Background and objective
Observational studies suggest an inverse association between circulating vitamin D levels and risk of breast cancer. However, the potential benefits of vitamin D supplementation to reduce the risk of breast cancer remain controversial, based on the results of current randomized controlled trials (RCTs). The aim of this study was to evaluate the value of vitamin D supplementation on breast cancer prevention.
PubMed, Embase, and Cochrane library were searched from inception to February 2020. We performed a trial sequential meta-analysis of RCTs reporting the effect of vitamin D supplementation, with or without calcium, on the risk of breast cancer. The effect was estimated using a relative risk reduction threshold of 30%.
Eight trials comprising 72,275 participants were included in this study, with a median follow-up period ranging from 1 to 11.9 years. The median dosage of vitamin D supplementation was 967 IU per day (range 400–3704 IU per day) across the trials. This study yielded a relative risk of 1.04 (95% CI 0.85–1.29, P = 0.68) for the effect of vitamin D supplementation (6 trials, 33,472 participants), and 0.99 (95% CI 0.91–1.07, P = 0.73) for co-administration of vitamin D and calcium (4 trials, 41,957 participants). The effect estimate for vitamin D with or without calcium on breast cancer risk lay within the futility boundary, indicating that vitamin D supplementation does not alter the relative risk by 30% or more.
Our analyses suggest that vitamin D supplementation, with or without calcium, does not reduce breast cancer risk by 30% or more. Future trials with similar designs are unlikely to alter this finding.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Randomized controlled trials
Trial sequential analysis
Vitamin D and calcium
Holick MF (2007) Vitamin D deficiency. N Engl J Med 357(3):266–281
Grant WB (2012) Ecological studies of the UVB-vitamin D-cancer hypothesis. Anticancer Res 32(1):223–236
John EM, Schwartz GG, Dreon DM, Koo J (1999) Vitamin D and breast cancer risk: the NHANES I epidemiologic follow-up study, 1971–1975 to 1992. Cancer Epidemiol Biomarkers Prev 8(5):399–406
Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H (2010) Meta-analysis: serum vitamin D and breast cancer risk. Eur J Cancer 46(12):2196–2205
Kim Y, Je Y (2014) Vitamin D intake, blood 25 (OH) D levels, and breast cancer risk or mortality: a meta-analysis. Br J Cancer 110(11):2772–2784
Sperati F, Vici P, Maugeri-Saccà M, Stranges S, Santesso N, Mariani L, Giordano A, Sergi D, Pizzuti L, Di Lauro L (2013) Vitamin D supplementation and breast cancer prevention: a systematic review and meta-analysis of randomized clinical trials. PLoS ONE 8(7):e69269
Brok J, Thorlund K, Gluud C, Wetterslev J (2008) Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol 61(8):763–769
Ng K, Scott JB, Drake BF, Chan AT, Hollis BW, Chandler PD, Bennett GG, Giovannucci EL, Gonzalez-Suarez E, Meyerhardt JA, Emmons KM, Fuchs CS (2014) Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial. Am J Clin Nutr 99(3):587–598
Aloia JF, Dhaliwal R, Shieh A, Mikhail M, Islam S, Yeh JK (2013) Calcium and vitamin D supplementation in postmenopausal women. J Clin Endocrinol Metab 98(11):E1702–E1709
Tran B, Armstrong BK, Carlin JB, Ebeling PR, English DR, Kimlin MG, Rahman B, Van Der Pols JC, Venn A, Gebski V, Whiteman DC, Webb PM, Neale RE (2012) Recruitment and results of a pilot trial of vitamin D supplementation in the general population of Australia. J Clin Endocrinol Metab 97(12):4473–4480
Pongprutthipan M, Alam M, Kim N, Pace N (2012) A randomized controlled trial: Comparison of total 25-hydroxy vitamin D level in premenopausal white women receiving vitamin D3 supplementation. J Am Acad Dermatol 66(4):AB126
Glendenning P, Zhu K, Inderjeeth C, Howat P, Lewis JR, Prince RL (2012) Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial. J Bone Miner Res 27(1):170–176
Laidlaw M, Cockerline CA, Almada AL (2011) Effect of a vitamin D supplement on circulating vitamin D status in pre- and post-menopausal women: a randomized controlled trial. FASEB J 25(1 suppl):214.2
Rohan TE, Negassa A, Chlebowski RT, Ceria-Ulep CD, Cochrane BB, Lane DS, Ginsberg M, Wassertheil-Smoller S, Page DL (2009) A randomized controlled trial of calcium plus vitamin D supplementation and risk of benign proliferative breast disease. Breast Cancer Res Treat 116(2):339–350
McCullough ML, Bostick RM, Daniel CR, Flanders WD, Shaukat A, Davison J, Rangaswamy U, Hollis BW (2009) Vitamin D status and impact of vitamin D3 and/or calcium supplementation in a randomized pilot study in the Southeastern United States. J Am Coll Nutr 28(6):678–686
LaCroix AZ, Kotchen J, Anderson G, Brzyski R, Cauley JA, Cummings SR, Gass M, Johnson KC, Ko M, Larson J, Manson JE, Stefanick ML, Wactawski-Wende J (2009) Calcium plus vitamin D supplementation and mortality in postmenopausal women: The women's health initiative calcium-vitamin D randomized controlled trial. J Gerontol Ser A Biol Sci Med Sci 64(5):559–567
Scragg R, Khaw K-T, Toop L, Sluyter J, Lawes CMM, Waayer D, Giovannucci E, Camargo CA Jr (2018) Monthly high-dose vitamin D supplementation and cancer risk: a post hoc analysis of the vitamin D assessment randomized clinical trial. JAMA Oncol 4(11):e182178–e182178
