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Clinical manifestations and diagnosis of Paget disease of bone

Clinical manifestations and diagnosis of Paget disease of bone
Author:
Julia F Charles, MD, PhD
Section Editor:
Ethel Siris, MD
Deputy Editor:
Monica Ramirez Curtis, MD, MPH
Literature review current through: Jul 2022. | This topic last updated: May 28, 2022.

INTRODUCTION — Paget disease of bone (PDB), also known historically as osteitis deformans, is a focal disorder of bone metabolism that occurs in the aging skeleton; it is characterized by an accelerated rate of bone remodeling, resulting in overgrowth of bone at single (monostotic PDB) or multiple (polyostotic PDB) sites and impaired integrity of affected bone. Commonly affected areas include the skull, spine, pelvis, and long bones of the lower extremity.

The majority of patients with PDB are asymptomatic. The diagnosis in such patients is usually made incidentally following a routine chemistry screen showing an elevated serum concentration of alkaline phosphatase of bone origin or an imaging study obtained for some other reason that shows pagetic changes in bone.

The two main clinical manifestations of Paget disease are pain due to the pagetic lesion in bone itself or from secondary consequences of bone overgrowth and deformities in affected areas, such as osteoarthritis or nerve impingement. Fractures, bone tumors, neurologic disease, and abnormalities in calcium and phosphate balance can also occur. In addition, because of the vascularity of pagetic bone, excessive bleeding may occur during orthopaedic surgery.

The pathogenesis, clinical manifestations, and diagnosis of PDB will be reviewed here. The treatment of this disorder is discussed elsewhere. (See "Treatment of Paget disease of bone".)

EPIDEMIOLOGY — Paget disease of bone (PDB) is a fairly common finding in aging bone, with estimates ranging from 2.3 to 9 percent in older patients within affected populations [1,2]; it is often asymptomatic. Its onset is typically after age 55, with a slight predominance in men in some but not all studies. It is common in England, Scotland, Central Europe, and Greece, as well as in countries and cities settled by European immigrants, such as those in Australia, Canada, and the United States. Even within these countries, there are geographical clusters of disease [1,3-7]. Paget disease is rarely reported in the Scandinavian countries and Asia [1,8-11].

PDB is an ancient disease, claimed to be identified in a Neanderthal skull, with scattered reports of skeletal remains throughout history demonstrating this disorganized pattern of bone overgrowth [12]. The recognition of both geographic and familial clusters of the disease led to a search for both environmental and genetic causes [3,13-16]. (See 'Pathogenesis' below.)

The best initial estimates of prevalence came from two autopsy series in Europe performed during the mid-20th century on patients over the age of 40, in whom the prevalence was 3 to 3.7 percent [12,17]. In one series, only 7 of 24 patients recognized as having Paget disease had been diagnosed during their lifetimes (29 percent) [17]. The prevalence may rise to as high as 9 percent in older adults [2]. Over the last quarter-century, the prevalence of Paget disease appears to have diminished (except in regions of Italy) [18]. The extent of skeletal involvement is diminishing, and cases of symptomatic disease are less frequent [15,19-25].

Most of the estimates generated by epidemiological studies have relied upon the distribution of skeletal lesions, deriving prevalence estimates from reports of pagetic bone detected on screening abdominal radiographs (a "KUB" [kidneys, ureters, and bladder] view). Paget disease can affect almost any bone in the body but has a predilection for the skull, spine, pelvis, and long bones of the lower extremity. Thus, abdominal radiographs tend to capture the proximal femurs, pelvis, and lumbar spine (common sites of Paget disease) but miss patients with monostotic disease of the skull, upper spine, or distal extremity. Other epidemiological studies have relied on elevations of serum alkaline phosphatase (sAP) from bone as a marker for disease. However, a study of a population-based cohort from the Netherlands suggested that although sAP is a marker for PDB, the sAP level is normal in the majority of patients with Paget disease, particularly those with monostotic disease [26].

Several issues are likely to have led to an underestimation of the prevalence of Paget disease, including the facts that it is often asymptomatic, that screening abdominal radiographs are no longer routine with hospital admission, and that the diminished skeletal extent of Paget disease has made it less likely to be incidentally detected.

