EBSCOhost: Etidronate for the Neurotologic Symptoms of Otosclerosis: Preliminary Study

The efficacy of etidronate, a bisphosphonate, was assessed as a treatment for the inner ear symptoms of otosclerosis in a retrospective case review of 896 patients diagnosed with otosclerosis, with primary complaints of dizziness, hearing loss, tinnitus or Meniere's syndrome. The diagnosis of otosclerosis was based on smallpixel computed tomography of the temporal bones. Of the 896 patients placed on an etidronate protocol, 545 were followed for more than six months and were analyzed. The symptomatic response to etidronate, as well as audiologic and computerized rotary chair results were used in the assessment. Patients who were previously on sodium fluoride were separately analyzed. In this preliminary study etidronate appeared to be an effective treatment for the neurotologic symptoms of otosclerosis. Prospective blinded efficacy studies of the bisphosphonates in the treatment of otosclerosis should be undertaken. Introduction Otosclerosis has been implicated in patients with symptoms of sensorineural hearing loss, tinnitus, dizziness and Meniere's syndrome.( n1-n39) The histopathologic basis of otosclerosis leads to an understanding of how clinical neurotologic symptoms occur without evidence of the expected middle ear findings. Otosclerosis is an osseous dyscrasia of the labyrinthine capsule.( n40) Findings in the active or the "spongiotic" phase of disorganized bone, rich in osteocytes, include enlarged marrow spaces containing blood vessels and connective tissue, and multinucleated osteoclasts in the center of the lesion absorbing the disorganized bone. These lesions, found anywhere in the otic capsule and oval window, can spread to varying degrees. The healed or "sclerotic" phase is characterized by totally disorganized dense bone with small vascular spaces and no evidence of absorptive Listen American Accent QUEEN'S UNIVERSITY LIBRARY 2012-11-12 3:52 PM EBSCOhost: Etidronate for the Neurotologic Symptoms of Otosclerosis: Preliminary Study Page 2 of 16 http://web.ebscohost.com.proxy.queensu.ca/ehost/detail?sid=521...id=112&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=a9h&AN=9708202028 activity. The hair cells appear to be normal.( n40) There are temporal bones with both otosclerotic lesions and endolymphatic hydrops.( n41-n43) The neurotologic symptoms appear to occur via the toxic suppression of hair cell activity by enzymes deposited into the inner ear fluid.( n40) The enzyme theory of inner ear symptoms was first proposed by Wolff and Bellucci in 1960( n44) and was further expanded by subsequent investigations.( n45n47) This theory was further evaluated with the use of sodium fluoride by virtue of its effect on rapidly remodeling bone such as that seen in association with spongiotic lesions; reducing the enzymatic activity and thereby arresting the middle ear and inner ear lesions.( n2, n45-n60) Sodium fluoride has been the only recommended medical treatment for otosclerosis.( n49, n57-n59, n61-n68) In the past, the neurotologic symptoms of some patients have responded to the use of fluoride.( n1, n5, n7, n36, n45, n46, n48, n54, n57, n61, n62) With the advent and availability of the bisphosphonates, etidronate (Didronel) has emerged as a possible treatment for otosclerosis. One paper was published on the agent's potential effect on the middle ear symptoms of otosclerosis,( n69) and another mentions the use of bisphosphonates with "surprisingly good" results, but without mentioning the clinical symptoms treated.( n59) There is experimental evidence suggesting that the bisphosphonates are useful in the treatment of the active phase of otosclerosis.( n70) The purpose of this study was to retrospectively evaluate the use of etidronate to treat the neurotologic symptoms of otosclerosis. Etidronate is a bisphosphonate primarily indicated for the treatment of Paget's disease of the bone in a continuous dosing schedule. Since 1990,( n118-n120) it has been recommended for the treatment of osteoporosis in a pulsed-dosing schedule. The bisphosphonates belong to a group of contemporary compounds developed to mimic the naturally occurring substance pyrophosphate.( n121-n123) Bisphosphonates are analogues of pyrophosphates that have a common phosphorus-carbon-phosphorus (P-C-P) chain, making them impervious to breakdown by pyrophosphatases.( n122-n126) They are resistant to cleavage by alkaline phosphate.( n123) Their structure reduces the membrane permeability which accounts for 1-10% of the absorption in the gastrointestinal tract.( n125) Approximately 2060% of the absorbed bisphosphonate is concentrated in active bone( n122, n125) and the remainder is rapidly excreted unchanged in the urine.( n124) Their chemical structure causes the bisphosphonates to be avidly absorbed onto the surface of hydroxyapatite crystals in bone at sites of active remodeling.( n123, n124) This strong affinity for the calcium phosphate apatite surface inhibits both the formation and dissolution of the crystals( n122) by inhibiting the activity of the osteoclasts when they engulf bisphosphonate-containing minerals during the resorption process.( n122) This is accomplished by local effects and/or by ingestion into the cell, but without destroying the cell.( n124) Implied local effects include inhibition of acid production, lysosomal enzymes, pyrophosphatases and prostaglandin synthesis.( n121, n122) There is also evidence that bisphosphonates, when added to osteoblasts, inhibit osteoblast-stimulating activity.( n127, n128) The serum half-life is about two hours; the half-life in bone is considerably longer.( n122, n123) Etidronate is the only bisphosphonate that inhibits mineralization,( n122, n124) and this is the reason for using a pulsed-dosing schedule.