CLINICAL THERAPEUTICSNOL. 19, NO.

6, 1997

Paget's Disease of Bone: Indications for Treatment and Goals of Therapy

Robert D. Tiegs, MD
Mayo Medical School, Mayo Clinic Rochester, Rochester, Minnesota

ABSTRACT Paget's disease of bone is a common disorder of unknown etiology characterized by increased bone remodeling and abnormal bone architecture. The pathologic process is initiated by an increase in osteoclast-mediated bone resorption, accompanied by a compensatory increase in bone formation. The increased bone remodeling results in a disorganized mosaic of woven and lamellar bone. This bone is highly vascular and gradually becomes enlarged and structurally weakened. Paget's disease is generally diagnosed in patients older than 40 years of age, usually as an incidental finding. The disease may be monostotic or polyostotic. The pelvis, femur, spine, tibia, skull, and humerus are most commonly involved. Most patients with Paget's disease are asymptomatic. Pain is the most common presenting
0149-2918/97/$3.50

symptom. Complications of the disease include bowing deformity of the long bones, fracture, and a variety of nerve compression syndromes. Malignant degeneration of Paget's disease is a rare complication. As safer, more effective therapies have become available, the indications for treatment and goals of therapy have changed. The difficult issue that clinicians are currently facing is whether to treat patients with asymptomatic disease. The progressive nature of the disease, the severity of its complications, its potential negative impact on quality of life, and the availability of therapy capable of controlling its activity have led many experts in the field to recommend treatment of asymptomatic patients who have active disease at sites where complications are likely to develop. There are, however, no data to prove that complications can be prevented by decreasing the
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rate of bone remodeling in Paget's disease, nor any data to define who is at risk for complications. Until more information is available, the management of patients with Paget's disease will continue to be based on clinical observation and theoretical considerations. This review examines the present understanding of Paget's disease, the rationale for the proposed indications for treatment, and the goals of therapy. Key words: Paget's disease of bone, osteoclasts, alkaline phosphatase, calcitonin, bisphosphonates. INTRODUCTION Paget's disease is a focal disorder of the skeleton characterized by abnormal bone remodeling. Its etiology is unknown. The pathologic process is initiated by an increase in osteoclast-mediated bone resorption. Because of the coupling of bone resorption and formation, the increased resorption results in a compensatory increase in formation and accelerated bone remodeling. Under normal physiologic conditions, the skeleton is remodeled to maintain its structural integrity. When the process of bone turnover is increased, as in Paget's disease, the new bone is formed haphazardly and appears on histologic examination as a disorganized mosaic of woven and lamellar bone. This pathologic process produces bone that is enlarged, mechanically weakened, and highly vascular. These changes may cause pain, bone deformity, or fracture. The clinical signs and symptoms of Paget's disease vary depending on the location, extent, and activity of the disease. Although Paget's disease may affect any bone, it most frequently affects the pelvis, femur, spine, tibia, skull, and humerus. 1-3 Most patients with Paget's disease are asymptomatic.4 The disease may 1310

be monostotic or polyostotic, may be familial or sporadic, and is typically asymmetric in its skeletal distribution. Sir James Paget provided the first detailed description of this disorder in 1877.5 Subsequent investigations have attempted to define the etiology of the disease, determine whom it affects, and identify its complications. The current understanding of Paget's disease is based largely on observational studies conducted in referral populations, surveys, and short-term treatment trials. Any study or discussion of the management of Paget's disease is limited by gaps in our understanding of its etiology, clinical spectrum, and natural history; the frequency and nature of its complications; its economic costs; how it affects quality of life; and its effect on long-term survival. A better understanding of the disease and the factors that predict an adverse outcome are needed to develop evidence-based management guidelines. This review provides a broad overview of the disease and suggests a rational approach to the evaluation and management of patients with Paget's disease based on current data. EPIDEMIOLOGY Currently available epidemiologic data do not allow a specific etiologic hypothesis. 6 Studies 7-11 have demonstrated marked variation in the geographic distribution of the disease, suggesting a dominant influence of environmental and ethnic factors. Paget's disease is most common in westem Europe (excluding Scandinavia), Australia, New Zealand, and North America. In contrast, it is rare in Asia and most of Africa. In the United States, Paget's disease is believed to affect 2% to 3% of the population older than 50 years of age. 12

