More than three million Americans suffer from otosclerosis, an often hereditary hearing disorder affecting the temporal bone – the part of the human skull in which the ear is located. As its name describes the malady – “oto,” meaning “ear,” and “sclerosis,” meaning a disease which causes a hardening of tissue – otosclerosis affects the otic capsule, the tissue surrounding the inner ear which is made up of cartilage at the embryonic stage of human life but which develops into bone. Otosclerosis is estimated to occur in 10 percent of Caucasians and produces hearing loss in one percent, while generally being less prevalent in other racial groups.
In seeking to understand otosclerosis, it is important to have a basic understanding of how the human ear works. Sound enters the outer ear via the auditory canal and is transmitted through to the ear drum, which forms the outer portion of the middle ear. The sound waves cause the ear drum to vibrate, which then transmits these vibrations via three tiny bones called the malleus, incus and stapes – informally known as the “hammer,” “anvil” and “stirrup” – into the inner ear. The oval window conveys vibrations into the fluid that fills this inner portion of the ear and which also contains the snail-shaped cochlea, a mechanism filled with tiny hair cells. When the vibrations cause these hair cells to move, they in turn create nerve impulses which are transmitted to the brain, which receives these and interprets them as sound.
When there is a problem that causes hearing loss in the outer or middle ear, it is referred to as conductive hearing loss; malfunctions in the inner ear lead to sensorineural hearing loss (SNHL). While otosclerosis can affect various parts of the middle ear, it most often causes stapes fixation, a situation which renders the “stirrup” immobile and therefore unable to transmit the vibrations which the brain would otherwise receive as sound.
Many studies over the past decades have established that a variety of factors can cause otosclerosis, including genetic mutations, infection with the measles virus, stress fractures in the otic capsule and autoimmune disorders (diseases in which a person’s immune system attacks that person’s own cells and tissues, e.g., multiple sclerosis and rheumatoid arthritis).
While most cases of conductive hearing loss can be effectively treated with either surgery or amplification, approximately 20 to 30 percent of people who develop progressive SNHL due to otosclerosis cannot be treated surgically and often suffer hearing loss in both ears. They are normally only partially helped by amplification and a significant portion of these people go on to develop profound deafness, becoming candidates for a cochlear implant.
Sadly, there are currently no medical or surgical therapies that have been effective in preventing the onset or progression of SNHL due to otosclerosis. Nevertheless, there are some hopeful developments in the research of otosclerosis which I will outline in this article.
Otosclerosis is exclusively confined to the otic capsule, an area which is unique when compared with other parts of the skeleton in that it exhibits little to no bone remodeling, a skeletal process in which old bone is removed (by osteoclasts) and replaced (by osteoblasts) with new bone. It must be kept in mind that bone remodeling in the rest of the body is normal, necessary and beneficial, but is abnormal and undesirable in the otic capsule. Since a properly functioning otic capsule does not undergo bone remodeling, otosclerosis then is simply the damaging process of bone remodeling which affects the otic capsule.
As the disease evolves, these areas begin to show evidence of bone resorption and replacement with abnormal bone, actively remodeling and giving rise to new otosclerotic bone. While considerable research has focused on the causative agents that might trigger otosclerosis, such as those mentioned above, little is known about the molecular factors which inhibit and promote bone remodeling within the otic capsule. Developing an understanding of these molecular factors is essential to understanding otosclerosis.
Recent research has established that bone remodeling is regulated by a delicate balance between three molecules called cytokines, that go by the acronyms OPG, RANK and RANK-L. They allow cells to communicate with one another. Osteoblasts put forth RANK-L, which binds to its receptor RANK on immature osteoclasts, thus creating mature osteoclasts that initiate the process of bone breakdown. OPG competes with RANK for the RANK-L receptor on osteoblasts, and thereby is a powerful inhibitor of bone remodeling. The ratio of OPG to RANK-L is critical in controlling local bone remodeling. Too much OPG causes excessive bone formation, or osteopetrosis, while too little OPG results in excessive bone breakdown, or osteoporosis. The OPG–RANK–RANK-L system is the means by which bone metabolism is regulated. Various biochemical, hormonal and biomechanical stimuli that influence bone remodeling do so via these inter-cell communicators.
Our laboratory examined levels of OPG, RANK and RANK-L to investigate the relevance of this cytokine system to bone remodeling in the otic capsule. We found that production of OPG here was significantly higher, by factors of 20 or more, than in other bones. This is our first molecular insight as to why the otic capsule does not remodel and why inhibition is greatest in proximity to the space surrounding the inner ear.
Developments in bone physiology and pharmacology over the last 10 years now make prevention of SNHL from otosclerosis a realistic goal. For decades, sodium fluoride has been prescribed for patients with SNHL caused by otosclerosis. It is usually given orally on a daily basis with the minor side effect of gastric irritation. However, its utility is not established and the only published double-blinded placebo study revealed limited effectiveness in a minority of subjects.
A number of compounds have been developed recently to inhibit bone remodeling and are used clinically for a variety of bone diseases. One of these, zoledronic acid, has particularly potent effects which makes it a very promising candidate for therapy of otosclerosis. Zoledronic acid increases OPG and decreases RANK-L expression in osteoblasts. A single administration of zoledronic acid has effects that last for several months. However, in one to two percent of individuals the bones making up the upper and lower jaw end up being severely damaged (osteonecrosis of the mandible or maxilla). There have been no comprehensive studies on the potential of zoledronic acid to cause damage to the ear, and especially the cochlea and auditory nerve.
Based on the established clinical potency of this drug and on what we have learned about the role of OPG in our animal model, it is compelling to consider zoledronic acid and other compounds as potential treatments for otosclerosis. It is conceivable that local administration of this drug, either by an intratympanic or an intracochlear route, may provide efficacy without subjecting individuals to systemic side effects such as osteonecrosis of the jaw.
For those suffering from otosclerosis, there is cause for encouragement, as research continues to reveal possible solutions to a problem affecting some three million Americans.
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