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Epidemiology

Vitamin D supplementation and total cancer incidence and mortality by daily vs. infrequent large-bolus dosing strategies: a meta-analysis of randomised controlled trials

British Journal of Cancer volume 127, pages 872–878 (2022)Cite this article

Subjects

Abstract

Background

Efficacy of vitamin D supplementation may vary by dosing strategies and adiposity. To address such heterogeneity, we performed a meta-analysis of randomised controlled trials of vitamin D supplementation and total cancer outcomes.

Methods

PubMed and Embase were searched through January 2022. Summary relative risk (SRR) and 95% confidence interval (CI) were estimated using the DerSimonian–Laird random-effects model.

Results

For total cancer incidence (12 trials), the SRR for vitamin D supplementation vs. control group was 0.99 (95% CI, 0.94–1.03; P = 0.54; I2 = 0%). No significant association was observed regardless of whether the supplement was given daily or infrequently in a large-bolus. Yet, among trials testing daily supplementation, a significant inverse association was observed among normal-weight individuals (SRR, 0.76; 95% CI, 0.64–0.90; P = 0.001, I2 = 0%), but not among overweight or obese individuals (Pheterogeneity = 0.02). For total cancer mortality (six trials), the SRR was 0.92 (95% CI, 0.82–1.03; P = 0.17; I2 = 33%). A significant inverse association emerged (SRR, 0.87; 95% CI, 0.78–0.96; P = 0.007; I2 = 0%) among studies testing daily supplementations but not among studies that testing infrequent large-bolus supplementations (Pheterogeneity = 0.09).

Conclusions

For vitamin D supplementation, daily dosing, but not infrequent large-bolus dosing, reduced total cancer mortality. For total cancer incidence, bolus dosing did not reduce the risk and the benefits of daily dosing were limited to normal-weight individuals.

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Fig. 1
Fig. 2: Forest plots for subgroup meta-analyses of vitamin D supplementation and total cancer incidence.
Fig. 3: Forest plots for subgroup meta-analyses of vitamin D supplementation and total cancer mortality.

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Data availability

The data used for this meta-analysis were extracted from the articles, which were retrieved from the online databases PubMed and Embase.

References

  1. Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ, et al. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer. 2011;128:1414–24.

    Article  CAS  PubMed  Google Scholar 

  2. Li M, Chen P, Li J, Chu R, Xie D, Wang H. Review: the impacts of circulating 25-hydroxyvitamin D levels on cancer patient outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99:2327–36.

    Article  CAS  PubMed  Google Scholar 

  3. He Y, Timofeeva M, Farrington SM, Vaughan-Shaw P, Svinti V, Walker M, et al. Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study. BMC Med. 2018;16:142.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Ong JS, Gharahkhani P, An J, Law MH, Whiteman DC, Neale RE, et al. Vitamin D and overall cancer risk and cancer mortality: a Mendelian randomization study. Hum Mol Genet. 2018;27:4315–22.

    CAS  PubMed  Google Scholar 

  5. Ong JS, Dixon-Suen SC, Han X, An J, Liyanage U, Dusingize JC, et al. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization. Nat Commun. 2021;12:246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Afzal S, Brøndum-Jacobsen P, Bojesen SE, Nordestgaard BG. Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts. BMJ. 2014;349:g6330.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Calderwood AH, Baron JA, Mott LA, Ahnen DJ, Bostick RM, Figueiredo JC, et al. No Evidence for posttreatment effects of vitamin D and calcium supplementation on risk of colorectal adenomas in a randomized trial. Cancer Prev Res. 2019;12:295–304.

    Article  CAS  Google Scholar 

  8. Jorde R, Sollid ST, Svartberg J, Schirmer H, Joakimsen RM, Njølstad 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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. J. Am Med Assoc. 2010;303:1815–22.