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A number of investigators 13-15 have identified a familial aggregation of patients with Paget's disease, but little is known about the true proportion of familial and nonfamilial cases or the possible differences in clinical spectrum or prognosis in these two groups. From the available data, it appears that familial cases are diagnosed at an earlier age, have more extensive involvement, and possibly have more aggressive disease. 14,15 Paget's disease appears to be transmitted by both the paternal and maternal sides, and pedigree analysis suggests an autosomal dominant pattern of inheritance.15 A first-degree relative of a pagetic patient is seven times more likely to develop Paget's disease than an individual who does not have an affected relative, according to familial aggregation studies conducted in the United States. 14 Although familial clustering is compatible with either a genetic or environmental etiology, this observation supports the role of inherited factors in Paget's disease. Familial expansile osteolysis is a rare hereditary bone dysplasia characterized by progressive osteoclast-mediated resorption that results in osteolysis, medullary and cortical expansion, and an abnormal trabecular pattern. 16,17 Involved bone has accelerated bone remodeling with histologic features that are similar to Paget's disease, including the presence of woven bone, large osteoclasts, and virallike inclusions in osteoclast nuclei. 18 The pathologic process results in severe and disabling deformity and fracture. Despite these similarities, there are a number of clinical features that establish familial expansile osteolysis as a clinical entity distinct from Paget's disease: onset at an earlier age, strong predilection for the long bones in the appendicular skeleton, early-

onset middle-ear deafness, premature loss of dentition, and lack of clinical response to bisphosphonates. 19 After studies in patients with familial expansile osteolysis showed linkage to chromosome 18q,2 similar findings were reported in a family with Paget's disease. Additional genetic studies of this condition may help to identify a gene locus for Paget's disease. A viral etiology for Paget's disease was first suggested by the presence of nuclear and cytoplasmic inclusions in pagetic osteoclasts. 21,22 These inclusions resemble the paramyxovirus family of viruses 23 and have been shown to contain measles and respiratory syncytial virus antigens. 24 Immunohistochemical studies have also demonstrated antigens to paramyxoviruses, including measles virus, 25,26 respiratory syncytial virus, 27,2s and parainfluenza virus type 3, 28 in pagetic osteoclasts. A variety of molecular techniques have been used to explore the possible role of viruses in the pathogenesis of Paget's disease and have produced conflicting results. In situ hybridization using a cDNA probe to measles virus 29 showed a positive result, which could not be confirmed using a ribonucleic acid probe. 23 Studies using reverse transcriptase polymerase chain reaction testing 3,31 and in situ polymerase chain reaction testing 32 also failed to detect paramyxovirus sequences. Other investigators have, however, demonstrated measles virus transcripts in osteoclast precursors using reverse transcriptase polymerase chain reaction testing but were not able to demonstrate transcripts in bone tissue. 33,34 Factors that suggest a viral etiology for Paget's disease include involvement of a single organ, prolonged latency period, absence of an acute inflammatory process, 1311

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and presence of giant cells and intranuclear inclusions. Studies showing virallike inclusions in other skeletal disorders, including giant cell tumor, as osteopetrosis, 36 pyknodysostosis,a7 familial expansile osteolysis, 18 and primary oxalosis, as suggest that the inclusions may be a secondary phenomenon related to abnormal cell function rather than a causative agent. The fact that there are marked differences in the geographic distribution and prevalence of Paget's disease despite the ubiquitous nature of paramyxoviruses suggests that additional factors are operative. The current epidemiologic data support the concept that Paget's disease may arise from an interaction between environmental factors, exposure to paramyxovirus, and generic susceptibility.
PATHOPHYSIOLOGY

Paget's disease progresses through three phases of remodeling: (1) an early osteolytic phase, (2) an intermediate or mixed phase during which increased resorption is coupled with increased new bone formarion, and (3) a late or sclerotic phase. Although Paget's disease may be monostotic, it is frequently polyostotic and asynchronous. In the earliest phase of the disease, the pathologic process is predominantly resorptive and is characterized radiographically by an advancing osteolytic wedge in long bones or osteoporosis circumscripta in the skull. In long bones, the lyric process progresses along the bone from one periarticular surface and may eventually involve the entire bone if not inhibited. Most commonly, patients present at an intermediate or mixed stage of remodeling during which increased resorption is coupled with increased new bone forma1312

tion. The bone is expanded by periosteal new bone formation that causes a thickening of the cortex. The abnormal remodeling process causes widening of the marrow cavity, expansion of the bone, and mechanical weakening. Ultimately, the involved bone becomes dense and sclerotic. The osteoclast that initiates the disease process is abnormal in morphology and function. In Paget's disease, osteoclasts are extremely large, containing up to 100 nuclei (a normal osteoclast contains 5 to 10), and have increased bone-resorbing activity,a9 As resorption advances, a phase of increased bone formation is initiated that is characterized by an increase in the number of osteoblasts and an increase in osteoid volume. Because of the dramatic increase in bone turnover, collagen fibers are deposited haphazardly during the process of bone formation, producing woven bone rather than normal lamellar bone, in which collagen fibers are laid down in well-organized parallel bands. In addition to the marked increases in osteoclasts, osteoblasts, and osteoid volume, the pathologic process is characterized by peritrabecular fibrosis that may progress to involve the entire marrow cavity. The ultimate outcome of the pathologic process is a disorganized, structurally weakened mosaic of woven and lamellar bone. Although the architecture is disrupted and the osteoid thickness and volume are increased, mineralization of the bone matrix is unimpaired. In the later phases of the disease process, there is a marked reduction in the cellularity of the bone and in bone turnover, producing a sclerotic, inactive-appearing bone. The basis for the pathologic changes in the osteoclast are unclear. Paramyxoviruses, which are capable of infecting bone, may induce osteoclasts and/or os-

