The Evolving Landscape of Cardiovascular Prediction in Diabetes
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality among individuals living with type 2 diabetes mellitus (T2DM). Despite significant advancements in glucose-lowering therapies and lipid management, the residual risk for heart failure, myocardial infarction, and stroke remains alarmingly high. Traditional risk factors such as age, smoking, hypertension, and LDL cholesterol provide a foundation for assessment, but they often fail to capture the complex biological interactions occurring at the vascular level. Emerging research suggests that the keys to better prediction may lie in an unexpected place: bone metabolism. The biological crosstalk between the skeleton and the cardiovascular system, often referred to as the bone-vascular axis, has become a focal point for identifying new biomarkers that can signal vascular damage long before clinical events occur.
Understanding the Molecular Players: OPG and TRAIL
To understand why bone proteins matter for the heart, we must look at the OPG/RANKL/TRAIL signaling pathway. Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor superfamily. Its primary role in the skeletal system is to act as a decoy receptor for RANKL (Receptor Activator of Nuclear Factor kappa-B Ligand). By binding to RANKL, OPG prevents it from interacting with its receptor, RANK, thereby inhibiting the maturation and activation of osteoclasts, the cells responsible for bone resorption. However, OPG is not confined to the bones; it is also expressed in the heart, arteries, and veins. In the vascular system, OPG is thought to play a role in regulating calcification and inflammation. Paradoxically, while OPG appears to be protective in some experimental models, clinical studies consistently show that elevated serum levels of OPG are associated with advanced atherosclerosis and increased cardiovascular risk. Tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is another protein that interacts with this system. TRAIL is known for its ability to induce programmed cell death (apoptosis) in various cells, including those within atherosclerotic plaques. A decrease in TRAIL levels, combined with an increase in OPG, creates a ratio that reflects a state of vascular vulnerability.
Clinical Evidence: The OPG/TRAIL Ratio in Type 2 Diabetes
A recent single-centre observational study involving 133 participants has shed new light on the diagnostic utility of these markers. The study compared individuals with T2DM who had a history of cardiovascular events within the last five years against those with a new diagnosis of T2DM and a healthy control group. The results were striking. Participants with both T2DM and established CVD exhibited significantly higher OPG/TRAIL ratios compared to the other groups. After adjusting for potential confounding variables such as age, body mass index, and duration of diabetes, the OPG/TRAIL ratio remained a robust independent predictor of CVD presence. Specifically, the researchers identified a cut-off value of 38.6 for the OPG/TRAIL ratio. This threshold predicted the presence of cardiovascular disease with a sensitivity of 80% and a specificity of 82%, suggesting that this ratio could serve as a valuable tool for clinicians to identify high-risk patients who require more intensive monitoring or aggressive preventive therapy.
The Impact of Bone Biomarkers on Major Adverse Cardiovascular Events
Further evidence of the importance of bone metabolism in cardiovascular health comes from the EXSCEL (Exenatide Study of Cardiovascular Event Lowering) trial. This large-scale randomized clinical trial utilized proteomic profiling to evaluate thousands of participants with type 2 diabetes. The analysis focused on four bone metabolism biomarkers: osteoprotegerin, osteopontin, sclerostin, and osteocalcin. The study aimed to determine if these markers could predict Major Adverse Cardiovascular Events (MACE), which include CV death, nonfatal myocardial infarction, and nonfatal stroke. The findings indicated that higher levels of both osteoprotegerin and osteopontin were significantly associated with an increased risk of MACE. Even when integrated into clinical predictive models that already included traditional risk factors, these biomarkers provided incremental value, though the clinical magnitude was modest. Interestingly, other markers like osteocalcin showed a non-linear association with mortality, highlighting the complexity of these pathways. These insights support the hypothesis that the pathways involved in bone turnover are deeply integrated with the mechanisms of vascular aging and atherosclerotic progression.
Vascular Dysfunction in Chronic Kidney Disease
The relationship between bone markers and the heart is perhaps most pronounced in patients with chronic kidney disease (CKD), particularly those in stage 5 or undergoing dialysis. These patients experience a unique phenomenon known as CKD-Mineral and Bone Disorder (CKD-MBD), where imbalances in calcium, phosphate, and bone proteins lead to rapid and severe vascular calcification. Research focusing on hemodialyzed patients has confirmed that OPG plasma concentrations are significantly higher in this population compared to healthy controls. In these patients, OPG and the OPG/TRAIL ratio are not just markers of existing disease but are predictive of long-term mortality. OPG levels have shown strong positive correlations with objective measures of vascular damage, such as aortic pulse wave velocity (AoPWV), which measures arterial stiffness, and carotid artery intima-media thickness (CCA-IMT), a marker of subclinical atherosclerosis. The fact that these relationships remain significant even after adjusting for classical risk factors underscores the potential of bone-derived proteins as independent indicators of cardiovascular health in the setting of renal failure.
Diagnostic Utility and Future Clinical Application
The clinical utility of measuring the OPG/TRAIL ratio or osteopontin lies in the potential for personalized medicine. Currently, many patients with type 2 diabetes or early-stage CKD may appear to be at moderate risk based on standard calculators but may actually harbor significant vascular pathology. By incorporating these biomarkers into routine screening, physicians could potentially stratify risk more accurately. For instance, a patient with T2DM and a high OPG/TRAIL ratio might be a candidate for more frequent cardiac imaging or the earlier initiation of cardioprotective agents like SGLT2 inhibitors or GLP-1 receptor agonists, regardless of their current lipid or glucose levels. However, challenges remain before these tests can be widely adopted. Standardizing ELISA measurements across different laboratories is crucial, as is the establishment of universal reference ranges across diverse ethnic populations. Furthermore, while the association between these markers and CV events is clear, more research is needed to determine if lowering OPG levels—or modulating the RANK/RANKL pathway directly—can actually reduce cardiovascular events.
Conclusion
The intersection of endocrinology, nephrology, and cardiology is revealing a sophisticated biological dialogue where the skeleton serves as a metabolic organ influencing vascular outcomes. The OPG/TRAIL ratio and associated bone biomarkers like osteopontin represent a significant leap forward in our understanding of cardiovascular risk in vulnerable populations. As we move away from a one-size-fits-all approach to diabetes and kidney care, these molecular insights provide a path toward earlier detection, more precise risk assessment, and ultimately, better survival for patients at risk of cardiovascular complications.
References：
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Kuźniewski M, Fedak D, Dumnicka P, Stępień E, Kuśnierz-Cabala B, Cwynar M, Sułowicz W. Osteoprotegerin and osteoprotegerin/TRAIL ratio are associated with cardiovascular dysfunction and mortality among patients with renal failure. Adv Med Sci. 2016 Sep;61(2):269-275. doi: 10.1016/j.advms.2016.03.003. Epub 2016 Mar 21. PMID: 27128817.
Maddaloni E, Nguyen M, Shah SH, Holman RR. Osteoprotegerin, Osteopontin, and Osteocalcin Are Associated With Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL. Diabetes Care. 2025 Feb 1;48(2):235-242. doi: 10.2337/dc24-1455. PMID: 39576722.
