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Imaging Paget’s disease of bone—from head to toe
Clinical Radiology 66 (2011) 662e672
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Clinical Radiology journal homepage: www.elsevierhealth.com/journals/crad
Pictorial Review
Imaging Paget’s disease of bonedfrom head to toe K. Cortis, K. Micallef, A. Mizzi* Medical Imaging Department, Mater Dei Hospital, Msida, Malta
article in formation Article history: Received 25 October 2010 Received in revised form 3 December 2010 Accepted 14 December 2010
Paget’s disease of the bone is a common, non-inflammatory, metabolic, skeletal disorder of unknown aetiology characterized by an increase in osteoclast-mediated bone resorption and compensatory excessive osteoblast activation. Prevalence increases with age, and a pronounced geographical variation is well documented. The disease is often an incidental finding on a radiological examination requested for an unrelated indication. The osteolytic, mixed osteolytic/osteoblastic, and osteosclerotic phases may occur in the same patient and same bone in a synchronous or metachronous fashion. Radiological features in each phase mirror the histopathological appearances, and are distinctive enough to establish a diagnosis with confidence. Using multi-technique imaging, this review illustrates the most common and the not so common radiological patterns of involvement in Paget’s disease of bone observed at our centre during the past 20 years. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction In 1877, Sir James Paget, a prominent English surgeon and pathologist, described five men suffering from “osteitis deformans”.1 He noted that this was a rare chronic inflammatory disorder with the following common features: change in shape and size together with deformity in the affected bones, slow rate of progression, no influence on general health, together with onset in middle age. One of the chief complaints was that of hats and old army helmets that would not fit any longer. This was related to the increase in skull size. By Paget’s own account, similar case reports had already appeared in other parts of Europe. None of these descriptions had the clarity and precision of Paget’s review, and by the end of the 19th century this condition was commonly known as Paget’s disease of bone. It is now known that Paget’s disease of the bone is a noninflammatory, metabolic disorder of unknown aetiology. * Guarantor and correspondent: A. Mizzi, Medical Imaging Department, Mater Dei Hospital, Msida MSD 2090, Malta. Tel.: þ356 25456740; fax: þ356 25456700. E-mail address: [email protected] (A. Mizzi).
The symptoms depend on the bones involved, the most common clinical manifestations being pain at the affected bone and nearby joints. Most patients are entirely asymptomatic. The diagnosis is usually radiological, by means of plain radiography. It may be monostotic or polyostotic and is characterized by excessive bone resorption followed by formation of bone that is structurally abnormal. Prevalence increases with age, and it is almost five-times more common in patients over 85 years of age than those under 60 years of age.2 Bone turnover markers, including bone specific alkaline phosphatase, reflect the level of osteoblast activation, and may be used to monitor the level of activity and therapeutic efficacy. Certain geographical and racial characteristics have been observed. It is most common in Great Britain, France, Germany, Italy, and in regions inhabited by emigrants from these areas (reported prevalence varies between 2.4 and 8.3% of individuals older than 40 years).3e5 The disease is rarely seen in Ireland, sub-Saharan Africa, the far East, and Scandinavia. Most series report a slight male predominance, with a 3:2 male-to-female ratio. In Europe, the incidence of Paget’s has been declining steeply over the last 20 years.6
0009-9260/$ e see front matter Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2010.12.016
K. Cortis et al. / Clinical Radiology 66 (2011) 662e672
Figure 1 Mixed osteolytic/osteoblastic phase of Paget’s disease in a 65-year-old man with an inability to bear weight following a fall. Coned down anteroposterior radiographs of the femur show a wedgeshaped leading edge of osteolysis at the cephalic third of the right femoral diaphysis (left). This is commonly referred to as the “blade of grass” or “cutting cone” sign. A spiral mid-diaphyseal fracture with external rotation of the distal portion is seen a few centimetres distal to this region of osteolysis (right).
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Figure 3 Anteroposterior radiograph of both hands showing the initial, mixed, and late phases of Paget’s disease of bone in a 70-yearold man. The proximal phalanx of the right index finger is slightly expanded, and shows homogeneous sclerosis with obliteration of the medullary cavity (“ivory phalanx”). On the left, the proximal phalanx of the ring finger is also expanded, and shows a lytic pattern together with sclerosis of its distal portion. The juxtaposed metacarpal head is sclerotic. Symmetrical cortical thickening and medullary canal narrowing is seen at the metacarpal of the left index finger.
Pathology The histopathological appearances mirror the radiographic features, and depend on the phase of the disease. Focal excessive osteoclastic bone resorption is seen in the initial osteolytic phase. Both resorption of bone and compensatory activation of osteoblasts and fibroblasts
Figure 2 Osteoporosis circumscripta, an incidental finding in a 53-year-old woman. Lateral and posteroanterior radiographs of the skull (left and top right) show a geographic lucency in the frontal bone, extending posteriorly in the region of the parietal and squamous temporal bones. The same process is also apparent in the occipital bone. A corresponding peripheral region of increased uptake is seen on skeletal scintigraphy (bottom right).
Figure 4 Lateral radiograph of the right calcaneum in a 75-year-old man with a long history of ankle pain. Prominent traberculation, sclerosis, and expansion of the calcaneum is evident. Bohler’s angle was measured at 21, which is at the lower limit of the normal range of values. This is suggestive of a degree of loss of calcaneal height, presumably secondary to the bone softening that is seen with Paget’s disease of bone. No other sites of uptake besides the right calcaneum on bone scintigraphy.
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Figure 6 The mixed osteolytic/osteoblastic phase, exemplified by a “picture frame vertebra” appearance of the fifth lumbar vertebra. Lateral coned down view of the lumbo-sacral spine shows condensed thickened endplates, sclerosis of the anterior and posterior cortex, and an increase in the antero-posterior diameter of the fifth lumbar vertebra. Vertical coarse trabercular thickening is also seen within the vertebral body.
