The role of M1 and M2 macrophage polarization in progression of medication-related osteonecrosis of the jaw.

OBJECTIVES: The aim of this study was to investigate the relationship between M1 and M2 macrophage polarization and clinical stage in patients with medication-related osteonecrosis of the jaw (MRONJ) who underwent treatment with bisphosphonates or denosumab. MATERIALS AND METHODS: M1 and M2 macrophage density and expression of interleukin (IL)-6 and IL-10 were assessed on biopsies of mucosal tissues surrounding necrotic bone in 30 MRONJ patients with stages 1-3 and controls. For identification of M1 and M2 macrophages, double CD68/iNOS and CD68/CD206 immunofluorescence staining was conducted, respectively. Computer-assisted immunofluorescence quantification of markers was performed. RESULTS: Early stage 1 MRONJ patients showed a switch toward the M2 phenotype, as indicated by the higher density of M2 macrophages, the decreased M1/M2 ratio, and the upregulation of IL-10. MRONJ patients with advanced stages 2 and 3 showed a shift toward M1-polarized macrophages, as suggested by the higher density of M1 macrophages, the increased M1/M2 ratio, and the overexpression of IL-6. The macrophage density of both M1 and M2 subsets was significantly enhanced in patients receiving bisphosphonates compared with those receiving denosumab. CONCLUSIONS: The M1-M2 macrophage polarization status in mucosal tissues bordering necrotic bone correlates with clinical stage of MRONJ. Patients with early-stage MRONJ show a switch toward M2-polarized macrophages, while MRONJ patients with advanced stage demonstrate a shift toward the M1 phenotype. CLINICAL RELEVANCE: Therapeutic molecules targeting the inflammatory microenvironment via the regulation of either M1 or M2 macrophage polarization may represent a novel strategy for treatment of MRONJ.

Chronic Osteomyelitis With Proliferative Periostitis of the Mandible in a Child: Report of a Case Managed by Immunosuppressive Treatment.

BACKGROUND: Osteomyelitis with proliferative periostitis is a relatively uncommon inflammatory condition of the jaws, mainly characterized by periosteal formation of reactive bone. It primarily affects children and adolescences, also referred to as Garre's osteomyelitis, more frequently involving the molar region of the mandible. Cases lacking an obvious source of infection may have an immunologically mediated etiopathogenesis, falling under the spectrum of primary chronic osteomyelitis or chronic recurrent multifocal osteomyelitis (CRMO). CASE REPORT: Herein, we present a case of chronic osteomyelitis in a 6.5-year-old girl, who suffered from recurrent painful episodes of swelling of the mandible for the last 2 years, previously requiring hospitalization and administration of intravenous (IV) antibiotics and NSAIDs with limited responsiveness. The biopsy showed features consistent with osteomyelitis with proliferative periostitis. The patient was initially managed with an IV combination antibiotic regimen with only partial improvement. The possibility of an autoimmune mechanism in the context of primary chronic osteomyelitis or CRMO was considered, and immunosuppressive therapy (TNF inhibitor etanercept along with corticosteroids and methotrexate) was administered, resulting in clinical resolution. CONCLUSIONS: Osteomyelitis and its childhood variants are relatively rare and their management presents several challenges. Although typically treated with administration of antibiotics, possibly along with surgical intervention, other treatment modalities may be necessary for resilient and persistent cases. In a subset of cases, especially in the absence of local infectious factors, immunologically mediated mechanisms may play an important role and appropriate immunosuppressive therapy may be effective.