Paget Disease

• Paget disease of bone (PDB), also known as osteitis deformans, is a chronic focal disorder of bone remodeling that is characterised by excessive and disorganised bone turnover.
• The disease involves accelerated bone resorption by abnormal osteoclasts, followed by disorganised bone formation by osteoblasts, leading to structurally weakened, enlarged, and highly vascular bone.

Genetic Factors

• Familial Aggregation: Paget disease of bone (PDB) exhibits a strong genetic component, with a positive family history reported in 12–40% of cases. Studies suggest an autosomal dominant inheritance pattern with variable penetrance.
• Genetic Loci: Genome-wide association studies have identified multiple loci linked to PDB, including SQSTM1, TNFRSF11A (RANK), CSF1, and OPTN.
• SQSTM1 Mutations: Mutations in the SQSTM1 gene, which encodes the sequestosome-1 protein, are detected in 30–50% of familial cases and in 5–10% of sporadic cases.
• Autophagy Genes: Mutations in genes involved in autophagy, such as VCP, OPTN, and ATG16L1, have been implicated in PDB pathogenesis, suggesting a possible role of disrupted protein degradation in osteoclast function.
• Cytokine Alterations: Increased expression of IL-6, RANKL, and M-CSF in PDB-affected bone suggests a dysregulated osteoclast activation process.
  
  

Environmental Factors

• Declining Incidence: The prevalence of PDB has declined significantly over recent decades, suggesting a role for environmental triggers.
• Geographic Clustering: PDB is most common in Europe, North America, Australia, and New Zealand, while rare in Asia and Africa, further supporting an environmental influence.
  
  

Viral Hypothesis

• Paramyxoviruses: Evidence from histopathological studies suggests that measles virus, canine distemper virus, and respiratory syncytial virus could be associated with PDB, as viral inclusions have been detected in osteoclasts.
• Uncertain Role: Despite these findings, no direct causative link has been confirmed, and studies using RT-PCR have failed to consistently detect viral RNA in pagetic bone.
• Measles Virus Nucleocapsid Protein (MVNP): Experimental models show that overexpression of MVNP in osteoclasts induces a pagetic phenotype, supporting the hypothesis that viral infections might trigger the disease in genetically susceptible individuals.
  
  

Coal and Environmental Toxins

• Bituminous Coal Exposure: A strong correlation has been noted between domestic coal use and PDB prevalence, particularly in areas with historical coal burning.
• Toxic Elements: Coal combustion releases polycyclic aromatic hydrocarbons, arsenic, cadmium, chromium, and cobalt, all of which have the potential to influence bone metabolism and osteoclast activity.

Phases of Disease Progression

1. Lytic Phase:
   • Dominated by abnormal osteoclastic activity, with osteoclasts appearing larger, more numerous, and multinucleated (up to 100 nuclei compared to the normal 5–10).
   • Bone resorption is excessive, leading to large irregular resorption pits.
   • Bone turnover rates may increase up to 20 times normal levels.
2. Mixed Phase (Lytic and Blastic):
   • Marked by simultaneous osteoclastic resorption and osteoblastic formation.
   • Osteoblasts increase in number, producing disorganised woven bone rather than structured lamellar bone.
   • The randomly oriented collagen fibers contribute to the formation of a weakened, structurally abnormal bone matrix.
3. Sclerotic (Burned-Out) Phase:
   • Osteoclastic activity declines, while osteoblasts continue abnormal bone formation.
   • Thickened, hypervascular bone replaces normal bone, leading to bone expansion and increased fragility.
   • Bone marrow is progressively infiltrated by fibrous connective tissue and blood vessels, contributing to increased bone vascularity.
     
