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Keywords:

  • Paget's disease;
  • epidemiology;
  • case series;
  • familial

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The analysis of 236 Italian patients with Paget's bone disease showed higher clinical severity and greater frequency of neoplastic degeneration among patients who live or descend from individuals living in the Campania region (southern Italy). A prevalent involvement of the spine and the skull, the sites preferentially involved in giant cell tumors complicating Paget's disease, was also shown in familial cases from this geographical region.

Introduction: The Campania region in southern Italy has been recently indicated as a high prevalence area for Paget's disease of bone (PDB), and most pagetic families with multiple occurrence of neoplasms in affected members were from this geographical region.

Materials and Methods: We evaluated the PDB epidemiological characteristics in 125 patients from Campania in comparison with 111 patients from other Italian regions. Twenty-three patients from Campania and 26 patients from other Italian areas had at least one first-degree relative affected by PDB (familial cases). The remaining patients made up the sporadic cases.

Results: Among subjects from Campania, the patients in the familial group tended to come from larger families and showed at diagnosis higher serum total alkaline phosphatase, larger extension of disease, and earlier mean age with respect to patients with PDB of the sporadic group. The skull, spine, and humerus were the sites preferentially involved in the familial cases. In contrast, no such differences were observed between familial and sporadic PDB cases among patients from the other geographical areas, except for a lower age at diagnosis. An increased PDB clinical severity was finally observed in the PDB cohort from Campania in comparison with patients from other Italian regions. Neoplastic degeneration of pagetic bones (osteosarcoma and giant cell tumor) was exclusively observed in patients with polyostotic PDB from Campania.

Conclusions: We showed a higher clinical severity of PDB with occurrence of neoplastic degeneration in the high prevalence area of Campania, with its maximum expression in cases with familial disease. This peculiar pattern might be traced to genetic predisposition and/or to the abnormal impact of a still undefined environmental trigger.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Paget's disease of bone (PDB) is a disorder of bone metabolism characterized by increased and grossly disordered bone remodeling, bone hypertrophy, and abnormal bone structure. It is a disease primarily of the osteoclasts, which show peculiar morphological and physiological abnormalities.(1 The etiology of PDB is not well understood, but at least one PDB-linked gene and several other susceptibility loci have been identified, and paramyxoviral gene products have been detected in pagetic osteoclasts.(2

PDB is the second most common bone remodeling disorder after osteoporosis, with an age-related increase in prevalence that reaches 2–3% of the population over age 60.(3 Moreover, the PDB geographic distribution is not uniform, with a higher prevalence of the disease in North America, Australia, and New Zealand. In Europe, the PDB prevalence shows a north-south gradient, with highest prevalence in England (4.6%) and a lower prevalence in Italy and Greece (1–0.5%).(3–7 Current estimates indicate that between 15% and 40% of PDB-affected individuals have at least one affected first-degree relative, and the cumulative risk of developing the disease is 9% for a first-degree relative of an affected subject compared with 2% for the general population.(8–12

Clinically, the most serious complication of the disease is neoplastic degeneration of involved bones that occurs however in <1% of the cases.(2,13–16 The majority of these tumors are classified as osteogenic osteosarcomas, but benign giant cell tumors may also occur.(2,13–16 Interestingly, the evidence for a familial influence on the occurrence of neoplastic complications in PDB is limited, but most cases of pagetic families with multiple neoplasms in affected members have been reported from the Campania region in southern Italy.(17–19 Moreover, a recent epidemiological study on the occurrence of PDB in Italy suggested the possibility of a concentration of PDB cases in rural areas of Campania.(20 An increased severity of disease in these patients was also apparent. These observations prompted to establish a registry of patients with PDB from Campania to assess their clinical and epidemiological characteristics and to evaluate whether the sporadic form of PDB actually differs from the familial type in this geographic area. The clinical features of PDB patients from Campania and PDB subjects from other geographical areas were also comparatively evaluated.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Subjects

