Medication-related osteonecrosis (MRONJ) of the mandible and maxilla

Abstract

In 2003, Marx reported the first case of osteonecrosis of the jaw in 36 cases related to zoledronic acid or pamidronate. Painful bone exposure in the mandible or maxilla unresponsive to medical or surgical management was observed. In 2014, the American Association of Oral and Maxillofacial Surgeons proposed the term ‘medication-related osteonecrosis of the jaw’ (MRONJ). However, a non-exposed variant may also occur. MRONJ can lead to debilitating clinical sequelae with limited treatment options. We present the case of a 73-year-old woman with metastatic breast cancer and MRONJ of her mandible and maxilla following treatment with intravenous zoledronic acid and denosumab. Six months following dental extractions, she was referred to the Department of Oral and Maxillofacial Surgery for assessment of extensive necrosis of her maxilla and mandible. Extraoral draining sinuses were observed. A CT mandible showed cortical destruction with an ill-defined mixed sclerotic–lucent pattern in keeping with osteonecrosis. Due to her metastatic breast cancer, the extent of her necrosis and poor performance status, free flap reconstruction of her mandible was ruled out. She was treated conservatively.

Background

The advent of various medications such as bisphosphonates, denosumab and antiangiogenic agents such as monoclonal antibodies has resulted in reported cases of medication-related osteonecrosis of the jaw (MRONJ).¹ Although MRONJ is a rare condition, it can have a potentially severe impact on the quality of life of affected patients, in particular, those individuals in higher stages of their disease, as illustrated in our case. Clinical manifestations can include exposed and non-exposed bony lesions, pain, infection, intraoral or extraoral fistulae, pathological fracture or hypoaesthesia.

Indeed, the non-exposed variant can occur in up to 25% of MRONJ cases and can be difficult to diagnose and treat, especially in frail cancer patients with multitreated progressing metastatic disease. Robust evidence-based guidance is available. Risk reduction strategies, for example, dental preventative measures and dose reduction where applicable, can minimise the risk of it developing. Although this case is not rare or novel, it provides a cautionary tale to physicians to be aware of the risk of developing MRONJ and its impact on the quality of life of affected individuals.

Case presentation

A 73-year-old woman was referred by her oncologist to the Department of Oral and Maxillo facial Surgery for assessment of exposed bone in her left mandible. She underwent extraction of her carious mobile lower left canine and lower left second premolar under local anaesthesia 6 months previously. Prophylactic antibiotics were administered. Exposed bone was present since her extractions and she was managed conservatively with chlorhexidine mouthwash and oral co-amoxiclav. Her medical history included a diagnosis of osteoporosis and left breast cancer, T2 N0 grade 3 oestrogen receptor (ER) negative ductal disease in 2001. Human epidermal growth factor receptor 2 (HER-2) status was negative. She underwent a left mastectomy and adjuvant chemotherapy with doxorubicin and cyclophosphamide. She commenced treatment with intravenous zoledronic acid, one infusion annually to reduce her risk of osteoporosis-induced fractures. She was not prescribed oral bisphosphonates prior to commencing zoledronic acid. She developed renal impairment and her zoledronic acid was held for one administration. In 2008, she underwent a right mastectomy for T2 N1 grade 3 ER⁺ disease and axillary node sampling. She required adjuvant radiation treatment and commenced treatment with anastrazole (2008–2011). In 2008, she was also diagnosed with non-metastatic renal cell carcinoma and underwent a left nephrectomy. In 2011, she developed bony metastatic disease and her anastrazole was switched to exemestane (2011–2013) plus intravenous zoledronic acid 4 mg administered monthly, which was continued until 2013. In September 2013, she sustained a pathological fracture to the distal third of her sternum and received palliative radiotherapy. Her zoledronic acid was switched to denosumab 120 mg administered subcutaneously every 4 weeks.

