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Paget disease of bone: Diagnosis and drug therapy

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CLINICAL PRESENTATION

Most patients with Paget disease have no symptoms and come to medical attention because of an elevated serum alkaline phosphatase level or characteristic findings on radiographs ordered for other indications.11 Paget disease is the second most common disorder of aging bone after osteoporosis. Yet unlike osteoporosis, which presents as a systemic fragility of bone, the clinical manifestations of Paget disease depend on which bones are affected and how enlarged or misshapen they have become.

Common complications

As a consequence of this abnormal bone remodeling and overgrowth, many patients present with bone pain. Bone deformity, headache, and hearing loss may also occur (Figure 1), as well as fractures and nerve compression syndromes (eg, spinal stenosis, sciatica, cauda equina syndrome).

Figure 1. Lateral view of the skull of an elderly person who suffers from headache and hearing loss due to Paget disease. Note the thickened skull (thin arrow), and the “cotton wool” spots (thick arrow) that characterize the osteoblastic response.

It is important to remember that “pagetic” bone may not be the source of pain, and that functional impairment caused by degenerative changes at affected sites is common (Figure 2).30,31

In a study from the New England Registry for Paget’s Disease,32 most patients knew fairly well which bones were affected and what complications resulted from this when deformity, fracture, or total joint replacement had occurred.32 Although Paget disease did affect their quality of life as measured by physical functioning on the Short Form-12 assessment, these impairments did not seem to affect their outlook, which was as good as or better than that in other people their age.

Metabolic complications

Figure 2. Long-standing Paget disease of the right hemipelvis, with thickening of the iliopectineal line (blue arrow) characteristic of Paget disease, and distortion and overgrowth of the right pelvis. Note that the disease does not cross joint lines, sparing the sacrum and left hemi-pelvis. This woman has monostotic Paget disease. She presented 20 years ago with an elevated serum alkaline phosphatase (765 U/L). She has not had pain, although degenerative changes are evident in the right hip, and physical examination showed some loss of range of motion. Treated for both breast and renal cancer during this time, she has never had any known metastases to bone (see text).

Metabolic complications of Paget disease are rare today but can occur in an elderly patient who has active, polyostotic (multibone) disease.33 The accelerated rate of bone remodeling and the increased vascularity of pagetic bone have been reported to lead to high-output heart failure. In theory, treatment should ease this by diminishing blood flow to pagetic bone and restoring bone turnover to more normal levels.34

Hypercalcemia can occur when patients with Paget disease are immobilized for any reason, and there is probably a higher incidence of renal stones in patients with Paget disease.35,36

Malignant complications

Osteosarcoma rarely arises in pagetic bone. Yet Paget disease may account for a significant number of cases of this cancer in the elderly.37 In these cases, osteosarcoma is presumed to be driven by a second genetic mutation, has a genetic signature distinct from that in osteosarcomas occurring in youth, and is quite resistant to treatment.38 In Scandinavia and Japan, where Paget disease is rare, the second peak of osteosarcoma that occurs with aging seems muted as well.39,40 These cancers present with pain, soft-tissue swelling, and variable elevations in serum alkaline phosphatase. Investigations to date suggest that pagetic lesions and osteosarcomas arising in pagetic bone are probably both driven to some extent by stromal cells overexpressing RANK ligand and may not represent defects intrinsic to the osteoclast.41

Giant-cell tumors of bone are also rare but can arise in pagetic bone. A cluster of cases was reported in Avellino and other towns of southern Italy.42 Again, the lesions occur in older individuals and in different sites than those seen in the benign giant-cell tumors recorded in patients without Paget disease.

Metastases from lymphomas, prostate cancer, and breast cancer certainly occur in bone, but rarely in pagetic sites.43 A recent case study noted that patients with prostate cancer who also had Paget disease had a later onset of metastasis to bone than patients without coincident Paget disease.44

A THOUGHTFUL ASSESSMENT

Evaluating a patient with Paget disease requires a thoughtful assessment of its musculoskeletal consequences in an aging skeleton. Pain in Paget disease is often multifactorial. In the elderly, end-stage degenerative disease of the spine, hip, and knees, mechanical instability, compression fractures of the spine, and neuropathies may compound the clinical picture. Therefore, a thorough evaluation is required to plan effective therapy.

