Folic Acid and Vitamin B12 Supplementation and the Risk of Cancer: Long-term Follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial

• Published in: Cancer epidemiology, biomarkers & prevention Vol. 28; no. 2; pp. 275 - 282
• Main Authors: Oliai Araghi, Sadaf, Kiefte-de Jong, Jessica C, van Dijk, Suzanne C, Swart, Karin M A, van Laarhoven, Hanneke W, van Schoor, Natasja M, de Groot, Lisette C P G M, Lemmens, Valery, Stricker, Bruno H, Uitterlinden, André G, van der Velde, Nathalie
• Format: Journal Article
• Language: English
• Published: United States 01.02.2019
• Subjects: Aged; Aged, 80 and over; Chair Nutrition and Health over the Lifecourse; Colorectal Neoplasms - chemically induced; Colorectal Neoplasms - epidemiology; Dietary Supplements; Double-Blind Method; Female; Folic Acid - adverse effects; Folic Acid - therapeutic use; Follow-Up Studies; Global Nutrition; HNE Nutrition and Health over the Lifecourse; HNE Voeding en Gezondheid in de Levenscyclus; Humans; Incidence; Male; Neoplasms - chemically induced; Neoplasms - epidemiology; Netherlands - epidemiology; Osteoporotic Fractures - prevention & control; Vitamin B 12 - adverse effects; Vitamin B 12 - therapeutic use; VLAG; Wereldvoeding; Netherlands
• ISSN: 1055-9965; 1538-7755
• DOI: 10.1158/1055-9965.epi-17-1198

Folic acid and vitamin B12 play key roles in one-carbon metabolism. Disruption of one-carbon metabolism may be involved in the risk of cancer. Our aim was to assess the long-term effect of supplementation with both folic acid and vitamin B12 on the incidence of overall cancer and on colorectal cancer in the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) trial. Long-term follow-up of B-PROOF trial participants ( = 2,524), a multicenter, double-blind randomized placebo-controlled trial designed to assess the effect of 2 to 3 years daily supplementation with folic acid (400 μg) and vitamin B12 (500 μg) versus placebo on fracture incidence. Information on cancer incidence was obtained from the Netherlands cancer registry (Integraal Kankercentrum Nederland), using the International Statistical Classification of Disease (ICD-10) codes C00-C97 for all cancers (except C44 for skin cancer), and C18-C20 for colorectal cancer. Allocation to B vitamins was associated with a higher risk of overall cancer [171 (13.6%) vs. 143 (11.3%); HR 1.25; 95% confidence interval (CI), 1.00-1.53, = 0.05]. B vitamins were significantly associated with a higher risk of colorectal cancer [43(3.4%) vs. 25(2.0%); HR 1.77; 95% CI, 1.08-2.90, = 0.02]. Folic acid and vitamin B12 supplementation was associated with an increased risk of colorectal cancer. Our findings suggest that folic acid and vitamin B12 supplementation may increase the risk of colorectal cancer. Further confirmation in larger studies and in meta-analyses combining both folic acid and vitamin B12 are needed to evaluate whether folic acid and vitamin B12 supplementation should be limited to patients with a known indication, such as a proven deficiency.