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. 2022 Jun 8;127(5):872–878. doi: 10.1038/s41416-022-01850-2

Vitamin D supplementation and total cancer incidence and mortality by daily vs. infrequent large-bolus dosing strategies: a meta-analysis of randomised controlled trials

N Keum 1,2,✉, Q-Y Chen 1, D H Lee 2, J E Manson 3,4, E Giovannucci 2,4
PMCID: PMC9427835  PMID: 35676320

Abstract

Background

Efficacy of vitamin D supplementation may vary by dosing strategies and adiposity. To address such heterogeneity, we performed a meta-analysis of randomised controlled trials of vitamin D supplementation and total cancer outcomes.

Methods

PubMed and Embase were searched through January 2022. Summary relative risk (SRR) and 95% confidence interval (CI) were estimated using the DerSimonian–Laird random-effects model.

Results

For total cancer incidence (12 trials), the SRR for vitamin D supplementation vs. control group was 0.99 (95% CI, 0.94–1.03; P = 0.54; I2 = 0%). No significant association was observed regardless of whether the supplement was given daily or infrequently in a large-bolus. Yet, among trials testing daily supplementation, a significant inverse association was observed among normal-weight individuals (SRR, 0.76; 95% CI, 0.64–0.90; P = 0.001, I2 = 0%), but not among overweight or obese individuals (Pheterogeneity = 0.02). For total cancer mortality (six trials), the SRR was 0.92 (95% CI, 0.82–1.03; P = 0.17; I2 = 33%). A significant inverse association emerged (SRR, 0.87; 95% CI, 0.78–0.96; P = 0.007; I2 = 0%) among studies testing daily supplementations but not among studies that testing infrequent large-bolus supplementations (Pheterogeneity = 0.09).

Conclusions

For vitamin D supplementation, daily dosing, but not infrequent large-bolus dosing, reduced total cancer mortality. For total cancer incidence, bolus dosing did not reduce the risk and the benefits of daily dosing were limited to normal-weight individuals.

Subject terms: Cancer epidemiology, Nutrition

Background

Vitamin D has been hypothesised to have a preventative role in cancer incidence and mortality. Observational studies, based on the measurement of circulating 25-hydroxy vitamin D (25(OH)D), have tended to show an inverse association for colorectal cancer [1], but data for other cancers have generally been null or conflicting [1]. In contrast, studies have generally shown that individuals with high 25(OH)D before diagnosis, around the time of diagnosis or shortly thereafter, have a better prognosis for various cancer types [2]. In Mendelian randomisation studies, genetic variation in 25(OH)D levels has generally not been associated with incidence of various cancers [3, 4], except for ovarian cancer [5], and have been conflicting for cancer mortality [4, 6]. While the observational studies are suggestive of the role of vitamin D on cancer progression [1], confirmation in randomised trials (RCTs) is critical. There have been a number of RCTs based on vitamin D supplementation, though most did not have cancer incidence or mortality as the primary endpoint [7–9]. Previously, we had conducted a meta-analysis on such RCTs, and similar to other such meta-analyses, there was evidence for benefit on cancer mortality but not on cancer incidence [10–12].

Despite these promising results for cancer mortality from RCTs [10–12], important questions remain. First, daily dosing and infrequent large-bolus dosing might yield different results. Specifically, infrequent large-bolus doses may cause non-physiologic fluctuations in vitamin D [13]. An increasing body of evidence from RCTs suggests that large-bolus dosing of vitamin D may have minimal or even adverse effects on a variety of outcomes, including rickets, musculoskeletal health (falls and fractures), and respiratory infections [14]. As noted by Mazess et al. “It has been difficult to isolate the influence of bolus dosing in meta-analyses because many authors have merged these trials with those using daily dosing [14].” Second, the individual’s level of adiposity may modify the efficacy of vitamin D supplementation. Vitamin D is fat-soluble and is sequestered in adipose tissue, and individuals with obesity have lower levels of 25(OH)D and an attenuated rise in 25(OH)D after supplementation [15]. Moreover, vitamin D supplementation reduces circulating parathyroid hormone (PTH) levels [16], and individuals with excess adiposity have a resistance to the vitamin D efficacy even when they were supplemented with high vitamin D and attained high levels of 25(OH)D [17]. We thereby conducted a meta-analysis of RCTs on cancer incidence and mortality, with the primary focus to examine whether results varied by daily vs. infrequent large-bolus dosing, and by whether the trial participants had obesity or not.

