Paget's disease of bone: Five regimens of pamidronate treatment

Summary The efficacy of five therapeutic regimens using (3-amino-1-hydro-xypropylidene)-1,1-bisphosphonate (APD or pamidronate) was assessed in patients with Paget's disease of bone. These regimens were as follows: (a) pamidronate 600 mg/day given orally during six months; (b) iv infusion of 20 mg daily for 10 days; (c) iv infusion of 40 mg daily for 5 days; (d) iv infusion of 10 mg daily for 4 days and (e) a single iv infusion of 10 mg. Six months after the initiation of therapy, urinary excretion of hydroxyproline and serum alkaline phosphatase activity (expressed as percent of their initial value) were: Group a: 30±10 (mean±SE) and 30±6, Group b: 55±8 and 46±6, Group c: 54±7 and 57±6, Group d: 53±7 and 69±4, and Group e: 85±10 and 98±4 respectively. Oral route was accompanied by digestive intolerance. On the contrary, except for rare and transient flu-like syndromes, the iv treatment was not associated with any serious secondary effect. Intravenous infusion of pamidronate, 20 mg for 10 days or 40 mg for 5 days, appears as an interesting alternative to the oral route in the treatment of Paget's disease of bone.     

Successful treatment of resistant Paget's disease of bone with pamidronate

Several agents are available for treatment of Paget's disease of bone, but their long-term use may be limited by resistance or adverse effects. I have treated two patients with exceptionally severe polyostotic Paget's disease (serum alkaline phosphatase values 25- to 30-fold above normal), in whom salmon calcitonin, sodium etidronate, and plicamycin each had become ineffective or could not be used. Pamidronate (3-amino-1-hydroxypropylidene-1,1-bisphosphonate) decreased serum alkaline phosphatase to normal or near-normal values and almost completely relieved symptoms, without recognizable adverse effects, except for transient mild hypocalcemia. The symptomatic and biochemical responses were maintained through 2 years of treatment and for more than 6 months after the treatment was discontinued. Thus, pamidronate can be very effective in severe, resistant cases of Paget's disease. Further study of this potent agent is needed to define the optimum regimen for maximum effectiveness and minimal long-term toxicity.     

Paget's disease of bone

Paget's disease is a chronic focal high turnover bone disorder that is primarily present in middle-aged or older adults. It seems to be restricted to humans and has no clear parallels with other diseases. Although much has been learnt about its pathology and epidemiology, and treatment is now highly effective we still lack a complete understanding of its etiology and biology. This review focusses on the natural history of the disorder, in particular its changing epidemiology, recent discoveries about its genetic basis and current approaches to diagnosis and treatment. While there is strong evidence for genetic predisposition to Paget's disease, there is also compelling evidence that it is becoming less prevalent, the age of patients at presentation is increasing and that the extent of skeletal involvement is diminishing, implying that there is an important, but as yet unidentified, environmental factor in its etiology. Contemporary patients are typically elderly and have few bones involved. Treatment with potent intravenous bisphosphonates provides prolonged remission and many will require only once in a lifetime treatment.     

Paget's disease of bone

Paget's disease is a relatively common bone disease. This review aims to present reasonable treatment recommendations with enough background to understand them. To accomplish this end, some aspects of basic bone cell biology, biochemistry, and pathology are presented, as are speculations about possible causes of this disease. Treatment of Paget's disease will be considered in three sections. The first two sections will review treatment with calcitonin and diphosphonates, respectively. These sections briefly will consider the mechanism of action of the drugs, review in detail clinical studies of drug effectiveness, and summarize the advantages and disadvantages of each drug. The third section details specific treatment recommendations for each of the six clinical settings in which treatment of Paget's disease is justified.     

Paget's disease of bone

Paget's disease of bone is defined as a process of increased bone remodeling; the primary event is increased resorption (osteoclastic activity) followed by subsequent reactive bone formation (osteoblastic activity). It is usually asymmetric and may be asymptomatic. The etiology is unknown, but recent evidence appears to support the theory that a virus is an important etiologic factor. It may present with a wide variation in the clinical and radiographic picture. The most frequent sites of involvement include the spine, femora, cranium, pelvis, and sternum. The most common complaints are pain, skeletal deformity, and change in skin temperature. Pathologic fractures may be the presenting manifestations or complications in a patient with known Paget's disease. They occur most frequently in the long weight-bearing bones of the lower extremities such as the femoral neck and subtrochanteric and tibial regions. The two major therapeutic agents available for treatment are calcitonins (porcine, salmon, or human) and diphosphonates. The aim of such therapy is to control the metabolic activity of the disease, to normalize the biochemical parameters, and to improve the symptoms. Fortunately, tumors are rare; early diagnosis may give rise to more effective palliation, if not a significant cure rate.     

