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Paget’s disease of bone: clinical review and update Mark J Bolland, Tim Cundy Department of Medicine, University of Auckland, Auckland, New Zealand Correspondence to Dr Mark Bolland, Bone and Joint Research Group, Department of Medicine, University of Auckland, Private Bag 92 019, Auckland 1142, New Zealand; , [email protected] – Received 9 June 2013 Revised 14 August 2013 Accepted 23 August 2013 Published Online First 16 September 2013 This is a reprint of a paper that first appeared in J Clin Pathol 2013, Volume 66, pages 924 927.
ABSTRACT Paget’s disease (PD) is a focal disorder of bone remodelling that occurs commonly in older people. In this article, we review clinical aspects of PD with an emphasis on recent findings. The epidemiology of PD appears to be changing rapidly, with several groups in different parts of the world reporting a marked reduction in the prevalence and incidence of PD, as well as in the severity of disease seen by clinicians. These findings seem most likely to be caused by changes in exposure to unknown environmental factors that have a role in the development of PD. However, genetic factors are also important. Mutations in SQSTM1 occur in 25–50% of familial PD. Genotype–phenotype relationships are present, as PD develops at an earlier age and is more extensive and severe in those with SQSTM1 mutations, and these findings are more pronounced in those with truncating mutations. However, the prevalence of PD in adults with SQSTM1 mutations is uncertain, and it is not known how such mutations might cause PD. Ultimately, if the cause of PD is determined, it seems likely that it will include both genetic and environmental factors. Lastly, clinical trials have shown that potent bisphosphonates are highly effective treatments for active PD, and reduce pain, improve quality of life, normalise bone turnover and heal lytic lesions on radiographs. They can also induce sustained remission that persists for many years.
INTRODUCTION Paget’s disease (PD) is a focal disorder of bone remodelling that occurs commonly in older people. While there are now safe and highly effective treatments, it remains an enigmatic condition with distinctive characteristics that are poorly understood. In this article, we will review clinical aspects of PD, with particular emphasis on recent findings related to its epidemiology, genetics and treatment.
EPIDEMIOLOGY
To cite: Bolland MJ, Cundy T. J Clin Pathol 2013;66:924–927. 328
PD is common in older people, and more common in men than women.1 The most common method for determining prevalence of PD is by radiological survey. Since the majority of patients with PD have involvement of at least one bone out of the pelvis, sacrum, lumbar spine or proximal femur,2 assessing consecutive abdominal X-rays gives a reasonable estimate of the prevalence. Worldwide the prevalence varies substantially,1 from very low in Japan (1%) in Western Europe, Australia and New Zealand. Although PD is believed to be uncommon in Asia, we have recently reported that on a population basis, the prevalence of PD in the Asian population in Auckland, New Zealand, appears to be similar to that in patients of European descent.3 A notable feature of the geographic variation in PD is that transmission of PD
appears to have occurred through migration, with areas of high prevalence in Australia, New Zealand, South Africa, Quebec and Brazil after significant migrations from Europe. There are also welldescribed areas of marked regional variation, with particular towns or regions with much higher prevalence than neighbouring regions.4–6 Several radiological surveys have been repeated in recent years, and the prevalence of PD compared between surveys. A recent systematic review identified nine paired surveys which showed on average a 36% reduction in the prevalence of PD over 8–19 years.1 figure 1 shows data from two paired surveys in New Zealand, highlighting the rapid, substantial fall in prevalence of PD over a 25– 30-year period.7 8 Studies based on medical records have also reported reductions in the incidence of PD in the USA9 and the UK.10 Alongside reductions in the prevalence and incidence of the disease, there are also reports from several groups that the severity of disease is declining.11–14 In our clinic, over a 30 -year period, the age at diagnosis increased by 10 years along with a decrease in the proportion of skeletal involvement in bone scintigraphy and a decrease in the alkaline phosphatase (ALP) level at diagnosis.13 The reasons for the striking epidemiological features of PD, both the marked variation in prevalence and the change in prevalence and disease severity, are unknown. The speed of the recent changes suggests that there has been a change in exposure to environmental factors that have a role in the development of PD.
