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New data on vitamin D safety

Vitamin D supplementation would appear to have a pristine safety record, at least at first glance. This meta-analysis takes another look at that issue, specifically at potential effects on excessive calcium levels.

Study under review: Hypercalcemia, hypercalciuria, and kidney stones in long-term studies of vitamin D supplementation: a systematic review and meta-analysis


Right next to fish oil and creatine monohydrate, vitamin D is one of the safest and most well-researched supplements with a known range of health benefits. Interestingly, research suggests that vitamin D may influence the expression of over 1,000 genes[1] in the human body (1/24th of the human genome), which would be unfortunate for the estimated 40%[2] of the general U.S. population who don’t currently meet the requirements for adequate levels of the vitamin. Adequate vitamin D levels are correlated with improved immune health, bone health, and well-being. Moreover, supplementation may have a role in reducing the risk of certain types of cancer[3], as well as heart disease[4], diabetes[5], and multiple sclerosis[6]. The benefits are well-known, and while it’s likely that we’ll continue to learn more about the various ways vitamin D affects the body, recent research has begun to shed light on the potential side effects of higher doses.

Some common vitamin D sources are shown in Figure 1. Human beings have developed certain biological mechanisms to prevent vitamin D toxicity from sun exposure and UVB light through the conversion of pre-vitamin D. However, this mechanism does not apply to the vitamin D[7] we ingest through supplementation or food. Supplementation of 1,000 - 2,000 IU/day vitamin D is considered safe and sufficient to meet the needs for most of the population. On the higher end, a recent systematic review[8] concluded that exceptionally large one-off doses up to 300,000 IU of vitamin D were still devoid of harmful side effects. Based on the available evidence, there is little data suggesting that doses up to this level present any significant health risk. While uncommon, negative effects of high-dose vitamin D do occur, and it’s important for researchers to quantify and make sense of them. Research[9] suggests that the safe upper limit is 10,000IU/day, and emerging research has begun to elucidate the potential consequences associated with high-dose vitamin D supplementation and its effect on calcium metabolism--the main area where complications tend to arise from vitamin D toxicity.

Figure 1: Forest plots for hypercalcemia, hypercalciuria, and kidney stones

Some of the most common negative effects of high-dose vitamin D on calcium metabolism are hypercalcemia, hypercalciuria, kidney stones, and renal insufficiency. Hypercalcemia is characterized by elevated blood calcium, and the effects can range from minor or nonexistent, to debilitating and life-threatening, affecting several different systems in the body. Hypercalciuria refers to an increased amount of calcium excreted through the urine. Chronic hypercalciuria can lead to impaired renal function, and is one of the most common complications in patients with kidney stones.

Two recent Cochrane reviews concluded that vitamin D supplementation increased the risk of hypercalcemia[10] in people who were elderly[10], and, when combined with calcium supplements, increased the risk of kidney stones[11]. Conversely, a different Cochrane review[12] of randomized controlled trials from 2014 reported no increased risk of hypercalcemia in cancer patients, but did observe an increased risk of kidney stones. The relationship between vitamin D supplementation and calcium metabolism has yielded some mixed findings, and this most recent meta-analysis sought to improve upon previous research by including more recent studies published after January 2013 (the cut-off point for the aforementioned Cochrane papers), and by including longer-term (more than 24 weeks) randomized, controlled trials.

Previous meta-analyses on vitamin D have largely been restricted to outcomes of mortality, cancer, or fractures, and did not include studies based on specific outcomes related to calcium metabolism. Additionally, previous reviews included short-term trials, which may have masked any effects of vitamin D over a longer duration of supplementation.

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