Denosumab-related osteonecrosis of the external auditory canal—benefit of the early surgical management

Abstract

Background: Antiresorptive drugs are widely used to reduce bone mineral loss in patients with osteoporosis and to prevent skeletal-related events in patients with metastatic cancers and multiple myeloma (MM). Both the bisphosphonates (BP) and denosumab typically used in this indication were shown to be effective and relatively safe. Obviously, this medication could have some adverse effects; one of them is osteonecrosis of the external auditory canal. Only sporadic cases of external auditory canal osteonecrosis have been published yet. Here, we provide a case of denosumab-related osteonecrosis of the external auditory canal successfully treated surgically in the early stage of the disease.

Case report: A 68-year-old patient with breast cancer underwent comprehensive oncological treatment, including denosumab administration. She was diagnosed with osteonecroses in the jaw and ear canal. The necrotic bones in both regions were resected with primary wound closure. Both affected sites healed well with no signs of necrosis recurrence.

Conclusions: Osteonecrosis of the external auditory canal is a rare but probably underdiagnosed complication of antiresorptive medication. It has a negative impact on patient quality of life if left untreated. Early surgical treatment appears to be effective. The authors highlight several similarities with medication-related osteonecrosis of the jaw. Therefore, an analogous disease staging and treatment rationale is suggested.

Introduction

Several antiresorptive drugs are used to reduce bone density loss and to decrease fracture incidence in postmenopausal women for a long period. They are also indicated in patients with multiple myeloma (MM) and other cancer patients with bone metastases. Denosumab is a human monoclonal antibody against RANKL (receptor activator of nuclear factor kappa-B ligand). Denosumab prevents the fusion of preosteoclasts into an osteoclast by competitive inhibition of their receptors. Another group of antiresorptive medications are bisphosphonates (BPs). Bisphosphonates reduces bone resorption by inhibiting osteoclast function and initiating their apoptosis, and they form toxic ATP analogues and chemically bind to bone minerals. Denosumab has been introduced into clinical practice (FDA approval in June 2010) as an alternative to BPs, with premise of its lower rate of side effects. Unlike BP, denosumab does not cause post-application flu-like syndrome, does not irritate the gastrointestinal tract, and is not nephrotoxic. After initial optimism, it became clear that denosumab has the same skeletal side effects as BP. These are mainly jaw osteonecrosis and atypical fractures of the femur (ATFF). Jaw osteonecrosis is an area of necrotic bone exposed intraorally or extraorally that persists for more than 8 weeks. At first, it was only referred to patients taking BPs, and the disease was called bisphosphonate-related osteonecrosis of the jaw (BRONJ). Now, other substances causing osteonecrosis are known, especially denosumab, antiangiogenic drugs, and kinase inhibitors, and therefore the condition is now called medication-related osteonecrosis of the jaw (MRONJ). ¹ Although MRONJ is the most common skeletal adverse effect of antiresorptive therapy, other bones could also be affected. Atypical fractures of the femur occur in patients treated with BP as a low-energy subtrochanteric or proximal diaphyseal femoral fracture. It is typically horizontal and starts in the lateral cortex. It has also been described in patients using denosumab. ²

Several cases of bisphosphonate-associated ear canal osteonecrosis (BPECO) have been described in recent literature. ^{3 -9} Recently, there were some published cases of osteonecrosis of the ear canal in patients receiving denosumab ^10,11 and also one case with a patient receiving a protein kinase inhibitor. ¹² It commonly presents as an exposed bone of the external auditory canal and in advanced stages, destruction of the middle ear and propagation to the skull base could occur. The quality of life of the patient severely deteriorates, and treatment of these advanced stages is challenging.

We present a unique case of denosumab-related external auditory canal osteonecrosis and its successful surgical treatment in the early stage of the disease.

