TNFRSF11B

Studies suggest that several normal variations (polymorphisms) in the TNFRSF11B gene may increase the risk of developing classic Paget disease of bone, particularly in women. These genetic changes could affect the amount or function of osteoprotegerin. However, it is unclear how polymorphisms in this gene influence disease risk.

At least six mutations in the TNFRSF11B gene have been found to cause juvenile Paget disease. Each of these mutations greatly reduces the function of osteoprotegerin or prevents cells from making any of this protein. Without osteoprotegerin, RANKL binds only to RANK. The resulting increase in chemical signaling stimulates the production of too many osteoclasts and triggers these cells to break down bone abnormally. In people with juvenile Paget disease, bone is broken down and replaced much faster than usual. When the new bone tissue grows, it is weaker and less organized than normal bone. These problems with bone remodeling cause bones throughout the skeleton to become unusually large, misshapen, and easily broken (fractured).