Paget Disease 

Updated: Dec 21, 2018
Author: Mujahed M Alikhan, MD; Chief Editor: Herbert S Diamond, MD 

Overview

Practice Essentials

Paget disease is a localized disorder of bone remodeling that typically begins with excessive bone resorption followed by an increase in bone formation.[1] This osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone.[2]

The English surgeon Sir James Paget first described chronic inflammation of bone as osteitis deformans in 1877.[3] 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 the following:

  • 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)

  • Neurologic complications (caused by the compression of neural tissues)

Paget disease may involve a single bone but is more frequently multifocal.[4] It has a predilection for the axial skeleton (ie, spine, pelvis, femur, sacrum, and skull, in descending order of frequency), but 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.

Sarcomatous degeneration of pagetic bone is an uncommon but often deadly complication. Pagetic sarcoma is malignant, and the course usually is rapid and fatal

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. In the United States, most, although not all, individuals with Paget disease are white. (See Epidemiology.)

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. This has not been demonstrated in most families with Paget disease, however, which suggests genetic heterogeneity.

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

Measurement of serum alkaline phosphatase—in some cases, bone-specific alkaline phosphatase (BSAP)—along with several urinary markers, can be useful in the diagnosis of Paget disease. Plain radiographs and bone scanning should be performed upon initial diagnosis. (See Workup.) Medical therapy is principally with bisphosphonates; surgical therapy may be indicated. (See Treatment and Medication.)

Pathophysiology

Three phases of Paget disease have been described: lytic, mixed lytic and blastic, and sclerotic. In an individual patient, different skeletal lesions may progress at different rates. Thus, at any one time, multiple stages of the disease may be demonstrated in different skeletal regions.

Paget disease begins with the lytic phase, in which normal bone is resorbed by osteoclasts that are more numerous, are larger, and have many more nuclei (up to 100) than normal osteoclasts (5-10 nuclei). Bone turnover rates increase to as much as 20 times normal.

The second phase, the mixed phase, is characterized by rapid increases in bone formation from numerous osteoblasts. Although increased in number, the osteoblasts remain morphologically normal. The newly made bone is abnormal, however, with collagen fibers deposited in a haphazard fashion rather than linearly, as with normal bone formation. As the osteoclastic and osteoblastic activities of bone destruction and formation repeat, a high degree of bone turnover occurs.

In the final phase of Paget disease, 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.

After a variable amount of time, osteoclastic activity may decrease, but abnormal bone formation continues. Some pockets of normal-appearing lamellar bone may replace immature woven bone. Eventually, osteoblastic activity also declines, and the condition becomes quiescent. This is the sclerotic, or burned-out, phase. Continued bone resorption and formation are minimal or absent.

Paget disease can affect every bone in the skeleton, but it has 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. Skull involvement may lead to the following:

  • Deafness
  • Vertigo
  • Tinnitus
  • Dental malocclusion
  • Basilar invagination
  • Cranial nerve disorders

Frequently, erythema is present over the affected bone area, which is due to the increased hypervascularity. 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.

Standard serum chemistry 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 the following:

  • Bone-specific alkaline phosphatase (marker of bone formation)
  • Deoxypyridinoline (marker of bone resorption)
  • N -Telopeptide of type I collagen (marker of bone resorption)
  • Alpha-alpha type I C-telopeptide fragments

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.[5] 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.[6]

Etiology

The cause of Paget disease is unknown. Both genetic and environmental factors have been implicated.

Genetic predisposition

The geographic distribution of the disease may be explained by genetic transmission and dissemination by population migration. Studies have found a positive family history in 12.3% of 788 patients in the United States, 13.8% of 407 patients in Great Britain, and 22.8% of 658 patients in Australia. In the former 2 studies, a 7- to 10-fold increase in the incidence of Paget disease was observed in relatives of patients diagnosed with the condition, compared with control groups.

In one study, 15-40% of affected patients had a first-degree relative with Paget disease. Numerous other studies have described families exhibiting autosomal dominant inheritance.

Studies of potential genetic markers for Paget disease have found an association between human leukocyte antigen–A (HLA-A), HLA-B, and HLA-C (class I) and clinical evidence of disease. Two studies reported an increased frequency of DQW1 and DR2 antigens (class II HLA). The studies on HLA have not been conclusive, however; variation among families tested suggests that genetic heterogeneity is likely.[7]

Subsequent genome linkage studies identified several loci associated with Paget disease. Mutations in the sequestosome SQSTM1/p62 gene were identified in 30% of familial Paget cases. The SQSTM1/p62 protein is a selective activator of NFB (nuclear factor kappa-B) transcription factor, which is involved in osteoclast differentiation and activation in response to the cytokines interleukin-1 (IL-1) and RANKL (receptor activator of nuclear factor kappa-B ligand). How germline DNA mutations can cause bone disease that is focal in nature remains unclear.

Alterations in cytokine expression have been found in persons with Paget disease[8] : elevated interleukin-6 (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.[9, 10]

Osteoclast precursors in patients with Paget disease also appear to be hyperresponsive to vitamin D (specifically, 1,25(OH)2 D3, the active form of vitamin D3[11] ) and calcitonin and have up-regulation of the c-fos proto-oncogene[12] and BC12, the antiapoptosis gene. Treatment efficacy of bisphosphonates in Paget disease may be due to suppression of RANKL-induced bone resorption, with decreases in RANKL and increased osteoprotegerin production.

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 Paget disease; however, its exact role remains to be determined.

The development of Paget disease of bone may be related to a deregulation of autophagy, a catabolic process responsible for the degradation of damaged organelles, cytoplasmic proteins, and protein aggregates. Structures observed in the cytoplasm of many osteoclasts in Paget disease may be protein aggregates that would normally be degraded via autophagy.[13]

Variants of several genes involved in the process of autophagy, such as SQSTM1, VCP, and OPTN have been linked with Paget disease. For example, 20–40% of patients with a positive family history of Paget disease and 5–10% of patients with sporadic Paget disease are carriers of a mutation in SQSTM1.[13]

A missense mutation in the zinc finger protein 687 gene (ZNF687) has been found in Paget disease–affected members of a large family, several of whom had giant cell tumors of bone associated with Paget disease. ZNF687 wasalso upregulated in the peripheral blood of Paget disease–affected family members with and without mutations in SQSTM1.[14]

A study of ATG genes, which code for proteins involved in autophagy, found that persons who are carriers of the C allele of the ATG16L1 rs2241880 and the G allele of ATG5 rs2245214 polymorphisms were associated with an increased risk of developing Paget disease, whereas carriers of the T allele of ATG10 rs1864183 polymorphism were at decreased risk.[13]

Environmental factors

Environmental factors also may contribute to the pathogenesis of Paget disease. Supporting observations include the variable penetrance of Paget disease within families with a genetic predisposition; the fact that the disease remains highly localized to a particular bone or bones rather than affecting the entire skeleton; and data that reveal a declining incidence and severity of the disease over the past 20-25 years.

Viral infection

The leading hypothesis for an infectious etiology in Paget disease is the slow virus theory. According to this hypothesis, bone marrow cells (the progenitors of osteoclasts) are infected by a virus, causing an abnormal increase in osteoclast formation. Clinical expression of these viral infections may take years, which may account for the advanced age of most people diagnosed with Paget disease. Familial and geographic clustering also may support the theory of a viral process.

Suspected viruses are paramyxoviruses, such as measles or canine distemper viruses. Respiratory syncytial virus also is suspected; however, no virus has been cultured from pagetic tissue, and extracted ribonucleic acid (RNA) has not confirmed a viral presence.

Some studies have found viral inclusion particles in pagetic osteoclasts.[15] 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 paramyxovirus-like 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.

