How should hypercalcemia be evaluated and managed, including initial stabilization, cause‑directed therapy, and refractory cases?

Hypercalcemia: Evaluation and Management

Initial Diagnostic Workup

Measure serum intact parathyroid hormone (PTH) immediately alongside ionized calcium (or corrected calcium), albumin, comprehensive metabolic panel, phosphorus, and magnesium to distinguish PTH-dependent from PTH-independent causes. 1, 2, 3

• Elevated or inappropriately normal PTH with hypercalcemia confirms primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) indicates malignancy or other PTH-independent causes. 1, 4
• Calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)]. 2, 3
• Ionized calcium is preferred when available to avoid pseudo-hypercalcemia from hemolysis or improper sampling. 1, 2

Additional Testing Based on PTH Results

If PTH is suppressed (<20 pg/mL):

• Measure PTH-related protein (PTHrP) to evaluate for malignancy-associated hypercalcemia, particularly with rapid onset, weight loss, or known cancer. 3
• Measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together—elevated 1,25-dihydroxyvitamin D despite low 25-hydroxyvitamin D suggests granulomatous disease or lymphoma. 2, 3
• Order age-appropriate cancer screening, chest imaging, and serum/urine protein electrophoresis if multiple myeloma is suspected. 3

If PTH is elevated or normal:

• Confirm 25-hydroxyvitamin D status to exclude secondary hyperparathyroidism masquerading as primary disease. 3
• Order 24-hour urine calcium or spot urine calcium/creatinine ratio to assess hypercalciuria and kidney stone risk. 3
• Obtain renal ultrasound for nephrocalcinosis or kidney stones and bone density scan to assess osteoporosis. 3

Medication and Supplement Review

• Document thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), vitamin A, calcium-based phosphate binders, and calcitriol/vitamin D analogs. 2, 3

---

Severity Classification and Initial Stabilization

Severity Definitions

• Mild: 10-11 mg/dL (2.5-2.75 mmol/L) 1
• Moderate: 11-12 mg/dL (2.75-3.0 mmol/L) 1
• Severe: >14 mg/dL (>3.5 mmol/L) 1

Immediate Management Algorithm

For moderate to severe hypercalcemia (≥11 mg/dL), initiate aggressive IV normal saline hydration immediately to correct hypovolemia and promote calciuresis, targeting urine output ≥100 mL/hour. 1, 2

• Administer boluses of 250-500 mL crystalloids every 15 minutes until rehydration is achieved, then maintain diuresis of 100-150 mL/hour. 2
• Avoid loop diuretics (furosemide) until complete volume repletion is achieved—premature use worsens dehydration and aggravates hypercalcemia. 2, 5
• Loop diuretics are reserved only for patients with renal or cardiac insufficiency to prevent fluid overload after adequate hydration. 1, 2

Discontinue Offending Agents Immediately

• Stop all calcium supplements, vitamin D supplements, calcium-based phosphate binders, and thiazide diuretics immediately. 2, 3
• Discontinue calcitriol and vitamin D analogs even if 25-hydroxyvitamin D levels are low, as supplementation worsens hypercalcemia. 2

---

Definitive Pharmacologic Treatment

First-Line: Bisphosphonates

Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate for moderate to severe hypercalcemia, with superior efficacy compared to pamidronate. 1, 2, 4

• Zoledronic acid normalizes calcium in 50% of patients by day 4, with infusion time of only 15 minutes versus 2 hours for pamidronate. 2
• Do not delay bisphosphonate therapy—initiate early without waiting for completion of rehydration, as bisphosphonates take 2-4 days to lower calcium. 1, 2
• Pamidronate 60-90 mg IV over 2-24 hours is an alternative if zoledronic acid is unavailable. 6

Renal dosing adjustments:

• Check serum creatinine before each bisphosphonate dose and withhold if renal deterioration occurs (increase >0.5 mg/dL from normal baseline or >1.0 mg/dL from abnormal baseline). 2, 6
• For creatinine clearance <60 mL/min, reduce zoledronic acid dose or consider denosumab. 2

Monitoring and prevention:

• Perform baseline dental examination before initiating bisphosphonates to prevent osteonecrosis of the jaw (ONJ). 2
• Monitor serum calcium, creatinine, and electrolytes every 6-12 hours until stable. 1, 2
• Discontinue bisphosphonates if unexplained albuminuria >500 mg/24 hours or serum creatinine increases as above. 2

Rapid-Acting Adjunct: Calcitonin

Calcitonin 4 IU/kg subcutaneously or intramuscularly every 12 hours provides rapid calcium reduction within 4-6 hours but has limited efficacy and tachyphylaxis develops within 48 hours. 1, 2