     

Cellular and Molecular Mechanisms

• Osteoclast Hyperactivity:
  • Osteoclasts in PDB demonstrate increased responsiveness to RANKL (receptor activator of nuclear factor kappa-B ligand), leading to enhanced bone resorption.
  • Osteoprotegerin (OPG), a natural inhibitor of RANKL, is often downregulated, exacerbating osteoclast activation.
  • Increased expression of inflammatory cytokines (IL-6, RANKL, and M-CSF) further stimulates osteoclastogenesis.
• Abnormal Osteoblastic Function:
  • Pagetic osteoblasts produce woven bone instead of organised lamellar bone, predisposing bones to microfractures and deformities.
  • The increased bone turnover accelerates the deposition of structurally weak bone, making it less resilient to mechanical stress.
• Vascular and Connective Tissue Changes:
  • The increased hypervascularity of affected bone may lead to erythema, localised warmth, and high-output cardiac failure in severe cases.
  • Fibrosis of bone marrow contributes to altered hematopoiesis and reduced bone strength.
    
    

• Axial skeleton predominance: The spine, pelvis, femur, sacrum, and skull are most frequently involved.
• Long bone deformities: Bowing of the femur and tibia can occur due to structural weakness.
• Skull involvement: Leads to cranial nerve compression, resulting in hearing loss, tinnitus, vertigo, and basilar invagination.
  
  

• Pathological Fractures: Weakened bones are susceptible to stress fractures, particularly in weight-bearing bones.
• Neurological Complications: Vertebral involvement may lead to nerve root compressions, cauda equina syndrome, or spinal stenosis.
• Secondary Osteoarthritis: Joint mechanics are disrupted by bone deformities, increasing the risk of osteoarthritis.
• Malignant Transformation: Rarely, pagetic bone can undergo sarcomatous degeneration, leading to osteosarcoma.
  
  

Biochemical Markers of Disease Activity

• Bone-Specific Alkaline Phosphatase (BSAP) – A marker of osteoblastic activity and bone formation.
• N-Telopeptide of Type I Collagen (NTx) – Reflects bone resorption.
• Deoxypyridinoline – A biochemical indicator of collagen degradation.
• C-Telopeptide Fragments (α-CTX and β-CTX) – Specific markers of bone resorption.
• Serum Osteocalcin – Not a reliable marker in PDB, as it does not correlate well with disease activity.

Global Prevalence

• Paget disease of bone (PDB) is the second most common metabolic bone disorder after osteoporosis.
• Estimated prevalence varies significantly by region, with higher rates in Western Europe, North America, Australia, and New Zealand, and lower rates in Asia and Africa.
• In the UK, prevalence is approximately 2%, while in continental Europe, rates are lower, around 0.3%.
• In the United States, PDB affects 1–3 million individuals, with an estimated prevalence of 1% in the general population and up to 2.3% in those aged 65–74 years.
• Prevalence is highest in individuals over 55 years, with rates reaching up to 9% in elderly populations in some regions.
  
  

Regional Variability

• Europe:
  • Highest prevalence is observed in England (4.6%) and France (2.4%) among hospitalized patients aged 55 and older.
  • Rates decrease from north to south, with Norway and Sweden having particularly low prevalence (0.3%).
  • Some British cities report rates of 2%, but localised clusters such as Lancaster, England, report a prevalence of 8.3%.
• North America:
  • PDB is most common in the northeastern United States and least common in the southern regions.
• Australia and New Zealand:
  • High prevalence, estimated at 3–4% in some populations.
• Asia and Africa:
  • Extremely rare, with prevalence below 0.02% in sub-Saharan Africa and Asia.
• South America:
  • Argentina (Buenos Aires) has a relatively high prevalence, likely due to Spanish and Italian ancestry, whereas rates in Chile and Venezuela are much lower.
    
    

Age and Sex Differences

• PDB primarily affects older individuals, with most cases diagnosed after age 55.
• The incidence increases with age, reaching 10% in individuals over 80 years.
• There is a slight male predominance, with a male-to-female ratio of approximately 1.8:1.
  
  

Historical Trends

• Declining Prevalence:
  • Reports suggest a significant decline in both prevalence and severity of PDB since the 1990s.
  • The UK incidence rate has decreased from 0.75 per 10,000 person-years in 1999 to 0.20 per 10,000 person-years in 2015.
  • Similar trends have been observed in Europe and New Zealand, likely due to environmental changes and possibly reduced exposure to infectious agents.
    
