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Keywords:

  • Paget's disease of bone;
  • epidemiology;
  • genetics;
  • prevalence;
  • pelvic X-ray

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PREVALENCE OF PAGET'S DISEASE IN ITALY
  5. DISEASE CHARACTERISTICS
  6. FAMILIAL INCIDENCE AND GENETICS
  7. REGIONAL CLUSTERING
  8. SECULAR TRENDS
  9. SUMMARY AND CONCLUSIONS
  10. Acknowledgements
  11. REFERENCES

Epidemiological studies of Paget's disease of bone (PDB) suggest a pronounced geographical variation in the prevalence of the disease and a decrease in prevalence and clinical severity over time. To analyze epidemiological and clinical features of PDB in Italy, we recently established a registry of Italian PDB cases and performed radiological, biochemical, and bone scan surveys in the towns of Siena and Turin. The overall prevalence of PDB in Italy varied between 0.7% and 2.4%. Prevalence rates increased with age and were higher in men than in women. We observed clinically confirmed familial aggregation in 15–26% of cases. Pedigree analysis indicated an autosomal dominant pattern of inheritance with variable penetrance. SQSTM1 gene analysis in two Italian studies revealed the presence of at least three different mutations accounting for both familial and sporadic cases. Interestingly, no decrease in the prevalence of PDB over time was observed, the opposite of what is described in populations of British descent. However, clinical severity of PDB cases included in the Registry in 2002–2004 seemed reduced with respect to that of PDB patients from the previous epidemiological studies, including a 1950–1956 Italian study. Of interest, a consistent association between PDB and animal-related factors and a significantly higher prevalence of the disease in rural than in urban districts were observed. These findings are in keeping with an important role of the environment in the pathogenesis of PDB, perhaps facilitating the expression of the disease in genetically susceptible subjects. Finally, there was also preliminary evidence indicating regional clustering of PDB in Italy, with a concentration of cases in rural districts of Campania and Tuscany. These districts may represent high prevalence areas of PDB in Italy, similar to what has been observed in other countries. Extrapolation estimates suggest that ∼150,000–300,000 subjects may be affected with PDB in our country. These results confirm PDB to be the most common bone remodeling disorder in elderly people in Italy, excluding osteoporosis.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PREVALENCE OF PAGET'S DISEASE IN ITALY
  5. DISEASE CHARACTERISTICS
  6. FAMILIAL INCIDENCE AND GENETICS
  7. REGIONAL CLUSTERING
  8. SECULAR TRENDS
  9. SUMMARY AND CONCLUSIONS
  10. Acknowledgements
  11. REFERENCES

Paget's disease of bone (PDB) is a chronic focal bone remodeling disorder that typically results in enlarged and deformed bones in one or more regions of the skeleton.(1,2) This disease is most often asymptomatic, but can cause a variety of medical complications resulting in considerable morbidity and reduced quality of life.(3) PDB is most common in white people of European descent, but it also occurs in blacks, whereas it is rare in people of Asian descent.(4,5) Clinical, radiological, and necropsy data from different countries suggests pronounced geographical variations in the prevalence of the disease. The highest prevalence rates have been described in Britain, followed by Australia, New Zealand, and the northeastern United States, countries with high rates of immigration of people of British descent in the 19th and 20th centuries.(4,5) Despite the impact of the disease on the population, only limited information about the epidemiology and the true prevalence of PDB in Italy has been available. More recently, the establishment of a registry of Italian PDB cases and the carrying out of radiological, biochemical, and bone scan surveys has furthered the knowledge about prevalence, characteristics, genetics, and environmental determinants of PDB in Italy.

