Medication‐Related Osteonecrosis of the Jaw: New Insights into Molecular Mechanisms and Cellular Therapeutic Approaches

Abstract

In recent years, medication-related osteonecrosis of the jaw (MRONJ) became an arising disease due to the important antiresorptive drug prescriptions to treat oncologic and osteoporotic patients, as well as the use of new antiangiogenic drugs such as VEGF antagonist. So far, MRONJ physiopathogenesis still remains unclear. Aiming to better understand MRONJ physiopathology, the first objective of this review would be to highlight major molecular mechanisms that are known to be involved in bone formation and remodeling. Recent development in MRONJ pharmacological treatments showed good results; however, those treatments are not curative and could have major side effects. In parallel to pharmacological treatments, MSC grafts appeared to be beneficial in the treatment of MRONJ, in multiple aspects: (1) recruitment and stimulation of local or regional endogenous cells to differentiate into osteoblasts and thus bone formation, (2) beneficial impact on bone remodeling, and (3) immune-modulatory properties that decrease inflammation. In this context, the second objective of this manuscript would be to summarize the molecular regulatory events controlling osteogenic differentiation, bone remodeling, and osteoimmunology and potential beneficial effects of MSC related to those aspects, in order to apprehend MRONJ and to develop new therapeutic approaches.

Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do?

“…The main side effect of N‐BPs on the adult craniofacial skeleton is bisphosphonate‐related osteonecrosis of the jaws (BRONJ) (Lombard, Neirinckx, Rogister, Gilon, & Wislet, ; Ruggiero & Dodson, ). BRONJ has received different definitions and its pathophysiology and epidemiology have been subject to wide controversy and investigation, to date without consensus (Lombard et al, ).…”

“…The main side effect of N‐BPs on the adult craniofacial skeleton is bisphosphonate‐related osteonecrosis of the jaws (BRONJ) (Lombard, Neirinckx, Rogister, Gilon, & Wislet, ; Ruggiero & Dodson, ). BRONJ has received different definitions and its pathophysiology and epidemiology have been subject to wide controversy and investigation, to date without consensus (Lombard et al, ). In 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS) defined BRONJ as an area of exposed or necrotic bone, or bone that can be probed through an intra‐oral or extra‐oral fistula, that fails to heal within 8 weeks in patients who have received or are receiving treatment with anti‐resorptive drugs (in the absence of maxillary radiotherapy) (Ruggiero & Dodson, ).…”

“…The incidence in osteoporotic patients treated by intravenous route N‐BPs is also higher (0–90 cases per 100,000 patients/year) than by oral route (1.04–69 cases per 100,000 patients/year). In cancer patients, the incidence ranges from 0.8% to 12% and is considered to be 12.222 per 100,000 patients/year (Lombard et al, ). Interestingly, multiple myeloma patients more frequently develop BRONJ than patients with solid tumors such as breast or prostate cancers (Hamadeh et al, ).…”

“…The authors concluded that using rhBMP‐2 without concomitant bone grafting materials was useful in promoting the healing of BRONJ (Cicciu et al, ). However, adequate randomized clinical trials are needed to ascertain the safety and efficacy of BMPs in the management of BRONJ (Lombard et al, ; Cicciu et al, ).…”

“…PDGF‐BB is considered to be a new alternative for the treatment of bone resorptive pathologies (Lombard et al, ). In experimental models, treatment with PDGF‐BB has been shown to increase vasculogenesis and bone formation (Lombard et al, ). Few reports have proposed the use of PDGF in the management of BRONJ (Lombard et al, ) but to date, no reports have been made regarding its use.…”