ABSTRACT

Sir James Paget described a skeletal disorder affecting one or more areas of the skeleton in 1876. It is most common in England and in countries to which the English migrated. In recent years the prevalence in most countries has decreased. A common feature is skeletal deformity which evolves over many years and is most visible in the skull and lower extremities. Pathological fractures are most likely to occur in the femurs. Pain is a common feature in patients with Paget’s disease and may be of skeletal, joint, neurologic, or muscle origin. The radiologic features begin with a localized area of osteolysis which advances very slowly in the absence of therapy. Over time the lesion becomes osteosclerotic and once an entire bone is affected the entire lesion is sclerotic with areas of osteolysis remaining. Bone scans utilizing technetium99m-labeled bisphosphonates exhibit markedly increased uptake in the untreated state. Histologic evaluation of early lesions reveals an increased number of osteoclasts advancing at the interface of normal bone. They are often larger than normal and contain many more nuclei than normal osteoclasts. Subsequently numerous osteoblasts are found to be producing a large amount of disorganized bone. Associated with the increase in osteoclasts and osteoblasts there is a highly vascular fibrocellular marrow replacing the hematopoietic marrow. The osteoclasts have an abnormal ultrastructure featuring nuclear inclusions, and sometimes, cytoplasmic inclusions resembling nucleocapsid-like structures of the Paramyxoviridae family. Measurement of serum or urine N- or C-telopeptides documents the degree of bone resorption and serum total alkaline phosphatase activity, serum bone specific alkaline phosphatase and serum procollagen type 1 amino-propeptide document bone formation. Serum total alkaline phosphatase activity is the least expensive and most widely used test. Patients may develop sarcomas or giant cell tumors in affected bone but this is rare. Metabolic complications include hypercalcemia associated with immobilization and hyperuricemia and gout in patients with more extensive disease. Increased cardiac output may occur in patients with extensive disease due to the vascularity of the lesions. The earliest effective treatment was calcitonin but with the increased efficacy of the more potent bisphosphonates calcitonin is seldom prescribed. The treatment of choice is presently an intravenous infusion of 5 mg zoledronate. This normalizes bone resorption and formation markers for up to six and a half years in most patients. Indications for treatment include bone pain, hypercalcemia, neurologic deficits with vertebral disease, congestive heart failure, preparation for orthopedic surgery, and prevention of complications such as hearing loss and deformity. Surgery most commonly is needed for lower extremity joint replacement and correction of deformities of the lower extremity. The etiology remains somewhat controversial with some studies indicating a role for measles virus. The observation that the prevalence of the disease has decreased could be explained by the introduction of measles vaccine in 1963. Clearly genetic factors also play a role. Mutations in the sequestosome 1 gene produce susceptibility to develop Paget’s disease but not all family members with the mutation develop Paget’s disease. Many other gene abnormalities may also increase disease susceptibility. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

HISTORICAL ASPECTS

In 1876, Sir James Paget (Figure 1), a prominent English surgeon, described five men who had at least two deformed areas of the skeleton (1). His description of the disorder he called osteitis deformans included clinical features, and gross and histologic pathology. He believed he was describing a rare inflammatory disorder, but by the start of the new century, numerous publications describing similar patients appeared in England, France, and the United States. A small number of reports also came from Australia, Germany, Holland, Italy, and Sweden. By this time, the condition commonly became known as Paget's disease of bone.

Figure 1.

The bust of Sir James Paget in the Museum of St. Bartholomew's Hospital.

Further realization that Paget's disease was not a rare disorder came about after the discovery of X-rays in 1895 by Roentgen. It was then possible to detect affected bones, which exhibited no external manifestations of the disease. The first X-ray report appeared in 1896 (2) and osteolytic disease was recognized by1901 (3).

The first biochemical marker of Paget's disease was recognized in 1929 by Kay (4). He reported elevated alkaline phosphatase activity in the patients' sera. Over time, it came to be appreciated that serum alkaline phosphatase activity could reach higher levels in Paget's disease than in any other disorder.

