Paget's Disease

Introduction and Facts

Paget's disease is a bone growth disorder in which abnormalities such as unusual bone growth can occur in several multifactorial ways. It is the second most frequently diagnosed metabolic bone disease after osteoporosis. Paget's disease is often manifested by widespread pain and radiologically visible bone changes throughout the musculoskeletal system. This disease can affect any bone in the body, but is more commonly seen in the spine, pelvis and skull. The disease does not spread to other bones, but it can worsen in the affected area and even develop into sarcoma, which may be a fatal bone cancer.

Paget's disease most often attacks elderly people, occurring in around 2%-3% of the population aged over 55 years. The cause of Paget's disease is still unknown, but there are genetic and environmental links. This disease is most common in Europe, North America and Australia, but is rare in Asia and Africa. Several viruses have been identified in diseased bone, but their role in the pathology of this disease remains uncertain.

Pathophysiology

Paget's disease occurs due to increased bone resorption which causes a decrease in bone mass and lytic structure. This process elicits osteoblasts from the bone by utilizing a sensing system that allows the osteoblasts to increase their activity.

The pathological process of Paget's disease occurs in 4 stages. It begins with osteoclastic activity, followed by a hybrid osteoclastic/osteoblastic process. In the third stage, osteoblastic activity is observed and reaches its peak in the late stage, where malignant degeneration is seen.

This disease occurs in isolated areas, but is usually progressive. There is often erythema and warmth in the affected bones due to hypervascularization, which can lead to heart failure with high cardiac output. This disease can affect almost any bone in the skeleton, but has an affinity for the long bones, axial skeleton, and skull. Involvement of the feet and hands is rare.

Etiology and Risk Factors

The cause of Paget's disease is unknown, but a number of risk factors have been identified that make a person more likely to develop the disease, including:

• Genetic. Paget's disease tends to run in families. In 25%-40% of cases, other family members also suffer from the disease.
• Age. Paget's disease is rare in people under 40 years of age. This disease occurs more often with age.
• Descendants. This disease is more common in people of Anglo-Saxon descent and those living in certain geographic areas, such as the United States, England, Australia, New Zealand, and Western Europe. This disease is not common in Scandinavia, China, Japan, or India.
• Environmental factor. Some studies suggest that certain environmental exposures may play a role in the development of Paget's disease. However, this has not been proven with certainty.

Several literature sources state that the paramyxovirus family only causes Paget's disease of the bones. However, many studies have found that the formation of a unique cytokine by osteoclasts found exclusively in the bone marrow of patients diagnosed with Paget's disease may be the primary cause. This cytokine is known as IL-6. A strong genetic predisposition to this disorder has been determined based on population studies. In addition to finding an association between HLA markers, siblings are also at high risk of developing the disorder.

Signs and Symptoms

Symptoms of Paget's disease of bone include bone or joint pain and problems caused by nerve compression or damage. However, in many cases, there are no obvious symptoms and the condition is only discovered during examinations carried out for other reasons.

One bone or several bones may be affected. Areas commonly affected include:

• Pelvis
• Spine
• Skull
• Shoulder
• Foot

Paget's disease can cause pain in the bones themselves and in the joints near the affected bones.

Bone pain that is felt is usually:

• dull or sore
• deep within the affected part of the body
• constant
• worse at night
• The affected area may also feel warm.

 Abnormal bone growth can cause the bones to be squashed (compressed) or damage the surrounding nerves.

Possible signs include:

• pain radiating from the spine to the legs (sciatica)
• numbness or tingling in the affected limb (peripheral neuropathy)
• partial loss of movement in the limbs
• balance problems
• loss of bowel control (bowel incontinence) or loss of bladder control (urinary incontinence)

Diagnosis

Many patients who present to the clinic with pathognomonic features associated with Paget's disease are usually asymptomatic. Most patients with this condition are often diagnosed based on incidental findings on x-ray examination. The disease will present with 1 bone affected in one third of cases. The spine and pelvis are commonly affected, and among the long bones, the femur is frequently affected. Symptomatic patients may present with the following symptoms:

• Pain involving bones and joints
• Diffuse joint stiffness
• An abnormally enlarged skull
• Musculoskeletal deformity
• Hearing loss (due to involvement of the petrous temporal bone)
• Migraine
• Fracture
• Heart failure
• Cranial nerve neuropathy
• Headache
• Skull and jaw deformities
• The lumbar spine, sacrum, and skull are involved in the majority of cases. Pain is a common symptom and is worse with weight bearing.

