A Systematic Review of the Effectiveness of Bisphosphonates for Otosclerosis.

OBJECTIVE: To systematically review the evidence for the use of bisphosphonate therapy in otosclerosis through clinically relevant outcomes. DATABASES REVIEWED: MEDLINE, EMBASE, PubMed, and CINAHL databases were searched up to July 12, 2021. METHODS: RCTs and cohort studies investigating the effect of bisphosphate therapy on adults or children diagnosed with otosclerosis were included. The risk of bias within trials was examined using the ROB2 tool for RCTs, and the ROBINS-I for non-RCTs. RESULTS: Three studies reported over five publications were included in the systematic review. Data from one RCT at 6 months did not demonstrate any improvement nor deterioration in audiological outcomes in participants treated with Sodium Alendronate. Data from MRI in this group demonstrated improvements in the SI of the otosclerotic foci at the RAOW compared to participants taking placebo. In another RCT, improvements in audiological outcomes were seen at 12 and 24 months in individuals treated with Etidronate Sodium. Long-term data from a retrospective cohort study demonstrated stabilisation of hearing in individuals with otosclerosis and progressive SNHL. CONCLUSION: There is insufficient evidence to recommend the routine use of bisphosphonates in otosclerosis patients at present. Long-term retrospective data has suggested a role for bisphosphonates in the subset of patients with deteriorating sensorineural hearing loss with the aim of hearing stabilisation. Adequately powered RCTs with long term follow up will be required to evaluate this further.

Mid-term evaluation of perioperative i.v. corticosteroid treatment efficacy on overall and audiological outcome following CO2 laser stapedotomy: a retrospective study of 84 cases.

PURPOSE: Our aim was to determine whether perioperatively administered corticosteroid treatment has any beneficial effect on the outcome of stapes surgery, with special regard to the audiological results and early postoperative morbidity. METHODS: 84 CO2 laser stapedotomies performed in our institute between 2013 and 2018 were included in our investigation. All cases underwent preoperative and mid-term postoperative pure-tone audiometric evaluation. Vestibular complications were also evaluated. The cases were subdivided into two groups, 23 patients received perioperative i.v. methylprednisolone treatment ("S") while the other 61 patients ("nS") did not receive any adjuvant pharmacological therapy. The data were analyzed retrospectively using IBM SPSS Statistics. RESULTS: CO2 laser stapedotomy proved to be a successful intervention with a significant improvement in ABG and AC thresholds as well. Long-term BC levels were significantly better compared to preoperative ones in the S group; however, in the nS group, no difference could be shown. Hearing and ABG gain were significantly superior in group S [28.1 dB (SD11.2) vs. 18.1 dB (SD 10.9) and 23.9 dB(SD 9.8) vs. 17.2 dB (SD 9.5), respectively]. CONCLUSION: No significant inner ear damage was detectable in the results of our CO2 laser stapedotomy method; however, the positive effect of corticosteroid treatment could be demonstrated through the postoperative hearing levels. We found no statistical difference in early postoperative morbidity. According to our data, the routine administration of corticosteroids during stapes surgery could be an issue worthy of consideration. The effects of perioperative treatment vs that on the first day after surgery, and topical vs. systemic treatment could be the subject of further investigation in a prospective manner.

Medical Management of Otosclerosis.

Otosclerosis/otospongiosis is a primary osteodystrophy of the otic capsule that affects genetically predisposed individuals and leads to progressive hearing loss. Diagnosis is usually clinical, based on the findings of anamnesis, physical examination, and audiometric evaluation. However, high-resolution computed tomography scan and MRI have played an important role in the diagnosis and therapeutic approach of otosclerosis and in assisting in the differential diagnosis. The therapeutic approach is aimed at preventing, or at least minimizing, disease progression while attempting to restore hearing. The use of sodium fluoride and bisphosphonates can be an important adjunct, perhaps even primary treatment, in managing active lesions.

Intracochlear Drug Delivery Through the Oval Window in Fresh Cadaveric Human Temporal Bones.

