Adverse events from large dose vitamin D supplementation taken for one year or longer

Journal of Steroid Biochemistry and Molecular Biology xxx (xxxx) xxx–xxx

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Review

Adverse events from large dose vitamin D supplementation taken for one year or longer Z. Malihi, Zhenqiang Wu, Carlene M.M. Lawes, Robert Scragg

⁎

School of Population Health, University of Auckland, New Zealand

A R T I C LE I N FO

A B S T R A C T

Keywords: Adverse events Hypercalcemia Hypercalciuria Meta-analysis Kidney stones Vitamin D supplementation

In recent years, clinical trials increasingly have given large doses of vitamin D supplements to investigate possible health benefits beyond bone at high 25-hydroxyvitamin D levels. However, there are few publications on the safety of high-dose vitamin D given long term. The study objective was to investigate the cumulative relative risk (RR) of total adverse events, kidney stones, hypercalcemia and hypercalciuria from ≥2800 IU/d vitamin D2 or D3 supplementation, followed for one year or more in randomized controlled trials (RCTs). A systematic review was conducted in Medline Ovid, EMBASE and Cochrane in March 2018 to update results of studies published since a previous review in October 2015. RCTs were included if they gave vitamin D2 or D3 at ≥2800 IU/d for at least one year and reported on total adverse events or at least one calcium-related adverse event. There were a total of 32 studies that met the inclusion criteria. Of these, only 15 studies (3150 participants) reported one or more event of the outcomes of interest. Long-term high-dose vitamin D supplementation did not increase total adverse events compared to placebo in 1731 participants from 10 studies (RR = 1.05; 95% CI = 0.88, 1.24; p = 0.61), nor kidney stones in 1336 participants from 5 studies (RR = 1.26; 95% CI = 0.35, 4.58; p = 0.72). However, there was a trend for vitamin D to increase risk of hypercalcemia in 2598 participants from 10 studies (RR = 1.93; 95% CI = 1.00, 3.73; p = 0.05); while its effect on hypercalciuria in only 276 participants from 3 studies was inconclusive (RR = 1.93; 95% CI = 0.83, 4.46; p = 0.12). In conclusion, one year or longer supplementation with a large daily, weekly or monthly dose of vitamin D2 /D3 did not significantly increase a risk of total adverse events or kidney stones, although there was a trend towards increased hypercalcemia, and possibly for hypercalciuria.

1. Introduction Vitamin D supplementation in high doses is being increasingly used in clinical trials to investigate potential beneficial effects for different health outcomes [1–5]. Examples of high vitamin D doses include increased quality of life of multiple sclerosis patients after receiving 50,000 IU vitamin D3 every five days for three months [6], decreased mortality in vitamin D deficient patients admitted to intensive care units after receiving a bolus dose of 540,000 IU followed by monthly doses of 90,000 over 6 months [7], and decreased loss of bone mineral density in vitamin D deficient participants after receiving 100,000 IU/ month for 2 years [8]. These trials have followed early findings from observational studies suggesting that optimal health status was associated with circulating levels of 25-hydroxyvitamin D (25(OH)D) ≥75 nmol/L (≥30 ng/ml) [9–12]. Therefore, large daily or bolus doses

of this vitamin, equivalent or higher than monthly supplementation of 100,000 IU [1,3,13,14], have been administered in randomized controlled trials (RCTs) to increase the 25(OH)D to ≥75 nmol/L where the suggested health benefits have been proposed [15–17]. However, vitamin D supplementation with very high annual doses could also be harmful as two RCTs have reported such doses have increased the risk of falls and/or fractures [18,19]. Although these findings have not been replicated in other trials which gave lower bolus doses [20–22], safety studies are warranted as the hazards of long-term consumption of high doses of this vitamin are currently unclear. The conventional indicator of vitamin D toxicity is hypercalcemia [23]. However, this has not always been considered as a sensitive indicator for this outcome. For instance, in accidental cases that received 2000,000 IU vitamin D3 in a single dose, serum calcium only increased slightly when serum 25(OH)D increased to 400–500 nmol/L [24]. This

