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Diagnostic Procedures for Paget’s Disease: Radiologic, Pathologic, and Laboratory Testing
ENDOCRINE ASPECTS OF AGING
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DIAGNOSTIC PROCEDURES FOR PAGET'S DISEASE Radiologic, Pathologic, and Laboratory Testing Robert M. Klein, MD, FACR, and Alex Norman, MD, FACR
Paget's disease of bone is characterized by abnormal remodeling and a high rate of turnover which determines its pathologic, radiologic, and biochemical findings. In 1877 Sir James Paget2"eported "a form of chronic inflammation of bones (osteitis deformans)." He described what we now recognize as classic advanced Paget's disease and many of its complications. Paget was an astute observer, and his description has remained difficult to improve upon. In subsequent years the discovery of x-rays and new laboratory techniques have allowed us to define and identify earlier stages of the disease. Paget's disease was for many years considered a related form of the disease known as osteitis fibrosa cystica. The two conditions were proved unrelated in 1926 when MandllRdetermined that osteitis fibrosa cystica was a systemic bone disorder secondary to parathyroid disease. l ~ ~ an Although Paget believed the disease to be rare, S ~ h m o rfound incidence of 3.3% in a series of 4614 autopsies in patients aged more than 40 years. The disease can affect virtually any bone of the skeleton. It is typically a disease of older persons and is uncommon under the age of 40 years. A patient with classic advanced disease will manifest an enlarged head, bowed lower extremities, and a shortened kyphotic trunk. Approximately 80% of patients are asymptomatic, and the disease is uncovered when the patient is examined radiographically for another condition or by a routine screening for serum alkaline phosphatase.
From the Department of Radiology, New York Medical College, Valhalla, New York
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA
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VOLUME 24. NUMBER 2 JUNE 1995
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SKELETAL DISTRIBUTION
Paget's disease may be monostotic or polyostotic. Seventeen percent to 31% of patients present with monostotic di~ease.~, 20 The incidence of the disease tends to increase with age. Disagreement exists as to whether the number of bones involved increases with age. Paget's disease demonstrates a predilection for the axial skeleton and lower extremities, which are involved in 75% to 90% of cases.9 Although the frequency of distribution within the skeleton varies somewhat in different series, the general pattern is clear. According to Meunier et a1,2O the major sites of involvement were the pelvis (72%),lumbar spine (58%), femur (55%), thoracic spine (45%), sacrum (43%), skull (42%), tibia (35%), humerus (31%), and cervical spine (11%). Florid polyostotic disease, such as that described by Paget, is seen in a distinct minority of cases. In Meunier's series of 170 patients, the distribution of monostotic disease was tibia (4.7%),ilium (4.7%),femur (3.5%),skull (2.9%),vertebra (0.6%) and humerus (O.~YO).~O A curious asymmetry has been described in which a right-sided predominance of lesions in the pelvis, femora, and clavicles occurs, particularly in men.9This pattern remains unexplained.
PATHOLOGY
Paget's disease evolves through three stages both pathologically and radiographically. Different stages of the disease can be recognized throughout the skeleton or even in a single bone. The three stages are the osteolytic (hot stage), the mixed or intermediate stage, and the static or late stage. The earliest phase is the osteolytic or hot form of the lesion. Only a small percentage of patients are seen with purely lytic involvement. This phase is characterized by active bone resorption with a sharply defined interface between pagetic and normal bone. Hyperactive osteoclastic .~~ activity outpaces osteoblastic activity resulting in bone r e s o r p t i ~ nConcurrently, osteoblastic activity results in the rimming of bony trabeculae. An advancing wedge of fibrovascular tissue replaces the resorbed bone and fills the void in the marrow spaces, resulting in highly vascular pagetic bone during this phase (Fig. 1). Histologically, the lytic stage of Paget's disease bears a striking resemblance to osteitis fibrosa cystica of hv~er~arathvroidism.~~ 6uring ihe mixed or intermediate phase of Paget's disease, both osteoclastic activity and osteoblastic activity occur simultaneously. Eventually, bone repair will become the dominant feature, and irregular trabeculae of woven and then lamellar bone are laid down. Bony trabeculae begin to thicken. Histologically, the newly formed trabeculae are architecturally altered by cement lines into a mosaic pattern classic for Paget's disease (Fig. 2). Progressive widening of the bone and cortical J I
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Figure 1. Photomicrograph of Paget's disease showing active bone remodel~ngwith prominent osteoclastic resorption and new bone formation (original magnification x 200). (Courtesy of German Steiner, MD, New York, NY).
