Association of circulating osteocalcin with cardiovascular disease and intermediate cardiovascular phenotypes: systematic review and meta-analysis

Background: 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). Aims: 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). Methods: Relevant studies were identified in a literature search of MEDLINE, EMBASE, and reference lists of relevant studies to April 2018. Mean differences and risk ratios with 95% CIs were aggregated using random-effects models. Results: Thirty observational studies (prospective cohort, case-control, and cross-sectional) with data on 20,212 unique participants were eligible. The pooled risk ratio in a comparison of extreme fourths of total OC levels was 0.93 (95% CI 0.69, 1.25) for composite CVD. Circulatingtotal OC levels were significantly lower in patients with cardiovascular conditions compared with those without these conditions -3.08 ng/ml (95% CI -4.75, -1.40; p<0.001). Prospective and cross-sectional data showed significant inverse associations between total OC and traits such as aortic or coronary calcification, 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 and independent 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.