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teoblasts to secrete cytokines and growth factors such as interleukin-6, which then act locally to stimulate osteoclast differentiation and activit3r4 and the formation of giant pagetic osteoclasts.41 CLINICAL FEATURES Investigators have suggested that up to 3% of individuals in the United States older than 55 years of age have Paget's disease of bone. 42 Most of these patients are white. The disease affects both men and women, possibly with a slight male predominance. It usually develops after age 40 and is rarely diagnosed in individuals younger than 25 years of age. The disease may be monostotic or polyostotic with asymmetric involvement. Although new sites rarely become involved after the initial diagnosis, the disease may progress at a given location. The pelvis, femur, spine, tibia, skull, humerus, and forearm are most frequently involved. Other commonly involved sites are the clavicles, scapula, ribs, and facial bones. The hands and feet are rarely affected.1-3

Symptoms and Signs

Approximately 90% of patients with Paget's disease are asymptomatic. 4 In symptomatic patients, bone pain is the most common symptom.1 This is typically not severe, is present at rest, may be described as a dull ache, and, if present in the spine, pelvis, or lower extremities, may be exacerbated by weight bearing. Patients with skull involvement frequently complain of headache or a bandlike tightness or discomfort. Bone pain associated with Paget's disease is believed to be caused by mechanical factors and possibly by the chemical stimulation of sen-

sory receptors (nociceptors) by interleukin-64 or other mediators. Mechanical factors possibly contributing to the pain include periosteal elevation and increased intraosseous pressure. Other potential causes of pain in Paget's disease include arthritis and neural compression. Discomfort due to secondary arthritis is usually more severe than bone pain and commonly involves the hips, knees, and ankles. Arthritic pain and pagetic bone pain can be difficult to distinguish, especially in the hips, pelvic region, and spine. An intra-articular injection in the hip may be a useful diagnostic procedure in this setting. Pain resulting from neural impingement is severe and is accompanied by a variety of neurologic deficits.43,~ Deformity in patients with long-standing Paget's disease typically involves the long bones and skull. The spectrum of skeletal deformities includes bowing deformities of the long bones, acetabular protrusion of the hips, frontal bossing, skull enlargement, kyphosis, and scoliosis.45 Involvement of the facial bones may result in dental, visual, and olfactory complications.46 Bowing deformity of the femur or tibia produces limb shortening, gait disturbance, and abnormal distribution of mechanical forces in the lower extremity. These abnormalities create a predisposition to secondary arthritis in the hips, knees, and ankles. Fissure or stress fractures occur along the convex surface of bowed long bones and are often asymptomatic. These fractures may be associated with focal discomfort that can last for days to weeks. The onset of sharp focal pain may signal an impending complete fracture at the site of a fissure fracture. Pathologic fracture is a common complication of Paget's disease. 47-49 All increase 1313

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in pain suggests a pathologic fracture and should be evaluated radiographically. The most common sites for pathologic fractures are the femur and tibia. The spine and humerus are less frequently involved. Fractures involving the femur frequently occur during the osteolytic phase, but pathologic fractures can occur at any stage of the disease process. Although the rate of healing is usually normal in fractures involving pagetic bone, healing may be complicated by delayed union. The increased vascularity associated with high bone turnover in patients with active disease may be associated with increased blood flow to adjacent soft tissue and increased skin temperature. These changes are most commonly noted over the tibia and skull and may cause the patient discomfort. The increased vascularity of pagetic bone may also result in excessive blood loss during orthopedic surgery and may produce neurologic syndromes resembling myelopathy or radiculopathy on the basis of a vascular steal phenomenon as a result of pagetic involvement in or near the spine. 44 Involvement of the skull is associated with a mixed sensory and conductive hearing loss and, less commonly, with cranial nerve palsies. The mechanism of hearing loss in Paget's disease may be related to alteration of capsular bone density. 5 With severe, long-standing skull involvement, patients may develop platybasia with basilar invagination. This deformity may be complicated by obstructive hydrocephalus, brain stem compression, or both. Patients with these complications may present with ataxia, dementia, and cranial nerve abnormalities. Other neurologic complications include radiculopathy, especially with lumbar spine involvement, and spinal stenosis. 1314

