Published: August 2018
Paget’s disease of bone (PDB) is a focal, chronic skeletal disorder characterized by enhanced resorption of bone as a result of overactivity of osteoclasts followed by the formation of bone by osteoblasts. This process results in a disorganized, mosaic pattern of woven and lamellar bone that is associated with increased vascularity, marrow fibrosis, and mechanical weakness. The affected bones can become enlarged, less able to resist stress, and deformed. PDB can affect 1 bone, termed monostotic PDB; however, it more commonly affects more than 1 bone and is polyostotic. The axial skeleton is primarily affected and typically includes the pelvis (72%), lumbar spine (58%), femur (55%), thoracic spine (45%), skull (42%), and tibia (35%), whereas the feet, hands, and facial bones are rarely affected.1 The most common locations for monostotic disease include the tibia and iliac bones.
It is difficult to estimate the incidence of PDB because most patients are asymptomatic. The global prevalence varies from 1.5% to 8.3% depending on factors such as age, country of residence, and sex.2,3 The incidence of PDB increases in individuals over 50 years of age.2 The prevalence is higher in the United Kingdom, France, Germany, Australia, New Zealand, and North America.2 It is rare in Asia, India, and Scandinavia. PDB is slightly more prevalent in men than in women.3
The exact cause of PDB is uncertain. However, available data suggest that genetic factors or viral infection, or both, might play a pathogenic role. PDB tends to aggregate in families, and between 14% and 25% of family members of patients with Paget’s disease eventually contract the disease.4, 5 First-degree relatives of patients with PDB have a 7- to 10-fold increased risk of developing the condition.4, 5 Other studies have also suggested that a viral infection might play a role in the etiology of PDB.
The theory for a viral basis originated from a study showing that both the nuclei and cytoplasm of osteoclasts from patients with PDB contained uncharacterized viral particles not found in normal osteoclasts.6 A subsequent study using electron microscopy confirmed the presence of nuclear and cytoplasmic virus-like inclusion bodies in pagetic osteoclasts that resembled paramyxoviral nucleocapsids.7 Proteins derived from the respiratory syncytial virus and measles virus are present in pagetic osteoclasts and in cells obtained from pagetic bone cultures.8,9 Although supported by some studies, this viral hypothesis remains controversial, but it does suggest that the development of PDB might result from a latent viral infection of osteoclasts in a genetically susceptible person.
Approximately 70% of patients with PDB are asymptomatic.10 The diagnosis is usually made by an incidental finding on radiograph or by routine chemistry screen showing an elevated serum alkaline phosphatase concentration. However, some patients present with a wide range of symptoms. The classic clinical manifestation of PBD is local bone pain that is usually continuous and present at rest.10 The temperature of the skin over the affected long bone or skull can be elevated, which is probably caused by increased vascularization of the surrounding tissue and bone.11 PBD can cause skeletal deformities, such as bowing of long bones, enlarged skull, pelvic alterations, and osteoarthritis if the afflicted area of bone is located in proximity to a joint. The bowing deformities, particularly in the tibia and femur, can cause gait changes and mechanical stresses.
PDB can lead to several comorbid conditions. Traumatic and pathologic fractures can occur.11 Fractures of long bones may be a serious complication, because excessive blood loss can occur as a result of the increased vascularity of pagetic bone. In less than 1% of patients with PDB, osteosarcomas can develop.2 These tumors have a poor prognosis, with a 5-year survival rate of approximately 10%.12 PDB is also associated with neurologic complications including deafness, facial nerve palsies, radiculopathies, and spinal cord compression.10 These neurologic symptoms generally result from nerve compression by enlarging bone or by interference with the blood supply. Vascular steal syndromes affecting the spinal cord and cerebral supply have been observed.10 Compression of the base of the skull, known as platybasia, can occur, leading to hydrocephalus, nerve entrapment, and cerebellar dysfunction.13 This can lead to symptoms of nausea, ataxia, incontinence, gait disturbance, or dementia.13
PDB is associated with high cardiac output, hypercalcemia, and hyperparathyroidism. High-output heart failure is rare and is a result of increased vascularization of metabolically active pagetic bone. Hypercalcemia is also rare and is normally seen in patients with severe disease who are immobile. Some studies have found an association between PDB and hyperparathyroidism, which could also account for the increase in calcium.14
Asymptomatic patients with PDB are usually initially identified incidentally by radiograph or by an elevated bone-specific alkaline phosphatase obtained on routine chemistry panels.