PATHOGENESIS — Paget disease of bone (PDB), which is characterized by an accelerated rate of bone remodeling resulting in overgrowth of bone at selected sites and impaired integrity of affected bone, is believed to be a disease of the osteoclast. Osteoclasts are the only cell known to resorb bone. Osteoclast differentiation requires pathways involving receptor activator for nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (MCSF), which are both necessary for osteoclast activation. RANKL binds to its receptor, RANK, on osteoclast precursors to promote osteoclast differentiation and activation via activation of nuclear factor kappa-B (NFkB)-dependent pathways. Osteoclast differentiation is inhibited by osteoprotegerin (OPG; a soluble decoy receptor for RANKL) and further modulated by cytokines and hormones. It is not known why some areas of bone are affected while others are not.

Evidence for the pivotal role of the osteoclast in PDB includes abnormalities in the following:

Osteoclast phenotype:

The osteoclasts in pagetic bone demonstrate an unusual appearance, with a disproportionate number of osteoclasts with too many nuclei.

Intranuclear inclusion bodies may be noted in the nuclei of pagetic osteoclasts, but not in the nuclei of osteoblasts or in osteoclasts from unaffected bone of the same patient.

Osteoclast physiology:

Osteoclasts from patients with PDB show a hypersensitivity to vitamin D [27-29].

Antiresorptive agents used to treat PDB suppress osteoclastic activity and restore bone remodeling towards normal levels. Treatment with bisphosphonates can result in clinical remission of disease in many patients.

Both genetic and environmental causes are thought to contribute to the pathogenesis of the disease [30]. While it is clear that genetic mutations underlie susceptibility, a marked decrease in prevalence that has been shown in Britain and New Zealand also supports a role for environmental determinants [20,22]. However, there are no consistent correlates found between the occurrence of Paget disease and varied environmental exposures, including exposure to measles, dog ownership, urban versus rural living, heavy metals, milk ingestion, or family size.

PDB occurs in both familial and sporadic forms. A positive family history may be elicited in 12 to 40 percent of patients [13,31]. Persons with familial Paget disease may differ from those with sporadic Paget disease by having an earlier onset, more skeletal involvement, deformity, and fracture [31-37].

Genetic — Significant evidence has accumulated that genetic factors influence the development of PDB [38]. The inheritance of familial PDB appears to be autosomal dominant with variable penetrance. Genome-wide association studies and candidate gene analyses have identified 15 genetic loci that are associated with PDB [39-43]. Most of these risk loci identify proteins known to affect bone physiology. Several directly affect RANK-RANKL pathway activity, such as the TNFRSF11A locus that encodes RANK.

The first and best-documented genetic association is with mutations in the ubiquitin-associated (UBA) domain of SQSTM1, which encodes the ubiquitin binding protein sequestosome-1. The SQTSM1 P392L mutation was first identified in several French-Canadian kindreds with familial PDB. Study of familial cases from multiple countries has led to the identification of 28 different SQSTM1 mutations associated with PDB, of which P392L is by far the most common, occurring in up to 50 percent of familial PDB [44,45]. Germline SQSTM1 mutations have also been identified in 2.6 to 16 percent of sporadic PDB [46,47], and somatic mutations have also been reported [48,49].

The presence of SQSTM1 mutations, particularly truncation mutations, correlates with a more severe clinical phenotype [50]. However, of adults with SQSTM1 mutations inherited from a parent with PDB, only 17 percent had evidence of PDB by bone scintigraphy, and their disease was attenuated compared with the affected parent [51]. This underscores the likely importance of gene-environment interactions for disease expression.

Many SQSTM1 mutations enhance NFkB activation and thus osteoclast differentiation [52], while other mutations associated with PDB may affect the bone marrow microenvironment [53]. Neither mice transgenic for human P392L SQSTM1 nor mice with the equivalent mutation at the endogenous locus develop PDB, although their osteoclasts have some characteristics of pagetic osteoclasts (eg, enhanced responsiveness to RANKL and tumor necrosis factor [TNF]) [54]. This provides further evidence that SQSTM1 mutation alone is insufficient to promote disease.

