Pagets Disease

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Pathogenesis and Pathophysiology. Paget's disease (osteitis deformans) is a metabolic bone disease of un

known etiology characterized by increased osteoclast size and activity that results in resorption of bone followed by reactive new bone formation. This process produces areas of bone resorption with new bone laid down in an abnormally dense mosaic pattern. The osteoclasts in affected bone contain nuclear and cytoplasmic virus-like inclusions, and evidence has been presented of an association with various paramyxoviruses, including measles virus, respiratory syncytial virus, and canine distemper virus. It has been speculated that the disorder represents the late effect of viral infection on osteoclasts or their precursors and that affected osteoclasts tend to form multinucleated syncytia, which have increased resorptive activity. Normal osteoblasts may then be stimulated by the primary pathological osteolytic disorder.

Epidemiology and Risk Factors. Paget's disease is the second most common metabolic bone disease in the elderly population, after osteoporosis. It is most common in patients of northern European ancestry and is uncommon among Asians and Africans. Males predominate slightly. The prevalence in the elderly population of the United States is 1 to 3 percent, with 0.1 to 0.2 percent of patients having significant symptoms. y The risk is increased in relatives of those affected, but pedigrees do not support direct inheritance.

Clinical Features and Associated Disorders. The disease typically begins in middle age or later and varies from limited asymptomatic involvement of a single or few sites to widespread symptomatic disease. The femur, pelvis, and spine are most commonly affected, although any bone may be involved. Skull involvement is also common. The most typical presenting symptoms are focal progressive bone pain, deformity due to expansion of bone, and structural failure such as vertebral compression fracture or bowing of weight-bearing long bones. Enlarging hat size due to progressive skull expansion is a classic symptom. Other typical facial changes include enlarged and coarsened orbits and prognathism. Patients may also notice focal increases in skin temperature due to increased blood flow at affected sites. The most common neurological symptoms are headache, deafness, and problems resulting from spinal disease. The cause of the deafness is unclear. Both auditory nerve compression and involvement of the middle ear ossicles have been suggested as mechanisms; however, autopsy studies have not borne out either hypothesis.y , y The main mechanisms presumed to cause neurological symptoms are compression of neural and vascular structures by overgrowth of bone into limited spaces, traction on neural structures displaced by bony deformity, and possibly a vascular steal phenomenon resulting from the local high blood flow demand of pagetic bone (.Table.2.9-4 ). Involvement of the skull may cause basilar impression with consequent problems, including headache, ataxia, hydrocephalus, myelopathy, or cranial neuropathies. Patients may develop intradiscal lesions with spinal stenosis and, rarely, extramedullary hematopoiesis. These lesions may cause back pain or may progress to cause spinal cord and nerve root compression. Yet compressive symptoms due to spinal disease are uncommon, and when they occur in patients with Paget's disease, the possibility of sarcomatous degeneration should be considered. High-output heart failure due to the highly vascular shunts is rare.

TABLE 29-4 -- NEUROLOGICAL COMPLICATIONS OF PAGET'S DISEASE

Deficit/Localization

Proposed Mechanisms of Injury

Hearing loss

Conductive

Involvement of middle ear ossicles

Sensorineural

Compression/traction of auditory nerve

Spinal cord and root involvement

Compression of central canal and foramina

Radiculopathy (esp. lumbosaeral)

Compression, traction

Myelopathy (esp. thoracie)

Compression, vascular compromise (?steal)

Cranial nerves and brain stem

Olfactory nerve

Sphenoid thickening compromising lamina cribosa

Optic nerve

Optic canal stenosis, orbital compression, ?vascular steal

Oculomotor nerves

Superior orbital fissure stenosis, ?vascular steal

Trigeminal nerve

Foraminal compression, ?vascular steal

Facial nerve

Facial canal stenosis, ?vascular steal

Lower cranial nerve, brain stem, cerebellum

Foraminal stenosis, basilar impression, platybasia, and vertebral artery compression from compression within foramina tranversaria

Major categories are listed in order of decreasing relative frequency. Among cranial nerve deficits, those of the lower cranial nerves are most common.

Major categories are listed in order of decreasing relative frequency. Among cranial nerve deficits, those of the lower cranial nerves are most common.

From 1 to 5.5 percent of patients with Paget's disease develop osteogenic sarcoma. pS Other tumors, such as giant cell tumor of bone, are less common. The pagetic osteogenic sarcoma is osteolytic, and pathologic fracture is the most common presentation. Malignant degeneration should also be suspected when a rapid increase in pain or growth is noted or when compressive spinal findings emerge. About 5 percent of patients have hyperparathyroidism, but the mechanism of this association is not known. A complex array of vitamin D-related disorders may also accompany Paget's disease.

