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A Clinical Approach to Diagnosis and Management of Paget's Disease of Bone

2001; Oxford University Press; Volume: 16; Issue: 8 Linguagem: Inglês

10.1359/jbmr.2001.16.8.1379

1523-4681

Kenneth W. Lyles, Ethel S. Siris, Frederick R. Singer, Pierre J. Meunier,

Cancer Diagnosis and Treatment

PAGET'S DISEASE of bone (osteitis deformans) is a focal disorder of accelerated skeletal remodeling that can involve a single bone (monostotic) or multiple bones (polyostotic) and leads to bone hypertrophy, cortical expansion, and an abnormal bone structure responsible for bone pain and bone deformity and skeletal fragility. Complications of this disease can involve bones (deformity, fracture, and neoplastic degeneration), joints (osteoarthritis), the nervous system, and the vascular system.1 The epidemiology of Paget's disease is unusual because of its distinctive geographic distribution, pointing to factors, both genetic and environmental, that may be involved with its occurrence.2 Paget's disease occurs commonly in the United Kingdom, North America, Australia, New Zealand, France, and Germany.3 In contrast, Paget's disease is uncommon in Switzerland, Scandinavia, southern Europe, and Ireland and rare in Africa and throughout Asia, including China, India, and the Middle East.2, 3 Paget's disease is a disorder of older people; in the United States it occurs in 1.5-3.0% of people over 60 years of age and appears to be less common in blacks in the northeastern United States.4, 5 Paget's disease affects women and men equally. In Great Britain, the overall prevalence is 3-4% of those older than the age 50 years.2, 3 In Britain, there has been marked geographic variation in prevalence with rates ranging from 8.3% in parts of northwest England to 4.6% in southern areas. Three recent studies suggest that there is a decline in the frequency and severity of Paget's disease in New Zealand and Great Britain.6-8 In a British referral center, the number and extent of bones involved with Paget's disease on scintigraphy was correlated negatively with year of birth.7 The prevalence of Paget's disease in 10 British medical centers in 1994 was 40% of that observed in a 1974 study.8-10 This study suggests a prevalence of 2.5% among men and 1.6% among women aged 55 years and older.8 The etiology of Paget's disease of bone is still unknown and there are two hypotheses about its etiology: one a viral etiology and the other a genetic susceptibility. Since the 1970s there have been studies suggesting that paramyxoviruses may play a role in this disorder. There also have been studies documenting familial clusters of Paget's disease, suggesting a genetic component to this disease.11 Several paramyxoviruses (measles virus, respiratory syncytial virus, and canine distemper virus) are postulated to play a role in the etiology of Paget's disease.12-18 This hypothesis was based on finding nucleocapsid-like structures in osteoclast nuclei and cytoplasm, nucleocapsid antigens in osteoclasts and their precursors, and in situ hybridization studies showing measle virus messenger RNA (mRNA) in osteoclasts and mononuclear cells. Paramyxovirus transcripts also have been identified in osteoclasts, their precursor cells by some but not all laboratories.14-20 However, no virus has ever been cultured from pagetic cells. A British study of 53 patients with Paget's disease found no evidence for the presence of measles virus or canine distemper virus using reverse-transcriptase polymerase chain reactions. In addition, in some patients there was no evidence for measles or canine distemper virus using in situ hybridization and immunocytochemistry.21 In three other skeletal disorders, osteoporosis, pycnodysostosis, and osteoclastoma, nuclear inclusion bodies have been identified.22-24 Osteopetrosis and pycnodysostosis have established genetic rather than environmental etiologies.25, 26 Until the nature of the nuclear inclusions is definitively determined, the role of paramyxoviruses is Paget's disease will remain controversial. Elevated interleukin-6 (IL-6) levels have been reported in bone marrow plasma and peripheral blood of pagetic patients and IL-6 has been shown to increase osteoclast formation when added to normal marrow cells,27 but elevated production of cytokines has not been confirmed by all reports. It is postulated that cytokines in the marrow microenvironment may influence the development of osteoclast precursors and thus limit the lesions to local sites once the initial lesion occurs. It is still unknown how the initial osseous lesion begins. A genetic etiology of Paget's disease is supported by the study showing that 15-30% of patients have a positive family history of the disorder.28, 29 A dominant mode of transmission of the disease has been reported. In Madrid, 40% of patients had an affected first-degree relative.30 Subjects with