One hundred sixty-eight consecutive patients referred for PDB to the Department of Clinical and Experimental Medicine of “Federico II” Medical School (Naples) from January 1, 2002 to December 31, 2003 were considered for the study. They represent 87.5% of the entire cohort of pagetic patients referred to all medical facilities of the Campania region in the same period (E de Campora, Regional Health Agency, personal communication). One hundred thirty-four of them agreed to participate and gave written, informed consent before entering the study, which was conducted according to the Declaration of Helsinki. One hundred sixteen patients were from the Campania region and were enrolled for this study. In addition, we decided to study first-degree relatives of these patients and, taking in account the usual age at onset of PDB, we choose the age of 40 as a cut-off. Thus, all first-degree relatives ≥40 years of age (n =507) were contacted by regular mail, e-mail, fax, and/or telephone, proposing to participate in the study. We also examined medical documentation or X-ray materials of first-degree relatives of patients who died over the age of 40 before the study (n =98). Like this, we made the diagnosis of PDB in nine additional cases. The clinical data of these patients were used in this analysis.

Disease characteristics of patients with PDB from Campania (n =125) were compared with those of cases from other Italian regions, represented by 111 consecutive patients with PDB recruited from the Bone Disease Unit of the Department of Internal Medicine, Endocrine-Metabolic Sciences and Biochemistry, University of Siena. Most of them (n =49) were resident in the city of Siena and its surroundings, whereas 62 came from other regions. Among the latter, 14 were from Campania and were analyzed separately.

Data collection

Enrollment started with a patient questionnaire exploring the place of birth and residence of participants and their parents, birth weight, sibship size, birth order, place of residence during childhood and adolescence, housing, animal contacts, occupation, and pharmacological history. We also asked when they were first told they had PDB, whether pain, X-rays, or blood tests brought them to medical attention, and whether a bone scan had been done. Finally, in symptomatic cases, patients were asked to estimate the age at onset of the PDB symptoms. When necessary, help by some well-informed relative was requested. First-degree relatives of pagetic patients were asked for an interview, and samples of blood and urine were collected for biochemical screening. Those having total serum total alkaline phosphatase (ALP) activity above the laboratory reference range (98–275 U/liter) without clinical or biochemical evidence of liver disease were invited to undergo a 99mTc-MDP bone scan, followed by X-ray examination of the areas of increased isotope uptake.

Clinical manifestations and radiological features of PDB were evaluated according to the criteria proposed by Selby et al.(16 The percentage of total skeletal volume involved by PDB in each patient was evaluated according to the criteria proposed by Davie et al.(21 In the cases in which X-ray patterns were similar to those of bone metastases and in the cases of suspect neoplastic degeneration, a bone biopsy was performed.

All patients were asked to fill in a pain assessment questionnaire. According to Tong et al.,(22 the pain was scored by multiplying its severity (none, mild, moderate, and severe) by its frequency (no pain, occasional, intermittent, and constant), with each of these measures being graded from 0 to 3. A score of 0 denoted absence of pain, whereas a score of 9 denoted severe and constant pain. It was at the patients' discretion to decide whether the pain was or was not related to PDB based on a previous discussion with their physicians. At the same time, a pain medication score was obtained by multiplying the type of pain medication prescribed (none, analgesic, mild, and strong narcotic) by the frequency of its assumption (never, less than daily, once per day, more frequently than once per day), with each of these measures graded from 0 to 3. A score of 0 denoted that no pain medication was taken, whereas a score of 9 denoted the assumption of strong narcotic medications more frequently than once per day.(22

Statistical analysis

According to Glantz,(23 statistical comparisons were based on Student's t-test for continuous variables and on χ2 test for dichotomous variables. All data were expressed as mean ± SD. Statistical analysis was performed using a SPSS statistics package, version 11.5. All statistical tests were two-tailed. A p value <0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

We first studied the 125 patients with PDB recruited in Naples and born in the Campania Region and their first-degree relatives over age 40. All patients had at least one parent and 119/125 (95.2%) had both parents born in Campania. Overall, 23 patients (18.4%) had at least one other first-degree relative affected by PDB (familial cases). Among the remaining 102 patients (81.6%), no relatives with the disease were detected (sporadic cases). As reported in Fig. 1, a higher prevalence of familial disease was observed in patients living in the cities of Salerno, Avellino, Benevento, and Caserta and its surroundings compared with the one observed in Naples and surroundings (p =0.018). No differences in mean age and male/female ratio between first-degree relatives of familial and sporadic cases were detected.

