Bone resorption and formation occur in a tightly regulated fashion reflecting the coupled activities of osteoclasts and osteoblasts. Several pathological conditions perturb this balance, including osteoporosis and skeletal metastases. In the case of metastases, the uncoupling of resorption and formation activities contributes to disseminated tumor cells homing to the bone and to tumor growth within the bone in highly localized regions. Therefore, a site-specific marker of bone remodeling is required to provide a reliable assessment of skeletal disease severity, to evaluate the efficacy of anti-resorptive interventions and to distinguish benign from malignant tumors. The purpose of this study was to determine if the fluorescent bisphosphonate imaging probe Osteosense could model changes in bone metabolism. Evaluation of the kinetic uptake of bisphosphonates in ovariectomized mice revealed significant changes in binding rate constants, as well as the binding plateau of bone. Binding kinetics also revealed differential binding kinetics of bisphosphonate to the knee and spine regions and was able to monitor the individuals regions bone loss resulting from ovariectomy. The utility of binding kinetics was further confirmed in a bone-gain model in which ovariectomized mice were treated intermittently with parathyroid hormone (PTH). Kinetic analysis revealed a significant increase in binding rate constant of fluorescent bisphosphonate in mice treated with PTH as compared to control mice. Localization of bisphosphonate binding at early and late time points after injection revealed initial binding adjacent to the growth plate, associated with high levels of osteoblast and osteoclast activity, and later throughout the bone at regions undergoing bone remodeling. Measurements of the soft tissue region, which show strong correlation to serum level bisphosphonates, were also used to generate KBone values with results consistent with those stated above. Kinetic modeling was also applied to mice with lytic bone tumor. Analysis revealed a strong correlation between kinetic binding capacity and the size of the tumor as assessed by bioluminescence. Our data suggests a highly sensitive method for monitoring changes in bone metabolism using the binding kinetics of fluorescent bisphosphonates and may serve as a useful tool to monitor pharmacological intervention and tumor progression.
17 May 2014 - 20 May 2014