a positive family history at diagnosis had an earlier onset of disease and a greater prevalence of bone deformity than those subjects with a negative family history. Association of Paget's disease with various histocompatibility antigens (HLA) groups has been reported in several studies, but no consistent pattern has been established.31-34 Two groups have reported a possible candidate susceptibility locus for Paget's disease on chromosome 18q.35, 36 This region was explored because of the observation that the gene for a very rare skeletal dysplasia resembling Paget's disease, familial expansile osteolysis (FEO), occurs at an 18q locus.37 Further work in families with FEO shows a mutation in RNFRS11A, the gene encoding receptor activator of nuclear factor κB (RANK).38 The mutation causes increased osteoclast activity, explaining the increased bone remodeling in this disorder.38 Additional genetic studies of families with Paget's disease show that most kindreds do not map to the 18q locus, suggesting that genetic heterogeneity is likely.39 Affected bone in Paget's disease is characterized by disorganization of both the architecture and the lamellar pattern of collagen distribution. The number of both osteoclasts and osteoblasts is increased, as is the production of new bone matrix of poor quality.40 The initial abnormality in Paget's disease is an increase in the rate of bone resorption at areas of increased bone remodeling. The pagetic osteoclasts are abnormal; they are greater in size and contain more nuclei than normal osteoclasts. In response to the increase in resorption activity, large numbers of osteoblasts are recruited to the remodeling sites, which results in an increase in the amount of new bone formation.40 These osteoblasts form new osteoid tissue at such a rapid rate that it is deposited in a disorganized woven pattern replacing the lamellar pattern found in normal bone-remodeling units. The initial phase of Paget's disease is characterized radiographically by an advancing lytic wedge or "blade of grass" lesion in long bones or a resorptive wave or border or osteoporosis circumscripta in the skull. As the lesions progress, the increased bone resorption is followed by an increase in bone formation resulting in an increase in the thickness of some trabecula and an irregular enlargement of cortical bone. This rapidly formed bone is less structurally sound than normal bone and can bow or fracture more easily. The bone marrow becomes infiltrated with an excess of fibrous connective tissue and blood vessels, leading to hypervascularity. Over time, the increased remodeling activity at a pagetic site decreases and leaves sclerotic or mosaic bone. The great majority of patients have one or several bones affected by Paget's disease. A small number have numerous bones involved by the disease. The most commonly involved bones include the pelvis, vertebrae, skull, femur, and tibia. However, any bone may be affected. A hallmark of the disease is skeletal deformity, which may be manifest as an increase in size and/or abnormal shape of a bone. Bowing of lower extremity long bones is particularly easy to discern. It also is not unusual to note an increase in skin temperature over the affected long bone. This is a sign of the increased vascularity of the surrounding soft tissue and the bone, which is a characteristic of active Paget's disease. Other bones in which deformity is a prominent feature clinically are the skull, jaws, and clavicles. Bone pain is another well-recognized feature of Paget's disease and often develops late rather than early in the disease process. This complaint does not occur in the majority of patients, even in those with considerably deformed bones. When present, the pain is usually mild to moderate in severity and is present at rest. When there is midshaft pain from disease in the femur or tibia, it often increases with weight bearing, particularly with an osteolytic lesion. A variety of complications may result from Paget's disease. These are listed in Table 1. Musculoskeletal complications are most common.41 Osteoarthritis adjacent to an affected bone is a cause of considerable morbidity. This is particularly common in the hips. Pathological fractures are less common. A recent study has indicated that these complications have a striking impact on the overall quality of life for many patients.42 The most common neurological complication is hearing loss in patients with Paget's disease of the temporal bone.43 Symptoms associated with spinal stenosis are much less common despite the high prevalence of pagetic involvement of the vertebrae. Acute paraplegia or quadriplegia may occur when there is spinal stenosis. Cardiac output increases with increasing extent of the disease44; another manifestation of increased vascularity of the bone and surrounding tissue. However, high-output failure is uncommon. One study has shown