Click here to view next page of this article

 

PAGET'S DISEASE OF BONE

Paget's disease is a chronic skeletal disorder characterized by increased bone remodeling and abnormal bone architecture. The pathologic process is initiated by osteoclasts that are abnormal in morphology and function. In Paget's disease, osteoclasts have increased bone-resorbing activity. The increase in resorption results in a compensatory increase in bone formation and accelerated bone turnover. Bone that is remodeled by this pathologic process is formed haphazardly. Ultimately, pagetic bone becomes enlarged, mechanically weakened, and highly vascular Paget's disease.

The etiology of Paget's disease is unknown. Epidemiologic studies have documented a marked variation in the geographic distribution of the disease, suggesting a dominant influence of environmental and ethnic factors. Paget's disease is most common.

A viral etiology for Paget's disease was first suggested by the presence of nuclear and cytoplasmic inclusions in pagetic osteoclasts. These inclusions resemble the paramyxovirus family of viruses and have been shown by immunohistochemical studies to contain measles virus, respiratory syncytial virus, and parainfluenza virus antigens. A variety of molecular techniques have been used.

CLINICAL FEATURES

Paget's disease usually develops after age 40 and is rarely diagnosed in individuals younger than 25 years of age. The disease may be monostotic or polyostotic with asymmetrical involvement. Although new sites rarely become involved after the initial diagnosis, the disease may progress.

Most patients with Paget's disease are asymptomatic. In symptomatic patients, bone pain is the most common symptom. The pain is typically characterized as dull and aching, is present at rest, and may be exacerbated by weight bearing if present in the back, pelvis, or lower extremity. Patients with skull involvement.

Deformity in patients with long-standing Paget's disease typically occurs in long bones and the skull. The spectrum of skeletal deformities includes bowing deformities of long bones, acetabular protrusion of the hips, frontal bossing, skull enlargement, kyphosis, and scoliosis. Fissure or stress fractures.

Pathologic fracture is a common complication of Paget's disease. The most common sites for pathologic fracture are the femur and tibia. The spine and humerus are less frequently involved.

Involvement of the skull is associated with a mixed sensory and conductive hearing loss and less commonly with cranial nerve palsies. Severe, long-standing skull involvement may result in platybasia. Malignant degeneration in Paget's disease probably occurs in less than 1% of patients. Most of the tumors are osteogenic sarcomas. Fibrosarcomas, chondrosarcomas, and malignant fibrous histiocytomas have also been reported. Malignant degeneration typically manifests as a change. Giant cell tumors are benign neoplasms that develop in patients with Paget's disease.

TREATMENT

The management of Paget's disease has benefited from the development of potent inhibitors of osteoclast-mediated bone resorption. Antiresorptive agents that can be used in the management of Paget's disease include calcitonin, bisphosphonates, and plicamycin.

When treating symptomatic patients, the clinician is challenged to identify patients who are likely to benefit from antiresorptive therapy. Patients with bone pain and increased warmth.

Treatment of asymptomatic patients who are at risk for developing complications has been proposed because of the progressive nature of the disease, the severity of its complications, and the observation that controlling the activity of the disease is associated with restoration of a more normal bone.

Calcitonin

Calcitonin is a polypeptide hormone secreted by C cells of the thyroid. In pharmacologic doses, calcitonin inhibits osteoclast-mediated bone resorption.

Bisphosphonates

Bisphosphonates are synthetic analogues of inorganic pyrophosphate (P-O-P) in which oxygen.

Etidronate

The usual dose of etidronate (Didronel) for the treatment of Paget's disease is 5 mg per kg of body weight daily for 6 months administered as a single dose in the middle of a 4-hour fast.

Alendronate

Alendronate (Fosamax) is an orally administered aminobisphosphonate approved for the treatment of Paget's disease. Comparative trials in patients with Paget's disease have established that alendronate is considerably more potent than etidronate. Unlike etidronate, therapeutic doses of alendronate.

Tiludronate

Tiludronate (Skelid) was recently approved for use in the treatment of Paget's disease.

Pamidronate

Pamidronate (Aredia) is an aminobisphosphonate that is available in the United States only as an intravenous preparation. The oral formulation was withdrawn from the United States market.

Other Bisphosphonates Under Development

Residronate is a potent bisphosphonate that has been shown to be effective when administered orally to patients with Paget's disease, including patients refractory to other therapies. Zoledronate and ibandronate are new bisphosphonates that are effective at microgram doses. Clinical investigations are under way using these drugs as an intravenous injection and in a transdermal drug-delivery system. With emergence of more potent bisphosphonates, it should be possible to return bone markers to normal and restore normal new bone formation in most patients.

Plicamycin

Plicamycin (formerly mithramycin) is an antibiotic that has been shown to be effective in treating patients with Paget's disease when administered as a 4- to 8-hour infusion at doses of 15 to 25 mug per kg of body weight per day. Doses are repeated every 2 to 3 days as required. Because plicamycin may cause hepatic, renal, and bone marrow toxicity, its use is limited to patients with severe, refractory disease.

Gallium Nitrate

Gallium, a group IIIa metal compound, is an inhibitor of bone resorption. It absorbs to calcium phosphate and localizes to sites of bone remodeling. Bone resorption is inhibited.