Original articleEnvironmental factors associated with familial or non-familial forms of Paget's disease of bone
Introduction
Paget's disease of bone (PDB) is characterized by an increased bone turnover in which osteoclasts are increased in size, number and nuclearity. This accelerated bone resorption by osteoclasts is coupled with increased osteoblast activity, resulting in a disorganised architecture of new bone, which is weak and subsequently prone to fracture [1]. Although often asymptomatic, PDB can be complicated in around 30% of cases by bone pain, osteoarthritis, shortening and deformation of limbs resulting in walking difficulties, fractures, headache, deafness, cranial nerve palsy and hydrocephalus [2]. Sarcomatous degeneration may happen in 0.3% of patients [2]. Populations originating from North-West Europe are more afflicted by PDB, which advocates for a genetic component. Both prevalence and disease extent have been reported to decrease, whereas the age at PDB diagnosis has increased over recent years [3], [4], even in offspring inheriting SQSTM1 gene mutations [5], [6]. Although significant regional differences were reported in several countries [7], [8], [9], [10], the decline of PDB prevalence was mostly reported in countries, which previously featured a high prevalence [11], [12]. This finding suggests that one or more environmental factors could be involved in PDB pathogenesis [11], [12]. The secular declining of both prevalence and severity of PDB in the British population also suggests a role for environmental factors [11], [12]. This observation may only be partially explained by the influx of migrants from relative low prevalence regions, such as the Indian subcontinent [13]. The high prevalence of PDB in Lancashire (England) may also be related to environmental factors, such as mining and outdoor air pollution.
One third of patients have a familial form of PDB, which is transmitted as an autosomal dominant mode of inheritance with high but incomplete penetrance [14]. Each first degree relative has a 50% theoretical risk of being afflicted with PDB [15], [16]. Detection of mutations in Sequestosome1 (SQSTM1) gene has put in evidence the strong genetic component of PDB [17]. The p.Pro392Leu mutation within SQSTM1 gene has been initially reported in 46% of familial forms and 16% of sporadic forms of PDB in the French-Canadian population [18]. Few epidemiological studies were performed, but no environmental factor has been clearly identified to date in p.Pro392Leu mutation carriers [19]. The hypothesis of a viral etiology remains controversial [20]. In addition, some studies have shown associations with rural lifestyle and animal contact [21], [22], [23], [24], but no specific substance has really been identified in epidemiological studies.
We made the assumption that exposure to environmental factors as reported above could be associated with PDB. Using data from our French-Canadian cohort, our exploratory study aimed at identifying potential environmental factors associated with familial or non-familial forms of PDB.
Section snippets
Recruitment of participants
The present study was approved by the CHU de Quebec-Université Laval Ethics Committee. After information on the study, all participants signed a consent form before recruitment. We performed a case-control study, including French-Canadian patients recruited at the rheumatology clinic of our university hospital, the CHU de Quebec, or via their relatives. More specifically, patients with a familial form of PDB and their affected relatives, unrelated affected individuals (non-familial form), and
Results
We contacted 617 individuals. Three hundred and firty of them consented to participate in the study. Among those participants, 323 completed the questionnaire, including 176 affected participants (86 with a familial form and 88 with a non-familial form) and 147 healthy controls (Fig. 1). General characteristics of affected participants are reported in Table 1 and Tables S1–S2 [See the supplementary material associated with this article online]. The proportion of males was higher in affected
Discussion
In this exploratory study, we reported association between PDB and wood fired heating in childhood and/or adolescence (OR = 2.10; 95% CI 1.13–3.90, P = 0.02). Although 60.2% of affected participants versus 46.3% of unrelated healthy controls were ever smoker in our study, this difference in tobacco exposure did not reach significance as opposed to the association previously shown in French families with PDB [27]. Exposure to particulate matter from the combustion of wood could link to the rural
Funding
This study was funded by the Fondation du CHU de Québec.
Author's contributions
Study design: MCA, CB, LM. Patient recruitment and acquisition of data: JD, MCA, JPB, LM. Analysis and interpretation of data: MCA, SJ, CB, JPB, LM. Revision of manuscript content: all authors. Approving final version of manuscript: all authors.
Disclosure of interest
The authors declare that they have no competing interest.
Acknowledgments
Dr. Michou is supported by a career award from the FRQ-S. This study was funded by the Fondation du CHU de Québec.
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