Paget’s disease of bone is a chronic disorder that disrupts the body’s normal process of bone renewal, known as remodeling. This condition primarily affects older adults, causing a breakdown in the organized cycle of bone resorption and formation, resulting in structural abnormalities. While the exact causes are complex, genetic factors play a demonstrable role, particularly when the condition appears in multiple family members. This genetic component increases the lifetime risk for certain individuals, prompting a closer look at the mechanisms of inheritance.
Understanding Paget’s Disease of Bone
The disease begins with an overactivity of osteoclasts, the cells responsible for breaking down old bone tissue, leading to excessive bone resorption. Osteoblasts, the cells that build new bone, then attempt to compensate for this rapid loss by creating new bone at an accelerated pace. This rushed production results in bone tissue that is abnormally large, disorganized, and mechanically weaker than healthy bone. The new bone is fragile and highly susceptible to developing fractures and deformities.
Commonly affected areas include the pelvis, spine, skull, and the long bones of the limbs, such as the femur and tibia. Many people with the condition remain asymptomatic, but for those who experience symptoms, the most frequent complaint is bone or joint pain. If the skull is involved, the abnormal bone growth can lead to headaches or hearing loss due to the compression of nerves. Advanced cases may present with visible bowing of the limbs or an enlarged head size.
The Role of Genetics in Inheritance
Paget’s disease occurs in two forms: sporadic, with no known family history, and familial, where the condition is inherited. Between 15% and 40% of patients report having at least one first-degree relative with the condition. Familial cases often follow an autosomal dominant inheritance pattern, meaning a person only needs to inherit one copy of the altered gene from a single parent to be at risk.
The most commonly implicated genetic mutation is found in the SQSTM1 gene, which is a major factor in both sporadic and familial cases. Mutations in SQSTM1 are found in up to 30% of people with the familial form and about 10% of those with the sporadic form. This gene provides instructions for making a protein involved in regulating osteoclast function, and its mutation leads to the hyperactive bone resorption seen in the disease.
The presence of an SQSTM1 mutation increases an individual’s risk, but it does not guarantee disease development; this is known as incomplete penetrance. This suggests that other factors, such as environmental or additional genetic variations, are required for the condition to fully manifest. Individuals who carry the SQSTM1 mutation tend to have an earlier age of onset and more extensive disease involvement. Other susceptibility genes have also been identified, highlighting the complex genetic background of the disease.
Screening and Monitoring Familial Risk
For individuals with a known family history of Paget’s disease, proactive screening and monitoring are important for early detection. The primary screening tool involves a blood test to measure serum alkaline phosphatase (ALP). Elevated ALP levels indicate increased bone turnover, which is a hallmark of active disease.
Some physicians suggest that asymptomatic first-degree relatives should undergo an ALP test approximately every two to three years. If the ALP level is found to be elevated, a skeletal scintigraphy, commonly known as a bone scan, is the next step to determine the extent and location of the bone lesions. This imaging technique is highly sensitive and can identify bone changes even before they cause symptoms or show up on standard X-rays.
Genetic counseling is valuable for individuals with a family history to assess their risk profile and understand the implications of testing for the SQSTM1 mutation. Recent studies show that prophylactic treatment can halt disease progression in high-risk, asymptomatic carriers of the SQSTM1 variant. This approach shifts the focus from treating complications to prevention, making genetic screening worthwhile for those with a strong familial link.
Current Treatment Methods
The main goal of managing Paget’s disease is to control the excessive bone turnover and alleviate pain caused by the structural changes. The medical management generally relies on the use of bisphosphonates, which are a class of medications that suppress the overactive osteoclast cells. These drugs help to normalize bone remodeling, slow the disease’s progression, and reduce symptoms.
Intravenous bisphosphonates, such as zoledronate, are highly potent and often provide long-lasting remission after a single dose. For pain management, nonsteroidal anti-inflammatory drugs (NSAIDs) may be used to address bone or joint pain related to the disease or its complications, like secondary arthritis. In cases where the disease has led to severe bone deformity, joint damage, or fractures, orthopedic surgery may be necessary. Surgical procedures can include joint replacement for severely damaged joints or fixation to stabilize a bone fracture.