Paget Bone Disease

Etiology

Some literature sources suggest that the family of paramyxoviruses solely causes Paget disease of the bone.[5] However, many studies have determined that the osteoclast generation of a unique cytokine found exclusively in the bone marrow of patients diagnosed with Paget disease may be the primary insult. This cytokine is known as IL-6.

A strong genetic predisposition to the disorder has been determined based on population studies.[6][7] Besides finding an association between HLA markers, siblings are at high risk for developing the disorder.

Epidemiology

Paget disease is usually seen in individuals older than 50 years of age. Around the world, it is reported that the prevalence of the disease has decreased during the past 2 decades, currently estimated between 1.5% to 8.3%.[8] It is common in Caucasians of northern European descent.[9] Paget disease is equally common in males and females. In the US, it is said to affect 1 to 3 million people, but most of the patients are asymptomatic. The disorder is slightly more common in white males. The disorder usually presents in the fourth to fifth decade of life, but the diagnosis is often made a decade later.

Pathophysiology

Paget disease of the bone occurs with an increase in bone resorption, leading to a decrease in bone mass and lytic structures. This process gives rise to osteoblasts from the bone utilizing a sensing system that allows them to increase their activity.

Paget disease's pathological process 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 culminates in the final stage, where malignant degeneration is seen.

The disease occurs in isolated pockets but is usually progressive. There is often erythema and warmth over the involved bone due to hypervascularity, which can lead to high-output heart failure.

The disease can affect almost every bone in the skeleton but has an affinity for the long bones, axial skeleton, and the skull. Involvement of the feet and hands is rare.

Histopathology

The key histopathological feature of Paget disease involves bone architecture and includes the 3 phases of the disease: mixed, osteolytic, and osteosclerotic. These phases may occur at the same time or separately. The osteolytic phase has areas of resorption due to a significant increase in the number of abnormal osteoclasts that contain dozens of nuclei. The osteoblastic phase that follows is disorganized. The bone development is fragmented and irregular. The presence of irregularly shaped bone particles appears like jigsaw-puzzle pieces and is the hallmark feature of Paget disease. As the disorder advances, the osteoblastic phase becomes dominant, resulting in excessive bone formation, which is fibrous and coarse. The marrow space is filled with vascularized fibrous tissue, which accounts for the persistent warmth and fever.

The bone in Paget disease does not have centralized blood vessels or Haversian systems. Once the osteoblastic phase subsides, the new bone is poorly mineralized and lacks structural integrity.[10][11][12]

History and Physical

Many patients who present to the clinic with pathognomonic features associated with Paget disease are usually asymptomatic. Most patients with the condition are often diagnosed by an incidental finding on an x-ray study. The disease will present with 1 bone affected in one-third of cases. The spine and pelvis are commonly affected (see Image. Paget Disease Pelvis), and among the long bones, the femur is often involved  (see Image. Paget Disease of the Long Bone). Symptomatic patients can present with the following:

• Pain involving the bones and joints
• Diffuse joint stiffness
• Abnormally enlarged skull
• Musculoskeletal deformities
• Loss of hearing (due to the involvement of the petrous temporal bone)
• Migraines
• Fractures
• Heart failure
• Cranial nerve neuropathies
• Headaches
• Skull and jaw deformity

The lumbar spine, sacrum, and skull are involved in most cases (see Image. Paget Disease Skull). Pain is a common feature and is worse with weight-bearing.

The patient's physical exam may show bone deformity or angulation, localized pain to palpation, and increased warmth. The patient's gait may be altered, and there may be balance problems.

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

Osteosarcoma is a rare complication but should be suspected in a patient with a sudden increase in swelling or bone pain. This disorder can be fatal. Giant cell tumors may also arise in pagetic bone and involve the facial bones. With vertebral fractures, acute spinal cord compression may occur.

An increase in cardiac output is noted in 20% of patients when the axial skeleton is involved. In addition, calcified aortic stenosis is common in this population.