PREVALENCE OF PAGET'S DISEASE IN ITALY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PREVALENCE OF PAGET'S DISEASE IN ITALY
  5. DISEASE CHARACTERISTICS
  6. FAMILIAL INCIDENCE AND GENETICS
  7. REGIONAL CLUSTERING
  8. SECULAR TRENDS
  9. SUMMARY AND CONCLUSIONS
  10. Acknowledgements
  11. REFERENCES

The first epidemiological observation of PDB in Italy was a radiological survey from Stuart who analyzed >100,000 nonselected skeletal radiographs in Siena (1950–1966) and found 94 PDB cases, consistent with an overall prevalence of 0.09%.(6) An age-related increase in the frequency of PDB reaching 0.20% in the seventh decade was observed, with a slight male predominance. Conversely, only four PDB cases (0.018%) were observed among the 21,777 radiographs from patients younger than 40 years of age. These estimates were comparable with those reported in similar studies from unselected skeletal radiographs in different populations and in the same period.(7) A reanalysis of selected skeletal radiographs involving the pelvis and spine showed prevalence rates >1.5–2.0% in subjects older than 40 years.(6)

In 1982, Detheridge et al.(8) performed an European study on the prevalence of PDB. The study was based on both postal questionnaires and radiological surveys performed in different European towns, including two Italian towns: Milan in northern Italy and Palermo in Sicily. The prevalence of PDB was higher in Britain (8.3–2.3%) and France (2.0–2.7%) than in any other Western European country.(8) In Italy, the prevalence of PDB from abdominal radiographs was reported to be 1.0% in Milan (1.6% in men and 0.4% in women) and 0.5% in Palermo (0.3% in men and 0.7% in women). The sample size, however, was too low to obtain a clear picture about the prevalence of PDB in Italy.

More recently, the prevalence of PDB was estimated in two Italian towns by different approaches: the district of Siena from radiological, biochemical, and bone scan surveys and the city of Turin from pelvic radiological surveys of different decades.(9) Siena is a town of central Italy, located in a rural region with a low immigration flow. In contrast, Turin, which is located in northwestern Italy, recognized from the 1960s with a strong immigration flow from other Italian regions (mainly from southern and northeastern, but also from central Italian regions) so that only ∼50% of the population was born in this district. Thus, the Turin population could be considered sufficiently representative of the whole Italian population. In these studies, the prevalence of PDB was estimated to be within 0.9–2.4% in Siena and 0.7–1.0% in Turin. Differences in prevalence rates between and within the two towns were mainly caused by the different approaches: radiological in Turin and radiological, scintigraphic, and biochemical in Siena (Fig. 1). In particular, the analysis of pelvic radiographs performed between 1999 and 2000 in Siena showed a radiological prevalence of 16/1778 (0.89%), consistent with an estimated overall prevalence of PDB from 0.98% to 1.48%, considering that the pelvic involvement is commonly described in 60–90% of patients. Slightly lower rates were observed in Turin, with a radiological prevalence of pelvic PDB of 41/6609 (0.62%) and an estimated overall prevalence ranging from 0.69% to 1.03%. Results from the biochemical screening in Siena are summarized in Table 1. Overall, 296 of the 7449 subjects showed elevated alkaline phosphatase (ALP) levels and normal liver enzymes, with a prevalence of “biochemical hyperphosphatasia” of 3.97%. Moreover, 236 of the 296 subjects with elevated ALP levels agreed to undergo a more detailed screening, including clinical examination, measurement of bone markers, and eventually, bone scan and skeletal X-rays. Interestingly, 87 (36.8%) of these 236 subjects had a diagnosis of PDB.(9) Thus, based on the observed 3.97% prevalence of biochemical hyperphosphatasia and the verified diagnosis of PDB in 36.8% of these subjects, the estimated prevalence of PDB from this survey was 1.46%. When prevalence was adjusted to take into account that ∼20% of patients with PDB have ALP levels within the normal range, the overall prevalence of PDB was 1.75%. Moreover, prevalence rates were higher in men (1.88%) than in women (1.14%) and increased steadily from the 40–49 year age group through the 80–89 year age group (Table 1; Fig. 1). In addition, we also diagnosed PDB in 12 of the 944 subjects (1.3%) with normal ALP levels that agreed to be further studied. In those subjects, the disease was diagnosed most often in one bone, with only four subjects having more than one affected bone. Prevalence estimates from the bone scan survey in 7906 scan performed in Siena from 2000 to 2004 were higher (2.4%).

