Third-generation bisphosphonates for cochlear otosclerosis stabilizes sensorineural hearing loss in long-term follow-up.

Objective: To assess long-term hearing outcomes in patients treated with third-generation bisphosphonates for otosclerosis-related progressive sensorineural hearing loss (SNHL). Study Design: Retrospective case series review. Methods: We performed a retrospective case series review of patients with otosclerosis and progressive SNHL. Patients were treated with either risedronate or zoledronate after a diagnosis of otosclerosis with a significant SNHL component. Bone conduction pure tone threshold averages (BC-PTAs) and word recognition scores (WRS) before and after bisphosphonate administration in long-term follow-up was analyzed. Significant change in BC-PTA was defined as greater than 10dB or between 4% and 18% in WRS based on binomial variance. Results: Seven patients were identified and 14 ears met inclusion criteria. Three patients were female and the mean age was 48.3 ± 10.3 years. The mean duration between treatment with bisphosphonate administration and long-term post-treatment follow-up audiometry was 87.6 ± 18.3 months, with a range of 61.6 to 109.1 months and median of 89.2 months. Analysis using BC-PTA and WRS demonstrated that 11 ears remained stable while 2 improved and 1 worsened. No patient experienced any major complication as the result of bisphosphonate therapy. Conclusion: Treatment with third-generation bisphosphonates is associated with stability in otosclerosis-related sensorineural hearing over 5- to 9-year period. These results suggest that such medications may prevent the progression of SNHL in patients with otosclerosis. Level of Evidence: 4 (Case series).

The Implications of the Sequestosome 1 Mutation P392L in Patients with Paget's Disease in a United States Cohort.

Paget's disease of bone (PDB) is associated with a germline mutation in Sequestosome1/p62 (SQSTM1) found in ≤16 % of sporadic cases worldwide, and in 19-46 % of those studied with familial PDB. The P392L is the most prevalent mutation identified to date. This mutation by itself does not confer PDB or define the phenotype of PDB in a given person. Environmental determinants remain elusive, although increasing age of the individual, other gene polymorphisms in the context of SQSTM1 mutations, and measles virus have been implicated. Measles exposure has been unexamined in this context. The goal of this study is to compare the background history and phenotype of patients with PDB carrying the SQSTM1 P392L mutation to those patients without. Focusing on age, ancestry, P329L mutation, family history, measles exposure, distribution of PDB, and age of onset, we examined outcomes at 10 years. We postulated that aging may play a role in defining phenotype, and that this may become more visible in a well-characterized cohort. This is an observational study focused on a cohort of patients with PDB drawn from the New England Registry in whom environmental and family history has been catalogued, linked to radiographic data. Of the 217 persons who were enrolled in the Registry, 42 (19 %) responded to a letter inviting them to participate in testing for the presence of the measles antibody, and in genetic testing for the P392L mutation. The mean age of the cohort in 2001 was 70 years (range 55-79); 27 were men (64 %). The measles antibody was found in all cases tested. Nine patients had the P392L mutation (21 %), 2 with familial PDB. In these persons, early diagnosis of disease and spinal stenosis marked the male phenotype only. European ancestry was noted in the minority of those with P392L mutation. Most deaths recorded occurred in the ninth decade of life or later. Spinal stenosis emerges as a prominent phenotype in SQSTM1 P392L-positive men with aging. In these 42 patients with PDB from the New England Registry, most do not carry the SQSTM1 P392L mutation, and many do not have European ancestry. Exposure to measles was confirmed in the majority.

Paget disease of bone: diagnosis and drug therapy.

Paget disease of bone is a focal disorder of aging bone that may be asymptomatic or may present with pain, bowing deformity, fracture, or a nonspecific rheumatic complaint. It is the second most common disease of bone in the elderly after osteoporosis, and the loss of structural integrity in affected bone conveys a risk of fracture. It may occur sporadically or in geographic or familial clusters. This article discusses the prevalence, pathology, workup, and treatment of Paget disease of bone.

Autosomal dominant hypophosphatemic rickets in an 85 year old woman: characterization of her disease from infancy through adulthood.

