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 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

Additional file 4: of Upper zone of growth plate and cartilage matrix associated protein protects cartilage during inflammatory arthritis

Recombinant Ucma does not affect bone phenotype during SIA. SIA induced in WT C57/Bl6 mice by K/BxN serum transfer at day 0 and treated with daily i.p. injection of recombinant Ucma or carrier (PBS). Bone histomorphometry at 10 days after serum transfer revealed no effect of systemic Ucma administration on bone erosion (A), absolute and relative osteophyte size (B, C) or osteoclast numbers (D) and surface (E) in hind paws. Er.V/BV volume of bone erosion per total bone volume, Op.Ar. maximal absolute osteophyte area, Op.Ar/B.Ar. relative osteophyte area (osteophyte area per bone area), N.Oc./B.Pm osteoclast numbers per bone perimeter, Oc.S/B.S. osteoclast surface/bone surface. Means ± SEM shown; n = 3 or 5 per group (PDF 474 kb

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

Additional file 3: of Upper zone of growth plate and cartilage matrix associated protein protects cartilage during inflammatory arthritis

Gene expression studies. A–H Gene expression in joint tissue from hind paws of non-arthritic controls (Ctrl.) and wild-type (WT) and Ucma-deficient (Ucma−/−) mice with serum-induced arthritis (SIA). Total RNA extracted from joint tissue from hind paws of respective mice. Gene expression analysed by real-time RT-PCR and normalised against cyclophilin A mRNA levels. Means ± SEM shown; n = 3 per group. ADAMTS A disintegrin-like and metalloproteinase with thrombospondin-1 motifs, MMP matrix metalloproteinase, Rankl receptor-activator of nuclear factor kappa B ligand, Opg osteoprotegerin (PDF 594 kb

Additional file 1: of Upper zone of growth plate and cartilage matrix associated protein protects cartilage during inflammatory arthritis

Primer sequences (DOCX 32 kb

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

Additional file 2: of Upper zone of growth plate and cartilage matrix associated protein protects cartilage during inflammatory arthritis

Ucma physically interacts with ADAMTS5. Ucma–ADAMTS5 interactions investigated by slot blot binding assays: indicated amounts of recombinant ADAMTS5 blotted onto PVDF membrane incubated with recombinant FLAG-tagged Ucma (upper panel) or BSA (lower panel) and bound Ucma detected using rabbit anti-Ucma antibody (UCMA-1; 1:1000) and anti-rabbit IgG-HRP. Collagen II blotted as positive control. Representative data from two independent experiments (PDF 254 kb

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