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Page 14 of 33 Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008

Table 4. Causes of hypercalcemia
Causes of hypercalcemia
Primary hyperparathyroidism Parathyroid adenoma (MEN1 and 2a), parathyroid carcinoma, familial hypocalciuric hypercalcemia,
isolated familial hyperparathyroidism
Secondary hyperparathyroidism Renal failure, lithium, tumors, bone metastasis
Drugs Lithium, thiazide diuretics, calcium containing antacids, vitamin A, estrogens, growth hormone,
vitamin D intoxication, theophylline
Immobilization Spinal cord injury, neurological diseases, pathological fracture, orthopedic surgery
Miscellanea Chronic granulomatous disorders, hyperthyroidism, acromegaly, pheochromocytoma, adrenal
insufficiency, parenteral nutrition

into primary and secondary hyperparathyroidism. Primary hyperparathyroidism, the most common cause
of hypercalcemia in the general population, is characterized by inappropriate secretion of PTH provoking
elevated serum calcium concentrations. Single parathyroid carcinoma is a frequent cause of primary
hyperparathyroidism, sometimes inducing a rare but life-threatening condition, hyperparathyroidism-
induced hypercalcemic crisis characterized by elevated PTH concentrations (3-10 times higher than
[89]
normal values) and serum calcium-levels . Secondary hyperparathyroidism, instead, is characterized by
elevated quantities of PTH, secreted by parathyroids. Several causes might contribute to this mechanism ,
[90]
in particular malnutrition and cancer anorexia are the most common cancer related causes. Malignancies
are an important cause of hypercalcemia. It was described as occurring in 20%-30% of cancer patients,
especially those hospitalized, and it represents one of the most common life-threatening metabolic
disorders . Even though several mechanisms underlay hypercalcemia in cancer patients, it seems to
[91]
be correlated, especially in some kinds of tumors (head and neck, lung, renal cell, ovarian, thyroid,
endometrial, colorectal, breast cancer, hepatocarcinoma, cholangiocarcinoma, thymomas, neuroendocrine
tumors, gastrointestinal stromal tumor, and leukemias), with the ectopic production of PTH or
parathormone-related peptide (PTHrP). These factors seem responsible for osteoclastic activation, through
an increased synthesis of RANKL, provoking bone destruction and calcium release. Furthermore, they
determine an increased renal calcium reabsorption, favoring the development of metastatic calcification
[92]
involving multiple organs, especially lungs, potentially resulting in pulmonary edema . Moreover, bone
metastases, in particular osteolytic ones, are often associated to hypercalcemia due to calcium release from
bone. It represents a common cause of hypercalcemia, occurring in approximately 20% of patients with
malignancy-related hypercalcemia. Bone metastasis releases several local factors, e.g., transforming growth
factor β, RANKL, lymphotoxin, interleukin-1, interleukin-6, hepatocyte growth factor, and macrophage
inflammatory protein (MIP-1alfa), that favor the release of PTHrP and bone remodeling resulting in
[93]
hypercalcemia . Rarely, hypercalcemia might be due to ectopic activity of 1-alpha-hydroxylase resulting in
calcitriol production that promotes increased bone resorption with calcium release and intestinal calcium
absorption. This mechanism is described in some kinds of tumors such as lymphomas (lymphoma-
[88]
associated calcitriol production) and ovarian germ cell tumors . Finally, immobilization due to bedridden
patients, a common condition of advanced cancer, can favor an acceleration of bone resorption resulting in
[94]
hypercalcemia .
(2) Cancer treatment: antineoplastic drugs can indirectly cause hypercalcemia, for example through kidney
[88]
damage .
(3) Concomitant drugs: several drugs might cause hypercalcemia. Thiazide diuretics, vitamin D
intoxication, and parenteral nutrition are the most common agents involved in this electrolyte disorder in
cancer patients.

(4) Concomitant diseases: several pathological conditions might cause hypercalcemia. It may depend
on excess of PTH (primary hyperparathyroidism due to parathyroid adenoma, familial hypocalciuric
hypercalcemia, isolated familial hyperparathyroidism, or most commonly secondary hyperparathyroidism