PATHOLOGY The distinctive pathologic feature of PD is focal areas of rapid bone remodelling. It is hypothesised that the primary abnormality is increased osteoclast activity, with an increase in the number and size of osteoclasts causing rapid bone resorption.15 Clinically, this can be seen as lytic areas, especially in long bones or the skull, that progress at approximately 1 cm/year.16 In response to the increased bone resorption, bone formation is also markedly increased. The newly formed bone is chaotic, lacking the normal lamellar pattern, and is enlarged, sclerotic and weaker than normal bone. Abnormal gene expression has been shown in other cells in PD, including osteoblasts and bone marrow stromal cells,17 which offers support to the hypothesis that the primary abnormality might lie outside the osteoclast.
GENETICS It has long been recognised that family clustering of PD occurs, with about one-third of patients with PD having a first-degree relative with PD.18 Two independent studies identified that mutations in the SQSTM1 gene are present in approximately
Postgrad Med J 2014;90:328–331. doi:10.1136/postgradmedj-2013-201688rep
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Figure 1 Prevalence of Paget’s disease on abdominal radiography by age in two paired surveys from New Zealand. 25–50% of cases with familial PD,19 20 with an autosomal dominant pattern of inheritance. Its protein product sequestosome 1 ( p62) is involved in the receptor activator of nuclear factor κB (RANK)-mediated activation of NF-κB. Most mutations identified to date affect the ubiquitin-binding domain of SQSTM1,21 but how this predisposes to PD is unknown. Several studies have reported genotype–phenotype relationships. PD develops at an earlier age and is more extensive and severe in those with SQSTM1 mutations than those without mutations.22 Furthermore, patients with truncating mutations of SQSTM1 have disease of earlier onset and greater extent than those with missense mutations or sporadic PD.22–26 Approximately 5–10% of patients with sporadic PD have SQSTM1 mutations.19 20 25–28 It is possible that some of these people may have unrecognised familial disease, as PD is commonly asymptomatic. While initial studies suggested that the penetrance of SQSTM1 mutations is high at about 80% in those over 60 years,20 29 these studies were carried out in families known to have very high penetrance of PD. More recent studies of the adult offspring of patients with PD and SQSTM1 mutations have challenged the view that PD is a genetic disorder with high penetrance.24 We have now studied 33 adults with an inherited SQSTM1 mutation from a parent with PD and performed bone scintigraphy. Only 6/33 (18%) had evidence of PD on bone scintigraphy, and in each case the extent of disease was much smaller in the offspring than the parent. There was a 60% reduction in the risk of being diagnosed with PD at a comparable age in the offspring compared with the parents, and the differences in the age of diagnosis were more marked when analyses were restricted to offspring who were older at bone scintigraphy than their parent was at clinical diagnosis of PD. A number of other genetic loci have been associated with PD in genome-wide association studies.30 31 These findings have recently been reviewed in detail,32 although at present the role of these genes remains uncertain.32 Animal models based on mutations in SQSTM1 have been developed, but these models are only partially congruent and lack important features of PD in humans.32 Similarly, a number of rare human genetic disorders with mutations affecting the RANK-NF-κB pathway have some phenotypic similarities to PD, but again there are important differences in the nature and distribution of the bone lesions.16
CONTROVERSIES ON NATURE AND AETIOLOGY Given the unusual epidemiology, it is not surprising that many theories have been proposed to explain PD. Some explanations Postgrad Med J 2014;90:328–331. doi:10.1136/postgradmedj-2013-201688rep
have focused on environmental factors such as exposure to viruses, particularly measles and canine distemper viruses. Support for these hypotheses include that virus-like inclusion bodies are seen in osteoclasts in PD, viral transcripts for measles virus and canine distemper viruses have been identified in bone cells in PD, osteoclast precursors develop a PD-like phenotype after transfection with measles or canine distemper virus and transgenic mice that express measles virus nucleocapsid gene and have SQSTM1 mutations develop bone lesions resembling PD.33–36 However, these hypotheses remain controversial and incongruent with some evidence.37–39 The epidemiology of PD is inconsistent with the epidemiology of measles and canine distemper virus,16 several laboratories have failed to identify viral sequences in bone cells in PD,40–42 false positive results for identification of viral sequences have been reported41 and the ‘inclusion bodies’ are now thought to be proteasomal degradation products. Other environmental explanations of PD have drawn from the observation that PD is associated with an increase in rural living,5 6 with a variety of potential explanations offered such as increased dog ownership.16 43 Other explanations have proposed that PD is a genetic disorder, which is supported by the association between SQSTM1 and PD. However, if PD is purely a genetic disorder, it is unclear how the rapid changes in epidemiology observed in recent years can be explained. Likewise, while SQSTM1 mutations in proposed mouse models of PD increase osteoclastogenesis, they do not induce the phenotype of PD.16 32 One of us (TC) has suggested that PD behaves like a benign multifocal neoplastic disorder:16 after treatment with bisphosphonates the kinetics of relapse (as judged by changes in ALP) follow the Gompertz curve, PD can be spread by bone grafting and occasionally PD can transform to a malignant osteosarcoma ( presumably the consequence of somatic mutation).16 Ultimately, if the cause of PD is determined, it seems likely that it will include both genetic and environmental factors.
