Paget's disease of bone (PDB) is a common disorder, characterized by focal rapid remodeling of affected bones. This can lead to complications such as fracture, deformity, bone pain, and secondary osteoarthritis. The prevalence of PDB varies significantly between countries, but it is common in Britain and Western Europe, where the archeological investigation of skeletal remains suggests that it emerged in the Roman era.1 New Zealand has a high prevalence of PDB, and it is assumed that the disorder was brought to the country by migrants who came in large numbers from Britain in the late 19th and early 20th centuries.2 There is strong evidence for a genetic predisposition to Paget's disease (through mutations in sequestosome 1 [SQSTM1]) that may underlie the apparent transmission of Paget's disease with migrant populations.3
The Paget's disease clinic at Auckland City Hospital (established in 1973) has kept a comprehensive database of all patients referred to the clinic. As published previously,4 we noted that in the period 1973 to 2003 there was a rise in the mean age at presentation and a decline in disease severity, suggesting an important secular trend. Over a similar period, radiographic surveys showed a significant decline in disease prevalence.5 However, despite a continuing decline in the total number of patients referred, we have noticed an increasing number of patients of Asian descent referred with Paget's disease.
Limited literature exists on the prevalence of PDB in Asian countries. In Japan, the prevalence of Paget's disease is said to be very low (<3 per million).6 Reports from large centers in India studying patients in the period 1995 to 2005 indicate that relatively few patients are diagnosed with the disease.7–9 The data from Southeast Asia and China are even more limited with only a small number of case reports.10–15 In light of this limited literature, we report clinical and epidemiological features of the patients of Asian descent referred to our clinic over the period 1973 to 2010.
Materials and Methods
From 1973 to the end of 2010 (37 years), a total of 1668 patients were referred for the first time to our clinic. Data recorded in the database were the year of birth, sex, the year and age at diagnosis, pretreatment total alkaline-phosphatase (ALP) activity, and skeletal involvement on scintigraphy. We defined Asian as being of East, South, or Southeast Asian descent. We identified 14 patients of Asian descent presenting to our clinic and extracted further information on their place of birth and date of arrival into New Zealand.
In the Auckland region, the population of Asian descent has increased in recent decades. To determine if the apparent increase in the number of patients with Paget's disease paralleled this change, we obtained census data on the Auckland region from Statistics New Zealand. In New Zealand, censuses are conducted every 5 years and include data on self-declared ethnicity. The populations of Europeans and all Asian ethnic groups for the ages >40 years were obtained from the censuses of 1986, 1991, 1996, 2001, and 2006.
SQSTM1 mutation screening
We obtained samples from 8 of the 14 Asian patients for SQSTM1 mutation testing. DNA was extracted from blood samples using the Progene DNA purification kit (Gentra Systems, Minneapolis, MN, USA). Exon 8 of the SQSTM1 gene was amplified by Platinum Taq polymerase (Invitrogen, Carlsbad, CA, USA) in 35 cycles of PCR at an annealing temperature of 62°C and MgCl2 concentration of 1.5 mM. The forward primer 5′-GGCAGAGTTGAGCAGTGTG-3′ and the reverse primer 5′-CCCGTACAGAGACCTGCAAT-3′ produced 445-bp products that were subsequently purified using the High Pure PCR product purification kit (Roche, Mannheim, Germany) and sequenced on ABI PRISM 3130XL Genetic Analyzer capillary sequencer (Applied Biosystems, Inc., Foster City, CA, USA).
No Asian patients were referred between 1973 and 1992. Between 1993 and 2010, 14 Asian patients presented with PDB, 12 of whom were diagnosed in the period 2002 to 2010. There were 13 men, 8 of whom were symptomatic at diagnosis. None of the patients were born in New Zealand, and the diagnosis was made at a median of 8 years after migration (Table 1). None had a family history of the disorder. The severity of the disease in the 14 Asian patients was comparable to that seen in patients of European descent in the same time period, although the Asian patients were somewhat younger (64.5 versus 72 years). None of the 8 patients tested carried mutations in exon 8 of the SQSTM1 gene.
