Send to

Choose Destination
Cancer Epidemiol Biomarkers Prev. 2018 Oct 19. pii: cebp.1198.2018. doi: 10.1158/1055-9965.EPI-17-1198. [Epub ahead of print]

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.

Author information

Intern Medicine, Erasmus University Medical Center.
Epidemiology, Erasmus Medical Center
Internal Medicine, Erasmus University Medical Center.
Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam.
Department of Medical Oncology, Academic Medical Center.
Human Nutrition and Health, Wageningen University.
Research, Comprehensive Cancer Organisation.
Epidemiology & Biostatistics, Erasmus Medical Center.
Department of Internal Medicine, Erasmus Medical Center.
Internal Medicine/Section of Geriatric Medicine, Department of Internal Medicine, Amsterdam Public Health Research Institute, Erasmus University Medical Center/Amsterdam UMC, (University) of Amsterdam.



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-PROOF trial.


Long-term follow-up of B-PROOF trial participants (N=2,524), a multi-center, double-blind randomized placebo-controlled trial designed to assess the effect of 2-3 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 CRC.


Allocation to B-vitamins was associated with a higher risk of overall cancer (171 [13.6%] vs. 143 [11.3%]), HR 1.25; 95%CI 1.00-1.53, p=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, p=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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center