Contacts: Robert Koski, Gopikrishnan M. Chandrasekharan, Danielle Boyce, Adam Bouras
Background
Medication-related osteonecrosis of the jaws (MRONJ) is a condition affecting the jaw bones in individuals who have received bisphosphonate (BP) treatment [1] or treatment with other antiresorptive or antiangiogenic medications. This disease, reminiscent of therapy-resistant osteomyelitis, may arise following an invasive procedure on the jaws or a traumatic incident [2].
What are Bisphosphonates?
BPs are a category of medications primarily employed to treat disorders such as osteoporosis and malignant bone disorders [3]. These drugs operate by impeding bone resorption, a process naturally carried out by osteoclast cells, by selectively binding to the mineral surface of the bone [4]. Osteoclasts use a biochemical process to break down bone tissue called bone resorption and release minerals into the bloodstream [5]. This process is crucial for maintaining an ideal balance of bone density and minerals in the body. The activity of osteoclasts is counterbalanced by osteoblasts, which contribute to bone formation as needed. Conditions like osteoporosis disrupt this equilibrium between bone resorption and formation, resulting in a net loss of bone.
BPs are therefore indicated in a wide variety of clinical conditions where the patients have a low bone mass or are at risk of increased bone loss [6]. Patients with reduced bone loss and at a high risk of fragility fractures are prescribed BPs to reduce the risk of future fractures. Osteoporosis can occur secondary to the consumption of drugs such as glucocorticoids and patients who consume glucocorticoids are at a high risk of bone fractures [7]. Osteoporosis can occur in post-menopausal women and women are at risk of losing 10-20% of their bone mineral density in 5-6 years following menopause [8]. Pagetâs disease is characterized by abnormal bone remodeling and results in bone pain, abnormal bone growths, bone fractures, joint stiffness, etc. BPs are moderately effective in reducing pain in patients with Pagetâs disease and are widely prescribed [4].
Certain types of cancer patients are at a high risk of metastatic bone disease. Patients with breast cancer have shown the highest incidence of skeletal complications, especially in patients who have undergone androgen deprivation therapy [9]. Other cancer types that are associated with metastatic bone disease include prostate, lung, kidney, and multiple myeloma [9]. BPs are recommended to overcome complications such as bone loss and loss of bone mineral density [6], [9]. Second and third-generation nitrogen-containing BPs such as Pamidronate, alendronate, ibandronate, risedronate, and zoledronic acid are the most potent drug types. They are prescribed more often than early non-nitrogen-containing first-generation variants [10].
Etiology
The underlying etiology of MRONJ is not well understood. Suspected contributing factors to MRONJ formation include infections, bone turnover suppression, diminished blood supply, and genetic predispositions [11]. While a definitive causal link between BPs and MRONJ has not been firmly established, there exists a significant association between the use of intravenous BPs and the occurrence of MRONJ [12].
Risk factors for MRONJ/MRONJ include:
Tooth extraction
More likely to be found in the mandible than maxilla
Pre-existing inflammatory dental disease, such as periodontal disease or periapical pathology
Corticosteroid use
Certain cancer types
Genetic predisposition
Incidence/Prevalence
The incidence of osteonecrosis in individuals who received elevated intravenous doses of BPs was markedly greater than in those who received lower intravenous doses or those who took BPs orally [11]. The prevalence of osteonecrosis of the jaw (ONJ) among patients receiving oral bisphosphonates for osteoporosis treatment varies, ranging from 0% to 0.04% [11]. The occurrence rate of MRONJ in oncology patients undergoing treatment with intravenous BPs ranges from 0% to 0.186% [11]. The risk of developing osteonecrosis of the jaws after a tooth extraction (or other traumatic dental procedures) in patients who are exposed to antiresorptive medication is 0.5% [13].
Clinical features of MRONJ
In response to the rising incidence of drug-induced osteonecrosis of the jaws, not limited to bisphosphonates, a special committee within the American Association of Oral and Maxillofacial Surgeons (AAOMS) revised their definition of jaw osteonecrosis. They proposed a shift in nomenclature to Medication-Related Osteonecrosis of the Jaws (MRONJ) to better encompass cases associated with various medications [13].
Denosumab (DMAB) is a human monoclonal antibody that is used for the treatment of osteoporosis and is also associated with osteonecrosis of the jaw. DMAB exerts antiangiogenic effects, disrupting the nutrient and oxygen supply to tumor cells by reducing the vascular network and preventing the formation of new blood vessels, and subsequently also has resorptive effects on bone [11]. There is an increased risk of osteonecrosis in patients who are treated with bevacizumab and BPs in combination [11].
The updated definition of MRONJ includes [13]:
Current or previous treatment with antiresorptive or antiangiogenic agents
Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for longer than 8 weeks
No history of radiation therapy to the jaws or obvious metastatic disease to the jaws
In 2014 the International Task Force on Osteonecrosis of the Jaw [11] defined osteonecrosis of the jaw as:
Exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a healthcare provider
Exposure to an antiresorptive agent
No history of radiation therapy to the craniofacial region.