Abbreviations: 25(OH)D, 25-hydroxyvitamin D; Ca, calcium; CI, confidence interval; COPD, chronic obstructive pulmonary disease; IU, international unit; RCT, randomized controlled trial; RevMan, review manager; RR, risk ratio; WHI, women’s health initiative ⁎ Corresponding author at: School of Population Health, University of Auckland, Private Bag 92019, Auckland Mail Centre, 1142, New Zealand. E-mail address: [email protected] (R. Scragg). https://doi.org/10.1016/j.jsbmb.2018.12.002 Received 11 August 2018; Received in revised form 23 November 2018; Accepted 6 December 2018 0960-0760/ © 2018 Elsevier Ltd. All rights reserved.

Please cite this article as: Malihi, Z., Journal of Steroid Biochemistry and Molecular Biology, https://doi.org/10.1016/j.jsbmb.2018.12.002

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2.4. Data collection

concurs with the suggested idea that hypercalcemia occurs when “pharmacological” doses of vitamin D, above 10,000 IU/d, are taken for a long period of time [23,25]. In contrast with hypercalcemia, hypercalciuria is thought to be a more sensitive indicator for vitamin D toxicity and may occur earlier than hypercalcemia [26]. Furthermore, there have been concerns that vitamin D supplementation with/without calcium could increase the risk of kidney stones and other calcium-related effects [27], as shown in a 2014 Cochrane review where the risk of kidney stones increased among participants in four trials taking vitamin D in combination with calcium (RR = 1.17; 95%CI 1.02, 1.34; p = 0.02), three of which were longterm trials with a supplementation period longer than 2 years [28]. However, this finding was not confirmed by a more recent meta-analysis of RCTs with any dose of vitamin D2/ D3 supplements given for 6months or longer [29]. As stated by the Institute of Medicine in a 2011 review of Dietary Reference Intakes (DRI) for vitamin D and calcium intake, there is still a “paucity of data” related to safety of chronic intakes of large doses of vitamin D [30]. This highlights the importance of a more comprehensive and systematic assessment of the safety of long-term large doses of vitamin D supplementation. In this systematic review and meta-analyses, we aimed to investigate total adverse events, and any calcium-related adverse events from large dose long-term vitamin D2 or D3 supplementation by including RCTs which gave an equivalent of daily ≥2800 IU, for a minimum of one year or followed participants up (in cases where several bolus doses were given) for one year. We considered 2800 IU/d as the cut-point in order to include studies that gave bolus doses equivalent or below 4000 IU/d, such as doses of 100,000 IU monthly, 50,000 IU fortnightly or 20,000 IU weekly [31–36]. This was done by updating results of recent meta-analyses on calcium-related adverse events from 2015 and total adverse events in 2016 [29,37].

Two researchers independently scanned the search results for the inclusion criteria, and any inconsistencies were discussed and resolved. We retrieved the full texts of potential studies that met the inclusion criteria for a closer assessment. Data were recorded individually by each investigator into an Excel spreadsheet. Quality assessment of individual studies was done by two investigators, using Cochrane quality assessment criteria for RCTs. Inconsistencies were discussed to reach a decision. 2.5. Study variables Characteristics of the study extracted were: sample size, percentage of women, mean age, vitamin D dosage, duration of study, main outcome, and mean baseline 25(OH)D or serum calcium, and the cut-points for hypercalcemia and hypercalciuria (when reported). 2.6. Procedures for checking the data Total adverse events, kidney stones, hypercalcemia, and hypercalciuria events that were reported per person per arm were extracted from the included studies. Studies that matched the inclusion but reported zero events or had not provided per person level data were excluded from the meta-analyses. The characteristics of these studies are provided in Table 1, Supplementary file. Of 14 studies in this Supplementary table, one had only 6 participants in each treatment arm and so was excluded [38] to prevent skewness of the weighting of the cumulative events in favour of either the vitamin D or placebo arm. In this study, 2 out of 6 participants in the vitamin D arm had transient hypercalcemia [38]. Another study reported participants with hypercalcemia events before and after randomization and it did not increase after randomization, so was considered as having zero hypercalcemia events [17]. A total of 8 studies reported zero events and therefore were not included in the meta-analysis [4,31,39–44]. A further three studies did not provide sufficient details on any of our outcomes of interest [2,45,46]. Pre-defined subgroup analyses were carried out to determine whether the primary outcomes in the vitamin D and placebo arms varied by: baseline 25-hydroxyvitamin D [25(OH)D] concentration (> 50 or ≤50 nmol/L); use of calcium in both arms, compared with vitamin D–only and placebo in the control arm.

