title: External auditory canal and middle ear cholesteatoma and osteonecrosis in bisphosphonate-treated osteoporosis patients: a Danish national register-based cohort study and literature review.
abstract: Long-term treatment with bisphosphonates against osteoporosis may cause atypical femur fractures and osteonecrosis of the jaw. Eight cases of bisphosphonate-associated osteonecrosis of the external auditory canal area are published. Based on Danish national registers, we report a time- and dose-dependent increased risk of cholesteatoma in osteoporosis patients treated with bisphosphonates.
  
  
  BACKGROUND
  In the recent years, there has been a focus on possible rare side effects of bisphosphonates (BPs). Eight cases of BP-associated osteonecrosis of the external auditory canal have been reported in the world literature. Our aim was to describe the incidence of external auditory canal and middle ear diseases in Danish patients exposed to BPs in the treatment of osteoporosis.
  
  
  METHODS
  This register-based nationwide cohort study was conducted on the Danish population of approximately 5.6 million individuals. Patients who were prescribed BP for treatment of osteoporosis from 2003 to 2010 (n = 131,794) were included in the study and compared with the age- and gender-matched controls, unexposed to BP.
  
  
  RESULTS
  The overall incidence of cholesteatoma in the ear was low. Only 350 events were seen in 527,176 cases and controls over 2,826,120.73 observation years. Totally, 119 events of cholesteatoma in the ear were recorded after initiation of BP therapy, 34 in the external auditory canal and 85 in the middle ear. Cholesteatoma in the external auditory canal was more frequent in the exposed than in the unexposed group (p < 0.0001). We found a significant dose-event relationship between incidence of cholesteatoma and dose of alendronate (p < 0.0001) and etidronate (p < 0.0001). Furthermore, we found an association between duration of treatment with alendronate and etidronate and risk of cholesteatoma in the external auditory ear canal (log rank, p = 0.002). No cases of bone destruction were observed during the 7-year observation period in either group.
  
  
  CONCLUSIONS
  The use of oral BP is associated with an increased risk of cholesteatoma of the external auditory canal. The risk is small and associated with duration and dosage of BP.
authors.affiliation: Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital-Hillerød, University of Copenhagen, Hillerød, Dyrehavevej 29, 3400, Hillerød, Denmark, Anne-Luise.Thorsteinsson@regionh.dk.
authors.forename: A-L
authors.initials: AL
authors.lastname: Thorsteinsson
authors.forename: P
authors.initials: P
authors.lastname: Vestergaard
authors.forename: P
authors.initials: P
authors.lastname: Eiken
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000453:epidemiology*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002781:Cholesteatoma / Q000139:chemically induced* / Q000453:epidemiology; D018424:Cholesteatoma, Middle Ear / Q000139:chemically induced / Q000453:epidemiology; D015331:Cohort Studies; D003718:Denmark / Q000453:epidemiology; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004424:Ear Canal; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000188:drug therapy / Q000453:epidemiology; D012042:Registries; D012189:Retrospective Studies
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates