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

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 active Paget's disease, such as bone pain to a pagetic site or fracture, in an involved skull, back pain in the of pagetic vertebrae, pain from pagetic or or other neurological associated with pagetic In a patient to on a pagetic site treatment is to to the increased blood flow in active pagetic bone in those patients with an elevated serum alkaline phosphatase and to blood loss a in hypervascularity. Treatment is indicated in the of that may occur in the of of a patient with disease and a very elevated serum alkaline phosphatase that treatment is indicated in an to local and the risk of complications even in asymptomatic patients sites of disease and of metabolic at risk of and This last include individuals with involvement of long bones at risk of those with skull involvement at risk for hearing those with pagetic changes in one or more with the risk of various neurological and those with Paget's disease in bones adjacent to joints with the risk of The that treatment is associated with of and in risk of complications is not supported by clear from may but evidence suggests that this hypothesis is failure to is associated with of lytic and of deformity of bone in at least some treatment is associated with of normal patterns of new bone as on examination of pagetic bone biopsy specimens there is evidence from one study that and skull of the more and such as and is associated with a of the elevated indices of bone from active Paget's disease the normal in a majority of it to be good clinical to both symptomatic patients are to to a in abnormal bone as as asymptomatic patients with active disease normal in serum alkaline phosphatase level or bone of disease at risk of complications. For patients with of a back or from spinal stenosis, such as or may with therapy may and may some types of pain is a there are by the and for the treatment of Paget's disease In of these include and is and are is as one or more intravenous with the of and number of based on the of the patient. disease often is successfully normal indices of bone with one or two More disease serum alkaline phosphatase more than three to four the limit of may several of or on an The is to biochemical indices to normal or normal with a of the in of in or normal and may be in be adequate to of flow on patient of which may be in the number of is the serum alkaline phosphatase can be in with follow-up If a normal value results from should be once the normal for many patients is a year or more initial treatment at a normal is once the level by and are recommended to which can occur of patients will a mild only the first ever the the of and The two are for and for or 3 Both are associated with of biochemical indices of the normal in more than of patients with moderate to and biochemical or levels may for or before is of these is as a single with a of or a of on an with of plain and by more for the which and other should be the the patient may not As with and is The is that usually is mild and and rare that are in some The used in Paget's disease is for an agent less than those A more recent new for 3 is an agent more than is once with a small amount of a also to be before or with of With should not be for several the Both are very at these with only of or than recommended or than without a of can cause which when therapy is from using in the of lytic disease in a weight-bearing bone to possible of lytic does not with at In clinical with these about of patients will normal indices with the first treatment of or and a majority of patients will have a in serum alkaline For those patients who have with the and are a to can and does there is a more than with it is that many patients a loss of with this agent with multiple of such patients usually will to the institution of a Recently, some have to that of also can be associated with and it is that of a of this is by was the first used therapy for Paget's disease It elevated indices of bone by decreases of bone over affected bones, some neurological and of lytic its is to those patients who do not It can be at a of for several often with a of to other with of the in a of patients are or and of which can be the is sometimes at a of with a increase in to the full to to these There is with the in Paget's disease which the does not to can a to therapy. is a agent used in the of the of which it is and an early agent in Paget's disease. 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