(A-117) Comparison of the Hypocalcemia Risk between Denosumab and Bisphosphonates in Patients with Osteoporosis and CKD – A Target Trial Emulation Study Using Multi-Institutional Electronic Health Records

Background: Hypocalcemia has been reported in patients with osteoporosis receiving denosumab or bisphosphonates. However, the comparison of hypocalcemia risk between the two treatments remains unclear, particularly in patients with chronic kidney disease (CKD), a high-risk population for hypocalcemia.

Objectives: To compare the risk of hypocalcemia between denosumab and bisphosphonates in patients with osteoporosis and CKD.

Methods: We emulated a target trial using the TriNetX US Collaborative Network, a multi-institutional electronic health records database from 2010 to 2024. We identified patients with osteoporosis and CKD who were newly prescribed either denosumab or bisphosphonate. Each patient was assigned to the corresponding treatment group based on their first prescription, with that date defined as the index date. To mimic randomization, we performed 1:1 propensity score matching at the index date. The primary outcome was hypocalcemia, defined as serum calcium < 8.5 mg/dL. We conducted an as-started analysis which is an analogue to intention-to-treat in the hypothetical trial, with follow-up starting from the index date until the occurrence of outcome, death, or the last clinical visits, whichever came first. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using the Cox proportional hazards model. Additionally, we restricted the outcome to severe hypocalcemia, defined as serum calcium < 7.5 mg/dL or the use of intravenous calcium supplementation.

Results: We identified 127,880 bisphosphonates and 34,124 denosumab users and 34,070 patients were subsequently matched. The observed event rate among denosumab users was 23.74 per 100 people, compared with 20.88 per 100 people among bisphosphonate users. Compared with bisphosphonates, denosumab was associated with an increased risk of hypocalcemia in patients with osteoporosis and CKD (HR 1.22; 95% CI 1.17-1.27). Moreover, denosumab was associated with an increased risk of severe hypocalcemia (HR 1.23; 95% CI 1.17-1.28), which was consistent with the primary findings.

Conclusions: Our study highlighted that denosumab may increase the risk of hypocalcemia compared to bisphosphonates in patients with osteoporosis and CKD. Physicians should monitor hypocalcemia and raise awareness of its potential symptoms in such patients.