Disease progression was confirmed in November 2013. She received palliative radiotherapy to T8–T12. Due to further disease progression, her exemestane was switched to tamoxifen and letrozole (2013–2016). Two years later in 2015, she received palliative radiotherapy to her cervical spine. Her current medications included megestrol acetate 160 mg once daily commenced in June 2017, as well as 120 mg of subcutaneous denosumab administered every 4 weeks. In addition, she was taking modified release morphine 10 mg two times per day, paracetamol 1 g four times daily and morphine sulfate oral solution 10 mg/5 mL every four hours as required for pain. She was an ex-smoker of 15 cigarettes daily and did not consume alcohol. Her observations were stable. There was no palpable lymphadenopathy. She reported halitosis and an adverse effect on her quality of life due to discomfort when eating. She was advised to remove her denture but felt psychologically unable to do so. Orocutaneous fistulae and multiple discharging sinuses in the submental region were observed. Intraorally, she was edentulous and was wearing a complete denture. Exposed bone was evident bilaterally in her mandible, with only a small area of mucosal coverage anteriorly. A small area of exposed bone in the maxilla on the right side was noted (figure 1). A sequestrum was noted in her lower right premolar region. Pus was evident in her lower left canine region. Clinically, she was classified as stage III osteonecrosis of the jaw (table 1).

Figure 1.

Discharging sinuses in the submental region. Clinical examination showed evidence of exposed bone in the maxilla and mandible.

Table 1.

A staging system for osteonecrosis of the jaw⁴

Stage	Clinically
0	Tooth and jaw pain with no findings on examination, unexplained tooth mobility.
I	Asymptomatic exposed and necrotic bone without infection.
II	Exposed and necrotic bone with pain and infection.
III	Exposed and necrotic bone with pain and infection plus pathological fracture or extra oral fistula/communication or necrosis extending beyond the region of alveolar bone or an oroantral/oronasal communication.

Investigations

An orthopantomogram (OPG) was performed to help determine the extent of the osteonecrosis (figure 2).

Figure 2.

A sequestrum was evident in the left mandible.

Further investigation with a CT Mandible showed cortical destruction with an ill-defined mixed sclerotic–lucent pattern in keeping with osteonecrosis. Numerous lucent lesions <2 cm with extensive sequestration were also noted. Thick, calcified, periosteal reaction and pathological fractures were observed (figure 3). An incisional biopsy was not performed.

Figure 3.

CT mandible showed cortical destruction with an ill-defined mixed sclerotic–lucent pattern in keeping with osteonecrosis.

Differential diagnosis

A diagnosis of medication-induced osteonecrosis (MRONJ) attributed to both her denosumab and bisphosphonate was rendered. The cumulative exposure to both medications was 108 months at the time of her dental extractions (zoledronic acid 60 months and denosumab 48 months).

Treatment

On the advice of her oncologist, her denosumab was stopped and she continued treatment with letrozole. However, 7 months later, there was no improvement clinically. There was no evidence of granulation. Furthermore, as a result of her MRONJ, chemotherapy was not considered a safe option as it posed a high risk of developing infection and acute clinical deterioration. She was prescribed oral co-amoxiclav 625 mg three times a day for 7 days to treat an acute infective episode. A pus swab cultured normal oral commensals only. Mild symptomatic improvement with a reduction in the volume of pus was observed.

Outcome and follow-up

She developed progression of her bone metastases with multiple lesions throughout her spine and diffuse infiltration of the pelvis and proximal femur. Due to her disease progression, poor performance status and extent of necrosis, free flap reconstruction was ruled out. She was treated conservatively with chlorhexidine mouthwash and intermittent oral antibiotics, even though there may be benefit from long-term oral antibiotics in stage 3 MRONJ. She was advised to stop wearing her denture. Three months later, she was admitted under the medical team with severe confusion. A CT head showed multiple lucencies within the skull vault suggestive of small metastases. There was progressive lytic destruction of the mandible bilaterally as well as the alveolar process of the maxilla. A diagnosis of sepsis caused by community-acquired pneumonia, chronic malignant hypercalcaemia and acute kidney injury was rendered. Her sinuses on her mandible were discharging pus. She was treated with intravenous co-amoxiclav. She was reviewed by tissue viability and an alginate dressing, an adhesive foam dressing and hydrofilm were applied to the sinuses. This dressing was changed to small pads in replacement of the foam to effectively manage the exudate. She was reviewed by the palliative care team and discharged to a nursing home for end-of-life care. She died 3 weeks later.