2. Methods 2.1. Search terms Search terms were (Vitamin D OR Vitamin D2 OR Vitamin D3 OR Ergocalciferol OR Cholecalciferol) AND (supplementation) AND RCTs (all terms searched) AND (“adverse events” OR “side effects” OR “Hypercalcemia” OR “Hypercalciuria” OR “Kidney stones”).

2.7. Data analysis Meta-analyses were conducted using a random-effects model in Review Manager Software (RevMan version 5.3; Cochrane Collaboration). The Mantel-Haenszel method for combining data from included studies was used. Risk Ratios (RR) with 95% confidence intervals (CIs) were the main summary measures in this study of dichotomous outcomes. Further heterogeneity of the included studies in meta-analyses were assessed using I2 test. The publication bias was assessed using funnel plots. Significance was assessed at 0.05.

2.2. Data sources Medline Ovid, EMBASE and Cochrane were searched on 29 March 2018 to update the results of a previous review of studies published since October 2015 [29].

2.3. Study selection criteria

3. Results

RCTs were included if they gave vitamin D2 or D3 at daily, monthly, yearly doses equivalent of ≥2800 IU/d for at least one year to adults (≥18 years old) and reported at least one adverse event, including hypercalcemia, hypercalciuria, kidney stones and/or total adverse events, by each study arm. If calcium was given too, it had to have been given to both arms. Included studies from the previous systematic reviews [29,37] were also included in this review if they met these criteria. Studies were excluded if they: i) were conducted in pregnant women, ii) gave any other vitamin D metabolite, iii) gave more than 600 IU/d vitamin D or bolus doses to the control arm, iv) had less than 10 participants in each arm. In addition, conference abstracts were excluded in the title and abstract screening phase. The PRISMA diagram in Fig. 1 depicts the inclusion/exclusion procedure.

From a total of 819 screened studies from the new search results, 8 studies both met the inclusion criteria and provided the required information on calcium-related adverse events or all serious/non-serious adverse events. These 8 studies were added to the 7 studies in our previous systematic review that also met the inclusion criteria for the current review [29]. The PRISMA diagram of the systematic review process is shown in Fig. 1. Characteristics of the 15 studies with 3150 participants which reported at least one event are presented in Table 1 [1,32,33,35,36,47–56]. Of these, only one study gave vitamin D2 supplement (8966 IU/d) for one year [52], whereas all other studies gave vitamin D3 (mean daily 9990 IU/d; range: 2,857-100,000 IU/d). The 2

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Fig. 1. PRISMA diagram of review process of long-term RCTS with calcium-related adverse events.

