Long-term outcomes following total hip and total knee arthroplasty in patients with Paget's disease of bone (PDB) - A national study.

BACKGROUND: The incidence of total hip and total knee arthroplasty (THA/TKA) is 3.1- and 1.7-fold higher in patients with Paget's disease of bone (PDB) compared to age-matched controls. No large studies or joint registry reports exist describing outcomes following THA or TKA in PDB patients. METHODS: The study objectives were to investigate the outcomes following THA or TKA in PDB patients using national registry data. Data were requested from the Scottish Arthroplasty Project for all PDB patients undergoing THA or TKA in Scotland from 1996 to 2013. RESULTS: Between 1996 - 2013, 144 patients underwent primary THA and 43 patients underwent primary TKA for PDB in Scotland. Following primary THA, the most common surgical complications within one year were haematoma (1.4%), and surgical-site infection (1.4%). The overall incidence of dislocation was 2.8%. Revision THA was performed in 2.8% of patients. THA implant survival was 96.3% (CI:92.8-99.8) at 10-years, and patient survival was 50.0% (CI:39.6-60.4) at 10-years. Following TKA, only one revision surgery occurred within one year (2.3%). Revision TKA was performed in 4.7% of patients, across the whole study period. TKA implant survival was 94.5% (CI:87.1-100) at 10-years; patient survival was 38.3% (CI:16.7-59.9) at 10-years. Compared with published literature and registry data, implant longevity and patient survival are comparable between PDB patients and the general population. CONCLUSION: This is the largest reported series of outcomes following primary THA/TKA in PDB patients. PDB patients are not at increased risk of surgical complications following primary THA or TKA compared with the general population.

Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia.

Valosin containing protein (VCP) disease associated with inclusion body myopathy, Paget disease of the bone and frontotemporal dementia is a progressive autosomal dominant disorder caused by mutations in Valosin containing protein gene. To establish genotype-phenotype correlations we analyzed clinical and biochemical markers from a database of 190 members in 27 families harboring 10 missense mutations. Individuals were grouped into three categories: symptomatic, presymptomatic carriers and noncarriers. The symptomatic families were further divided into ten groups based on their VCP mutations. There was marked intra and inter-familial variation; and significant genotype-phenotype correlations were difficult to establish because of small numbers. Nevertheless when comparing the two most common mutations, R155C mutation was found to be more severe, with an earlier onset of myopathy and Paget (p = 0.03). Survival analysis of all subjects revealed an average life span after diagnosis of myopathy and Paget of 18 and 19 years respectively, and after dementia only 6 years. R155C had a reduced survival compared to the R155H mutation (p = 0.03).We identified amyotrophic lateral sclerosis (ALS) was diagnosed in 13 individuals (8.9%) and Parkinson's disease in five individuals (3%); however, there was no genotypic correlation. This study represents the largest dataset of patients with VCP disease and expands our understanding of the natural history and provides genotype-phenotype correlations in this unique disease.

Osteosarcoma in the elderly over 60 years: a multicenter study by the Japanese Musculoskeletal Oncology Group.

BACKGROUND: Few studies have described the characteristics and prognostic factors of osteosarcoma patients aged over 60 years. METHODS: The Japanese Musculoskeletal Oncology Group (JMOG) carried out a retrospective review of patients over the age of 60 years with osteosarcoma. RESULTS: Only 12 patients had secondary osteosarcoma, with none associated with Paget's disease. The primary disease sites were the extremities in 63% and trunk in 33%. The overall survival was 42.8% and disease-free survival was 40.8% at 5 years in the high grade group. An univariate analysis indicated that significant poor prognostic factors for overall survival were axial location, lung metastasis at initial presentation, and absence of surgical treatment. Multivariate analysis revealed that a significant poor prognostic factor for overall survival was the absence of surgical treatment. Secondary osteosarcoma did not lower the overall or the disease-free survival in any group. CONCLUSIONS: The current study indicates that the number of osteosarcoma patients over 60 years is increasing. The number of cases with secondary osteosarcoma over 60 years is relatively small in Japan, with no patients having osteosarcomas related to Paget's disease. Although there is a predilection for axial localization, surgical treatment has a significant impact on patient's prognosis.