HYPOTHESIS: Drug delivered to the oval window can diffuse to the apex of the human cochlea. BACKGROUND: We have previously demonstrated that zoledronate, a nitrogen-containing bisphosphonate, can arrest the sensorineural hearing loss in cochlear otosclerosis. We have also shown that, in animals, delivery of bisphosphonate into the cochlea can dramatically increase delivery efficiency. Intracochlear drug delivery has the potential to increase local concentration of drug while decreasing the risk of systemic toxicity. In the present study, a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) was introduced into the human cochlea through the oval window and its distribution within the temporal bone was quantified. METHODS: In three fresh human temporal bones, we introduced 6-FAM-ZOL via the oval window. We compared these specimens to control specimens treated with artificial perilymph alone. Specimens were then processed, embedded into methyl methacrylate, and ground to the mid-modiolar axis. We quantified the fluorescence in confocal images. RESULTS: We found 6-FAM-ZOL to be distributed up to the apical cochlear turn. In specimens treated with 6-FAM-ZOL, we identified a strong baso-apical gradient of fluorescent signal along the lateral cochlear wall and the modiolus both in the scala vestibuli and in the scala tympani. CONCLUSION: Bisphosphonate introduced via the oval window in the human cochlea can be delivered up to the apical cochlear turn. Interscalar communication is likely to play an important role in determining patterns of drug delivery in the inner ear.

Cochlear Lymph Fluid Signal Increase in Patients with Otosclerosis after Intravenous Administration of Gadodiamide.

PURPOSE: Increased cochlear lymph fluid signals on three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) images obtained several minutes after intravenous administration of a single dose of gadolinium-based contrast agent (IV-SD-GBCA) in a patient with severe retrofenestral type otosclerosis had been reported. This increase was thought to represent breakdown of the blood-labyrinthine barrier. The purpose of this study was to evaluate cochlear lymph signal on heavily T2-weighted 3D-FLAIR (HF) images obtained 4 hours after IV-SD-GBCA in patients with otosclerosis, Ménière's disease, and healthy subjects. MATERIALS AND METHODS: Twenty-two ears from 12 patients with otosclerotic plaques determined by computed tomography (CT), 16 ears from 8 healthy volunteers, and 10 ears from 9 Ménière's disease patients with significant endolymphatic hydrops on magnetic resonance (MR) images were retrospectively analyzed. Images were obtained 4 hours after IV-SD-GBCA. Patients and healthy volunteers underwent MR cisternography (MRC) for anatomical reference of the fluid space and HF at 3T. The region of interest (ROI) was manually drawn on MRC images around the scala tympani in the basal cochlear turn. The reference ROI was set in the cerebellum. ROIs were copied onto HF images and the signal intensity ratio (SIR) of cochlear perilymph to cerebellum was measured. Differences in the SIR on HF images among the three groups were tested by one-way analysis of variance (ANOVA). RESULTS: The mean SIR was 24.0 ± 10.1 in otosclerosis patients, 7.9 ± 1.5 in volunteers, and 11.6 ± 3.9 in Ménière's disease patients. The mean SIR was significantly higher in the otosclerosis group than in the other groups (P < 0.001). In the otosclerosis group, there was a significant difference in the SIR between the retrofenestral type and the fenestral type (P = 0.033). CONCLUSIONS: In patients with otosclerosis, the SIR was higher than in Ménière's disease patients or in healthy volunteers. The SIR was higher in the retrofenestral type than in the fenestral type.

Non-Ototoxic Local Delivery of Bisphosphonate to the Mammalian Cochlea.

HYPOTHESIS: Local delivery of bisphosphonates results in superior localization of these compounds for the treatment of cochlear otosclerosis, without ototoxicity. BACKGROUND: Otosclerosis is a common disorder of abnormal bone remodeling within the human otic capsule. It is a frequent cause of conductive hearing loss from stapes fixation. Large lesions that penetrate the cochlear endosteum and injure the spiral ligament result in sensorineural hearing loss. Nitrogen-containing bisphosphonates (e.g., zoledronate) are potent inhibitors of bone remodeling with proven efficacy in the treatment of metabolic bone diseases, including otosclerosis. Local delivery to the cochlea may allow for improved drug targeting, higher local concentrations, and the avoidance of systemic complications. In this study, we use a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) to determine drug localization and concentration within the otic capsule. Various methods for delivery are compared. Ototoxicity is evaluated by auditory brainstem responses and distortion product otoacoustic emissions. METHODS: 6-FAM-ZOL was administered to guinea pigs via intraperitoneal injection, placement of alginate beads onto the round window membrane, or microfluidic pump infusion via a cochleostomy. Hearing was evaluated. Specimens were embedded into resin blocks, ground to a mid-modiolar section, and quantitatively imaged using fluorescence microscopy. RESULTS: There was a dose-dependent increase in fluorescent signal after systemic 6-FAM-ZOL treatment. Local delivery via the round window membrane or a cochleostomy increased delivery efficiency. No significant ototoxicity was observed after either systemic or local 6-FAM-ZOL delivery. CONCLUSION: These findings establish important preclinical parameters for the treatment of cochlear otosclerosis in humans.

