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Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial.
Am J Clin Nutr 2014; 100(6):1578-86AJ

Abstract

BACKGROUND

Elevated plasma homocysteine concentrations are a risk factor for osteoporotic fractures. Lowering homocysteine with combined vitamin B-12 and folic acid supplementation may reduce fracture risk.

OBJECTIVE

This study [B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF)] aimed to determine whether vitamin B-12 and folic acid supplementation reduces osteoporotic fracture incidence in hyperhomocysteinemic elderly individuals.

DESIGN

This was a double-blind, randomized, placebo-controlled trial in 2919 participants aged ≥65 y with elevated homocysteine concentrations (12-50 μmol/L). Participants were assigned to receive daily 500 μg vitamin B-12 plus 400 μg folic acid or placebo supplementation for 2 y. Both intervention and placebo tablets also contained 600 IU vitamin D3. The primary endpoint was time to first osteoporotic fracture. Exploratory prespecified subgroup analyses were performed in men and women and in individuals younger than and older than age 80 y. Data were analyzed according to intention-to-treat and per-protocol principles.

RESULTS

Osteoporotic fractures occurred in 61 persons (4.2%) in the intervention group and 75 persons (5.1%) in the placebo group. Osteoporotic fracture risk was not significantly different between groups in the intention-to-treat analyses (HR: 0.84; 95% CI: 0.58, 1.21) or per-protocol analyses (HR: 0.81; 95% CI: 0.54, 1.21). For persons aged >80 y, in per-protocol analyses, osteoporotic fracture risk was lower in the intervention group than in the placebo group (HR: 0.27; 95% CI: 0.10, 0.74). The total number of adverse events (including mortality) did not differ between groups. However, 63 and 42 participants in the intervention and placebo groups, respectively, reported incident cancer (HR: 1.56; 95% CI: 1.04, 2.31).

CONCLUSIONS

These data show that combined vitamin B-12 and folic acid supplementation had no effect on osteoporotic fracture incidence in this elderly population. Exploratory subgroup analyses suggest a beneficial effect on osteoporotic fracture prevention in compliant persons aged >80 y. However, treatment was also associated with increased incidence of cancer, although the study was not designed for assessing cancer outcomes. Therefore, vitamin B-12 plus folic acid supplementation cannot be recommended at present for fracture prevention in elderly people. The B-PROOF study was registered with the Netherlands Trial Register (trialregister.nl) as NTR1333 and at clinicaltrials.gov as NCT00696414.

Authors+Show Affiliations

From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (JPvW, RAMD-R, EMB-B, NLvdZ, and LCPGMdG); the Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research (KMAS, ES, NMvS, JB, and PL) and the Department of Internal Medicine, Endocrine Section (PL), VU University Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (AWE, SCvD, ACH, JBJvM, MCZ, NvdV, and AGU); and the Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, The Netherlands (NvdV).

