title: Effect of L-000845704, an alphaVbeta3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women.
abstract: The alphaVbeta3 integrin (vitronectin receptor) plays a pivotal role in bone resorption. We hypothesized that L-000845704, an alphaVbeta3 integrin antagonist, would potently inhibit bone resorption, thereby increasing bone mass as assessed by bone mineral density (BMD) in women with postmenopausal osteoporosis. In a multicenter, randomized, double-blind, placebo-controlled, 12-month study, 227 women (average 63 yr) with low lumbar spine or femoral neck BMD were randomly assigned to receive 100 or 400 mg L-000845704 once daily (qd), 200 mg L-000845704 twice daily (bid), or placebo. L-000845704 increased lumbar spine BMD (2.1, 3.1, and 3.5% for the 100-mg-qd, 400-mg-qd, and 200-mg-bid treatment groups, respectively, vs. -0.1% for placebo; P < 0.01 all treatments vs. placebo). Only 200 mg L-000845704 bid significantly increased BMD at the hip (1.7 vs. 0.3% for placebo; P < 0.03) and femoral neck (2.4 vs. 0.7% for placebo; P < 0.05). No L-000845704 group increased total body BMD. All doses of L-000845704 resulted in a similar approximately 42% decrease from baseline of N-telopeptide cross-links (P < 0.001 vs. placebo). L-000845704 was generally well tolerated; adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the antiresorptive effect of the alphaVbeta3 integrin antagonist L-000845704 translated into significant increases in lumbar spine BMD. Furthermore, 200 mg L-000845704 bid provided efficacy at the hip sites. These data suggest that the alphaVbeta3 integrin antagonist L-000845704 could be developed as an effective therapeutic agent for osteoporosis.
authors.affiliation: Merck Research Laboratories, Building 5W, Sentry Rahway, NJ 07065, USA. Gail_Murphy@Merck.com
authors.forename: M G
authors.initials: MG
authors.lastname: Murphy
authors.forename: K
authors.initials: K
authors.lastname: Cerchio
authors.forename: S A
authors.initials: SA
authors.lastname: Stoch
authors.forename: K
authors.initials: K
authors.lastname: Gottesdiener
authors.forename: M
authors.initials: M
authors.lastname: Wu
authors.forename: R
authors.initials: R
authors.lastname: Recker
mesh_terms: D000368:Aged; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D001862:Bone Resorption / Q000517:prevention & control; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D010012:Osteogenesis / Q000187:drug effects; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*
chemical_list: D039302:Integrin alphaVbeta3