Figure 5 Monostotic Paget’s disease of the first metatarsal. Anteroposterior radiograph of the right foot shows cortical thickening with encroachment of the medullary cavity, prominent coarse trabercular markings and osseous expansion in the first metatarsal.
(resulting in new bone formation) can occur simultaneously in the intermediate osteoclastic/osteoblastic phase of the disease. In time osteoblastic activity predominates, with rapid random deposition of disorganized structurally weakened new bone. This translates into increasing bone density and thickening of the remaining traberculae, and in a classic histological “mosaic pattern” of woven and lamellar bone, which replaces the parallel Haversian systems that characterize normal bone.7,8 Replacement of the bone marrow with vascular and fibrous tissue is also seen in this stage.9 In the late osteosclerotic “burnt-out” phase, osteoclastic activity declines and bone turnover may return to an almost normal level. The thickened
Figure 7 An incidental finding on a postero-anterior radiograph of the chest: expansion and sclerosis of the right clavicle are seen, affecting the medial portion to a greater extent than the lateral portion.
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Figure 8 Significant expansion and sclerosis of the distal left fibula with obliteration of the medullary cavity (left) is evident on this anteroposterior radiograph. A corresponding solitary region of homogeneous markedly increased uptake is seen on isotope bone scintigraphy (right).
trabeculated bone and prominent mosaic pattern persist, and there is restoration of the marrow. The aetiology of Paget’s disease is still an area of intense investigation and controversy. Numerous studies have described an autosomal dominant mode of inheritance with variable penetrance, possibly in conjunction with a paramyxoviral infection.10e12
Figure 10 A 75-year-old patient with polyostotic Paget’s disease and recurrent periodontal infections. Coronal reformatted CT image show bone thickening and heterogeneity of the facial bones and also of the petrous temporal bone. A focus of chronic osteomyelitis at the bottom left corner of the maxilla with apparent communication to the left maxillary sinus is evident (top). Another coronal reformatted CT image shows involvement of the temporal bones, with relative sparing of the otic capsule (bottom).
Distribution
Figure 9 Lateral radiograph of the skull of an 82-year-old man reveals pronounced sclerosis and calvarial thickening. This has been referred to as the “Tam O’Shanter” sign, with reference to a Scottish hat named after the character in Robert Burn’s poem bearing the same name.
Paget’s disease exhibits a predilection for the axial skeleton, but any bone may be affected. Monostotic disease (10e35%) is much less frequent than asymmetrical polyostotic involvement (65e90%).13,14 The most commonly affected sites are the pelvis (21e75% of cases), vertebrae (29e57%), and skull (28e40%).15,16 In the long bones, Paget’s disease typically starts in one focus and eventually spreads to involve the entire bone, but does not progress to adjacent bones.17 Proximal long bones are frequently involved, with the proximal femur affected in 25e46% of cases. When involving the spine, Paget’s disease can affect a single level or more than one level. The vertebral body is almost always
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Figure 11 A 62-year-old woman with a longstanding history of sciatic back pain. Sagittal T2-weighted fast spin-echo (top left) and T1-weighted (top right) MRI images of the lower thoracic and lumbar spine showing heterogeneous generalized reduction of the bone marrow signal intensity, coarsening of the vertebral traberculae, and a “picture frame” appearance of some vertebrae. Reduction of the anteroposterior spinal canal dimension is seen at the level of the L2/L3, L3/L4, and L4/L5 discs, secondary to annular disc bulges and Pagetic facet joint hypertrophy. Correlation with the anteroposterior radiograph (bottom left) shows generalized sclerosis, osseous expansion, and scoliosis of the lower thoracic and lumbar vertebrae. The distribution of disease was assessed using bone scintigraphy (bottom right). Homogeneous pronounced uptake is seen in the skull, thoraco-lumbar spine, and also at the distal subarticular portion of the left femur.
involved, together with a variable portion of the posterior elements. The lumbar spine, especially the L4 and L5 vertebrae, is the commonest site (58%), followed by the thoracic spine (45%) and the cervical spine (14%).18 Less
Figure 12 Involvement of the pelvis in Paget’s disease in two different patients. The first patient, a 53-year-old woman, had an anteroposterior radiograph of the pelvis (top) taken following a fall. This demonstrates generalized expansion of the right hemipelvis with associated coarse trabercular pattern. The iliopectineal line is thickened, and loss of joint space is seen in the right hip joint due to secondary osteoarthritis at this site. Incidental note is made of calcified uterine fibroids in the lesser pelvis. The second patient, a 55-year-old man, was being investigated for right-sided hip pain. A selected coronal T1-weighted MR image shows thickened cortex with low to intermediate signal, coarsened traberculae, and osteolytic foci of low signal intensity in the right hemipelvis.
commonly affected sites include tibia (35%), humerus (31%), scapula (24%), clavicle (11%), facial bones (11%), calcaneum (10%), patella (7%), and the small bones of the hands or feet (6 and 5%, respectively).19,20
Conventional radiography Paget’s disease is associated with a plethora of radiological signs. Each phase has distinctive radiographic features that are usually sufficient to establish a diagnosis with confidence. All three phases may occur in the same
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Figure 13 Osteolytic phase of Paget’s disease of the skull, in a 55-year-old man being investigated for headaches. Selected images from an axial CT (top and bottom left) reveal a lytic lesion with demarcated borders in both frontal bones and in the right occipital bone. In contrast to metastases, the bone matrix is preserved and only demineralized. The same region is heterogeneous on MRI, as seen on selected axial T2-weighted and coronal T1-weighted images (top middle and bottom middle, respectively). Avid enhancement of the lytic process in the skull is seen on T1-weighted imaging, after intravenous gadolinium administration (top and bottom right).
