Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating condition characterized by the exposure of necrotic bone, primarily associated with the prolonged use of anti-resorptive and anti-angiogenic medications such as bisphosphonates (BPs) and Denosumab (Dmab)¹⁾. As the incidence of MRONJ cases has increased especially related to dental implants, there has been a corresponding rise in research and case reports^2,3). These drugs are vital for managing conditions such as osteoporosis and bone metastases, however it can disrupt normal bone remodeling by inhibiting osteoclast activity, rendering jaw bones more susceptible to ischemia, impaired healing, and necrosis following trauma or dental procedures⁴⁾. After the discontinuation of anti-resorptive medication, the patient showed partial improvement. Extraction of mobile implants and sequestrectomy under local anesthesia was enable indicating bone healing and stabilization of MRONJ.

This case highlights several key considerations for clinicians managing MRONJ:

1.Early and Accurate Diagnosis: Misdiagnosis can delay appropriate treatment and worsen outcomes. Clinicians should maintain a high index of suspicion for MRONJ in patients presenting with jaw pain, swelling, or infection, particularly those with a history of anti-resorptive therapy and steroid use⁵⁾.

2.Comprehensive Patient Evaluation: A thorough medical history, including medication use and underlying conditions such as RA, is crucial for assessing MRONJ risk and tailoring treatment strategies⁶⁾.

3.Multidisciplinary Approach: Effective management of MRONJ often requires collaboration between oral and maxillofacial surgeons, endocrinologists, rheumatologists, and other healthcare providers to optimize patient outcomes.

Among various predisposing factors, long-term steroid use in patients with rheumatoid arthritis (RA) has been recognized as a potential risk factor for MRONJ. Steroids, commonly used to manage inflammatory symptoms in RA, can impact bone metabolism and immune response, contributing to the susceptibility of the jaw bones to osteonecrosis when combined with anti-resorptive therapies such as Dmab. Recently, clinical observations suggest an accelerated onset of MRONJ in patients who have a history of prolonged steroid therapy prior to initiation of Dmab treatment⁷⁾.

Recent studies have explored the correlation between MRONJ risk and serum levels of bone turnover markers, including serum C-telopeptide of collagen type 1 (CTx), procollagen type 1 N-terminal propeptide (P1NP), and osteocalcin (OC). Marx's categorization of serum CTx levels (<100 pg/ml as high risk, 100∼150 pg/ml as moderate risk, and >150 pg/ml as minimal risk) provides a framework for assessing MRONJ susceptibility before initiating anti-resorptive therapy^2,8).

Despite advancements in understanding, managing MRONJ remains complex due to its multifaceted etiology and clinical variability. Strategies to prevent MRONJ focus on meticulous oral hygiene and proactive dental care before starting anti-resorptive treatment. Once MRONJ occurs, treatment options vary depending on the severity of clinical symptoms, ranging from conservative approaches such as antibiotic therapy and local debridement to more aggressive surgical interventions aimed at removing necrotic bone and promoting tissue regeneration^9-11).

This paper provides a case study of an 86-year-old female patient with a history of long-term steroid use for RA, who developed peri-implant MRONJ following Dmab treatment and subsequent surgical procedures.

An 86-year-old female patient first visited the Department of Oral and Maxillofacial Surgery (OMFS) at Yonsei University Dental Hospital referred from the Department of periodontology. Before visiting OMFS department, the patient has been managed in the Rheumatology department since 1997 for RA. The patient was treated with long-term steroid use (2.5 mg) and non-steroidal anti-inflammatory drugs. There were no specific symptoms related to MRONJ before Dmab injection. The patient received dental implant treatment and regular follow-up at the department of periodontology for 13 years before visiting OMFS.

After use of steroid over 20 years, the patient received first Dmab injection (prolia prefilled, 60mg/ml, Amgen Inc, California, USA), followed by a full disc removal surgery in December 2019. The patient developed acute gingiva-related symptoms with swelling, bleeding, and mal-odor around dental-implant, presenting 4 months after the initial Dmab injection. CT scans showed an osteonecrosis pattern around dental implants on the maxillary premolar implants (Fig. 1).

