Multidisciplinary approach for medication-related osteonecrosis of the jaws: a case report and literature review
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Abstract
Medication-related osteonecrosis of the jaw (MRONJ) is a relatively rare but well-documented complication of bisphosphonate therapy. Bisphosphonates are prescribed to millions of patients for the treatment of osteoporosis, Paget’s disease, multiple myeloma, bone metastases, and other bone-related conditions. These drugs inhibit bone resorption by binding to hydroxyapatite, particularly in areas of active resorption, thereby preventing osteoclasts from attaching to the bone. Long-term bisphosphonate therapy is considered a primary risk factor for MRONJ. Bisphosphonate-induced osteonecrosis typically manifests as exposed alveolar bone, which may occur spontaneously or following invasive dental procedures such as extractions, apicectomies, or implant placement. This case report describes a female who developed osteonecrosis in the maxilla and mandible after undergoing bisphosphonate therapy for multiple myeloma and subsequent tooth extractions.
INTRODUCTION
Bisphosphonates are a broad class of drugs used to treat various metabolic and malignant bone diseases. They are analogs of endogenous pyrophosphate, a potent inhibitor of osteoclast-mediated bone resorption [1]. These drugs play a therapeutic role in managing hypocalcemia of malignancy, bone involvement in multiple myeloma, solid tumors, osteoporosis, and Paget’s disease. Medication-related osteonecrosis of the jaw (MRONJ) is characterized by non-healing exposed bone in the maxillofacial region persisting for more than 8 weeks in patients who have undergone bisphosphonate therapy [2]. MRONJ resembles “phossy jaw,” a condition observed in 19th century and early 20th century workers exposed to phosphorus during match production. While MRONJ can be asymptomatic for months, it often becomes painful upon infection or trauma to surrounding soft tissues. The exposed bone may appear small but often conceals more extensive necrotic bone beneath. Oral bisphosphonate induced necrosis is less frequent, less aggressive, and more responsive to treatment compared to intravenous forms. This case report discusses a rare presentation of MRONJ affecting both the maxilla and mandible simultaneously, a phenomenon reported in only 4% of cases in the literature.
CASE REPORT
A 55-year-old female patient presented to the Department of Oral & Maxillofacial Surgery, Tamil Nadu Government Dental College & Hospital, Chennai, with a chief complaint of pain and ulceration in the lower right posterior tooth region for the past 3 months. Her medical history revealed a 5-year course of bisphosphonate therapy for multiple myeloma and the extraction of multiple teeth under local anesthesia 1 year prior at a private clinic. She had also undergone partial sequestrectomy under local anesthesia 5 months earlier. Intraoral examination revealed necrotic bone in the lower right alveolar regions (teeth 45, 46, 47, and 48) (Fig. 1A) and the left upper alveolar regions (teeth 24, 25, 26, 27, and 28), with multiple missing teeth (Fig. 1B). Sharp bony margins impinging on the mucosa over the floor of the mouth on the right side were evident. An orthopantomogram demonstrated radiolucent sequestrum in both the maxillary and mandibular dentoalveolar regions (Fig. 2). Differential diagnoses included giant cell tumor, ameloblastoma, radicular cyst, odontogenic tumor, and fibrous dysplasia. A provisional diagnosis of MRONJ was made, and the patient was scheduled for sequestrectomy and excisional biopsy under local anesthesia to confirm the diagnosis.
A 55-year-old female patient presented with a chief complaint of pain and an ulcer with sharp bony margins on the right lower jaw, which was tender upon palpation. (A) Preoperative photograph showing osteonecrosis in the right mandibular molar region. (B) Preoperative photograph showing osteonecrosis in the left maxillary molar region.
Orthopantomogram of the patient reveals irregular radioopacity in the left maxillary and right mandibular molar regions, accompanied by bone erosion. Additionally, multiple missing teeth, impacted maxillary molars, a root stump in relation to tooth 15, and generalized alveolar bone loss are evident.
Under local anesthesia, a crevicular and crestal incision was made from teeth 41 to 46, and a full-thickness mucoperiosteal flap was elevated. The sequestrum was identified and removed, followed by copious irrigation and debridement (Fig. 3A). The wound was closed with 3-0 vicryl sutures. About 2 months later, a similar sequestrectomy procedure was performed in the left maxillary posterior dentoalveolar region under local anesthesia (Fig. 3B) The patient was prescribed routine oral antibiotics and analgesics, and follow-up visits confirmed satisfactory wound healing (Fig. 4).
Intraoperative photographs. (A) Intraoperative photograph of the mandibular lesion showing the extent of the osteonecrosis. (B) Intraoperative photograph displaying the sequestered bony lesion in the maxilla.
Healing of the mandibular surgical site at a 1-month followup. The photograph showing the site of intervention with healthy mucosa.
Specimen of the sequestered bone was sent for histopathological examination (Fig. 5), which revealed areas of active acute inflammation, particularly in the peripheral regions of the samples, where significant bone loss was observed. The samples contained numerous osteoclast-like cells at the interface with residual bone spicules, along with an inflammatory infiltrate composed of polymorphonuclear cells, plasma cells, monocytes, and lymphocytes. Acellular necrotic debris, thin-walled dilated blood vessels, and scattered residual deeply basophilic bone spicules were also noted.