A randomised, double blind trial of N-Acetylcysteine for hearing protection during stapes surgery.

BACKGROUND: Otosclerosis is a disorder that impairs middle ear function, leading to conductive hearing loss. Surgical treatment results in large improvement of hearing at low sound frequencies, but high-frequency hearing often suffers. A likely reason for this is that inner ear sensory cells are damaged by surgical trauma and loud sounds generated during the operation. Animal studies have shown that antioxidants such as N-Acetylcysteine can protect the inner ear from noise, surgical trauma, and some ototoxic substances, but it is not known if this works in humans. This trial was performed to determine whether antioxidants improve surgical results at high frequencies. METHODS: We performed a randomized, double-blind and placebo-controlled parallel group clinical trial at three Swedish university clinics. Using block-stratified randomization, 156 adult patients undergoing stapedotomy were assigned to intravenous N-Acetylcysteine (150 mg/kg body weight) or matching placebo (1:1 ratio), starting one hour before surgery. The primary outcome was the hearing threshold at 6 and 8 kHz; secondary outcomes included the severity of tinnitus and vertigo. FINDINGS: One year after surgery, high-frequency hearing had improved 2.7 ± 3.8 dB in the placebo group (67 patients analysed) and 2.4 ± 3.7 dB in the treated group (72 patients; means ± 95% confidence interval, p = 0.54; linear mixed model). Surgery improved tinnitus, but there was no significant intergroup difference. Post-operative balance disturbance was common but improved during the first year, without significant difference between groups. Four patients receiving N-Acetylcysteine experienced mild side effects such as nausea and vomiting. CONCLUSIONS: N-Acetylcysteine has no effect on hearing thresholds, tinnitus, or balance disturbance after stapedotomy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00525551.

Perspectives of pharmacological treatment in otosclerosis.

To review our current knowledge of the pathologic bone metabolism in otosclerosis and to discuss the possibilities of non-surgical, pharmacological intervention. Otosclerosis has been suspected to be associated with defective measles virus infection, local inflammation and consecutive bone deterioration in the human otic capsule. In the early stages of otosclerosis, different pharmacological agents may delay the progression or prevent further deterioration of the disease and consecutive hearing loss. Although effective anti-osteoporotic drugs have become available, the use of sodium fluoride and bisphosphonates in otosclerosis has not yet been successful. Bioflavonoids may relieve tinnitus due to otosclerosis, but there is no data available on long-term application and effects on sensorineural hearing loss. In the initial inflammatory phase, corticosteroids or non-steroidal anti-inflammatory drugs may be effective; however, extended systemic application may lead to serious side effects. Vitamin D administration may have effects on the pathological bone loss, as well as on inflammation. No information has been reported on the use of immunosuppressive drugs. Anti-cytokine targeted biological therapy, however, may be feasible. Indeed, one study on the local administration of infliximab has been reported. Potential targets of future therapy may include osteoprotegerin, RANK ligand, cathepsins and also the Wnt-ß-catenin pathway. Finally, anti-measles vaccination may delay the progression of the disease and potentially decrease the number of new cases. In conclusion, stapes surgery remains to be widely accepted treatment of conductive hearing loss due to otosclerosis. Due to lack of solid evidence, the place of pharmacological treatment targeting inflammation and bone metabolism needs to be determined by future studies.

Third-generation bisphosphonates for treatment of sensorineural hearing loss in otosclerosis.