thickening occur following the laying down of periosteal and endosteal pagetic bone. The static or late stage of Paget's disease is characterized by a lack of active remodeling of bone, and the fibrovascular tissue seen in the marrow during earlier stages is replaced by fat. Focal areas of fatty marrow and hemorrhage may accumulate in sizeable spaces between
Figure 2. Paget's disease in a later stage. The bone trabecula is thick and irregular, and numerous cement lines in the bone give the appearance of a "mosaic" pattern. (original magnification x 100). (Courtesy of German Steiner, MD, New York, NY)
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thickened trabeculae, which may give a cystic appearance radiographicall^.'^, l3
Despite the lack of abnormal activity in the static stage, the pagetic bone remains and is not replaced by normal bone. RADIOLOGY
The radiographic changes of Paget's disease mirror the pathologic findings and progress over a number of years. During the osteolytic stage, active resorption advances along a well-defined front at a rapid pace, destroying the compact cortical bone which is replaced by abnormal pagetic bone. The rate of progression of the advancing wedge has been determined to be approximately 8 mm per year.17 LONG BONES
Paget's disease begins at the end of a long bone and progresses to the other end in almost all cases. Occasionally, in the tibia, the disease process begins in the d i a p h y s i ~ . ~ ~ In the osteolytic stage, the lytic area demonstrates a wedge front at the interface with normal bone (Fig. 3A). This has been described as "flame-shaped" or a "blade of grass." This finding - is characteristic of osteolytic Paget's disease in a long bone. In this stage, the cortex is thinned by the active resorptive process. The bone may be expanded by periosteal new bone apposition, giving the cortex a layered appearance. As the disease progresses into the mixed stage, coarsely trabeculated bone replaces both the old cortex and the cancellous bone. This stage is characterized by widened bones, thickened cortices, and coarse trabeculae in the medullary space (Fig. 3B). This results in a significant increase in bone density. Often, one can identify an advancing wedge of osteolytic resorption in the shaft while the disease has progressed to the mixed stage near the end of the bone where the process began (Fig. 4). During the static or late phase of Paget's disease, a diffuse increase in bone density occurs. The corticomedullary definition may be lost. The structural remodeling of the bone results in bowing; the- femur bows laterally and the tibia anteriorly. SKULL
The initial osteolytic stage is described as osteoporosis circumscripta (Fig. 5). This is a well-demarcated zone, often large, which represents marked resorption of both the inner and outer tables of the calvarium. The frontal bone is most commonly affected (osteoporosis circumscripta frontalis). Multiple lesions may involve the parietal, temporal, and occip-
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Figure 3. A, Anteroposterior view of left humerus demonstrates the osteolyi~cphase of Paget's disease with an advancing wedge of lytic disease and thinned cortices extending from the humeral head down the shaft. B, The left humerus has now developed thickened cortices and coarsened trabeculae representing the intermediate phase Paget's disease. Figure 4. Anteroposterior view of right tibia demonstrates the mixed phase of Paget's disease in the most proximal portion with an advancing wedge of osteolytic disease more distally. Note that the disease began at the most proximal end of the bone and progressed down the shaft.
ital bones. Osteoporosis circumscripta lesions are notable for their capacity to cross suture lines and may remain unchanged for several years. With the increase in osteoblastic activity, focal islands of sclerosis occur in the calvarium. Because of the radiographic features, they have been said to have a cotton-wool appearance (Fig. 6). Gradually, the demarcation between the cranial tables and the diploic space is obscured, and thickening of the calvarium progresses. When a markedly thickened calvarium is examined grossly, its cut surface is said to resemble pumice stone.13 The thickening of the cranial tables may be lumpy, giving a corrugated appearance both internally and externally in some cases. When this thickening of the internal table is marked, it may compress the underlying brain (Fig. 7). Basilar impression is seen in about approximately one third of cases.26Pagetic bone formation at the skull base may encroach upon cranial nerve foramina or involve the middle and inner ear structures. The previously mentioned panoply of pagetic involvement may result in a host of neurologic disturbances.
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Figure 5. Lateral view of skull with large lytic lesion in frontal and parietal bones. The lesion does not have a sclerotic margin and crosses the coronal suture. These features are typical of osteoporosis circumscripta.
Figure 6. Lateral view of skull with "cotton wool" appearance. Multiple ill-defined sclerotic foci are scattered in the calvarium. The tables of the skull are starting to thicken.
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Figure 7 . Lateral proton density MR image of skull. The calvar~urnis markedly thickened and has lumpy inner surface. This has compressed the underlying brain and indented its surface. (Courtesy of Denise Leslie, MD, Valhalla, NY)
SPINE
The lumbar spine and sacrum are most frequently involved, followed in decreasing frequency by the thoracic and cervical region^.^ The third and fourth lumbar vertebrae are the most frequently i n v ~ l v e d . ~ Monostotic Paget's disease of the spine is well-known. Paget's disease may affect both the vertebral body and the posterior elements. The osteolytic stage of Paget's disease is infrequently documented in the spine. Most common is the mixed stage, which typically presents with an enlarged vertebral body and thickened cortices. This results in a "picture frame" appearance. In addition, coarsened trabeculae frequently are oriented in a vertical striated fashion within the cancellous portion of the vertebral body (Fig. 8). This may simulate the appearance of a hemangioma, but the vertebral enlargement and picture frame presentation will suggest the correct diagnosis. Under the load of weight bearing, the structurally weakened vertebrae may become biconcave or collapse, resulting in neurologic impairment. Neurologic changes may also result from spinal stenosis, impairment upon neural foramina, and a vascular steal syndrome caused by highly vascular pagetic bone. Occasionally, a vertebra will be homogeneously sclerotic, the socalled "ivory vertebra." This may sunulate a vertebra involved with lymphoma or metastasis, and only the vertebral enlargement in Paget's disease may allow differentiation. PELVIS AND OTHER SITES
Involvement in the pelvis tends to be asymmetric. A common early finding is thickening of the iliopubic and ilioischial lines, the "brim
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Figure 8. Lateral view of "picture frame" vertebrae in lumbar spine. Thickened cortices form the "picture frame" with coarsened trabeculae in medullary space.
sign."19 The iliac wings often appear lucent centrally from significant resorption, whereas the periphery becomes thickened and sclerotic. The pubis and ischium may become obviously enlarged (Fig. 9). Protrusio acetabulae may occur secondary to structural weakness of the involved bone. When involvement is extensive, the coarse trabecular pattern may
Figure 9. Anteroposterior view of pelvis. The cortices are thickened bilaterally, particularly along the pelvic brim. The bones are widened and there is coarse trabeculation. The iliac wings appear lucent centrally.
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be interspersed with areas of radiolucency, simulating cystic areas. Jaffe demonstrated that these cystic areas represent focal accumulations of fatty m a r r ~ w Occasionally, .~ Paget's disease may manifest in the pelvis as a homogeneously sclerotic process, which is difficult to differentiate from metastasis or lymphoma. The scapula and clavicle are involved in approximately 10% to 20% of cases (Fig. 10).9,20 The ribs and sternum are involved in approximately 3% of cases. These sites usually present with a mixed pattern but, rarely, may be totally sclerotic. Even the patella may be affected.32 COMPLICATIONS
The structural weakness of pagetic bone commonly leads to pathologic fractures, either spontaneous or following minor trauma. In asymptomatic patients, it may be the initial finding. Fractures are most common in the femur and tibia, followed by the spine, humerus, and pelvis. Stress or insufficiency fractures are the most frequently seen type.