Figure 14 Three different patients with a longstanding history of polyostotic Paget’s disease of bone. An incomplete transverse fracture oriented perpendicular to the cortex is seen at the medial aspect of the right ischial bone on this coronal reformatted CT image (left). The edges are well corticated (in keeping with a chronic, insufficiency type of fracture). Cortical thickening and a coarse trabercular pattern can be also appreciated on this view. A similar stress fracture is seen at the convex lateral aspect of a laterally bowed femur on an anteroposterior radiograph of the left proximal femur (middle), together with cortical thickening that narrows the medullary cavity, and osteoarthritic changes in the left hip joint. These fractures are often incremental, and are sometimes referred to as “banana fractures” due to the associated bowing. Anteroposterior radiograph of the left femur in another patient (right), presenting with inability to bear weight and gross deformity of his left thigh following minimal trauma, shows a complete transverse mid-diaphyseal fracture of the left femour with generalized osteosclerosis.
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Figure 15 “Sabre tibia” in an 80-year-old man with bone deformities in the long bones of the left lower limb. This lateral radiograph of the left tibia shows anterior bowing, pronounced osseous expansion, cortical thickening, and endosteal bone formation with resultant decreased size of the medullary cavity and loss of the corticomedullary differentiation. Coarse trabercular markings are seen to extend to the proximal subarticular portion of the tibia.
patient and same bone in a synchronous or metachronous fashion. In most cases, the disease is an incidental finding on a radiological examination requested for unrelated indications. The initial incipient osteolytic phase is characterized by geographic osteolysis with an advancing edge of resorption. In the long bones, a sharp wedge-shaped leading edge of osteolysis (Fig 1) is seen to advance from the subarticular or metaphyseal to the diaphyseal region. This is referred to as a “cutting-cone”, “blade of grass”, or “candle flame sign”.21,22 In the tibia, osteolysis may commence in the diaphysis without subarticular or metaphyseal involvement. The same process is known as “osteoporosis circumscripta” in the calvaria (Fig 2). Here, osteolysis assumes a well-defined, oval configuration; crosses sutures; and shows predilection for the frontal and occipital bones.23
Figure 16 Osteosclerotic phase of Paget’s involving the right humerus. Anteroposterior radiograph demonstrates cortical and endosteal thickening with partial obliteration of the medullary cavity (left). A pathological fracture is seen at the surgical neck of the right humerus; the interface between Pagetic and normal bone. Strong homogeneous avid uptake is evident in the right humerus on an inverted whole-body bone scintigram (right). Uptake is also seen in the skull and subarticular distal portion of the right femur with diaphyseal extension.
The intermediate mixed lyticesclerotic phase is the stage at which Paget’s disease of bone is most commonly diagnosed. It is characterized by cortical thickening, osseous expansion, loss of corticomedullary differentiation (due to endosteal new bone formation encroaching the medullary cavity) and accentuated coarse trabecular markings (Figs 3e5). The advancing wedge of resorption may be also seen. In most long bones, sclerosis and expansion are first seen in a subarticular or metaphyseal location, at the site of initial osteolysis. At this stage, the osteolytic front may be seen to have advanced towards the diaphysis and may be separated from bone showing signs of the middle or late sclerotic phase by a few centimetres (Fig 1). The mixed lytic and blastic foci are referred to as a “cotton-wool” pattern when affecting the skull, and “picture-frame” appearance when affecting the vertebrae (Fig 6). In the late sclerotic form of Paget’s disease, considerable new bone formation is evident as a diffuse increase in density, medullary sclerosis, and markedly increased bone size (Figs 3,7e9) (Supplementary Material Figs S1–3).
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Figure 17 Monostotic Paget’s disease of the radius. Lateral (left) and anteroposterior (middle) radiographs of the right forearm show sclerosis and a coarse trabercular pattern in the distal two-thirds of the radius, with relative sparing of the proximal third. An associated bowing deformity can be also seen. Whole-body bone scintigraphy (right) shows isolated increased uptake in the right radius.
Cross-sectional imaging The radiological findings on computed tomography (CT) reflect the plain radiographic findings, and provide limited additional radiological information in cases of uncomplicated Paget’s (Supplementary Material Figs S4 and 5). CT is useful if the affected regions are difficult to assess by plain radiography alone. This includes involvement of the facial bones, neural formina, and middle ear (Fig 10). Administration of intravenous iodinated contrast media results in dense enhancement of lytic lesions. Magnetic resonance imaging (MRI) or CT may be also used in patients with changes in the nature or severity of their pain to assess the possibility of fracture or sarcomatous degeneration. The exact role of MRI in the detection of Paget’s disease is less established. MRI may present a confusing picture unless radiographs are available for comparison (Fig 11).24 The cortex is thickened and striated on T1-weighted imaging. Foci of osteolysis demonstrate high signal intensity on T2-weighted sequences, low intensity on T1-weighted sequences (Fig 12), and
enhancement following the administration of intravenous chelating agents (Fig 13). The fatty marrow signal is preserved in advanced Paget’s disease unless it is complicated by an acute fracture or sarcoma.25 MRI can be useful in evaluating neurological complications in patients with Paget’s disease, such as spinal cord compression or compression of spinal nerve roots and cranial nerves.26
Nuclear medicine imaging Isotope bone scintigraphy using a 99mTc-labelled bisphosphonate tracer is more sensitive than plain radiography for the identification of Paget’s lesions. Increased homogeneous tracer uptake is seen secondary to the high perfusion of Pagetic bone and high affinity of the tracer to woven bone (Figs 8,11,16, and 17) (Supplementary Material Fig S7). Osteoporosis circumscripta may demonstrate a peripheral region of increased uptake and central photopaenia (Fig 2). In the long bones, increased radiotracer uptake typically abuts one joint and extends into the diaphysis to a variable extent. Lesions seen only on scintigraphy are more
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Figure 18 A 78-year-old man presenting with a 3 month history of right knee pain. Lateral radiograph (right) of the distal femur reveals a region of cortical disruption at the posterior aspect of the distal femoral metaphysis. Signs of advanced Paget’s disease are seen in the visible portion of the femur. Selected axial CT images (left) confirm cortical disruption with irregular zones of radiolucency in the medullary and cortical bone at this site. A large, soft-tissue mass is seen to extend posterolaterally, displacing the muscular fat planes and distal femoral vascular bundle. Histopathological analysis revealed an osteosarcoma on a background of Pagetic changes.
likely to correlate with early symptomatic manifestations of Paget’s. Conversely, lesions seen only on plain radiography represent older “burned out” type lesions.27 In contrast, scintigraphy is less specific than plain radiography. Changes detected by isotope bone scintigraphy may need to be confirmed by conventional radiography of at least one site. The technique also has the advantage of being able to visualize the whole skeleton and thus assess distribution of disease in order to guide further management.