    Article  CAS  Google Scholar 

  10. Haykal T, Samji V, Zayed Y, Gakhal I, Dhillon H, Kheiri B, et al. The role of vitamin D supplementation for primary prevention of cancer: meta-analysis of randomized controlled trials. J Community Hosp Intern Med Perspect. 2019;9:480–8.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Keum N, Lee DH, Greenwood DC, Manson JE, Giovannucci E. Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials. Ann Oncol. 2019;30:733–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang Y, Fang F, Tang J, Jia L, Feng Y, Xu P, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ. 2019;366:l4673.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hollis BW, Wagner CL. Clinical review: The role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab. 2013;98:4619–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mazess RB, Bischoff-Ferrari HA, Dawson-Hughes B. Vitamin D: bolus is bogus—a narrative review. JBMR. 2021;5:e10567.

    CAS  Google Scholar 

  15. Pourshahidi LK. Vitamin D and obesity: current perspectives and future directions. Proc Nutr Soc. 2015;74:115–24.

    Article  CAS  PubMed  Google Scholar 

  16. Lotito A, Teramoto M, Cheung M, Becker K, Sukumar D. Serum parathyroid hormone responses to vitamin D supplementation in overweight/obese adults: a systematic review and meta-analysis of randomized clinical trials. Nutrients. 2017;9:241.

  17. Kim H, Chandler P, Ng K, Manson JE, Giovannucci E. Obesity and efficacy of vitamin D(3) supplementation in healthy black adults. Cancer Causes Control. 2020;31:303–7.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842–56.

    Article  CAS  PubMed  Google Scholar 

  20. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  21. Chao YS, Brunel L, Faris P, Veugelers PJ. The importance of dose, frequency and duration of vitamin D supplementation for plasma 25-hydroxyvitamin D. Nutrients. 2013;5:4067–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Dalle Carbonare L, Valenti MT, Del Forno F, Caneva E, Pietrobelli A. Vitamin D: daily vs. monthly use in children and elderly-what is going on? Nutrients. 2017;9:652.

  23. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. LaCroix AZ, Kotchen J, Anderson G, Brzyski R, Cauley JA, Cummings SR, et al. Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci. 2009;64:559–67.

    Article  PubMed  CAS  Google Scholar 

  25. Lappe J, Watson P, Travers-Gustafson D, Recker R, Garland C, Gorham E, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. J Am Med Assoc. 2017;317:1234–43.

    Article  CAS  Google Scholar 

  26. Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N. Engl J Med. 2006;354:684–96.

    Article  CAS  PubMed  Google Scholar 

  27. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

    Article  PubMed  Google Scholar 

  28. Cashman KD, van den Heuvel EG, Schoemaker RJ, Prévéraud DP, Macdonald HM, Arcot J. 25-Hydroxyvitamin D as a biomarker of vitamin D status and its modeling to inform strategies for prevention of vitamin D deficiency within the population. Adv Nutr. 2017;8:947–57.

  29. Chandler PD, Chen WY, Ajala ON, Hazra A, Cook N, Bubes V, et al. Effect of vitamin D3 supplements on development of advanced cancer: a secondary analysis of the VITAL randomized clinical trial. JAMA Netw Open. 2020;3:e2025850.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chatterjee R, Fuss P, Vickery EM, LeBlanc ES, Sheehan PR, Lewis MR, et al. Vitamin D supplementation for prevention of cancer: the D2d cancer outcomes (D2dCA) ancillary study. J Clin Endocrinol Metab. 2021;106:2767–78.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N. Engl J Med. 2019;380:33–44.

    Article  CAS  PubMed  Google Scholar 

  32. Neale RE, Baxter C, Romero BD, McLeod DSA, English DR, Armstrong BK, et al. The D-Health trial: a randomised controlled trial of the effect of vitamin D on mortality. Lancet Diabetes Endocrinol. 2022;10:120–8.

    Article  CAS  PubMed  Google Scholar 

  33. Virtanen JK, Nurmi T, Aro A, Bertone-Johnson ER, Hyppönen E, Kröger H, et al. Vitamin D supplementation and prevention of cardiovascular disease and cancer in the Finnish Vitamin D Trial-a randomized controlled trial. Am J Clin Nutr. 2022;115:1300–10.

  34. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586–91.

