The association of homocysteine, folate, vitamin B12, and vitamin B6 with fracture incidence in older adults: a systematic review and meta-analysis

Background: Diverse conclusions have been drawn regarding the association of homocysteine (HCY) deficiency and supplements of B vitamins with fracture incidence in older adults. The aim of this meta-analysis was to investigate the association of HCY and B vitamins (folate, vitamin B12, and B6) with fracture incidence in older adults and whether supplements of B vitamins reduce the risk of fracture. Methods: The PubMed, Embase, and Cochrane library databases were systematically searched from their inception dates to 1 July 2019 to identify relevant published articles. Meta-analysis was performed to pool hazard ratios (HRs) or risk ratios (RRs) and 95% confidence intervals (CIs) using a random effects model. Results: A total of 28 studies fulfilled the inclusion criteria. High serum HCY was an independent risk factor for fractures in older persons (HR =1.25, 95% CI: 1.12 to 1.40), but only at the highest quartile level (>15 mu mol/L) (HR =1.71, 95% CI: 1.37 to 2.12), rather than the second and third quartile. Multiple sensitivity and subgroup analyses supported the consistency and stability of this result. A severe deficiency of folate, instead of vitamin B12 and B6, was found to increase the risk of fracture in older adults (HR =1.46, 95% CI: 1.06 to 2.02; 1.24, 95% CI: 0.79 to 1.95; 1.36, 95% CI: 0.90 to 2.06, respectively). For the interventional effect, there was no significant association of combined folate and vitamin B12, combined folate, vitamin B12 and B6, or single vitamin B6 supplementation with the decrease of fracture risk. Discussion: This meta-analysis revealed that significantly elevated serum level of HCY is positively associated with fracture incidence in older adults, yet the necessity and threshold for intervention by B vitamins require further large-scale high-quality clinical trials to validate. PROSPERO identifier: CRD42019122586.