EPIDEMIOLOGY

The distribution of Paget's disease throughout the world is one of its most striking features. While commonly found in the population of England, the United States, Australia, New Zealand, Canada, South Africa, and France, it appears to be rare throughout Asia and Scandinavia. Estimates of the prevalence in individual British cities even suggest a striking variability within one country (5). Analysis of hospital radiographs indicated prevalence ranging from 2.3% in Aberdeen, Scotland to 8% in Lancaster, England. Recently analysis of 1000 CT scans of the abdomen revealed a striking decrease in prevalence to 0.8% in the Lancashire region (6). The most recent prevalence estimate in the United States is 1-2% (7), and in France is 1.1-1.8% (8). In many countries the prevalence of Paget’s disease appears to have decreased (9-13) although this has not been observed in Italy (14) or in the Salamanca province of Spain (15). It is particularly difficult to obtain a true estimate of prevalence in a population as serum alkaline phosphatase activity may be elevated in as few as 14% of individuals with x-ray evidence of Paget’s disease (16).

Paget's disease probably occurs equally often in men and women and clearly increases in prevalence with age (17). The diagnosis is nearly always determined in individuals over the age of 50 years. The prevalence in the past approached 10% by 90 years and affected individuals are rarely discovered before 20 years.

The occurrence of Paget's disease in more than one member of a family was first reported in 1883 (18). Analysis of numerous kindreds indicates an autosomal dominant mode of inheritance (19). A positive family history of Paget's disease was reported in nearly 15% of patients in two large studies (20,21). In a clinic in Spain, 40% of the patients had at least one first-degree relative with Paget's disease after screening with bone scans (22). Gene analysis of Paget's disease kindreds will be discussed subsequently.

CLINICAL FEATURES

Paget's disease is a localized disorder of the skeleton with a wide range of skeletal involvement. One bone was affected in 5% of patients whereas the average number of lesions was about 6.5 per patient in a series of 197 patients (23). In a more recent study younger patients had a 47% prevalence of monostotic disease while 28% of older patients had monostotic disease (24). In patients with familial disease there may be somewhat more bones affected than in patients with sporadic disease (25).

Deformity

A common feature of Paget's disease is skeletal deformity. This clearly evolves over a period of many years (probably decades) in most patients. The deformity is most visible in the skull and lower extremities.

Asymmetric enlargement of the cranium may first come to attention in those individuals who notice an increase in hat size. An increase in the size of superficial scalp veins, best appreciated over the frontal and temporal bones, is not uncommon. In patients with cranial enlargement, hearing loss is a common complication. Hearing loss correlates with loss of bone mineral density in the cochlear capsule (26). Inexplicably, despite the common skull involvement, Paget's disease is quite unusual in the facial bones. Facial disfigurement may be a consequence of enlargement of the maxilla and/or mandible and can be accompanied by spreading of the teeth, malocclusion, and loss of teeth (27).

One or, less often, two clavicles may become enlarged. An enlarged scapula is uncommonly appreciated perhaps because of its location.

The spine is a common source of morbidity from Paget's disease. The lumbar vertebrae and sacrum are most frequently affected. A single vertebra or multiple vertebrae may be involved. Over time, the vertebrae generally enlarge, but in some instances, vertebral compression may produce significant kyphosis.

Although Paget's disease is commonly found to affect the pelvis, only in its most severe form is it apparent on physical examination that the bone is thicker than normal. It is much easier to detect in the extremities, particularly when bowing of the femur and/or tibia is present (Figure 2). An increase in skin temperature is more readily detected over the tibia, a reflection of increased blood flow to the bone and surrounding soft tissue. Bowing of the upper extremity long bones is much less common than in the lower extremity, presumably because these are not weight-bearing bones.

Figure 2.

