HSS Manual Ch. 54 - Paget's Disease of Bone

From the HSS Manual of Rheumatology and Outpatient Orthopedic Disorders


John H. Healy, MD
Professor of Orthopedic Surgery
Weill Medical College of Cornell University
Chief, Orthopedic Service
Memorial Sloan-Kettering Cancer Center
Andrea Piccioli, MD
Orthopedic Surgeon
Centro Traumatologico e Ortopedico
Rome, Italy
  1. Epidemiology
  2. Etiopathogenesis
  3. Clinical Presentation
  4. Diagnostic Studies
  5. Differential Studies
  6. Medical Treatment
  7. Orthopedic Treatment
  8. Prognosis

Originally called osteitis deformans, Pagetís 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 over-activity 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 Pagetís disease is much less common. Persons of English extraction are most commonly affected, but no clear inheritance pattern has been identified. There is a slight male predominance. Pagetís disease is rare in patients less than 40 years old (<6% of cases). Analysis of 1487 PDB patients 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

  1. Etiology. The etiology is unknown. Evidence is accumulating, however, that Pagetís disease of bone may be a ďslow-virusĒ 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 RANK 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.

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

  3. 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 cases.

  4. Pathophysiology. Hyperemia can produce achiness and pain. It can also create a steel 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 Pagetís disease are asymptomatic. The disease is usually recognized fortuitously when a roentgenogram is obtained for another purpose or an elevated alkaline phosphatase is assessed. Symptomatic patients present with pain, deformity, or pathologic fracture. Hearing loss is also common. Clinically important degenerative arthritis, neural compression, changes in skin temperature, high-output heart failure, and bone sarcoma (1%) can occur in an area of Pagetís disease (Table 54-1).

  1. Sites of involvement
    1. Sacrum (56%).
    2. Spine (50%), lumbar most frequently.
    3. Right femur (31%).
    4. Cranium (28%).
    5. Sternum (23%).
    6. Pelvis (21%).
    7. Left femur (21%).

  2. Associated conditions
    1. Hyperparathyroidism.
    2. Hyperuricemia (40%).
    3. Heart diseaseócongestive failure or valvular disease in most extensive cases.
    4. Hearing loss.
    5. Hypercalcemia in severe untreated cases, immobilization or fracture.
    6. Osteoporosis resulting both from disuse and concomitant hyperparathyroidism.

Table 54-1. Radiographic and clinical manifestations of Pagetís disease of bone

Location Radiographic findings Clinical symptoms
Skull Osteoporosis circumscripta None
Cranial enlargement Occasionally painful
Basilar invagination Occipital neuralgia; lower cranial nerve impingement; medullary compression; ventricular obstruction and increased intracranial pressure; vertebral basilar artery insufficiency
Temporal bone involvement Hearing loss
Auditory ossicle involvement Hearing loss
Face, jawbones Unilateral changes Proptosis; trigeminal neuralgia; displacement of teeth
Spine ďWindow frameĒ vertebra(e) Nerve root compression; spinal stenosis
Pelvis, hip Acetabular and femoral head disease with degenerative arthritis; protrusio acetabuli; sacroiliac joint ankylosis Pain; end-stage arthritis
Knee joint Bone and joint deformity Pain; arthritis; fracture
Tibia, femur, humerus Bowing, with or without fracture Pain; arthritis; fracture



DIAGNOSTIC STUDIES

  1. Laboratory studies
    1. Elevated serum alkaline phosphatase indicates increased bone formation.
    2. Elevated collagen breakdown products: N- and C-terminal telopeptides, N-pyridinolines, hydroxyproline (less sensitive and slower to respond to therapy) correspond to bone resorption and turnover.
    3. Chemical and hematologic tests, calcium and phosphorus are normal.

  2. Imaging Studies
    1. Features: Pagetís disease begins at one epiphysis and progresses to the other epiphysis of bone. A resorptive ďlytic flameĒ is seen early at the leading edge of the lesion. Reactive bone formation enlarges the overall bone. The inflamed, weakened long bones bow. The cortex thickens (e.g. iliopectineal line of pelvis), and trabeculae coarsen. Circumscribed skull lucency (osteitis circumscripta) may occur. Pagetís sarcoma is suggested by the appearance of lytic areas within sclerotic pagetic bone or the development of an associated soft tissue mass.
    2. Imaging Work-up
      1. Radiographs: Anteroposterior and lateral views of entire involved bone and other sites are identified by plain radiography.
      2. Scintigraphy: Survey for sites of involvement. Differential nuclear scans, e.g., gallium scan is hot in cancer but cool in the surrounding pagetic bone.
      3. Magnetic Resonance Imaging or Computed Topography: Evaluate the degree of spinal stenosis in patients with back pain or neurologic findings.
      4. Positron Emission Tomography Look for sarcoma in suspicious lesion.