Other suggested etiologies

The possibility of an inflammatory cause of Paget disease is supported by evidence of clinical improvement after treatment with anti-inflammatory medications. Elevated parathyroid hormone in Paget disease also has been observed, but no firm evidence links the 2 disorders, and one case of Paget disease was diagnosed in a patient with idiopathic hypoparathyroidism. An osteogenic mechanism also has been proposed. Autoimmune, connective tissue, and vascular disorders are proposed as other possible etiologies.

Epidemiology

United States statistics

Paget disease is estimated to affect 1 to 3 million people in the United States. Epidemiologic studies are inherently imprecise, however, because many individuals with Paget disease are asymptomatic.

According to a 2000 study by Altman et al, the prevalence of pelvic Paget disease in the United States was 0.71% ± 0.18%, 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 increases with age, with the highest prevalence in persons older than 65 years. A survey study suggested that the prevalence in the United States is 2.3% of the population between ages 65 and 74 years.[16] Paget disease is estimated to occur in 1-3% of individuals older than 45-55 years and in up to 10% of persons older than 80 years. Geographically, pelvic Paget disease was least common in the southern United States and most common in the northeastern United States.[16]

International statistics

The prevalence of Paget disease varies greatly in different areas of the world. The highest prevalence is in Europe (predominantly England, France, and Germany).[17] The United States, Australia, and New Zealand have high prevalence rates because of significant populations with northern European ancestry and a large population of British immigrants.[18] The disease is rare in Asian countries, especially China, India, and Malaysia, and in the Middle East and Africa.

Prevalence may vary even within the same country.[19] A prevalence of 2% in certain British cities can be contrasted with rates in Lancaster, England, which had a prevalence of 8.3%.[20]

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-Saharan Africa is 0.01-0.02%. 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.

Research from Europe and New Zealand indicates that the prevalence of Paget disease has decreased since the 1980s but that increased incidence with age has been maintained.[21] The estimated prevalence of Paget's disease in patients aged 55 years or older has decreased to approximately 2%.

Race-, sex-, and age-related differences in incidence

Paget disease is not known to demonstrate a predilection for any race. Nevertheless, unusual patterns of prevalence have been noted. Paget disease is more common in males than females. The male-to-female ratio is approximately 1.8:1.

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 the fifth decade of life and is most commonly diagnosed in the sixth decade. The incidence of Paget disease in persons older than 80 years is approximately 10%. There is a juvenile form of Paget disease, but it is very different from the adult form.[22]

Prognosis

The general outlook for patients with Paget disease is good, especially if treatment is administered before major changes have occurred in the bones. Treatment does not cure Paget disease, but it can control it. Patients with severe polyostotic Paget disease have a less favorable prognosis than those with monostotic disease. Patients with polyostotic disease are at higher risk for complications.

Morbidity from Paget disease can be extensive. The excessive remodeling of bone associated with Paget disease may result in pain, fractures, and bone deformities. Complications associated with fractures, such as articular and neurologic problems, may increase mortality in patients with Paget disease. The hypervascularity of bone that may result from Paget disease may cause excessive bleeding following fractures or surgery.

The prognosis is extremely unfavorable if the patient has any type of sarcomatous degeneration, especially if there is multicentricity. The 5-year survival rate for a patient with Paget disease and sarcoma is 5-7.5%; however, it may be as high as 50% for those who undergo operative tumor ablation and chemotherapy before metastases occur. The 5-year survival rate for elderly patients with primary nonpagetic sarcoma is 37%.

Higher doses of radiation may be delivered if the neoplasm is located on the limb. Consequently, a more central lesion carries a less favorable prognosis.

Patient Education

Patient education about the pathophysiology of Paget disease and its complications is essential. The patient needs to understand the importance of proper posture, body mechanics, and avoidance of trauma. Precautions against falling should be reinforced. At the same time, the hazards of immobility increase greatly with Paget disease. The patient should understand the necessity of staying active.

Knowledge of the signs and symptoms of complications is important. For instance, increased local pain with soft tissue mass should be reported to a physician immediately, as this may represent a sarcoma.

Understanding the potential side effects of medications is helpful and reassuring to the patient. For example, patients taking bisphosphonates should be aware of the potential for osteonecrosis of the jaw.

Patient education about delayed bone healing and the long rehabilitation process is important in situations of fracture and postsurgery. Reinforcement about the importance of careful, prolonged, protected weight bearing is crucial because the pagetic bone is abnormal and weak. Nonunion and refracture rates are high among patients with Paget disease.

Family members should be informed of the increased incidence of Paget disease in families. Proper patient education on the nature of Paget disease is essential. The Paget Foundation for Paget's Disease of Bone and Related Disorders (telephone: 800-237-2438) can provide useful information for patients.

 

Presentation

History

Paget disease is a localized disorder that may be monostotic (affecting only one bone) or polyostotic (affecting 2 or more bones). Monostotic disease accounts for 10-35% of cases.

Paget disease has a predilection for the axial skeleton. The condition commonly affects the pelvis and spine, particularly the lumbar spine, with a frequency of 30-75%. The sacrum is involved in 30-60% of cases and the skull in 25-65% of cases. The proximal long bones, especially the femur, also are frequently affected (25-35% of cases). Involvement of the shoulder girdle and proximal humerus is not uncommon. Though any bone may be affected, the fibula, ribs, and bones in the hands and feet are involved infrequently.

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.[22] In these patients, the incidental finding of an elevated serum alkaline phosphatase level or characteristic radiographic abnormality may lead to detection of the disease. However, when symptoms do occur, bone pain is the most common complaint. The bone pain is dull, constant, boring, and deep below the soft tissues. It may persist or exacerbate during the night.

Hip pain is most common when the acetabulum and proximal femur are involved, especially in the sclerotic stage. Bowing of the femur and long bones or protrusion of the acetabulum causes pain that becomes worse with weightbearing and is relieved with rest. Knee and shoulder pain may occur because of altered mechanical forces across the articular joints from deformed bones.

Other patients with Paget disease present with a range of manifestations related to complications. These include musculoskeletal, neurologic, and cardiovascular problems.

Pathologic fractures commonly result from weakened pagetic bone. Subtrochanteric femur fractures are the most common fractures affecting the lower limbs.

Nonspecific headaches, impaired hearing, and tinnitus commonly result from skull involvement. The patient's hat size may increase (or, less commonly, decrease) as a result of skull enlargement or deformity.

The most common cranial symptom is hearing loss, occurring in 30-50% of patients with skull involvement. The most common neurologic complication is deafness as a result of involvement of the petrous temporal bone. The hearing loss or deafness may be conductive (due to involvement of the middle-ear ossicles), sensorineural (due to auditory nerve compression/cochlear involvement), or mixed. Vertigo or tinnitus may occur with a frequency of 25% in patients who have Paget disease with cranial involvement.

Cranial nerve palsies can affect nerves other than the auditory nerve; however, this development is uncommon. Changes in vision may occur secondary to optic nerve involvement.

Back and neck pain are common complaints, as Paget disease frequently affects the spine, especially the lumbar and sacral regions. Softened bone at the base of the skull may lead to platybasia, the descent of the cranium onto the cervical spine. Progressive pain, paresthesias, limb paresis, gait difficulties, or bowel and bladder incontinence may be caused by compression of the spinal cord or spinal nerve secondary to platybasia or vertebral fractures.

Skull deformities may lead to hydrocephalus, basilar invagination, and cerebellar or brainstem compressive syndromes. These may manifest as nausea, dizziness, syncope, ataxia, incontinence, gait disturbances, or dementia.

