Discussion

The British National Formulary describes bisphosphonates being absorbed onto hydroxyapatite crystals in bone, which slows down both their rate of growth and dissolution, and the overall effect is reduction of the rate of bone turnover.² Furthermore, regarding side effects of alendronic acid, the British National Formulary lists: gastrointestinal disorders, joint swelling and vertigo as common or very common; haemorrhage as uncommon; and femoral stress fracture, oropharyngeal ulceration, photosensitivity reaction and severe cutaneous adverse reactions as rare or very rare. There are no ear-related symptoms listed as side effects. However, in the Important Safety Profile of 2015, the Medicines and Healthcare products Regulatory Agency and the Commission on Health Medicine reported bisphosphonate-induced osteonecrosis of the mandible and external auditory canal, especially bisphosphonates given intravenously, and caution has been advised.

Marx, in 2003, was the first to report bisphosphonate-induced osteonecrosis, in a case affecting the jaws.^{Reference Marx4} Since then, several case reports have been published. There have also been reports of bisphosphonate-induced femur fractures.^{Reference Khosla, Bilezikian, Dempster, Lewiecki, Miller and Neer5} The recent International Classification of Diseases (11th edition), released in June 2018, included bisphosphonate-induced osteonecrosis as a side effect (Mortality and Morbidity Statistics code: FB81.2), although no specific organ was mentioned.⁶

Bisphosphonates inhibit the resorption of bone, leading to an increase in calcium and mineral deposition, and a decrease in ectopic calcification.^{Reference Froelich, Radeloff, Kohler, Mlynski, Muller and Hagen1} This occurs via the inactivation and reduced recruitment of osteoclasts, and the induction of osteoclast apoptosis. Bisphosphonates incorporate calcium into the bone matrix, but the impaired bone turnover leads to compromised bone healing, especially when the bone is exposed following trauma or a surgical procedure such as dental extraction. Osteonecrosis is believed to happen when the bone has decreased its ability to cope with the physiological demands associated with the bisphosphonate-induced reduction of bone remodelling and blood flow.^{Reference McCadden, Leonard and Primrose7}

Bisphosphonates could either be nitrogen-containing (i.e. alendronate sodium, pamidronate disodium, zoledronic acid, risedronate sodium) or nitrogen-free (i.e. etidronate disodium, clodronate disodium, tiludronate disodium).^{Reference Froelich, Radeloff, Kohler, Mlynski, Muller and Hagen1} The presence of nitrogen seems to play an important role in its toxicity; at least 3000 cases of bisphosphonate-induced osteonecrosis of the jaws have been reported related to nitrogen-containing forms, whilst only 10 similar cases have been reported so far for non-nitrogen-containing bisphosphonates.^{Reference Salzman, Hoza, Perina and Starek8} In a Danish national-register-based cohort study of 131 794 patients, the risk factors associated with osteonecrosis of the jaws included infection, intravenous bisphosphonates, cancer and anti-cancer therapy, glucocorticoids, alcohol and tobacco use, co-morbidities (i.e. malignancy), and dental trauma including extraction.^{Reference Thorsteinsson, Vestergaard and Eiken3}

There are a few reports of bisphosphonate-related osteonecrosis of the ear canal, but this adverse effect is not well recognised in the medication literature. The association of prolonged bisphosphonate use and ear canal osteonecrosis is not widely known; even ENT specialists have confused this diagnosis with ear canal cholesteatoma, malignant otitis externa or temporal bone malignancy.^{Reference Salzman, Hoza, Perina and Starek8}

Management of bisphosphonate-induced ear canal osteonecrosis ranges from drug cessation, topical treatment, to surgical debridement.^{Reference Thorasteinsson, Lomholt and Eiken9} Oral or intravenous bisphosphonate use as a risk factor for external canal osteonecrosis is dose- and duration-related.^{Reference Thorsteinsson, Vestergaard and Eiken3}

The huge benefits of bisphosphonates in the prevention of fracture and pain control should be recognised, and if complications arise, such as osteonecrosis, a shift to non-nitrogen-containing forms should be considered prior to complete cessation of the medication. It is also important to note that there is limited evidence on the benefits of bisphosphonate use beyond three to five years, and some advocate ‘drug holidays’ with breaks in treatment.^{Reference Whitaker, Guo, Kehoe and Benson10}

In our cases, the disease progression slowed and symptom control was achieved following drug cessation and regular aural toileting with topical antibiotics, although re-epithelialisation of the denuded bony canal was minimal. As regular microsuctioning provided symptomatic relief, we continued to see patients regularly, every four to six weeks. However, it appears that this was not necessary, and may well have caused iatrogenic trauma that hindered the re-epithelialisation process. When the patients’ ears were left for four to five months during the lockdown period (associated with the Covid-19 pandemic) in 2020, they recovered, and the patients remained symptomatically well. We thus conclude that excessive and repeated microsuctioning in bisphosphonate-induced osteonecrosis of the external ear canal can delay re-epithelialisation, and gradually prolonging the intervals between microsuctioning could aid overall resolution of the disease.

In summary, bisphosphonates, acting as potent inhibitors of bone resorption, are commonly prescribed for extended periods of time. Many ENT specialists are unaware that prolonged bisphosphonate use may cause osteonecrosis of the external ear canal. Thus, a full drug history should be taken among elderly patients who present with chronic ear symptoms and an exposed bony ear canal. Rational use of bisphosphonates should be considered. Conservative management of external ear canal osteonecrosis includes debridement, regular microsuctioning, and the application of topical antibiotics and steroids. However, excessive and repeated microsuctioning with short intervals may delay re-epithelialisation.