DIFFERENTIAL DIAGNOSIS

  1. Metastatic carcinoma. Prostate and breast carcinoma in bone may resemble Pagetís disease, but bony expansion is lacking and cortical destruction is more frequent. In any site, if destruction of bone, extracortical extension, or a possible soft-tissue mass is present, neoplasia must be ruled out, especially if pain is increasing.

  2. Hemangioma of bone (especially of vertebrae) may be sclerotic and resemble monostotic Pagetís disease.

  3. Caffeyís disease. Infantile cortical hyperostosis affects a young age group, may be more widespread, and predominantly affects cortical bone, although radiographic and histologic findings closely resemble those of juvenile Pagetís disease.

  4. Hyperparathyroidism. Histology may be similar, and the conditions can coexist (7% to 14%). Biochemical and radiographic findings differ, however.


MEDICAL TREATMENT

  1. Asymptomatic patients: Treat if a major joint, nerve, or weight-bearing bone is affected.

  2. Symptomatic patients: Symptoms usually respond to treatment in 1 to 3 months, and improvement in biochemical parameters usually parallels improvement in symptoms. All agents now used inhibit osteoclast activity and block the initial resorptive phase of Pagetís disease.
    1. Bisphosphonates block osteoclast function and recruitment. However, they inhibit mineralization and osteoblast function to a variable degree. In a randomized trial of patients with previously untreated Paget's disease of bone, alendronate and pamidronate have similar efficacy in achieving biochemical remission.
      1. Dosage
        1. Alendronate: 10 to 40 mg daily orally.
        2. Pamidronate: 30 to 90 mg every week to month intravenously for 3 months.
        3. Risedronate: 30 mg daily orally for 2 months. 
        4. Etidronate: 5 to 20 mg/kg daily orally for 3 to 6 months. Lower dosages are preferred except in severe cases. A 6-month interval should elapse before a course is repeated.
      2. Response. Rapid improvement in symptoms and biochemical parameters is usually seen. A paradoxical increase in pain is observed in 15% of patients.
      3. Side effects. Increased pain, diarrhea, osteomalacic fractures, and delayed fracture healing.
    2. Calcitonin is a polypeptide hormone with receptors in osteoclasts that decrease bone resorption. May be used in conjunction with bisphosphonate in refractory cases.
      1. Dosage. Salmon calcitonin is the preferred agent because of its high activity and low antigenicity and cost. Initial dosages of 50 to 150 U daily subcutaneously for 1 to 3 months may be used, then tapered to a maintenance dosage of 50 U three times weekly for 3 to 6 months.
      2. Response. In two-thirds of patients, symptomatic relief and biochemical improvement may last 6 to 12 months after a therapeutic course is completed. Antibody formation does not preclude a good response but may require a switch to human calcitonin.
      3. Side effects include nausea, flushing, local reactions at injection sites, and urticaria; these respond to anti-emetics and antihistamines.
    3. Combination calcitonin and bisphosphonates (low dose) may produce a faster, longer-lasting response and be more cost-effective.
    4. Gallium nitrate blocks osteoclasts and may promote activity of osteoblasts. It is also a very effective treatment for hypercalcemia.
    5. Mithramycin, a DNA inhibitor, has been successful in treating hypercalcemia of malignancy. Toxicity restricts its use to cases of acute neurologic compression syndromes in Pagetís disease.

  3. Follow up: Treatment benefit seen within 6 months of treatment. Biochemical deterioration occurs after 12-24 months. Therefore follow-up every 6-12 months for alkaline phosphatase and annually for radiographs is recommended.


ORTHOPEDIC TREATMENT

  1. Surgery. General Considerations. It may be successful, but deformity, poor bone quality, and soft-tissue hyperemia make surgery difficult. Calcitonin treatment for at least 6 weeks before procedures is recommended. Etidronate should be avoided if an osteotomy is to be performed. The effect of pamidronate or other bisphosphonates on osteotomy healing is unknown.

  2. Fractures
    1. Pseudo-fractures may persist for 6 to 12 months and should not be over treated once symptoms subside.
    2. Completed fractures usually heal with closed methods, but healing may be delayed.
    3. Bisphosphonates should be avoided if possible.
    4. Biopsy occasionally is necessary to exclude sarcoma.

  3. Immobilization. Intravenous bisphosphonates, gallium nitrate, calcitonin, and occasionally mithramycin (now called plicamycin) will be necessary to treat hypercalcemia.

  4. Joint Replacement. Results of total hip arthroplasty using uncemented components in patients with Paget's disease are excellent during the first decade after implantation. These patients may be at higher risk for heterotopic bone formation and increased perioperative blood loss because of hypervascularity of the bone. Thus, disease control pre-operatively is necessary.

  5. Spine Decompression. Neural compression may require surgery.

  6. Cochlear Implants.

PROGNOSIS

Bone sarcomas occur in fewer than 1% of patients and are almost always fatal. Benign giant cell tumors also occur and may respond to corticosteroid therapy.

Uncomplicated Pagetís disease generally responds to medical management and becomes quiescent. Degenerative arthritis and deformity usually require surgery. Medical management may prevent disease progression and is usually warranted. 


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