Methods

The conduct and reporting of this meta-analysis followed the PRISMA guideline [18]. Two authors (QYC and NK) participated independently in the database search, study selection, data abstraction and resolved any discrepancy through discussion.

Study selection

PubMed and Embase were searched for relevant RCTs published up to January 2022, following the search terms provided (Supplementary Table 1). Besides English language and human subjects, no other restrictions were imposed. Abstracts and unpublished results were excluded. The reference lists of previous meta-analyses were reviewed for additional papers.

To be included in this meta-analysis, studies had to be a RCT where relative risk (RR; risk ratio or hazard ratio) and 95% confidence interval (CI) for the effect of vitamin D supplementation (provided as cholecalciferol or ergocalciferol, with or without other nutrients) on total cancer incidence/mortality were reported or could be estimated based on the number of incident outcome in each arm. Consistent with our previous meta-analysis [11], we excluded RCTs when the total number of outcome was ≤10 due to their unreliable effect size, or when the follow-up period was ≤1 year to account for potential latent cancers and the time required to reach a steady level of circulating 25(OH)D after supplementation initiation [19]. When there were multiple publications from the same trial, the publication with the longest follow-up or reporting the results in RR rather than in the number of cases was selected. This study selection process was summarised in Fig. 1.

Fig. 1.

Fig. 1

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Flowchart for study selection.

Data abstraction

From each RCT, the following information was extracted: definition (i.e., type, dose, frequency and period) of intervention and control, RR and corresponding 95% CI or the number of participants and total cancer cases/death in each arm, concentration of circulating 25(OH)D (at baseline, at follow-up), and major characteristics of the study population (Supplementary Tables 2 and 3).

To conduct secondary analyses on total mortality, a robust endpoint that answers the ultimate question of whether vitamin D supplementation improves overall survival, we also extracted RR and corresponding 95% CI for all-cause death or the number of total deaths in each arm.

Statistical analyses

The summary relative risk (SRR) and 95% CI were calculated using the DerSimonian–Laird random-effects model for the effect of vitamin D supplementation on primary endpoints (total cancer incidence, total cancer death) and secondary endpoint (total mortality) [20]. Given accumulating evidence and controversy on differential effects of vitamin D supplements by dose and frequency of intake, all meta-analyses were conducted separately for daily and infrequent large-bolus dosing [21, 22]. The potential for small-study effects, such as publication bias, were assessed using Egger’s test [23].

Given that some RCTs tested combined intervention of vitamin D and calcium against placebo [24–26], a sensitivity analysis was conducted after excluding these RCTs. For total mortality, to understand the degree to which the effect of vitamin D supplementation on total mortality may be contributed by its effect through total cancer mortality, we conducted an additional meta-analysis among trials that reported outcomes for both total mortality and total cancer mortality.

The degree of true heterogeneity in the relationship across trials was assessed by the I2 statistic [27]. To explore whether the relationship varied by attained levels of circulating 25(OH)D, a reliable marker of vitamin D status [28], we performed subgroup analysis and meta-regression by mean/median levels of attained circulating 25(OH)D in the participants. Of note, some trials reported their results according to body mass index (BMI) groups (normal weight, BMI < 25; overweight, 25 ≤ BMI < 30; obese, BMI ≥ 30 kg/m2) of the participants [24, 29–33]. Thus, subgroup meta-analysis by adiposity was conducted based on individual level BMI (rather than group level BMI). As mentioned above, all subgroup meta-analyses were performed separately for daily and infrequent large-bolus dosing.