Mutations in ZNF687, a zinc finger protein and possible transcriptional target of NFkB, were identified in an Italian family with severe PDB complicated by giant cell tumor [55]. As SQSTM1 mutations are rare in Southern Italian PDB patients, who frequently have severe PDB, ZNF687 was investigated in a cohort of 30 Southern Italian patients with polyostotic disease, and mutations in ZNF687 were found in one-third [56]. Additionally, a common allelic variant in the locus for OPTN, encoding optineurin, an autophagy adaptor protein that appears to be involved in activation of the NFkB pathway, is strongly associated with PDB in multiple linkage studies. This variant was shown to increase OPTN expression and cause increased nuclear translocation of NFkB [57].

PDB is also observed in association with multisystem proteinopathy, a rare disease with a broad phenotypic spectrum, variably including PDB, inclusion body myopathy, motor neuron disease, parkinsonism, and frontotemporal dementia. This disease was first reported to be due to mutations in valosin-containing protein (VCP) [58]. Additional causative mutations have been reported in SQSTM1 and several ribonucleic acid (RNA)-binding proteins [59]. The causative mutations are thought to alter the process of proteasomal degradation resulting in accumulation of undegraded proteins in stress granules and promoting tissue degeneration.

Three rare autosomal dominant skeletal dysplasias have been described that share some features with PDB (enlarged osteoclasts, skeletal enlargement, and deformity) but have additional manifestations that render them clinically distinct, including age of onset, hearing loss, and early loss of adult teeth. Early-onset Paget disease, familial expansile osteolysis, and expansile skeletal hyperphosphatasia are all caused by insertion mutations in the TNFRSF11A gene encoding RANKL and result in increased osteoclast activity.

A fourth disorder, called juvenile Paget disease (or hyperphosphatasia), is an autosomal recessive bone dysplasia with childhood onset that is unrelated to PDB in adults. Most reported cases are caused by a germline mutation in the gene for OPG, the decoy receptor for receptor activator for NFkB ligand (RANKL), leading to a deficiency of OPG. (See "Osteogenesis imperfecta: An overview", section on 'Other skeletal syndromes'.)

Viral — Compared with the genetic findings, more limited information is available regarding potential environmental influences on PDB, including the possible role of viral infection. Findings of clusters of disease and observations that exposure to unvaccinated dogs, cats, or birds might be associated with a heightened risk of PDB led to the speculation that PDB might have a viral etiology [60]. The evidence for measles virus as an etiologic factor is substantial, and measles vaccination is postulated to explain the declining incidence of PDB. However, while measles remains a problem worldwide where vaccinations have not reached vulnerable populations [5], PDB has not been described as more prevalent in these populations.

The possibility that viral infection may play an important early role in the genetically susceptible host remains controversial and continues to be investigated. Initial observations pointed to intranuclear inclusions in pagetic osteoclasts resembling paramyxoviruses, with a structure similar to the nucleocapsids of measles. The expression of measles virus nucleocapsid protein (MVNP) in normal mouse osteoclasts promoted an osteoclast phenotype similar to pagetic osteoclasts [61,62] and caused a significant PDB phenotype in the presence of a SQSTM1 mutation [63]. MVNP expression in osteoclasts has also been linked to increased osteoblast differentiation [64]. However, immunohistochemical and molecular approaches to confirming the presence of virus in bone biopsies from PDB patients have generated conflicting findings [65-67].

Modifiable factors — There are no known modifiable factors that contribute to PDB pathogenesis.

HISTOPATHOLOGY — The osteoclasts in patients with Paget disease of bone (PDB) are bizarre in appearance, multinucleated, and excessive in number. Accelerated bone turnover results in the abnormal deposition of lamellar bone interspersed with woven bone. The bone is disorganized in appearance, with variably thickened trabeculae rimmed by numerous osteoblasts. The characteristic mosaic pattern is formed by randomly arrayed units of lamellar bone, which are delineated by irregular cement lines. The disorganized woven bone increases the bone volume, leading to many of the complications of the disease. The normal marrow is replaced by highly vascular stromal tissue (picture 1).

CLINICAL MANIFESTATIONS

Signs and symptoms — The majority of patients with Paget disease of bone (PDB) are asymptomatic, although estimates vary widely [68-70]. When symptoms do arise, these are usually due to overgrowth, deformity, or pathologic fracture of the affected bone at a given skeletal location. Pain may arise either directly, from a pagetic lesion in bone, or from secondary causes, including osteoarthritis, nerve impingement, and tumor.

