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Paget's disease
BONE DISORDERS
Paget’s disease
Pathogenesis The main abnormality in bones affected by Paget’s disease is a marked increase in bone resorption. This is caused by abnormally large osteoclasts with very many nuclei. As a result of increased resorption, there is increased bone formation, but the bone that is laid down is abnormal, with a mosaic appearance on microscopy. Although the changes of Paget’s disease spread through individual bones (typically at a rate of 1 cm/year), it is rare for the disease to move between bones. Thus, when patients present with Paget’s disease, the distribution within their skeleton is likely to remain fixed for the rest of their life. These bone changes lead to increased bone size and deformity. The abnormal bone is weak and subject to fracture, which can be complete or can comprise ‘incremental fractures’ along the convex surface of deformed bones. These fractures are a common cause of pain in pagetic bone. The increased metabolic rate in the affected bones leads to increased blood flow, which appears to contribute to the pain of the disease and can lead to a local vascular steal syndrome, which causes neurological signs and symptoms.
Peter Selby
Abstract Paget’s disease is the result of local increase in bone turnover, leading to pain and deformity. It is particularly common in the UK, North America and Australasia, where its prevalence increases with age. The abnormal bone is weak, leading to fracture, and can also cause pressure symptoms because of expansion. Diagnosis is usually on the basis of typical radiological appearance. Treatment with potent bisphosphonates is primarily given for pain but there remains disagreement as to whether or not it also arrests the development of disease complications.
Keywords bisphosphonates; deformity fracture; Paget’s disease; pamidronate; risedronate; zoledronate
Clinical features
Paget’s disease is a condition in which there is locally increased bone turnover. Evidence of the condition is seen on radiography in 2.5% of men and 1.6% of women over the age of 55 years, but only 1/12 of these suffer symptoms. Thus, although the average general practitioner may have 10e20 patients with radiological Paget’s disease, only one or two are likely to be symptomatic.
Many patients with Paget’s disease are asymptomatic. The most common symptoms are pain and deformity of the affected bones. Occasionally, patients present with a complication of the disease; this is often a fracture of pagetic bone or hearing loss as a consequence of Paget’s disease in the skull .
Diagnosis and investigations
Epidemiology
Diagnosis of Paget’s disease is primarily based on the radiographic appearance (Figure 1). In the early stages of the disease, there is a loss of bone; this is replaced with chaotic new bone formation with lack of distinction between cortex and medullary
Paget’s disease is most commonly seen in individuals of British origin, including those from areas that were colonized during the time of the British Empire. The prevalence is substantial in Australia, New Zealand and North America, but Paget’s disease is rare in Asia and Africa. Recent studies from the UK and New Zealand have shown that the incidence of new cases of Paget’s disease appears to be declining, as does the severity of symptoms at presentation.
Aetiology There are several theories regarding the aetiology of Paget’s disease, but none has been established beyond doubt. It has recently been suggested that the condition results from a genetic abnormality that becomes manifest later in life, or is the late result of a viral infection. The changes in prevalence and severity make a purely genetic cause seem unlikely; it is most plausible that individuals with a genetic susceptibility develop the disease when exposed to an environmental stimulus such as viral infection.
Peter Selby MA MD FRCP is Consultant Physician and Senior Lecturer in Medicine at Manchester Royal Infirmary, Manchester, UK, and chairman of the National Association for the Relief of Paget’s Disease. Competing interests: the author has received research support and lecture fees from Novartis and Procter and Gamble.
MEDICINE 37:9
Figure 1 Radiograph of pelvis showing typical Pagetic changes in right hemipelvis. Note the abnormal trabecular pattern with loss of distinction of cortical bone and ‘‘cotton-wool’’ appearance. There is secondary osteoarthritis of the right hip joint.
481
Ó 2009 Published by Elsevier Ltd.
BONE DISORDERS
Current treatments for Paget’s disease in the UK Drug
Route
Dose
Comments
Pamidronate
Intravenous
Given in saline infusion; flu-like symptoms are common
Risedronate Zoledronic acid
Oral Intravenous
60 mg fortnightly 3 or 30 mg weekly 6 30 mg daily 56 5 mg single dose
Must be taken fasting and food delayed for 30 minutes Given in saline infusion; flu-like symptoms are common
Table 1
disease is indicated in asymptomatic patients to prevent problems in future. Such instances might include: involvement of the skull (increased risk of deafness) Paget’s disease of long bones (increased risk of deformity, fracture and arthritis) disease in the spine (increased the risk of spinal cord compression or vascular steal syndrome). In most patients, it is sufficient to monitor treatment through clinical symptoms alone. If biochemical confirmation is required, it is normally necessary to measure only total alkaline phosphatase activity. Current treatments usually suppress disease activity for 18e36 months. Recurrent disease (clinical symptoms or worsening biochemistry) usually responds to re-treatment, although it is sometimes necessary to change to a more potent drug or from the oral to the intravenous route. A
bone. The internal architecture of the bone is often disrupted. With increased use of biochemical profiles, including alkaline phosphatase measurements without any real indication, more asymptomatic patients are being discovered with raised total or bone-specific alkaline phosphatase measurements. All other markers of calcium metabolism and liver function are normal. An important radiological feature of bones affected by Paget’s disease is that they are expanded. This feature is often helpful in differentiating pagetic bone from sclerotic metastases. In the latter case, the bone should be of normal size. In rare cases, usually affecting a single vertebra, it is impossible to determine whether the radiological appearance is that of Paget’s disease or metastases; it may then be necessary to undertake computed tomography-guided biopsy. Isotope bone scanning is useful for determining the extent of skeletal involvement, but is not sufficiently specific for diagnosis. Increased bone turnover measured by biochemical markers (usually total alkaline phosphatase) is useful for monitoring treatment, but is also non-specific.
