eMedicine Specialties > Physical Medicine and Rehabilitation > Medical Diseases

Paget Disease

David Chow, MD, Medical Director, California Spine Center
Curtis W Slipman, MD, Director, University of Pennsylvania Spine Center; Associate Professor, Department of Physical Medicine and Rehabilitation, University of Pennsylvania Medical Center; Debra Braverman, MD, Director of Alternative and Complementary Medicine, Assistant Professor, Department of Rehabilitation Medicine, University of Pennsylvania Health System

Updated: Dec 18, 2008

Introduction

Background

Paget's disease (Paget disease), characterized by excessive and abnormal remodeling of bone, is a common disorder in middle-aged and elderly patients. The excessive remodeling gives rise to bones that are extensively vascularized, weak, enlarged, and deformed, with subsequent complications. Paget's disease is named after Sir James Paget, an English surgeon who described the clinical course of this disorder in his 1877 paper.¹ He originally named the condition osteitis deformans because he believed the disease was caused by chronic inflammation.

Related eMedicine articles:
Paget Disease [Radiology]
Paget Disease [Rheumatology]

Pathophysiology

Paget's disease of bone is characterized by enhanced resorption of bone by giant, multinucleated osteoclasts, with formation by osteoblasts of disorganized, woven bone. This process evolves through various phases of activity, followed by a quiescent stage.

Excessive osteoclastic activity — with resorption of normal bone by giant, multinucleated cells — begins the cycle. Subsequently, an intense osteoblastic response produces increased disorganized bone formation (in the form of vascular, primitively woven bone) and connective tissue reaction. As the osteoclastic and osteoblastic activities of bone destruction and formation repeat, a high degree of bone turnover occurs.

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. Sclerotic bone is the hallmark of this stage, and continued bone resorption and formation are minimal or absent. Hence, Paget's disease typically consists of the following 3 phases: (1) lytic, (2) mixed lytic and blastic, and (3) sclerotic or burned out.

Note that the above sequence of stages (characterized by increased osteoclastic and then osteoblastic activity, followed by decreased osteoclastic activity and finally by decreased osteoblastic activity) is variable. Each skeletal lesion also has its own pathophysiology and its own unique rate of progression. At any one time, multiple stages of the disease may be demonstrated in different skeletal regions.

Frequency

United States

International

Great variability in the prevalence of Paget's disease is noted in different areas of the world and even within the same country.³ A prevalence of 2% in certain British cities can be contrasted with rates in Lancaster, England, which had a prevalence of 8.3%.⁴ The United States, Great Britain, Australia, and New Zealand have high prevalences because of significant populations with northern European ancestry and a large population of British migrants.⁵ The disease is rare in Asia, Africa, Scandinavia, India, and Japan.

Paget's disease prevalence varies significantly based on age; it can be 5 times more prevalent in people aged 85 years or older than it is in persons younger than 60 years. Research from Europe and New Zealand indicates that the prevalence of Paget's disease has decreased since the 1980s but that increased incidence with age has been maintained.⁶  The estimated prevalence of Paget's disease in patients aged 55 years or older has decreased to approximately 2%.

Mortality/Morbidity

The excessive remodeling of bone associated with Paget's 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's disease. Sarcomatous degeneration also may occur but is less prevalent. 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's disease and sarcoma is 5-7.5% but may be as high as 50% for those who undergo operative tumor ablation and chemotherapy before metastases. 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.

Race

Paget's disease is not known to demonstrate a predilection for any race, but unusual patterns of prevalence have been noted (see Frequency, International).

Sex

Paget's disease is more common in males than in females. The male-to-female ratio is approximately 1.8:1.

Age

Paget's disease is recognized most commonly after 50 years of age and rarely is diagnosed in people younger than 20 years. By the ninth decade of life, prevalence reaches nearly 10%.

Clinical

History

Many individuals with Paget's disease are asymptomatic. Clinical features are extremely variable and depend on which bones are affected. The diagnosis most commonly is made incidentally during an unrelated radiologic or biochemical investigation. On occasion, the disease manifests with severe musculoskeletal impairments with neurologic and cardiovascular complications.

Paget's disease has a predilection for the axial skeleton and may be widespread at the time of diagnosis. 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 (in 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 only infrequently.

Paget's disease may affect one bone and then remain limited in its course or progress from a few localized areas to the rest of the skeleton.

• Monostotic Paget's disease occurs in 10-35% of cases. The most common presenting complaint is pain.
  • The bone pain is perceived as a dull, constant, boring pain 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 weight bearing and is relieved with rest.
    • Knee and shoulder pain may occur due to altered mechanical forces across the articular joints from deformed bones.
• Other typical findings and complaints of patients with Paget's disease may include the following:
  • 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 are common symptoms of Paget's disease with skull involvement. The patient's hat size may increase or change due to skeletal deformity and enlargement, especially of the skull.
  • 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's 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's 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.
  • Nausea, dizziness, syncope, ataxia, incontinence, gait disturbances, and dementia can be observed with hydrocephalus, basilar invagination, and cerebellar or brainstem compressive syndromes.
  • Involvement of the jaw and facial bone is uncommon in Paget's 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.

Physical

Typically, patients with Paget's disease present without any signs or symptoms.

• Visual inspection may reveal bony deformities, such as an enlarged skull, spinal kyphosis, and bowing of the long bones of the extremities.
• 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 bone and bone pain.
• Auscultation may reveal bruits of the tibia or skull.
• Bone angulation and deformity may affect joints, with resulting pain and decreased range of motion (ROM).
• A soft-tissue mass with increased pain may be caused by neoplasms, such as osteosarcoma.
• Decreased hearing and findings consistent with other cranial nerve palsies can be caused by nerve compression.
• Muscle weakness, paraparesis, and sensory loss compatible with spinal cord injury (SCI) may be present.
• Ataxia, gait disturbances, dementia, and neurologic compromise can be observed with hydrocephalus and cerebellar compression.

Causes

The etiology of Paget's disease is unknown. Genetic and nongenetic factors have been implicated in the pathogenesis of this disease.

• Evidence exists of a genetic link; a positive family history was obtained 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's disease was observed in relatives of patients diagnosed with the condition, compared with control groups. A study demonstrated 15-40% of affected patients have a first-degree relative with Paget's disease, and numerous other studies have described families exhibiting autosomal dominant inheritance.
  • The geographic distribution of the disease may be explained by genetic transmission and dissemination by population migration. Studies also have examined potential genetic markers for Paget's disease. An association was found between 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).
  • Subsequent genome linkage studies identified several loci associated with Paget's 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 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.
• Environmental factors also may contribute to the pathogenesis of Paget's disease. Observations that support this include the variable penetrance of Paget's 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.
• Another possible etiology is related to viral infection. Some studies have shown the presence of viral inclusion particles in pagetic osteoclasts.⁷ Furthermore, dense fibrillar material associated with some inclusions is similar to that found in the nuclei of virus-infected cells.
  • Certain immunocytologic data and viral antibody titers against the measles virus reinforce the viral hypothesis. The presence of minimal inflammation and few inflammatory cells in bone and peripheral blood is consistent with a chronic infectious process.
  • Viral infections may take several years for clinical expression, which may account for the advanced age of most people diagnosed with Paget's 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.
• Other suggested etiologies include an inflammatory cause, which is supported by evidence of clinical improvement after treatment with anti-inflammatory medications. Elevated parathyroid hormone in Paget's disease also has been observed; however, no firm evidence links the 2 disorders. Furthermore, one case of Paget's 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.