Paget's disease of bone

Paget's disease of bone is characterized by an anarchic bone remodelling, associated with morphological and functional abnormalities of osteoclasts. Its prevalence and incidence rates decreased gradually over the past two decades; the reason for this remains unclear. The aetiology of the disease is still obscure, the paramyxoviral theory being very controversial. Recent advances in understanding of the disease come from genetic studies, with the identification of specific mutations in the p62-sequestosome gene, which could be involved in pathogenetic mechanisms leading to increased osteoclast activity. The disease affects one or several bone pieces, leading to bone pain, deformities, characteristic imaging features, and increased markers of bone remodelling. The long-lasting disease activity leads to complications, including arthropathies, neurological compressions, fissures or fractures and, rarely, osteosarcomatous transformation of a pagetic lesion. Potent bisphosphonates have proven their efficacy in reducing symptoms and disease activity. They are currently used as the first-line treatment with the goal of normalizing bone remodelling and, hopefully, preventing late complications.     

Paget's disease of bone

Paget's disease of bone is a focal disorder of bone remodeling accompanied initially by an increase in bone resorption, followed by a disorganized and excessive formation of bone, leading to pain, fractures and deformities. It exhibits a marked geographical variation in its prevalence. In Brazil it predominantly affects persons of European descent. The majority of the reported cases of the disease in Brazil are from Recife, owing to its peculiar mixed European colonization over approximately four centuries. The etiology is complex and involves both genetic and environmental factors. The disease is often asymptomatic and diagnosis is usually based on biochemical markers of bone turnover, radionuclide bone scan and radiological examination. Bisphosphonates, in particular zoledronic acid, are regarded as the treatment of choice for Paget's disease of bone.     

Mechanisms of disease: genetics of Paget's disease of bone and related disorders

Paget's disease of bone (PDB) is a common disorder in which focal abnormalities of increased bone turnover lead to complications such as bone pain, deformity, pathological fractures, and deafness. PDB has a strong genetic component and several susceptibility loci for the disease have been identified by genome-wide scans. Mutations that predispose individuals to PDB and related disorders have been identified in four genes. The rare PDB-like syndromes of familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia are caused by insertion mutations in TNFRSF11A, which encodes receptor activator of nuclear factor (NF)kappaB (RANK)-a critical regulator of osteoclast function. Inactivating mutations in TNFRSF11B, which encodes osteoprotegerin (a decoy receptor for RANK ligand) cause idiopathic hyperphosphatasia, and polymorphisms in this gene seem to increase the risk for classical PDB. Mutations of the sequestosome 1 gene (SQSTM1), which encodes an important scaffold protein in the NFkappaB pathway, are a common cause of classical PDB. The rare syndrome of hereditary inclusion body myopathy, PDB, and fronto-temporal dementia is caused by mutations in the valosin-containing protein (VCP) gene. This gene encodes VCP, which has a role in targeting the inhibitor of NFkappaB for degradation by the proteasome. Several additional genes for PDB remain to be discovered, and it seems likely that they will also involve the RANK-NFkappaB signaling pathway or components of the proteasomal processing of this pathway, underscoring the critical importance of this signaling pathway in bone metabolism and bone disease.     

Sarcomatous degeneration in Paget's bone disease

Summary The authors report 12 cases (8 men and 4 women) of sarcomatous degeneration in Paget's bone disease, with an average age of 72.3 years. Sarcomatous degeneration occurred often in polyostotic Paget's disease, and osteitis deformans was seen in 4 cases. Femur and pelvis were the most affected bones. Pain was a constant feature, whereas tumefaction and fracture were less common. Osteolytic lesions were more frequent than condensed or mixed lesions and radiological signs of malignancy were usually found. Seven cases were histologically clasiified as osteogenic sarcoma and 3 cases as fibrosarcoma. Electron microscopy was performed on 2 osteogenic sarcomas and in 1 case revealed microcylindrical inclusion in Pagetic osteoclasts and in multinucleated giant tumor cells, but none in mononucleated tumor cells. The average survival time for the patients in this study was only 4.5 months.     

Disorder of bone quality in Paget's disease

Paget's disease is a localized and progressive disorder of bone, characterized by increased bone remodeling. The increase of bone turnover changed bone quality in Paget's disease. The assessment of bone quality is consisted on two properties of structure and material. Bone quality is evaluated clinically by the bone turnover. Treatment of bisphosphonate in Paget's disease controlled bone turnover. There's a possibility that treatment of bisphosphonate improve not only the property of structure but also that of material. It's hoped that the newer and stronger bisphosphonates play an increasingly important role in the treatment for bone quality of Paget's disease.     