Table Table 1.. Prevalence of High Alkaline Phosphatase and Paget's Disease in Siena
  1. Adapted with permission from Gennari L et al. J Bone Miner Res 20:1845–1850, 2005.(9)

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Figure Fig. 1.. Age-related prevalence of PDB in Siena from radiological, biochemical, and scintigraphic surveys (adapted with permission from Gennari L, et al. J Bone Miner Res 20:1845–1850, 2005).

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Considering these prevalence rates and according to census data (ISTAT 2002, http://demo.istat.it/pop2002/index.html), the estimated number of PDB patients in Turin and in Siena was 4476 and 1334, respectively. Moreover, even though an extrapolation of these results to the entire Italian population may not be accurate, it can be estimated that there may be currently from 124,788 to 338,576 people (considering the radiographic and scintigraphic prevalence rates, respectively) potentially affected with PDB in Italy (Table 2). These data confirm PDB to be the most common bone remodeling disorder in elderly people in Italy, excluding osteoporosis, with an estimated prevalence of at least 1%, which is comparable with that observed in United States and other European countries but lower than that described in high prevalence areas such as Britain, Australia, and New Zealand.

DISEASE CHARACTERISTICS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PREVALENCE OF PAGET'S DISEASE IN ITALY
  5. DISEASE CHARACTERISTICS
  6. FAMILIAL INCIDENCE AND GENETICS
  7. REGIONAL CLUSTERING
  8. SECULAR TRENDS
  9. SUMMARY AND CONCLUSIONS
  10. Acknowledgements
  11. REFERENCES

Characteristics of PDB subjects from Italy have been recently studied by a study of 147 consecutive Italian PDB patients from Siena, included in the Italian Registry of PDB.(10) These subjects underwent a detailed medical history and clinical examination. Their characteristics were compared with those obtained from nonpagetic outpatient control subjects. All the PDB patients included in the study were white and of Italian descent. The mean age at diagnosis was 59.5 ± 11.7 years; 27 patients (18.4%) reported that pain led to the diagnosis of PDB; the remaining 120 cases were diagnosed because of high levels of serum ALP and/or X-ray findings. Similar to previous epidemiological studies, there was a slight male predominance (88 men, 59 women), with a male to female ratio of 1.5:1. There were no statistically significant differences in constitutional features between PDB patients and controls, even though a trend for increased prevalence of light eye color was observed (34.0% versus 28.2%), consistent with a previous report on PDB cases from Spain.(11) Based on bone scintigraphy and X-ray examination of areas of increased isotope uptake, 62 patients had monostotic, whereas 85 had polyostotic, PDB. However, clinical severity of disease was lower with respect to that of PDB patients from the previous epidemiological studies in different populations, with a mean number of involved skeletal sites of 2.2 ± 1.6 (range, 1–8). Sites of involvement, in order of frequency, included pelvis (67%), vertebrae (34%), femur (32%), tibias (25%), skull (23%), humerus (11%), ribs (7%), calcaneus (4%), ulna (2%), scapula (2%), hands (2%), mandible (1%), and sternum (1%). The skull, pelvis, and spine were significantly more affected in polyostotic than in monostotic cases (skull: 27 versus 6, p < 0.01; pelvis: 64 versus 34, p < 0.05; spine: 43 versus 7, p < 0.0001).

Table Table 2.. Estimated Number of Subjects With Paget's Disease in Siena, Turin, and Italy According to Census Data
  1. * Based on radiological surveys, assuming that 22% of patients with Paget's disease have skeletal involvement not detected by pelvic radiography (estimated from 78% involvement of pelvic sites in 120 consecutive cases in Siena). For estimates in the overall Italian population, prevalence rates were calculated from the total available abdominal X-rays of Siena and Turin (n = 8387).

