Predictors for development of denosumab-induced hypocalcaemia in cancer patients with bone metastases determined by ordered logistic regression analysis

Abstract

This retrospective study was undertaken to identify predictors for the development of hypocalcaemia even with prophylactic administration of calcium and vitamin D, and to help guide future strategies to improve the safety, efficacy, and QOL of patients receiving denosumab. Between January 2016 and February 2020, a total of 327 advanced cancer patients at our hospital who were receiving denosumab were enrolled. Variables associated with the development of hypocalcaemia were extracted from the clinical records. The level of hypocalcaemia was evaluated using CTCAE version 5. Multivariate ordered logistic regression analysis was performed to identify predictors for the development of hypocalcaemia. Optimal cut off thresholds were determined using ROC analysis. Values of P < 0.05 (2-tailed) were considered significant. 54 patients have developed hypocalcemia (≥ Grade 1). Significant factors identified included concomitant use of vonoprazan [odds ratio (OR) = 3.74, 95% confidence interval (CI) 1.14–12.26; P = 0.030], dexamethasone (OR = 2.45, 95%CI 1.14–5.42; P = 0.022), pre-treatment levels of serum calcium (OR = 0.27, 95%CI 0.13–0.54; P < 0.001), ALP/100 (OR = 1.04, 95%CI 1.01–1.07; P = 0.003), and haemoglobin (OR = 0.79, 95%CI 0.68–0.93; P = 0.004). ROC curve analysis revealed that the threshold for pre-treatment levels of serum calcium was ≤ 9.3 mg/dL, ALP was ≥ 457 U/L, and haemoglobin was ≤ 10.4 g/dL. In conclusion, concomitant use of vonoprazan or dexamethasone, and pre-treatment levels of serum calcium (low), ALP (high) and haemoglobin (low) were identified as significant predictors for the development of denosumab-induced hypocalcaemia.

Development of Risk Prediction Model for Grade 2 or Higher Hypocalcemia in Patients With Bone Metastasis Treated With Denosumab Plus Cholecalciferol (Vitamin D3)/Calcium Supplement

“…This may be because calcium absorption in the intestinal tract is reduced by suppression of gastric acid secretion, 24,25 and bone resorption is suppressed by proton pump inhibition in osteoclasts 26 . Furthermore, only vonoprazan has been reported to be a risk factor for hypocalcemia 3 . However, the number of patients taking vonoprazan in the reported single‐center study was only 14.…”

“…This study was based on the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis statement. 11 In this study, all data were used for model development to ensure a sufficient number of cases, considering that the incidence of grade ≥2 hypocalcemia is <10% 2,3 and that about 10 candidate factors should be extracted, according to previous studies.…”

“…Severe hypocalcemia, including fatal cases, was reported soon after the launch of denosumab, and supplementation with calcium and vitamin D has been recommended. However, some patients develop clinically significant grade ≥2 hypocalcemia even under calcium/vitamin D supplementation, [1][2][3] and many of these cases occur within the first course (28 days) of denosumab administration. Therefore, it is clinically important to predict the risk of grade ≥2 hypocalcemia in the short term with denosumab under calcium and vitamin D supplementation.…”

Hypocalcaemia and hypophosphataemia following denosumab and IV ferric carboxymaltose in an older patient with normal renal function

“…This is a novel and potentially life‐threatening interaction of which clinicians have been increasingly aware. It has been reported previously in a patient with CKD 3 and also in patients with malignancy 7 . To the best of our knowledge, this potential interaction has not yet been described in a patient with normal renal function and no other risk factors for developing electrolyte abnormalities.…”

Electrolytes disturbances in cancer patients

“…Similarly, bisphosphonates and denosumab that are routinely used in the treatment of hypercalcemia of malignancy and metastatic bone disease can prevent osteoclastic bone resorption and leaving the osteoblasts activity to be unopposed. Risk factors to develop hypocalcaemia in a patient receiving denosumab and bisphosphonate, include elevated alkaline phosphatase, calcium level at lower end of normal range, reduced kidney function, anaemia and vitamin D deficiency [39][40][41].…”