Paget's disease of the bone; osteitis deformans

Etiology

• genetic factors
• 'slow virus'

Epidemiology

• rare before age 20
• affects 3% of population > 45 years of age & 10% of population > 80 years of age
• slight predominance in men

Pathology

• focal monostotic or polyostotic bone disorder
• disorganized bone remodelling
  • disordered osteoclast function
    • acceleration of bone turnover
    • disruption of normal bone architecture
      • gross deformities of bone may occur
  • local impingement of adjacent structures may occur
• structural weakening of bone with tendency to fracture
• increased vascularity
• bone enlargement occurs in 3 phases:
  • lytic phase
  • mosaic pattern
  • sclerotic phase
• predilection for
  • sacrum
  • spine
  • femur
  • tibia
  • skull
  • pelvis
• disease may be confined to 1 or several adjacent bones or involvement may be more generalized

Genetics

• associated with defects in the SQSTM1 gene
• associated with defects in the TNFRSF11A gene (type 2)

Clinical manifestations

• most patients are asymptomatic
  • diagnosis is generally made fortuitously after noting isolated increase in serum alkaline phosphatase or incidental abnormal radiography
• clinical presentation depends upon bone involved
• skeletal pain (bone pain) may occur
• bone deformities may occur
  • long bones
    • femur, tibia (bowing)
    • overlying skin may be warm & hyperemic
  • skull (enlargement of skull)
  • spine
  • pelvis
  • bone fractures
• degenerative arthritis from altered weight distribution
• impingement syndromes from disorganized bone remodelling
  • cranial nerve impingement syndromes
  • hearing loss may result from impingement on the inner ear & auditory nerve
  • pain syndromes or neurologic dysfunction may result from impingement on the spinal cord & nerve roots (spinal stenosis)
• headaches occur secondary to enlargement of skull structures
• high output heart failure
• angioid retinal streaks

Laboratory

• increased serum alkaline phosphatase
  • isolated increase in serum alkaline phosphatase
  • most useful marker for disease activity
  • useful for evaluation of response to therapy
• serum calcium (all patients) is generally normal, but may be increased during periods of immobility
• 25-OH vitamin D in serum (all patients)
• parathyroid hormone (PTH) in serum may be increased
• urine N-telopeptide (OsteoMark) assay reflects osteoclast activity

Radiology

• plain radiographs
  • more specific than bone scan to identify
    • lytic areas
      • focal osteolysis, coarse trabecular pattern
    • fissure fractures
    • extent of deformities
    • 'cotton wool' appearance of skull
    • thickening of bone cortex
  • follow-up radiograph 1 year after diagnosis for patients with osteolytic lesions
• pyrophosphate bone scan (all patients) shows focal areas of increased uptake
• skull
• femur
• pelvis

* radiograph & bone scan images

Complications

• fractures
• increased incidence of bone tumors (1% of cases)
  • most commonly osteosarcomas
    • pelvis
    • femur
    • humerus
    • skull
    • facial bones
  • poor prognosis
• neurologic complications
  • impingement of nerves by enlarging bone
    • especially cranial nerves II, V, VII, VIII
  • compromise of vascular supply by enlarging bone
• high output congestive heart failure (rare) due to vascular shunts through involved skeleton

Differential diagnosis

• hypertrophic pulmonary osteoarthropathy
  • clubbing of fingers
  • hemoptysis, blood-tinged sputum
  • periostitis, periosteal thickening at long bones (femur, tibia)*
  • arthritis*
  • elevated erythrocyte sedimentation rate (ESR)
  • elevated serum C-reactive protein
• osteomalacia:
  • hypophosphatemia, hypocalcemia, elevated serum alkaline phosphase
  • bone pain, aching pain with weight bearing, proximal muscle weakness

* also seen in primary hypertrophic osteoarthopathy

Management

• objectives
  • relieve symptoms (bone pain, headache, back pain, radiculopathy)
  • treat & prevent complications
  • treat lytic involvement of vertebrae, skull, weight-bearing bones, areas adjacent to major joints
  • serum alkaline phosphatase is a useful marker for disease activity & response to therapy
• non-steroidal anti-inflammatory drugs (NSAIDs)
  • no specific role in treatment of Paget's disease of the bone
• antiresorptive drugs, bisphosphonates 1st line (IV for symptomatic disease)
  • zoledronate* IV
    • a single 5-mg dose of IV zoledronate for patients at high risk of complications
    • often reduces pain & normalizes serum alkaline phosphatase
  • pamidronate 60-90 mg IV over 4 hours
    • sustained effect for 12-18 months
    • reduction or normalization of alkaline phosphatase in 50-75% of patients
    • repeat dose if necessary
    • adverse effects reduced by supplementing calcium
      • 1000 mg/day for 1 to 2 weeks after pamidronate
  • alendronate*
  • calcitonin
  • etidronate less effective than zoledronate; risk of fracture
  • risedronate*
• monitor response to therapy by measuring serum alkaline phosphatase
• surgery for impingement on nerves or blood supply
  • elective - pretreat with pamidronate
  • urgent - comcomittant pamidronate

* drug(s) of choice

More general terms

• osteitis

More specific terms

• juvenile Paget's disease; hyperostosis corticalis deformans juvenilis; hereditary hyperphosphatasia; chronic congenital idiopathic hyperphosphatasia

Additional terms

• extramammary Paget's disease
• osteoclast
• Paget's disease of the breast or nipple
• sequestosome-1; phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kD; ubiquitin-binding protein p62; EBI3-associated protein of 60 kD; p60; EBIAP (SQSTM1, ORCA, OSIL)

Patient information

Paget's disease of the bone patient information

Database

• OMIM: https://mirror.omim.org/entry/602080