Elevated homocysteine levels and low vitamin B12 and folate levels have been associated with deteriorated bone health. This systematic literature review with dose-response meta-analyses summarizes the available scientific evidence on associations of vitamin B12, folate, and homocysteine status with fractures and bone mineral density (BMD). Twenty-seven eligible cross-sectional ( ) and prospective ( ) observational studies and one RCT were identified. Meta-analysis on four prospective studies including 7475 people showed a modest decrease in fracture risk of 4% per 50？pmol/L increase in vitamin B12 levels, which was borderline significant (RR = 0.96, 95% CI = 0.92 to 1.00). Meta-analysis of eight studies including 11511 people showed an increased fracture risk of 4% per μmol/L increase in homocysteine concentration (RR = 1.04, 95% CI = 1.02 to 1.07). We could not draw a conclusion regarding folate levels and fracture risk, as too few studies investigated this association. Meta-analyses regarding vitamin B12, folate and homocysteine levels, and BMD were possible in female populations only and showed no associations. Results from studies regarding BMD that could not be included in the meta-analyses were not univocal. 1. Introduction Osteoporosis is a chronic, multifactorial disorder which is characterized by low bone mass and microarchitectural deterioration of bone tissue [1]. Its major consequence is fractures. Especially hip fractures are frequently associated with institutionalization and increased mortality, and thus with an increased social and economic burden. This burden is expected to increase substantially in Europe in the coming decades due to a rise in life expectancy [2]. Elevated homocysteine concentrations and low vitamin B12 and folate status have been associated in several studies with lower bone mineral density (BMD) and higher fracture risk in elderly [3–11]. An elevated plasma homocysteine level (>15？μmol/L) is prevalent in 30–50% of people older than 60 years [12–14]. The cause is multifactorial; a combination of environmental and genetic factors, nutrition, lifestyle, and hormonal factors [15]. Vitamin B12 and folate are major determinants of homocysteine metabolism [16, 17] and supplementation with vitamin B12 and folic acid has been shown to be effective in normalizing homocysteine levels [18, 19]. Reversing elevated homocysteine levels through folic acid and vitamin B12 supplementation could theoretically prevent the problem of impaired bone health and osteoporosis. However, at present, no consensus is reached on the magnitude of
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