Paget Disease

Introduction

virus and respiratory remain unknown. Pathophysiology

syncytial

virus,

located

within

osteoclasts. However, the putative antigen or antigens

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 disease symptom), occurs secondary osteoarthritis (when a joint), bony deformity Paget (most around

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

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

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. Serum osteocalcin, a marker
1

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 0.010.02%, 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

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-tofemale 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,

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.

Clinical History

the most common pagetic bone to fracture. Most pagetic bone fractures heal normally.

Paget disease is a localized disorder that may be monostotic (affecting only one bone). This type accounts for approximately one third of all Paget disease cases. It also may be polyostotic (affecting 2 or more bones).

Causes

The cause of Paget disease is unknown. The leading hypothesis is the slow virus theory, but more work is required before this enigma is resolved. The measles virus messenger RNA sequences have been found in osteoclasts and other mononuclear cells of pagetic bones. Canine distemper virus nucleocapsid antigens have also been found in osteoclasts from patients with Paget disease. However, the presence of these paramyxoviruslike nuclear inclusions does not prove that these are responsible for the development of pagetic lesions; rather, these inclusions may be markers of the disease itself.

Paget disease does not spread from one bone to another, and new sites of involvement are rare after the initial diagnosis; instead, lesions may continue to progress if left untreated.

Most persons with Paget disease are asymptomatic. In these patients, the disease is detected based on the incidental finding of an elevated serum alkaline phosphatase level or characteristic radiographic abnormality. However, when symptoms do occur, bone pain is the most common complaint.

Several

genetic

theories

suggest

that

human

leukocyte antigen (HLA) on chromosome 6 and the gene on chromosome arm 18q may play important roles; however, the studies on HLA have not been conclusive and the gene on chromosome arm 18q has not been shown to be the focus in all families tested, suggesting that genetic heterogeneity is likely.4

Other patients with Paget disease present with a range of symptoms that may include pathologic fractures,congestive heart failure, hearing loss, and dysesthesias compression. and weakness due to nerve-root

Physical

According to the infectious theory of Paget disease, bone marrow cells (the progenitors of osteoclasts) are infected by a virus, causing an abnormal increase in osteoclast formation. Recent studies demonstrate some alterations in cytokine expression in persons with Paget disease.5 Elevated interleukin6 (IL-6) levels are found in bone marrow plasma and peripheral blood in patients with Paget disease but not in healthy controls. One hypothesis is that some unidentified viral infection up-regulates IL-6 and the IL-6 receptor genes; however, this has not been shown conclusively.6,7

The physical examination findings may be normal in patients with Paget disease. However, physical signs of Paget disease may be present, including increased skeletal warmth, bowing deformities (with gait abnormalities), changes of secondary osteoarthritis, and hyperexpansion of the skull. Hearing loss may be apparent during the physical examination. Because patients with Paget disease may also have gouty arthritis, they also should be evaluated for the presence of tophi.

The spine is the second most commonly involved site of Paget disease. In the lumbar spine, spinal stenosisor kyphosis may develop. If Paget disease affects the thoracic spine, the patient may have spinal cord compression, which can lead to neural function loss.

In Paget disease, osteoclast precursors have also been shown to be hyperresponsive to the RANK ligand (RANKL), a member of the tumor necrosis factor-alpha superfamily, which promotes osteoclast genesis. One possibility is that increased expression of RANKL contributes to the localized nature of the disease. These osteoclast precursors also appear to be hyperresponsive to 1,25(OH)2D3 8 and calcitonin and have up-regulation of the c-fos protogene. oncogene9 and BC12, the antiapoptosis

Paget disease of the skull may be asymptomatic; however, deformity approximately (frontal one third of patients enlarged experience an increase in head size with or without bossing, maxilla), headaches, hearing loss, and, rarely, nerve damage leading to a loss of sensation.