Figure 10. A view of right shoulder. The scapula is homogeneously sclerotic, a so called "ivory" appearance. Figure 11. Anteroposterior view of left humerus with intermediate phase of Paget's disease. Note the transverse "banana" type fracture of the distal shaft.
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These typically occur on the convex surface of weight-bearing bones, laterally in the femur and anteriorly in the tibia. This type of fracture frequently is multiple, and, in a case seen by one of the authors, 19 insufficiency fractures were detected along the anterolateral surface of the femur. Insufficiency fractures may heal or go on to complete fractures. The subtrochanteric region of the femur is the most common location of complete fract~res.~ Complete fractures of long bones have been described as "banana" fractures, because of the horizontal orientation of the fracture with minimal comminution (Fig. 11). Complete fractures may follow biopsy. Fractures are reported to occur most commonly in the osteolytic stage but may occur in the mixed or static stages as well. Fractures in pagetic bone usually heal at the same rate as in normal bones or slower. However, nonunion, particularly in the femur, may be en~ountered.~ Pathologic fractures may herald the presence of sarcomatous degeneration, and, therefore, biopsy is recommended in such cases.1°
TUMORS
Both benign and malignant tumors are associated with Paget's disease. Sarcomatous transformation of Paget's disease is its most ominous complication. It was first recognized by Paget and described in his initial report.24The incidence of sarcomatous transformation has been reported to be as high as 5% to 10% in patients with extensive disease 13, 25 The and as low as 0.15O/0 in patients with limited inv~lvement.~, overall incidence is probably closer to the lower figure. Sarcomatous transformation may occur in monostotic Paget's disease.6While solitary lesions are usually found, Paget's sarcoma may be multicentric. The mean age at presentation has been reported to be 61.8 years, and there is a 1.5 to 1.0 male-to-female ratio.31The most frequent sites of involvement in decreasing order are the pelvis, humerus, femur, skull, and tibia. The onset of pain, fracture, further elevation of the serum alkaline phosphatase, or a soft-tissue mass are all signs of possible sarcomatous transformation. Osteosarcoma is the predominant histologic type and accounted for 88% of Paget's sarcomas in a recent series.31The remainder are fibrosarcoma, chondrosarcoma, malignant fibrous histiocytoma, and malignant giant cell tumor. The predominant radiographic manifestation is that of a destructive, lytic process. Much less commonly, mixed lytic and sclerotic changes or a purely sclerotic process are noted. The sarcoma results in destruction of pagetic bone with extension of the mass into the soft tissues (Fig. 12). Paget's sarcoma metastasizes to the lungs and rarely to other bones. Most cases involving more than one bone are considered to be multicen-
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of paget's dlsease. A Paget's sarcoma has caused extenslve lytlc destruction of the shaft followed b; a pathological fracture.
tric in origin. The 5-year survival in patients with Paget's sarcoma remains poor, and the mean survival is less than 1 year.31 Rarely, giant cell tumors may be associated with Paget's disease.l'~~~ Most giant cell tumors in Paget's disease occur in the skull and facial bones. Other reported sites include the pelvis, clavicle, spine, and long bones. Of note is the fact that giant cell tumors in the skull may be multiple. Familial and geographic clustering has been reported.ll Metastatic disease to pagetic bone may occur.', However, the frequency is less than one might expect, as both are common in the elderly. Common primary tumors are found in the breast, lung, kidney, colon, and prostate. Radiographic findings are similar to those with Paget's sarcoma and may be confused initially. In addition, clinical and laboratory findings are similar to those in patients with Paget's sarcoma. ~ , ~ is ~ a Rare instances of pseudosarcoma have been r e p ~ r t e d .This benign focal lesion that may exhibit cortical destruction, exuberant periosteal reaction, and a soft-tissue mass most commonly in the lower extremity. It frequently is mistaken for a sarcoma, and biopsy is needed to determine the true nature of the lesion. Similar paraosseous masses in the spine of patients with Paget's disease may result in neurologic signs from extradural compression. To be distinguished from the previous lesions are paraspinal masses of extramedullary hematopoiesis which have been described in association with Paget's disease.14
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ARTHRITIS
A form of osteoarthritis occurs in patients with Paget's disease, most commonly in the hip and knee.7,l6 This arthritis differs from primary osteoarthritis in that there is axial or medial narrowing of the hip joint, rather than superior narrowing. Large osteophytic formation is not as common in Paget's arthritis. Protrusio acetabulae is commonly present. It has been proposed that Paget's arthritis results from active bone remodeling, structural weakness of the articular surface, and bone deformity secondary to the Paget's disease.16 OTHER IMAGING MODALITIES
Radionuclide bone scintigraphy using 99mTcdiphosphonate is an excellent modality for determining the distribution, extent, and activity of skeletal involvement in Paget's disease.15 Bone scanning generally correlates well with the pathophysiologic activity of the disease. The sensitivity of bone scans is such that it may identify some lesions before radiographic detection. One study detected 8.2% more lesions on bone scans than were apparent radiographi~ally.~~ However, osteoporosis circumscripta in the skull and old nonactive lesions in the late phase of Paget's disease may not be detected on bone scans. The use of quantitative bone scans can be useful in evaluating disease activity following treatment. In sarcomatous transformation, bone scans usually demonstrate a decreased uptake of radionuclide in the area of the tumor, resulting in a cold area. However, gallium scans typically demonstrate an increased uptake of radionuclide in the tumor. Computed tomography and MR imaging generally do not have a significant role in the diagnosis of Paget's disease. However, these modalities may be useful in evaluating complications of Paget's disease, including neurologic abnormalities, neoplastic involvement, and arthriti^.^^, 34 A variety of MR signal patterns have been described in Paget's disease depending upon the skeletal location and the stage of disease. LABORATORY EVALUATION