included studies (1336 Participants) that gave large dose vitamin D supplements for one year or longer (RR = 1.26; 95% CI = 0.35, 4.58) [1,33,50,55,56]. There was only a handful of kidney stone events with cumulatively five and three participants experienced at least one kidney stone event, in vitamin D and placebo arms, respectively (Fig. 3). For hypercalcemia, 10 studies reported this outcome (2598 participants) [1,32,33,36,47,49,52–5456], with 27 and 11 people in the vitamin D and placebo arms, respectively, having at least one hypercalcemia event (Fig. 4). The cumulative RR for this outcome was just at the borderline of statistical significance with a trend to increased hypercalcemia risk (RR = 1.93; 95% CI: 1.00, 3.73; p = 0.05). Similarly, the effect size for hypercalciuria was increased, insignificantly (RR = 1.93; 95% CI = 0.83, 4.46) after pooling three studies with our inclusion criteria (276 participants) [35,47,49] (Fig. 5). Sub-group analyses based on additional calcium supplementation and baseline 25(OH)D status did not change these results for any of the outcomes. Tests for interaction between sub-groups did not find any significant differences between subgroups (Table 2).

average is high because of the Brohult et al. (1973) study which had given 100,000 IU/d for one year [47]. Excluding the latter study, the average vitamin D3 supplementation in the included studies was 3323 IU/d given for one year or longer (range: 1–5 years). The mean baseline 25(OH)D of participants of included studies was 48.4 and 47.9 nmol/L in participants of vitamin D and placebo arms, respectively. Only 6 out of 15 studies included participants with a mean baseline 25(OH) D < 50 nmol/L (their mean was 36.5 nmol/L or 14.6 ng/dL). Of the 15 included studies, 10 studies (with 1731 participants) reported on total adverse events, with a cumulative 118 people (out of 893) in vitamin D versus 73 (out of 838) in the placebo arm with at least one adverse event [1,47,48,50–5355,57,58]. The risk of total adverse events was not increased in vitamin D supplemented arm compared with placebo (RR = 1.05; 95% CI = 0.88, 1.24; Fig. 2). Further sub-group analyses based on baseline serum 25(OH)D or additional calcium supplementation did not change the risk, significantly, as shown by the interaction test results in Table 2 (p for interaction > 0.05). The cumulative RR of kidney stones was not increased in the five 3

50 rheumatoid arthritis outpatients 72 ambulatory adults with epilepsy diagnosis visiting neurologist 445 subjects from the public and local clinic outpatients with BMI < 47 & > 28 kg/m2. 71 ambulatory Multiple Sclerosis (MS) patients

Brohult, [47] Mikati, [48]

4 38.5

22 Rheumatoid Arthritis (RA) patients from a rheumatology clinic with a 35 < 25(OH)D < 67 nmol/L

257 Overweight (BMI > 25) elderlies aged ≥65 y with a 30 < 25(OH)D level < 75 nmol/l 511 subjects at risk of developing DM-type 2

223 Chronic heart failure patients who were vitamin D deficient 5108 participants from general practice and some from communities aged 50-80.

Hansen, [35]

El-Hajj et al. [56]; Rahme, et al. [58] Jorde, et al. [1]

Witte et al. [53]

55#

56.5

44.8

17

65.9

68.7

41.9

20.9

58.8

0

61.0

59.6

41.9

D3 4000 IU/d Placebo/d

D3 100,000 IU/ mo Placebo/ mo

D3 100,000 IU/d D3 4000 IU/d D3 400 IU/d D3 40,000 IU/w Placebo/w Both received + 500 mg Ca/d D3 20,000 IU /week Placebo/w + all received 500 mg Ca/d D3 4000 IU/d Placebo D3 4800 IU/d D3 4000 IU/d D3 3200 IU/d Placebo D 100,000IU/w Placebo D2 50 000 IU/wk Placebo weekly All took 400 IU/d for entire study period D3 50,000 IU/d for 15 days, then one fortnightly for 11.5 m.( + 1500 mg Ca/d) Placebo for 15 days, then 1 fortnightly for 11.5 m ( + 1500 mg Ca/d) D3 3750 IU/d D3 600 IU/d Both arms received 1 g Ca/d D3 20,000 IU/week Placebo/week D3 4000 IU/d Placebo/d D3 100,000 IU/mo Placebo/mo

Vitamin D and dosage

COPD = Chronic Obstructive Pulmonary Disease; CLAD = Chronic lung allograft dysfunction; NR = not reported. * Converted to nmol/L by multiplying ng/dL by 2.496. # Median; Ca = calcium; se Ca = serum calcium; ur Ca = urinary calcium.

