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

https://doi.org/10.1016/j.jsbmb.2018.12.002Get rights and content

Highlights

  • There is uncertainty about the safety of long-term high-dose vitamin D supplementation.

  • This systematic review included clinical trials which gave ≥2800 IU/d vitamin D supplementation for one year or longer.

  • Long-term high-dose vitamin D supplementation did not increase the risk of total adverse events or kidney stones.

  • However, there was borderline increased risk of hypercalcemia, and possibly of hypercalciuria.

Abstract

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.

Introduction

Vitamin D supplementation in high doses is being increasingly used in clinical trials to investigate potential beneficial effects for different health outcomes [[1], [2], [3], [4], [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], [10], [11], [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], [16], [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], [21], [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 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 long-term 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 6-months 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], [32], [33], [34], [35], [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].

Section snippets

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”).

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].

Study selection criteria

RCTs were included if they gave vitamin D2 or D3 at daily, monthly, yearly doses equivalent of ≥2800

Results

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

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

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

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

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