The two main clinical manifestations of Paget disease are pain, presumed to be due to the consequences of bone overgrowth, and deformities in affected areas. However, fractures, bone tumors, neurologic disease, and abnormalities in calcium and phosphate balance can also occur, though this is infrequent. Intrinsic cardiac disease due to PDB directly does not occur, but extensive polyostotic disease has rarely been associated with high-output heart failure as a secondary phenomenon. In addition, because of the vascularity of pagetic bone, excessive bleeding may occur during orthopaedic surgery.

Pain due to pagetic involvement of bone generally develops later in the course of disease and is typically a mild to moderate, deep, aching discomfort that persists through the day and at rest [71]. It may worsen with weightbearing and may be present at night. The etiology of the pain associated with the changes in bone is unclear. It may be due to periosteal changes caused by bone enlargement in association with hyperemia or microfractures in weightbearing bones.

The frequency of clinical findings depends upon the population studied (eg, registry versus clinical trial population, or the age of the study patients) and the methods by which data are obtained (eg, by patient or clinician questionnaires or by chart review) [22,68,72-74]; thus, estimates of different manifestations vary widely. The reason for this relates to the tendency of patients with Paget disease to be older adults and to assign their musculoskeletal complaints to this disorder of bone.

Symptoms and findings likely to be related to PDB among two cohorts of patients included [68,73]:

Arthritis (40 to 50 percent)

Pain (40 to 45 percent)

Bone deformity (12 to 36 percent)

Fracture (4 to 16 percent)

Other problems that may be attributed to PDB include [22,68,72-74]:

Radiculopathy due to nerve compression syndromes

Chronic back pain

Impaired functional status

Hearing loss

Headache

Joint replacement surgery

Paget disease has a predilection for the skull, thoracolumbar spine, pelvis, and long bones of the lower extremities. It can be useful to think of the clinical manifestations of PDB in terms of these anatomical correlates:

Skull – Involvement of the skull may lead to deformity, hearing loss (due to cochlear involvement), headache, dizziness and spinning sensations, and, rarely, neurological sequelae including hydrocephalus with instability of gait, dementia, or apathy from vascular steal due to heightened bone vascularity [75]. Enlargement of the skull, which can occur after many years of disease, may lead to a "tam-o-shanter" shape radiographically and may result in basilar invagination. Involvement of the mandible or maxillary bones may result in jaw deformity, malocclusion, and periodontal disease (image 1) [2,29]. Angioid streaks can be found on ophthalmologic examination in up to 20 percent of patients with skull involvement as a component of active and more extensive Paget disease, compared with 15 percent of patients with active disease regardless of location and less than 2 percent of nonselected patients [76,77]. Wide, dilated scalp veins are commonly seen.

Spine and pelvis – Paget disease affecting the spine may lead to spinal stenosis at any level, bone pain, and nerve compression with attendant pain. A vascular steal may cause spinal cord dysfunction [78]. The abnormal bone may lead to a crippling compression fracture (image 2). In the pelvis, Paget disease is often asymptomatic, unless it abuts a joint where softening of the bone may lead to pain, arthritis, and protrusio acetabuli (image 3).

Long bones – Bowing deformities in the long bones and early arthritis of affected joints are common, with a heightened risk of fracture over the lifetime of the individual. The deformities are caused by enlarging and abnormally contoured bones, which result in bowing; the tibia and femur typically bow anteriorly and anterolaterally, respectively. Bowing may result in changes in gait and increased mechanical stresses that increase the likelihood of back and joint pain and of osteoarthritis. Patients with PDB have an increased likelihood of undergoing hip or knee replacement surgery for osteoarthritis compared with non-pagetic controls [22]. The skin overlying involved areas may feel warm due to increased blood flow.

Traumatic and pathologic fractures are the most common complications of pagetic lesions in the long bones. Femoral fractures are more frequent than tibial fractures. The most common femoral site is in the area below the lesser trochanter. Fractures are usually transverse and perpendicular to the cortex. They can be either complete or incomplete (fissure fractures). Fissure fractures tend to occur along the convex surfaces of the curved bones but may progress to become complete fractures over time [71,79]. Fracture of pagetic bone may be associated with substantial blood loss.

