Paget's disease of the bone is a condition of dysregulated bone remodeling, characterized by rapid osteoclastic bone resorption followed by increased osteoblastic bone formation. The resulting new bone is dense but structurally weak. The spine, skull, pelvis, femur, and tibia are the most common sites of disease. Bone overgrowth may cause pain, arthritis, and deformities (the latter giving rise to the condition’s historical name, osteitis deformans). The bone in Paget's disease is also susceptible to fracture. Although rare, a region of bone affected by Paget's disease can undergo malignant transformation into a sarcoma. Many cases of Paget’s disease are asymptomatic and detected incidentally on radiographs.

Structure and Function

Paget’s disease may affect any bone in the body, though the pelvis, spine, skull, femur, and tibia are most commonly affected.

Paget’s disease encompasses three phases: lytic, mixed, and sclerotic. During the lytic phase, osteoclastic resorption predominates. In the mixed phase, equal rates of bone resorption and bone formation occur simultaneously (Figure 1). In the sclerotic phase, osteoblastic bone formation predominates. All three phases of Paget’s disease may occur simultaneously in the same bone.

Paget’s disease encompasses three phases: lytic, mixed, andsclerotic. During the lytic phase, osteoclastic resorption predominates. In the mixed phase, equal rates of bone resorption and bone formation occursimultaneously (Figure 1). In the sclerotic phase, osteoblastic bone formation predominates. All three phases of Paget’s disease may occur simultaneously in the same bone.

Figure 1: Paget’s disease under light microscopy. (Left) Low-power magnification reveals a predominance of lamellar bone. (Right) High-power magnification reveals both prominent osteoblastic and osteoclastic activity. Many nuclei are visible within osteoclasts. (Courtesy of Human Pathology Reports Volume 26, November 2021, 300562)

Patient Presentation

Individuals with Paget’s disease may be asymptomatic and diagnosed incidentally. Other individuals may experience pain and swelling of the affected extremity. Acute onset pain may be caused by pathologic fracture of the affected bone.

The bone overgrowth seen in Paget’s disease may cause spinal stenosis, with resulting lower extremity or spinal signs and symptoms.
Additionally, patients may present with abnormal angulation or bowing (Figure 2).

Increased bone formation in the skull can lead to cranial nerve compression, resulting in hearing loss and vision changes. Increased bone formation in the skull can also cause loosening of the teeth.

Individuals with Paget’s disease may develop high-output heart failure secondary to increased blood flow within the bones.

The most serious complication of Paget’s disease is the transformation of a lesion into a malignant tumor, such as osteosarcoma. Other tumors such as fibrosarcomas or chondrosarcomas may also develop. Thus, if a known Paget’s patient develops acute worsening pain and swelling of the affected extremity, a clinician must suspect and rule out malignant transformation.

Objective Evidence

X-rays are often the initial imaging modality used to evaluate patients for Paget’s disease. The affected bone may demonstrate different radiographic findings depending on which phase is occurring.

During the lytic phase, there are regions of lucency with thinned cortices from the increased osteoclastic resorption. These areas are often described as a “blade of grass” or “flame-shaped” (Figure 3).

During the sclerotic phase, there are thickened cortices due to the increased osteoblastic activity and subsequent bony formation.

During the mixed phase, there are regions suggestive of both the lytic and sclerotic phases (Figure 4).

Pathologic fractures may be identified as a result of weakened bone from increased osteoclastic resorption.

Classically, “cotton wool exudates” may be observed in the skull–a highly specific finding for Paget’s disease known as osteoporosis circumscripta (Figure 5).

If a patient is known to have Paget’s disease and a radiograph identifies cortical bony destruction with an associated soft tissue mass, Paget’s secondary sarcoma is a likely diagnosis that must be excluded.

A bone scan may be obtained to identify the sites of disease (Figure 6). The lesions will demonstrate increased uptake (“hot lesions”) in the lytic and mixed phases secondary to increased osteoblastic activity.

Routine blood tests are not particularly helpful for diagnosing Paget’s disease, as even calcium levels are often normal. However, specialized tests, particularly alkaline phosphatase, can be useful. Alkaline phosphatase is an enzyme of osteoblasts, and its level reflects osteoblastic synthetic activity.

A biopsy from a Paget’s bony lesion will reveal woven bone with irregular broad trabeculae in a mosaic pattern with interspersed fibrous vascular tissue. There will be numerous multinucleated osteoclasts with virus-like inclusion bodies. The osteoclasts in a Paget’s lesion can be distinguished from normal osteoclasts by their increased nuclei and larger size.

Epidemiology

Paget's disease is found in approximately 3% of all people over 50 years of age in the United States, with its prevalence rising to 10% in people over 80 years of age. The disorder rarely presents before age 40, making its overall prevalence about 1% of the entire US population. Paget's disease is approximately four times more common in people who have relatives with the condition. Paget's disease is also more prevalent in countries such as England, western Europe, and the United States, and less prevalent in countries such as China, Japan, and India. These data suggest a genetic contribution to the risk of disease.

Lesions may occur singularly or multiply in numerous bones. The bones most commonly affected are the femur, pelvis, tibia, skull, and spine.

Differential Diagnosis

If a patient presents with a bony lesion and is older than 40 years of age, a clinician must always suspect bony metastasis, lymphoma, and myeloma. If the patient is over 50 years of age, hyperparathyroidism and bony infarcts must also be included in the differential. Infection, as a general rule, must be considered and excluded for all bony lesions.

Red Flags

Paget’s disease can appear in more than one bone. If a single lesion is found, a skeletal survey (complete body radiography) is indicated to look for other lesions. Alternatively, a bone scan can be performed first so that radiographic examinations can be limited to sites of “hot lesions” on the scan.)

If a patient is known to have Paget’s disease and presents with an acute worsening of pain and swelling in the affected extremity, a clinician must suspect malignant transformation. Although secondary sarcomas occur in less than 1% of all patients with Paget’s, the rate is considerably higher than that for the general population. A bone biopsy may be indicated.

Treatment Options and Outcomes

Individuals who are asymptomatic may be treated with observation and supportive therapy, such as physical therapy and anti-inflammatories.

Bisphosphonates can be used for patients with symptomatic Paget’s disease. Bisphosphonates target osteoclasts to decrease bone resorption activity. Bisphosphonates may be administered orally or intravenously. Calcitonin is another treatment for Paget’s disease that also targets osteoclasts. Calcitonin may be administered intramuscularly or subcutaneously.

Patients with severe knee and hip osteoarthritis may be candidates for total joint arthroplasty. Total hip replacement in Paget’s is associated with significant blood loss. Thus, preoperative medical treatment (bisphosphonates or calcitonin) to decrease disease activity and intraoperative bleeding is indicated. The extent of preoperative disease reduction can be assessed by monitoring serum alkaline phosphatase levels.

Patients with significant angulation or bowing of the femur or tibia may be candidates for realignment osteotomies.

Patients who have sustained pathologic fractures are candidates for operative fixation. Those with impending fractures may be fixed prophylactically.

Risk Factors and Prevention

Most cases of Paget’s disease occur spontaneously. Genetic mutations appear to play a role in Paget’s disease, but the specific genes/mechanisms are not well known.

Miscellany

Paget’s disease of the bone is named after Sir James Paget, who also described Paget's disease of the breast, a form of breast cancer involving the nipple.

Key Terms

Bone remodeling, high-output heart failure

Skills

Recognize Paget’s disease on imaging. Recognize signs of malignant transformation.