2-[18F]-Fluoro-2-deoxy-D-glucose positronemission tomography/CT fusion imaging A consensus regarding the exact role of 2-[18F]-fluoro-2deoxy-D-glucose positron-emission tomography (PET)/CT in imaging Paget’s disease has yet to be reached. Pagetic bone exhibits a variable degree of FDG uptake in up to one-third of patients.28 This may represent an obstacle when staging oncological patients with concurrent Paget’s disease of bone, due to a potential overlap of imaging appearances of Pagetic bone with skeletal metastases.29e31 Conversely, bone lesions showing the characteristic radiological appearances of uncomplicated Paget’s disease are usually evident on CT. This highlights the importance of fusion
imaging, in relation to FDG PET alone in the proper evaluation and characterization of skeletal lesions.
Complications Complications depend on the site/s affected and on the activity of the disease. Incremental stress fractures (“banana fractures” or “pseudofractures”) may be seen in the long bones (Fig 14). These are typically incomplete transverse fractures oriented perpendicular to the cortex at the convex surface of long bones. Typical sites include the lateral aspect of a laterally bowed femur or anteriorly along an anteriorly bowed tibia (Fig 15). Stress fractures may become complete pathological fractures following minor or no trauma (Figs 1,14 and 16) (Supplementary Material Fig S6). Such fractures are typically transverse and show poor healing with a high rate of non-union.32 Bowing may be also seen at nonweight-bearing long bones less commonly affected by Paget’s, including the radius (Fig 17). Paget’s disease of bone adjacent to the joint margin is thought to cause accelerated osteoarthritis of the affected joint (Figs 12 and 14). The bony deformities in Paget’s may also contribute to osteoarthritis due to the resulting altered mechanics of weight bearing.33
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Figure 19 Malignant sarcomatous transformation arising in the humerus of an 81-year-old woman with a long history of polyostotic Paget’s disease. A mixed lytic/sclerotic lesion centred around the medullary cavity is seen at the mid-diaphysis of a Pagetic left humerus, with an associated pathological fracture, large, soft-tissue mass, and sunburst periosteal reaction.
Malignant sarcomatous transformation is a wellrecognized complication, typically in longstanding polyostotic disease. It was originally reported to occur in 0.7% of cases but is declining in incidence and is now reported to occur in 0.3%.34 Osteosarcomas, usually of the osteogenic type, carry a poor prognosis and most commonly arise in the femur (Fig 18), pelvis, and humerus (Fig 19).35 The focal proliferation of periosteal new bone in the context of Paget’s disease of bone might be radiologically indistinguishable from malignant transformation. This process is often referred to as “pseudo-sarcoma”, and is often diagnosed following a negative biopsy.36 Fibrosarcoma, chondrosarcoma, and malignant fibrous histiocytoma may also be rarely seen in the context of Paget’s.37,38 Giant cell tumours are even rarer complications, occurring more frequently in patients with the polyostotic form of Paget’s and usually involve the skull and facial bones.39 Complications related to the spine are mainly neurological due to spinal stenosis, compression fractures, and sarcomatous degeneration.40,41,42 Cranial nerve palsies or vascular compression may result when the foramina at the base of the skull are encroached upon. In advanced disease, basilar invagination (Fig 20) may cause compression of the brainstem and also hydrocephalus.43
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Figure 20 A 60-year-old man being investigated for cerebellar symptoms using CT angiography. A sagittal reformatted CT image (top) shows an irregular heterogeneous lucent and sclerotic pattern expanding the outer and inner tables of the skull and obscuring the diploic space (“cotton wool” skull). The tip of the odontoid process was noted to be almost 9 mm above Chamberlain’s line (a line drawn from the posterior margin of the hard palate to the posterior margin of the foramen magnum). This indicates a degree of basilar invagination, a known complication of Paget’s disease of bone. A coronal reformatted CT image (bottom left) and an axial CT image at the level of the pedicles (bottom right) show Pagetic involvement of the axis and atlas. The left lateral mass of the atlas, C2 vertebral body, odontoid process, and posterior neural arch appear heterogeneous and sclerotic. The atlanto-dens interval is obliterated, with signs of osteoarthritis. The spinal canal remains widely patent despite the vertebral enlargement.
Temporal bone involvement (Fig 10) may result in deafness both due to involvement of the ossicles (conductive deafness) or from compression of the vestibulo-cochlear nerve (sensori-neural deafness). High-output heart failure may occur due to the osseous hypervascularity seen in polyostotic disease and the associated increase in demand for cardiac output. This is a rare complication, and may be associated with osseous auscultatory bruits. Other complications related to the relative bone softening that occurs in Paget’s disease of bone include protrusio acetabuli and dental malocclusion.
Acknowledgements The authors are grateful to the following colleagues from Mater Dei Hospital and St James Hospital: Dr K. Saliba for providing Fig 5, Mr T. Cesare for help with the reformatted images, Dr M. A. Aquilina for reviewing the PET/CT fusion imaging section, and Dr A. Samuel for reviewing the nuclear imaging section.
