Incidence of antiresorptive agent-related osteonecrosis of the jaw: A multicenter retrospective epidemiological study in Hyogo Prefecture, Japan.

Background/purpose: The incidence of medication-related osteonecrosis of the jaw is increasing worldwide, mostly due to the use of antiresorptive agents (ARAs) such as bisphosphonate (BP) and denosumab (Dmab). However, the proportion of BP-related osteonecrosis of the jaw (BRONJ) and Dmab-related osteonecrosis of the jaw (DRONJ) among all ARA-related osteonecrosis of the jaw (ARONJ) cases is not clear; this hinders appropriate treatment, recurrence-prevention planning, and avoidance of unnecessary Dmab withdrawal. Moreover, the causative drug administered at each disease stage remains unknown. Therefore, we conducted a retrospective study of patients with ARONJ who visited oral and maxillofacial surgery departments at hospitals in Hyogo Prefecture, Japan, over 3 years to classify and compare patient characteristics with those having BRONJ and DRONJ. We sought to identify the proportion of DRONJ in ARONJ. Materials and methods: After excluding stage 0 patients, 1021 patients were included (471 high-dose; 560 low-dose). ARA treatment for bone metastases of malignant tumors and multiple myeloma was considered high dose, while that for cancer treatment-induced bone loss and osteoporosis was low dose. Results: Low doses of BP and Dmab accounted for >50% patients; the results differed from those in other countries. DRONJ accounted for 58% and 35% of high-dose and low-dose cases, respectively. Stage 3 ARONJ cases comprised 92 (19.5%) low-dose BRONJ, 39 (20.1%) high-dose BRONJ, 24 (30%) low-dose DRONJ, and 68 (24.5%) high-dose DRONJ. Eighty-nine patients who received switch therapy were divided into BRONJ or DRONJ, but there was no difference in the ratio of each stage compared to the non-switch therapy. Conclusion: To the best of our knowledge, this is the first study to clarify the proportion of BRONJ and DRONJ cases, causative drug, and its doses by disease stages. DRONJ accounted for approximately 30% of the ARONJ, approximately 60% of which was due to high doses.

Local levels of interleukin-1beta, -4, -6 and tumor necrosis factor alpha in an experimental model of murine osteomyelitis due to staphylococcus aureus.

The purpose of this study is to evaluate local levels of interleukin-1 beta (IL-1 beta), -4 (IL-4), -6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha), in a model of murine osteomyelitis due to Staphylococcus aureus. Cytokine levels in supernatants derived from bone homogenates were determined by enzyme-linked immunosorbent assay, for 28 days following the direct implantation of murine tibiae with S.aureus. Levels of IL-1 beta and IL-6 in infected bone were elevated in the early post-infection period and then decreased. In contrast, TNF-alpha levels remained elevated 3 to 28 days post-infection, while IL-4 levels were elevated late in the course of infection. The histopathology of infected bone showed predominant infiltration of inflammatory cells and bone resorption 3 to 7 days after infection, and bone resorption and adjacent areas of formation 14 to 28 days after infection. These results suggest that the elevated IL-1 beta and IL-6 levels induced by infection may be related to bone damage mainly in the early phase of infection, and that TNF-alpha and IL-4 may at least in part be associated with histopathological changes, including both bone resorption and formation in the later phase of this osteomyelitis model.

Inhibitory effect of roxithromycin on the local levels of bone-resorbing cytokines in an experimental model of murine osteomyelitis.

OBJECTIVES: The purpose of this study was to evaluate the inhibitory effect of roxithromycin on the production of interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) in a murine tibial osteomyelitis model using Staphylococcus aureus. METHODS: Cytokine levels in supernatants derived from bone homogenates were measured by enzyme-linked immunosorbent assay for 28 days, after oral administration of roxithromycin at 5 mg/kg/day. RESULTS: There was no significant difference in IL-6 levels between a group receiving roxithromycin administration and a group not receiving roxithromycin. IL-1beta and TNF-alpha levels were significantly lower for the administration group after 7-14 days and after 21-28 days, respectively. However, a significant difference in bacterial counts in bone between the groups was not observed. CONCLUSION: These results indicate that roxithromycin suppresses the local expression of IL-1beta and TNF-alpha, and may exhibit an anti-inflammatory effect in this osteomyelitis model.