Asymptomatic patients can benefit from treatment if disease is active, polyostotic or the lesions are located in bones with future risk of complications such as long bones, vertebrae and skull. Bisphosphonates are still the mainstay of treatment and alendronate is a useful therapeutic option for treatment. Background
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Subcutaneous injection of salmon calcitonin was the first widely used therapy for Paget’s disease. Salmon calcitonin has been shown to reduce elevated indices of bone turnover by 50 percent, decrease symptoms of bone pain, reduce warmth over affected bones, improve some neurological complications and promote healing of lytic lesions.
Paget's disease of bone is a chronic, slowly progressive skeletal condition of abnormally rapid bone destruction (osteolytic) and reformation (osteoblastic). The new bone may occur in one or more regions of the body and is structurally abnormal, dense and fragile.
A blood test may reveal elevated levels of the enzyme alkaline phosphatase suggesting the diagnosis of Paget’s disease. A bone scan or x-ray may also be used to determine abnormalities in the bones. Urine tests, such as pyrilinks and osteomark, may also be used to assist in the diagnosis of Paget’s disease.
In approximately 15-30 percent of cases there is a family history of the disorder. Researchers have discovered several genes that may predispose individuals to developing Paget’s disease (genetic predisposition).
Osteoporosis drugs (bisphosphonates) are the most common treatment for Paget's disease of bone. Bisphosphonates are typically given by injection into a vein, but they can also be taken by mouth. When taken orally, bisphosphonates are generally well tolerated but can irritate the stomach.
Bisphosphonates are first-line therapy for Paget's disease, and the advent of the new bisphosphonates permits a dramatic improvement in treatment.
Paget's disease is usually asymptomatic. The characteristic skeletal lesions or elevated serum alkaline phosphatase levels are often incidentally detected during the evaluation of an unrelated illness. Non-osseous symptoms in Paget's disease are the direct or indirect manifestations of the bone pathology.
There is widespread agreement that a single intravenous injection (5 mg) of zoledronate (also known as zoledronic acid) is the first-line therapy for Paget's disease 18, 19.
Paget's disease can affect many parts of the body. You may need to see more than one type of doctor, including: Endocrinologists, who treat hormonal and metabolic disorders. Rheumatologists, who treat joint and muscle disorders.
Commonly affected areas include the pelvis, spine and skull. Symptoms can include: constant, dull bone pain. joint pain, stiffness and swelling. a shooting pain that travels along or across the body, numbness and tingling, or loss of movement in part of the body.
There's currently no cure for Paget's disease of bone, but treatment can help relieve the symptoms. If you do not have any symptoms, your doctor may suggest keeping an eye on your condition and delaying treatment until any problems occur.
The key histopathological feature of Paget disease involveS the bone architecture and includes the three phases of the disease: mixed, osteolytic, and osteosclerotic. These phases may occur at the same time or separately.
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.
Nitrogen-containing bisphosphonates are among the first line medications being used to treat Paget's disease of bone. They suppress disease activity by reducing osteoclast-mediated bone resorption and bone turnover, which is reflected by the reduction or normalization of the raised serum ALP level.
A single infusion of zoledronic acid is safe and effective for the treatment of Paget's disease. Oral bisphosphonates, which are currently used for the treatment of Pagets disease, are given to patients daily for 2–6 months.
Prevalence of vitamin D deficiency is higher in patients with Paget's disease of bone compared with age-matched controls. Arq Bras Endocrinol Metabol. 2013 Oct;57(7):509-12. doi: 10.1590/s0004-27302013000700002.
X-ray and bone scan An X-ray can show whether your bones have become enlarged as a result of Paget's disease of bone. Sometimes a bone scan called scintigraphy may also be carried out to check how much of your body is affected by the condition.
The cause of Paget's disease of bone is unknown. Scientists suspect a combination of environmental and genetic factors contribute to the disease. Several genes appear to be linked to getting the disease.