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Supplementary data Supplementary data associated with this article can be found in online version at doi:10.1016/j.crad.2010.12.016.
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Pictorial Review
Imaging Paget’s disease of bonedfrom head to toe K. Cortis, K. Micallef, A. Mizzi* Medical Imaging Department, Mater Dei Hospital, Msida, Malta
article in formation Article history: Received 25 October 2010 Received in revised form 3 December 2010 Accepted 14 December 2010
Paget’s disease of the bone is a common, non-inflammatory, metabolic, skeletal disorder of unknown aetiology characterized by an increase in osteoclast-mediated bone resorption and compensatory excessive osteoblast activation. Prevalence increases with age, and a pronounced geographical variation is well documented. The disease is often an incidental finding on a radiological examination requested for an unrelated indication. The osteolytic, mixed osteolytic/osteoblastic, and osteosclerotic phases may occur in the same patient and same bone in a synchronous or metachronous fashion. Radiological features in each phase mirror the histopathological appearances, and are distinctive enough to establish a diagnosis with confidence. Using multi-technique imaging, this review illustrates the most common and the not so common radiological patterns of involvement in Paget’s disease of bone observed at our centre during the past 20 years. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction In 1877, Sir James Paget, a prominent English surgeon and pathologist, described five men suffering from “osteitis deformans”.1 He noted that this was a rare chronic inflammatory disorder with the following common features: change in shape and size together with deformity in the affected bones, slow rate of progression, no influence on general health, together with onset in middle age. One of the chief complaints was that of hats and old army helmets that would not fit any longer. This was related to the increase in skull size. By Paget’s own account, similar case reports had already appeared in other parts of Europe. None of these descriptions had the clarity and precision of Paget’s review, and by the end of the 19th century this condition was commonly known as Paget’s disease of bone. It is now known that Paget’s disease of the bone is a noninflammatory, metabolic disorder of unknown aetiology. * Guarantor and correspondent: A. Mizzi, Medical Imaging Department, Mater Dei Hospital, Msida MSD 2090, Malta. Tel.: þ356 25456740; fax: þ356 25456700. E-mail address: [email protected] (A. Mizzi).
The symptoms depend on the bones involved, the most common clinical manifestations being pain at the affected bone and nearby joints. Most patients are entirely asymptomatic. The diagnosis is usually radiological, by means of plain radiography. It may be monostotic or polyostotic and is characterized by excessive bone resorption followed by formation of bone that is structurally abnormal. Prevalence increases with age, and it is almost five-times more common in patients over 85 years of age than those under 60 years of age.2 Bone turnover markers, including bone specific alkaline phosphatase, reflect the level of osteoblast activation, and may be used to monitor the level of activity and therapeutic efficacy. Certain geographical and racial characteristics have been observed. It is most common in Great Britain, France, Germany, Italy, and in regions inhabited by emigrants from these areas (reported prevalence varies between 2.4 and 8.3% of individuals older than 40 years).3e5 The disease is rarely seen in Ireland, sub-Saharan Africa, the far East, and Scandinavia. Most series report a slight male predominance, with a 3:2 male-to-female ratio. In Europe, the incidence of Paget’s has been declining steeply over the last 20 years.6
0009-9260/$ e see front matter Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2010.12.016
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Figure 1 Mixed osteolytic/osteoblastic phase of Paget’s disease in a 65-year-old man with an inability to bear weight following a fall. Coned down anteroposterior radiographs of the femur show a wedgeshaped leading edge of osteolysis at the cephalic third of the right femoral diaphysis (left). This is commonly referred to as the “blade of grass” or “cutting cone” sign. A spiral mid-diaphyseal fracture with external rotation of the distal portion is seen a few centimetres distal to this region of osteolysis (right).
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Figure 3 Anteroposterior radiograph of both hands showing the initial, mixed, and late phases of Paget’s disease of bone in a 70-yearold man. The proximal phalanx of the right index finger is slightly expanded, and shows homogeneous sclerosis with obliteration of the medullary cavity (“ivory phalanx”). On the left, the proximal phalanx of the ring finger is also expanded, and shows a lytic pattern together with sclerosis of its distal portion. The juxtaposed metacarpal head is sclerotic. Symmetrical cortical thickening and medullary canal narrowing is seen at the metacarpal of the left index finger.
Pathology The histopathological appearances mirror the radiographic features, and depend on the phase of the disease. Focal excessive osteoclastic bone resorption is seen in the initial osteolytic phase. Both resorption of bone and compensatory activation of osteoblasts and fibroblasts
Figure 2 Osteoporosis circumscripta, an incidental finding in a 53-year-old woman. Lateral and posteroanterior radiographs of the skull (left and top right) show a geographic lucency in the frontal bone, extending posteriorly in the region of the parietal and squamous temporal bones. The same process is also apparent in the occipital bone. A corresponding peripheral region of increased uptake is seen on skeletal scintigraphy (bottom right).
Figure 4 Lateral radiograph of the right calcaneum in a 75-year-old man with a long history of ankle pain. Prominent traberculation, sclerosis, and expansion of the calcaneum is evident. Bohler’s angle was measured at 21, which is at the lower limit of the normal range of values. This is suggestive of a degree of loss of calcaneal height, presumably secondary to the bone softening that is seen with Paget’s disease of bone. No other sites of uptake besides the right calcaneum on bone scintigraphy.
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Figure 6 The mixed osteolytic/osteoblastic phase, exemplified by a “picture frame vertebra” appearance of the fifth lumbar vertebra. Lateral coned down view of the lumbo-sacral spine shows condensed thickened endplates, sclerosis of the anterior and posterior cortex, and an increase in the antero-posterior diameter of the fifth lumbar vertebra. Vertical coarse trabercular thickening is also seen within the vertebral body.
