Elsevier

Joint Bone Spine

Volume 84, Issue 6, December 2017, Pages 719-723
Joint Bone Spine

Original article
Environmental factors associated with familial or non-familial forms of Paget's disease of bone

https://doi.org/10.1016/j.jbspin.2016.11.010Get rights and content

Abstract

Objectives

The most frequent mutation linked to Paget's disease of bone (PDB), p.Pro392Leu within SQSTM1 gene, leads to phenotypic characteristics of PDB, but this mutation is seemingly insufficient to result in complete pagetic osteoclast phenotype, suggesting that possible environmental factors play a role in PDB pathogenesis. We performed an exploratory study to identify environmental factors potentially associated with familial or non-familial form of PDB in the French-Canadian population.

Methods

We investigated environmental factors through a questionnaire in 176 pagetic patients, including 86 patients with a familial form, and 147 healthy controls. All participants lived in the same geographic area, within a 120 km radius of Quebec City. Associations between environmental factors and familial and non-familial forms of PDB were searched.

Results

In the multivariate model adjusted for intra-familial correlation, PDB was associated with wood fired heating in childhood and/or adolescence (OR = 2.10; 95% CI 1.13–3.90, P = 0.02). In the multivariate model without considering correlation for family relatedness, familial form of PDB was associated with residency near a mine (OR = 11.70; 95% CI 2.92–46.80, P < 0.01) and hunting (OR = 2.92; 95% CI 1.14–7.47, P = 0.03). Wood fired heating during childhood and/or adolescence (P = 0.02) was associated with both familial and non-familial forms.

Conclusions

In conclusion, PDB was significantly associated with wood fired heating in childhood and/or adolescence, regardless of the form of PDB, familial or not.

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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