Utilizing time-lapse micro-CT-correlated bisphosphonate binding kinetics and soft tissue-derived input functions to differentiate site-specific changes in bone metabolism in vivo

Abstract

The turnover of bone is a tightly regulated process between bone formation and resorption to ensure skeletal homeostasis. This process differs between bone types, with trabecular bone often associated with higher turnover than cortical bone. Analyses of bone by micro-computed tomography (micro-CT) reveal changes in structure and mineral content, but are limited in the study of metabolic activity at a single time point, while analyses of serum markers can reveal changes in bone metabolism, but cannot delineate the origin of any aberrant findings. To obtain a site-specific assessment of bone metabolic status, bisphosphonate binding kinetics were utilized. Using a fluorescently-labeled bisphosphonate, we show that early binding kinetics monitored in vivo using fluorescent molecular tomography (FMT) can monitor changes in bone metabolism in response to bone loss, stimulated by ovariectomy (OVX), or bone gain, resulting from treatment with the anabolic bone agent parathyroid hormone (PTH), and is capable of distinguishing different, metabolically distinct skeletal sites. Using time-lapse micro-CT, longitudinal bone turnover was quantified. The spine showed a significantly greater percent resorbing volume and surface in response to OVX, while mice treated with PTH showed significantly greater resorbing volume per bone surface in the spine and significantly greater forming surfaces in the knee. Correlation studies between binding kinetics and micro-CT suggest that forming surfaces, as assessed by time-lapse micro-CT, are preferentially reflected in the rate constant values while forming and resorbing bone volumes primarily affect plateau values. Additionally, we developed a blood pool correction method which now allows for quantitative multi-compartment analyses to be conducted using FMT. These results further expand our understanding of bisphosphonate binding and the use of bisphosphonate binding kinetics as a tool to monitor site-specific changes in bone metabolism in vivo.

In vitro and in vivo toxicity of 5-FdU-alendronate, a novel cytotoxic bone-seeking duplex drug against bone metastasis

“…The bone-targeting delivery could then result in a local enrichment of the duplex drug in the skeleton due to its high affinity of the BP residue for the hydroxylapaptite of bone [14]. It has also been recently shown that bisphosphonates preferentially localize to regions of high bone turnover, suggesting bisphosphonate duplex drugs may preferentially enrich to the metabolically active tumorburdened regions of the skeleton [24]. It is well known that the P-C-P function of BPs is the prerequisite for the bonetargeting activity, whereby the intensity of the antiosteoclastic activity and the cytotoxic potential is exclusively dependent upon the side chain [25].…”

Knee loading protects against osteonecrosis of the femoral head by enhancing vessel remodeling and bone healing

“…We would determine the effect of knee loading to collateral circulation around the femoral head in the further study. In bone homeostasis, balance between bone formation by osteoblasts and bone resorption by osteoclasts is required [46]. We conducted in vitro assays and evaluated the role of knee loading in the fate of bone marrow-derived cells.…”

Different bone remodeling levels of trabecular and cortical bone in response to changes in Wnt/β‐catenin signaling in mice

“…In addition, cortical bone and trabecular bone show different metabolic behaviors in many physiological and pathological processes, such as glycation, pharmacokinetics, and their response to diet and implant insertion . The difference in metabolic activity is best demonstrated by their different remodeling process, which has significant clinical relevance for the treatment of osteoporosis . Trabeculae, as thin plates, have a low matrix volume and a large surface area; therefore, signals within the matrix can readily traverse the matrix volume to locate a surface to initiate trabecular remodeling.…”

“…Trabeculae, as thin plates, have a low matrix volume and a large surface area; therefore, signals within the matrix can readily traverse the matrix volume to locate a surface to initiate trabecular remodeling. By contrast, cortical bone has a large matrix volume and a small surface area; therefore, signals deep within the matrix may not locate a surface as readily to initiate remodeling, allowing for the accumulation of microdamage, particularly in interstitial bone that is less remodeled . Furthermore, different mechanoresponsiveness levels in cortical and trabecular bone lead to different bone formation abilities in response to the mechanical load on the bone .…”