Figure 5 Monostotic Paget’s disease of the first metatarsal. Anteroposterior radiograph of the right foot shows cortical thickening with encroachment of the medullary cavity, prominent coarse trabercular markings and osseous expansion in the first metatarsal.
(resulting in new bone formation) can occur simultaneously in the intermediate osteoclastic/osteoblastic phase of the disease. In time osteoblastic activity predominates, with rapid random deposition of disorganized structurally weakened new bone. This translates into increasing bone density and thickening of the remaining traberculae, and in a classic histological “mosaic pattern” of woven and lamellar bone, which replaces the parallel Haversian systems that characterize normal bone.7,8 Replacement of the bone marrow with vascular and fibrous tissue is also seen in this stage.9 In the late osteosclerotic “burnt-out” phase, osteoclastic activity declines and bone turnover may return to an almost normal level. The thickened
Figure 7 An incidental finding on a postero-anterior radiograph of the chest: expansion and sclerosis of the right clavicle are seen, affecting the medial portion to a greater extent than the lateral portion.
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Figure 8 Significant expansion and sclerosis of the distal left fibula with obliteration of the medullary cavity (left) is evident on this anteroposterior radiograph. A corresponding solitary region of homogeneous markedly increased uptake is seen on isotope bone scintigraphy (right).
trabeculated bone and prominent mosaic pattern persist, and there is restoration of the marrow. The aetiology of Paget’s disease is still an area of intense investigation and controversy. Numerous studies have described an autosomal dominant mode of inheritance with variable penetrance, possibly in conjunction with a paramyxoviral infection.10e12
Figure 10 A 75-year-old patient with polyostotic Paget’s disease and recurrent periodontal infections. Coronal reformatted CT image show bone thickening and heterogeneity of the facial bones and also of the petrous temporal bone. A focus of chronic osteomyelitis at the bottom left corner of the maxilla with apparent communication to the left maxillary sinus is evident (top). Another coronal reformatted CT image shows involvement of the temporal bones, with relative sparing of the otic capsule (bottom).
Distribution
Figure 9 Lateral radiograph of the skull of an 82-year-old man reveals pronounced sclerosis and calvarial thickening. This has been referred to as the “Tam O’Shanter” sign, with reference to a Scottish hat named after the character in Robert Burn’s poem bearing the same name.
Paget’s disease exhibits a predilection for the axial skeleton, but any bone may be affected. Monostotic disease (10e35%) is much less frequent than asymmetrical polyostotic involvement (65e90%).13,14 The most commonly affected sites are the pelvis (21e75% of cases), vertebrae (29e57%), and skull (28e40%).15,16 In the long bones, Paget’s disease typically starts in one focus and eventually spreads to involve the entire bone, but does not progress to adjacent bones.17 Proximal long bones are frequently involved, with the proximal femur affected in 25e46% of cases. When involving the spine, Paget’s disease can affect a single level or more than one level. The vertebral body is almost always
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Figure 11 A 62-year-old woman with a longstanding history of sciatic back pain. Sagittal T2-weighted fast spin-echo (top left) and T1-weighted (top right) MRI images of the lower thoracic and lumbar spine showing heterogeneous generalized reduction of the bone marrow signal intensity, coarsening of the vertebral traberculae, and a “picture frame” appearance of some vertebrae. Reduction of the anteroposterior spinal canal dimension is seen at the level of the L2/L3, L3/L4, and L4/L5 discs, secondary to annular disc bulges and Pagetic facet joint hypertrophy. Correlation with the anteroposterior radiograph (bottom left) shows generalized sclerosis, osseous expansion, and scoliosis of the lower thoracic and lumbar vertebrae. The distribution of disease was assessed using bone scintigraphy (bottom right). Homogeneous pronounced uptake is seen in the skull, thoraco-lumbar spine, and also at the distal subarticular portion of the left femur.
involved, together with a variable portion of the posterior elements. The lumbar spine, especially the L4 and L5 vertebrae, is the commonest site (58%), followed by the thoracic spine (45%) and the cervical spine (14%).18 Less
Figure 12 Involvement of the pelvis in Paget’s disease in two different patients. The first patient, a 53-year-old woman, had an anteroposterior radiograph of the pelvis (top) taken following a fall. This demonstrates generalized expansion of the right hemipelvis with associated coarse trabercular pattern. The iliopectineal line is thickened, and loss of joint space is seen in the right hip joint due to secondary osteoarthritis at this site. Incidental note is made of calcified uterine fibroids in the lesser pelvis. The second patient, a 55-year-old man, was being investigated for right-sided hip pain. A selected coronal T1-weighted MR image shows thickened cortex with low to intermediate signal, coarsened traberculae, and osteolytic foci of low signal intensity in the right hemipelvis.
commonly affected sites include tibia (35%), humerus (31%), scapula (24%), clavicle (11%), facial bones (11%), calcaneum (10%), patella (7%), and the small bones of the hands or feet (6 and 5%, respectively).19,20
Conventional radiography Paget’s disease is associated with a plethora of radiological signs. Each phase has distinctive radiographic features that are usually sufficient to establish a diagnosis with confidence. All three phases may occur in the same
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Figure 13 Osteolytic phase of Paget’s disease of the skull, in a 55-year-old man being investigated for headaches. Selected images from an axial CT (top and bottom left) reveal a lytic lesion with demarcated borders in both frontal bones and in the right occipital bone. In contrast to metastases, the bone matrix is preserved and only demineralized. The same region is heterogeneous on MRI, as seen on selected axial T2-weighted and coronal T1-weighted images (top middle and bottom middle, respectively). Avid enhancement of the lytic process in the skull is seen on T1-weighted imaging, after intravenous gadolinium administration (top and bottom right).
