Pathophysiology of Medication-Related Osteonecrosis of the Jaw-A Minireview

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse effect of antiresorptive medications administered for control of osseous malignancy, osteoporosis, or other bone metabolic diseases. Despite being reported in the literature two decades ago, MRONJ etiology, pathophysiology, and progression remain largely unknown, and current nonoperative or operative treatment strategies are mostly empirical. Several hypotheses that attempt to explain the mechanisms of MRONJ pathogenesis have been proposed. However, none of these hypotheses alone is able to capture the complex mechanistic underpinnings of the disease. In this minireview, we aim to highlight key findings from clinical and translational studies and propose a unifying model for the pathogenesis and progression of MRONJ. We also identify aspects of the disease process that require further investigation and suggest areas for future research efforts toward calibrating methodologic approaches and validating experimental findings. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Keywords: ANIMAL MODELS; BONE MODELING AND REMODELING; DISEASES AND DISORDERS OF/RELATED TO BONE; MOLECULAR PATHWAYS‐REMODELING; PRECLINICAL STUDIES.

Fig. 1

Bone remodeling occurs both within cortical bone and on bone surfaces. A central tenet of bone physiology is remodeling, where the coordinated spatial and temporal actions of osteoblasts and osteoclasts renew damaged/compromised bone tissue. Remodeling occurs both within cortical bone (intracortical/osteonal remodeling) and on bone surfaces. Image taken from a dog mandible (~15 months old). Blue arrows point to osteonal remodeling within the alveolar cortical bone. Yellow arrows point to surface remodeling on the surface adjacent to the tooth.

Fig. 2

Response of alveolar bone to periapical disease in vehicle (Veh)‐ and zoledronate (ZOL)‐treated animals. (A) μCT sections demonstrate significant periapical bone loss in Veh‐treated animals. (B) Inhibition of bone resorption by ZOL results in minimal periapical bone loss. (C) Histologic assessment of Veh‐treated animals demonstrates bone resorption away from the nidus of the infection at the root apex. A strong inflammatory response with abscess formation at the apical areas and a more fibrous periphery are noted. (D) In ZOL‐treated animals, the bone is in very close proximity to the apex. A strong inflammatory response at the nidus of the infection at the root apex is noted. The inflammatory infiltrate extends to the marrow spaces of the periapical bone. Blue arrows point to the extent of periapical bone loss. Yellow arrows point to areas of inflammatory infiltrate. (Figure modified from Hadaya and colleagues^{( 90 )}).

Fig. 3

Onset of medication‐related osteonecrosis of the jaw (MRONJ) around teeth with periapical disease in zoledronate (ZOL)‐treated mice. Red arrows point to localized osteonecrotic areas at the alveolar crest marked by empty osteocytic lacunae, green arrows to presence of osteocytes marking vital bone, double white arrows to periosteal bone deposition adjacent to osteonecrotic areas, blue arrows to inflammatory infiltrate, and yellow arrows to vascular structures. (Figure modified from Kang and colleagues^{( 46 )}).

Fig. 4

Progression of medication‐related osteonecrosis of the jaw (MRONJ) onset with developing bone exposure in mice treated with various antiresorptives. (A) Vehicle (VEH)‐treated healthy animal. (B) Vehicle‐treated animal with dental disease shows strong inflammatory infiltrate (blue arrow) and apical epithelial migration (yellow arrow). Alveolar bone is resorbed apically, away from the epithelium (white arrow). (C) RANK‐Fc (a denosumab surrogate)‐treated mouse with dental disease. Bone resorption is inhibited and necrotic bone is present at the alveolar crest (green arrow). Epithelial migration extends to the necrotic bone (yellow arrow). Inflammatory infiltrate is present (blue arrow). (D) OPG‐Fc (a denosumab surrogate)‐treated mouse with dental disease. Bone resorption is inhibited and necrotic bone is present at the alveolar crest (green arrows). Epithelium has migrated apically (yellow arrow) and reams the necrotic bone, which is exposed to the oral cavity. (E) Zoledronate (ZOL)‐treated mouse. Bone resorption is inhibited and necrotic bone is present at the alveolar crest (green arrows). Epithelium has migrated apically (yellow arrow) and demonstrates prominent reaming of the necrotic bone, resulting in extensive bone exposure.

Fig. 5

Extraction of healthy teeth or teeth with periapical disease in zoledronate (ZOL)‐treated animals. (A) Clinically extraction sockets of healthy teeth healed with normal mucosa (white arrows). (B) In contrast, extraction sockets of teeth with periapical disease showed areas of bone exposure (red arrows). (C) μCT assessment demonstrated extraction sockets of healthy teeth filled with woven bone (yellow arrow). Socket outlines are clearly demarcated. (D) Extraction sockets of teeth with periapical disease lack bone formation and appear empty, with socket outlines clearly defined (red arrows). (E) Histologic assessment demonstrates woven bone formation in the extraction socket of healthy teeth (white arrow). The margins of the extraction socket and the woven bone are clearly outlined. (F) In contrast, sockets of extracted teeth with periapical disease are void of bone formation, with the socket outlines visible and presence of osteonecrosis (blue arrows), debris, and bone exposure (aqua arrow). (Figure modified from Hadaya and colleagues^{( 90 )}).

Fig. 6

Proposed model for medication‐related osteonecrosis of the jaw (MRONJ) pathogenesis. AR = antiresorptive; BP = bisphosphonate.