Case report

In December 2014, a 68-year-old patient was referred to the oral, jaw, and facial surgery clinic by a treating oncologist with suspicion of MRONJ. The patient underwent a comprehensive oncological treatment of breast cancer. Therapy included left mastectomy with axillar dissection, radiation therapy, and aromatase inhibitor. In March 2011, the patient started on denosumab (120 mg subcutaneously) once every 3 months. The last dose of denosumab was administered in September 2014.

A clinical examination confirmed a necrotic bone in the right molar region of the mandible under a partial overdenture. Necrosis was painless and did not show signs of inflammation. Therefore, it was classified as stage 1 of MRONJ by the American Association of Oral and Maxillofacial Surgeons. ¹ During examination, the patient also complained of a 4-month–lasting discharge from the right ear, which was repeatedly unsuccessfully treated with ear drops.

Denosumab was discontinued and the necrotic bone of the mandible was resected under local anesthesia and antibiotic coverage (amoxicillin with clavulanic acid 875 mg/125 mg BID, beginning 1 week before and lasting 2 weeks after surgery). Since only the surface of the mandibular alveolus was necrotic, its resection could continue to bleeding edges and subsequent soft tissue hermetic closure did not cause problems. Healing in the oral cavity took 3 weeks without complications. Histopathological examination showed fragments of the necrotic bone with clusters of branching microbial filaments (Actinomyces). Consequently, the patient had been sent to the ENT department. The otoscopy revealed a suppurating skin defect on the floor of the right auditory canal. The defect was located approximately above the border of the bony and cartilaginous part of the auditory canal. Around the wound, there was adhering incrustation. The tympanic membrane has a normal appearance.

The necrotic bone was removed and the defect was covered with a free skin graft (from the retroaurical region) under general anesthesia. Postoperative healing was again uneventful. The bone sample from the defect was fragmented, so histopathological examination was not possible. The patient has been asymptomatic and has no signs of recurrence of both carcinoma and bone necrosis for 5 years.

Discussion

To the best of our knowledge, this is the first description of the benefit of early surgical management in denosumab-related osteonecrosis of the external auditory canal. Most patients with osteonecrosis of the ear canal underwent a different prolonged unsuccessful conservative therapy for chronic suppuration of the ear canal. The final solution was often a surgical removal of the affected bone and a defect closure—Table 1. Early removal of the necrotic bone could lead to complete healing of the defect, without the need for extensive resection of the affected bone and adjacent structures. This concept is analogous to the preferred MRONJ treatment strategy. ^13,14

Table 1.

Overview of MRECO cases.

Author	Age/Gender	Main diagnosis	Antiresorptive Drug	Symptoms	Final treatment
Bast	N/A	Multiple myeloma	Pamidronate/Zolendronate	Bilateral ear canal necrosis, mastoid invasion. MRONJ	Bone resection, cartilaginous and skin graft
Wickham	64 y M	Multiple myeloma	Clodronate	Exposed bone, bone irregularity	None
	72 y F	Osteoporosis	Alendronate	Otitis externa. Mastoid and facial nerve canal invasion	Radical mastoidectomy
Kharazmi	74 y F	Osteoporosis	Alendronate	Exposed bone, inflammation. Bilateral	None
	67 y F	Osteoporosis	Alendronate	Exposed bone. Irritation	None
	88 y F	Osteoporosis	Alendronate	Exposed Bone	None
Salzman	79 y F	Osteoporosis	Alendronate	Otorrhea, mastoid, and temporomandibular joint invasion	Debridement of necrotic bone
Froelich	51 y F	Breast cancer	Zolendronate	Exposed bone. Bilateral	Debridement of necrotic bone
	70 y F	Breast cancer	Pamidronate/Zolendronate	Exposed bone	Debridement of necrotic bone
	64 y F	Multiple myeloma	Pamidronate	Exposed bone. Suppuration	Debridement of necrotic bone. Skin graft
Pollizotto	64 y M	Multiple myeloma	Pamidronate/Zolendronate	Exposed bone. MRONJ	Debridement of necrotic bone
True	79 y F	Osteoporosis	Bisphosphonates/Denosumab	Hearing loss, otalgia. Bilateral	Conservative
Takeda	81 y F	Osteoporosis	Denosumab	Hearing loss, destruction of temporal bone, external ear canal, tympanic cavity, mastoid. Jugular bulb exposion	Radical mastoidectomy
Canzano	58 y M	Renal cell carcinoma	Sorafenib	Ottorhea, ear canal destruction, mastoid and temporomandibular joint invasion	Subtotal petrosectomy and fat graft
This case	68 y F	Breast cancer	Denosumab	Exposed bone. MRONJ	Debridement of necrotic bone, skin graft
Not published case	67 y F	Rheumatoid arthritis	Zolendronate/Denosumab	Destruction of the middle ear, facial nerve palsy. MRONJ	None