Involvement of the jaw and facial bone is uncommon in Paget disease, but it does occur. Facial disfigurement and malocclusion may be observed following enlargement of the maxilla or mandible. Tooth loss may occur with progressive root resorption. Absent periodontal membranes and lamina dura are associated with excessive cementum formation.

Increased bone pain with an enlarging soft tissue mass and a lytic lesion is suggestive of a neoplasm (osteosarcoma), especially if a pathogenic fracture is present. This is an uncommon but potentially deadly complication.

Physical Examination

The physical examination findings may be normal in patients with Paget disease. In symptomatic cases, visual inspection may reveal bony deformities, such as an enlarged skull, spinal kyphosis, and bowing of the long bones of the extremities. Bone angulation and deformity may affect joints, with resulting pain and decreased range of motion. Because patients with Paget disease may also have gouty arthritis, they also should be evaluated for the presence of tophi.

Localized pain and tenderness may be elicited with manual palpation. Superficial pressure reveals increased warmth of the skin at the affected site. Skin temperature may be correlated with metabolic activity of underlying bone and bone pain. Auscultation may reveal bruits of the tibia or skull. A soft tissue mass with increased pain may be caused by neoplasms, such as osteosarcoma.

Paget disease of the skull may be asymptomatic; however, approximately one third of patients experience an increase in head size with or without deformity (frontal bossing, enlarged maxilla). The most common neurologic problem is hearing loss from 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. Ataxia, gait disturbances, dementia, and neurologic compromise may result from hydrocephalus and cerebellar compression.

With involvement of the lumbar spine, spinal stenosis or kyphosis may develop. If Paget disease affects the thoracic spine, the patient may have spinal cord compression, which can lead to neural function loss. Muscle weakness, paraparesis, and sensory loss compatible with spinal cord injury (SCI) may be present.

Fracture of a pagetic bone is an occasional and serious complication and may be either traumatic or spontaneous. The femur is the most common site of pagetic fracture. Most pagetic bone fractures heal normally.

Complications

Complications of Paget disease include the following:

  • Fractures
  • Neoplasms
  • Neuromuscular syndromes
  • Joint disease
  • Cardiovascular abnormalities

Angioid streaks of the retina have been found more commonly in patients with Paget disease and are quite frequent in pseudoxanthoma elasticum. Angioid streaks are linear disruptions of the Bruch membrane, with proliferative connective tissue emerging through the defects.

Other complications of Paget disease include the following:

  • Hashimoto thyroiditis
  • Dupuytren contracture
  • Chondrocalcinosis
  • Osteogenesis imperfecta
  • Osteopetrosis

Fractures

Incomplete stress fractures frequently occur in Paget disease. Cortical stress fractures are common in the femur and tibia, with distinctive horizontal radiolucencies affecting the convex surface of the bone, whereas in osteomalacia, similar findings are seen on the concave aspects of the bone. Cartilaginous calluses, which do not mineralize fully in the fracture clefts, account for the relative radiolucency. Incomplete fissure fractures can extend into complete fractures.

Mild injuries may cause acute true pathologic fractures in weakened pagetic bone. Pathologic fractures are more common in women than in men. The most frequent site of these fractures is the femur, but fractures commonly occur in the tibia, humerus, spine, and pelvis. Femur fractures are most common in the subtrochanteric region, followed by the upper third of the femoral shaft and then the neck.

Nonunion and refracture at the same sites are much more common, as developing calluses may be affected by Paget disease. The rate of nonunion has been reported to be 40%.[23] Biopsies of pathologic fractures may be recommended to rule out sarcoma.

Neoplasm

Sarcomatous degeneration of pagetic bone is a deadly complication. Osteosarcoma is a rare complication, but it should be suspected in patients who have a sudden increase in bone pain or swelling.[24] Pagetic sarcoma is malignant, and the course usually is rapid and fatal. Sarcomatous degeneration may occur in 5-10% of patients with extensive pagetic skeletal involvement, but it may occur in less than 1% of patients with less widespread involvement.

Men are affected with sarcomatous degeneration slightly more frequently than are women. Peak incidence is in the seventh and eighth decades of life. The femur is the most commonly affected site, followed by the proximal humerus; however, no bone is exempt, including sites of previously healed fractures.

Sarcomas appear to originate from the fibrotic substrate of pagetic bone, and the predominance of certain cells determines the diagnosis. Osteosarcoma is the most common type of pagetic sarcoma (50-60%), followed by fibrosarcoma (20-25%), chondrosarcoma (10%), and sarcoma of myeloid and mesenchymal elements. Sarcomatous bone destruction or osteolysis is more characteristic of pagetic sarcoma than osteosclerosis. Overall, the proportion of Paget disease patients with sarcoma has fallen steadily since Paget's original report and is now about 0.3%,[24] likely related to availability of effective therapies.

Other clinical and radiographic findings include the following:

  • Increased pain with a progressive lytic lesion

  • An enlarging soft tissue mass

  • Bony speculation

  • Persistent fracture without healing

  • Cortical destruction

In 33% of cases, the presentation involves a pathologic fracture of an affected long bone.

Giant cell tumors are benign and may arise from pagetic bone. They usually involve the facial bones and mandible, although other sites, such as the pelvis, may be affected in rare cases. Giant cell tumors commonly affect elderly patients. They share some characteristics of sarcomas, as they typically affect patients with widespread polyostotic Paget disease and present as a soft tissue mass with a lytic lesion.

The prognosis for patients with Paget disease who have giant cell tumors usually is good. High doses of steroids have been shown to reduce tumor mass. Radiation and surgery also have been used to treat symptomatic giant cell tumors.

Lymphomas, multiple myelomas, Hodgkin lymphoma, leukemias, and metastatic disease all have been found in association with Paget disease. However, these neoplasms probably represent chance occurrences rather than true complications.

Neuromuscular syndromes

Acute spinal cord compression may occur from pathologic fractures, such as vertebral body compression fractures. Enlargement of the pedicle, lamina, or vertebral body from the pagetic process also may cause spinal cord injury. Likewise, nerve root or spinal nerve compromise may occur. Spinal cord compression is most frequent in the upper thoracic spine because of the small vertebral canal.

Spastic quadriplegia can result from platybasia. Basilar invagination or compression of posterior fossa structures may lead to cerebellar or brainstem compressive syndromes. The vertebrobasilar blood supply also may be compromised by kinking of the blood vessels. Extradural fat ossification has been observed to be a cause of cauda equina syndrome. Hydrocephalus can be a complication, albeit a rare one.

Entrapment of cranial nerves by pagetic bone may result in the expected cranial nerve palsies. The most common of these is injury to the eighth cranial nerve (the vestibulocochlear nerve), with resultant impaired hearing and deafness. The hearing loss may be sensorineural, conductive, or mixed and may be caused by compression from pagetic bone involvement of the temporal bone and labyrinth. Structural abnormalities of the ossicles of the middle ear and toxic effects to the inner ear have been observed.

The optic nerve may be the second most commonly affected cranial nerve. Sciatic nerve compression between an enlarged ischium and lesser trochanter of the femur in external rotation or between the ilium and the piriformis muscle in internal rotation also has been described.

Joint disease

Degenerative joint disease is associated with Paget disease. The most commonly reported site of articular abnormality is the hip. The knee also is commonly affected. The glenohumeral joint also may be affected, impairing rotator cuff function.

Degenerative joint disease of the hip associated with Paget disease differs in appearance from primary degenerative joint disease. Osteophyte formation is not prominent.

The frequency of joint-space narrowing of the hip in patients with Paget disease varies in several studies from 50-96%.[25] Joint space loss at the superior aspect of the hip articulation is the most common pattern, with a frequency of 80-85%. Acetabular involvement may cause either medial or axial joint space narrowing, especially if the femoral head also is affected. Acetabular protrusion may occur, causing hip pain that is aggravated by ambulation.