Evaluation

Tests to assist in the diagnosis of Paget disease include the following:

• Bone scan
• Bone x-ray
• Elevated markers of bone breakdown, such as N-telopeptide

 The disease may also present with the following findings: 

• Elevated alkaline phosphatase (ALP) 
• Normal serum calcium and phosphate

Measurement of serum ALP is useful, as are urine levels of hydroxyproline, C-telopeptide, and N-telopeptide.

Procollagen N-terminal peptide is also a sensitive serum marker for bone formation.

Hyperuricemia is common and is due to a high turnover of bone.

Secondary hyperparathyroidism occurs in approximately 10% of patients due to inadequate calcium in the face of increased demand.[13]

Plain x-rays may reveal cortical and trabecular thickening, osteosclerosis that looks like arthritis, bone expansion, or osteolytic areas.[2]

Bone scans can help document the extent of disease and should be used to follow treatment (see Image. Abnormal Uptake in the Left Hemipelvis). In addition, a bone scan can pick up early changes in bone even before the patient develops symptoms.

Treatment / Management

Some patients diagnosed with Paget disease may not require treatment.[14][15][16] This patient cohort includes the following:(A1)

• Patients with no abnormal blood tests
• Patients who have no active signs of the disease and those who are asymptomatic

The most commonly treated patients diagnosed with Paget disease include the following:

• Patients with abnormal bone defects
• Patients who have weight-bearing bones involved
• Patients with skull deformities
• Patients with evidence of a rapidly progressing bone change
• Patients with complaints of diffuse pain

Several treatment regimens aid in prophylactically preventing bone breakdown and subsequent bony formation.[17] Some of the more common drug therapies include the following:

• Bisphosphonates have been approved as the first-line treatment option due to their influence on bone remodeling.[18]
• Calcitonin is usually a second-line treatment and can also have an analgesic effect. This drug assists in bone absorption.
• Denosumab has been used off-label in cases of bisphosphonate intolerance or contraindication, with good results.
• Supplements such as calcium and vitamin D have been known to provide some symptomatic benefits.[19]
• Pain management is usually achieved by either NSAIDs or acetaminophen.

Surgery is only offered as an option to patients diagnosed with Paget disease with a progression into osteosarcoma. Most patients diagnosed with osteosarcoma are often offered palliative options such as amputating the affected limb. In many cases, clinicians are tasked with making judgment calls about which treatment options to offer to the wide spectrum of patients diagnosed with Paget disease. For example, younger patients are usually offered a surgical procedure where they could potentially salvage the limb by resecting the tumor with wide margins. This may not be a viable alternative for an older patient with multiple comorbidities and risk factors. Patients may also develop pathological fractures that require radiation and internal fixation to relieve pain. Chemotherapy is an ineffective option for patients diagnosed with sarcoma. It is important to note that surgical failure rates are high in this group of patients. Often, revision surgery is indicated.

Patients with cauda equina and other nerve compression complications will frequently require laminectomy.

Differential Diagnosis

The differential diagnosis of Paget disease includes the following:

• Osteomalacia
• Osteoporosis
• Malignancy of the bone, primary or metastatic
• Renal osteodystrophy
• Osteoarthritis
• Osteopenia
• Fibrous dysplasia

Prognosis

The prognosis for treated patients is good, especially if the disease is in its early stages. Paget disease of the bone has no cure, but the disorder can be controlled by slowing down or even stopping its progression. Patients with polyostotic disease have poorer outcomes than those with monostotic disease. The morbidity is usually due to fractures, chronic pain, bone deformity, and neurological complications. Once the patient develops sarcomatous degeneration, the survival rate may be very poor.

Complications

Complications include the following:

• Secondary osteoarthritis
• Vertigo
• Deafness
• Dental malocclusion
• Tinnitus
• Cranial nerve compression
• Basilar invagination
• Cauda equina syndrome
• Fractures
• Hashimoto thyroiditis
• Osteopetrosis
• Dupuytren contracture
• Development of osteosarcoma
• High-output cardiac failure