Osteoprotegerin Quartile Research Articles

Prediction of Fractures and Major Cardiovascular Events in Men Using Serum Osteoprotegerin Levels: The Prospective STRAMBO Study.

Fragility fractures and cardiovascular diseases often coincide. However, data on shared risk factors and markers are scarce. Our aim was to assess the independent associations of serum osteoprotegerin (OPG) levels with the risk of fracture and cardiovascular outcomes (acute coronary syndrome, cardiac death) in older men. A cohort of 819 home-dwelling men aged 60 to 87 years was followed prospectively for 8 years. Serum OPG was measured at baseline by ELISA. Bone mineral density (BMD) at femoral neck and Trabecular Bone Score (TBS) were assessed by DXA. Clinical risk factors and Fracture Risk Assessment Tool (FRAX) were assessed. The incident events (self-reported peripheral fractures and acute coronary syndrome, cardiac death reported by a proxy) confirmed by a health professional were retained for the statistical analysis. Incident vertebral fractures were assessed on lateral DXA scans after 4 and 8 years. Hazard risk (HR) was assessed using the Cox model. After adjustment for FRAX corrected for femoral neck BMD and TBS, diabetes mellitus, ischemic heart disease, and prior falls, the risk of fracture was twofold higher in the highest versus the lowest OPG quartile (HR 2.35; 95% CI, 1.35 to 4.10). The risk of vertebral and nonvertebral fracture was higher in the highest versus the lowest OPG quartile (OR 2.76 [95% CI, 1.08 to 7.05] and HR 2.46 [95% CI, 1.23 to 4.92]). The risk of major osteoporotic fracture was higher in the fourth versus the first OPG quartile (HR 2.43; 95% CI, 1.16 to 5.10). The risk of cardiovascular outcome (adjusted for confounders) was higher in the highest versus the lowest OPG quartile (HR 3.93; 95% CI, 1.54 to 10.04). The risk of fracture and cardiovascular outcome was higher in the highest OPG quartile versus the lower quartiles combined (HR 2.06 [95% CI, 1.35 to 3.14] and HR 2.98 [95% CI, 1.60 to 5.54], respectively). In conclusion, in older men, higher serum OPG levels represent an independent risk factor for cardiovascular and fracture risk. © 2017 American Society for Bone and Mineral Research.

Prediction of subclinical atherosclerosis by serum osteoprotegerin in premenopausal women with systemic lupus erythematous: correlation of osteoprotegerin with monocyte chemotactic protein-1

Patients with systemic lupus erythematosus (SLE) have increased risk for cardiovascular disease. Previous studies disclosed the association of serum osteoprotegerin (OPG) with the presence of symptomatic atherosclerosis in the general population and several disease conditions. We thus investigated the association between serum OPG levels and subclinical atherosclerosis in premenopausal SLE patients. Serum OPG levels and carotid artery intima-media thickness (IMT) were measured in 181 premenopausal SLE patients and age-matched 85 control subjects. Traditional cardiovascular risk factors and SLE-related factors were analyzed. Patients with SLE had significantly increased serum OPG levels (1086 versus 517 pg/ml, p < 0.001) and carotid IMT (0.63 versus 0.45 mm, p < 0.001) compared with control subjects. Carotid IMT significantly increased across the quartiles of OPG. Logistic regression analysis revealed that compared to the lowest OPG quartile, the odds ratio (OR, 95% confidence interval) for increased carotid IMT in quartile 2, 3, and 4 was 1.126 (1.013-1.801), 1.562 (1.268-2.799), and 4.460 (1.126-7.128), respectively, after multiple adjustments (p for trend across quartiles < 0.001). These associations remained significant after further adjustment for inflammatory parameters. Interestingly, serum monocyte chemotactic protein-1 (MCP-1) levels were positively correlated with serum OPG levels (γ = 0.332, p < 0.001). Parallel analysis showed that serum MCP-1 was also an independent predictor of carotid IMT incrassation, but this association was lost when serum OPG was included in the model. Serum OPG levels were increased and correlated with serum MCP-1 levels in premenopausal SLE patients. Increased serum OPG was independently associated with subclinical atherosclerosis in these patients.

