What is the initial management for an adult patient with hypercalcaemia, likely due to malignancy or other underlying medical conditions?

Management of Hypercalcaemia

Immediately initiate aggressive IV normal saline hydration (2-3 liters/day) targeting urine output of 100-150 mL/hour, followed by zoledronic acid 4 mg IV infused over 15 minutes as first-line definitive therapy. 1, 2

Immediate Assessment and Severity Classification

Measure corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4.0 - patient albumin (g/dL)], or preferably measure ionized calcium directly to avoid pseudo-hypercalcaemia from hemolysis or improper sampling. 1, 2, 3

Classify severity to determine urgency of intervention: 1, 2

• Mild: 10-11 mg/dL (2.5-2.75 mmol/L)
• Moderate: 11-13.5 mg/dL (2.75-3.4 mmol/L)
• Severe: >14 mg/dL (>3.5 mmol/L)

Obtain diagnostic workup including serum intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, phosphorus, creatinine, and BUN to determine underlying cause. 1, 2, 3 Malignancy-associated hypercalcaemia is characterized by suppressed iPTH levels, elevated PTHrP, and low or normal calcitriol levels. 2

Initial Rehydration Protocol

Administer IV normal saline aggressively with boluses of 250-500 mL every 15 minutes until rehydration is achieved, then continue at 2-3 liters per day. 1, 2 This corrects hypercalcaemia-associated hypovolemia and promotes calciuresis. 1

Target urine output of 100-150 mL/hour (3 mL/kg/hour in children <10 kg). 1, 2 Continue hydration to maintain diuresis >2.5 L/day in adults while waiting for bisphosphonates to take effect. 1

Monitor fluid status carefully to avoid hypervolemia, especially in patients with cardiac or renal insufficiency. 3 Loop diuretics (furosemide) should only be used after complete volume repletion and only in patients at risk of congestive heart failure—never before adequate rehydration. 3, 4

Definitive Bisphosphonate Therapy

Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred first-line bisphosphonate, superior to pamidronate in both efficacy and duration of response. 1, 2, 4 Zoledronic acid normalizes calcium in approximately 50% of patients by day 4, compared to 33% with pamidronate. 1, 2

Do not delay bisphosphonate administration—initiate zoledronic acid early without waiting for completion of rehydration. 3 The 4 mg dose is recommended for initial treatment; reserve the 8 mg dose only for relapsed or refractory cases. 1, 2

For patients with impaired renal function (CrCl <60 mL/min), dose adjustments are required: 4

• CrCl 50-60 mL/min: 3.5 mg
• CrCl 40-49 mL/min: 3.3 mg
• CrCl 30-39 mL/min: 3.0 mg

Pamidronate 60-90 mg IV over 2-4 hours is an alternative if zoledronic acid is unavailable. 3, 5 For moderate hypercalcaemia (corrected calcium 12-13.5 mg/dL), use 60-90 mg; for severe hypercalcaemia (>13.5 mg/dL), use 90 mg. 5 However, pamidronate has slower onset and shorter duration than zoledronic acid. 6

Adjunctive Rapid-Acting Therapy

Calcitonin 100 IU subcutaneously or intramuscularly provides rapid onset within hours but has limited efficacy and tachyphylaxis develops quickly. 2, 3 Use calcitonin only as a bridge therapy in severe symptomatic hypercalcaemia while waiting for bisphosphonates to take effect—it is not a standalone treatment. 3, 7

Corticosteroids (prednisone 20-40 mg/day orally or methylprednisolone IV equivalent) are indicated specifically for hypercalcaemia due to excessive intestinal calcium absorption: vitamin D intoxication, granulomatous diseases (sarcoidosis), some lymphomas, and multiple myeloma. 3 Corticosteroids are not effective for most solid tumor malignancies. 7, 8

Refractory or Special Situations

Denosumab 120 mg subcutaneously is indicated for bisphosphonate-refractory hypercalcaemia, reducing serum calcium in 64% of patients within 10 days. 1, 2, 9 Denosumab is preferred over bisphosphonates in patients with renal disease (CrCl <30 mL/min or serum creatinine >3.0 mg/dL) as it does not require renal dose adjustment. 1, 2, 9

For hypercalcaemia of malignancy with loading: Administer denosumab 120 mg on Day 1, Day 8, and Day 15, then every 4 weeks thereafter. 9

Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for severe hypercalcaemia complicated by renal insufficiency or oliguria unresponsive to medical therapy. 2, 3, 8

Critical Monitoring Parameters

Monitor serum calcium, creatinine, and electrolytes (especially potassium and magnesium) every 6-12 hours during the acute phase. 1, 3

Measure serum creatinine before each dose of zoledronic acid. 1, 4 Discontinue bisphosphonates if: 2

• Unexplained albuminuria >500 mg/24 hours
• Serum creatinine increases >0.5 mg/dL
• Absolute creatinine >1.4 mg/dL in patients with normal baseline

Perform baseline dental examination before initiating bisphosphonate therapy to prevent osteonecrosis of the jaw (ONJ). 1, 2, 4 Monitor for ONJ symptoms throughout treatment, especially with chronic use. 1, 4

Monitor calcium levels closely post-treatment due to higher risk of hypocalcaemia with denosumab compared to bisphosphonates. 1, 9 Correct pre-existing hypocalcaemia before initiating denosumab and supplement all patients with calcium 500 mg plus vitamin D 400 IU daily during treatment. 3, 9

Essential Pitfalls to Avoid

Never use loop diuretics before adequate volume repletion—this worsens dehydration and renal function. 3, 4

Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent further deterioration of kidney function. 2, 3

Do not exceed 4 mg zoledronic acid for initial treatment and ensure infusion duration is at least 15 minutes to minimize renal toxicity. 1, 4 Single doses exceeding 4 mg or infusions <15 minutes significantly increase risk of renal failure. 4

Do not store undiluted zoledronic acid in a syringe to avoid inadvertent injection. 4

Immediately discontinue all calcium and vitamin D supplements in the acute setting. 3 Also stop calcium-based phosphate binders and vitamin D analogues (calcitriol, paricalcitol) if patient has CKD. 3

Prognostic Considerations

Median survival after discovery of malignant hypercalcaemia in lung cancer patients is approximately 1 month. 1, 2 Both hypercalcaemia and delirium are independent negative prognostic factors for survival in cancer patients. 1

Treatment of the underlying malignancy is essential for long-term control of hypercalcaemia. 1, 2 For patients with poor prognosis and no viable treatment options, the most humane course may be no treatment at all since encephalopathy will cloud consciousness. 8

Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases, as this reduces skeletal-related events by 41% and significantly reduces bone pain. 3