CLINICAL FEATURES In many patients, PD is asymptomatic. On the other hand, some patients have symptoms for long periods before the diagnosis is made. The most common symptom is bone pain—typically a low-grade pain that is worse at rest and at night. Pain can also result from secondary complications. Because pagetic bone is enlarged and weaker than normal bone it is associated with increased rates of osteoarthritis from altered joint dynamics, pathologic fractures, bone deformity and spinal stenosis. In the skull, bony enlargement can cause nerve compression leading to deafness and enlarged hat size.2 Because many of these conditions are also common in older adults without PD, it can be challenging to determine what symptoms are caused by PD. A treatment course can sometimes be helpful in deciding this. While other conditions such as osteosarcoma and high-output heart failure are classically described in PD, these are extremely rare today.
INVESTIGATION In asymptomatic patients, PD is usually diagnosed either after the finding of an elevated ALP in the presence of normal liver enzyme tests or on a radiograph taken for other purposes. The classical features on radiography are focal lytic areas with a coarse trabecular pattern and bone thickening. Bone scintigraphy is useful to determine disease extent, especially as new PD lesions do not tend to appear over time. In untreated patients, ALP measurements correlate well with skeletal involvement as judged by scintigraphy. Occasionally, there can be 329
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Republished best practice diagnostic uncertainty even after plain radiographs and scintigraphy, typically in bones where PD is uncommon. In this rare situation, bone biopsy can be undertaken. Histology of PD lesions shows increased osteoclasts, which are often enlarged and multinucleated, and disorganised woven bone. When untreated, ALP tends to increase slowly over time. The rate of increase varies greatly, with some patients having little change in ALP over decades, while in others, the ALP steadily increases. In most patients, ALP measurements eventually reach a plateau. Some patients have dense sclerotic bone on radiographs but normal ALP measurements, sometimes referred to as ‘burnt-out’ PD, but it is not clear how commonly this occurs.
BONE TURNOVER MARKERS As PD is characterised by accelerated bone remodelling, measurement of markers of bone turnover are one of the key investigations in management and diagnosis. The performance of a variety of markers of bone formation and bone resorption has been assessed for the diagnosis and monitoring of PD. We assessed seven turnover markers in a trial of patients with active PD treated with ibandronate (n=20) or placebo (n=9).44 All participants had PD confirmed on plain X-ray and ALP at least twice the upper reference range. Participants were randomised to 6 mg intravenous ibandronate at baseline, or 6 mg ibandronate at baseline and 1 month, or placebo and blood samples were taken at baseline and 6 months. Figure 2 shows that there were substantial differences in the performance of these markers. Of the bone formation markers, total ALP, bone alkaline phosphatase (bALP) and procollagen type-I N-terminal propeptide (PINP) had similar results. At baseline, these markers were elevated in all patients and were highly correlated. With treatment, they declined by 70–80%, and again changes were highly correlated. Of the bone turnover markers, only urine N-telopeptide of type I collagen cross-links (NTx) had similar results to these three bone formation markers. In contrast, osteocalcin, a bone formation marker, and C-telopeptide of type I collagen cross-links (CTx) and free deoxpyridinoline (fDPD), two bone resorption markers, had much lower proportions of abnormal results at baseline and smaller decreases with
Figure 2 Performance of bone turnover markers in Paget’s disease (PD). The left axis shows the percentage of patients with PD with abnormal bone turnover markers at baseline, and the right axis, the average decrease in marker after treatment with ibandronate. ALP, total serum alkaline phosphatase; bALP, bone alkaline phosphatase; OC, osteocalcin; PINP, procollagen type-I N-terminal propeptide; NTx, urine N-telopeptide of type I collagen cross-links; fDPD, free deoxpyridinoline; β-CTx, C-telopeptide of type I collagen cross-links. 330
treatment.44 Therefore, the best markers appear to be total ALP, bALP, PINP and urine NTx. Of these, urine NTx and bALP have higher interassay and intra-assay coefficients of variation.44 Because of its widespread availability, low assay variation and low cost, total ALP is the single best marker for clinical use in PD. PINP is more specific and can be useful as second line test when ALP is normal and mild but active PD is suspected, or in patients with other abnormal liver enzyme tests.
