Toggle Health Problems and D

Monthly 100,000 IU of vitamin D is safe (and may be better than daily) – RCT Aug 2018

Monthly high-dose vitamin D3 supplementation and self-reported adverse events in a 4-year randomized controlled trial

Clinical Nutrition, DOI: https://doi.org/10.1016/j.clnu.2018.07.034
Zarintaj Malihi, Carlene M.M. Lawes, Zhenqiang Wu, Ying Huang, Debbie Waayer, L. Toop, Kay-Tee Khaw, Carlos A. Camargo Jr., Robert Scragg : r.scragg at auckland.ac.nz

 Download the PDF from Sci-Hub via VitaminDWiki

Background: The use of high-dose vitamin D supplementation has increased in recent years. However, relatively little is known about the safety of long-term high doses.

Aims: To investigate the safety of a monthly high-dose of vitamin D3 supplementation taken for up to 4 years.

Data were collected in a randomized, double blind, placebo-controlled trial of 5108 adults aged 50–84 years old from Auckland, New Zealand. Participants were given monthly doses of 100,000 IU vitamin D3 or placebo, for a median of 3.3 years (range 2.5–4.2 years). They answered an open-ended question in a monthly questionnaire about any adverse events they attributed to the study capsules, which were coded blindly. Incidence rates per person months were calculated for categories of adverse events. Cox regression model used to calculate hazard ratio of time to first adverse-event.

In total, 419 (16.5%) participants taking vitamin D and 399 (15.8%) taking placebo reported ≥1 adverse event. Compared to placebo, the hazard ratio (HR) of reporting first adverse event in the vitamin D group was 1.03 (95% CI: 0.90, 1.18; p = 0.63). Despite a slightly higher incidence of recurrent adverse events in vitamin D arm, the incidence rate ratio (1.17) was not significantly higher in vitamin D (95% CI: 0.97, 1.41; p = 0.10). All regression results were adjusted for age, sex, and ethnicity. There was no difference between study arms in terms of participants’ allocation perception (p = 0.52).

Monthly supplementation of 100,000 IU vitamin D3 for a median of 3.3 years did not affect participant-reported adverse events.



