What is Paget's disease of bone?

Paget's Disease of Bone: Overview

Definition and Pathophysiology

Paget's disease of bone (PDB) is a focal skeletal disorder characterized by disorganized bone remodeling, where excessive osteoclast-mediated bone resorption is followed by compensatory but chaotic bone formation, resulting in structurally weakened, enlarged, and highly vascular bone. 1, 2

• The disease affects 1-2% of the population, typically those over 55 years of age 1
• The pathologic process begins with increased osteoclast activity, recruiting numerous osteoblasts that produce large quantities of disorganized bone matrix in a mosaic pattern of woven and lamellar bone 3, 2
• The most likely etiology involves a slow paramyxoviral infection in genetically susceptible individuals, though the exact cause remains unknown 2
• The disease has a strong genetic component with familial clustering 4

Clinical Presentation

Most patients with Paget's disease are asymptomatic, with diagnosis often made incidentally through elevated serum alkaline phosphatase or characteristic radiographic findings. 1, 2

Common Symptomatic Presentations:

• Bone pain is the most frequent presenting symptom 1, 3
• Bone deformities including bowing of long bones and enlarged skull 4, 2
• Pathological fractures due to structurally weakened bone 1, 3
• Secondary osteoarthritis at affected sites 4
• Nerve compression syndromes including hearing loss/deafness 4, 2

Skeletal Distribution:

• The disease may be monostotic (single bone) or polyostotic (multiple bones) 3
• Most commonly affects the pelvis, femur, spine, tibia, skull, and humerus 3

Diagnostic Approach

Initial Evaluation:

Simple radiographs of suspected skeletal regions should be obtained as the first-line investigation, showing a characteristic mixed osteolytic and osteosclerotic appearance. 5

Biochemical Testing:

• Total serum alkaline phosphatase (ALP) is the primary biochemical screening test and should be performed in combination with liver function tests 5
• Elevated ALP correlates with disease activity 2
• More specific markers such as PINP (procollagen type I N-terminal propeptide) or CTX (C-terminal telopeptide) can be used as needed 5

Imaging Studies:

• Bone scintigraphy with radionuclides should be used to determine the full extent of disease once diagnosis is confirmed 5
• Nuclear scintigraphy is the most sensitive test for detecting pagetic lesions 2

Key Diagnostic Features:

The diagnosis is distinguished from other pathologies by: 5, 6

• Family history of Paget's disease
• Typical localization to pelvis or skull
• Elevated alkaline phosphatase
• Bone deformities
• Typical age of onset over 50 years
• Mixed osteolytic/sclerotic lesions on imaging

Treatment

First-Line Therapy:

Bisphosphonates are the mainstay of treatment for Paget's disease, with zoledronic acid 5 mg as a single intravenous dose being the treatment of choice for patients without contraindications. 5, 1

Specific Bisphosphonate Options:

Zoledronic acid:

• Single infusion leads to sustained reduction in bone pain and markers of bone turnover 1
• Most effective agent available 1

Pamidronate:

• Has sustained effects for months following a single injection 7, 5
• Recommended dose: 30 mg per day by infusion over 4 hours for 3 consecutive days (total dose 90 mg) 5

Risedronate:

• Effective for Paget's disease but contraindicated in patients with GFR <30 ml/min/1.73 m² 7

Alendronate:

• Not recommended in patients with GFR <35 ml/min/1.73 m² 7

Treatment Indications:

Treatment is mandatory for all symptomatic patients at diagnosis. 8

For asymptomatic patients: 1, 8

• Bisphosphonates should be reserved for symptomatic patients, as treatment has been associated with increased fracture rates in asymptomatic PDB 1
• However, given the safety and long-term efficacy of potent intravenous bisphosphonates like zoledronate, many experts suggest treating most if not all cases at diagnosis, particularly those with active disease at sites where complications are likely to develop 8, 3

Alternative Therapy:

• Patients who do not tolerate bisphosphonates can be treated with calcitonin 2

Critical Precautions:

It is extremely important to ensure sufficient calcium and vitamin D levels before and during treatment to prevent hypocalcemia, with regular monitoring of serum creatinine and periodic evaluation of treatment response. 5

Complications

Common Complications:

• Bowing deformity of long bones 3
• Pathological fractures 3
• Nerve compression syndromes including deafness 3, 4
• Secondary osteoarthritis 4

Rare but Serious:

• Malignant degeneration (sarcomatous transformation) is a rare complication occurring in 2-5% of cases, often associated with pre-existing Paget's disease 9, 3
• These malignant spindle cell sarcomas typically present in older patients and require treatment strategies similar to osteosarcoma 9

Important Clinical Caveats

• Pain in Paget's disease can arise not only from increased bone turnover but also from complications such as osteoarthritis and nerve compression, which do not respond well to antiresorptive therapy alone 4
• Many patients require additional therapy with analgesics and anti-inflammatory agents 4
• Currently available treatments have not been proven to prevent complications such as deafness, fracture, or bone deformity, or to alter the natural history of the disease 4
• The progressive nature of the disease and severity of potential complications must be weighed against treatment risks when managing asymptomatic patients 3