Zitterman, [54]

Vos et al [55]

87 patients who were lung transplantation recipients aged > 18 y included if could take oral capsules 400 outpatients with Heart Failure and baseline 25(OH)D < 75 nmol/l

62

55.4

173 Prediabetic African American men with vitD deficiency with a 72.4 > 25(OH)D > 12.5 nmol/L

Barengolts et al. [52]

Scragg, et al. [32]

70

100

patients with moderate to severe COPD disease

67

Lehouck, [36]

100

81 postmenopausal women

53.1

Gallagher, [49,57]

72.8

140 patients from immunodeficiency unit

40.0

47.6

64.3 70.5

52 28.7

Mean age (y)

68 54.1

% women

Bergman, [51]

Steffensen [50] Rosjo, [74]

Sneve, [33]

Characteristics of sample(s)

Study

Table 1 Characteristics of RCTs with long-term large dose (≥2800 IU/d) vitamin D supplementation included in meta-analyses.

3y

2y 3 y follow up

3.3 y

1y

5y

1y

1y

1y

1y

1y

1y

All-cause mortality

Prevention of progression of prediabetic status to DM-2 Difference in change in 6min walk test distance Cardiovascular events; respiratory infections; Falls & Fractures Chronic lung allograft dysfunction (CLAD)

HOMA-IR index & BMD

Increase in BMD and total fractional calcium absorption (TFCA)

Incidence of COPD exacerbation Improvements in Insulin sensitivity and secretion, glycemic status

Reduce infection symptoms and antibiotic consumption 25(OH)D achievement & Parathyroid Hormone (PTH)

Prevention of bone loss

1.8 y

1y

Clinical improvement long-term anticonvulsant medication therapy Weight loss

Main outcome(s)

1y 1y

Duration of study

34.5

31.2

se Ca > 2.75 mmol/L

59.9

35.2#

62.1

31.3#

62.9*

63.6* se Ca > 2.50 mmol/L

se Ca > 3.50 mmol/L

36.4

61.1

49.9

38.2

59.9

52.2

52.4*

49.9*

49.9*

52.4*

38.2

46.9

57.3

53.2

NR 32.7

Placebo

35.2 37.7 31.9

51.5

55.6

54.5

NR 34.2

Vitamin D

Mean baseline serum 25(OH)D (nmol/L)

se Ca > 2.60 mmol/L

se Ca > 2.55 mmol/L

se Ca > 2.65 mmol/L

se Ca ≥ 2.60 mmol/L ur Ca > 400 mg/d

se Ca > 2.63 mmol/L ur Ca > 300 mg/d se Ca ≥2.55 mmol/L

Se Ca: > 2.55 mmol/L ur Ca: > 300 mg/d

se Ca NR

se Ca > 2.55 mmol/L ur Ca > 8.0 mmol/L se Ca: NR

se Ca: NR se Ca: NR

Cut-points for hypercalcemia and hypercalciuria

Z. Malihi et al.

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Fig. 2. Long-term-bolus dose supplementation and risk of total adverse events.

noteworthy that we also included transient hypercalcemia events in both meta-analyses to capture any event [36]. Similarly, the higher effect size for hypercalciuria events in this review (RR = 1.93; 95% CI = 0.83, 4.46) was in agreement with increased risk of this outcome in our previous review from 14 included studies (RR = 1.64; 95% CI = 1.06, 2.53). Interestingly, among the three included studies for hypercalciuria in this review, Gallagher et al. (2014) systematically assessed urinary calcium and serum calcium in 163 women who were given a wide range of vitamin D3 daily doses from 400IU/d to 4800 IU/d for one year [49]. The number of women with at least one hypercalciuria event was not significantly different between lower (400IU/d, 800 IU/d and 1600 IU/d) and higher doses (3600 IU/d, 4200 IU/d and 4800 IU/d). Although, the number of included studies in this review was small, it seems that the bolus dosing or high daily doses of studies in this review did not substantially increase the risk for both hypercalcemia and hypercalciuria compared to our previous review [29]. This is consistent with a meta-regression results showing no association between vitamin D dose and risk of hypercalcemia [29]. The supplementation time limit of one year restricted inclusion of many large dose RCTs with shorter supplementation term with 2800 IU/d or higher vitamin D [7,59–64], some of which had already found hypercalcemia events within 6-months [59,61,60–64]. Nevertheless, the main aim of this review was tracking of the prolonged supplementation, as it was hypothesized that long-term supplementation