    Article  CAS  PubMed  Google Scholar 

  35. Avenell A, MacLennan GS, Jenkinson DJ, McPherson GC, McDonald AM, Pant PR, et al. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial). J Clin Endocrinol Metab. 2012;97:614–22.

    Article  CAS  PubMed  Google Scholar 

  36. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003;326:469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Scragg R, Khaw KT, Toop L, Sluyter J, Lawes CMM, Waayer D, et al. Monthly high-dose vitamin D supplementation and cancer risk: a post hoc analysis of the vitamin d assessment randomized clinical trial. JAMA Oncol. 2018;4:e182178.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Dusso AS. Kidney disease and vitamin D levels: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and VDR activation. Kidney Int Suppl. 2011;1:136–41.

    Article  CAS  Google Scholar 

  39. Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, et al. Vitamin D supplementation and prevention of type 2 diabetes. N. Engl J Med. 2019;381:520–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Barbarawi M, Zayed Y, Barbarawi O, Bala A, Alabdouh A, Gakhal I, et al. Effect of Vitamin D supplementation on the incidence of diabetes mellitus. J Clin Endocrinol Metab. 2020;105:2857–68.

  41. Hahn J, Cook NR, Alexander EK, Friedman S, Walter J, Bubes V, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ. 2022;376:e066452-e.

    Article  Google Scholar 

  42. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72:690–3.

    Article  CAS  PubMed  Google Scholar 

  43. Mendes MM, Hart KH, Lanham-New SA, Botelho PB. Suppression of parathyroid hormone as a proxy for optimal vitamin D status: further analysis of two parallel studies in opposite latitudes. Nutrients. 2020;12:942.

  44. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132:2169–80.

    Article  CAS  PubMed  Google Scholar 

  45. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Han J, Guo X, Yu X, Liu S, Cui X, Zhang B, et al. 25-Hydroxyvitamin D and total cancer incidence and mortality: a meta-analysis of prospective cohort studies. Nutrients. 2019;11:2295.

    Article  CAS  PubMed Central  Google Scholar 

  47. Grant WB, Al Anouti F, Boucher BJ, Dursun E, Gezen-Ak D, Jude EB, et al. A narrative review of the evidence for variations in serum 25-hydroxyvitamin D concentration thresholds for optimal health. Nutrients. 2022;14:639.

  48. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–30.

    Article  CAS  PubMed  Google Scholar 

  49. Sempos CT, Binkley N. 25-Hydroxyvitamin D assay standardisation and vitamin D guidelines paralysis. Public Health Nutr. 2020;23:1153–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tawfik GM, Giang HTN, Ghozy S, Altibi AM, Kandil H, Le H-H, et al. Protocol registration issues of systematic review and meta-analysis studies: a survey of global researchers. BMC Med Res Methodol. 2020;20:213.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Niedermaier T, Gredner T, Kuznia S, Schöttker B, Mons U, Brenner H. Vitamin D supplementation to the older adult population in Germany has the cost-saving potential of preventing almost 30 000 cancer deaths per year. Mol Oncol. 2021;15:1986–94.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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Funding

NK and QYC were supported by the BK21-plus education programme funding from the National Research Foundation of Korea. JEM is supported by R01 AT 011729 and R01 HL34594.

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Authors and Affiliations

  1. Department of Food Science and Biotechnology, Dongguk University, Goyang, South Korea

    N. Keum & Q-Y. Chen

  2. Departments of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA

    N. Keum, D. H. Lee & E. Giovannucci

  3. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    J. E. Manson

  4. Departments of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA

    J. E. Manson & E. Giovannucci

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NK collected, analysed and interpreted the data, and drafted the manuscript. QYC collected and analysed the data, and drafted the manuscript. DL, JEM and EG interpreted the date and drafted the manuscript.

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Keum, N., Chen, QY., Lee, D.H. et al. Vitamin D supplementation and total cancer incidence and mortality by daily vs. infrequent large-bolus dosing strategies: a meta-analysis of randomised controlled trials. Br J Cancer 127, 872–878 (2022). https://doi.org/10.1038/s41416-022-01850-2

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