that aortic stenosis, atherosclerosis, and intracardiac calcification are more common than in age-matched individuals.45 Osteosarcoma or other types of sarcoma occur in less than 1% of patients with Paget's disease but at a much higher incidence than in aged-matched individuals without Paget's disease.46 Giant cell tumors of bone, usually benign, arise in a much smaller percentage of patients.47 Both types of bone tumors evolve only in the pagetic bone. Hypercalcemia is an unusual complication, which mainly is found with total immobilization. Nephrolithiasis can occur but is unusual. Hyperuricemia is sometimes seen.7 The diagnosis of Paget's disease is nearly always accomplished by roentgenographic examination of the skeleton.48 In the earliest stage of the disease, an osteolytic lesion may be observed most readily in the skull or a long bone. The osteolytic process has been observed to progress in a long bone at an average rate of about 1 cm/year. The second stage of the disease is manifested by sclerotic changes in the previously osteolytic lesion. Plain X-rays reveal both osteolytic and sclerotic changes in the same bone. In the last stage of the disease, the sclerotic lesion predominates and there may be an increase in the dimensions of a bone. Physicians who are highly experienced in evaluating patients with Paget's disease usually can determine the presence of Paget's disease by X-ray evaluation. If there is uncertainty concerning the diagnosis, a bone biopsy is the definitive means of establishing the diagnosis. However, biopsy specimens should be avoided in weight-bearing bone because of the risk of fracture or other complications. In selected patients computerized tomography or magnetic resonance imaging of the spine is useful in assessing back pain. Magnetic resonance imaging is of value in detecting a soft tissue component of a tumor arising in a pagetic lesion. The most efficient means of detecting Paget's disease in the skeleton is by means of the radionuclide bone scan, which generally is accomplished with a radiolabeled bisphosphonate.49 After intravenous injection, the agent preferentially is concentrated in areas of increased blood flow and high levels of bone formation, common characteristics of Paget's disease. Although there are typical patterns of tracer uptake, plain X-ray films are required to verify a diagnosis of Paget's disease. In a small percentage of patients, the bone scan may be positive before appearance of an X-ray abnormality. Rarely a sclerotic lesion in an untreated patient exhibits no tracer uptake presumably because disease activity is negligible. Generally, bone scans are not used for follow-up of patients but primarily to establish the full extent of skeletal involvement. However, in patients with quite localized disease and normal biochemical indices, serial quantitative bone scans may be used to determine the objective response to therapy. The histological evidence of increased bone resorption and bone formation in pagetic lesions is reflected by biochemical indices of bone turnover. A variety of biochemical tests reflecting bone matrix resorption provide good indices of disease activity.50 For many years, measurement of 24-h or second-morning void urinary hydroxyproline/creatinine has been used successfully as an index of bone collagen resorption. More specific tests of bone collagen resorption have been developed in recent years. These include urinary and serum deoxypyridinoline, N-telopeptide, and C-telopeptide and are not affected by dietary intake.1 Any of these tests provide a more immediate index of response to therapy of Paget's disease compared with indices of osteoblastic activity. The first biochemical index of Paget's disease was measurement of serum total alkaline phosphatase activity. The enzyme is found on the plasma membrane of osteoblasts and its serum level provides a clinically useful index of osteoblastic activity in the absence of significant liver disease or pregnancy. Recently, assays for bone-specific alkaline phosphatase have been developed, which provide a more reliable index of bone formation in a small percentage of patients who have monostotic involvement. However, there are no convincing data to indicate that there is an advantage of this test over the cheaper standard alkaline phosphatase assay in the average patient. With the institution of treatment of Paget's disease, alkaline phosphatase levels fall more slowly than bone resorption parameters, but within 4-8 weeks, a clear response usually is noted. Serum osteocalcin, another product of the osteoblast, may be increased in patients with Paget's disease but usually to a much lesser extent than alkaline phosphatase. It is not recommended as a standard means of evaluating Paget's disease. The carboxy-terminal propeptide of type I procollagen in serum of patients with Paget's disease may be evaluated but has not proven to