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Figure Figure 1. Campania map with identification of principal cities. The prevalence of familial and sporadic PDB was reported for each of them. The hatched portion of the circles around each city means a percentage of the patients with Paget's disease of bone that have the familial version. *Cities which families have been identified with PDB and multiple occurrence of neoplastic complications in affected members.

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Table 1 compares the main biological and clinical features of familial and sporadic cases from Campania. The mean age of patients (63.26 ± 14.81 versus 68.97 ± 11.36 years; p =0.042) and the age of PBD onset (50.04 ± 12.93 versus 56.94 ± 12.14 years; p =0.017) were significantly lower in familial than in sporadic cases. Patients with a family history of PDB also tended to come from larger families (number of family members 7.26 ± 2.24 versus 5.43 ± 1.45; p =0.009). At diagnosis and before any specific therapeutical approach, serum total ALP values (2054 ± 1254 versus 1165 ± 886; p =0.012), extension of disease (number of sites involved =4.65 ± 2.46 versus 2.96 ± 1.74; p < 0.001), and percentage of skeleton involved (42.43 ± 21.17 versus 28.18 ± 14.91; p =0.001) were significantly higher in familial compared with sporadic cases. Recognized risk factors for PDB such as birth order, unpasteurized milk consumption, and history of dog ownership showed similar patterns in both groups.

Table Table 1.. Clinical Characteristics of Pagetic Patients From Campania, Southern Italy
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As reported in Table 2, the distribution of pagetic lesions among familial cases was significantly different compared with that observed in sporadic cases, the skull (OR =6.07; 95% CI, 2.08–17.66), the lumbar spine (OR =4.37; 95% CI, 1.65–11.63), the cervical spine (OR =21.87; 95% CI, 4.17–114.79), and the humerus (OR =4.93; 95% CI, 1.85–13.09) being sites preferentially involved in familial cases.

Table Table 2.. Skeletal Distribution of Bone Lesions Between Pagetic Patients With or Without Family History of Disease From Campania
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The clinical manifestations and the sequelae of PDB among patients from Campania are reported in Table 3. The occurrence of headache (OR =3.85; 95% CI, 1.45–10.21), pagetic bone pain (OR =3.45; 95% CI, 1.26–9.46), bone pain score (2.97 ± 2.19 versus 1.88 ± 1.38; p =0.011), and medication score (3.01 ± 2.39 versus 1.39 ± 0.98; p =0.012) were significantly greater in the familial than in the sporadic cases. Occurrence of neoplastic degeneration in pagetic bones was found in six patients, all with a polyostotic disease and acquired resistance to antiresorptive treatments (intramuscular calcitonin, intravenous clodronate, intravenous pamidronate). We found a single case of osteosarcoma in pagetic lumbar spine in a man with no family history of PDB and five cases of giant cell tumor, all in subjects with familial disease (four from a single family from Avellino and one from a family in Naples). Two patients showed multifocal giant cell tumor. The mean number of affected sites and the percentage of skeleton involved by disease in patients with giant cell tumor were 4.9 ± 2.2 and 47.32 ± 19.45, respectively. All of these patients showed a severe disease involving skull and pelvis in all cases. However, in this setting, the disease did not show a peculiar localization compared with what observed in first-degree relatives affected by PDB.

Table Table 3.. Clinical Manifestation and Sequelae of PDB Between Pagetic Patients With or Without Family History of Disease From Campania
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The analysis of first-degree relatives of the 111 participants recruited in Siena indicated that 26 patients (23.4%) had at least one family member affected by PDB. The age at onset of PDB was significantly lower in familial than in sporadic cases (53.1 ± 13.9 versus 59.4 ± 11.8, p =0.02). However, at variance with the patients from Campania, the differences observed between familial and sporadic cases with respect to total ALP (538 ± 398 versus 460 ± 295), number of affected sites (2.42 ± 1.9 versus 2.20 ± 1.5), percentage of affected skeleton (23.18 ± 16.1 versus 21.37 ± 15.5), and proportion of polyostotic cases (60.7% versus 47.8%) were not statistically significant, although the general trend was similar. A trend for increased family size among familial PDB cases was also observed (2.5 ± 1.6 versus 1.9 ± 1.5; p =0.08). Environmental and lifestyle characteristics such as animal contacts or unpasteurized milk ingestion did not significantly differ between the two groups. Moreover, no major differences in the distribution of pagetic lesions were observed, even though there was evidence of a trend for increased involvement of the skull in familial compared with sporadic cases (33.3% versus 17.9%; p =0.09).