The pathophysiology of arthritic changes associated with Paget disease is unknown. Enlargement of joints and altered biomechanics may cause abnormal stress across joints, giving rise to degenerative changes. Abnormal endochondral ossification that may compromise articular cartilage has been reported. For cases that require surgery, successful outcomes of total hip and knee arthroplasties have been reported.

Conditions that have been found to coexist with Paget disease, but that have no proven relationship with Paget disease, include the following:

  • Rheumatoid arthritis

  • Psoriatic arthritis

  • Ankylosing spondylitis

  • Diffuse idiopathic skeletal hyperostosis

  • Pseudogout

  • Peyronie disease

  • Pigmented villonodular synovitis

Hyperuricemia may cause clinical gout in some patients.

Cardiovascular abnormalities

Increased cardiac output has been observed in patients with Paget disease involving at least 15% of the skeleton. Left ventricular hypertrophy is an associated finding. Increased soft tissue and pagetic bone vascularity has been implicated as a contributing factor. High-output congestive heart failure may occur, but it is rare. The condition has been reported only in patients with severe, widespread Paget disease.

Calcific aortic stenosis is 4 times more common in patients with Paget disease, especially those with severe disease, than in individuals without Paget disease. Calcifications may be produced by the turbulent blood flow across cardiac valves caused by increased cardiac output. Calcifications have been found in the interventricular septum, which may cause heart block and conduction abnormalities.

 

DDx

Diagnostic Considerations

The differential diagnosis of Paget disease includes osteomalacia, which may be part of the spectrum of osseous abnormalities accompanying chronic renal insufficiency. Patients with mild osteomalacia may present with nonspecific bone pain and tenderness. Elevated levels of bone-specific alkaline phosphatase may occur in osteomalacia or in Paget disease.

Both disorders may result in fractures. However, in Paget disease, distinctive horizontal radiolucencies are visible on the convex surface of the bone, whereas in osteomalacia they are visible on the concave aspects of the bone.

Both Paget disease and skeletal metastasis can produce bone pain and radiographically similar lytic lesions. Diagnostic confirmation may require biopsy.[4]

Differential Diagnoses

 

Workup

Approach Considerations

Measurement of serum alkaline phosphatase—in some cases, bone-specific alkaline phosphatase (BSAP)—can be useful in the diagnosis of Paget disease. Elevated levels of urinary markers, including hydroxyproline, deoxypyridinoline, C-telopeptide,[5] and N -telopeptide, may help identify patients with Paget disease.

Procollagen I N -terminal peptide (PINP) has emerged as a sensitive serum marker for bone formation. Serum osteocalcin, which is produced specifically by osteoblasts, does not reflect disease activity.

Serum calcium and phosphate levels should be within the reference range in patients with Paget disease. Urinary excretion of calcium also should be normal. However, hypercalcemia or hypercalciuria may develop with immobilization or coincident primary hyperparathyroidism.

Hyperuricemia from Paget disease is more common in men than women and appears to be caused by the increased turnover of nucleic acids from high bone turnover. Elevated serum uric acid levels have been found in men with severe Paget disease and have been associated with gouty arthritis. Paget disease was found in 23% of a group of patients with gout.[26]

Serum total acid phosphatase is an osteoclastic enzyme that may be elevated in active Paget disease. In males, however, the clinical value of this finding is compromised, as acid phosphatase levels also may be elevated in the presence of metastatic prostate carcinoma.

Secondary hyperparathyroidism may occur in 10-15% of patients with Paget disease. This development may be due to inadequate calcium intake in the face of increased demand from extensive bone remodeling. An increased incidence of primary hyperparathyroidism does not seem to exist among patients with Paget disease.

Plain radiographs and bone scanning should be performed upon initial diagnosis. 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.

Plain radiographs are less sensitive than bone scan scintigraphy in the diagnosis of Paget disease. An entire skeletal survey with plain radiographs to assess the extent of skeletal involvement is not recommended when bone scanning would be more sensitive and involve less radiation exposure.

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) are not needed for the diagnosis of Paget disease of bone. However, both are useful in the evaluation of complications of Paget disease, such as neoplastic degeneration, articular abnormalities, and spinal involvement with neurologic compromise. (See Paget Disease Imaging.) Bone biopsies may be indicated to evaluate for malignant transformation.

Alkaline Phosphatase

Because of increased osteoblastic activity and bone formation, bone-specific alkaline phosphatase (BSAP) levels are elevated. Measuring total alkaline phosphatase levels may be useful in patients with normal liver function. However, BSAP is more specific than total alkaline phosphatase for Paget disease.

A strong relationship exists between the extent of disease activity measured by scintigraphy and the degree of the elevation of alkaline phosphatase in persons with untreated Paget disease.

In patients with monostotic disease or local disease, the total alkaline phosphatase level may be normal. Consequently, a normal alkaline phosphatase level does not exclude the disorder. In this scenario, a BSAP level should be ordered. In patients with abnormal liver function or other causes of elevated alkaline phosphatase activity not due to bone, BSAP is a reasonable means of assessing Paget disease activity.

BSAP had the highest diagnostic sensitivity (84%) in a comparative study of different markers of bone turnover in patients with Paget disease. The next most sensitive marker was total alkaline phosphatase, which had a sensitivity of 74%.[27]

Urinary Markers

Urinary hydroxyproline levels are elevated in Paget disease, as a reflection of increased osteoclastic activity and bone resorption. Hydroxyproline is a product of collagen breakdown. Approximately 20-30% of total hydroxyproline levels are from bone resorption.

Measurement of total urinary hydroxyproline previously was the criterion standard as a marker for bone resorption, hydroxyproline levels having been demonstrated to correlate with the extent and activity of disease. However, the hydroxyproline assay is difficult to perform and is not widely available.

Dietary sources of collagen may increase hydroxyproline excretion in 24-hour urine collections; therefore, an overnight fast often is necessary before testing. Patients with skin disease also may have elevated hydroxyproline levels, since the skin is a major site of collagen synthesis.

Measurement of the urinary excretion of bone-specific pyridinium collagen cross-links has been found to be a sensitive and specific index of bone resorption. Additionally, levels of excreted bone-specific pyridinium collagen cross-links may be better indicators of bone resorption and response to treatment than the hydroxyproline assay. The urinary pyridinoline collagen cross-link assay may replace assessment of hydroxyproline levels as the test of choice.

Urinary N -telopeptide (NTx) and alpha-C telopeptide (CTx) have emerged as sensitive biochemical markers for bone resorption. An abnormally high alpha-CTx/beta-CTx ratio is present in patients with active Paget disease. This ratio returns to the reference range following treatment with bisphosphonates.[28]

Radiographs

The radiographic appearance of pagetic bone reflects the underlying process. Lytic lesions may be the only finding early in the disease. As the disease progresses, radiographs may demonstrate both osteolysis and excessive bone formation. (See the images below.)

Radiograph showing a 44-year-old African American Radiograph showing a 44-year-old African American man with characteristic changes of Paget disease in the left hemipelvis.
Radiograph showing a 72-year-old white woman with Radiograph showing a 72-year-old white woman with Paget disease of the lower leg and typical bowing.

The initial pathologic lesion, which is osteolysis, appears as a radiolucency on the radiograph and is particularly evident in the frontal and occipital bones of the skull, where it is termed osteoporosis circumscripta. The body’s 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.

