Sclerostin downregulation in aseptic loosening

Aims: Aseptic loosening is one of the leading indications for revision surgery after total hip and knee arthroplasty, yet its diagnosis and underlying mechanisms remain poorly defined. In this exploratory study, we investigated synovial fluid biomarkers and periprosthetic bone tissue characteristics to identify molecular signatures associated with aseptic loosening. Methods: A total of 40 patients were included across three groups: primary osteoarthritis (OA; n = 13), aseptic loosening (n = 15), and other aseptic revisions (n = 12). Routine blood tests and synovial cytology were obtained. Synovial fluid underwent targeted proteomic profiling. Trabecular bone was assessed by histomorphometry, quantitative backscattered electron imaging, and immunofluorescence. Results: Routine blood (CRP, white blood cell (WBC) count) and synovial (WBC count and differential) analyses showed no differences between groups, underscoring their limited diagnostic utility. In contrast, bone-focused multiplex synovial fluid profiling identified sclerostin as the strongest discriminatory marker, with significantly lower levels in aseptic loosening than in OA and other aseptic revisions. Dickkopf-1 showed a concordant but weaker reduction, reaching significance versus OA. Histomorphometric analysis of periprosthetic trabecular bone samples demonstrated preserved microarchitecture and turnover across groups. However, quantitative backscattered electron imaging revealed enlarged osteocyte lacunae specifically in aseptic loosening. Immunofluorescence confirmed reduced sclerostin expression within periprosthetic bone, mirroring synovial fluid findings. Synovial sclerostin demonstrated promising diagnostic potential, achieving an area under the curve (AUC) of 0.82 for differentiating aseptic loosening from other revision indications. Conclusion: This study showcases osteocyte dysregulation as a key feature of aseptic loosening, and suggests that reduced osteocyte-derived sclerostin may reflect adaptive responses to abnormal mechanical and inflammatory stimuli at the implant-bone interface. Larger prospective studies are required to validate these findings, but osteocyte-derived sclerostin may represent a promising biomarker and potential therapeutic target in aseptic loosening.