  2. Adapted with permission from Gennari L, et al. J Bone Miner Res 20:1845–1850, 2005.(9)

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Interestingly, the analysis of questionnaires from PDB patients and controls indicated a significant association between PDB and contacts with animals in rural districts (OR = 2.22; p = 0.001; χ2 test). In particular, previous or current contact with animals such as pigs, rabbits, and cattle seemed to be a predisposing factor for the disease. In contrast, no significant association with dog or cat ownership was observed, even though when analyses were limited to subjects living in rural areas, an increased prevalence of PDB was evident in subjects who had contacts with cats and dogs (67% versus 44%, PDB versus controls, respectively). These associations are somewhat different from those previously reported in PDB populations from other countries, where an increased risk caused by dog or cat ownership was clearly indicated.(12–14) Conversely, the association with exposure to cattle was also observed in PDB cases from Spain.(12) All these findings are in keeping with an important role of the environment in the pathogenesis of PDB. It is likely that exposure to an environmental trigger (i.e., viral infection) may facilitate the expression of the disease in genetically susceptible subjects. Interestingly, different infective agents may be involved in the pathogenesis of PDB. Typical paramyxoviruses that have been previously associated with PDB are canine distemper virus and measles virus.(5,15) However, newly recognized paramyxoviruses have been associated with disease status in several animal species, including horses and swine, and limited information is actually available on the public health risk of many of these infective agents.(16–18) Importantly, whereas cats and dogs are commonly vaccinated against most of the common paramyxovirus infections such as distemper virus,(19) swine and cattle are often unvaccinated in rural areas from Italy and might represent a vehicle for virus transmission to humans. Similarly, the reported association with cat and dog ownership in rural but not urban areas may indicate an increased risk of exposure to viral agents and to contacts with other animal species. Moreover, vaccination of cats and dogs may be more common in urban than in rural areas. Taken all together, these results from different studies indicate that a latent viral infection may be involved in the etiology of PDB and that different viral agents, infecting distinct animal species in different geographical areas or similar viral agents infecting different hosts, could account for the observed discrepancies.

Osteoarthritis and fractures represented the most important complications of PDB in Italy.(10) Analysis of questionnaires and available clinical records showed the presence of 23 fractures in 20 of the 147 PDB patients (9 vertebrae, 4 hip, 3 wrist, 3 radius, and 4 tibias) and of osteoarthritis in 67 subjects, with 2 knee and 3 hip replacements. Overall, 15 of the 23 fractures occurred in PDB sites, whereas 8 (4 vertebrae, 1 hip, and 3 wrist) occurred in skeletal sites not affected with PDB. Osteoarthritis at the hip, knee, and the lumbar spine was more common at or nearby affected skeletal sites. Other recorded complications included hearing loss, cranial nerve disorders, and headache, which occurred in PDB patients with skull involvement. Back pain, bone deformities, and kidney stones were also observed. Similar results have been recently described in 202 American PDB subjects enrolled in the New England Registry of Paget's Disease.(20) Moreover, a consistent number of PDB subjects from our sample also had cardiovascular complications, particularly involving cardiac valve calcification. This latter issue has been recently confirmed in a preliminary echocardiographic assessment of heart function in 70 of these PDB patients.(21) No osteosarcoma cases or other bone or cartilage neoplasms were observed.

FAMILIAL INCIDENCE AND GENETICS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PREVALENCE OF PAGET'S DISEASE IN ITALY
  5. DISEASE CHARACTERISTICS
  6. FAMILIAL INCIDENCE AND GENETICS
  7. REGIONAL CLUSTERING
  8. SECULAR TRENDS
  9. SUMMARY AND CONCLUSIONS
  10. Acknowledgements
  11. REFERENCES

Numerous observations from the literature clearly indicate that PDB has an important genetic component, with familial PDB accounting for 10–40% of cases in different studies. Familial PDB cases in Italy have been described for many years.(6,22,23) However the difficulty in ascertaining the familial distribution of the disease (because of the late onset of the symptoms and the high frequency of asymptomatic bone involvement) makes it impossible to obtain a clear estimate of familial and sporadic cases. A recent analysis of 147 consecutive Italian PDB patients from Siena showed clinically confirmed familial aggregation in 15% of cases.(10) Pedigree analysis indicated an autosomal dominant pattern of inheritance with variable penetrance. No significant differences between familial and sporadic cases were observed concerning age of diagnosis, disease extension, and male to female ratio, even if PDB seemed to be diagnosed earlier in familial than sporadic cases. Similar estimates were reported in a survey of 125 PDB subjects from Campania, showing family history in 23 (18.4%).(24) In this case, however, an increased clinical severity and a preferential involvement of the skull and the spine was observed in familial with respect to sporadic PDB cases. Taken together, these results are in keeping with previous studies from different populations of British descent, where the proportion of familial cases ranged from 12% to 20%.(20,25–27) Differences between these studies may be caused by the lack of detailed clinical evaluation of the families of affected patients that may reveal more persons with asymptomatic PDB. Indeed, in a study from Spain, Morales Piga et al.,(11) after detailed clinical analysis of 35 PDB patients and their 128 first-degree relatives, showed familial PDB in 40% of cases. A similar preliminary observation in PDB patients from Turin showed familial aggregation of disease in 26% of cases.(28) The hypothesis that the true prevalence of familial PDB is actually underestimated has been also sustained by recent genetic studies, indicating the existence of SQSTM1 gene mutations in a consistent number of patients without apparent family history for the disease and thus coded as sporadic PDB.(29,30) It is likely that a significant number of apparent sporadic PDB cases actually are familial.

