Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial | Osteoporosis | JAMA | JAMA Network
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Original Investigation
August 27, 2019

Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial

Author Affiliations
  • 1McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, Calgary, Canada
  • 2Research Facilitation, Alberta Health Services, Calgary, Canada
JAMA. 2019;322(8):736-745. doi:10.1001/jama.2019.11889
Key Points

Question  Does higher-dose vitamin D supplementation improve bone mineral density (BMD, measured using high-resolution peripheral quantitative computed tomography) and bone strength (measured as failure load)?

Findings  In this randomized clinical trial that included 311 healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD (calcium hydroxyapatite; −3.9 mg HA/cm3 and −7.5 mg HA/cm3, respectively); tibial BMD was significantly lower only with the daily dose of 10 000 IU. There were no significant differences in bone strength at either the radius or tibia.

Meaning  Among healthy adults, supplementation with higher doses of vitamin D did not result in improved bone health; further research would be needed to determine whether it is harmful.


Importance  Few studies have assessed the effects of daily vitamin D doses at or above the tolerable upper intake level for 12 months or greater, yet 3% of US adults report vitamin D intakes of at least 4000 IU per day.

Objective  To assess the dose-dependent effect of vitamin D supplementation on volumetric bone mineral density (BMD) and strength.

Design, Setting, and Participants  Three-year, double-blind, randomized clinical trial conducted in a single center in Calgary, Canada, from August 2013 to December 2017, including 311 community-dwelling healthy adults without osteoporosis, aged 55 to 70 years, with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30 to 125 nmol/L.

Interventions  Daily doses of vitamin D3 for 3 years at 400 IU (n = 109), 4000 IU (n = 100), or 10 000 IU (n = 102). Calcium supplementation was provided to participants with dietary intake of less than 1200 mg per day.

Main Outcomes and Measures  Co-primary outcomes were total volumetric BMD at radius and tibia, assessed with high resolution peripheral quantitative computed tomography, and bone strength (failure load) at radius and tibia estimated by finite element analysis.

Results  Of 311 participants who were randomized (53% men; mean [SD] age, 62.2 [4.2] years), 287 (92%) completed the study. Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L for the 400-IU group; 81.3, 115.3, and 132.2 for the 4000-IU group; and 78.4, 188.0, and 144.4 for the 10 000-IU group. There were significant group × time interactions for volumetric BMD. At trial end, radial volumetric BMD was lower for the 4000 IU group (−3.9 mg HA/cm3 [95% CI, −6.5 to −1.3]) and 10 000 IU group (−7.5 mg HA/cm3 [95% CI, −10.1 to −5.0]) compared with the 400 IU group with mean percent change in volumetric BMD of −1.2% (400 IU group), −2.4% (4000 IU group), and −3.5% (10 000 IU group). Tibial volumetric BMD differences from the 400 IU group were −1.8 mg HA/cm3 (95% CI, −3.7 to 0.1) in the 4000 IU group and −4.1 mg HA/cm3 in the 10 000 IU group (95% CI, −6.0 to −2.2), with mean percent change values of −0.4% (400 IU), −1.0% (4000 IU), and −1.7% (10 000 IU). There were no significant differences for changes in failure load (radius, P = .06; tibia, P = .12).

Conclusions and Relevance  Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10 000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful.

Trial Registration  ClinicalTrials.gov Identifier: NCT01900860