Osteonecrosis is broadly defined as necrosis of bone due to obstruction of blood supply.
20, 21 Osteonecrosis of the jaw (ONJ) is an oral lesion involving exposed mandibular or maxillary bone, which usually manifests with pain and purulent discharge, although it may be asymptomatic.
21 ONJ typically occurs following tooth extractions or other dentoalveolar surgeries, but in some cases, it can occur spontaneously.
4, 20, 22 ONJ associated with use of antiresorptive drugs such as bisphosphonates or denosumab is referred to as “medication-related ONJ” or MRONJ.
23 The mechanism by which denosumab and bisphosphonates cause MRONJ has not been clearly elucidated; however, it has been suggested that suppression of bone turnover and remodeling by the drugs impairs the body’s ability to repair microfractures in the maxilla and mandible.
23-25 The reported incidence of MRONJ varies, but it is generally considered to be between 1% and 10% of patients taking IV bisphosphonates for the management of bone metastatic disease and between 0.001% and 0.01% in patients taking oral bisphosphonates for the management of osteoporosis.
4
The differential diagnosis of MRONJ includes other conditions such as alveolar osteitis, sinusitis, gingivitis/periodontitis, or periapical pathosis.
23, 24 According to a 2015 systematic review and international consensus paper,
24 patient history and clinical examination remain the most sensitive diagnostic tools for MRONJ. While it is not possible to identify who will develop MRONJ and who will not, research suggests the following as risk factors:
4, 9, 22, 23, 25-29
- age older than 65 years;
- periodontitis;
- poor oral hygiene;
- dentoalveolar surgery, including tooth extraction;
- high dose and/or prolonged use of antiresorptive agents (more than 2 years);
- smoking;
- malignant disease (multiple myeloma, and breast, prostate, and lung cancer);
- chemotherapy, corticosteroid therapy, or treatment with antiangiogenic agents;
- denture wearing;
- diabetes.
The “Warnings and Precautions” sections of the FDA-approved package inserts for bisphosphonate drugs,
5-8 as well as denosumab,
11 state that both MRONJ and atypical femoral fractures have been reported rarely with use of these drugs; however, these are not included as so-called “black box” warnings (which is a specially designated warning designed to call attention to serious or life-threatening risks
30). A 2016 consensus task force report,
9 based on a literature search, from the American Society for Bone and Mineral Research (ASBMR) concluded that “the risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with [bisphosphonate] therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients.”