Bisphosphonate resistance in Paget's disease of bone

OBJECTIVE: To determine whether resistance to one bisphosphonate predicts resistance to another bisphosphonate. METHODS: One hundred patients with Paget's disease were treated with intravenous (IV) pamidronate. The initial dose was 120 mg, followed by further doses of 240 mg, until either biochemical remission was achieved or a total dose of 1 gm was given. Biochemical remission was defined as an alkaline phosphatase level within the reference range. Patients whose disease failed to respond to pamidronate were then treated with alendronate for 6 months. Patients whose disease failed to respond to alendronate were given either tiludronate for 3 months, or clodronate for 6 months. RESULTS: Sixteen of the 100 patients treated with pamidronate failed to achieve a biochemical response despite a cumulative dose of 1 gm. Of the 16 nonresponders, 1 died of an unrelated cause, and the remaining 15 patients were treated with alendronate. In 2 of these patients, the treatment was changed to another bisphosphonate because of gastrointestinal intolerance to alendronate. Of the remaining 13 patients, 9 (69%) achieved full biochemical remission. In 4 other patients, both pamidronate and alendronate therapy were unsuccessful (1 patient responded to tiludronate, tiludronate therapy was unsuccessful in 1, clodronate was unsuccessful in 1, and 1 patient elected to receive no further treatment). Of the 2 patients who could not receive alendronate because of gastrointestinal intolerance, 1 achieved normalization with tiludronate, and a repeat course of pamidronate was unsuccessful in the other. In total, 73% of patients in whom initial treatment with IV pamidronate was unsuccessful responded to a change in bisphosphonate treatment. CONCLUSION: Failure to achieve biochemical normalization is likely to be specific to the individual drug rather than indicative of bisphosphonate class resistance.     

Management of Paget's disease of bone

Paget's disease of bone is a common condition with a strong genetic component, characterized by focal increases in bone turnover, affecting one or more bones throughout the skeleton. Paget's disease can be asymptomatic but is frequently associated with bone pain, bone deformity, pathological fracture, secondary osteoarthritis and deafness. Inhibitors of osteoclastic bone resorption, such as bisphosphonates and calcitonin, suppress bone turnover and improve bone pain in Paget's disease. Many patients also require therapy with analgesics and anti-inflammatory agents, since pain in Paget's disease can arise not only from increased bone turnover but also from complications such as osteoarthritis and nerve compression syndromes, which do not respond well to antiresorptive therapy. Comparative studies have shown that second- and third-generation bisphosphonates, such as tiludronate, alendronate and risedronate, are more effective than etidronate at inhibiting bone turnover in Paget's disease but they have not been found to be significantly more effective in controlling bone pain. Importantly, none of the treatments that are currently available for Paget's disease have been shown to prevent complications such as deafness, fracture or bone deformity, or to alter the natural history of the disease. More research is required to define the long-term effects of antiresorptive treatment on clinical outcomes in Paget's disease, so that clinicians and their patients can make better-informed choices about the risks and benefits of treatment.     

Treatment of Paget's disease of bone

Paget's disease of bone is the paradigm of bone focal distortion with accelerated bone turnover. Over the years, a number of different drugs have been used to control its activity but, since biphosphonates were introduced for the treatment of the disease, they have become the preferred treatment. This review will update the therapeutic indications, available drugs and therapeutic response monitoring.     

Paget's disease of bone in early adult life

OBJECTIVE: To determine the range and activity of the clinical and biological features of patients aged <40 with Paget's disease of bone. METHODS: A retrospective two centre study of 314 patients with Paget's disease of bone from two university hospitals. The disease was diagnosed by radiological, serum alkaline phosphatase (AP) levels, or clinical features, and bone scintigraphy in most patients. Demographic data, reason for diagnosis, bones affected, disease extent using Coutris' index, complications during progression, and disease activity using Renier's index were assessed. Patients over and under 40 were compared. RESULTS: 18/314 (5.7%) patients were diagnosed before the age of 40; median (SD) age was 35.4 (5.5) (range 18-40) and AP 555.6 (566.3) IU/l (range 70-1949). Coutris' extension index was 12.8 (10.5) and Renier's activity index 35.9 (31.9). Younger patients had more affected bones (p<0.05) than those aged >40, higher level of extension (p<0.05), higher AP value (p = 0.05), and greater incidence of thoracolumbar spine disease. Disease activity did not differ significantly between the groups. CONCLUSIONS: Paget's disease diagnosed before the age of 40 is more extensive but not more active, with higher AP values than in those diagnosed after age 40.