Management of Paget Disease

David M. Slovik

Paget disease of bone, or osteitis deformans, is a focal disorder characterized by excessive resorption and rapid, disorganized formation of new bone leading to bony deformity. Paget disease typically involves one bone (monostotic), although more severe cases involve several bones (polyostotic). Genetic factors and viral infection are believed to play roles in pathogenesis. The incidence is 3.3% in autopsy series and 0.1% to 4.0% in radiologic studies. Approximately 2% of the US population older than age 60 years has evidence of Paget disease, mostly asymptomatic. Discovery is often incidental, on encountering an isolated serum alkaline phosphatase elevation or characteristic bony changes on plain films. At other times, it may be noted in the workup of back or extremity pain, gait disturbance, hearing loss, or high-output cardiac failure. The primary physician needs to be able to recognize the condition and know how and when to use agents that suppress osteoclastic activity.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5 and 6)

Pathophysiology

The pathophysiologic hallmarks of Paget disease are excessive osteoclastic destruction and resorption of bone, followed by the unregulated osteoblastic formation of new bone. The initial stimulus for bone resorption is unknown, but the process culminates in an abnormal pattern of lamellar bone. Excessive local vascularity and an increase in fibrous tissue, which extends into the marrow, are characteristic. Both cortical and cancellous bone may be involved, each with several foci at different stages. The nature of the resultant bone, which is mechanically defective, distorted, and enlarged, leads to the cardinal manifestations of Paget disease—bone pain and pathologic fractures.

Clinical Presentation

Although any bone may become involved, the common sites are spine, pelvis, skull, femur, and tibia. Most patients are asymptomatic, with Paget disease presenting as an incidental finding on x-ray films or an isolated elevation in alkaline phosphatase. Those who are symptomatic present with bone pain, bony deformity, fracture, or a complication of increased marrow vascularity or bony encroachment on neural structures. About 15% of patients have very localized (so-called “monostotic”) disease.

Bone pain may result from fracture or be due to lytic activity. In the latter instance, it is usually located over areas of bone where very active osteoclastic resorption is taking place. The severity of pain does not always parallel the extent of radiographic involvement. Exacerbating factors include weight bearing, muscular activity, and cold weather. Fractures may affect the vertebrae or long bones, especially the lumbar and sacral regions of the spine and the lesser trochanter of the femur and the upper one third of the tibia. A history of trauma can usually be elicited, but some of these fractures may occur spontaneously. Pain may result, but vertebral fractures are often painless, although they can lead to a loss of height, kyphoscoliosis, and, in rare instances, spinal cord compression.

Bony deformity and encroachment are most notable in the skull, which may become visibly enlarged in the frontal and occipital regions. The overlying superficial blood vessels often become prominently dilated and visibly pulsatile. Hearing loss can ensue from the involvement of the ossicles in the middle ear, which impinge on the eighth cranial nerve in the temporal bone. Cerebellar and long-tract signs are complications of posterior fossa encroachment. Vertebral encroachment on the spinal cord or nerve roots is a rare but very serious consequence that can cause a compression syndrome leading to paraplegia. Deformity of the long bones is manifested as anterolateral bowing with resultant gait abnormalities, low back pain, joint pain, and increased susceptibility to fracture.

Degenerative joint disease can ensue when hypertrophy of subchondral bone damages the overlying cartilage and causes joint dysfunction; it accounts for about 50% of the discomfort experienced by patients. Hip pain can develop from long-standing subchondral disease of the acetabulum and femoral head, leading to protrusio acetabuli. Degenerative disease of the knee joint may occur in a similar fashion if the distal femur or patella becomes pagetic.

Extensive and severe skeletal involvement increases the risk for osteogenic sarcoma, an uncommon but uniformly fatal cancer that affects less than 1% of pagetic patients. It is heralded by localized pain, bony enlargement, and a very high and rapidly increasing alkaline phosphatase.

Hyperuricemia leading to gouty arthritis and hypercalciuria resulting in renal calculi are among the biochemical consequences of disrupted bony metabolism. Hypercalcemia can be precipitated by immobilization. High-output heart failure may occur in patients with extensive Paget disease because of the marked increase in the vascular bed.

Clinical Course

Although many patients manifest slow radiologic progression, most never develop symptoms. Others are noted to have radiologic changes that remain stable; a few have rapidly progressive disease. Although clinical remission after treatment is the rule, new complications can occur in those who do not achieve full biochemical remission (see later discussion).

DIAGNOSIS (3,7)

Most patients present with asymptomatic disease, either as an incidental finding on a plain film of the spine, pelvis, skull, femur, or tibia or as an isolated elevation in alkaline phosphatase. Serum alkaline phosphatase produced by osteoblasts is usually increased and correlates with the degree of new bone formation. Urinary hydroxyproline—a measure of bone matrix resorption—is also increased. In most patients, these parameters are complementary markers of disease activity and parallel radionuclide uptake on bone scan, which is the most sensitive measure of disease activity. In patients with disease localized to a single bone, the results of standard serum and urine tests may be normal. The bone-specific alkaline phosphatase level provides a more sensitive determination of new bone formation, and the urinary level of pyridinoline and N-telopeptide (a specific component of bone matrix) are better measures of bone resorption. Although these tests are substantially more expensive than the unfractionated
alkaline phosphatase, they are better indicators of disease activity, especially in persons with involvement limited to a single bone. However, the serum alkaline phosphatase correlates well with the other tests, and for routine monitoring, it alone can be measured.

Technetium bone scan demonstrates areas of increased uptake before diagnostic changes are visible on standard radiography. The first radiologic bony changes occur in the lytic phase and are well-demarcated areas of decalcification (seen best in the skull). With the onset of new bone formation, areas of increased density become evident, as does the expansion of bone and coarse trabeculation. In later phases, sclerosis, enlargement, and increased bone density are observed. The localized enlargement of bone that results is unique to Paget disease and helps to distinguish it from other causes of bony sclerosis, such as prostatic cancer. Radiologic changes are most commonly evident in the pelvis, femur, and skull. A bone scan should be obtained on all patients with known or suspected Paget disease, followed by plain radiographs of the pagetic area.