Increased Bone Formation and Bone Mass by Sclerostin Antibody Was Not Blunted by Pretreatment with Alendronate in Ovariectomized Rats with Established Osteopenia
Category: Osteoporosis - Treatment (Preclinical)
Oral Presentations, Presentation Number: 1065
Session: Concurrent Oral Session 11: Osteoporosis Treatment (Preclinical) - Anabolic Agents
Saturday, September 12, 2009 3:30 PM - 3:45 PM, Colorado Convention Center, Hall A
* Xiaodong Li, Amgen, Inc., USA, Kelly Warmington, Amgen, USA, Qing-Tian Niu, Amgen, USA, Mario Grisanti, Amgen Inc., USA, Denise Dwyer, Amgen, USA, Marina Stolina, Amgen Inc., USA, Paul Kostenuik, Amgen Inc., USA, William Simonet, Amgen, Inc., USA, Chris Paszty, Amgen, Inc., USA, Hua Zhu (David) Ke, Amgen Inc., USA
Inhibition of sclerostin by treatment with a sclerostin monoclonal antibody has been shown to increase bone formation, bone mass and bone strength in ovariectomized (OVX) rats with established osteopenia. In the current study, we examined whether pretreatment with an anti-resorptive agent such as alendronate (ALN) would result in a blunting of the bone anabolic effects induced by sclerostin antibody in OVX rats. Ten-month-old OVX rats (3.5 months post-ovariectomy) were pretreated with ALN (2x/week, s.c., 0.028 mg/kg) for 6 weeks (n=30) and then transitioned to sclerostin antibody (Scl-AbIII, 25 mg/kg, sc, 1x/week) alone (n=10), or to a combination of Scl-AbIII plus ALN (n=10) for an additional 6 weeks (12 weeks of total treatment). The 10 remaining ALN-treated OVX rats were euthanized at the week 6 timepoint to serve as baseline controls. As additional controls for the study, a separate set of OVX rats (n=30) were pretreated with vehicle for 6 weeks and then transitioned to Scl-AbIII alone or vehicle for another 6 weeks. Histomorphometric analysis of the 3rd lumbar vertebrae revealed that 6 weeks of ALN treatment significantly reduced trabecular mineralizing surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR/BS) in OVX rats. Transition to Scl-AbIII from ALN or vehicle (Figure) was equally effective at restoring trabecular bone volume (BV/TV) and increasing trabecular thickness (Tb.Th), indicating that ALN pretreatment did not blunt the bone restorative effects of Scl-AbIII in OVX rats. Consistent with these findings, dynamic histomorphometric analysis showed that transition to Scl-AbIII from ALN or vehicle was equally effective at increasing trabecular MS/BS, MAR and BFR/BS at the lumbar vertebrae. Similar findings for MS/BS, MAR and BFR/BS were observed on both the periosteal and the endocortical surfaces of the tibial shaft. Transition to Scl-AbIII from ALN or vehicle was equally effective at increasing serum osteocalcin, a marker of bone formation. Furthermore BV/TV, Tb.Th, trabecular and cortical bone formation parameters, and serum osteocalcin did not differ significantly between Scl-AbIII alone and the combination of Scl-AbIII plus ALN in OVX rats pretreated with ALN. In summary, the increases in bone formation and bone mass resulting from treatment with a sclerostin antibody were not blunted by pretreatment with alendronate in OVX rats, with or without alendronate co-treatment.
Disclosures: M. Stolina, Amgen: Employment (full or part-time). X. Li, Amgen : Employment (full or part-time). X. Li, Amgen : Stock options or bond holdings in a for-profit corporation or self-directed pension plan. D. Dwyer, Amgen: Employment (full or part-time). K. Warmington, Amgen: Employment (full or part-time). M. Grisanti, Amgen: Employment (full or part-time). C. Paszty, Amgen: Employment (full or part-time). H. Ke, Amgen: Employment (full or part-time). P. Kostenuik, Amgen: Employment (full or part-time). W. Simonet, Amgen: Employment (full or part-time). Q. Niu, Amgen: Employment (full or part-time).
* Presenting Authors(s): Xiaodong Li, Amgen, Inc., USA