The principal mode of diagnosis of PDB is radiographic examination of the skeleton. Plain radiographs of an affected bone reveal osteolytic, osteoblastic, or mixed lesions. Other characteristic radiologic findings include transverse lucent areas, enlargement of bones, expanding lytic changes, thickened cortices, or osteoporosis circumscripta, which refers to extensive lytic involvement in the skull.10
Although the radiograph is a powerful diagnostic tool for PDB, bone scanning is a more sensitive test in identifying pagetic lesions.15 Bone scanning detects up to 50% more lesions than can be observed on radiographs.15 Thus, bone scans are particularly useful when a patient first presents with symptoms of PDB. As soon as abnormalities are identified by bone scan, they should be confirmed by conventional radiography in at least one site of bone.15 Repeat bone scans and radiographs are not needed unless the patient has new or progressive symptoms.
Bone biopsy may be necessary if malignant transformation of the bone is suspected.15 The most important feature of malignant change of the bone is cortical destruction and the presence of a soft tissue mass outside of the bone.12
PDB is characterized by accelerated bone turnover. Therefore, elevated levels of biochemical markers of bone turnover provide a general indication of the extent of disease activity. Total serum alkaline phosphatase activity, which is a reflection of increased bone formation, is elevated in 85% of untreated PDB patients.15 In studies that compare various markers of bone turnover in patients with PDB, bone-specific alkaline phosphatase has a diagnostic sensitivity of 84%, and total serum alkaline phosphatase has a diagnostic sensitivity of 74%.16 The alkaline phosphatase is a useful marker of disease activity, extent and severity of disease, and treatment efficacy. Accelerated bone resorption also occurs in PDB. Thus, increased urinary excretion of pyridinoline and hydroxyproline, markers of bone resorption, are observed.16
The indications for treatment of PDB include bone pain, bone deformity, extensive skull involvement, hypercalcemia, fractures, neurologic compromise, monostotic disease of a tibia or femur in whom progression is likely, and high-output heart failure.2,15 Treatment is also indicated in the presence of moderately active asymptomatic disease, with serum alkaline phosphatase at least 3 to 4 times the upper limit of normal, in patients with disease at sites where complications could occur. These sites include weight-bearing bones, areas near major joints, and vertebral bodies. For patients with moderately active disease before elective surgery on the affected bone(s), prophylactic therapy is also used to reduce hypervascularity and blood loss.2 Some studies indicate that antipagetic treatment is valuable for symptomatic as well as asymptomatic patients, with the goal of reducing local disease progression and the risk of future complications.2 In general, because therapy is effective and safe, treatment should be withheld only in asymptomatic patients whose disease is located only in areas with no risk of complications.17
The drugs used to treat PDB suppress osteoclastic activity. The medications that are currently approved by the Food and Drug Administration in the United States are salmon and human calcitonin, given subcutaneously, and various bisphosphonates.
The most commonly used agents are the bisphosphonates, which are pyrophosphate analogues that inhibit bone resorption. Etidronate was the first clinically available agent for the treatment of PDB. It is administered at a dose of 5 mg/kg/day orally for 6 months. Although etidronate has been shown to be effective for treating PDB, the newer generation of bisphosphonates are superior at achieving normalization of biochemical indices of bone turnover.18 Tiludronate can be used for treatment at a dose of 400 mg/day orally for 3 months. Alendronate is given at 40 mg/day orally for 6 months, and risedronate is given at a dose of 30 mg/day orally for 2 months.
The oral bisphosphonates have the drawback of gastrointestinal side effects, especially esophagitis. They should be taken with 6 to 8 ounces of water and the patient should be in the upright position for at least 30 minutes without other oral intake. There are intravenous bisphosphonate options for the treatment of PDB. In the United States, pamidronate is given as an intravenous infusion.15 Zoledronic acid is a highly potent bisphosphonate also given as an intravenous infusion. It was shown that a single infusion of zoledronic acid 5 mg produced a more rapid, more complete, and more sustained response in Paget’s disease than did daily treatment with risedronate.19
Treatment efficacy can be monitored via clinical and biochemical responses. Effective therapy for PDB results in a reduction in bone turnover, with a substantial decrease in the serum alkaline phosphatase. It is recommended to check the alkaline phosphatase every 3 months for the first 6 months of therapy and thereafter at intervals of every 6 months.15