Unfavorable risk–benefit profile of odanacatib for osteoporosis treatment
medwireNews: The cathepsin K inhibitor odanacatib reduces the incidence of fracture in postmenopausal women with osteoporosis, but at the cost of an increased risk for cardiovascular events, indicate findings from the LOFT trial.
Therefore, “further development of odanacatib as a potential treatment for patients with osteoporosis was stopped based on the overall balance between benefit and risk,” say Keith Kaufman (Merck Sharp & Dohme Corp, Rahway, New Jersey, USA) and co-investigators.
The trial, conducted at 388 centers across 40 countries, involved over 16,000 participants who were randomly assigned to receive once-weekly treatment with oral odanacatib 50 mg or placebo, in addition to vitamin D3 and calcium supplementation.
As reported in The Lancet Diabetes & Endocrinology, patients in the odanacatib group had significantly lower risk for radiographic vertebral fractures, hip fractures, and nonvertebral fractures over a median follow-up of 36.5 months compared with those given placebo, with cumulative incidence rates of 3.7% versus 7.8%, 0.8% versus 1.6%, and 5.1% versus 6.7%, respectively.
LOFT (Long-term Odanacatib Fracture Trial) was continued until 237 incident osteoporotic hip fractures had occurred, explain Kaufman et al, after which time patients who had received treatment for less than 5 years entered the LOFT Extension study and continued to receive their assigned treatment until the 5-year follow-up.
When the LOFT and LOFT Extension results were combined, the researchers found consistent anti-fracture efficacy of odanacatib over 5 years. They note that the efficacy of odanacatib for reducing nonvertebral fracture risk “tended to be greater over time” in both studies.
However, odanacatib was associated with significantly higher rates of the composite endpoint of cardiovascular death, myocardial infarction, or stroke in the combined analysis, at 5.0% versus 4.3% for the placebo arm. The team notes that this elevated risk “was primarily due to an increased risk of stroke” among patients treated with odanacatib versus placebo, with rates of 2.3% versus 1.7%.
“To put the fracture efficacy and cardiovascular safety results in context, the results of LOFT suggest that for every 1000 women treated with odanacatib for 3 years, odanacatib might be expected to prevent approximately 40 vertebral and eight hip fractures, but could also lead to an increase of four strokes,” report Kaufman and colleagues.
Writing in an accompanying commentary, Louise Statham and Terry Aspray, both from Newcastle upon Tyne Hospitals Trust in the UK, say that “these cardiovascular risks should be viewed in the context of other drug treatments for osteoporosis, some of which have also shown potential cardiovascular risks.”
They point to zoledronic acid, which has been associated with an elevated risk for atrial fibrillation, and romosozumab, which was initially refused European approval due to an increased risk for major adverse cardiovascular events compared with alendronic acid, but recently received a positive opinion for severe postmenopausal osteoporosis following a re-examination.
The commentators believe that “[t]here is plenty to work on, while we await the magic bullet” for treating osteoporosis.
And they conclude: “Given that inexpensive efficacious treatments are already available, we could make better use of such drugs by targeted case finding and treatment in primary care.”
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