Paget disease of bone is a focal disorder of the aging skeleton that can be asymptomatic or can present with pain, bowing deformities, fractures, or nonspecific rheumatic complaints. Physicians often discover it in asymptomatic patients when serum alkaline phosphatase levels are elevated or as an incidental finding on radiography. Despite evidence of germline mutations and polymorphisms that predispose to Paget disease, the environmental determinants that permit disease expression in older people remain unknown.
A STRIKING GEOGRAPHIC DISTRIBUTION
Researchers have been studying the determinants and distribution of Paget disease ever since Sir James Paget first described it in 1877.1
Paget disease has a predilection for the axial skeleton, particularly the lumbosacral spine and pelvis, as well as the skull, femur, and tibia.2 Knowing this, investigators have used screening plain films of the abdomen (kidney-ureter-bladder views) to estimate its prevalence in different populations, as these images capture the lumbosacral spine, pelvis, and proximal femurs. Other means of assessing prevalence have included autopsy series, questionnaires, and screens for biochemical markers of bone turnover, such as elevated serum alkaline phosphatase from bone.3–6
Using these methods, Paget disease has been estimated to occur in 1% to 3% of people over age 55, and in as many as 8% of people over age 80 in certain countries.7
This disease has a striking geographic distribution, being frequent in Europe, Canada, the United States, Australia, New Zealand, and cities of South America, but rare in Scandinavia and Japan. It seems to be equally rare in other countries of the Far East and in India, Russia, and Africa, although its prevalence in these areas has not been thoroughly investigated.8
That it is an ancient disease has been corroborated by excavations in churchyards in Great Britain.9,10 It may be familial or sporadic, but its expression is delayed until late middle age in most persons, and it does not occur in children. For reasons unclear, the prevalence seems to be decreasing in many countries.11–13
GENETICS IS NOT THE WHOLE STORY
The variable prevalence of Paget disease in different geographic regions and its sometimes-familial expression suggest a genetic predisposition, environmental factor, or both.
Mutations in SQSTM1
In 2002, scientists investigating a cohort of French Canadian families found a mutation in the SQSTM1 gene that was present in almost 50% of people with familial Paget disease and in 16% of those with sporadic Paget disease.14 Hocking and his colleagues in the United Kingdom subsequently found the same mutation in 19% of cases of familial Paget disease and in 9% of sporadic cases.15
Further, investigators noted that the mutation was often present on a conserved haplotype, consistent with a stable genetic change occurring in the affected population.16 This observation of a “founder effect” dovetailed with the epidemiology of Paget disease,17 but only with this SQSTM1 mutation.
Throughout Europe, Australia, and the United States, comparable rates of the SQSTM1 mutation were reported in or around the ubiquitin-associated domain. Several specific mutations exist, the most common one being P392L, ie, a prolineto-leucine substitution at amino acid 392. Scientists have tried to correlate severity of disease with genotype, but the findings have been inconsistent.18–21
Investigations into the mechanism of disease have pointed to the role of p62, the product of SQSTM1, in signaling osteoclast activation via nuclear factor kappa B. Since this initial discovery, polymorphisms in the genes affecting osteoclast maturation, activation, and fusion pathways have been shown to predispose to Paget disease. Examples:
- TNFRSF11A, which codes for receptor activator of nuclear factor kappa B, or RANK
- TNFRSF11B, which codes for osteoprotegerin, or OPG
- CSF1, which codes for macrophage colony-stimulating factor 1, and
- OPTN, which codes for optineurin, a member of the nuclear factor kappa B-modulating protein family.
Clinicians interested in these details can read an excellent review of the pathogenesis of Paget disease.22
Other possible factors
Although there is good evidence that measles and canine distemper virus can infect osteoclasts and modify their phenotype, there is no good evidence that these infections by themselves cause Paget disease.23–25 It is, however, tempting to think of these RNA paramyxoviruses as precipitating factors; conceivably, an infectious agent might seed the ends of long bones, accounting for the fixed distribution of Paget disease and its late expression.
Epidemiologic studies from around the world have failed to identify conclusively any environmental exposure that predisposes to Paget disease, although a rural setting, trauma, infection, and milk ingestion have all been proposed.26–28 It is also possible that as bone ages and the marrow becomes less cellular and more fatty, these changes may permit the disease to develop.
The greatest risk factor for Paget disease is perhaps aging, followed by ancestry and a known family history of it. That genetics is not the whole story is evident by reports of people with SQSTM1 mutations who show no clinical evidence of Paget disease in their old age, and patients with Paget disease who have no SQSTM1 mutation.20,29