The management of hypercalcaemia should be addressed at the underlying cause/ mechanisms and the prevention/ management of target organ damages. The timing and the type of therapy are related to the cause and severity of hypercalcaemia, clinical symptoms, and renal function impairment. When hypercalcaemia is mild and the underlying cause has been identified, the treatment could be limited at the underlying cause. When hypercalcaemia in moderate to severe, the aim is also and most importantly directed to decrease serum calcium, by increasing renal calcium excretion and decreasing bone resorption and intestinal calcium absorption.
increase Renal calcium Excretion
Dehydration occurs in hypercalcaemic states because of a decreased fluid intake due to anorexia, nausea and vomiting, and polyuria due to a decreased renal water reabsorption. Therefore, signs and symptoms of vascular volume depletion are present in patients with hypercalcaemia. Hydration should be the first therapeutic approach to promote extracellular volume expansion, using oral fluids in patients with mild hypercalcaemia and intravenous saline in those with severe hypercalcaemia.
Patients with severe hypercalcaemia require an immediate treatment which includes intravenous 0.9% saline administration 3– 4 litres per day or a bolus of 1– 2 litres followed by 200– 250 ml saline/ hour. Patients with heart or kidney failure should be carefully monitored for the risk of fluid overload. After volume expansion, loop diuretics, such as furosemide, may be considered to further increase renal calcium excretion, but caution is mandatory for the risk of dehydration and electrolytes imbalance. This view is not generally accepted nowadays. As a matter of fact, a metanalysis published in 2008 did not show benefit of adding loop diuretics to hydration in RCT. When the aforementioned treatments fail, haemodialysis with low- calcium dialysate could be an option, which does not treat the cause of hypercalcaemia, but leads to a rapid solution in emergency situations. Some studies have shown that continuous veno- venus haemofiltration using citrate as calcium chelator could be more effective that haemodialysis. Haemodialysis may be complicated by infections, thromboembolism, and hypotension.
Decrease Bone Resorption
Increased osteoclastic activity and bone resorption is the most common mechanism responsible of hypercalcaemia. Bisphosphonates decrease bone resorption by several mechanisms: inhibition of monocyte/ macrophages differentiation into mature osteoclasts, increased osteoclasts apoptosis, and binding to hydroxyapatite crystals thus decreasing their degradation. The use of bisphosphonates is limited to patients with moderate- to- severe hypercalcaemia. The intravenous route is preferable since bisphosphonates are poorly adsorbed when given orally and large doses are needed. Etidronate and clodronate were initially used but have been subsequently replaced by the novel and more po tent aminobisphosphonates. Pamidronate and zoledronate have been approved by the Food and Drug Administration (FDA) in the United States and by the European Medicines Agency (EMEA) in Europe for the management of hypercalcaemia of malignancy. Both agents have proved their efficacy and safety in several randomized clinical trials. Either pamidronic acid or zoledronic acid should be started as soon as possible, because both require 48– 72 hours for the initial response and the serum calcium nadir is obtained 4– 7 days after the intravenous administration. Zoledronic acid compared with pamidronic acid has a more rapid onset of action and greater hypocalcaemic effect. Zoledronic acid is usu ally administered at the dose of 4 mg in 100 ml of saline over 15 minutes and normocalcaemic state is restored in a few days in the large majority of patients. In patients with kidney failure and serum creatinine exceeding 3 mg/ dl, the American Society of Oncology recommends a reduction in the dose of zoledronic acid, because of potential nephrotoxic effect. A worsening of renal failure has been reported after multiple infusions of zoledronic acid. When there are concerns for renal toxicity, ibandronate, a less potent but less toxic bisphosphonate, could be used. Subcutaneous administration of clodronate is an option in those endstage cancer patients who need domiciliary therapy.
Calcitonin also is effective in rapidly reducing serum calcium and its effect begins within 2 hours. Salmon calcitonin is generally more effective than human calcitonin and is preferably used at the dose of 4– 8 units/ kg of body weight, either intramuscularly or subcutaneously. However, tolerance to the drug (or tachyphylaxis) generally occurs and the hypocalcaemic effect wanes. In clinical practice calcitonin could be used when a rapid hypocalcaemic effect is aimed, while waiting for the more potent hypocalcaemic effect of bisphosphonates.
Denosumab, a fully human monoclonal antibody directed to the RANK ligand, decreases osteoclasts differentiation and survival. Denosumab is approved for the management of postmenopausal osteoporosis and in the prevention and management of osteo porosis due to adjuvant therapy in patients with breast and prostate cancers. Preclinical studies in a mice model of malignant hypercalcaemia due to PTHrP showed that denosumab rapidly decreases serum calcium. Recently some case reports have shown a potent hypocalcaemic effect of denosumab in cancer patients [89, 90]. The value of denosumab in the management of hypercalcaemia of malignancy has been further proved in a single- arm, multicentre, international phase II study who enrolled 33 patients with malignant hypercalcaemia and no- response to bisphosphonates treatment. Patients were treated with 120 mg sc of denosumab every 4 weeks. The large majority (70%) of patients shoved a decrease of serum calcium from 13.7 mg/ dl to value ≤11.5 mg/ dl and 64% reached serum calcium levels ≤10.8 mg/ dl; the median duration of response was 104 days. Serious adverse events were reported in two cases. In 2014 the FDA approved denosumab for the treatment of malignant hypercalcaemia refractory to bisphosphonate therapy. More recently a meta- analysis of two randomized double- blind trials in cancer patients with bone metastases has shown that denosumab treatment significantly delayed, compared to zoledronic acid, the occurrence of malignant hypercalcaemia.
Preclinical studies, in a mice model of PTHrP- dependent malignant hypercalcaemia administration of monoclonal PTHrP antibodies was shown to have a hypocalcaemic effect, opening the potential development of this therapeutic approach also in selected cases in humans.
Decrease intestinal calcium Absorption
Increased intestinal calcium absorption contributes to the development of hypercalcaemia, particularly when due to vitamin D in toxication. A general measure in these patients consists of avoiding calcium and vitamin D intake. Glucocorticoids represent the first- choice option, because of their inhibitory effect on 1α hydroxylase enzyme, thus reducing intestinal calcium absorption. No guidelines are available to guide this treatment: a generally accepted schedule is the intravenous administration of hydrocortisone at a daily dose of 200– 400 mg for 3– 5 days, followed by oral daily prednisone at the dose of 10– 20 mg for 7 days.
calcimimetics
Cinacalcet, a calcimimetic agent, is approved for the management of hypercalcaemia in patients with PHPT, in whom parathyroidectomy would be indicated on the basis of serum calcium concentration but not performed because contraindicated or refused by the patient. The efficacy of cinacalcet in lowering and often normalizing serum calcium has been shown in several PHPT settings, including patients with intractable hypercalcaemia related to parathyroid cancer. Interestingly, cinacalcet was effective in reducing hypercalcaemia in two cases of humoral malignant hypercalcaemia due to metastatic renal cell and breast carcinomas.