All statistical analyses were two-sided and P value <0.05 was considered statistically significant. Analyses were conducted using STATA 17 (StataCorp, College Station, TX).

Results

Characteristics of included RCTs

Out of 2479 articles screened, a total of 13 RCTs (from 14 publications) contributed to the meta-analyses for total cancer incidence (12 trials), total cancer mortality (6 trials), and total mortality (10 trials) (Supplementary Tables 2 and 3). Six RCTs were conducted in the USA [7, 25, 26, 30, 31, 34], four RCTs in Europe [8, 33, 35, 36] and two in Australia [9, 32] and one in New Zealand [37]. By dosing frequency, eight RCTs provided vitamin D3 supplements daily (400–4000 IU/day) [7, 25, 26, 30, 31, 33–35] while five RCTs provided a large-bolus dose infrequently (20,000 IU/week to 500,000 IU/year) [8, 9, 32, 36, 37]. The mean/median levels of circulating 25(OH)D in the participants ranged approximately 38–83 nmol/L at baseline, and the levels in the intervention groups elevated to 54–136 nmol/L at a point during the follow-up. The mean duration of the total follow-up period, combining intervention and post-intervention follow-up, ranged ~3–10 years.

Primary meta-analysis: vitamin D supplementation and total cancer incidence

Based on a total of 12 trials [7–9, 25, 26, 30, 31, 33–37], the SRR for vitamin D supplementation vs. control group was 0.99 (95% CI, 0.94–1.03; P = 0.54), with no evidence of heterogeneity (I2 = 0%) (Fig. 2a). The relationship did not vary significantly by dosing frequency (daily vs. infrequent large-bolus dosing) (Pheterogeneity = 0.40, Fig. 2a). Small-study effects, such as publication bias, were not indicated in the overall and subgroup analyses (PEgger > 0.55). The aforementioned results remained unchanged in the sensitivity analysis excluding two studies [25, 26] that tested the combined effect of vitamin D3 and calcium against placebo (data not shown).

Fig. 2. Forest plots for subgroup meta-analyses of vitamin D supplementation and total cancer incidence.

Fig. 2

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a By dosing frequency. b By attained 25(OH)D level among studies that provided daily supplementation. c By attained 25(OH)D level among studies that provided infrequent large-bolus supplementation. d By individual BMI among studies that provided daily supplementation.

Within the level of dosing frequency, subgroup analysis by the attained level of 25(OH)D was performed. Albeit not statistically significant, the direction of an association between vitamin D supplementation and total cancer risk was inverse (SRR, 0.95; 95% CI, 0.87–1.04; P = 0.28; I2 = 0%) among studies that achieved circulating 25(OH)D levels of >100 nmol/L through daily supplementations (Fig. 2b). However, among studies that provided infrequent large-bolus vitamin D supplements, an increased risk was suggested regardless of attained levels of circulating 25(OH)D (Fig. 2c).

Out of the eight studies that tested daily vitamin D supplementation [7, 25, 26, 30, 31, 33–35], three studies [30, 31, 33] conducted subgroup analyses based on individual BMI levels. When meta-analyses were conducted for each category of BMI, the results were significantly heterogeneous across BMI levels (Pheterogeneity = 0.02, Fig. 2d), with a significant inverse association observed only among normal-weight individuals (SRR, 0.76; 95% CI, 0.64–0.90; P = 0.001; I2 = 0%), but not among overweight or obese individuals (Fig. 2d).

