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Randomized Controlled Trial
. 2019 Aug 27;322(8):736-745.
doi: 10.1001/jama.2019.11889.

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

Lauren A Burt  1 , Emma O Billington  1 , Marianne S Rose  2 , Duncan A Raymond  1 , David A Hanley  1 , Steven K Boyd  1
Affiliations
Randomized Controlled Trial

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

Lauren A Burt et al. JAMA. .

Erratum in

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Billington reported receipt of grants and other (for scientific advisory board participation) from Amgen and Eli Lilly outside the submitted work. Dr Hanley reported receipt of grants and personal fees (for speaker honorarium) from Amgen and grants from Eli Lilly outside the submitted work. Dr Boyd reported other (co-owner of software company that performs finite element analysis; the software was used to analyze the data in this study, but it was provided completely free of charge and no compensation was received for this work) from Numerics88 Solutions and other (for panel participation honorarium) from Amgen outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of Participants Through the Study
Participants who received at least 1 dose of study drug and underwent at least 1 follow-up measurement were included in the primary analyses.
Figure 2.
Figure 2.. Data Distribution for Serum 25-Hydroxyvitamin D, Parathyroid Hormone, and C-Telopeptide of Type 1 Collagen Throughout the 3-Year Study
The horizontal line in the middle of each box indicates the median, the top and bottom borders of the box mark the 75th and 25th percentiles, the whiskers above and bolow the box indicate the 90th and 10th percentiles, and the points beyond the whiskers are outliers beyond the 90th or 10th percentiles.
Figure 3.
Figure 3.. Data Distribution and Change in Total Bone Mineral Density (BMD) and Failure Load During 3 Years of Vitamin D Supplementation
The horizontal line in the middle of each box (left column) indicates the median, the top and bottom borders of the box mark the 75th and 25th percentiles, the whiskers above and bolow the box indicate the 90th and 10th percentiles, and the points beyond the whiskers are outliers beyond the 90th or 10th percentiles. The modeled data (right column) show the mean 95% CIs for the predicted values using the random-effects model. P values indicate the group × time interaction effect.
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References

    1. Macdonald HM, Reid IR, Gamble GD, Fraser WD, Tang JC, Wood AD. 25-Hydroxyvitamin D threshold for the effects of vitamin D supplements on bone densityl. J Bone Miner Res. 2018;33(8):1464-1469. doi:10.1002/jbmr.3442 - DOI - PubMed
    1. Reid IR, Horne AM, Mihov B, et al. . Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial. J Intern Med. 2017;282(5):452-460. doi:10.1111/joim.12651 - DOI - PubMed
    1. Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density. Lancet. 2014;383(9912):146-155. doi:10.1016/S0140-6736(13)61647-5 - DOI - PubMed
    1. Bolland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health. Lancet Diabetes Endocrinol. 2018;6(11):847-858. doi:10.1016/S2213-8587(18)30265-1 - DOI - PubMed
    1. Avenell A, Mak JCS, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev. 2014;39(4):CD000227. doi:10.1002/14651858.CD000227.pub4. - DOI - PMC - PubMed

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