Practice Essentials
Paget disease of bone (osteitis deformans) is a metabolic disorder characterized by abnormal osseous remodeling. Sir James Paget first described Paget disease in 1877 as a chronic inflammatory remodeling disease of bones. He termed the condition osteitis deformans. [1, 2, 3, 4] Paget disease of bone is caused by a localized increase in osteoclastic and osteoblastic activity and can progress to involve the entire bone. Deformed, enlarged bones are a common feature, especially in weight-bearing areas. [5] Genetic factors play an important role in pathogenesis, with evidence that susceptibility may be determined by variants in or near genes that regulate osteoclast function. [6, 7, 8, 9, 10, 11]
Paget disease of bone is the second most common bone disorder in elderly persons after osteoporosis. The disease occurs most commonly in the pelvis, spine, skull, and long bones. [12, 13] The disorder is most common in Europe, North America, and Australia but is rare in Asia and Africa. The prevalence of Paget disease has been found to be higher in regions with people of British descent, [10, 11, 14] but there is evidence that the disease has become less common and less severe in these regions over the past 25 years. [8, 10, 11] Linkage analysis identified SQSTM1, at chromosome 5q35, as directly related to the disease, [8] and genome-wide association studies have identified OPTN and RIN3 as causal genes. [9, 7]
Paget disease evolves through 3 stages: (1) an early lytic or hot phase; (2) an intermediate or mixed phase; and (3) a final or cold phase, marked by dense bone formation.
Imaging modalities
The radiographic findings of Paget disease are diagnostic in many patients, particularly in the lytic phase. [15, 16, 17] The lytic stage most commonly is observed in the skull and long bones. The typical appearance in the long bones is osteolysis, which begins in the epiphysis and advances along the diaphysis. Trabecular coarsening and distortion and cortical thickening are observed in the sclerotic phase, typically involving the axial skeleton. However, given the variable imaging appearance of Paget disease in different stages, as well as the many different bones involved, the differential diagnosis may vary substantially among patients. [1, 10]
The changes caused by Paget disease can also be detected by computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) CT, which can help distinguish Paget disease from other potential causes and assess complications. Isotopic bone scans have been recommended to define the extent of metabolically active disease. [18, 19, 20]
(Paget disease is shown in the images below.)
Paget disease rarely is diagnosed in the initial lytic phase. At this early point of the disease, osteoclastic activity is predominant. Paget disease usually begins at the end of a bone, except when it occurs in the tibia. A characteristic sharply demarcated zone of osteolysis may begin in the subcortical bone and advance along the diaphysis. Osteoblastic activity lags behind; thus, radiolucent fibrous tissue replaces normal bone.
The intermediate or mixed phase reveals evidence of osteolytic and disorganized osteoblastic activity. New bone forms abnormally and demonstrates characteristically coarsened trabeculae and cortical thickening in the cancellous and compact bone, respectively. Characteristic intracytoplasmic inclusions may be observed microscopically, supporting evidence for the viral etiology theory.
The final or cold phase demonstrates less evidence of continual osseous remodeling. Previously laid down woven bone is converted to dense lamellar bone. Histologic features of disorganized bone are prominent. The intersecting lines of remodeled bone have a characteristic mosaic pattern histologically.
Insufficiency fractures in patients with Paget disease may present with pain that can last up to several weeks. If pain is focal and severe, it may be a sign of an impending, complete fracture, and radiographic evaluation is warranted. Insufficiency fractures most frequently affect the femur and tibia. Involvement in critical weight-bearing locations may lead to fracture or severe secondary arthritis. [21, 22, 23]
(See the images below.)
Other complications incude deafness, hydrocephalus, and osteosarcoma. [18] Involvement of the spine may cause nerve entrapment and even spinal canal stenosis. Paget diesease is also associated with aortic stenosis, atherosclerosis, and intracardiac calcification. [19]
Treatment
Treatment with nitrogen-containing bisphosphonates (eg, zoledronic acid, pamidronate, alendronate, risedronate) is recommended in cases of active disease or in individuals at risk of possible complications such as arthritis, gait changes, hearing loss, nerve compression syndromes, or osteosarcoma. [13] Patients who do not tolerate bisphosphonates can be treated with calcitonin. [24]
Bisphosphonates are considered to be the treatment of choice because they are highly effective at suppressing increased bone turnover. Studies have shown that treatment with alendronate and risedronate, for example, can promote formation of lamellar bone in affected sites. Bisphosphonates have also been shown to improve bone pain. [25]
A single 5-mg intravenous infusion of zoledronic acid has been found to be able to normalize alkaline phosphatase levels for up to 6.5 years. [26] Increased serum alkaline phosphatase level correlates with disease activity. [24]
In a Cochrane database review by Corral-Gudino et al, 10 trials (801 participants) compared bisphosphonates (etidronate, tiludronate, ibandronate, pamidronate, olpadronate, alendronate, risedronate, zoledronate) with placebo, and the bisphosphonates were found to have tripled the percentage (31% versus 9%) of patients whose bone pain resolved. [27]
Guidelines
Guidelines for Paget disease of bone were developed by the Paget’s Association and include the following [28, 29, 30] :
-
Radionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of metabolically active disease.
