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Denosumab and bisphosphonate associated bilateral osteonecrosis of the external auditory canal
  1. Harry David True1,
  2. Rupert George Ricks2,
  3. Joel Anthony Smith2
  1. 1 University of Exeter Medical School, Exeter, UK
  2. 2 Ear, Nose and Throat (ENT) Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
  1. Correspondence to Joel Anthony Smith; joel.smith2{at}nhs.net

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In conjunction with BMJ Case Reports, DTB will feature occasional drug-related cases that are likely to be of interest to readers. These will include cases that involve recently marketed drugs for which there is limited knowledge of adverse effects and cases that highlight unusual reactions to drugs that have been marketed for several years.

Summary

We present a case of non-surgically managed bilateral osteonecrosis of the external auditory canal with a history of long-term medical therapy for osteoporosis. A 79-year-old woman with severe osteoporosis and destructive osteoarthritis received >10 years of once weekly bisphosphonate therapy before switching to denosumab. Four months later, the patient presented with bilateral loss of hearing and right-sided otalgia. Necrotising otitis externa, cholesteatoma and malignancy were considered but with histology, microbiological and CT assessment, bilateral osteonecrosis of the external auditory canal was diagnosed. Surgical debridement with canalplasty was avoided due to our patient’s comorbidities. Treatment continued for 5 months with regular aural toilet, Terra-Cortril ointment and bismuth-iodine-paraffin paste packing. At 1-year follow-up, bilateral external auditory canals were completely re-epithelialised with no pain or affected hearing. We report the first case of bilateral osteonecrosis of the external auditory canal associated with denosumab and bisphosphonates with successful conservative management.

Background

Osteoporosis is increasing in prevalence alongside an ageing population and oral bisphosphonates are the recommended first-line antiresorptive therapy.1 Concerningly, these antiresorptives are associated with rare presentations of osteonecrosis. This occurs relatively frequently in the jaw but there are very rare reports of ear canal involvement.2–4 An increased risk of developing osteonecrosis is associated with intravenous administration or when treatment is sustained over 3–5 years.5 The most common management for temporal bone involvement is surgical debridement, canalplasty or mastoidectomy although topical steroids and antibacterial ointment can be effective.6

If patients are at risk of a significant number of frailty fractures while on bisphosphonates, they may be switched to denosumab therapy.7 Denosumab is a monoclonal antibody therapy targeting ‘receptor activator of nuclear factor kappa-Β ligand’ to inhibit osteoclast activity and prevent bone resorption.8 The association of denosumab with osteonecrosis of the external auditory canal is acknowledged by the Medicines and Healthcare products Regulatory Agency (MHRA) after receiving five unpublished reports.9 There has been only one published case of osteonecrosis associated with denosumab however, this presented as unilateral disease and was managed surgically.10 In our report we describe a conservative approach to bilateral osteonecrosis of the external auditory canal in a patient with significant comorbidities.

Case presentation

This case report concerns a 79-year-old woman, ex-smoker, with severe osteoporosis and destructive osteoarthritis, no history of diabetes mellitus, radio/chemotherapy or otological surgery. There was also no history of external auditory canal trauma or pre-existing conditions such as external auditory canal cholesteatoma. She was prescribed alendronate (70 mg) weekly for over 10 years for a loss of height. A DEXA scan in 2016 showed spine −1.1, right forearm −2.6 with wedge vertebral fractures at L2 and in lower thoracic spine with marked osteopenia, kyphosis and scoliosis. Due to progressive osteoporosis, alendronate was switched to denosumab (60 mg) six monthly. Four months after her initial dose of denosumab our patient presented with progressive bilateral conductive loss of hearing and right-sided otalgia/otorrhoea. No facial palsy or nystagmus was observed.

Bilateral and extreme soft tissue canal swelling was noted, with polyp and granulation tissue formation in the base of the left ear while necrotic bony sequestra was removed from the right canal. Necrotising otitis externa was suspected and the patient was admitted to hospital for microbiology sampling, subsequent intravenous aztreonam was given and denosumab was stopped. Her general physical condition was normal.