Osteoprotegerin Predicts Long-Term Outcome in Patients with ST-Segment Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention

Background: Osteoprotegerin (OPG) is a glycoprotein with a regulatory role in immune, skeletal and vascular systems. Data suggest that high circulating OPG levels are associated with an increased risk of cardiovascular disease. We analyzed the association between OPG and long-term outcome in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). Methods: We included 716 consecutive STEMI patients admitted to a single high-volume invasive heart center from September 2006 to December 2008. Endpoints were all-cause mortality, repeat myocardial infarction, admission due to heart failure and combinations thereof. Median follow-up lasted 27 months (interquartile range: 22–33). Results: OPG levels exhibited a non-Gaussian distribution and were therefore divided into quartiles. High levels of OPG were significantly associated with a worse outcome. After adjustment for conventional risk factors (e.g. C-reactive protein, estimated glomerular filtration rate, symptom-to-balloon time and troponin I) using Cox regression, OPG remained a significantly independent predictor of death (HR per increase in OPG quartile: 1.28; CI: 1.03–1.59; p = 0.03), repeat myocardial infarction (HR: 1.30; CI: 1.00–1.68; p = 0.05) and admission with heart failure (HR: 1.50; CI: 1.18–1.90; p = 0.001). Conclusion: This study shows that OPG independently predicts long-term outcome in STEMI patients treated with pPCI. Eventually, this knowledge could improve risk stratification and overall outcome.

Osteoprotegerin is associated with hip fracture incidence: the Tromso Study

Osteoprotegerin (OPG) is a cytokine essential for the regulation of bone resorption, but large longitudinal studies on its relationship to fracture risk in humans are lacking. In this population-based study of 2740 men and 2857 post-menopausal women, it was examined whether serum OPG was associated with hip fracture incidence. The participants were followed for 15 years. Baseline measurements included height, weight and serum OPG, and information about lifestyle, prevalent diseases and use of medication. Men with OPG in the highest quartile were 2.79-fold [95% confidence interval (CI) 1.34-5.82] more likely to have a hip fracture during follow-up, compared with those with OPG in the lowest quartile (P-trend over OPG quartiles ≤ 0.001, after adjustments for age and other confounders). In women not using post-menopausal hormone therapy (HT), the risk of hip fracture was 1.64-fold higher (95% CI 0.94-2.86) in the highest quartile compared with the lowest OPG quartile (P-trend over OPG quartiles = 0.05). No relationship was found in post-menopausal women using HT (P-trend over OPG quartiles = 0.23). In men, OPG was positively associated with the incidence of hip fracture. In post-menopausal women not using HT a similar, but weaker, relationship was found.

Cortical Bone Status Is Associated with Serum Osteoprotegerin Concentration in Men: The STRAMBO Study

Osteoprotegerin (OPG) is an inhibitor of bone resorption, but its relationship to bone microarchitecture remains unclear. Our objective was to study the relationship between OPG concentration and bone microarchitecture in men. We conducted a cross-sectional study of a population-based cohort of 1149 men aged 20-87 yr. We assessed bone microarchitecture at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (XtremeCT Scanco) and measured serum OPG concentration and bone turnover markers: osteocalcin, bone-specific alkaline phosphatase, N-terminal extension type I collagen propeptide, C-terminal type 1 collagen telopeptide, and urinary deoxypyridinoline. Differences were assessed in bone microarchitectural parameters across the OPG quartiles in the models adjusted for age, weight, height, physical activity, ischemic heart disease, diabetes mellitus, calcium intake, serum levels of free testosterone, bioavailable 17β-estradiol, PTH, 25-hydroxycholecalciferol, and creatinine. After adjustment for the confounders, men in the highest (fourth) quartile of OPG levels (>4.55 pmol/liter) had higher total cross-sectional area and trabecular area at the distal radius and distal tibia (3.3-6.0%, P < 0.05). At both skeletal sites, the highest OPG quartile was associated with lower cortical thickness (8.2%, P < 0.001, and 3.7%, P < 0.05) and volumetric bone mineral density (vBMD, 2.7%, P < 0.001, and 1.6%, P < 0.005) compared with the three lower quartiles combined. Associations of OPG level with trabecular vBMD, number, thickness, and distribution were not significant. Men in the fourth OPG quartile had higher levels of bone resorption markers (11.8-13.1%, P < 0.01-0.001). Men with higher serum OPG concentration had lower cortical thickness and vBMD, probably due to accelerated endo- and intracortical bone turnover, but higher cross-sectional area possibly due to periosteal apposition.