Workup

Laboratory Studies

• Because of increased osteoblastic activity and bone formation, biochemical indices reveal elevated alkaline phosphatase levels of bone origin.
  • Analysis of alkaline phosphatase isoenzymes helps to identify the hepatic contribution to total levels of alkaline phosphatase.
  • 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's 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 bone-specific alkaline phosphatase level should be ordered. In patients with abnormal liver function or other causes of elevated alkaline phosphatase activity not due to bone, bone-specific alkaline phosphatase is a reasonable means of assessing Paget's disease activity. Bone-specific alkaline phosphatase had the highest diagnostic sensitivity (84%) in a comparative study of different markers of bone turnover in patients with Paget's disease. The next most sensitive marker was total alkaline phosphatase, which had a sensitivity of 74%.⁸
  • Urinary hydroxyproline levels are elevated because they reflect 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. 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. The hydroxyproline assay is difficult to perform and is not widely available.
• More recently, 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 recently as sensitive biochemical markers for bone resorption.
  • An abnormally high alpha-CTx/beta-CTx ratio is present with active Paget's disease.
  • This ratio returns to the reference range following treatment with bisphosphonates.⁹
• Sensitive plasma or serum markers for assessing bone resorption have not been developed.
  • Serum total acid phosphatase is an osteoclastic enzyme that may be elevated in active Paget's disease, but it is of little clinical value, as it also may be elevated in the presence of metastatic prostate carcinoma.
  • Serum calcium and phosphate levels should be within the reference range in patients with Paget's disease.
  • Urinary excretion of calcium also should be normal.
• Hypercalcemia or hypercalciuria may develop with immobilization or coincident primary hyperparathyroidism.
• Secondary hyperparathyroidism may occur in 10-15% of patients with Paget's disease. This development may be due to inadequate calcium intake in the face of increased demand from extensive bone remodeling. Increased incidence of primary hyperparathyroidism does not seem to exist among patients with Paget's disease.
• Procollagen I N-terminal peptide (PINP) has recently emerged as a sensitive serum marker for bone formation. Serum osteocalcin, which is produced specifically by osteoblasts, does not reflect disease activity.
• Many patients with elevated alkaline phosphatase levels have been found to have osteocalcin measurements within the reference range. Levels of osteocalcin also may increase while alkaline phosphatase levels decrease during treatment with bisphosphonates.
• Paget's disease was found in 23% of a group of patients with gout.¹⁰
  • Elevated serum uric acid levels have been found in men with severe Paget's disease and have been associated with gouty arthritis.
  • Hyperuricemia is more common in men than in women and appears to be caused by the increased turnover of nucleic acids from high bone turnover.

Imaging Studies

• Radiographs
  • Typical expanding lytic lesions, transverse lucent areas or osteoporosis circumscripta, thickened cortices, sclerotic changes, and bone expansion with coarse, disorganized trabecular patterns are seen on plain radiographs.
  • Lytic lesions may be the only finding early in the disease.
  • Plain radiographs are less sensitive than bone scan scintigraphy in the diagnosis of Paget's 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.
  • Radiographic features are diagnostic with an initial osteolytic phase, commonly in the skull and tubular bones, followed by an osteosclerotic phase that is most notable in the axial skeleton and pelvis. An enlarged bone with increased radiodensity and trabeculations is characteristic.
  • Osteolysis of the cranial vault is most frequent in the frontal or occipital regions. 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.
  • Later in the disease, evidence of lysis may be absent because only sclerotic thickened bones may remain.
  • Radiographic evidence of remineralization may occur after initiation of appropriate treatment, such as with the bisphosphonates.
  • Paget's disease 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's 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.
• Computed tomography (CT) scanning and magnetic resonance imaging (MRI)
  • CT scanning and MRI are not needed for the diagnosis of Paget's disease of bone. Both are useful in the evaluation of complications of Paget's disease, such as neoplastic degeneration, articular abnormalities, and spinal involvement with neurologic compromise.
  • 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.

Other Tests

• Bone scan
  • Bone scanning is the most sensitive test for evaluating the extent of lesions in the whole skeleton affected by Paget's disease. Bone scintigraphic abnormalities are observed earlier than radiographic changes during the active stage of Paget's 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.
  • Plain radiographs and bone scanning should be performed upon initial diagnosis.
    • 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.
  • 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.
    • Quantitative bone scintigraphy is useful for assessing a monostotic lesion with a normal alkaline phosphatase.
    • Serial bone scans may provide objective evidence of the effect of therapeutic agents.

Histologic Findings

The initial osteolytic phase is marked by disordered areas of resorption 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's disease.¹¹

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

Rehabilitation Program

Physical Therapy

Physical therapy (PT) can play an important role in the treatment process and rehabilitation of patients with Paget's disease. PT can help to maintain or improve muscle strength, maintain joint ROM and flexibility, increase endurance, and avoid deconditioning.

Patients may have leg-length discrepancies as a result of fracture or deformity. The physical therapist can aid in correcting this problem by providing inserts or making appropriate shoe modifications. Functional fracture bracing may be useful with open reduction and internal fixation limb surgeries. The physical therapist typically completes gait and transfer training with the patient to ensure safety in using the assistive device. Ambulatory assistive devices, such as a cane or walker, can reduce the weight-bearing load and pain following these surgeries.

Modalities, such as superficial heat, transcutaneous electrical nerve stimulation (TENS), and massage, may be helpful for muscle pain, tenderness, and tightness. Proper bracing and spinal immobilization and support should be provided when warranted to decrease pain or in cases of spinal instability. Spinal orthoses can decrease pain associated with weight bearing, thus improving the patient's ability to participate in ambulatory activities and reducing effects related to immobility, such as muscle atrophy, bone loss, and cardiovascular deconditioning. Increased activity also decreases the patient's risk for developing skin breakdown or decubitus ulcers. Equally important, the patient's feeling of well-being often is improved with participation in physical activities.

Efforts to support and protect malaligned limbs, such as functional prosthetic bracing, are important. Aerobic exercise should be incorporated into PT or a home exercise program.

Functional ROM should be maintained in major joints. Examples of joint-specific measurements for functional ROM include the following:

• ROM of the shoulder should allow for abduction of at least 90°, with adequate external rotation to touch the back of the head and internal rotation to touch the low back.
• Forearm ROM should be adequate to allow a minimum of 45° of supination and pronation, with wrist flexion of 45° and extension of 30°.
• Finger flexion should be within 1 inch of the palm.
• Hip flexion should be at least 90°, with hip extension to at least neutral.
• Knee flexion should be to 110°, with knee extension to at least neutral.
• Ankle dorsiflexion should be to neutral.

Arthritic joint involvement with limited ROM may require modification of the therapy program. Spinal flexion exercises should be avoided to decrease the risk of anterior wedge compression fractures. Inpatient rehabilitation may be appropriate for patients with Paget's disease who have become deconditioned and are unable to be independent or care for themselves at home. Rehabilitation is required after total joint replacement, fracture repair, laminectomy, or other major surgery. Pain management and education regarding proper bracing are important. Gait and balance training also is necessary for ataxic and weak patients.