be a particularly useful clinical index of the disease. The minimum evaluation of a patient with Paget's disease should include X-rays of affected bones and at least one parameter of bone metabolic activity. In patients with lytic lesions in weight-bearing long bones, serial radiographs should be performed to document healing. In most patients, changes in the total serum alkaline phosphatase activity are adequate to determine changes in overall disease activity, but the total serum alkaline phosphatase level in any patient is a reflection of both the total bone surface affected by Paget's disease and the total activity of the disease at those sites. Consequently, serum alkaline phosphatase can be normal in patients with a small focus of symptomatic Paget's disease. A bone scan is valuable in defining the full extent of the disease and identify still asymptomatic lesions located in "at risk" areas. Treatment is based on antiresorptive therapy and there are four general indications for treatment: (1) Symptoms caused by metabolically active Paget's disease, such as bone pain referable to a pagetic site or fatigue fracture, headache in an involved skull, back pain in the setting of pagetic vertebrae, pain from pagetic radiculopathy or arthropathy, or other neurological syndromes associated with pagetic changes, warrant treatment. (2) In a patient planning to undergo elective surgery on a pagetic site (e.g., elective hip replacement), treatment is warranted to attempt to minimize the increased blood flow in metabolically active pagetic bone (e.g., in those patients with an elevated serum alkaline phosphatase level) and to reduce operative blood loss through a reduction in hypervascularity. (3) Treatment is indicated in the management of hypercalcemia that may rarely occur in the setting of prolonged immobilization of a patient with polyostotic disease and a very elevated serum alkaline phosphatase level. (4) Many investigators believe that treatment is indicated in an attempt to decrease local progression and reduce the risk of future complications even in asymptomatic patients whose sites of disease and degree of metabolic hyperactivity place them at risk of progression and complications.1, 7 This last group would include individuals with involvement of long bones at risk of future bowing deformities, those with extensive skull involvement at risk for future hearing loss, those with pagetic changes in one or more vertebrae with the risk of various neurological complications, and those with Paget's disease in bones adjacent to major joints with the risk of secondary arthritis. The concept that aggressive treatment is associated with prevention of progression and reduction in risk of future complications is not yet supported by clear findings from long-term placebo-controlled trials (and may never be), but indirect evidence suggests that this hypothesis is reasonable.51, 52 First, failure to treat is associated with extension of lytic fronts and progression of deformity of bone in at least some patients.1 Second, successful treatment is associated with restoration of normal patterns of new bone deposition as appreciated on examination of pagetic bone biopsy specimens after treatment.52 Third, there is evidence from one study that facial and skull deformities improved after successful treatment.53 Use of the more potent second- and third-generation bisphosphonates such as pamidronate, alendronate, and risedronate is associated with a reduction of the elevated indices of bone turnover from active Paget's disease into the normal range in a majority of patients.54-57 Thus, it would appear to be good clinical practice to treat both symptomatic patients whose symptoms are likely to respond to a reduction in abnormal bone turnover as well as asymptomatic patients with active disease (elevations above normal in serum alkaline phosphatase level or urine bone turnover markers) whose location of disease places them at risk of future complications. For patients with bowing deformities of a limb, gait alterations, chronic back pain, or difficulties from spinal stenosis, walking aids such as canes, shoe lifts, or orthotics may help with function. Physical therapy may improve muscle strength and may help control some types of pain especially if muscle spasm is a factor. Presently, there are five bisphosphonate agents approved by the U.S. Food and Drug Administration (FDA) for the treatment of Paget's disease (Table 2). In order of ascending potency, these include etidronate, tiludronate, pamidronate, alendronate, and risedronate. Pamidronate is given intravenously; etidronate, tiludronate, alendronate, and risedronate are given orally. Pamidronate is given as one or more intravenous infusions, with the selection of dose and number of treatments based on the requirements of the individual patient. Mild disease often is suppressed successfully (i.e., achieving