Paget's Disease of Bone

Aka: Paget's Disease of Bone, Paget's Disease, Paget Disease of Bone, Paget Disease, Osteitis Deformans, Pagetic Lesion

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II. Definitions

  1. Paget Disease of Bone
    1. Benign skeletal condition of increased focal bone resorption and disordered bone formation
  2. Pagetic Lesion
    1. Focal region of bone resorption and disordered bone formation

III. Epidemiology

  1. Prevalence (United States)
    1. Overall: 1-2%
    2. Age over 80 years: 10%
  2. Onset over age 50 years
    1. Incidence doubles every decade over age 50 years old
    2. Rare under age 40 years old
  3. Gender
    1. Males are slightly more likely than women to be affected (RR 1.5)
  4. Ethnicity and Regions
    1. Uncommon in Asia and Scandanavia
    2. Common in United States, Europe, Australia, and New Zealand

IV. Pathophysiology

  1. Focal bone resorption and disordered bone formation
    1. Phase 1: Intense Osteoclastic activity
      1. Bone resorption predominates
      2. Bone turnover is 20 times normal rate
    2. Phase 2: Osteolytic-Osteoblastic activity
      1. Osteoclastic activity stimulates reflexive Osteoblastic activity
      2. Results in poorly organized, woven bone formation
      3. Ineffective mineralization
    3. Phase 3: Dense bone deposition
      1. Resulting bone is disorganized, deformed and sclerotic with increased vascularity
      2. Resulting bone is more fragile, weaker than normal bone
      3. Involved Bone Marrow is also fibrotic
  2. Pagetic Lesions (focal areas of bone abnormalities)
    1. Monostotic Pagetic Lesions
      1. Single site focus of bone abnormality
    2. Polyostotic Pagetic Lesions
      1. Multiple focal sites of bone abnormality
  3. Distribution
    1. Pelvis (72%)
    2. Spine
      1. Lumbar (58%)
      2. Thoracic (45%)
      3. Cervical (14%)
    3. Skull (42%)
    4. Long bones
      1. Femur (55%)
      2. Tibia (35%)
      3. Humerus (31%)
  4. Associated factors (etiology unknown)
    1. Viral Antigen association (especially paramyxoviruses including Measles)
    2. Diet and toxin exposure may also play a role
    3. Family History
      1. Autosomal Dominant (with incomplete penetrance)
      2. Positive Family History present in 10-20% of cases
      3. Family History may confer up to a 10 fold increased risk
      4. Sequestrome-1 or SQSTM1 (on Chromosome 5) encodes ubiquitin-binding p62 Protein
        1. SQSTM1 Mutations are responsible for 50% of familial and 30% of sporadic cases

V. Symptoms

  1. Asymptomatic in 70% of cases
    1. Most cases are found incidentally (elevated Alkaline Phosphatase, xray abnormalities)
  2. Pain (74%)
    1. Most common presenting symptom (but typically occurs later in course)
    2. Mild to moderate constant pain (severe sharp pain may suggest pathologic Fracture)
    3. Results from osteolytic activity, bone deformities or adjacent Osteoarthritis
    4. Pain provocative factors
      1. Rest or night pain
      2. Weight bearing
      3. Warming
    5. Pain palliative measures
      1. Activity
  3. Bone deformity (18%)
  4. Hearing Loss (8%)
  5. Pathologic Fractures (6%)
  6. Headaches
  7. Radiculopathy
  8. References
    1. Tan (2014) Calcif Tissue Int 95(5): 385-92 [PubMed]

VI. Signs

  1. Kyphosis
  2. Limb shortening or bowing
    1. Tibia anterior bowing
    2. Femur anterolateral bowing
  3. Frontal forehead bossing
  4. Skull enlargement
  5. Loose teeth
  6. Limp

VII. Labs: Diagnosis

  1. Liver Function Tests with Alkaline Phosphatase
    1. Total Serum Alkaline Phosphatase
    2. Bone specific Alkaline Phosphatase
  2. Other markers
    1. Procollagen Type 1 N-Terminal Proptide
    2. Urinary cross-linked N-terminal telopeptide of type 1 Collagen
    3. Urinary hydroxyproline is no longer used as marker

VIII. Labs: Monitoring

  1. Screening if first degree relative has Paget's Disease
    1. Alkaline Phosphatase every 3 years (over age 50)
  2. Monitoring of diagnosed Paget's Disease
    1. Alkaline Phosphatase every 3 to 12 months