Polyostotic disease – Polyostotic Paget disease may lead to metabolic disturbances, but these are rare with currently available therapies such as the nitrogen-containing bisphosphonates. Metabolic complications of Paget disease include high-output heart failure and hypercalciuria with a heightened frequency of kidney stones [12]. Casting or immobility may lead to profound osteopenia of the pagetic bone [80].

Bone tumors — Patients with PDB are at increased risk for primary bone neoplasms, particularly osteosarcoma [22,81]. Osteosarcoma may arise in pagetic bone and presents with increased bone pain that is poorly responsive to medical therapy, local swelling, and, less often, a pathologic fracture (image 4) [68,82,83]. Estimates of prevalence among patients with PDB range from 0.2 to 1 percent. An almost invariably fatal event, the osteosarcoma of PDB classically presents in those with extensive, longstanding skeletal disease. However, the epidemiology of this may be changing, and polyostotic, active disease may no longer predict those at risk for this disease [84,85]. The osteosarcoma affecting Paget patients probably has a distinct genetic signature from that of adolescent osteosarcomas [82,84]. (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Paget disease and other benign bone processes'.)

Less commonly, giant cell tumors may arise in pagetic bone and are usually benign [86]. Similar to osteosarcomas, they may present with localized pain and swelling and typically occur in patients with polyostotic disease. Distinguishing between osteosarcoma and giant cell tumor is critical, as the former is generally fatal while the latter can be managed with medical therapy. While giant cell tumors typically arise in or adjacent to skeletal structures affected by PDB, they can occur in nonosseous tissues, in which case they are termed extraskeletal osteoclastomas. Giant cell tumors in PDB have several distinct characteristics when compared with non-PDB-associated disease, including a predilection for the axial skeleton (particularly the skull, facial bones, and pelvis), later age of onset, and frequency of multiple neoplasms [87]. (See "Giant cell tumor of bone".)

Laboratory findings — Laboratory findings that result from increased bone turnover are typical of untreated disease in most patients. The following findings characterize this disorder:

The serum alkaline phosphatase (sAP), like the bone-specific alkaline phosphatase (bAP), is frequently elevated in patients with PDB. The degree of elevation generally reflects the extent and activity of the disease, but this correlation is not as consistent as it was historically [88-91]. A normal or minimally elevated level may be seen in patients with monostotic disease and in some patients with polyostotic disease. [92]. As an example, a normal sAP can be seen in patients with an isolated pelvic lesion, with several vertebral bodies involved, or with end-stage sclerotic disease. By contrast, isolated Paget disease of the skull may produce very marked elevations in sAP [69].

Other tests for markers of bone turnover that are often elevated with active disease include procollagen type I N-terminal propeptide (PINP), serum C-telopeptide (CTx), urinary N-telopeptide (NTx), and urinary hydroxyproline [83,88-91]. Serum CTx and urinary NTx reflect osteoclast activity (bone resorption), which is inhibited within days to weeks of treatment with a nitrogen-containing bisphosphonate. SAP, bAP, and PINP are measures of osteoblast function and return to normal gradually, sometimes over several months [93]. (See "Bone physiology and biochemical markers of bone turnover".)

Serum calcium and phosphorus are normal in most patients. The finding of hypercalcemia in an ambulatory patient with PDB suggests the presence of a second disorder, such as primary hyperparathyroidism. (See "Diagnostic approach to hypercalcemia" and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

Imaging — Several imaging modalities, including plain radiography and bone scintigraphy, are useful in patients with suspected PDB, and findings on plain radiographs may be diagnostic, reflecting the abnormal bone turnover characteristic of disease. Additional imaging studies, including computed tomography (CT) and magnetic resonance imaging (MRI), may be useful in further evaluating unusual bone lesions or in other selected circumstances, particularly if malignancy is suspected.

Plain radiographs — Plain films early in the disease course may show a predominantly osteolytic lesion. Over time, however, there is evidence of an osteoblast response, and the bone thickens and enlarges (image 5). In late Paget disease, there may be dense bone by plain film, with little evidence of remodeling by biochemical parameters. Characteristic radiographic findings include [94]:

"Osteoporosis circumscripta," which describes the osteolytic lesions that may be seen in the skull in early disease.

Mixed lytic/sclerotic lesions, which gradually progress over time, resulting in thickening of cortical bone, heightened trabecular markings, and distortion and overgrowth of involved bone.

