Paget Disease

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.
• Present in 5–10% of sporadic cases.

Autophagy genes

• Mutations in autophagy-related genes such as VCP, OPTN, and ATG16L1 have been implicated in PDB pathogenesis.
• Suggests disrupted protein degradation contributes to abnormal osteoclast function.

Cytokine alterations

• Increased expression of IL-6, RANKL, and M-CSF in pagetic bone.
• Indicates dysregulated osteoclast activation.

Environmental Factors

Declining incidence

• Prevalence of PDB has declined significantly over recent decades.
• Suggests that environmental triggers may play a role.

Geographic clustering

• PDB is most common in Europe, North America, Australia, and New Zealand.
• Rare in Asia and Africa, supporting environmental influence.

Viral Hypothesis

Paramyxoviruses

• Histopathological studies suggest involvement of measles virus, canine distemper virus, and respiratory syncytial virus.
• Viral inclusions have been detected in osteoclasts in affected bone.

Uncertain role

• No consistent detection of viral RNA using RT-PCR.
• Direct causative link remains unconfirmed.

Measles virus nucleocapsid protein (MVNP)

• Experimental models show overexpression of MVNP in osteoclasts induces a pagetic phenotype.
• Supports the hypothesis that viruses may trigger disease in genetically predisposed individuals.

Coal and Environmental Toxins

Bituminous coal exposure

• Strong correlation noted between domestic coal use and PDB prevalence.
• Particularly evident in regions with historical coal burning.

Toxic elements

• Coal combustion releases polycyclic aromatic hydrocarbons, arsenic, cadmium, chromium, and cobalt.
• These elements can influence bone metabolism and osteoclast activity.

Phases of Disease Progression

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.

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 fibres contribute to the formation of a weakened, structurally abnormal bone matrix.

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.
• Osteoprotegerin (OPG), a natural inhibitor of RANKL, is often downregulated.
• Increased expression of IL-6, RANKL, and M-CSF stimulates osteoclastogenesis.

Abnormal osteoblastic function

• Pagetic osteoblasts produce woven bone instead of lamellar bone.
• Structurally weak bone is deposited, reducing mechanical resilience.

Vascular and connective tissue changes

• Hypervascular bone may cause erythema, warmth, and high-output cardiac failure.
• Marrow fibrosis alters haematopoiesis and bone strength.

Affected Skeletal Sites

• Axial skeleton predominance: spine, pelvis, femur, sacrum, and skull.
• Long bone deformities: femoral and tibial bowing.
• Skull involvement: cranial nerve compression, hearing loss, vertigo, basilar invagination.

Complications of Paget Disease

Pathological fractures

• Weakened bones are susceptible to stress fractures, particularly in weight-bearing bones.
• Result in pain, reduced mobility, and impaired quality of life.

Neurological complications

• Vertebral involvement may compress nerves, causing cauda equina or spinal stenosis.
• Skull deformities may impinge cranial nerves.

• Bone deformities disrupt joint mechanics.
• Increased risk of premature osteoarthritis.

Malignant transformation

• Rare development of osteosarcoma in pagetic bone.
• Associated with worsening pain and poor prognosis.

Biochemical Markers of Disease Activity

Bone-specific alkaline phosphatase (BSAP)

• Marker of osteoblastic activity.

N-telopeptide of type I collagen (NTx)

• Reflects bone resorption.

Deoxypyridinoline

• Indicates collagen degradation.

C-telopeptide fragments (α-CTX and β-CTX)

• Specific to bone resorption.

Serum osteocalcin

• Unreliable in PDB; does not correlate 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 hospitalised 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.
• 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.

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.

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.

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.

Fractures

• Pathologic fractures occur in weakened pagetic bone, commonly in:
  • Subtrochanteric femur (most affected site).
  • Tibia, humerus, and pelvis.
• Nonunion and refractures are common.

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).

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.

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 orthopaedic 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

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.

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.

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.

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

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.

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).

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.

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.

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

Serum Calcium and Phosphate

• Typically normal, but hypercalcemia may occur in immobilised patients.
• Hyperphosphatemia is not characteristic of Paget disease.

Liver Function Tests

• Performed to rule out hepatic causes of elevated alkaline phosphatase.

Serum 25-Hydroxyvitamin D

• Measured to exclude vitamin D deficiency or osteomalacia.

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 tumour).
• CT is superior for bone details, while MRI is preferred for soft tissue involvement.

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: Generalised 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: Localised 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 orthopaedic surgery (e.g., hip or knee arthroplasty) to reduce bleeding risk.

Pharmacological Treatment

Bisphosphonates (First-Line Therapy)

• 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.
  • Hypocalcaemia – Calcium and vitamin D supplementation is necessary to prevent deficiency.

Calcitonin (Second-Line Therapy)

• 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

Physiotherapy & Rehabilitation

• Improves mobility and strength.
• Walking aids and orthotics may be required for deformities.

Pain Management

• Analgesics (NSAIDs, acetaminophen) for symptomatic relief.
• Opioids reserved for severe pain unresponsive to other treatments.

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

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.

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.

Risk of Complications

• Fractures: PDB weakens bones, increasing fracture risk, particularly in weight-bearing bones.
• Osteoarthritis: Joint degeneration due to abnormal bone remodelling 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 haemorrhage 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 tumour 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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