-
Serum total alkaline phosphatase (ALP) is recommended as a first-line biochemical screening test in combination with liver function tests.
-
Bisphosphonates are recommended for the treatment of bone pain. Zoledronic acid is recommended as the bisphosphonate most likely to provide a favorable pain response.
Radiography
In the skull, the lytic phase (osteoporosis circumscripta) typically involves the frontal or occipital bones and progresses to a mixed pattern with multifocal sclerotic patches in the intermediate stage of the disease, referred to as a cotton wool appearance. [31]
(See the images below.)
The vertebral bodies typically become enlarged with a prominent cortical margin (picture frame vertebrae) or become densely sclerotic, mimicking lymphoma or metastatic disease (ivory vertebra). (See the images below.)
In the pelvis, typical findings include thickening of the iliopectineal line in early stages, progressing to patchy sclerosis and lucency in later stages. (See the image below.)
Weakening of the pagetic acetabular bone may lead to protrusio acetabuli and insufficiency fracture. (See the image below.)
In the long bones, early involvement consists of lysis of the subarticular bone, which advances along the diaphysis with the characteristic shape of a blade of grass. Long bones are affected first in the epiphyseal region, with the exception of the tibia, where Paget disease frequently begins in the tubercle.
Later stages of disease show development of enlarged, sclerotic, deformed bones with thickened coarse trabeculae. The weakened femur and tibia eventually may become bowed under the stress of weight bearing. Insufficiency fractures may occur, characteristically involving the convex cortical surface. Conversely, Looser zones of osteomalacia typically occur on the concave cortical surface. (See the images below.)
Development of secondary sarcoma in pagetic bone is the most lethal complication of Paget disease, occurring in 1% or fewer of patients with Paget disease (see the image below). These sarcomas are aggressive and may be multicentric. Short-term interval follow-up and/or cross-sectional imaging may prevent diagnostic errors and initiate prompt attention to a newly developing lesion. [32, 33, 34]
Computed Tomography
Cross-sectional MRI and CT demonstrate the altered bone structure seen in Paget disease, such as coarsened trabeculae, thickened cortices, and bone hypertrophy. Findings that are present on plain radiography are often better displayed on CT. MRI does not depict the changes in mineralization as well as traditional radiography or CT. MRI, however, can show alterations in marrow characteristics that can mirror the pathologic changes occurring during the course of the disease. Thus, earlier in the disease, marrow signal can be normal or hypervascular, while later changes can show fatty replacement of the marrow. [35]
The anatomy is well demonstrated by cross-sectional imaging in complex structures, such as the spine, where spinal or nerve root compression may be an issue. Cross-sectional imaging also helps delineate the pathology in complicated Paget disease, which includes nerve or spinal cord compression, as well as basilar invagination at the skull base and osseous encroachment involving cranial nerve foramina.
Secondary sarcomatous development also is better evaluated with cross-sectional imaging. Additionally, should biopsy be indicated for the diagnosis of sarcoma, CT typically is the guidance modality of choice. (See the images below.)
Magnetic Resonance Imaging
In a study of the use of MRI in patients with Paget disease of the spine, MRI showed a mixed pattern of increased/decreased T1 signal (fine trabecular or coarse) of the vertebral bodies. Band-like decreased T1 and T2 signal of the endplates was also present, correlating with the mixed osteolytic and blastic phase of the disease. Subtle or conspicuous picture-frame appearance was also noted. In most cases, there was expansion of the vertebral body and/or posterior elements/spinous process. [36]
(See the images below.)
Nuclear Imaging
Skeletal scintigraphy is useful. Radionuclide bone scans are more sensitive than radiographs for the diagnosis of Paget disease. Additionally, bone scans help survey the different sites of involvement with polyostotic disease.
Characteristically, a marked uptake of radiopharmaceutical in the involved bones is observed. However, late-stage involvement may not reveal intense radiopharmaceutical uptake, and osteoporosis circumscripta may demonstrate only a peripheral rim of increased uptake. Scintigraphy tends to follow the physiologic activity of disease and may monitor treatment.
Polyostotic Paget disease often can be distinguished from multiple metastatic lesions, although occasional difficulties occur. Perform radiographic correlation when this situation arises. Furthermore, the diagnosis of fracture or sarcoma may be challenging, often requiring multimodality correlation. (See the images below.)