High-output cardiac failure can occur in patients with extensive skeletal involvement and increased cardiac output, but this probably develops only in patients with underlying cardiac disease. M6nckeberg-type vascular calcification51 and cardiac conduction defects have also been associated with Paget's disease. Malignant degeneration in Paget's disease, which was described by Sir James Paget in 1877, 5 can occur in patients with either monostotic or polyostotic disease. 52-54 Based on the experience of referral centers, the frequency of this complication is probably less than 1%. Most of these tumors are osteogenic sarcomas. Fibrosarcomas, chondrosarcomas, and malignant fibrous histiocytomas have also been reported. Diagnosis of these tumors is frequently delayed, and the clinical course is usually rapid and fatal. Malignant degeneration typically presents as a change in the patient's symptoms (eg, new pain, intensified pain, or pain that has changed in character) or as a pathologic fracture. These neoplasms may be associated with a further increase in the serum alkaline phosphatase level but can occur in patients with normal or only mildly elevated values as well. The most common sites of malignant degeneration are the pelvis, humerus, femur, and craniofacial bones. On radiography, this typically appears as cortical destruction with an associated soft tissue mass. The cortical destruction may be difficult to identify on plain bone radiographs. Magnetic resonance imaging (MRI) or computed tomography (CT) should be considered if malignant degeneration is suspected clinically and plain bone radiographs are negative. Giant cell tumors are benign neoplasms that usually occur in the skull or facial

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bones and occasionally occur in long bones. 55-57 Biopsy reveals clusters of osteoclasts that have been described as giant cell reparative granulomas. These lesions have been shown to respond to corticosteroids. 57 Paget's disease has been associated with a number of other conditions, including primary hyperparathyroidism, renal lithiasis, gout, pseudogout, ankylosing spondylitis, rheumatoid arthritis, diabetes, and Peyronie's disease. 45,58--6Additional study is needed to define the significance of these associations.

Biochemistry
Biochemical markers of skeletal turnover are useful in making the diagnosis of Paget's disease, determining prognosis (since patients with marked elevations in these markers have more symptoms and complications of the disease), monitoring the natural history of the disease, assessing the response to therapy, and monitoring treatment. 61-63 Although there is no ideal marker of bone turnover, there are disease-specific differences in the utility of these markers. Serum alkaline phosphatase is a marker of bone formation and in Paget's disease is an accurate indicator of bone turnover and disease activity. Because the serum alkaline phosphatase level may be affected by extraskeletal sources of the enzyme, bone-specific alkaline phosphatase has a slightly better diagnostic accuracy. Bonespecific alkaline phosphatase is useful for evaluating and monitoring patients with limited areas of involvement or monostotic disease, since the total serum alkaline phosphatase level may be normal or only mildly elevated in these individuals. Bone-specific alkaline phosphatase is also

useful in patients with abnormal liver function test results in whom there is a question about the hepatic contribution to the total serum alkaline phosphatase level. Osteocalcin is a noncollagenous, vitamin D--dependent protein of bone that is predominantly a marker of bone formation but, for reasons that remain unclear, is not a reliable indicator of pagetic activity.64 Urinary markers of bone resorption such as hydroxyproline, pyridinium cross-links, 65 and the N-telopeptide of type I collagen, which constitutes 90% of the organic matrix of bone, are rapid and sensitive indicators of therapeutic response and can be used to monitor disease activity in patients with a predominantly lytic process and normal serum alkaline phosphatase levels. 66 With the use of the newer, more potent antipagetic agents, changes in markers of bone resorption can be detected in days, whereas the alkaline phosphatase nadir may lag for 3 months. Most patients can be followed by monitoring a single variable of bone remodeling. The bone-specific alkaline phosphatase level is a sensitive, specific, and convenient marker for following patients with Paget's disease. Measurement of total serum alkaline phosphatase activity is a reasonable alternative in patients who do not have liver disease. Quantitative imaging studies have been proposed for monitoring pharmacologic treatment, but they are not recommended because of cost, radiation exposure, and the fact that clinical remission cannot be assessed with this method. Radio/ogy The appearance of Paget's disease on routine bone radiographs is sufficient to 1315

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establish the diagnosis in most cases. On x-ray examination, pagetic bone typically has a thick, coarse trabecular pattern with mixed lyric and sclerotic areas. In addition, the bone is expanded, with widening of the marrow cavity and thickening of the cortex. Early in the disease, patients may present with lytic disease characterized by an osteolytic wedge-shaped lesion advancing along a long bone (blade of grass sign) or osteoporosis circumscripta involving the skull. The osteolytic phase of the disease can occasionally cause diagnostic difficulties. Although bone biopsy can clarify the diagnosis, this procedure should be avoided in long bones, if possible, because of the risk of fracture. Sclerotic lesions may suggest the presence of an osteoblastic metastasis from prostate cancer, breast cancer, Hodgkin's disease, or lymphoma. 67,68 In male patients with sclerotic involvement of the pelvis, the possibility of metastatic prostatic carcinoma must be considered. Thickening of the iliopectineal lines and coarsening of the sacroiliac joint are useful diagnostic criteria in this setting and suggest the diagnosis of Paget's disease. Measurement of prostate-specific antigen levels is useful in excluding the possibility of coexisting metastatic prostatic carcinoma, since metastatic disease can be present in pagetic bone. Plain bone radiographs have a number of uses in Paget's disease. They help establish the diagnosis, evaluate symptomatic areas, assess fracture risk, confirm areas of suspected pagetic involvement on bone scan, provide data on the status of joints adjacent to involved sites, evaluate lytic lesions in weight-bearing bones and their response to treatment, demonstrate the presence of fracture, and identify areas of malignant degeneration when there has been a change in symptoms. 1316

