•  
     
     
    Type Size
     
    ASBMR 31st Annual Meeting

    Effects of Odanacatib on Bone Mass, Turnover and Strength in the Femoral Neck of Estrogen Deficient Adult Rhesus Monkeys

    Categories:
     Osteoporosis - Treatment (Preclinical)
     Osteoclasts (Basic)

    Poster Sessions, Presentation Number: FR0416
    Session: Welcome Reception & Plenary Poster Session
    Friday, September 11, 2009 12:00 AM - 12:00 AM, Colorado Convention Center, Exhibit Hall F

    Poster Sessions, Presentation Number: SA0416
    Session: Poster Session I
    Saturday, September 12, 2009 12:00 AM - 12:00 AM, Colorado Convention Center, Exhibit Hall F

    * Tara Cusick, Merck & Co., Inc., USA, Brenda Pennypacker, Merck Research Laboratories, USA, Kevin Scott, Merck, USA, Le Duong, Merck Research Laboratories, USA, Donald Kimmel, Kimmel Consulting Services, USA

    Cathepsin K (CatK) is a cysteine protease highly expressed in bone resorbing osteoclasts and its inhibition represents a novel and promising mechanism for the treatment of osteoporosis. Odanacatib (ODN) is a selective, reversible CatK inhibitor and appears to be a bone formation-sparing antiresorptive. We previously demonstrated that ODN, fully prevented bone mineral density (BMD) loss at the spine and hip and maintained normal bone strength at the central femur in 21-mo. old ovariectomized (OVX) rhesus monkeys. Here we characterize ODN effects on cortical and trabecular bone in the femoral neck (FN). Rhesus monkeys (13-19 yrs) were assigned to four groups (n=8-11): intact and OVX + vehicle or ODN (6 and 30mg/kg, q.d., p.o.). For histomorphometry, two 15-d interval labels were given with calcein at 10-mo. and tetracycline just prior to necropsy. Bone strength in shearing mode, surface-based mineralizing surface (MS/BS), mineral apposition rate (MAR), and bone formation rate (BFR) were determined in the FN. Short term and long-term (LT)BFR represented the distance between 15-d tetracycline labels and between tetracycline and calcein labels, respectively. ODN treatment led to BMD gains of 11% and 15% (p<0.01, vs. vehicle), and peak-load increases of 17% and 19% in the 6 and 30mg/kg ODN groups, respectively. In trabecular FN, MS/BS and BFR were unaltered by the 6mg/kg dose, but trended lower with the 30mg/kg dose vs. vehicle. MAR, TbTh, TbN and TbSp. were unaffected by ODN. Periosteal FN MS/BS, MAR and BFR were also not affected by low dose treatment, but trended higher with 30mg/kg ODN vs. vehicle. Dose-dependent effects of ODN on periosteal FN BFR were clearly demonstrated by a LTMAR increase of 1.5-fold and a 3.5-fold LTBFR increase with the 30mg/kg dose vs. vehicle. In summary, we show that in OVX monkeys, both doses of ODN treatment protected against BMD loss and preserved normal bone quality in the FN. Similar to previous findings in the spine and proximal femur of these monkeys, ODN appeared to have differential effects on FN trabecular and cortical bone at doses which fully prevented OVX-induced bone loss. While 6mg/kg ODN left bone formation unaffected, at 30mg/kg it partially stimulated periosteal BFR. Our findings in the femoral neck suggest that ODN, unlike conventional antiresorptives, can effectively inhibit trabecular bone remodeling while simultaneously building cortical bone, at least in part via stimulating periosteal bone formation.

    Disclosures: None

    * Presenting Authors(s): Tara Cusick, Merck & Co., Inc., USA