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Denosumab Tied to Infection Risk

January 13, 2020

By Marilynn Larkin

NEW YORK (Reuters Health) - The osteoporosis drug denosumab is associated with a higher incidence of serious infections compared to placebo, but the risk is similar to comparator drugs, a systematic review and meta-analysis reveals.

Dr. Talia Diker-Cohen of Tel Aviv University and colleagues searched the literature through May 2019 for randomized controlled trials of denosumab (60 mg every six months) versus any comparator (e.g., bisphosphonates, teriparatide, placebo).

As reported in the Journal of Clinical Endocrinology and Metabolism, 33 studies involving 22,253 patients were included. The incidence of serious adverse events related to infection was higher during denosumab treatment versus any comparator (RR, 1.21), mainly involving the ear, nose and throat (RR, 2.66) and gastrointestinal system (RR, 1.43).

However, in a sensitivity analysis, the risk ratio was similar to comparator groups, and the risk ratios of any infection (RR, 1.03) and infection-related mortality (RR, 0.50) were comparable between groups.

Further, a subgroup analysis by comparator showed an increased relative risk of serious infection for denosumab versus placebo (RR, 1.23; 16 studies) but not compared to bisphosphonates or teriparatide.

The authors conclude, "A higher incidence of (serious adverse events of infection) is demonstrated during treatment with denosumab in an osteoporosis dose. Nevertheless, the overall risk for any infection or related mortality is similar to comparator groups. These findings merit consideration before therapy initiation."

Dr. Diker-Cohen did not respond to requests for comment; however, U.S. endocrinologists commented on the findings in emails to Reuters Heath.

Dr. Deena Adimoolam, Associate Fellowship Program Director in the Division of Endocrinology, Diabetes, and Bone Disease at Icahn School of Medicine at Mount Sinai, in New York City, said, "Denosumab has the known side effect of potentially leading to increased risk for infection - especially infections of the skin. It should only be considered in patients who have a normal immune response and who are not on immunosuppressive medications, such as certain cancer treatments."

"This risk for the side effects of infection is very rare," she added.

Dr. Maria Pena, Director of Endocrine Services at Mount Sinai Doctors Forest Hills, in New York City, told Reuters Health, "I don't believe that a definitive conclusion can be made from this study alone and further investigation is warranted. Therefore, general prescribing practices should not change, especially since osteoporosis is associated with so much morbidity and mortality."

"This being said," she added, "I believe the value of this study is that it increases awareness amongst clinicians to counsel patients and to monitor for (infection)."

Dr. Kristin Criner, Adjunct Clinical Assistant Professor of Medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, pointed out, "The best data we have to compare this to is the FREEDOM Trial ( ... (which was) the largest randomized control trial comparing denosumab versus placebo in the prevention of fractures in postmenopausal women with osteoporosis."

"While the primary endpoint was new vertebral fractures at 36 months and secondary endpoints included nonvertebral and hip fractures, there was no significantly higher risk for serious adverse events due to infection in the denosumab group," she said. "This result held true for the 7-year extension trial." (FREEDOM Extension;

"I have not found an increased incidence of serious adverse events of infection in denosumab-treated patients; however, I am selective in the patients that I choose to use the drug for - i.e., no predisposing risk for infection," she added. "I think we need a prospective, randomized, controlled trial looking at serious adverse events of infection in denosumab-treated patients as a primary endpoint to see if this meta-analysis really holds true."

SOURCE: Journal of Clinical Endocrinology and Metabolism, online January 3, 2020.

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