We finally compared environmental and clinical characteristics in patients with PDB from Siena with those observed in PDB subjects from Campania (Table 4). Because 14 of the 111 patients recruited in Siena reported current or previous residence in Campania, we categorized PDB subjects into three groups: group 1, including patients recruited in Campania (n =125); group 2, composed by patients from Siena and living outside of Campania (n =97); and group 3, including patients recruited in Siena with current or previous residence in Campania (n =14). A greater clinical severity of disease was observed in PDB cases from Campania (groups 1 and 3), irrespective of the site of recruitment compared with patients from all other regions who had been recruited in Siena (group 2). In particular, a higher proportion of polyostotic cases, a greater number of sites involved, elevated serum ALP levels at diagnosis, and prevalent involvement of the skull were observed in patients with PDB from Campania (groups 1 and 3) with respect to those from other regions (group 2). Neoplastic degeneration (osteosarcoma and giant cell tumor) was observed only in patients from Campania. Moreover, among the other complications of PDB, a higher prevalence of bone deformities, headache, and nerve injury was observed in cases from Campania with respect to cases from other regions (Table 5). The analysis of environmental characteristics revealed a greater use of unpasteurized milk (68%, group 1; 46%, group 2; 80%, group 3; p =0.02, group 2 versus group 3; p =0.001, group 2 versus group 1) and of fresh homemade meat products without sanitary control (79%, group 1; 49%, group 2; 81%, group 3; p =0.02, group 2 versus group 3; p =0.01, group 2 versus group 1) in patients with PDB from Campania with respect to patients with PDB from other geographical areas. A lower tendency toward vaccination of animals, particularly against distemper, a paramyxovirus-induced disease, in rural areas was also observed among patients with PDB from Campania (18%, group 1; 47%, group 2; 17%, group 3; p =0.03, group 2 versus group 3; p =0.02, group 2 versus group 1).

Table Table 4.. Differences in Clinical Characteristics Between Patients With PDB From Naples, Campania (Group 1) and PDB Subjects From Siena Living Outside Campania (Group 2) or Originally From Campania (Group 3)
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Table Table 5.. Complications of Paget's Disease in Patients From Naples, Campania (Group 1) and Patients From Siena Living Outside Campania (Group 2) or Originally From Campania (Group 3)
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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Although PDB is considered a relatively common skeletal disorder in elderly people, its pathogenesis still remains largely unknown. Several studies showed both a familial incidence and geographic clustering, with recent reports from high prevalence areas suggesting a temporal decrease in rate of occurrence and severity of the disease.(24–28 This observation might reflect either a modification in the genetic background caused by immigration flows or a decreased exposure to a hypothetical environmental trigger. A previous epidemiological survey of Italian patients with PDB suggested a remarkably localized area of high prevalence in the Campania region, especially within the surroundings of Naples, Salerno, Avellino, and Caserta.(20 Moreover, differences in characteristics and clinical severity of patients with PDB from these high prevalence areas were also suggested.(20 This study confirmed and extended these preliminary reports, indicating that patients with PDB from the high prevalence area of Campania show increased clinical severity and a particularly higher risk of neoplastic degeneration of pagetic lesions. This could be caused by differences in both genetic and environmental background between Campania and other Italian regions.