Key laboratory findings in Paget's disease are a reflection of the high rate of bone turnover associated with active bone r e m ~ d e l i n g . ~ ~ Alkaline phosphatase is a ubiquitous enzyme found in many body tissues. In bone, it is concentrated in the osteoblasts. In Paget's disease, markedly high levels of serum alkaline phosphatase occur as osteoblasts lay down bone in response to extremely increased osteoclastic activity.33 It is not unusual to see values from 10 to 25 times the upper limit of normal. In the late static phase of Paget's disease, serum alkaline phosphatase levels may fall to the normal range. Serum alkaline phos-
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phatase levels may increase significantly in the presence of neoplastic involvement. Increased levels of urinary hydroxyproline reflect elevated osteoclastic activity.'O The serum alkaline phosphatase and urinary hydroxyproline levels usually parallel one another, but the latter may be a more sensitive indicator of disease activity. Serial chemistry levels, as well as scintigraphic examinations, are useful in monitoring the activity of Paget's disease and the response to treatment. Because of the high rate of bone turnover, serum uric acid levels frequently are elevated. Despite the high rate of bone turnover, a balance is maintained between calcium removed from the skeleton and calcium deposited in new bone.20 Therefore, the serum calcium is usually within normal limits. Elevations of serum calcium do occur when patients with Paget's disease are immobilized or sustain fractures. References 1. Agha FP, Norman A, Hirschl S, et al: Paget's disease: Coexistence with metastatic carcinoma. NY State J Med 76:734, 1976 2. Barry HC: Paget's Disease of Bone. Edinburgh, Livingstone, 1969 3. Bowerman JW, Altman J, Hughes JL, et al: Pseudo-malignant lesions in Paget's disease of bone. AJR Am J Roentgenol 124:57,1975 4. Burgener FA, Perry PE: Solitary renal cell carcinoma metastasis in Paget's disease simulating sarcomatous degeneration. AJR Am J Roentgenol 128:853, 1977 5. Dove J: Complete fractures of the femur in Paget's disease of the bone. J Bone Joint Surg (Br) 62:12, 1980 6. Edeiken J, Dalinka M, Karasick D: Roentgen Diagnosis of Diseases of Bone, vol 2. Baltimore, Williams and Wilkins, 1990, p 123 7. Goldman AB, Bullough P, Kammermans S, et al: Osteitis deformans of the hip joint. AJR Am J Roentgenol 128:601, 1977 8. Greditzer H, McLeod R, Unni K, et al: Bone sarcomas in Paget's disease. Radiology 146:327, 1983 9. Guyer PB, Clough PWL: Paget's disease of bone: Some observations on the relation of the skeletal distribution to pathogenesis. Clin Radiol 29:421, 1978 10. Hamdy RC: Paget's Disease of Bone:Assessment and Management. New York, Praeger Publishers, 1981 11. Jacobs TP, Michelsen J, Polay JS, et al: Giant cell tumor in Paget's disease of bone: Familial and geographic clustering. Cancer 44:742, 1979 12. Jaffe HL: The classic Paget's disease of bone. Clin Orthop 127:4, 1977 13. Jaffe HL: Metabolic, Degenerative and Inflammatory Diseases of Bones and Joints. Philadelphia, Lea and Febiger, 1972, p 240 14. Kadir S, Kalisher L, Schiller AL: Extramedullary hematopoiesis in Paget's disease of bone. AJR Am J Roentgenol 129:493,1977 15. Lentle BC, Russell AS, Heslip PG, et al: The scintigraphic findings in Paget's disease of bone. Clin Radiol 27:129, 1976 16. Machtey I, Rodman GP, Benedek TG: Paget's disease of the hip joint. Am J Med Sci 251:524, 1966 17. ~ a l d a g u eB, Malghem J: Dynamic radiologic patterns of Paget's disease. Clin Orthop 217:126, 1987 18. Mandl F: Klinisches und experimentalles zur frage der lokalisierten und generalisierten ostitis fibrosa. Arch Klin Chir 143:l and 245, 1926 19. Marshall TR, Ling JT: The brim sign: A new sign found in Paget's disease (osteitis deformans) of the pelvis. AJR Am J Roentgenol 90:1267, 1963
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20. Meunier PJ, Salson C, Mathiew L, et al: Skeletal distribution and biochemical parameters of Paget's disease. Clin Orthop 21737, 1987 21. Milgram JW: Radiographical and pathological assessment of the activity of Paget's disease of bone. Clin Orthop 127:43, 1977 22. Mirra JM: Bone Tumors: Clinical, Radiologic, and Pathologic Correlations. Philadelphia, Lea and Febriger, 1989, p 893 23. Monson DK, Finn HA, Dawson PJ, et al: Pseudosarcoma in Paget's disease of bone. J Bone Joint Surg 71[A]:453,1989 24. Paeet I: On a form of chronic inflammation of bones (osteitis deformans). Med Chir ~ru60:;7, 1877 25. Price CHG, Goldie W: Paget's sarcoma of bone. J Bone Joint Surg [Br] 51:205, 1969 26. Resnick D, Niwayama G: Diagnosis of Bone and Joint Disorders, ed 2., Philadelphia, WB Saunders, 1988, p 2127 27. Roberts MC, Kressel HY, Fallon MD, et al: Paget's disease: MR imaging findings. Radiology 173:341, 1989 28. Schajowicz F, Blullital I: Giant cell tumor associated with Paget's disease of bone. J Bone Joint Surg 48[A]:1340, 1966 29. Schlesinger A, Naimark A, Lee V: Diaphyseal presentation of Paget's disease in long bones. Radiology 14783, 1983 30. Schmorl G: Ueber Ostitis deformans Paget. Virchows Arch (Path01Anat) 283:694,1932 31. Smith J, Botet J, Yeh S: Bone sarcomas in Paget's disease: A study of 85 patients. Radiology 152:583 1984 32. Stull MA, Moser JR, Vinh TN, et al: Paget's disease of the patella. Skeletal Radio1 19:407, 1990 33. Tietz NW: Textbook of Clinical Chemistry. Philadelphia, WB Saunders, 1986, p 704 34. Zlatkin MB, Lander PH, Hadjipavlou AG, et al: Paget's disease of the spine: CT with clinical correlation. Radiology 160:155, 1986
Addvess reprint requests to Robert M. Klein, MD, FACR Department of Radiology New York Medical College Valhalla, NY 10595
0889-8529195 $0.00+ .20
DIAGNOSTIC PROCEDURES FOR PAGET'S DISEASE Radiologic, Pathologic, and Laboratory Testing Robert M. Klein, MD, FACR, and Alex Norman, MD, FACR
Paget's disease of bone is characterized by abnormal remodeling and a high rate of turnover which determines its pathologic, radiologic, and biochemical findings. In 1877 Sir James Paget2"eported "a form of chronic inflammation of bones (osteitis deformans)." He described what we now recognize as classic advanced Paget's disease and many of its complications. Paget was an astute observer, and his description has remained difficult to improve upon. In subsequent years the discovery of x-rays and new laboratory techniques have allowed us to define and identify earlier stages of the disease. Paget's disease was for many years considered a related form of the disease known as osteitis fibrosa cystica. The two conditions were proved unrelated in 1926 when MandllRdetermined that osteitis fibrosa cystica was a systemic bone disorder secondary to parathyroid disease. l ~ ~ an Although Paget believed the disease to be rare, S ~ h m o rfound incidence of 3.3% in a series of 4614 autopsies in patients aged more than 40 years. The disease can affect virtually any bone of the skeleton. It is typically a disease of older persons and is uncommon under the age of 40 years. A patient with classic advanced disease will manifest an enlarged head, bowed lower extremities, and a shortened kyphotic trunk. Approximately 80% of patients are asymptomatic, and the disease is uncovered when the patient is examined radiographically for another condition or by a routine screening for serum alkaline phosphatase.
