Paget disease is a localized disorder of bone remodeling that typically begins with excessive bone resorption followed by an increase in bone formation. This osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone.
The English surgeon Sir James Paget first described chronic inflammation of bone as osteitis deformans in 1877.[1] Paget disease, as the condition came to be known, is the second most common bone disorder (after osteoporosis) in elderly persons.
Approximately 70-90% of persons with Paget disease are asymptomatic; however, a minority of affected individuals experience various symptoms, including the following:
Paget disease may involve a single bone but is more frequently multifocal. It has a predilection for the axial skeleton (ie, spine, pelvis, femur, sacrum, and skull, in descending order of frequency), but any bone may be affected. After onset, Paget disease does not spread from bone to bone, but it may become progressively worse at preexisting sites.
Sarcomatous degeneration of pagetic bone is an uncommon but often deadly complication. Pagetic sarcoma is malignant, and the course usually is rapid and fatal
Although the etiology of Paget disease is unknown, both genetic and environmental contributors have been suggested. Ethnic and geographic clustering of Paget disease is well described. Paget disease is common in Europe (particularly Lancashire, England), North America, Australia, and New Zealand. It is rare in Asia and Africa. In the United States, most, although not all, individuals with Paget disease are white. (See Epidemiology.)
A familial link for Paget disease was first reported by Pick in 1883, who described a father-daughter pair with Paget disease. This was followed shortly thereafter with a sibling case of Paget disease described by Lunn in 1885. Approximately 40% of persons with Paget disease report a family history of the disease, although the true prevalence of the disease is likely higher.
Some studies suggest a genetic linkage for Paget disease located on chromosome arm 18q. This has not been demonstrated in most families with Paget disease, however, which suggests genetic heterogeneity.
An environmental trigger for Paget disease has long been considered but never proven. Bone biopsies in patients with Paget disease have demonstrated antigens from several different Paramyxoviridae viruses, including measles virus and respiratory syncytial virus, located within osteoclasts. However, the putative antigen or antigens remain unknown.
Measurement of serum alkaline phosphatase—in some cases, bone-specific alkaline phosphatase (BSAP)—along with several urinary markers, can be useful in the diagnosis of Paget disease. Plain radiographs and bone scanning should be performed upon initial diagnosis. (See Workup.) Medical therapy is principally with bisphosphonates; surgical therapy may be indicated. (See Treatment.)
A 2014 Endocrine Society Clinical Practice Guideline on Paget disease recommends the following[2] :
Three phases of Paget disease have been described: lytic, mixed lytic and blastic, and sclerotic. In an individual patient, different skeletal lesions may progress at different rates. Thus, at any one time, multiple stages of the disease may be demonstrated in different skeletal regions.
Paget disease begins with the lytic phase, in which normal bone is resorbed by osteoclasts that are more numerous, are larger, and have many more nuclei (up to 100) than normal osteoclasts (5-10 nuclei). Bone turnover rates increase to as much as 20 times normal.
The second phase, the mixed phase, is characterized by rapid increases in bone formation from numerous osteoblasts. Although increased in number, the osteoblasts remain morphologically normal. The newly made bone is abnormal, however, with collagen fibers deposited in a haphazard fashion rather than linearly, as with normal bone formation. As the osteoclastic and osteoblastic activities of bone destruction and formation repeat, a high degree of bone turnover occurs.
In the final phase of Paget disease, the sclerotic phase, bone formation dominates and the bone that is formed has a disorganized pattern (woven bone) and is weaker than normal adult bone. This woven bone pattern allows the bone marrow to be infiltrated by excessive fibrous connective tissue and blood vessels, leading to a hypervascular bone state.
After a variable amount of time, osteoclastic activity may decrease, but abnormal bone formation continues. Some pockets of normal-appearing lamellar bone may replace immature woven bone. Eventually, osteoblastic activity also declines, and the condition becomes quiescent. This is the sclerotic, or burned-out, phase. Continued bone resorption and formation are minimal or absent.
Paget disease can affect every bone in the skeleton, but it has an affinity for the axial skeleton, long bones, and the skull. The skeletal sites primarily affected include the pelvis, lumbar spine, femur, thoracic spine, sacrum, skull, tibia, and humerus. The hands and feet are very rarely involved.