REFERENCES 1 Selby PL, Davie MWJ, Ralston SH, et al. Guidelines on the management of Paget’s disease of bone. Bone 2002; 31: 366e73. 2 Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 2005; 353: 898e908. 3 Ralston SH, Langston AL, Campbell MK, et al. Preliminary results from the PRISM study: a multicentre randomised controlled trial of intensive vs. symptomatic management for Paget’s disease of bone. Endocrine Abstracts 2006; 12: OC15.
Management Many treatments have been used in Paget’s disease, but potent bisphosphonates are the mainstay of modern therapy (Table 1). These agents have rendered calcitonin and older bisphosphonates such as etidronate and tiludronate obsolete.1 Pamidronate and risedronate normalize alkaline phosphatase activity in about three-quarters of patients; zoledronic acid treatment leads to normal alkaline phosphatase in over 90%.2 All these treatments lead to a marked reduction in pain. Controversy remains about the indications for therapy in Paget’s disease. Clinical evidence is available to support treatment for pain and to reduce the biochemical activity of the disease. Although a recent clinical trial indicates that treatment of Paget’s disease has only a limited effect on subsequent complications3 many clinicians believe that treatment of the
MEDICINE 37:9
FURTHER READING Kanis JA. Pathophysiology and treatment of Paget’s disease of bone. 2nd edn. London: Dunitz, 1998. Ralston SH, Langston AL, Reid IR. Pathogenesis and management of Paget’s disease of bone. Lancet 2008; 372: 155e63.
482
Ó 2009 Published by Elsevier Ltd.
Paget’s disease
Pathogenesis The main abnormality in bones affected by Paget’s disease is a marked increase in bone resorption. This is caused by abnormally large osteoclasts with very many nuclei. As a result of increased resorption, there is increased bone formation, but the bone that is laid down is abnormal, with a mosaic appearance on microscopy. Although the changes of Paget’s disease spread through individual bones (typically at a rate of 1 cm/year), it is rare for the disease to move between bones. Thus, when patients present with Paget’s disease, the distribution within their skeleton is likely to remain fixed for the rest of their life. These bone changes lead to increased bone size and deformity. The abnormal bone is weak and subject to fracture, which can be complete or can comprise ‘incremental fractures’ along the convex surface of deformed bones. These fractures are a common cause of pain in pagetic bone. The increased metabolic rate in the affected bones leads to increased blood flow, which appears to contribute to the pain of the disease and can lead to a local vascular steal syndrome, which causes neurological signs and symptoms.
Peter Selby
Abstract Paget’s disease is the result of local increase in bone turnover, leading to pain and deformity. It is particularly common in the UK, North America and Australasia, where its prevalence increases with age. The abnormal bone is weak, leading to fracture, and can also cause pressure symptoms because of expansion. Diagnosis is usually on the basis of typical radiological appearance. Treatment with potent bisphosphonates is primarily given for pain but there remains disagreement as to whether or not it also arrests the development of disease complications.
Keywords bisphosphonates; deformity fracture; Paget’s disease; pamidronate; risedronate; zoledronate
Clinical features
Paget’s disease is a condition in which there is locally increased bone turnover. Evidence of the condition is seen on radiography in 2.5% of men and 1.6% of women over the age of 55 years, but only 1/12 of these suffer symptoms. Thus, although the average general practitioner may have 10e20 patients with radiological Paget’s disease, only one or two are likely to be symptomatic.
Many patients with Paget’s disease are asymptomatic. The most common symptoms are pain and deformity of the affected bones. Occasionally, patients present with a complication of the disease; this is often a fracture of pagetic bone or hearing loss as a consequence of Paget’s disease in the skull .
Diagnosis and investigations
Epidemiology
Diagnosis of Paget’s disease is primarily based on the radiographic appearance (Figure 1). In the early stages of the disease, there is a loss of bone; this is replaced with chaotic new bone formation with lack of distinction between cortex and medullary
Paget’s disease is most commonly seen in individuals of British origin, including those from areas that were colonized during the time of the British Empire. The prevalence is substantial in Australia, New Zealand and North America, but Paget’s disease is rare in Asia and Africa. Recent studies from the UK and New Zealand have shown that the incidence of new cases of Paget’s disease appears to be declining, as does the severity of symptoms at presentation.