Osteolysis of the tubular bones usually occurs subchondrally in the epiphysis, with extension into the metaphysis and diaphysis. Advancing osteolysis may appear as a V- or wedge-shaped radiolucent area that may resemble a blade of grass or flame. The remaining trabeculae may be obliterated and a hazy ground-glass or washed-out pattern observed. Focal radiodensities have a cotton-wool appearance. Areas of lysis and radiodensities may be separate or superimposed. In the pelvis, Paget disease may produce the "brim sign," which is the thickened iliopectineal line.

Paget disease of the spine typically affects the vertebral bodies and posterior elements. The enlarged coarse trabeculae combined with the prominent radiodense peripheral contour of the vertebral body gives the appearance of a picture frame that is diagnostic of Paget disease. A homogeneous increase in osseous density in the vertebral body gives the manifestation of an ivory vertebra. Skeletal metastasis and lymphoma also may produce ivory vertebrae.

Furthermore, altered vertebral body shape is common as a result of structurally weak pagetic bone. Biconcave-shaped vertebral bodies, also called fish vertebrae, may be seen in osteomalacia, hyperparathyroidism, and osteoporosis. The biconcave shape is caused by intervertebral disc compression of the weakened vertebrae.

Intervertebral disc space narrowing may occur from secondary degenerative disc and joint disease. Vertebral body ankylosis may be seen. Loss of vertebral height is observed commonly as a result of bone remodeling and compression fractures. Posterior element involvement may manifest as increased pedicular radiodensities that also are seen in osteoblastic metastasis.

Later in the disease, evidence of lysis may be absent because only sclerotic thickened bones may remain. The osteosclerosis is most notable in the axial skeleton and pelvis. An enlarged bone with increased radiodensity and trabeculations is characteristic; as seen in advanced disease, burnt out bones are widened and heterogeneously ossified.[29] Radiographic evidence of remineralization may occur after initiation of appropriate treatment, such as with the bisphosphonates.

Bone Scans

Radionuclide bone scans have several uses in Paget disease. Initially, scans are helpful for documenting the extent of the disease. Serial bone scans may provide objective evidence of the effect of therapeutic agents. If a patient experiences increases in pain, elevation in BSAP levels, or pathologic fractures, further studies are important to help exclude neoplasms, including sarcomas and giant cell tumors.

Bone scanning is the most sensitive test for evaluating the extent of lesions in the whole skeleton affected by Paget disease. Bone scintigraphic abnormalities are observed earlier than radiographic changes during the active stage of Paget disease. However, bone scanning is less specific than plain radiography, and changes detected by scintigraphy may need to be confirmed by a plain radiograph of at least one site.

With bone scanning, the percentage of isotope retention after 24 hours may provide an index of total pagetic nuclear imaging. The concentration of scintigraphic uptake in a pagetic lesion may correlate with the grade of radiologic deformation and the frequency of pain. Total skeletal uptake may correlate with levels of serum alkaline phosphatase and urinary hydroxyproline; however, bone scans are sensitive but not specific. Quantitative bone scintigraphy is useful for assessing a monostotic lesion with a normal alkaline phosphatase.

During the aggressive osteoclastic resorptive phase, bone scanning may underestimate disease activity, as in multiple myeloma. In the quiescent osteosclerotic stage, pagetic lesions may be detected radiographically but not scintigraphically.

CT and MRI

Articular abnormalities require CT scanning or MRI to delineate the extent of involvement. CT scanning and MRI are useful to diagnose and evaluate neurologic complications, such as basilar invagination, spinal cord compression, or hydrocephalus. Spinal stenosis and vertebral involvement are assessed best with CT scanning or MRI.

CT scanning provides better visualization of bone and the posterior fossa, while MRI gives superior detailing of the brain, spinal cord, cauda equina, and soft tissue. Thus, neoplastic entities, such as pagetic sarcomas, and their extent of involvement are evaluated better with MRI.

Histologic Findings

The major histologic feature of Paget disease is abnormal bony architecture. The 3 distinct phases in Paget disease (osteolytic, mixed, and osteosclerotic) may exist separately or in the same bone at one time.

The initial osteolytic phase is marked by disordered areas of resorption produced by an increased number of overly large osteoclasts. These abnormal osteoclasts may contain as many as 100 nuclei. The subsequent osteoblastic phase follows, with haphazard laying of new bone matrix and formation of woven bone. Repeated episodes of bone removal and formation result in the appearance of many small, irregularly shaped bone fragments that appear to be joined in a jigsaw or mosaic pattern. This pattern is the histologic hallmark of Paget disease.[30]

As the disease progresses, the osteoblastic phase predominates, and excessive abnormal bone formation occurs, resulting in more compact and dense bone. The pagetic bone is coarse and fibrous, with avidity for calcium and phosphorus.

Marrow spaces fill with loose, highly vascularized connective tissue. The hypervascular bone, combined with cutaneous vasodilation, causes an increase in the regional blood flow and accounts for the rise in skin temperature seen clinically. The hypervascularity consists of an increased number of patent capillaries and dilated arterioles, as well as of larger venous sinuses.

The normal trabecular appearance is distorted, with a mosaic pattern of irregular cement lines joining areas of lamellar bone. Pagetic bone shows no tendency to form haversian systems or to center on blood vessels; the bones are very hard and dense. Eventually, the osteoblastic activity diminishes, and an osteosclerotic or burned-out phase predominates. The new bone is disordered, is poorly mineralized, and lacks structural integrity.

 

Treatment

Approach Considerations

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

Indications for drug treatment of Paget disease are as follows[31] :

  • Metabolic active disease - Bone pain, fatigue fracture, skull/spine fracture, radiculopathy, osteolytic lesions, bony deformities, weight-bearing bone involvement, compression of spinal cord and nerve roots, bone compression of the eighth cranial or optic nerve

  • Preparation for orthopedic surgery (joint replacement anticipated at involved sites within 6 months)

  • Hypercalcemia or hypercalciuria - Recurrent renal calculi due to hypercalciuria, or fractures; serum alkaline phosphatase or urine hydroxyproline levels greater than twice the upper limit of the reference range; immobilization

When Paget disease occurs around a joint, treatment is often administered in an attempt to prevent development of osteoarthritis. In addition, young patients with Paget disease and those with high levels of bone-specific alkaline phosphatase (BSAP) are often treated to avoid future complications. The concept that aggressive treatment is associated with prevention of progression and reduction in risk of future complications is not yet supported by clear findings from long-term placebo-controlled trials; however, indirect evidence suggests that this hypothesis is reasonable.

Drug therapy for Paget disease should include bisphosphonate treatment with serial monitoring of bone markers. Response to therapy is indicated by reduction of symptoms and decreases in levels of BSAP (a bone formation marker) and deoxypyridinoline, C-telopeptide,[5] or N-telopeptide (bone resorption markers).  A sustematic review of 20 studies found moderate-quality evidence that bisphosphonates improved pain in patients with Paget disease.[32]

Patients should receive 1000-1500 mg of calcium and at least 400 U of vitamin D daily. This recommendation is especially important in conjunction with bisphosphonate treatments.

Secondary osteoarthritic pain may be reduced by nonsteroidal anti-inflammatory drugs or other nonnarcotic analgesics. In contrast, bone pain in Paget disease typically responds poorly to these pain medications. 

Orthotic devices, including canes and walkers, may be useful for patients with gait abnormalities resulting from Paget disease that involves the lower limbs. See Rehabilitation for Paget Disease.

Because of the increased risk of malignancy, patients with Paget disease should be monitored indefinitely. Chemotherapy, radiation, or both may be used to treat neoplasms that arise from pagetic bone. Amputation may also be necessary in the presence of a malignant transformation.