Complications of Paget disease depend on the site affected and the activity of the disease. When Paget disease occurs around a joint, secondary osteoarthritis may ensue. Skull involvement may lead to the following:
Frequently, erythema is present over the affected bone area, which is due to the increased hypervascularity. In patients with Paget disease who have extensive bony involvement, this increased bone vascularity may cause high-output cardiac failure and an increased likelihood of bleeding complications following surgery.
Vertebral involvement of Paget disease may be associated with serious complications, including nerve root compressions and cauda equina syndrome. Fractures, which are the most common complication of Paget disease, may occur and may have potentially devastating consequences. Rarely, pagetic bone may undergo a sarcomatous transformation.
Standard serum chemistry values, including serum calcium, phosphorus, and parathyroid hormone levels, are normal in persons with Paget disease. However, hypercalcemia may complicate the course of Paget disease, most frequently in the setting of immobilization. Elevated levels of uric acid and an increased prevalence of gout have been reported in patients with Paget disease.
Levels of bone turnover markers (including markers of bone formation and resorption) are elevated in patients with active Paget disease and may be used to monitor the course of disease. The degree of elevation of these biomarkers helps identify the extent and severity of bone turnover.
Markers of bone turnover that are useful to monitor in persons with Paget disease include the following:
Alpha-alpha type I C-telopeptide fragments are sensitive markers of bone resorption for assessing disease activity and monitoring treatment efficacy in persons with Paget disease.[3] Serum osteocalcin, a marker of bone formation, is not a useful parameter to assess in persons with Paget disease. Upon successful treatment of Paget disease, the level of these bone markers is expected to decrease.
The juvenile form of Paget disease differs greatly from the adult version. Juvenile Paget disease is characterized by widespread skeletal involvement and has distinctly different histologic and radiologic features.
The cause of Paget disease is unknown. Both genetic and environmental factors have been implicated.
The geographic distribution of the disease may be explained by genetic transmission and dissemination by population migration. Studies have found a positive family history in 12.3% of 788 patients in the United States, 13.8% of 407 patients in Great Britain, and 22.8% of 658 patients in Australia. In the former 2 studies, a 7- to 10-fold increase in the incidence of Paget disease was observed in relatives of patients diagnosed with the condition, compared with control groups.
In one study, 15-40% of affected patients had a first-degree relative with Paget disease. Numerous other studies have described families exhibiting autosomal dominant inheritance.
Studies of potential genetic markers for Paget disease have found an association between human leukocyte antigen–A (HLA-A), HLA-B, and HLA-C (class I) and clinical evidence of disease. Two studies reported an increased frequency of DQW1 and DR2 antigens (class II HLA). The studies on HLA have not been conclusive, however; variation among families tested suggests that genetic heterogeneity is likely.[4]
Subsequent genome linkage studies identified several loci associated with Paget disease. Mutations in the sequestosome SQSTM1/p62 gene were identified in 30% of familial Paget cases. The SQSTM1/p62 protein is a selective activator of NFB (nuclear factor kappa-B) transcription factor, which is involved in osteoclast differentiation and activation in response to the cytokines interleukin-1 (IL-1) and RANKL (receptor activator of nuclear factor kappa-B ligand). How germline DNA mutations can cause bone disease that is focal in nature remains unclear.
Alterations in cytokine expression have been found in persons with Paget disease[5] : elevated interleukin-6 (IL-6) levels are found in bone marrow plasma and peripheral blood in patients with Paget disease but not in healthy controls. One hypothesis is that some unidentified viral infection up-regulates IL-6 and the IL-6 receptor genes; however, this has not been shown conclusively.[6, 7]
Osteoclast precursors in patients with Paget disease also appear to be hyperresponsive to vitamin D (specifically, 1,25(OH)2 D3, the active form of vitamin D3[8] ) and calcitonin and have up-regulation of the c-fos proto-oncogene[9] and BC12, the antiapoptosis gene. Treatment efficacy of bisphosphonates in Paget disease may be due to suppression of RANKL-induced bone resorption, with decreases in RANKL and increased osteoprotegerin production.