Rarely, Paget cells may invade the dermis. The cause of primary EMPD is unknown, but is thought to arise as a primary intraepidermal neoplasm from the apocrine gland ducts or pluripotent keratinocyte stem cells. Toker cells have also been suggested as potential precursors.
Tests and procedures used to diagnose Paget's disease of the breast include: Breast exam. Your doctor will check both of your breasts and the lymph nodes in your armpit, feeling for any lumps or other abnormalities. Mammogram.
Surgical options include: Removing the entire breast (mastectomy).
Medicine can help reduce the breakdown of bone tissue, control symptoms such as bone pain, and prevent other problems such as arthritis, fractures, or nerve damage. Bisphosphonates are usually the first medicines prescribed for Paget's disease. They often make the disease inactive, sometimes for years or decades.
Many people don't need treatment for Paget's disease. But even if you don't need treatment, you will still need to see your doctor on a regular basis from now on. This will let your doctor watch for other problems you might get from the disease, such as arthritis, fractures, or nerve problems.
12 To prevent excessive hemorrhage in patients with Paget’s disease who are undergoing elective orthopedic surgery involving a pagetic bone , drug therapy should be given for 2 to 3 months prior to surgery to reduce the bone’s vascularity. Treatment should be considered to prevent the progression of skeletal deformities, especially in patients with a long life expectancy. 2 Early treatment may be considered in asymptomatic Paget’s disease patients to reverse osteolytic lesions and reduce skeletal deformity, arthritis, and neurologic complications; however, evidence is lacking regarding the ability of pharmacotherapy to prevent complications. 2,4
The clinical presentation of Paget’s disease ranges from no symptoms to bone pain, painful skeletal deformities, or fractures. It often is discovered because of an elevated serum alkaline phosphatase (ALK-P) of unknown origin or upon radiography. The goals of treatment are to alleviate symptoms and to reduce bone turnover to prevent complications.
Pamidronate, risedronate, alendronate, and zoledronic acid are nitrogen-containing bisphosphonates; etidronate and tiludronate, the older bisphosphonates, do not contain nitrogen. Dyspepsia, esophagitis, esophageal reflux, gastritis, nausea, and other manifestations of GI pain or discomfort are the most common adverse effects (AEs) associated with oral nitrogen-containing bisphosphonates. 10 Diarrhea is the most common AE associated with older, nonnitrogen-containing bisphosphonates. 10 To reduce GI AEs, the patient should be instructed to refrain from lying down for 30 minutes after administration of an oral bisphosphonate. Other AEs have been tied to bisphosphonate therapy, but at a much lower incidence rate. Bisphosphonates disrupt the process of bone remodeling that repairs microdamage by reducing bone turnover; therefore, atypical femoral fractures could result. 10
Pathophysiology. Increased osteoclastic bone resorption, greater vascularity, marrow fibrosis, and disorganized bone formation occur in Paget’s disease. 4 Osteoclasts, which predominate in the early course of disease, contain more nuclei and are larger and more numerous in pagetic lesions of the bone.
Follow-up for Paget’s disease includes radiographs of the lesions at 1 year and serum ALK-P activity every 3 months during the first year. 2 If drug treatment is used, serum ALK-P activity should be measured every 3 to 12 months, depending upon which agent is used. These levels typically decrease within a few months of therapy. 6 If serum ALK-P activity rises at least 25% and/or bone pain recurs, retreatment should be considered. 2
Since Paget’s disease often is asymptomatic, it frequently is discovered accidentally because of an elevated serum alkaline phosphatase (ALK-P) of unknown origin or upon radiography performed to evaluate abdominal symptoms or bone, pelvic, or hip pain. 1,2 Ninety-five percent of untreated patients with Paget’s disease have an elevated serum ALK-P level; however, a normal concentration does not exclude the diagnosis. 4 Serum ALK-P may be normal in patients with monostotic or metabolically inactive disease. Serum ALK-P elevations are reflective of an increased number of osteoblasts in the lesions. 2 The level is indicative of both disease extent and disease activity. 6 Serum total ALK-P levels are appropriate for following the disease, but the bone-specific isoform should be used in patients with coexisting hepatobiliary disease. Urinary deoxypyridinoline and cross-linked N-telopeptide of type I collagen, other markers of bone resorption, have not been found to confer additional benefit on serum ALK-P, and they are more costly. 6
Genetic factors play a role in the development of Paget’s disease. The disorder occurs more frequently in individuals of European descent aged 55 years and older. 1,4 Individuals of Scandinavian, Eastern European, or Asian descent rarely develop Paget’s disease.
