Paget Disease of Bone

Snapshot

• A 65-year-old man presents with worsening left-sided hearing loss and mild headache. He reported that his symptoms began a few months prior to presentation. He denies starting any new medications but has noticed he can no longer fit the hat he has owned for many years. Physical examination is unremarkable. Laboratory testing is notable for an elevated serum alkaline phosphatase. A radiograph of the skull is shown. 

Introduction

• Clinical definition
  • a progressive metabolic bone disorder of abnormal bone remodeling 
    • there is excessive bone resorption and formation resulting in
      • immature woven bone with collagen fibers arranged irregularly 
• Background
  • adult bone constantly undergoes bone remodeling and is accomplished by
    • osteoclasts
      • contains receptor activator for NF-κB (RANK) transmembrane receptors which
        • responds to RANK ligand (RANKL) on osteoblasts and osteocytes to differentiate and activate in order to resorb bone
    • osteocytes
      • secrete growth factors to regulate bone formation
        • bone formation is stimulated when mechanical forces are applied to bone
      • contains RANKL
    • osteoblasts
      • contain RANKL and osteoprotegerin (OPG)
        • OPG inhibits RANKL from binding to RANK on osteoclasts, thus inhibiting bone remodeling
      • functions in bone formation
  • bone matrix has two histological forms
    • woven
      • has less structural integrity
      • seen in fetal development and fracture repair
      • always considered abnormal in adults
    • lamellar
      • has more structural integrity
• Pathogenesis
  • genetic and environmental factors may be involved
  • increased multinucleated osteoclastic and osteoblastic activity leads to a high bone remodeling rate, leading to 
    • abnormal bone architecture
  • 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
• Associated findings
  • neurologic
    • nerve root compression
    • hearing loss
    • spinal stenosis
  • orthopedic
    • pathologic fractures
    • secondary osteoarthritis
  • oncologic
    • osteosarcoma
  • cardiovascular
    • high-output heart failure
  • labs
    • normal serum phosphate, calcium, and parathyroid hormone 
    • elevated alkaline phosphatase 
  • histology
• mosaic pattern of lamellar bone with prominent cement lines 

Normal Biology and Anatomy

• adult bone constantly undergoes bone remodeling and is accomplished by
  • osteoclasts
    • contains receptor activator for NF-κB (RANK) transmembrane receptors which
      • responds to RANK ligand (RANKL) on osteoblasts and osteocytes to differentiate and activate in order to resorb bone
  • osteocytes
    • secrete growth factors to regulate bone formation
      • bone formation is stimulated when mechanical forces are applied to bone
    • contains RANKL
  • osteoblasts
    • contain RANKL and osteoprotegerin (OPG)
      • OPG inhibits RANKL from binding to RANK on osteoclasts, thus inhibiting bone remodeling
    • functions in bone formation
• bone matrix has two histological forms
  • woven
    • has less structural integrity
    • seen in fetal development and fracture repair
    • always considered abnormal in adults
  • lamellar
    • has more structural integrity

Presentation

• Symptoms
  • usually asymptomatic
  • bone and/or joint pain
  • bone deformity
    • bowing deformity
  • hearing loss 
    • with skull involvement that lead to narrowing of the auditory foramen
• Physical exam
• typically unremarkable

Treatment

• Medical
  • bisphosphonates
    • mechanism of action
      • impregnates the bone that will be acted upon by osteoclasts
        • when osteoclasts release the bisphosphonates during resorption, it impairs osteoclast activity