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Updated: Dec 24 2023

Paget's Disease

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  • summary
    • Paget's Disease is an idiopathic condition of abnormal bone remodeling with normal bone being replaced through an active interplay between excessive bone resorption and abnormal new bone formation. The condition typically present in patients age > 40 with asymptomatic lesions discovered incidentally on radiographs.
    • Diagnosis is made with radiographs showing characteristic findings of lesions with diffuse blastic appearance and labs showing elevated serum ALP and elevated urinary collagen cross-links.
    • Treatment is observation for asymptomatic patients. Medical management with bisphosphonates is indicated in symptomatic patients. 
  • Epidemiology
    • Demographics
      • peak incidence in the 5th decade of life
      • common in Caucasians (northern European / Anglo-Saxon descent)
      • males = females
    • Anatomic location
      • may be monostotic or polyostotic
      • common sites include femur > pelvis > tibia > skull > spine
  • Etiology
    • Pathophysiology
      • increased osteoclastic bone resorption is the primary cellular abnormality
      • cause is thought to be a slow virus infection (intra-nuclear nucleocapsid-like structure)
        • paramyxovirus
        • respiratory syncytial virus
    • Genetics
      • inheritance
        • most cases are spontaneous
        • hereditary
          • familial clusters have been described with ~40% autosomal dominant transmission
      • genetics
        • most important is 5q35 QTER (ubiquitine binding protein sequestosome 1) SQSTM1 (p62/Sequestosome)
          • tend to have severe Paget disease
        • also insertion mutation in TNFRSF11A for gene encoding RANK
    • Orthopaedic manifestations
      • bone pain
      • long bone bowing
      • fractures, due to brittle bone and tend to be transverse
      • large joint osteoarthritis
        • excessive bleeding during THA
        • malalignment during TKA
      • secondary sarcoma
    • Associated conditions
      • high output heart failure
  • Classification
    • Phases
      • lytic phase
        • intense osteoclastic resorption
      • mixed phase
        • resorption and compensatory bone formation
      • sclerotic phase
        • osteoblastic bone formation predominates
      • all three phases may co-exist in the same bone
  • Presentation
    • Symptoms
      • asymptomatic
        • frequently asymptomatic and found incidentally
      • pain
        • pain may be the presenting symptom due to
          • stress fractures
          • increased vascularity and warmth
        • new intense pain and swelling
          • suspicious for Paget's sarcoma in a patient with history of Paget's + new intense pain and swelling
      • cardiac symptoms
        • can present with high-output cardiac failure particularly if large/multiple lesions & pre-existing diminished cardiac function
  • Imaging
    • Radiographs
      • coarsened trabeculae which give the bone a blastic appearance
        • both increased and decreased density may exist depending on phase of disease
          • lytic phase
            • lucent areas with expansion and thinned, intact cortices
            • 'blade of grass' or 'flame-shaped' lucent advancing edge
          • mixed phase
            • combination of lysis + sclerosis with coarsened trabeculae
          • sclerotic phase
            • bone enlargement with cortical thickening, sclerotic and lucent areas
      • remodeled cortices
        • loss of distinction between cortices and medullary cavity
      • long bone bowing
        • bowing of femur or tibia
      • fractures
      • hip and knee osteoarthritis
      • osteitis circumscripta
        • (cotton wool exudates) in skull
      • Paget's secondary sarcoma
        • shows cortical bone destruction
        • soft tissue mass
    • MRI
      • may show lumbar spinal stenosis
    • Bone scan
      • accurately marks site of disease
      • intensely hot in lytic and mixed phase
      • less hot in sclerotic phase
    • CT scan
      • cortical thickening and coarsened trabeculae
  • Evaluation
    • Laboratory findings
      • elevated serum ALP
      • elevated urinary collagen cross-links
      • elevated urinary hydroxyproline (collagen breakdown marker)
      • increased urinary N-telopeptide, alpha-C-telopeptide, and deoxypyridinoline
      • normal calcium levels
  • Histology
    • Characteristic histology
      • woven bone and irregular broad trabeculae with disorganized cement lines in a mosaic pattern
      • profound bone resorption - numerous large osteoclasts with multiple nuclei per cell
        • virus-like inclusion bodies in osteoclasts
        • Paget's osteoclasts larger, more nuclei than typical osteoclasts
      • fibrous vascular tissue interspersed between trabeculae
  • Differential
      • Differential of Paget's Disease
      • Benign lesion in older patient (40-80)
      • Multiple lesions in the older patient
      • Treatment is Observation only
      • (assuming no imp. path. fx.)
      • Benefits from Bisphosphonate therapy
      • Paget's disease
      • o
      • o
      • o
      • o
      • Enchondroma
      • o
      • o
      • Bone island
      • o
      • Bone infarct
      • o
      • o
      • Hyperparathyroidism
      • o
      • o
      • Metastatic bone disease
      • o
      • o
      • Myeloma
      • o
      • o
      • Lymphoma
      • o
      • NOF
      • o
      • Osteochondroma
      • o
      • Eosinophillic granuloma
      • o
      • Fibrous Dysplasia
      • o
  • Treatment
    • Nonoperative
      • observation and supportive therapy
        • treatment for asymptomatic Paget's disease
          • physiotherapy, NSAIDS, oral analgesics
      • medical therapy aimed at osteoclast inhibition
        • bisphosphonates are 1st line treatment for symptomatic Pagets
          • oral
            • alendronate and risedronate
            • etidronate disodium (Didronel)
              • older generation medication
              • inhibits osteoclasts and osteoblasts
              • cannot be used for more than 6 months at a time
          • intravenous
            • pamidronate, zoledronic acid (Zometa)
              • newer generation medications that only inhibit osteoclasts
              • disadvantageous in that they only come in IV form
              • single 5mg IV infusion of zoledronic acid shown to be most efficacious means by which to retard osteoclast activity in Paget's disease
                • can normalize ALP levels for up to 6.5 years following a single IV infusion
        • calcitonin are 2nd line (after bisphosphonates)
          • causes osteoclasts to shrink in size and decreases their bone resorptive activity within minutes
          • administered subcutaneously or intramuscularly
        • teriparatide is contraindicated in Paget's disease due to risk of secondary osteosarcoma
    • Operative
      • THA / TKA
        • indications
          • affected patients with degenerative joint disease
        • technique
          • treat Paget's with pharmacologic agents prior to arthroplasty to reduce bleeding
        • outcomes
          • greater incidence of suboptimal alignment secondary to pagetoid bone
          • the most common complications include
            • malalignment with knee arthroplasty
            • bleeding with hip arthroplasty
      • metaphyseal osteotomy and plate fixation
        • indications
          • fractures through pathologic bowing of long bones
          • impending pathologic fracture of long bone with bowing
  • Prognosis
    • Paget's sarcoma
      • less than 1% will develop malignant Paget's sarcoma (secondary sarcoma)
      • osteosarcoma > fibrosarcoma and chondrosarcoma
      • most common in pelvis, femur, and humerus
      • poor prognosis
        • 5-year survival for metastatic Paget's sarcoma < 10%
        • treatment includes chemotherapy and wide surgical resection
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