Paget Disease of Bone

Typically seen in older adults without clinical symptoms, manifests with thickened, sclerotic cotton-wool bone and elevated ALP.

Description

Paget’s disease of the bone is a metabolic bone disorder of excess disordered and architecturally unsound bone mass. The newly formed bone is larger, disorganised, and mechanically weaker. The disease is commonly seen in older adults, predominantly affecting the axial skeleton.

Historically known as osteitis deformans.

Pathogenesis

The pathogenesis of PDB is thought to be related to an increase in osteoclast activity, leading to increased bone resorption. The subsequent increase in osteoblast activity results in disorganised new bone formation, leading to the characteristic pagetic bone with its mosaic pattern. Aetiology is unknown but environmental and genetic factors are implicated. The family of paramyxoviruses has been studied as a causative agent but unproven. Mutations in the SQSTM1 gene (enhancing RANK signaling) increase susceptibility. Found in 40-50% of familial cases and 5-10% of sporadic cases.

Three sequential stages are described:

1. Osteolytic phase – Resorption by number of large osteoclasts
2. Mixed phase – Osteoclasts and osteoblasts lining bone surfaces with disordered woven and lamellar bone formation. Adjacent marrow spaces are replaced by loose connective tissue. Lamellar bone assumes a pathognomonic mosaic pattern.
3. Burn-out phase – Bone sclerosis composed of coarsely thickened trabeculae and cortices. Bone is soft and porous. No structure stability.

Subtypes

There are no recognised subtypes of Paget’s disease of bone.

Epidemiology, Risk Factors & Associations

• Paget’s is the second most common metabolic bone disorder after osteoporosis.
• The disease is more common in Europe, especially in Britain, and less common in Asia and Africa.
• The prevalence increases with age, affecting about 5% of individuals over 55 years and up to 10% of those over 80 years.
• Men are slightly more affected than women.
• There is a genetic predisposition, with 15-40% of patients having a first-degree relative with the disease.

Clinical Features

• Majority of patients are asymptomatic 
• Mostly polyostotic. Monostotic in <35% of cases.
• Diffuse musculoskeletal pain, associated with fractures, nerve compression, osteoarthritis. Often located in the lower back or hips if the pelvis or spine is involved.
• Skeletal deformities: tibial bowing, skull enlargement

Complications

• Fractures are a common complication due to weakened bone.
• Deformities can occur: basilar skull invagination, insufficiency fractures, protusion acetabuli, proximal femoral varus and tibial bowing.
• Osteoarthritis can occur in adjacent joints.
• Osteomyelitis – may relate to hypervascularity of affecte bones and subsequent increased risk of organisms such as Staphyloccus aureus seeding these areas
• Crystal deposition diseases (gout and calcium pyrophosphate dihydrate deposition disease) – may relate to increased calcium mobilisation.
• Neurologic complications related to osseous expansion include sensorineural and conductive hearing loss (due to involvement of petrous temporal bone) and spinal stenosis

Rarely:

• The vascularity of polyostotic lesions can cause high-output heart failure. Secondary anaemia may occur due to increased plasma volume associated with high-output heart failure.
• Secondary giant cell tumours – more common in the skull
• Malignant transformation to osteosarcoma (<1% of cases), with a predilection for the pelvis and skull. Prognosis is very poor. Pulmonary metastasis may be seen. New-onset pain is a worrying feature.

Pathological Features

Histopathology

• Macroscopic: Pagetic bone is typically larger, thicker, and harder.
• Microscopic: Characteristic “mosaic” pattern due to haphazard orientation of bone lamellae.

Serology

• ALP – Elevated alkaline phosphatase (reflecting increased osteoblastic activity) and hydroxyproline (reflecting increase resorption).

Biochemistry

• Normal serum calcium and phosphorus levels.

