Paget's Disease of Bone

Definition

• Harrison's Principles of Internal Medicine 22E

Epidemiology

• Prevalence ~0.5-3% in populations over 40-55 years of age; autopsy series show ~3% over age 40
• More common in males; prevalence rises sharply with age
• High prevalence in Western Europe (UK, France, Germany) and among people of European descent who migrated to Australia, New Zealand, South Africa, and the Americas
• Rare in native populations of the Americas, Africa, Asia, and the Middle East
• For unclear reasons, prevalence and severity have been decreasing over recent decades, and age at diagnosis is increasing

Etiology

• Positive family history in 15-25% of patients; raises risk 7-10-fold in first-degree relatives
• Autosomal dominant pattern with variable penetrance in familial cases
• Key genetic associations:
  • TNFRSF11B (OPG gene) homozygous deletion → juvenile Paget's (familial idiopathic hyperphosphatasia) - uncontrolled osteoclastic resorption
  • TNFRSF11A (RANK gene) mutations → familial expansile osteolysis, expansile skeletal hyperphosphatasia
  • Profilin 1 mutations → early-onset Paget's with predisposition to osteosarcoma
  • Valosin-containing protein mutations → inclusion body myopathy with Paget's disease and frontotemporal dementia

• Cytoplasmic and nuclear inclusions resembling paramyxoviruses (measles, RSV, canine distemper virus) found in pagetic osteoclasts
• Measles virus nucleocapsid/matrix gene vectors can convert osteoclast precursors into pagetic-like osteoclasts
• The decline in Paget's disease incidence coincides with widespread measles vaccination
• However, no live virus has been cultured from pagetic bone, and full-length viral genes have not been cloned from patients

Pathophysiology

• Pagetic osteoclasts are 10-100 times more numerous, much larger, and have up to 100 nuclei (vs 3-5 in normal osteoclasts)
• Create a sevenfold increase in resorptive surfaces; erosion rate of 9 μg/day (normal 1 μg/day)
• Mechanisms driving hyperactive osteoclasts:
  1. Hypersensitivity to 1,25(OH)₂D₃
  2. Hyperresponsiveness to RANKL (osteoclast stimulatory factor)
  3. Increased RANKL expression by marrow stromal cells in pagetic lesions
  4. Elevated IL-6 (overexpressed in pagetic osteoclasts and elevated in blood)
  5. Upregulation of proto-oncogene c-fos (increases osteoclastic activity)
  6. Overexpression of antiapoptotic oncogene Bcl-2 in pagetic bone

Three Phases of Paget's Disease

Clinical Manifestations

• Bone pain - the most common symptom; arises from increased vascularity, expanding lytic lesions, fractures, or bowing
• Skeletal deformities - bowing of femur/tibia, enlarged skull with frontal bossing, short stature with simian posturing
• Secondary osteoarthritis - at joints adjacent to pagetic bone
• Fractures - in 10-30% of patients; most common at femoral shaft and subtrochanteric regions; "banana fractures" - short fissure fractures traversing the cortex
• Neurological complications - from bone expansion compressing neural tissue: hearing loss (most common; due to cochlear or auditory nerve compression), cranial nerve palsies, spinal cord/nerve root compression, basilar invagination causing brainstem or cerebellar signs
• Cardiovascular complications - in patients with >15-35% skeletal involvement; extensive arteriovenous shunting through hypervascular pagetic bone leads to high-output state and cardiac enlargement; high-output heart failure is rare and usually requires coexisting cardiac pathology; calcific aortic stenosis and diffuse vascular calcifications also associated
• Sarcomatous transformation - rare, <0.5-1% of patients; mostly osteosarcoma; presents as new pain in a long-standing pagetic lesion; incidence appears to be decreasing with effective treatment
• Osteoclast-rich benign giant cell tumors may arise adjacent to pagetic bone; respond to glucocorticoids
• Hypercalcemia - rarely from immobilization; hypercalcemia even with immobilization warrants a search for another cause

Diagnosis

Clinical examination findings

• Enlarged skull with frontal bossing
• Bowing of extremities; leg-length discrepancy
• Warmth and tenderness over a bone
• Simian posturing (short stature, bowed legs)

Radiographic features

• Enlargement or expansion of the entire bone or a segment of a long bone
• Cortical thickening; coarsening of trabecular markings
• Skull: "cotton wool" appearance, osteoporosis circumscripta, thickening of diploic areas
• Vertebrae: cortical thickening of endplates → "picture frame" vertebra; diffuse sclerosis → "ivory vertebra"
• Pelvis: thickened iliopectineal line (brim sign), protrusio acetabuli, whorls of coarse trabeculation
• Long bones: bowing deformity, "blade of grass" lytic front

Paget's disease of the skull - lateral X-ray (left) and ⁹⁹mTc bone scan (right) - Harrison's 22E

Paget's disease of the right proximal femur and pelvis - note coarsened trabecular markings, cortical thickening, and joint space narrowing - Harrison's 22E

Imaging

• ⁹⁹mTc bone scan - most sensitive for identifying active skeletal lesions (but less specific)
• CT - useful for fracture assessment
• MRI - needed when sarcoma, giant cell tumor, or metastatic disease is suspected
• Bone biopsy - required for definitive diagnosis of malignancy

Biochemical markers

• Serum total alkaline phosphatase (ALP) - the test of choice for both diagnosis and monitoring therapy; reflects extent and severity; can be elevated up to 10x normal in active disease
• Bone-specific ALP - useful when total ALP is normal but a single site is progressing symptomatically
• PINP (procollagen type I N-terminal propeptide) - reflects disease activity; a useful bone formation marker
• Serum osteocalcin - not reliably elevated; NOT recommended for diagnosis or management
• Urinary hydroxyproline - elevated (marker of bone resorption); useful for monitoring
• Serum calcium and phosphate are normal in Paget's disease
• Mild secondary hyperparathyroidism may develop during bisphosphonate therapy if calcium/vitamin D intake is insufficient

Treatment

Indications for treatment

• Bone pain or headache from metabolically active disease
• Fracture prevention in active lytic lesions of weight-bearing bones
• To decrease local blood flow before elective bone surgery (reduces operative blood loss)
• To prevent progression of neurologic complications
• Correction of hypercalcemia from immobilization

Bisphosphonates (first-line)

• Long-term remissions (months to years) expected in bisphosphonate responders
• Treatment should not exceed 6 months per course but can be repeated after 6 months
• Key toxicity of etidronate: osteomalacia and increased fractures at doses above 5 mg/kg/day
• Key toxicity of alendronate/newer bisphosphonates at Paget doses: gastric irritation (reversible on stopping)
• Adequate calcium and vitamin D intake must be ensured before bisphosphonate therapy to prevent hypocalcemia/secondary hyperparathyroidism

Calcitonin (second-line)

• Subcutaneous/IM: 50-100 MRC units daily or every other day
• Nasal inhalation: 200-400 units/day
• Weeks to months for response (pain relief, ALP reduction)
• Limitation: patients often lose response over time (not correlated with antibody development)

Surgery

• Joint replacement for severe secondary arthritis
• Internal fixation for fractures or impending fractures in weight-bearing bones
• Decompressive surgery for neurological complications

Summary Table