BACKGROUND: Although vitamin K antagonists (VKA) lower serum values of bone deposition markers, the link with osteoporosis and fractures remains controversial. OBJECTIVES: To assess whether the use of VKA is associated with an increased prevalence and/or incidence of osteoporosis, fractures, or lower bone mineral density (BMD) values METHODS: A systematic PubMed and EMBASE literature search until 08/31/2014 and meta-analysis of cross-sectional and longitudinal studies investigating and BMD, comparing patients treated with VKA and healthy controls (HCs) or with patients with medical illness (MCs). Standardized mean differences (SMDs)+/-95% and confidence intervals (CIs) were calculated for BMD; risk ratios (RRs) for prevalent and incident fractures. RESULTS: Of 4,597 initial hits, 21 studies were eligible, including 79,663 treated with VKA vs. 597,348 controls. Compared to HCs, VKA-treated individuals showed significantly higher fracture risk in cross-sectional (studies=3; RR=1.24; 95%CI:1.12-1.39, p<0.0001) and longitudinal studies (studies=7; RR=1.09; 95%CI:1.01-1.18, p=0.03), and more incident hip fractures (studies=4; RR=1.17; 95%CI:1.05-1.31, p=0.003). Analysing studies that matched VKA participants with HCs (studies=4), both these findings in longitudinal studies became non-significant. Notably, the VKA and MC group had similar BMD at all investigated sites. Compared to HCs, one single study showed significantly lower spine T-scores in the VKA-treated group (SMD=-0.45; 95%CI: -0.75, -0.14, p=0.004). CONCLUSION: VKAs neither increased prospectively-assessed fracture risk compared to MCs when matching eliminated confounding factors nor reduced BMD beyond effects of medical illness. Future studies, using careful matching and/or adequate MC groups are needed to further clarify the short- and long-term effects of VKA on bone health. This article is protected by copyright. All rights reserved