Figure 1. 4 months after Dmab injection. (A) Panoramic radiograph. (B) Showing radiolucency around middle portion of implant fixture. (C) Conebeam CT view showing sequestrum formation around dental implants.

After 4 months from the initial Dmab injection, a neurosurgeon consulted the periodontist due to gum bleeding and pus discharge around the upper left dental implants. After 6 months from the initial Dmab injection, surgical curettage was performed by the periodontologists with caution regarding potential exacerbation of MRONJ. The patient was referred to an endodontist due to pus discharge from same region concerning a periapical abscess originating from upper canine. Despite this, the patient received additional Dmab treatment two weeks later.

After two doses of Dmab injections with 6-month intervals, the patient first visited OMFS (9 months and 3 months after Dmab injection). At the first visit of OMFS, necrotic bone exposure on both bilateral posterior maxilla were observed. History taking of anti-resorptive and anti-angiogenic drugs was conducted thoroughly and comprehensively. In collaboration with an endocrinologist, anti-resorptive medication was discontinued. With short-term follow up under antibiotics therapy, non-movable necrotic bone exposure persisted in the affected areas, with sequestra formation observed on Computed Tomography scans (axial view), necessitating further follow-up (Fig. 2).

Figure 2. 9 months after Dmab injection #1, 3 months after Dmab injection #2. (A) CT scans (axial view), (B, C) Clinical photo shows necrotic bone exposure on bilateral Maxilla.

During discontinuation of Dmab, the patient’s CTx level increased in response (Table 1). Following check-ups confirmed that the extent of necrosis in maxilla bone did not expand and remained stable. 6 Months after the second Dmab injection, the upper left canine spontaneously fell out. After one month, mobility test of upper left dental implants confirmed sequestra formation in the maxilla (Fig. 3). The implants and sequestra could be easily extracted under local anesthesia, preserving the surrounding healthy bone.

Table 1 . Change in CTx, P1N, OC level with discontinuation of Dmab

	Before Dmab	1 month after Dmab#1	6 months after Dmab#1	3 months after Dmab#2	4 months after Dmab#2	5 months after Dmab#2	8 months after Dmab#2	11 months after Dmab#2	13 months after Dmab#2	16 months after Dmab#2
CTx	0.144	0.052	0.127	0.050	0.067	0.076	0.103	0.272	0.519	0.703
OC	-	-	-	-	-	5.68	-	-	13.50	-
P1NP	19.0	37.4	62.5	142.0	61.8	22.7	32.3	71.4	80.2	133.0

Dmab: denosumab.

Figure 3. 11 months after Dmab injection #1, 5 months after Dmab injection #2. CT scans (axial view). Extensive bone necrosis in the bilateral maxillary molar regions and sequestrum formation around the implants.

The management of MRONJ poses significant clinical challenges due to its multifactorial etiology and varied clinical manifestations. Many studies have been reported that MRONJ is linked to bacterial, viral, or fungal infections, trauma, smoking, steroids, immunocompromised host, autoimmune disease, diabetes, and chemotherapy¹⁾. Dental implants can be a possible risk factor of MRONJ with the treatment of anti-resorptive agents, leading to dental implant failure and osteonecrosis around successfully osseointegrated implant. Even though the mechanism of MRONJ around dental implants is not fully understood, the installation of dental implant and functional loading can both be related to the onset of osteonecrosis. However, the occurrence of MRONJ was significantly higher after the implants were loaded compared to after implant placement¹²⁾. This case report indicates that MRONJ can also occur even at well-maintained dental implants, highlighting the importance of medical history assessment in patients.