Durability of Response to Zoledronate Treatment and Competing Mortality in Paget's Disease of Bone.

There has been a marked secular trend in recent decades toward patients with Paget's disease presenting at a greater age and having less extensive skeletal involvement. Over a similar time frame more potent bisphosphonates with a long duration of effect have been developed, raising the prospect of many patients needing only once in a lifetime treatment. We studied a cohort of 107 patients who had been treated with intravenous zoledronate for the first time at a mean age of 76 years. Sequential measurements of the bone turnover marker procollagen-1 NT-peptide (P1NP) were made for up to 10 years. By 9 years, 64% showed some loss of zoledronate effect (defined as a doubling of P1NP from the nadir value after treatment), but only 14% had a biochemical relapse (defined as a P1NP value >80 µg/L). The mortality rate was substantially greater than the relapse rate-by 10 years more than half the cohort had died (p < 0.0001). We conclude that for the majority of older people with Paget's disease a single intravenous infusion of zoledronate will provide disease suppression for the remainder of their lives. © 2016 American Society for Bone and Mineral Research.

Evidence for secular change in Paget's disease.

Death certification data has shown that death rates due to Paget's disease of bone and osteosarcoma in older people (assumed to be attributable to Paget's) declined in the latter part of the 19th and in the early 20th century, suggesting that there may be a secular trend toward less severe disease. We have reviewed a 21 year experience in a clinic specializing in Paget's disease. Data from all 1041 patients attending the clinic in this period were reviewed. Despite an increase in the susceptible population and an increased rate of referral to the clinic over this time (p = 0.012), there was a fall in the absolute numbers of patients referred with severe disease, as judged by the initial plasma alkaline phosphatase activity at presentation. In the years 1973-1978 the initial plasma alkaline phosphatase was > 500 U/L in an average of 22 new patients per year and > 1000 U/L in 12 per year. In the years 1988-1993, the figures were 12 and 3 per year, respectively. During this period, there were no other facilities offering scintigraphy or intravenous treatment for Paget's disease in the Auckland region, making it unlikely that patients with severe disease were being seen and treated elsewhere. The average age of newly referred patients rose steadily from a mean 62 years, in 1971-1973 to 71 years in 1991-1993 (p < 0.001). 534 subjects had scintiscans (52%) from which the extent of skeletal involvement was calculated. Skeletal involvement showed a significant negative correlation with year of birth (p < 0.01) but not with age or year of presentation. The proportion of patients with > 20% skeletal involvement had fallen by a third in the cohort born after 1926, compared to the cohort born before 1915. Our data demonstrate that, on average, newly referred patients with Paget's disease have less severe disease and are significantly older at diagnosis than was the case two decades ago.

Osteosarcoma over the age of forty.

The European Musculo Skeletal Oncology Society (EMSOS) has carried out a retrospective review of patients over the age of 40 years with osteosarcoma. 481 patients from 12 centres or multicentric groups were included. 42 patients had osteosarcoma arising in Paget's disease, median survival was 9 months. Patients with axial or metastatic tumours also did badly whilst 41 patients with radiation-induced osteosarcoma had a prognosis paralleling conventional osteosarcoma matched for patient age and site of the tumour. 238 patients had high grade non-metastatic osteosarcoma and had a survival of 46% at 5 years. Older patients had less chemotherapy and fared worse. Osteosarcoma in the elderly is a curable condition and warrants intensive treatment with chemotherapy and surgical resection.

Mortality from malignant tumours of bone and Paget's disease in the United States and in England and Wales.

Changes in death rates from malignant tumours of bone among successive cohorts in the U S A and in England and Wales are shown to be remarkably similar. Since cohorts born in the 1870's there have been simultaneous and equal declines in both countries and in both sexes. Comparable cohort trends are also shown for Paget's disease, although the death rates in the U S A are only about one-fifth of those in England and Wales.

Morbidity and mortality associated with Paget's disease of bone: a population-based study.

