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Effect of L-000845704, an _Vß₃ Integrin Antagonist, on Markers of Bone Turnover and Bone Mineral Density in Postmenopausal Osteoporotic Women

Merck Research Laboratories (M.G.M., K.C., A.S., K.G., M.W.), Rahway, New Jersey 07065; and Creighton Osteoporosis Center (R.R.), Omaha, Nebraska 68131

Address all correspondence and requests for reprints to: M. Gail Murphy, M.D., Merck Research Laboratories, Building 5W, Sentry Parkway, Bluebell, Pennsylvania 19422. E-mail: Gail_Murphy{at}Merck.com.

The _Vß₃ integrin (vitronectin receptor) plays a pivotal role in bone resorption. We hypothesized that L-000845704, an _Vß₃ 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 _Vß₃ 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 _Vß₃ integrin antagonist L-000845704 could be developed as an effective therapeutic agent for osteoporosis.

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