The diagnosis of Paget’s disease may be confirmed by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests, such as blood tests, x-rays, and urine tests. A blood test may reveal elevated levels of the enzyme alkaline phosphatase suggesting the diagnosis of Paget’s disease, usually confirmed by x-ray. A bone scan may also be used to determine the extent of the abnormalities in the bones. Urine tests, such as pyrilinks and osteomark, may also be used to assist in the diagnosis and response to therapy of Paget’s disease.
Paget’s disease of bone is a chronic, slowly progressive skeletal condition of abnormally rapid bone destruction (osteolytic) and reformation (osteoblastic). The new bone may occur in one or more regions of the body and is structurally abnormal, dense and fragile. This abnormal development may cause bone pain, arthritis, deformities and fractures.
In this case, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), or the cox-2 inhibitors may be helpful for the management of pagetic pain, in addition to the main pagetic therapy chosen. Surgery. Different orthopedic interventions may be necessary in individuals with Paget’s disease. These include: 1.
Genes associated with this condition are the sequestosome 1 gene, the TNFRSFIIA gene that codes for the RANK protein, and the VCP gene.
This abnormal development may cause bone pain, arthritis, deformities and fractures. The bones most frequently affected are in the spine, skull, pelvis and lower legs. The exact cause of Paget’s disease is not known.
Paget’s disease is rarely diagnosed in people under the age of 40 years but may occur in up to three percent of the population over the age of 60 years. Paget’s disease affects individuals of all ethnic and racial groups. However, it affects individuals of Asian descent less frequently. Both men and women ca be affected with a slight male predominance. The prevalence of Paget’s disease in the United States is estimated to be 1-2 percent of the general population.
In the case of secondary resistance to salmon calcitonin, a switch to bisphosphonate therapy is essential. Miacalcin, an injection taken daily or three times a week, is the only calcitonin approved for Paget’s disease.
Drug therapy for Paget disease should include bisphosphonate treatment with serial monitoring of bone markers. Response to therapy is indicated by reduction of symptoms and decreases in levels of BSAP (a bone formation marker) and deoxypyridinoline, C -telopeptide, [ 5] or N -telopeptide (bone resorption markers). A sustematic review of 20 studies found moderate-quality evidence that bisphosphonates improved pain in patients with Paget disease. [ 32]
When Paget disease occurs around a joint, treatment is often administered in an attempt to prevent development of osteoarthritis. In addition, young patients with Paget disease and those with high levels of bone-specific alkaline phosphatase (BSAP) are often treated to avoid future complications. The concept that aggressive treatment is associated with prevention of progression and reduction in risk of future complications is not yet supported by clear findings from long-term placebo-controlled trials; however, indirect evidence suggests that this hypothesis is reasonable.
Response rates were 93.3% at 1 year, 89.5 % at 2 years, and 91.6 % at 3 years. [ 50]
In one study, 6 months of oral alendronate at the recommended 40-mg regimen produced normalization of alkaline phosphatase in 63% of patients with Paget disease, compared with 17% after treatment with 400 mg/day of etidronate. The mean initial alkaline phosphatase level was 5 times the upper limit of reference range.