Occupational Therapy

Occupational therapy (OT) may be indicated for patients with Paget's disease who need training in activities of daily living (ADL), especially those who undergo surgery for various pagetic-related conditions. The occupational therapist can advise patients in home modifications when necessary, to increase the patients' independence and safety with mobility. Patients may also require the use of adaptive equipment to perform their ADL. OT can work in conjunction with PT to maintain or improve muscle strength of the upper extremities, maintain flexibility and ROM, and prevent deconditioning.

Speech Therapy

Speech therapy may be indicated for patients who acquire speech and hearing deficits as a result of Paget's disease.

Medical Issues/Complications

Fractures

Incomplete stress fractures frequently occur in Paget's disease. Cortical stress fractures are common in the femur and tibia, with distinctive horizontal radiolucencies affecting the convex surface of the bone, in contrast to similar findings in osteomalacia on the concave aspects of the bone. Cartilaginous calluses, which do not mineralize fully in the fracture clefts, account for the relative radiolucency. The 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's disease. The rate of nonunion has been reported to be 40%.¹² Biopsies of pathologic fractures may be recommended to rule out sarcoma.

Neoplasm

Sarcomatous degeneration of pagetic bone is a deadly complication. 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. In less widespread involvement, osteosarcoma occurs in less than 1% of patients with Paget's disease.

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.

Other clinical and radiographic findings include increased pain with a progressive lytic lesion, an enlarging soft-tissue mass, bony spiculation, persistent fracture without healing, and 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's disease and present as a soft-tissue mass with a lytic lesion.

The prognosis for patients with Paget's 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's disease, leukemias, and metastatic disease all have been found in association with Paget's disease but 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 due to 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's disease. The most commonly reported site of articular abnormality is the hip. The knee also is commonly affected. Degenerative joint disease of the hip associated with Paget's 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's disease varies in several studies from 50-96%.¹³ 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's 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. The glenohumeral joint also may be affected, impairing rotator cuff function. Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, pseudogout, Peyronie disease, and pigmented villonodular synovitis all have been found to coexist with Paget's disease, but no relationship has been proven. Hyperuricemia may cause clinical gout in some patients.

Cardiovascular abnormalities

Increased cardiac output has been observed in patients with widespread Paget's disease, those with at least 15% involvement 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's disease. Calcific aortic stenosis is 4 times more common in patients with Paget's disease, especially those with severe disease, than in individuals without Paget's 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.

Retinal streaks and other associations

Angioid streaks of the retina have been found more commonly in patients with Paget's 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. Hashimoto thyroiditis, Dupuytren contracture, chondrocalcinosis, osteogenesis imperfecta, and osteopetrosis all have been associated with Paget's disease.

Surgical Intervention

Surgery is indicated in cases of certain complications of Paget's disease.

Neoplasm

Amputation usually is the most appropriate treatment because of the aggressive behavior of this type of sarcoma, 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

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's 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 based on well-accepted scales of pain relief and function. Preoperative treatment with bisphosphonates or calcitonin reduces intraoperative bleeding by decreasing disease activity.⁹ 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.⁹ Surgical decompression rarely is needed. Decompressive laminectomies may be helpful for pagetic spinal stenosis and persistent mechanical pain unresponsive to nonsurgical treatment.

Consultations

Consultations sometimes are indicated for patients with Paget's 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's and joint disease
• Cardiologist for evaluation of cardiac status, including the following:
  • Left ventricular hypertrophy (LVH)
  • High cardiac output
  • Calcific aortic stenosis
• Ophthalmologist for the following conditions:
  • Optic atrophy
  • Angioid retinal streak
• Hematologist oncologist
• Radiation oncologist
• Surgical oncologist for neoplastic complications
• Radiologist for any of the following tests:
  • Radiologic films
  • Bone scanning
  • CT scanning
  • MR
• Physical medicine and rehabilitation specialist for any of the following:
  • Physical therapy
  • Occupational therapy
  • Speech therapy
  • Electrodiagnostic examination (electromyelogram [EMG]/nerve conduction study [NCS])
  • Evaluation for rehabilitation

Other Treatment

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

With safer and more effective new drugs for Paget's disease, support has accumulated for earlier aggressive treatment with the goal of maintaining normal alkaline phosphatase levels.

Indications for drug treatment of Paget's disease are as follows: bone pain, osteolytic lesions, bony deformities, skull or spinal disease, weight-bearing bone involvement, neurologic or cardiac complications, preparation for orthopedic surgery (joint replacement anticipated at involved sites within 6 months), serum alkaline phosphatase or urine hydroxyproline levels greater than twice the upper limit of the reference range, immobilization, prevention of future complications, and hypercalcemia or hypercalciuria.

Seven prescription drugs currently have been approved and are available for treating Paget's disease in the United States (ie, etidronate, pamidronate, alendronate, tiludronate, risedronate, zoledronic acid, salmon calcitonin).^14,15 Pamidronate and salmon calcitonin are administered parenterally. Human calcitonin is no longer available.

In the United States, ibandronate and olpadronate are potent new bisphosphonates not approved by the Food and Drug Administration (FDA) for the treatment of Paget's disease. They may play a role in the future, depending on the results of clinical trials. (Ibandronate is approved by the FDA for the treatment of osteoporosis.)

Preliminary European studies have shown that a single 2-mg injection of ibandronate is capable of suppressing disease activity in patients with Paget's disease over a 12-month period.¹⁶ In patients in whom this was insufficient to suppress disease activity, application of a higher dose was sometimes more effective.

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's disease.¹⁷

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 performed in which bisphosphonates were compared with one another (ie, tiludronate vs etidronate, alendronate vs etidronate, risedronate vs etidronate), conclusions can be made regarding these medications for the treatment of Paget's disease.^{9,14,18,19,20}

• Etidronate was less effective than the other bisphosphonates in suppressing biochemical markers of disease activity. No significant difference was noted between the bisphosphonates with regard to bone pain.²¹
• Oral tiludronate (400 mg/d for 12 wk), oral risedronate (30 mg/d for 2 mo), and intravenous pamidronate (3 infusions of 60 mg at 2-wk intervals or 6 infusions of 30 mg at weekly intervals) have each been shown to be effective and superior to etidronate.²¹ Etidronate should not be used as a first-line agent if the other bisphosphonates are available. Bisphosphonates should be used as first-line agents over salmon calcitonin.
• Pain in pagetic bone is a definite indication for antipagetic treatment with bisphosphonates and/or calcitonin.
• Patients who relapse can be re-treated effectively with potent bisphosphonates. The general consensus opinion is that re-treatment is indicated when continued relapse/persistence of disease or biochemical relapse occurs.
  • 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.
  • Regarding biochemical relapse, in situations in which treatment was based on the presence of asymptomatic disease in a critical site, re-treatment 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.
  • Offering re-treatment is appropriate if a patient has not responded after 6 months following treatment. Some patients may respond better to a more potent bisphosphonate.

Medication

The goals of pharmacotherapy are to reduce disease activity and morbidity and to prevent complications.