PDB is a genetically heterogeneous disorder with at least seven genetic loci initially reported to be associated with a higher risk to develop the disease. Genetic studies revealed a mutation in the TNFRSF11A gene (encoding RANK) in an Asian family with early-onset PDB(31,32) and at least 10 different mutations in the SQSTM1 gene in both familial and nonfamilial PDB cases.(29,30,33,34) In a preliminary analysis in Italian PDB patients, no mutations in the exon 1 of the TNFRSF11A gene were reported,(35) consistent with other studies in white populations.(36,37) In contrast, two different studies recently identified three different mutations of SQSTM1 gene in Italian PDB patients. In a first study, a common P392L mutation was described in 10% sporadic and 30% familial PDB cases.(38) In another similar study in sporadic PDB patients,(39) the overall prevalence of SQSTM1 mutations was lower (4.8%), and three different mutations were described (P392L, M404V, and G425R). A more detailed study of pedigree of the patient with the M404V mutation provided evidence for a familial form of PDB, and the extension of genetic analysis confirmed the mutation in four affected subjects and six unaffected family members.(40) A different study identified the P392L mutation of the SQSTM1 gene in two polyostotic members of a PDB Italian family.(41) A summary of genetic studies in Italian PDB patients is reported in Table 3.

Table Table 3.. Genetic Studies in Italian Cases of PDB
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REGIONAL CLUSTERING

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PREVALENCE OF PAGET'S DISEASE IN ITALY
  5. DISEASE CHARACTERISTICS
  6. FAMILIAL INCIDENCE AND GENETICS
  7. REGIONAL CLUSTERING
  8. SECULAR TRENDS
  9. SUMMARY AND CONCLUSIONS
  10. Acknowledgements
  11. REFERENCES

The geographical distribution of PDB has been shown to differ significantly not only between different countries but also within the same country. Areas of remarkably high prevalence have been described in Lancashire (northwestern England), in northeastern United States, and in some delineated territories of central and western Spain.(42–45) Apart from the 2-fold higher prevalence of disease observed in Milan than Palermo in the 1982 European study of Detheridge et al.,(8) smaller differences were shown in the more recent radiological surveys in the towns of Siena and Turin.(9) In addition, two studies suggested a remarkably higher prevalence of PDB in the region of Campania, especially within the surrounding districts of Naples, Salerno, Avellino, and Caserta. In the first study performed in Siena, the analysis of demographic and immigration history (family provenance and actual or childhood place of residence) of 147 consecutive PDB patients compared with age- and sex-matched controls indicated that about 14% of PDB subjects and 2% of controls reported present or previous residence in rural districts of Campania.(10) Moreover, when the analysis was restricted to subjects living in the administrative district of Siena, an increased prevalence of PDB was observed within the Chianti area, whereas a reduced prevalence was observed in the urban area.(10) A similar preliminary analysis of 75 PDB patients in Turin confirmed an increased prevalence of cases with present or previous residence in Campania with respect to age-matched controls.(28)

