Osteomyelitis (OM) is a major challenge in orthopedic surgery. The diagnosis of OM is based on imaging and laboratory tests, but it still presents some limitations. Therefore, a deeper comprehension of the pathogenetic mechanisms could enhance diagnostic and treatment approaches. OM pathogenesis is based on an inflammatory response to pathogen infection, leading to bone loss. The present study aims to investigate the potential diagnostic role of a panel of osteoimmunological serum biomarkers in the clinical approach to OM. The focus is on the emerging infection biomarker sCD14-ST, along with osteoimmunological and inflammatory serum biomarkers, to define a comprehensive biomarker panel for a multifaced approach to OM. The results, to our knowledge, demonstrate for the first time the diagnostic and early prognostic role of sCD14-ST in OM patients, suggesting that this biomarker could address the limitations of current laboratory tests, such as traditional inflammatory markers, in diagnosing OM. In addition, the study highlights a relevant diagnostic role of SuPAR, the chemokine CCL2, the anti-inflammatory cytokine IL-10, the Wnt inhibitors DKK-1 and Sclerostin, and the RANKL/OPG ratio. Moreover, CCL2 and SuPAR also exhibited early prognostic value.

Background/Objectives: The COVID-19 pandemic has increased interest in osteoimmunology because of the impact of SARS-CoV-2 on both the immune system and the bone microenvironment. Soluble CD14ST could influence the production of the osteoimmunological regulators of osteoclast differentiation. The aim of this study is to evaluate the role of sCD14ST in COVID-19’s effects on bone remodeling—evaluating, in particular, the correlation with new-generation osteoimmunological biomarkers—and to acquire comprehensive knowledge of the effects of the disease on the immune and skeletal system. Methods: The serum level of sCD14ST was measured in COVID-19-positive and COVID-19-negative patients undergoing orthopedic surgery and correlated with the inflammatory and osteoimmunological biomarkers RANKL/OPG, FGF23, IL-6, C-reactive protein (CRP), procalcitonin (PCT), sRAGE, and SuPAR. Results: In our patients, sCD14ST showed a strong increase in COVID-19-positive patients, and a significant decrease in tandem with the infection resolution, confirming its diagnostic and prognostic value. sCD14ST was more clinically relevant than the two canonically inflammatory makers used in the clinical protocols, CRP and PCT, and displayed a good positive correlation with FGF23, RANKL/OPG, IL-6, and SuPAR and a negative correlation with sRAGE. Conclusions: Monitoring sCD14ST along with SuPAR may offer valuable insights into immune system dysregulation and bone-related complications in conditions characterized by inflammation. These soluble receptors represent important links between immune activation and bone metabolism, especially in the context of diseases like COVID-19, where the inflammatory response may impact bone fragility.