Typical bowing of the leg due to Paget's disease involving the right tibia.

Pathological fractures in the lower extremity are most likely to occur in the femur and typically are transverse in nature (Figure 3). They are much more likely to result in nonunion than are tibial fractures (28).

Figure 3.

Transverse fracture of the left femur.

Pain

Pain is a quite common symptom in patients with Paget's disease. It may be of skeletal, joint, neurologic, or muscle origin. Surprisingly, bone pain is usually absent even in patients with extensive disease or, when present, is mild to moderate in severity. The pain is usually dull in quality and often persists during the night. Weight bearing seldom produces a significant increase in bone pain.

Severe pain in a patient with Paget's disease is most likely to be due to osteoarthritis. This commonly occurs in the hip joint. Deterioration of the cartilage can occur when Paget's disease affects the acetabulum alone (Figure 4), but is likely to be more severe when both the acetabulum and head of the femur are affected by Paget's disease. If the femoral head is the only site of the disease, osteoarthritis is a less likely complication. A major feature of the pain in these patients is a significant increase in severity with weight bearing. In some patients, the combination of pain and impaired motion of the joint severely limits mobility. Knee pain and joint effusion may be prominent features in patients with bowing of the tibia. Back pain due to osteoarthritis also occurs in association with Paget's disease (Figure 5). Pain from osteoarthritis of the shoulder joint is relatively uncommon.

Figure 4.

Paget's disease involving the left hemipelvis and right femur. There is severe osteoarthritis of the left hip but a relatively normal joint space in the right hip.

The most severe chronic pain in patients with Paget's disease is probably of neurologic origin. Pain from compression of the spinal cord or nerve roots may follow from enlargement of the vertebral bodies, pedicles, or laminae as well as from compression fractures. Pain from this source is more likely to arise from Paget's disease affecting the thoracic spine.

Figure 5.

Patient with back pain who has multiple vertebrae affected by Paget's disease, large osteophytes, and narrowed disc spaces.

In a number of individuals, the weight of the skull may be so great that they have difficulty in keeping the head erect. This can produce neck pain and tension headaches due to muscle spasm. Deformity of the spine may also be associated with intermittent pain due to spasm of the paravertebral muscles.

RADIOLOGY

The radiologic features of Paget's disease include osteolytic, osteosclerotic, and mixed lesions.

The earliest lesions are osteolytic in character and are most readily appreciated in the skull (Figure 6). Circumscribed osteolytic skull lesions were called "osteoporosis circumscripta" by Schuller (29). These most often are seen in the frontal and occipital regions and with time may slowly coalesce. The other region where osteolytic lesions are commonly observed is the long bones of the lower extremity. The lesions usually arise at either end of the bone, seldom in the diaphysis. At the junction of the lesion with normal bone, the osteolytic lesion has the shape of a flame or inverted V (Figure 7). Such lesions have been noted to extend into normal bone at an average rate of about 1 cm per year (30).

Figure 6.

Large osteolytic lesion in the skull of a woman with Paget's disease.

Figure 7.

Osteolytic lesion of the distal left femur which is progressing proximally.

A heterogeneous region of osteosclerotic bone slowly develops in areas of the skeleton previously exhibiting a purely osteolytic character. This can be readily seen in long bones where the advancing front of osteolysis is trailed by patchy sclerosis superimposed on the earlier osteolytic process. With more time, the character of the bone may evolve into a dominant osteosclerotic appearance. This is often accompanied by periosteal new bone formation, which results in an increase in circumference of the bone. In the first observations reported by Paget, the thickness of the calvarium was fourfold greater than normal in one patient (1). The most severe skull involvement may be associated with basilar impression (Figure 8) which can produce compression of the structures in the posterior fossa resulting in ataxia, muscle weakness, and respiratory distress. With the evolution of the sclerotic phase of the disease, the lower extremity long bones often exhibit lateral and anterior bowing. Another radiologic feature in the long bones of the lower extremity is the presence of linear transverse radiolucencies in the cortex of the convex aspect of the bowed bone. These have been termed fissure fractures. Multiple fissure fractures may be seen. Although they usually remain stable, a small percent progress to complete transverse fractures.