MANAGEMENT Bisphosphonates are the mainstay of pharmacologic treatment of PD. Etidronate was the first bisphosphonate used to treat PD in the 1970s but has now been superseded by more potent agents. All of the potent bisphosphonates reduce bone turnover and are effective in treating PD, but the degree depends on the potency of agent, and the dose and duration of treatment. The most common oral treatment regimens are risedronate 30 mg/daily for 2 months or alendronate 40 mg daily for 6 months, but based on a recent study, arguably the gold standard treatment is intravenous zoledronate. In a randomised controlled trial of 349 patients with active PD (mean age 70 years, mean ALP 430 IU/L), a single dose of 5 mg of zoledronate was compared with a 2 -month course of oral risedronate.45 At 6 months, ALP was within the normal range in 89% treated with zoledronate and 58% with risedronate, and quality of life tended to be better with zoledronate.45 Two years after this treatment course, only 2% treated with zoledronate had an ALP above the normal range compared with 43% treated with risedronate,46 and by 6.5 years the corresponding figures were 12.5% and 62%.47 Bone markers at 6 months after treatment were a strong predictor of relapse. For ALP levels at 6 months of 120 IU/L, the corresponding percentages were 15–16% and 67%, respectively.47 Thus, it seems reasonable that a goal of treatment with PD is to bring bone turnover into the lower half of the normal range. Patients who are asymptomatic with mild PD and who are not at risk of secondary complications do not need any specific treatment and can be monitored with periodic clinical review and measurement of ALP. In patients who have extensive PD or are symptomatic, treatment with bisphosphonates should be considered. Effective treatment of active PD leads to reduced pain, improved quality of life, normal ALP and reduced activity on bone scans. On bone biopsy, new bone formed has a normal lamellar structure, but while lytic lesions heal, radiographs generally do not return to normal. There is some debate as to whether bisphosphonates can prevent complications of PD such as fracture, osteoarthritis or nerve compression.48 Currently, there is no evidence to suggest this, but equally such evidence is very unlikely to be acquired as it would require prolonged follow-up of patients without treatment.49 In the absence of such evidence, many clinicians will treat patients where they are concerned complications may develop—for example, where PD is in long bones to prevent fracture, adjacent to joints to prevent osteoarthritis and in the skull or spine to prevent nerve compression. Bones with active PD have increased metabolism and blood flow. In patients undergoing orthopaedic surgery who have active PD at the site of surgery, substantial blood loss can occur during the procedure. Treatment with bisphosphonates prior to surgery to reduce bone vascularity can be considered. Simple analgesics and nonpharmacologic treatments such as weight loss and exercise programmes are often useful in treating secondary complications of PD such as osteoarthritis.
Courtney D, et al. Postgrad Med J 2014;90:328–331. doi:10.1136/postgradmedj-2013-201688rep
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Republished best practice After initial treatment, monitoring of ALP every 1–2 years is reasonable, and retreatment could be considered if symptoms recur, and/or if ALP becomes markedly elevated (>3 times the upper reference range). Many patients with mild disease affecting only one or a few bones have prolonged normalisation of ALP following a single dose of zoledronate, and this sustained remission means that the PD will not relapse within their lifetime. Contributors MB drafted the manuscript and TC critically reviewed and improved it. Funding MB is the recipient of a Health Research Council (HRC) Sir Charles Hercus Health Research Fellowship. Funded by the Health Research Council (HRC) of New Zealand. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
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Republished: Paget's disease of bone: clinical review and update Mark J Bolland and Tim Cundy Postgrad Med J 2014 90: 328-331
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Republished best practice
Paget’s disease of bone: clinical review and update Mark J Bolland, Tim Cundy Department of Medicine, University of Auckland, Auckland, New Zealand Correspondence to Dr Mark Bolland, Bone and Joint Research Group, Department of Medicine, University of Auckland, Private Bag 92 019, Auckland 1142, New Zealand; , [email protected] – Received 9 June 2013 Revised 14 August 2013 Accepted 23 August 2013 Published Online First 16 September 2013 This is a reprint of a paper that first appeared in J Clin Pathol 2013, Volume 66, pages 924 927.