From the Department of Radiology, New York Medical College, Valhalla, New York
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA
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VOLUME 24. NUMBER 2 JUNE 1995
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KLEIN & NORMAN
SKELETAL DISTRIBUTION
Paget's disease may be monostotic or polyostotic. Seventeen percent to 31% of patients present with monostotic di~ease.~, 20 The incidence of the disease tends to increase with age. Disagreement exists as to whether the number of bones involved increases with age. Paget's disease demonstrates a predilection for the axial skeleton and lower extremities, which are involved in 75% to 90% of cases.9 Although the frequency of distribution within the skeleton varies somewhat in different series, the general pattern is clear. According to Meunier et a1,2O the major sites of involvement were the pelvis (72%),lumbar spine (58%), femur (55%), thoracic spine (45%), sacrum (43%), skull (42%), tibia (35%), humerus (31%), and cervical spine (11%). Florid polyostotic disease, such as that described by Paget, is seen in a distinct minority of cases. In Meunier's series of 170 patients, the distribution of monostotic disease was tibia (4.7%),ilium (4.7%),femur (3.5%),skull (2.9%),vertebra (0.6%) and humerus (O.~YO).~O A curious asymmetry has been described in which a right-sided predominance of lesions in the pelvis, femora, and clavicles occurs, particularly in men.9This pattern remains unexplained.
PATHOLOGY
Paget's disease evolves through three stages both pathologically and radiographically. Different stages of the disease can be recognized throughout the skeleton or even in a single bone. The three stages are the osteolytic (hot stage), the mixed or intermediate stage, and the static or late stage. The earliest phase is the osteolytic or hot form of the lesion. Only a small percentage of patients are seen with purely lytic involvement. This phase is characterized by active bone resorption with a sharply defined interface between pagetic and normal bone. Hyperactive osteoclastic .~~ activity outpaces osteoblastic activity resulting in bone r e s o r p t i ~ nConcurrently, osteoblastic activity results in the rimming of bony trabeculae. An advancing wedge of fibrovascular tissue replaces the resorbed bone and fills the void in the marrow spaces, resulting in highly vascular pagetic bone during this phase (Fig. 1). Histologically, the lytic stage of Paget's disease bears a striking resemblance to osteitis fibrosa cystica of hv~er~arathvroidism.~~ 6uring ihe mixed or intermediate phase of Paget's disease, both osteoclastic activity and osteoblastic activity occur simultaneously. Eventually, bone repair will become the dominant feature, and irregular trabeculae of woven and then lamellar bone are laid down. Bony trabeculae begin to thicken. Histologically, the newly formed trabeculae are architecturally altered by cement lines into a mosaic pattern classic for Paget's disease (Fig. 2). Progressive widening of the bone and cortical J I
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Figure 1. Photomicrograph of Paget's disease showing active bone remodel~ngwith prominent osteoclastic resorption and new bone formation (original magnification x 200). (Courtesy of German Steiner, MD, New York, NY).
thickening occur following the laying down of periosteal and endosteal pagetic bone. The static or late stage of Paget's disease is characterized by a lack of active remodeling of bone, and the fibrovascular tissue seen in the marrow during earlier stages is replaced by fat. Focal areas of fatty marrow and hemorrhage may accumulate in sizeable spaces between
Figure 2. Paget's disease in a later stage. The bone trabecula is thick and irregular, and numerous cement lines in the bone give the appearance of a "mosaic" pattern. (original magnification x 100). (Courtesy of German Steiner, MD, New York, NY)
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thickened trabeculae, which may give a cystic appearance radiographicall^.'^, l3
Despite the lack of abnormal activity in the static stage, the pagetic bone remains and is not replaced by normal bone. RADIOLOGY
The radiographic changes of Paget's disease mirror the pathologic findings and progress over a number of years. During the osteolytic stage, active resorption advances along a well-defined front at a rapid pace, destroying the compact cortical bone which is replaced by abnormal pagetic bone. The rate of progression of the advancing wedge has been determined to be approximately 8 mm per year.17 LONG BONES
Paget's disease begins at the end of a long bone and progresses to the other end in almost all cases. Occasionally, in the tibia, the disease process begins in the d i a p h y s i ~ . ~ ~ In the osteolytic stage, the lytic area demonstrates a wedge front at the interface with normal bone (Fig. 3A). This has been described as "flame-shaped" or a "blade of grass." This finding - is characteristic of osteolytic Paget's disease in a long bone. In this stage, the cortex is thinned by the active resorptive process. The bone may be expanded by periosteal new bone apposition, giving the cortex a layered appearance. As the disease progresses into the mixed stage, coarsely trabeculated bone replaces both the old cortex and the cancellous bone. This stage is characterized by widened bones, thickened cortices, and coarse trabeculae in the medullary space (Fig. 3B). This results in a significant increase in bone density. Often, one can identify an advancing wedge of osteolytic resorption in the shaft while the disease has progressed to the mixed stage near the end of the bone where the process began (Fig. 4). During the static or late phase of Paget's disease, a diffuse increase in bone density occurs. The corticomedullary definition may be lost. The structural remodeling of the bone results in bowing; the- femur bows laterally and the tibia anteriorly. SKULL
The initial osteolytic stage is described as osteoporosis circumscripta (Fig. 5). This is a well-demarcated zone, often large, which represents marked resorption of both the inner and outer tables of the calvarium. The frontal bone is most commonly affected (osteoporosis circumscripta frontalis). Multiple lesions may involve the parietal, temporal, and occip-
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Figure 3. A, Anteroposterior view of left humerus demonstrates the osteolyi~cphase of Paget's disease with an advancing wedge of lytic disease and thinned cortices extending from the humeral head down the shaft. B, The left humerus has now developed thickened cortices and coarsened trabeculae representing the intermediate phase Paget's disease. Figure 4. Anteroposterior view of right tibia demonstrates the mixed phase of Paget's disease in the most proximal portion with an advancing wedge of osteolytic disease more distally. Note that the disease began at the most proximal end of the bone and progressed down the shaft.
