Paget's disease of bone

Paget's disease of bone is a localized disorder of bone remodeling. Increased numbers of larger than normal osteoclasts initiate the process at affected skeletal sites, and the increase in bone resorption is followed by an increase in new bone formation, altering bone architecture. The signs and symptoms of Paget's disease are varied, depending in part on the location of the involved sites and the degree of increased bone turnover. Recent progress in Paget's disease research includes new data regarding the etiology of this disorder and the ongoing development of more effective therapies. Although the cause of Paget's disease remains unproven, the creation of pagetic osteoclasts seems ever more likely to result from both genetic and environmental factors. Many studies indicate that in patients with Paget's disease, both osteoclasts and their precursors harbor evidence of a paramyxovirus infection, although not all studies confirm this finding. Very recent genetic investigations have identified one candidate gene on chromosome 18q, although genetic heterogeneity is almost certainly present. Advances in treatment have resulted from the availability of several potent bisphosphonate compounds (e.g., pamidronate, alendronate, and risedronate) that, unlike earlier treatments, produce normal or near normal bone turnover indices in a majority of patients. New bone formation after such treatment has a more normal, lamellar pattern, and mineralization abnormalities are rare to absent with the newer compounds. The availability of such agents has prompted a more aggressive management philosophy in which both symptomatic disease and also asymptomatic disease at sites with a risk of progression and future complications are viewed as clear indications for pharmacologic intervention.     

Paget's disease and sensori-neural deafness: temporal bone histopathology of Paget's disease

Four cases with Paget's disease of the temporal bone are presented to illustrate the pathogenesis of the associated deafness. One case illustrates the combination of severe deafness due to bilateral otosclerosis with probably asymptomatic bilateral Paget's disease. One case with advanced Paget's disease presents features to explain early stages of sensori-neural deafness before actual cellular invasion of the inner ear. One case of profound deafness due to Paget's disease presents a different stage of cellular invasion of the inner ear by the disease on each side. One case illustrates invasion of the internal auditory meatus by Paget's disease with infiltration of the acoustic division of the nerve and profound deafness.     

Quantitative bone scintigraphy in the management of monostotic Paget's disease of bone

OBJECTIVE: To assess the use of quantitative bone scanning (QBS) in the monitoring of patients with intravenous pamidronate-treated symptomatic monostotic Paget's disease of bone in whom biochemical markers of bone turnover are relatively normal. METHODS: QBS was performed in 9 patients and the results were expressed as a ratio, obtained by comparing isotope uptake at an affected and a control (unaffected) site. RESULTS: Serum alkaline phosphatase levels were normal in 7 of the 9 patients and changed minimally with treatment. The median QBS ratio was 2.72 (range 1.69-24.6) at baseline and 1.49 (range 0.63-4.18) posttreatment (P = 0.008). The median symptom score decreased with treatment, but QBS ratios provided the only objective measure of disease activity by which response to pamidronate therapy could be judged. CONCLUSION: QBS may be a useful technique for evaluating the effects of treatment in patients with Paget's disease of bone.     

Paget's disease of bone complicated by giant cell tumor

Paget's disease is uncommon in patients younger than 50 years of age. Multifocal giant cell tumors arising in bone affected by Paget's disease have been described previously in 37 cases. A case of a 38-year-old man with polyostotic Paget's disease and multifocal giant cell tumors responsive to steroid therapy is presented.     

Significance of renal visualization during bone scanning in Paget's disease

In 17 of 26 patients with extensive, symptomatic Paget's disease poor renal visualization was noted on bone scanning with 99mTc-diphosphonate. Renal function was normal in all patients. The intensity of the renal image proved to be inversely related to the extent and metabolic activity of the Pagetic process. This finding supports the hypothesis that in Paget's disease the balance between skeletal and renal extraction of circulating tracer amy be displaced in favor of the former.     

