Zebaze Roger, Takao-Kawabata Ryoko, Peng Yu, Zadeh Ali Ghasem, Hirano Kyoko, Yamane Hiroshi, Takakura Aya, Isogai Yukihiro, Ishizuya Toshinori, Seeman Ego
Dept Endocrinology and Medicine, Austin Health, University of Melbourne, Melbourne, Australia; StraxCorp PTY LTD, Melbourne, Australia.
Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Tokyo, Japan.
Bone. 2017 Jun;99:80-84. doi: 10.1016/j.bone.2017.03.042. Epub 2017 Mar 18.
The pharmacokinetic profile of parathyroid hormone (PTH) determines its effects on bone resorption and formation. When administered intermittently, anabolic effects are favored in comparison with the continuous treatment. Among the intermittent treatment regimens, lower frequency of administration may have a lower effect on bone remodeling. We therefore hypothesized that weekly administration of teriparatide will produce less increase in intracortical remodeling and porosity than reported using daily treatment.
We treated 17 female New Zealand white rabbits aged 6months for 1month with teriparatide [human PTH(1-34)] as follows. (i) Vehicle-treated Control (n=4); (ii) 20μg/kg daily (n=3); (iii) 40μg/kg daily (n=3); (iv) 140μg/kg weekly (n=3); (v) 280μg/kg weekly (n=4). Proximal femurs were imaged ex vivo using micro-CT (Scanco Viva CT-40) at 15μmvoxel size. Areas, pore size, and porosity were analyzed on the total, compact cortex (CC), and transitional zones in a 10mm length region of interest (ROI) starting at the midshaft using StrAx1.0.
Compared to controls, the 20μg/kg daily was associated with 3.0% higher porosity in the transitional zone (p=0.09) while the 40μg/kg daily was associated with a higher porosity in the cortex (8.7%; p=0.04) and in the transitional zone (5.7%; p=0.007). The daily regimens were also associated with a greater proportion of porosity due to pores >15μm; particularly in the transitional zone where 20 and 40μg/kg daily increased porosity 2 fold (p=0.06) and 5 fold (p=0.04) relative controls respectively. The 140 and 280μg/kg weekly were not associated with an increase in porosity. There was no difference in total, compact or transitional zone cross sectional areas between the groups.
Effects of intermittent teriparatide depend on the dose and frequency of administration. Daily dosing, particularly the higher dose, but not weekly dosing, increased cortical porosity. Work is needed to investigate the effects of the regimens on bone formation.
甲状旁腺激素（PTH）的药代动力学特征决定了其对骨吸收和形成的影响。间歇性给药时，与持续治疗相比，更有利于产生合成代谢效应。在间歇性治疗方案中，较低的给药频率可能对骨重塑的影响较小。因此，我们假设与每日给药相比，每周一次给予特立帕肽将使皮质内重塑和孔隙率的增加更少。
我们用特立帕肽[人PTH(1-34)]对17只6个月大的雌性新西兰白兔进行了为期1个月的治疗，具体如下。（i）赋形剂处理的对照组（n = 4）；（ii）每日20μg/kg（n = 3）；（iii）每日40μg/kg（n = 3）；（iv）每周140μg/kg（n = 3）；（v）每周280μg/kg（n = 4）。使用微CT（Scanco Viva CT - 40）以15μm体素大小对离体近端股骨进行成像。使用StrAx1.0在从骨干中部开始的10mm长度的感兴趣区域（ROI）内，对总面积、孔径和孔隙率在总体、致密皮质（CC）和过渡区进行分析。
与对照组相比，每日20μg/kg组在过渡区的孔隙率高3.0%（p = 0.09），而每日40μg/kg组在皮质（8.7%；p = 0.04）和过渡区（5.7%；p = 0.007）的孔隙率更高。每日给药方案还与孔径>15μm导致的更大比例的孔隙率相关；特别是在过渡区，每日20μg/kg和40μg/kg组的孔隙率相对于对照组分别增加了2倍（p = 0.06）和5倍（p = 0.04）。每周140μg/kg和280μg/kg组与孔隙率增加无关。各组之间在总体、致密或过渡区的横截面积没有差异。
间歇性特立帕肽的作用取决于给药剂量和频率。每日给药，尤其是较高剂量，但不是每周给药，会增加皮质孔隙率。需要开展研究来调查这些给药方案对骨形成的影响。
