A side from osteoporosis, Paget's disease is the most common bone disorder.¹ Paget's disease is equally prevalent in men and women, with increased incidence in persons older than 50 years. It affects approximately 3 percent of persons in the United States, and as many as 10 percent of persons older than 80 years.^2,3

Paget's disease occurs in three phases.^1,4 The initial phase consists of intense osteoclastic activity and bone resorption, with bone turnover as high as 20 times the normal rate.⁵ This phase is followed by an osteolytic-osteoblastic phase during which osteoblasts begin to produce an abundance of woven bone, but mineralization is ineffective. In the final phase, dense cortical and trabecular bone deposition dominates, but it is sclerotic, disorganized, and weaker than normal bone.⁴

Paget's disease most commonly involves the axial skeleton, but it can affect any area (Table 1).⁴ In the majority of patients, Paget's disease affects at least two bones, but in one third of patients only one bone is affected.¹

Etiology

Although the etiology of Paget's disease is unknown, studies have provided some support for both viral and hereditary causes. Viral antigens have been detected in affected osteoclasts by numerous methods and research teams.⁵ In the United States, the measles virus antigen is most commonly detected in patients with Paget's disease.^6–8

A positive family history is reported in as many as 40 percent of patients with Paget's disease. Much attention has been focused on a pagetic susceptibility locus at human chromosome 18q.^1,4,5,9–11

Diagnosis

An estimated 70 percent of patients who have Paget's disease have no symptoms.⁴ The diagnosis is typically found incidentally on radiographs and laboratory investigations. Clinical manifestations, when present, may be wide in spectrum (Table 2).¹²

Patients with bone pain caused by Paget's disease usually describe the pain as continuous. Unlike osteoarthritis, pagetic bone pain usually increases with rest, on weight bearing, when the limbs are warmed, and at night.^1,4 Paget's disease can cause osteoarthritis if the affected section of bone is near a joint.¹

A variety of deformities may occur, including kyphosis; shortened or bowed limbs⁹ (Figure 1); leonine facies³; frontal bossing of the forehead³; dental abnormalities; and, in severe cases, an enlarged cranium that may be difficult to hold erect.

Neurologic symptoms arise from the compression of nerves, which is caused by osseous growth. Resulting sequelae include cranial nerve, brain stem and cerebellar deficits, and deficits caused by spinal stenosis. Although cardiovascular involvement is uncommon, patients with widespread Paget's disease and extensive hypervascularization of the bone marrow can present with an arteriovenous shunt leading to high output cardiac failure.

The incidence of malignant degeneration of pagetic bone ranges from less than 1 percent to 10 percent, depending on disease severity.¹ Usually, these tumors are highly malignant osteosarcomas, fibrosarcomas, or undifferentiated spindle cell sarcomas.^13,14 Radiologic characteristics suggestive of malignant transformation include cortical breakthrough and soft tissue masses.¹⁵

Patients with Paget's disease may also develop several types of pseudomalignancy, including pseudosarcoma and pseudo giant cell tumors that are responsive to corticosteroids. Paget's pseudosarcoma typically presents as a slow-growing, localized, periosteal mass on pagetic bone. It has a predilection for long bones, especially the femur, and differs from a true sarcoma in that it does not destroy cortical bone or invade surrounding soft tissue.¹⁶ Patients may present with metabolic abnormalities, including hypercalcemia, hypercalcuria, and hyperuricemia.¹

Diagnosis of Paget's disease may be suspected based on the symptoms, but radiographs are the most specific diagnostic test. Asymptomatic patients with a first-degree relative with Paget's disease should be screened with a serum alkaline phosphatase test every two to three years. If the serum alkaline phosphatase level is elevated, a bone scan can be performed to determine the extent and activity of Paget's disease. Radiographs should be taken to confirm the diagnosis in a patient with bone scans suggestive of Paget's disease.

BIOCHEMICAL MARKERS

There are many biochemical markers for Paget's disease, but the two most important are total serum alkaline phosphatase and urinary pyridinoline.¹⁷ These markers may be normal in patients with the monostotic form of Paget's disease (15 percent of patients) therefore, serum bone-specific alkaline phosphatase measurements may be useful. Urinary hydroxyproline is no longer considered an accurate marker of activity or extent of the disease.^18–20

RADIOGRAPHY

Radiographs include both lytic (early) and sclerotic findings (Table 3). Many patients are diagnosed incidentally in the asymptomatic phase by plain radiographs that show localized enlargement of bone. These radiographs often have a high specificity because of their classic nature, but a low sensitivity. Bone scans can be used to increase the sensitivity in patients suspected of having Paget's disease; however, the bone scan is less specific and should be interpreted cautiously.²¹ Once a diagnosis of Paget's disease is confirmed, repeat radiographs are required only to monitor degeneration around weight-bearing joints. Computed tomography and magnetic resonance imaging are not necessary.

If the results of the biochemical markers and radiography are inconclusive, a biopsy of the affected bone may be indicated in rare cases.

Treatment

Treatment of Paget's disease does not cure the disease but can provide prolonged periods of remission. Bisphosphonates, which decrease bone resorption by inhibiting osteoclast resorption, are the treatment of choice. Disease activity stays low for months or years after cessation of these medications. Alendronate (Fosamax) and pamidronate (Aredia) are used most frequently and will cause about a 70 percent decrease in biochemical markers in one half of patients.² Newer-generation bisphosphonates that are still in development are thousands of times more potent than first-generation agents. Calcitonin (Calcimar) also inhibits osteoclastic bone resorption. Calcitonin-salmon is available in injectable and nasal-spray forms, but only the injectable form is approved for treatment of Paget's disease by the U.S. Food and Drug Administration^22,23 (Table 4¹²). Compared with the bisphosphonates, calcitonin is not as powerful and does not suppress the disease activity for as long after cessation. Patients with Paget's disease should receive adequate doses of calcium (1,000 to 1,500 mg per day) and vitamin D (400 IU per day). Exercise is recommended to maintain skeletal health in patients with Paget's disease; however, exercise programs should be individualized to prevent stress on affected bones.

SURGICAL

Rarely, surgical treatment with elective joint replacements or osteotomy may be required in patients with the following conditions: progressive bowing of the tibia or femur; delayed union of fractures; unstable fractures; arthritis refractory to medical treatment; or focal nerve compression of the spine or cranium.^1,23

INITIATION OF TREATMENT

Although no established standard for initiating therapy exists, the literature generally supports treating the following patients: all symptomatic patients; asymptomatic patients whose biochemical markers suggest an increase in bone remodeling; and patients with pagetic lesions located at weight-bearing regions or adjacent to joints.^1,3,4 Many sources^2,21 recommend initiating treatment when the serum alkaline phosphatase level rises to 125 to 150 percent of normal values. Recommendations for follow-up serum alkaline phosphatase monitoring range from every three months to annually. Patients should be followed indefinitely because of the increased risk of malignant transformation in patients with longstanding Paget's disease. Treatment goals should also include aggressive pain control.