Hypercalcaemia and hypocalcaemia: finding the balance

Abstract

Calcium metabolism in cancer and hypercalcaemia of malignancy: The balance between bone formation and resorption may be disrupted in patients with cancer, leading either to increased bone resorption, calcium release, and possibly hypercalcaemia, or to increased bone formation, sequestration of calcium, and possibly hypocalcaemia. In adults, hypercalcaemia of malignancy is most common in patients with tumours that produce factors that induce osteoclast activation and enhance bone resorption. Impaired renal function and increased renal tubular calcium resorption may further affect calcium levels.

Treatment of hypercalcaemia of malignancy: Inhibitors of bone resorption, first the bisphosphonates and, later, denosumab, have been shown to be effective in hypercalcaemia treatment. Bisphosphonates (which are administered intravenously) are approved for hypercalcaemia of malignancy and are the current mainstay of treatment, whereas denosumab (which is administered subcutaneously) may offer an option for patients who do not respond to bisphosphonates or suffer from renal insufficiency.

Hypocalcaemia: TREATMENT AND PREVENTION: Hypocalcaemia is most common in patients with prostate cancer and osteoblastic bone metastases, but can occur in patients with a variety of tumour types who are receiving inhibitors of bone resorption. While patients often respond to calcium and vitamin D supplementation, prevention should be the aim; at-risk patients should be identified before starting treatment with inhibitors of bone resorption, be closely monitored during at least the first few months of treatment, and receive concomitant calcium and vitamin D supplementation unless hypercalcaemia is present.

Conclusion: Both hypercalcaemia and hypocalcaemia can be serious if left untreated. It is therefore important that patients with cancer are closely monitored and receive adequate prevention and treatment measures to maintain normal blood calcium levels.

Keywords: Bisphosphonates; Denosumab; Hypercalcaemia; Hypercalcaemia of malignancy; Hypocalcaemia.

Fig. 1

Mechanisms underlying osteolytic and osteoblastic metastasis. Adapted from Cell, Vol: 151, Ell B. and Kang Y. Snapshot: bone metastasis, Pages: 690–90. Copyright (2015), with permission from Elsevier [3]. BMP bone morphogenetic protein, CSF-1 colony-stimulating factor 1, DKK1 Dickkopf Wnt signalling pathway inhibitor 1, ET-1 endothelin 1, FGF fibroblast growth factor, GM-CSF granulocyte-macrophage colony-stimulating factor, IGF insulin-like growth factor, IGF 1/2 insulin-like growth factor 1/2, IL-6 interleukin 6, IL-8 interleukin 8, MIP-1a macrophage inflammatory protein 1 alpha, MMP matrix metalloproteinase, PSA prostate-specific antigen, PTHrP parathyroid hormone-related protein, RANK receptor activator of nuclear factor kappa B, RANKL receptor activator of nuclear factor kappa B ligand, SPARC secreted protein acidic and cysteine rich, TGF transforming growth factor beta, VEGF vascular endothelial growth factor, Wnt1 wingless-type MMTV integration site family member 1

Fig. 2

Responses to treatment with bisphosphonates or denosumab. a Proportion of patients demonstrating a complete response at day 10 in a pooled analysis of two randomised, double-blind phase 3 trials of patients with moderate-to-severe hypercalcaemia of malignancy who received zoledronic acid or pamidronate (N = 275). Complete response was defined as CSC ≤ 10.8 mg/dL (2.7 mmol/L). [52]. b Proportion of patients demonstrating a response or complete response at day 10 in a single-arm, open-label study of patients who had hypercalcaemia of malignancy (CSC levels >12.5 mg/dL [3.125 mmol/L]) despite receiving bisphosphonate treatment. During the study, patients (N = 33) received denosumab 120 mg s.c. and response was defined as CSC < 11.5 mg/dL (2.9 mmol/L; CTCAE grade 0 or 1). Complete response was defined as CSC ≤ 10.8 mg/dL (2.7 mmol/L). [53]. *P = 0.002 versus pamidronate. CSC albumin-corrected serum calcium, CTCAE Common Terminology Criteria for Adverse Events, i.v. intravenous, s.c. subcutaneous

Fig. 3

Incidence of laboratory grade ≥ 2 hypocalcaemia by tumour type. Reproduced with permission from European Journal of Cancer, Vol: 51, Body JJ et al. Pages: 1812–1821 (10.1016/j.ejca.2015.05.016) Copyright (2015), with permission from Elsevier (https://creativecommons.org/licenses/by-nc-nd/2.0/) [29]. NSCLC non-small-cell lung cancer, SCLC small-cell lung cancer