Bisphosphonates and Calcitonin Analogues

The following prescription drugs have been approved and are available for treating Paget disease in the United States[33, 34] :

  • Etidronate
  • Pamidronate
  • Alendronate
  • Tiludronate
  • Risedronate
  • Zoledronic acid
  • Salmon calcitonin

Pamidronate and salmon calcitonin are administered parenterally. (Human calcitonin is no longer available.) Ibandronate (Boniva) and olpadronate are potent bisphosphonates but are not approved by the Food and Drug Administration (FDA) for the treatment of Paget disease. (Ibandronate is approved by the FDA for the treatment of osteoporosis.) They may play a role in the future, depending on the results of clinical trials.

Preliminary European studies have shown that a single 2-mg injection of ibandronate is capable of suppressing disease activity in patients with Paget disease over a 12-month period.[35] In patients in whom this was insufficient to suppress disease activity, application of a higher dose was sometimes more effective.

In a long-term follow-up study of 25 patients with active Paget disease who were treated with a single intravenous dose of  6 or 12 mg of ibandronate, Reid et al reported that although some patients showed gradual increases in alkaline phosphatase levels after 20-30 months, levels remained normal 3 years after treatment in 15 of the 25 patients, and after 6 years, six of the patients continued to maintain normal levels without further intervention.[36]

Olpadronate is chemically similar to pamidronate, with the nitrogen atom being converted to a tertiary amine by the addition of 2 methyl groups. Preliminary studies in Europe and South America have suggested that olpadronate may be useful in the treatment of Paget disease.[37]

All bisphosphonates have poor absorption from the gut. Furthermore, they also combine with any calcium in the stomach, further inhibiting absorption. Thus, an oral bisphosphonate should not be ingested with food or any drink containing calcium.

Given the comparative double-blinded studies in which bisphosphonates were compared with one another (ie, tiludronate vs etidronate, alendronate vs etidronate, risedronate vs etidronate, pamidronate vs alendronate, zoledronic acid vs risedronate), the following conclusions can be made regarding these medications for the treatment of Paget disease[28, 33, 38, 39, 40, 41, 42, 43] :

  • Etidronate was less effective than the other bisphosphonates in suppressing biochemical markers of disease activity and should not be used as a first-line agent if the other bisphosphonates are available

  • No significant difference was noted between the bisphosphonates with regard to bone pain

  • Oral tiludronate (400 mg/day for 12 weeks), oral risedronate (30 mg/day for 2 months), and intravenous pamidronate (3 infusions of 60 mg at 2-week intervals, or 6 infusions of 30 mg at weekly intervals) have each been shown to be effective and superior to etidronate[41]

  • Bisphosphonates should be used as first-line agents over salmon calcitonin

  • Zoledronic acid infusions at 6 months shows significant normalization of alkaline phosphatase over oral risedronate[43]

Retreatment is indicated if a patient has not responded after 6 months following treatment or if clinical or biochemical relapse occurs. Some of these patients may respond better to a more potent bisphosphonate. Continued relapse or persistence can be evidenced by pain, but it should be confirmed by objective evidence of continuing disease activity. In the absence of continuing disease activity, other sources of pain should be investigated.

In situations in which treatment was based on the presence of asymptomatic disease in a critical site, retreatment must be based on biochemical criteria. No clinical-trial evidence supports this base criterion. However, the general consensus opinion is that an increase of alkaline phosphatase of 25% above nadir (even if the total is still within the normal range) indicates significant relapse.

The PRISM study, a randomized trial, concluded that intensive bisphosphonate therapy confers no clinical advantage over symptom-driven management in patients with established Paget disease. PRISM compared two treatment strategies with bisphosphonates: an aggressive approach in which patients were treated when they had alkaline phosphatase elevation, irrespective of symptoms, with a goal of primary biochemical normalization; and another, treating only symptomatic patients. On follow-up for a median of 3 years, no differences were found between groups in the number of prosthetic hip replacements, number of fractures, or hearing loss. Neither strategy provided significant pain relief or improvement in quality of life.[44]

A 3-year extension of the PRISM study using zoledronic acid (PRISM-EZ) reported that intensive bisphosphonate therapy may actually be harmful. In PRISM-EZ, patients in the intensive therapy arm were significantly more likely to experience a fracture or undergo orthopedic surgery than those in the symptomatic arm (hazard ratio 1.94, P=0.029).[45]

In patients who present with Paget disease at an older age, treatment may require only a single intravenous infusion of zoledronic acid. In a study of 107 patients who had been treated with intravenous zoledronate for the first time at a mean age of 76 years, Cundy et al found that by 9 years, only 14% had a biochemical relapse (defined as a procollagen-1 NT-peptide [P1NP] value >80 µg/L), although 64% of patients showed some loss of bisphosphonate effect (defined as a doubling of the P1NP level from the nadir value after treatment). The mortality rate was substantially greater than the relapse rate; by 10 years, more than half the cohort had died.[46]

Alendronate

In one study, 6 months of oral alendronate at the recommended 40-mg regimen produced normalization of alkaline phosphatase in 63% of patients with Paget disease, compared with 17% after treatment with 400 mg/day of etidronate. The mean initial alkaline phosphatase level was 5 times the upper limit of reference range.

In this study, after 18 months, 25 of 29 patients whose alkaline phosphatase levels had normalized and who were available for follow-up still had levels in the reference range. After 25-30 months, 15 patients still had alkaline phosphatase levels the in reference range. This study showed alendronate to be more potent at suppressing Paget disease activity than etidronate. Studies have also shown that alendronate treatment can lead to cessation of radiologic progression and healing of radiologic lesions.

Pamidronate

Anderson et al induced biochemical remission with one or more complex courses of pamidronate in 90% of patients with elevated alkaline phosphatase levels. Average remission was 2 years, with a supposed permanent remission in 10-15%. The regimen consisted of a 30-mg infusion over 2 hours, followed by 3 infusions of 60 mg each over 4 hours for alkaline phosphatase levels less than 500 IU/L; levels greater than 500 IU/L required 6 infusions of 60 mg each at 2-week intervals.

Many single-dose regimens have been studied. Watts et al used a single infusion of 105 mg and achieved a remission rate of 71%, with a mean enzyme nadir at 6 months. Excellent symptomatic control was achieved at 1.5-2 years. Some patients required a second infusion, with a mean interval of 19 months after the first dose. Another single-dose regimen by Chakravarty et al, using 60 mg of IV pamidronate, provided efficacy similar to that of the Watts et al study.

Although a 30-mg IV infusion over 4 hours on 3 consecutive days is the approved therapeutic regimen, it is not used often. Infusions of 60 or 90 mg over 2-4 hours are more common. A single infusion is effective in mild disease, while 2-3 infusions may be needed in severe disease.

Depending on initial response, pamidronate may be readministered at irregular intervals. In general, more severe disease produces more severe biochemical and radiographic abnormalities that require higher dosages to achieve remission.

In a 2-year, open-label study comparing intravenous administration of pamidronate 60 mg every 3 months with daily oral administration of alendronate 40 mg in 3-month blocks, there were no significant differences in the proportion of patients whose alkaline phosphatase levels normalized (86% and 91%, respectively) or the proportion of patients who had an improvement in symptoms.[42]

Risedronate

In a comparative study, normalization of alkaline phosphatase was achieved in 77% of patients treated with risedronate, compared with 10% using a 400-mg etidronate regimen. After 12 and 18 months, respectively, 60% and 53% of patients treated with risedronate still had alkaline phosphatase levels in the reference range. A randomized, double-blinded comparison study of risedronate with etidronate showed that alkaline phosphatase levels were normalized in 75% of patients taking risedronate but in only 1 in 7 patients taking etidronate.

