Burt LA, Billington EO, Rose MS, et al. Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. JAMA. 2019 Aug 27;322(8):736-745. doi: 10.1001/jama.2019.11889. (Original study)

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.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Rheumatology 6 / 7
Public Health 6 / 7
Geriatrics 6 / 7
Surgery - Orthopaedics 6 / 7
Endocrine 5 / 7
Comments from MORE raters

Endocrine rater

This study seems deeply flawed and is potentially misleading. This includes degraded supplements and patients were not vitamin D deficient. Further, the result is not biologically plausible.

Endocrine rater

This is important information since vitamin D3 supplementation is widely advertised without having enough evidence. This study shows that it may even be harmful.

General Internal Medicine-Primary Care(US) rater

I think this is an important message to get out there since providers are being pushed constantly to give more.

General Internal Medicine-Primary Care(US) rater

A surprising result.

General Internal Medicine-Primary Care(US) rater

This important study demonstrates potential harms of too much of a good thing, so it may be difficult to repeat this study of very high-dose vitamin D.

Geriatrics rater

Although recent systematic reviews and public health publications highlight that Vitamin D supplementation in otherwise healthy older adults cannot be supported by research, many physicians providing care for older adults likely remain unaware of this evolving bone health story.

Public Health rater

Interestingly, this trial showed that higher doses of vitamin D were associated with poorer bone density in normal people. Unfortunately, it gives us no information on Vitamin D supplementation vs no supplementation in an at-risk cohort.

Surgery - Orthopaedics rater

The study showed no benefit. The paper is very important in this era of extensive abuse of vitamins and supplements.
Comments from EvidenceAlerts subscribers

Mr. Eduard Bokan (10/1/2019 4:18 PM)

Very puzzling that they did not include vit D-deficient patients in their study.

Ms. Franka Steenhuis (10/1/2019 11:31 AM)

Seems likely those 3% who take such a high dosage of vitamin D take vitamin K as well. Very trendy :-) If you fight osteoporosis, you don't just take your pharmacotherapy (be it alendronate or vitamin D), you do your appropriate (and trendy) weight-bearing exercises, too. Would it have been a better idea to incorporate both vitamin K and exercise in such a trial?