Biomarkers of the Osteoprotegerin Pathway

Objective— Experimental evidence identified the osteoprotegerin (OPG)/receptor activator of nuclear factor–κB (RANK)/RANK ligand (RANKL) pathway as a candidate system modulating vascular remodeling and cardiovascular disease (CVD). Methods and Results— Serum concentrations of OPG and RANKL were measured in 3250 Framingham Study participants (54% women, 61±9 years). During a mean follow-up of 4.6 years, 143 (of 3084 free of CVD at baseline) participants developed a first CVD event, and 235 died. In multivariable models, OPG was associated with increased hazards for incident CVD and mortality (hazard ratio, 1.27; 95% CI, 1.04 to 1.54; and hazard ratio, 1.25; 95% CI, 1.07 to 1.47, per 1-SD increment in log-OPG, respectively). Log-OPG was positively related to multiple CVD risk factors, including age, smoking, diabetes, systolic blood pressure, and prevalent CVD. In a subsample (n=1264), the prevalence of coronary artery calcification, measured by computed tomography, increased nonsignificantly with OPG quartiles. RANKL concentrations displayed inverse associations with multiple CVD risk factors, including smoking, diabetes, and antihypertensive treatment, and were not related to coronary artery calcification or incident CVD or mortality. Conclusion— Our prospective data reinforce OPG as marker for CVD risk factor burden and predictor for CVD and mortality in the community.

Osteoprotegerin and Soluble Receptor Activator of Nuclear Factor-κB Ligand and Risk for Coronary Events

The purpose of this study was to examine the association between serum levels of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) and future coronary artery disease (CAD) in apparently healthy individuals. The identification of OPG as a novel cardiovascular risk marker suggests an association between mediators of bone homeostasis and cardiovascular disease. Serum levels of OPG and RANKL were analyzed in a prospective case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study, a cohort study of 25 663 men and women, where 951 apparently healthy individuals who developed a coronary event during 6 years' follow-up were matched by sex and age with 1705 healthy controls. Baseline OPG, but not RANKL, was higher in cases than in controls, and OPG was higher in women than in men. Both men and women in the highest OPG quartile had a higher risk for future CAD. These associations were independent of established cardiovascular risk factors, and when using OPG as a continuous variable, also after adjustment for CRP. In contrast, RANKL showed no association with coronary events. OPG is associated with the risk of future CAD in apparently healthy men and women, independent of established cardiovascular risk factors.

Increased Plasma Osteoprotegerin Concentrations Are Associated with Indices of Bone Strength of the Hip

Osteoprotegerin (OPG) is an important regulator of bone turnover through its effects on osteoclastogenesis, yet findings from previous studies of circulating OPG and commonly measured bone indices in humans have been conflicting. We conducted a cross-sectional study to evaluate the association between plasma OPG and femoral neck (FN) bone density (BMD) and geometry in a large cohort of women and men. Participants included 1379 postmenopausal women and 1165 men, aged 50-89 yr (mean, 64 yr), in the Framingham Offspring Study. Dual x-ray absorptiometry was used to evaluate FN BMD and geometry (bone width, section modulus, and cross-sectional area at the narrow neck region). Plasma OPG concentrations were measured by ELISA. Sex-specific analysis of covariance was used to calculate means and assess linear trend in BMD and geometry values across OPG quartiles, adjusted for confounders. OPG concentrations were greater in women than men, increased with age, and were greater in smokers and those with diabetes and heart disease. Multivariable-adjusted mean FN BMD in women increased from the lowest to the highest OPG quartile (trend, P < 0.01). However, no linear trend between FN BMD and OPG was observed in men (trend, P = 0.34). Section modulus and bone width increased with OPG in men (trend, P < 0.01), whereas no association between hip geometry indices and OPG was observed in women. Higher OPG concentration may indicate greater skeletal strength in women and men, possibly through reducing bone loss in women and increasing periosteal apposition in men.