ABSTRACT Paget’s disease (PD) is a focal disorder of bone remodelling that occurs commonly in older people. In this article, we review clinical aspects of PD with an emphasis on recent findings. The epidemiology of PD appears to be changing rapidly, with several groups in different parts of the world reporting a marked reduction in the prevalence and incidence of PD, as well as in the severity of disease seen by clinicians. These findings seem most likely to be caused by changes in exposure to unknown environmental factors that have a role in the development of PD. However, genetic factors are also important. Mutations in SQSTM1 occur in 25–50% of familial PD. Genotype–phenotype relationships are present, as PD develops at an earlier age and is more extensive and severe in those with SQSTM1 mutations, and these findings are more pronounced in those with truncating mutations. However, the prevalence of PD in adults with SQSTM1 mutations is uncertain, and it is not known how such mutations might cause PD. Ultimately, if the cause of PD is determined, it seems likely that it will include both genetic and environmental factors. Lastly, clinical trials have shown that potent bisphosphonates are highly effective treatments for active PD, and reduce pain, improve quality of life, normalise bone turnover and heal lytic lesions on radiographs. They can also induce sustained remission that persists for many years.
INTRODUCTION Paget’s disease (PD) is a focal disorder of bone remodelling that occurs commonly in older people. While there are now safe and highly effective treatments, it remains an enigmatic condition with distinctive characteristics that are poorly understood. In this article, we will review clinical aspects of PD, with particular emphasis on recent findings related to its epidemiology, genetics and treatment.
EPIDEMIOLOGY
To cite: Bolland MJ, Cundy T. J Clin Pathol 2013;66:924–927. 328
PD is common in older people, and more common in men than women.1 The most common method for determining prevalence of PD is by radiological survey. Since the majority of patients with PD have involvement of at least one bone out of the pelvis, sacrum, lumbar spine or proximal femur,2 assessing consecutive abdominal X-rays gives a reasonable estimate of the prevalence. Worldwide the prevalence varies substantially,1 from very low in Japan (1%) in Western Europe, Australia and New Zealand. Although PD is believed to be uncommon in Asia, we have recently reported that on a population basis, the prevalence of PD in the Asian population in Auckland, New Zealand, appears to be similar to that in patients of European descent.3 A notable feature of the geographic variation in PD is that transmission of PD
appears to have occurred through migration, with areas of high prevalence in Australia, New Zealand, South Africa, Quebec and Brazil after significant migrations from Europe. There are also welldescribed areas of marked regional variation, with particular towns or regions with much higher prevalence than neighbouring regions.4–6 Several radiological surveys have been repeated in recent years, and the prevalence of PD compared between surveys. A recent systematic review identified nine paired surveys which showed on average a 36% reduction in the prevalence of PD over 8–19 years.1 figure 1 shows data from two paired surveys in New Zealand, highlighting the rapid, substantial fall in prevalence of PD over a 25– 30-year period.7 8 Studies based on medical records have also reported reductions in the incidence of PD in the USA9 and the UK.10 Alongside reductions in the prevalence and incidence of the disease, there are also reports from several groups that the severity of disease is declining.11–14 In our clinic, over a 30 -year period, the age at diagnosis increased by 10 years along with a decrease in the proportion of skeletal involvement in bone scintigraphy and a decrease in the alkaline phosphatase (ALP) level at diagnosis.13 The reasons for the striking epidemiological features of PD, both the marked variation in prevalence and the change in prevalence and disease severity, are unknown. The speed of the recent changes suggests that there has been a change in exposure to environmental factors that have a role in the development of PD.