Intermittent treatment of Paget's disease of bone with calcitonin: histological study

The authors report the results of a semi-quantitative histological study of bone carried out in 6 patients with Paget's disease treated with salmon calcitonin (about thirty injections of an average of 50 MRC units) over 8 to 14 weeks. The treatment led to a decrease in the resorption surfaces, in the number and the nucleation of the osteoclasts, and in the level of hydroxyprolinuria. Cessation of treatment led to an increase in these parameters, but starting from the fifth month after the cessation renewed improvement was noted, concerning in particular the hydroxyprolinuria and the nucleation of the osteoclasts and this lasted until the tenth month. The possibility of a prolonged action of calcitonin indicates that discontinuous therapy of Paget's disease should be considered (4 months per year, for example).     

Pamidronate infusions as single-agent therapy for bone metastases: a phase II trial in patients with breast cancer

Pamidronate is a potent biphosphonate which modulates tumour-induced osteolysis (TIO) by inhibiting osteoclast-mediated bone resorption. In a phase II trial, 69 breast cancer patients with symptomatic progressive bone metastases were given infusions of pamidronate 60 mg over 1 or 4 h every 2 weeks for a maximum of 13 infusions or until progressive disease (PD) at any site. No other systemic anticancer therapy was allowed. Pain was measured using a visual analogue scale, mobility using a detailed eight-point questionnaire and analgesic intake using a six-point scale. Improvements in pain, mobility and analgesic scores occurred in 61, 50 and 30% of patients, respectively, with 33, 21 and 16% achieving a 40% improvement for > or = 8 weeks. At trial discontinuation, baseline levels of pain and mobility had improved by 27% (P = 0.001) and 20% (P = 0.004), respectively, despite a one category reduction in analgesic intake in 27% of patients. Using this relatively high dose of pamidronate, symptomatic response was independent of the number of bone metastases and also of infusion rate. The infusions were well tolerated with no major toxicities reported. Pamidronate infusions provide useful palliation for breast cancer patients with symptomatic bone metastases.     

Alzheimer''s disease: the advent of effective therapy

PURPOSE: To investigate the astigmatic keratotomy effect of a modified single-hinge cataract incision. SETTING: Department of Ophthalmology, San Juan de Dios Hospital, Tenerife, Spain. METHODS: This prospective study evaluated the astigmatic changes resulting from preincision grooves of less than 40, 45, and 55 degrees in arc length used with a single-hinge, self-sealing cataract incision in 144 eyes that had against-the-rule corneal astigmatism preoperatively. The intended 90% depth preincision was centered on the steep meridian and lengthened according to the amount of preoperative astigmatism. Outcome measurements were obtained by calculating the surgically induced astigmatism vectors and the postoperative keratometry changes 1 day, 1 week, and 1, 3, and 6 months after surgery. RESULTS: Three months postoperatively, astigmatism decreased by 0.03, 0.30, and 0.68 diopter in the less than 40, 45, and 55 degree incision length groups, respectively. The differences between the 45 and 55 degree groups and the less than 40 degree group was statistically significant (P < .05). Similar results were observed 6 months after surgery. CONCLUSION: The astigmatic preincision modification produced statistically significant increasing reductions in preoperative astigmatism according to preincision length.     

Diphosphonate treatment of Paget's disease

Ethane-1-hydroxy-1, 1-diphosphonate (EHDP) was administered in a dose of 20 mg/kg/d to 21 patients with symptomatic Paget's disease. All patients were treated for 6 months and then followed for an additional 6 months. There was a striking decline in serum alkaline phosphatase and urinary hydroxy-proline excretion observed after 3 months of therapy which was not significantly improved in the succeeding 3 months. Concomitantly there was marked improvement in clinical symptoms and bone scans. Following cessation of therapy, continued biochemical and clinical evidence of remission persisted. Several patients on repeat treatment with EHDP appeared to respond promptly. Side effects were minimal except for a possibly related osteomalacia and increased incidence of pathologic fractures.     