Radiological Features

General Features

• Characteristically demonstrates increased bone density with cortical thickening.
• The cotton wool appearance on radiographs is characteristic.
• Bone-within-bone appearance results from endosteal new bone formation, though is non-specific.
• Must exclude secondary osteosarcoma – aggressive bone tumour with ossified matrix, with possible pulmonary metastasis.
• The pathognomonic triad of findings in the mixed lytic and sclerotic phase of Paget disease is bone expansion, cortical bone thickening, and trabecular bone thickening.
• Skull
  • Osteoporosis circumscripta – seen in the osteolytic stage as large, well-defined lytic lesions involving the inner aspect of the outer table of the skull (sparing inner table), reflecting the acutely marginated bone demineralisation.
  • Widening of diploic space – involvement of inner (more extensively) and outer tables
  • Cotton wool appearance – seen in later stages as focal regions of sclerosis within thickened calvaria
  • Tam o’ Shanter sign
    • Platybasia – abnormal flattening of the skull base
    • Basilar invagination
    • Considered pathognomonic
• Spine
  • Picture frame sign – seen in mixed-phase stage as cortical thickening and sclerosis encasing the vertebral margins
    • Considered pathognomonic
  • Squaring of vertebrae – seen on lateral radiographs as flattening of the normal concavity of the anterior margin of the vertebral body also adds to the rectangular appearance
  • Vertical trabecular thickening
  • Ivory vertebra – seen in late blastic phase
  • Vertebral body enlargement
• Pelvis
  • Pelvic brim sign – cortical thickening and sclerosis of the iliopectineal and ischiopubic lines and obliteration of Köhler’s​ teardrop
  • Acetabular protrusion
  • Enlargement of the pubic rami and ischium
• Long bones
  • Disease usually involves ends of bones and extends approximately 1 cm per year towards the diaphysis.
  • Blade of grass or candle flame sign – V-shaped region of lucency originating from the subchondral/proximal bone and pointing towards the diaphysis. It has a sharp oblique delineation at the border with normal bone and represents the leading edge. Considered pathognomic.
  • Bowing – lateral curvature of the femur or anterior curvature of the tibial
  • Banana fractures– incomplete horizontal insufficiency fractures at the convex side of a long bone
  • Fibular involvement is rare for unknown reasons

XR

• The acute (active, osteolytic) phase is characterised by aggressive bone resorption secondary to disordered osteoclastic activity. This manifests as lucency within the medulla of the long bones, typically in a flame shape or blade of grass configuration.
• The chronic (osteoblastic) phase is characterised by osteosclerosis, cortical thickening and increased trabeculation. This manifests as sclerotic patches which are poorly defined and fluffy giving a cotton wool apperance.
• Banana fracture is a complete, horizontally-oriented pathological fracture, usually at the convex margin of the bone.
• Tam o’ Shanter sign of the skull is due to widening of the dipoloic space and enlargement of the cranium, with platybasia

CT

• Non-contrast: Shows cortical thickening and trabecular coarsening.
• Contrast-enhanced: Not typically required for diagnosis.

MR

• Shows markedly heterogeneous marrow signal reflecting the mixed lytic and sclerotic phases of disordered bone turnover.
• T1: Variable signal, often showing areas of low intensity corresponding to fibrotic or sclerotic bone, interspersed with high-signal fatty marrow (particularly in the chronic or inactive phase).
• T2/STIR: Characteristically heterogeneous high signal from vascular fibrous tissue and active bone remodelling. The overall pattern is chaotic and patchy, rather than uniform.
• Additional features:
  • Bone expansion with preservation of overall shape.
  • Thickened cortex and coarse trabeculae appearing low signal on all sequences.
  • Bone deformity and bowing in weight-bearing bones.
  • Soft-tissue mass or extraosseous extension suggests sarcomatous transformation (rare).

NM

• Bone scintigraphy: Shows intense uptake in involved areas, useful in detecting asymptomatic disease.

Grading and Staging

No established grading and staging system.

