Osteoprotegerin concentration and risk of cardiovascular outcomes in nine general population studies: Literature-based meta-analysis involving 26,442 participants

<div><p>Background</p><p>Recent experimental and epidemiological studies have suggested that osteoprotegerin, a key regulator in bone metabolism, may be involved in vascular calcification and atherosclerosis. Our aim was to reliably quantify the associations of osteoprotegerin concentration and incidence of first-ever cardiovascular disease outcomes in the general population.</p><p>Methods</p><p>Using the electronic databases MEDLINE, EMBASE and Web of Science (January 1975 and April 2017, no language restrictions), nine relevant studies were identified involving a total of 26,442 participants recruited from the general population. Over a mean follow-up of 8.5 years, 2,160 cardiovascular disease, 2,123 coronary heart disease, and 1,102 stroke outcomes were recorded. Study-specific risk ratios were combined with random-effects meta-analysis.</p><p>Results</p><p>When comparing individuals in the top with those in the bottom third of osteoprotegerin concentration, the combined risk ratio was 1.83 (95% confidence interval: 1.46, 2.30; P<0.001; <i>I</i>² = 76.8%) for cardiovascular disease, 1.72 for coronary heart disease (1.26, 2.37; P = 0.001; <i>I</i>² = 83.5%), and 1.58 for stroke (1.18, 2.12; P = 0.002; <i>I</i>² = 65.2%). Associations appeared stronger at younger age (P = 0.018 for cardiovascular disease), in studies that did not employ statistical adjustment (P = 0.023 for cardiovascular disease and 0.018 for coronary heart disease), and potentially in studies that measured osteoprotegerin in plasma rather than in serum (P = 0.005 for cardiovascular disease and 0.018 for coronary heart disease). Magnitudes of associations did not differ according to the proportion of males, geographical region, or osteoprotegerin assay manufacturer. There was no evidence for publication bias for any of the outcomes assessed (all P>0.05).</p><p>Conclusions</p><p>Elevated osteoprotegerin concentration is associated with an increased risk of incident cardiovascular disease in the general population. The mechanisms underlying this observation deserve further investigation.</p></div

Relative risks for cardiovascular outcomes in the top vs bottom third of osteoprotegerin concentration according to categories of study characteristics.

<p>^aP values were derived from meta-regression. Levels of adjustment: o, unadjusted; +, adjusted for age and sex; ++, additionally adjusted for at least one non-blood based risk factor and one blood-based risk factor.</p

Relative risks for cardiovascular outcomes in the top vs bottom third of osteoprotegerin concentration according to average age and proportion of males in contributing studies.

<p>P values were derived from meta-regression. The marker size is proportionate to the inverse variance of the study-specific relative risk.</p

Relative risks for cardiovascular outcomes in the top vs bottom third of osteoprotegerin concentration according to average age and proportion of males in contributing studies.

<p>P values were derived from meta-regression. The marker size is proportionate to the inverse variance of the study-specific relative risk.</p

Search terms used to identify relevant articles.

<p>Search terms used to identify relevant articles.</p

Characteristics of nine prospective population-based studies included in the meta-analysis.

<p>Characteristics of nine prospective population-based studies included in the meta-analysis.</p

Combined relative risk for cardiovascular outcomes in the top vs. the bottom third of OPG concentration.

<p>CHD = coronary heart disease; CI = confidence interval; CVD = cardiovascular disease; OPG = osteoprotegerin. Full study names are listed in the footnote of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0183910#pone.0183910.t002" target="_blank">Table 2</a>. Sizes of data markers indicate the weight of each study in the analysis. Study-specific relative risks were pooled using random-effects meta-analysis.</p

Baseline characteristics of coronary heart disease cases and matched controls in the Reykjavik Study, and correlations with t-PA antigen, D-dimer and VWF.

<p>Abbreviations: ESR, erythrocyte sedimentation rate; IQR, inter-quartile range.</p>*<p>Means (SDs) of log_e transformed values in cases and controls were 0.2 (0.5) and 0.0 (0.4) for triglycerides; 4.4 (1.6) and 4.0 (1.7) for lipoprotein (a); 0.8 (0.8) and 0.7 (0.8) for interleukin 6; 0.5 (1.1) and 0.2 (1.1) for C-reactive protein; 2.0 (1.0) and 1.9 (1.0) for erythrocyte sedimentation rate; 2.6 (0.5) and 2.5 (0.5) for t-PA antigen; 4.8 (1.0) and 4.8 (1.0) for D-dimer; and 4.7 (0.4) and 4.6 (0.4) for VWF.</p>†<p>Percentage differences and 95% CIs were calculated per 1 SD higher level or compared to the reference category of variables shown in the left column (adjusted for age, sex and period of recruitment).</p

Characteristics of 21 published prospective studies of t-PA antigen, D-dimer and VWF.

<p><b>Abbreviations:</b><b>AmB</b>, American Bioproducts; <b>AmD</b>, American Diagnostica; <b>AP</b>, angina pectoris; <b>ARIC</b>, Atherosclerosis Risk in Communities Study; <b>BRHS</b>, British Regional Heart Study; <b>BWHHS</b>, British Women’s Heart and Health Study; <b>Caerphilly</b>, Caerphilly Prospective Study; <b>CHD</b>, coronary heart disease endpoint (composed of nonfatal myocardial infarction and coronary death); <b>CHS</b>, Cardiovascular Health Study; <b>CS</b>, coronary surgery; <b>DStago</b>, Diagnostica Stago; <b>EAS</b>, Edinburgh Artery Study; <b>ELISA</b>, enzyme-linked immunosorbent assay; <b>FHS</b>, Framingham Heart Study; <b>Fletcher</b>, Fletcher Challenge Study; <b>Glostrup</b>, Glostrup population studies; <b>IRE</b>, Ireland; <b>IT</b>, immunoturbidometry; <b>MESA</b>, Multi-Ethnic Study of Atherosclerosis; <b>MI</b>, myocardial infarction; <b>NPHS-I</b>, Northwick Park Heart Study I; <b>NSHDS</b>, Northern Sweden Health and Diseases Study cohort; <b>PHS</b>, Physicians’ Health Study; <b>PRIME</b>, Prospective Epidemiological Study of Myocardial Infarction; <b>PROSPER</b>, Prospective Study of Pravastatin in the Elderly at Risk; <b>NI</b>, Northern Ireland; <b>NL</b>, Netherlands; <b>NR</b>, not reported; <b>NZ</b>, New Zealand; <b>R&D Sys</b>, R&S Systems; <b>RE</b>, rocket electrophoresis; <b>Rotterdam</b>, Rotterdam Study; <b>SCO</b>, Scotland; <b>Speedwell</b>, Speedwell Study; <b>Three-City</b>, Three-City cohort study; <b>WHI</b>, Women’s Health Initiative; <b>WOSCOPS</b>, The West of Scotland Coronary Prevention Study.</p>*<p>Reports with two different study baselines and non-overlapping follow-up periods are available.</p>†<p>Median.</p>‡<p>Maximum.</p>§<p>Range.</p>||<p>Geometric mean.</p