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.

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