Endocrinol Metab.  2011 Dec;26(4):303-309. 10.3803/EnM.2011.26.4.303.

The Effects of Combination Therapy of Cathepsin K Inhibitor and PTH on Change in Bone Mineral Density in an Animal Model of Osteoporosis

• Lee SH
• Koh JM
• Lee YS
• Kim BJ
• Choi JY
• Kim GS

• KMID: 2169260
• DOI: http://doi.org/10.3803/EnM.2011.26.4.303

Abstract

BACKGROUND
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.

Keyword

Bisphosphonate; Cathepsin K inhibitor; Combination therapy; Coupling phenomenon; Parathyroid hormone

MeSH Terms

Animals
Bone Density
Bone Resorption
Cathepsin K
Cathepsins
Diphosphonates
Female
Humans
Imidazoles
Mice
Models, Animal
Osteoporosis
Parathyroid Hormone
Salicylamides
Teriparatide
Cathepsin K
Cathepsins
Diphosphonates
Imidazoles
Parathyroid Hormone
Salicylamides
Teriparatide

Figure

• 

  Fig. 1 Inhibition of human cathepsin K activity by OST-4077.

• 

  Fig. 2 Change of whole body bone mineral density (BMD) during the preliminary experiment. *P < 0.05 vs. CTKi group. SHAM, sham-operated mice; OVX, ovariectomized mice; CTKi, ovariectomized mice orally administered with OST-4077 100 mg/kg twice a day; ZA10 and ZA20, ovariectomized mice intraperitoneally injected with zoledronic acid 10, 20 µg/kg once; ZA10 + PTH10 and ZA10 + PTH20, ovariectomized mice intraperitoneally injected with zoledronic acid 10 µg/kg once and subcutaneously injected with teriparatide 10, 20 µg/kg daily; ZA20 + PTH10 and ZA20 + PTH20, ovariectomized mice intraperitoneally injected with zoledronic acid 20 µg/kg once and subcutaneously injected with teriparatide 10, 20 µg/kg daily. CTKi, cathepsin K inhibitor; OVX, ovariectomized; PTH, parathyroid hormone; ZA, zoledronic acid.

• 

  Fig. 3 Body weight before starting treatments and at the end of treatments during the main experiment (n = 8 in each group). *P < 0.05. †P < 0.10 vs. OVX control group. SHAM, sham-operated mice; OVX, ovariectomized mice; ZA, ovariectomized mice intraperitoneally injected with zoledronic acid 10 µg/kg once; CTKi, ovariectomized mice orally administered with OST-4077 100 mg/kg twice a day; PTH, ovariectomized mice subcutaneously injected with teriparatide 10 µg/kg daily; ZA + PTH, ovariectomized mice intraperitoneally injected with zoledronic acid 10 µg/kg once and subcutaneously injected with teriparatide 10 µg/kg daily; CTKi + PTH; ovariectomized mice orally administered with OST-4077 100 mg/kg twice a day and subcutaneously injected with teriparatide 10 µg/kg daily. BMD, bone mineral density; CTKi, cathepsin K inhibitor; OVX, ovariectomized; PTH, parathyroid hormone; ZA, zoledronic acid.

• 

  Fig. 4 Whole body bone mineral density (BMD) before starting treatments and at the end of treatments during the main experiment (n = 8 in each group). *P < 0.05 vs. OVX control group. †P < 0.05 vs. PTH group. SHAM, sham-operated mice; OVX, ovariectomized mice; ZA, ovariectomized mice intraperitoneally injected with zoledronic acid 10 µg/kg once; CTKi, ovariectomized mice orally administered with OST-4077 100 mg/kg twice a day; PTH, ovariectomized mice subcutaneously injected with teriparatide 10 µg/kg daily; ZA + PTH, ovariectomized mice intraperitoneally injected with zoledronic acid 10 µg/kg once and subcutaneously injected with teriparatide 10 µg/kg daily; CTKi + PTH; ovariectomized mice orally administered with OST-4077 100 mg/kg twice a day and subcutaneously injected with teriparatide 10 µg/kg daily. CTKi, cathepsin K inhibitor; NS, not significant; OVX, ovariectomized; PTH, parathyroid hormone; ZA, zoledronic acid.

• 

  Fig. 5 Change of whole body bone mineral density (BMD) before starting treatments and at the end of treatments during the main experiment (n = 8 in each group). *P < 0.05 vs. OVX control group. †P < 0.05 vs. PTH group. SHAM, sham-operated mice; OVX, ovariectomized mice; ZA, ovariectomized mice intraperitoneally injected with zoledronic acid 10 µg/kg once; CTKi, ovariectomized mice orally administered with OST-4077 100 mg/kg twice a day; PTH, ovariectomized mice subcutaneously injected with teriparatide 10 µg/kg daily; ZA + PTH, ovariectomized mice intraperitoneally injected with zoledronic acid 10 ug/kg once and subcutaneously injected with teriparatide 10 ug/kg daily; CTKi + PTH; ovariectomized mice orally administered with OST-4077 100 mg/kg twice a day and subcutaneously injected with teriparatide 10 µg/kg daily. CTKi, cathepsin K inhibitor; OVX, ovariectomized; PTH, parathyroid hormone; ZA, zoledronic acid.

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