Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States.
Department of Medicine - Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States.
Bone. 2019 Oct;127:419-426. doi: 10.1016/j.bone.2019.07.007. Epub 2019 Jul 9.
Chronic kidney disease (CKD) results in a dramatic increase in skeletal fracture risk. Bisphosphates (BP) are an effective treatment for reducing fracture risk but they are not recommended in advanced CKD. We have recently shown higher acute skeletal accumulation of fluorescently-tagged zoledronate (ZOL) in the setting of CKD but how this accumulation is retained/lost over time is unclear. Furthermore, it is unknown if alternative dosing approaches can modulate accumulation in the setting of CKD.
To address these two questions normal (NL) and Cy/+ (CKD) rats were divided into control groups (no dosing), a single dose of a fluorescent-tagged ZOL (FAM-ZOL), a single dose of non-labelled zoledronate (ZOL) or ten weekly doses of FAM-ZOL each at 1/10th the dose of the single dose group. Half of the CKD animals in each group were provided water with 3% calcium in drinking water (CKD + Ca) to suppress PTH and remodeling. At 30 or 35 weeks of age, serum, tibia, ulna, radius, vertebra, femora, and mandible were collected and subjected to assessment methods including biochemistry, dynamic histomorphometry and multi-spectral fluorescence levels (using IVIS SpectrumCT).
FAM-ZOL did not significantly reduce bone remodeling in either NL or CKD animals while Ca supplementation in CKD produced remodeling levels comparable to NL. At five- and ten-weeks post-dosing, both CKD and CKD + Ca groups had higher levels of FAM-ZOL in most, but not all, skeletal sites compared to NL with no difference between the two CKD groups suggesting that the rate of remodeling did not affect skeletal retention of FAM-ZOL. Fractionating the FAM-ZOL into ten weekly doses led to 20-32% less (p < 0.05) accumulation/retention of compound in the vertebra, radius, and ulna compared to administration as a single dose.
The rate of bone turnover does not have significant effects on levels of FAM-ZOL accumulation/retention in animals with CKD. A lower dose/more frequent administration paradigm results in lower levels of accumulation/retention over time. These data provide information that could better inform the use of bisphosphonates in the setting of CKD in order to combat the dramatic increase in fracture risk.
慢性肾病（CKD）会导致骨骼骨折风险显著增加。双膦酸盐（BP）是降低骨折风险的有效治疗方法，但不建议在 CKD 晚期使用。我们最近发现，在 CKD 环境下，荧光标记的唑来膦酸（ZOL）的急性骨骼积累更高，但这种积累随时间如何保留/丢失尚不清楚。此外，尚不清楚替代剂量方法是否可以调节 CKD 环境中的积累。
为了解决这两个问题，正常（NL）和 Cy/+（CKD）大鼠被分为对照组（不给予剂量）、单次给予荧光标记的 ZOL（FAM-ZOL）、单次给予非标记的唑来膦酸（ZOL）或每周给予 10 次 FAM-ZOL，剂量为单次剂量组的 1/10。每组一半的 CKD 动物给予含 3%钙的饮用水（CKD+Ca）以抑制 PTH 和重塑。在 30 或 35 周龄时，收集血清、胫骨、尺骨、桡骨、椎骨、股骨和下颌骨，并进行包括生化、动态组织形态计量学和多光谱荧光水平（使用 IVIS SpectrumCT）在内的评估方法。
FAM-ZOL 并未显著减少 NL 或 CKD 动物的骨重塑，而 CKD 中的 Ca 补充产生了与 NL 相当的重塑水平。在给药后 5 周和 10 周，与 NL 相比，两组 CKD 和 CKD+Ca 动物的大多数（但不是全部）骨骼部位的 FAM-ZOL 水平更高，两组 CKD 之间没有差异，表明骨重塑率对 FAM-ZOL 的骨骼保留没有影响。将 FAM-ZOL 分为每周 10 次剂量，与单次给药相比，在椎骨、桡骨和尺骨中的化合物累积/保留量减少 20-32%（p<0.05）。
在 CKD 动物中，骨转换率对 FAM-ZOL 积累/保留水平没有显著影响。较低的剂量/更频繁的给药方案会导致随时间推移积累/保留水平降低。这些数据提供了信息，可以更好地指导 CKD 环境中双膦酸盐的使用，以对抗骨折风险的显著增加。
