Endocrinol Metab > Volume 26(4); 2011 > Article
Endocrinology and Metabolism 2011;26(4):303-309.
DOI: https://doi.org/10.3803/EnM.2011.26.4.303    Published online December 1, 2011.
The Effects of Combination Therapy of Cathepsin K Inhibitor and PTH on Change in Bone Mineral Density in an Animal Model of Osteoporosis.
Seung Hun Lee, Jung Min Koh, Young Sun Lee, Beom Jun Kim, Je Yong Choi, Ghi Su Kim
1Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. jmkoh@amc.seoul.kr
2Asan Institute for Life Sciences, Seoul, Korea.
3Department of Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Korea.
We hypothesized that combination therapy of cathepsin K inhibitor (CTKi) and human parathyroid hormone (1-34) (teriparatide, PTH) would overcome the coupling phenomenon of bone resorption and formation and thus may rapidly increase bone mass. METHODS: We selected a dose of zoledronic acid (ZA) that had shown similar effects with CTKi on body bone mineral density (BMD) change during the preliminary experiment. Female mice were subjected to ovariectomized (OVX control) or a sham operation (SHAM group). The mice were treated with CTKi (CTKi group), ZA (ZA group), PTH (PTH group) or with a combination of PTH with ZA (ZA + PTH group) or CTKi (CTKi + PTH group) for 8 weeks. Total BMD was measured before the operation and at 4 and 8 weeks. RESULTS: In the preliminary results, 10 microg/kg of ZA showed similar BMD changes with CTKi. Compared with the OVX control, BMD in the SHAM, ZA, CTKi, PTH, ZA + PTH, and CTKi + PTH groups was significantly increased after treatment. BMD in the CTKi + PTH group, but not in the ZA + PTH group increased more significantly than in the PTH group at the end of treatment. Compared with the OVX control, changes in BMD in the SHAM, ZA, CTKi, PTH, ZA + PTH, and CTKi + PTH groups increased significantly after 8 weeks of treatment. The change in BMD in the CTKi + PTH group, but not in the ZA + PTH group was more significantly increased than the change in BMD in the PTH group. CONCLUSION: When combined with PTH, CTKi augmented the anabolic action of PTH. Therefore, combination therapy with CTKi and PTH might be a new therapeutic modality capable of overcoming the coupling phenomenon, thereby markedly and rapidly increasing bone mass.
Key Words: Bisphosphonate, Cathepsin K inhibitor, Combination therapy, Coupling phenomenon, Parathyroid hormone

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