  • Ross AC, Taylor CL, Yaktine AL, Valle HB Del. Dietary reference intakes for calcium and vitamin D. Washington, D.C (US): National Academies Press (US); 2011.
  • Tellioglu A, Basaran S, Guzel R, Seydaoglu G. Efficacy and safety of high dose intramuscular or oral cholecalciferol in vitamin D deficient/insufficient elderly. Maturitas 2012;72:332—8. https://doi.org/10.1016/j.maturitas.2012.04.011.
  • Martineau AR, Timms PM, Bothamley GH, Hanifa Y, Islam K, Claxton AP, et al. High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 2011;377:242—50. https://doi.org/10.1016/S01406736(10)61889-2.
  • Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010;303:1815—22. https://doi.org/10.1001/jama.2010.594.
  • Kearns MD, Binongo JNG, Watson D, Alvarez JA, Lodin D, Ziegler TR, et al. The effect of a single, large bolus of vitamin D in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial. Eur J Clin Nutr 2015;69:193—7. https://doi.org/10.1038/ejcn.2014.209.
  • Grossmann RE, Zughaier SM, Kumari M, Seydafkan S, Lyles RH, Liu S, et al. Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial. Derm Endocrinol 2012;4:191—7. https://doi.org/10.4161/derm.20332.
  • Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C. Effect of annual intramuscular vitamin D on fracture risk in elderly men and women-a population-based, randomized, double-blind, placebo-controlled trial. Rheumatology (Oxford) 2007;46:1852—7. https://doi.org/10.1093/rheumatology/kem240.
  • Khaw K, Stewart AW, Waayer D, Lawes CMM, Toop L, Camargo CA, et al. Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures : secondary and post-hoc outcomes from the randomised , doubleblind ,placebo-controlled ViDA trial. Lancet Diabetes Endocrinol 2017;8587: 1—10. https://doi.org/10.1016/S2213-8587(17)30103-1.
  • Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D 3 (chole- calciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326:469.
  • Rosjo E, Lossius A, Abdelmagid N, Lindstrom JC, Kampman MT, Jorgensen L, et al. Effect of high-dose Vitamin D3 supplementation on antibody responses against Epstein-Barr virus in relapsing-remitting multiple sclerosis. Mult Scler 2017;23:395—402. https://doi.org/10.1177/1352458516654310.
  • Narula N, Cooray M, Anglin R, Muqtadir Z, Narula A, Marshall JK. Impact of high-dose vitamin D3 supplementation in patients with Crohn's disease in remission: a pilot randomized double-blind controlled study. Dig Dis Sci 2017;62:448—55. https://doi.org/10.1007/s10620-016-4396-7.
  • Irani M, Seifer DB, Grazi RV, Irani S, Rosenwaks Z, Tal R. Vitamin D decreases serum VEGF correlating with clinical improvement in vitamin d-deficient women with PCOS: a randomized placebo-controlled trial. Nutrients 2017;9. https://doi.org/10.3390/nu9040334.
  • Mazahery H, Stonehouse W, von Hurst PR. The effect of monthly 50 000 IU or 100 000 IU vitamin D supplements on vitamin D status in premenopausal Middle Eastern women living in Auckland. Eur J Clin Nutr 2015;69:367—72. https://doi.org/10.1038/ejcn.2014.264.
  • Valimaki V-V, Loyttyniemi E, Pekkarinen T, Valimaki MJ. How well are the optimal serum 25OHD concentrations reached in high-dose intermittent vitamin D therapy? a placebo-controlled study on comparison between 100 000 IU and 200 000 IU of oral D 3 every 3 months in elderly women. Clin Endocrinol 2016;84:837—44. https://doi.org/10.1111/cen.13014.
  • Martineau a R, Hanifa Y, Witt KD, Barnes NC, Hooper RL, Patel M, et al. Doubleblind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). Thorax 2015;25:1—8. https://doi.org/10.1136/thoraxjnl-2015-206996.
  • Martineau AR, James WY, Hooper RL, Barnes NC, Jolliffe DA, Greiller CL, et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. Lancet Respir Med 2015;3:120—30. https://doi.org/10.1016/S2213-2600(14)70255-3.
  • Martineau AR, MacLaughlin BD, Hooper RL, Barnes NC, Jolliffe DA, Greiller CL, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax 2015;70:451—7. https://doi.org/10.1136/thoraxjnl-2014-206449.
  • Daley P, Jagannathan V, John KR, SarojiniJ, Latha A, Vieth R, et al. Adjunctive vitamin D for treatment of active tuberculosis in India: a randomised, doubleblind, placebo-controlled trial. Lancet Infect Dis 2015;15:528—34. https://doi.org/10.1016/S1473-3099(15)70053-8.
  • Steffensen LH, Brustad M, Kampman MT. What is needed to keep persons with multiple sclerosis vitamin D-sufficient throughout the year? J Neurol 2013;260:182—8. https://doi.org/10.1007/s00415-012-6611-6.
