Bisphosphonates may reduce the incidence of bone metastases in women with breast cancer, but survival data are inconsistent. The Southwest Oncology Group is therefore conducting a 3 year clinical protocol enrolling 6,000 women with randomization to clodronate, ibandronate or zoledronate to determine whether high doses of these bisphosphonates can prevent bone metastases and improve survival in women with breast cancer. The doses are two to ten times greater than those used to treat osteoporosis, and the effects of high-dose bisphosphonates on the bone health in these women are uncertain. Animal studies have shown that high-dose bisphosphonates caused microdamage accumulation and abnormal material properties of the bone. The breast cancer study provides an exceptional opportunity to evaluate bisphosphonate-induced changes in bone quality and bone physiology in humans. The hypothesis is that high-dose bisphosphonate therapy will result in profound depression of bone resorption and formation, increased mineralization density and decreased intrinsic toughness of the bone. For this proposal, a subset of 90 premenopausal women will undergo tetracycline-labeled iliac crest bone biopsies, bone density measurements by dual x ray absorptimetry and serum biochemical markers of bone turnover before and after bisphosphonate treatment. The bone will be measured with micro-computed tomography for structural parameters including connectivity, bone volume, and cortical thickness. Biomechanical testing in compression will determine the stiffness (Young's modulus), yield point, toughness and strength. Histomorphometric measurements of bone surfaces will allow calculations of bone formation rates and activation frequency. Mineralization density will be measured using backscattered electron imaging. A subset of 27 women will undergo kinetic analysis of fluoride deposition in bone by 18-Fluoride PET scans. Results of the study will provide valuable information about skeletal effects of high-dose bisphosphonates in humans.
