What is Paget's disease?

Causes and Symptoms

Paget’s disease of bone is a disorder characterized by excessive and abnormal formation of bone, most commonly in the spine, skull, pelvis, thighs, and lower legs. (Paget’s disease of the nipple is a different disorder related to breast cancer.) The cause of this disease is under investigation. Genetic factors are a major component. Between 15 and 40 percent of all patients with Paget’s disease have a positive family history of the disease, and the risk of developing Paget’s disease is seven to ten times higher in relatives of those who have Paget’s disease compared with relatives of those who do not have this disease. Several genes are known to regulate the cells that remodel bone, and mutations in some of these genes seem to be the main cause of Paget’s disease in some patients.

In adult, nongrowing bone, the structure of bone is the result of the interplay between two types of cells—one that deposits bone, the osteoblast, and another that resorbs bone, a multinucleate cell called the osteoclast. A signaling system called the RANK-RANKL-OPG system regulates osteoclast recruitment. RANK is a receptor on the surface of osteoclast precursor cells. RANKL is the ligand, or molecule, that binds to RANK to activate it. RANKL is secreted by bone marrow cells; when RANKL binds to the RANK molecules on the surface of osteoclast precursor cells, it activates an internal protein called p62. The activation of p62 pushes osteoclast precursor cells toward becoming mature, bone-resorbing osteoclasts. Osteoblasts, however, also secrete OPG, a soluble receptor that competitively binds RANKL and prevents osteoclast recruitment (see figure on page 2244). Mutations in the genes that encode RANK, OPG, or p62 cause various inherited forms of Paget’s disease with varying severities and times when the disease manifests itself. Not all individuals who harbor these mutations, however, suffer from full-blown Paget’s disease.

Paget’s disease might also result from viral infections. Experimental infection of mouse osteoblasts with measles virus can cause Paget’s disease in mice. Furthermore, osteoblasts from human patients with Paget’s disease sometimes harbor measles virus or other closely related viruses. It is possible that the presence of mutations in genes that increase osteoclast activity in combination with chronic infection of osteoclasts by measles virus or similar viruses create an environment that nurtures the development of clinical Paget’s disease.

Paget’s disease is more common in people over the age of forty. The disease usually starts without any symptoms. It is often diagnosed when a person has radiographs taken for other reasons or has a higher-than-normal level of alkaline phosphatase in the blood. As the disease progresses, the patient may develop an enlarging skull, sometimes accompanied by headaches; increased risk of fractures; curving of the spine or legs; and bone and joint pain. Rarely, Paget’s disease may lead to kidney stones, loose teeth when bones of the face are involved, and loss of hearing and vision when the enlarging skull compresses nerves to the eye and ear. People with severe Paget’s disease may have heart problems such as congestive heart failure or abnormal heart rhythms. Less than 1 percent of people with Paget’s disease will develop bone cancer.

Treatment and Therapy

Bisphosphonates (such as etidronate, pamidronate, alendronate, risedronate, or tiludronate) are the main treatment for Paget’s disease. Subcutaneous injections of salmon calcitonin successfully reverse the symptoms of Paget’s disease, but 50 percent of all patients who receive this treatment develop an immune response against calcitonin and 10 to 20 percent of all patients become resistant to it. In patients with severe symptoms who do not respond to these more typical treatments, the antibiotic mithramycin has been used successfully, but the toxicity of this drug militates against its use for anything but worst-case scenarios.

Treatment is given when patients experience pain, deformities, nerve compression, or other symptoms or to prevent the risk of future complications when the skull, spine, legs, and/or pelvis are involved. Therapy is given until the levels of alkaline phosphatase in the blood return to normal, and it may need to be repeated if that level increases again. Acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) may be used to treat pain. Exercise and adequate intake of calcium and vitamin D are also recommended. Surgery may be needed to stabilize fractures, replace joints affected with severe pain from arthritis, or decompress nerves.

Perspective and Prospects

Paget’s disease likely has been around for many centuries, as it has been observed in a grossly thickened Egyptian skull dating from about 1000 BCE. The disorder is named after a British surgeon, Sir James Paget, who was the first to describe this condition in 1876. He noted five patients with thickened bones that were prone to fracture and deformity. Paget thought that the disorder resulted from chronic inflammation and named it osteitis deformans. Subsequently, researchers have shown that Paget’s disease of bone arises from the overproduction of poor-quality bone, rather than from chronic inflammation.

Identification of mutations in candidate genes in patients who have active Paget’s disease, coupled with the expression of these mutant genes in transgenic mice in which the endogenous copy of the same gene has been eliminated (so-called knockout mice), represents one of the most powerful techniques for studying the cause and pathology of Paget’s disease. Combining Paget’s disease-specific mutations in transgenic mice whose osteoblasts have been chronically infected with measles virus or respiratory syncytial virus has also greatly elucidated the nongenetic causes of this disease.

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