  • Vos R, Ruttens D, Verleden SE, Vandermeulen E, Bellon H, Herck A Van, et al. High-dose vitamin D after lung transplantation: a randomized trial. J Heart Lung Transplant 2017;36:897—905. https://doi.org/10.1016Zj.healun.2017.03.008.
  • Jorde R, Sollid ST, Svartberg J, Schirmer H, Joakimsen RM, Njolstad I, et al. Vitamin D 20,000 IU per Week for Five Years Does Not Prevent Progression From Prediabetes to Diabetes. J Clin Endocrinol Metab 2016;101:1647—55.
  • Steffensen LH, Jorgensen L, Straume B, Mellgren SI, Kampman MT. Can vitamin D3 supplementation prevent bone loss in persons with MS? A placebo-controlled trial. J Neurol 2011;258:1624—31. https://doi.org/10.1007/s00415-011-5980-6.
  • Scragg R, Waayer D, Stewart AW, Lawes CMM, Toop L, Murphy J, et al. The Vitamin D Assessment (ViDA) Study: design of a randomized controlled trial of vitamin D supplementation for the prevention of cardiovascular disease, acute respiratory infection, falls and non-vertebral fractures. J SteroidBiochem Mol Biol 2016;164:318—25. https://doi.org/10.1016/j.jsbmb.2015.09.010.
  • Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J, et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment Study : a randomized clinical trial. JAMA Cardiol 2017;2:608—16. https://doi.org/10.1001/jamacardio.2017.0175.
  • Sachs MC, Shoben A, Levin GP, Robinson-Cohen C, Hoofnagle AN, Swords- Jenny N, et al. Estimating mean annual 25-hydroxyvitamin D concentrations from single measurements: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr 2013;97:1243—51. https://doi.org/10.3945/ajcn.112.054502.
  • Sanders KM, Stuart AL, Williamson EJ, Jacka FN, Dodd S, Nicholson G, et al.
  • Annual high-dose vitamin D3 and mental well-being: randomised controlled trial. Br J Psychiatry 2011;198:357—64. https://doi.org/10.1192/bjp.bp.110.087544.
  • Jin X, Jones G, Cicuttini F, Al E. Effect of vitamin d supplementation on tibial cartilage volume and knee pain among patients with symptomatic knee osteoarthritis: a randomized clinical trial. J Am Med Assoc 2016;315: 1005—13.
  • Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669—83. https://doi.org/10.1056/NEJMoa055218.
  • Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005;365: 1621—8. https://doi.org/10.1016/S0140-6736(05)63013-9.
  • Malihi Z, Wu Z, Mm Lawes C, Scragg R. Noncalcemic adverse effects and withdrawals in randomized controlled trials of long-term vitamin D2 or D3 supplementation: a systematic review and meta-analysis. Nutr Rev 2017;75: 1007—34. https://doi.org/10.1093/nutrit/nux059.
  • Bergman P, Norlin A-C, Hansen S, Rekha RS, AgerberthB, Bjorkhem-BergmanL, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open 2012;2:e001663. https://doi.org/10.1136/bmjopen-2012-001663.
  • Khaw KT, Stewart AW, Waayer D, Lawes CMM, Toop L, Camargo CA, et al. Effect of monthly high-dose vitamin D supplementation on falls and non- vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial. Lancet Diabetes Endocrinol 2017. https://doi.org/10.1016/S2213-8587%2817%2930103-1 (no pagina.
  • Jorde R, Sollid ST, Svartberg J, Joakimsen RM, Grimnes G, Hutchinson MYS. Prevention of urinary tract infections with vitamin D supplementation 20,000IU per week for five years. Results from an RCT including 511 subjects. Infect Dis (Auckl) 2016;48:823—8.
  • Sadiya A, Ahmed SM, Carlsson M, Tesfa Y, George M, Ali SH, et al. Vitamin D supplementation in obese type 2 diabetes subjects in Ajman, UAE: a randomized controlled double-blinded clinical trial. Eur J Clin Nutr 2015;69: 707—11. https://doi.org/10.1038/ejcn.2014.251.
  • Courbebaisse M, Alberti C, Colas S, Prie D, Souberbielle J-C, Treluyer J-M, et al. VITamin D supplementation in renAL transplant recipients (VITALE): a prospective, multicentre, double-blind, randomized trial of vitamin D estimating the benefit and safety of vitamin D3 treatment at a dose of 100,000 UI compared with a dose of 12,000 UI. Trials 2014;15:430. https://doi.org/10.1186/1745-6215-15-430.
  • Neale RE, Armstrong BK, Baxter C, Duarte Romero B, Ebeling P, English DR, et al. The D-Health Trial: a randomized trial of vitamin D for prevention of mortality and cancer. Contemp Clin Trials 2016;48:83—90. https://doi.org/10.1016/j.cct.2016.04.005.

Created by admin. Last Modification: Monday June 28, 2021 10:44:52 GMT-0000 by admin. (Version 13)

Attached files

ID Name Comment Uploaded Size Downloads
13562 Monthly Carm.pdf admin 01 Mar, 2020 676.32 Kb 674