Bisphosphonates

Also known as diphosphonates. They are analogues of inorganic pyrophosphate, a compound thought to play a role in bone mineralization. The pyrophosphate analogues have a P-C-P backbone instead of the P-O-P bond of pyrophosphate. The precise mechanism of action of bisphosphonates is not known yet, but they have been found to bind to hydroxyapatite crystals and inhibit osteoclast-mediated bone resorption. Studies have suggested that their effects on cells may be of greater importance. For maximum gut absorption, all oral bisphosphonates should be taken at least 2 h 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.^9,14,15

Etidronate (Didronel)

First bisphosphonate to be studied in humans and approved in the United States (1978) for the treatment of Paget's disease.
Reduces bone formation and does not alter renal tubular resorption of calcium. Does not affect hypercalcemia in patients with hyperparathyroidism.
Serum alkaline phosphatase and urinary hydroxyproline levels decrease and reach a nadir 3-6 mo after initiation of treatment and still are suppressed at 12 mo.

Dosing

Adult

5-20 mg/kg/d PO for up to 6 mo; second course after 6-mo drug-free period; to avoid mineralization defects, now recommended at dosage of 400 mg/d for no longer than 6 mo

Pediatric

Not established

Interactions

Coadministration with calcium-containing products and other multivalent cations decrease absorption

Contraindications

Documented hypersensitivity, hypocalcemia, and renal impairment

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, and potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution if active upper GI problems; not to administer with alendronate for osteoporosis in postmenopausal women; adverse effects include transient increase of bone pain, mild GI symptoms (eg, nausea, loose stools), and a reversible mineralization defect, increasing the risk of fracture; paradoxical increase in bone pain (10%) and failure of osteolytic lesions to heal may be related to its inhibitory effect on bone mineralization (makes goals of long-term control of disease activity and complete suppression difficult to achieve); subset of patients (15-24%) develop resistance to etidronate, usually between the second and third courses of therapy

Pamidronate (Aredia)

Potent second-generation bisphosphonate. IV pamidronate has been shown to be effective in the treatment of Paget's disease and in patients unresponsive to treatment with etidronate or calcitonin. Various dosage regimens have been studied. Few data have been published based on prospective studies to evaluate frequency of normalization after pamidronate therapy; too much variability exists between treatment protocols. Optimal dosing regimen not yet determined. Successful treatment consists of normalization of alkaline phosphatase level (biochemical remission) and stabilization of symptoms.
Anderson et al (1994) induced biochemical remission with one or more complex courses in 90% of patients with elevated alkaline phosphatase levels. Average remission was 2 y with a supposed permanent remission in 10-15%. Regimen consisted of a 30-mg infusion over 2 h, followed by 3 infusions of 60 mg each over 4 h for alkaline phosphatase levels <500 IU/L; levels >500 IU/L required 6 infusions of 60 mg each at 2-wk intervals.
Many single-dose regimens have been studied. Watts et al (1993) used a single infusion of 105 mg and achieved a remission rate of 71%, with a mean enzyme nadir at 6 mo. Excellent symptomatic control was achieved for 1.5-2 y. A few patients required a second infusion, with a mean interval of 19 mo after the first dose.
Another single-dose regimen by Chakravarty et al (1994), using 60 mg of IV pamidronate, provided similar efficacy to the Watts et al study. Dose of 30 mg IV infusion over 4 h on 3 consecutive days is approved therapeutic regimen but is not used often. Infusions of 60 mg or 90 mg over 2-4 h are more common. 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 manifests more severe biochemical and radiographic abnormalities that require greater dosages to achieve remission.

Dosing

Adult

30 mg IV infusion over 4 h on 3 consecutive days; 60-90 mg infusion over 2-4 h; in severe disease, 2-3 infusions may be needed

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; hypocalcemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution if active upper GI problems; not to administer with alendronate for osteoporosis in postmenopausal women; adverse effects of IV pamidronate include an acute-phase febrile reaction within 24 h (ie, fever, myalgia, mild leukopenia), usually with the first infusion; transient increased bone pain; hypocalcemia; and eye inflammation (rare)

Alendronate (Fosamax)

Potent aminobisphosphonate (third-generation bisphosphonate) that is also used to treat osteoporosis. Retreatment may be considered after 6-mo posttreatment evaluation in patients whose serum alkaline phosphatase level did not normalize.
In one study, 6 mo of oral alendronate using recommended 40-mg regimen produced normalization of alkaline phosphatase in 63%, compared with 17% after treatment with 400 mg/d etidronate. Mean initial alkaline phosphatase level was 5 times upper limit of reference range. After 18 mo, 25 of 29 patients whose alkaline phosphatase levels had normalized and who were available for follow-up still had levels in reference range. After 25-30 mo, 15 patients still had alkaline phosphatase levels in reference range. Study showed alendronate to be more potent at suppressing Paget's disease activity than etidronate. Studies also showed that alendronate treatment led to cessation of radiological progression and healing of radiological lesions.

Dosing

Adult

40 mg/d PO for 6 mo; must be taken with 6-8 oz of tap water at least 30 min before breakfast; recent data suggest 3 mo of treatment adequate for many patients

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity, hypocalcemia, renal impairment

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution if active upper GI problems; adverse effects include esophagitis, pain, and transient hypocalcemia and hypophosphatemia; esophagitis can be prevented by drinking a large glass of water and remaining upright for at least 30 min after administration

Tiludronate (Skelid)

Sulfur-containing bisphosphonate of intermediate potency between etidronate and new nitrogen-containing bisphosphonates. No food, indomethacin, or calcium should be ingested within 2 h before or after. A 3-mo posttreatment evaluation follows. Given for 12 wk, the 400-mg/d regimen demonstrated reduced alkaline phosphatase activity by 58% at 24 wk. Pretreatment alkaline phosphatase levels were twice those of reference range. Double-blinded controlled studies demonstrate that bone turnover markers are better suppressed by tiludronate than placebo (level Ib 51,102) or etidronate (level III 106). These studies suggest tiludronate treatment is associated with 40-72% reduction in alkaline phosphatase activity. Pagetic bone pain also improved.

Dosing

Adult

400 mg/d PO for 3 mo with 6-8 oz tap water on empty stomach

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; sulfur allergy; hypocalcemia; renal impairment

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution if active upper GI problems; not to administer with alendronate for osteoporosis in postmenopausal women; adverse effects include nausea and diarrhea (uncommon)

Risedronate (Actonel)

Potent aminobisphosphonate. In comparative study, normalization of alkaline phosphatase was achieved in 77% of patients treated with risedronate, compared with 10% using 400-mg etidronate regimen. After 12 and 18 mo, 60% and 53% of patients treated with risedronate still had alkaline phosphatase levels in reference range. Randomized double-blinded study of risedronate with etidronate showed that alkaline phosphatase levels were normalized in 75% of patients, while only 1 in 7 etidronate patients reached normal alkaline phosphatase levels.

Dosing

Adult

30 mg/d PO for 2 mo with 6-8 oz of tap water at least 30 min before breakfast; patient should remain upright for at least 30 min

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity, hypocalcemia, and renal impairment

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution if active upper GI problems; not to administer with alendronate for osteoporosis in postmenopausal women; adverse effects include diarrhea, headache, and arthralgia

Zoledronate (Reclast)

Inhibits bone resorption. Inhibits osteoclastic activity and induces osteoclast apoptosis.

