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.
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.
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.
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.
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,
but there is evidence that the disease has become less common and less severe in these regions over the past 25 years.
Linkage analysis identified SQSTM1, at chromosome 5q35, as directly related to the disease,
and genome-wide association studies have identified OPTN and RIN3 as causal genes.
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.
The radiographic findings of Paget disease are diagnostic in many patients, particularly in the lytic phase.
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.
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.
(Paget disease is shown in the images below.)
Lateral radiograph of the tibia in a patient with Paget sarcoma reveals a destructive bone-forming mass in the proximal tibia (osteosarcoma).
Lateral skull radiograph in a patient with Paget disease demonstrates a large, well-circumscribed lytic lesion (arrows) in the frontal and parietal bones (osteoporosis circumscripta).
CT image of the first sacral vertebra demonstrates marked cortical thickening (arrows) and trabecular coarsening. Courtesy of Lee F. Rogers.
Axial T1-weighted MRI of the knee in a patient with Paget disease reveals prominent dark lines in the medullary bone, indicating trabecular coarsening (arrows). Courtesy of Lee F. Rogers.
Whole-body bone scan in a patient with polyostotic Paget disease reveals intense uptake of radiopharmaceutical in the femur, pelvis, spine, and proximal right humerus. The cortical discontinuity of the proximal right humerus represents an insufficiency fracture (arrow). Courtesy of Lee F. Rogers.
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.
(See the images below.)
Anteroposterior radiograph of the hip in a patient with Paget disease demonstrates dense sclerosis involving the femoral head and neck (arrows). This is a high-risk area for insufficiency fracture.
Anteroposterior radiograph of the femur in a patient with late-stage Paget disease reveals a transverse insufficiency fracture through the proximal femoral shaft (banana fracture).
Other complications incude deafness, hydrocephalus, and osteosarcoma.
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.
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.
Patients who do not tolerate bisphosphonates can be treated with calcitonin.
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.
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.
Increased serum alkaline phosphatase level correlates with disease activity.
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.
Guidelines for Paget disease of bone were developed by the Paget’s Association and include the following
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.