Vitamin K antagonists' use and fracture risk: Results from a systematic review and meta-analysis

Although vitamin K antagonists (VKAs) lower serum values of bone deposition markers, the link with osteoporosis and fractures remains controversial. To assess whether the use of VKAs is associated with an increased prevalence and/or incidence of osteoporosis, fractures, or lower bone mineral density (BMD) values. We conducted a systematic PubMed and EMBASE literature search until August 31, 2014, and a meta-analysis of cross-sectional and longitudinal studies investigating fractures and BMD, comparing patients treated with VKAs and healthy controls (HCs) or with patients with medical illness (medical controls, MCs). Standardized mean differences95% and confidence intervals (CIs) were calculated for BMD, and risk ratios (RRs) were calculated for prevalent and incident fractures. Of 4597 initial hits, 21 studies were eligible, including 79 663 individuals treated with VKAs vs. 597348 controls. Compared with HCs, VKA-treated individuals showed significantly higher fracture risk in cross-sectional (three studies; RR=1.24; 95% CI: 1.12-1.39, P<0.0001) and longitudinal studies (seven studies; RR=1.09; 95% CI: 1.01-1.18, P=0.03) and more incident hip fractures (four studies; RR=1.17; 95% CI: 1.05-1.31, P=0.003). Analyzing studies that matched VKA participants with HCs (four studies), both these findings in longitudinal studies became non-significant. Notably, the VKA and MC group had similar BMD values at all investigated sites. Compared with HCs, a single study showed significantly lower spine T-scores inthe VKA-treated group (standardized mean difference=-0.45; 95% CI: -0.75, -0.14, P=0.004). VKAs neither increased prospectively-assessed fracture risk compared with 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 VKAs on bone health.