Radiation Effects on Bone

Post-radiotherapy fragility fractures are a frequent complication of orthopedic oncology care of sarcoma patients, who often receive radiotherapy (XRT) as adjunctive treatment. Prediction of these fractures is difficult as there has been no demonstrable relationship shown, to date, between bone density and fracture risk for this population. Treatment for an impending fracture due to radiotherapy does exist in the form of prophylactic operative stabilization with an intramedullary nail to prevent the bone from breaking. Without the ability to predict those patients at higher risk for fracture, clinical indications for prophylactic treatment are difficult to develop.

Bone density has been investigated as a possible fracture prediction tool. Work by Dhakal et al. suggested specifically that bone density, as measured by dual-energy x-ray absorptiometry (DXA), of the irradiated limb is not decreased following therapeutic doses of radiotherapy (50 Gy) administered for soft tissue sarcomas. However, their technique did not measure pre-radiotherapy bone mineral density (BMD), but rather compared post-radiotherapy BMD of the irradiated site to contralateral and ipsilateral non-irradiated long bones of the extremity. While this technique accounted for disuse osteopenia (bone loss due to decreased use of the afflicted limb), it did not account for any systemic effects of radiation therapy. This is important, because largely based on their work, BMD has not been utilized as a predictor of risk of fracture, and other measures have been sought for this particular clinical situation without success. Others have also failed to show decreased BMD within the irradiated field. However, these studies have either lacked power to show statistical significance or the patient population was pediatric, a growing population in which age related accrual of bone density was a potential confounder.

What Dhakal and others did not account for was the possibility of abscopal (systemic) effects of radiotherapy that might also affect the contralateral and distant sites. Recent work in this investigators laboratory and others using small animal models has suggested that radiation to one limb has statistically significant effects on the contralateral limb in terms of decreased bone mineral density and loss of bone strength. The importance and clinical implications of such an abscopal effect is as of yet unclear. At the very least, its presence calls into question the conclusion that bone density is not decreased at the site of radiation, since differences may only be able to be shown when compared to non-irradiated control subjects. Moreover, there may be an adverse effect on distant bones, further lowering BMD and contributing to fragility fractures, particularly in post-menopausal women who are already at some increased risk. There is mixed clinical data on this topic, with one series of 45,662 prostate cancer patients showing a 76% increased risk of hip fracture (regional bone) following pelvic radiation, but no increased risk of fractures outside the field of radiation in three studies of patients with pelvic radiation for cervical and other female cancers or prostate cancer.

The investigators of this study propose to determine whether human subjects undergoing radiotherapy for soft tissue sarcomas exhibit for abscopal bone loss. Patients in the PI's (Dr. Damron) practice obtain baseline-staging studies, including computerized tomography (CT) of the chest/abdomen/pelvis prior to treatment. Post-treatment, patients then undergo oncology surveillance utilizing routine repetitive computerized tomography of the chest and sometimes of the abdomen/pelvis for a subset where the baseline abdomen/pelvis CT scans show abnormalities that need to be followed. These CT scans, when combined with calibration phantoms of known density, afford a prime opportunity to quantify bone mineral density based on those scans at sites distant to the primary site of radiotherapy (typically in the extremity).

This project will also evaluate a secondary aim, that of comparing effectiveness of utilization of CT vs BMD as a tool to evaluate bone loss in short term with a potential for long term fracture prediction in this patient population. In order to accomplish this aim, simultaneously, in a subset of patients who give consent for non-standard of care DXA scans, the investigators will evaluate the potential abscopal bone loss by assessing changes in BMD as measured by DXA, a tool that is a gold standard for bone density evaluation and for fracture prediction in routine clinical practice. The investigators will compare BMD pre- and post-radiotherapy at the site of irradiation, and further compare this change to that of the change in BMD at distant sites.