Since the majority of the included studies were published within the past 10 years, there was sufficient information provided on their research design, including blinding, randomization, baseline characteristics and reporting of the primary and secondary results. Therefore, included studies were overall of high quality and low risk of bias in terms of random sequence, allocation concealment, blinding and attrition (Supplementary file; Figs. 1 and 2). Similarly, there was no suggestion of publication bias in funnel plots for the four study outcomes (Supplementary file; Figs. 3–6).

4. Discussion This review did not find an increased risk from large dose long-term vitamin D supplementation for total adverse events, kidney stones, and hypercalciuria events. The finding for total adverse events was consistent with the latest review [37] and therefore provides further evidence for the safety of this vitamin in terms of general health. However, we found a borderline increased risk for hypercalcemia, with the effect size (RR = 1.93; 95% CI = 1.00, 3.17) being higher than results for this outcome from our previous systematic review (RR = 1.54; 95% CI-1.09, 2.18) [29], albeit with overlapping confidence intervals. This was expected given the inclusion criteria for long-term and large-dose supplementation which resulted in the inclusion of only 10 studies, compared to 37 included in the previous review which included lower vitamin D dose studies [29]. It is

Table 2 Summary table of relative risk for each outcome and its subgroups for long-term large dose RCTs of vitamin D supplementation. Outcome or Subgroup

•

Total adverse events Total adverse events in studied with additional calcium Total adverse events in studies without additional calcium Total adverse events in studies with baseline 25(OH)D≤50 nmol/l Total adverse events in studies with baseline 25(OH)D > 50 nmol/l Kidney stones Kidney stone in studies with additional calcium Kidney stone in studies without additional calcium Kidney stone in studies with baseline 25(OH)D≤50 nmol/l Kidney stone in studies with baseline 25(OH)D > 50 nmol/l Hypercalcemia Hypercalcemia in studies with additional calcium Hypercalcemia in studies without additional calcium Hypercalcemia in studies with mean baseline 25(OH)D≤50 nmol/l Hypercalcemia in studies with mean baseline 25(OH)D > 50 nmol/l Hypercalciuria Hypercalciuria in studies with additional calcium Hypercalciuria in studies without additional calcium Hypercalciuria in studies with baseline 25(OH)D≤50 nmol/l Hypercalciuria in studies with baseline 25(OH)D > 50 nmol/l

• • •

Studies

10 3 7 4 5 5 3 2 0 5 10 3 7 4 5 3 2 1 1 1

Participants

1731 409 1322 615 1066 1336 738 598 0 1336 2598 640 1958 877 1672 276 72 204 72 155

5

Effects size (Relative risk)

1.05 1.02 1.14 1.02 1.11 1.26 0.77 2.29 – 1.26 1.93 1.58 2.05 1.80 2.05 1.93 1.77 5.20 1.52 3.85

(0.88, (0.83, (0.81, (0.84, (0.77, (0.35, (0.13, (0.34,

1.24) 1.24) 1.60) 1.24) 1.60) 4.58) 4.39) 15.50)

(0.35, (1.00, (0.39, (0.97, (0.77, (0.68, (0.83, (0.74, (0.26, (0.59, (0.44,

4.58) 3.73) 6.35) 4.32) 4.22) 6.14) 4.46) 4.24) 103.0) 3.96) 33.65)

