Long-Term Ligature-Induced Periodontitis Exacerbates Development of Bisphosphonate-Related Osteonecrosis of the Jaw in Mice

Abstract

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a detrimental intraoral lesion that occurs in patients with long-term or high-dose use of anti-resorptive agents such as bisphosphonates. Tooth extraction is a known risk factor for BRONJ, and such intervention is often performed to eliminate existing pathological inflammatory conditions. Previously, we determined that ligatureinduced periodontitis (LIP) is a risk factor for the development of osteonecrosis in mice, but it remains unclear whether the chronicity of LIP followed by extraction influences osteonecrosis development. In this study, we assess the effect of short-term and long-term LIP (ligature placed for 3 weeks [S-LIP] or 10 weeks [L-LIP], respectively) on osteonecrosis development in mice receiving 250 μg/kg/ week zoledronic acid (ZOL). When compared to S-LIP, L-LIP caused 70% (p ≤ 0.0014) more bone loss without altering microbe composition. In the presence of ZOL, bone loss mediated by LIP was prevented and bone necrosis was induced. When the ligated tooth was extracted, histologic hallmarks of osteonecrosis including empty lacunae and necrotic bone were increased by 88% (p = 0.0374) and 114% (p = 0.0457), respectively, in L-LIP compared to S-LIP. We also observed significant increases in serum platelet factor 4 (PF4) and macrophage inflammatory factor 1 γ (MIP1γ) in mice that received ZOL treatment and had tooth extractions compared to controls, which may be systemic markers of inflammation-associated osteonecrosis development. Additionally, CD3+ T cells were identified as the major immune population in both health and disease, and we observed a 116% (p = 0.0402) increase in CD3+IL23R+ T cells in L-LIP compared to S-LIP lesions following extraction. Taken together, our study reveals that extracting a periodontally compromised tooth increases the formation of necrotic bone compared to extracting a periodontally healthy tooth and that osteonecrosis may be associated with the duration of the preexisting pathological inflammatory conditions.

Chronic Periodontal Infection and Not Iatrogenic Interference Is the Trigger of Medication-Related Osteonecrosis of the Jaw: Insights from a Large Animal Study (PerioBRONJ Pig Model)

“…The literature states that periodontitis develops faster in models where silk threads are placed into artificially created periodontal defects [ 29 , 50 ]. Therefore, infectious processes of higher severity developed in the maxilla, which sparked MRONJ of higher stages.…”

Sirt6 Activation Ameliorates Inflammatory Bone Loss in Ligature-Induced Periodontitis in Mice

“…First, female mammals have more severe inflammatory responses against ligatures [ 39 ], but we used male mice. Second, although long-term ligation (10 weeks) induces a more severe systemic inflammatory response compared with short-term ligation (three weeks) [ 40 ], we performed experiments with short-term ligation. Third, we did not additionally apply other conditions (pathogen injection, high-fat diet, or genetic modulation) that could exacerbate systemic inflammation to the periodontitis model [ 36 ].…”

Pathophysiology of Medication‐Related Osteonecrosis of the Jaw—A Minireview

“…This increased Th17 cell population and resultant cytokine secretion promote macrophage polarization toward a classically activated M1 pro‐inflammatory phenotype versus an alternatively activated M2 anti‐inflammatory phenotype. ( 16 , 17 , 26 , 105 ) Thus, a perpetual forward feedback loop is established that promotes inflammation and inhibits healing around areas of osteonecrosis.…”

“…However, prominent expression of collagen type III and increased numbers of cells expressing high MMP‐9 and MMP‐13 levels or cells positive for a‐SMA, presumably myofibroblasts, are found apical to migrating epithelium and around sites of osteonecrosis. ( 94 ) Interestingly, increased duration of periodontal disease augments the incidence of MRONJ, ( 95 , 105 ) while prevention or decrease of periodontal disease severity reduces MRONJ presence, ( 106 ) demonstrating a time dependence between the two entities.…”