Influence of Bone Affinity on the Skeletal Distribution of Fluorescently Labeled Bisphosphonates In Vivo
Influence of Bone Affinity on the Skeletal Distribution of Fluorescently Labeled Bisphosphonates In Vivo
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DOI：
10.1002/jbmr.1543
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发表时间：
2012-04-01
影响因子：
6.2
通讯作者：
Coxon, Fraser P.
中科院分区：
文献类型：
--
作者：
Roelofs, Anke J.;Stewart, Charlotte A.;Coxon, Fraser P.
双膦酸盐是广泛使用的与钙结合的抗吸收药物。很明显，这些药物对骨矿物质具有不同的亲和力;然而，尚不清楚这些差异是否会影响它们在矿物质表面的分布。在这项研究中，利塞膦酸钠，其低亲和力类似物脱氧利塞膦酸钠和3-PEHPC的荧光共轭物，被用来比较本地化的化合物在体内具有不同的矿物质亲和力。结合到牙本质在体外证实了化合物之间的矿物质结合的差异，这主要是由母体化合物的特性，但也通过选择荧光标记的影响。在生长期大鼠中，给药后1天，所有化合物优先结合形成皮质骨内，而不是吸收皮质骨中的骨膜表面。在再吸收表面，低亲和力的化合物表现出优先结合再吸收陷窝，而最高亲和力的化合物表现出更均匀的标记。在形成表面，渗透到矿化类骨质被发现与矿物质亲和力呈负相关。在静止表面未观察到再吸收和成形表面分布的这些差异。低亲和力的化合物也表现出相对较高程度的骨细胞腔隙壁的标记和标记的骨皮质内更深的腔隙，表明骨细胞小管网络的渗透增加。在矿化表面和骨细胞网络渗透之间的高和低亲和力的化合物的相似的差异是明显的7天后给药，与荧光共轭物在形成表面埋在一个新的骨层。荧光化合物被掺入这些新形成的骨骼区域，表明循环已经发生，尽管水平很低。综上所述，这些发现表明双膦酸盐的骨矿物质亲和力可能会影响其在骨骼中的分布。(c)2012年美国骨与矿物质研究学会。
Bisphosphonates are widely used antiresorptive drugs that bind to calcium. It has become evident that these drugs have differing affinities for bone mineral; however, it is unclear whether such differences affect their distribution on mineral surfaces. In this study, fluorescent conjugates of risedronate, and its lower-affinity analogues deoxy-risedronate and 3-PEHPC, were used to compare the localization of compounds with differing mineral affinities in vivo. Binding to dentine in vitro confirmed differences in mineral binding between compounds, which was influenced predominantly by the characteristics of the parent compound but also by the choice of fluorescent tag. In growing rats, all compounds preferentially bound to forming endocortical as opposed to resorbing periosteal surfaces in cortical bone, 1 day after administration. At resorbing surfaces, lower-affinity compounds showed preferential binding to resorption lacunae, whereas the highest-affinity compound showed more uniform labeling. At forming surfaces, penetration into the mineralizing osteoid was found to inversely correlate with mineral affinity. These differences in distribution at resorbing and forming surfaces were not observed at quiescent surfaces. Lower-affinity compounds also showed a relatively higher degree of labeling of osteocyte lacunar walls and labeled lacunae deeper within cortical bone, indicating increased penetration of the osteocyte canalicular network. Similar differences in mineralizing surface and osteocyte network penetration between high- and low-affinity compounds were evident 7 days after administration, with fluorescent conjugates at forming surfaces buried under a new layer of bone. Fluorescent compounds were incorporated into these areas of newly formed bone, indicating that recycling had occurred, albeit at very low levels. Taken together, these findings indicate that the bone mineral affinity of bisphosphonates is likely to influence their distribution within the skeleton. (c) 2012 American Society for Bone and Mineral Research.