• Steven T Bird, Kate Gelperin, Elizabeth R Smith, Tae Hyun Jung, Hai Lyu, Aliza Thompson, Olivia Easley, Kushal B Naik, Yueqin Zhao, Rekha Kambhampati, Michael Wernecke, Ali Niak, Marina Zemskova, Yoganand Chillarige, Jeffrey A Kelman, and David J Graham.
• Office of Pharmacovigilance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (S.T.B., K.G., A.N., D.J.G.).
• Ann. Intern. Med. 2024 Nov 19.

BackgroundThere is a paucity of data on treatment of osteoporosis in patients with advanced chronic kidney disease (CKD).ObjectiveTo assess the risk for emergently treated hypocalcemia with denosumab by stage of CKD and presence of CKD-mineral and bone disorder (CKD-MBD).DesignTarget trial emulation.SettingMedicare fee-for-service data with prescription drug coverage, 2012 to 2020.ParticipantsFemale patients aged 65 years or older initiating denosumab, oral bisphosphonates, or intravenous (IV) bisphosphonates for osteoporosis.MeasurementsHospital and emergency department admissions (that is, emergent care) for hypocalcemia were assessed in the first 12 treatment weeks. Inverse probability of treatment weighted cumulative incidence and weighted risk differences (RDs) were calculated.ResultsA total of 361 453 patients treated with denosumab, 829 044 treated with oral bisphosphonates, and 160 413 treated with IV bisphosphonates were identified. Risk for emergently treated hypocalcemia with denosumab versus oral bisphosphonates increased with worsening CKD stage (P < 0.001), with greatest risk among dialysis-dependent (DD) patients (3.01% vs. 0.00%; RD, 3.01% [95% CI, 2.27% to 3.77%]) and non-dialysis-dependent (NDD) patients with CKD stages 4 and 5 (0.57% vs. 0.03%; RD, 0.54% [CI, 0.41% to 0.68%]). Among patients with stages 4 and 5 CKD (NDD + DD), denosumab had a greater risk for emergently treated hypocalcemia versus oral bisphosphonates in those with CKD-MBD (1.53% vs. 0.02%; RD, 1.51% [CI, 1.21% to 1.78%]) than in those without CKD-MBD (0.22% vs. 0.03%; RD, 0.19% [CI, 0.08% to 0.31%]). Denosumab also showed increased risk compared with IV bisphosphonates.LimitationGeneralizability to men and non-Medicare populations.ConclusionRisk for emergently treated hypocalcemia with denosumab increased with worsening CKD stage and was highest in DD patients and those with CKD-MBD.Primary Funding SourceU.S. Food and Drug Administration.

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