ital bones. Osteoporosis circumscripta lesions are notable for their capacity to cross suture lines and may remain unchanged for several years. With the increase in osteoblastic activity, focal islands of sclerosis occur in the calvarium. Because of the radiographic features, they have been said to have a cotton-wool appearance (Fig. 6). Gradually, the demarcation between the cranial tables and the diploic space is obscured, and thickening of the calvarium progresses. When a markedly thickened calvarium is examined grossly, its cut surface is said to resemble pumice stone.13 The thickening of the cranial tables may be lumpy, giving a corrugated appearance both internally and externally in some cases. When this thickening of the internal table is marked, it may compress the underlying brain (Fig. 7). Basilar impression is seen in about approximately one third of cases.26Pagetic bone formation at the skull base may encroach upon cranial nerve foramina or involve the middle and inner ear structures. The previously mentioned panoply of pagetic involvement may result in a host of neurologic disturbances.
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Figure 5. Lateral view of skull with large lytic lesion in frontal and parietal bones. The lesion does not have a sclerotic margin and crosses the coronal suture. These features are typical of osteoporosis circumscripta.
Figure 6. Lateral view of skull with "cotton wool" appearance. Multiple ill-defined sclerotic foci are scattered in the calvarium. The tables of the skull are starting to thicken.
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Figure 7 . Lateral proton density MR image of skull. The calvar~urnis markedly thickened and has lumpy inner surface. This has compressed the underlying brain and indented its surface. (Courtesy of Denise Leslie, MD, Valhalla, NY)
SPINE
The lumbar spine and sacrum are most frequently involved, followed in decreasing frequency by the thoracic and cervical region^.^ The third and fourth lumbar vertebrae are the most frequently i n v ~ l v e d . ~ Monostotic Paget's disease of the spine is well-known. Paget's disease may affect both the vertebral body and the posterior elements. The osteolytic stage of Paget's disease is infrequently documented in the spine. Most common is the mixed stage, which typically presents with an enlarged vertebral body and thickened cortices. This results in a "picture frame" appearance. In addition, coarsened trabeculae frequently are oriented in a vertical striated fashion within the cancellous portion of the vertebral body (Fig. 8). This may simulate the appearance of a hemangioma, but the vertebral enlargement and picture frame presentation will suggest the correct diagnosis. Under the load of weight bearing, the structurally weakened vertebrae may become biconcave or collapse, resulting in neurologic impairment. Neurologic changes may also result from spinal stenosis, impairment upon neural foramina, and a vascular steal syndrome caused by highly vascular pagetic bone. Occasionally, a vertebra will be homogeneously sclerotic, the socalled "ivory vertebra." This may sunulate a vertebra involved with lymphoma or metastasis, and only the vertebral enlargement in Paget's disease may allow differentiation. PELVIS AND OTHER SITES
Involvement in the pelvis tends to be asymmetric. A common early finding is thickening of the iliopubic and ilioischial lines, the "brim
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Figure 8. Lateral view of "picture frame" vertebrae in lumbar spine. Thickened cortices form the "picture frame" with coarsened trabeculae in medullary space.
sign."19 The iliac wings often appear lucent centrally from significant resorption, whereas the periphery becomes thickened and sclerotic. The pubis and ischium may become obviously enlarged (Fig. 9). Protrusio acetabulae may occur secondary to structural weakness of the involved bone. When involvement is extensive, the coarse trabecular pattern may
Figure 9. Anteroposterior view of pelvis. The cortices are thickened bilaterally, particularly along the pelvic brim. The bones are widened and there is coarse trabeculation. The iliac wings appear lucent centrally.
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be interspersed with areas of radiolucency, simulating cystic areas. Jaffe demonstrated that these cystic areas represent focal accumulations of fatty m a r r ~ w Occasionally, .~ Paget's disease may manifest in the pelvis as a homogeneously sclerotic process, which is difficult to differentiate from metastasis or lymphoma. The scapula and clavicle are involved in approximately 10% to 20% of cases (Fig. 10).9,20 The ribs and sternum are involved in approximately 3% of cases. These sites usually present with a mixed pattern but, rarely, may be totally sclerotic. Even the patella may be affected.32 COMPLICATIONS
The structural weakness of pagetic bone commonly leads to pathologic fractures, either spontaneous or following minor trauma. In asymptomatic patients, it may be the initial finding. Fractures are most common in the femur and tibia, followed by the spine, humerus, and pelvis. Stress or insufficiency fractures are the most frequently seen type.