Aetiology There are several theories regarding the aetiology of Paget’s disease, but none has been established beyond doubt. It has recently been suggested that the condition results from a genetic abnormality that becomes manifest later in life, or is the late result of a viral infection. The changes in prevalence and severity make a purely genetic cause seem unlikely; it is most plausible that individuals with a genetic susceptibility develop the disease when exposed to an environmental stimulus such as viral infection.
Peter Selby MA MD FRCP is Consultant Physician and Senior Lecturer in Medicine at Manchester Royal Infirmary, Manchester, UK, and chairman of the National Association for the Relief of Paget’s Disease. Competing interests: the author has received research support and lecture fees from Novartis and Procter and Gamble.
MEDICINE 37:9
Figure 1 Radiograph of pelvis showing typical Pagetic changes in right hemipelvis. Note the abnormal trabecular pattern with loss of distinction of cortical bone and ‘‘cotton-wool’’ appearance. There is secondary osteoarthritis of the right hip joint.
481
Ó 2009 Published by Elsevier Ltd.
BONE DISORDERS
Current treatments for Paget’s disease in the UK Drug
Route
Dose
Comments
Pamidronate
Intravenous
Given in saline infusion; flu-like symptoms are common
Risedronate Zoledronic acid
Oral Intravenous
60 mg fortnightly 3 or 30 mg weekly 6 30 mg daily 56 5 mg single dose
Must be taken fasting and food delayed for 30 minutes Given in saline infusion; flu-like symptoms are common
Table 1
disease is indicated in asymptomatic patients to prevent problems in future. Such instances might include: involvement of the skull (increased risk of deafness) Paget’s disease of long bones (increased risk of deformity, fracture and arthritis) disease in the spine (increased the risk of spinal cord compression or vascular steal syndrome). In most patients, it is sufficient to monitor treatment through clinical symptoms alone. If biochemical confirmation is required, it is normally necessary to measure only total alkaline phosphatase activity. Current treatments usually suppress disease activity for 18e36 months. Recurrent disease (clinical symptoms or worsening biochemistry) usually responds to re-treatment, although it is sometimes necessary to change to a more potent drug or from the oral to the intravenous route. A
bone. The internal architecture of the bone is often disrupted. With increased use of biochemical profiles, including alkaline phosphatase measurements without any real indication, more asymptomatic patients are being discovered with raised total or bone-specific alkaline phosphatase measurements. All other markers of calcium metabolism and liver function are normal. An important radiological feature of bones affected by Paget’s disease is that they are expanded. This feature is often helpful in differentiating pagetic bone from sclerotic metastases. In the latter case, the bone should be of normal size. In rare cases, usually affecting a single vertebra, it is impossible to determine whether the radiological appearance is that of Paget’s disease or metastases; it may then be necessary to undertake computed tomography-guided biopsy. Isotope bone scanning is useful for determining the extent of skeletal involvement, but is not sufficiently specific for diagnosis. Increased bone turnover measured by biochemical markers (usually total alkaline phosphatase) is useful for monitoring treatment, but is also non-specific.
REFERENCES 1 Selby PL, Davie MWJ, Ralston SH, et al. Guidelines on the management of Paget’s disease of bone. Bone 2002; 31: 366e73. 2 Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 2005; 353: 898e908. 3 Ralston SH, Langston AL, Campbell MK, et al. Preliminary results from the PRISM study: a multicentre randomised controlled trial of intensive vs. symptomatic management for Paget’s disease of bone. Endocrine Abstracts 2006; 12: OC15.
Management Many treatments have been used in Paget’s disease, but potent bisphosphonates are the mainstay of modern therapy (Table 1). These agents have rendered calcitonin and older bisphosphonates such as etidronate and tiludronate obsolete.1 Pamidronate and risedronate normalize alkaline phosphatase activity in about three-quarters of patients; zoledronic acid treatment leads to normal alkaline phosphatase in over 90%.2 All these treatments lead to a marked reduction in pain. Controversy remains about the indications for therapy in Paget’s disease. Clinical evidence is available to support treatment for pain and to reduce the biochemical activity of the disease. Although a recent clinical trial indicates that treatment of Paget’s disease has only a limited effect on subsequent complications3 many clinicians believe that treatment of the
MEDICINE 37:9
FURTHER READING Kanis JA. Pathophysiology and treatment of Paget’s disease of bone. 2nd edn. London: Dunitz, 1998. Ralston SH, Langston AL, Reid IR. Pathogenesis and management of Paget’s disease of bone. Lancet 2008; 372: 155e63.
482
Ó 2009 Published by Elsevier Ltd.