Ochi Yasuo, Yamada Hiroyuki, Mori Hiroshi, Kawada Naoki, Tanaka Makoto, Imagawa Akira, Ohmoto Kazuyuki, Kawabata Kazuhito
Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan.
J Bone Miner Metab. 2016 Jan;34(1):33-40. doi: 10.1007/s00774-014-0643-1. Epub 2015 Mar 12.
This study examined the effects of a novel cathepsin K inhibitor, ONO-KK1-300-01 (KK1-300), used concurrently with parathyroid hormone (PTH) in ovariectomized (OVX) rats. KK1-300 (3 mg/kg, twice daily), alendronate (1 mg/kg, once daily) or vehicle were orally administered to OVX rats for 56 days, starting the day after ovariectomy, followed by combination treatment with or without PTH (3 μg/kg, subcutaneously three times a week) for another 28 days. OVX control animals exhibited a significant increase in both bone resorption (urinary deoxypyridinoline; DPD) and formation markers (serum osteocalcin) as well as microstructural changes associated with decreased bone mineral density (BMD). Combination treatment with KK1-300 and PTH significantly decreased urinary DPD and increased serum osteocalcin, indicating a sustained beneficial effect compared to the effect of each mono-therapy. On the other hand, combination therapy with alendronate and PTH weakened the PTH-induced increase in osteocalcin. In proximal tibia, combination treatment with KK1-300 and PTH increased BMD to a level significantly higher than that achieved following single treatment with KK1-300 or PTH alone. On the other hand, combination treatment with alendronate and PTH failed to produce any significant additive effect on BMD following single treatment with alendronate or PTH alone. Microstructural analysis revealed that the PTH-induced increase in bone formation (MS/BS and BFR/BS) was fully maintained following combination treatment with KK1-300 and PTH, but not following combination treatment with alendronate and PTH. These findings indicate that KK1-300, unlike alendronate, has an additive effect on the preventive action of PTH on bone loss in OVX rats.
本研究考察了新型组织蛋白酶K抑制剂ONO-KK1-300-01（KK1-300）与甲状旁腺激素（PTH）同时用于去卵巢（OVX）大鼠时的作用。在大鼠卵巢切除术后次日开始，对OVX大鼠口服给予KK1-300（3mg/kg，每日两次）、阿仑膦酸钠（1mg/kg，每日一次）或赋形剂，持续56天，随后再联合给予或不给予PTH（3μg/kg，皮下注射，每周三次）治疗28天。OVX对照动物的骨吸收（尿脱氧吡啶啉；DPD）和形成标志物（血清骨钙素）均显著增加，同时伴有与骨矿物质密度（BMD）降低相关的微观结构变化。KK1-300与PTH联合治疗显著降低了尿DPD并增加了血清骨钙素，表明与各单一疗法相比具有持续的有益作用。另一方面，阿仑膦酸钠与PTH联合治疗减弱了PTH诱导的骨钙素增加。在胫骨近端，KK1-300与PTH联合治疗使BMD增加至显著高于单独使用KK1-300或PTH单一治疗所达到的水平。另一方面，阿仑膦酸钠与PTH联合治疗在单独使用阿仑膦酸钠或PTH单一治疗后，对BMD未产生任何显著的相加作用。微观结构分析显示，KK1-300与PTH联合治疗后，PTH诱导的骨形成增加（骨小梁面积分数/骨组织面积；骨形成率/骨组织面积）得以充分维持，但阿仑膦酸钠与PTH联合治疗后则未维持。这些发现表明，与阿仑膦酸钠不同，KK1-300对PTH预防OVX大鼠骨质流失的作用具有相加效应。