    

Detection and Diagnosis Challenges

• Many cases remain asymptomatic, leading to underestimation of true prevalence.
• Historically, prevalence estimates were based on autopsy studies, radiographic surveys, and biochemical markers.
• Serum alkaline phosphatase (sAP), commonly used as a marker for PDB, may miss monostotic cases, leading to an underdiagnosis in population studies.
  
  

General Overview

• Majority of cases are asymptomatic, with incidental diagnosis based on elevated serum alkaline phosphatase or radiographic abnormalities.
• When symptomatic, pain is the most common complaint, followed by bone deformities, fractures, and neurological complications.
• Symptoms vary based on skeletal site involvement and disease progression.
  
  

Common Symptoms

1. Bone Pain:
   • Most frequent symptom and often mild to moderate, deep, aching.
   • Persists at rest and may worsen with weight-bearing.
   • Possible causes:
     • Microfractures in weight-bearing bones.
     • Periosteal irritation due to bone enlargement and hypervascularity.
     • Osteoarthritis from altered joint mechanics.
2. Deformities and Skeletal Involvement:
   • Bone overgrowth and deformities may lead to:
     • Bowing of long bones (femur, tibia).
     • Frontal bossing and skull enlargement (patients may report an increase in hat size).
     • Spinal kyphosis or compression fractures.
3. Fractures:
   • Pathologic fractures occur in weakened pagetic bone, commonly in:
     • Subtrochanteric femur (most affected site).
     • Tibia, humerus, and pelvis.
   • Nonunion and refractures are common.
4. Neurological Symptoms (Due to Nerve Compression or Skull Involvement):
   • Hearing Loss (seen in up to 30–50% of cases with skull involvement).
   • Tinnitus and Vertigo (associated with inner ear involvement).
   • Radiculopathy and Chronic Back Pain (due to spinal stenosis or nerve root compression).
   • Headaches (from thickened skull or increased intracranial pressure).
   • Facial Pain and Malocclusion (from maxillary or mandibular overgrowth).
   • Hydrocephalus and Brainstem Compression (may cause ataxia, syncope, and cognitive decline).
5. Arthritis and Joint Symptoms:
   • Osteoarthritis develops in 40–50% of cases due to joint malalignment and mechanical stress.
   • Knee and hip pain due to acetabular protrusion or femoral bowing.
   • Increased risk of joint replacement surgery.
6. Rare but Serious Complications:
   • High-Output Heart Failure: Occurs rarely in severe, polyostotic disease due to increased bone vascularity.
   • Excessive Bleeding: Risk is higher during orthopedic procedures because of hypervascular pagetic bone.
   • Malignant Transformation: Osteosarcoma is a rare but serious complication (presents as rapidly worsening bone pain and a soft-tissue mass).

General Findings

• Many patients are asymptomatic, and physical examination findings may be normal, especially in early or mild cases.
• When symptomatic, visible skeletal deformities and localised symptoms are the most prominent clinical findings.
  
  

Skeletal Deformities and Bone Changes

1. Skull Involvement:
   • Frontal bossing and skull enlargement, leading to an increase in head size (patients may report a need for larger hats).
   • Facial bone changes including maxillary or mandibular overgrowth, which may cause malocclusion, dental crowding, or loose teeth.
   • Temporal bone involvement may cause external auditory canal narrowing, leading to conductive hearing loss.
2. Spine and Axial Skeleton:
   • Spinal kyphosis or lordosis due to vertebral remodeling.
   • Palpable vertebral tenderness in cases with active lesions.
   • Neurological deficits (in advanced cases) due to spinal stenosis or nerve root compression, presenting as muscle weakness, gait disturbances, or radiculopathy.
3. Long Bone Changes:
   • Bowing deformities:
     • Anterior bowing of the tibia (saber shin deformity).
     • Anterolateral bowing of the femur.
   • Enlarged, thickened long bones, often warm to the touch due to hypervascularity.
   • Localised pain and tenderness over affected bones.
4. Joint and Soft Tissue Findings:
   • Restricted joint mobility due to adjacent bone overgrowth.
   • Secondary osteoarthritis, especially in hips and knees.
   • Palpable swelling or warmth over affected bones due to increased vascularity.
   • Tophi may be present in cases with concurrent gout.
     