Investigations

Temporal CT identified bilateral destruction of the floor of the external auditory canal with mastoid opacification and erosion without cranial base involvement. There was also bilateral middle ear fluid, and the vestibulocochlear apparatus and ossicles were unremarkable (figure 1). A previous 2017 CT head showed well defined canals and mastoids (image not shown).

Figure 1

Temporal CT (1) displaying bilateral destruction of the floor of the external auditory canal (white arrows). Axial CT (2) displaying mastoid opacification (white arrows) and oedematous occlusion of both canals. Right (A) and left (B).

On presentation, bilateral posterior canal wall biopsies revealed severely inflamed granulation tissue showing intense neutrophil infiltration with accompanying plasma cells and focal fibrinous exudate. There was also a polypoid fragment with underlying inflamed and fibrotic dermis. No evidence of malignancy. Microbiology swabs and culture from both ear canals, on admission, revealed normal skin flora: alpha haemolytic Streptococcus, Candida and anaerobe species. The right ear also grew coliform organisms although unspecified.

Differential diagnosis

As bilateral canal oedema and granulation settled, an area of denuded bone was revealed which raised the possibility of bilateral canal wall cholesteatoma. Throughout treatment the differential diagnosis of canal wall cholesteatoma, necrotising otitis externa and the diagnosis by exclusion of osteonecrosis of the external auditory canal was considered. However, cholesteatoma would reveal an epithelial cyst, offensive purulent otorrhoea with bony erosion and could present with facial palsy although these signs were not observed in our patient.11 Necrotising otitis externa usually presents unilaterally and can include cranial nerve palsy but is more common in diabetic patients caused by pseudomonas infection.12 With radiological (figure 1) and visual absence of masses and a negative histology from biopsy at the time of admission, malignancy was unlikely.13 Therefore, by exclusion, osteonecrosis of the external auditory canal was a more likely diagnosis due to the bony sequestra that was present, as seen in osteonecrosis of the jaw associated with bisphosphonates and denosumab.14

Treatment

Due to bilateral disease and significant comorbidities, conservative treatment was favoured for our patient. After clinical improvement on intravenous aztreonam for 8 days (following local guidelines), the treatment was changed to oral ciprofloxacin (750 mg, two times per day for 7 days) with ciprofloxacin ear drops (two times per day, 6 weeks) as advised by microbiology and in reference to otitis externa and perioperative cholesteatoma guidelines.15 16

On discharge from hospital, the left canal was patent but oedematous and displayed a polyp medial to an inferior area of exposed bone. The patient’s right ear remained oedematous and occluded with ongoing bony sequestration. Ongoing aural toilet led to an improved clinical picture of reduced otalgia and an improvement in hearing. Over 1 month, microsuction was performed weekly then extended to bi-monthly for a further 4 months. During this period, with bone sequestra and mastoid mucoid discharge removal, healthy epithelial edges were exposed. The epithelium was initially granulation tissue and Otomize Ear Spray (neomycin/dexamethasone/acetic acid) was briefly used (7 days, three times per day, 60 mg spray into both auditory canals) to reduce oedema and prevent infection. At each appointment, the canals were packed with Terra-Cortril ointment and wick dressing. As the oedema reduced, the patients hearing improved and normal tympanic membranes were revealed. Bilateral external auditory canal epithelium contained polypoid areas as the exposed canal bones were re-epithelialised. The canals had inferior areas of exposed bone and these were left dry and open to the air. The canals eventually displayed normal epithelium with a single polyp in the left ear and bilateral areas of exposed canal bone with healthy skin edges. Bony canalplasty was considered as the areas of exposed canal bone remained. With no sign of auditory canal inflammation or infection and our patient’s comorbidities, surgery was contraindicated and considered unnecessary.

Outcome and follow-up

The patient’s right ear was slower to improve, displaying a greater area of canal bone exposure and necrosis, although following a similar clinical course to the left. The exposed canal bones were completely re-epithelialised by 1-year follow-up with no pain, infection or hearing loss.

