The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis.

BACKGROUND: MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA). METHODS: Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 µmol/kg and (4) ACLT + MIV-711, 100 µmol/kg. Subchondral bone and articular cartilage structures were assessed by µCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 µmol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured. RESULTS: In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p < 0.001) and CTX-II levels by up to 74% (p < 0.001) compared to ACLT vehicle controls. ACLT surgery significantly reduced the total thickness of the subchondral bone plate and reduced trabecular bone volume in the femur and tibia. These effects were reversed by MIV-711. ACLT resulted in cartilage thickening, which was attenuated by MIV-711. MIV-711 did not affect osteophyte formation or Mankin scores. In dogs, MIV-711 reduced CTX-I and CTX-II levels by 86% (p < 0.001) and 80% (p < 0.001), respectively. Synovial CTX-II levels were reduced by 55-57% (p < 0.001) compared to baseline. MIV-711-treated animals had 25-37% lower macroscopic scores in the femur condyles and 13-33% lower macroscopic scores in the tibial plateaus. CONCLUSIONS: MIV-711 prevents subchondral bone loss and partially attenuates cartilage pathology in two animal models of OA. These beneficial effects of MIV-711 on joint pathology are observed in conjunction with decreases in bone and cartilage biomarkers that have been shown to be clinically attainable in human. The data support the further development of MIV-711 for the treatment of OA.

Microdamage accumulation in the monkey vertebra does not occur when bone turnover is suppressed by 50% or less with estrogen or raloxifene.

Long-term suppression of bone turnover with alendronate has previously been shown to increase the degree of mineralization and accumulation of microdamage in animal bones. In an effort to ascertain if other suppressors of bone resorption can also affect mineralization and microdamage accumulation, we evaluated bones from cynomolgus macaques treated with raloxifene or conjugated equine estrogens (CEE). Cynomolgus monkeys (Macaca fascicularis) were randomized, ovariectomized (except for Sham controls), and orally treated each day for 2 years with vehicle (Sham and Ovx controls), 1 mg/kg raloxifene (R1), 5 mg/kg raloxifene (R5), or 0.04 mg/kg CEE. The functional quality of the mineralized matrix was analyzed postnecropsy by biomechanical testing, histomorphometry, biochemistry, and nanoindentation. Failure testing of the whole vertebra showed no significant differences in vertebral strength among groups. Similarly, failure testing of a beam of pure bone that was machined from the femoral diaphysis also showed no differences in material strength (ultimate stress) between groups. Histomorphometry of the L2 centrum showed that Ovx tended to increase activation frequency relative to Sham controls. Estrogen (CEE) treatment for 2 years at about four times the clinical exposure tended to reduce activation frequency (Ac.f) by 41% compared to Ovx. Treatment with raloxifene at either approximately the clinical dose or five times higher nonsignificantly lowered Ac.f by 34% and 23%, respectively, relative to Ovx. Raloxifene had similar effects on serum osteocalcin, a biochemical measure of systemic bone turnover. Analysis of microcrack surface density in the cancellous bone of L3 showed a 40% reduction for Ovx relative to Sham. CEE microcrack surface density was not different than Sham whereas the R5 crack density was significantly less than Sham and CEE. R1 microcrack surface density was not significantly different from Sham or Ovx. No significant differences in crack length were observed among the groups. Hardness, which is a measure of the state of mineralization, and elastic modulus were measured for both trabecular bone on a micron scale by nanoindentation. No significant differences between groups were observed. In summary, differences in functional bone quality of the lumbar spine were not observed between Sham, Ovx, or treated monkeys. CEE increased microcracks from Ovx to Sham levels, whereas raloxifene had no effect on microdamage accumulation. We conclude that suppressing bone turnover by 40% or less offers protection against microdamage accumulation that could result in an increased risk of vertebral fracture.