Primary meta-analysis: vitamin D supplementation and total cancer mortality

Based on a total of six trials [26, 31, 32, 35–37], the SRR of total cancer mortality for vitamin D supplementation vs. control group was 0.92 (95% CI, 0.82–1.03; P = 0.17), with modest heterogeneity (I2 = 33%) (Fig. 3a). A significant inverse association was emerged among studies that tested daily vitamin D supplementations (SRR, 0.87; 95% CI, 0.78–0.96; P = 0.007; I2 = 0%), but not among studies that tested infrequent large-bolus supplementations (SRR, 1.05; 95% CI, 0.88–1.26; P = 0.56; I2 = 12%) (Fig. 3a). The heterogeneity in the relationship by dosing frequency was marginally insignificant (Pheterogeneity = 0.09, Fig. 3a). Small-study effects, such as publication bias, were not indicated in the overall and subgroup analysis (PEgger > 0.25). In the sensitivity analysis excluding one study [26] that tested the combined effect of vitamin D3 and calcium against placebo, the effect of daily vitamin D supplementations on total cancer mortality became stronger (SRR, 0.84; 95% CI, 0.72–0.98; P = 0.03; I2 = 0%).

Fig. 3. Forest plots for subgroup meta-analyses of vitamin D supplementation and total cancer mortality.

Fig. 3

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a By dosing frequency. b By attained 25(OH)D level among studies that provided daily supplementation. c By attained 25(OH)D level among studies that provided infrequent large-bolus supplementation. d By individual BMI among studies that provided daily supplementation.

Within each level of dosing frequency, subgroup analysis by the attained level of 25(OH)D was performed, although a small number of trials limited statistical power to explore heterogeneity. Indeed, no significant heterogeneity was indicated by attained 25(OH)D levels, with Pheterogeneity = 0.73 for daily supplementations (Fig. 3b) and Pheterogeneity = 0.39 for infrequent large-bolus supplementations (Fig. 3c). Nevertheless, in response to a daily intake of vitamin D supplements, a significantly reduced cancer mortality was observed, even at ≤100 nmol/L of attained circulating 25(OH)D levels (SRR, 0.88; 95% CI, 0.78–0.99; P = 0.04; I2 = 0%) (Fig. 3b). In contrast, in response to an infrequent large-bolus vitamin D supplementation, even when >100 nmol/L of circulating 25(OH)D levels was attained, the association was statistically insignificant and its directionality was even direct (SRR, 1.13; 95% CI, 0.95–1.34; P = 0.17; I2 = 0%) (Fig. 3c).

Out of the six trials included in this meta-analysis, one study that tested daily vitamin D supplementation conducted a subgroup analysis based on individual BMI levels [29], precluding meta-analysis by BMI categories. Yet, in the trial, a significant inverse association was observed only among normal-weight individuals (RR, 0.58; 95% CI, 0.39–0.86), but not among overweight or obese individuals (Fig. 3d).

Secondary meta-analysis: vitamin D supplementation and total mortality

Based on a total of ten trials [7, 9, 24, 25, 31–33, 35–37], the SRR for vitamin D supplementation vs. control group was 0.95 (95% CI, 0.90–0.99; P = 0.03), with no evidence of heterogeneity (I2 = 0%) and small-study effect (PEgger > 0.44) (Supplementary Fig. 1A). When the analysis was restricted to six trials [24, 31, 32, 35–37] that contributed data in the meta-analysis of total cancer mortality outcome, an inverse association with total mortality remained virtually unchanged (SRR, 0.95; 95% CI, 0.90–0.997; P = 0.04; I2 = 0%).

When stratified by dosing frequency, a significant inverse association was manifest among studies that tested daily vitamin D supplementations (SRR, 0.93; 95% CI, 0.88–0.99; P = 0.03; I2 = 0%), but not among studies that tested infrequent large-bolus dosing (SRR, 0.98; 95% CI, 0.89–1.07; P = 0.61; I2 = 0%) (Supplementary Fig. 1A). The heterogeneity in the relationship by dosing frequency was not statistically significant (Pheterogeneity = 0.45, Supplementary Fig. 1A). Small-study effects, such as publication bias, were not indicated in the overall and subgroup analysis (PEgger > 0.31). In the sensitivity analysis excluding two studies [24, 25] that tested the combined effect of vitamin D3 and calcium against placebo, evidence for an inverse association between daily vitamin D supplementation on total mortality became weaker (SRR, 0.95; 95% CI, 0.88–1.02; P = 0.15; I2 = 0%).

