Long-term effects of folic acid and vitamin-B12 supplementation on fracture risk and cardiovascular disease: Extended follow-up of the B-PROOF trial

Abstract

Background & aims: In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues. Therefore, our aim was to investigate the long-term effects (5e7 years follow-up) of an intervention with folic acid and vitamin-B12 supplementation on fracture and cardiovascular disease risk. Methods: Extended follow-up of the B-PROOF trial, a multi-center, double-blind randomized placebocontrolled trial designed to assess the effect of 2e3 years daily supplementation with folic acid (400 mg) and vitamin-B12 (500 mg) versus placebo (n ¼ 2,919). Primary outcome was verified selfreported fracture incidence and secondary outcomes were self-reported cardiovascular endpoints, which were collected through a follow-up questionnaires Proportional hazard analyses was used for the effect of the intervention on risk of fracture(s) and logistic regression for the effect of the intervention on risk of cardiovascular disease. Results: A total of 1,298 individuals (44.5%) participated in the second follow-up round with median of 54 months [51e58], (n ¼ 662 and n ¼ 636, treatment versus placebo group). Median age at baseline was 71.0 years [68.0e76.0] for both groups. No effect was observed of the intervention on osteoporotic fracture or any fracture risk after a follow-up (HR: 0.99, 95% CI: 0.62e1.59 and HR: 0.77; 95% CI: 0.50 e1.19, respectively), nor on cardiovascular or cerebrovascular disease risk (OR: 1.05; 95%CI: 0.80e1.44 and OR: 0.85; 95%CI: 0.50e1.45, respectively). Potential interaction by baseline homocysteine concentration was observed for osteoporotic-and any fracture (p ¼ 0.10 and 0.06 respectively), which indicated a significantly lower risk of any fracture in the treatment group with higher total homocysteine concentrations (>15.1 mmol/l). No age-dependent effects were present.Conclusions: This study supports and extends previous null-findings of the B-PROOF trial and shows that supplementation of folic acid and vitamin-B12 has no effect on fracture risk, nor on cardiovascular disease in older individuals over a longer follow-up period. However, B-vitamin supplementation may be

Hyperhomocysteinemia in Cardiovascular Diseases: Revisiting Observational Studies and Clinical Trials

“…The most recent Cochrane systematic review and meta-analysis of the effect of t-Hcy lowering by B vitamin supplementation reviewed 15 RCTs of subjects with CHD and stroke as preexisting diseases ( Table 1 ). 64 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 The meta-analysis included RCTs evaluating the occurrence of myocardial infarction and stroke during at least 1 year in patients without end-stage renal disease. 64 This Cochrane meta-analysis observed a small reduction in stroke outcomes with high-quality evidence.…”

“…S1 [available in the online version]) ( Table 1 ). 64 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 The 5 to 7 year long-term effects of folic acid and vitamin-B12 supplementation had a null effect on CVD risk. 90 In contrast, the percent lowering in t-Hcy was significantly associated with a reduction in the risk of first stroke event in CSPPT Chinese adults with hypertension.…”

“…64 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 The 5 to 7 year long-term effects of folic acid and vitamin-B12 supplementation had a null effect on CVD risk. 90 In contrast, the percent lowering in t-Hcy was significantly associated with a reduction in the risk of first stroke event in CSPPT Chinese adults with hypertension. 88 In these trials, the vascular functional outcomes and thromboembolic disorders drew less attention than the global risk for stroke and myocardial infarction.…”

Precision Nutrition for Cardiovascular Disease Prevention

“…Similarly, a reciprocal relationship has been shown between vitamin D levels and DNA methylation of genes of the cytochrome P450 family involved in its metabolism [40]. These mechanisms warrant further investigation as interindividual variability could help explain why neither vitamin D nor B12 supplementation have shown to be beneficial for CVD prevention in individuals without deficiencies [41][42][43].…”

Current Status of the Diagnosis and Management of Osteoporosis

“…The consumption of folic acid and vitamin B-12 is expected to reduce the amount of homocysteine in the blood by a quarter or a third [ 190 ], which would slow down its degradative action on the extracellular matrix and decrease BMD [ 191 ]. However, the results showed that a chronic intake of folic acid and B-12 has no effect on the risk of fracture [ 192 ].…”