eMedicine Specialties > Physical Medicine and Rehabilitation > Medical Diseases

Paget Disease

Author: David Chow, MD, Medical Director, California Spine Center
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; Debra Braverman, MD, Director of Alternative and Complementary Medicine, Assistant Professor, Department of Rehabilitation Medicine, University of Pennsylvania Health System
Contributor Information and Disclosures

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

Studies of incidence of Paget's disease are inherently imprecise because many affected individuals are asymptomatic. The prevalence of the disease is believed to be 3% or more in people aged 40 years or older. A survey study suggested that the prevalence in the United States is 2.3% of the population between age 65 and 74 years.2

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.

More on Paget Disease

Overview: Paget Disease
Differential Diagnoses & Workup: Paget Disease
Treatment & Medication: Paget Disease
Follow-up: Paget Disease
References
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Further Reading

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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

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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
Disclosure: Nothing to disclose.

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, Assistant Professor, Departments of Orthopedic Surgery and Pediatrics, Wake Forest University School of Medicine
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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CME Editor

Kelly L Allen, MD, Regional Medical Director, IMX-Medical Management Services
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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
Denise I Campagnolo, MD, MS is a member of the following medical societies: Alpha Omega Alpha, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, Association of Academic Physiatrists, and Consortium of Multiple Sclerosis Centers
Disclosure: Teva Neuroscience Honoraria Speaking and teaching; Serono-Pfizer Honoraria Speaking and teaching

 
 
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