BEYOND MECHANICAL FAILURE: HISTOPATHOLOGICAL AND METABOLIC-BIOCHEMICAL DETERMINANTS OF FRACTURE NONUNION: A NARRATIVE REVIEW

Abstract

Fracture non-union remains a difficult problem in orthopaedic practice despite substantial advances in fixation technique and biologically oriented surgery. Mechanical instability, persistent fracture gap, malalignment and implant-related problems are well-established causes of failure, yet some fractures fail to unite even when fixation appears satisfactory. In these patients the explanation often lies beyond mechanics. Local vascular compromise, altered inflammatory signalling, occult infection, impaired cellular function, nutritional deficiency and systemic metabolic or endocrine abnormalities can each interfere with bone regeneration. Histopathology provides direct evidence of tissue viability, fibrosis, vascularity, osteogenic activity and infection, while biochemical evaluation may identify potentially modifiable abnormalities of vitamin D status, calcium-phosphate metabolism, parathyroid function, glycaemic control and nutrition. Recent work on angiogenic-osteogenic coupling, bone turnover markers, cellular senescence, osteoimmunology, microRNAs, mesenchymal stromal cells and extracellular vesicles has further broadened the conceptual basis of non-union. This narrative review examines fracture non-union from an integrated orthopaedic, pathological and biochemical perspective, with emphasis on work published over the past five years. A phenotype-directed approach that combines reassessment of mechanical stability with histopathology, microbiology and targeted metabolic-biochemical investigation may identify otherwise overlooked causes of failed healing and support more individualised management.