Paget’s disease

Paget’s disease, also known as osteitis deformans, is a chronic disorder of bone remodeling characterized by excessive and disorganized bone turnover. First described by Sir James Paget in 1877, the condition remains one of the most common metabolic bone diseases after osteoporosis. Although its prevalence has declined in some regions, it continues to pose a significant clinical challenge, particularly in older adults.

This article provides a comprehensive overview of Paget’s disease, including its history, epidemiology, pathophysiology, clinical features, diagnostic approach, management strategies, and ongoing research. The aim is to integrate current knowledge for clinicians, researchers, and students interested in metabolic bone disorders.

Historical Background

Sir James Paget, a renowned British surgeon and pathologist, first described the condition in 1877 in a paper titled “On a Form of Chronic Inflammation of Bones (Osteitis Deformans).” He reported patients with enlarged, deformed bones and speculated on an inflammatory etiology. Over time, advances in histology and imaging have revealed that the disease is not primarily inflammatory but rather a disorder of bone remodeling.

Subsequent research clarified that the excessive activity of osteoclasts (bone-resorbing cells) triggers rapid, disorganized bone formation by osteoblasts, leading to structurally abnormal bone.

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Epidemiology

Prevalence

  • Paget’s disease primarily affects older adults, rarely appearing before the age of 40.
  • The prevalence increases with age, peaking in individuals over 70.
  • Historically, the condition was more common in Western Europe (especially the UK), North America, Australia, and New Zealand.

 

Geographic Distribution

  • High prevalence: UK, France, Australia, New Zealand, and parts of North America.
  • Low prevalence: Scandinavia, Asia, and Africa.
  • Recent studies suggest a decline in incidence and severity in previously high-prevalence regions, possibly due to environmental changes or reduced exposure to potential viral triggers.

 

Gender Distribution

Slight male predominance has been consistently reported.

 

Pathophysiology

The hallmark of Paget’s disease is accelerated and disorganized bone remodeling.

Normal Bone Remodeling

  • Osteoclasts resorb bone.
  • Osteoblasts form new bone in an organized fashion.
  • The balance maintains skeletal strength and calcium homeostasis.

 

Disordered Remodeling in Paget’s Disease

1. Excessive Osteoclastic Activity

  • Osteoclasts are unusually large, multinucleated, and hyperactive.
  • This leads to rapid and excessive bone resorption.

 

2. Compensatory Osteoblastic Activity

  • Osteoblasts attempt to repair the resorption sites.
  • New bone is laid down in a haphazard, woven pattern rather than strong lamellar bone.

 

3. Resulting Bone Structure

  • The affected bone is enlarged, deformed, vascular, and fragile.
  • This predisposes patients to deformities, fractures, and complications.

 

Etiological Factors

The exact cause remains uncertain, but several factors are implicated:

Genetic Factors

  • Familial clustering occurs in 10–30% of cases.
  • Mutations in the SQSTM1 gene, which regulates NF-κB signaling and osteoclast activity, are strongly associated.

 

Viral Hypothesis

  • Some researchers propose a slow viral infection (paramyxoviruses such as measles or canine distemper) within osteoclast precursors.
  • Viral-like inclusions have been observed in osteoclasts, but definitive proof remains elusive.

 

Environmental Factors

  • Geographic clustering suggests environmental influences.
  • Reduced prevalence in newer generations may reflect changing environmental exposures.

 

Clinical Manifestations

Paget’s disease is often asymptomatic and detected incidentally through imaging or elevated alkaline phosphatase levels. However, when symptomatic, it produces a wide range of features depending on the bones involved.

General Features

  • Age of onset: Typically >40 years.
  • Course: Chronic, slowly progressive.

 

Symptoms

1. Bone Pain

  • The most common symptom, often dull, deep, and localized.
  • Pain may worsen at night and not always related to activity.

 

2. Skeletal Deformities

  • Tibial bowing (“saber shin”).
  • Enlarged skull leading to frontal bossing and increased hat size.
  • Spinal deformities such as kyphosis.

 

3. Pathological Fractures

Bones are fragile and prone to transverse fractures, especially in long bones.

4. Neurological Complications

  • Skull involvement may cause hearing loss (sensorineural or conductive).
  • Nerve compression can lead to radiculopathy, spinal stenosis, or cranial nerve palsies.