BACKGROUND: Autosomal dominant hypophosphatemic rickets (ADHR) is a rare genetic disorder of phosphate homeostasis characterized, when severely expressed, by osteomalacia, suppressed levels of calcitriol, and renal phosphate wasting due to elevated levels of fibroblast growth factor 23 (FGF23). The disease is caused by heterozygous FGF23 mutations at the RXXR site that prevent cleavage of the intact hormone. OBJECTIVES: An FGF23 mutation was identified in the proband an 85-year-old woman with elevated FGF23 levels, and her clinical course was characterized. Medical records revealed she was treated for rickets as an infant. She was then asymptomatic until soon after her 4th pregnancy, when she suffered incapacitating bone pain and weakness, age 37. Symptoms remitted with brief treatment. RESULTS: The proband and one son, but not other family members, were found to be heterozygous for the R176Q mutation in FGF23. Expression of this germ line mutation was strikingly different in both individuals in terms of skeletal health, FGF23 levels and disease activity. CONCLUSIONS: The identified FGF23 mutation in two members of this family raises questions about molecular mechanisms that have led to intermittent increases in FGF23 synthesis and secretion, and disease expression.

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.

Somatic mutations in SQSTM1 detected in affected tissues from patients with sporadic Paget's disease of bone.

Paget's disease of bone (PDB) is a focal disorder of bone remodeling that leads to overgrowth of affected bone, with rare progression to osteosarcoma. Extensive studies of familial PDB showed that a majority of cases harbor germline mutations in the Sequestosome1 gene (SQSTM1). In contrast, little is known about the mutational status of SQSTM1 in sporadic PDB. We hypothesized that somatic SQSTM1 mutations might occur in the affected tissues of sporadic PDB and pagetic osteosarcoma. We used laser capture microdissection to capture homogeneous populations of cells from the affected bone or tumor of patients with sporadic PDB or pagetic osteosarcoma, respectively. DNA from these samples and appropriate controls was used for sequence analysis and allelic discrimination analysis. Two of five patients with sporadic PDB had SQSTM1(C1215T) mutations detected in their affected bone but not in their blood samples, indicating a somatic origin of the mutations. Samples from three of five sporadic pagetic osteosarcoma patients had the SQSTM1(C1215T) mutation, whereas the normal adjacent tissue from two of these tumors clearly lacked the mutation, again indicating an occurrence of somatic events. No SQSTM1 mutations were found in primary adolescent osteosarcomas. The discovery of somatic SQSTM1 mutations in sporadic PDB and pagetic osteosarcoma shows a role for SQSTM1 in both sporadic and inherited PDB. The discovery of somatically acquired mutations in both the diseased bone and tumor samples suggests a paradigm shift in our understanding of this disease.

Paget's disease: epidemiology and pathophysiology.

Paget's disease of bone is a focal disorder of aging bone. The classic late-onset Paget's disease is often caused by a P392L mutation in the gene SQSTM1, which disturbs signaling pathways in osteoclasts on cell activation. This prevalent mutation is neither necessary nor sufficient to cause Paget's disease. Its identification, along with the elucidation of other mutations underlying early-onset Paget's and Paget's disease seen in association with inclusion body myopathy and frontotemporal dementia, have redefined our understanding of genetic disorders of bone remodeling by emphasizing the importance of environmental determinants in their pathophysiology.

Bisphosphonate use in the treatment of Paget's disease of the bone: analysis of claims in a large database.

This study examines the use of bisphosphonates for treating Paget's disease of the bone through an analysis of drug, dose, and therapy-duration data. Data were obtained from a national, multi-managed care plan claims database (based on claims filed from 1996-2004). Patient eligibility criteria included at least one claim with Paget's disease International Classification of Diseases, Ninth Revision code 731.0, at least one bisphosphonate pharmacy claim, at least six months' continuous enrollment after initiating bisphosphonate therapy (index date), and no more than one claim for osteoporosis. The proportion of patients with bisphosphonate therapy extending beyond the initial recommended treatment regimen (incremental drug use) and associated costs were calculated for each drug. Of 433 patients with Paget's disease receiving bisphosphonate treatment (mean age, 65.0 yr; 64.3% women), 53.1% were prescribed alendronate at the index date; 34.9% and 7.4%, were prescribed risedronate and etidronate, respectively. More than 40% of patients with Paget's disease receiving at least one bisphosphonate were prescribed bisphosphonates beyond the recommended regimen duration at substantial incremental costs.

Use of zoledronic acid in the treatment of Paget's disease.

This review examines the use of zoledronic acid in the treatment of Paget's disease of bone. It begins with a brief discussion of the theories of pathogenesis of Paget's disease, its clinical manifestations, and the history of bisphosphonate treatment in this disorder. Risk of oversuppression of bone by the more potent bisphosphonates and their association with avascular necrosis of the jaw are noted.

Medical care costs of Paget's disease of bone in a privately insured population.

