Risk of Hypocalcemia in in Patients with Nondialysis-Dependent CKD Stage 4/5 Who Are Treated with Denosumab: Real-World Observation in an Integrated Health Care System

Background: Denosumab, used for the treatment of osteoporosis in patients with advanced chronic kidney disease (CKD), carries a Food and Drug Administration black box warning of severe hypocalcemia in this patient population. Within a population-based cohort of non-dialysis CKD patients drawn from a large, diverse membership of an integrated healthcare system, we estimated the risk of hypocalcemia after receiving a denosumab dose and evaluated risk factors associated with hypocalcemia. Methods: This retrospective cohort study, conducted within Kaiser Permanente Southern California from 1/1/2014-12/31/2023, comprised non-dialysis CKD patients with estimated glomerular filtration rates (eGFR) of <30 and who received denosumab 60 mg. Outcomes were incident hypocalcemia (albumin-adjusted serum calcium < 8.5 mg/dl) or severe hypocalcemia (albumin-adjusted serum calcium ≤ 7.6 mg/dl) occurring within 90 days after a denosumab dose. Multivariable logistic regression was used to estimate associations between eGFR quintiles and incident hypocalcemia, and several other patient-level demographic/clinical characteristics were evaluated for inclusion in the model. Results: Of the 1072 doses of denosumab given to 553 patients with an eGFR < 30, 681 (64%) had serum calcium drawn within 90 days of a dose. Hypocalcemia occurred in 18.6%, and severe hypocalcemia occurred in 5.3% of our cohort. The odds of incident hypocalcemia were highest in the lowest quintile eGFR (4-21) (OR: 2.93, 95% CI: 1.28-6.73) compared to the highest eGFR group, after adjustment for age, sex, race, parathyroidectomy, vitamin D, and phosphatemia. History of parathyroidectomy (OR 2.57, CI 1.41-4.70) was also associated with higher odds of hypocalcemia. Patients of Asian race had lower odds of hypocalcemia (OR 0.43, CI 0.21-0.86) compared to white patients. Conclusion: The risk of hypocalcemia was associated with lower eGFR. Given the high risk of hypocalcemia and the significant proportion of our patients who did not have calcium drawn after the denosumab injection, clinicians may consider being more vigilant about having patients check the calcium after denosumab dosing in patients with severe chronic kidney disease. Funding: Clinical Revenue Support