Indiana AMWA chapter member Laura Wright, PhD, from the Indiana University School of Medicine's Department of Medicine, is the lead author of a new article in the Journal of Bone and Mineral Research. The article, "Single-Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model," was e-published ahead of print on January 15, 2015.
Radiation therapy has proven to be an effective anticancer treatment that reduces mortality rates when it’s paired with surgery or chemotherapy. But as disease-free survival continues to improve, long-term side effects of radiotherapy on the skeletal system have emerged.
Despite efforts to minimize side effects by protecting healthy tissue, the incidence of pathological fracture is higher at bone sites that are in the direct path of radiation than in nonirradiated bone sites.
In addition to the direct effects of radiation on bone, cancer patients experience a system-wide reduction in bone mineral density within the first year of radiotherapy. And radiation-treated breast cancer patients have hip fracture rates that are up to 20 times higher than the average breast cancer patient.
These striking clinical findings implicate both direct and systemic mechanisms in the pathology of radiation-induced bone loss. The deleterious effects of ionizing radiation on bone are widely accepted, but the cellular response is not well characterized. In order to develop therapies that prevent adverse skeletal events in cancer patients, the identification of mediators and mechanisms of radiation-induced bone loss could be important. Wright's article contributes to that effort.
In the article, Wright and her coauthors present results from a preclinical mouse model that mimics the clinical setting of radiotherapy. The right hindlimb was selectively irradiated at a relatively low dose (2 Gy), and changes in bone volume were monitored for one week in both irradiated and contralateral-shielded bone sites.
The skeletal response to irradiation was further characterized at the cellular level in vivo through histological analysis and in vitro with proliferation and cell-death assays. Similar to what is reported clinically, they found that bone volume declined in irradiated bone by up to 22% and in contralateral-shielded bone by up to 14%.
At the cellular level, radiation exposure activated bone-destructive osteoclast cells and impaired the survival and function of osteocyte and osteoblast cells, which promote bone formation and healing. Fat cell or adipocyte numbers in irradiated bone marrow also increased nearly threefold, with no differences detected at distant sites.
Wright says that further studies will be necessary to assess the full time-course of changes in bone after irradiation and to identify the molecular mechanisms that are responsible for altered cellular function. These studies expand our current understanding of bone’s radiosensitivity to ionizing radiation and emphasize the multicellular and often complex nature of bone loss.
Thanks to Laura Wright for her contributions to this article.
