Approach

Therapy directed at hypercalcemia can temporarily restore normocalcemia. Long-term maintenance of normocalcemia requires eradication of the underlying malignancy.

While there is no universally accepted classification of mild, moderate, or severe hypercalcemia, the following criteria are widely used:[6][7][8]

  • Mild hypercalcemia: total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4 to 2.0 mmol/L)

  • Moderate hypercalcemia: total calcium of 12.0 to 13.9 mg/dL (3.0 to 3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L)

  • Severe hypercalcemia: 14 mg/dL or greater (≥3.5 mmol/L) or ionized calcium of 10 to 12 mg/dL (2.5 to 3.0 mmol/L).

Supportive measures and monitoring

For all patients with hypercalcemia of malignancy, maintain adequate hydration. Ensure any medications that can worsen hypercalcemia (e.g., thiazide diuretics, calcitriol [(1,25-dihydroxyvitamin D)], calcium supplementation, antacids, lithium) or worsen symptoms of hypercalcemia (e.g., sedatives, hypnotics, analgesics) are avoided, if possible.[1][10]

Patients with mild hypercalcemia or with moderate hypercalcemia who are asymptomatic should be monitored, have adequate fluid intake, and receive treatment for the underlying malignancy. Serum calcium should be tested again after 1 week to confirm the diagnosis.[13]

Initiation of treatment

Therapy for hypercalcemia should be initiated for symptomatic patients with moderate or severe hypercalcemia (serum calcium concentrations >12.0 mg/dL [>3.0 mmol/L]).[2][6] If the person has severe hypercalcemia or severe symptoms, emergency hospital admission should be arranged.[13] 

Once the presence of moderate or severe hypercalcemia has been established, treatment with intravenous normal saline, an antiresorptive agent (intravenous bisphosphonate or denosumab), and calcitonin (for patients with severe hypercalcemia) can begin immediately.

In cases of hypercalcemic crisis, urgent initiation of therapy is required to achieve adequate diuresis. Once the results of additional tests are available, further targeted treatment can be started, mainly for calcitriol (1,25-dihydroxyvitamin D)-induced hypercalcemia. For parathyroid hormone-related peptide (PTHrP)-induced hypercalcemia, humoral hypercalcemia, and hypercalcemia due to metastatic skeletal involvement, no additional specific treatments are available other than treatment of the underlying malignancy.

First-line therapy

  • Intravenous normal saline reverses dehydration secondary to hypercalcemia-induced nephrogenic diabetes insipidus in addition to oral hydration, and promotes calciuresis.[1] An initial bolus of 1-2 L should be administered, followed by 200-500 mL/hour depending on volume status, cardiac function, and kidney function.[6]​​

  • Intravenous bisphosphonates are the most effective agents for treating malignancy-associated hypercalcemia. Bisphosphonates effectively block osteoclastic bone resorption. Therapy should be instituted immediately upon diagnosis, because response takes 2-3 days.[4]​ Options include pamidronate or zoledronic acid, which are administered as a single dose.[1][10][26]​​​ Although one study suggests that zoledronic acid is superior to pamidronate, the evidence overall is unclear and both are acceptable options.[1][27]​ Potential adverse effects associated with intravenous bisphosphonate therapy include transient flu-like syndrome with aches/chills/fever, acute kidney injury, acute osteonecrosis of the jaw, and hypocalcemia if high-dose bisphosphonates are given to hypercalcemic patients with critical vitamin D deficiency.​[2][4]​[5][27]

