title: 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.
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.
  
  
  METHODS
  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.affiliation: 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).
authors.forename: Janneke P
authors.initials: JP
authors.lastname: van Wijngaarden
authors.affiliation: 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).
authors.forename: Karin M A
authors.initials: KM
authors.lastname: Swart
authors.affiliation: 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).
authors.forename: Anke W
authors.initials: AW
authors.lastname: Enneman
authors.affiliation: 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).
authors.forename: Rosalie A M
authors.initials: RA
authors.lastname: Dhonukshe-Rutten
authors.affiliation: 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).
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: van Dijk
authors.affiliation: 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).
authors.forename: Annelies C
authors.initials: AC
authors.lastname: Ham
authors.affiliation: 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).
authors.forename: Elske M
authors.initials: EM
authors.lastname: Brouwer-Brolsma
authors.affiliation: 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).
authors.forename: Nikita L
authors.initials: NL
authors.lastname: van der Zwaluw
authors.affiliation: 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).
authors.forename: Evelien
authors.initials: E
authors.lastname: Sohl
authors.affiliation: 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).
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.affiliation: 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).
authors.forename: M Carola
authors.initials: MC
authors.lastname: Zillikens
authors.affiliation: 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).
authors.forename: Natasja M
authors.initials: NM
authors.lastname: van Schoor
authors.affiliation: 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).
authors.forename: Nathalie
authors.initials: N
authors.lastname: van der Velde
authors.affiliation: 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).
authors.forename: Johannes
authors.initials: J
authors.lastname: Brug
authors.affiliation: 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).
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: 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).
authors.forename: Paul
authors.initials: P
authors.lastname: Lips
authors.affiliation: 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).
authors.forename: Lisette C P G M
authors.initials: LC
authors.lastname: de Groot
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D023381:Endpoint Determination; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D005500:Follow-Up Studies; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000188:drug therapy; D015994:Incidence; D008297:Male; D009043:Motor Activity; D009426:Netherlands; D058866:Osteoporotic Fractures / Q000453:epidemiology* / Q000517:prevention & control*; D012307:Risk Factors; D016896:Treatment Outcome; D014805:Vitamin B 12 / Q000008:administration & dosage*
chemical_list: D006710:Homocysteine; D005492:Folic Acid; D014805:Vitamin B 12
keywords: bone; folic acid; fractures; homocysteine; vitamin B-12