Treatment efficacy of bisphosphonates in Paget disease may be due to suppression of RANKLinduced bone resorption with decreases in RANKL and increased osteoprotegerin production.

The most common neurologic problem is hearing loss, which is due to compression of cranial nerve VIII and cochlear dysfunction.

If the facial bones are affected, a patient may have facial deformity problems and, rarely, narrowing of the airway.

Macrophage-colony stimulating factor (M-CSF) may play a role in Paget disease. M-CSF is a growth factor produced by many cells, including osteoblasts and marrow fibroblasts. Significantly high levels of M-CSF have been found in patients with untreated

Fracture of a pagetic bone is an occasional and serious complication and may be either traumatic or spontaneous. Because it is a long bone, the femur is

Paget disease; however, its exact role remains to be determined. Differential Diagnoses Osteoarthritis Osteoporosis Other Problems to Be Considered Osteomalacia (may be associated with high bone-specific alkaline phosphatase [BSAP] levels) Malignancy with skeletal metastasis Workup Laboratory Studies

vertical striations produce the characteristic radiograph vertebrae." picture of the "framed

Radiography is typically used for diagnostic purposes. Repeated radiography may be helpful in monitoring an osteoarthritis program or in evaluating for malignant degeneration. In the appropriate clinical setting, radiography may also be indicated to evaluate for fracture.

Approximately 1% of patients with Paget disease develop sarcomas, which has a distinct radiologic appearance.

BSAP levels are elevated. Measuring total alkaline phosphatase levels may be useful in patients with normal liver function. However, disease. BSAP is more specific than total alkaline phosphatase for Paget

Patients with Paget disease have elevated levels of urinary excretion calcium, of deoxypyridinoline, and Ctelopeptide,1and N -telopeptide.

Serum

phosphorus,

parathyroid Radiograph African showing American a 44-year-old man with

hormone levels usually remain normal; however, in the setting of immobilization, hypercalcemia may ensue. Imaging Studies

characteristic changes of Paget disease in the left hemipelvis.

The radiographic appearance of pagetic bone reflects the underlying process. Radiographs may demonstrate both osteolysis and excessive bone formation.

The

initial

pathologic

lesion,

which

is

osteolysis, appears as a radiolucency on the radiograph and is particularly evident in the skull, where it is termed osteoporosis circumscripta. Previous attempts to repair these areas are seen as areas of increased density or as coarsened trabecula. In some areas, an overt sclerotic appearance may be seen.

Several relatively specific findings for Paget disease include a classic V-shaped pattern discriminating between healthy and pagetic bone in the long bones of the skeleton known as "the blade of grass" lesion; the "brim sign," which is the thickened Radiograph showing a 72-year-old

white woman with Paget disease of the lower leg and typical bowing.

Radionuclide bone scans are helpful for documenting the extent of the disease. If increases in pain or BSAP levels are noted or if pathological fractures occur, further imaging studies are important to help exclude neoplasms, including sarcomas and giant cell tumors.

iliopectineal line in the pelvis; osteoporosis circumscripta in the frontal and occipital bones of the skull; and the "cotton wool" pattern in the skull characteristic of the mixed phase of Paget disease.

In the spine, enlargement of the vertebral bodies with thickened cortical shells and Other Tests

Bone biopsies may be indicated to evaluate for malignant transformation.

Total hip replacement and tibial osteotomy are effective for relieving pain and restoring mobility. Pharmacological therapy, including bisphosphonates, should be used preoperatively to try to reduce disease activity in order to prevent severe blood loss during surgery.

Histologic Findings The major histologic feature of Paget disease is abnormal bony architecture. The 3 distinct phases in Paget disease may all exist separately or in the same bone at one time. The first phase consists of osteolysis of bone, which is soon accompanied by accelerated deposition of pieces of bone in a random fashion (mixed phase). The final phase consists of accelerated osteoblastic bone formation with an increase in the number and activity of the osteoblasts. This results in increased osteoid volume and replacement of the normal marrow with fibrous tissue. Treatment Medical Care

After surgery, bone healing may be prolonged, and lengthy rehabilitation may be necessary. Amputation may also be necessary in the presence of a malignant transformation. Decompressive laminectomies may be necessary if medical therapy cannot induce recovery in those with neurologic sequelae due to spinal cord compression.

