Bisphosphonate Therapy Ameliorates Hearing Loss in Mice Lacking Osteoprotegerin

Abstract

Three auditory ossicles including the malleus, incus, and stapes conduct sound in the middle ear from the tympanic membrane to the inner ear. Auditory ossicles are massively resorbed by osteoclasts in Opg −/− mice, which lack osteoprotegerin (OPG), a soluble decoy receptor for the osteoclastogenic cytokine RANKL. Opg −/− mice exhibit progressive hearing loss and are a model for juvenile Paget's disease. However, effects of antiresorptive treatment on auditory ossicles and on hearing function in Opg −/− mice are unknown. We intraperitoneally injected Opg −/− mice with bisphosphonate risedronate 5 d/wk for 9 wk. Morphology of auditory ossicles was examined microscopically, radiographically, and histologically. Hearing function was monitored by measuring the auditory brain stem response (ABR). Control Opg −/− mice exhibited thinning of all three ossicles and tibia. In contrast, risedronate treatment significantly inhibited bone loss in auditory ossicles as well as in long bones of Opg −/− mice. Bony fusion of the junction between the stapes and the otic capsule was reduced after treatment. Moreover, ABR measurement showed that hearing in Opg −/− mice was significantly improved by risedronate treatment. These data suggest that hearing loss in pathologies characterized by excessive resorption of the auditory ossicles may be prevented by bisphosphonates.

Loss of osteoprotegerin expression in the inner ear causes degeneration of the cochlear nerve and sensorineural hearing loss

“…Nonetheless, a relative comparison of ABR and DPOAE threshold shifts, as well as ABR amplitudes and latencies can provide insight in animals (Qin et al, 2010), especially when combined with detailed histologic analyses. While our results are in general agreement with the reported hearing tests in Opg −/− mice of 7 and 16 wk (Kanzaki et al, 2009), or 8 and 21 wk (Zehnder et al, 2006), we present a more thorough characterization of the auditory phenotype as it develops. Kanazaki et al (2009) only measured ABR, not DPOAE, and concluded that ABR shifts in Opg −/− mice were purely conductive due to age-related resorption of middle-ear ossicles.…”

“…Opg −/− mice are known to have progressive hearing loss due to resorption of ossicles in the middle ear (Kanzaki et al, 2009, Zehnder et al, 2005; Zehnder et al, 2006); a recent study suggested an additional sensorineural component (Qin et al, 2010). Here we elucidate mechanisms of the sensorineural hearing loss due to OPG deficiency by complementing functional tests of hearing with detailed histopathologic analyses, and pharmacologic studies in cultured spiral ganglion cells (SGC) and stem cells.…”

Cancellous Bone Volume Is an Indicator for Trabecular Bone Connectivity in Dialysis Patients

“…Virtual three-dimensional images were reconstructed from the serial tomographic data with an image analyzer (Ratoc System Engineering Co. Ltd., Tokyo, Japan) (12). The three-dimensional BV/TV, namely, the ratio of space occupied by the mineralized bone in the inner space 500 m distant from the cortical bone, was defined as vBV/TV.…”

Parallel mechanisms suppress cochlear bone remodeling to protect hearing

“…The suppression of bone remodeling is lost in OPG deficient mice, which have both sensorineural hearing loss due to demyelination of the cochlear nerve 15 and conductive hearing loss due to bony overgrowth of the ear 14 . This phenotype, however, can be ameliorated with bisphosphonate treatment 16 .…”