External auditory canal and middle ear cholesteatoma and osteonecrosis in bisphosphonate-treated osteoporosis patients: a Danish national register-based cohort study and literature review.

UNLABELLED: 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. INTRODUCTION: 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. CONCLUSION: 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.

The effect of naproxen sodium on experimental otitis media.

OBJECTIVES: We evaluated the effect of naproxen sodium on propylene glycol-induced otitis media in guinea pig ears. MATERIALS AND METHODS: Twenty adult guinea pigs were randomized to the study and control groups equal in number. A single dose of propylene glycol (0.2 ml, 60%) was applied to the left ears of the control group and to both ears of the study group. Saline solution was applied to the right ears of the control group. After propylene glycol application, the study group received naproxen sodium (oral, 10 mg/kg daily) for 15 days, whereas the control ears were left untreated. At the end of four weeks, the animals were decapitated under anesthesia. Otoscopic examination was performed and temporal bones were removed for histologic examination under light microscopy. RESULTS: Nine animals were alive in each group at the end of four weeks. In the control group, all the right ears receiving saline solution were normal, whereas otitis media and inflammatory changes were observed in six of the left ears receiving propylene glycol. In the study animals treated with naproxen sodium, otitis media and tympanic membrane perforation were seen in 14 ears. Of these, three ears had purulent, 11 ears had serous effusion. Epithelial hyperplasia (n=10), keratinizing epithelium and cholesteatoma formation (n=4) were also observed. CONCLUSION: Our results suggest that the administered dose of systemic naproxen sodium has no inhibitory effect on the development of inflammation and otitis media.

Effect of trans-retinoic acid in the inhibition of cholesteatoma in guinea pigs.

UNLABELLED: Middle ear cholesteatoma affected more than 5 million people until the 80;s. Many animal models were used, unsuccessfully, to study an alternative therapy to cholesteatoma. AIM: observe the effect of the trans-retinoic acid in the inhibition of middle ear cholesteatomas induced by propylene glycol. STUDY DESIGN: Clinical and Experimental. METHODS: 25 guinea pigs were submitted to the application of a 100% propylene glycol solution in their bulla bilaterally and a solution of trans-retinoic acid was applied locally in the external right ear, while in the left ear saline solution was applied (control ear). The guinea pigs were slaughtered and their temporal bones were prepared for macroscopic and histological analysis. RESULTS: The macroscopic findings had evidenced the presence of cholesteatoma in 25% of the right ears and 85% of the left ears (P=0.0003 *). The histological study had evidenced the presence of cholesteatoma in 30% of right ears and 75% of the left ears (P=0.0104*). CONCLUSION: The local use of the trans-retinoic acid is effective in inhibiting the induced formation of cholesteatomas in guinea pigs.

Single dose intratympanic mesna application inhibits propylene glycol induced cholesteatoma formation.

OBJECTIVE: Mesna (i.e. sodium 2-mercaptoethanesulfonate; C2H5NaO3S2) has been used in otological surgery such as cholesteatoma dissection and tympanic membrane lateralisation in atelectatic ears. However, this study aimed to investigate its effect on cholesteatoma formation. METHODS: A total of 20 Wistar rats were divided into two groups of 10 animals. The right and left ears of control animals were treated with saline (saline control group; n = 10 ears) and propylene glycol plus saline (propylene glycol control group; n = 10 ears), respectively. In the mesna group, both ears were treated with propylene glycol plus mesna (n = 20 ears). On days 1, 8 and 15, the saline control group had intratympanic injections of 0.2 ml saline and the propylene glycol control and mesna groups had intratympanic injections of 0.2 ml 100 per cent propylene glycol. On day 22, the propylene glycol control group had a single intratympanic injection of 0.2 ml saline and the mesna group had a single intratympanic injection of 10 per cent mesna. Animals were killed 12 weeks after the last injection and the temporal bones were sent for histopathological evaluation. RESULTS: The cholesteatoma formation rate was 88 per cent in the propylene glycol control group, but was significantly lower in the mesna group (p = 0.01). There were no significant differences in granulation tissue formation (p = 0.498), cyst formation in the bulla (p = 0.381), fibrosis (p = 0.072) and epithelial hyperplasia (p = 0.081) among experimental groups. CONCLUSION: Intratympanic propylene glycol administration is an effective method of promoting experimental cholesteatoma formation. Administration of a single dose of intratympanic mesna inhibited cholesteatoma formation in an animal model.

