MRONJ and denosumab: the challenge of progression after treatment discontinuation

Medication-Related Osteonecrosis of the Jaw (MRONJ) represents a major complication in oncological patients treated with bone-modifying agents (BMA). While the initial incidence in these patients is estimated between 1 and 2%, it can rise up to 32.1% after eight years of exposure to denosumab. Despite this prevalence, the clinical behavior of MRONJ after denosumab discontinuation remains poorly understood, with some observations even suggesting a paradoxical acceleration of osteolysis following treatment cessation.

This case report details the follow-up of a 71-year-old patient with metastatic prostate cancer, illustrating rapid mandibular degradation following the discontinuation of denosumab. The objective is to document the evolution of the pathology from stage 2 to stage 3 in just a few months and to evaluate the effectiveness of a conservative surgical strategy. The study tests the hypothesis that a marginal mandibulectomy with cortical preservation, although risky in the face of a loss of bone continuity, can induce sustainable tissue regeneration in a context of post-denosumab metabolic rebound.

Design and Clinical Protocol

This case report details the surgical management of a 71-year-old patient with stage 3 medication-related osteonecrosis of the jaw (MRONJ). The subject, initially treated with denosumab for metastatic prostate adenocarcinoma (PSA > 10,000 ng/mL), presented with bilateral mandibular involvement that progressed from stage 2 to stage 3 with a pathological fracture and cutaneous fistula.

The therapeutic protocol was structured around the following phases:

• Preparation phase (8 months): Discontinuation of denosumab 6 months before the procedure. Infection management with amoxicillin (750 mg/day for 1 month) and a rigorous hygiene protocol (benzethonium chloride 0.004% rinses and professional cleanings with benzalkonium 0.025%).
• Surgical procedure: Marginal mandibulectomy via intra-oral approach under general anesthesia. The procedure lasted 2.5 hours with a blood loss of 300 mL. The strategy prioritized selective curettage of necrotic bone and maximum preservation of the periosteum and residual cortex (notably the lingual cortex and the inferior border).
• Post-operative follow-up: Removal of the suction drainage on the 5th day, intravenous antibiotic therapy (flomoxef) and a protocol of 20 hyperbaric oxygen therapy sessions initiated 2 weeks after the procedure.

The analysis relied on imaging surveillance (dental panoramic and CT scan) and histopathological evaluation of the resected tissues using hematoxylin-eosin (H&E) staining, revealing empty osteocyte lacunae pathognomonic of bone necrosis.

Evolution to Stage 3 after discontinuation of denosumab

Initially managed at stage 2 (AAOMS/Japanese criteria) in March 2019, the patient presented with a mouth opening of 30 mm and an involuntary weight loss of 5 kg. Initial CT imaging showed diffuse sclerosis of the cancellous bone with preserved mandibular continuity.

Eight months after the first visit, and six months after the discontinuation of denosumab, major osteolytic progression was observed. Clinical examination revealed the appearance of a purulent right submandibular cutaneous fistula and spontaneous exfoliation of several teeth. Imaging examinations from November 2019 confirmed the progression to stage 3 MRONJ:

• Panoramic radiograph: Large radiolucent area extending from the symphysis to the right mandibular body, reaching the inferior border.
• Scanner (CT): Extensive osteolysis, presence of bone sequestra and pathological fracture with complete rupture of mandibular continuity.

Operative data and histopathological analysis

A marginal mandibulectomy via an intra-oral approach was performed. The procedure lasted 2.5 hours with an estimated blood loss of 300 mL. Intraoperative observations revealed necrosis of the right inferior alveolar nerve. Histopathological analysis (H&E staining) confirmed the diagnosis:

• Presence of necrotic bone with empty lacunae (absence of viable osteocytes).
• Infiltration of bacterial colonies and inflammatory debris.

Immediate post-operative follow-up

The care protocol included intravenous antibiotic therapy (Flomoxef) and 20 sessions of hyperbaric oxygen therapy. At six weeks postoperatively, a minor wound dehiscence with bone exposure was noted, requiring the excision of small sequestered bone fragments.

Discussion: The rebound effect after discontinuation of denosumab

This clinical case highlights a paradoxical phenomenon: the rapid worsening of osteonecrotic lesions following the discontinuation of denosumab. Initially diagnosed at stage 2 (without pathological fracture or extra-oral fistula), the patient presented marked osteolytic progression during the treatment interruption period prior to surgery. This observation suggests that the interruption of denosumab, unlike bisphosphonates with a long half-life, could trigger a sudden resumption of bone remodeling and an acceleration of resorption, complicating surgical management.

The success of the marginal mandibulectomy, despite the extent of the lesions, highlights the value of a cautious surgical approach. Long-term bone regeneration suggests that, even in the presence of aggressive lysis, healing potential remains mobilizable provided there is adequate debridement and rigorous infection management. This case illustrates the complexity of surgical timing in patients receiving bone-modifying agents (BMA).

The limitations of this report lie in its nature as a single case study. Although the progression suggests a direct link between drug discontinuation and the progression of MRONJ, cohort studies are necessary to confirm whether this "rebound" is a clinical constant or an individual variability related to the underlying cancer pathology.

Study summary

This clinical case reports a marked mandibular osteolytic progression in a 71-year-old patient following the discontinuation of denosumab. While mandibular continuity was initially preserved at the initial stage 2 diagnosis, a rapid degradation of the bone structures occurred during the eight months of preoperative follow-up, requiring a marginal mandibulectomy.

In concrete terms, for the practitioner:

• Post-denosumab discontinuation vigilance: Treatment interruption does not systematically stabilize lesions; a risk of osteolytic "rebound" exists, requiring very close clinical and radiographic monitoring.
• Surgical responsiveness: In the event of worsening symptoms, do not wait for spontaneous improvement related to the suspension of the medication. Early intervention can prevent more extensive loss of substance.
• Conservative option: A marginal mandibulectomy focused on the meticulous curettage of the necrotic bone while preserving the healthy cortical walls allows for the maintenance of mandibular function.

Technical lexicon of the study

MRONJ (Medication-related osteonecrosis of the jaw): Medication-related osteonecrosis of the jaw, a serious complication linked to the prolonged use of bone-modifying agents, impacting mandibular integrity and the patient's quality of life.

Bone Modifying Agents (BMAs): Therapeutic class grouping bisphosphonates and denosumab, prescribed at various dosages to treat osteoporosis or prevent skeletal events related to malignant bone metastases.

Denosumab: Systemic agent targeting bone metabolism (used here for metastatic prostate cancer) whose sudden discontinuation may, according to reported clinical observations, coincide with an accelerated progression of osteolytic lesions.

Marginal mandibulectomy: Surgical strategy of limited bone resection aimed at the excision of necrotic tissue and curettage of infected bone while attempting to preserve the continuity of the mandibular base and the periosteum.

Sequestrum: Segment of devitalized necrotic bone that separates from the surrounding healthy bone, identified by CT imaging as an isolated mass within areas of bone lysis.

Osteolysis: Process of active bone tissue destruction which manifested, in this patient, by extensive resorption from the symphysis menti to the inferior border of the mandibular body.

Pathological fracture: Rupture of bone continuity occurring spontaneously due to structural weakening caused by the progression of osteonecrosis and underlying infection.

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