Randomized Clinical Trials of Vitamin D for the Primary Prevention of Cancer and Cardiovascular Disease With a Focus on the VITamin D and OmegA-3 TriaL (VITAL)

Vitamin D: Health, Disease and Therapeutics, Fourth Edition: Volume 2

Volumn 2, Issue , 2017, Pages 167-176

  Bassuk, Shari S ^a   Manson, JoAnn E ^a,b  

^a HARVARD MEDICAL SCHOOL   (United States)

^b HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

Author keywords

Cancer; Cardiovascular disease; Cholecalciferol; Marine omega 3 fatty acids; Primary prevention; Randomized controlled trial; Vitamin D

Indexed keywords

EID: 85054947070     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1016/B978-0-12-809963-6.00066-3     Document Type: Chapter

References (64)

1. Institute of Medicine (2011) Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press
2. K. Greider (July 5, 2012) Has vitamin D been oversold? AARP Bull http://www.aarp.org/health/drugs-supplements/info-07-2012/how-much-vitamin-d-is-enough.1.html Available at
3. K. Kupferschmidt (2012) Uncertain verdict as vitamin D goes on trial. Science 337 1476-1478.
4. J.E. Manson, S.S. Bassuk, I.M. Lee, N.R. Cook, M.A. Albert, D. Gordon, E. Zaharris, J.G. Macfadyen, E. Danielson, J. Lin, S.M. Zhang and J.E. Buring (2012) The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials 33 159-171.
5. V.A. Moyer (2014) Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 160 558-564.
6. J.E. Manson and S.S. Bassuk (2015) Vitamin D research and clinical practice: at a crossroads. JAMA 313 1311-1312.
7. D.P. Trivedi, R. Doll and K.T. Khaw (2003) 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 326 469.
8. J.M. Lappe, D. Travers-Gustafson, K.M. Davies, R.R. Recker and R.P. Heaney (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85 1586-1591.
9. J.M. Lappe and R.P. Heaney (2008) Calcium supplementation: results may not be generalisable. BMJ 336 403. author reply 404
10. J. Wactawski-Wende, J.M. Kotchen, G.L. Anderson, A.R. Assaf, R.L. Brunner, M.J. O’Sullivan, K.L. Margolis, J.K. Ockene, L. Phillips, L. Pottern, R.L. Prentice, J. Robbins, T.E. Rohan, G.E. Sarto, S. Sharma, M.L. Stefanick, L. Van Horn, R.B. Wallace, E. Whitlock, T. Bassford, S.A. Beresford, H.R. Black, D.E. Bonds, R.G. Brzyski, B. Caan, R.T. Chlebowski, B. Cochrane, C. Garland, M. Gass, J. Hays, G. Heiss, S.L. Hendrix, B.V. Howard, J. Hsia, F.A. Hubbell, R.D. Jackson, K.C. Johnson, H. Judd, C.L. Kooperberg, L.H. Kuller, A.Z. LaCroix, D.S. Lane, R.D. Langer, N.L. Lasser, C.E. Lewis, M.C. Limacher and J.E. Manson (2006) Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 354 684-696.
11. R.D. Jackson, A.Z. LaCroix, M. Gass, R.B. Wallace, J. Robbins, C.E. Lewis, T. Bassford, S.A. Beresford, H.R. Black, P. Blanchette, D.E. Bonds, R.L. Brunner, R.G. Brzyski, B. Caan, J.A. Cauley, R.T. Chlebowski, S.R. Cummings, I. Granek, J. Hays, G. Heiss, S.L. Hendrix, B.V. Howard, J. Hsia, F.A. Hubbell, K.C. Johnson, H. Judd, J.M. Kotchen, L.H. Kuller, R.D. Langer, N.L. Lasser, M.C. Limacher, S. Ludlam, J.E. Manson, K.L. Margolis, J. McGowan, J.K. Ockene, M.J. O’Sullivan, L. Phillips, R.L. Prentice, G.E. Sarto, M.L. Stefanick, L. Van Horn, J. Wactawski-Wende, E. Whitlock, G.L. Anderson, A.R. Assaf and D. Barad (2006) Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 354 669-683.
12. R.T. Chlebowski, K.C. Johnson, C. Kooperberg, M. Pettinger, J. Wactawski-Wende, T. Rohan, J. Rossouw, D. Lane, M.J. O’Sullivan, S. Yasmeen, R.A. Hiatt, J.M. Shikany, M. Vitolins, J. Khandekar and F.A. Hubbell (2008) Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 100 1581-1591.
