Introduction
Denosumab, a RANK ligand inhibitor, is a bone-modifying agent initially approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture in 2010, marketed as Prolia® 60 mg administered once every six months. Its role has expanded and is now frequently used in cancer patients, most notably in the management of hypercalcemia of malignancy and to decrease skeletal-related events (SREs) with both multiple myeloma patients and patients with bone metastases from solid tumors. For oncology-related indications, denosumab has been marketed as Xgeva® 120 mg, as these patients require a dose that is twice as high compared to other indications and administered once monthly. Currently, oncology societies such as the National Comprehensive Cancer Network (NCCN) recommend denosumab over bisphosphonates for cancer patients with decreased kidney function1. This comes as a result of an increased risk of nephrotoxicity with the use of zoledronic acid, the requirement for dose adjustment at a creatinine clearance of <60 mL/minute, and the recommendation against its use in patients with a clearance of <30 mL/minute.
Increased Risk of Severe Hypocalcemia
On January 19th, 2024, the FDA issued a Drug Safety Communication highlighting an increased risk of severe hypocalcemia in patients with advanced chronic kidney disease (CKD) on denosumab (Prolia®)2. This updated boxed warning comes as an update to the FDA’s announced investigation of the risk of hypocalcemia in November 20223. Patients with severe hypocalcemia may have an albumin-corrected total serum calcium level below 7.5 mg/dL, which puts the patient at risk of potentially life-threatening complications such as arrhythmias or seizures. The hypocalcemia risk in these patients is likely attributed to CKD-associated secondary hyperparathyroidism. The FDA has since investigated this adverse event through two studies and the review of 77 cases received through the FDA Adverse Events Reporting System (FAERS) database between July 2010 and May 2021.
The first study assessed the incidence and risk of severe hypocalcemia in female dialysis-dependent Medicare patients using denosumab (n=1,523) or oral bisphosphonates (n=1,281). Of note, this study excluded patients with malignancy to reduce confounders. As a result, a 12-week weighed cumulative incidence of severe hypocalcemia occurred among 41.1% of denosumab patients versus 2.0% among patients with oral bisphosphonates, with the greatest risk observed in weeks 2-54.
The second study assessed a similar population in addition to patients receiving intravenous bisphosphonates and stratified patients by stage of CKD and the presence of CKD-mineral and bone disorder (CKD-MBD). The study included data from more than 1.6 million women and indicated a higher rate of severe hypocalcemia requiring emergent treatment among those receiving denosumab (218.9 per 100,000 person-years) than those receiving intravenous bisphosphonates (52.1 per 100,000 person-years) and oral bisphosphonates (19.4 per 100,000 person-years). The worsening CKD stage was also found to be associated with increases in the rate of severe hypocalcemia induced by denosumab. Among the 242 patients with denosumab-induced hypocalcemia, 21 (8.7%) patients developed seizures or cardiac arrhythmias, and 8 (3.3%) patients died2. In this study, the exclusion of cancer patients was not explicitly stated in the FDA’s report; however, it did analyze patients receiving Prolia® rather than patients that may be receiving Xgeva®.
FDA Recommendations
Following the presented data, the FDA recommends educating patients on the risks and symptoms of hypocalcemia and involving the patient’s nephrologist when initiating and continuing denosumab administration. Subsequently, managing CKD-MBD, correcting hypocalcemia and supplementing with calcium and activated vitamin D before and during treatment with denosumab may decrease the risk of severe hypocalcemia and its complications. The Prolia® package insert advises prescribers to supplement their patients with “calcium 1000mg daily and at least 400 IU vitamin D daily”. Serum calcium monitoring post-denosumab administration is also recommended5.