INTRODUCTION: Limited information is available about the clinical features of Paget's disease of bone among unselected patients in the community. We examined morbidity and mortality associated with this condition in a large inception cohort of Olmsted County, MN, residents with a new diagnosis of Paget's disease from 1950 through 1994. MATERIALS AND METHODS: Survival was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to assess the impact of various covariates on death. RESULTS: Paget's disease of bone was diagnosed in 236 Olmsted County residents (mean age at diagnosis, 69.6 yr; 55% men). The majority were symptomatic at diagnosis (58%), and the proportion with symptoms did not change from the prescreening era (1950 to June 1974) to the postscreening era (July 1974-1994). Most patients had polyostotic disease (72%), and the pelvis (67%), vertebra (41%), and femur (31%) were the most common sites of involvement. Skeletal complications attributable to Paget's disease included bowing deformities (7.6%), fracture of pagetic bone (9.7%), and osteosarcoma (0.4%). Osteoarthritis was observed in 73% of patients, and 11% had a hip or knee replacement. Nonskeletal complications related to Paget's disease included cranial nerve (0.4%), peripheral nerve (1.7%), and nerve root (3.8%) compression, basilar invagination (2.1%), hypercalcemia (5.2%), and congestive heart failure (3.0%). Hearing loss, noted in 61%, was significantly higher than previously reported. CONCLUSIONS: Compared with white Minnesota residents, overall survival was slightly better than expected (p = 0.010). No clinical risk factors were identified that were associated with an increased risk of death.

Sarcomas arising in Paget disease of bone: a clinicopathologic analysis of 70 cases.

CONTEXT: Sarcomatous transformation is a rare complication of Paget disease of bone. Prognosis in patients with other types of sarcomas arising in bone has improved in the last several decades because of therapeutic advances. However, because of the rarity of Paget sarcoma, outcome studies in these patients are limited. OBJECTIVE: To determine whether prognosis for Paget sarcoma has improved. DESIGN: Seventy cases of sarcomas arising in the setting of Paget disease were collected, and the histologic and clinical findings were reviewed. Clinical follow-up was obtained in 67 cases. RESULTS: Sarcoma arising in Paget disease tended to arise in older men (46 men, 24 women; age range, 31-88 years; mean age, 66 years) and predominated in the axial skeleton (n = 37), especially in the pelvis. Thirty-three patients had a clinical history of Paget disease ranging in duration from 16 months to 30 years (mean, 15 years). No significant difference in incidence between monostotic (n = 33) and polyostotic (n = 36) disease was noted. Most tumors were osteosarcomas (88%). All tumors were high grade. Follow-up information was obtained in 67 of 70 cases (range of follow-up, 1-252 months). Survival ranged from 1 month to 20 years, with a 5-year survival rate of 10%. CONCLUSIONS: Prognosis remains poor in patients with Paget sarcoma. There is no significant correlation between the number of bones involved with Paget disease or the duration of disease and development of Paget sarcoma. Poor prognosis in Paget sarcoma is unrelated to site or stage at presentation.

Paget's sarcoma: a historical and outcome review.

UNLABELLED: Paget's sarcoma is a rare entity that principally occurs in elderly people with extensive Paget's disease. The primary sites of occurrence are the pelvis, proximal femur, proximal humerus, and calvarium. The lesions are highly malignant and the patients frequently are found to have metastases at the time of discovery. The survival rate reported in the literature generally is very poor. We were able to locate 16 patients with Paget's sarcoma in the Dr. Henry L. Jaffe Pathology Collection treated from 1942 to 1967. These were added to 27 patients treated for the disease by the Harvard Orthopaedic Oncology Group from 1972 to 2001. Three were giant cell tumors, which are occasionally found in patients with florid Paget's disease but are not malignant. Of the remaining 40 patients, outcome data were available on 35 patients. The rate of Musculoskeletal Tumor Society Stage III tumors was very high (35%) and the rate of survival was 14% at approximately 2.5 years, without differences between the two series. In view of the remarkable concordance in the poor survival figures for patients treated between 1946 and 1967 and those treated between 1972 and 2001 it appears that little progress has occurred in the treatment of Paget's sarcoma over the years, which is in sharp contrast with the current statistics for standard osteosarcoma. LEVEL OF EVIDENCE: Prognostic study, Level IV (case series). See the Guidelines for Authors for a complete description of levels of evidence.

The epidemiology of Paget's disease.

