Long-term Supplementation with 3200 to 4000 IU of Vitamin D Daily and Adverse Events: a Systematic Review and Meta-analysis of Randomized Controlled Trials

Overview

Journal Eur J Nutr

Specialty Nutritional Sciences

Date 2023 Feb 28

PMID 36853379

Authors

Armin Zittermann

Christian Trummer

Verena Theiler-Schwetz

Stefan Pilz

Affiliations

Soon will be listed here.

Abstract

Purpose: The upper tolerable intake level for vitamin D in the general population has been set at 4000 international units (IU) daily, but considerable uncertainty remains. We summarized reported harmful effects of a daily vitamin D supplement of 3200-4000 IU in trials lasting ≥ 6 months.

Methods: We performed a systematic review and meta-analysis of randomized controlled trials in several databases and identified 22 trials reporting safety data. Parameters of calcium metabolism, falls, hospitalization, and mortality were assessed.

Results: The selected trials comprised a total number of 12,952 participants. All trials used supplemental vitamin D. The relative risk (RR) of hypercalcemia in the vitamin D vs. control arm was 2.21 (95%CI: 1.26-3.87; 10 studies), with a vitamin D-induced frequency of hypercalcemia of 4 cases per 1000 individuals. Subgroup analysis in trials with > 100 and ≤ 100 study participants revealed an RR of 2.63 (95%CI: 1.30-5.30; 7 studies) and 0.80 (95%CI: 0.24-2.62; 3 studies), respectively (P = 0.06). Risks of falls and hospitalization were also significantly increased in the vitamin D arm with an RR of 1.25 (95%CI: 1.01-1.55; 4 studies) and 1.16 (95%CI: 1.01-1.33; 7 studies), respectively. Risks of hypercalciuria, kidney stones, and mortality did not differ significantly between study arms. Quality assessment revealed high risk of incomplete reporting of safety-related outcome data.

Conclusion: Supplemental vitamin D doses of 3200-4000 IU/d appear to increase the risk of hypercalcemia and some other adverse events in a small proportion of individuals, indicating that this dose is not completely safe. In future studies, rigorous reporting of safety-related outcomes is needed when using moderately high doses of vitamin D.

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References

Zittermann A, Prokop S, Gummert J, Borgermann J . Safety issues of vitamin D supplementation. Anticancer Agents Med Chem. 2012; 13(1):4-10. View

Malihi Z, Wu Z, Lawes C, Scragg R . Adverse events from large dose vitamin D supplementation taken for one year or longer. J Steroid Biochem Mol Biol. 2018; 188:29-37. DOI: 10.1016/j.jsbmb.2018.12.002. View

Bischoff-Ferrari H, Dawson-Hughes B, Orav E, Staehelin H, Meyer O, Theiler R . Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline: A Randomized Clinical Trial. JAMA Intern Med. 2016; 176(2):175-83. DOI: 10.1001/jamainternmed.2015.7148. View

Sanders K, Stuart A, Williamson E, Simpson J, Kotowicz M, Young D . Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010; 303(18):1815-22. DOI: 10.1001/jama.2010.594. View

Ginde A, Blatchford P, Breese K, Zarrabi L, Linnebur S, Wallace J . High-Dose Monthly Vitamin D for Prevention of Acute Respiratory Infection in Older Long-Term Care Residents: A Randomized Clinical Trial. J Am Geriatr Soc. 2016; 65(3):496-503. PMC: 5357189. DOI: 10.1111/jgs.14679. View

Michos E, Kalyani R, Blackford A, Sternberg A, Mitchell C, Juraschek S . The Relationship of Falls With Achieved 25-Hydroxyvitamin D Levels From Vitamin D Supplementation: The STURDY Trial. J Endocr Soc. 2022; 6(6):bvac065. PMC: 9113179. DOI: 10.1210/jendso/bvac065. View

Zittermann A, Ernst J, Prokop S, Fuchs U, Dreier J, Kuhn J . Effect of vitamin D on all-cause mortality in heart failure (EVITA): a 3-year randomized clinical trial with 4000 IU vitamin D daily. Eur Heart J. 2017; 38(29):2279-2286. DOI: 10.1093/eurheartj/ehx235. View

Rooney M, Harnack L, Michos E, Ogilvie R, Sempos C, Lutsey P . Trends in Use of High-Dose Vitamin D Supplements Exceeding 1000 or 4000 International Units Daily, 1999-2014. JAMA. 2017; 317(23):2448-2450. PMC: 5587346. DOI: 10.1001/jama.2017.4392. View

Moher D, Liberati A, Tetzlaff J, Altman D . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009; 151(4):264-9, W64. DOI: 10.7326/0003-4819-151-4-200908180-00135. View

10.

Higgins J, Thompson S . Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11):1539-58. DOI: 10.1002/sim.1186. View

11.

Macaskill P, Walter S, Irwig L . A comparison of methods to detect publication bias in meta-analysis. Stat Med. 2001; 20(4):641-54. DOI: 10.1002/sim.698. View

12.

Hollis B, Johnson D, Hulsey T, Ebeling M, Wagner C . Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011; 26(10):2341-57. PMC: 3183324. DOI: 10.1002/jbmr.463. View

13.

Gallagher J, Sai A, Templin 2nd T, Smith L . Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann Intern Med. 2012; 156(6):425-37. DOI: 10.7326/0003-4819-156-6-201203200-00005. View

14.

Bergman P, Norlin A, Hansen S, Rekha R, Agerberth B, Bjorkhem-Bergman L . Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open. 2012; 2(6). PMC: 3533016. DOI: 10.1136/bmjopen-2012-001663. View

15.

Belenchia A, Tosh A, Hillman L, Peterson C . Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial. Am J Clin Nutr. 2013; 97(4):774-81. DOI: 10.3945/ajcn.112.050013. View

16.

Castro M, King T, Kunselman S, Cabana M, Denlinger L, Holguin F . Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA. 2014; 311(20):2083-91. PMC: 4217655. DOI: 10.1001/jama.2014.5052. View

17.

Arora P, Song Y, Dusek J, Plotnikoff G, Sabatine M, Cheng S . Vitamin D therapy in individuals with prehypertension or hypertension: the DAYLIGHT trial. Circulation. 2014; 131(3):254-62. DOI: 10.1161/CIRCULATIONAHA.114.011732. View

18.

Garg G, Kachhawa G, Ramot R, Khadgawat R, Tandon N, Sreenivas V . Effect of vitamin D supplementation on insulin kinetics and cardiovascular risk factors in polycystic ovarian syndrome: a pilot study. Endocr Connect. 2015; 4(2):108-16. PMC: 4422012. DOI: 10.1530/EC-15-0001. View

19.

Munoz-Aguirre P, Flores M, Macias N, Quezada A, Denova-Gutierrez E, Salmeron J . The effect of vitamin D supplementation on serum lipids in postmenopausal women with diabetes: A randomized controlled trial. Clin Nutr. 2014; 34(5):799-804. DOI: 10.1016/j.clnu.2014.10.002. View

20.

Witte K, Byrom R, Gierula J, Paton M, Jamil H, Lowry J . Effects of Vitamin D on Cardiac Function in Patients With Chronic HF: The VINDICATE Study. J Am Coll Cardiol. 2016; 67(22):2593-603. PMC: 4893154. DOI: 10.1016/j.jacc.2016.03.508. View