Discussion

Medication related osteonecrosis most often presents in the jaw and while cases involving the external auditory canal are very rare (<1 in 10 000), both are reported in bisphosphonate therapy of osteoporosis.2 9 17 Greater risk of these complications arises with recent chemo/radiotherapy, canal trauma, infection and diabetes.9 17 Osteonecrosis of the jaw is also a recognised side effect of denosumab therapy.14 Common side effects of denosumab include: Abdominal discomfort; cataract; constipation; hypocalcaemia; increased risk of infection; pain; sciatica; second primary malignancy and skin reactions (cellulitis). There are also very rare complications of atypical femur fracture, hypersensitivity, and osteonecrosis (although unspecified).18

Guidance for medication related osteonecrosis of the jaw (MRONJ) for bisphosphonates and denosumab is to manage conservatively to avoid infection and improve patient quality of life.19 As the disease becomes more severe so surgery is used to a variable extent, that is, debridement, marginal osteotomy and buccal fat pad flaps. As there are no guidelines for osteonecrosis of the external ear canal, guidelines for preoperative care of cholesteatoma and otitis externa were initially followed with the view to perform canalplasty in our case.15 16 However, due to surgical contraindications and well healing auditory canals, topical therapy of ciprofloxacin/dexamethasone drops and aural care was maintained for an extended period.

Although there are yellow card reports to MHRA associating denosumab and osteonecrosis of the external auditory canal, there has been only one published case.9 20 Takeda et al described the surgical management of a unilateral osteonecrosis of the external auditory canal in an 81-year-old woman who had received three doses of denosumab.10 After left sided radical mastoidectomy and recovery the authors reported the development of right external auditory canal bone erosion, although no treatment was provided. Therefore, our case represents the first report of bilateral presentation in osteonecrosis of the external auditory canal associated with denosumab and bisphosphonate therapy, managed conservatively.

However, surgery remains the optimum treatment for many cases of auditory canal osteonecrosis with canalplasty and debridement often resulting in re-epithelialisation and a resolution of symptoms.4 21–26 The use of conservative therapy for this condition has only been documented in three papers, all developing from bisphosphonate only therapy.

In the first report, Salzman et al described unilateral disease in a 79-year-old woman with 2 months of otalgia, on bisphosphonates for >10 years. Intravenous antibiotics with local debridement of canal bone sequestra resulted in ~50% re-epithelialisation of exposed canal bone and the resolution of her symptoms.27 In a subsequent report, Kharazmi et al described three cases of suspected osteonecrosis of the external auditory canals in elderly patients with a history of bisphosphonates therapy.28 Two patients responded to topical treatments (Terra-Cortril ointment) but were not followed up more than 7 months, at which point they both displayed areas of exposed canal bones with no other symptoms. The other patient’s treatment and follow-up was not reported, just that they had presented to ear, nose and throat (ENT).

A further six cases were reported by McCadden et al five of which were successfully treated with topical steroids and antibiotic ointment including a case of bilateral disease which was slower to respond.3 All five were stable at 12 months while one patient did not respond to conservative therapy and required surgery. Based on these findings and from our own experience in a patient not amenable to surgery, a regularly reviewed conservative approach can be followed to completely resolve symptoms.

In accordance with the initial management of MRONJ and the afore-mentioned cases of osteonecrosis of the external ear canal, conservative therapy was attempted in our case. The differential diagnosis of cholesteatoma, necrotising otitis externa or malignancy were excluded by symptoms and radio/histological reports. With contraindications to surgical management, our conservative approach was successful. Our patient represents the first reported case of bilateral osteonecrosis of the external auditory canal associated with denosumab and bisphosphonate therapy, managed conservatively. We recommend considering osteonecrosis of the external auditory canal in presentations of bony sequestra with otalgia/otitis externa in patients on denosumab or bisphosphonate therapy. If surgery is not appropriate, the use of topical steroids and antibiotics is recommended although recovery may be slower.

Learning points

  • Our patient represents the first reported case of bilateral osteonecrosis of the external auditory canal associated with denosumab and bisphosphonate therapy.

  • In patients treated with denosumab or bisphosphonates who present with ongoing ear pain, osteonecrosis of the external auditory canal should be suspected and referred to ear, nose and throat.

  • In cases where surgery is contraindicated, a topical steroid and antibiotic approach is recommended, although recovery is slower.

Ethics statements

Patient consent for publication

Acknowledgments

We wish to thank our patient for her consent to our presentation of this unique case.

References

Footnotes

  • Contributors HDT was the main author. RGR was the treating clinician and coauthor. JAS was a coauthor.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.