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25411293

Citation

van Wijngaarden, Janneke P., et al. "Effect of Daily Vitamin B-12 and Folic Acid Supplementation On Fracture Incidence in Elderly Individuals With an Elevated Plasma Homocysteine Concentration: B-PROOF, a Randomized Controlled Trial." The American Journal of Clinical Nutrition, vol. 100, no. 6, 2014, pp. 1578-86.
van Wijngaarden JP, Swart KM, Enneman AW, et al. Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial. Am J Clin Nutr. 2014;100(6):1578-86.
van Wijngaarden, J. P., Swart, K. M., Enneman, A. W., Dhonukshe-Rutten, R. A., van Dijk, S. C., Ham, A. C., ... de Groot, L. C. (2014). Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial. The American Journal of Clinical Nutrition, 100(6), pp. 1578-86. doi:10.3945/ajcn.114.090043.
van Wijngaarden JP, et al. Effect of Daily Vitamin B-12 and Folic Acid Supplementation On Fracture Incidence in Elderly Individuals With an Elevated Plasma Homocysteine Concentration: B-PROOF, a Randomized Controlled Trial. Am J Clin Nutr. 2014;100(6):1578-86. PubMed PMID: 25411293.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial. AU - van Wijngaarden,Janneke P, AU - Swart,Karin M A, AU - Enneman,Anke W, AU - Dhonukshe-Rutten,Rosalie A M, AU - van Dijk,Suzanne C, AU - Ham,Annelies C, AU - Brouwer-Brolsma,Elske M, AU - van der Zwaluw,Nikita L, AU - Sohl,Evelien, AU - van Meurs,Joyce B J, AU - Zillikens,M Carola, AU - van Schoor,Natasja M, AU - van der Velde,Nathalie, AU - Brug,Johannes, AU - Uitterlinden,André G, AU - Lips,Paul, AU - de Groot,Lisette C P G M, Y1 - 2014/10/01/ PY - 2014/11/21/entrez PY - 2014/11/21/pubmed PY - 2015/2/24/medline KW - bone KW - folic acid KW - fractures KW - homocysteine KW - vitamin B-12 SP - 1578 EP - 86 JF - The American journal of clinical nutrition JO - Am. J. Clin. Nutr. VL - 100 IS - 6 N2 - BACKGROUND: Elevated plasma homocysteine concentrations are a risk factor for osteoporotic fractures. Lowering homocysteine with combined vitamin B-12 and folic acid supplementation may reduce fracture risk. OBJECTIVE: This study [B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF)] aimed to determine whether vitamin B-12 and folic acid supplementation reduces osteoporotic fracture incidence in hyperhomocysteinemic elderly individuals. DESIGN: This was a double-blind, randomized, placebo-controlled trial in 2919 participants aged ≥65 y with elevated homocysteine concentrations (12-50 μmol/L). Participants were assigned to receive daily 500 μg vitamin B-12 plus 400 μg folic acid or placebo supplementation for 2 y. Both intervention and placebo tablets also contained 600 IU vitamin D3. The primary endpoint was time to first osteoporotic fracture. Exploratory prespecified subgroup analyses were performed in men and women and in individuals younger than and older than age 80 y. Data were analyzed according to intention-to-treat and per-protocol principles. RESULTS: Osteoporotic fractures occurred in 61 persons (4.2%) in the intervention group and 75 persons (5.1%) in the placebo group. Osteoporotic fracture risk was not significantly different between groups in the intention-to-treat analyses (HR: 0.84; 95% CI: 0.58, 1.21) or per-protocol analyses (HR: 0.81; 95% CI: 0.54, 1.21). For persons aged >80 y, in per-protocol analyses, osteoporotic fracture risk was lower in the intervention group than in the placebo group (HR: 0.27; 95% CI: 0.10, 0.74). The total number of adverse events (including mortality) did not differ between groups. However, 63 and 42 participants in the intervention and placebo groups, respectively, reported incident cancer (HR: 1.56; 95% CI: 1.04, 2.31). CONCLUSIONS: These data show that combined vitamin B-12 and folic acid supplementation had no effect on osteoporotic fracture incidence in this elderly population. Exploratory subgroup analyses suggest a beneficial effect on osteoporotic fracture prevention in compliant persons aged >80 y. However, treatment was also associated with increased incidence of cancer, although the study was not designed for assessing cancer outcomes. Therefore, vitamin B-12 plus folic acid supplementation cannot be recommended at present for fracture prevention in elderly people. The B-PROOF study was registered with the Netherlands Trial Register (trialregister.nl) as NTR1333 and at clinicaltrials.gov as NCT00696414. SN - 1938-3207 UR - https://www.unboundmedicine.com/medline/citation/25411293/Effect_of_daily_vitamin_B_12_and_folic_acid_supplementation_on_fracture_incidence_in_elderly_individuals_with_an_elevated_plasma_homocysteine_concentration:_B_PROOF_a_randomized_controlled_trial_ L2 - https://academic.oup.com/ajcn/article-lookup/doi/10.3945/ajcn.114.090043 DB - PRIME DP - Unbound Medicine ER -