Dosing

Adult

5 mg IV once; infuse over 15 min

Pediatric

Not established

Interactions

Concurrent administration with loop diuretics may increase risk of hypocalcemia

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal insufficiency (hold dose with increased CrCl); risk of renal deterioration increased with <15 min IV infusion; flulike syndrome (fever, arthralgias, myalgias, skeletal pain), gastrointestinal reactions, anemia, insomnia, dyspnea, and electrolyte and mineral disturbances, such as low serum phosphate, calcium, magnesium, and potassium, may occur

Human calcitonin analogues

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.

Calcitonin (Osteocalcin, Miacalcin)

Peptide hormone that binds to calcitonin receptors on osteoclasts and rapidly inhibits bone resorption. Osteoclasts do not induce cytotoxic effects in bone cells. Induces reductions in urinary hydroxyproline and serum alkaline phosphatase levels. Serum alkaline phosphatase begins to decline 4 wk 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 noted by 3 mo, 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 noted. Reduction of hemorrhage from orthopedic procedures demonstrated with preoperative calcitonin treatment; however, only partially suppresses disease while treatment continues.

Dosing

Adult

50-100 U SC 3-7 times/wk; in view of weaker activity, shorter duration of action, and adverse effect profile compared with bisphosphonates, likely should not be used as first-line agent for Paget's disease (still has role in patients who do not tolerate bisphosphonates or whose disease is refractory to bisphosphonates)

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hypocalcemia may occur; examine urine sediment during prolonged therapy; adverse effects include nausea and facial flushing that occur within 30 min of injection, vomiting, diarrhea, abdominal pain, polyuria, tetany, and allergic reactions; the nasal spray has not been shown to be consistently effective in treating Paget's disease

Antineoplastic agents

Potent cytotoxic agent that is highly effective in the treatment of Paget's disease.

Plicamycin (Mithracin)

Not FDA approved for treatment of Paget's disease. Also known as mithramycin. Inhibits cellular RNA and enzymatic RNA synthesis. Possibly blocks hypercalcemic action of pharmacologic doses of vitamin D and may act on osteoclasts or block action of parathyroid hormone. Effect in lowering calcium is not related to tumoricidal activity. Provides pain relief (in 3 d) and biochemical improvement. Reserved for rare patient whose condition is refractory or for urgent treatment of acute spinal cord compression or neurologic deterioration in which quick control of bone blood flow and periosteal edema can yield remarkable improvement. Extremely cytotoxic; use limited by systemic toxicity.

Dosing

Adult

15 mcg/kg/d IV for 7-10 d

Pediatric

Not established

Interactions

Coadministration with glucagon, calcitonin, and etidronate may increase toxicity

Contraindications

Documented hypersensitivity, thrombocytopenia, coagulation disorders, and impairment of bone marrow function

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor platelets, PT, and bleeding times periodically during therapy and for several days after last dose; discontinue therapy if significant prolongation of bleeding times occurs and thrombocytopenia is observed; correct any electrolyte imbalance (especially hypokalemia, hypocalcemia, and hypophosphatemia) prior to treatment

Follow-up

Further Inpatient Care

• Inpatient care may be necessary for individuals with Paget's disease who are experiencing intractable pain. Complications, such as fractures and neurologic compromise, necessitate inpatient monitoring and treatment.

Further Outpatient Care

• Paget's disease can be managed in an outpatient setting.
  • Patient education about safety and awareness is important.
  • Home exercise and PT are important in maintaining skeletal health, avoiding weight gain, and maintaining joint mobility.
  • Nonsteroidal anti-inflammatory agents, simple analgesics, oral bisphosphonates, and calcitonin can be prescribed for patients for outpatient use. Intravenous doses of bisphosphonates can be administered in an outpatient clinic.
  • 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.

Inpatient & Outpatient Medications

• See Medication.

Transfer

• Patients with Paget's disease usually are medically stable. Complications (such as 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's disease, because the etiology remains unknown. No long-term prospective studies have been conducted to support the preventive effects of chronic suppressive therapy on the risk of pagetic complications. If the patient has a family history of Paget's disease and is older than 40 years, he or she 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.

Complications

• See Medical Issues/Complications.

Prognosis

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

Patient Education

• Patient education about the pathophysiology of Paget's disease and its complications is critical. The patient needs to understand the importance of proper posture, body mechanics, and avoidance of trauma. Precautions against falling should be reinforced with the patient. At the same time, the hazards of immobility increase greatly with Paget's disease. The patient should understand that staying active still is essential.
• 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. Understanding the potential side effects of medications is helpful and reassuring to the patient. 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's disease.

References

1. Paget J. On a form of chronic inflammation of bones. Medico-chirurgical Transactions. 1877;65:37-63.

2. Altman RD, Bloch DA, Hochberg MC, et al. Prevalence of pelvic Paget's disease of bone in the United States. J Bone Miner Res. Mar 2000;15(3):461-5. [Medline].

3. Guanabens N, Garrido J, Gobbo M, et al. Prevalence of Paget's disease of bone in Spain. Bone. Aug 16 2008;[Medline].

4. Barker DJ, Chamberlain AT, Guyer PB, et al. Paget's disease of bone: the Lancashire focus. Br Med J. Apr 26 1980;280(6222):1105-7. [Medline]. [Full Text].

5. Cooper C, Dennison E, Schafheutle K, et al. Epidemiology of Paget's disease of bone. Bone. May 1999;24(5 Suppl):3S-5S. [Medline].

6. Doyle T, Gunn J, Anderson G, et al. Paget's disease in New Zealand: evidence for declining prevalence. Bone. Nov 2002;31(5):616-9. [Medline].

7. Rebel A, Basle M, Pouplard A, et al. Towards a viral etiology for Paget's disease of bone. Metab Bone Dis Relat Res. 1981;3(4-5):235-8. [Medline].

8. Alvarez L, Guañabens N, Peris P, et al. Discriminative value of biochemical markers of bone turnover in assessing the activity of Paget's disease. J Bone Miner Res. Mar 1995;10(3):458-65. [Medline].

9. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. Sep 2008;83(9):1032-45. [Medline].

10. Lluberas-Acosta G, Hansell JR, Schumacher HR Jr. Paget's disease of bone in patients with gout. Arch Intern Med. Dec 1986;146(12):2389-92. [Medline].

11. Seitz S, Priemel M, Zustin J, et al. Paget's disease of bone - histologic analysis of 754 patients. J Bone Miner Res. Sep 3 2008;[Medline].

12. Dove J. Complete fractures of the femur in Paget's disease of bone. J Bone Joint Surg Br. Feb 1980;62-B(1):12-7. [Medline]. [Full Text].

13. Goldman AB, Bullough P, Kammerman S, et al. Osteitis deformans of the hip joint. AJR Am J Roentgenol. Apr 1977;128(4):601-6. [Medline].

14. Silverman SL. Paget disease of bone: therapeutic options. J Clin Rheumatol. Oct 2008;14(5):299-305. [Medline].

15. Abelson A. A review of Paget's disease of bone with a focus on the efficacy and safety of zoledronic acid 5 mg. Curr Med Res Opin. Mar 2008;24(3):695-705. [Medline].