Progression of lesions originating in the subchondral bone and moving in one direction through the bone in a pattern sometimes described as "flame shaped," with cortical tunneling and trabecular thickening sometimes present (image 6).

Pseudofractures, which may be seen as small fissures on the convex surface of long bones affected by bowing [94].

Very infrequent identification of new bone lesions over time, although individual lesions evolve as noted above.

Pelvic involvement that results in protrusio acetabuli, which can give the pelvis a triangular appearance.

Iliopectineal line involvement, which is sometimes described as appearing in the shape of the number "3."

An ivory appearance of the affected spine in some patients. An affected vertebra is often enlarged in all three planes or may have the appearance of a picture frame. Additionally, vertebral enlargement may cause a loss of the normal lumbar lordosis and may accentuate the dorsal kyphosis.

Bone scintigraphy — Increased uptake is seen focally at the sites of active pagetic bone lesions on radionuclide bone scanning and is more sensitive than plain radiography, particularly in early disease. The enhanced radionuclide uptake at pagetic lesions represents increased bone remodeling and blood flow (image 7) [71]. The plain film (image 6) demonstrates the radiographic correlates of this in the same patient (see 'Plain radiographs' above). Bone scanning can help establish the extent and distribution of bony lesions.

Findings on bone scans, however, are not specific. Sometimes evidence of Paget disease on bone scan antedates corresponding findings on plain radiographs.

The radionuclide uptake may decrease or normalize in the absence of significant disease activity (eg, patients with more longstanding or effectively treated disease). The degree of uptake may increase or decrease in patients with malignant transformation to osteosarcoma.

Other imaging modalities — Other imaging technologies, such as CT or MRI, may be helpful in the evaluation of bone lesions if malignancy is a concern [71,95]. CT scanning may be useful for verifying whether the cortices of bone are intact and for defining the consequences of fractures or overgrowth of bone in the spine or skull. MRI may be helpful in distinguishing lytic or intermediate lesions of Paget disease from sarcoma [96]. Positron emission tomography (PET) scanning for malignancy may be "falsely positive," with increased uptake seen in active pagetic bone lesions [97]. The role of PET scanning in this setting is not well-defined. (See "Bone tumors: Diagnosis and biopsy techniques", section on 'Imaging' and "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Diagnostic evaluation'.)

DIAGNOSIS — The diagnosis of Paget disease of bone (PDB) is primarily radiologic. In many patients, the serum alkaline phosphatase (sAP) is elevated, and additional tests of bone turnover are not required [98]. We diagnose PDB in patients with clinical or laboratory findings suggestive of disease upon the demonstration of characteristic radiographic changes at one or more affected skeletal sites.

Role of imaging — Radiographs are usually diagnostic, showing the characteristic deformity of bone, with thickened cortices marked by tunneling, and accentuated trabeculae. Plain films obtained earlier in the course of illness may show a predominantly lytic lesion. Over time, however, there is evidence of an osteoblast response, and the bone thickens and enlarges (image 5). In some cases of Paget disease, there may be dense bone by plain film, with little evidence of remodeling by biochemical parameters. (See 'Plain radiographs' above.)

A skeletal survey is not required, but a baseline radionuclide bone scan should be obtained in all patients with PDB to document the extent and locations of skeletal involvement (image 7). A complete understanding of the locations of skeletal involvement is essential to determining indications for treatment. Note that the sites involved rarely change over a patient's lifetime. Findings on bone scans, however, are not specific, and plain film imaging of areas of increased uptake needs to be obtained to confirm the diagnosis. PDB-related changes on bone scan sometimes antedate corresponding findings on plain radiographs.

In a patient with known Paget disease, where bone scintigraphy is performed to assess the extent, distribution, and activity of disease, we obtain plain radiographs to confirm involvement at additional sites and evaluate for other bone lesions. In a patient in whom bone scintigraphy performed for other reasons is suggestive of Paget disease, then plain radiographic confirmation is also necessary.

We also obtain radiographs of affected sites to identify the musculoskeletal consequences of Paget disease, including fractures (image 2), potential malignant lesions (image 4), osteoarthritis, or other bone abnormalities (image 3).

This approach is generally consistent with the clinical practice guidelines of the Endocrine Society and the 2019 Paget's Association guidelines [99,100].