PATHOLOGY The distinctive pathologic feature of PD is focal areas of rapid bone remodelling. It is hypothesised that the primary abnormality is increased osteoclast activity, with an increase in the number and size of osteoclasts causing rapid bone resorption.15 Clinically, this can be seen as lytic areas, especially in long bones or the skull, that progress at approximately 1 cm/year.16 In response to the increased bone resorption, bone formation is also markedly increased. The newly formed bone is chaotic, lacking the normal lamellar pattern, and is enlarged, sclerotic and weaker than normal bone. Abnormal gene expression has been shown in other cells in PD, including osteoblasts and bone marrow stromal cells,17 which offers support to the hypothesis that the primary abnormality might lie outside the osteoclast.
GENETICS It has long been recognised that family clustering of PD occurs, with about one-third of patients with PD having a first-degree relative with PD.18 Two independent studies identified that mutations in the SQSTM1 gene are present in approximately
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Republished best practice
Figure 1 Prevalence of Paget’s disease on abdominal radiography by age in two paired surveys from New Zealand. 25–50% of cases with familial PD,19 20 with an autosomal dominant pattern of inheritance. Its protein product sequestosome 1 ( p62) is involved in the receptor activator of nuclear factor κB (RANK)-mediated activation of NF-κB. Most mutations identified to date affect the ubiquitin-binding domain of SQSTM1,21 but how this predisposes to PD is unknown. Several studies have reported genotype–phenotype relationships. PD develops at an earlier age and is more extensive and severe in those with SQSTM1 mutations than those without mutations.22 Furthermore, patients with truncating mutations of SQSTM1 have disease of earlier onset and greater extent than those with missense mutations or sporadic PD.22–26 Approximately 5–10% of patients with sporadic PD have SQSTM1 mutations.19 20 25–28 It is possible that some of these people may have unrecognised familial disease, as PD is commonly asymptomatic. While initial studies suggested that the penetrance of SQSTM1 mutations is high at about 80% in those over 60 years,20 29 these studies were carried out in families known to have very high penetrance of PD. More recent studies of the adult offspring of patients with PD and SQSTM1 mutations have challenged the view that PD is a genetic disorder with high penetrance.24 We have now studied 33 adults with an inherited SQSTM1 mutation from a parent with PD and performed bone scintigraphy. Only 6/33 (18%) had evidence of PD on bone scintigraphy, and in each case the extent of disease was much smaller in the offspring than the parent. There was a 60% reduction in the risk of being diagnosed with PD at a comparable age in the offspring compared with the parents, and the differences in the age of diagnosis were more marked when analyses were restricted to offspring who were older at bone scintigraphy than their parent was at clinical diagnosis of PD. A number of other genetic loci have been associated with PD in genome-wide association studies.30 31 These findings have recently been reviewed in detail,32 although at present the role of these genes remains uncertain.32 Animal models based on mutations in SQSTM1 have been developed, but these models are only partially congruent and lack important features of PD in humans.32 Similarly, a number of rare human genetic disorders with mutations affecting the RANK-NF-κB pathway have some phenotypic similarities to PD, but again there are important differences in the nature and distribution of the bone lesions.16
CONTROVERSIES ON NATURE AND AETIOLOGY Given the unusual epidemiology, it is not surprising that many theories have been proposed to explain PD. Some explanations Postgrad Med J 2014;90:328–331. doi:10.1136/postgradmedj-2013-201688rep
have focused on environmental factors such as exposure to viruses, particularly measles and canine distemper viruses. Support for these hypotheses include that virus-like inclusion bodies are seen in osteoclasts in PD, viral transcripts for measles virus and canine distemper viruses have been identified in bone cells in PD, osteoclast precursors develop a PD-like phenotype after transfection with measles or canine distemper virus and transgenic mice that express measles virus nucleocapsid gene and have SQSTM1 mutations develop bone lesions resembling PD.33–36 However, these hypotheses remain controversial and incongruent with some evidence.37–39 The epidemiology of PD is inconsistent with the epidemiology of measles and canine distemper virus,16 several laboratories have failed to identify viral sequences in bone cells in PD,40–42 false positive results for identification of viral sequences have been reported41 and the ‘inclusion bodies’ are now thought to be proteasomal degradation products. Other environmental explanations of PD have drawn from the observation that PD is associated with an increase in rural living,5 6 with a variety of potential explanations offered such as increased dog ownership.16 43 Other explanations have proposed that PD is a genetic disorder, which is supported by the association between SQSTM1 and PD. However, if PD is purely a genetic disorder, it is unclear how the rapid changes in epidemiology observed in recent years can be explained. Likewise, while SQSTM1 mutations in proposed mouse models of PD increase osteoclastogenesis, they do not induce the phenotype of PD.16 32 One of us (TC) has suggested that PD behaves like a benign multifocal neoplastic disorder:16 after treatment with bisphosphonates the kinetics of relapse (as judged by changes in ALP) follow the Gompertz curve, PD can be spread by bone grafting and occasionally PD can transform to a malignant osteosarcoma ( presumably the consequence of somatic mutation).16 Ultimately, if the cause of PD is determined, it seems likely that it will include both genetic and environmental factors.
