Decoupling Structural and Vascular Biomarkers in Contrast-Enhanced Mammography: A Methodological Synthesis and Perspective.

Background: Breast density (BD) and background parenchymal enhancement (BPE) have long been considered related descriptors of breast tissue composition, yet growing evidence shows that they represent distinct and non-interchangeable physiological domains. Objective: This study aims to evaluate whether BD and BPE represent independent imaging biomarkers with distinct systemic associations, and to investigate their potential role in preventive medicine beyond breast cancer detection. Methods: Drawing on linear modeling, neural analyses, inverse prediction, and correlation studies conducted across five coordinated investigations, we evaluated the systemic associations of BD and BPE. We also performed model ablation analyses to confirm biomarker independence and assessed the impact of AI support on inter-reader agreement and workflow efficiency. Results: BD is strongly associated with bone mineral density, supporting its role as a structural marker linked to osteoporotic risk. Conversely, BPE correlates with systolic blood pressure (SBP), reflecting vascular tone and perfusion. Importantly, the systemic information carried by BD can be extracted not only from contrast enhanced mammography (CEM) but also from standard mammography. When CEM is available, BPE adds complementary insight into vascular physiology. Furthermore, AI support improved inter-reader agreement and workflow efficiency. Conclusions: These findings support a dual biomarker framework in which BD and BPE independently contribute to systemic risk stratification. This approach suggests potential for opportunistic osteoporosis risk assessment from routine screening examinations, though prospective validation is required before clinical implementation. This framework may shift breast imaging toward a broader, sustainable, and human-centered approach to preventive health.