Figure 14 Three different patients with a longstanding history of polyostotic Paget’s disease of bone. An incomplete transverse fracture oriented perpendicular to the cortex is seen at the medial aspect of the right ischial bone on this coronal reformatted CT image (left). The edges are well corticated (in keeping with a chronic, insufficiency type of fracture). Cortical thickening and a coarse trabercular pattern can be also appreciated on this view. A similar stress fracture is seen at the convex lateral aspect of a laterally bowed femur on an anteroposterior radiograph of the left proximal femur (middle), together with cortical thickening that narrows the medullary cavity, and osteoarthritic changes in the left hip joint. These fractures are often incremental, and are sometimes referred to as “banana fractures” due to the associated bowing. Anteroposterior radiograph of the left femur in another patient (right), presenting with inability to bear weight and gross deformity of his left thigh following minimal trauma, shows a complete transverse mid-diaphyseal fracture of the left femour with generalized osteosclerosis.
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Figure 15 “Sabre tibia” in an 80-year-old man with bone deformities in the long bones of the left lower limb. This lateral radiograph of the left tibia shows anterior bowing, pronounced osseous expansion, cortical thickening, and endosteal bone formation with resultant decreased size of the medullary cavity and loss of the corticomedullary differentiation. Coarse trabercular markings are seen to extend to the proximal subarticular portion of the tibia.
patient and same bone in a synchronous or metachronous fashion. In most cases, the disease is an incidental finding on a radiological examination requested for unrelated indications. The initial incipient osteolytic phase is characterized by geographic osteolysis with an advancing edge of resorption. In the long bones, a sharp wedge-shaped leading edge of osteolysis (Fig 1) is seen to advance from the subarticular or metaphyseal to the diaphyseal region. This is referred to as a “cutting-cone”, “blade of grass”, or “candle flame sign”.21,22 In the tibia, osteolysis may commence in the diaphysis without subarticular or metaphyseal involvement. The same process is known as “osteoporosis circumscripta” in the calvaria (Fig 2). Here, osteolysis assumes a well-defined, oval configuration; crosses sutures; and shows predilection for the frontal and occipital bones.23
Figure 16 Osteosclerotic phase of Paget’s involving the right humerus. Anteroposterior radiograph demonstrates cortical and endosteal thickening with partial obliteration of the medullary cavity (left). A pathological fracture is seen at the surgical neck of the right humerus; the interface between Pagetic and normal bone. Strong homogeneous avid uptake is evident in the right humerus on an inverted whole-body bone scintigram (right). Uptake is also seen in the skull and subarticular distal portion of the right femur with diaphyseal extension.
The intermediate mixed lyticesclerotic phase is the stage at which Paget’s disease of bone is most commonly diagnosed. It is characterized by cortical thickening, osseous expansion, loss of corticomedullary differentiation (due to endosteal new bone formation encroaching the medullary cavity) and accentuated coarse trabecular markings (Figs 3e5). The advancing wedge of resorption may be also seen. In most long bones, sclerosis and expansion are first seen in a subarticular or metaphyseal location, at the site of initial osteolysis. At this stage, the osteolytic front may be seen to have advanced towards the diaphysis and may be separated from bone showing signs of the middle or late sclerotic phase by a few centimetres (Fig 1). The mixed lytic and blastic foci are referred to as a “cotton-wool” pattern when affecting the skull, and “picture-frame” appearance when affecting the vertebrae (Fig 6). In the late sclerotic form of Paget’s disease, considerable new bone formation is evident as a diffuse increase in density, medullary sclerosis, and markedly increased bone size (Figs 3,7e9) (Supplementary Material Figs S1–3).
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Figure 17 Monostotic Paget’s disease of the radius. Lateral (left) and anteroposterior (middle) radiographs of the right forearm show sclerosis and a coarse trabercular pattern in the distal two-thirds of the radius, with relative sparing of the proximal third. An associated bowing deformity can be also seen. Whole-body bone scintigraphy (right) shows isolated increased uptake in the right radius.
Cross-sectional imaging The radiological findings on computed tomography (CT) reflect the plain radiographic findings, and provide limited additional radiological information in cases of uncomplicated Paget’s (Supplementary Material Figs S4 and 5). CT is useful if the affected regions are difficult to assess by plain radiography alone. This includes involvement of the facial bones, neural formina, and middle ear (Fig 10). Administration of intravenous iodinated contrast media results in dense enhancement of lytic lesions. Magnetic resonance imaging (MRI) or CT may be also used in patients with changes in the nature or severity of their pain to assess the possibility of fracture or sarcomatous degeneration. The exact role of MRI in the detection of Paget’s disease is less established. MRI may present a confusing picture unless radiographs are available for comparison (Fig 11).24 The cortex is thickened and striated on T1-weighted imaging. Foci of osteolysis demonstrate high signal intensity on T2-weighted sequences, low intensity on T1-weighted sequences (Fig 12), and
enhancement following the administration of intravenous chelating agents (Fig 13). The fatty marrow signal is preserved in advanced Paget’s disease unless it is complicated by an acute fracture or sarcoma.25 MRI can be useful in evaluating neurological complications in patients with Paget’s disease, such as spinal cord compression or compression of spinal nerve roots and cranial nerves.26
Nuclear medicine imaging Isotope bone scintigraphy using a 99mTc-labelled bisphosphonate tracer is more sensitive than plain radiography for the identification of Paget’s lesions. Increased homogeneous tracer uptake is seen secondary to the high perfusion of Pagetic bone and high affinity of the tracer to woven bone (Figs 8,11,16, and 17) (Supplementary Material Fig S7). Osteoporosis circumscripta may demonstrate a peripheral region of increased uptake and central photopaenia (Fig 2). In the long bones, increased radiotracer uptake typically abuts one joint and extends into the diaphysis to a variable extent. Lesions seen only on scintigraphy are more
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Figure 18 A 78-year-old man presenting with a 3 month history of right knee pain. Lateral radiograph (right) of the distal femur reveals a region of cortical disruption at the posterior aspect of the distal femoral metaphysis. Signs of advanced Paget’s disease are seen in the visible portion of the femur. Selected axial CT images (left) confirm cortical disruption with irregular zones of radiolucency in the medullary and cortical bone at this site. A large, soft-tissue mass is seen to extend posterolaterally, displacing the muscular fat planes and distal femoral vascular bundle. Histopathological analysis revealed an osteosarcoma on a background of Pagetic changes.
likely to correlate with early symptomatic manifestations of Paget’s. Conversely, lesions seen only on plain radiography represent older “burned out” type lesions.27 In contrast, scintigraphy is less specific than plain radiography. Changes detected by isotope bone scintigraphy may need to be confirmed by conventional radiography of at least one site. The technique also has the advantage of being able to visualize the whole skeleton and thus assess distribution of disease in order to guide further management.