Role of biochemical studies — The sAP is usually adequate for assessment and monitoring of disease activity [88-91]. In patients with an elevated sAP, serum calcium and 25-hydroxy vitamin D levels should be obtained to exclude other causes of this elevation and in anticipation of treatment with a bisphosphonate.

Occasionally, bone-specific alkaline phosphatase (bAP) is measured in patients with liver disease or a characteristic bone lesion but who have normal sAP. Serum C-telopeptide (CTx) or procollagen type I N-terminal propeptide (PINP) are alternative markers that can be followed in patients with liver disease or in whom sAP is normal (see 'Laboratory findings' above). All three tests are commercially available.

In patients in whom sAP is not elevated with active disease documented by increased radionuclide uptake on bone scintigraphy, we obtain measurement of the bAP, serum CTx, and PINP to determine if there is a serum marker that can be followed for response to treatment. However, these additional markers may occasionally be normal, despite evidence of active disease on bone scintigraphy. If sAP is elevated, there is no clear utility to sending additional markers, in our experience.

Role of biopsy — It is unusual that a bone biopsy is required to document the diagnosis of PDB, unless there is concern regarding the radiographic appearance of the lesion or possible metastatic disease (eg, a blastic lesion such as that seen in metastatic prostatic carcinoma or a lytic bone lesion in a patient with multiple myeloma). A biopsy of bone is required in the setting of monostotic lesions that do not show the characteristic radiographic findings of Paget disease. A biopsy may also be useful in a person suspected of Paget disease but in whom Paget disease would be unlikely, such as an individual from a country in which Paget disease is rare (eg, Korea) or a young adult. A biopsy is also indicated in the case of worsening pain or swelling at the site of known PDB to evaluate for osteosarcoma or giant cell tumor.

Additional diagnostic considerations

Osteoarthritis – In patients with known PDB and concurrent osteoarthritis, pain in or near a joint may be due to PDB close to the affected joint and/or the osteoarthritis. Improvement with treatment with an antiresorptive agent, such as a bisphosphonate, favors the PDB as the cause of pain. However, many older patients have pain from this as well as osteoarthritis of the joint, and while a bisphosphonate eases a component of their distress, attention to alleviating the pain from osteoarthritis is also necessary.

Hyperparathyroidism – Primary hyperparathyroidism can coexist in patients with PDB. Serum calcium is typically normal in PDB, so the presence of hypercalcemia in an ambulatory patient with PDB should raise the question of whether hyperparathyroidism is also present, and appropriate laboratory studies should be performed [101]. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

DIFFERENTIAL DIAGNOSIS — Paget disease of bone (PDB) occurs in an aging population that also has an increased prevalence of malignancy, osteoarthritis, and osteoporosis. Although the diagnosis of PDB is usually evident from radiographic findings, other conditions may also be present or have overlapping features.

Metastatic disease – The mixed lytic/sclerotic appearance of PDB may make it difficult to radiographically distinguish metastatic malignancy in some patients. However, new lesions on bone scan generally do not occur in PDB over time. Thus, comparison with baseline plain radiographs and radionuclide bone scintigraphy can be helpful in determining whether a lesion requires further study. A biopsy may sometimes be required if imaging studies, including CT or MRI, are unable to distinguish these conditions with sufficient confidence.

Osteomalacia – Osteomalacia, like PDB, may present with bone pain and an elevated serum alkaline phosphatase (sAP). The radiographic findings characteristic of PDB are absent. Pseudofractures may be present in osteomalacia (Looser's zones) but occur on the concave portion of the bone, unlike the fissure fractures in PDB that are present on the convex aspect. Osteomalacia is due to impaired mineralization of bone. The combined radiographic and laboratory features should allow these conditions to be readily distinguished. (See "Epidemiology and etiology of osteomalacia" and "Clinical manifestations, diagnosis, and treatment of osteomalacia".)