  • Denosumab (a monoclonal antibody directed against the receptor activator of nuclear factor-KappaB ligand [RANKL]) is also an option for treating hypercalcemia of malignancy.[6][20]​ It reduces osteoclast differentiation and bone resorption. It is easier to administer (subcutaneous injection) than intravenous bisphosphonates and requires less monitoring of renal function. In the US, denosumab is approved for treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. Endocrine Society guidelines recommend denosumab as an alternative to first-line bisphosphonate therapy and favor its use in patients with renal impairment.[6] The guidelines also suggest that it may be used in preference to bisphosphonates for patients with moderate hypercalcemia. However, the recommendation is based on indirect evidence from randomized trials assessing outcomes such as skeletal-related events and hypocalcemia rather than hypercalcemia. Potential adverse effects of denosumab include skin infections, acute osteonecrosis of the jaw, and hypocalcemia in patients with vitamin D deficiency. Rebound hypercalcemia has been observed in patients taking denosumab. In June 2018, the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued a safety alert following a pooled analysis of four phase 3 studies of denosumab in patients with advanced malignancies involving bone.[28]​ New primary malignancies were reported more frequently among patients receiving denosumab than those receiving zoledronic acid (cumulative incidence of new primary malignancy at 1 year was 1.1% for denosumab and 0.6% for zoledronic acid). No treatment-related patterns for individual cancers or cancer groupings were identified. It is not known whether there is an increased risk of new primary malignancy when denosumab is prescribed for the treatment of hypercalcemia of malignancy.

  • ​​Measure vitamin D (and correct if deficient) prior to administration of a bisphosphonate or denosumab to avoid the risk of hypocalcemia.[2] Regular monitoring of calcium levels is also important.

Adjunctive therapies to consider

  • Calcitonin interferes with osteoclastic bone resorption and renal tubular reabsorption of calcium.[1][2]​​ It may effect a more rapid correction of hypercalcemia than bisphosphonates or denosumab alone.[29][30]​​ The clinical utility of calcitonin is limited by its transient effect and lack of availability.[1][10][29][30]​​ A combination of calcitonin and a bisphosphonate or denosumab should be used for initial treatment of severe hypercalcemia.[6] Calcitonin treatment should be limited to 48-72 hours while awaiting the therapeutic effect of bisphosphonate or denosumab therapy.[6][31]​ Potential adverse effects include flushing and nausea.[1]

  • Furosemide is reserved for managing fluid overload in conjunction with intravenous hydration. Caution should be taken to avoid overdiuresis, which depletes sodium stores relative to calcium, causing intravascular volume depletion and worsening hypercalcemia.[10]

Recurrent or refractory hypercalcemia

  • If hypercalcemia is improved with the initial infusion of bisphosphonate, but serum calcium levels begin to increase again, the bisphosphonate infusion may be repeated:[6]

    • in 7 days, and then every 3-4 weeks thereafter (zoledronic acid)

    • every 2-3 weeks (pamidronate).

  • Endocrine Society guidelines recommend that denosumab should be used for patients with recurrent or refractory hypercalcemia on an intravenous bisphosphonate.[6]

Therapy in advanced kidney disease

  • Dialysis can be considered in patients who have cancers that are likely to respond to therapy, but in whom renal and cardiac function limits utilization of intravenous hydration or accepted pharmacologic therapy.[1][32]

  • Denosumab may be considered as an adjunct to dialysis.[33] However, patients with severe renal impairment (creatinine clearance <30 mL/minute) or who are receiving dialysis are at increased risk for hypocalcemia. Regular monitoring of calcium levels is important.

Calcitriol (1,25-dihydroxyvitamin D)-mediated hypercalcemia

Glucocorticoid therapy may be efficacious in treating calcitriol (1,25-dihydroxyvitamin D)-mediated hypercalcemia. Endocrine Society guidelines provide advice on dosing and duration of therapy.​[6]

An intravenous bisphosphonate or denosumab may be added to glucocorticoid therapy in patients already receiving glucocorticoid therapy who continue to have severe or symptomatic hypercalcemia.[6]

Ectopic parathyroid hormone production

Removal of primary malignancy/ectopic parathyroid hormone-secreting source can reverse hypercalcemia.[34]

If surgery is not possible or further management of hypercalcemia is needed for patients with parathyroid carcinoma, treatment options may include cinacalcet or an intravenous bisphosphonate or denosumab. Endocrine Society guidelines include advice on dosing and duration of therapy, and second-line treatment.[6]​ See Primary hyperparathyroidism.

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