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MD Consult: Books: Goldman: Cecil Medicine: Chapter 268 – PAGET’S DISEASE OF BONE

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 268 – PAGET’S DISEASE OF BONE

G. David Roodman

Definition

Paget’s disease is a focal disorder of the skeleton that is the second most common bone disease, exceeded only by osteoporosis. It affects approximately 1 to 2% of adults older than 55 years in the United States and up to 4 to 6% of adults 55 years old or older in certain areas of the United Kingdom. Paget’s disease is the most exaggerated form of bone remodeling, with increases in all phases of the bone remodeling process. The initial phase is characterized by markedly increased bone resorption, followed by exuberant new bone formation. The bone that is formed is abnormal and woven, with disorganized collagen. This increased bone formation results in bone enlargement and deformity because of the poor quality of the bone.

Epidemiology and Etiology

The cause of Paget’s disease is unknown. However, a genetic predisposition to Paget’s disease has been clearly established. Approximately 40% of patients with Paget’s disease have an affected first-degree relative, and large numbers of families with vertical transmission of Paget’s disease and an autosomal dominant pattern of inheritance have been described. At least six genetic loci have been linked to Paget’s disease, and mutations in the sequestosome-1 gene (SQSTM1), also known as p62, are the most frequent. SQSTM1 mutations have been detected in 30% of patients with familial Paget’s disease and in 10% of patients with sporadic Paget’s disease. Although the penetrance for Paget’s disease is high, it can vary in families with a genetic predisposition. Elderly patients with SQSTM1 mutations may have no evidence of Paget’s disease even though they are homozygous for the mutation.

The primary cellular abnormality in Paget’s disease resides in the osteoclast. These cells contain nuclear inclusions that resemble paramyxoviral nucleocapsids. Both measles virus and respiratory syncytial virus nucleocapsid proteins and transcripts have been detected in osteoclasts from patients with Paget’s disease, but some studies have not detected paramyxoviral transcripts or proteins in pagetic osteoclasts. Furthermore, a cause-and-effect relationship between Paget’s disease and paramyxovirus infection has not been definitively established. Nevertheless, in vitro studies in which normal osteoclast precursors were transfected with measles virus transcripts or infected with measles virus have demonstrated that osteoclast precursors containing the measles virus nucleocapsid gene can form pagetic-like osteoclasts.

As noted earlier, Paget’s disease is the second most common bone disease. However, the prevalence of Paget’s disease varies among different populations. In the United Kingdom, for instance, Paget’s disease affects up to 6% of the population older than 55 years. Further, the frequency of symptomatic Paget’s disease increases with age. Similarly, Paget’s disease occurs in Western Europe and in the white populations in New Zealand and Australia. However, Paget’s disease is extremely rare in Scandinavia and in the Far East, and it does not affect indigenous populations in either Australia or New Zealand. The prevalence of Paget’s disease appears to have decreased since the early 1980s. In England and New Zealand, the prevalence of Paget’s disease was reported to have decreased from approximately 8 to 4% and from 5 to approximately 3%, respectively. The basis for this decrease in prevalence in England and New Zealand is unknown. In addition, the severity of Paget’s disease in these populations has decreased.

