Paget’s Disease of Bone (PDB) is a chronic disorder defined by the acceleration and disorganization of the body’s natural bone remodeling process. This condition causes bones to become enlarged, structurally abnormal, and weaker, often leading to pain, deformity, and fracture. PDB is considered hereditary in a significant minority of cases, with up to 40% of patients reporting at least one other affected family member. However, a genetic predisposition does not guarantee that an individual will develop the disease, highlighting the complex interplay between inherited risk and other factors.
Understanding Paget’s Disease
Bone tissue is constantly being renewed through a balanced process called remodeling, which involves the breakdown of old bone by osteoclasts and the formation of new bone by osteoblasts. In PDB, this balance is severely disrupted, beginning with an abnormal increase in osteoclast activity. These cells absorb bone at an excessively fast rate, prompting osteoblasts to rapidly create new bone tissue.
The resulting bone is structurally inferior, disorganized, and fragile, lacking the typical structure of healthy bone. The disease can affect any one or several bones, most commonly the pelvis, spine, skull, and long bones of the limbs. When the disease occurs without a known family history, it is classified as Sporadic Paget’s Disease, which accounts for the majority of cases. Cases where the disease clusters within a family are classified as Familial Paget’s Disease (FPD), observed in approximately 15% to 40% of all PDB patients.
The Hereditary Link: Genes and Inheritance Patterns
The primary genetic mutation identified in familial PDB involves the SQSTM1 gene, which provides instructions for making the sequestosome 1 protein, or p62. This protein regulates the function of osteoclasts, the cells responsible for bone resorption. Mutations in SQSTM1 are the most common genetic cause, found in approximately 30% of familial cases and a smaller percentage of sporadic cases.
The specific genetic changes typically affect the ubiquitin-associated (UBA) domain of the p62 protein. When the UBA domain is mutated, it leads to increased activity of a signaling pathway inside the osteoclast, causing the cells to become hyperactive and over-resorb bone. PDB is generally inherited in an Autosomal Dominant pattern, meaning only one copy of the altered gene is sufficient to increase the risk of developing the disorder.
The disease exhibits incomplete or “variable penetrance.” This means that not every person who inherits the mutated gene will develop PDB symptoms. Even within the same family, individuals carrying the same SQSTM1 mutation can have vastly different clinical outcomes, ranging from severe disease to being completely asymptomatic. While SQSTM1 is the major player, other genes, including TNFRSF11A and VCP, have been implicated, underscoring the complex, multi-gene nature of the disease.
When Genetics Aren’t the Cause: Sporadic Cases and Environmental Factors
The majority of PDB cases are sporadic, occurring without a known family history or identifiable SQSTM1 mutation. These non-familial cases suggest PDB results from multiple factors, where genetic susceptibility must be activated by environmental influences. Several non-genetic risk factors have been observed in the sporadic form of the disease.
The condition is strongly associated with age, rarely appearing before age 40 and increasing in prevalence after age 55. Geographic location also plays a significant role, with the highest prevalence rates historically reported in Anglo-Saxon populations, particularly the United Kingdom, Australia, and parts of Western Europe. Conversely, PDB is uncommon in regions like Scandinavia, China, Japan, and India.
The interaction between genetic predisposition and environmental exposure often centers on the hypothesis of a slow viral infection. The theory suggests that an early-life infection with a paramyxovirus, such as the measles virus, may trigger the disease decades later in susceptible individuals. While characteristic viral inclusions have been observed inside the osteoclasts of Pagetic bone, the link remains controversial, as modern studies have not definitively confirmed the presence of active virus. Sporadic PDB is thought to arise from an underlying genetic susceptibility triggered by a yet-to-be-identified environmental factor.
Family Planning and Screening Recommendations
For individuals with a family history of PDB, especially a first-degree relative such as a parent or sibling, the risk of developing the disease is elevated seven to ten times compared to the general population. Due to this increased risk, a proactive approach to monitoring is recommended. Early detection allows treatment to slow or halt disease progression and prevent complications like bone deformity and nerve compression.
The most practical screening tool for at-risk family members is the regular measurement of serum alkaline phosphatase (ALP) levels, a simple blood test. Since ALP is often elevated in active PDB due to high bone turnover, a baseline reading and subsequent checks every two to three years can help catch the disease in its early, asymptomatic stage.
If a known familial gene mutation, such as in SQSTM1, has been identified, genetic counseling and testing may be an option to clarify an individual’s inherited risk. A positive genetic test is not a diagnosis of the disease itself, but it reinforces the need for consistent biochemical monitoring.