Consultations Orthopedic surgeons, neurosurgeons, physical therapists, and oncologists control disease activity. The long-term may play useful adjunctive roles in the management of Paget disease. Diet No specific dietary modifications are necessary in patients with Paget disease. However, in patients with Paget disease who are receiving bisphosphonate therapy, ensure adequate intake of calcium and vitamin D. Activity No specific adjustments in physical activity levels are

The short-term objective of Paget disease treatment is to objectives of treatment are to minimize or prevent disease progression and to decrease complications from the disease, if possible.

Indications for treatment include complications of Paget disease, including bone pain, progressive skeletal deformity, high-output congestive heart failure, hypercalcemia, compression of spinal cord and nerve roots, bone compression of the eighth cranial or optic nerve, recurrent renal calculi due to hypercalciuria, or fractures. When Paget disease occurs around a joint, treatment is often administered in an attempt to prevent development of osteoarthritis. Also, young patients with Paget disease and those with high levels of BSAP are often treated to avoid future complications.

necessary in patients with Paget disease. If secondary osteoarthritis occurs in the knee, quadriceps-strengthening exercises may be helpful. If bone pain occurs with weight bearing or if gait abnormalities are present, individualized adjustment in physical activity regimens may be necessary. Medication Treatment with bisphosphonates should be considered firstline therapy in patients with Paget disease. Note that osteonecrosis of the jaw has recently been described in patients taking bisphosphonates and this should be discussed with patients before initiating treatment, when possible. 10 Bisphosphonates These agents are analogs of pyrophosphate and act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals. They prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.

Medical therapy for Paget disease should include bisphosphonate treatment with serial monitoring of bone markers. Bone markers should be rechecked 23 months following bisphosphonate treatment.

Because of the increased risk of malignancy, patients with Paget disease should be monitored indefinitely. Nonsteroidal acetaminophen management. anti-inflammatory may be drugs for and pain effective

Orthotic devices, including canes and walkers, may be useful for patients with Paget disease that involves the lower limbs who have gait abnormalities.

Chemotherapy, radiation, or both may be used to treat neoplasms that arise from pagetic bone.

Surgical Care

Alendronate (Fosamax) Principally acts by inhibiting osteoclastic bone resorption. Recommended for treatment of Paget disease.

Indications for surgical treatment of Paget disease include bony deformities, pathologic fractures, nerve compression, and degenerative arthritis, particularly of the hip or knee.

Dosing


Adult

Interactions Contraindications Precautions

5 mg/kg/d PO for 6 mo followed by at least 6 mo of no treatment; dose limited because drug may impair mineralization Pediatric Not established; not recommended for use in pediatric

40 mg/d PO for 6 mo Pediatric Not established; not recommended for use in pediatric patients

patients

Tiludronate (Skelid) Principally acts by inhibiting osteoclastic bone resorption. Pamidronate (Aredia) Principally acts by inhibiting osteoclastic bone resorption. Recommended to treat Paget disease.

Adult

Dosing Interactions Contraindications Precautions

Adult

Dosing Interactions Contraindications Precautions

400 mg PO qd for 3 mo Pediatric Not established; not recommended for use in pediatric patients

Approved regimen is 30 mg IV over 4 h on 3 consecutive days in 500 mL of sterile 0.45% or 0.9% sodium chloride; other dosing regimens including 60-90 mg pamidronate IV in 500 mL 0.45% or 0.9% saline over 2-4 h have been used

Zoledronate (Reclast) Pediatric Not established; not recommended for use in pediatric patients Inhibits bone resorption. Inhibits osteoclastic activity and induces osteoclast apoptosis.

