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Long-term Effect of Folic Acid and Vitamin B12 Supplementation on Fracture Risk and Cardiovascular Disease: Follow-up Study of B-PROOF Trial (P24-031-19).

Objectives
To investigate the possible effects of the intervention with folic acid and vitamin B12 supplementation on fracture and cardiovascular disease risk: 5-7 years after the end of the intervention period of 2-3 years.


Methods
Extended follow-up of B-PROOF trial, a multi-center, double-blind randomized placebo-controlled trial designed to assess the effect of 2-3 years daily supplementation with folic acid (400 µg) and vitamin-B12 (500 µg) versus placebo on fracture incidence. Fracture and cardiovascular outcomes were assessed by follow-up questionnaire. Fracture incidence (and a part of cardiovascular disease incidence) was verified by general practitioners (GPs).


Results
A total of 1298 individuals participated in the second follow-up round. Median age at baseline was 71.0 years [68.0-76.0] for both groups (n = 662 in the treatment group and n = 636 in the placebo group). No effect of the intervention on first osteoporotic fracture and other fracture risk after a follow up of 5-7 years was observed (HR: 0.99, 95% CI: 0.62; 1.59 and HR: 0.77; 95% CI: 0.50; 1.19, respectively) and also not for cardiovascular- or cerebrovascular disease (OR: 1.14; 95%CI: 0.74-1.74 and OR: 1.01; 95%CI: 0.76-1.33, respectively). Significant interaction for total homocysteine level was observed for osteoporotic- and any fracture (P = 0.10 and 0.06 resp.), which indicated a significantly lower risk of fracture in the intervention group with higher total homocysteine level.


Conclusions
This study does not support a prolonged effect of supplementation of folic acid and vitamin B12 on fracture risk, or on cardiovascular disease in older individuals with elevated homocysteine concentration. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with higher total homocysteine levels.


Funding Sources
The initial B-PROOF study has received funding so far by The Netherlands Organization for Health Research and Development (ZonMw), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovationn, the Hague; Wageningen University, Wageningen; VUmc, Amsterdam; Erasmus Medical Center, Rotterdam.


Supporting Tables Images and/or Graphs