Effect of intratympanic steroid application on the development of experimental cholesteatoma.

By introducing certain irritants into the middle ear it is possible to produce cholesteatoma. Propylene glycol, the main agent used for this purpose, produces a long-standing inflammation that causes hyperplasia and migration of the epithelium through an intact tympanic membrane. In the present investigation topical prednisolone was used in order to inhibit the production of cholesteatoma. The results indicate that there is a marked decrease in inflammation and hence experimental cholesteatoma production when prednisolone is administered into the middle ear.

Ototoxicity of topical ticarcillin and clavulanic acid in the chinchilla.

BACKGROUND: Currently available topical otic preparations contain a variety of antibiotics and other ingredients that are potentially damaging to the middle and inner ear. There is therefore a need to identify agents that are safe as well as effective for topical otologic use. In pursuit of that goal, we used an animal model to evaluate the ototoxic potential of the broad-spectrum, penicillin derivative ticarcillin--both alone and combined with clavulanic acid (a beta-lactamase inhibitor). METHODS: Twenty chinchillas served as subjects. Ten of the animals were given a single middle ear application of ticarcillin; the remaining 10 animals received ticarcillin disodium plus clavulanate potassium (Timentin). Five animals from each of the two groups were killed after 1 week to assess short-term effects and the other five animals in each group were kept for 4 weeks before their temporal bones were removed for histologic study. RESULTS: Significant toxic effects, involving both the middle and inner ear, were observed in all experimental groups. Alterations of the middle ear at 1 week included inflammation, hemorrhage, and effusions. Middle ear cholesteatomas were observed at 4 weeks. Inner ear changes seen at 1 and 4 weeks included hair cell loss, supporting cell degeneration, and strial damage. CONCLUSION: The study results indicate that ticarcillin should not be considered for further evaluation as a possible antibiotic for use in ototopical preparations.

Experimental cholesteatoma in the rat.

The etiology of cholesteatoma is still enigmatic. Of the current theories, none has been confirmed with adequately convincing evidence. A completely suitable animal model has not hitherto been available and there is still a need for further experimental studies of this entity. As a possible experimental model we suggest dimethyl-benzanthracene induced cholesteatoma in the rat.

Pathogenesis of experimental aural cholesteatoma in the chinchilla.

Histopathological observation of celloidin serial sections of the chinchilla middle ear after treatment with propylene glycol disclosed the development of severe inflammation of the middle ear mucosa and tympanic membrane, papillary proliferation of the epidermis of the tympanic membrane and external auditory meatus, and retraction and adhesion of the tympanic membrane. The findings for the tympanic membrane, impedance testing and histopathological examination suggested that there were two types of acquired cholesteatoma formation, probably with a difference in the pathogenesis. In one type, the proliferated epidermal layer of the tympanic membrane penetrated into the middle ear cavity making tympanic perforations. In the other type, there was progressive retraction of the tympanic membrane forming a retraction pocket. We discuss the two different patterns of cholesteatoma development.

Effect of topical hyaluronic acid on experimental cholesteatoma.

PURPOSE: Inflammation and connective tissue hyperplasia are believed to be important etiological factors in cholesteatoma pathogenesis. Previous work has shown that topically applied hyaluronic acid can reduce connective tissue proliferation in healing wounds and accelerate healing of tympanic membrane perforations. This study was undertaken to determine whether the antiproliferative effect of hyaluronic acid may inhibit propylene glycol-induced cholesteatoma in an animal model. MATERIALS AND METHODS: A 60% propylene glycol solution was injected bilaterally into the middle ear cavities of 20 adult chinchillas. The control group (N = 10) received propylene glycol alone. In addition to propylene glycol injections, the experimental group (N = 10) received repeated bilateral topical applications of 1.5% hyaluronic acid onto the tympanic membranes. Animals were killed at 4 weeks for gross and light microscopic examination. RESULTS: Seven control and 10 experimental animals survived the full 1-month study period. At the end of that time, cholesteatoma was found in 71% (10/14) of control ears and 70% (14/20) of experimental ears. Tympanic membrane structure did not differ significantly between groups by light microscopy and, in all animals, cholesteatomas originated by migration of hyperplastic epidermis through the tympanic membrane, as has been observed in previous studies using this animal model. CONCLUSION: Under the conditions of this study, topical hyaluronic acid had no significant effect on cholesteatoma formation.