     

Neurological Findings

• Hearing Loss:
  • Common with skull involvement, caused by middle ear ossicle sclerosis or compression of cranial nerve VIII.
  • Tinnitus and vertigo may be present.
• Cranial Nerve Palsies:
  • Facial nerve (CN VII) compression leading to facial weakness.
  • Optic nerve involvement (CN II) in advanced skull disease may result in visual disturbances.
• Spinal Cord and Nerve Compression:
  • Lumbar spine involvement can cause cauda equina syndrome, with bladder or bowel dysfunction.
  • Thoracic spine lesions may result in myelopathy or paraparesis.
    
    

Fractures and Vascular Findings

• Pathological fractures:
  • Commonly affect the femur, tibia, pelvis, and spine.
  • Subtrochanteric femur fractures are the most frequently observed.
  • Transverse fractures perpendicular to the cortex are characteristic.
• Hypervascularity of Pagetic Bone:
  • Warmth over affected areas due to increased blood flow.
  • Auscultation may reveal bruits, particularly in the skull and tibia.
  • Excessive bleeding risk during surgery due to increased vascularity.
    
    

Primary Diagnostic Investigations

1. Plain Radiography (X-ray)
   • First-line imaging for suspected Paget disease.
   • Findings depend on disease stage:
     • Early-stage: Predominantly lytic lesions; osteoporosis circumscripta in the skull.
     • Progressive-stage: Mixed lytic and sclerotic changes, V-shaped ("blade of grass") lytic lesions in long bones.
     • Advanced-stage: Thickened trabeculae, cortical thickening, and bone expansion.
   • Common sites: Pelvis, skull, spine, femur, and tibia.
   • Fractures: Typically transverse and perpendicular to the cortex in weight-bearing bones.
2. Radionuclide Bone Scan (Technetium-99m Scan)
   • Most sensitive for detecting all affected sites, even asymptomatic ones.
   • Shows increased isotope uptake in active lesions due to high bone turnover.
   • Not specific for PDB; requires correlation with X-rays to confirm diagnosis.
   • Used to monitor treatment response (but not routinely recommended for serial follow-ups).
3. Serum Alkaline Phosphatase (sAP)
   • Key biochemical marker of bone turnover.
   • Elevated in 85–100% of cases but may be normal in monostotic disease.
   • Used to assess disease activity and response to therapy.
4. Bone-Specific Alkaline Phosphatase (BSAP)
   • More specific for bone formation than total sAP.
   • Preferred in patients with liver disease, where total sAP may be misleading.
5. Urinary and Serum Bone Resorption Markers
   • N-Telopeptide (NTx) and C-Telopeptide (CTx): Indicators of collagen breakdown.
   • Deoxypyridinoline: A marker of bone resorption.
   • Procollagen Type I N-Terminal Propeptide (P1NP): Reflects bone formation.
   • Used to track treatment response, especially in patients with normal sAP.
     
     

Secondary Investigations

1. Serum Calcium and Phosphate
   • Typically normal, but hypercalcemia may occur in immobilised patients.
   • Hyperphosphatemia is not characteristic of Paget disease.
2. Liver Function Tests
   • Performed to rule out hepatic causes of elevated alkaline phosphatase.
3. Serum 25-Hydroxyvitamin D
   • Measured to exclude vitamin D deficiency or osteomalacia.
4. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI)
   • Not required for diagnosis but useful in cases of:
     • Spinal stenosis.
     • Basilar invagination of the skull.
     • Suspected neoplastic transformation (osteosarcoma or giant cell tumor).
   • CT is superior for bone details, while MRI is preferred for soft tissue involvement.
5. Bone Biopsy
   • Rarely needed but indicated in:
     • Unusual lesions not showing classic radiographic findings.
     • Atypical monostotic lesions in patients from regions where PDB is rare.
     • Suspected sarcomatous transformation, presenting with progressive bone pain and soft tissue mass.
       