The reasons for these geographic variations in prevalence rates of PDB are unknown and may be caused by either genetic or environmental factors. It was speculated that arsenic pesticide in imported cotton might have been a possible environmental factor underlying the increased prevalence of the disease in Lancashire cotton mill towns.(46) On the other hand, the high prevalence areas located in central and western Spain mainly represent rural regions that remained fairly isolated until recent times.(12,43,44,47) Such populations could be strongly influenced by their genetic background and their habits of meat consumption without sanitary control.(12,47) Similarly, the area of Chianti near Siena, and the districts of Caserta, Salerno, and Avellino in Campania, mainly include rural and fairly isolated places where the possibility of animal contacts could be higher than in other parts of Italy. Consumption of unpasteurized milk is also particularly frequent in these areas. Future population-based studies will be needed to confirm these associations and to explore the possible environmental and/or genetic determinants. Indeed, the hypothesis of a high prevalence of PDB in the region of Campania was also supported by studies from other countries that described this Italian region as a parental place of origin of their PDB cases.(20,48,49)

Importantly, a recent study indicated significant differences in clinical severity of PDB patients from Campania with respect to PDB cases from other part of Italy.(28) PDB patients from Campania had an earlier onset of disease, an increased skeletal extent, and a higher tendency toward neoplastic degeneration than patients from Turin and Siena. Together with a case of osteosarcoma, 5 cases of giant cell tumor were observed in the 125 PDB patients living in Campania, consistent with a prevalence of 6/125 (4.8%). The latter association represents a quite unusual clinical feature. In fact, the association between PDB and giant cell tumor is uncommon, and <60 cases have been described worldwide since the first report.(50–52) This complication usually occurs in patients with severe polyostotic disease and may be multifocal, with up to 27 lesions described in a single patient. Remarkably, >50% of described PDB cases with giant cell tumor have been observed in subjects originating in or descending from ancestors who lived in the region of Campania, particularly from the town of Avellino.(48,53,54) Familial clustering has been recently described in these subjects.(54)

SECULAR TRENDS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PREVALENCE OF PAGET'S DISEASE IN ITALY
  5. DISEASE CHARACTERISTICS
  6. FAMILIAL INCIDENCE AND GENETICS
  7. REGIONAL CLUSTERING
  8. SECULAR TRENDS
  9. SUMMARY AND CONCLUSIONS
  10. Acknowledgements
  11. REFERENCES

Data from several countries support the view that there are important secular trends in the prevalence and severity of PDB. Recent epidemiological observations indicated a decrease in the prevalence of PDB that was particularly evident in those populations of British descent where the highest incidence rates had been described. A remarkable example is given by a 1999 radiological survey from Cooper et al.(55) that replicated a previous study performed in 1974 and showed about a 3-fold decrease in prevalence rates (from 5.0% to 2.0%) over a 20-year period in the same 10 British towns. The decrease was much more marked in the high prevalence area of Lancashire than in other British regions. Similar results were reported in New Zealand.(56,57) Moreover, the annual incidence of new cases of PDB has declined significantly in Britain and the United States over the past 20 years.(58,59) In Italy, there are not similar studies to confirm this trend. However, the comparison of Italian prevalence estimates from different periods does not seem to indicate a clear reduction in prevalence rates over the past 20–30 years (Table 4). Moreover, the analysis of the longitudinal survey in Turin showed no significant reduction in radiological prevalence of pelvic PDB among the four selected periods: 1986–1987 (0.43%), 1992–1993 (0.73%), 1999–2000 (0.60%), and 2001–2002 (0.90%).(9) On the contrary, an increase in prevalence rates can be observed between 1986–1987 and 2001–2002 that could reflect the immigration flow of young individuals from possible hot spot regions of southern Italy that occurred in Turin between 1960 and 1970 (Table 4).