Differential Diagnosis and Evaluation. The differential diagnosis includes primary and metastatic bony tumors, especially prostate cancer, and other metabolic bone disorders that produce lytic lesions and hyperostosis. Degenerative arthritis may cause confusion, especially when one is trying to determine the source of symptoms when the two diseases coexist.

Plain radiographs of affected bones are still the primary means of diagnosis. The bones are expanded, often with thickening of the cortex. There may be a peripheral edge of lytic fronts and a small intracortical lytic area. It is common to find lytic lesions predominating in the skull. The most striking feature is typically osteosclerosis, which may have a fluffy appearance. The sclerosis is often intermixed with lytic disease. Uniformly sclerotic ivory vertebrae may be seen. Radionuclide scanning demonstrates greatly increased uptake and is the most sensitive test to establish the extent of involvement. Computed tomography can be used to distinguish osteolytic lesions missed on plain radiographs and can identify soft tissue masses (.F..iC,.2.9.-6. ). In this regard, it may be an important adjunct in the differentiation of benign lesions from tumor. The urinary

Figure 29-6 Paget's disease of bone. Head CT bone windows show thickening of the bony calvarium with osteosclerotic and lytic lesions.

hydroxyproline-creatinine ratio is elevated, reflecting increased bone resorption. Greatly elevated bone alkaline phosphatase levels reflect increased osteoblastic activity and are characteristic. The relative elevations of these values reflect the predominance of either lytic (early) or blastic (late) disease. Serum calcium is usually normal unless some other factor, such as immobilization, tips the balance in favor of resorption and hypercalcemia. Inorganic phosphorus is normal or slightly elevated. When malignant degeneration is suspected, as in a patient with a pathological fracture, early biopsy should be pursued.

Management. The management of Paget's disease has changed in recent years. Both bisphosphonate and calcitonin attack the underlying metabolic disorder by inhibiting bone resorption. Although there is no consensus on the best therapy, both are now being applied to prevent the development of long-term complications. Etidronate, the first bisphosphonate available, provides definite benefit by inhibiting osteoclast activity. However, it interferes with the normal mineralization of new bone. The newer bisphosphonates, such as pamidronate, are similarly effective without impairing mineralization. These agents may be given in short courses intravenously or chronically by mouth. The urinary hydroxyproline level begins to fall within days of an intravenous dose, and the serum alkaline phosphatase declines later and more gradually. These substances remain in bone for a long time and may promote prolonged remissions. Subcutaneous or nasally administered calcitonins also inhibit osteoclasts. Symptomatic relief follows; however, the effect is short-lived, and the agents must be continued to maintain this effect. A loss of effect during therapy may be due to the formation of neutralizing antibodies, which occurs in about one fourth of those treated. The cytotoxic plicamycin used for hypercalcemia of malignancy causes a rapid improvement but is more toxic than the bisphosphonates or calcitonins. Gallium nitrate has antiosteoclastic activity, but data on its clinical use do not yet support its use outside of controlled trials. The goals of treatment are to normalize metabolism as evidenced by biochemical markers and to relieve symptoms. Most patients obtain relief from bone pain. Reversal of neurological deficits and stabilization--and rarely improvement--of hearing often follows therapy. There has been radiological evidence of healing of osteolytic lesions. Malignant lesions should be treated aggressively with radical resection for best results. Chemotherapy has not yet been shown to be effective. Early detection is currently the only available way to improve survival. Patients require life-long surveillance for tumor recurrence. With the currently available array of effective therapies for Paget's disease, it is most important that patients be properly referred for expert care.

Prognosis and Future Perspectives. Many patients remain asymptomatic. Newer drug therapies can now address bone pain and other rarer symptoms and may offer long-term remission. However, as noted previously, prevention or early detection of neurological deficits is essential to avoid loss of function, since therapy is more likely to arrest than to reverse them. The prognosis after malignant degeneration has occurred, however, remains poor, with only about 10 percent of patients surviving 5 years.y Research in Paget's disease has produced advances in the understanding of the possible underlying etiology, the metabolic processes that promote the disorder, and the application of several new therapies. Further clarification of the viral hypothesis, development of improved diagnostic metabolic markers, and refinement of management with antiosteoclastic agents are expected in the future.

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