Paget's Disease of Bone

(Osteitis Deformans)

Paget's disease of bone is a progressive focal disorder of bone remodeling in which normal bone matrix is removed and replaced with softened, enlarged bone matrix. Some patients develop bone pain or deformity. Diagnosis is confirmed by plain x-rays. Treatment includes symptomatic measures and sometimes drugs (usually bisphosphonates).

Geriatric Essentials

• Paget's disease primarily affects elderly people.
• Paget's disease should be considered in elderly patients with bone pain, deformity, compression neuropathy, an elevated alkaline phosphatase level, and typical x-ray abnormalities or in those who develop hypercalcemia while on bed rest.
• Hypercalcemia may occur in patients with Paget's disease who are immobilized.

Paget's disease of bone is initiated by the proliferation of abnormally large osteoclasts, which resorb bone at local affected sites. Resorption is followed by a variable, but often marked, increase in the formation of new bone that is architecturally disorganized.

Paget's disease is estimated to occur in 2 to 3% of people > 60 in the US. It is most common in Europe (except Scandinavia), Australia, and New Zealand. The relative risk is increased about 7-fold in first-degree relatives of patients with the disease.

Etiology has not been established, but genetic factors and a paramyxovirus infection may be involved. Several genetic abnormalities have been identified, but these may be different in different kindreds, indicating genetic heterogeneity. Structures resembling viral nucleocapsids have been identified in osteoclasts affected by Paget's disease, but the results of studies of viral RNA expression in affected bone are inconsistent.

Pathophysiology

Lesions may be single or multiple and can involve any part of the skeleton, most commonly the pelvis, femur, skull, tibia, spine, clavicle, and humerus. Osteoclasts affected by Paget's disease are large and have many more nuclei than normal. Similarly, the osteoblastic response is exuberant and disorganized, producing mosaic bone with a woven pattern of collagen deposition. The adjacent marrow is vascular and often shows fibroblastic proliferation and decreased hematopoiesis. The hypercellularity may diminish, leaving sclerotic bone with little cellular activity, the so-called burned-out phase of Paget's disease. Frequently, all phases of the process occur simultaneously in a patient or even in a single lesion.

Overgrown bone may compress nerves and other structures passing through small foramina. Osteoarthritis may develop in joints adjacent to involved bone. Some patients with Paget's disease develop secondary hyperparathyroidism.

Symptoms and Signs

Patients may be asymptomatic for many years. Deformities, compression neuropathies, pathologic fractures, bone pain, hypervascularity, and osteoarthritic changes in adjacent joints may be initial symptoms. Changes in the skull often lead to impaired CNS function, particularly hearing loss due to involvement of the petrous bone. Involvement of the base of the skull may produce platybasia and basilar invagination, which leads to the rare, but serious, complication of brain stem compression. Vertebral deformity may lead to spinal stenosis or cord compression. Although long bones affected by Paget's disease often show increased density, their irregular structure leads to fragility and increased risk of fracture as well as skeletal deformity, including kyphosis. The bone deformity can lead to damage to articular cartilage with consequent osteoarthritis, especially in the knee and hip. Bowed legs may cause abnormal gait. Bone hypervascularity may produce palpable local warmth and increase cardiac output, aggravating coexisting heart failure. Angioid streaks in the retina may occur but rarely impair vision.

Sarcomatous changes in affected bone probably occur in < 1% of patients; however, osteosarcoma in the elderly is often associated with Paget's disease. Fibrosarcoma and chondrosarcoma may also occur. Such tumors may result in pathologic fractures. Benign giant cell tumors, which are called reparative granulomas or osteoclastomas, can also occur adjacent to lesions affected by Paget's disease.

The increased incidence of primary hyperparathyroidism among patients with Paget's disease may be real or may be due to more intense investigation by health care practitioners at the metabolic bone disease clinics to which these patients are referred. Hypercalcemia, although uncommon, occurs in immobilized patients with the disease or may be caused by secondary hyperparathyroidism; thus, patients with Paget's disease who require immediate bed rest should be monitored. Hypercalciuria, hyperuricemia, and gout occur more frequently in patients with Paget's disease, but the incidence of renal calculi does not seem to increase much.

