A complication of treatment with osteoporosis drugs is that they can result in a debilitating and painful condition known as osteonecrosis of the jaw, which is areas of bone loss within the jaw bone. It is defined as exposed dying bone and unclosed overlaying oral mucosa that is present for at least eight weeks. Researchers at the UCLA School of Dentistry have attained an understanding of how osteonecrosis of the jaw progresses as well as its structural and cellular activators. Their discovery could lead to prevention and treatment of the debilitating jaw disorder. The study appears in the November edition of the American Journal of Pathology.
Osteoporosis drugs that can cause osteonecrosis of the jaw include bisphosphonates (Fosamax, Boniva, Actonel, Atelvia, and Reclas) and denosumab (Xgeva and Prolia). Many women take them to prevent or reverse the course of osteoporosis. They are also taken by men for osteoporosis treatment and are administered to cancer patients whose tumors have spread to the bones. These drugs counteract the functions of osteoclasts, which are the cells that dissolve bone; thus, allowing the osteoblasts, which produce bone, to increase bone density and strength.
Researchers have hypothesized that these osteoporosis medications cause the problem by directly affecting osteoclasts; however, the degree to which osteoclasts contribute to the development of osteonecrosis remains unclear. A research team led by Dr. Reuben Kim, associate professor of restorative dentistry and oral biology and medicine have developed and compared two different mouse models, one for osteonecrosis caused by bisphosphonates and another for the condition caused by denosumab. In both models, the investigators removed teeth to assess the physical characteristics that marked how osteonecrosis progressed within the mouse’s mouth.
The bisphosphonate model was developed by treating mice with bisphosphonate and the denosumab model was created with a mouse version of denosumab (anti-mouse-RANKL¬-neutralizing antibody) that negates the functions of RANKL, which plays a key role in determining how osteoclasts differentiate and form. When the two mouse models were compared, the researchers found that lesions developed in 20% of the bisphosphonate models and in 50% of the denosumab models.
Interestingly, osteonecrosis developed in the denosumab model in the absence of osteoclasts because anti-mouse-RANKL antibody completely prevented osteoclast formation. The authors note that this was an important finding because it suggests that the presence of osteoclasts may not be solely related to osteonecrosis development. Instead, dysfunctional osteoclasts failed to dissolve all the bone at the damaged jaw areas, and that may in itself have produced the lesions. With this new finding, the researchers theorized that it may be possible that progression of osteonecrosis is primarily associated with structural defects, such as bone surfaces that failed to dissolve because of impaired functions or the formation of mature osteoclasts by bisphosphonates and denosumab, and not osteoclasts alone.
The investigators took this new finding one step further by examining the disrupted bone structure around the osteonecrosis lesion that formed where the tooth was removed in both mouse models. The comparison revealed a remarkable correlation between new bone formation within the sockets where teeth were extracted and complete wound healing. They noted that this finding suggested that newly formed bone or woven bone plays a crucial role during the healing process in the oral cavity. This led the researchers to theorize that woven bone acts as a bridge between soft and hard tissues in the oral cavity; thus, enhancing woven bone formation when osteoclasts fail to dissolve bone may help prevent osteonecrosis development for patients who are taking osteoporosis medications.