Table 1. Demographic and Clinical Features of Asian Patients With Paget's Disease
Data obtained from Statistics New Zealand showed that in the Auckland region in the period 1986 to 2006, the European population >40 years increased from 271,000 to 317,000, whereas the Asian population >40 years increased from 4000 to 75,000 (Fig. 1). The number of new PDB referrals expressed as a proportion of the total Auckland population >40 years of age increased from being undetected in 1986 to 1991 to 1/104 in 2006 to 2010 in those of Asian descent, whereas in those of European descent the corresponding value decreased from 10/104 in 1986 to 1991 to 2/104 in 2006 to 2010 (Fig. 1).
Our study has shown that the increased number of people of Asian descent diagnosed with PDB and referred to our clinic has paralleled the increasing size of the Asian population in the Auckland region. There has been a concurrent decline in the apparent prevalence of PDB in the European population, so that the proportion of the potentially at-risk population referred in the period 2006 to 2010 is now similar in Asians and Europeans. Our data do not necessarily suggest that Paget's disease is becoming more prevalent in people of Asian descent; it could simply be more visible as the size of this population grows. An unusually high proportion of our patients were men, but given the small number of patients in total, the significance of this is uncertain.
Paget's disease is most prevalent in people of Northwestern European origin, but it has also been observed in populations of non-European descent. Prevalence surveys in a number of US cities and South Africa have found no difference in disease prevalence between people of African and European descent.16–18 PDB has also been identified in patients of Caribbean or Asian descent in London.19 Our patients had lived in New Zealand for a median of 8 years before diagnosis, although, of course, we cannot determine when their disease first developed. The most frequently seen group were Fijian Indian migrants to New Zealand, whose ancestors came from widely dispersed rural areas of India to Fiji, predominantly between 1879 and 1916.
There are limitations to our data. First, some patients may have been managed by their general practitioners or other providers and not referred to us. Second, the geographical area defined as Auckland was increased between the censuses of 1986 and 1991. Despite these limitations, our study suggests the emergence of PDB in Asians—a population who were hitherto thought not to be susceptible.
The etiology of Paget's disease is unknown, but both environmental and genetic factors are thought to be important. Mutations in the SQSTM1 gene are associated with familial PDB,3 and genome-wide association studies have demonstrated that polymorphisms in several genes are present in higher frequency in patients with Paget's disease.20 The absence of SQSTM1 mutations in our patients is not surprising, given that 5% or fewer of patients with with nonfamilial Paget's disease carry such mutations.3 However, the recent decline in disease prevalence and severity in populations of European descent argues strongly that there are also significant environmental determinants of the disease. The fact that we have demonstrated both a continuing decline in the European population in conjunction with the appearance of the disease in Asian subjects in our region as the local population has increased suggests not only that there is an environmental determinant but also that Asians are not genetically protected from PDB. It further implies that the recent reduction of Paget's disease prevalence in cities in formerly high prevalence areas cannot be explained, as has been suggested,3 by the rising Asian population in these areas. The nature of the environmental agent (or agents) is not known. Viruses (possibly acquired from animals), environmental pollutants, trauma, and nutritional deficiencies have all been suggested, but no definitive proof of any of these possibilities has been established.3
All the authors state that they have no conflicts of interest.
We thank Greg Gamble for his help with the statistical analyses, and the Health Research Council of New Zealand for financial support.
Authors' roles: Study design: AG and TC. Study conduct: SS and TC. Data collection: SS and DN. Data analysis: SS and TC. Data interpretation: SS, DN, AG, and TC. Drafting manuscript: SS and TC. Revising manuscript content: DN and AG. Approving final version of manuscript: SS, DN, AG, and TC. TC takes responsibility for the integrity of the data analysis.