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Denosumab discontinuation increases risk for major osteoporotic, vertebral fractures
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Older adults who discontinue denosumab are at greater risk for major osteoporotic fractures and multiple vertebral fractures than those who persist with treatment, according to findings from a real-world database analysis published in Bone.
“This study provides data on the real-life incidence of multiple vertebral fractures following denosumab discontinuation that was awaited by researchers and clinicians in the field since the first reports in 2015,” Liana Tripto-Shkolnik, MD, MMedSc, deputy director of the division of endocrinology, diabetes and metabolism at Sheba Medical Center in Tel Hashomer, Israel, told Endocrine Today. “We showed, for the first time, that among discontinuers, risk factors for those fractures were renal and cerebrovascular disease.”
Tripto-Shkolnik and colleagues analyzed longitudinal data from 3,110 patients who were new initiators of denosumab (Prolia/Xgeva, Amgen) with two or more consecutive purchases between January 2012 and March 2017, using data from Maccabi Healthcare Services, the second largest health care provider and insurer in Israel. Treatment discontinuation was defined as a refill gap of 3 months or more (gap of 9 months or more after a last denosumab dispensation). The date of expected refill (6 months after the last refill) was considered the discontinuation date. Median follow-up time until treatment reinitiation, disenrollment or end of data collection was 9 months for denosumab discontinuers and 16 months for persistent users. Primary outcome was major osteoporotic fractures, identified by an osteoporosis registry. Fractures occurring within 1 year from discontinuation among denosumab discontinuers (n = 1,500; 92% women; mean age, 72 years) and from the second year of treatment onward for persistent users (n = 1,610; 91% women; mean age, 72 years) were included.
Researchers calculated fracture incidence rates per 100 patient-years of follow-up as incidence density ratios (IDR). Relative risk was calculated by dividing the IDR in the denosumab discontinuation group by the IDR in the persistent users group.
At baseline, the groups were comparable in fracture history, bisphosphonate exposure, smoking status and bone density. The researchers observed multiple vertebral fractures among 12 (0.8%) denosumab discontinuers vs. two (0.1%) persistent users (P = .006). The overall rate of fractures per 100 patient-years of follow-up was higher among denosumab discontinuers vs. persistent users (incidence rate ratio [IRR] = 3.2; 95% CI, 2.2-4.8), as well as the rate of vertebral fracture (IRR = 4.7; 95% CI, 2.3-9.6) and multiple vertebral fractures (IRR = 14.6; 95% CI, 3.3-65.3).
In a multivariate analysis among denosumab discontinuers, the researchers found that incident fracture after denosumab discontinuation was correlated with cerebrovascular disease (HR = 2.29; 95% CI, 1.09-4.83) and chronic kidney disease (HR = 1.96; 95% CI, 1.03-3.71), but not with prior blood pressure or prevalent fractures.
“Inadvertent treatment dropout should be avoided, and planned discontinuation should be thoughtfully managed, especially in high-risk groups,” Tripto-Shkolnik said. “The optimal course of action following denosumab discontinuation is currently unknown and is a subject of several ongoing trials.” – by Regina Schaffer
For more information:
Liana Tripto-Shkolnik, MD, MMedSc, can be reached at Sheba Medical Center, Division of Endocrinology, Diabetes and Metabolism, Derech Sheba 2, Ramat Gan, Israel; email: lianatrish@gmail.com.
Disclosures: Amgen supported this study. Tripto-Shkolnik and one other author report receiving personal fees from Amgen and Eli Lilly.
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