In keeping with the hypothesis of modification in the genetic background, a particularly severe phenotype was observed in familial PDB cases from Campania. In fact, these patients showed a peculiar distribution of pagetic lesions and a more aggressive clinical pattern compared with patients with sporadic PDB cases. Earlier onset of disease, stronger disease activity, greater proportion of skeleton involved, and higher prevalence of bone pain and of neoplastic complications were observed in familial versus sporadic PDB cases. An increased prevalence of other complications such as headache, fractures, and osteoarthritis was also observed in familial than in sporadic PDB. These results are in keeping with a previous study investigating the characteristics of patients with PDB included in the New England Registry of Paget's Disease of Bone, showing greater clinical severity with earlier deformity and fractures in familial than in sporadic cases.(12 Our data also confirm previous studies suggesting that pagetic patients with familial disease based in the Campania region seem to have a greater predisposition to develop PDB-related tumors, in particular giant cell tumor.(17–19 On the other hand, patients with sporadic PDB from this geographical area also showed a higher prevalence of this neoplasm, which in patients with PDB shows peculiar clinical characteristics.(29–31 Indeed, classic giant cell tumors affect patients between 20 and 40 years of age, whereas tumors in pagetic bones occur in patients older than 50 years. Moreover, in patients with PDB, giant cell tumor preferentially involves craniofacial and vertebral bones. This anatomic distribution is different from that observed in nonpagetic giant cell tumors of bone, 75% of which arise in long tubular bones, predominantly affecting the distal femur, proximal tibia, and distal radius.(32 Interestingly, in patients with familial PDB from Campania, the disease preferentially affected the sites most frequently involved by the giant cell tumor complicating PDB (i.e., craniofacial and vertebral bones). This distribution of bone lesions is significantly different compared with that observed in sporadic pagetic patients from the same geographic area, even though a prevalent involvement of craniofacial bone was also observed in sporadic PDB cases from Campania with respect to patients with PDB from other regions. To our knowledge, such a different distribution of pagetic bone lesions between patients with sporadic or familial disease as well as between PDB cases from different geographical areas was not previously reported in other studies. This feature may explain, at least in part, the increased prevalence of giant cell tumors in familial and sporadic PDB from Campania. Remarkably, >50% of giant cell tumors associated with PDB have been described in patients from Campania.

According to Zlotogora,(33 an explanation for the peculiar characteristics of PDB in patients with familial disease from Campania could be attributed to a founder effect, as recently shown for patients of British descent with PDB or genetic drift.(34 The Campania region is historically a land of emigration, spreading its population out to many different countries around the world. Between 1900 and 1914, −1,000,000 people expatriated, especially to North America. On the other hand, an immigration flux to Campania, represented mostly by people coming from the old communist block (Poland, Albania, Rumania), has been observed in the last two decades.(35 Thus, this region still represents a relatively uniform genetic isolate. As indirect evidence of these speculations, in Italy, the families' last names of pagetic patients affected by familial disease in our cohort occur to a significant extent only in the Campania region.(36 The evidence that neoplastic degeneration in pagetic patients from Campania occurs even if they have lived for several years in other countries or continents suggests environmental factors in the pathogenesis of this phenomenon.(17,18,29,30 On the other hand, considering the possible viral etiology of PDB and the considerably low prevalence of anti-paramixovirus vaccination in Campania, an epistemological interaction between genetic and viral factors in the pathogenesis and clinical manifestations of disease cannot be excluded.(37 Moreover, the analysis of lifestyle and dietary habits of patients recruited in this study showed some environmental differences with a greater use of unpasteurized milk and of fresh, homemade meat products without sanitary control in the group of patients from Campania with PDB with respect to patients with PDB from other geographical areas.

This study has some limitations. The main weakness is that the study is not population based, because the patient enrollment is entirely voluntary. Moreover, the observed increase in sibship size as a determinant of familial PDB may reflect the fact that, the larger the family size, the more likely another family member is to develop PDB. Major strengths of the study are given by the robustness of the database in characterizing clinical and epidemiological findings of PDB from different regions, including a geographic area harboring an unusually high incidence of neoplastic degeneration. With further increasing the number of observations and with family histories and strong clinical characterizations in place, we could start to examine the genetics of this cohort and answer to the following questions. Is there a genetic difference between familial and sporadic PDB? Is there genetic difference between PDB cases from Campania with respect to PDB cases from other regions? Will these genetic differences account for the observed phenotypic variations? Is the genetic predisposition to PDB modulated by differences in lifestyle and/or environmental habits?

In conclusion, our analysis of patients from Campania with PDB, a region with high prevalence of PDB, showed a greater clinical severity of the disorder in comparison with other Italian areas. In particular, patients with the familial form of PDB from Campania showed a remarkably aggressive disease, also characterized by the preferential localization of lesions in craniofacial and vertebral bones, the sites most frequently involved by the giant cell tumor complicating PDB. There is evidence that this geographical area has a significant and unusually higher incidence of neoplastic degeneration that reaches its maximum in patients with familial PDB. An extension of our registry of patients with PDB from Campania and other Italian regions has been scheduled to try and explain these results and to improve our knowledge about the pathogenesis of this invalidating disorder.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES