Oral Biol Res 2024; 48(2): 45-51  https://doi.org/10.21851/obr.48.02.202406.45
Surgical treatment of medication-related osteonecrosis of the jaw in patients with autoimmune diseases
Young Hoon Kang1* and Na Young Lee2
1Associate Professor, Department of Dentistry, Institute of Medical Science, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
2Clinical Instructor, Department of Dentistry, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
Correspondence to: Young Hoon Kang, Department of Dentistry, Gyeongsang National University School of Medicine, 15 Jinju-daero 816beon-gil, Jinju 52727, Republic of Korea.
Tel: +82-55-214-3886, Fax: +82-55-214-3265, E-mail: omfs00@gnu.ac.kr
Received: April 14, 2024; Accepted: May 8, 2024; Published online: June 30, 2024.
© Oral Biology Research. All rights reserved.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
This retrospective, single-center study compares the factors influencing the surgical outcomes of medication-related osteonecrosis of the jaw (MRONJ) in patients with and without autoimmune diseases (AIDs). The total surgical success rate was 92% during the mean 2-year follow-up period, and treatment failure was observed in 8% of all patients without AID and 12% of patients with AIDs. Bisphosphonate duration and administration route (intravenous) were found to be risk factors of MRONJ. A careful treatment plan should be developed with a multidisciplinary team including a rheumatologist and a maxillofacial surgeon to avoid the use of drugs that may adversely affect treatment results when MRONJ occurs in patients with AIDs.
Keywords: Autoimmune diseases; Bisphosphonate; Osteoporosis; Surgical treatment

Bisphosphonate-related osteonecrosis of the jaw was first reported by Marx [1] in 2003, and medication-related osteonecrosis of the jaw (MRONJ) was known by the American Association of Oral and Maxillofacial Surgery (AAOMS) [2]. MRONJ is defined as necrosis of the jaw bone caused by medications used to treat osteoporosis, inhibit bone metabolism, or prevent the metastasis of cancer via the inhibition of angiogenesis. Although the incidence is extremely low, MRONJ can cause serious complications, especially in patients with AIDs [3].

AIDs, such as rheumatoid arthritis (RA), are chronic, systemic disorders with a pathophysiology involving both inflammatory and autoimmune mechanisms. Medications used to treat AIDs, such as glucocorticoids, chemotherapeutic agents, and disease-modifying antirheumatic drugs (DMARDs), may be related to the development of MRONJ [4,5].

Therefore, in this retrospective, single-center clinical study, factors affecting MRONJ in patients with and without AIDs were identified and compared.

Materials and Methods

Study design

This study was approved by the Institutional Review Board of Changwon Gyeongsang National University Hospital (approval number: CGNUH-2020-03-009-001). Patients with MRONJ who underwent surgical treatment from May 2013 to April 2020 and received follow-up care at the Department of Oral and Maxillofacial Surgery of Gyeongsang National University Hospital were included in this study. All patients had a history of receiving anti-resorptive or antiangiogenic medications (orally or intravenously) for the treatment of osteoporosis, breast cancer, or prostate cancer. The AAOMS guidelines for the diagnosis and staging of MRONJ were used [2].

MRONJ is diagnosed based on the following conditions: (1) current or previous treatment with antiresorptive or antiangiogenic agents; (2) exposed bone or bone that can be probed through an intraoral or extraoral fistula(e) in the maxillofacial region that has persisted for more than eight weeks; and (3) no history of radiation therapy to the jaw or obvious metastatic disease of the jaw.

This study included patients with RA, vasculitis, mixed connective tissue disease (MCTD), scleroderma, spondylarthritis, Sjogren syndrome, and systemic lupus erythematous (SLE) [6].

The exclusion criteria were follow-up of less than three months, and a history of uncontrolled metabolic diseases. The final analysis included 149 patients.

Upon presentation to our department, patients received 625 mg of amoxicillin with clavulanic acid and performed a chlorhexidine gargle (chlorhexidine gluconate solution 0.005 mL/g) three times daily for seven days. Antiresorptive and antiangiogenic medications were discontinued for at least three months before and after surgical treatment.

Follow-up visits were performed at one, three, and six months postoperatively, and treatment was discontinued when complete mucosal healing was identified. A radiographic dental panoramic radiography was done at each follow-up visit to confirm jaw recovery.

Data collection

Demographic, clinical, and radiological (panoramic radiograph and cone beam computed tomography and bone scintigraphy) data were analyzed in this study. We assessed the stage of the disease, type of antiangiogenic or anti-resorptive agent, administration route and duration of antiangiogenic or anti-resorptive agent, cause of jaw necrosis, location of jaw necrosis, surgical treatment method, and treatment results. The surgical treatment methods were categorized as a sequestrectomy, in which only floating necrotic bone was removed or saucerization, in which the adjacent cortical bones were removed to achieve blood circulation.

The treatment results were categorized as successful when new oral epithelium lined in treated areas and no infection or symptoms were observed. Infections were diagnosed due to the lack of mucosal continuity; presence of exudate, an abscess, or pain; or exposure of necrotic jaw bone [7].

The use and duration of autoimmune medications including glucocorticoids, chemotherapeutic agents, and DMARDs were recorded, and the severity of AIDs was classified according to the American College of Rheumatology classification criteria for RA [8], SLE [9], and scleroderma [10]; Bohan and Peter’s [9,10] criteria for polymyositis and dermatomyositis; and Bennet’s [11] criteria for overlap syndromes and criteria for Sjögren’s syndrome [12] and Kahn and Appelboom’s [13] criteria for MCTD.

Statistical analysis

Categorical variables are presented as frequencies and percentages, and continuous variables are presented as means±standard deviations. Fisher’s exact test was used to compare categorical variables and the independent test or Mann–Whitney U-test was used to compare continuous variables. A logistic regression analysis was performed to identify prognostic factors independently related to surgical treatment outcomes. Statistical analyses were performed using SPSS statistical software (version 24.0; IBM Corp., Armonk, NY, USA), and p-values<0.05 were considered statistically significant.


Patient characteristics

A total of 149 patients were included in this study. The majority of the patients were female (n=128; 85.9%), with a male to female ratio of 1:16. The mean patient age was 73.25 years (range: 47–83 years; median: 72 years) (Table 1).

Baseline and clinical characteristics

Variable Group p-value

Female 107 (85.6) 21 (87.5) 0.172
Male 18 (14.4) 3 (12.5) 0.562
Age (y) 72.03±5.00 75.57±10.57 0.216
MRONJ stage
1 7 (5.6) 0 (0.0) >0.999
2 96 (76.8) 12 (50.0) 0.853
3 22 (17.6) 12 (50.0) 0.346
Occurrence of location
Posterior region of mandible 109 (87.2) 21 (87.5) 0.588
Anterior region of mandible 12 (9.6) 3 (12.5) 0.357
Posterior region of maxilla 3 (2.4) 0 (0.0) >0.999
Anterior region of maxilla 1 (0.8) 0 (0.0) >0.999
Drug type
Alendronate 36 (24.2) 5 (3.4) 0.424
Risedronate 20 (13.4) 8 (5.4) 0.322
Zoledronate 9 (6) 6 (4) 0.018*
Ibandronate 29 (19.5) 2 (1.3) >0.999
Pamidronate 14 (9.4) 2 (1.3) 0.361
Unknown 17 (11.4) 1 (0.7) >0.999
Administrative route
Intravenous 13 (10.4) 15 (62.5) 0.030*
Oral 112 (89.6) 9 (37.5) 0.139
Medication duration (mo) 52.81±2.54 50.89±2.06 0.001
Causes of necrosis
Implantation 16 (10.7) 4 (2.7) 0.925
Extraction 65 (43.6) 14 (9.4) 0.015*
Periodontitis 33 (22.1) 6 (4) 0.450
Denture irritation 8 (5.4) 3 (2) >0.999

Categorical variables are presented as frequency and percentage and continuous variables are presented as mean±standard deviation. Fisher’s exact test and the Mann–Whitney U-test were used to compare the data.

MRONJ, medication-related necrosis of the jaw; AID, autoimmune disease.

*p<0.05, p<0.01.

A total of 131 patients received an antiresorptive agent (bisphosphonate), and 18 patients received an antiangiogenic agent (denosumab). Of the 131 patients who received bisphosphonates, 16 patients were administered pamidronate, 41 were administered alendronate, 31 were administered ibandronate, 28 were administered risedronate, and 15 were administered zolendronate. The average durations of oral and intravenous administrations were 52.81 months (range: 15–66 months) and 50.89 months (range: 1–10 months), respectively. Most patients (n=121; 81.2%) used oral medications, while 18.8% of patients (n=28) used intravenous medications.

Necrosis of the jaw was attributed to extraction in 53.0% of patients (n=79), implant placement in 13.4% of patients (n=20), periodontal disease in 26.1% of patients (n=39), and denture irritation in 7.3% of patients (n=11).

Lesions were located in the maxilla in 2.7% of patients (n=4) and mandible in 97.3% of patients (n=145), resulting in a maxillary to mandibular ratio of 1:36. The anterior teeth were involved in 10.7% of patients (n=16) and the posterior teeth were involved in 89.3% of patients (n=133), resulting in an anterior to posterior ratio of 1:8. Successful treatment was achieved in 90.6% of the patients (n=135), and treatment failure occurred in 9.4% of patients (n=14) (Table 2). Table 2 summarizes the influence of patient factors on the outcomes. Zolendronate and IV injections were found to be related with poor treatment results, though the results were not statistically significant (Table 1).

Surgical treatment types and outcomes

Treatment MRONJ
Curettage & sequestrectomy 95 (76.0) 16 (66.7) >0.999
Decortication & saucerization 22 (17.6) 4 (16.7) 0.452
Marginal mandibulectomy 6 (4.8) 3 (12.5) 0.015*
Segmental mandibulectomy 2 (1.6) 1 (4.1) 0.531
Treatment outcome
Success 115 (92.0) 20 (83.3) 0.762
Failure 10 (8.0) 4 (16.7) 0.162

Categorical variables are presented as frequency and percentage and continuous variables are presented as mean±standard deviation. Fisher’s exact test was used to compare the data.

MRONJ, medication-related necrosis of the jaw; AID, autoimmune disease.


In six patients in whom surgical treatment failed, stage 2 MRONJ worsened to stage 3. One patient with stage 3 MRONJ experienced progression of the lesions that required the removal of adjacent tissues. Treatment was discontinued in 82.6% of the patients during the first six postoperative months.


This study determined whether AIDs are a risk factor for MRONJ and the most effective treatment method for MRONJ.

Bisphosphonates are mainly used as inhibitors of bone resorption in patients diagnosed with osteoporosis, advanced breast cancer, multiple myeloma, Paget’s disease, and hyperparathyroidism [14,15], as they prevent and treat osteoporosis and bone metastasis [16]. The incidence of MRONJ may increase due to the use of bisphosphonates.

There have since been several case reports, case series, retrospective studies, and prospective studies suggesting a significant association between bisphosphonate therapy and MRONJ [17,18]; however, a definitive cause-and-effect relationship between the two has yet to be clearly established. Recently, denosumab, a receptor activator of nuclear factor-κB ligand inhibitor that was approved for similar indications to bisphosphonate, has also been associated with MRONJ [19]. The incidence of MRONJ in oncology patients treated with bisphosphonates or denosumab ranges from 1.5% to 15%, which is lower than that in patients treated with these agents for benign conditions (0.01% to 0.001%) [20].

Recently, pharmacological treatments for RA have been associated with the development of MRONJ. RA is a systemic immunologic disease characterized by persistently high levels of pro-inflammatory cytokines and inflammatory cells. Medications prescribed for patients with AIDs, including steroids and methotrexate, may play a major role in the development of MRONJ. Steroids can induce bone necrosis, predominantly in long bones, and do not lead to bone exposure [6].

All of the patients in this study were referred to our department by dentists or physicians due to patient symptoms or exposed bone. Of the 149 patients included in this study, 24 had chronic AIDs that were clinically and radiographically identical to MRONJ (Table 3). Autoimmune-associated MRONJ is less common than other MRONJ and is associated with methotrexate, prednisone, and local steroid injections.

Clinical features of MRONJ lesions in patients with autoimmune diseases

Case Age Sex AID Medication MRONJ stage Site Treatment
AID severity
1 83 F RA MTX 2 Mn.ant. Success Mild
2 52 F FM Prednisolone 2 Mn.post. Failure Moderate
3 70 M RA MTX 2 Mn.post. Success Severe
4 54 F RA Prednisolone 2 Mx.post. Success Moderate
5 74 F RA Leflunomide 3 Mn.post. Failure Severe
6 81 F SS Prednisolone 3 Mn.post. Success Moderate
7 75 M RA Leflunomide 2 Mn.post. Success Moderate
8 77 F SLE Prednisolone 1 Mn.post. Success Mild
9 79 F RA MTX 2 Mn.post. Failure Severe
10 77 F RA Leflunomide 2 Mn.post. Success Moderate
11 69 F RA MTX 3 Mx.post. Success Severe
12 84 F RA Prednisolone 2 Mn.post. Success Moderate
13 73 F Arthritis MTX 2 Mn.post. Failure Severe
14 74 M RA Leflunomide 2 Mn.post. Success Severe
15 84 F SLE MTX 3 Mn.post. Success Moderate
16 69 F RA Prednisolone 2 Mn.post. Success Moderate
17 79 F RA MTX 2 Mn.post. Success Mild
18 65 F MS Prednisolone 2 Mn.ant. Success Severe
19 75 F RA Leflunomide 3 Mn.post. Success Moderate
20 77 F RA MTX 3 Mn.post. Success Moderate
21 79 F SLE Leflunomide 2 Mn.post. Success Mild
22 58 F RA MTX 2 Mn.post. Success Severe
23 66 F RA Prednisolone 3 Mn.post. Success Mild
24 75 F RA Prednisolone 3 Mn.post. Success Moderate

AID, autoimmune disease; MRONJ, medication-related osteonecrosis of the jaw; F, female; M, male; RA, rheumatoid arthritis; FM, fibromyalgia; SS, Sjogren syndrome; SLE, systemic lupus erythematosus; MS, multiple sclerosis; MTX, methotrexate; Mn, mandible; Mx, maxilla; ant, anterior; post, posterior.

Henien et al. [21] recently reported that patients with MRONJ who are administered oral bisphosphonates due to diseases such as RA had a lower probability of healing and a longer median healing time than patients without comorbid diseases. Although RA has been considered a risk factor for MRONJ, the relationship between these diseases has not yet been elucidated (Table 4).

Risk factors for treatment failure

Variable Treatment outcome p-value

Success (n=135) Failure (n=14)
Female 118 (79.2) 10 (6.7) 0.172
Male 17 (11.4) 4 (2.7) 0.421
Age (y) 74.15±3.41 68.57±4.32 0.425
MRONJ stage
1 7 (4.7) 0 (0.0) >0.999
2 102 (68.5) 6 (4.0) 0.362
3 26 (17.4) 8 (5.4) 0.254
Occurrence of location
Posterior teeth of mandible 121 (81.0) 9 (6.0) >0.999
Anterior teeth of mandible 12 (8.0) 3 (2.0) 0.654
Posterior teeth of maxilla 1 (1.0) 2 (1.0) 0.424
Anterior teeth of maxilla 1 (1.0) 0 (0.0) 0.322
Drug type
Alendronate 38 (25.5) 3 (2.0) 0.532
Risedronate 26 (17.4) 2 (1.3) 0.469
Zoledronate 9 (6.0) 6 (4.0) 0.018*
Ibandronate 29 (19.5) 2 (1.3) >0.999
Pamidronate 15 (10.1) 1 (0.7) 0.361
Unknown 18 (12.1) 0 (0.0) 0.241
Administrative route
Intravenous 18 (18.1) 10 (81.8) 0.05*
Oral 117 (81.9) 4 (18.2) 0.139
Medication duration (y) 5.98±5.54 (median: 4.5) 7.29±2.06 (median: 3) 0.230
Causes of necrosis
Implantation 17 (11.4) 3 (2.0) 0.925
Extraction 69 (46.3) 10 (6.7) 0.351
Periodontitis 39 (26.2) 0 (0.0) 0.537
Denture irritation 10 (6.7) 1 (0.7) 0.452
Curettage & sequestrectomy 101 (67.8) 10 (6.7) >0.999
Decortication & saucerization 24 (16.1) 2 (1.3) 0.013*
Marginal mandibulectomy 7 (4.7) 2 (1.3) 0.356
Segmental mandibulectomy 3 (2.0) 0 (0.0) 0.342