Table Table 4.. Prevalence Rates of PDB in Italy
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Together with a reduction in prevalence rates, several studies also showed a decrease in clinical severity of PDB, with less extensive skeletal involvement and a reduced incidence of serious complications such as osteosarcoma.(56,60,61) This secular trend toward milder disease seems to be maintained in recent years.(62) The analysis of the 147 Italian subjects from Siena did not show any significant correlation between birth year and extent of bone involvement or skeletal distribution of lesions.(10) Similarly, no differences in clinical severity were observed when PDB patients were divided into two groups according to the birth date cut-off of 1930, which represented the median value of this population. Thus, there was no apparent evidence toward a decrease of severe PDB in Italy over the last decades. However, the skeletal extension and the mean number of affected sites of the 147 Italian PDB cases were lower with respect to many other studies from different countries. This may reflect a reduced clinical severity of PDB in Italy. Interestingly, the comparison of clinical characteristics of PDB subjects from Siena described by Merlotti et al. in 2002–2004(10) with those reported by Stuart in PDB subjects from the same hospital in 1950–1956(6) shows a decrease in the number of affected skeletal sites and a reduction of neoplastic degeneration over time (Table 5). Possibly, the decrease in clinical severity of PDB might have occurred earlier in Italy than in other countries and does not seem to be maintained through recent years.

Table Table 5.. Comparison of Disease Characteristics of Patients With Paget's Disease in Siena in the 1950–1956 and 2000–2004 Studies
  1. p < 0.01 χ2 test or Fisher exact test (if n < 5).

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SUMMARY AND CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PREVALENCE OF PAGET'S DISEASE IN ITALY
  5. DISEASE CHARACTERISTICS
  6. FAMILIAL INCIDENCE AND GENETICS
  7. REGIONAL CLUSTERING
  8. SECULAR TRENDS
  9. SUMMARY AND CONCLUSIONS
  10. Acknowledgements
  11. REFERENCES

Most epidemiological studies on PDB have been performed in the United Kingdom and in other populations of British descent such as those in the United States, Australia, and New Zealand. In contrast, few data are available about the epidemiology and characteristics of PDB in other European populations, with most studies limited to the Spanish and French populations. Results from the recent radiological, biochemical, and bone scan surveys in Siena and Turin, together with the analysis of PDB cases included in the Italian Registry, indicated that, excluding osteoporosis, PDB represents the most common bone remodeling disorder in elderly people in Italy. Based on prevalence rates ranging from 0.7% (radiological studies) to 2.4% (bone scan study), it can be estimated that ∼150,000–300,000 subjects may be affected with PDB in our country. Even though familial clustering has been observed in 15–26% of PDB patients and mutations in the SQSTM1 gene have been described in both sporadic and familial cases in Italy, our data indicate an important role of the environment in the pathogenesis of PDB, perhaps facilitating disease expression in genetically susceptible subjects. In particular, PDB appeared more prevalent in rural than in urban areas of Italy, and a significant association with animal contacts was shown, providing further support for a role of infective agents. Moreover, high prevalence areas of PDB were described in rural districts of Campania, and an increased severity was observed in PDB cases who had a present or previous residence in this high prevalence area, as indicated by a reduced age at diagnosis, increased number of affected skeletal sites, and increased occurrence of osteosarcoma or giant cell tumor. Population-based studies in these high prevalence areas and expansion of our Registry, together with genetic testing of a large number of PDB patients, may prove very useful in the near future for a better understanding of the environmental and genetic mechanisms underlying PDB.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PREVALENCE OF PAGET'S DISEASE IN ITALY
  5. DISEASE CHARACTERISTICS
  6. FAMILIAL INCIDENCE AND GENETICS
  7. REGIONAL CLUSTERING
  8. SECULAR TRENDS
  9. SUMMARY AND CONCLUSIONS
  10. Acknowledgements
  11. REFERENCES

The work was supported by the Italian Association of Patients with Paget's Disease (AIP, www.pagetitalia.com). The authors thank Drs Giancarlo Isaia and Marco Di Stefano from the University of Turin and Drs Giuseppe Mossetti and Domenico Rendina from the University of Naples for collaboration in the Italian epidemiology projects on PDB. The authors also thank Dr Frederick Singer for helpful discussion and suggestions during the preparation of the manuscript and Drs Vincenzo De Paola and Annalisa Avanzati for technical assistance.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PREVALENCE OF PAGET'S DISEASE IN ITALY
  5. DISEASE CHARACTERISTICS
  6. FAMILIAL INCIDENCE AND GENETICS
  7. REGIONAL CLUSTERING
  8. SECULAR TRENDS
  9. SUMMARY AND CONCLUSIONS
  10. Acknowledgements
  11. REFERENCES
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