Excerpt from Paget Disease

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Background

Paget disease is a localized disorder of bone remodeling that typically begins with excessive bone resorption followed by an increase in bone formation. This osteoclastic activity followed by compensatory bone formation (osteoblastic activity) leads to a structurally disorganized mosaic of bone (woven bone), which is weaker mechanically, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone.

Sir James Paget first described chronic inflammation of bone as osteitis deformans in 1877. Paget disease, as the condition came to be known, is the second most common bone disorder (after osteoporosis) in elderly persons.

Approximately 70-90% of persons with Paget disease are asymptomatic; however, a minority of affected individuals experience various symptoms, including bone pain (the most common symptom), secondary osteoarthritis (when Paget disease occurs around a joint), bony deformity (most commonly bowing of an extremity), excessive warmth (due to hypervascularity), and neurologic complications (caused by the compression of neural tissues). Paget disease may be monostotic (17%) but is more frequently multifocal, with predilection for the axial skeleton (ie, spine, pelvis, femur, sacrum, and skull in descending order of frequency). However, any bone may be affected. After onset, Paget disease does not spread from bone to bone, but it may become progressively worse at preexisting sites.

Although the etiology of Paget disease is unknown, both genetic and environmental contributors have been suggested. Ethnic and geographic clustering of Paget disease is well described. Paget disease is common in Europe (particularly Lancashire, England), North America, Australia, and New Zealand. It is rare in Asia and Africa, and most, although not all, Americans with Paget disease are white. A familial link for Paget disease was first reported by Pick in 1883, who described a father-daughter pair with Paget disease. This was followed shortly thereafter with a sibling case of Paget disease described by Lunn in 1885. Approximately 40% of persons with Paget disease report a family history of the disease, although the true prevalence of the disease is likely higher. Some studies suggest a genetic linkage for Paget disease located on chromosome arm 18q, although this has not been demonstrated in most families with Paget disease, which suggests genetic heterogeneity.

An environmental trigger for Paget disease has long been considered but never proven. Results from bone biopsies in patients with Paget disease demonstrate several different Paramyxoviridae viral antigens, including measles virus and respiratory syncytial virus, located within osteoclasts. However, the putative antigen or antigens remain unknown.

Pathophysiology

Three phases of Paget disease have been described. Paget disease begins with the lytic phase, an increase in bone resorption with an abnormality in the osteoclasts found at the site of bony involvement. These osteoclasts are more numerous and have many more nuclei (up to 100) than normal osteoclasts (5-10 nuclei). This results in a bone turnover rate up to 20 times more rapid than normal. This significant increase in bone resorption leads to a second phase (known as the mixed phase) of rapid increases in bone formation with numerous osteoblasts, which are increased in number but remain morphologically normal. The newly made bone is abnormal; the newly formed collagen fibers are deposited in a haphazard fashion rather than linearly (as with normal bone formation).

In the final phase of Paget disease, known as the sclerotic phase, bone formation dominates and the bone that is formed has a disorganized pattern (woven bone) and is weaker than normal adult bone. This woven bone pattern allows the bone marrow to be infiltrated by excessive fibrous connective tissue and blood vessels, leading to a hypervascular bone state. Eventually, the hypercellularity may diminish, leaving a pagetic bone, which is known as burned-out Paget disease.

Paget disease can affect every bone in the skeleton, with an affinity for the axial skeleton, long bones, and the skull. The skeletal sites primarily affected include the pelvis, lumbar spine, femur, thoracic spine, sacrum, skull, tibia, and humerus. The hands and feet are very rarely involved.

Complications of Paget disease depend on the site affected and the activity of the disease. When Paget disease occurs around a joint, secondary osteoarthritis may ensue. When the skull is involved, the patient may develop deafness, vertigo, tinnitus, dental malocclusion, basilar invagination, vertebral insufficiency, and cranial nerve involvement.

Frequently, erythema is present over the affected bone area, which is due to the increased skin temperature from the hypervascularity. Hypervascularity occurs because the abnormal woven bone pattern of pagetic bone permits the bone marrow to be infiltrated by large numbers of blood vessels. In patients with Paget disease who have extensive bony involvement, this increased bone vascularity may cause high-output cardiac failure and an increased likelihood of bleeding complications following surgery.

