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Medication-Related Osteonecrosis of the Jaw: Dentistry Phenotype

Contacts: Robert Koski, Gopikrishnan M. Chandrasekharan, Danielle Boyce, Adam Bouras


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]. Paget’s 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 Paget’s 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].


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


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


Dental caries

Dental pain


Periapical pathology

Cemento-osseous dysplasia

Atypical neuralgias

Fibro-osseous lesions


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 ≥1 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-CDM​. 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). “The best therapeutic approach is prevention” (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 patients’ 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?


[1] S. L. Ruggiero, “Bisphosphonate-related osteonecrosis of the jaw: an overview,” Ann. N. Y. Acad. Sci., vol. 1218, no. 1, pp. 38–46, 2011, doi: 10.1111/j.1749-6632.2010.05768.x.

[2] F. Beninati, R. Pruneti, and G. Ficarra, “Bisphosphonate-related osteonecrosis of the jaws (Mronj),” Med. Oral Patol. Oral Cir. Bucal, vol. 18, no. 5, pp. e752–e758, Sep. 2013, doi: 10.4317/medoral.18076.

[3] S. L. Ruggiero, “Guidelines for the diagnosis of bisphosphonate-related osteonecrosis of the jaw (MRONJ),” Clin. Cases Miner. Bone Metab., vol. 4, no. 1, pp. 37–42, 2007.

[4] L. Corral‐Gudino, A. J. Tan, J. del Pino‐Montes, and S. H. Ralston, “Bisphosphonates for Paget’s disease of bone in adults,” Cochrane Database Syst. Rev., vol. 2017, no. 12, p. CD004956, Dec. 2017, doi: 10.1002/14651858.CD004956.pub3.

[5] V. Everts, I. D. C. Jansen, and T. J. de Vries, “Mechanisms of bone resorption,” Bone, vol. 163, p. 116499, Oct. 2022, doi: 10.1016/j.bone.2022.116499.

[6] C. Reyes, M. Hitz, D. Prieto-Alhambra, and B. Abrahamsen, “Risks and Benefits of Bisphosphonate Therapies,” J. Cell. Biochem., vol. 117, no. 1, pp. 20–28, 2016, doi: 10.1002/jcb.25266.

[7] K. Briot and C. Roux, “Glucocorticoid-induced osteoporosis,” RMD Open, vol. 1, no. 1, p. e000014, 2015, doi: 10.1136/rmdopen-2014-000014.

[8] M.-X. Ji and Q. Yu, “Primary osteoporosis in postmenopausal women,” Chronic Dis. Transl. Med., vol. 1, no. 1, pp. 9–13, Mar. 2015, doi: 10.1016/j.cdtm.2015.02.006.

[9] R. Coleman, J. J. Body, M. Aapro, P. Hadji, and J. Herrstedt, “Bone health in cancer patients: ESMO Clinical Practice Guidelines†,” Ann. Oncol., vol. 25, pp. iii124–iii137, Sep. 2014, doi: 10.1093/annonc/mdu103.

[10] M. T. Drake, B. L. Clarke, and S. Khosla, “Bisphosphonates: Mechanism of Action and Role in Clinical Practice,” Mayo Clin. Proc. Mayo Clin., vol. 83, no. 9, pp. 1032–1045, Sep. 2008.

[11] A. A. Khan et al., “Diagnosis and Management of Osteonecrosis of the Jaw: A Systematic Review and International Consensus,” J. Bone Miner. Res., vol. 30, no. 1, pp. 3–23, 2015, doi: 10.1002/jbmr.2405.

[12] S. L. Ruggiero, T. B. Dodson, L. A. Assael, R. Landesberg, R. E. Marx, and B. Mehrotra, “American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw – 2009 Update,” Aust. Endod. J., vol. 35, no. 3, pp. 119–130, 2009, doi: 10.1111/j.1747-4477.2009.00213.x.

