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This version published online on February 1, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2126
A more recent version of this article appeared on April 1, 2005
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Submitted on October 29, 2004
Accepted on January 26, 2005

Effect of L-000845704, an {alpha}V{beta}3 Integrin Antagonist, on Markers of Bone Turnover and Bone Mineral Density in Postmenopausal Osteoporotic Women

MG Murphy*, K Cerchio, SA. Stoch, K Gottesdiener, M Wu, and R Recker

Merck Research Laboratories (MGM, KG, AS, KC, MW), Rahway, NJ, USA; Creighton Osteoporosis Center, Omaha, NE 68131 (RR)

* To whom correspondence should be addressed. E-mail: Gail Murphy{at}Merck.com.

The {alpha}V{beta}3 integrin (vitronectin receptor) plays a pivotal role in bone resorption. We hypothesized that L-000845704, an {alpha}V{beta}3 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 L-000845704 100 mg or 400 mg once daily (q.d.), L-000845704 200 mg twice daily (b.i.d.) or placebo. Results: L-000845704 increased lumbar spine BMD (2.1, 3.1 and 3.5% for the 100 mg q.d., 400 mg q.d. and 200 mg b.i.d. treatment groups, respectively, vs. -0.1% for placebo; P < 0.01 all treatments vs. placebo). Only L-000845704 200 mg b.i.d 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 ~42% decrease from baseline of NTx (P < 0.001 vs. placebo). L-000845704 was generally well tolerated; adverse events resulting in discontinuation from the study were relatively infrequent.

Conclusions: The antiresorptive effect of the {alpha}V{beta}3 integrin antagonist L-000845704 translated into significant increases in lumbar spine bone mineral density. Furthermore, 200 mg L-000845704 b.i.d. provided efficacy at the hip sites. These data suggest that the {alpha}V{beta}3 integrin antagonist L-000845704 could be developed as an effective therapeutic agent for osteoporosis.
Key words: bone resorption inhibitor • {alpha}V{beta}3 Integrin Antagonist • markers of bone turnover • bone mineral density




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