Orthotic devices, including canes and walkers, may be useful for patients with gait abnormalities resulting from Paget disease that involves the lower limbs. See Rehabilitation for Paget Disease.
In a long-term follow-up study of 25 patients with active Paget disease who were treated with a single intravenous dose of 6 or 12 mg of ibandronate, Reid et al reported that although some patients showed gradual increases in alkaline phosphatase levels after 20-30 months, levels remained normal 3 years after treatment in 15 of the 25 patients, and after 6 years, six of the patients continued to maintain normal levels without further intervention. [ 36]
The short-term objective of Paget disease treatment is to control disease activity. The long-term objectives of treatment are to minimize or prevent disease progression and to decrease complications from the disease, if possible.
These may be painful and in some cases may progress to a complete fracture. Joints adjacent to Pagetic bone, in particular the hip, may develop secondary degenerative change. In the spine, affected vertebrae may increase in size and press on spinal nerves or the spinal cord, resulting in various neurological compression syndromes. Involvement of the skull may lead to pressure on the auditory nerve, leading to deafness. Skull base involvement may lead to pressure on the brainstem. One of the most serious complications of the disease is the development of primary bone tumours, in particular the very rare bone osteosarcoma (Price, 1962). Due to its increased metabolic activity, Pagetic bone is vascular and if the disease is extensive, a large proportion of blood may be diverted to the affected bone, potentially leading to high output cardiac failure, though this is rare. Individuals who require surgery involving an affected bone, such as total hip replacement, may be at increased risk of bleeding due to increased bone vascularity.
Pathogenesis. In bone affected by Paget’s disease, the osteoclasts (the cells responsible for bone resorption) are larger and more active than normal , and consequently resorption of bone is increased. Because the process of bone resorption and bone formation are tightly coupled, there is a subsequent increase in the rate of bone formation.
In most patients, Paget’s disease is diagnosed on the basis of the appearance of affected bone on plain radiographs. The radiographic changes are characteristic (Figure 1), although radiographs may appear normal in the early stages of the disease. Bone scintigraphy.
The disease progresses slowly through bone at a rate of about 1cm per year. Aetiology. The cause of Paget’s disease is unknown, though both genetic and environmental factors have been implicated. One of the major focuses of research has been to look for an infectious viral cause.
Worldwide the disease is most common in the UK, particularly in the North West of England, with the Lancashire towns of Preston, Bolton and Lancaster having the highest frequency (Barker et al, 1980) (Box 1). After the UK, Australia and New Zealand are the countries where the disease is most common (Barker, 1984). The disease is rare in North Europe, Africa and Asia. Evidence from several countries suggests that the disease may have become less frequent and severe over the past 50 years or so, although the reason for this is unknown (Cundy et al, 1997; Cooper et al, 1999).
Paget’s disease of bone was first described by the English surgeon, Sir James Paget, in 1876 . Prevalence varies throughout the world but is particularly high in the UK. Affected bones change in size and shape and the disease may cause considerable morbidity. Until relatively recently there was no effective treatment.
Paget’s disease may affect any bone but the most frequently affected are the pelvis, femur, spine and skull (Collins, 1956) (Box 2). The disease is monostotic (affects only one bone) in about a third of patients. Once a bone is affected, the disease progresses within that bone but does not spread to others.
Paget disease of bone is a focal disorder of the skeleton that can affect one or more bones. Many patients are discovered accidentally because of elevated serum alkaline phosphatase activity or an abnormal skeletal radiograph intended to evaluate an unrelated condition.
In 1877 sir James Paget published his classic study of patients he had seen with focal enlargement and de formity of the skeleton. [1] Later, with the advent of radiologic evaluation of the skeleton, [2] it was appreciated that the earliest phase of Paget disease was characterized by one or more focal osteolytic lesions, which developed over many years into sclerotic lesions that could then be detected on physical examination (Figure 1).