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Chapter 47 Paget's Disease of Bone

Manual of Rheumatology and Outpatient Orthopedic Disorders

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Chapter 47 Paget's Disease of Bone

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John H. Healey

Epidemiology
Pathogenesis
Clinical presentation
Laboratory studies
Differential diagnosis
Medical treatment
Orthopedic treatment
Prognosis

Sir James Paget, in 1877, described a condition he termed osteitis deformans, a disease of bone characterized by metabolic overactivity of affected bone and bony deformity. Paget's disease of bone is an age- related , localized disorder of bone metabolism in which increased bone resorption is followed by excessive production of woven bone. The result is enlarged and weakened bones. The disease may be monostotic or polyostotic (asymmetric).

I. Epidemiology. The disease is present radiographically in 3% of the population. Symptomatic Paget's disease is much less common. Persons of English extraction are most commonly affected, but no clear genetic pattern has been identified. There is a slight male predominance. Paget's disease is rare in patients less than 40 years old.

II. Pathogenesis

1. Etiology . The etiology is unknown. Evidence is accumulating , however, that Paget's disease of bone may be a slow-virus infection since the first report in 1974.
2. 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.
3. Genetics. There is probably a significant genetic component. The disease is rare in Scandinavia and Japan.
4. Radiology. Paget's disease begins at one epiphysis and progresses to the other epiphysis of bone. Resorptive lytic flame is seen early at the leading edge of the lesion. Reactive bone formation enlarges the overall bone dimensions and leaves coarsened trabeculae and sclerosis.

III. Clinical presentation. Most patients with Paget's disease are asymptomatic. The disease is usually recognized fortuitously when a roentgenogram is obtained for another purpose or a lone elevated alkaline phosphatase is assessed. Symptomatic patients present with pain, deformity, or pathologic fracture. Clinically important degenerative arthritis, neural compression, changes in skin temperature, high-output heart failure, and bone sarcoma can occur in an area of Paget's disease (Table 47-1).

Table 47-1. Radiographic and clinical manifestations of Paget's disease of bone

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 diseasecongestive failure or valvular disease in most extensive cases.
   4. Hearing loss.
   5. Hypercalcemia in severe untreated cases, immobilized patients, or patients with fracture.
   6. Osteoporosis resulting both from disuse and concomitant hyperparathyroidism.

IV. 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 ).
3. Results of other chemistry and hematologic tests, [calcium, phosphorus] are usually normal.
4. Radiographs
   1. Workup. Anteroposterior and lateral views of entire involved bone and bone scan (to identify other sites of involvement) are necessary.
   2. Diagnostic features. See section II.D .
   3. Associated findings
      1. Degenerative arthritis.
      2. Bowing of long bones.
      3. Spinal stenosis.
      4. Paget's sarcoma, suggested by the appearance of lytic areas within sclerotic pagetic bone.

V. Differential diagnosis

1. Metastatic carcinoma . Prostate and breast carcinoma in bone may resemble Paget's 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 Paget's disease.
3. Caffey's 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 Paget's disease.
4. Hyperparathyroidism. Histology may be similar, and the conditions can coexist (7% to 14%). Biochemical and radiographic findings differ , however.

VI. Medical treatment

1. Asymptomatic patients should be treated 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 Paget's disease.
   1. Bisphosphonates block osteoclast function and recruitment. However, they inhibit mineralization and osteoblast function to a variable degree.
      1. Dosage
         1. Alendronate: 10 to 40 mg daily PO.
         2. Pamidronate: 30 to 90 mg every week to month IV.
         3. Etidronate: 5 to 20 mg/kg daily PO for 3 to 6 months. Lower dosages are preferred except in severe cases. A 6-month interval should elapse before a course is repeated.
         4. Risedronate: 30 mg daily for 2 months.
      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 decreases bone resorption.
      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 SC 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 Paget's disease.

VII. Orthopedic treatment

1. Surgery 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. Bisphosphonates should be avoided if an osteotomy is to be performed.
2. Fractures
   1. Pseudofractures may persist for 6 to 12 months and should not be overtreated once symptoms subside.
   2. Completed fractures usually heal with closed methods , but healing may be delayed.
   3. Bisphosphonates should not be used.
   4. Biopsy occasionally is necessary to exclude sarcoma.
3. Immobilization. Gallium nitrate, calcitonin, and occasionally mithramycin (now called plica mycin) will be necessary to treat hypercalcemia.

VIII. 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. Multiple myeloma and metastases are also seen.

Uncomplicated Paget's 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.

Bibliography

Blumsohn A, et al. Different responses of biochemical markers of bone resorption to bisphosphonate therapy in Paget's disease. Clin Chem 1992;41:1592.

Mirra JM. Pathogenesis of Paget's disease based on viral etiology. Clin Orthop 1987; 217:162.

Reginster JY, Lecart MP. Efficacy and safety of drugs for Paget's disease of bone. Bone 1995;17 [Suppl 5]:485S.

Smidt WR, et al. An algorithmic approach to the treatment of Paget's disease of the spine. Orthop Rev 1994;23:715.

Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders

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