TY - JOUR
T1 - Cathepsin K inhibition preserves compressive load in lumbar vertebrae of osteoporotic monkeys
AU - Colón-Bernal, Isabel D.
AU - Duong, Le T.
AU - Pennypacker, Brenda
AU - Henderson, James
AU - Kozloff, Kenneth M.
AU - Banaszak Holl, Mark M.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
KW - Alendronate
KW - Cathepsin-k
KW - Micro computed tomography
KW - Osteoporosis
UR - http://www.scopus.com/inward/record.url?scp=85055675763&partnerID=8YFLogxK
U2 - 10.1016/j.bonr.2018.10.001
DO - 10.1016/j.bonr.2018.10.001
M3 - Article
C2 - 30406161
AN - SCOPUS:85055675763
SN - 2352-1872
VL - 9
SP - 159
EP - 164
JO - Bone Reports
JF - Bone Reports
ER -