OBJECTIVE: To evaluate hearing outcomes in patients treated with third generation bisphosphonates for otosclerosis-related sensorineural hearing loss (SNHL). HYPOTHESIS: Otosclerosis is a disease of abnormal bone remodeling in the otic capsule. In recent years, third generation bisphosphonates, with more powerful anti-resorptive properties and increased bone affinity, have demonstrated effectiveness in the treatment of osteoporosis and other metabolic bone diseases. We hypothesized that newer generation bisphosphonates, such as risedronate and zoledronate, would be effective in slowing the progression of SNHL in patients with otosclerosis. STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center, ambulatory care. INTERVENTIONS: Risedronate or zoledronate administration. MAIN OUTCOME MEASURES: Bone conduction pure tone threshold averages (PTAs) and word recognition (WR) scores were examined for each ear before and after bisphosphonate treatment. Criteria for significant change were defined as greater than 10 decibels in PTA or between 4% and 18% in WR based on binomial variance. RESULTS: All 10 patients had audiometric progression of SNHL in the pretreatment monitoring interval and 12 ears met criteria for significant progression. All 10 patients (19 ears) showed at least no significant progression of SNHL (i.e., stabilization) at an average follow-up of 13 months. Two patients (3 ears) showed improvement by defined audiometric criteria. There were no major complications. CONCLUSION: Treatment with zoledronate or risedronate stabilized progressive SNHL related to otosclerosis in this small group of patients. Further evaluation of third-generation bisphosphonate treatments is warranted.

The effectiveness of audiometric evaluation in drug treatment for otospongiosis.

UNLABELLED: Otospongiosis is a primary osteodystrophy of the otic capsule that affects genetically predisposed individuals and leads to a progressive hearing loss. AIM: To evaluate the applicability of audiometric evaluation during drug treatment for otospongiosis. MATERIALS AND METHODS: A prospective, randomized, controlled, double-blind study involving 26 patients with clinical, audiometric and CT scan image of otosclerosis. Patients eligible for the study were divided into three groups (A, B and C) and received treatment with alendronate sodium (B), sodium fluoride (C) and placebo (A) for 6 months. After this period they were submitted to new tests. RESULTS: There were not statistically significant differences between air and bone conduction (gap). We also found no differences in the speech recognition threshold (SRT) and speech discrimination (IRF) between before and after treatment. CONCLUSION: After six months of drug treatment the audiometric evaluation kept the same hearing thresholds, suggesting stabilization of the otospongiotic lesions.

Eficácia da avaliação audiométrica no tratamento medicamentoso da otospongiose / The effectiveness of audiometric evaluation in drug treatment for otospongiosis

A otospongiose é uma osteodistrofia focal primária da cápsula ótica que acomete indivíduos geneticamente predispostos e promove perda auditiva progressiva. OBJETIVO: Verificar a aplicabilidade da avaliação audiométrica no tratamento medicamentoso da otospongiose. MATERIAL E MÉTODO: Estudo prospectivo, randomizado, controlado, duplo-cego, envolvendo 26 pacientes com diagnóstico clínico, audiométrico e tomográfico de otospongiose. Os pacientes elegíveis para o estudo foram alocados em três grupos (A, B e C) e receberam o tratamento com alendronato de sódio (B), fluoreto de sódio (C) e placebo (A) por 6 meses. Após este período, os mesmos realizaram nova avaliação audiométrica. RESULTADOS: Na análise das diferenças entre as vias aérea e óssea (gap), não houve diferença estatisticamente significante. Também não foram encontradas diferenças em relação ao limiar de reconhecimento da fala (SRT) e a discriminação vocal (IRF) entre os períodos pré e pós-tratamento. CONCLUSÃO: Após seis meses de tratamento medicamentoso, a avaliação audiométrica evidenciou manutenção dos limiares auditivos, sugerindo estabilização da atividade da lesão otospongiótica.

Otospongiosis is a primary osteodystrophy of the otic capsule that affects genetically predisposed individuals and leads to a progressive hearing loss. AIM: To evaluate the applicability of audiometric evaluation during drug treatment for otospongiosis. MATERIALS AND METHODS: A prospective, randomized, controlled, double-blind study involving 26 patients with clinical, audiometric and CT scan image of otosclerosis. Patients eligible for the study were divided into three groups (A, B and C) and received treatment with alendronate sodium (B), sodium fluoride (C) and placebo (A) for 6 months. After this period they were submitted to new tests. RESULTS: There were not statistically significant differences between air and bone conduction (gap). We also found no differences in the speech recognition threshold (SRT) and speech discrimination (IRF) between before and after treatment. CONCLUSION: After six months of drug treatment the audiometric evaluation kept the same hearing thresholds, suggesting stabilization of the otospongiotic lesions.

Sodium fluoride in otosclerosis treatment: review.