Within each level of dosing frequency, in response to daily administration of vitamin D supplements, a significantly reduced mortality was observed, even at ≤100 nmol/L of attained circulating 25(OH)D levels (SRR, 0.92; 95% CI, 0.86–0.98; P = 0.01; I2 = 0%) (Supplementary Fig. 1B). In contrast, in response to an infrequent large-bolus vitamin D supplementation, even when >100 nmol/L of circulating 25(OH)D levels were attained, there was no evidence of an association (SRR, 1.03; 95% CI, 0.92–1.15; P = 0.65; I2 = 0%) (Supplementary Fig. 1C).

Within each level of dosing frequency, only one trial conducted subgroup analyses based on individual BMI levels [24, 32]. Thus, no meta-analysis was conducted by BMI categories. Yet, given daily vitamin D supplementation, an inverse association, albeit statistically insignificant, was suggested regardless of BMI status (Supplementary Fig. 1D). In contrast, in response to an infrequent large-bolus vitamin D supplementation, a non-significant but elevated risk of total death was observed among normal-weight individuals (Supplementary Fig. 1E).

Discussion

Our meta-analysis of RCTs examined the effect of vitamin D supplementation on cancer incidence and mortality stratified by daily vs. infrequent large-bolus dosing. For cancer incidence, neither dosing frequency indicated a statistically significant protective effect. Yet, among daily dosing studies, a decreased cancer risk was suggested when circulating 25(OH)D levels of >100 nmol/L were attained. Among bolus-dosing studies, a suggestive increased risk was observed regardless of attained circulating 25(OH)D levels. For cancer mortality, a significantly reduced risk was observed in studies that tested daily vitamin D supplementation, but not in studies that tested infrequent large-bolus supplementations. When additionally stratified by attained levels of circulating 25(OH)D, among daily dosing studies, a significantly reduced cancer mortality was observed at ≤100 nmol/L, but among bolus-dosing studies, a non-significantly increased risk was observed at >100 nmol/L of attained 25(OH)D levels.

Our results suggest that large-bolus dosing may have different physiologic effects from daily dosing. The action of vitamin D is generally assumed to require its conversion to 25(OH)D (major circulating form) in the liver and subsequent conversion to 1,25-dihydroxy vitamin D (1,25(OH)2D, biologically active form) in the kidney. The hormonal 1,25(OH)2D is then circulated into cells within which it binds to vitamin D receptor (transcription factor) and regulates gene expression, conferring diverse health benefits [38]. While vitamin D is primarily delivered to the liver, vitamin D also circulates and diffuses into all cells in the body [13]. With many cell types possessing 25 hydroxylase and 1-α hydroxylase, cells are able to metabolise vitamin D to the active form in an autocrine manner, precluding the requirement of vitamin D conversions in the liver and kidney [13]. Of note, most of circulating vitamin D is bound to vitamin D-binding protein and, due to its low binding affinity, vitamin D diffuses into cells more readily than 25(OH)D and has a shorter circulating half-life of 1 day [13]. Thus, when vitamin D supplements are provided as an infrequent large-bolus dose, vitamin D gets rapidly cleared from the circulation and becomes undetectable in the circulation after a week [13], making effects of vitamin D short-lived. Further, large-bolus dosing activates 24-hydroxylase (CYP24A1), which results in the downregulation of 1,25(OH)2D [14]. In contrast, given daily dosing, especially with relatively high doses such as 2000 IU/d, circulating vitamin D levels are maintained daily [13] and such stable concentration may lead to the constant action of vitamin D. Although greater understanding of the physiologic roles of vitamin D vs. its metabolites is required, current knowledge is compatible with the concept that maintaining daily high levels of vitamin D is physiologically different from infrequent large-bolus dose.