CLINICAL FEATURES In many patients, PD is asymptomatic. On the other hand, some patients have symptoms for long periods before the diagnosis is made. The most common symptom is bone pain—typically a low-grade pain that is worse at rest and at night. Pain can also result from secondary complications. Because pagetic bone is enlarged and weaker than normal bone it is associated with increased rates of osteoarthritis from altered joint dynamics, pathologic fractures, bone deformity and spinal stenosis. In the skull, bony enlargement can cause nerve compression leading to deafness and enlarged hat size.2 Because many of these conditions are also common in older adults without PD, it can be challenging to determine what symptoms are caused by PD. A treatment course can sometimes be helpful in deciding this. While other conditions such as osteosarcoma and high-output heart failure are classically described in PD, these are extremely rare today.
INVESTIGATION In asymptomatic patients, PD is usually diagnosed either after the finding of an elevated ALP in the presence of normal liver enzyme tests or on a radiograph taken for other purposes. The classical features on radiography are focal lytic areas with a coarse trabecular pattern and bone thickening. Bone scintigraphy is useful to determine disease extent, especially as new PD lesions do not tend to appear over time. In untreated patients, ALP measurements correlate well with skeletal involvement as judged by scintigraphy. Occasionally, there can be 329
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Republished best practice diagnostic uncertainty even after plain radiographs and scintigraphy, typically in bones where PD is uncommon. In this rare situation, bone biopsy can be undertaken. Histology of PD lesions shows increased osteoclasts, which are often enlarged and multinucleated, and disorganised woven bone. When untreated, ALP tends to increase slowly over time. The rate of increase varies greatly, with some patients having little change in ALP over decades, while in others, the ALP steadily increases. In most patients, ALP measurements eventually reach a plateau. Some patients have dense sclerotic bone on radiographs but normal ALP measurements, sometimes referred to as ‘burnt-out’ PD, but it is not clear how commonly this occurs.
BONE TURNOVER MARKERS As PD is characterised by accelerated bone remodelling, measurement of markers of bone turnover are one of the key investigations in management and diagnosis. The performance of a variety of markers of bone formation and bone resorption has been assessed for the diagnosis and monitoring of PD. We assessed seven turnover markers in a trial of patients with active PD treated with ibandronate (n=20) or placebo (n=9).44 All participants had PD confirmed on plain X-ray and ALP at least twice the upper reference range. Participants were randomised to 6 mg intravenous ibandronate at baseline, or 6 mg ibandronate at baseline and 1 month, or placebo and blood samples were taken at baseline and 6 months. Figure 2 shows that there were substantial differences in the performance of these markers. Of the bone formation markers, total ALP, bone alkaline phosphatase (bALP) and procollagen type-I N-terminal propeptide (PINP) had similar results. At baseline, these markers were elevated in all patients and were highly correlated. With treatment, they declined by 70–80%, and again changes were highly correlated. Of the bone turnover markers, only urine N-telopeptide of type I collagen cross-links (NTx) had similar results to these three bone formation markers. In contrast, osteocalcin, a bone formation marker, and C-telopeptide of type I collagen cross-links (CTx) and free deoxpyridinoline (fDPD), two bone resorption markers, had much lower proportions of abnormal results at baseline and smaller decreases with
Figure 2 Performance of bone turnover markers in Paget’s disease (PD). The left axis shows the percentage of patients with PD with abnormal bone turnover markers at baseline, and the right axis, the average decrease in marker after treatment with ibandronate. ALP, total serum alkaline phosphatase; bALP, bone alkaline phosphatase; OC, osteocalcin; PINP, procollagen type-I N-terminal propeptide; NTx, urine N-telopeptide of type I collagen cross-links; fDPD, free deoxpyridinoline; β-CTx, C-telopeptide of type I collagen cross-links. 330
treatment.44 Therefore, the best markers appear to be total ALP, bALP, PINP and urine NTx. Of these, urine NTx and bALP have higher interassay and intra-assay coefficients of variation.44 Because of its widespread availability, low assay variation and low cost, total ALP is the single best marker for clinical use in PD. PINP is more specific and can be useful as second line test when ALP is normal and mild but active PD is suspected, or in patients with other abnormal liver enzyme tests.
