Cathepsin K inhibition preserves compressive load in lumbar vertebrae of osteoporotic monkeys

Isabel D Colón-Bernal,Le T Duong,Brenda Pennypacker,James Henderson,Kenneth M Kozloff,Mark M Banaszak Holl

doi:10.1016/j.bonr.2018.10.001

Abstract

Anti-resorptive drugs treat bone loss by blocking osteoclast activity through a variety of mechanisms of action. Once significant bone loss has occurred, the ability to restore biomechanical function may differ based on the drug chosen. To assess this question, bisphosphonate (alendronate, ALN) and cathepsin K inhibitor (MK-0674, CatKi) were employed in treatment mode to compare the relative changes to cancellous bone microstructure and mechanical properties in ovariectomized (OVX) cynomolgus monkeys. Lumbar vertebrae (LV) bone mineral density (BMD) values taken two years post-surgery prior to drug treatment show a 10–15% decrease (p < 0.05) for all OVX animals. OVX animals were then treated with vehicle (VEH), ALN (0.03 mg/kg weekly), or CatKi MK-0674 (0.6 or 2.5 mg/kg daily, CatKi-L and H respectively) for two years and compared to a control Sham surgery group. Ex-vivo microcomputed tomography (μCT) of LV2 and compression testing of LV4–6 were used to measure cancellous bone microstructure and changes in bone mechanics, respectively. After two years of treatment, ALN-treated animals showed no significant difference in μCT or biomechanical parameters when compared to Veh. However, treatment with CatKi-H resulted in a 30% increase in yield and peak loads, and apparent peak and yield stress as compared to Veh (p < 0.05) and gave average mechanical values greater than the Sham sample. Treatment with CatKi-L exhibited a similar trend of increase to CatKi-H (p < 0.08). Intriguingly, these changes were realized despite no significant differences in mean values of trabecular bone morphologic parameters. Together these data suggest matrix-level changes in bone composition that are unique to the CatK inhibition mechanism, resulting in the preservation of bone compressive load with treatment.

Highlights

Osteoporosis is characterized by a net bone loss due to an increase in bone resorption (Chen and Sambrook, 2011)
Two years after initial surgery, but prior to drug treatment, all experimental groups demonstrated similar loss (10–15%) of bone mineral density (BMD) at Lumbar vertebrae (LV) when compared to Sham-operated controls (Table 1 and Fig. 1) with no difference between individual groups, indicating a well-balanced study allocation
Bone loss was consistent with previous work demonstrating an 11% decrease in BMD for OVX animals vs. sham controls over 21 months (Masarachia et al, 2012)

Summary

Introduction

Osteoporosis is characterized by a net bone loss due to an increase in bone resorption (Chen and Sambrook, 2011). Despite the effectiveness of ALN, serious but rare associated adverse effects can occur such as atypical fractures, atrial fibrillation, and osteonecrosis of the jaw (Jha et al, 2015; Jan et al, 2012; Drake et al, 2008; Kim et al, 2016) While these associated adverse effects are extremely rare and occur more commonly when bisphosphonates are used to treat cancer instead of osteoporosis, statements released by the Food and Drug Administration have raised concern regarding bisphosphonate use (Kim et al, 2016). New drugs, as well as a better understanding of antiresorptive mechanisms, are desired

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Conclusion