Macrophage-colony stimulating factor (M-CSF) may play a role in Paget disease. M-CSF is a growth factor produced by many cells, including osteoblasts and marrow fibroblasts. Significantly high levels of M-CSF have been found in patients with untreated Paget disease; however, its exact role remains to be determined.
The development of Paget disease of bone may be related to a deregulation of autophagy, a catabolic process responsible for the degradation of damaged organelles, cytoplasmic proteins, and protein aggregates. Structures observed in the cytoplasm of many osteoclasts in Paget disease may be protein aggregates that would normally be degraded via autophagy.[10]
Variants of several genes involved in the process of autophagy, such as SQSTM1, VCP, and OPTN have been linked with Paget disease. For example, 20–40% of patients with a positive family history of Paget disease and 5–10% of patients with sporadic Paget disease are carriers of a mutation in SQSTM1.[10]
A study of ATG genes, which code for proteins involved in autophagy, found that persons who are carriers of the C allele of the ATG16L1 rs2241880 and the G allele of ATG5 rs2245214 polymorphisms were associated with an increased risk of developing Paget disease, whereas carrier sof the T allele of ATG10 rs1864183 polymorphism were at decreased risk.[10]
Environmental factors also may contribute to the pathogenesis of Paget disease. Supporting observations include the variable penetrance of Paget disease within families with a genetic predisposition; the fact that the disease remains highly localized to a particular bone or bones rather than affecting the entire skeleton; and data that reveal a declining incidence and severity of the disease over the past 20-25 years.
Viral infection
The leading hypothesis for an infectious etiology in Paget disease is the slow virus theory. According to this hypothesis, bone marrow cells (the progenitors of osteoclasts) are infected by a virus, causing an abnormal increase in osteoclast formation. Clinical expression of these viral infections may take years, which may account for the advanced age of most people diagnosed with Paget disease. Familial and geographic clustering also may support the theory of a viral process.
Suspected viruses are paramyxoviruses, such as measles or canine distemper viruses. Respiratory syncytial virus also is suspected; however, no virus has been cultured from pagetic tissue, and extracted ribonucleic acid (RNA) has not confirmed a viral presence.
Some studies have found viral inclusion particles in pagetic osteoclasts.[11] Measles virus messenger RNA sequences have been found in osteoclasts and other mononuclear cells of pagetic bones. Canine distemper virus nucleocapsid antigens have also been found in osteoclasts from patients with Paget disease. However, the presence of these paramyxovirus-like nuclear inclusions does not prove that these are responsible for the development of pagetic lesions; rather, these inclusions may be markers of the disease itself.
The possibility of an inflammatory cause of Paget disease is supported by evidence of clinical improvement after treatment with anti-inflammatory medications. Elevated parathyroid hormone in Paget disease also has been observed, but no firm evidence links the 2 disorders, and one case of Paget disease was diagnosed in a patient with idiopathic hypoparathyroidism. An osteogenic mechanism also has been proposed. Autoimmune, connective tissue, and vascular disorders are proposed as other possible etiologies.
Paget disease is estimated to affect 1 to 3 million people in the United States. Epidemiologic studies are inherently imprecise, however, because many individuals with Paget disease are asymptomatic.
According to a 2000 study by Altman et al, the prevalence of pelvic Paget disease in the United States was 0.71% ± 0.18%, based on data from the National Health and Nutrition Examination Survey I (NHANES I, 1971-1975). The male-to-female ratio was 1.2:1, and the prevalence of pelvic Paget disease was the same in white persons and black persons.
The prevalence of pelvic Paget disease increases with age, with the highest prevalence in persons older than 65 years. A survey study suggested that the prevalence in the United States is 2.3% of the population between ages 65 and 74 years.[12] Paget disease is estimated to occur in 1-3% of individuals older than 45-55 years and in up to 10% of persons older than 80 years. Geographically, pelvic Paget disease was least common in the southern United States and most common in the northeastern United States.[12]
The prevalence of Paget disease varies greatly in different areas of the world. The highest prevalence is in Europe (predominantly England, France, and Germany).[13] The United States, Australia, and New Zealand have high prevalence rates because of significant populations with northern European ancestry and a large population of British immigrants.[14] The disease is rare in Asian countries, especially China, India, and Malaysia, and in the Middle East and Africa.
