Effect of Combination Folic Acid, Vitamin B6, and Vitamin B12 Supplementation on Fracture Risk in Women: A Randomized, Controlled Trial

Katie L. Stone*, Li Yung Lui, William G. Christen, Aron M. Troen, Douglas C. Bauer, Deborah Kado, Christopher Schambach, Steven R. Cummings, Jo Ann E. Manson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B12, B6, and folic acid are cofactors in homocysteine metabolism, and supplementation with B vitamins is effective in lowering homocysteine levels in humans. However, randomized trials of supplemental B vitamins for reduction of fracture risk have been limited. Therefore, we performed an ancillary study to the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a large randomized trial of women with preexisting cardiovascular disease or three or more coronary risk factors, to test whether a daily B vitamin intervention including folic acid (2.5 mg/day), vitamin B6 (50 mg/day), and vitamin B12 (1 mg/day) reduces nonspine fracture risk over 7.3 years of treatment and follow-up. Among 4810 women, we confirmed 349 nonspine fracture cases by centralized review of medical records. In a substudy of 300 women (150 in treatment group and 150 controls) with paired plasma samples at randomization and follow-up (7.3 years later), we measured two bone turnover markers, including C-terminal cross-linking telopeptide of type I collagen (CTX) and intact type I procollagen N-propeptide (P1NP). In Cox proportional hazards models based on intention-to-treat, we found no significant effects of B vitamin supplementation on nonspine fracture risk (relative hazard = 1.08; 95% confidence interval, 0.88 to 1.34). In a nested case-cohort analysis, there were no significant effects of B vitamins on fracture risk among women with elevated plasma homocysteine levels, or low levels of vitamins B12 or B6, or folate at baseline. Furthermore, treatment with B vitamins had no effect on change in markers of bone turnover. We found no evidence that daily supplementation with B vitamins reduces fracture risk or rates of bone metabolism in middle-aged and older women at high risk of cardiovascular disease.

Original languageAmerican English
Pages (from-to)2331-2338
Number of pages8
JournalJournal of Bone and Mineral Research
Issue number12
StatePublished - Dec 2017

Bibliographical note

Funding Information:
This work was supported by grant funding through the National Institutes of Health, including the National Heart, Lung and Blood Institute (R01 HL46959) and the National Institute of Arthritis, Musculoskeletal and Skin Diseases (R01 AR052817). Vitamin E and its placebo were supplied by Cognis Corporation (La-Grange, IL, USA). All other agents and their placebos were supplied by BASF Corporation (Mount Olive, NJ, USA). Pill packaging was provided by Cognis and BASF. We are indebted to the 5442 participants in the Women’s Antioxidant and Folic Acid Cardiovascular Study for their dedicated and conscientious collaboration; to the entire staff of the Women’s Antioxidant and Folic Acid Cardiovascular Study: including Marilyn Chown, BS, MPH, Shamikhah Curry, Margarette Haubourg, Felicia Zangi, Tony Laurinaitis, Geneva McNair, Philomena Quinn, Harriet Samuelson, MA, Ara Sarkissian, MM, and Martin Van Denburgh, BA; and to the following individuals for their assistance in conducting this trial: Michelle Albert, MD, MPH, Tobias Kurth, MD, ScD, I-Min Lee, MBBS, ScD, Aruna Pradhan, MD, MPH, Paul Ridker, MD, MPH, and Jacqueline H. Suk, MD, MPH, Brigham and Women’s Hospital, Boston, Massachusetts; Gavin Blake, MBBS, Mater Misericordiae University Hospital, Dublin, Ireland; Claudia Chae, MD, MPH, Massachusetts General Hospital, Boston; Carlos Kase, MD, Boston University Medical Center, Boston, Massachusetts; and James O. Taylor, MD, East Boston Neighborhood Health Center, Boston, Massachusetts.

Publisher Copyright:
© 2017 American Society for Bone and Mineral Research




Dive into the research topics of 'Effect of Combination Folic Acid, Vitamin B6, and Vitamin B12 Supplementation on Fracture Risk in Women: A Randomized, Controlled Trial'. Together they form a unique fingerprint.

Cite this