Callus geometry as a reflection of fracture healing biology and a candidate imaging biomarker: A systematic review of biological, mechanical, and clinical evidence.

Abstract

Fracture healing is a complex, multiscale process governed by the interaction between biological activity and mechanical environment, and fracture callus geometry represents an integrated manifestation of these processes. Although callus morphology is routinely assessed during healing, its value as an objective and predictive marker of mechanical competence and clinical outcome has not been systematically established. This review synthesizes current experimental and clinical evidence to clarify the determinants of callus geometry and to evaluate its potential as an early indicator of fracture healing. A systematic review was conducted in accordance with the PRISMA guidelines, using major databases to identify preclinical and clinical studies reporting qualitative or quantitative measures of fracture callus geometry. Eligible studies examined biological, mechanical, systemic, or pharmacologic influences on callus formation, or assessed associations between callus morphology and biomechanical strength or clinical healing outcomes. Extracted data included study design, fracture model, imaging modality, geometric parameters, and functional endpoints. Given substantial heterogeneity in models, measurement techniques, and assessment timing, findings were synthesized narratively. Forty-eight studies met the inclusion criteria. Across species and fracture models, callus geometry consistently reflected the underlying healing environment. Angiogenic and osteoanabolic interventions, including deferoxamine, platelet-rich plasma, and sclerostin inhibition, were associated with larger, more mineralized, or better-organized calluses, highlighting the importance of vascular and osteoblastic signaling. In contrast, chronic PTH or PTHrP stimulation often produced smaller yet structurally organized calluses, underscoring the need to interpret geometric measures within a biological context. Advanced imaging studies demonstrated strong associations between microarchitectural features and mechanical strength, while automated and CT-based methods improved reproducibility and translational feasibility. Non-modifiable factors such as metabolic disease, systemic inflammation, and traumatic brain injury also produced characteristic alterations in callus morphology. Overall, callus geometry emerges as a biologically meaningful and mechanically informative marker of fracture repair. Standardized, quantitative assessment of callus geometry shows promise as a candidate imaging biomarker of healing trajectory and warrants prospective clinical validation before a prognostic role can be established.