1

Z

0.51 0.16 0.74 0.19 0.58 0.35 0.30 0.85 – 0.35 1.96 0.64 1.88 1.35 1.28 1.53 1.28 1.08 0.86 1.22

P-value

0.61 0.87 0.46 0.85 0.58 0.72 0.77 0.39 – 0.72 0.05 0.52 0.06 0.18 0.20 0.12 0.20 0.28 0.39 0.22

Interaction tests

2

Z

P-value

– −0.55

– 0.58

−0.40

0.68

– −0.82

– 0.41

– – – −0.32

– – – 0.75

−0.18

0.85

– −0.67

– 0.49

−0.77

0.44

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Fig. 3. Long-term, high-dose vitamin D supplementation and kidney stone events.

on the safety of vitamin D supplementation.

might affect the metabolism pathway of vitamin D overtime resulting in symptoms and signs of hypervitaminosis. According to the Institute of Medicine, 25(OH)D levels higher than 125 nmol/L may result in negative outcomes [30,65]. In theory, if concentration of urinary calcium is constantly increased as a result of excess vitamin D intake, via increased intestinal calcium absorption, risk of kidney stones should increase [66]. The concern of increased risk of kidney stone events has come from the Women’s Health Initiative (WHI) study results, which gave 1000 mg/d calcium in combination with 400 IU/d vitamin D3 for 7 years [67]. In addition, a recent systematic review of observational studies (including 23,228 participants) found higher circulating 1,25-dihydroxyvitamin D concentrations in calcium-stone formers compared with non-stone formers [68]. In contrast, a recent study that investigated the relationship between kidney stones and vitamin D intake including 193,551 people from three big cohorts did not find an increased risk [69]. This concurs with results of the current review. However, the effect size in our review with five studies (1336 participants) is much higher (RR = 1.26; 95%CI = 0.35, 4.58) than the previous review (RR = 0.66; 95%CI = 0.41, 1.09) which included many studies with a smaller supplementation dose, such as the one in WHI study. Whether a higher supplementation dose for a longer period triggered the stone forming in participants who were sensitive or had a genetic predisposition that made them susceptible to high prolonged vitamin D supplement intake is not entirely understood [70]. Additional safety data from further studies with large dose supplementation of vitamin D should provide more evidence to answer this question. Our meta-analysis highlights some important limitations regarding the reporting of adverse events from RCTs of vitamin D supplementation. These include: reporting of the number of events per arm, not per participant [31,39,71], reporting side effects only in the treatment arm [2], reporting on serious adverse events only and excluding non-serious events [17], and not specifying the arm of the study with observed adverse events [2]. These limitations need to be addressed by a more consistent reporting approach from future RCTs so that additional information can be added to extend the power of current meta-analyses

4.1. Strengths and limitations Many RCTs have been conducted with vitamin D supplementation. This provided an opportunity to specifically assess large-dose long-term supplementation of vitamin D, which is reported for the first time in this review. Since we controlled the effect of calcium in this review, we could assess the safety issues of vitamin D supplementation independent of calcium supplements. In addition, the safety of intermittent bolus dosing is captured in this review with the inclusion of nine studies that given weekly, monthly or few monthly vitamin D supplementation. This is particularly important for the ongoing debate of cost-effectiveness for daily or intermittent dosing as the latter may have higher adherence [72]. However, we could only use information from 15 studies with at least one adverse event, and there were 12 more studies with zero calcium-related adverse events or insufficient data that met the other inclusion criteria (Supplementary Table 1). Since no estimate is calculated in meta-analysis using RevMan if both arms have zero events, we did not include them in the main results. However, it has been shown that inclusion of these, using other statistical methods, such as adding a continuity correction of 0.5 to each cell, is unlikely to change the effect size for RR or odds ratio [73]. But the power to detect any adverse effect from vitamin D supplements on kidney stones and hypercalciuria was limited by their exclusion. In addition, definitions of vitamin D toxicity were different between studies, since the cut-point for hypercalcemia was different from one to another. For instance, one study that gave 3300 IU/d for one year to the vitamin D arm, found three participants in the vitamin D arm and one participant in the placebo arm with 25(OH)D levels of 250 nmol/L, whereas the serum calcium level of these participants remained < 2.70 mmol/L, the cut-point used in that study [44]. Although the researchers included participants from the general public, the cut-point for hypercalcemia was high compared to most studies and the IOM cutpoint for hypercalcemia (2.62–2.63 mmol/L) [30]. Furthermore, the

