Osteonecrosis of the Jaw and Antiresorptive Agents in Benign and Malignant Diseases

A Critical Review Organized by the ECTS

Athanasios D. Anastasilakis; Jessica Pepe; Nicola Napoli; Andrea Palermo; Christos Magopoulos; Aliya A. Khan; M. Carola Zillikens; Jean-Jacques Body


J Clin Endocrinol Metab. 2022;107(5):1441-1460. 

In This Article

Abstract and Introduction


Context: Antiresorptive therapy significantly reduces fracture risk in patients with benign bone disease and skeletal-related events (SREs) in patients with bone metastases (BM). Osteonecrosis of the jaw (ONJ) is a rare but severe condition manifested as necrotic bone lesion or lesions of the jaws. ONJ has been linked to the use of potent antiresorptive agents, termed medication-related ONJ (MRONJ).

Objective: We aimed to identify the differences various aspects of MRONJ among distinct patient categories and provide recommendations on how to mitigate the risk and optimally manage MRONJ in each of them.

Methods: A working group of the European Calcified Tissue Society (ECTS) and 2 experts performed an updated detailed review of existing literature on MRONJ incidence, characteristics, and treatment applied in bone diseases with variable severity of skeletal insult, ranging from osteoporosis to prevention of cancer treatment–induced bone loss and SREs in cancer patients with BM.

Results: The risk for MRONJ is much higher in patients with advanced malignancies compared to those with benign bone diseases because of the higher doses and more frequent administration of antiresorptive agents in individuals with compromised general health, along with coadministration of other medications that predispose to MRONJ. The overall risk for MRONJ is considerably lower than the benefits in all categories of patients.

Conclusion: The risk for MRONJ largely depends on the underlying bone disease and the relevant antiresorptive regimen applied. Physicians and dentists should keep in mind that the benefits of antiresorptive therapy far outweigh the risk for MRONJ development.


An imbalance of bone turnover, with relatively increased osteoclast-mediated bone resorption rate, characterizes a broad spectrum of bone diseases, ranging from osteoporosis (OP) and other benign bone diseases to cancer treatment–induced bone loss (CTIBL; aromatase inhibitor (AI)-induced bone loss, and androgen deprivation–induced bone loss) and bone metastases (BM) in advanced malignancies. In all these conditions, targeting the osteoclast with antiresorptive agents is currently the cornerstone of treatment of the respective bone disease. Among them, bisphosphonates (BPs), and denosumab (Dmab) are the more potent and more frequently used agents in everyday clinical practice.

BPs are divided into oral, including alendronate (ALN), risedronate (RIS), clodronate (CLO), and ibandronate (IBN), and intravenous (IV) agents, including IBN, pamidronate (PAM), and zoledronate (ZOL). In general, oral BPs are preferred in OP and other benign bone diseases, whereas for prevention of CTIBL and the management of BM, IV BPs are mostly used (Table 1). Dmab binds the receptor activator of nuclear factor κ-B ligand (RANKL), thus inhibiting osteoclast differentiation, function, and survival.[1] BPs and Dmab both significantly decrease the risk of vertebral (by 41%-77% and 68%, respectively) and hip (by 30%-51% and 40%, respectively) fractures in OP patients[2,3] and the incidence of skeletal-related events (SREs) in cancer patients.[4,5] The regimen of each BP and of Dmab varies depending on the disease (see Table 1).