Medication-Related Osteonecrosis of the Jaw Case Definition
Citation: Neville, B. W., Damm, D. D., Allen, C. M., & Chi, A. C. (2016). Oral and maxillofacial pathology. Elsevier.
Current or previous treatment with antiresorptive or antiangeoginic agent
Exposed bone in maxillofacial region for longer than 8 weeks
No history or radiation therapy or obvious metastatic disease to the jaws
Differential Diagnosis
Patients who are at risk for or already have Medication-Related Osteonecrosis of the Jaws (MRONJ) may also exhibit other prevalent clinical conditions that should not be mistaken for MRONJ. These conditions [11], [13] include:
Alveolar osteitis
Sinusitis
Dental caries
Dental pain
Gingivitis/Periodontitis
Periapical pathology
Cemento-osseous dysplasia
Atypical neuralgias
Fibro-osseous lesions
Sarcoma
Chronic sclerosing osteomyelitis
Temporomandibular joint disorders
Staging and Management of MRONJ
At risk - no apparent necrotic bone in patients who have been treated with oral or intravenous bisphosphonates
Stage 0 - no clinical evidence of necrotic bone but nonspecific clinical findings, radiographic changes, and symptoms
Stage 1 - exposed and necrotic bone or fistulas that probe to the bone in patients who are asymptomatic and have no evidence of infection
Stage 2 - exposed and necrotic bone or fistulas that probe to bone associated with infection as evidenced by pain and erythema in the region of exposed bone with or without purulent drainage
Stage 3 - exposed and necrotic bone or a fistula that probes to the bone in patients with pain, infection, and âĽ1 of the following: exposed and necrotic bone extending beyond the region of alveolar bone (ie, inferior border and ramus in mandible, maxillary sinus, and zygoma in the maxilla) resulting in pathologic fracture, extraoral fistula, oral antral or oral nasal communication, or osteolysis extending to the inferior border of the mandible or sinus floor
In planning treatment for individuals who might receive antiresorptive or antiangiogenic therapy, it is crucial to conduct a comprehensive examination of the oral cavity, including a radiographic assessment when deemed necessary [13].
MRONJ as a Candidate for Phenotype Phebruary
Medication-related osteonecrosis of the jaw was selected by the OHDSI Dentistry Workgroup (DWG) for consideration in the community event Phenotype Phebruary 2024. Previous work by the DWG (Koski, R., Chandrasekharan, G., & Duncan, W. (2023, October). Mapping Dental Use Cases to the OMOP-CDMâ. https://www.ohdsi.org/2023showcase-39)
suggests that dental data is rarely, if ever mapped to the OMOP-CDM. The DWG reviewed several potential candidates for phenotyping before ultimately selecting MRONJ. During selection, several factors were considered.
MRONJ has a large amount of existing literature documenting its clinical features, differential diagnoses, treatments, and epidemiology of the disease. A thorough description of the condition is advantageous to phenotyping as it permits sensitive and specific selection of cohort definitions to capture relevant terminology associated with the condition as well as exclude potential confounding cohorts from consideration.
MRONJ has defined diagnostic terminology in the standardized vocabulary utilized by the OMOP-CDM. There is adequately descriptive terminology to capture the diagnosis of the disease as well as treatments and features of the condition.
MRONJ can be identified in the dental office following trauma (e.g., tooth extraction), but it is nearly universally treated in hospital systems or in oral and maxillofacial surgery offices. These treatment locations are typically connected to an EHR and have thorough documentation of diagnostic and treatment codes. Dental EHRs in the United States and most other countries are not mapped to the OMOP-CDM, unlike many hospital EHRs. Based on this assumption, MRONJ patients should be documented and available in the OMOP-CDM.
No large, randomized, controlled studies have been done concerning the prevention or treatment of the complications of the administration of antiresorptive or antiangiogenic agents (cite Neville). âThe best therapeutic approach is preventionâ (Neville, B. W., Damm, D. D., Allen, C. M., & Chi, A. C. (2016). Oral and maxillofacial pathology. Elsevier.). While some therapies exist, the evidence supporting their use is limited. Investigating current patterns of intervention could give insight into best practices in the treatment and management of MRONJ.
Finally, the DWG mission statement is to understand how dentistry can leverage observational research to improve oral health outcomes and further investigate the links between oral health and systemic disease. MRONJ is a good candidate for furthering this mission because it is an oral manifestation of a systemic condition. While there are correlations between antiresorptive and antiangiogenic medications with osteonecrosis of the jaw, treatment of the condition and reporting of true incidence rates require further study.
Potential Use Cases for MRONJ with the OMOP-CDM
Clinical Characterizations:
Amongst patients who are diagnosed with MRONJ, what are the patientsâ characteristics from their medical history?
Amongst patients who have been diagnosed with ___,which txs were pts exposed to amongst [list of txs]?
Population level effect estimation:
Does exposure to [drug A] have a different risk of MRONJ than exposure to [drug B] within [usual tx/follow up window]?
Time of exposure and high dosage is correlated with increased incidence of MRONJ and could be studied
Patient level prediction:
For a given a patient who has MRONJ, what is the likelihood that they will have osteonecrosis in other areas of the body?
Other questions: imaging informatics? Early detection/disposition toward development of MRONJ?
References
References: