Effect of bisphosphonate treatment in patients with Paget's disease of the skull

J. Donáth, M. Krasznai1, B. Fornet2, P. Gergely, Jr. and G. Poór

National Institute of Rheumatology and Physiotherapy, Budapest, 1Semmelweis University of Medicine, Department of Otorhinolaryngology, Head and Neck Surgery, Budapest, and 2International Medical Center, Budapest, Hungary.

Correspondence to: J. Donáth, National Institute of Rheumatology and Physiotherapy, Budapest, Frankel Leó u. 38–40, 1023, Hungary. E-mail: orfireum{at}axelero.hu

Abstract

Objectives. Hearing loss has long been known to be a complication of Paget's disease of bone. The aim of this study was to investigate Paget's disease of the temporal bone with special attention to hearing loss.

Methods. Twenty-five patients with skull involvement were treated with either pamidronate or tiludronate. Imaging included radiography, quantitative bone scintigraphy (QBS), single photon emission computed tomography (SPECT) and high-resolution computed tomographic (HRCT) scanning. Audiometric assessment was also performed.

Results. Twenty-three of the 25 patients with skull involvement suffered from hearing loss. Bisphosphonate treatment resulted in a decreased serum total alkaline phosphatase (serum tAP) level and QBS ratio, and also seemed to improve the complaints of the patients. HRCT demonstrated involvement of the middle ear ossicles (n = 7), involvement of the petrous pyramids (n = 14), demineralization of the otic capsule (n = 10), porosis pericochlearis (n = 8), narrowing of the external auditory meatus (n = 12), mastoid process thickening (n = 5) and stapedial footplate thickening (n = 4). The audiometric examination did not show any significant changes 1 yr after bisphosphonate treatment.

Conclusions. HRCT imaging is a well suited tool for demonstrating the complication of Paget's disease. QBS and measurement of serum tAP level may also be regarded as useful techniques for monitoring treatment. However, hearing may remain impaired in spite of the improved scintigraphy and laboratory parameters, therefore, audiometric assessment is also important in pagetic patients with skull involvement.

KEY WORDS: Paget's disease of the temporal bone, Hearing loss, Bisphosphonate.

Paget's disease of the bone (osteitis deformans) is a chronic illness, first described by Sir James Paget. It is a localized disorder of bone remodelling characterized by an increase in osteoclast-mediated bone resorption and a compensatory increase in new bone formation [1].

Its incidence varies widely across the world (2–8%). The disease can be manifested in monostotic or, more commonly, in disseminated polyostotic forms. If the disease process involves the temporal bone, a severe and progressive loss of hearing may occur. Hearing loss is found in 30–50% of patients with skull involvement, the mechanism of which seems to be multifactorial [2]. A predominant component is sensorineural hearing loss due to involvement of the petrous temporal bone and a progressive involvement of the internal auditory canal [3]. Bisphosphonate treatment may slow the progression of hearing loss [4].

We studied 25 patients with Paget's disease in the skull and investigated their hearing loss and the effectivity of bisphosphonate treatment.

Patients and methods

Twenty-five patients with temporal bone involvement were identified on bone scintigraphy and selected from 100 patients with Paget's disease (10 men, 15 women, with a median age of 70 yr, range 55–82 yr). Nine of the 25 patients studied had monostotic disease and 16 had the polyostotic form.

Fifteen patients were treated with oral tiludronate (400 mg/day) for 3 months and 10 patients received a pamidronate infusion (30 mg/day) for 6 days. Previously, patients were not given any bisphosphonate. Informed consent was obtained from all patients and the investigation was approved by the Ethical Committee of the National Institute of Rheumatology and Physiotherapy.

Baseline investigations included a clinical assessment and measurement of serum alkaline phosphatase (tAP) levels (colorimetric method) before and 1 yr after the treatment.

Imaging included radiography (n = 25), quantitative bone scintigraphy (QBS) (n = 25), single photon emission computed tomography (SPECT) (n = 25) and high-resolution computed tomographic (HRCT) scanning (n = 25). The QBS ratio was obtained from the affected hemicranium using the unaffected side or, where there was bilateral involvement, the cervical spine as reference. SPECT and QBS measurements were carried out before and 1 yr after the treatment. Bone scintigraphy was performed using a ELSCINT SPX-6 HR gamma detector, and HRCT was performed with ELSCINT CT TWIN flash: coronal and axial reconstructions were used with a 1-mm bone slice thickness algorithm.

The audiometric assessment and hearing threshold examinations were performed in every patient before and 1 yr after bisphosphonate treatment. The control group consisted of 25 healthy individuals matched for age and sex on whom we carried out hearing threshold examinations.

Statistical analysis included Wilcoxon test and Spearman correlation.