Risedronate, a highly effective oral agent in the treatment of patients with severe Paget's disease

Thirteen patients with severe Paget's disease of bone [mean serum alkaline phosphatase (SAP) level 17 times the upper limit of normal] were treated with 30 mg oral risedronate daily for 8 weeks. Patients were followed for 16 weeks without treatment. The change from baseline SAP was the primary end point. Those patients whose SAP levels did not reach the normal range were retreated with 30 mg for another 8 weeks. There was a mean percent decrease in SAP of 77% after the first course of risedronate treatment and 87% after the second course of treatment. All patients who completed the study had a decrease in SAP of at least 77% from the baseline. The urinary hydroxyproline/creatinine level was decreased by 64% and 79%, respectively, during the first and second treatment courses. There were transient asymptomatic decreases in serum calcium and phosphorus levels. The urinary calcium/creatinine ratio also decreased in these patients. Serum intact PTH and 1,25-dihydroxyvitamin D levels increased transiently during risedronate treatment. Oral risedronate was well tolerated by the patients. Only one patient discontinued treatment because of an adverse event (diarrhea) thought to be related to risedronate therapy.     

Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin''s disease and non-Hodgkin''s lymphoma

There is national and international interest in increasing the community-based component of undergraduate medical education, but more research is needed on its potential, practicability and effectiveness. The objective of the study was to examine the feasibility and efficacy of general practitioners teaching basic clinical skills to first year clinical medical students in the community. The structure and methods of evaluation of the programme are described. Evaluation tools included semistructured interviews of general practitioner tutors; student questionnaires; assessment of student performance; and costs of the programme. The great majority of the students found the programme enjoyable (81 out of 81, 100%) and educational (79 out of 81, 97%). Students' performance in the end of rotation Objective Structured Clinical Examination suggested that clinical skills are acquired at least as well in the community as in the hospital. Tutors identified the personal benefits of this teaching as development of their own clinical skills and the stimulation of teaching. The programme has been successfully expanded from 24 students to 230 students annually and has demonstrated that community-based teaching can usefully contribute to undergraduate medical education in the area of clinical skills teaching. Key practical issues for schools contemplating similar initiatives are presented.     

Risedronate in the treatment of Paget's disease of bone: an open label, multicenter study

An open-label, multicenter study was conducted to determine the efficacy and safety of oral risedronate (a pyridinyl bisphosphonate) in 162 patients (102 men, 60 postmenopausal women; mean age, 68 years) with moderate to severe Paget's disease of bone (mean serum alkaline phosphatase [ALP] approximately seven times the upper limit of normal). Patients were treated with oral risedronate, 30 mg/day for 84 days, followed by 112 days without treatment. This 196-day cycle was repeated once if serum ALP did not normalize or increased from the nadir value by > or = 25%. At the end of the first and second cycles, the mean percentage decreases for serum ALP were 65.7% and 69.1%, and for urinary hydroxyproline/creatinine 50.4% and 66.9%, respectively. The decreases from baseline in ALP and urinary hydroxyproline/creatinine were significant (p < 0.001). Normalization of serum ALP was observed in 86 patients (53.8%): 53 during the first treatment cycle and 33 during the second. There was a significant proportion of patients reporting a decrease in the pagetic bone pain at days 84 and 196 (p < 0.001). Overall, risedronate was well tolerated. Five patients withdrew due to adverse events, none of which were considered to be drug related. In conclusion, 30 mg of oral risedronate administered daily for 84 days significantly reduced the biochemical indices of disease activity and was associated with pain reduction in patients with moderate to severe Paget's disease of bone. Normalization of ALP was observed in the majority of patients. Repeated administration of risedronate was shown to be beneficial. In general, risedronate was well tolerated and demonstrated a good safety profile.     

Cyclophosphamide pulse therapy for refractory rheumatic diseases

Meta-analysis was proposed more than 20 years ago as an innovative technique for pooling the results of a series of clinical studies. This technique has a two-fold purpose: i) to retrieve pertinent clinical information without introducing selection biases; ii) to combine these clinical data obtained from different sources into a single synthetic index that summarises all available information. This review highlights the current perspectives in the application of meta-analysis and places particular emphasis on discussing the limitations of this technique that have been identified in recent years. Specific controversies in this area include: i) comparison between meta-analysis of the literature and meta-analysis of individual patient data; ii) heterogeneity of the clinical material introduced in the meta-analytic pooling; and iii) survival meta-analysis as a method for pooling long-term outcome data. After debating these three controversial points, this review examines the newest uses of meta-analysis that have been proposed for the evaluation of cost-effectiveness data and tries to identify the meta-analytic applications that will probably be expanded in the near future as opposed to those that will instead be developed less and less.