Prevalence may vary even within the same country.[15] A prevalence of 2% in certain British cities can be contrasted with rates in Lancaster, England, which had a prevalence of 8.3%.[16]
In Europe, the prevalence rates of Paget disease appear to decrease from north to south, with the exception of Norway and Sweden, which both have very low rates (0.3%). The highest prevalence in Europe is found in England (4.6%) and France (2.4%) in hospitalized patients older than 55 years. Other European countries, such as Ireland, Spain, Germany, Italy, and Greece, report prevalence rates of Paget disease that range from 0.5% to approximately 2%. The prevalence rates of Paget disease in Australia and New Zealand range from 3-4%.
The prevalence of Paget disease in sub-Saharan Africa is 0.01-0.02%. In Israel, Paget disease is predominantly found in Jews; however, cases have recently been reported in Israeli Arabs.
In South America, the incidence of Paget disease is relatively high in Argentina (around Buenos Aires), which was settled by Spanish and Italian immigrants, and lower in Chile and Venezuela.
Research from Europe and New Zealand indicates that the prevalence of Paget disease has decreased since the 1980s but that increased incidence with age has been maintained.[17] The estimated prevalence of Paget's disease in patients aged 55 years or older has decreased to approximately 2%.
Paget disease is not known to demonstrate a predilection for any race. Nevertheless, unusual patterns of prevalence have been noted. Paget disease is more common in males than females. The male-to-female ratio is approximately 1.8:1.
Paget disease is distinctly rare in persons younger than 25 years and increases in frequency with increasing age. Paget disease is believed to develop in persons in the fifth decade of life and is most commonly diagnosed in the sixth decade. The incidence of Paget disease in persons older than 80 years is approximately 10%. There is a juvenile form of Paget disease, but it is very different from the adult form.
The general outlook for patients with Paget disease is good, especially if treatment is administered before major changes have occurred in the bones. Treatment does not cure Paget disease, but it can control it. Patients with severe polyostotic Paget disease have a less favorable prognosis than those with monostotic disease. Patients with polyostotic disease are at higher risk for complications.
Morbidity from Paget disease can be extensive. The excessive remodeling of bone associated with Paget disease may result in pain, fractures, and bone deformities. Complications associated with fractures, such as articular and neurologic problems, may increase mortality in patients with Paget disease. The hypervascularity of bone that may result from Paget disease may cause excessive bleeding following fractures or surgery.
The prognosis is extremely unfavorable if the patient has any type of sarcomatous degeneration, especially if there is multicentricity. The 5-year survival rate for a patient with Paget disease and sarcoma is 5-7.5%; however, it may be as high as 50% for those who undergo operative tumor ablation and chemotherapy before metastases occur. The 5-year survival rate for elderly patients with primary nonpagetic sarcoma is 37%.
Higher doses of radiation may be delivered if the neoplasm is located on the limb. Consequently, a more central lesion carries a less favorable prognosis.
Patient education about the pathophysiology of Paget disease and its complications is essential. The patient needs to understand the importance of proper posture, body mechanics, and avoidance of trauma. Precautions against falling should be reinforced. At the same time, the hazards of immobility increase greatly with Paget disease. The patient should understand the necessity of staying active.
Knowledge of the signs and symptoms of complications is important. For instance, increased local pain with soft tissue mass should be reported to a physician immediately, as this may represent a sarcoma.
Understanding the potential side effects of medications is helpful and reassuring to the patient. For example, patients taking bisphosphonates should be aware of the potential for osteonecrosis of the jaw.
Patient education about delayed bone healing and the long rehabilitation process is important in situations of fracture and postsurgery. Reinforcement about the importance of careful, prolonged, protected weight bearing is crucial because the pagetic bone is abnormal and weak. Nonunion and refracture rates are high among patients with Paget disease.
Family members should be informed of the increased incidence of Paget disease in families. Proper patient education on the nature of Paget disease is essential. The Paget Foundation for Paget's Disease of Bone and Related Disorders (telephone: 800-237-2438) can provide useful information for patients.
Clinical Presentation
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