normal indices of bone turnover) with one or two 60-mg infusions. More severe disease (e.g., serum alkaline phosphatase more than three to four times the upper limit of normal) may require several infusions of 60-90 mg given weekly or twice weekly on an outpatient basis. The goal is to return biochemical indices to normal or near normal with a course of treatment. Each infusion involves the given dose placed in 250-500 ml of 5% dextrose in water or normal saline and may be infused in 2-4 h (volume must be adequate to avoid superficial venous irritation; rapidity of flow depends on patient tolerance of fluid infusion, which may be impaired in elderly patients). Once the desired number of infusions is provided, the serum alkaline phosphatase can be measured in 2-3 months, with follow-up testing every 3-4 months thereafter. If a normal value results from treatment, retreatment should be initiated once the values rise above normal (which for many patients is a year or more after initial therapy); if values after treatment stabilize at a near normal level, retreatment is appropriate once the nadir level rises by 25%. Oral calcium and vitamin D supplementation are recommended to lessen hypocalcemia, which can occur after pamidronate infusion. About one-third of patients will experience a mild flulike episode, typically only after the first ever dose, the day after the infusion, consisting of fever, myalgias, headache, and malaise. The two newest oral agents are alendronate (40 mg given daily for 6 months) and risedronate (30 mg given daily for 2 months or occasionally 3 months). Both drugs are associated with reduction of biochemical indices of turnover into the normal range in more than 50% of patients with moderate to severe disease,56-59 and biochemical remission or stable nadir levels may persist for 6-18 months or longer before retreatment is indicated. Each of these agents is taken as a single daily dose with a 40-mg tablet of alendronate or a 30-mg tablet of risedronate on rising after an overnight fast, with 6-8 ounces of plain water, and nothing by mouth (except more water) for the next 30 minutes, after which breakfast and other morning medications should be taken. During the 30 minutes, the patient may not lie down. As with pamidronate, calcium, and vitamin D supplementation is recommended. The main side effect is upper gastrointestinal distress that usually is mild and nonspecific and rare esophageal erosions that are drug related in some patients. The original bisphosphonate used in Paget's disease is etidronate, 400 mg daily for 6 months, an agent less potent than those mentioned previously. A more recent new addition (tiludronate, 400 mg daily for 3 months) is an agent slightly more potent than etidronate. Etidronate is taken once daily with a small amount of water halfway through a 4-h fast; tiludronate also needs to be taken 2 h before or after eating food with 6-8 ounces of water. With each agent, calcium supplements should not be taken for several hours after the bisphosphonate dose. Both drugs are very well tolerated at these dosages, with only occasional reports of minor upper gastrointestinal distress or slight diarrhea. Higher than recommended dosages or prolonged use (greater than 6 months without a 6-month drug-free period) of etidronate can cause osteomalacia, which resolves when therapy is discontinued. Many investigators refrain from using etidronate in the setting of lytic disease in a weight-bearing bone to avoid possible etidronate-induced extension of lytic change. Tiludronate does not produce problems with mineralization deficits at therapeutic doses. In clinical trials with these agents about one-third of patients will achieve normal indices with the first treatment course of etidronate or tiludronate, and a majority of patients will have a 50% decrease in serum alkaline phosphatase.60-62 For those patients who have esophageal problems with the newer bisphosphonates etidronate and possibly Tiludronate are a viable option. Secondary resistance to individual bisphosphonates can and does occur.63 Because there is a more than 20-year experience with etidronate, it is recognized that many patients develop a loss of efficacy with this agent with multiple courses of treatment64; however, such patients usually will respond well to the institution of a different bisphosphonate. Recently, some investigators have begun to report that repeated use of pamidronate also can be associated with secondary resistance, and again it is apparent that use of a different member of this class is effective.65 Salmon calcitonin by subcutaneous injections was the first widely used therapy for Paget's disease (Table 2). It reduces elevated indices of bone turnover by 50%, decreases symptoms of bone pain, reduces warmth over affected bones, improves some neurological complications, and promotes healing of lytic lesions. Today its use probably is