Association of Circulating Osteocalcin with Cardiovascular Disease and Intermediate Cardiovascular Phenotypes: Systematic Review and Meta-Analysis

Objectives: Circulating osteocalcin (OC), a marker which is central in bone mineralization, may be involved in the atherosclerotic process and influence the risk of developing cardiovascular disease (CVD). We conducted a systematic review and meta-analysis of published observational evidence, to assess and quantify the associations of circulating OC (total, undercarboxylated, and carboxylated OC) with cardiovascular outcomes (clinical CVD endpoints and intermediate cardiovascular phenotypes). Design: Relevant studies were identified in a literature search of MEDLINE, EMBASE, and reference lists of relevant studies to March 2019. Mean differences and risk ratios with 95% CIs were aggregated using random-effects models. Results: Thirty-three observational studies (prospective and retrospective cohort, case-control, and cross-sectional) with data on 21,021 unique participants were eligible. The pooled risk ratio in a comparison of extreme fourths of total OC levels was 0.98 (95% CI 0.89, 1.08) for composite CVD. Circulating total OC levels were significantly lower in patients with cardiovascular conditions compared with those without these conditions -2.58 ng/ml (95% CI -3.85, -1.32; p < 0.001). Prospective and cross-sectional data showed significant inverse associations between total OC and traits such as aortic or coronarycalcification, coronary atherosclerosis or calcification, carotid intima-media thickness, and plaque score. There was limited data on carboxylated and undercarboxylated OC, with no evidence of associations. Conclusion: Observational evidence generally supports inverse associations of circulating total OC with risk of atherosclerotic outcomes and CVD endpoints; however, the data were mostly based on cross-sectional evaluations. Large-scale prospective data are needed.