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

Am J Clin Nutr. 2016 Oct;104(4):1039-1051. doi: 10.3945/ajcn.116.134981. Epub 2016 Sep 7.

Abstract

Background: Vitamin D supplementation is increasingly being used in higher doses in randomized controlled trials (RCTs). However, adverse events from very large annual doses of vitamin D have been shown in 2 RCTs, whereas in a third RCT, low-dose vitamin D, with calcium supplements, was shown to increase kidney stone risk.

Objective: We analyzed the side effects related to calcium metabolism in RCTs, specifically hypercalcemia, hypercalciuria, and kidney stones, in participants who were given vitamin D supplements for ≥24 wk compared with in subjects in the placebo arm.

Design: The following 3 main online databases were searched: Ovid Medline (PubMed), EMBASE, and the Cochrane Library. Software was used for the meta-analysis.

Results: A total of 48 studies with 19,833 participants were identified, which reported ≥1 of the following side effects: hypercalcemia, hypercalciuria, or kidney stones. Of these studies, kidney stones were reported in only 9 trials with a tendency for fewer subjects reporting stones in the vitamin D arm than in the placebo arm (RR: 0.66, 95% CI: 0.41, 1.09; P = 0.10). In 37 studies, hypercalcemia was shown with increased risk shown for the vitamin D group (RR: 1.54; 95% CI: 1.09, 2.18; P = 0.01). Similar increased risk of hypercalciuria was shown in 14 studies for the vitamin D group (RR: 1.64; 95% CI: 1.06, 2.53; P = 0.03). In subgroup analyses, it was shown that the effect of vitamin D supplementation on risk of hypercalcemia, hypercalciuria, or kidney stones was not modified by baseline 25-hydroxyvitamin D, vitamin D dose and duration, or calcium co-supplementation.

Conclusions: Long-term vitamin D supplementation resulted in increased risks of hypercalcemia and hypercalciuria, which were not dose related. However, vitamin D supplementation did not increase risk of kidney stones. Additional large RCTs of long-term vitamin D supplementation are required to confirm these findings.

Keywords: hypercalcemia; hypercalciuria; kidney stones; randomized controlled trials; vitamin D supplements.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Calcium / metabolism*
  • Dietary Supplements / adverse effects*
  • Female
  • Humans
  • Hypercalcemia / etiology*
  • Hypercalciuria / etiology*
  • Kidney Calculi / etiology*
  • Male
  • Middle Aged
  • Vitamin D / administration & dosage
  • Vitamin D / adverse effects*
  • Vitamin D / analogs & derivatives
  • Vitamin D / blood
  • Vitamins / administration & dosage
  • Vitamins / adverse effects*
  • Vitamins / blood
  • Young Adult

Substances

  • Vitamins
  • Vitamin D
  • 25-hydroxyvitamin D
  • Calcium