limited to those patients who do not tolerate bisphosphonates. It can be initiated at a dosage of 100 U/day for several months, often with a subsequent reduction of dose to 50-100 U every other day with maintenance of benefit. Because the main side effects in a minority of patients are nausea or facial and palmar flushing, each of which can be annoying problems, the drug is sometimes started at a dose of 25 U, with a gradual increase in dose every few days to the full 100 U to attempt to minimize these problems. There is limited experience with the salmon calcitonin nasal spray formulation in Paget's disease (for which the FDA does not approve). Secondary resistance to salmon calcitonin can occur,66 necessitating a change to bisphosphonate therapy. Formerly called mithramycin, plicamycin is a cytotoxic agent formerly used in the management of the hypercalcemia of cancer (for which it is FDA approved) and an early experimental agent in Paget's disease. It is rarely indicated at this time because of the availability of the potent newer bisphosphonates and its toxicity to liver, bone marrow, skin, and kidney. Judicious use of pain-relieving medications such as a acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and, potentially, the new cox-2 inhibitors in addition to antiosteoclastic agents may be helpful for the management of pagetic pain. Pain directly attributable to Paget's disease generally is relieved by adequate treatment. However, some of the pain may be the result of mechanical aspects related to bone deformity or arthritic or neurological complications. Use of addicting agents such narcotics should be avoided if it is likely that the problem will be chronic. Orthopedic intervention may be indicated in several situations.67 Complete fracture through pagetic bone often requires some form of internal fixation especially if the fracture is unstable. It has been stressed that complete immobilization of a pagetic fracture site should be avoided if possible, and internal fixation of such fractures may enable the patient to be mobilized more quickly. Tibial osteotomy is sometimes used to realign the knee and decrease mechanical pain, particularly if medical therapy is unsuccessful in managing severe pain symptoms. Total joint arthroplasty, typically of the hip and less commonly of the knee, is indicated for patients with severe mechanical joint pain unresponsive to antiosteoclastic treatment and therapy for the osteoarthritis. Control of Paget's disease activity in these patients is recommended to minimize the chance of loosening of the prosthesis. Finally, spinal stenosis, usually caused by a combination of pagetic and nonpagetic changes in vertebrae and facet joints, may require orthopedic or neurosurgical management. In any case of surgical intervention, pretreatment with a potent bisphosphonate, typically pamidronate by infusion if time is a factor, is of great importance. The hypervascularity of active Paget's disease may cause serious bleeding at operation, and pretreatment with a bisphosphonate will reduce the hypervascularity and greatly decrease the risk of greater than normal operative blood loss. In conclusion, the treatment of Paget's disease of bone has undergone major changes in the past 25 years because of the development of specific inhibitors of osteoclast-mediated resorption and particularly the development of potent bisphosphonates. With these newer agents, suppression of abnormal pagetic turnover into the normal range for periods of several years is attainable in a majority of patients. The effects of disease suppression on the natural history of progression of Paget's disease are unknown. However, the capacity to restore bone remodeling to normal in many patients gives reason to believe that reduction in long-term complications and their attendant morbidity is now possible. This manuscript was prepared at the request of Robert R. Recker, M.D., a chair of the Professional Practice Committee of the American Society for Bone and Mineral Research. The authors were asked to prepare guidelines for diagnosis and management of Paget's disease of bone. The document was reviewed and revised by the Board of Directors of the Paget Foundation for Paget's Disease of Bone and Related Diseases, as well as its Advisory Medical Panel. When these changes were completed, the document was forwarded to the Professional Practice Committee of the ASBMR where it was again reviewed and revisions were made. Finally, the manuscript was submitted to the JBMR, where it was peer-reviewed. Support for this work was provided by the VA Medical Research Service (AG11268), the Division of Research Resources (RR30), GCRC, National Institutes of Health (NIH; RR000645), and the Paget Foundation. K.W.L. received research support from Pfizer, Merck, Novartis, and Procter and Gamble and E.S.S. received research support from Merck, Procter and Gamble/Avetis.