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Page 16 of 33 Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008

Figure 4. Algorithm of hypercalcemia management [48,88,94-104] . To treat hypercalcemia, a correct diagnostic framework is essential,
which is based on the parathyroid dosage to distinguish between hyperparathyroidism and other causes. In the case of low blood PTH
concentrations, the dosage of PTHrP is useful to exclude paraneoplastic hypercalcemia and vitamin D intoxication. PTH: parathyroid
hormone; PTHrP: parathyroid hormone-related protein; MEN: multiple endocrine neoplasia; FHH: familial hypocalciuric hypercalcaemia;
FIHP: familial isolated hyperparathyroidism

Treatment depends on clinical manifestation, grade of hypercalcemia, and underlying cause, which should
be correct whenever possible [Figure 4]. In the case of mild symptoms, serum calcium levels are below
11.5 mg/dL, which could sufficiently remove the cause of hypercalcemia.

In the case of severe hypercalcemia (total serum calcium over 15 mg/dL) or severe symptoms or signs, a
treatment aimed to reduce serum calcium levels is recommended, in order to restore adequate intravascular
[96]
volume and to improve glomerular filtration rate . Since hypercalcemia induces polyuria, most patients
are dehydrated. Therefore, intravenous isotonic saline solution (NaCl 0.9%) should be administered with an
infusion rate of 100/120 mL/h, in order to obtain a urine output of 100-150 mL/h and a reduction of serum
[97]
calcium concentration . Two to three liters of isotonic saline solution/day with a close monitoring of
[98]
serum electrolyte levels and urinary volume is recommended . In patients with edematogenic syndromes
(e.g., congestive heart failure) or anuria isotonic solution should be administered with caution in order to
avoid fluid overload. However, only 30% of patients reach normocalcemia with fluids alone. Loop diuretics
(e.g., furosemide) might be considered mostly in patients with edematogenic syndromes, in whom it is
required to improve diuresis. The use of furosemide should be limited in dehydrated patients or in patients
[99]
presenting other electrolyte abnormalities (magnesium and, potassium) .
In patients with malignant hypercalcemia, salmon calcitonin administration (4-8 IU/kg s.c. or i.m. every
12 h) was demonstrated to control serum calcium levels (estimated a maximal serum calcium drop of
2 mg/dL in 4 h after administration), and it can be used also in patents with renal injuries, in which
intravenous saline is not recommended [100] . Furthermore, calcitonin is more efficacious and quicker
than bisphosphonates in normalizing calcemia and it can be used with bisphosphonates or in the case
of bisphosphonates’ resistance. However, due to the risk of tachyphylaxis, the duration of treatment with
calcitonin should not exceed 48 h [101] .