BoneKEy-Osteovision | Commentary

The cause of paget's disease?

Tim Cundy

DOI:10.1138/20040125

A friendly competitor once asked Albright if he knew the cause of Paget's disease. “No,” he said. “But look out, I may think of it any minute.”

For over 60 years, we have had a pretty clear understanding of the pathology, radiology, epidemiology, and clinical manifestations of Paget's disease, and for more than 30 years, we have had effective treatments at our disposal. The cause of Paget's disease has, however, remained elusive; despite the boast, even the formidable Fuller Albright could not come up with a hypothesis to explain its many peculiarities (). Several new lines of inquiry are being pursued, but these are to some extent contradictory. So where are we on the cause of Paget's disease?

Genes for paget's disease

The unusual geographic distribution of Paget's disease and its well-recognized familial clustering have stimulated research into genetic factors that might cause or predispose to the disease. Two groups — from Quebec () and Scotland () — studying families with more than one affected member have independently identified mutations in the gene SQSTM1 (located on chromosome 5q35) that are associated with familial Paget's disease . SQSTM1 encodes sequestosome 1 (also known as p62), a protein thought to function as a scaffold in the tumor necrosis factor-α (TNF-α) and interleukin 1 pathway for selective activation of NF-κB. Sequestosome 1 has the ability to bind ubiquitin at its C-terminal domain, and all of the Paget's disease-associated mutations identified to date are located in this domain. The speculation is that failure to degrade p62 through the ubiquitin-proteasome pathway somehow leads to activation of NF-κB in affected osteoclasts. Between 40% and 80% of familial Paget's disease, and a lower proportion of nonfamilial cases, seem to be linked to SQSTM1 mutations (). There are many unanswered questions. Why, even within families, does the same mutation can result in phenotypes of markedly varying severity, and why do not all people inheriting the mutations seem to develop the disease ()? How does a germline mutation give rise to a focal skeletal disease? Can variation in the prevalence of these genetic mutations explain the differences in the prevalence of Paget's disease around the world? Linkage studies in familial Paget's disease have suggested that genes at other loci (in particular, at 2q36, 10p31, and 18q23) are also involved (), leading Johnson-Pais et al. () to suggest that Paget's disease may be a digenic disorder — that is, an affected individual must have mutations in each of two unlinked genes to develop the disease.

Changing epidemiology

While the genetic story is unfolding, we need to consider the changes in prevalence and incidence of Paget's disease that seem to be taking place. Since the 1970s, the customary method of determining prevalence has been to review large series of consecutive unselected abdominal x-rays. These films include the pelvis, sacrum, lumbar spine, and upper femora, and about 80% of people with Paget's disease have at least one of these sites involved. Two recent prevalence studies have revisited cities surveyed 20 years or so earlier. In 10 cities in the United Kingdom () and in Dunedin, New Zealand (), very similar results were obtained: the prevalence of Paget's disease seems to be only about one-half of what it had been two decades earlier. Some reservations about this conclusion have been expressed. The ethnic demography in many of these cities has changed over the same period, and the indications for performing abdominal x-rays have also changed because of increased use of ultrasound for hepatobiliary and renal tract imaging. However, there is other evidence that Paget's disease is changing. Specialist clinics are now seeing older patients with milder disease, and severe disease has become something of a rarity (). Moreover, data from the UK General Practice Research Database (information from about five million subjects older than age 18 years registered with British general practices from 1988 to 1998) show that the annual incidence of new cases of Paget's disease had declined significantly — by more than 30% in only 10 years (). Taken together, this evidence argues strongly that there must be some environmental determinant to Paget's disease — the rate of change is too rapid to be genetic — and that exposure to the environmental agent(s) has declined in recent years.

The environmental factor?

The presence of paramyxovirus-like inclusion particles in osteoclasts first noted by Rebel et al. () makes a virus the most popular candidate for the environmental agent. Attention is currently focused on the measles virus. David Roodman's group have reported the detection of measles virus nucleocapsid mRNA transcripts () and the isolation of measles nucleocapsid gene fragments () from marrow cells from pagetic bone. This group has further been able to induce a pagetic phenotype in osteoclasts transfected with measles virus (). Is measles then the missing link? Possibly, but Paget's disease is extremely rare in parts of the world where measles is common. Could the decline in the prevalence of Paget's disease be related to the introduction of measles vaccines in the late 1960s and early 1970s? Possibly, but the 60-year olds of today, in whom Paget's disease is much less common than in earlier generations, would have been exposed to measles in childhood. Has some Paget's disease-causing measles strain become extinct? And again, how does a systemic viral infection result in focal bone disease?

Although there are unmistakable signs of progress, we are still some way from a cohesive theory that accounts for all of the features of Paget's disease. More secrets that will have a profound effect on our understanding of bone biology and bone diseases are sure to be revealed.

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.