Safety of High-Dose Vitamin D Supplementation: Secondary Analysis of a Randomized Controlled Trial

Context: More than 3% of adults report vitamin D intakes of 4000 IU/day or more, but the safety of this practice is unknown.

Objective: The objective of this work is to establish whether vitamin D doses up to 10 000 IU/day are safe and well tolerated.

Design: The Calgary Vitamin D Study was a 3-year, double-blind, randomized controlled trial.

Setting: A single-center study was conducted at the University of Calgary, Canada.

Participants: Participants included healthy adults (n = 373) ages 55 to 70 years with serum 25-hydroxyvitamin D 30 to 125 nmol/L.

Interventions: Participants were randomly assigned 1:1:1 to vitamin D3 400, 4 000, or 10 000 IU/day. Calcium supplementation was initiated if dietary calcium intake was less than 1200 mg/day.

Main Outcome Measures: In these prespecified secondary analyses, changes in serum 25-hydroxyvitamin D, calcium, creatinine, 24-hour urine calcium excretion, and incidence of adverse events were assessed. Between-group differences in adverse events were examined using incident rate differences and logistic regression.

Results: Of 373 participants (400: 124, 4000: 125, 10 000: 124), 49% were male, mean (SD) age was 64 (4) years, and 25-hydroxyvitamin D 78.0 (19.5) nmol/L. Serum calcium, creatinine, and 24-hour urine calcium excretion did not differ between treatments. Mild hypercalcemia (2.56-2.64 mmol/L) occurred in 15 (4%) participants (400: 0%, 4000: 3%, 10 000: 9%, P = .002); all cases resolved on repeat testing. Hypercalciuria occurred in 87 (23%) participants (400: 17%, 4000: 22%, 10 000: 31%, P = .01). Clinical adverse events were experienced by 365 (97.9%) participants and were balanced across treatment arms.

Conclusions: The safety profile of vitamin D supplementation is similar for doses of 400, 4000, and 10 000 IU/day. Hypercalciuria was common and occurred more frequently with higher doses. Hypercalcemia occurred more frequently with higher doses but was rare, mild, and transient.