.
^a Although this estimate could be considered imprecise based on strict interpretation of optimal information size criteria, the event rates were very low, resulting in excessively wide CIs around the relative effect measure, which was 1.13 (95% CI, 0.39-3.28). Because of this, evaluation of the ARD was prioritized, and the CI was determined precise enough to exclude a clinically meaningful benefit or harm. This approach is consistent with current Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) recommendations for assessing precision.^96
b The pooled RR was 0.84 (9% CI, 0.58-1.21); although this estimate could be considered imprecise based on strict interpretation of optimal information size criteria, evaluation of the ARD was prioritized, and the CI was determined precise enough to exclude a clinically meaningful absolute benefit or harm. This approach is consistent with current GRADE recommendations for assessing precision.^96
c The pooled RR was 0.86 (95% CI, 0.50-1.47). Required sample size would be 13,658, assuming 5% control group risk, 80% power, α = .05 for detecting effect size of RR 0.8.
^d Findings are inconsistent between outcomes (incidence of ≥1 falls vs total falls). For incidence of falls, 2 studies among community-dwelling populations both conducted by the same author showed a larger beneficial effect compared with the other 3 studies that had findings close to and on both sides of the null effect. The RCT using a more stringent definition of falls (≥2) also showed no association even among participants with the lowest of vitamin D levels (<12 ng/mL); however, these estimates were imprecise. For total falls, a small, statistically significant benefit of treatment was observed among community-dwelling populations.
^e Required sample size of 834 for RR 0.8, control risk 50%, so optimal information size criteria are met, but CI does not exclude the null, and the 95% CI cannot rule out a clinically meaningful effect.
^f Required sample size of 2944 for RR 0.8, control risk 20%, so optimal information size criteria met. Pooled RR, 0.96 (95% CI, 0.80-1.15); however, CIs around ARD exclude a clinically meaningful effect.
^g Required sample size of 9920, 7% control risk, RR 0.8, α = .05. Data to calculate ARD not provided; cannot exclude a clinically meaningful treatment effect based on the RR alone.
^h Required sample size of 11,476, 6% control risk, RR 0.8, α = .05 to meet optimal information size criteria. Data not provided to calculate ARDs.
ⁱ Optimal information size criteria will vary depending on outcome used but sample size combined with rare events means that optimal information size criteria are unlikely to be met.