16. Woitge HW, Oberwittler H, Heichel S, et al. Short- and long-term effects of ibandronate treatment on bone turnover in Paget disease of bone. Clin Chem. May 2000;46(5):684-90. [Medline]. [Full Text].

17. González DC, Mautalen CA. Short-term therapy with oral olpadronate in active Paget's disease of bone. J Bone Miner Res. Dec 1999;14(12):2042-7. [Medline].

18. Miller PD, Brown JP, Siris ES, et al. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Paget's Risedronate/Etidronate Study Group. Am J Med. May 1999;106(5):513-20. [Medline].

19. Roux C, Gennari C, Farrerons J, et al. Comparative prospective, double-blind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget's disease of bone. Arthritis Rheum. Jun 1995;38(6):851-8. [Medline].

20. Siris E, Weinstein RS, Altman R, et al. Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone. J Clin Endocrinol Metab. Mar 1996;81(3):961-7. [Medline].

21. Selby PL, Davie MW, Ralston SH, et al. Guidelines on the management of Paget's disease of bone. Bone. Sep 2002;31(3):366-73. [Medline].

22. Altman RD, Brown M, Gargano F. Low back pain in Paget's disease of bone. Clin Orthop Relat Res. Apr 1987;(217):152-61. [Medline].

23. Anderson DC, Richardson PC, Brown JK, et al. Intravenous pamidronate: evolution of an effective treatment strategy. Semin Arthritis Rheum. Feb 1994;23(4):273-5. [Medline].

24. Arnalich F, Plaza I, Sobrino JA, et al. Cardiac size and function in Paget's disease of bone. Int J Cardiol. Apr 1984;5(4):491-505. [Medline].

25. Avioli LV, Krane SM, eds. Metabolic Bone Disease and Clinically Related Disorders. 3^rd ed. Philadelphia, Pa: WB Saunders; 1990:546-615.

26. Barker DJ, Clough PW, Guyer PB, et al. Paget's disease of bone in 14 British towns. Br Med J. May 7 1977;1(6070):1181-3. [Medline]. [Full Text].

27. Berg C, Hanebuth L. Paget's disease. Nurs Care. Apr 1977;10(4):25-6. [Medline].

28. Braddom, RL, ed. Physical Medicine and Rehabilitation. Philadelphia, Pa: WB Saunders; 1996:813-75, 1237-50.

29. Buckler H, Fraser W, Hosking D, et al. Single infusion of zoledronate in Paget's disease of bone: a placebo-controlled, dose-ranging study. Bone. May 1999;24(5 Suppl):81S-85S. [Medline].

30. Chakravarty K, Merry P, Scott DG. A single infusion of bisphosphonate AHPrBP in the treatment of Paget's disease of bone. J Rheumatol. Nov 1994;21(11):2118-21. [Medline].

31. Chen JR, Rhee RS, Wallach S, et al. Neurologic disturbances in Paget disease of bone: response to calcitonin. Neurology. Apr 1979;29(4):448-57. [Medline].

32. Clarke PR, Williams HI. Ossification in extradural fat in Paget's disease of the spine. Br J Surg. Jul 1975;62(7):571-2. [Medline].

33. Collins DH. Paget's disease of bone; incidence and subclinical forms. Lancet. Jul 14 1956;271(6933):51-7. [Medline].

34. Cooper C, Schafheutle K, Dennison E, et al. The epidemiology of Paget's disease in Britain: is the prevalence decreasing?. J Bone Miner Res. Feb 1999;14(2):192-7. [Medline].

35. Cotran RS, Kumar V, Robbins SL. Robbins Pathologic Basis of Disease. 5^th ed. Philadelphia, Pa: WB Saunders; 1994:1223-4.

36. Crisp AJ, Smith ML, Skingle SJ, et al. The localization of the bone lesions of Paget's disease by radiographs, scintigraphy and thermography: pain may be related to bone blood flow. Br J Rheumatol. Jun 1989;28(3):266-8. [Medline].

37. Damjanov I, Linder J, eds. Anderson's Pathology. vol 2. 10^th ed. St Louis, Mo: Mosby; 1996:2606-7.

38. Davies DG. Paget's disease of the temporal bone. A clinical and histopathological survey. Acta Otolaryngol. 1968;(Suppl 242):3+. [Medline].

39. Degroot LJ, et al, eds. Endocrinology. vol 2. 3^rd ed. Philadelphia, Pa: WB Saunders; 1995:1259-73.

40. Delisa J, ed. Rehabilitation Medicine: Principles and Practice. Philadelphia, Pa: WB Saunders; 1998:1423-76.

41. Delmas PD. Biochemical markers of bone turnover in Paget's disease of bone. J Bone Miner Res. Oct 1999;14(Suppl 2):66-9. [Medline].

42. Dickinson CJ. The possible role of osteoclastogenic oral bacterial products in etiology of Paget's disease. Bone. Feb 2000;26(2):101-2. [Medline].

43. Durán A, Serrano M, Leitges M, et al. The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell. Feb 2004;6(2):303-9. [Medline].

44. el Sammaa M, Linthicum FH Jr, House HP, et al. Calcitonin as treatment for hearing loss in Paget's disease. Am J Otol. Jul 1986;7(4):241-3. [Medline].

45. Eretto P, Krohel GB, Shihab ZM, et al. Optic neuropathy in Paget's disease. Am J Ophthalmol. Apr 1984;97(4):505-10. [Medline].

46. Füessl HS. [Optimizing therapy in Paget disease]. MMW Fortschr Med. Dec 15 2005;147(51-52):32. [Medline].

47. Garnero P, Gineyts E, Schaffer AV, et al. Measurement of urinary excretion of nonisomerized and beta-isomerized forms of type I collagen breakdown products to monitor the effects of the bisphosphonate zoledronate in Paget's disease. Arthritis Rheum. Feb 1998;41(2):354-60. [Medline].

48. Genuth SM, Klein L. Hypoparathyroidism and Paget's disease: the effect of parathyroid hormone administration. J Clin Endocrinol Metab. Nov 1972;35(5):693-9. [Medline].

49. Grauer A, Bone H, McCloskey EV, et al. Discussion: Newer bisphosphonates in the treatment of Paget's disease of bone: where we are and where we want to go. J Bone Miner Res. Oct 1999;14(Suppl 2):74-8. [Medline].

50. Grauer A, Heichel S, Knaus J, et al. Ibandronate treatment in Paget's disease of bone. Bone. May 1999;24(5 Suppl):87S-89S. [Medline].

51. Hadjipavlou A, Lander P. Paget disease of the spine. J Bone Joint Surg [Am]. Oct 1991;73(9):1376-81. [Medline].

52. Hadjipavlou A, Lander P, Srolovitz H, et al. Malignant transformation in Paget disease of bone. Cancer. Dec 15 1992;70(12):2802-8. [Medline].

53. Hamdy RC. Paget's Disease of Bone: Assessment and Management. New York, NY: Praeger Publishers; 1981.

54. Harrington KD. Surgical management of neoplastic complications of Paget's disease. J Bone Miner Res. Oct 1999;14(Suppl 2):45-8. [Medline].