Abbreviations: MRECO, Medication-Related Ear Canal Osteonecrosis; MRONJ, Medication-Related Osteonecrosis of the Jaw.

Osteonecrosis of the external auditory canal is certainly quite rare. However, it is necessary to consider this complication in differential diagnosis, as the quality of life of an affected patient could be dramatically impacted. The authors of this article had previously treated another patient who suffered complete destruction of the middle ear caused by osteonecrosis. The disease resulted in hearing loss and facial nerve paresis on the affected side (the case had not been published as the patient died early from cardiac comorbidity)—Figure 1.

Figure 1.

Destruction of the posterior wall of the auditory canal. CT transversal section

Due to the analogy with MRONJ and the existence of denosumab-related necrosis of the ear canal, we propose to unify the terminology on medication-related ear canal osteonecrosis (MRECO). Diagnostic criteria include necrotic bone of the ear canal exposed for 8 weeks in the patient using risk medication (especially BP, denosumab, bevacizumab, temsirolimus, and sunitimib), absence of previous radiotherapy in the temporal area, exclusion of metastases, and cholesteatoma. ¹⁵

To determine the severity of the disease and the prospective simplification of the choice of an adequate therapeutic approach, we propose a classification of MRECO into stages analogous to MRONJ (see Table 2).

Table 2.

MRECO stages.

Stage 0	Non-specific problems, atrophy of the ear canal skin
Stage 1	Exposed bone without signs of infection
Stage 2	Exposed bone with signs of infection, ear canal discharge
Stage 3	Mastoid involvement. TMJ, middle and/or inner ear destruction. Facial nerve palsy. Destruction of the skull base. Bone exposed externally

Abbreviations: MRECO, Medication-Related Ear Canal Osteonecrosis; TMJ, Temporo-Mandibular Joint.

Because only a few cases of MRECO have yet been described, conclusions on the most appropriate treatment strategy are difficult. Based on the analogy with MRONJ, therapy should be initiated conservatively by systemic administration of antibiotics and local therapy with antiseptic rinses. In insufficient response to treatment, complete resection of the necrotic bone with free graft overlap should follow. In advanced stages, radical resection of affected structures with subsequent reconstruction is considered necessary. The purpose of the surgical procedure is to remove all necrotic bones until fresh bleeding edges are reached. Prolonged antibiotic administration until complete healing of the defect is commonly indicated. On the contrary, a cessation of antiresorptive/antiangiogenic therapy (so-called drug holidays) is not universally recommended. It must be individually decided based on the general condition of the patient and the risks and benefits of discontinuing therapy evaluation.

Due to the rarity of MRECO, all-encompassing prevention is useless. Detection of this complication and ensuring further professional treatment remains in the hands of specialists prescribing this risk medication. They should actively ask for signs of MRECO, particularly a history of ear discharge, and eventually refer such a patient to an  Ear, Nose and Throat (ENT) department. ENT specialists should consider the possibility of osteonecrosis when treating patients with chronic ear disorders. Similarly, oral surgeons should be aware of MRECO when treating patients with MRONJ who simultaneously suffer from ear problems.

Conclusions

The article pointed out the benefit of early surgical management of MRECO in comparison to the late approach.