Current evidence suggests both genetic and environmental causes of Paget disease. Approximately 50% of familial Paget disease and 10% of sporadic cases harbor mutations in the SQSTM1 gene. The mutations increase the activity of NF-κB, which, in turn increases osteoclast activity. Activating mutations in RANK and inactivating mutations in OPG account for some cases of juvenile Paget disease. The geographic distribution is suggestive of some environmental influence. Of note in this regard, cell culture studies have shown that infection of osteoclast precursors with viruses such as measles or other RNA viruses alters vitamin D sensitivity and IL-6 secretion, both of which can lead to increased bone resorption.
Paget disease shows remarkable histologic variation throughout time and from site to site. The hallmark, seen in the sclerotic phase, is a mosaic pattern of lamellar bone (
Fig. 21.11 ). The jigsaw puzzle–like appearance is produced by unusually prominent cement lines, which join haphazardly oriented units of lamellar bone. In the sclerotic phase, the bone is thickened but lacks structural stability making it vulnerable to deformation and fracture. The findings during the other phases are less specific. The initial lytic phase is characterized by numerous large osteoclasts and resorption pits. The osteoclasts may have 100 or more nuclei. Osteoclasts persist in the mixed phase, but many of the bone surfaces are also lined by prominent osteoblasts.
Paget disease is monostotic in about 15% of cases and polyostotic in the remainder. The axial skeleton or proximal femur is involved in up to 80% of cases. Most cases are asymptomatic and are discovered as an incidental radiographic finding. Pain localized to the affected bone is a common symptom. Pain is caused by microfractures or by bone overgrowth that compresses spinal and cranial nerve roots. Enlargement of the craniofacial skeleton may produce leontiasis ossea (lion face) and a cranium so heavy that is difficult for the person to hold the head erect. The weakened Pagetic bone may lead to invagination of the skull base (platybasia) and compression of the posterior fossa. Weight bearing causes anterior bowing of the femurs and tibiae
Fig. 21.11 Mosaic pattern of lamellar bone pathognomonic of Paget disease.
and distorts the femoral heads, resulting in the development of severe secondary osteoarthritis. Chalk stick–type fractures are another frequent complication and usually occur in the long bones of the lower extremities. Compression fractures of the spine result in spinal cord injury and the development of kyphosis. The diagnosis can frequently be made from the radiographic findings. Many affected individuals have elevated serum alkaline phosphatase levels but normal serum calcium and phosphorus.
A variety of tumor and tumorlike conditions develop in Pagetic bone. Secondary osteosarcoma occurs in less than 1% of all individuals with Paget disease, but appears in 5% to 10% of those with severe polyostotic disease. In the absence of malignant transformation, Paget disease is usually not a serious or life-threatening disease. Most affected individuals have mild symptoms that are readily suppressed by treatment with calcitonin and bisphosphonates.
A fracture is defined as loss of bone integrity resulting from mechanical injury and/or diminished bone strength.