2-[18F]-Fluoro-2-deoxy-D-glucose positronemission tomography/CT fusion imaging A consensus regarding the exact role of 2-[18F]-fluoro-2deoxy-D-glucose positron-emission tomography (PET)/CT in imaging Paget’s disease has yet to be reached. Pagetic bone exhibits a variable degree of FDG uptake in up to one-third of patients.28 This may represent an obstacle when staging oncological patients with concurrent Paget’s disease of bone, due to a potential overlap of imaging appearances of Pagetic bone with skeletal metastases.29e31 Conversely, bone lesions showing the characteristic radiological appearances of uncomplicated Paget’s disease are usually evident on CT. This highlights the importance of fusion
imaging, in relation to FDG PET alone in the proper evaluation and characterization of skeletal lesions.
Complications Complications depend on the site/s affected and on the activity of the disease. Incremental stress fractures (“banana fractures” or “pseudofractures”) may be seen in the long bones (Fig 14). These are typically incomplete transverse fractures oriented perpendicular to the cortex at the convex surface of long bones. Typical sites include the lateral aspect of a laterally bowed femur or anteriorly along an anteriorly bowed tibia (Fig 15). Stress fractures may become complete pathological fractures following minor or no trauma (Figs 1,14 and 16) (Supplementary Material Fig S6). Such fractures are typically transverse and show poor healing with a high rate of non-union.32 Bowing may be also seen at nonweight-bearing long bones less commonly affected by Paget’s, including the radius (Fig 17). Paget’s disease of bone adjacent to the joint margin is thought to cause accelerated osteoarthritis of the affected joint (Figs 12 and 14). The bony deformities in Paget’s may also contribute to osteoarthritis due to the resulting altered mechanics of weight bearing.33
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Figure 19 Malignant sarcomatous transformation arising in the humerus of an 81-year-old woman with a long history of polyostotic Paget’s disease. A mixed lytic/sclerotic lesion centred around the medullary cavity is seen at the mid-diaphysis of a Pagetic left humerus, with an associated pathological fracture, large, soft-tissue mass, and sunburst periosteal reaction.
Malignant sarcomatous transformation is a wellrecognized complication, typically in longstanding polyostotic disease. It was originally reported to occur in 0.7% of cases but is declining in incidence and is now reported to occur in 0.3%.34 Osteosarcomas, usually of the osteogenic type, carry a poor prognosis and most commonly arise in the femur (Fig 18), pelvis, and humerus (Fig 19).35 The focal proliferation of periosteal new bone in the context of Paget’s disease of bone might be radiologically indistinguishable from malignant transformation. This process is often referred to as “pseudo-sarcoma”, and is often diagnosed following a negative biopsy.36 Fibrosarcoma, chondrosarcoma, and malignant fibrous histiocytoma may also be rarely seen in the context of Paget’s.37,38 Giant cell tumours are even rarer complications, occurring more frequently in patients with the polyostotic form of Paget’s and usually involve the skull and facial bones.39 Complications related to the spine are mainly neurological due to spinal stenosis, compression fractures, and sarcomatous degeneration.40,41,42 Cranial nerve palsies or vascular compression may result when the foramina at the base of the skull are encroached upon. In advanced disease, basilar invagination (Fig 20) may cause compression of the brainstem and also hydrocephalus.43
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Figure 20 A 60-year-old man being investigated for cerebellar symptoms using CT angiography. A sagittal reformatted CT image (top) shows an irregular heterogeneous lucent and sclerotic pattern expanding the outer and inner tables of the skull and obscuring the diploic space (“cotton wool” skull). The tip of the odontoid process was noted to be almost 9 mm above Chamberlain’s line (a line drawn from the posterior margin of the hard palate to the posterior margin of the foramen magnum). This indicates a degree of basilar invagination, a known complication of Paget’s disease of bone. A coronal reformatted CT image (bottom left) and an axial CT image at the level of the pedicles (bottom right) show Pagetic involvement of the axis and atlas. The left lateral mass of the atlas, C2 vertebral body, odontoid process, and posterior neural arch appear heterogeneous and sclerotic. The atlanto-dens interval is obliterated, with signs of osteoarthritis. The spinal canal remains widely patent despite the vertebral enlargement.
Temporal bone involvement (Fig 10) may result in deafness both due to involvement of the ossicles (conductive deafness) or from compression of the vestibulo-cochlear nerve (sensori-neural deafness). High-output heart failure may occur due to the osseous hypervascularity seen in polyostotic disease and the associated increase in demand for cardiac output. This is a rare complication, and may be associated with osseous auscultatory bruits. Other complications related to the relative bone softening that occurs in Paget’s disease of bone include protrusio acetabuli and dental malocclusion.
Acknowledgements The authors are grateful to the following colleagues from Mater Dei Hospital and St James Hospital: Dr K. Saliba for providing Fig 5, Mr T. Cesare for help with the reformatted images, Dr M. A. Aquilina for reviewing the PET/CT fusion imaging section, and Dr A. Samuel for reviewing the nuclear imaging section.
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Supplementary data Supplementary data associated with this article can be found in online version at doi:10.1016/j.crad.2010.12.016.
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