About 2% of people over age 40 in the United States; about 1 million of Western European heritage; early-onset rare
Osseous Paget's disease; osteitis deformans; Paget disease, bone; Paget's disease of bone; PDB
Sir James Paget, who lived and worked during the nineteenth century, was known as one of the founders of medical pathology. He wrote many works that paved the pathway for the tremendous developments in medicine that were part of the last half of the 1800s. The works were called Lectures on Tumours (1851) and Lectures on Surgical Pathology (1853). Paget researched and described many diseases and had three diseases named for him. The one that most associated with his name is Paget disease of the bone.
The most known disorder that Paget is remembered for and is usually just called Paget disease is the one related to the bones. In Paget disease, the bones grow larger, become weaker, and tend to break easily. Appearing in middle age or later in only one or two bones, the condition may not have a lot of symptoms and only be detected when the person goes for an X-ray for another condition.
The classic form of the disease may affect any bone and cause symptoms of other conditions depending upon which bone is affected. Following are the bone areas that may be affected:
Legs: One of the most common places that Paget disease affects is the leg. In Paget disease the bone is distorted, causing arthritis in near-by joints. Some people with the disorder experience pain, bowed legs, and difficulty walking.
Knees: Distortion in any of the bones in the legs can lead to extra wear and tear and cause arthritis to develop in the knee.
Hips: If the bones in the hips are distorted, arthritis can also affect many of the pelvic joints. Fractures are also common.
Spine: If the disorder affects the spine, the person may experience numbness, tingling due to pinched nerves, and abnormal curvature of the spine.
Skull: Paget disease can affect the skull, causing the head to enlarge. The person may also experience dizziness, headaches, and hearing loss.
Bone cancer: Osteosarcoma is a rare type of cancer that may occur in fewer than 1 in 1,000 people with the disorder.
Although the classic condition causes weakened and misshapened bones, it does not appear to spread from one bone to another.
Much less common is an early-onset form that occurs in the teens or the early 20s. The symptoms vary somewhat from the classic form in that it appears to affect the bones of the skull, spine, ribs, and small bones of the hands. The form may also cause hearing loss in early life.
This disease is one in which environment may play a role. Several genes increase the risk for the disorder, but other factors may trigger the disorder. For example, certain viruses may cause the disorder. The genes that create risk and possibly cause Paget disease are SQSTM1, TNFRSF11A, and TNFRSF11B.
Mutations in the SQSTM1 gene, officially known as the “sequestosome 1” gene, may put the person at risk for Paget disease. Normally, SQSTM1 instructs for a protein called p62, which is essential for breaking down old bone and replacing it with new bone. Osteoclasts are specialized bone cells that break down old bone; osteoblasts are the cells that build up new bone. The p62 protein controls the formation of osteoclasts. It may also play a role in recycling the worn-out cell parts and the body's immune response.
About 20 mutations in the SQSTM1 gene cause Paget disease. Most of the mutations occur when the amino acid leucine replaces proline. The mutations appear to overactivate the chemical signals that form the osteoclasts, thereby triggering the cells to break down bone before it is time to do so. The broken down bone is then replaced with weaker and less organized normal bone. The bones are then larger, more misshapened, and easily fractured. SQSMT1 is inherited in an autosomal dominant pattern and is located on the long arm (q) of chromosome 5 at position 35.
Mutations in the TNFRSF11A gene, officially known as the “tumor necrosis factor receptor superfamily, member 11a, NFKB activator” gene, increase the risk for Paget disease. Normally, TNFRSF11A instructs for the protein receptor activator of NF-kB, also called RANK. The RANK protein plays an active role in bone remodeling, the process in which old bone cells are broken down and replaced with new bones. RANK is located on the surface of immature osteoclasts and receives the signals as to when it is time for these cells to mature and do the work of breaking down unneeded cell parts.
Two mutations in TNFRSF11A have been found to cause the early-onset form of Paget disease. An abnormal copy of genetic material is in the gene, causing RANK to have extra protein building blocks. The extra material appears to cause RANK to send signals to the osteoclasts to start breaking down old bone. This signal then calls upon the osteoblasts to start building up bone. The new bone that was quickly produced is much weaker and less organized than normal bone and is easily fractured and misshapened. TNFRSF11A is inherited in an autosomal dominant pattern and is located on the long arm (q) of chromosome 18 at position 22.1.
Mutations in TNFRSF11B, or the “tumor necrosis factor receptor superfamily, member 11b” gene, increase the risk of Paget disease. Normally, TNFRSF11B instructs for a protein called osteoprotegerin. This protein is essential for the bone remodeling process. In bone remodeling, osteoclasts break down old bone and osteoblasts from new bone. Osteoprotegerin is one of two receptors that can bind to the activator NF-κB ligand (RANKL). The other is NF-κB (RANK). Because only one receptor at a time can bind with the ligand, the two compete with each other. When RANKL binds to RANK, it triggers the immature osteoclasts to mature and begin breaking down bone cells. When osteoprotegerin binds to RANKL, the signal prevents the activation of osteoclasts, and no action takes place. The two help balance each other so that the amount of production of the osteoclasts is normal.
About six mutations in TNFRSF11B cause juvenile Paget disease. Each mutation disrupts the function of osteoprotegerin, letting RANL bind only to RANK and thereby producing too many osteoclasts to break down bone. When bone is broken down so rapidly, the osteoblasts work to replace quickly bone cells, causing bone cells that are weaker and less organized.
Although mostly connected with the juvenile form, one mutation of TNFRSF11B indicates that the gene may increase the risk of Paget disease especially in women. TNFRSF11B is inherited in an autosomal dominant pattern and is located on the long arm (q) of chromosome 8 at position 24.
Because the disease is one of the more common bone disorders, several researchers have investigated and developed treatments that can slow down the rate of bone breakdown and pain. Following are several of the interventions:
Bisphosphonates: These pharmaceuticals have been shown to be effective in several conditions relating to bone loss. The drugs target the excessive breakdown that happens in Paget disease. Examples are alendronate or Fosamax and risedronate or Actonel.
Calcitonin: An injectable form can treat Paget disease, but it might not be as effective as bisphosphonates.
Pain relievers: These include acetaminophen, aspirin, or ibuprofen.
Exercise: Regular exercise is recommended to keep bone strength.
Diet: Adequate amount of calcium and vitamin D helps bone strength.
Surgery: Surgery may be necessary on the affected bone or joint. Hip and knee replacement may help.
See also Aging and Genetics: A Special Topic
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