Discussion

In 2003, Marx first described bisphosphonate-induced avascular necrosis of the jaws and Migliorati first proposed its designation as osteochemonecrosis.^{2 3} MRONJ is the latest term proposed by the American Association of Oral and Maxillofacial Surgeons (AAOMS) to accommodate the growing number of osteo necrosis cases involving the maxilla and mandible associated with other antiresorptive and antiangiogenic therapies. In their position paper, AAOMS emphasise current or previous treatment with antiresorptive or antiangiogenic medications associated with exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region of >8 weeks and not related to radiation therapy or metastatic disease to the jaws.⁴ In patients with cancer exposed to denosumab, the risk of MRONJ ranges from 0.7% to 1.9%, a comparable risk to cancer patients exposed to zoledronic acid and is further supported by the findings of pivotal phase III trials.⁵ Fung et al’s multicentre retrospective cohort study showed a median time to onset of 6 years in patients treated with oral alendronate and 2.2 years in those treated with intravenous zoledronic acid.⁶ MRONJ has a female predilection.⁴ As in our reported case, the majority of cases of MRONJ of the jaw report dental procedures such as a tooth extraction as the precipitating factor.³ Other risk factors include immunosuppression, concomitant chemotherapy, pre-existing dental disease, antiangiogenic biologics, previous treatment with bisphosphonates, corticosteroids and smoking.⁷ Therapy duration and cumulative dosage are also risk factors. A non-exposed variant of the condition may occur in up to 25% of cases.⁸ Their symptoms do not conform to the traditional case definition.

Spontaneous cases can also occur. One-third of patients present with pain and an area of exposed bone typically surrounded by inflamed erythematous soft tissue. As in our case, fistula formation and severe extended bone necrosis may be observed. Furthermore, 20% can progress to a pathological fracture.⁹ Other common signs and symptoms include loosening of previously stable teeth, paraesthesia of the lip, gingival swelling, pus and non-healing sockets. Ruggiero’s staging system for osteonecrosis of the jaw was subsequently revised by the AAOMS¹⁰ (table 1). The diagnosis is rendered based on clinical examination, with a heightened index of suspicion in individuals receiving potent bone-targeted agents. An OPG will help determine the extent of necrosis and presence of a sequestrum. The differential diagnosis includes alveolar osteitis, chronic sclerosing osteomyelitis or metastatic disease.