Specimen obtained for a histopathological examination.
LITERATURE REVIEW
Mavrokokki et al. [3] reported that the incidence of MRONJ in patients receiving intravenous bisphosphonate therapy ranges from 1% to 12%. Studies by Filleul et al. [4] found that 60% of MRONJ cases occur in woman, primarily in the fourth to sixth decades of life, likely due to post-menopausal estrogen deficiency, which increases osteoporosis risk and necessitates bisphosphonate therapy. Bamias et al. [5] highlighted that MRONJ is most prevalent in patients with multiple myeloma (9.9%) and breast cancer (2.9%) receiving bisphosphonates.
Bisphosphonates inhibit osteoclastic activity by blocking the mevalonate pathway, impairing osteoclasts’ ability to form ruffled borders essential for bone resorption. Their high affinity for hydroxyapatite crystals leads to accumulation in areas of high bone turnover, such as the alveolar bone, making the jaws particularly susceptible to osteonecrosis [6]. Among bisphosphonates, intravenous zoledronate is the most frequently implicated (83%) due to its potency as a nitrogen-containing bisphosphonate.
According to American Society for Bone and Mineral Research (2007), MRONJ is diagnosed based on the following criteria: (1) current or prior bisphosphonate therapy; (2) exposed necrotic bone in the maxillofacial region for more than 8 weeks; or (3) no history of radiation therapy to the jaws.
Singh and Gonegandla [6] found that the mandible (68%) is more commonly affected than the maxilla (28%), likely due to its relatively reduced blood supply. Rarely, both jaws are involved (4%). Common sites for MRONJ, as identified by Payne et al. [7], include non-healing dentoalveolar sites (70%), traumatized tori, and exposed portions of the mylohyoid ridge. Approximately 75% of MRONJ cases are triggered by invasive dental procedures, such as extractions, while the remaining 25% occur spontaneously [6]. Common risk factors include diabetes, obesity, smoking, use of glucocorticoids and cytotoxic drugs [8].
Morag et al. [2] described imaging characteristics of MRONJ. Computed tomography scans often reveal osteolysis and sclerotic lesions with marrow space narrowing. Magnetic resonance imaging findings include decreased T1-weighted signal intensity, with variable signal intensities in early disease stages and consistently decreased intensity in advanced disease. Technetium-99m bone scintigraphy shows decreased uptake in early disease and increased uptake in later stages [2].
Singh and Gonegandla [6] categorized MRONJ management into medical, hyperbaric oxygen therapy, and surgical approaches. Medical management includes infection control with antibiotics and analgesics. Hyperbaric oxygen therapy promotes angiogenesis and enhances wound healing. Surgical management, reserved for advanced cases, involves debridement or resection to alleviate pain and infection [1].
Preventive strategies include atraumatic extractions under aseptic conditions, pre-extraction oral prophylaxis, and postprocedure antibiotic coverage. A multidisciplinary approach involving dental practitioners, oral surgeons, oncologists, and other specialists is essential for comprehensive care and early intervention.
This review highlights a unique case of MRONJ involving both the maxilla and mandible, a rare occurrence reported in only 4% of cases. Early diagnosis, careful surgical protocols, and interdisciplinary collaboration are crucial for improving outcomes and preserving patients’ quality of life.
DISCUSSION
The American and Canadian Associations of Oral and Maxillofacial Surgeons define MRONJ as exposed bone in the maxillofacial region persisting for more than 8 weeks in patients with current or prior bisphosphonate therapy and no history of jaw radiation [9]. MRONJ is a significant complication of bisphosphonate therapy, particularly with intravenous formulations like zoledronate, and poses a clinical challenge due to its chronic nature and impact on patients’ quality of life.
In the case under discussion, both the maxilla and mandible were affected, a rare phenomenon documented in only 4% of cases within maxillofacial literature. This concurrent involvement of both jaws highlights the importance of increased vigilance for patients receiving bisphosphonate therapy. The jaws’ distinct vascular architecture, particularly the mandible’s limited blood supply, renders it more prone to osteonecrosis than the maxilla. The exact mechanism through which bisphosphonates induce bone necrosis remains unclear. The metabolic theory suggests that this condition results from a disrupted balance between the activities of osteoblasts and osteoclasts. This theory aligns with the pathophysiology of osteopetrosis and may also explain the elevated incidence of osteonecrosis observed in patients with osteopetrosis.
This type of osteonecrosis is particularly common in the jaws because the remodeling processes, such as bone resorption and bone deposition observed in the alveolar crest, occur at a rate 10 times higher than in the tibia. Consequently, the jawbones accumulate a significantly higher concentration of bisphosphonates [10].
