Post-dental Extraction Healing Following Anti-resorptive Therapy (ART) - Pilot Translational Study

Objectives: Our goal was to characterize the clinical, imaging and proteomic changes that accompany physiological healing post-dental extraction in naïve and anti-resorptive therapy (ART) exposed rats. We hypothesized that distinct alterations heralded adverse events such as Medication-related Osteonecrosis of the Jaw (MRONJ) lesions and can potentially serve to enable timely diagnosis, assessment, and ultimately, develop therapeutic interventions.
Methods: Six naïve and ART-exposed (3 weeks of daily up to 1 mg/kg dexamethasone and weekly 7.5 µg/ kg zoledronate administered intraperitoneally) were subjected to unilateral maxillary molar extractions. Serial computed tomography (baseline, 2 weeks, 5 weeks and 8 weeks post-dental extraction) was used to non-invasively characterize changes in bone structure and mineralization gradients. Image voxel intensity of the jaw bone, which reflects bone mineral density, was segmented into three (3) arbitrary ranges to visualize the dynamics of bone resorption, remodeling and mineralization. Serum samples were serially obtained for proteomic assessment using NanoLC-MSMS. Histopathological assessment was also performed at the end of the experiment.
Results: A. Control rats that underwent dental extractions demonstrated a distinct pattern of hypo- and re-mineralization in the region of the extractions
- ART therapy distinctly altered post-dental extraction mineralization profile with evidence for overall hypermineralization
- Mineralization patterns after dental extractions appear to distinguish between MRONJ-positive and -negative rats- with prominent hypomineralization and delayed macroscopic socket remodeling in the zone of suspected MRONJ, along with histopathological evidence of rare bony sequestration
B. There appears to be a global proteomic signature for normal post-dental extraction healing. Whether ART treatment alters this signature and whether there are key aberrations that correlate with MRONJ need to be verified.
Conclusions: Our early results are suggestive of a distinct MRONJ phenotype characterized by altered mineralization profile. The potential for altered mineralization and proteomic profile to facilitate early diagnosis of MRONJ needs to be explored.