55. Hartman JT, Dohn DF. Paget's disease of the spine with cord or nerve-root compression. J Bone Joint Surg Am. Sep 1966;48(6):1079-84. [Medline].

56. Hocking LJ, Lucas GJ, Daroszewska A, et al. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum Mol Genet. Oct 15 2002;11(22):2735-9. [Medline].

57. Hocking LJ, Lucas GJ, Daroszewska A, et al. Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis, and structural consequences. J Bone Miner Res. Jul 2004;19(7):1122-7. [Medline].

58. Huvos AG. Osteogenic sarcoma of bones and soft tissues in older persons. A clinicopathologic analysis of 117 patients older than 60 years. Cancer. Apr 1 1986;57(7):1442-9. [Medline].

59. Jaffe HL. Metabolic, Degenerative and Inflammatory Diseases of Bones and Joints. Philadelphia, Pa: Lea & Febiger; 1972:240.

60. Kanis JA. Pathophysiology and Treatment of Paget's Disease of Bone. London, England: Martin Dunitz; 1998:99.

61. Kaplan FS. Surgical management of Paget's disease. J Bone Miner Res. Oct 1999;14(Suppl 2):34-8. [Medline].

62. Kaplan FS, Haddad JG, Singer FR. Paget's disease: complications and controversies. Calcif Tissue Int. Aug 1994;55(2):75-8. [Medline].

63. Kelly WH, Harris ED Jr. Textbook of Rheumatology. vol 2. 5^th ed. Philadelphia, Pa: WB Saunders; 1997:1574-77.

64. Khairi MR, Altman RD, DeRosa GP, et al. Sodium etidronate in the treatment of Paget's disease of bone. A study of long-term results. Ann Intern Med. Dec 1977;87(6):656-63. [Medline].

65. Khairi MR, Wellman HN, Robb JA, et al. Paget's disease of bone (osteitis deformans): symptomatic lesions and bone scan. Ann Intern Med. Sep 1973;79(3):348-51. [Medline].

66. Laurin N, Brown JP, Morissette J, et al. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet. Jun 2002;70(6):1582-8. [Medline]. [Full Text].

67. Lindsay JR, Lehman RH. Histopathology of the temporal bone in advanced Paget's disease. Laryngoscope. Feb 1969;79(2):213-27. [Medline].

68. Ludkowski P, Wilson-MacDonald J. Total arthroplasty in Paget's disease of the hip. A clinical review and review of the literature. Clin Orthop. Jun 1990;(255):160-7. [Medline].

69. Lyles KW, Siris ES, Singer FR, et al. A clinical approach to diagnosis and management of Paget's disease of bone. J Bone Miner Res. Aug 2001;16(8):1379-87. [Medline].

70. McClung MR, Tou CK, Goldstein NH, et al. Tiludronate therapy for Paget's disease of bone. Bone. Nov 1995;17(5 Suppl):493S-496S. [Medline].

71. McKusick VA. Heritable Disorders of Connective Tissue. 4^th ed. St Louis, Mo: Mosby; 1972.

72. Meunier PJ. Paget's disease: treatment results and expectations with present therapies. J Bone Miner Res. Oct 1999;14(Suppl 2):70-3. [Medline].

73. Meunier PJ, Salson C, Mathieu L, et al. Skeletal distribution and biochemical parameters of Paget's disease. Clin Orthop Relat Res. Apr 1987;37-44. [Medline].

74. Meunier PJ, Vignot E. Therapeutic strategy in Paget's disease of bone. Bone. Nov 1995;17(5 Suppl):489S-491S. [Medline].

75. Meyers MH, Singer FR. Osteotomy for tibia vara in Paget's disease under cover of calcitonin. J Bone Joint Surg [Am]. Sep 1978;60(6):810-4. [Medline].

76. Milgram JW. Orthopedic management of Paget's disease of bone. Clin Orthop Relat Res. 1977;(127):63-9. [Medline].

77. Mirón-Canelo JA, Del Pino-Montes J, Vicente-Arroyo M, et al. Epidemiological study of Paget's disease of bone in a zone of the Province of Salamanca (Spain). The Paget's disease of the bone study group of Salamanca. Eur J Epidemiol. Oct 1997;13(7):801-5. [Medline].

78. Montagu MFA. Paget's disease (osteitis deformans) and hereditary. Am J Hum Gene. 1949;1:94-5.

79. Morales-Piga AA, Rey-Rey JS, Corres-González J, et al. Frequency and characteristics of familial aggregation of Paget's disease of bone. J Bone Miner Res. Apr 1995;10(4):663-70. [Medline].

80. Nagant de Deuxchaisnes C, Krane SM. Paget's disease of bone: clinical and metabolic observations. Medicine (Baltimore). May 1964;43:233-66. [Medline].

81. Nagant de Deuxchaisnes CN, Maldague B, Malghem J, et al. The action of the main therapeutic regimes on Paget's disease of bone with a note on the effect of Vitamin D deficiency. Arthritis Rheum. 1980;23:1215-34.

82. Nager GT. Paget's disease of the temporal bone. Ann Otol Rhinol Laryngol. Jul-Aug 1975;84(4 Pt 3 Suppl 22):1-32. [Medline].

83. O'Doherty DP, Bickerstaff DR, McCloskey EV, et al. Treatment of Paget's disease of bone with aminohydroxybutylidene bisphosphonate. J Bone Miner Res. May 1990;5(5):483-91. [Medline].

84. Maddison PJ, ed. Oxford Textbook of Rheumatology. vol 2. 2^nd ed. Oxford, England: Blackwell Science; 1998:1610-17.

85. Papapoulos SE, Hoekman K, Löwik CW, et al. Application of an in vitro model and a clinical protocol in the assessment of the potency of a new bisphosphonate. J Bone Miner Res. Oct 1989;4(5):775-81. [Medline].

86. Posen S. Paget's disease: current concepts. Aust N Z J Surg. Jan 1992;62(1):17-23. [Medline].

87. Potter HG, Schneider R, Ghelman B, et al. Multiple giant cell tumors and Paget disease of bone: radiographic and clinical correlations. Radiology. Jul 1991;180(1):261-4. [Medline].

88. Price CH, Goldie W. Paget's sarcoma of bone. A study of eighty cases from the Bristol and the Leeds bone tumour registries. J Bone Joint Surg Br. May 1969;51(2):205-24. [Medline]. [Full Text].

89. Pygott F. Paget's disease of bone; the radiological incidence. Lancet. Jun 8 1957;272(6980):1170-1. [Medline].

90. Reginster JY, Colson F, Morlock G, et al. Evaluation of the efficacy and safety of oral tiludronate in Paget's disease of bone. A double-blind, multiple-dosage, placebo-controlled study. Arthritis Rheum. Aug 1992;35(8):967-74. [Medline].

91. Reid IR, Nicholson GC, Weinstein RS, et al. Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med. Oct 1996;101(4):341-8. [Medline].

92. Resnick D. Diagnosis of Bone and Joint Disorders. vol 4. 3^rd ed. Philadelphia, Pa: WB Saunders; 1995:1923-68.

93. Resnick D. Patterns of migration of the femoral head in osteoarthritis of the hip. Roentgenographic-pathologic correlation and comparison with rheumatoid arthritis. Am J Roentgenol Radium Ther Nucl Med. May 1975;124(1):62-74. [Medline].