Reporting

• Map anatomical extent: mono- vs polyostotic; side and proportion of bone involved (epiphysis/metaphysis/diaphysis; subchondral extension)
• Correlate with prior bone scan if available (high uptake = active), or suggest baseline NM bone scan for staging/activity assessment; note interval change on follow-up
• Identify complications:
  • Impending or established fractures (transverse through thickened cortex; stress lines), deformity (anterolateral tibial/femoral bowing), and malalignment that alters joint mechanics
  • Secondary osteoarthritis at adjacent joints (hip, knee); acetabular protrusio risk when hemipelvis involved
  • Spinal canal/foraminal stenosis and nerve compression in pagetic vertebrae; specify levels and degree
  • Skull base involvement: foramen magnum stenosis, cranial canal narrowing (optic canal, internal auditory canal), platybasia/basilar invagination (assess Chamberlain/McGregor lines if abnormal)
  • Suspicion for sarcomatous transformation (new aggressive lysis, cortical breakthrough, soft-tissue mass, periosteal reaction); flag urgently and recommend cross-sectional imaging ± biopsy
• On CT/MRI, detail marrow and soft-tissue components: cortical integrity, extraosseous mass, neural element compression; on MRI, describe fatty transformation vs oedema-like signal in active lesions
• In pelvis/hip, report acetabular coverage, limb-length discrepancy, and hardware implications for arthroplasty (bone quality, canal shape, deformity)
• In long bones, comment on deformity angles and risk areas (anterolateral tibial cortex; femoral subtrochanteric region); advise weight-bearing radiographs if surgical planning required
• State recommended follow-up or adjuncts: baseline ALP for activity correlation, interval radiographs for deformity/fracture surveillance, and NM bone scan for whole-skeleton mapping when disease first identified
• If prior treatment (bisphosphonates), compare for radiographic quiescence (reduced lysis, increased sclerosis; clinical/biochemical correlation advised). Assess for impending subtrochanteric femoral fractures (volcano sign).

Diagnosis

The diagnosis is typically made with radiographs and is confirmed by elevated serum alkaline phosphatase levels.

Differential Diagnoses

• Sclerotic metastases – blastic lesions in the same distribution as Paget disease. No trabecula coarsening or bony enlargement. Metastatic cancer rarely causes a homogeneous structural alteration of bone, and only in its late stages.
• Fibrous dysplasia – calvarial lesions difficult to distinguish from Paget disease. May enlarge bone but typically without trabeculae coarsening or cortical thickening
• Multiple myeloma – early lytic lesions difficult to distinguish. No trabecula coarsening or bony enlargement
• Treated malignancy – coarsened trabeculae and cortical thickening may result from a treated expansile lesion.

Imaging-based

Other differentials for bone-within-bone appearance:

• Sickle cell disease
• Thalassaemia
• Gaucher’s disease
• Acromegaly
• Hypervitaminosis D
• Scurvy
• Rickets

Other differentials for ivory vertebra appearance:

• Osteoblastic metastasis – uniform sclerosis without vertebral enlargement, no cortical thickening or bony expansion, may have adjacent soft-tissue mass (Paget’s shows enlargement, cortical thickening, coarse trabeculae).
• Lymphoma – ivory vertebra with minimal cortical change, often paraspinal soft-tissue mass, no bony expansion (Paget’s expands vertebra with coarse trabeculae, no soft-tissue mass).
• Osteosarcoma – heterogeneous sclerosis with cortical destruction and aggressive periosteal reaction, soft-tissue extension (Paget’s has orderly cortical thickening and expansion).
• Chronic sclerosing osteomyelitis – sclerosis with irregular endplates and disc space narrowing, possible sequestrum/cloaca (Paget’s spares discs and shows uniform vertebral expansion).
• Sclerotic haemangioma – uniform vertebral sclerosis with preserved vertical trabeculae (corduroy sign), no cortical thickening or expansion (Paget’s has cortical thickening, bone enlargement, coarsened trabeculae).
• Osteopoikilosis / systemic sclerosis mimics – multiple enostoses or diffuse sclerosis in a systemic distribution, vertebra not expanded (Paget’s is localised, expanded, and trabeculae are thickened).

Management

• Bisphosphonates are first-line therapy
  • Zoledronic acid is most commonly used
  • Suppresses osteoclastic activity and reduces bone turnover
• Imaging may detect disease incidentally before symptoms.
• Asymptomatic radiological findings alone may not require treatment
• Treatment indicated if:
  • Bone pain is attributable to Paget’s
  • Weight-bearing bones are involved (e.g. femur, tibia)
  • Surgery is planned through active bone
  • Complications are present (e.g. deformity, fracture risk, skull base involvement)
• MRI or CT may be required to evaluate complications (e.g. neural compression, sarcoma)