Radioisotope bone scanning is the most sensitive means of identifying sites of pagetic involvement. Clinicians should consider obtaining a bone scan at the rime of presentation to define the extent of involvement and facilitate subsequent management. Because the findings on bone scan are nonspecific, plain bone radiographs are needed to confirm pagetic involvement in areas with increased isotope uptake. Bone surveys using plain bone radiographs are not recommended for determining the extent of involvement, because they are less sensitive than bone scans. Repeat bone scans and radiographs are usually unnecessary during follow-up but should be considered in certain cases: (1) when new symptoms develop; (2) when current symptoms become significantly worse, suggesting the possibility of an impending fracture or, rarely, of malignant degeneration; (3) when patients have lyric areas in weight-bearing bones; and (4) when a fracture is suspected. Fissure fractures typically do not change with treatment and probably do not require routine radiographic monitoring, provided they remain asymptomatic. MRI, CT, or both are useful to evaluate patients with suspected malignant degeneration in whom plain radiographs are negative. A bone scan may fail to identify malignant degeneration.
TREATMENT

The treatment of Paget's disease has undergone considerable change over the past three decades with the development of progressively more potent inhibitors of osteoclast-mediated bone resorption.42 Inhibitors of bone resorption that are used in the management of Paget's disease in-

R.D. TIEGS patients with predominantly lytic disease or in those with limited skeletal involvement (monostotic disease), because these individuals can have active disease despite having a normal or only mildly elevated serum alkaline phosphatase level. Because the risk of complications is related to life expectancy as well as to the location and severity of disease, the patient's age and medical status may be considered when deciding whether treatment is warranted. The use of antipagetic therapy has been suggested before elective orthopedic surgery involving pagetic bone, even though efficacy has not been established. The rationale is that antipagetic therapy reduces the vascularity of involved bone, thus reducing intraoperative blood loss. In summary, the following indications have been proposed 71,72 for the treatment of patients with Paget's disease based on sound theoretical considerations and years of clinical experience: (1) the presence of symptoms likely to respond to antipagetic therapy (ie, in patients with bone pain, increased warmth, or head pain due to skull involvement and in selected patients with syndromes caused by neural compression), (2) the prevention of local progression and future complications, and (3) the preoperative treatment of patients scheduled for elective orthopedic surgery involving pagetic bone. With the availability of potent and safe antipagetic drugs, experts have suggested that the only reason for not treating patients with Paget's disease is an absence of symptoms in those who are unlikely to develop complications. The iliac crest, sacrum, scapula, and ribs are sites of involvement associated with a low risk for complications. If the goal of treatment is to control disease activity in an attempt to prevent 1317

clude the calcitonins, the bisphosphonates, plicamycin, and gallium nitrate. When treating symptomatic patients, the challenge for the clinician is to identify which of these patients is likely to benefit from antipagetic therapy. Patients with bone pain and with increased warmth associated with hypervascularity respond well to antiresorptive agents. With the development of more potent antipagetic agents, clinicians ca~anot only control pagetic symptoms but can achieve clinical remission, defined as the normalization of biochemical markers of bone remodeling, in a large percentage of patients. Investigators have shown that reducing bone turnover restores a more normal lamellar pattern to the bone 69 and is associated with clinical, biochemical, and radiographic improvement. These observations support the concept that controlling the activity of Paget's disease may alter its natural history and decrease the risk of complications. The progressive nature of the disease, the severity of its complications, and its potential negative impact on quality of life lend credence to the view that asymptomatic individuals who are likely to have an adverse outcome should be treated. Data showing that treatment is most effective in mild disease also support instituting therapy early in the course of the disease. 7 Based on these considerations, investigators 71,72have recommended treating patients with asymptomatic Paget's disease who have evidence of active disease (eg, a serum alkaline phosphatase level two to three times the upper limit of normal) and involvement at sites where complications are likely to develop (ie, skull, spine, long bones, areas near major joints). The serum alkaline phosphatase level should not be used as an indicator of disease activity in

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complications, the biochemical indices of bone remodeling should be maintained within the normal range whenever possible. Relapse can be arbitrarily defined as a 25% increase in the serum alkaline phosphatase level (or other marker of bone turnover) above the prior nadir or above the upper limit of the normal range. If patients show evidence of recurrent disease activity, they can generally be retreated with the same drug regimen that induced the initial remission. 71 Because there may be some loss of responsiveness with each successive cycle of therapy, clinicians should consider using a higher dose of the same drug or a different medication if the patient has a suboptimal response or does not respond to treatment. In addition to periodic clinical assessment, biochemical indices of bone remodeling should be measured to determine the response to treatment or the need for retreatment. The frequency of follow-up depends on the severity of disease and the presence of complications. When following patients with active disease, clinicians should assess biochemical markers of bone remodeling at 3- to 6-month intervals.