INTRODUCTION: Medical care costs are difficult to calculate in diseases such as Paget's disease because they have low detection rates and a wide range of clinical manifestations that commonly occur in aging patient populations. MATERIALS AND METHODS: Using 2001-2002 MarketScan Research databases, this study linked medical claims, prescription records, and encounter data on 2.8 million active and retired employees to create a longitudinal panel with 24 months of observation. Patients with Paget's disease were identified by ICD-9 code 731.0. Matched controls (MC) were identified through an exact match procedure using gender, age, and predicted Medicare costs estimated with a risk adjuster. Diagnostic and expenditure records were extracted for the sample and prevalence rates calculated for 20 conditions with well-documented associations to Paget's disease. Comorbidities and health care costs of Paget's disease patients were compared to those of the MCs, and the differences tested using Chi-square and t tests. RESULTS: Our study identified 244 matched pairs. The average age was 72.7 years; 50.8% were female. Significantly higher comorbidities (P < 0.05) were detected in Paget's disease patients relative to MCs for: pathological fractures (4.9% vs. 0.4%), heart murmurs (3.3% vs. 0.4%), low back pain (19.7% vs. 8.6%), spinal stenosis (16.4% vs. 9.8%), and hearing loss (13.5% vs. 5.7%), respectively. Biannual per patient outpatient costs were significantly higher in Paget's disease patients (Paget's disease $9301 vs. MC $6339, P < 0.05), especially for services associated with physician visits and diagnostic tests. Prescription costs for antiresportive agents and analgesics were also higher (Paget's disease $1115 vs. MC $507, P < 0.05). Inpatient costs (Paget's disease $16,144 vs. MC $21,480) were comparable. CONCLUSION: This study is the first to describe the excessive costs of Paget's disease, based on known patterns of disease expression, evaluation, and treatment.

Osteosarcoma in Paget's disease of bone.

Paget's disease of bone (PDB) is a focal disorder of bone metabolism first described by Sir James Paget in 1876. It is presumed benign in nature and mediated by abnormal osteoclast function. The incidence of osteosarcomas complicating PDB is estimated at <1%. These cancers occur mostly in persons with long-standing, polyostotic disease and affect patients in their seventh decade or when osteosarcoma is remarkably rare in the general population. Epidemiological studies suggest that this late peak of osteosarcomas is absent in regions where Paget's is infrequently reported. Whereas PDB has a predilection for the axial skeleton, skull, femurs, and tibias, pagetic osteosarcoma tend to spare the spine, and are reported more commonly in the pelvis, femur, humerus, and skull. A molecular basis for the association of osteosarcoma with Paget's disease is unclear. These osteosarcomas are osteogenic in origin, consistently arise in sites of pagetic bone, and may present as metachronous, multifocal lesions. On histopathology, the lesions are usually osteoblastic, and the tumor phenotype is sometimes characterized as an exaggerated, chaotic form of the accelerated bone remodeling that characterizes PDB. New insights from the biology of adolescent osteosarcomas, VCP and SQSTM1 mutations now defined in patients with Paget's disease, and emerging evidence that stromal lesions are present in patients with Paget's disease are changing the way we think about the pathogenesis of PDB and the rare complication of pagetic osteosarcomas.

Low 25-hydroxyvitamin D and osteopenia are prevalent in persons > or =55 yr with fracture at any site: a prospective, observational study of persons fracturing in the community.

Ethnic diversity and lower socioeconomic populations are poorly captured in most studies of osteoporosis and fracture risk. This article describes a prospective, observational study designed to analyze risk factors for fracture in an ambulatory, ethnically diverse, urban population aged > or =55 yr. The goal of the study was to determine the number of fractures associated with hypovitaminosis D (< or =15 ng/mL serum 25-hydroxyvitamin D) and osteopenia (T-score <-1.5) by bone mineral density (BMD). From January 1 to July 31, 2001, we identified 262 persons who fractured in our community; 83 chose to enroll in the study. Enrolled patients had a BMD examination at two sites; their blood was drawn for 25-hydroxyvitamin D (25VitD), calcium, phosphorus, albumin, and alkaline phosphatase. At the completion of the study a letter was sent to the patients detailing the findings, and a copy sent to their physician. Of the 83 persons enrolled, 73 (88%) had evidence of osteopenia or osteoporosis (T-score <-1.5) and/or low 25VitD. All fractures in the community in person > or =55 yr, with or without a history of antecedent trauma, should be assessed with BMD and screening for 25VitD.