Paget's Disease of Bone (Osteitis Deformans)

Overview

Epidemiology

• Affects 2-3% of persons aged ≥55 years; prevalence rises sharply with age (up to 3-3.7% in those over 40 at autopsy)
• Predominantly a disease of Northern European descent - most prevalent in Great Britain, France, Spain, Italy, Australia, and New Zealand; rare in Asia and India
• Men slightly more affected than women (ratio ~1.4-1.7:1)
• 10-40% of patients report a positive family history
• A notable decline in both prevalence and clinical severity has been observed in recent decades, particularly in formerly high-prevalence areas

Pathogenesis

Genetic Factors

• SQSTM1 (sequestosome 1) on chromosome 5q35, encoding the scaffold protein p62
• Over 20 mutations described, mostly in the ubiquitin-associated (UBA) domain
• The most common mutation, p.P392L, activates NF-κB signaling - the master regulator of osteoclast differentiation and bone resorption
• This mutation is a gain-of-function mutation, amplifying NF-κB activity and thus osteoclast hyperactivity

Environmental Factors

• Paramyxovirus infection (measles, respiratory syncytial virus, canine distemper) - viral nuclear inclusions have been found in pagetic osteoclasts
• Rural lifestyle exposure, possible toxin exposure
• These environmental triggers likely "unmask" genetic susceptibility

Histopathology

1. Osteolytic phase - giant multinucleated osteoclasts (with up to 100 nuclei, vs. normal 3-5) aggressively resorb bone
2. Mixed phase - coupled, chaotic bone formation produces the hallmark "mosaic" or "jigsaw puzzle" pattern of lamellar cement lines on histology
3. Sclerotic phase - bone formation predominates; bone becomes dense but structurally inferior (like "woven" rather than organized lamellar bone)

Clinical Features

Skeletal Sites

• Most commonly affected: skull, lumbosacral spine, pelvis, and proximal femur
• Can be monostotic (single bone) or polyostotic (multiple bones)
• Disease is focal - once established in a bone it spreads locally but does not disseminate systemically

Symptoms by Site

"Leontiasis Ossea" - facial deformity from maxillary Paget disease:

Paget disease of pelvis and proximal femurs (X-ray):

Complications

• Pathological fractures - "chalk-stick" fractures in weight-bearing bones
• Secondary osteoarthritis - in joints adjacent to pagetic bone
• Deafness - temporal bone involvement compresses cranial nerve VIII
• Heart failure (high-output) - due to increased vascularity of extensive pagetic bone (arteriovenous shunting)
• Osteosarcoma - rare but feared complication (~1% of long-standing cases); presents as sudden increase in pain, swelling, and markedly elevated ALP; carries a very poor prognosis
• Hypercalcemia - especially during immobilization

Diagnosis

Biochemical Markers

• Total serum alkaline phosphatase (ALP) - the most widely used marker of disease activity; reflects the rate of bone formation
• Bone-specific ALP - more specific, particularly useful when total ALP is confounded by liver disease
• Urinary markers of bone resorption (e.g., N-telopeptide, C-telopeptide) - indicate osteoclast activity
• ALP can be normal in monostotic or inactive disease

Imaging

1. Bone scintigraphy (bone scan) - recommended first for assessing extent of disease; very sensitive, shows all active lesions
2. Conventional radiographs - required to confirm diagnosis of lesions found on bone scan; characteristic features:
   • Osteoporosis circumscripta - sharply defined osteolytic lesion in skull (early)
   • Bone expansion and cortical thickening
   • Coarsened, disorganized trabeculae
   • "Blade of grass" / "flame-shaped" advancing lytic front in long bones
   • "Cotton wool" appearance in skull (later sclerotic phase)
   • "Picture frame" vertebra
3. CT/MRI - used when spinal stenosis, neural compression, or sarcomatous transformation is suspected

Treatment

Indications for Treatment

• Active disease with bone pain attributable to Paget disease
• Preparation for elective surgery on pagetic bone (reduces vascularity and blood loss)
• Disease at sites at risk for complications (skull base, spine, weight-bearing bones)
• Active disease adjacent to major joints (to reduce secondary OA risk)
• Hypercalcemia

Bisphosphonates (First-Line)

Calcitonin

• Salmon calcitonin (intranasal or SC injection) is an older agent; less effective than bisphosphonates but still used in patients who cannot tolerate bisphosphonates or pre-/post-operatively
• It decreases osteoclastic activity and reduces perioperative blood loss

Analgesics

• NSAIDs and simple analgesics for pain not directly from pagetic activity (e.g., secondary OA, nerve compression)

Surgical Management

• Total hip arthroplasty (THA) - for painful secondary osteoarthritis or femoral neck fracture; technically challenging due to bone deformity and hypervascularity
  • Reported 7-10 year implant survival ~86%
  • Bisphosphonates and calcitonin pre-operatively reduce blood loss
  • Heterotopic bone formation is a common post-op complication
• Spinal decompression - for spinal stenosis or cord compression
• Osteotomy - if severe long bone bowing prevents intramedullary stem placement during THA

Monitoring and Follow-up

• Serum ALP every 3-6 months during treatment; then every 6-12 months during remission
• Bone scan at diagnosis (to map all lesions); repeat only if new symptoms arise
• Radiographs of symptomatic or high-risk sites periodically
• Watch for sudden worsening of pain or swelling - this should prompt suspicion for osteosarcomatous transformation

Key Associations to Remember