Calcitonin
Calcitonin is a 32-amino-acid polypeptide hormone secreted by C cells of the thyroid that in pharmacologic doses inhibits osteoclast-mediated bone resorption. Since its introduction in the early 1970s, calcitonin has been used extensively to treat Paget's disease. At present, the only form of calcitonin available in the United States is synthetic salmon calcitonin that has been formulated for parenteral or intranasal use. Human calcitonin was withdrawn from the market due 1318

to production problems. At this time, there are no plans to market this product. The usual starting dose of salmon calcitonin is 100 U per day injected subcutaneously. After a response has been achieved, the dosage can be reduced to 50 to 100 U every other day or three times weekly with maintenance of the response. The duration of therapy depends on clinical response and disease activity. Patients with moderate or severe disease may require continuous treatment. A disadvantage of calcitonin is the relatively rapid loss of therapeutic effect after stopping treatment; this is in contrast to the bisphosphonates, which have the potential to induce a prolonged remission. Calcitonin and etidronate have similar response rates; a 50% lowering in the biochemical markers of bone turnover can be achieved in approximately two thirds of patients. 73 Patients with severe disease are less likely to respond to calcitonin initially. Secondary failures of treatment are relatively common and occur after a variable period of time. 74-76 In some patients, loss of clinical response is due to the development of neutralizing antibodies. These patients are responsive to human calcitonin, which is not available at this time. When using nasal calcitonin, 200 to 400 U daily are required to decrease bone turnover in Paget's disease, because of the reduced bioavailability with this method of delivery. 77 At the present time, treatment of Paget's disease is not an approved indication for nasal calcitonin. A significant number of patients treated with calcitonin experience problems with flushing, especially of the face and upper body, and nausea. These adverse reactions occur less frequently with the nasal spray than with injectable calcitonin and can be minimized or avoided by starting with a

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low dose and gradually titrating the dosage upward or by administering calcitonin at mealtime or bedtime. The nasal spray may cause rWmifis, epistaxis, or sinusitis. There are no data to indicate that calcitonin is superior to the newer bisphosphonates for the treatment of acute neurologic complications, pain, fissure fractures, or osteolytic lesions in Paget's disease.

Bisphosphonates
Bisphosphonates are analogues of pyrophosphate (P-O-P) in which oxygen has been replaced by a carbon atom (P-C-P) that has two side-chains. Modification of the side-chains alters the potencies of the various bisphosphonates. The phosphate groups are responsible for adsorption to bone, poor gastrointestinal absorption, and rapid urinary excretion. Inhibition of osteoclast-mediated bone resorption by bisphosphonates occurs through a variety of mechanisms that include a direct effect on osteoclasts, effects on molecular mechanisms and the cellular metabolism of osteoclasts, inhibition of osteoclast differentiation and recruitment, and induction of apoptosis. The mechanisms of action of the different bisphosphonates probably vary with the compound. 7s,79 Bisphosphonates have a high affinity for calcium phosphate crystals (hydroxyapatite) and localize to resorbing surfaces. As a consequence of the distribution of bisphosphonates in the skeleton, osteoclasts are exposed to a high concentration of the drug. The intestinal absorption of bisphosphonates is poor (approximately 1%). s After absorption, these drugs go primarily to bone. The residual drug is rapidly excreted in the urine. Because the half-life

in the circulation is short (minutes) and the half-life in bone is very long 0nonths to years), the effects of bisphosphonates are predominantly restricted to the skeleton, with few systemic side effects. When prescribing bisphosphonates, clinicians should be aware that patients with more severe disease, defined by the number of sites affected and the level of serum alkaline phosphatase, will be more refractory to treatment and will require higher doses. The duration of the therapeutic response depends on the degree of suppression of the serum alkaline phosphatase level or of other markers of bone turnover, sl-84 Prolonged remissions have resulted from suppressing this level to the lower portion of the normal range. When using bisphosphonates, patients should have an adequate calcium intake to limit the increase in parathyroid hormone, since secondary hyperparathyroidism induced by bisphosphonates may reduce their effectiveness.

Etidronate
The usual dose of etidronate (ethane-1hydroxy-l,l-bisphosphonate) for the treatment of Paget's disease is 5 mg/kg of body weight per day for 6 months, a5-87 Etidronate should be taken as a single dose with water in the middle of a 4-hour fast. This regimen typically lowers the biochemical indices of bone turnover by 50% and improves symptoms in approximately two thirds of patients. Current recommendations are to treat for 6 months and then withhold etidronate for 6 months to avoid problems with impaired mineralization. An increased incidence of fractures has been reported in patients with Paget's disease who received high doses of etidronate (10 to 20 mg/kg/d).8s-9 His1319