The pathology of MRONJ has not been fully elucidated. Hypotheses include the inhibition of osteoclastic bone resorption and remodelling, inflammation, infection, inhibition of angiogenesis, soft tissue toxicity and immune dysfunction.³ In November 2010, the Food and Drug Administration (FDA) approved denosumab (XGEVA) as a subcutaneous injection 120 mg every 4 weeks for the prevention of skeletal-related events, such as pathological fracture or spinal cord compression, in patients with bone metastases from solid tumours. It is also licensed for the treatment of osteoporosis in postmenopausal women. Both European Medicines Agency (EMA) and FDA have approved denosumab for use in multiple myeloma. Denosumab, an antiresorptive agent, is a fully humanised antibody affecting the receptor activator of nuclear factor Kb ligand, resulting in a non-reversible deactivation of osteoclasts which persists until osteoclastic cell death.¹¹ The effect of the drug is generally 2–5 months duration after administration, with a half-life of about 25.4 days and their effects on bone remodelling are mostly diminished within 6 months of treatment cessation. A recent systematic analysis has shown that denosumab combined with risk factors such as a dental extraction, poor oral hygiene and chemotherapy may favour the development of MRONJ.¹² Since 2010, 26 well-documented cases of denosumab-related MRONJ have been reported.⁴ In clinical trials, the incidence of MRONJ increased with duration of denosumab 120 mg exposure. The patient-year adjusted cumulative incidence of confirmed MRONJ was 1.1% in the first year of treatment, 3.7% in the second year and 4.6% per year thereafter.¹³ The overall prevalence was 6%–8% in the cancer population. Although the Study of Transitioning from Alendronate to Denosumab (STAND) trial suggests the safety of taking bisphosphonates and denosumab in tandem for the treatment of osteoporosis, sequential treatment with bisphosphonates and denosumab might lead to an overlapping treatment effect, due to the addition of the effect of denosumab on the residual bisphosphonate effect.^{11 14 15} Although the concomitant use of both medications is not approved, the limited data on the safety of sequential use of bisphosphonates is relatively reassuring. In 2015, Stopeck described the safety results of extended denosumab therapy in patients with metastatic breast and prostate cancer from the open-label extension phase of two phase III trials. No new safety signals were identified, thus confirming the safety profile of denosumab after long-term exposure, or after switching to denosumab.¹⁶ In Belgium, in 2017, Loyson showed that cancer patients with bone metastasis treated with a bone resorption inhibitor had a slightly higher risk of MRONJ early after switching from a bisphosphonate to denosumab (15%), compared with those individuals remaining on bisphosphonates. Nevertheless, based on the global MRONJ incidence, the switch from bisphosphonates to denosumab can be considered as safe as an equivalent exposure to denosumab from the start.¹⁶ MRONJ can produce significant morbidity in affected individuals with an adverse effect on the quality of life due to its chronic nature and relatively low recovery rate. In general, patients should be managed by a team including an oral and maxillofacial surgeon, a dentist and an oncologist. Patients with full or partial dentures should be examined for areas of mucosal trauma. Management strategies are multidisciplinary, with the medicines and healthcare products.

Regulatory agency stating that before starting denosumab a dental examination and appropriate preventative dentistry are recommended. They also advise not starting denosumab 120 mg in cancer patients with a dental or jaw condition requiring surgery or in patients who have not recovered following oral surgery. If MRONJ develops the oncologist may consider discontinuing therapy until soft tissue closure has occurred, depending on disease status. In small case series, pentoxifylline and tocopherol have shown efficacy.^{17 18} Management includes resection of necrotic bone with more recent studies suggesting that surgery might be curative in a selected group of patients. In individuals with stage III osteoradionecrosis (ORN), as in our case, removal of the necrotic bone and immediate reconstruction are advocated. Due to the extent of the MRONJ and underlying patient comorbidities, this option was not possible in our case.

Risk reduction strategies include antibiotic prophylaxis, which may prevent MRONJ after dental procedures and medication dose reduction.¹⁸ This case highlights the importance of requesting a dental examination prior to commencing treatment with denosumab to reduce the risk of developing MRONJ. Increased awareness among oncologists and physicians is required, with a multidisciplinary approach to managing its sequelae.

Learning points.

• Medication-related osteonecrosis of the jaw (MRONJ) can have an important impact on the quality of life of affected individuals. It is important to remind physicians of its existence and maintain awareness of this condition. Non-exposed MRONJ can occur in up to 25% of cases and can pose a diagnostic challenge.

• Surgery is a potentially curative intervention. However, it is currently unclear what subgroup of patients would benefit most from this treatment approach. Further trials are needed to define the safety and efficacy of surgery for MRONJ.

• Multidisciplinary consultation is important in elderly and frail patients both prior to and during treatment with antiresorptive agents. All patients prior to commencing treatment with denosumab or a bisphosphonate should undergo a dental examination to reduce the risk of developing MRONJ. If possible, dental extractions should be avoided. Cumulative exposure to these agents is an important risk factor for developing MRONJ.