       

Osteoarthritis

• Similarities with PDB:
  • Joint pain and stiffness, particularly in weight-bearing joints.
  • Secondary osteoarthritis can develop in patients with Paget disease due to bone deformities affecting joint mechanics.
• Distinguishing Features:
  • PDB: Bone deformity, cortical thickening, and increased trabecular pattern on imaging.
  • Osteoarthritis: Joint space narrowing, osteophytes, and subchondral sclerosis; absence of primary bone overgrowth.
    
    

Osteoporosis

• Similarities with PDB:
  • Both conditions present in older adults and increase fracture risk.
  • May coexist in the same patient.
• Distinguishing Features:
  • PDB: Focal areas of bone enlargement, cortical thickening, and high bone turnover markers.
  • Osteoporosis: Generalized reduction in bone mass with normal bone architecture; fractures are typically vertebral compression or femoral neck fractures.
    
    

Osteomalacia

• Similarities with PDB:
  • Bone pain, increased alkaline phosphatase levels.
• Distinguishing Features:
  • PDB: Elevated alkaline phosphatase with normal calcium and phosphate levels; radiographic changes include mixed lytic and sclerotic lesions.
  • Osteomalacia: Low serum 25-hydroxyvitamin D levels; radiographs may show Looser’s zones (pseudofractures).
    
    

Fibrous Dysplasia

• Similarities with PDB:
  • Bone deformities, pain, and increased bone turnover markers.
• Distinguishing Features:
  • PDB: Polyostotic disease involving spine, pelvis, skull, and long bones; characteristic "cotton wool" appearance on skull radiographs.
  • Fibrous Dysplasia: Ground-glass appearance on radiographs, absence of trabecular thickening, and lack of bone expansion.
    
    

Primary or Metastatic Bone Malignancies

• Similarities with PDB:
  • Bone pain, pathological fractures, increased bone turnover markers.
• Distinguishing Features:
  • PDB: No periosteal reaction or soft tissue mass; lesions remain stable over time.
  • Malignancy: Aggressive lytic lesions, periosteal reaction, and soft tissue involvement; elevated serum calcium may be present in metastatic bone disease.
    
    

Renal Osteodystrophy

• Similarities with PDB:
  • Bone pain, increased alkaline phosphatase, and secondary bone deformities.
• Distinguishing Features:
  • PDB: Localized bone lesions with thickened trabeculae.
  • Renal Osteodystrophy: Diffuse skeletal involvement, secondary hyperparathyroidism, and elevated phosphate levels.
    
    

Key Investigations for Differentiation

• Serum 25-Hydroxyvitamin D → Low in osteomalacia, normal in PDB.
• Bone-Specific Alkaline Phosphatase (BSAP) → Elevated in PDB and fibrous dysplasia, but with different imaging patterns.
• Serum Calcium and Phosphate → Abnormal in osteomalacia and renal osteodystrophy; normal in PDB.
• Imaging:
  • X-ray: Paget’s disease shows thickened cortices, trabecular coarsening, and bone expansion.
  • Bone Scan: Increased uptake in PDB; useful for mapping extent of disease.
    
    

Treatment Goals

• Reduce excessive bone turnover and osteoclastic activity.
• Alleviate pain and skeletal deformities.
• Prevent complications, such as fractures, neurological compression, and osteoarthritis.
• Improve quality of life and minimise disease progression.
  
  

Indications for Treatment

• Symptomatic patients with bone pain, fractures, deformities, or secondary osteoarthritis.
• Patients with high-risk skeletal sites, including:
  • Skull (to prevent cranial nerve compression and hearing loss).
  • Spine (to reduce risk of vertebral fractures and spinal stenosis).
  • Weight-bearing bones (to prevent bowing and pathological fractures).
  • Bones adjacent to joints (to mitigate mechanical joint dysfunction).
• Preoperative therapy: Treatment before orthopedic surgery (e.g., hip or knee arthroplasty) to reduce bleeding risk.
  
