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. Design: This was a double-blind, randomized, placebo-controlled trial in 2919 participants aged $65 y with elevated homocysteine concentrations (12-50 mmol/L). Participants were assigned to receive daily 500 mg vitamin B-12 plus 400 mg folic acid or placebo supplementation for 2 y. Both intervention and placebo tablets also contained 600 IU vitamin D 3 . 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.Am J Clin Nutr 2014;100:1578-86.

Results of 2-year vitamin B treatment on cognitive performance

“…Post hoc analyses of adverse events in the B-PROOF population showed that participants in the B-vitamin group reported cancer more often than those in the placebo group. 33 Nevertheless, a recent meta-analysis did not observe a significant negative effect based on 13 studies. 34 Our dose of folic acid was well below the upper tolerable limit that is used in the Netherlands (1 mg/d).…”

“…33 Nevertheless, a recent meta-analysis did not observe a significant negative effect based on 13 studies. 34 Our dose of folic acid was well below the upper tolerable limit that is used in the Netherlands (1 mg/d). 35 Although our finding could be attributed to chance, we should interpret it with care and it makes daily supplementation with folic acid in the given dose questionable.…”

Dietary Approaches for Bone Health: Lessons from the Framingham Osteoporosis Study

“…Thus, the evidence from Framingham and other studies suggests folate may not be important for bone health, while low vitamin B12 status may be a modest risk factor for fracture. Supplementation with vitamin B12 and folic acid has shown mixed results [41–44]. Thus, little evidence supports folate or vitamin B12 supplementation as a means to prevent fracture.…”

Effect of vitamin B12 and folic acid supplementation on biomarkers of endothelial function and inflammation among elderly individuals with hyperhomocysteinemia

“…Details regarding laboratory techniques are described elsewhere. 26,28 The estimated glomerular filtration rate (eGFR) was calculated with the Modification of Diet in Renal Disease (MDRD) formula in ml/min/1.73 m 2 . 29 …”