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Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008 Page 11 of 33

Table 3. Causes of hypocalcemia
Causes of hypocalcemia
Reduction of serum Not ionized calcium: hypoalbuminemia, nephrotic syndrome, liver disease, malnutrition
calcium Ionized calcium: hyperlipidemia, parenteral nutrition enriched of free fatty acid
Extravascular deposition: osteoblastic metastases, pancreatitis
Renal failure Iatrogenic, post-renal obstruction, compression and infiltration by malignancy, tumor lysis syndrome,
hyperuricemia, sepsis, contrast agent nephropathy
Endocrine disorders Vitamin D deficiency or resistance: inadequate dietary intake, reduced absorption due to hepatobiliary or
intestinal malabsorption, liver disease
PTH deficiency or resistance: parathyroidectomy, autoimmune disorders, hungry bone syndrome
Concomitant electrolyte Hypomagnesemia
disorders Hyperphosphatemia
Drugs Antiepileptics: phenytoin, phenobarbital
Anticancer agents: fluorouracil, leucovorin, nab-paclitaxel, estramustine, octreotide, imatinib, axitinib,
panitumumab, cetuximab, cisplatin
Others: bisphosphonates, denosumab, rifampicin, calcium chelators, radiographic contrast agent,
furosemide, foscarnet, EDTA, cinacalcet
PTH: parathyroid hormone

PMCA2 (ATP2B2) is most frequently overexpressed in HER2-receptor-positive breast cancer . Calcium
[66]
channels are also described in androgen-responsive prostate cancer. In fact, they mediate androgen-
induced effects . Transient receptor potential cation channel (TRPC), subfamily C, is a group of
[67]
channels expressed in cancer cells. In breast cancer, TRPC1 correlates with low proliferation and TRPM8
[68]
overexpression correlates with ER-positive and well-differentiated lower-grade breast cancer . In prostate
cancer, TRPM8 expression is regulated by androgens. Decreased expressions of TRPM8 and TRCP1 are
[67]
associated with the progression to androgen-independent phase and poor prognosis . Contrariwise,
TRPV6 ion channel’s expression seems to be controlled by androgen receptors and it is highly expressed
in cancer prostate cells, regardless of androgen dependence, representing a potential biomarker of cancer.
In fact, it is not expressed in the healthy prostate cells and benign prostatic hyperplasia. Furthermore, its
expression correlates with Gleason score and presence of metastases .
[69]

Hypocalcemia
Definition
Hypocalcemia is defined as a lower serum calcium concentration (total serum calcium of < 2.1 mmol/L or
[70]
< 8.5 mg/dL or ionized form of < 1.1 mmol/L or > 4.5 mg/dL) .
Causes
Several causes can induce hypocalcemia in cancer patients [Table 3]:
(1) Cancer: malnutrition due to anorexia, cancer cachexia or bowel obstruction, malabsorption related
to bowel tumor infiltration or previous intestinal surgery, abnormal liver function due to liver metastasis
[70]
might promote the development of hypoalbuminemia and subsequent hypocalcemia . Furthermore,
malabsorption and malnutrition might frequently cause vitamin D deficiency and then hypocalcemia
[70]
in cancer patients . Another condition leading to hypocalcemia is PTH deficiency. It is a common
condition of patients undergoing total thyroidectomy with subtotal or total parathyroidectomy for
[71]
cancer . Paraneoplastic disorders are also involved in hypocalcemia in cancer syndrome. Such as
tumor lysis syndrome or the hungry bone syndrome. The “hungry bone syndrome” is frequent in
metastatic parathyroid and prostate cancer and it is characterized by osteoblastic metastases causing an
increased deposition of calcium and phosphate in bone and decreased serum calcium and phosphate
[72]
concentrations .

(2) Cancer treatment: hypocalcemia is also reported in cancer patients receiving bisphosphonates or
denosumab, an anti-RANKL (receptor activator of nuclear factor kappa B ligand) monoclonal antibody,
employed in cancer patients with bone metastasis in order to delay or prevent skeletal-related events. In