Efeito do ácido trans-retinóico na inibição de colesteatoma em cobaias / Effect of trans-retinoic acid in the inhibition of cholesteatoma in guinea pigs

O colesteatoma de orelha média atingia mais de 5 milhões de pessoas até a década de 80. Vários modelos animais já foram utilizados para alternativas de tratamento do colesteatoma sem sucesso. OBJETIVO: Estudar os efeitos do ácido trans-retinóico, uso tópico na orelha externa em cobaias, na inibição da formação do colesteatoma de orelha média induzido pelo propilenoglicol. Estudo experimental prospectivo. MATERIAL E MÉTODOS: 25 cobaias foram submetidas à aplicação de propilenoglicol a 100 por cento na bula timpânica bilateralmente e uma solução de ácido trans-retinóico foi aplicada topicamente (total de 5 aplicações) na orelha externa, região justa-timpânica, na orelha direita, enquanto na orelha esquerda aplicou-se solução fisiológica (orelha controle). As cobaias foram sacrificadas após 6 semanas do procedimento inicial e os ossos temporais foram separados, fixados e descalcificados, para análise macroscópica e histológica. RESULTADOS: Os achados macroscópicos evidenciaram a presença e suspeita de colesteatoma em 25 por cento das orelhas direitas e 85 por cento das orelhas esquerdas (P=0,0003*). Os achados histológicos dos 40 ossos temporais evidenciaram a presença de colesteatoma em 30 por cento das orelhas direitas e 75 por cento das orelhas esquerdas (P=0,0104*). CONCLUSÃO: O uso tópico do ácido trans-retinóico é efetivo na inibição da formação de colesteatoma induzido pelo propilenoglicol em cobaias.

Middle ear cholesteatoma affected more than 5 million people until the 80`s. Many animal models were used, unsuccessfully, to study an alternative therapy to cholesteatoma. AIM: observe the effect of the trans-retinoic acid in the inhibition of middle ear cholesteatomas induced by propylene glycol. STUDY DESIGN: Clinical and Experimental. METHODS: 25 guinea pigs were submitted to the application of a 100 percent propylene glycol solution in their bulla bilaterally and a solution of trans-retinoic acid was applied locally in the external right ear, while in the left ear saline solution was applied (control ear). The guinea pigs were slaughtered and their temporal bones were prepared for macroscopic and histological analysis. RESULTS: The macroscopic findings had evidenced the presence of cholesteatoma in 25 percent of the right ears and 85 percent of the left ears (P=0.0003 *). The histological study had evidenced the presence of cholesteatoma in 30 percent of right ears and 75 percent of the left ears (P=0.0104*). CONCLUSION: The local use of the trans-retinoic acid is effective in inhibiting the induced formation of cholesteatomas in guinea pigs.

Efeito do ácido trans-retinóico na inibição da formação de colesteatoma em cobaias / Effects of trans-retinoic acid on inhibition's development of cholesteatoma in guinea pigs

Objetivo : Estudar os efeitos do ácido trans-retinóico, uso tópico na orelha externa e região justa à membrana timpânica em cobaias, na inibição da formação do colesteatoma de orelha média induzido pelo propilenoglicol a 100 por cento. Métodos : 25 cobaias foram submetidas à aplicação de propilenoglicol a 100 por cento na bula timpânica bilateralmente e uma solução de ácido trans-retinóico foi aplicada topicamente (total de 5 aplicações) na orelha externa, região justa-timpânica, na orelha direita, enquanto na orelha esquerda aplicou-se solução fisiológica (orelha controle). As cobaias foram sacrificadas após 6 semanas do procedimento inicial e os ossos temporais foram separados, fixados e descalcificados, para análise macroscópica e histológica. Resultados: Das 25 cobaias, 20 terminaram o estudo. As alterações otoscópicas mais comuns foram a opacidade da membrana timpânica e a formação de cerume no meato acústico externo. Os achados macroscópicos evidenciaram a presença de colesteatoma e suspeita de colesteatoma em 25 por cento das orelhas direitas e 85 por cento das orelhas esquerdas (P=0,0003*). Os achados histológicos dos 40 ossos temporais evidenciaram a presença de colesteatoma em 30 por cento das orelhas direitas e 75 por cento das orelhas esquerdas (P=0,0104*)...