title: Binding kinetics of a fluorescently labeled bisphosphonate as a tool for dynamic monitoring of bone mineral deposition in vivo.
abstract: Bone mineral deposition during the modeling of new bone and remodeling of old bone can be perturbed by several pathological conditions, including osteoporosis and skeletal metastases. A site-specific marker depicting the dynamics of bone mineral deposition would provide insight into skeletal disease location and severity, and prove useful in evaluating the efficacy of pharmacological interventions. Fluorescent labels may combine advantages of both radioisotope imaging and detailed microscopic analyses. The purpose of this study was to determine if the fluorescent bisphosphonate OsteoSense could detect localized changes in bone mineral deposition in established mouse models of accelerated bone loss (ovariectomy) (OVX) and anabolic bone gain resulting from parathyroid hormone (PTH) treatment. We hypothesized that the early rate of binding, as well as the total amount of bisphosphonate, which binds over long periods of time, could be useful in evaluating changes in bone metabolism. Evaluation of the kinetic uptake of bisphosphonates revealed a significant reduction in both the rate constant and plateau binding after OVX, whereas treatment with PTH resulted in a 36-fold increase in the bisphosphonate binding rate constant compared with untreated OVX controls. Localization of bisphosphonate binding revealed initial binding at sites of ossification adjacent to the growth plate and, to a lesser extent, along more distal trabecular and cortical elements. Micro-computed tomography (CT) was used to confirm that initial bisphosphonate binding is localized to sites of low tissue mineral density, associated with new bone mineral deposition. Our results suggest monitoring binding kinetics based on fluorescently labeled bisphosphonates represents a highly sensitive, site-specific method for monitoring changes in bone mineral deposition with the potential for translation into human applications in osteoporosis and bone metastatic processes and their treatment.
authors.affiliation: Section Biomedical Imaging, Department of Diagnostic Radiology, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Tower
authors.forename: Graeme M
authors.initials: GM
authors.lastname: Campbell
authors.forename: Marc
authors.initials: M
authors.lastname: Müller
authors.forename: Olga
authors.initials: O
authors.lastname: Will
authors.forename: Claus C
authors.initials: CC
authors.lastname: Glüer
authors.forename: Sanjay
authors.initials: S
authors.lastname: Tiwari
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000378:metabolism*; D004164:Diphosphonates / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008819:Mice, Nude; D008903:Minerals / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D013194:Staining and Labeling / Q000379:methods*
chemical_list: D004164:Diphosphonates; D005456:Fluorescent Dyes; D008903:Minerals
keywords: BISPHOSPHONATES; BONE MINERALIZATION; BONE TURNOVER; MOLECULAR IMAGING; OSTEOPOROSIS