Tiludronate

When given for 12 weeks, a daily regimen of 400 mg of tiludronate reduced alkaline phosphatase activity by 58% at 24 weeks. Pretreatment alkaline phosphatase levels were twice those of the reference range. Double-blinded controlled studies demonstrate that bone turnover markers are better suppressed by tiludronate than by placebo. These studies suggest tiludronate treatment is associated with 40-72% reduction in alkaline phosphatase activity. Pagetic bone pain also improved.

Zoledronic acid

In a randomized, double-blind trial comparing a single intravenous infusion of 5 mg of zoledronic acid with oral administration of 30 mg of risedronate daily for 2 months, normalization of alkaline phosphatase levels was achieved at 6 months in 89% and 58% of patients, respectively. Those receiving zoledronic acid had greater improvement in some domains of health-related quality of life, but the changes observed were small—1 to 2 points—which is below the threshold of 5 points for a change that is considered to be clinically significant.[43]

Given the development of several intravenous infusions for treatment of Paget bone disease, a 15-month, randomized study compared different intravenous bisphosphonates in patients with active disease. The medications used were pamidronate or zoledronate. After 6 months, the nonresponders to pamidronate were crossed over to zoledronate or neridronate. It was concluded that zoledronic acid was more effective and associated with an earlier response and longer remission.[47]

A follow-up study of the subset of patients whose alkaline phosphatase levels had been normalized during the trial compared the use of a single infusion of zoledronic acid,[43, 48] with a 2-month course of oral risedronate. Better quality-of-life scores and more prolonged suppression of alkaline phosphatase levels were reported for the patients receiving zoledronic acid.[49]

A study by Devogelaer and colleagues examining Paget disease remission after treatment with a 5 mg intravenous infusion of zoledronic acid in routine clinical practice found effectiveness and safety data similar to those observed in the original trial populations. Response rates were 93.3% at 1 year, 89.5 % at 2 years, and 91.6 % at 3 years.[50]

These studies have shown that a single infusion of 5 mg of zoledronic acid is associated with a greater percentage of normalization of serum alkaline phosphatase in treated patients and a prolonged biochemical remission with lower relapse rate,[49] making it the most effective therapy available to date.

Neoplasm

Amputation usually is the most appropriate treatment for neoplasms because of the aggressive behavior of this type of sarcoma, which is the typical late presentation in elderly patients. Amputation has been the most effective palliative or curative surgical management, especially with a spontaneous pathologic fracture. A localized long-bone lesion without metastases may be treated with preoperative chemotherapy, followed by wide tumor resection and limb-salvage procedure.

Management of metastatic sarcomas with pathologic fractures may involve internal fixation and local irradiation as a palliative approach. Pagetic sarcomas have a less favorable prognosis than primary nonpagetic osteosarcomas. Chemotherapy regimens effective for nonpagetic sarcomas are ineffective against pagetic sarcomas.

Joint Disease

Though few patients with Paget disease ever need surgical treatment, successful surgical management of severe orthopedic complications of this disease has improved the quality of life for these patients.[51] Indications for surgery include unstable fractures and severe arthritis refractory to medical and physical therapy. Malalignment of major weight-bearing bones may be treated with functional bracing and antipagetic medications. Realignment of severe lower limb deformities may help reduce mechanical joint pain and restore function. Joint replacement surgery may be indicated for end-stage joint disease if nonsurgical treatment fails to relieve pain adequately.

Total hip replacement is the most common orthopedic surgery performed on patients with Paget disease. The indication for total hip replacement is severe mechanical joint pain unrelieved by antipagetic medication. Thus, it is important to differentiate mechanical joint pain from pagetic bone pain.

Flexible intramedullary fixation devices are preferred over plate and screw fixation, which is associated with increased risks of perioperative complications, such as acetabular protrusion, aseptic loosening, and varus deformity of the femoral components. Heterotopic ossification is a common complication.

Mechanical failure requiring revision of the operation occurred in 10-15% of patients in several studies; however, total hip arthroplasties have been quite successful in relieving pain and improving mobility, with good to excellent results in 75-85% of patients on the basis of well-accepted scales of pain relief and function.

Preoperative treatment with bisphosphonates or calcitonin reduces intraoperative bleeding by decreasing disease activity.[28] Antipagetic medication should be started at least 6 weeks prior to elective surgery.

Tibial and fibular osteotomies have been effective in correcting tibial varus deformities and in relieving knee and ankle pain associated with these deformities. The indication for a tibial osteotomy is severe joint pain unresponsive to medical treatment.

Patient education about delayed bone healing and a long rehabilitation process is important. Reinforcement about the importance of careful, prolonged, protected weight bearing should be provided because the pagetic bone is abnormal and weak. Complete immobilization should be avoided because of its association with osteopenia and increased risk for hyperkalemia and hypercalciuria.

Spinal Disease

The most common cause of neurologic dysfunction from pagetic spinal stenosis is osseous compression from an enlarged vertebral body. Symptomatic pagetic spinal stenosis can be treated successfully with bisphosphonates and calcitonin.[28]

Surgical decompression rarely is needed. Decompressive laminectomies may be helpful for pagetic spinal stenosis and persistent mechanical pain unresponsive to nonsurgical treatment.[52]

Diet and Activity

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.

No specific adjustments in physical activity levels are necessary in patients with Paget disease. If secondary osteoarthritis occurs in the knee, quadriceps-strengthening exercises may be helpful. If bone pain occurs with weightbearing or if gait abnormalities are present, individualized adjustment in physical activity regimens may be made.

Transfer

Patients with Paget disease usually are medically stable. Complications (eg, neurologic compromise from spinal cord compression or hydrocephalus; brainstem compression from platybasia, basilar invagination, vertebral fracture, spinal stenosis) require transfer to the neurosurgical service.

Neoplastic complications, such as pagetic sarcomas, may require surgical debridement, radiation, or chemotherapy, with subsequent transfer to an oncologic service.

Deterrence

No preventive programs exist for Paget disease, because the etiology remains unknown, and no long-term prospective studies have been conducted to support the preventive effects of chronic suppressive therapy on the risk of pagetic complications.

A patient who has a family history of Paget disease and is older than 40 years may wish to have an alkaline phosphatase blood test every 2-3 years. If the alkaline phosphatase level is within the reference range, radiography or bone scanning also may be performed.

Consultations

Consultations sometimes are indicated for patients with Paget disease. Because each patient has a unique combination of symptoms, the appropriate consultations may include any or all of the following:

  • Orthopedic surgeon for fractures, dislocations, and bony deformities

  • Neurosurgeon or orthopedic surgeon for spinal complications

  • Ear, nose, and throat (ENT) specialist or neurologist for impaired hearing or cranial nerve palsies

  • Rheumatologist or endocrinologist for management of Paget and joint disease

  • Ophthalmologist for optic atrophy or angioid retinal streak

  • Oncologist for neoplastic complications

Cardiology consultation is indicated for evaluation of cardiac status, including the following:

  • Left ventricular hypertrophy (LVH)

  • High cardiac output

  • Calcific aortic stenosis

Radiologist consultation is indicated for any of the following tests:

  • Radiologic films

  • Bone scanning

  • Computed tomography scanning

  • Magnetic resonance imaging

A physical medicine and rehabilitation specialist is indicated for any of the following:

  • Physical therapy

  • Occupational therapy

  • Speech therapy

  • Electrodiagnostic examination (electromyelogram [EMG]/nerve conduction study [NCS])

  • Evaluation for rehabilitation

Long-Term Monitoring

Careful follow-up of patients with Paget disease is indicated for life. Untreated patients with mild disease should be scheduled for annual serum alkaline phosphatase levels and annual radiographs of osteolytic lesions.