  

Pharmacological Treatment

• Most effective drugs for PDB, acting as potent inhibitors of bone resorption.
• Preferred agents:
  • Zoledronic acid (5 mg IV, single infusion) – Most effective, induces biochemical remission in 96% of patients.
  • Risedronate (30 mg/day for 60 days, oral) – Second-line option for those avoiding IV therapy.
  • Alendronate (40 mg/day for 6 months, oral) – Effective but requires prolonged use.
  • Pamidronate (IV infusion over 2–4 days) – Less potent than zoledronic acid, used in select cases.
• Efficacy:
  • Reduces bone pain and normalises alkaline phosphatase (sAP).
  • Prevents disease progression and skeletal complications.
• Adverse effects:
  • Acute-phase reactions (flu-like symptoms) – More common with IV bisphosphonates.
  • Gastrointestinal intolerance (oral bisphosphonates).
  • Osteonecrosis of the jaw (ONJ) – Rare, but requires dental assessment before therapy.
  • Hypocalcemia – Calcium and vitamin D supplementation is necessary to prevent deficiency.
    
    

• Indicated for patients who cannot tolerate bisphosphonates.
• Subcutaneous or intranasal formulations available.
• Less potent than bisphosphonates, primarily used for pain relief.
• Adverse effects: Flushing, nausea, and antibody formation.
  
  

Supportive and Adjunctive Therapy

1. Physiotherapy & Rehabilitation:
   • Improves mobility and strength.
   • Walking aids and orthotics may be required for deformities.
2. Pain Management:
   • Analgesics (NSAIDs, acetaminophen) for symptomatic relief.
   • Opioids reserved for severe pain unresponsive to other treatments.
3. Hearing Aids:
   • Early use recommended for patients with progressive hearing loss due to skull involvement.
     
     

Surgical Treatment

• Indications:
  • Pathological fractures requiring fixation.
  • Severe joint arthritis needing total joint replacement.
  • Spinal stenosis with nerve compression → laminectomy or decompression surgery.
  • Severe long bone deformities → corrective osteotomy.
• Preoperative bisphosphonate therapy recommended to reduce surgical bleeding.
  
  

Monitoring and Retreatment

• Serum Alkaline Phosphatase (sAP) every 6–12 months to track disease activity.
• Bone scans and X-rays as needed for progressive symptoms.
• Retreatment Criteria:
  • Recurrence of pain or elevated sAP.
  • Worsening radiographic changes.
  • Newly affected skeletal sites.

General Prognosis

• Paget disease of bone (PDB) is a chronic but manageable disorder.
• Early treatment improves outcomes, reducing complications such as bone pain, fractures, and deformities.
• Disease control is possible, but PDB is not curable, and recurrence may occur over time.
• Asymptomatic patients often have a stable prognosis, while symptomatic, polyostotic disease carries a higher risk of complications.
  
  

Factors Influencing Prognosis

1. Extent of Disease:
   • Monostotic disease (involving a single bone) has a better prognosis.
   • Polyostotic disease (multiple bones affected) is associated with higher morbidity due to increased risk of fractures, joint dysfunction, and neurological complications.
2. Response to Treatment:
   • Bisphosphonates effectively control disease activity, often leading to long-term remission.
   • Patients who achieve normal alkaline phosphatase levels after treatment tend to have better long-term outcomes.
3. Risk of Complications:
   • Fractures: PDB weakens bones, increasing fracture risk, particularly in weight-bearing bones.
   • Osteoarthritis: Joint degeneration due to abnormal bone remodeling is a major cause of morbidity.
   • Neurological complications: Hearing loss, spinal stenosis, and cranial nerve compression impact quality of life.
   • High-output cardiac failure: A rare but serious complication in cases with severe polyostotic disease.
   • Excessive bleeding: Hypervascularity of pagetic bone may lead to significant intraoperative hemorrhage during surgery.
     
     

Prognosis in Malignant Transformation

• Osteosarcoma is a rare but devastating complication of Paget disease.
• Occurs in <1% of cases, but carries an extremely poor prognosis.
• 5-year survival rate:
  • 5–7.5% in advanced cases.
  • Up to 50% in localised cases treated with early tumor ablation and chemotherapy.
• Multicentric sarcomas and axial skeleton involvement have worse outcomes.
  
  

Long-Term Outlook

• Patients with controlled disease can maintain good quality of life with pain management and supportive therapy.
• Hearing loss and bone deformities are often irreversible, even with treatment.
• Regular monitoring is essential to detect disease recurrence and prevent complications.

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