 

5. Vascular Complications

Hypervascular bone can lead to high-output cardiac failure in extensive disease.

6. Arthritis

Adjacent joint involvement leads to secondary osteoarthritis.

7. Neoplastic Transformation

Rarely, Paget’s disease may transform into osteosarcoma or other sarcomas (<1% of cases).

Commonly Affected Sites

  • Pelvis (most common)
  • Lumbar spine
  • Femur
  • Tibia
  • Skull

 

Diagnostic Evaluation

Laboratory Tests

  • Serum Alkaline Phosphatase (ALP): Typically elevated due to increased bone turnover.
  • Calcium and Phosphate: Usually normal unless complicated by other conditions.
  • Bone-specific ALP and other markers (e.g., urinary hydroxyproline, serum PINP): Helpful in monitoring activity.

 

Imaging Studies

1. X-rays

  • Classical findings: cortical thickening, bone enlargement, mixed lytic and sclerotic changes.
  • “Cotton wool” appearance in skull lesions.

 

2. Radionuclide Bone Scan

Highly sensitive for identifying the extent and distribution of disease.

3. CT and MRI

Useful in assessing complications such as fractures, sarcomatous changes, or neural compression.

Differential Diagnosis

  • Osteoporosis
  • Metastatic bone disease
  • Fibrous dysplasia
  • Primary bone tumors

 

Management

The primary goals of treatment are to reduce symptoms, control disease activity, prevent complications, and improve quality of life.

General Principles

  • Asymptomatic patients with limited disease may not require immediate treatment.
  • Indications for treatment include bone pain, risk of fracture, neurological symptoms, progressive deformity, or preparation for orthopedic surgery.

 

Pharmacological Therapy

Bisphosphonates (first-line agents)

Potent inhibitors of osteoclast-mediated bone resorption.

Options:

  • Zoledronic acid (single IV infusion; most effective and long-lasting).
  • Risedronate, alendronate, pamidronate (oral or IV).

 

Benefits:

  • Normalizes ALP in majority of patients.
  • Provides long-term remission.
  • Relieves bone pain.

 

Calcitonin

  • Alternative for patients intolerant to bisphosphonates.
  • Less potent, requires injection, and limited by tachyphylaxis.

 

Symptomatic Management

  • Analgesics and NSAIDs for bone pain.
  • Orthopedic interventions for fractures and deformities.
  • Hearing aids for auditory loss.
  • Cardiac management in cases of high-output heart failure.

 

Monitoring

  • Regular follow-up with ALP levels to assess biochemical remission.
  • Periodic imaging to evaluate structural changes or complications.

 

Prognosis

  • Many patients remain asymptomatic throughout life.
  • With modern bisphosphonates, disease activity can be effectively controlled.
  • Complications such as fractures, deformities, and neurological deficits impact quality of life.
  • Malignant transformation is rare but carries poor prognosis.

 

Paget’s Disease Variants

  • Monostotic Paget’s Disease: Involves a single bone (15–20% of cases).
  • Polyostotic Paget’s Disease: Multiple bones affected, more common and often more symptomatic.

 

Complications

  • Skeletal: Fractures, osteoarthritis, deformities.
  • Neurological: Hearing loss, spinal stenosis, neuropathies.
  • Cardiovascular: High output cardiac failure.
  • Malignancy: Osteosarcoma, fibrosarcoma, chondrosarcoma.

 

Current Research and Future Directions

  • Genetics: Understanding the role of SQSTM1 mutations and other susceptibility genes.
  • Molecular Pathways: NF-κB signaling, RANK/RANKL/OPG system in osteoclast activity.
  • Novel Therapies: Investigational agents targeting osteoclast regulation.
  • Epidemiological Trends: Ongoing studies to understand the declining incidence.

 

Conclusion

Paget’s disease is a fascinating and complex disorder of bone remodeling with significant historical, clinical, and scientific importance. Though less prevalent today in many regions, it remains an important consideration in older adults presenting with bone pain, deformities, or elevated alkaline phosphatase.

Advances in genetics and molecular biology have illuminated potential mechanisms, while modern therapies such as potent bisphosphonates have revolutionized management. Continued research is crucial to fully unravel the etiology, improve treatment, and further reduce the disease burden.