Relation of Osteoprotegerin to Coronary Calcium and Aortic Plaque (from the Dallas Heart Study)

Circulating osteoprotegerin (OPG) has been shown to be elevated in patients with vascular disease. The role of OPG as a biomarker for atherosclerosis in a large, unselected population is not well known. Plasma OPG levels were measured in 3,386 subjects in the Dallas Heart Study, a multiethnic, population-based probability sample of adults aged 30 to 65 years. Coronary artery calcium (CAC) was measured by electron beam computed tomography. Aortic plaque was assessed by magnetic resonance imaging. Multivariable logistic regression was used to assess associations among OPG, cardiovascular risk factors, CAC, and aortic plaque. Age, female gender, black race, smoking, personal and family history of coronary artery disease (CAD), diabetes mellitus, hyperlipidemia, CAC, and aortic plaque were significantly associated with higher plasma OPG levels (p <0.01) in univariable analyses. The prevalence of CAC and aortic plaque increased across OPG quartiles (p <0.001 for each). An OPG level in the fourth quartile was independently associated with CAC (RR 1.39, 95% confidence interval 1.01 to 1.93) and aortic plaque (RR 1.42, 95% confidence interval 1.09 to 1.86) after adjustment for age, gender, smoking, diabetes, hyperlipidemia, and family history of premature CAD. In conclusion, plasma OPG is independently associated with CAC and aortic plaque in an unselected population, suggesting it may be a novel biomarker for atherosclerosis in humans.

Assessment of a Serum Assay for Quantification of Abdominal Aortic Calcification

Intimal vascular calcification is an important marker of atherosclerosis, and its severity is an independent risk factor for cardiovascular events. Measurement of coronary or aortic calcification requires CT-based imaging and elaborate data analysis to ensure accuracy. A blood assay which could quantify the severity of vascular calcification would be less expensive, avoid exposure to radiation, and be more accessible than present imaging based methods. Osteoprotegerin (OPG) and osteopontin (OPN) are present in human serum and have been implicated in vascular calcification. In this prospective study we assessed the value of a number of serum assays for OPG and OPN in determining abdominal aortic calcification. Firstly, we investigated the assay characteristics and reproducibility of 5 ELISAs using a subset of patients. Based on the findings of these assessments, we selected 3 assays for full evaluation in the entire cohort.

Abstract 4204: Osteoprotegerin Levels and Risk of Future Cardiovascular Events in Apparently Healthy Men and Women: the Prospective EPIC-Norfolk Population Study 1993–2003

Introduction: The identification of osteoprotegerin (OPG) as a novel cardiovascular risk marker suggests an association between mediators of bone homeostasis and cardiovascular disease. OPG is a member of the tumour necrosis factor (TNF) superfamily, and functions as a soluble decoy receptor for RANKL. There is no epidemiological evidence that OPG levels predict future coronary events in healthy individuals. It was therefore our objective to study the prospective relationship between plasma levels of OPG and the risk of future CAD in such a population. Methods and Results: A nested case-control study among participants of the European prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study, a prospective population study of 25 663 men and women between 45 and 79 years of which 988 apparently healthy individuals developed coronary artery disease (CAD) were matched by sex and age with 1812 healthy controls which did not develop CAD. Baseline OPG was higher in cases than in controls [6957 pg/ml (5778 – 8727) vs. 6602 pg/ml (5434–8242) (p&lt;0.005) median and interquartile range], and significantly higher in women than men in both cases and controls. Using OPG quartiles based on the distribution among controls, baseline OPG levels were independently correlated with fatal and non fatal coronary events and the risk increased continuously (p for linearity= 0.008 men, p=0.01 women), also when adjusted for age, smoking, diabetes, body mass index, LDL, HDL, systolic blood pressure, this strong relationship still existed. When adjusted for log (CRP) as well, the OR in the highest OPG quartile was 2.17(0.86–5.49)(95% CI)(p=0.04) for women and 2.78 (1.45–5.32)(p&lt;0.001) for men. Conclusion: Among apparently healthy men and women, an elevated level of OPG is associated with increased risk of future fatal and non fatal CAD.