13. A. Avenell, G.S. MacLennan, D.J. Jenkinson, G.C. McPherson, A.M. McDonald, P.R. Pant, A.M. Grant, M.K. Campbell, F.H. Anderson, C. Cooper, R.M. Francis, W.J. Gillespie, C.M. Robinson, D.J. Torgerson and W.A. Wallace (2012) Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D3 and/or calcium (RECORD trial). J Clin Endocrinol Metab 97 614-622.
14. M. Chung, E.M. Balk, M. Brendel, S. Ip, J. Lau, J. Lee, A. Lichtenstein, K. Patel, G. Raman, A. Tatsioni, T. Terasawa and T.A. Trickalinos (2009) Vitamin D and calcium: a systematic review of health outcomes. Evidence Report No. 183 (prepared by the Tufts Evidence-based Practice Center under Contract No. HHSA 290-2007-10055-I). AHRQ publication No. 09-E015. Rockville, MD: Agency for Healthcare Research and Quality http://www.ahrq.gov/downloads/pub/evidence/pdf/vitadcal/vitadcal.pdf Available at
15. M.B. Elamin, N.O. Abu Elnour, K.B. Elamin, M.M. Fatourechi, A.A. Alkatib, J.P. Almandoz, H. Liu, M.A. Lane, R.J. Mullan, A. Hazem, P.J. Erwin, D.D. Hensrud, M.H. Murad and V.M. Montori (2011) Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab 96 1931-1942.
16. N. Keum and E. Giovannucci (2014) Vitamin D supplements and cancer incidence and mortality: a meta-analysis. Br J Cancer 111 976-980.
17. E. Theodoratou, I. Tzoulaki, L. Zgaga and J.P. Ioannidis (2014) Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ 348 g2035.
18. P. Welsh and N. Sattar (2014) Vitamin D and chronic disease prevention. BMJ 348 g2280.
19. G. Bjelakovic, L.L. Gluud, D. Nikolova, K. Whitfield, G. Krstic, J. Wetterslev and C. Gluud (2014) Vitamin D supplementation for prevention of cancer in adults. Cochrane Database Syst Rev 6 CD007469.
20. R.E. Neale, B.K. Armstrong, C. Baxter, C. Duarte Romero, C. Ebeling, D.R. English, M.G. Kimlin, D.S. McLeod, R.L. OConnell, J.C. van der Pols, A.J. Venn, P.M. Webb, D.C. Whiteman and L. Wockner (2016) The D-Health Trial: a randomized trial of vitamin D for prevention of mortality and cancer. Contemp Clin Trials 48 83-90.
21. Peto J. Vitamin D and Longevity (VIDAL) trial – randomised feasibility study. National Institute for Health Research. Available at: http://www.nets.nihr.ac.uk/projects/hta/0811648.
22. S.S. Bassuk, J.E. Manson, I.M. Lee, N.R. Cook, W.G. Christen, V.Y. Bubes, D.S. Gordon, T. Copeland, G. Friedenberg, D.M. D’Agostino, C.Y. Ridge, J.G. MacFadyen, K. Kalan and J.E. Buring (2016) Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL). Contemp Clin Trials 47 235-243.
23. S.S. Harris (2006) Vitamin D and African Americans. J Nutr 136 1126-1129.
24. C.E. Moore, M.M. Murphy and M.F. Holick (2005) Vitamin D intakes by children and adults in the United States differ among ethnic groups. J Nutr 135 2478-2485.
25. S.S. Harris (2011) Does vitamin D deficiency contribute to increased rates of cardiovascular disease and type 2 diabetes in African Americans? Am J Clin Nutr 93 1175S-1178S.
26. American Cancer Society (2009-2010) Cancer facts & figures for African Americans. Atlanta: American Cancer Society
27. K.M. Flegal, M.D. Carroll, B.K. Kit and C.L. Ogden (2012) Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA 307 491-497.
28. D. Martins, M. Wolf, D. Pan, A. Zadshir, N. Tareen, R. Thadhani, A. Felsenfeld, B. Levine, R. Mehrotra and K. Norris (2007) Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 167 1159-1165.
29. S.S. Harris and B. Dawson-Hughes (2007) Reduced sun exposure does not explain the inverse association of 25-hydroxyvitamin D with percent body fat in older adults. J Clin Endocrinol Metab 92 3155-3157.
30. S.S. Bassuk and J.E. Manson (2008) Health consequences of obesity/overweight. H.K. Heggenhougen, S. Quah (Eds) International encyclopedia of public health Volume 4 San Diego: Academic Press 589-602.