Vertebral involvement of Paget disease may be associated with serious complications, including nerve-root compressions and cauda equina syndrome. Fractures, which are the most common complication of Paget disease, may occur and may have potentially devastating consequences. Rarely, pagetic bone may undergo a sarcomatous transformation.

Laboratory values, including serum calcium, phosphorus, and parathyroid hormone levels, are normal in persons with Paget disease. However, hypercalcemia may complicate the course of Paget disease, most frequently in the setting of immobilization. Elevated levels of uric acid and an increased prevalence of gout have been reported in patients with Paget disease.

Levels of bone-turnover markers (including markers of bone formation and resorption) are elevated in patients with active Paget disease and may be used to monitor the course of disease. The degree of elevation of these biomarkers helps identify the extent and severity of bone turnover. Markers of bone turnover that are useful to monitor in persons with Paget disease include bone specific alkaline phosphatase (marker of bone formation), deoxypyridinoline (marker of bone resorption), and N-telopeptide of type I collagen (marker of bone resorption). Alpha-alpha type I C-telopeptide fragments are sensitive markers of bone resorption for assessing disease activity and monitoring treatment efficacy in persons with Paget disease.¹ Serum osteocalcin, a marker of bone formation, is not a useful parameter to assess in persons with Paget disease. Upon successful treatment of Paget disease, the level of these bone markers is expected to decrease.

The juvenile form of Paget disease differs greatly from the adult version. Juvenile Paget disease is characterized by widespread skeletal involvement and has distinctly different histologic and radiologic features.

Frequency

United States

Paget disease is estimated to occur in 1-3% of individuals older than 45-55 years and in up to 10% in persons older than 80 years. It is estimated to affect 1 to 3 million people in the United States alone.

According to a 2000 study by Altman et al, the prevalence of pelvic Paget disease was 0.71% ±0.18% in the United States based on data from the National Health and Nutrition Examination Survey I (NHANES I, 1971-1975). The male-to-female ratio was 1.2:1, and the prevalence of pelvic Paget disease was the same in white persons and black persons. The prevalence of pelvic Paget disease increased with age, with the highest prevalence in persons older than 65 years. Geographically, pelvic Paget disease was least common in the southern United States and most common in the northeastern United States.²

International

The prevalence of Paget disease varies greatly among countries, with the greatest prevalence in Europe (predominantly England, France, and Germany), Australia, and New Zealand. In Europe, the incidence of Paget disease has been decreasing over the last 20 years.³ Paget disease is very rare in Asian countries, especially China, India, and Malaysia, and in the Middle East and Africa.

In Europe, the prevalence rates of Paget disease appear to decrease from north to south, with the exception of Norway and Sweden, which both have very low rates (0.3%). The highest prevalence in Europe is found in England (4.6%) and France (2.4%) in hospitalized patients older than 55 years. Other European countries, such as Ireland, Spain, Germany, Italy, and Greece, report prevalence rates of Paget disease that range from 0.5% to approximately 2%.

The prevalence rates of Paget disease in Australia and New Zealand range from 3-4%.

The prevalence of Paget disease in Sub-Sahara Africa is 0.01-0.02%, and, in Israel, Paget disease is predominantly found in Jews; however, cases have recently been reported in Israeli Arabs.

In South America, the incidence of Paget disease is relatively high in Argentina (around Buenos Aires), which was settled by Spanish and Italian immigrants, and lower in Chile and Venezuela.

Mortality/Morbidity

• Morbidity due to Paget disease can be extensive and most commonly results from bone pain, osteoarthritis, and fractures.
• The increased mortality rate associated with Paget disease is due most commonly to complications of the disease, principally those related to fractures and sarcoma. Most patients with Paget disease who develop sarcoma die within 3 years of diagnosis.
• The hypervascularity of bone that may result from Paget disease may cause excessive bleeding following fractures or surgery and is associated with potentially serious consequences.

Sex

• Paget disease occurs in both men and women, with a 3:2 male-to-female ratio.

Age

• Paget disease is distinctly rare in persons younger than 25 years and increases in frequency with increasing age.
• Paget disease is believed to develop in persons in their fifth decade and is most commonly diagnosed in people in the sixth decade of life. The incidence of Paget disease among persons older than 80 years is approximately 10%.
• A juvenile form of Paget disease exists; however, it is very different from the adult form.

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