• Use calcitonin as a bridge until bisphosphonates take effect, particularly in severe symptomatic hypercalcemia. 2, 7
• Combining calcitonin with bisphosphonates enhances the rate of calcium decline. 8

Refractory or Severe Hypercalcemia with Renal Failure

Denosumab 120 mg subcutaneously is preferred for patients with impaired renal function (creatinine clearance <30 mL/min), with lower rates of renal toxicity but higher risk of hypocalcemia. 2, 4

• Denosumab lowers calcium in 64% of patients within 10 days for bisphosphonate-refractory hypercalcemia. 2
• Correct hypocalcemia before initiating denosumab and administer oral calcium 500 mg plus vitamin D 400 IU daily during treatment to prevent severe hypocalcemia. 2

Dialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for severe hypercalcemia (>14 mg/dL) complicated by renal insufficiency or oliguria. 1, 2, 9

---

Cause-Directed Therapy

Malignancy-Associated Hypercalcemia

• Hydration plus zoledronic acid 4 mg IV is the cornerstone of treatment. 2
• For multiple myeloma: Add corticosteroids (prednisone 20-40 mg/day or methylprednisolone IV equivalent) and continue bisphosphonates for up to 2 years. 2
• Plasmapheresis is adjunctive therapy for symptomatic hyperviscosity in multiple myeloma. 2
• Treat the underlying cancer when possible—median survival with malignancy-associated hypercalcemia is approximately 1 month. 2, 4

Granulomatous Disease and Vitamin D Intoxication

Corticosteroids are primary therapy for hypercalcemia due to excessive intestinal calcium absorption (sarcoidosis, granulomatous diseases, some lymphomas, vitamin D intoxication). 2, 4

• Start prednisone 20-40 mg/day orally or methylprednisolone IV equivalent, targeting the lowest effective dose ≤10 mg/day. 2
• Allow 3-6 months to demonstrate responsiveness before escalation. 2
• If unable to wean below 10 mg/day after 3-6 months, add methotrexate as a steroid-sparing agent. 2
• Provide pneumocystis pneumonia prophylaxis for patients receiving ≥20 mg methylprednisolone equivalent for ≥4 weeks and GI prophylaxis with proton pump inhibitor. 2

Primary Hyperparathyroidism

• Parathyroidectomy is definitive treatment for patients meeting criteria: age <50 years, serum calcium >1 mg/dL above upper normal limit, evidence of skeletal or kidney disease (osteoporosis, nephrocalcinosis, kidney stones). 3, 4
• Patients >50 years with calcium <1 mg/dL above upper limit and no skeletal/kidney disease may be observed with monitoring: calcium every 3-6 months, creatinine every 6-12 months, bone density annually. 3

Tertiary (Persistent) Hyperparathyroidism

• Parathyroidectomy is considered for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy, particularly post-transplant. 2
• Calcimimetic agents (cinacalcet) can effectively lower elevated calcium levels, though clear thresholds for initiation are not established. 2, 5

---

Critical Pitfalls to Avoid

• Do not restrict calcium intake excessively without medical supervision—this worsens bone disease. 2
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further kidney injury. 2
• Do not order parathyroid imaging before confirming biochemical diagnosis of primary hyperparathyroidism—imaging is for surgical planning, not diagnosis. 3
• Do not assume hypercalcemia is benign even if asymptomatic—untreated hypercalcemia leads to nephrocalcinosis, kidney stones, osteoporosis, and cardiac arrhythmias. 3
• Do not rely on corrected calcium instead of ionized calcium—it can lead to inaccurate diagnosis. 2
• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy in PTH-independent hypercalcemia. 2

---

When to Escalate Care

Refer to emergency department or urgent hospitalization if:

• Calcium ≥12 mg/dL with symptoms 3
• Calcium ≥14 mg/dL regardless of symptoms 1, 3
• Acute kidney injury, ECG changes (QT prolongation), mental status changes, seizures, or cardiac arrhythmias 1, 3

---

Expected Course and Prognosis

• Hydration alone reduces calcium by 1-3 mg/dL within 24-48 hours. 1
• Calcitonin reduces calcium within 4-6 hours but tachyphylaxis develops within 48 hours. 1
• Bisphosphonates begin lowering calcium at 2-4 days, with normalization in 50% by day 4. 1, 2
• Primary hyperparathyroidism has excellent prognosis with medical or surgical management. 1, 4
• Malignancy-associated hypercalcemia has poor prognosis with median survival approximately 1 month. 1, 2