31. H.A. Bischoff-Ferrari, E. Giovannucci, W.C. Willett, T. Dietrich and B. Dawson-Hughes (2006) Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84 18-28.
32. B. Dawson-Hughes, R.P. Heaney, M.F. Holick, P. Lips, P.J. Meunier and R. Vieth (2005) Estimates of optimal vitamin D status. Osteoporos Int 16 713-716.
33. J.F. Aloia, M. Patel, R. Dimaano, M. Li-Ng, S.A. Talwar, M. Mikhail, S. Pollack and J.K. Yeh (2008) Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr 87 1952-1958.
34. W.S. Harris (2007) International recommendations for consumption of long-chain omega-3 fatty acids. J Cardiovasc Med (Hagerstown) 1(8 Suppl.), S50-S52.
35. P.M. Ridker, N.R. Cook, I.M. Lee, D. Gordon, J.M. Gaziano, J.E. Manson, C.H. Hennekens and J.E. Buring (2005) A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 352 1293-1304.
36. M.S. LeBoff, A.Y. Yue, T. Copeland, N.R. Cook, J.E. Buring and J.E. Manson (2015) VITAL-Bone Health: rationale and design of two ancillary studies evaluating the effects of vitamin D and/or omega-3 fatty acid supplements on incident fractures and bone health outcomes in the VITamin D and OmegA-3 TriaL (VITAL). Contemp Clin Trials 41 259-268.
37. D.R. Gold, A.A. Litonjua, V.J. Carey, J.E. Manson, J.E. Buring, I.M. Lee, D. Gordon, J. Walter, G. Friedenberg, J.L. Hankinson, T. Copeland and H. Luttmann-Gibson (2016) Lung VITAL: rationale, design, and baseline characteristics of an ancillary study evaluating the effects of vitamin D and/or marine omega-3 fatty acid supplements on acute exacerbations of chronic respiratory disease, asthma control, pneumonia and lung function in adults. Contemp Clin Trials 47 185-195.
38. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS). Bridged-Race Population Estimates, U.S. July 1 resident population by state, county, age, sex, bridged-race, and Hispanic origin. Compiled from 1990-1999 bridged-race intercensal population estimates (released by NCHS on 7/26/2004); revised bridged-race 2000-2009 intercensal population estimates (released by NCHS on 10/26/2012); and bridged-race Vintage 2013 (2010-2013) postcensal population estimates (released by NCHS on 6/26/2014). Available on CDC WONDER Online Database. Accessed at: http://wonder.cdc.gov/bridged-race-v2013.html.
39. U.S. Census (2012) Current Population Survey, annual social and economic supplement. http://www.census.gov/population/age/data/2012.html Internet release date 2013. Available at
40. Centers for Disease Control, Prevention (March 27, 2014) Early release of selected estimates based on data from the January-September 2013. National Health Interview Survey www.cdc.gov/nchs/nhis/released201403.htm Available at
41. National Center for Health Statistics (2015) Health, United States, 2014: with special feature on adults aged 55-64. Hyattsville, MD: National Center for Health Statistics http://www.cdc.gov/nchs/data/hus/hus14.pdf Accessed at
42. C.D. Harris, K.B. Watson, S.A. Carlson, J.E. Fulton, J.M. Dorn and L. Elam-Evans (2011) Adult participation in aerobic and muscle-strengthening physical activities–United States. MMWR 2013(62), 326-330.
43. H.L. Nicastro, R.L. Bailey and K.W. Dodd (2015) Using 2 assessment methods may better describe dietary supplement intakes in the United States. J Nutr 145 1630-1634.
44. B.L. Sprague, A. Trentham-Dietz and K.A. Cronin (2012) A sustained decline in postmenopausal hormone use: results from the National Health and Nutrition Examination Survey, 1999–2010. Obstet Gynecol 120 595-603.
45. U.S. Department of Agriculture (2015) Scientific report of the 2015 Dietary Guidelines Advisory Committee. http://www.health.gov/dietaryguidelines/2015-scientific-report/ Available at