Alkaline phosphatase and other markers

A screening serum alkaline phosphatase level is usually sufficient to measure bone turnover. Produced by osteoblasts, alkaline phosphatase is a marker of bone formation, but an imperfect one. Often it is elevated in active Paget disease—but not always.45 Many patients have normal serum alkaline phosphatase levels, particularly if they have monostotic (single-bone) disease. It is unclear why, in a disorder marked by accelerated bone remodeling, the biochemical markers are inconsistent measures of bone turnover.

Research into biochemical markers of Paget disease has had two aims: to identify the single best marker for baseline assessment of pagetic bone activity and to find out whether this measurement responds to therapy.46,47 Measures of bone formation such as bone-specific alkaline phosphatase, osteocalcin, and the procollagen type I peptides, and measures of bone resorption including the pyridinolines, hydroxyproline, and cross-linked collagens, have been analyzed as markers of bone remodeling and show no real advantage over the serum alkaline phosphatase level as reflections of bone turnover. As alkaline phosphatase measurement is inexpensive, available, and reliable, it should be used preferentially, with gamma-glutamyl transpeptidate or 5′ nucleotidase confirming the source as either liver or bone. Readers are directed to a recent review in which the utility of these markers is explored in more detail.48

Imaging studies

Figure 3.

Bone scans can give us an idea of the extent, location, and general activity of the disease (Figure 3). Uptake is avid in affected bones, beginning in the subchondral region and spreading throughout the bone. Bone scans can be particularly useful in defining sites of active disease when the serum alkaline phosphatase level is normal.

Plain radiography of the affected bones outlines the anatomy of the problem and gives some insight into the cause of pain (Figure 3).

Figure 4. (A) Compression fracture of the lumbar spine through a pagetic vertebral body (arrow) in a middle-aged man presenting with pain and clinical symptoms of spinal stenosis. (B) With computed tomography, a reconstructed view of the fourth lumbar vertebral body shows disorganized trabeculae, with Paget disease extending into the posterior processes.

Computed tomography or magnetic resonance imaging may prove useful in cases of spinal stenosis, cauda equina syndrome, compression fractures, or suspected malignancy (Figure 4), but these studies are expensive and generally are not needed.

Radiographic features. Paget disease is presumed to be a disease of the osteoclast, and the earliest lesion is described as lytic. In my own experience, it is unusual to see a purely lytic lesion, although sometimes the disease presents in the skull in this way—osteoporosis circumscripta—or in the femur or tibia with an advancing edge of pure osteolysis.

Figure 5. Classic changes of Paget disease, beginning in the proximal tibia, with thickened bone, cortical tunneling (thick arrow) and mixed scleroticlytic lesions. An advancing leading edge of bone resorption is present (thin arrow).

More often, one sees evidence of both resorption by osteoclasts and formation by osteoblasts, reflecting the coupling of these two processes in this disease. Radiographic findings on plain films are usually definitive, showing enlargement of the affected bone, deformity, coarsened trabeculae, and thickened cortices with tunneling (Figure 5).49 In weightbearing bones, pseudofractures may stud the convex surface. These incongruities of bone may persist for years, heralding fracture only when there is focal pain (Figure 6).50

Biopsy is infrequently needed

Figure 6. (A) Plain radiography of the left femur of a woman with Paget disease shows advanced disease, with coarsened trabeculae at the femoral head (short arrow), deformation of the femur, and pseudofractures studding the lateral cortex. The long blue arrow marks the focal area of tenderness described by the patient. Visible is some attendant, reactive sclerosis associated with the pseudofracture. Osteopenia is present in the pelvis. (B) An atraumatic “chalk-stick” fracture occurred at the site of tenderness (arrow). Despite surgical stabilization, pain persisted for more than 6 months after the diaphyseal fracture. (C) Zoledronic acid was prescribed, which resulted in a thickened callus and a return to weight-bearing.

If these diagnostic findings are not present, then biopsy is indicated. In the United Sates and Canada, where Paget disease is fairly common, biopsy is infrequently needed and is usually reserved for situations in which the differential diagnosis includes cancer, as when the cortex cannot be clearly visualized, the lesions are atypical in pattern or location, or there is a single sclerotic vertebral body on imaging.51

The other indication for biopsy is a “new” pagetic lesion. For reasons unknown, the pattern of skeletal involvement in Paget disease tends to be stable throughout the patient’s lifetime. This is another reason why a baseline bone scan is useful.

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