Figure 10. A view of right shoulder. The scapula is homogeneously sclerotic, a so called "ivory" appearance. Figure 11. Anteroposterior view of left humerus with intermediate phase of Paget's disease. Note the transverse "banana" type fracture of the distal shaft.
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These typically occur on the convex surface of weight-bearing bones, laterally in the femur and anteriorly in the tibia. This type of fracture frequently is multiple, and, in a case seen by one of the authors, 19 insufficiency fractures were detected along the anterolateral surface of the femur. Insufficiency fractures may heal or go on to complete fractures. The subtrochanteric region of the femur is the most common location of complete fract~res.~ Complete fractures of long bones have been described as "banana" fractures, because of the horizontal orientation of the fracture with minimal comminution (Fig. 11). Complete fractures may follow biopsy. Fractures are reported to occur most commonly in the osteolytic stage but may occur in the mixed or static stages as well. Fractures in pagetic bone usually heal at the same rate as in normal bones or slower. However, nonunion, particularly in the femur, may be en~ountered.~ Pathologic fractures may herald the presence of sarcomatous degeneration, and, therefore, biopsy is recommended in such cases.1°
TUMORS
Both benign and malignant tumors are associated with Paget's disease. Sarcomatous transformation of Paget's disease is its most ominous complication. It was first recognized by Paget and described in his initial report.24The incidence of sarcomatous transformation has been reported to be as high as 5% to 10% in patients with extensive disease 13, 25 The and as low as 0.15O/0 in patients with limited inv~lvement.~, overall incidence is probably closer to the lower figure. Sarcomatous transformation may occur in monostotic Paget's disease.6While solitary lesions are usually found, Paget's sarcoma may be multicentric. The mean age at presentation has been reported to be 61.8 years, and there is a 1.5 to 1.0 male-to-female ratio.31The most frequent sites of involvement in decreasing order are the pelvis, humerus, femur, skull, and tibia. The onset of pain, fracture, further elevation of the serum alkaline phosphatase, or a soft-tissue mass are all signs of possible sarcomatous transformation. Osteosarcoma is the predominant histologic type and accounted for 88% of Paget's sarcomas in a recent series.31The remainder are fibrosarcoma, chondrosarcoma, malignant fibrous histiocytoma, and malignant giant cell tumor. The predominant radiographic manifestation is that of a destructive, lytic process. Much less commonly, mixed lytic and sclerotic changes or a purely sclerotic process are noted. The sarcoma results in destruction of pagetic bone with extension of the mass into the soft tissues (Fig. 12). Paget's sarcoma metastasizes to the lungs and rarely to other bones. Most cases involving more than one bone are considered to be multicen-
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of paget's dlsease. A Paget's sarcoma has caused extenslve lytlc destruction of the shaft followed b; a pathological fracture.
tric in origin. The 5-year survival in patients with Paget's sarcoma remains poor, and the mean survival is less than 1 year.31 Rarely, giant cell tumors may be associated with Paget's disease.l'~~~ Most giant cell tumors in Paget's disease occur in the skull and facial bones. Other reported sites include the pelvis, clavicle, spine, and long bones. Of note is the fact that giant cell tumors in the skull may be multiple. Familial and geographic clustering has been reported.ll Metastatic disease to pagetic bone may occur.', However, the frequency is less than one might expect, as both are common in the elderly. Common primary tumors are found in the breast, lung, kidney, colon, and prostate. Radiographic findings are similar to those with Paget's sarcoma and may be confused initially. In addition, clinical and laboratory findings are similar to those in patients with Paget's sarcoma. ~ , ~ is ~ a Rare instances of pseudosarcoma have been r e p ~ r t e d .This benign focal lesion that may exhibit cortical destruction, exuberant periosteal reaction, and a soft-tissue mass most commonly in the lower extremity. It frequently is mistaken for a sarcoma, and biopsy is needed to determine the true nature of the lesion. Similar paraosseous masses in the spine of patients with Paget's disease may result in neurologic signs from extradural compression. To be distinguished from the previous lesions are paraspinal masses of extramedullary hematopoiesis which have been described in association with Paget's disease.14
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ARTHRITIS
A form of osteoarthritis occurs in patients with Paget's disease, most commonly in the hip and knee.7,l6 This arthritis differs from primary osteoarthritis in that there is axial or medial narrowing of the hip joint, rather than superior narrowing. Large osteophytic formation is not as common in Paget's arthritis. Protrusio acetabulae is commonly present. It has been proposed that Paget's arthritis results from active bone remodeling, structural weakness of the articular surface, and bone deformity secondary to the Paget's disease.16 OTHER IMAGING MODALITIES
Radionuclide bone scintigraphy using 99mTcdiphosphonate is an excellent modality for determining the distribution, extent, and activity of skeletal involvement in Paget's disease.15 Bone scanning generally correlates well with the pathophysiologic activity of the disease. The sensitivity of bone scans is such that it may identify some lesions before radiographic detection. One study detected 8.2% more lesions on bone scans than were apparent radiographi~ally.~~ However, osteoporosis circumscripta in the skull and old nonactive lesions in the late phase of Paget's disease may not be detected on bone scans. The use of quantitative bone scans can be useful in evaluating disease activity following treatment. In sarcomatous transformation, bone scans usually demonstrate a decreased uptake of radionuclide in the area of the tumor, resulting in a cold area. However, gallium scans typically demonstrate an increased uptake of radionuclide in the tumor. Computed tomography and MR imaging generally do not have a significant role in the diagnosis of Paget's disease. However, these modalities may be useful in evaluating complications of Paget's disease, including neurologic abnormalities, neoplastic involvement, and arthriti^.^^, 34 A variety of MR signal patterns have been described in Paget's disease depending upon the skeletal location and the stage of disease. LABORATORY EVALUATION