Risedronate (Actonel) Principally acts by inhibiting osteoclastic bone resorption. Recommended to treat Paget disease.

Adult 5 mg

Dosing Interactions Contraindications Precautions

IV

once;

infuse

over

minimum

15

min

Adult

Dosing Interactions Contraindications Precautions

requires monitoring of creatinine and calcium levels prior to infusion Pediatric Not established Calcitonin analogs These agents directly inhibit osteoclastic bone resorption.

30 mg/d PO for 2 mo Pediatric Not established; use in pediatric patients not recommended

Salmon calcitonin (Miacalcin, Calcimar injection) Etidronate (Didronel) Principally acts by inhibiting bone resorption. Least potent of currently available bisphosphonate drugs. Recommended bone resorption. for treatment of Paget disease if

bisphosphonates are contraindicated. Inhibits osteoclastic

Adult

Dosing Interactions Contraindications Precautions

Adult

Dosing Interactions Contraindications Precautions

100 U/d SC qd; dose of 50-100 U SC 3 times/wk for 6-18 mo has also been used Pediatric Not established Follow-up Further Inpatient Care Inpatient care may be useful for surgical complications of Paget disease. Further Outpatient Care Response to therapy is indicated by reduction of symptoms and decreases in BSAP (bone formation marker) and (bone deoxypyridinoline, C-telopeptide,1 or N -telopeptide

disease may exist as well. Clustering within families has been reported, differences supporting in this theory. In addition, a regional significant disease prevalence support

environmental influence.3,4,5 Paget disease evolves through 3 stages as follows:

An early lytic or hot phase An intermediate or mixed phase A final or cold phase, marked by dense bone formation

Paget disease rarely is diagnosed in the initial lytic phase. At this early point of the disease, osteoclastic activity is predominant. Paget disease usually begins at the end of a bone, except when it occurs in the tibia. A characteristic sharply demarcated zone of osteolysis may begin in the subcortical bone and advance along the diaphysis. Osteoblastic activity lags behind; thus, radiolucent fibrous tissue replaces normal bone. The intermediate abnormally compact or mixed and bone, phase reveals evidence of

resorption markers) levels. Deterrence/Prevention No preventive measures for Paget disease are known. Complications Complications of Paget disease include deafness, spinal stenosis, stroke, vascular steal syndrome, congestive heart failure, fractures, osteoarthritis, sarcomas, nephrocalcinosis, and the development of bone tumors (principally sarcomas). Prognosis Many reports have described long-term remissions following successful treatment of Paget disease. However, if sarcomas arise in the setting of Paget disease, the prognosis is dismal and most patients die within 1-3 years of diagnosis. Patient Education Proper patient education on the nature of Paget disease is essential. The Paget Foundation for Paget's Disease of Bone and Related Disorders can provide useful information for patients. Call (800) 23-Paget (ie, [800] 237-2438). Miscellaneous Medicolegal Pitfalls Careful follow-up of patients with Paget disease is indicated for life. Periodic monitoring of bone marker levels (every 3-6 mo in those without active disease) is recommended. Special Concerns Family members patient. Pathophysiology The etiology of Paget disease is uncertain, but it may be caused by a viral infection, possibly of the Paramyxoviridae family.2 Genetic predisposition to the development of Paget should be informed of the increased

osteolytic and disorganized osteoblastic activity. New bone forms and demonstrates respectively. characteristically Characteristic coarsened trabecula and cortical thickening in the cancellous intracytoplasmic inclusions may be observed microscopically, supporting evidence for the viral etiology theory. The final or cold phase demonstrates less evidence of continual osseous remodeling. Previously laid down woven bone is converted to dense lamellar bone. Histologic features of disorganized bone are prominent. The intersecting lines of remodeled bone have a characteristic mosaic pattern histologically (see the image below).

http://emedicine.medscape.com/article/334607overview

incidence of Paget disease in family members of the affected