Our meta-analysis also examined whether vitamin D’s effect may differ by adiposity level. This exploration was prompted by recent evidence from other disease outcomes that the effect of vitamin D may be weaker in individuals with obesity. Specifically, in an RCT, vitamin D supplementation of 4000 IU/day reduced the risk of type 2 diabetes compared with placebo among adults with BMI < 30 kg/m2 (RR, 0.71; 95% CI, 0.53–0.91), but not among those with BMI ≥ 30 kg/m2 (RR, 0.97; 95% CI, 0.80–1.17) [39]. Further, a meta-analysis of RCTs conducted among prediabetic patients indicated that vitamin D supplementation at doses of ≥1000 IU/day significantly lowered the risk of type 2 diabetes compared with placebo only among trials with a mean baseline BMI of <30 kg/m2 (SRR, 0.68; 95% CI, 0.53–0.89) but not among trials with a mean baseline BMI of ≥30 kg/m2 (SRR, 0.98; 95% CI, 0.83–1.16) (Pheterogeneity = 0.03) [40]. In addition, in the VITAL trial, RR of autoimmune disease comparing vitamin D supplementation of 2000 IU/day vs. placebo was 0.47 (95% CI, 0.29–0.77), 0.69 (95% CI, 0.52–0.90), and 0.90 (95% CI, 0.69–1.19) for participants with a BMI of 18, 25, and 30 kg/m2, respectively (Pinteraction = 0.02) [41].

Our meta-analysis provided further evidence of a differential effect of daily vitamin D supplementation by adiposity level. For cancer incidence, subgroup analysis based on individual BMI levels rather than the population mean BMI showed significantly heterogeneous results, with an inverse association observed among normal-weight individuals, but not among overweight or obese individuals. For cancer mortality, only the VITAL trial reported results stratified by BMI and a significant inverse association was observed only among normal-weight individuals but not among overweight or obese individuals [29]. Notably, the VITAL trial further examined advanced (metastatic or fatal) cancers and found a significant risk reduction limited to those with normal BMI (RR, 0.62; 95% CI, 0.45–0.86) but not among those with a higher BMI (Pinteraction = 0.03) [29].

While emerging evidence indicates that vitamin D is more efficacious in individuals with a normal BMI, the biologic explanation is unclear. As a fat-soluble vitamin, absorbed vitamin D is stored in adipocyte lipid droplet [15]. This sequestration explains the well-known observations that obese individuals have lower 25(OH)D concentrations and consequently higher PTH concentrations in the blood compared with lean individuals, when given the same vitamin D dose [17, 42]. Moreover, even at the same 25(OH)D level, individuals with excess adiposity have higher PTH than lean individuals [17]. While the actions of vitamin D in lowering PTH levels is considered one of the indicators of vitamin D adequacy [43], it is unknown if this mechanism would be relevant for cancer. Alternatively, obesity is characterised by chronic subclinical inflammation and high levels of various inflammatory markers [44], which may have immunomodulatory effects. As inflammation and immunity are implicated in cancer development and progression [45], chronic inflammation and immune response induced by obesity could affect vitamin D efficacy on cancer outcomes.

There are several strengths in our study. To our knowledge, this is the first meta-analysis of RCTs that thoroughly explored potential heterogeneity by dosing strategies, further stratifying by attained 25(OH)D levels and by individual BMIs. By including only RCTs, our results are less prone to potential biases (e.g., confounding, selection bias, recall bias) than results from meta-analysis of observational studies.