Categorical variables are presented as frequency and percentage and continuous variables are presented as mean±standard deviation. Fisher’s exact test and the Mann–Whitney U-test were used to compare the data. Shapiro–Wilk’s test was used to determine normality.

MRONJ, medication-related osteonecrosis of the jaw.


Although the pathophysiology of RA may modify or worsen MRONJ, our study shows that the clinical, radiological, and histological aspects of MRONJ were similar between patients with and without RA (Table 3-5). We did not observe a significant difference between these groups of patients regarding the onset of MRONJ or the treatment course.

Radiographic and histologic features of MRONJ lesions

Variable Group p-value

Radiographic feature
Sclerotic bony change 108 (72.5) 18 (12.0) 0.172
Sequestration 9 (6.0) 5 (3.4) 0.254
Periosteal reaction 8 (5.4) 1 (0.7) 0.568
Histologic feature
Actinomycosis 58 (38.9) 17 (11.4) >0.999
Histiocytic aggregation 48 (32.2) 4 (2.7) 0.856
Plasma cell/fibrosis 19 (12.8) 3 (2.0) 0.125

Variables are presented as frequency and percentage. Fisher’s exact test and the Mann–Whitney U-test were used to compare the data.

MRONJ, medication-related necrosis of the jaw; AID, autoimmune disease.

The appropriate management of patients with MRONJ remains undefined, and no widely-accepted treatment protocol exists. Although it has been stated that surgical procedures may achieve better outcomes in non-neoplastic patients, Marx [1] stated that surgical procedures are not effective in patients with MRONJ and that these procedures lead to further exposed bone, worsening of the symptoms, and a greater risk of pathologic fractures. The results of this study showed contradictory results, confirming the importance of surgical treatment.

Oral hygiene, patient education, and the use of the most effective MRONJ treatment is important. Several investigators have reported that curettage, surgical resection of the jawbone (including procedures such as marginal and segmental mandibulectomy), and antibacterial therapy result in long-term resolution of patients’ symptoms and remission of MRONJ, especially in patients with stage 3 MRONJ. The majority of patients with MRONJ require surgical treatment, including sequestrectomy, debridement, and curettage. However, surgery may increase the risk of additional exposed and necrotic bones, inducing disease progression and nerve injury [22].

Even in a large retrospective study using significant data manipulation, it may be difficult to determine whether AIDs with or without the use of steroids or DMARDs are significant risk factors for the development of MRONJ [21]. Therefore, a well-designed randomized control trial is required. The prevention of MRONJ is important. All patients should undergo a thorough oral examination before receiving bisphosphonates.

MRONJ can be detected early and treated successfully when rheumatologists and maxillofacial surgeons work together closely. Patients with AIDs who are exposed to antiresorptive agents may be more susceptible to MRONJ than patients who do not have AIDs. Proper surgical treatment can be curative for all patients.


This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI22C1377).

This work was supported by the Gyeongsang National University Fund for Professors on Sabbatical Leave, 2023.

Conflicts of Interest

The authors declare that they have no competing interests.

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