IX. Imaging: XRay

  1. Indications
    1. Focal pain or deformity
    2. Alkaline Phosphatase with unexplained elevation but no focal pain or deformity to guide imaging
      1. Skull XRay
      2. Facial Bone XRay
      3. Abdominal XRay
      4. Tibia-Fibula XRay
  2. General changes
    1. Combined focal osteolytic lesions with nearby osteosclerosis
    2. Bone deformity or enlargement
    3. Cortical thickening
    4. Loss of corticomedullary distinction
    5. Pronounced bone trabeculae
  3. Skull changes
    1. Osteoporosis circumscripta cranii
  4. Long bone changes
    1. Flame-shaped changes
    2. Limb bowing
    3. Fractures (banana-shaped transverse Fractures)

X. Imaging: Bone Scan (Technetium-99m)

  1. Focal areas of intense and homogenous radiotracer uptake
  2. Appearance of Mouse-face on Vertebrae

XI. Complications

  1. Pathologic Fractures
    1. Long Bone Fractures
    2. Vertebral Compression Fractures
  2. Neurologic (esp. Nerve Compression Syndromes from direct pressure)
    1. Hearing Loss (Cochlear involvement)
    2. Vertigo
    3. Cranial Nerve palsy
    4. Spinal stenosis or radiculopathy resulting in weakness, numbness or Paresthesias
    5. Hydrocephalus
    6. Headache
  3. Hypercalciuria and Hypercalcemia (uncommon)
    1. Associated with polyostotic disease (multiple focal Pagetic Lesions) AND immobilization or Fracture
    2. Ureterolithiasis risk
    3. Significant Hypercalcemia is rare
  4. High Output Cardiac Failure (rare)
    1. Associated with severe polyostotic disease (multiple focal Pagetic Lesions) with marked increased vascularity
  5. Malignant degeneration (1% of Paget's Disease)
    1. Osteosarcoma (most common of malignant complications)
    2. Chondrosarcoma
    3. Giant Cell tumors
    4. Fibrosarcoma
    5. Spindle cell Sarcoma
  6. Other complications
    1. Pseudomalignancy (Pseudosarcoma or pseudo giant cell)
    2. Osteoarthritis (Paget's Disease involving joint)

XII. Management: General Measures

  1. Adequate pain control
  2. Low impact Exercise
  3. Avoid straining affected bone
  4. Calcium Supplementation 1000 mg orally daily
  5. Vitamin D 400 IU per day

XIII. Management: Suppress bone resorption (Osteoclasts)

  1. Indications
    1. Symptomatic patients
      1. Bone pain
      2. Hearing Loss
      3. Nerve Compression Syndromes
      4. XRay identified osteolytic lesions
    2. Active Paget's Disease (or complication risk of untreated Paget's Disease)
    3. Alkaline Phosphatase >125 to 150% of normal
  2. First line agents: Bisphosphonates
    1. Avoid in advanced Chronic Kidney Disease, Hypocalcemia, pregnancy
    2. Zoledronic acid (Reclast) 5 mg IV once (preferred)
      1. Re-evaluate with total Serum Alkaline Phosphatase at 1-2 years
      2. Retreatment may be needed after 5 years from prior dose
    3. Alternative Bisphosphonate protocols
      1. Risedronate (Actonel) 30 mg daily for 2 months
      2. Alendronate (Fosamax) 40 mg daily for 6 months
  3. Alternatives (not as potent as Bisphosphonates)
    1. Calcitonin 100 U SC or IM daily for 6 to 18 months
    2. Avoid Teriparatide (Forteo) due to increased risk of Osteosarcoma
  4. Monitoring
    1. Total Serum Alkaline Phosphatase
      1. Baseline
      2. Month 3-6 after treatment
        1. Consider retreatment if no response to therapy (esp. when not using Zoledronic Acid)
      3. Every 6-12 months (every 1-2 years if Zoledronic acid used)
    2. XRay
      1. Repeat XRay at one year after treatment if osteolytic lesions were present before treatment

XIV. References

  1. Simon in Klippel (1997) Primer Rheumatic, p. 382-4
  2. Schneider (2002) Am Fam Physician 65(10):2069-72 [PubMed]
  3. Rianon (2020) Am Fam Physician 102(4): 224-8 [PubMed]

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