Key laboratory findings in Paget's disease are a reflection of the high rate of bone turnover associated with active bone r e m ~ d e l i n g . ~ ~ Alkaline phosphatase is a ubiquitous enzyme found in many body tissues. In bone, it is concentrated in the osteoblasts. In Paget's disease, markedly high levels of serum alkaline phosphatase occur as osteoblasts lay down bone in response to extremely increased osteoclastic activity.33 It is not unusual to see values from 10 to 25 times the upper limit of normal. In the late static phase of Paget's disease, serum alkaline phosphatase levels may fall to the normal range. Serum alkaline phos-
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phatase levels may increase significantly in the presence of neoplastic involvement. Increased levels of urinary hydroxyproline reflect elevated osteoclastic activity.'O The serum alkaline phosphatase and urinary hydroxyproline levels usually parallel one another, but the latter may be a more sensitive indicator of disease activity. Serial chemistry levels, as well as scintigraphic examinations, are useful in monitoring the activity of Paget's disease and the response to treatment. Because of the high rate of bone turnover, serum uric acid levels frequently are elevated. Despite the high rate of bone turnover, a balance is maintained between calcium removed from the skeleton and calcium deposited in new bone.20 Therefore, the serum calcium is usually within normal limits. Elevations of serum calcium do occur when patients with Paget's disease are immobilized or sustain fractures. References 1. Agha FP, Norman A, Hirschl S, et al: Paget's disease: Coexistence with metastatic carcinoma. NY State J Med 76:734, 1976 2. Barry HC: Paget's Disease of Bone. Edinburgh, Livingstone, 1969 3. Bowerman JW, Altman J, Hughes JL, et al: Pseudo-malignant lesions in Paget's disease of bone. AJR Am J Roentgenol 124:57,1975 4. Burgener FA, Perry PE: Solitary renal cell carcinoma metastasis in Paget's disease simulating sarcomatous degeneration. AJR Am J Roentgenol 128:853, 1977 5. Dove J: Complete fractures of the femur in Paget's disease of the bone. J Bone Joint Surg (Br) 62:12, 1980 6. Edeiken J, Dalinka M, Karasick D: Roentgen Diagnosis of Diseases of Bone, vol 2. Baltimore, Williams and Wilkins, 1990, p 123 7. Goldman AB, Bullough P, Kammermans S, et al: Osteitis deformans of the hip joint. AJR Am J Roentgenol 128:601, 1977 8. Greditzer H, McLeod R, Unni K, et al: Bone sarcomas in Paget's disease. Radiology 146:327, 1983 9. Guyer PB, Clough PWL: Paget's disease of bone: Some observations on the relation of the skeletal distribution to pathogenesis. Clin Radiol 29:421, 1978 10. Hamdy RC: Paget's Disease of Bone:Assessment and Management. New York, Praeger Publishers, 1981 11. Jacobs TP, Michelsen J, Polay JS, et al: Giant cell tumor in Paget's disease of bone: Familial and geographic clustering. Cancer 44:742, 1979 12. Jaffe HL: The classic Paget's disease of bone. Clin Orthop 127:4, 1977 13. Jaffe HL: Metabolic, Degenerative and Inflammatory Diseases of Bones and Joints. Philadelphia, Lea and Febiger, 1972, p 240 14. Kadir S, Kalisher L, Schiller AL: Extramedullary hematopoiesis in Paget's disease of bone. AJR Am J Roentgenol 129:493,1977 15. Lentle BC, Russell AS, Heslip PG, et al: The scintigraphic findings in Paget's disease of bone. Clin Radiol 27:129, 1976 16. Machtey I, Rodman GP, Benedek TG: Paget's disease of the hip joint. Am J Med Sci 251:524, 1966 17. ~ a l d a g u eB, Malghem J: Dynamic radiologic patterns of Paget's disease. Clin Orthop 217:126, 1987 18. Mandl F: Klinisches und experimentalles zur frage der lokalisierten und generalisierten ostitis fibrosa. Arch Klin Chir 143:l and 245, 1926 19. Marshall TR, Ling JT: The brim sign: A new sign found in Paget's disease (osteitis deformans) of the pelvis. AJR Am J Roentgenol 90:1267, 1963
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20. Meunier PJ, Salson C, Mathiew L, et al: Skeletal distribution and biochemical parameters of Paget's disease. Clin Orthop 21737, 1987 21. Milgram JW: Radiographical and pathological assessment of the activity of Paget's disease of bone. Clin Orthop 127:43, 1977 22. Mirra JM: Bone Tumors: Clinical, Radiologic, and Pathologic Correlations. Philadelphia, Lea and Febriger, 1989, p 893 23. Monson DK, Finn HA, Dawson PJ, et al: Pseudosarcoma in Paget's disease of bone. J Bone Joint Surg 71[A]:453,1989 24. Paeet I: On a form of chronic inflammation of bones (osteitis deformans). Med Chir ~ru60:;7, 1877 25. Price CHG, Goldie W: Paget's sarcoma of bone. J Bone Joint Surg [Br] 51:205, 1969 26. Resnick D, Niwayama G: Diagnosis of Bone and Joint Disorders, ed 2., Philadelphia, WB Saunders, 1988, p 2127 27. Roberts MC, Kressel HY, Fallon MD, et al: Paget's disease: MR imaging findings. Radiology 173:341, 1989 28. Schajowicz F, Blullital I: Giant cell tumor associated with Paget's disease of bone. J Bone Joint Surg 48[A]:1340, 1966 29. Schlesinger A, Naimark A, Lee V: Diaphyseal presentation of Paget's disease in long bones. Radiology 14783, 1983 30. Schmorl G: Ueber Ostitis deformans Paget. Virchows Arch (Path01Anat) 283:694,1932 31. Smith J, Botet J, Yeh S: Bone sarcomas in Paget's disease: A study of 85 patients. Radiology 152:583 1984 32. Stull MA, Moser JR, Vinh TN, et al: Paget's disease of the patella. Skeletal Radio1 19:407, 1990 33. Tietz NW: Textbook of Clinical Chemistry. Philadelphia, WB Saunders, 1986, p 704 34. Zlatkin MB, Lander PH, Hadjipavlou AG, et al: Paget's disease of the spine: CT with clinical correlation. Radiology 160:155, 1986
Addvess reprint requests to Robert M. Klein, MD, FACR Department of Radiology New York Medical College Valhalla, NY 10595