Figure 8.

Far advanced Paget's disease of the skull. Note the thickened inner and outer tables, the chaotic new bone deposition termed cotton-wool patch, and basilar impression.

It has been observed that after a dominant sclerotic lesion has developed, there may be secondary osteolytic lesions superimposed upon the sclerotic bone. These are most readily seen as clefts in the cortex of the long bones.

Computerized tomography (CT) and magnetic resonance imaging (MRI) are generally not needed in the evaluation of most patients (31). CT may be needed to detect subtle fractures, spinal stenosis and secondary neoplasms. MRI may be particularly useful in evaluating spinal complications.

The commercial availability of a technetium99m-labeled bisphosphonate in 1974 ushered in the era of routine use of bone scans in clinical medicine (32). In patients with Paget's disease, the affected bone has increased nuclide activity five minutes after intravenous administration of the bone-seeking tracer when compared with normal bone. The nuclide activity is 3-5 times higher than in normal bone. A bone scan is a very effective means of determining the extent of the disease and is clearly more sensitive than X-rays in determining the presence of small osteolytic areas of the disease (Figure 9). Since occult fractures and bone metastases may mimic some lesions of Paget's disease, it is necessary to do X-rays or CT scans of areas of increased nuclide uptake to distinguish the nature of the lesions. Very seldom is it necessary to do a bone biopsy to ascertain the diagnosis.

Figure 9.

A technetium 99m-bisphosphonate bone scan of a patient with polyostotic Paget's disease.

In addition to the classical bone scan using a technetium-labeled bisphosphonate, gallium scans (33), fluorine-18-FDG PET scans (34), and Tl-201 scans (35) have been observed to delineate lesions of Paget's disease. In one study, the response to calcitonin treatment was more rapid with gallium scan than with a bone scan (33).

PATHOLOGY

Based on histological examinations of the interface of normal bone with an advancing osteolytic focus of Paget's disease, it has been concluded that the primary abnormality is a localized excess of osteoclastic bone resorption. An increased number of osteoclasts are present in Howship's lacunae in cortical and trabecular bone (Figure 10). They are frequently larger than normal and may have up to 100 nuclei in a single cross-section rather than the 3-10 found in normal osteoclasts (36). With progression of osteoclastic activity in the cortex, bone volume is reduced and individual osteons become confluent. The bone volume in trabecular bone of the medullary cavities is similarly reduced by osteoclastic activity. In association with the intense osteoclastic activity, the normal fatty or hematopoietic marrow is replaced by a fibrocellular stroma, which is highly vascular.

Figure 10.

A bone biopsy of the iliac crest revealing an intense area of osteoclastic bone resorption. The osteoclasts are increased in size and have a greater number of nuclei than average.

In the mature lesion, there is a mixture of lamellar and woven bone, which transforms the matrix into a chaotic "mosaic" pattern of irregularly juxtaposed pieces of lamellar bone, interspersed with woven bone (Figure 11). The normal outer and inner circumferential lamellae and interstitial lamellae of the cortex are completely disrupted. Plump osteoblasts are found in large numbers on surfaces of new bone formation. There is an abundance of osteoid on bone surfaces but there is no increase in thickness of the osteoid seams (37). It has been noted that the size of the periosteocytic lacunae in the woven bone is greater than in the lamellar bone of Paget’s disease (37). Since this is also the finding in woven bone from non-pagetic individuals the relevance of this observation is unclear.

Figure 11.

A bone biopsy demonstrating the "mosaic" pattern of bone matrix in Paget's disease. Note the chaotic lamellar pattern intermixed with woven bone as demonstrated with polarized light.

