Paget’s disease of the bone is a common skeletal disorder often referred to orthopedic surgeons for evaluation and treatment. It occurs in up to 2% of the population older than age 55 in the United States and up to 4% of the population in the United Kingdom.
It is characterized by an excess in bone remodeling. The first phase involves bone resorption followed by a greatly increased new bone formation with a woven, disorganized collagen structure. The resulting bones become abnormally enlarged.
Genetics
The exact mechanism that initiates the development of Paget’s disease of the bone is unknown. However, there appears to be a genetic component as 40% of patients with the condition have a first degree relative with the disease. In some families, there appears to be an autosomal dominant pattern of inheritance.
Researchers have identified six genetic foci that are linked to the condition. The most closely associated is p62, also known as the sequestosome-1 gene (SQSTM1). This gene has been identified in approximately 30% of familial cases of Paget’s and 10% of sporadic cases.
The penetrance of Paget’s disease varies in families with genetic predispositions. There are cases of patients who are homozygous (having both gene loci positive) who remain asymptomatic and without the sequelae of the disease.
Pathophysiology
The most striking cellular abnormality of Pagets is the presence of osteoclasts containing nuclear inclusions. Many of these nuclear inclusions resemble paramyxoviral nucleocapsids. Proteins linked to both the measles virus and the respiratory syncytial virus have been isolated from these nuclear inclusions. Although normal osteoclasts infected in vitro (in the lab) with measles or measles proteins can transform into the abnormal osteoclasts that mark the disease, definitive cause and effect between infection with a paramyxovirus and the development of Paget’s has not been established.