Paget's Disease of Bone (Osteitis Deformans)

Classification

• Monostotic (~15% of cases): one bone affected
• Polyostotic (~85% of cases): multiple, non-contiguous skeletal sites involved

1. Initial osteolytic (resorptive) phase
2. Mixed osteoclast-osteoblast phase
3. Final osteosclerotic (burned-out) phase

Fig. Diagrammatic representation of Paget disease of bone demonstrating the three phases - Robbins, Cotran & Kumar Pathologic Basis of Disease

Epidemiology

• Prevalence ~0.5-1% in the UK and US; autopsy studies reveal ~3% in those over age 40
• More common in males (ratio ~1.4-1.7:1), rising with age
• High prevalence in Western Europe (UK, France, Germany), Australia, New Zealand, and among European immigrants
• Rare in Scandinavia, East Asia, sub-Saharan Africa, and native populations of the Americas
• Prevalence and severity have decreased in recent decades for unclear reasons

Etiology

Genetic Factors

• SQSTM1 (sequestosome-1/p62) mutation is the most important: found in ~60% of familial cases and ~10-16% of sporadic cases; more than 20 mutations described in or near the ubiquitin-associated (UBA) domain. p62 is a scaffold protein regulating NF-κB signaling, the master pathway for osteoclast differentiation. Mutations increase NF-κB activity and thus osteoclast activity.
• RANK (TNFRSF11A) activating mutations: cause familial expansile osteolysis and early-onset Paget disease
• OPG (TNFRSF11B) inactivating mutations: loss of osteoprotegerin leads to uncontrolled osteoclastogenesis; homozygous deletions cause juvenile Paget disease (familial idiopathic hyperphosphatasia)
• VCP mutations: cause multisystem proteinopathy - inclusion body myopathy + Paget disease + frontotemporal dementia (± ALS)
• ZNF687 mutations: rare syndrome of Paget disease with giant cell tumors
• PFN1 (profilin-1) mutations: early-onset disease with predisposition to osteosarcoma
• Genome-wide association studies identified 7 additional loci near genes including CSF1 (M-CSF), TM7SF4 (DC-STAMP), OPTN (optineurin), and RIN3 - all converging on osteoclast function and autophagy
• Autosomal dominant transmission with variable penetrance; positive family history in 15-25% of patients (raises prevalence 7-10-fold in first-degree relatives)

Environmental / Viral Factors

• In vitro studies raised the possibility of chronic paramyxoviral infection (measles virus, canine distemper virus, respiratory syncytial virus) of osteoclast precursors - nuclear inclusions in pagetic osteoclasts resemble nucleocapsids of paramyxoviruses
• Geographic variation and declining incidence over time support an environmental trigger
• Mechanical loading, skeletal injuries, rural exposures, and toxins have also been proposed

Pathogenesis

1. Osteoclast hyperactivation: pagetic osteoclasts are increased in number, markedly enlarged, and hypernucleated (up to 100 nuclei vs. normal 3-5). They show hypersensitivity to RANKL and 1,25(OH)₂D₃
2. RANKL/OPG imbalance: marrow stromal cells from pagetic lesions overexpress RANKL; osteoclast precursor recruitment is amplified by IL-6 (elevated in blood of active disease)
3. Osteoblastic response: compensatory osteoblastic new bone formation is markedly increased, exceeding the amount resorbed - producing enlarged, deformed bones
4. Woven bone: the new bone is deposited in a disorganized (woven) pattern with impaired mechanical strength
5. Autophagy defects: nuclear inclusions in pagetic osteoclasts may represent aggregates of undegraded proteins due to defects in autophagy; proteins encoded by VCP, OPTN, and SQSTM1 all regulate autophagy
6. Marrow fibrosis and hypervascularity: increased vascularity causes warmth overlying lesions; marrow is replaced by loose fibrovascular tissue in active phases
7. Focal nature: possibly explained by somatic mutations in affected bones causing local osteoclast hyperactivity, or by early-life mechanical injury creating a focus for remodeling

Clinical Manifestations

Symptoms

Skeletal Distribution

• Axial skeleton and proximal femur involved in up to 80% of cases
• Most commonly: pelvis > lumbar spine > femur > thoracic spine > skull > tibia

Radiologic Features

Skull

• "Cotton-wool" appearance: mixed lytic and sclerotic foci
• Osteoporosis circumscripta: well-defined lytic area (early/active phase) in frontal or occipital bone
• Thickening of diploic tables; enlargement and sclerosis of calvarium
• Bone scan: diffuse intense isotope uptake by frontal, parietal, occipital, and petrous bones

FIGURE - Paget's disease of the skull: lateral radiograph (left) showing cotton-wool pattern; bone scan with anterior, posterior, and lateral views showing diffuse isotope uptake - Harrison's Principles of Internal Medicine 22E