[13] S. L. Ruggiero et al., “American Association of Oral and Maxillofacial Surgeons Position Paper on Medication-Related Osteonecrosis of the Jaw—2014 Update,” J. Oral Maxillofac. Surg., vol. 72, no. 10, pp. 1938–1956, Oct. 2014, doi: 10.1016/j.joms.2014.04.031.


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Concept type


ICD-9 [1]

526.4: Inflammatory conditions of jaw

526.5: Alveolitis of jaw

730: Acute osteomyelitis, site unspecified

730.08: Acute osteomyelitis involving other specified sites

730.1: chronic osteomyelitis

730.1: Chronic osteomyelitis, site unspecified

730.18: Chronic osteomyelitis involving other specified sites

730.2: Unspecified osteomyelitis, site unspecified

730.28: Unspecified osteomyelitis, other specified sites

733.4: Aseptic necrosis of bone

733.4: Aseptic necrosis of bone, site unspecified

733.45: Osteonecrosis of the jaws

733.49: Aseptic necrosis of other bone sites

526.4, 526.5, 730, 730.08, 730.1, 730.1, 730.18, 730.2, 730.28, 733.4, 733.4, 733.45, 733.49,

ICD-10 [1]

K08.9: disorder of teeth and supporting structures, unspecified,

K10.2: inflammatory conditions of the jaw, 

K10.8: other specified disease of the jaw, 

M87.0: idiopathic aseptic necrosis of bone

M87.1: osteonecrosis due to drugs 

M87.9: unspecified osteonecrosis

K10.3: alveolitis of the jaw,

K10.9: disease of the jaw, unspecified

M87.3: other secondary osteonecrosis

86.x: osteomyelitis

M87.8: other osteonecrosis

K08.9, K10.2, K10.8, M87.0, M87.1, M87.9, K10.3, K10.9, M87.3, 86.x, M87.8

Comorbidities [1]

Hypertension (ICD-9-CM codes 401–405),(ICD-10-CM codes I10,I15)

Diabetes mellitus (ICD-9-CM code 250),(ICD-10-CM codes E08,09,10,11,13)

Malignancy (ICD-9-CM codes 140–208).

Malignant neoplasms in the head and neck regions (ICD-10-CM codes C00–C14) 

Chronic kidney disease (ICD-9-CM codes 585),(ICD-10-CM codes N18,N18X,O102,O103)

Hypothyroidism(ICD-9-CM codes 243,244),(ICD-10-CM codes E03)

Hyperthyroidism(ICD-9-CM codes 242),(ICD-10-CM codes E05)

Anemia (ICD-9-CM codes 280-285),(ICD-10-CM codes D46,D50-59,D61-64)

Rheumatoid arthritis(ICD-9-CM codes 714),(ICD-10-CM codes M05,M051-059,M06,M08)

Other characteristics to identify the cohort [1]

any orodental disease diagnoses, radiograph examinations, edentulous or not, presence of other stated medical conditions, medications and smoking habits.

Medication associated with MRONJ [2]

  • Antiresorptives
  • Most frequently prescribed 
  • Bisphosphonates (BPs)
  • Alendronate oral (Fosamax)
  • Ibandronate (Boniva)
  • Zoledronic acid (Reclast; Zometa) 
  • Oral and infusion admin
  • Receptor Activator of Nuclear-kB Ligand (RANKL) Inhibitors
  • Denosumab (Prolia; XGEVA)
  • SQ admin
  • Anti-angiogenics
  • Tyrosine kinase inhibitors (TKIs)
  • Imatinib (Gleevec)
  • Monoclonal antibodies (MABs)
  • Adalimumab (Humira)
  • Risk likely increases when combined with antiresorptives 
  • Other agents
  • Classic chemotherapy agents
  • Immunosuppressants
  • Methotrexate
  • Glucocorticoids
  • Selective estrogen receptor modulators (SERMs)
  • Raloxifene (Evista)