Identification of the Risk Factors Associated with Hypocalcemia Induced by Denosumab

Abstract

Denosumab, a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor-κB ligand, inhibits the activation of osteoclasts. Some clinical trials have shown that denosumab suppresses bone resorption in patients with advanced cancer, but hypocalcemia has been reported as a serious adverse effect after the administration of denosumab. It is difficult to predict hypocalcemia in such cases because the risk factors for denosumab-induced hypocalcemia have not been reported. Accordingly, the aim of the present study was to identify the risk factors for hypocalcemia induced by denosumab. We retrospectively reviewed the records of patients who had received denosumab at Tokushima University Hospital between April 2012 and May 2013. Fifty-three patients were analyzed and eleven patients had hypocalcemia after administration of denosumab. Univariate logistic regression analysis revealed that the patients who had not been administered zoledronic acid before receiving denosumab or had lower creatinine clearance (CCr) appeared to have a higher risk of hypocalcemia (p<0.05). The cut off value of CCr was 50.4 mL/min calculated by receiver-operator characteristics curves. Moreover, multivariate logistic regression analysis revealed that non-administration of zoledronic acid (odds ratio 10.43, p<0.05) and CCr less than 50.0 mL/min (odds ratio 5.90, p<0.05) were independent risk factors for denosumab-induced hypocalcemia. These findings provide useful information regarding the monitoring of hypocalcemia in patients receiving denosumab.Key words denosumab; hypocalcemia; risk factor; zoledronic acid; creatinine clearance Bone metastases are common in advanced cancer.1) Bone metastases lead to fractures and spinal compression due to the born resorption induced by activated osteoclasts.2) As a result, the quality of life (QOL) in patients with advanced cancer is decreased significantly. Therefore, prevention of bone resorption is important for maintaining QOL. Zoledronic acid, which inhibits farnesyl pyrophosphate synthetase in osteoclasts, has been used for preventing skeletal-related events caused by metastatic bone disease. [3][4][5] Recently, many studies have reported that the interaction between the receptor activator of nuclear factor-κB (RANK), which is expressed in osteoclasts, and the RANK ligand (RANKL), which is expressed in osteoblasts, is associated with the activation of osteoclasts. 6) RANKL is the essential mediator of osteoclast differentiation, activation, and survival, and thereby a key contributor to bone resorption. In a murine model of established bone metastases, inhibition of RANKL was shown to prevent osteoclast-mediated bone resorption. 7)Denosumab, a fully human monoclonal RANKL antibody, was shown to prevent the activation of osteoclasts via the inhibition of RANKL in a human model. 8) Moreover, some clinical trials have shown that denosumab suppresses bone resorption more effectively than zoledronic acid in patients with advanced cancer. 9-13) Therefore, denosumab can be considere...

Severe Refractory Hypocalcemia in a Patient with Metastatic Prostate Carcinoma Following Denosumab Injection

“…Aggressive metastatic disease as reflected by higher PSA and alkaline phosphatase levels, and baseline Vitamin D deficiency tended to be risk factors for severe hypocalcemia whereas prior bisphosphonate therapy and concurrent steroid administration did not appear to be risk factors [14]. Another analysis identified reduced creatinine clearance (less than 50 ml/min) and no prior exposure to bisphosphonates as risk factors for severe hypocalcemia [15]. It is interesting to note that prior treatment with Zoledronic acid did not appear to be a risk factor despite its long half-life in the bones.…”

High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis

“…To prevent hypocalcemia following denosumab administration, prophylactic administration of calcium and/or vitamin D is recommended for osteoporosis and bone metastases patients unless albumin-adjusted serum calcium concentrations are high 15–18. While prophylactic administration of calcium and/or vitamin D is now deemed essential, reports of severe hypocalcemia despite calcium and vitamin D supplementation exist 8,11,17,18. Therefore, identification of potential risk factors for hypocalcemia is critical.…”

Risk Factors for Hypocalcemia following Treatment with Denosumab in Patients with Bone Metastases from Prostate Cancer

“…However, the risk factors for the development of hypocalcemia following Denosumab in patients with bone metastases have not been studied in detail. In a retrospective review of the records of patients who had received Denosumab, univariate logistic regression analysis illuminated that the patients without a history of receiving zoledronic acid before Denosumab or with low creatinine clearance (CCr) were found to have a high risk of hypocalcemia (P=0.040 and 0.030, respectively) [24]. The cut off value of CCr was 50.4 mL/min calculated by receiver-operator characteristics curves.…”