Diagnosis

Diagnosis of Paget's disease may be suggested by bone pain, deformity, compression neuropathy, or other typical symptoms. Asymptomatic Paget's disease may be detected incidentally by finding an elevated serum alkaline phosphatase level, by finding a suggestive x-ray abnormality, or by finding hypercalcemia in an elderly patient on bed rest. Further evaluation consists of plain x-rays; a bone scan using technetium-labeled phosphonates; and measurement of serum alkaline phosphatase, Ca, and phosphate levels. Occasionally, measuring urinary markers of bone resorption (eg, pyridinoline cross-links) can be helpful.

Increased uptake on bone scan is not diagnostic but indicates the sites at which x-rays should be taken; it is particularly useful in differentiating degenerative joint disease from lesions of Paget's disease. X-ray lesions may be largely osteolytic, osteoblastic, or mixed (see Photo 49-1). The initial osteolytic lesion in the skull, termed osteoporosis circumscripta, may be followed by a marked increase in bone formation, ultimately leading to a thickened calvaria with an irregular "cotton wool" appearance (see Photo 49-2).

Typical laboratory findings include an elevated serum alkaline phosphatase level (increased anabolic activity of bone) but usually normal serum phosphate levels. Serum Ca is usually normal but can increase because of immobilization or hyperparathyroidism. If the alkaline phosphatase level is not elevated or it is unclear whether the increased serum alkaline phosphatase is of bony origin, a bone-specific fraction can be measured.

Alkaline phosphatase levels should be tested yearly in patients with Paget's disease who are being monitored without therapy. Hearing should be checked at 1- to 2-yr intervals.

Prognosis

With currently available treatment, prolonged biochemical remission and arrest of the disease process are usually possible. However, complications such as bone deformities and osteoarthritis cannot be reversed by using drugs that treat Paget's disease. Patients who develop osteosarcoma, fibrosarcoma, or chondrosarcoma have a grave prognosis and respond poorly to chemotherapy. However, benign giant cell tumors can be sensitive to glucocorticoids and antiosteolytic drugs (eg, bisphosphonates, calcitonin).

Treatment

Localized asymptomatic disease may be monitored without treatment unless lesions are at sites where complications often develop (eg, long bones, vertebrae, joints).

Drug therapy: Drugs (see Table 49-1) should be given to patients at risk of developing complications, including those with demonstrable osteopenia or osteoporosis and those whose disease affects weight-bearing sites (eg, long bones, vertebrae), joints, or sites where neurologic damage is likely to occur. Severe deformities, neurologic symptoms (including hearing loss), and degenerative joint changes in patients with more advanced disease are frequently irreversible. However, drug treatment can slow or prevent further deterioration.

Patients being treated with drugs should have their serum alkaline phosphatase levels measured to assess biochemical remission, but measurements of urinary collagen cross-link excretion are more sensitive for early detection of clinical remission and relapse. In general, drug treatment should be continued until a biochemical remission has occurred; however, remission cannot always be achieved in severe cases.

Bisphosphonates are the drugs of choice, and recent studies indicate that IV therapy is most effective (see Table 49-1). Shorter courses of oral bisphosphonates may be effective in treating milder cases.

Surgery: Patients with severe deformities and irreversible osteoarthritic changes in the hip or knee joints may be treated surgically. Hip and knee replacements can be successful. Osteotomies can relieve nerve compression.

Ancillary measures: Ca and vitamin D intake should be adequate to prevent impairment of mineralization in bone that is turning over rapidly and to help reduce the rate of bone remodeling; daily requirements are usually about 1000 mg for Ca and 400 to 800 IU for vitamin D. Antiarthritic drugs should be used in patients with joint involvement in whom pain often persists despite biochemical remission. Orthotics can help correct abnormal gait caused by bowed legs. Weight bearing should be encouraged and bed rest should be avoided. If a patient with Paget's disease must be on bed rest, bisphosphonate therapy and hydration are indicated to prevent hypercalcemia.

This topic was last updated February 2006.