Pathobiology

Bone remodeling is increased five- to tenfold in patients with Paget’s disease. Paget’s disease is highly localized, with focal areas of involvement. In pagetic lesions, osteoclast numbers are increased, and the osteoclasts are hyper-multinucleated with up to 100 nuclei/cell. This finding is in contrast to normal osteoclasts, which contain 3 to 20 nuclei/osteoclasts. The bone resorbing capacity of pagetic osteoclasts is decreased compared with normal osteoclasts. However, because of the large numbers of osteoclasts in the pagetic lesion, bone resorption is markedly increased ( Fig. 268-1 ). The increased bone resorption phase is followed by new bone formation. As the disease progresses, the bone formation begins to predominate, and the bones become enlarged ( Fig. 268-2 ). Large numbers of osteoblasts are often found near areas of resorbed bone and may even be prominent in a lesion that appears purely osteolytic by roentgenogram. The osteoblasts contain abundant rough endoplasmic reticulum, mitochondria, and a well-developed Golgi zone. These features of heightened cellular activity are consistent with the increased bone formation in active lesions. In addition to the increased numbers of osteoclasts and osteoblasts, the marrow in pagetic lesions is often grossly abnormal. The normal hematopoietic elements are usually absent and are replaced by mononuclear cells of indeterminate origin intermixed with highly vascular connective tissue. The bone matrix structure in Paget’s disease is extremely abnormal and arises as a consequence of disordered bone resorption and formation. The matrix consists of a “mosaic” of irregularly shaped pieces of lamellar bone with an erratic pattern of cement lines. The matrix is interspersed with numerous foci of woven bone, which, in adults, is ordinarily found associated with fracture healing. After a long time, the lesions become sclerotic. This rapid and abnormal deposition of bone results in the characteristic irregular cement lines that give rise to the mosaic appearance on radiographs and on tissue sections. Marrow vascularity is markedly increased in pagetic lesions such that the involved bones often feel warm to the touch. Electron microscopy studies of pagetic osteoclasts show nuclear inclusions that resemble paramyxovirus nucleocapsids. However, these nuclear inclusions are not unique to Paget’s disease and have been reported in rare cases of osteopetrosis and other bone diseases such as giant cell tumors of bone.

FIGURE 268-1  Sequential radiographs of the distal end of the femur at the dates shown. A, Distinction between Paget’s and normal bone (arrows), the osteolytic front, and expansion of bone diameter at the affected site. B, Treatment with a bisphosphonate induced in-filling of the resorption font. C, Relapse after treatment was associated with a new area of osteolysis (thick arrow) and progression of the resorption front.  (From Kanis JA: Pathophysiology and Treatment of Paget’s Disease of Bone, 2nd ed. London, Martin Dunitz, 1998.)

FIGURE 268-2  Advanced involvement of the skull with marked thickening of the entire vault, areas of osteolysis, and patchy new bone formation resulting in a “cotton-wool” appearance.

Clinical Manifestations

Most patients with Paget’s disease are elderly, and the age at diagnosis is usually greater than 50 years. Paget’s disease affects both men and women, with a slight male predominance. Although Paget’s disease is often asymptomatic, 10 to 30% of patients experience pain, skeletal deformity, neurologic symptoms, pathologic fractures, or deafness. Patients may have only one affected bone or pagetic lesions in multiple bones. Patients with familial Paget’s disease tend to have more bones affected and more deformity than patients with sporadic Paget’s disease. Paget’s disease remains highly localized, and patients rarely develop new lesions in previously unaffected bones after diagnosis. Table 268-1 lists the common clinical features and complications of Paget’s disease.


TABLE 268-1   — 
CLINICAL FEATURES AND COMPLICATIONS OF PAGET’S DISEASE

COMMON

   Pagetic or articular bone pain
   Fracture of long bones and vertebral bodies
   Neurologic deafness
   Deformity and enlargement of bones
UNCOMMON

   Spinal neurologic syndromes
   Hypercalciuria of immobilization or fracture
   Vascular bleeding from bone during surgery
   Extraskeletal (aortic) calcification
   Osteosarcoma and other bone tumors
RARE

   Cardiovascular disease
   Cranial nerve lesions (except VIII)
   Brain stem and cerebellar lesions
   Hypercalcemia of immobilization
   Extramedullary hematopoiesis
   Epidural hematoma
SIGNIFICANCE UNCERTAIN

   Gout
   Pseudogout
   Angioid streaks
   Hyperparathyroidism
   Urolithiasis
Diagnosis

The biochemical findings in Paget’s disease reflect the cellular events occurring throughout the skeleton of affected patients. Measurement of collagen cross-link degradation products in urine provides a specific measurement of skeletal matrix degradation. Urinary N-telopeptide, pyridinoline, and deoxypyridinoline have all been used as measures of skeletal matrix resorption. Serum tartrate–sensitive acid phosphatase, released by osteoclasts, is another index of bone resorption in Paget’s disease research laboratories.

