Paget’s Disease of Bone

John H. Healey

Andrea Piccioli

Originally called osteitis deformans, Paget’s disease of bone (PDB) is a disease characterized clinically by inflammatory and mechanical bone/joint pain and bony deformity. Microscopically, it is characterized by metabolic overactivity of the affected bone. Increased bone resorption is followed by excessive production of woven bone. This enlarges and weakens bones. The disease may be monostotic or polyostotic (asymmetric).

EPIDEMIOLOGY

The disease is present radiographically in 3% of the population. Symptomatic Paget’s disease is much less common. Individuals of white origin are most commonly affected, but no clear inheritance pattern has been identified. There is a slight male predominance. Paget’s disease is rare in patients younger than 40 years (<6% of cases). Analysis of 1,487 patients with PDB over three decades shows that there may be a continued secular trend for PDB to present in older subjects with less extensive skeletal involvement, and a declining prevalence of Paget’s disease.

ETIOPATHOGENESIS

I. ETIOLOGY

The etiology is unknown. Evidence is accumulating, however, that PDB may be a “slow-virus” infection since the first report in 1974. Mutations in the ubiquinone sequestosome 1 gene (SQSTM1; also known as p62) have recently been identified as the cause of 5q35-linked PDB. Osteoclasts and osteoclast precursors from patients with Paget’s disease contain paramyxoviral transcripts and appear hyperresponsive to 1,25-dihydroxy vitamin D and receptor activator of NF-κB ligand (RANKL). A common polymorphism of the osteoprotegerin protein predisposes to the development of sporadic PDB and familial PDB that is not caused by SQSTM1 mutations.

II. GENETICS

There is probably a significant genetic component. The disease is rare in Scandinavia and Japan. Giant cell tumors are frequent among PDB families from Avellino, Italy.

III. HISTOLOGY

Increased bone turnover is evident. Osteoclast resorption may dominate. New bone is woven and has a mosaic pattern. Cement lines (reversal lines) are conspicuous. Changes consistent with hyperparathyroidism and marrow fibrosis are seen in 15% of the cases.

IV. PATHOPHYSIOLOGY

Hyperemia can produce aches and pain. It can also create a steal syndrome that causes neurologic compromise or congestive heart failure due to high output mechanisms. Hearing loss develops through a cochlear mechanism that is closely related to loss of bone mineral density in the cochlear capsule. This mechanism accounts well for both the high-frequency–sensorineural hearing loss and the air-bone gap.

CLINICAL PRESENTATION

Most patients with Paget’s disease are asymptomatic. The disease is usually recognized fortuitously when a radiograph is obtained for another purpose, or an elevated alkaline phosphatase is found and assessed. Symptomatic patients present with pain, deformity, or pathologic fracture. Hearing loss is also common. Clinically important secondary degenerative arthritis, neural compression, changes in skin temperature, high-output heart failure, and bone sarcoma (1%) can be related to or occur in an area of Paget’s disease (Table 54-1).

I. SITES OF INVOLVEMENT