Osteosarcoma and giant cell tumors of bone – Osteosarcoma related to PDB typically presents with increasing localized bone pain and may be accompanied by soft tissue swelling in the affected area. Monitoring for the evolution of osteosarcoma arising in pagetic bone is not indicated. MRI can be helpful to define soft tissue anatomy and other changes of a malignancy such as cortical disruption by a mass. The diagnosis of osteosarcoma is made on bone biopsy. Giant cell tumors of bone are benign, but sometimes aggressive tumors that present with localized pain, swelling, and limitation of joint motion. In PDB, these tumors typically occur in the skull or pelvis of patients with polyostotic disease and can also arise in nonosseous tissues as extraskeletal osteoclastomas. Imaging studies and biopsy can help distinguish these lesions from each other and from PDB. (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis" and "Bone tumors: Diagnosis and biopsy techniques" and "Giant cell tumor of bone".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Paget disease of bone".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Paget disease of bone (The Basics)")

Beyond the Basics topic (see "Patient education: Paget disease of bone (osteitis deformans) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Paget disease of bone (PDB) is a fairly common finding in aging bone; it is often asymptomatic. Its onset is typically after age 55, with a slight predominance in men. It is common in England, Scotland, Central Europe, and Greece, as well as in countries and cities settled by European immigrants. Within these countries, there are geographical clusters of disease. Estimates of prevalence in some populations range from 3 percent in patients over 40 to up to 9 percent in older adults. (See 'Epidemiology' above.)

PDB is characterized by abnormalities of the osteoclast [53]; there are accelerated bone turnover and abnormal bone remodeling. Both genetic and environmental causes are thought to contribute to its pathogenesis. Inheritance appears to be autosomal dominant with variable penetrance, and multiple genetic loci have been associated with PDB. A pathogenic role for viral infection remains controversial. (See 'Pathogenesis' above and 'Genetic' above and 'Viral' above and 'Histopathology' above.)

The majority of patients with PDB are asymptomatic. Symptoms are usually due to overgrowth of the affected bone. Pain may arise directly, from a pagetic lesion in bone, or from secondary causes, including osteoarthritis, fracture, nerve impingement, or, rarely, tumor. Paget disease has a predilection for the skull, thoracolumbar spine, pelvis, and long bones of the lower extremities. The common clinical manifestations include bone pain or chronic back pain, bone deformities, and arthritis, and depend upon the region involved. (See 'Clinical manifestations' above.)

Osteosarcoma is a rare, usually fatal complication of PDB, which typically presents in those with longstanding skeletal disease. Such patients may report increased bone pain that is poorly responsive to medical therapy, local swelling, and, less often, a pathologic fracture. Giant cell tumors may arise in pagetic bone and are usually benign. (See 'Bone tumors' above.)

Laboratory findings, which reflect increased bone turnover and are typical of untreated disease, include elevated levels of serum alkaline phosphatase (sAP) and bone-specific alkaline phosphatase (bAP). The degree of elevation generally reflects the extent and activity of the disease, although this is not always the case. A normal or minimally elevated alkaline phosphatase may be seen in more limited disease. Serum calcium and phosphorus are normal in most patients. (See 'Laboratory findings' above.)

Plain radiographs reflect the abnormal bone turnover characteristic of disease. A predominantly osteolytic lesion may be seen early in disease. Over time, however, there is evidence of an osteoblast response, and the bone thickens and enlarges, with thickened cortices marked by tunneling and accentuated trabeculae at one or more affected skeletal sites. In late disease, there may be dense bone by plain film, with little evidence of remodeling by biochemical parameters. Increased uptake is seen focally at the sites of active pagetic bone lesions on radionuclide bone scanning. Bone scintigraphy is more sensitive than plain radiography, particularly in early disease. (See 'Plain radiographs' above and 'Bone scintigraphy' above.)

Diagnosis of PDB in patients with clinical or laboratory findings suggestive of disease is confirmed by the demonstration of characteristic radiographic changes. In most patients, the sAP is elevated, and additional tests of bone turnover are not required. We obtain a baseline radionuclide bone scan to document the extent and locations of skeletal involvement; we perform radiographs of affected sites to identify impending fractures, potential malignant lesions, osteoarthritis, or other bone abnormalities. (See 'Diagnosis' above and 'Role of imaging' above and 'Role of biochemical studies' above.)

PDB occurs in an aging population that also has an increased prevalence of malignancy, osteoarthritis, and osteoporosis. Although the diagnosis of PDB is usually evident from radiographic findings, other conditions may also be present or may have overlapping features. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Margaret Seton, MD, who contributed to an earlier version of this topic review.

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References