Limitations of our meta-analysis also warrant consideration. First, as trials compared the effect of supplementation vs. no-supplementation, we could not evaluate the dose-response relationship, though a meta-analysis of prospective studies provided evidence for a non-linear relationship between circulating 25(OH)D levels and cancer outcomes, with the risks decreasing with increasing 25(OH)D levels especially among individuals with <50 nmol/L [46, 47] (i.e., the cut-off to define vitamin D deficiency by the Endocrine Society [48]). Yet, in most of the RCTs included, the population mean/median 25(OH)D levels at baseline were ≥50 nmol/L and participants including controls were allowed to take non-protocol vitamin D supplements (<200 to <2000 IU/day). Thus, our study might have underestimated the benefit of vitamin D supplementations. Second, the study populations were largely composed of whites, though in the VITAL trial, a suggestive inverse association between vitamin D supplementation and the risk of total invasive cancer was observed in African-Americans (RR, 0.77; 95% CI, 0.59–1.01) [31]. Third, most of the RCTs included were not initially designed to test the hypothesis that vitamin D may influence the risk of cancer incidence or mortality. Fourth, some inter-study variabilities deserve attention. The range of doses varied, and in the bolus-dosing studies, the frequency and amount of vitamin D varied widely. Some of the doses used in several earlier trials (e.g., 400, 800 IU/day) were relatively low compared to some more recent trials (e.g., 2000, 4000 IU/day) and had a lower effect in increasing vitamin D status. There was also variability in assays to measure circulating 25(OH)D levels. Given the increased demand for assay standardisation to resolve differences in vitamin D status guidelines [49], results from our subgroup analyses stratified by attained levels of circulating 25(OH)D assays should not be used as evidence to set a specific cut-off for any vitamin D guidelines. Yet, within each study, the relative ranking of circulating 25(OH)D levels is largely intact and thus, results based on the broad distinction of high vs. low levels provide valid evidence to suggest that high circulating 25(OH)D levels achieved through different dosing strategies may have differential physiological consequences. Fifth, as we evaluated the effects of vitamin D supplementation against multiple outcomes, our study may suffer from multiple testing problems, which warrants cautious interpretation of statistically significant findings and confirmation by future studies. Finally, while protocol registration is highly recommended before conducting a meta-analysis [50], this update to our previous meta-analysis was not preregistered.

In conclusion, our findings largely confirm previous meta-analyses on this topic that suggest vitamin D supplementation may lower the risk of cancer mortality. A cost-benefit analysis calculated that a 13% lower cancer mortality achieved through vitamin D supplementation of adults aged >50 years would prevent 30,000 deaths per year, with a net savings of ~$300 million in Germany [51]. Most importantly, our results indicate that daily dosing may be more efficacious than infrequent large-bolus dosing. Given the theoretical and emerging empirical evidence for lack of efficacy and perhaps even harm of bolus dosing to cancer and other outcomes, future efforts should focus on daily dosing and avoid bolus dosing even if they are considered more feasible. The emerging finding for cancer outcomes as well as other endpoints that individuals with excess body adiposity may be relatively resistant to the benefits of vitamin D should be evaluated further. Specifically, whether higher doses are needed in obese individuals should be evaluated, and potential mechanisms inhibiting the actions of vitamin D, such as subclinical inflammation, should be studied.

Supplementary information

Supplementary material (234.3KB, docx)

Acknowledgements

None.

Author contributions

NK collected, analysed and interpreted the data, and drafted the manuscript. QYC collected and analysed the data, and drafted the manuscript. DL, JEM and EG interpreted the date and drafted the manuscript.

Funding

NK and QYC were supported by the BK21-plus education programme funding from the National Research Foundation of Korea. JEM is supported by R01 AT 011729 and R01 HL34594.

Data availability

The data used for this meta-analysis were extracted from the articles, which were retrieved from the online databases PubMed and Embase.

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Not applicable.

Consent to publish

Not applicable.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

The online version contains supplementary material available at 10.1038/s41416-022-01850-2.

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Associated Data

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Supplementary Materials

Supplementary material (234.3KB, docx)

Data Availability Statement

The data used for this meta-analysis were extracted from the articles, which were retrieved from the online databases PubMed and Embase.

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

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