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tologic evidence of osteomalacia has been demonstrated in pagetic and nonpagetic bone after treatment with etidronate 10 to 20 mg/kg per day for 3 to 6 months and occasionally at lower doses. In view of the potential to impair mineralization, etidronate should be avoided in patients who are planning to undergo orthopedic surgery, who have healing fractures, or who have osteolytic lesions in weightbearing bones. Etidronate should also be avoided in patients with renal failure. Other side effects include abdominal discomfort and diarrhea. With the availability of more potent bisphosphonates that do not impair mineralization at clinically effective doses, etidronate will probably have more limited use in the treatment of patients with Paget's disease. Pamidronate Pamidronate (3-amino- 1,hydroxypropylidene- 1,1-bisphosphonate) is an aminobisphosphonate that is available in the United States only as an intravenous preparation. The oral formulation was withdrawn from the US market because it caused esophageal and gastric erosions. 91 Intravenous pamidronate has been reported to be effective for the treatment of Paget's disease in a variety of therapeutic regimens. 92-95 Response seems to correlate with total dose rather than with duration of infusion or interval between infusions. In general, patients with more severe disease require a higher total dose and frequently require multiple infusions to achieve maximal suppression of bone turnover. In patients with mild disease, a single 60-mg infusion may completely suppress disease activity, whereas patients with severe polyostotic involvement may require doses of 180 to 480 mg adminis1320

tered over several weeks or months. The dose must be individualized according to clinical and biochemical response and the goals of therapy. Sixty to 90 mg of pamidronate can be administered over 4 hours. Mineralization defects have been associated with cumulative doses of 180 to 360 mg delivered over 6 to 9 weeks96; the significance of this finding is uncertain. Patients with resistant symptomatic disease have been treated with doses of up to 2.52 g administered over 12 to 42 w e e k s . 97 Biopsies on two of these patients demonstrated no evidence of impaired mineralization or osteomalacia. Of interest is the fact that successive 120-mg doses of pamidronate produced progressively smaller decrements in the serum alkaline phosphatase level. Pamidronate has been used safely before orthopedic surgery in patients with Paget's disease and does not appear to impair healing of bone, but this has not been formally studied in humans. The potency of pamidronate 97'98 and its rapid onset of action with intravenous administration make it an attractive agent for treating patients with neural compression syndromes. Adverse reactions associated with intravenous pamidronate infusion are usually mild and include febrile reactions associated with influenzalike symptoms (eg, malaise, myalgia, nausea, headache); transient hypocalcemia, hypophosphatemia, hypomagnesemia, and lymphopenia; exacerbation of bone pain; venous irritation, especially with small infusion volumes; uveitis and scleritis99'100; and ototoxicity. 11 Febrile reactions probably occur in 10% to 20% of patients, although considerably higher estimates have been reported. Symptoms begin 1 to 48 hours after the infusion. This reaction typically occurs with the

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initial infusion, is less severe or absent with subsequent infusions, appears to be dose related, may be specific for aminobisphosphonates, and is probably related to cytokine release. 12

Tiludronate
Tiludronate (4-chlorophenylthiomethylene bisphosphonate) is an orally administered bisphosphonate recently approved for use in the United States and several European countries. It has been shown to be effective for treating patients with Paget's disease when given at a dosage of 400 mg per day for 12 weeks. 15,16Tiludronate is to be taken as a single dose with 6 to 8 ounces of water and should not be taken within 2 hours of ingesting food, calcium, aspirin, indomethacin, or antacids. The drug has been shown to be more effective than etidronate, and the therapeutic response was not compromised by the prior administration of bisphosphonates. Bone biopsy data showed no evidence of impaired mineralization. The most common adverse events were gastrointestinal disturbances, including diarrhea, abdominal pain, nausea, and vomiting. The serious gastrointestinal complications that have been associated with the use of oral aminobisphosphonates (ie, pamidronate and alendronate) have not been reported with tiludronate, but at this point clinical use of tiludronate has been limited.

Alendronate
Alendronate (4-amino- 1-hydroxybutylidene bisphosphonate) is an orally administered aminobisphosphonate approved for treatment of Paget's disease in the United States and Europe. Comparative trials in patients with Paget's disease have established that alendronate is considerably more potent than etidronate. 13 Unlike etidronate, therapeutic doses of alendronate are not associated with abnormal mineralization. For the treatment of patients with Paget's disease, alendronate is given at 40 mg per day for 6 months. The drug should be taken 30 to 60 minutes before the first food, beverage, or medication of the day. Taking it with anything other than water will impair its absorption. To reduce the potential for esophagitis and esophageal ulceration, alendronate should be taken with 6 to 8 ounces of water, the patient should remain upright until the food has been ingested, and the drug should be discontinued immediately if esophageal symptoms develop. In addition, alendronate should be avoided in patients with impaired swallowing or abnormal esophageal motility. Following the widespread use of alendronate for osteoporosis, a number of cases of severe esophagitis have been reported. 14 In these instances, esophagitis developed in patients who swallowed alendronate with little or no water, lay down after ingesting the drug, continued to take alendronate after the onset of symptoms, and had preexisting esophageal disorders.