46. Q. Gu, R. Paulose-Ram, V.L. Burt and B.K. Kit (2014) Prescription cholesterol-lowering medication use in adults aged 40 and over: United States, 2003-2012. NCHS data brief, no. 177. Hyattsville, MD: National Center for Health Statistics http://www.cdc.gov/nchs/data/databriefs/db177.pdf Available at
47. R.S. Sebastian, J.D. Goldman, C. Wilkinson Enns and R.P. LaComb (September 2010) Fluid milk consumption in the United States: what we eat in America, NHANES 2005-2006. Available at: http://www.ars.usda.gov/SP2UserFiles/Place/80400530/pdf/DBrief/3_milk_consumption_0506.pdf Food Surveys Research Group Dietary Data Brief No. 3
48. B.W. Hollis and C.L. Wagner (2013) 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 98 4619-4628.
49. Tuomainen T-P. Finnish Vitamin D Trial (FIND). ClinicalTrials.gov identifier: NCT01463813. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01463813.
50. R. Scragg, D. Waayer, A.W. Stewart, C.M. Lawes, L. Toop, J. Murphy, K.T. Khaw and C.A. Camargo Jr. (2016;164:318–25) 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 Steroid Biochem Mol Biol
51. Lappe JM. Clinical Trial of Vitamin D3 to Reduce Cancer Risk in Postmenopausal Women (CAPS). ClinicalTrials identifier: NCT01052051. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01052051.
52. Yusuf S. The International Polycap Study 3 (TIPS-3). ClinicalTrials.gov Identifier: NCT01646437. Available at: http://clinicaltrials.gov/ct2/show/NCT01646437.
53. Bischoff-Ferrari HA. DO-HEALTH/Vitamin D3-Omega3-Home Exercise - Healthy Ageing and Longevity Trial. ClinicalTrials.gov identifier: NCT01745263. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01745263.
54. A.G. Pittas, B. Dawson-Hughes, P.R. Sheehan, C.J. Rosen, J.H. Ware, W.C. Knowler and M.A. Staten (2014) D2d Research Group. Rationale and design of the Vitamin D and Type 2 Diabetes (D2d) study: a diabetes prevention trial. Diabetes Care 37 3227-3234.
55. P.M. Kris-Etherton, A.H. Lichtenstein, B.V. Howard, D. Steinberg and J.L. Witztum (2004) Antioxidant vitamin supplements and cardiovascular disease. Circulation 110 637-641.
56. I.M. Lee, N.R. Cook, J.M. Gaziano, D. Gordon, P.M. Ridker, J.E. Manson, C.H. Hennekens and J.E. Buring (2005) Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA 294 56-65.
57. G. Bjelakovic, D. Nikolova, L.L. Gluud, R.G. Simonetti and C. Gluud (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297 842-857.
58. T. Byers (2010) Anticancer vitamins du jour–The ABCED’s so far. Am J Epidemiol 172 1-3.
59. M.J. Bolland, A. Avenell, J.A. Baron, A. Grey, G.S. MacLennan, G.D. Gamble and I.R. Reid (2010) Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 341 c3691.
60. T.J. Wang, M.J. Pencina, S.L. Booth, P.F. Jacques, E. Ingelsson, K. Lanier, E.J. Benjamin, R.B. D’Agostino, M. Wolf and R.S. Vasan (2008) Vitamin D deficiency and risk of cardiovascular disease. Circulation 117 503-511.
61. D.M. Freedman, A.C. Looker, S.C. Chang and B.I. Graubard (2007) Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst 99 1594-1602.
62. R.Z. Stolzenberg-Solomon, R.B. Hayes, R.L. Horst, K.E. Anderson, B.W. Hollis and D.T. Silverman (2009) Serum vitamin D and risk of pancreatic cancer in the Prostate, Lung, Colorectal, and Ovarian Screening Trial. Cancer Res 69 1439-1447.
63. M.L. Melamed, E.D. Michos, W. Post and B. Astor (2008) 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 168 1629-1637.
64. K.M. Sanders, A.L. Stuart, E.J. Williamson, J.A. Simpson, M.A. Kotowicz, D. Young and G.C. Nicholson (2010) Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 303 1815-1822.