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)

Abstract

Background and Objectives: Antiresorptive drugs are widely used in osteology and oncology. An important adverse effect of these drugs is medication-induced osteonecrosis of the jaw (MRONJ). There is scientific uncertainty about the underlying pathomechanism of MRONJ. A promising theory suspects infectious stimuli and local acidification with adverse effects on osteoclastic activity as crucial steps of MRONJ etiology. Clinical evidence showing a direct association between MRONJ and oral infections, such as periodontitis, without preceding surgical interventions is limited. Large animal models investigating the relationship between periodontitis and MRONJ have not been implemented. It is unclear whether the presence of infectious processes without surgical manipulation can trigger MRONJ. The following research question was formulated: is there a link between chronic oral infectious processes (periodontitis) and the occurrence of MRONJ in the absence of oral surgical procedures? Materials and Methods: A minipig large animal model for bisphosphonate-related ONJ (BRONJ) using 16 Göttingen minipigs divided into 2 groups (intervention/control) was designed and implemented. The intervention group included animals receiving i.v. bisphosphonates (zoledronate, n = 8, 0.05 mg/kg/week: ZOL group). The control group received no antiresorptive drug (n = 8: NON-ZOL group). Periodontitis lesions were induced by established procedures after 3 months of pretreatment (for the maxilla: the creation of an artificial gingival crevice and placement of a periodontal silk suture; for the mandible: the placement of a periodontal silk suture only). The outcomes were evaluated clinically and radiologically for 3 months postoperatively. After euthanasia a detailed histological evaluation was performed. Results: Periodontitis lesions could be induced successfully in all animals (both ZOL and NON-ZOL animals). MRONJ lesions of various stages developed around all periodontitis induction sites in the ZOL animals. The presence of MRONJ and periodontitis was proven clinically, radiologically and histologically. Conclusions: The results of this study provide further evidence that the infectious processes without prior dentoalveolar surgical interventions can trigger MRONJ. Therefore, iatrogenic disruption of the oral mucosa cannot be the decisive step in the pathogenesis of MRONJ.

Inflammation Can Be a High-Risk Factor for Mucosal Nonunion of MRONJ by Regulating SIRT1 Signaling When Treated with an Oncologic Dose of Zoledronate

“… 14 In addition, differences in drug concentration may affect the elasticity of the mucosa to environmental stimuli, thereby transforming non-risk factors at low concentrations into risk factors at high concentrations, further aggravating mucosal toxicity. 15 Therefore, clarifying the risk of mucosal injury caused by environmental factors at different doses of ZA will bring important inspiration for the precise prevention and treatment of MRONJ in clinical practice.…”

Editorial: Immunological processes in maxillofacial bone pathology

“…The truth is that a thorough understanding of physiological and biochemical processes within the jawbone is essential to provide superb clinical care. Maxillofacial bone pathology is omnipresent: periodontitis, periimplantitis, dry socket, osteomyelitis, medication-related osteonecrosis of the jaw (MRONJ), arthritis of the temporomandibular joint – just to name a few “mundane” diseases that are caused and maintained by immunological processes ( 2 – 4 ). Causative treatment of those diseases is only possible if their pathophysiology is understood which is the link between research and practice (translational medicine).…”

“…MRONJ is triggered by decreased defense capacities of the jawbone due to antiresorptive-drug-induced immune suppression, acidification, and osteoclast inhibition ( 2 ). While many factors have been investigated and discussed, the inflammatory stimulus (immunological process) is the decisive factor for the onset and maintenance of MRONJ is unquestionably the decisive step ( 8 ).…”