There is some evidence of a "burned out" phase of Paget's disease in which the abnormal matrix persists but cellular activity is nearly absent and the marrow space is mainly filled with fat. It is more likely that such a finding does not occur throughout an entire lesion, but is found with all stages of the disease in a single bone.

Studies of the ultrastructure of osteoclasts in Paget's disease have demonstrated that many of these cells harbor microfilaments in the nucleus and occasionally, in the cytoplasm (38,39) (Figure 12). The microfilaments have the same structural features as nucleocapsids of viruses of the Paramyxoviridae family, a family of RNA viruses known to cause childhood infections such as measles and pneumonia due to respiratory syncytial virus. The nucleocapsid-like structures have not been found in osteoblasts, osteocytes, or bone marrow cells in the same specimens containing the osteoclast microfilaments. Identical microfilaments have been found in a small percentage of the osteoclasts in giant cell tumors of bone and in the osteoclasts of some patients with osteopetrosis and pyknodysostosis (40).

Figure 12.

Electron microscopic examination of an iliac crest biopsy revealing microfilaments within remnants of a degenerating osteoclast nucleus. The arrow indicates microfilaments in adjacent cytoplasm. Magn. x 25,800

In addition to the structural evidence for the presence of viral nucleocapsids in the osteoclasts of Paget's disease, evidence of paramyxoviridae nucleocapsid proteins (41,42), and mRNA (43) has been reported, although not by all investigators (44). In one study addressing the identity of the osteoclast microfilaments, the full-length sequence for the measles virus nucleocapsid gene was delineated from the bone marrow of one patient as were more than 700 base pairs of the nucleocapsid gene in three additional patients (45).

BIOCHEMICAL ASSESSMENT

The radiologic and histologic evidence of increased bone resorption and formation in patients with Paget's disease is readily assessed by measuring biochemical markers of bone turnover. In general, these tests reflect the extent and activity of the disease.

NEOPLASTIC COMPLICATIONS

Sarcoma

Sarcomas develop in the lesions of Paget's disease more often than in an age-matched normal population, although the incidence is less than 1% overall (56). However, in patients with extensive disease, the incidence has been estimated at 10% (57), although a subsequent study suggests this is not so (58). Rarely, sarcomas have been known to develop in multiple members of a family.

A sarcoma should be suspected when new pain and swelling develop in a bone previously affected by Paget's disease. The most common sites are in the pelvis, femur, humerus, skull, and facial bones.

There is a variable histology of the sarcomas of Paget's disease including osteosarcoma, fibrosarcoma, chondrosarcoma, and anaplastic sarcoma (57). Several types of histology may be present in a single tumor. Multinucleated giant cells (probably osteoclasts) may be scattered throughout a tumor. They may contain the nuclear microfilaments seen in the osteoclasts and are not thought to be neoplastic in nature (59).

Because of the underlying distortion of the pagetic bone, it is difficult to detect an early stage of a sarcoma. Typically, a radiolucent focus with speckled regions of calcification will be observed to disrupt the cortex of the bone (Figure 13). The best means of delineating the extent of the tumor mass is by CT or MRI.

Figure 13.

Multiple sites of osteogenic sarcoma in a patient with Paget's disease of the right hemipelvis. Note the extension of the tumor through the cortex of right ischium.

Perhaps because of a failure of early diagnosis in most patients with sarcoma arising in Paget's disease, survival is brief. Only 7.5%-10% of patients survive five years and despite the multiple modalities of therapy presently available, the prognosis remains poor (56,60).

SYSTEMIC COMPLICATIONS AND ASSOCIATED DISEASES

TREATMENT

Prior to 1975, a number of nonspecific treatments were used to attempt to alleviate some of the manifestations of Paget's disease. With the exception of pain medications none were of value. With the development of salmon calcitonin, a new era of effective treatment began. Presently, there are a number of highly effective agents which make possible excellent control of the disease.

ETIOLOGY

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