Hypercalcemia of malignancy

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

mild hypercalcemia or asymptomatic moderate hypercalcemia

1st line – treatment of underlying malignancy + supportive measures + monitoring

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1st line –

treatment of underlying malignancy + supportive measures + monitoring

Treatment is based on severity of hypercalcemia and symptoms. 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).

Maintain adequate hydration and 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 asymptomatic moderate hypercalcemia 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]

Therapy for hypercalcemia should be initiated for symptomatic patients with moderate or severe hypercalcemia (serum calcium concentration >12.0 mg/dL [>3.0 mmol/L]).[2][6]

Long-term maintenance of normocalcemia requires eradication of the underlying malignancy.

Serial monitoring of calcium is important.

symptomatic moderate or severe hypercalcemia: without advanced kidney disease

1st line – intravenous normal saline

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1st line –

intravenous normal saline

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).

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.

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]

Plus – intravenous bisphosphonate or denosumab

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Plus –

intravenous bisphosphonate or denosumab

Treatment recommended for ALL patients in selected patient group

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 generally takes 2-3 days.[4] Options include pamidronate and zoledronic acid, which are both 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]

If hypercalcemia is improved with the initial infusion of bisphosphonate, but serum calcium levels begin to increase again, the bisphosphonate infusion may be repeated: in 7 days, and then every 3-4 weeks thereafter (zoledronic acid); every 2-3 weeks (pamidronate).[6]

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

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. Regular monitoring of calcium levels is also important.

Primary options

pamidronate: 60-90 mg intravenous infusion given over 2-24 hours (dose depends on serum calcium level); dose may be repeated every 2-3 weeks if necessary

zoledronic acid 4 mg injection: 4 mg intravenous infusion given over at least 15 minutes; dose may be repeated after 7 days if necessary and then every 3-4 weeks thereafter

Secondary options

denosumab: consult specialist for guidance on dose

Consider – calcitonin (while awaiting effect of bisphosphonate or denosumab)

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Consider –

calcitonin (while awaiting effect of bisphosphonate or denosumab)

Treatment recommended for SOME patients in selected patient group

Calcitonin interferes with osteoclastic bone resorption and renal tubular reabsorption of calcium.[1][2] It may effect a more rapid correction of hypercalcemia than initial treatment with a bisphosphonate or denosumab alone.[29][30] The clinical utility of calcitonin is limited by its transient effect and 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]

Primary options

calcitonin-salmon: 4-8 units/kg intramuscularly/subcutaneously every 6-12 hours

Consider – furosemide

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Consider –

furosemide

Treatment recommended for SOME patients in selected patient group

Furosemide is a loop diuretic reserved for managing fluid overload in conjunction with intravenous hydration. The initial dose is variable.

Caution should be taken to avoid overdiuresis, which depletes sodium stores relative to calcium, causing intravascular volume depletion and worsening hypercalcemia.[10]

Primary options

furosemide: consult specialist for guidance on dose

Plus – avoidance of exacerbating medications

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Plus –

avoidance of exacerbating medications

Treatment recommended for ALL patients in selected patient group

It is important to avoid medications that can worsen hypercalcemia (e.g., thiazide diuretics, calcitriol [(1,25-dihydroxyvitamin D)], calcium supplementation, antacids, lithium) and those that may worsen symptoms of hypercalcemia (e.g., sedatives, hypnotics, analgesics, if possible).[1][10]

Plus – treatment of underlying malignancy

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Plus –

treatment of underlying malignancy

Treatment recommended for ALL patients in selected patient group

Long-term maintenance of normocalcemia requires eradication of the underlying malignancy.

If hypercalcemia is secondary to the rare occurrence of ectopic parathyroid hormone secretion by the underlying malignancy, removal of the primary malignancy 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.

with established calcitriol (1,25-dihydroxyvitamin D)-mediated hypercalcemia

Plus – corticosteroid

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Plus –

corticosteroid

Treatment recommended for ALL patients in selected patient group

Once the results of additional tests are available, further targeted treatment can be started for calcitriol (1,25-dihydroxyvitamin D)-induced hypercalcemia.

Glucocorticoid therapy may be efficacious. Endocrine Society guidelines provide advice on dosing and duration of therapy.[1][6]

Primary options

prednisone: 60 mg orally once daily for 10 days; or 10-20 mg orally once daily for 7 days

hydrocortisone sodium succinate: 200-400 mg/day intravenously for 3-5 days

symptomatic moderate or severe hypercalcemia: with advanced kidney disease

1st line – renal dialysis ± denosumab

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1st line –

renal dialysis ± denosumab

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]

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.

Primary options

denosumab: consult specialist for guidance on dose

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Hypercalcemia of malignancy

Treatment algorithm

mild hypercalcemia or asymptomatic moderate hypercalcemia

treatment of underlying malignancy + supportive measures + monitoring

symptomatic moderate or severe hypercalcemia: without advanced kidney disease

intravenous normal saline

intravenous bisphosphonate or denosumab

Primary options

Secondary options

calcitonin (while awaiting effect of bisphosphonate or denosumab)

Primary options

furosemide

Primary options

avoidance of exacerbating medications

treatment of underlying malignancy

corticosteroid

Primary options

symptomatic moderate or severe hypercalcemia: with advanced kidney disease

renal dialysis ± denosumab

Primary options