Spine

• "Picture-frame" vertebra: cortical thickening of superior and inferior endplates with central lucency
• "Ivory vertebra": diffuse radiodense enlargement of the entire vertebral body

Pelvis

• Disruption or fusion of sacroiliac joints
• Mixed porotic and radiodense lesions of ilium with coarse trabeculation (whorls)
• Brim sign: thickened and sclerotic iliopectineal line
• Softening with protrusio acetabuli; axial migration of hips

Long Bones

• Enlargement/expansion of the whole bone or involved segment
• Cortical thickening (both periosteal and endosteal)
• Coarsening of trabecular markings
• Bowing deformity (typically anterior in tibia/femur)
• Mixed lucency and sclerosis
• "Blade of grass" or "flame" sign: advancing lytic front at the edge of lesion in active phase

Plain radiograph of the leg in severe Paget disease - tibia is bowed, enlarged, and sclerotic with irregular thickening of both cortical and cancellous bone - Robbins & Kumar Basic Pathology

Other Imaging

• ⁹⁹ᵐTc bone scan: most sensitive modality for identifying active lesions and disease extent; less specific than plain films
• CT: useful for assessment of fracture, cortical detail, and nerve compression
• MRI: necessary when sarcomatous transformation, giant cell tumor, or metastatic disease is suspected in pagetic bone

Morphologic Features

Gross Pathology

• Affected bones are enlarged, thickened, and deformed
• Cortices are soft and porous - lack structural stability
• Coarsely thickened trabeculae
• Cut surface shows increased vascularity

Histology - Phase-Dependent

Phase 1: Osteolytic Phase

• Numerous abnormally large osteoclasts with up to 100 nuclei (normally ≤4)
• Prominent resorption pits (Howship's lacunae)
• Thin trabeculae being actively destroyed
• Some osteoclasts contain intranuclear inclusions (paramyxovirus-like)

Phase 2: Mixed Phase

• Both osteoclasts and osteoblasts active simultaneously
• Osteoblastic new bone formation alongside continued resorption
• Poorly mineralized woven bone being laid down
• Marrow replaced by loose fibrovascular connective tissue rich in osteoprogenitor cells and blood vessels
• Large osteoclasts visible close to areas of new bone formation; extensive marrow fibrosis

Phase 3: Osteosclerotic (Burned-out) Phase

• Hallmark: mosaic pattern of lamellar bone (jigsaw puzzle-like)
• Produced by unusually prominent, haphazardly oriented cement lines joining units of lamellar bone in all directions
• Cell activity decreases; fibrovascular tissue recedes and is replaced by normal marrow
• Coarsely thickened trabeculae; soft, porous cortices

Fig. 26.13 - (A) Mosaic pattern of lamellar bone in Paget disease - the hallmark histologic feature showing jigsaw puzzle-like cement lines. (B) Plain radiograph of severe Paget disease tibia - enlarged, sclerotic, with bowing and irregular trabecular thickening - Robbins, Cotran & Kumar Pathologic Basis of Disease

Complications

1. Fractures

• "Chalk-stick" (transverse) fractures: characteristic of Paget disease; typically involve weight-bearing long bones (femur, tibia)
• Result from structurally inferior woven bone and cortical softening
• Vertebral compression fractures can cause kyphosis or spinal cord injury

2. Secondary Osteoarthritis

• Most common joint affected: hip (from femoral head deformity and protrusio acetabuli)
• Also knee and spine; results from bony deformity distorting joint mechanics

3. Neurologic Complications

• Sensorineural and conductive deafness: most common; temporal bone involvement affecting the ossicles and cochlea
• Spinal stenosis and radiculopathy from vertebral enlargement
• Cranial nerve palsies (VII, II)
• Platybasia with posterior fossa compression
• Spinal cord compression and myelopathy

4. Neoplastic Transformation (most feared)

• Secondary osteosarcoma: occurs in <1% of all Paget disease patients overall, but 5-10% of those with severe polyostotic disease; rapidly fatal with very poor prognosis
• Other tumors: giant cell tumor (especially in ZNF687 mutation carriers), fibrosarcoma, chondrosarcoma
• Suspect when a previously stable lesion rapidly enlarges or becomes increasingly painful

5. Cardiovascular Complications

• High-output cardiac failure: rare; seen in severe polyostotic disease where increased bone vascularity functions as an arteriovenous shunt
• May exacerbate underlying coronary artery disease

6. Hypercalcemia

• Typically only during immobilization (when osteoclastic resorption is uncoupled from osteoblastic deposition) - may precipitate nephrolithiasis

7. Systemic Proteinopathy (VCP mutations)

• Inclusion body myopathy + frontotemporal dementia + ALS in addition to bone disease

Biochemical Markers

Summary