Osteoblast activity can be assessed by measurement of total serum alkaline phosphatase activity, serum bone-specific alkaline phosphatase concentration, serum osteocalcin concentration, and serum type 1 carboxy-terminal procollagen peptide concentration. The most useful of these are the total serum alkaline phosphatase and bone-specific alkaline phosphatase determinations. Total serum alkaline phosphatase measurements are routinely used to monitor disease activity in the clinic.

Treatment

Medical Therapy

Patients with Paget’s disease who are symptomatic require treatment. No data support treatment of asymptomatic patients except in the presence of rapidly advancing osteolytic lesions in long bones that are weight bearing, in which the risk of pathologic fractures is increased. Because the osteoclast is the primary cell involved in Paget’s disease, medical treatment focused on inhibiting osteoclast activity, in particular the use of bisphosphonates, calcitonin, and mitomycin, has been successful in treating Paget’s disease. Salmon calcitonin by injection, which has been used since the early 1980s, is an effective treatment for Paget’s disease. This treatment suppresses the biochemical parameters of the disease by 50%. Bisphosphonates, which can inhibit osteoclast formation but predominantly induce osteoclast apoptosis, are the most frequently used treatments for Paget’s disease. Bisphosphonates are pyrophosphate derivatives with a high affinity for bone. They are incorporated into sites of bone resorption, released during the resorption process, and taken up by osteoclasts. This process results in the death of osteoclasts. In addition, bisphosphonates have been shown to affect angiogenesis as well as cytokine production by osteoclasts. Because biochemical markers strongly correlate with disease activity, following serum alkaline phosphatase activity is a simple method for monitoring the activity of the disease. Some treatments may result in normalization of both some skeletal abnormalities and the bone scan in these patients. With the availability of more potent bisphosphonates to treat patients with Paget’s disease, the prognosis has greatly improved ( Table 268-2 ). A single intravenous dose of 5 mg of zoledronic acid can provide a 96% response rate for the next 6 months and is more effective than 2 months of oral risedronate.[1] Patients treated with bisphosphonates can usually attain remission of the disease. However, after variable periods of time, patients suffer a relapse and require treatment.

Surgical Therapy

Surgery is used to treat fractures and to correct deformity of bowed bones as well as to treat bone disease in the hip. In addition, surgical treatment may relieve the neurologic complications of overgrowth of pagetic bone with resultant nerve root compression. Before elective surgery, patients with Paget’s disease are usually treated with bisphosphonates to decrease the vascularity and activity of the bone and to prevent increased bleeding.


TABLE 268-2   — 
BISPHOSPHONATES USED IN TREATMENT OF PAGET’S DISEASE

Agent Route Dose (mg/day) Duration of Effect
Alendronate Oral 40 6 mo
Clodronate[*] Oral 1600 3–6 mo
  Intravenous 300 5 days
Etidronate Oral 400 6 mo
Pamidronate Intravenous 30–60[] 3 days
Risedronate Oral 30 2 mo
Tiludronate Oral 400 3 mo
Zoledronic arid Intravenous 5 one-time dose 6 mo

* Has not been approved by the Food and Drug Administration at the time of publication.
Lower dose approved; higher dose used by investigators.

Prognosis

Pagetic bone pain responds to medical treatment. Much of the bone pain associated with Paget’s disease results from arthritis or joint pain arising from the bone deformity, rather than pain from the pagetic bone per se. Unless treated, pagetic lesions continue to increase in size, but rarely if ever do patients develop new lesions in a previously unaffected bone. In patients for whom analgesic or other specific treatments are unsuccessful, joint replacement can be performed. The most dreaded complication in Paget’s disease is the development of osteosarcoma in the pagetic lesion. Although osteosarcoma is an extremely rare complication, affecting less than 1% of patients with Paget’s disease, it is the most common cause of osteosarcoma in adults. Once patients develop osteosarcoma, their prognosis is extremely poor, and the outcome is usually fatal. Active treatment of Paget’s disease decreases the biochemical abnormalities, with near normalization of alkaline phosphatase activity, and improves the neurologic syndromes associated with this disease.

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