MANAGEMENT Bisphosphonates are the mainstay of pharmacologic treatment of PD. Etidronate was the first bisphosphonate used to treat PD in the 1970s but has now been superseded by more potent agents. All of the potent bisphosphonates reduce bone turnover and are effective in treating PD, but the degree depends on the potency of agent, and the dose and duration of treatment. The most common oral treatment regimens are risedronate 30 mg/daily for 2 months or alendronate 40 mg daily for 6 months, but based on a recent study, arguably the gold standard treatment is intravenous zoledronate. In a randomised controlled trial of 349 patients with active PD (mean age 70 years, mean ALP 430 IU/L), a single dose of 5 mg of zoledronate was compared with a 2 -month course of oral risedronate.45 At 6 months, ALP was within the normal range in 89% treated with zoledronate and 58% with risedronate, and quality of life tended to be better with zoledronate.45 Two years after this treatment course, only 2% treated with zoledronate had an ALP above the normal range compared with 43% treated with risedronate,46 and by 6.5 years the corresponding figures were 12.5% and 62%.47 Bone markers at 6 months after treatment were a strong predictor of relapse. For ALP levels at 6 months of 120 IU/L, the corresponding percentages were 15–16% and 67%, respectively.47 Thus, it seems reasonable that a goal of treatment with PD is to bring bone turnover into the lower half of the normal range. Patients who are asymptomatic with mild PD and who are not at risk of secondary complications do not need any specific treatment and can be monitored with periodic clinical review and measurement of ALP. In patients who have extensive PD or are symptomatic, treatment with bisphosphonates should be considered. Effective treatment of active PD leads to reduced pain, improved quality of life, normal ALP and reduced activity on bone scans. On bone biopsy, new bone formed has a normal lamellar structure, but while lytic lesions heal, radiographs generally do not return to normal. There is some debate as to whether bisphosphonates can prevent complications of PD such as fracture, osteoarthritis or nerve compression.48 Currently, there is no evidence to suggest this, but equally such evidence is very unlikely to be acquired as it would require prolonged follow-up of patients without treatment.49 In the absence of such evidence, many clinicians will treat patients where they are concerned complications may develop—for example, where PD is in long bones to prevent fracture, adjacent to joints to prevent osteoarthritis and in the skull or spine to prevent nerve compression. Bones with active PD have increased metabolism and blood flow. In patients undergoing orthopaedic surgery who have active PD at the site of surgery, substantial blood loss can occur during the procedure. Treatment with bisphosphonates prior to surgery to reduce bone vascularity can be considered. Simple analgesics and nonpharmacologic treatments such as weight loss and exercise programmes are often useful in treating secondary complications of PD such as osteoarthritis.
Courtney D, et al. Postgrad Med J 2014;90:328–331. doi:10.1136/postgradmedj-2013-201688rep
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Republished best practice After initial treatment, monitoring of ALP every 1–2 years is reasonable, and retreatment could be considered if symptoms recur, and/or if ALP becomes markedly elevated (>3 times the upper reference range). Many patients with mild disease affecting only one or a few bones have prolonged normalisation of ALP following a single dose of zoledronate, and this sustained remission means that the PD will not relapse within their lifetime. Contributors MB drafted the manuscript and TC critically reviewed and improved it. Funding MB is the recipient of a Health Research Council (HRC) Sir Charles Hercus Health Research Fellowship. Funded by the Health Research Council (HRC) of New Zealand. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
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Republished: Paget's disease of bone: clinical review and update Mark J Bolland and Tim Cundy Postgrad Med J 2014 90: 328-331
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