Keum N, Giovannucci E (2014) Vitamin D supplements and cancer incidence and mortality: a meta-analysis. Br J Cancer 111(5):976–980
Wood ME, Kingsley F, Ambaye AB, Yee L, Jung SH, Marshall JR, Paskett E (2011) A randomized phase II trial of vitamin D vs placebo in premenopausal women: CALGB 70806. Cancer Res. https://doi.org/10.1158/0008-5472.SABCS11-OT2-04-01
Waterhouse M, English DR, Armstrong BK, Baxter C, Duarte Romero B, Ebeling PR, Hartel G, Kimlin MG, McLeod DSA, O'Connell RL et al (2019) A randomized placebo-controlled trial of vitamin D supplementation for reduction of mortality and cancer: statistical analysis plan for the D-health trial. Contemp Clin Trials Commun. https://doi.org/10.1016/j.conctc.2019.100333
Brunner RL, Wactawski-Wende J, Caan BJ, Cochrane BB, Chlebowski RT, Gass MLS, Jacobs ET, Lacroix AZ, Lane D, Larson J, Margolis KL, Millen AE, Sarto GE, Vitolins MZ, Wallace RB (2011) The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomized clinical trial. Nutr Cancer 63(6):827–841
Chlebowski RT, Johnson KC, Kooperberg C, Pettinger M, Wactawski-Wende J, Rohan T, Rossouw J, Lane D, O'Sullivan MJ, Yasmeen S, Hiatt RA, Shikany JM, Vitolins M, Khandekar J, Hubbell FA (2008) Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 100(22):1581–1591
Chlebowski RT, Johnson KC, Kooperberg C, Hubbell A, Lane D, O'Sullivan M, Cummings S, Rohan T, Yasmeen S, Khandekar J (2006) The Women's Health Initiative randomized trial of calcium plus vitamin D: Effects on breast cancer and arthralgias. J Clin Oncol 24:Lba6
Cauley JA, Chlebowski RT, Wactawski-Wende J, Robbins JA, Rodabough RJ, Chen Z, Johnson KC, O'Sullivan MJ, Jackson RD (2002) Manson JE (2013) Calcium plus vitamin D supplementation and health outcomes five years after active intervention ended: the Women's Health Initiative. J Women's Health 22(11):915–929
Wood AD, Secombes KR, Thies F, Aucott L, Black AJ, Mavroeidi A, Simpson WG, Fraser WD, Reid DM, Macdonald HM (2012) Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT. J Clin Endocrinol Metab 12:1
Murdoch DR, Slow S, Chambers ST, Jennings LC, Stewart AW, Priest PC, Florkowski CM, Livesey JH, Camargo CA, Scragg R (2012) Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA 308(13):1333–1339
Avenell A, MacLennan GS, Jenkinson DJ, McPherson GC, McDonald AM, Pant PR, Grant AM, Campbell MK, Anderson FH, Cooper C, Francis RM, Gillespie WJ, Robinson CM, Torgerson DJ, Wallace WA, Khaw KT, Eastell R, Marsh D (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(2):614–622
Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85(6):1586–1591
Trivedi DP, Doll R, Khaw KT (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(7387):469
Lappe J, Watson P, Travers-Gustafson D, Recker R, Garland C, Gorham E, Baggerly K, McDonnell SL (2017) Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA 317(12):1234–1243
Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S (2012) Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. Am J Clin Nutr 95(1):91–100
Mohr SB, Gorham ED, Kim J, Hofflich H, Garland CF (2014) Meta-analysis of vitamin D sufficiency for improving survival of patients with breast cancer. Anticancer Res 34(3):1163–1166
Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL (2013) Plasma vitamin D levels, menopause, and risk of breast cancer: dose-response meta-analysis of prospective studies. Medicine (Baltimore) 92(3):123–131
Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC (2010) Benefit–risk assessment of vitamin D supplementation. Osteoporos Int 21(7):1121–1132
Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Gordon D, Copeland T, D'Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE (2018) Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. https://doi.org/10.1056/NEJMoa1809944
Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, Newmark H, Holick MF, Garland FC (2007) Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol 103(3):708–711
Sheng L, Callen DF, Turner AG (2018) Vitamin D signaling and breast cancer: insights from transgenic mouse models. J Steroid Biochem Mol Biol 178:348–353
Sheng L, Turner AG, Barratt K, Kremer R, Morris HA, Callen DF, Anderson PH, Tarulli GA (2019) Mammary-specific ablation of Cyp24a1 inhibits development, reduces proliferation and increases sensitivity to vitamin D. J Steroid Biochem Mol Biol 189:240–247
Huss L, Butt ST, Borgquist S, Elebro K, Sandsveden M, Rosendahl A, Manjer J (2019) Vitamin D receptor expression in invasive breast tumors and breast cancer survival. Breast Cancer Res 21(1):84
This work was supported by the National Natural Science Foundation of China (Grant No. 81802642).
Conflict of interest
The authors have no conflict of interest to disclose.
This article is a review and does not contain any studies with human participants performed by any of the authors.
Informed consent was obtained from all individual participants included in the RCTs.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Liguang Zhou and Bo Chen have contributed equally to this work.
About this article
Cite this article
Zhou, L., Chen, B., Sheng, L. et al. The effect of vitamin D supplementation on the risk of breast cancer: a trial sequential meta-analysis. Breast Cancer Res Treat 182, 1–8 (2020). https://doi.org/10.1007/s10549-020-05669-4
- Vitamin D
- Breast cancer
- Randomized controlled trials