Rethinking Bacterial Osteolysis: Translational Evidence From a Porcine Model and Fracture-Related Infections.

Bone and joint infections (BJIs) are debilitating conditions that reduce quality of life. Key features include interosseous bacteria, biofilm formation, suppurative inflammation, and osteolysis. Traditionally, bacteria-associated osteolysis has been attributed to RANKL-mediated osteoclast activation, based largely on in vitro and murine studies, but emerging evidence challenges this view. In this translational study, a porcine implant-associated osteomyelitis (IAO) model was combined with clinical fracture-related infection (FRI) data to investigate mechanisms of bone loss. In the IAO model, RANKL signaling was inhibited using Denosumab, yet pathological and radiographic osteolysis remained unchanged. Local RANKL mRNA expression and active osteoclast numbers also did not correlate with bone destruction. In FRI patients, mRNA in situ hybridization showed that MMP1 expression was higher in osteolytic cases compared to non-osteolytic ones, whereas RANKL expression did not differ. The technique revealed heterogeneous expression of MMP1 and RANKL, in contrast to uniform C3 expression. The number of active osteoclasts likewise did not correlate with osteolysis severity, and a patient with chronic osteomyelitis receiving Denosumab for osteoporosis still experienced extensive bone loss. These findings do not refute the RANKL-osteoclast pathway but indicate that bacteria-associated osteolysis is multifactorial, shaped by inflammatory and osteoimmunological interactions, proteolysis, neutrophil activity, and impaired osteogenesis.