Treated patients should have serum alkaline phosphatase levels every 3-4 months and should undergo annual radiographs of osteolytic lesions, if present. Alternatively, urinary hydroxyproline or collagen cross-links can be used.

 

Guidelines

Guidelines Summary

A 2014 Endocrine Society Clinical Practice Guideline on Paget disease recommends the following[53] :

  • Plain radiographs of the pertinent regions of the skeleton in patients with suspected Paget disease

  • A radionucleotide bone scan to determine the extent of the disease if the diagnosis is confirmed

  • Measurement of serum total alkaline phosphatase or, when warranted, a more specific marker of bone formation or bone resorption to assess the response to treatment or evolution of the disease in untreated patients

  • Consider treatment with a bisphosphonate for most patients with active Paget disease who are at risk for future complications

  • Consider a single 5-mg dose of intravenous zoledronate as the treatment of choice in patients who have no contraindication

  • Consider measurement of a specific marker of bone formation and bone resorption in patients with monostotic disease who have a normal serum total alkaline phosphatase

  • Consider serial radionuclide bone scans to determine the response to treatment if the markers are normal

  • Bisphosphonate treatment may be effective in preventing or slowing the progress of hearing loss and osteoarthritis in joints adjacent to Paget disease and may reverse paraplegia associated with spinal Paget disease

  • Consider treatment with a bisphosphonate before surgery on pagetic bone

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce disease activity and morbidity and to prevent complications. Treatment with bisphosphonates should be considered first-line 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.[54]

Metabolic & Endocrine, Other

Class Summary

Bisphosphonates are analogues of inorganic 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.

For maximum gut absorption, all oral bisphosphonates should be taken at least 2 hours before or after meals. The newer bisphosphonates are not completely free of the risk of causing a mineralization defect, but their safe therapeutic window is much wider. They clearly are more potent than etidronate in reducing disease activity and normalizing alkaline phosphatase levels.[28, 33, 34]

Calcitonin analogues directly inhibit osteoclastic bone resorption and have a significant analgesic effect on bone. Human calcitonin is no longer available. Salmon calcitonin is more likely than human calcitonin to cause resistant antibodies. As many as 26% of patients treated with salmon calcitonin demonstrated loss of biochemical responsiveness after initial improvement. High titers of salmon calcitonin antibodies produce resistance. All patients resistant to salmon calcitonin responded to human calcitonin.

Alendronate (Fosamax)

Alendronate is a potent third-generation bisphosphonate that principally acts by inhibiting osteoclastic bone resorption. It is recommended for treatment of Paget disease. Retreatment may be considered after 6-month posttreatment evaluation in patients whose serum alkaline phosphatase level did not normalize.

Pamidronate (Aredia)

Pamidronate is a potent second-generation bisphosphonate that acts principally by inhibiting osteoclastic bone resorption. Intravenous (IV) pamidronate has been shown to be effective in the treatment of Paget disease and in patients unresponsive to treatment with etidronate or calcitonin.

Optimal dosing regimen has not yet been determined. Successful treatment consists of normalization of alkaline phosphatase level (biochemical remission) and stabilization of symptoms.

Risedronate (Actonel, Atelvia)

Risedronate is a potent aminobisphosphonate that principally acts by inhibiting osteoclastic bone resorption. It is recommended for the treatment of Paget disease.

Etidronate (Didronel)

Etidronate was the first bisphosphonate to be studied in humans and approved in the United States (1978) for the treatment of Paget disease. It is the least potent of currently available bisphosphonate drugs.

Tiludronate (Skelid)

Tiludronate is a sulfur-containing bisphosphonate of intermediate potency between etidronate and newer nitrogen-containing bisphosphonates. No food, indomethacin, or calcium should be ingested within 2 hours before and 2 hours after. A 3-month posttreatment evaluation follows.

Zoledronate (Reclast, Zometa)

Zoledronate inhibits bone resorption. It inhibits osteoclastic activity and induces osteoclastic apoptosis

Salmon calcitonin (Miacalcin, Calcimar injection)

Salmon calcitonin is recommended for treatment of Paget disease if bisphosphonates are contraindicated. This agent is a peptide hormone that binds to calcitonin receptors on osteoclasts and rapidly inhibits bone resorption. Osteoclasts do not induce cytotoxic effects in bone cells.

Salmon calcitonin induces reductions in urinary hydroxyproline and serum alkaline phosphatase levels. Serum alkaline phosphatase begins to decline 4 weeks after initiation of treatment. Levels of urinary hydroxyproline may decrease quickly, indicating inhibition of bone resorption. These laboratory markers slowly increase back to pretreatment levels if treatment is stopped. If no response is noted by 3 months, treatment should be discontinued.

Restoration of more normal bone can be seen radiographically, especially after chronic calcitonin treatment. Bone biopsy samples also reflect reduced disease activity because decreased bone cells, marrow fibrosis, and woven bone are present. Reduction in bone pain, cardiac output, and skin temperature over lower limb bones can be observed. Improvement of neurologic deficits and stabilization of hearing have been noted.

Reduction of hemorrhage from orthopedic procedures has been demonstrated with preoperative calcitonin treatment. However, salmon calcitonin only partially suppresses disease while treatment continues.

 

Questions & Answers

Overview

What is Paget disease?

What is the pathophysiology of Paget disease?

What causes Paget disease?

What is the role of genetics in the etiology of Paget disease?

Which environmental factors increase the risk of Paget disease?

What is the role of inflammation in the etiology of Paget disease?

What is the prevalence of Paget disease in the US?

What is the global prevalence of Paget disease?

Which patient groups have the highest prevalence of Paget disease?

What is the prognosis of Paget disease?

What is included in patient education about Paget disease?

Presentation

Which clinical history findings are characteristic of Paget disease?

Which physical findings are characteristic of Paget disease?

What are the possible complications of Paget disease?

What are the possible skeletal complications of Paget disease?

Which malignancies are associated with Paget disease?

What are the possible neuromuscular complications of Paget disease?

Which degenerative joint diseases are associated with Paget disease?

What are the possible cardiovascular complications of Paget disease?

DDX

How is osteomalacia differentiated from Paget disease?

How is Paget disease differentiated from skeletal metastasis?

What are the differential diagnoses for Paget Disease?

Workup

How is Paget disease diagnosed?

What is the role of bone-specific alkaline phosphatase (BSAP) measurement in the workup of Paget disease?

What is the role of urinary markers in the workup of Paget disease?

What is the role of radiography in the workup of Paget disease?

What is the role of nuclear imaging in the workup of Paget disease?

What is the role of MRI and CT scanning in the workup of Paget disease?

Which histologic findings are characteristic of Paget disease?

Treatment

How is Paget disease treated?

What is the role of medications in the treatment of Paget disease?

What is the role of alendronate in the treatment of Paget disease?

What is the role of pamidronate in the treatment of Paget disease?

What is the role of risedronate in the treatment of Paget disease?

What is the role of tiludronate in the treatment of Paget disease?

What is the role of zoledronic acid in the treatment of Paget disease?

How are malignancies treated in patients with Paget disease?

What is the role of surgery in the treatment of Paget disease?

How is spinal stenosis treated in patients with Paget disease?

Which dietary modifications are used in the treatment of Paget disease?

Which activity modifications are used in the treatment of Paget disease?

When is transfer indicated for the treatment of Paget disease?

How is Paget disease (PD) prevented?

Which specialist consultations are beneficial to patients with Paget disease?

What is included in the long-term monitoring of Paget disease?

Guidelines

What are the Endocrine Society guidelines on diagnosis and treatment of Paget disease?

Medications

What is the first-line medication used in the treatment of Paget disease?

Which medications in the drug class Metabolic & Endocrine, Other are used in the treatment of Paget Disease?