The patient's physical examination may reveal bone deformity or angulation, local tenderness to palpation, and increased warmth. The patient's gait may change, and there may be balance problems.

Incomplete fractures are common in Paget's disease and are seen in the tibia and femur. Even minor injuries can result in bone fractures. Femur fractures often involve the subtrochanteric region.

Some tests that can be done to help diagnose Paget's disease include:

• Bone scanner (including x-ray)
• Increased markers of bone damage, such as N-telopeptide

This disease can also appear with the following symptoms:

• Elevated alkaline phosphatase (ALP)
• Serum calcium and phosphate were normal

Measurement of serum ALP is useful, as are urine levels of hydroxyproline, C-telopeptide, and N-telopeptide. The N-terminal procollagen peptide is also a sensitive serum marker for bone formation. Hyperuricemia is common and is caused by high bone turnover. Secondary hyperparathyroidism occurs in approximately 10% of patients due to calcium deficiency in the face of increased requirements.

Plain x-rays may show cortical and trabecular thickening, arthritis-like osteosclerosis, bony expansion, or osteolytic areas.

Bone scans can help document the extent of the disease and should be used after treatment. In addition, bone scans can detect early changes in the bones even before the patient experiences symptoms.

Management and Care

Some patients diagnosed with Paget's disease may not require treatment. Groups of patients who do not require treatment are as follows:

1. Patients without abnormal blood tests
2. Patients who have no active signs of disease and those who are asymptomatic

The most frequently treated patients diagnosed with Paget's disease are as follows:

• Patients with abnormal bone abnormalities
• Patients whose bones are weight-bearing
• Patients with skull abnormalities
• Patients with evidence of rapidly progressing bone changes
• Patients with complaints of widespread pain

Several treatment regimens help prevent bone destruction and subsequent bone formation prophylactically. Some of the more common drug therapies are as follows:

• Bisphosphonates have been approved as a first-line treatment option because of their effects on bone remodeling.
• Calcitonin is usually a second-line treatment and can also have analgesic effects. This drug helps bone resorption.
• Denosumab has been used off-label in cases of bisphosphonate intolerance or contraindications, with good results.
• Supplements such as calcium and vitamin D are known to provide some symptomatic benefits.
• Pain management is usually achieved with NSAIDs or acetaminophen.

Surgery is only offered as an option for patients diagnosed with Paget's disease that progresses to osteosarcoma. Most patients diagnosed with osteosarcoma are often offered palliative options such as amputating the affected limb. In many cases, physicians are tasked with making decisions regarding which treatment options to offer to the broad spectrum of patients diagnosed with Paget's disease. For example, younger patients will usually be offered a surgical procedure that allows them to save the limb by resection of the tumor with wide margins. It may not be an appropriate alternative for elderly patients with multiple comorbidities and risk factors. Patients may also experience pathologic fractures that require radiation and internal fixation for pain relief. Chemotherapy is an ineffective option for patients diagnosed with sarcoma. It is important to note that the rate of surgical failure in this group of patients is high. Often, revision surgery is indicated. Patients with cauda equina and other nerve compression complications often require laminectomy.

Reference:

1. Bouchette P, Boktor SW. Paget Bone Disease. National Library of Medicine [Internet]. 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430805/
2. OrthoInfo. Paget’s Disease of Bone. American Academy of Orthopaedic Surgeons [Internet]. 2023. Available from: https://orthoinfo.aaos.org/en/diseases--conditions/pagets-disease-of-bone
3. National Health Service UK. Paget’s disease of Bone [Internet]. 2023. Available from: https://www.nhs.uk/conditions/pagets-disease-bone/diagnosis/