Paget's disease is commoner in men and its prevalence increases with age. It has a remarkable geographical localisation. Britain has the highest recorded prevalence. Somewhat lower rates have been recorded in North America, Australia and Western Europe. The disease is rare in Scandinavia. Within Britain there is a localised area of high prevalence in Lancashire. In North America prevalence is markedly higher in New York than in Atlanta. Rates in American blacks and whites are similar although the disease is rare in Africa. In Australia the prevalence among British born immigrants is intermediate between the British rate and that of native born Australians. There is evidence of a decline in incidence of the disease in Britain and North America. The epidemiological characteristics of the disease suggest that environmental influences are important in its aetiology. They provide data against which new hypotheses on causation must be tested.

Osteosarcoma: then and now. A fifty year review at Royal Prince Alfred Hospital.

The purpose of this study is to review survival, treatment methods and criteria for diagnosis of osteosarcoma at Royal Prince Alfred Hospital during two periods in the last 50 years. The records of 22 patients diagnosed with osteosarcoma and nine with osteosarcoma in Paget's disease (from 1939 to 1950) were reviewed. All but one had died within three years. One patient survived six years. The second series was taken from 1983 to 1990. Forty-nine patients, including three with Paget's sarcoma, were studied. Probability of survival was estimated by actuarial analysis using Kaplan-Meier curves. Overall survival was estimated at 45%. Those patients who were free of metastatic disease at the conclusion of their treatment were estimated to have a probability of survival of 85%.

Survival and management considerations in postirradiation osteosarcoma and Paget's osteosarcoma.

Postirradiation and Paget's osteosarcomas are high-grade malignancies. The five-year survival was only 10% in recent experience at the author's institution. Progressive pain is an important clinical feature in both conditions. Careful roentgenographic studies demonstrate cortical destruction and a soft-tissue mass in virtually all patients. Metastasis was present in 25% of both groups of patients at presentation. In contrast to previous series, more than 80% of the patients with postirradiation osteosarcoma had had irradiation for malignant entities and more than 70% had been treated with modern radiotherapy regimens (cobalt-60 or linear accelerator). Twice as many patients with postirradiation osteosarcoma were evaluated and treated in the 1980s than in the previous decade. The initial indication for irradiation often was carcinoma of the breast, uterus, or cervix, or lymphoma. Two-thirds of the patients had progressive disease that was not controllable within six months after diagnosis. Early detection may be the only effective means of improving survival with postirradiation or Paget's osteosarcoma. These patients require lifelong follow-up evaluations.

Fourteen cases of sarcomatous degeneration in Paget's disease.

OBJECTIVE: To describe characteristics of cases of sarcomatous degeneration in Paget's disease (SDP) recorded over 10 years in 2 French university hospitals, with particular emphasis on the pattern of this entity on magnetic resonance imaging (MRI). METHODS: Fourteen cases are described. Epidemiological, clinical, radiological, histological, and MRI features (in 3 cases) are compared to others in the literature. RESULTS: Nine men and 5 women (mean age 75.2+/-7.7 yrs) were studied. Paget's disease was monostotic in 5 cases and polyostotic in 9. Neurological complications were present in 10 cases. The mean interval between the first clinical signs and diagnosis was 4.4+/-4.7 months. The locations were: limbs 2, skull 2, pelvis 7, sacrum 3. The radiological pattern was lytic in 9 cases, sclerotic in 3, and mixed in 2. MRI revealed a similar pattern in all 3 cases studied (heterogeneous low signal intensity of the tumor on T1 weighted images increased after intravenous gadolinium administration and high signal intensity on T2 weighted images), whereas the radiological pattern was lytic in 2 cases and sclerotic in one case. The diagnosis was proved by histological investigation in 11/14 patients (osteogenic sarcoma of different appearance in 7 patients, fibroblastic sarcoma in one, fibrous histiocytoma-like sarcoma in one, and undifferentiated sarcoma in 2). Four patients had pulmonary metastases and 4 patients are still alive with followup ranging from 5 months to 5 years. CONCLUSION: Paget sarcomas remain the most threatening sarcomas of bone, their prognosis being far more negative than primary sarcomas. Improvement in therapy strategies including surgery, radiation therapy, and chemotherapy might together provide better prognosis for SDP.