94. Roodman GD, Windle JJ. Paget disease of bone. J Clin Invest. Feb 2005;115(2):200-8. [Medline]. [Full Text].

95. Russell RG, Rogers MJ, Frith JC, et al. The pharmacology of bisphosphonates and new insights into their mechanisms of action. J Bone Miner Res. Oct 1999;14(Suppl 2):53-65. [Medline].

96. Schmorl G. Ueber ostitis deformans paget. Virchows Arch (Pathol Anat). 1932;283:694.

97. Schweitzer DH, Zwinderman AH, Vermeij P, et al. Improved treatment of Paget's disease with dimethylaminohydroxypropylidene bisphosphonate. J Bone Miner Res. Feb 1993;8(2):175-82. [Medline].

98. Singer FR, Wallach S. Paget's Disease of Bone: Clinical Assessment, Present and Future Therapy. New York, NY: Elsevier; 1991:86-99.

99. Siris ES. Perspectives: a practical guide to the use of pamidronate in the treatment of Paget's disease. J Bone Miner Res. Mar 1994;9(3):303-4. [Medline].

100. Siris ES, Ottman R, Flaster E, et al. Familial aggregation of Paget's disease of bone. J Bone Miner Res. May 1991;6(5):495-500. [Medline].

101. Smith J, Botet JF, Yeh SD. Bone sarcomas in Paget disease: a study of 85 patients. Radiology. Sep 1984;152(3):583-90. [Medline].

102. Sofaer JA, Holloway SM, Emery AE. A family study of Paget's disease of bone. J Epidemiol Community Health. Sep 1983;37(3):226-31. [Medline].

103. Suda T, Takahashi N, Udagawa N, et al. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. Jun 1999;20(3):345-57. [Medline]. [Full Text].

104. Taylor S. Endocrinology. London, England: W Heinemann; 1974:409-24.

105. Tilyard MW, Gardner RJ, Milligan L, et al. A probable linkage between familial Paget's disease and the HLA loci. Aust N Z J Med. Oct 1982;12(5):498-500. [Medline].

106. Uebelhart D, Gineyts E, Chapuy MC, et al. Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Miner. Jan 1990;8(1):87-96. [Medline].

107. van Staa TP, Selby P, Leufkens HG, et al. Incidence and natural history of Paget's disease of bone in England and Wales. J Bone Miner Res. Mar 2002;17(3):465-71. [Medline].

108. Vega E, Mautalen C, Roldán EJ, et al. Preliminary study of multiple increasing oral doses of dimethyl-APD on bone metabolism dynamics and safety profile. Drugs Exp Clin Res. 1994;20(3):103-8. [Medline].

109. Vellenga CJ, Pauwels EK, Bijvoet OL. Some characteristics of local scintigraphic and radiologic patterns of Paget's disease of bone (osteitis deformans). Diagn Imaging Clin Med. 1985;54(5):273-81. [Medline].

110. Vellenga CJ, Pauwels EK, Bijvoet OL. Untreated Paget disease of bone studied by scintigraphy. Radiology. Dec 1984;153(3):799-805. [Medline].

111. Wallace E, Wong J, Reid IR. Pamidronate treatment of the neurologic sequelae of pagetic spinal stenosis. Arch Intern Med. Sep 11 1995;155(16):1813-5. [Medline].

112. Wallach S, Siris E, Singer F, et al. Risedronate produces sustained remission in patients with Paget's disease. Bone. 1998;23(5 Suppl):S454.

113. Walsh JP. Paget's disease of bone. Med J Aust. Sep 6 2004;181(5):262-5. [Medline]. [Full Text].

114. Walsh JP, Ward LC, Stewart GO, et al. A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone. Bone. Apr 2004;34(4):747-54. [Medline].

115. Waltner JG. Stapedectomy in Paget's disease. Histological and clinical studies. Arch Otolaryngol. Oct 1965;82(4):355-8. [Medline].

116. Watts RA, Skingle SJ, Bhambhani MM, et al. Treatment of Paget's disease of bone with single dose intravenous pamidronate. Ann Rheum Dis. Aug 1993;52(8):616-8. [Medline]. [Full Text].

117. Wimalawansa SJ, Gunasekera RD. Pamidronate is effective for Paget's disease of bone refractory to conventional therapy. Calcif Tissue Int. Oct 1993;53(4):237-41. [Medline].

118. Woodhouse NJ, Crosbie WA, Mohamedally SM. Cardiac output in Paget's disease: response to long-term salmon calcitonin therapy. Br Med J. Dec 20 1975;4(5998):686. [Medline]. [Full Text].

119. Wootton R, Reeve J, Veall N. The clinical measurement of skeletal blood flow. Clin Sci Mol Med. Apr 1976;50(4):261-8. [Medline].

120. Wootton R, Tellez M, Green JR, et al. Skeletal blood flow in Paget's disease of bone. Metab Bone Dis Relat Res. 1981;3(4-5):263-70. [Medline].

121. Yochum TR. Paget's sarcoma of bone. Radiologe. Sep 1984;24(9):428-33. [Medline].

Keywords

Paget disease, Paget's disease, bone pain, bone disease, Paget's disease of bone, Paget's bone disease, osteoblast, osteoclast, osteoblasts, osteoclasts, osteoblastic, Paget disease of bone, osteitis deformans, osteoclastic, bone deformity

Contributor Information and Disclosures

Author

David Chow, MD, Medical Director, California Spine Center
David Chow, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Society of Interventional Pain Physicians, North American Spine Society, and Physiatric Association of Spine, Sports and Occupational Rehabilitation
Disclosure: Nothing to disclose.

Coauthor(s)

Curtis W Slipman, MD, Director, University of Pennsylvania Spine Center; Associate Professor, Department of Physical Medicine and Rehabilitation, University of Pennsylvania Medical Center
Curtis W Slipman, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, Association of Academic Physiatrists, International Association for the Study of Pain, and North American Spine Society
Disclosure: Nothing to disclose.

Debra Braverman, MD, Director of Alternative and Complementary Medicine, Assistant Professor, Department of Rehabilitation Medicine, University of Pennsylvania Health System
Debra Braverman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, and Association of Academic Physiatrists
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Medical Editor

Patrick J Potter, BSc, MD, FRCP(C), Associate Professor, Physical Medicine and Rehabilitation, The University of Western Ontario; Consulting Staff, Department of Physical Medicine and Rehabilitation, St Joseph's Health Care Centre
Patrick J Potter, BSc, MD, FRCP(C) is a member of the following medical societies: American Paraplegia Society, Canadian Association of Physical Medicine and Rehabilitation, Canadian Medical Association, College of Physicians and Surgeons of Ontario, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada
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Kat Kolaski, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine and American Academy of Physical Medicine and Rehabilitation
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Chief Editor

Denise I Campagnolo, MD, MS, Director of Multiple Sclerosis Clinical Research and Staff Physiatrist, Barrow Neurology Clinics, St Joseph's Hospital and Medical Center; Investigator for Barrow Neurology Clinics; Director, NARCOMS Project for Consortium of MS Centers
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