Vitamin K antagonists' use and fracture risk: results from a systematic review and meta‐analysis

Abstract

use and fracture risk: results from a systematic review and meta-analysis. J Thromb Haemost 2015; 13: 1665-75.Summary. Background: Although vitamin K antagonists (VKAs) lower serum values of bone deposition markers, the link with osteoporosis and fractures remains controversial. Objectives: 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. Methods: 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 differences AE 95% and confidence intervals (CIs) were calculated for BMD, and risk ratios (RRs) were calculated for prevalent and incident fractures. Results: Of 4597 initial hits, 21 studies were eligible, including 79 663 individuals treated with VKAs vs. 597 348 controls. Compared with HCs, VKA-treated individuals showed significantly higher fracture risk in crosssectional (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 in the VKA-treated group (standardized mean difference = À 0.45; 95% CI: À 0.75, À 0.14, P = 0.004). Conclusion: 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.

Vitamin K antagonists' use and fracture risk: results from a systematic review and meta‐analysis: comment

“…We thank Zhao et al [1] for their careful reading of our recently published meta-analysis [2], in which we assessed the potential relationship between vitamin K antagonists (VKAs) and both bone mineral density and fracture risk, and for their thoughtful comments. The authors raise the following five concerns regarding study methodology and data display: multiple testing; potential for type I error; handling of heterogeneity of results and the use of randomeffects models throughout; method of quality assessment; and data display in forest and funnel plots.…”

Vitamin K antagonists' use and fracture risk: results from a systematic review and meta‐analysis: reply

“…Meta-analysis may result in type I errors because of systematic errors (bias) or random errors (chance) resulting from sparse data and repeated significance testing when a meta-analysis is updated with new trials. In our study [2], we found that the use of VKAs was associated with an increased risk of fractures in prospective studies (relative risk 1.09, 95% confidence interval 1.01-1.18, P = 0.03, I 2 = 0%). With TSA, Zhao et al [1] confirmed our findings of incident fractures, as shown in their Fig.…”

“…Vitamin K antagonists' use and fracture risk: results from a systematic review and meta-analysis: reply We thank Zhao et al [1] for their careful reading of our recently published meta-analysis [2], in which we assessed the potential relationship between vitamin K antagonists (VKAs) and both bone mineral density and fracture risk, and for their thoughtful comments. The authors raise the following five concerns regarding study methodology and data display: multiple testing; potential for type I error; handling of heterogeneity of results and the use of randomeffects models throughout; method of quality assessment; and data display in forest and funnel plots.…”

“…Thus, the issue to guard against in this case is not a type I error, as pointed to by Zhao et al, but a type II error, which would have been more likely had we used the suggested Bonferroni correction. Furthermore, Zhao et al [2] proposed the use of trial sequential analysis (TSA) to account for the risk of random error resulting from repeated testing [3]. Briefly, TSA is a methodology that combines information size calculation (i.e.…”

Level of serum undercarboxylated osteocalcin correlates with bone quality assessed by calcaneal quantitative ultrasound sonometry in young Japanese females

“…Shiraki et al (3) also documented that fracture risk was associated with serum ucOC but not with BMD in osteoporotic patients. A meta-analysis indicated that vitamin K antagonists increased the fracture risk, but did not affect BMD (23). Therefore, vitamin K status should be associated with fracture risk, independent of BMD.…”