Results

Prior to the commencement of bisphosphonate treatment, 16 of the 25 patients suffered from frequent headaches, 13 had vertigo, nine complained about tinnitus and 23 had hearing loss, while seven were symptom free.

The skull showed characteristic features of the disease: osteoporosis circumscripta (nine cases) and osteosclerosis with typical cotton wool appearance (10 cases); however, no abnormalities on skull radiography were seen in six cases. Bone scintigraphy showed an increased uptake on the pagetic bones of the skull in all cases (Fig. 1). SPECT demonstrated an increased uptake in the petrous pyramids in 14 cases (Table 1).



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FIG. 1. Bone scintigraphy shows extensive uptake in the skull.. After 12 months of the bisphosphonate treatment there is a mild activity.

 

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TABLE 1. Clinical and radiological characteristics of the patients

 
HRCT identified the involvement of the middle ear ossicles (28%, n = 7), involvement of the petrous pyramids (56%, n = 14), demineralization of the otic capsule (40%, n = 10), porosis pericochlearis (32%, n = 8), narrowing of the external auditory meatus (48%, n = 12), mastoid process thickening (20%, n = 5) and stapedial footplate thickening (16%, n = 4) (Figs 2 and 3).



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FIG. 2. The HRCT demonstrates involvement of the petrous pyramids, demineralization of the otic capsule and narrowing of the external and internal auditory meatus..

 


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FIG. 3. The HRCT demonstrates involvement of the middle ear ossicles and demineralization of the otic capsule..

 
Audiometry demonstrated sensorineural hearing loss in 12 cases, conductive hearing loss in four cases and mixed-type hearing loss in six cases. Three patients had no audiometric abnormalities (Table 2).


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TABLE 2. Data regarding audiometry and HRCT of each patient

 
The audiograms in Figs 4 and 5 display the level of hearing loss in sensorineural and mixed-type cases compared with the age- and sex-matched control group. In all cases we found normal tympanic pressure and intact stapedius reflex.



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FIG. 4. The audiogram shows the comparative analysis of the 12 patients with sensorineural hearing loss and 12 healthy, age- and sex-matched individuals..

 


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FIG. 5. The audiogram shows the mixed hearing loss average of the six patients..

 
One year after bisphosphonate treatment, the serum tAP level decreased significantly in all cases (z = 4.171, P < 0.01).

The QBS ratio following either pamidronate or tiludronate therapy decreased significantly in all patients (z = 4.300, P < 0.01) demonstrating the beneficial effect of bisphosphonates on focal disease activity. We also found a significant correlation between change in tAP levels and QBS ratio after bisphosphonate treatment (r = 0.739, P < 0.001) (Fig. 6). Significant correlation was also found between the change in tAP levels and QBS when the monostotic and polyostotic forms were calculated separately (r = 0.740, P < 0.023; r = 0.671, P < 0.004, respectively). Therefore, it seems that (mono- or polyostotic) localization does not affect the efficacy of bisphosphonate treatment in Paget's disease.



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FIG. 6. Correlation between tAP and QBS in 25 pagetic patients..

 
Symptomatic complaints assessed by the patients also improved: headaches in 10 cases, tinnitus in five cases and vertigo in eight cases decreased after treatment.

Twelve months after the treatment we repeated the hearing threshold examinations. Six of 12 patients with sensorineural hearing loss seemed to show a small, although not significant (mean: 7.5 dB), enhancement in the high frequency region, while there was no improvement in patients suffering from conductive or mixed hearing loss.

Eight of the 23 patients with impaired hearing had greater than 30–50 dB hearing loss. Two of these patients were already using hearing aids and we recommended the use of hearing aids to the rest of the patients having more than 30–50 dB hearing loss at 500–1000 Hz.

Discussion

According to the literature, skull involvement in Paget's disease occurs in 65–70% of advanced polyostotic cases [5]. Data concerning the epidemiology of Paget's disease in Hungary are few. In our present study we identified 25 patients with cranial manifestations among our 100 pagetic patients of whom 16 showed polyostotic involvement. Patients with skull involvement often complain about various symptoms, but in many cases the disease is symptom free. A population-based study by van Staa et al. [6] found that approximately 0.3% of British men and women who were >55yr old have clinically diagnosed Paget's disease of bone. In their study, 15.9% of the patients with Paget's disease reported impaired hearing compared with 10% of the controls. The exact prevalence of hearing loss among Hungarian patients with Paget's disease is unknown. However, in our study 23 of the selected 25 pagetic patients with skull involvement had hearing loss. Since the original population included 100 patients with Paget's disease, the proportion of patients affected with hearing loss can be estimated at about 23%.

Rosenkrantz et al. [7] found that in 111 patients with Paget's disease, bone pain was present in 55 cases, defective hearing in 14, headaches in 14 and vertigo in eight cases.