The diagnosis of this condition primarily depends on clinical presentation, which typically includes bone exposure accompanied by tenderness [11]. While histological examination usually confirms the diagnosis, an incisional biopsy is often avoided due to potential healing issues at the surgical site. Consequently, the diagnosis frequently relies solely on clinical observations and a history of bisphosphonate use. Three-phase bone scanning [99Tc(m)-MDP] has been identified as a valuable screening tool for detecting subclinical MRONJ in patients undergoing BP therapy. Additionally, computed tomography and magnetic resonance imaging are effective in delineating the characteristics and scope of osteolytic lesions [9]. In this case, the diagnosis was made based on the presence of exposed necrotic bone with tenderness, persisting for over 8 weeks, and without any prior radiation therapy to the jaws. This highlights the necessity of a systematic approach to diagnosing MRONJ.
A significant precipitating factor in MRONJ is invasive dental procedures, observed in 75% of cases. This underscores the importance of preventive strategies, including pre-procedure oral prophylaxis, atraumatic extraction protocols, and antibiotic coverage. Additionally, patients should receive comprehensive post-procedure instructions to minimize risks.
The treatment of the condition requires a multidisciplinary team that includes an oral and maxillofacial surgeon, an oncologist, and a general dentist. After diagnosing the condition, the team evaluates the risks and benefits of either continuing or discontinuing the use of bone-modifying agents.
Management of the condition depends on its stage, functional impact, symptom severity, and prognosis. According to the American Association of Oral and Maxillofacial Surgeons, the staging of the condition is outlined as follows:
· At risk: there is no visible necrotic bone in patients undergoing treatment with IV or oral antiresorptive therapy.
· Stage 0: patients exhibit no clinical evidence of necrotic bone but may experience nonspecific symptoms such as dull aching bone pain, sinus pain, or altered sensation.
· Stage 1: this stage is characterized by exposed necrotic bone or a fistula that extends to the bone in patients who show no signs of infection or inflammation.
These stages of the condition can be conservatively managed by improving oral hygiene, treating active dental and periodontal diseases, and using topical antibiotic mouthwashes.
· Stage 2: The clinical presentation is similar to that of stage 1, but it includes active inflammation or infection. Patients may also exhibit localized alveolar bone loss. Management of this stage generally follows the protocols of earlier stages, with the addition of systemic antibiotics and surgical debridement.
· Stage 3: In addition to the characteristics observed in stage 2, patients may exhibit necrotic bone that extends beyond the alveolar bone. They might also experience pathological fractures, extraoral fistulas, oroantral or oronasal communications, or osteolysis that reaches the inferior border of the mandible or the floor of the sinus. This stage often necessitates surgical debridement or resection, followed by reconstruction of the jaw if required.
Following the management of the lesion, the patient should undergo regular follow-up every 8 weeks to evaluate the status of the lesion, as follows: (1) resolved–complete healing; (2) improving–significant improvement (more than 50% mucosal coverage); (3) stable–mild improvement (less than 50% mucosal coverage); or (4) progressive–no improvement.
An early intervention is necessary to prevent progression to advanced stages, which may require surgical intervention. Medical management primarily aims to control pain and prevent infection. Surgical approaches, including debridement or resection, are reserved for severe cases. Hyperbaric oxygen therapy serves as an adjunctive treatment option to enhance healing in selected patients.
This case underscores the necessity for clinicians to recognize the risks linked to bisphosphonate therapy and to adopt a proactive stance in both prevention and management. The affliction of both jaws in this patient illustrates the variability in clinical presentations, emphasizing the complexity of MRONJ and the need for customized treatment strategies to enhance patient outcomes.
MRONJ significantly impairs quality of life [4]. Medication-related osteonecrosis of the jaws predominantly affects the mandible, which accounts for 75% of cases, whereas 25% occur in the maxilla. However, cases involving both the mandible and maxilla have an incidence ranging from 4.5% to 6.5%, highlighting the rarity of this case [12]. When performing dental extractions on patients undergoing bisphosphonate therapy, it is crucial to maintain the most aseptic environment possible and to ensure that the extraction is atraumatic to minimize the risk of osteonecrosis of the jaws. Dental practitioners and oral and maxillofacial surgeons should be cognizant of the common sites where osteonecrosis typically occurs, enabling early intervention to avoid unnecessary surgical resection. A multidisciplinary approach is essential, involving departments such as medical oncology, surgical oncology, and diabetology, which can greatly benefit the patient.
Notes
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Funding
None.
Ethical approval
The report was approved by the Institutional Review Board of Tamil Nadu Government Dental Hospital (IRB No. 1/II/IERB/2024/TNGDCH).
Patient consent
The patient provided written informed consent for the publication and use of her images.
Author contributions
Conceptualization: Senthilkumar Annamalai, Arunkumar Kamalakaran, Balaji Jayaraman. Writing - original draft: Anushya Selvakumar. Writing - review & editing: Harish Suresh Kulkarni, Senthilkumar Annamalai, Arunkumar Kamalakaran, Balaji Jayaraman. Supervision: Senthilkumar Annamalai, Arunkumar Kamalakaran, Balaji Jayaraman. Validation: Senthilkumar Annamalai, Arunkumar Kamalakaran, Balaji Jayaraman. All authors read and approved the final manuscript.
Abbreviations
MRONJ
medication-related osteonecrosis of the jaw