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



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.



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



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.



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.
School of Population Health, University of Auckland, Auckland, New Zealand.
Zarintaj
Z
Malihi
School of Population Health, University of Auckland, Auckland, New Zealand.
Zhenqiang
Z
Wu
School of Population Health, University of Auckland, Auckland, New Zealand.
Alistair W
AW
Stewart
School of Population Health, University of Auckland, Auckland, New Zealand.
Carlene Mm
CM
Lawes
School of Population Health, University of Auckland, Auckland, New Zealand r.scragg@auckland.ac.nz.
Robert
R
Scragg
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002118:Calcium / Q000378:metabolism*; D019587:Dietary Supplements / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology*; D053565:Hypercalciuria / Q000209:etiology*; D007669:Kidney Calculi / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D014807:Vitamin D / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000097:blood; D014815:Vitamins / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D055815:Young Adult
D014815:Vitamins; D014807:Vitamin D; C104450:25-hydroxyvitamin D; D002118:Calcium
hypercalcemia; hypercalciuria; kidney stones; randomized controlled trials; vitamin D supplements