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Summary

Vitamin D is essential for optimal musculoskeletal health because it promotes calcium absorption, mineralization of osteoid tissue formation in bones, and the maintenance of muscle function [1]. Vitamin D supplementation has been considered beneficial for the prevention and treatment of osteoporosis. Burt et al. [2], conducted a 3-year, double-blind, randomized clinical trial. The dose-response effects of daily vitamin D supplementation (400, 4,000, 10,000 IU) on total volumetric bone mineral density (BMD) and bone strength in 287 healthy older adults (55 to 77 years) were explored. It was hypothesized that a higher dose of vitamin D would have a positive effect on HR-pQCT measurements of volumetric density and strength at the distal radius and tibia. At the end of the trial, the radial volumetric BMD was lower for the 4,000 IU group and the 10,000 IU group compared to the 400 IU group. Differences in tibial volumetric BMD in the 400 IU group were −1.8 mg HA/cm3 in the 4,000 IU group and −4.1 mg HA/cm3 in the 10,000 IU group (95% CI, – 6.0 to -2.2). The researchers conclude that among healthy adults, vitamin D treatment for 3 years at a dose of 4,000 IU or 10,000 IU per day, compared to 400 IU per day, resulted in a statistically significant lower radial BMD; and tibial BMD was significantly lower only with the 10,000 IU per day dose. Significant differences weren’t found in bone strength or radius or tibia. Therefore, high-dose vitamin D supplementation shows no benefit and further studies are required to determine if it is harmful.

Commentary

In this commented study, the authors reviewed the dose-response effects of daily vitamin D supplementation (400, 4,000, 10,000 IU) on total volumetric BMD and bone strength in healthy subjects [2] aged 55 to 70 years, without any osteoporosis background and with baseline 25-hydroxyvitamin D (25[OH]D) levels of 30 to 125 nmol/L. Some results of the study were as follows: supplementation with high doses of vitamin D (10,000 IU/day) was associated with a significantly higher bone loss, and episodes of hypercalcaemia and hypercalciuria and were more common when increasing vitamin D dosage. At the end of the study the authors concluded that among healthy adults, treatment with vitamin D for 3 years at a dose of 4,000 IU per day or 10,000 IU per day, compared to 400 IU per day, resulted in a statistically significant lower radial BMD and tibial BMD was significantly lower only with the 10,000 IU daily dose. There were no significant differences in bone strength or radius or tibia. These findings suggest that there is no benefit of high-dose vitamin D supplementation for bone health, a finding that has been evidenced in other studies such as the clinical trial by Burt et al [3], which was designed to investigate the effects of daily supplementation of vitamin D in high doses on bone density and strength. In this prior study they suggested that supplementation with vitamin D in healthy women at a dose of 4,000 IU or 10,000 IU per day, compared to 400 IU per day, resulted in higher TtBMD and CtBMD losses over 3 years, these findings do not support a benefit of high-dose vitamin D supplementation for bone health and increase the possibility of harm in women [4].

In different reviews it has been shown that randomized controlled trials, with 800 IU/day of vitamin D, the levels of 25[OH]D reach the threshold of sufficiency of 50 nmol/L, being safe and effective levels in correcting insufficient levels of vitamin D [5]. Due to their potential harm, higher doses administered in long-term or in intermittent regimens should not be performed. The clinical expression of vitamin D overdose includes hypercalcemia, hypercalciuria, and mineral deposits in soft tissues [5].

In conclusion, vitamin D supplementation is recommended due to their beneficial effects for the prevention and treatment of osteoporosis, however, in high doses an additional benefit on bone health has not been found and on the contrary adverse effects have been suggested. There is need for more studies to evidence the effectiveness/risk of high doses of vitamin D3 supplementation.

Camilo Rueda, MD
Universidad de la Sabana, Chía, Colombia
Clínica del Country-La Colina
Bogotá, Colombia

Diana M. Hoyos-Guerrero, MD
Universidad de la Sabana, Clínica Universidad de La Sabana
Chía, Colombia

References

  1. Yao P, Bennett D, Mafham M, et al. Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis. JAMA Netw Open. 2019;2(12):e1917789.
    https://pubmed.ncbi.nlm.nih.gov/31860103/
  2. Burt LA, Billington EO, Rose MS, Raymond DA, Hanley DA, Boyd SK. Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. JAMA. 2019;322(8):736-745.
    https://pubmed.ncbi.nlm.nih.gov/31454046/
  3. Burt LA, Gaudet S, Kan M, et al. Methods and procedures for: A randomized double-blind study investigating dose-dependent longitudinal effects of vitamin D supplementation on bone health. Contemp Clin Trials. 2018;67:68-73.
    https://pubmed.ncbi.nlm.nih.gov/29471124/
  4. Burt LA, Billington EO, Rose MS, Kremer R, Hanley DA, Boyd SK. Adverse Effects of High-Dose Vitamin D Supplementation on Volumetric Bone Density Are Greater in Females than Males. J Bone Miner Res. 2020;35(12):2404-2414.
    https://pubmed.ncbi.nlm.nih.gov/32777104/
  5. Rizzoli R. Vitamin D supplementation: upper limit for safety revisited? Aging Clin Exp Res. 2021;33(1):19-24.
    https://pubmed.ncbi.nlm.nih.gov/32857334/

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