Paget Disease

PAGET DISEASE OF THE BONE

• Definition and Pathology
  • Also called osteitis deformans.
  • Characterized by uncontrolled, highly active, large osteoclasts → increased bone resorption.
  • Marked compensatory osteoblastic activity causes new bone that is disorganized (lacking normal lamellar structure).
  • Increased local bone blood flow and fibrous tissue in the adjacent marrow.
  • Prevalence ~3% in adults >40 years; often asymptomatic, evolves slowly.
• Epidemiology
  • Same prevalence in men and women, but more commonly symptomatic in men.
  • Typically detected in the sixth decade of life.
  • Often found incidentally (e.g., elevated alkaline phosphatase on labs or suspicious findings on radiographs).

CLINICAL MANIFESTATIONS

• Symptoms
  • Bone pain due to periosteal stretching or microfractures; worse with weight bearing.
  • Warmth over the affected bone from increased local blood flow.
  • Can be monostotic (one bone) or polyostotic (multiple).
  • Most commonly involves pelvis, spine, femur, skull, tibia.
    • Femur/tibia: Bowing of legs, gait changes.
    • Spine: Kyphosis, possible spinal cord compression.
    • Skull: Hearing loss (cranial nerve VIII compression), skull deformities (frontal/occipital), rare facial nerve palsy.
    • Others: Visual disturbances (optic nerve), platybasia, hydrocephalus (skull base involvement).
• Complications
  • Fractures (transverse; low threshold because of bone architecture).
  • Bony neoplasia: Increased frequency of giant cell tumor, fibrosarcoma, chondrosarcoma, osteosarcoma.
  • Primary hyperparathyroidism more frequent.
  • High-output cardiac failure when >20% of skeleton is involved (increased vascularity).

EVALUATION

• History & Examination
  • Evaluate for bone pain, skeletal deformities, hearing changes, possible nerve compressions.
• Imaging
  • Radionuclide bone scan: Focal areas of increased uptake in pagetic bone.
  • Plain radiographs: Confirm Paget disease, assess extent (e.g., lytic, mixed, or sclerotic lesions).
• Laboratory
  • Serum alkaline phosphatase: Typically elevated in active disease.
  • Calcium: Normal unless immobilization or coexisting hyperparathyroidism.
• Additional Tests
  • Serum calcium to assess for hyperparathyroidism.
  • Audiogram if skull involvement.
  • Bone biopsy if suspicion of malignancy or if imaging is inconclusive.
• Markers of Bone Turnover
  • Bone formation markers: Bone-specific alkaline phosphatase, osteocalcin, propeptides of type I collagen (PINP).
  • Bone resorption markers: Urinary hydroxyproline, collagen crosslinks (N-telopeptide, C-telopeptide).
  • In Paget disease, both formation and resorption markers increase and normalize with successful treatment.

PATHOGENESIS AND TREATMENT

• Potential Cause
  • Believed to be viral (paramyxovirus) trigger + genetic predisposition.
  • Viral inclusions found in pagetic osteoclasts.
  • ~30% have family history of Paget disease; SQSTM1 (sequestosome 1) mutations implicated.
• When to Treat
  • Many patients asymptomatic → no treatment needed if minimal disease.
  • Indications: Pain, risk of bone or nerve complications, moderate-high disease activity, extensive skull involvement, major weight-bearing bones, or younger patients.
• Main Goal
  • Suppress osteoclast activity.
• Bisphosphonates
  • First-line therapy to inhibit osteoclasts.
  • Examples: etidronate, pamidronate, alendronate, tiludronate, risedronate, zoledronic acid.
  • Routes: High-dose oral or IV.
  • Effective for remission >1 year in many cases.
  • Side effects:
    • IV forms → ~20% get transient ‘flu-like’ symptoms 1–2 days after infusion.
    • Oral forms → esophageal irritation; must take upright, fasting, with water.
  • Monitoring: Discontinue once bone turnover markers normalize; retreat if/when they rise again.
• Other Therapies
  • Calcitonin: Historically used but less potent than bisphosphonates.
  • Plicamycin (mithramycin): Rarely used (toxicity).
• Supportive
  • Adequate calcium and vitamin D supplementation.
  • Monitor 25-hydroxyvitamin D levels to ensure repletion.
  • Physical therapy, analgesics for pain control.