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

Abstract

BackgroundRecent 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.MethodsUsing 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.ResultsWhen 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; I2 = 76.8%) for cardiovascular disease, 1.72 for coronary heart disease (1.26, 2.37; P = 0.001; I2 = 83.5%), and 1.58 for stroke (1.18, 2.12; P = 0.002; I2 = 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).ConclusionsElevated osteoprotegerin concentration is associated with an increased risk of incident cardiovascular disease in the general population. The mechanisms underlying this observation deserve further investigation.

Osteoprotegerin and Cardiovascular Events in High‐Risk Populations: Meta‐Analysis of 19 Prospective Studies Involving 27 450 Participants

“…We have previously demonstrated in a literature‐based meta‐analysis that osteoprotegerin is associated with incident CVD in people recruited from the general community 16. A combination of findings from 9 general population studies yielded a pooled relative risk for CVD of 1.83 (95% CI, 1.46‐2.30) for a comparison of extreme osteoprotegerin tertiles.…”

“…Furthermore, genetic studies have demonstrated associations of osteoprotegerin gene polymorphisms with CVD 11, 12, 13, 14, 15. In a literature‐based meta‐analysis of 9 general population studies, we recently demonstrated robust positive associations between osteoprotegerin concentration and incident CVD 16. However, it is unclear whether these associations equally apply to high‐risk populations.…”

Bone markers and cardiovascular risk in type 2 diabetes patients

“…Based on previous meta-analyses, we mainly expected to find an association between osteoprotegerin, alkaline phosphatase and CVD risk [ 17 , 31 ]. A recent meta-analysis showed that elevated osteoprotegerin concentration was associated with increased CVD risk in the general population [ 31 ]. Another study showed increased osteoprotegerin levels in patients with PAD compared to patients without PAD in participants with type 2 diabetes [ 32 ].…”

Osteoprotegerin and Myocardial Fibrosis in Patients with Aortic Stenosis

“…OPG has been shown to induce vascular fibrosis in aortic samples of apolipoprotein E knockout (ApoE[−/−]) mice, via transforming growth factor-β1 (TGF-β1), which also mediates OPG release in response to angiotensin II in vascular smooth muscle cells 41 . A recent meta-analysis including a total of 26,442 participants from the general population demonstrated an association between raised baseline serum OPG and an increased risk of incident cardiovascular disease at a mean follow-up of 8.5 years, independent of age and clinically-relevant risk factors 35 .…”