A Multidimensional Definition of Pre-Osteoarthritis: Toward 21st-Century Subclinical Detection and Targeted Intervention.

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Osteoarthritis (OA) is a leading cause of pain, disability, and healthcare utilization worldwide, yet clinical diagnosis commonly occurs after irreversible structural damage, limiting opportunities for prevention. Advances in molecular profiling, quantitative imaging, biomechanics, and longitudinal cohort studies have identified a reproducible preclinical interval, termed pre-osteoarthritis (pre-OA), during which molecular, compositional, and biomechanical perturbations emerge long before persistent symptoms or radiographic changes. The recognition of pre-OA as a distinct pathophysiologically meaningful stage supports the possibility of earlier targeted interception. Cross-disciplinary studies have consistently reported very early cartilage matrix alterations, pro-catabolic and low-grade inflammatory signatures, and biomechanical and biochemical marker shifts, indicating a critical detection window. Building on these findings, I propose a pheno-endotype-oriented framework to align emerging detection strategies with interventions matched to underlying mechanisms, including lifestyle modification, metabolic modulation, and candidate disease-modifying therapies. These conceptual models are presented for evaluation by clinicians, researchers, and healthcare decision-makers. Translation into practice remains constrained by heterogeneous case definitions, lack of validated thresholds, variability in assays and imaging standards, and limited prospective trials addressing early disease diagnosis. Addressing these barriers will require harmonized consensus criteria, standardized analytic protocols, prospective validation cohorts enriched with high-risk populations, and adaptive biomarker-driven trial designs. Reconceptualizing OA as a continuum with an identifiable preclinical stage provides a foundation for earlier personalized interception strategies with the potential to alter the natural history of the disease and reduce its global burden. If translated successfully, early identification and targeted interception of pre-OA could transform OA from an inevitable consequence of aging into a largely preventable and manageable condition, which would be a paradigm shift with major clinical and public health implications.