The most common site of the discomfort in patients with skull involvement was the occiput, but the temporal and frontal region was also frequently affected. When the Paget's disease was mild, headaches were not pronounced and often well-localized. In the earlier stages the headaches were intermittent, but as pagetic changes became more severe, the headaches became constant [8]. Among our 25 patients, 16 had headaches and 13 complained about vertigo.

The progress of Paget's disease can be evaluated by conventional radiography. The incipient phase is characterized by a zone of rarefraction, described as osteoporosis circumscripta by Schuller in 1926. The later phase includes a thickened skull with a patchy, cotton wool appearance of the vault.

Bone scintigraphy detects pathological changes earlier than radiography and six of our patients had Paget's disease of the skull without any evidence of radiographic involvement. The patients with negative radiographic findings showed a characteristic scintigraphy pattern in our study. Nineteen patients with typical radiographic changes also showed positive bone scintigraphy. Besides confirming the diagnosis of Paget's disease, radiometric QBS is used to monitor the effect of medical treatment [911].

CT is known to be one of the most efficacious methods of studying the changes of the temporal bone. These include early pagetic lesions at the petrous apex and later demineralization of the otic capsule. CT can also reveal thickening of the stapedial footplate, which may significantly contribute to hearing loss. The mastoid process might show bone thickening, demineralization or a mosaic pattern [12].

If the Paget's disease process involves the temporal bone surrounding the inner ear, a more severe and progressive loss of hearing may occur [5]. Paget in his first report from1877 stated that his original patient began to be somewhat deaf, and his second paper in 1882 also described a case with impairment of hearing [1].

The exact mechanism underlying the conductive, sensorineural or mixed-type pattern of hearing loss in Paget's disease is not well understood. Original theories suggested that the sensorineural hearing loss in this disorder was due to encroachment on neural structures by bone overgrowth and subsequent narrowing of the internal auditory canal [2]. Conductive hearing loss may result from involvement of the ossicles of the middle ear, resulting in rigidity of the footplate of the stapes [13].

Findings support the principle that hearing loss in Paget's disease is generally associated with intact auditory nerve function and also support a cochlear site of the lesion [14]. Monsell et al. [15] measured a decreased density of the thickened auditory bones in Paget's disease. They stated that alterations in bone density of the cochlear capsule might be related to the mechanism of hearing loss.

Therapy for symptomatic Paget's disease with skull involvement is almost exclusively non-surgical, usually using calcitonin or bisphosphonates. However, some causes of the conductive component of the hearing loss may be correctable through surgical stabilization [14].

Some case reports and retrospective reviews suggest that patients may experience a variety of clinical benefits or even improvement of sensorineural hearing loss during long-term drug therapy [16]. Calcitonin use for hearing loss in Paget's disease has had variable success [1719]. Bisphophonates are potent inhibitors of bone resorption and have been widely used to treat Paget's disease. Lando et al. [4] reviewed combined calcitonin and sodium etidronate therapy and reported stabilized or even reversed hearing loss in patients with Paget's disease, and this combination has been shown to improve serum chemistry measurement and bone biopsy appearances [20]. A dose of 180 mg of pamidronate weekly does not induce a mineralization defect but seems to be effective in treating Paget's disease. Delmas and Meunier [21] reviewed the protocols for the administration of intravenous pamidronate, which has usually been given in daily doses ranging from 10 to 90 mg, either as a single infusion or for three consecutive days, or as weekly or monthly infusions. Tiludronate at 400 mg per day for 3 months led to a reduction of alkaline phosphatase in some cases [22]. Based upon the suggestions of Delmas and Meunier [21] and Siris [22], in our study we chose to use pamidronate in a total dose of 180 mg once a year intravenously or tiludronate at 400 mg per day for 3 months.

In rare cases bisphosphonates can cause ototoxicity. Reid et al. [23] reported ototoxicity as a serious side-effect after pamidronate infusion in Paget's disease of bone. In our study, patients already had hearing impairment before pamidronate treatment and we did not observe any worsening of the hearing loss of the patients. Therefore, pamidronate caused no ototoxicity in our study.

We found no significant improvement in hearing after bisphosphonate therapy, although treatment was effective in decreasing focal disease activity as shown by decreased serum tAP level and QBS ratio. The subjective complaints (headache, tinnitus and vertigo) also improved.

Hearing loss is an important complication of Paget's disease and even if diagnosed and treated with bisphosphonates early, it is difficult to control. Our data suggest that audiometric assessment is also an important tool in monitoring the complications of Paget's disease. New studies are needed to elucidate further the pathophysiology of the hearing loss occurring in Paget's disease in order to select the appropriate treatment.

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Submitted 21 March 2003; Accepted 30 June 2003