Randomized, controlled trial to assess the safety and efficacy of odanacatib in the treatment of men with osteoporosis
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ORIGINAL ARTICLE
Randomized, controlled trial to assess the safety and efficacy of odanacatib in the treatment of men with osteoporosis N. Binkley 1
&
E. Orwoll 2 & R. Chapurlat 3
&
B. L. Langdahl 4
&
B. B. Scott 5
&
H. Giezek 6 & A. C. Santora 5
Received: 5 June 2020 / Accepted: 13 October 2020 # International Osteoporosis Foundation and National Osteoporosis Foundation 2020
Abstract Summary Odanacatib (ODN) was investigated as an osteoporosis treatment in 292 men. Compared with placebo, odanacatib improved bone mineral density and led to sustained bone resorption decreases while producing relatively little bone formation reduction that leveled off with time. However, increased risk of stroke in another study stopped further odanacatib development. Introduction ODN, a selective oral cathepsin K inhibitor, was in development for osteoporosis treatment. This phase 3, doubleblind, randomized, placebo-controlled, 24-month study investigated ODN safety and efficacy in men with osteoporosis. Methods Men with idiopathic osteoporosis or osteoporosis due to hypogonadism and a lumbar spine or hip (total hip [TH], femoral neck [FN], or trochanter) bone mineral density (BMD) T-score of ≤ − 2.5 to ≥ − 4.0 without prior vertebral fracture or ≤ − 1.5 to ≥ − 4.0 with one prior vertebral fracture were randomized (1:1) to once-weekly ODN 50 mg or placebo. All received 5600 IU vitamin D3 weekly and calcium supplementation as needed (≥ 1200 mg daily). The primary efficacy outcome was changed from baseline in lumbar spine BMD versus placebo. Results Overall, 292 men, mean age 68.8 years, were randomly assigned to ODN or placebo. Versus placebo, ODN increased BMD from baseline at the lumbar spine, TH, FN, and trochanter by 5.6%, 2.0%, 1.7%, and 2.1%, respectively (all p < 0.01), and decreased uNTx/Cr (68%, p < 0.001), sCTx (77%, p < 0.001), sP1NP (16%, p = 0.001), and sBSAP (8%, p = 0.019). The between-group bone formation marker decrease peaked at 3 months, then returned toward baseline. The safety profile, including cardiovascular events, was similar between groups. Conclusion Though a promising osteoporosis therapy for men, ODN development was discontinued due to increased risk of stroke in the LOFT phase 3 trial. Trial registration Clinicaltrials.gov NCT01120600 (registered May 11, 2010). Keywords Bone mineral density . Bone turnover markers . Men . Odanacatib . Osteoporosis
Introduction
* N. Binkley [email protected] 1
University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
2
Oregon Health & Science University, Portland, OR, USA
3
INSERM UMR 1033, Université de Lyon, Hôpital Édouard Herriot, Lyon, France
4
Aarhus University Hospital, Aarhus, Denmark
5
Merck & Co., Inc., Kenilworth, NJ, USA
6
MSD Europe Inc., Brussels, Belgium
Osteoporosis in men is associated with significant morbidity, mortality, and societal expense [1]. The lifetime osteoporosisrelated fracture risk of a 50-year-old man is 13–22%, including a hip fracture risk of 3–11% [2]. Approximately one-third of all hip fract
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