Other Bisphosphonates Under

Development
Residronate 17 is a potent bisphosphonate that has been shown to be effective when administered orally to patients with Paget's disease, including patients refractory to other therapies. Zolendronate I8 and ibandronate 19 are new bisphosphonates that are effective at microgram doses. Clinical investigations of these drugs as an intravenous injection and in a transdermal drug-delivery system are under way. 1321

CLINICAL THERAPEUTICS*

Plicamycin
Plicamycin (previously mithramycin) is an antibiotic that has been shown to be effective in treating patients with Paget's disease when administered as a 4- to 8hour infusion at doses of 15 to 25 v~g/kg of body weight per day. llAll Doses are repeated every 2 or 3 days, as required. Because plicamycin may cause hepatic, renal, and bone marrow toxicity, its use is limited to patients with severe, refractory disease. Adverse reactions also include nausea and vomiting. The availability of potent new bisphosphonates should eliminate the need for plicamycin in the management of patients with Paget's disease.

Gallium Nitrate
Gallium, a group IIIa metal compound, is an inhibitor of bone resorption. It absorbs to hydroxyapatite, localizes to sites of bone remodeling, and reversibly inhibits the adenosine triphosphate-dependent proton pump of osteoclasts. In a recent study, 112 cyclic, low-dose, subcutaneously administered gallium nitrate was shown to be effective in reducing bone turnover in patients with Paget's disease. Although patients frequently experienced minor discomfort at the injection site, no serious adverse reactions were observed. The role of gallium nitrate in the treatment of patients with Paget's disease is yet to be determined. DISCUSSION AND CONCLUSIONS With the availability of potent antipagetic agents capable of achieving and maintaining prolonged remissions, clinicians must determine whom to treat. Considering the large number of patients with Paget's disease who may be at risk for complications, 1322

the fact that multiple courses of treatment will probably be required to control disease activity, and the fact that patients must be monitored for years for evidence of disease recurrence, the cost of treating asymptomatic patients to prevent complications will have a major impact on medical expenditures in countries with a high prevalence of the disease. Current indications for treatment are empiric and based on theoretical considerations. The broad clinical spectrum, long natural history of the disease, and heterogeneity of the patient population have limited our ability to study Paget's disease. These factors, along with the rapidly evolving drug armamentarium, make it difficult to suggest an optimal drug, dose, schedule, or duration of therapy or to determine the optimal method of monitoring therapy and preventing complications. To answer the question of who should be treated and to develop evidence-based management guidelines, we must be better able to determine the incidence of the disease, its clinical spectrum and natural history, the risk factors for complications and adverse outcomes, the economic cost of the disease and its treatment, and the impact of the disorder on quality of life and long-term survival. Until these data are available, the strategy of early treatment for symptomatic patients and asymptomatic patients who are at risk for complications is justified. In these patients, the aim of treatment should probably be maximal suppression of disease activity. ACKNOWLEDGMENTS Support for this study was provided by Sanofi Pharmaceuticals, Inc. The author is grateful to Mrs. Denise Bargsten for

R.D. TIEGS

her invaluable secretarial assistance in preparing this manuscript.

9. Barker DJP. The epidemiology of Paget's disease of bone. Br Med Bull. 1984;40: 396-400. 10. Dolev E, Samuel R, Foldes J, et al. Some epidemiological aspects of Paget's disease in Israel. Semin Arthritis Rheum. 1994; 23:228. Abstract. 11. Mautalen C, Pumaftno H, Blanco MC, et al. Paget's disease: The South American experience. Semin Arthritis Rheum. 1994; 23:226-227. 12. Sifts ES, Canfield RE. Paget's disease of bone. In: Becker KL, ed. Principles and Practice of Endocrinology and Metabolism. Philadelphia: JB Lippincott; 1990: 504-512. 13. Sofaer JA, Holloway SM, Emery AE. A family study of Paget's disease of bone. J Epidemiol Community Health. 1983;37: 226--231. 14. Siris ES, Ottman R, Flaster E, Kelsey JL. Familial aggregation of Paget's disease of bone. J Bone Miner Res. 1991;6:495-500. 15. Morales-Piga AA, Rey-Rey JS, CorresGonzalez J, et al. Frequency and characteristics of familial aggregation of Paget's disease of bone. J Bone Miner Res. 1995; 10:663-670. 16. Osterberg PH, Wallace RGH, Adams DA, et al. Familial expansile osteolysis. J Bone Joint Surg Br 1988;70B:255-260. 17. Crone MD, Wallace RGH. The radiographic features of familial expansile osteolysis. Skeletal Radiot. 1990;19:245-250. 18. Dickson GR, Shirodria PV, Kanis JA, el al. Familial expansile osteolysis: A morphological, histomorphometric and serological study. Bone. 1991;12:331-338. 1323

Address correspondence to: Robert D.

Tiegs, MD, Mayo Clinic Rochester, 200 1st Street SW, Rochester, M N 55905.

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