Odanacatib for the treatment of postmenopausal osteoporosis

1. The cathepsin K inhibitor odanacatib reduced the risk of fracture but was associated with significantly increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis compared to placebo.

Evidence Rating Level: 1 (Excellent)

Odanacatib, a cathepsin K inhibitor, reduces bone resorption without compromising bone formation, with further findings suggesting that it increases bone mineral density in postmenopausal women with low bone mass. Data from the Long-term Odanacatib Fracture Trial (LOFT) and LOFT Extension conducted at 388 outpatient clinics across 40 countries was utilized to assess the safety and efficacy of odanacatib to reduce bone fracture risk in postmenopausal women with osteoporosis. Women included in this double-blind, placebo-controlled study were postmenopausal for at least five years, had a reduced femoral neck or total hip bone mineral density (T-score -2.5 to -4.0) if no radiographic vertebral fracture, or T-score bone mineral density of -1.5 to -4.0 if concomitant with previous vertebral fracture. These participants were randomly assigned to oral odanacatib (50mg once weekly) or matching placebo, assessed using radiographs at baseline and then at six-month and 12-month follow-ups each year of the study. Cumulative incidence was significantly lower (p<0.001) in the odanacatib group compared to placebo for radiographic vertebral fractures (difference 4.1%; HR 0.46, 95% CI 0.40 to 0.53), hip fractures (difference 0.8%; HR 0.53, 95% CI 0.39 to 0.71), and non-vertrebral fractures (difference 1.6%; HR 0.77, 95% CI 0.68 to 0.87). Similar findings were noted when including the LOFT Extension study. Differences in composite cardiovascular endpoints from the LOFT odanacatib and placebo groups were not significant. While incidence of new-onset atrial fibrillation or flutter and myocardial infarction were not statistically significant between groups, odanacatib was associated with a significantly increased risk of stroke (difference 0.4%; HR 1.32, 95% CI 1.02 to 1.70, p=0.034). When including the LOFT Extension study, the odanacatib group was associated with increased risk of at least one cardiovascular endpoint compared to the placebo group (difference 0.7%; HR 1.17, 95% CI 1.02 to 1.36, p=0.29), as well as stroke (difference 0.6%; HR 1.37, 95% CI 1.10 to 1.71, p=0.0051). Therefore, this study suggests that vertebral fracture risk was reduced by odanacatib but this medication was also associated with elevated risk of cardiovascular events, specifically stroke. Due to these findings, it is important to consider the risks of odanacatib for the treatment of osteoporosis in postmenopausal women.

Click to read the study in Lancet Diabetes & Endocrinology

Image: PD

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