MRONJ is primarily associated with the prolonged use of anti-resorptive agents such as BPs and Dmab. These agents inhibit osteoclast activity, thereby reducing bone resorption and turnover. However, this inhibition also disrupts normal bone remodeling processes, leading to microdamage accumulation and compromised vascularity in the jaw bones¹⁾. In this case, the patient's long-term steroid use for RA further complicated the etiology. Steroids can negatively impact bone metabolism and immune response, increasing the susceptibility of jaw bones to osteonecrosis when combined with potent anti-resorptive therapies⁵⁾.

In the case of this patient, although the dental implants were well maintained, MRONJ occurred at the multiple sites with increased severity after Dmab injection during steroid treatment. We have considered that systemic steroid use combined with Dmab is a possible risk factor of MRONJ, rather than oral hygiene or the characteristics of dental implants.

The accelerated onset of MRONJ observed in this patient highlights the synergistic effect of these medications on bone health and the necessity for careful patient monitoring. Managing MRONJ requires a multifaceted approach, balancing the therapeutic benefits of anti-resorptive therapies against their potential adverse effects on jaw bone health. Prevention strategies emphasize meticulous oral hygiene and proactive dental care before starting anti-resorptive treatment. Once MRONJ manifests, treatment options range from conservative treatments such as antibiotic therapy and local debridement to more aggressive surgical interventions aimed at removing necrotic bone and promoting tissue regene-ration¹³⁾.

Cessation of at-risk medication prior the dental procedure is still controversial. Traditionally, drug holidays were used to lower the risk of MRONJ after dental procedures. However, this practice can result in Skeletal-Related Events (SREs) and bone fracture. When considering drug holiday, several factors should be evaluated including disease-related risk, drug-dosing frequency, duration of therapy, comorbidities, other medications (especially chemotherapy, steroids, or antiangiogenics), underlying inflammation, and type of surgery¹⁾. It is crucial to consult with the medicine specialist to determine it a drug holiday is appropriate. After discussing with endocrinologist, our patient was able to stop the antiresorptive agent. Consequently, the CTx level elevated, and sequestrum separated with a sufficient margin, which allowed for a successful surgical procedure

Our case report underscores the need for a comprehensive patient evaluation, including a thorough medical history and consideration of underlying conditions like rheumatoid arthritis, to tailor treatment effectively. It is important to diagnosis of MRONJ accurately, as misdiagnosis can delay treatment and worsen outcomes. Additionally, managing MRONJ requires a multidisciplinary approach involving oral and maxillofacial surgeons, endocrinologists, rheumatologists, and other healthcare providers to optimize patient outcomes.

This case report suggests that implant-related MRONJ could occur even in asymptomatic dental implants across multiple regions due to systemic medications of denosumab and high-dose steroids. As the incidence of implant-related MRONJ increases, it highlights the need for clinicians to be aware of this risk. When managing MRONJ patients, it is crucial to conduct a detailed oral examination and review the patient’s medical history; consultation with medical specialists is also essential to regulate anti-resorptive drugs. Early diagnosis, careful patient evaluation, and appropriate treatment strategies can significantly impact the outcome of MRONJ. Continued research and clinical observations are essential for refining treatment protocols and improving patient care in this challenging condition.

Ethics approval and consent to participate: The requirement for ethical review and approval was waived for this study, owing to the nature of the study (case report). Informed consent was obtained from the patient involved in the case report.

None.

Written informed consent was obtained from the patient for the publication of this paper including the images.

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to patient privacy and confidentiality.

The authors declare no conflict of interest.

None.

Conceptualization and patient management by J. Y. K.; original draft preparation by J.M.C.; review and editing by H.J. and J. Y. K.; visualization by J.M.C.; validation, editing, supervision, critical revision by H.J.; project administration by J. Y. K. All authors have read and agreed to the published version of this manuscript.

This study received approval from the institutional Research Ethics Committee of Yonsei University College of Dentistry (IRB No.2-2024-0036). For this paper is retrospective case report, the IRB waived the requirement for individual informed consent. All radiographic and computed tomography (CT) images were anonymized to maintain confidentiality, aligning this study with the principles of the Declaration of Helsinki.