Fig. 4. Long-term, high-dose vitamin D supplementation and hypercalcemia events. 6

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Fig. 5. Long-term, high-dose vitamin D supplementation and hypercalciuria events.

inclusion of studies with both patients and healthy participants could have increased heterogeneity between studies and contributed to wide CIs. However, we did not find statistically significant heterogeneity between studies included the current review.

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5. Conclusion Supplementation with ≥2800 IU/d vitamin D2/D3 for one year or longer did not significantly increase risk of total adverse events or of kidney stones. However, there was a borderline increased risk for hypercalcemia from long-term high-dose vitamin D supplementation, which requires further investigation given small number of included studies in this review, as does the effect of vitamin D on hypercalciuria. Nevertheless, it is difficult to draw conclusions regarding kidney stones and hypercalciuria due to the limited number of these events in the reviewed studies. Source of funding No funding was received for this specific study. The first and second authors were recipients of doctoral scholarship. Zarintaj Malihi received a doctoral scholarship from the University of Auckland and Zhenqiang Wu received the State Scholarship Fund of the China Scholarship Council. Declarations of interest None Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jsbmb.2018.12.002. References [1] R. Jorde, S.T. Sollid, J. Svartberg, H. Schirmer, R.M. Joakimsen, I. Njolstad, O.M. Fuskevag, Y. Figenschau, M.Y.S. Hutchinson, Vitamin d 20,000 IU per week for five years does not prevent progression from prediabetes to diabetes, J. Clin. Endocrinol. Metab. 101 (2016) 1647–1655 http://ovidsp.ovid.com/ovidweb.cgi? T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med8&AN=26829443. [2] Y. Wang, Y. Liu, Y. Lian, N. Li, H. Liu, G. Li, Efficacy of high-dose supplementation with oral vitamin D3 on depressive symptoms in Dialysis patients with vitamin D3 insufficiency: a prospective, randomized, double-blind study, J. Clin. Psychopharmacol. 36 (2016) 229–235, https://doi.org/10.1097/JCP. 0000000000000486. [3] N. Narula, M. Cooray, R. Anglin, Z. Muqtadir, A. Narula, J.K. Marshall, Impact of high-dose vitamin D3 supplementation in patients with Crohn’s disease in remission: a pilot randomized double-blind controlled study, Dig. Dis. Sci. 62 (2017) 448–455, https://doi.org/10.1007/s10620-016-4396-7. [4] K.E. Hansen, C.M. Bartels, R.E. Gangnon, A.N. Jones, J. Gogineni, An evaluation of high-dose vitamin D for rheumatoid arthritis, J. Clin. Rheumatol. 20 (2014) 112–114, https://doi.org/10.1097/RHU.0000000000000072. [5] J.I. Schall, M.L. Hediger, B.S. Zemel, R.M. Rutstein, V.A. Stallings, Comprehensive safety monitoring of 12-Month daily 7000-IU vitamin d 3 supplementation in human immunodeficiency virus–infected children and young adults, South Afr. J. Clin. Nutr. 40 (2016) 1057–1063, https://doi.org/10.1177/0148607115593790. [6] F. Ashtari, N. Toghianifar, S.H. Zarkesh-Esfahani, M. Mansourian, High dose Vitamin D intake and quality of life in relapsing-remitting multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial, Neurol. Res. 38 (2016)

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