Date of Award
Doctor of Philosophy (PhD)
Bateman, Ted A
Simionescu , Dan
Nagatomi , Jiro
Benson , Lisa
Robbins , Michael
Skeletal complications from radiation therapy have been described for breast, brain, pelvic, and blood cancers. These problems include atrophy, fractures, and osteoradionecrosis. Improved survivorship rates of cancer patients receiving radiotherapy increases the importance of understanding the causal mechanisms and long-term effects of radiation-induced bone loss. One such long-term effect is bone fractures following radiation therapy for cancer treatment. The incidence of hip fractures is significantly increased following targeted radiotherapy for cancer. This decline in bone health can have a severe impact on the patient's functional capabilities. This damage to bone following irradiation is thought to involve damage to both osteoblasts and vascularity within bone. However, the relationship between radiation and osteoclast activity (bone resorption) is unknown and poorly studied. Very few studies have examined the effects of radiation on osteoclast number and activity, and those that have reveal conflicting results. The studies presented herein will examine the response of bone to ionizing radiation in order to assess if radiation can increase osteoclast activity. The primary goal is to determine if increased osteoclast activation and number occur as a result of exposure to ionizing radiation, thus contributing to radiation-induced osteoporosis. Our hypothesis is that exposure to ionizing radiation increases osteoclast activity and number, resulting in elevated resorption early after exposure.
The results from these studies indicate that exposure to ionizing radiation can induce osteoporosis within two weeks of treatment. The degree of bone loss at this point is substantial, with corresponding deterioration of trabecular microarchitecture. Osteoclast number and function as determined by in vitro assays is likewise increased during the first two weeks of treatment. Histological evidence identifies an increase in the surface of irradiated trabeculae covered by osteoclasts by three days after treatment. Serum proteins indicate overall whole-body increase in resorption by only one day after exposure. Similar patterns of reduced bone volume and microarchitecture are observed in irradiated rat tibia by two weeks after treatment with doses of X-rays modeling what human pelvic bones might receive during cancer treatment. Administration of bisphosphonates largely mitigates these changes. Thus ionizing radiation increases bone resorption within these animal models early after exposure.
Future studies must more specifically identify how radiation induces osteoclast activation. This information can then be used to identify targets to suppress bone resorption after irradiation. Ultimately, these data need to be correlated with the effects of radiation on bone strength and how radioprotective (or antiresorptive) agents can influence this response. These investigations may prove useful in eventually reducing the incidence of hip fractures among cancer survivors.
Willey, Jeffrey, "RADIATION-INDUCED OSTEOPOROSIS: BONE QUANTITY, ARCHITECTURE, AND INCREASED RESORPTION FOLLOWING EXPOSURE TO IONIZING RADIATION" (2008). All Dissertations. 181.