OBJECTIVES: To review the current literature on the use of sodium fluoride in the treatment of otosclerosis. DESIGN: A literature review was conducted, searching the Medline and PubMed database from 1966 to 2009, using the terms 'otosclerosis' and 'fluoride'. Article abstracts were reviewed and relevant full articles acquired. RESULTS: There has been only one double-blind, placebo-controlled trial of the use of sodium fluoride in otosclerosis patients, and this found a reduced incidence of deterioration in hearing after two years in the treatment group. Several case-control series have described a hearing benefit in the sodium fluoride treated group. Treatment doses vary greatly, and there is no evidence regarding the optimum duration of treatment. CONCLUSIONS: There is low quality evidence suggesting that sodium fluoride may be of benefit to preserve hearing and reduce vestibular symptoms in patients with otosclerosis.

Otosclerosis 2: the medical management of otosclerosis.

The rationale for medical therapy for otospongiosis is to slow down and eventually stop the phase of bone resorption. There is some increase in the incidence of stapedial otospongiosis in a low-fluoride area compared with a high-fluoride area. Sodium fluoride treatment has a role to play in preventing the onset and progression of hearing loss in patients suffering from otosclerosis. Sodium fluoride therapy has been shown to have some beneficial effect on dizziness associated with otosclerosis. In view of the possibility of systemic side effects of sodium fluoride therapy, a regular follow up of patients is warranted. Biphosphonates can be used as an alternative treatment to sodium fluoride in cases where the patient is intolerant to sodium fluoride therapy. Hearing aid is also a treatment option, but it does not halt the disease process.

Surgical and medical treatment of hearing loss in mixed otosclerosis.

OBJECTIVES: We assessed the effect of using preoperative sodium fluoride (NaF) on the difficulty of working with the footplate during stapedectomy and its effect on the postsurgical hearing gain in patients with mixed otosclerosis (i.e., otosclerosis and/or otospongiosis). METHODS: There were 2 groups of patients with mixed otosclerosis. The experimental group was made up of patients with an active focus of the disease; they received NaF for 6 months and then underwent stapedectomy. The control group was made up of patients with an inactive focus of the disease; they underwent stapedectomy without administration of NaF. RESULTS: The difference between the study groups in the degree of difficulty in extracting the footplate was not found to be statistically significant. Both groups had hearing gains in bone and air conduction. The level of posttreatment hearing gain in the group exposed to NaF was greater than that in the nonexposed group. CONCLUSIONS: Sodium fluoride administered to patients with mixed otosclerosis and an active focus of disease does not increase the difficulty of working with the footplate during stapedectomy, and it increases the hearing gain after the procedure.

Does exogenous nitric oxide influence tympanosclerosis? An experimental study.

OBJECTIVE: We aimed to elucidate the effects of exogenous nitric oxide application via myrigotomized rat tympanic membranes on tympanosclerosis. MATERIALS AND METHODS: Forty male rats were included in the study. After myringotomy, nitric oxide was given to the left tympanic cavities and saline was given to the right as the control group. The procedure was repeated 3 times with weekly intervals. Three months after the first procedure, otomicroscopic examination was made and the rats were sacrificed for histologic examination. RESULTS: Neither otomicroscopic examination, nor histologic examination of middle ears and tympanic membranes revealed any significant difference between the right and left sides. Tympanic membrane thicknesses were also similar on both sides without showing any significant difference. CONCLUSIONS: Data from this study indicate that exogenous nitric oxide application did not change the occurence of tympanosclerosis in the rat model. Other cytokine interactions are needed to start the reaction sequence leading to tympanosclerosis.

Medical treatment of otosclerosis: rationale for use of bisphosphonates.

Otosclerosis is a bony dyscrasia characterized by histopathological findings of osteoclast production. Osteoclastogenesis explains the pathogenesis of otosclerosis. Basic science research in the experimental animal otic capsule has given insight into the process of evolution of otosclerosis. The normal otic capsule is preserved with very little bone turnover as a result of the production of osteoprotegerin (OPG) by the membranous inner ear that prevents the activation of osteoclasts. Animals genetically unable to produce OPG demonstrated the production of hearing loss and histopathology of the temporal bones consistent with that seen in otosclerosis. Applying the understanding of osteoclastogenesis to the treatment of otosclerosis has led to the clinical use of the class of drugs called bisphosphonates. The bisphosphonate group of drugs specifically targets osteoclasts by reducing production of osteoclasts and accelerating their early cell death. The rationale for use of bisphosphonates to treat the sensorineural hearing loss of otosclerosis is explained, with cases that illustrate the bisphosphonates treatment algorithms and the response to treatment.