Evidence and Implications in Cancer Patients
While the studies mentioned by the FDA do not tackle the incidence of denosumab-induced hypocalcemia in cancer patients, the risk still stands as highlighted in the literature, albeit from smaller sample sizes. A 2018 study comparing denosumab to zoledronic acid for bone disease treatment in multiple myeloma showed a higher rate of hypocalcemia in the denosumab group with 144 events (17%) compared to 106 (12%) in the zoledronic acid group6. The Xgeva® package insert also highlights an increased risk of hypocalcemia for patients on dialysis or with a creatinine clearance of < 30 mL/minute. Accordingly, the Xgeva® package insert recommends to “administer calcium and vitamin D as necessary to treat or prevent hypocalcemia”7. This recommendation aligns with the FDA’s recent Drug Safety Communication, and it may be considered for most cancer patients on denosumab. The use of denosumab in the management of hypercalcemia of malignancy presents a more complicated situation. While the preemptive administration of calcium is not feasible in this setting, close monitoring of calcium levels and supplementation alongside vitamin D may also be considered following its correction.
The risk of hypocalcemia among cancer patients seems to be consistent with the administration of denosumab, even when considering alternate, off-label dosing. A lower dose of 60 mg has been previously suggested for patients with renal dysfunction and hypercalcemia of malignancy. Among these few case reports, hypocalcemia was still reported as a side effect8,9. Another debatable administration schedule for denosumab includes the extended interval dosing of every three months compared to the approved monthly interval. A retrospective study conducted at a healthcare system in the state of Georgia compared the safety and efficacy of extended interval dosing of denosumab. The study showed an incidence of hypocalcemia among 76 (31.5%) patients receiving denosumab at a short interval (< 5 weeks) compared to 8 (17.4%) patients receiving denosumab at a long interval (≥ 12 weeks), a difference that was neither powered nor significant10.
While the current FDA warnings do not single out cancer patients, patients with kidney impairment on denosumab remain at risk of hypocalcemia. At this time, no current alternate dosing regimen has been approved and further analyses evaluating the incidence of hypocalcemia in cancer patients is needed to better understand the implications of this adverse event. Frequent corrected serum calcium measurement following the administration of denosumab still plays a major role in monitoring for the efficacy in managing hypercalcemia, as well as avoiding complications through early identification of hypocalcemia and supplementation with vitamin D and calcium when needed.
References:
1.NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed 9 February 2024.
2.Center for Drug Evaluation and Research. Osteoporosis drug prolia increases the risk of severe hypocalcemia. U.S. Food and Drug Administration. January 19, 2024. Accessed February 9, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease.
3.Center for Drug Evaluation and Research. FDA investigating risk of severe hypocalcemia in patients on dialysis. U.S. Food and Drug Administration. November 22, 2022. Accessed February 9, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-investigating-risk-severe-hypocalcemia-patients-dialysis-receiving-osteoporosis-medicine-prolia.
4.Bird ST, Smith ER, Gelperin K, et al. Severe hypocalcemia with denosumab among older female dialysis-dependent patients. JAMA. 2024;331(6):491. doi:10.1001/jama.2023.28239
5.Prolia (Denosumab). Package insert. Amgen. 2024
6.Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: An international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018;19(3):370-381. doi:10.1016/s1470-2045(18)30072-x
7.Xgeva (Denosumab). Package insert. Amgen. 2020
8.Cicci JD, Buie L, Bates J, van Deventer H. Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction. Clin Lymphoma Myeloma Leuk. 2014;14(6). doi:10.1016/j.clml.2014.07.005
9.Dietzek A, Connelly K, Cotugno M, Bartel S, McDonnell AM. Denosumab in hypercalcemia of malignancy: A case series. J Oncol Pharm Pract. 2014;21(2):143-147. doi:10.1177/1078155213518361
10.Abousaud AI, Barbee MS, Davis CC, et al. Safety and efficacy of extended dosing intervals of denosumab in patients with solid cancers and bone metastases: A retrospective study. Ther Adv Med Oncol. 2020;12:175883592098285. doi:10.1177/175883592098285
