Approach to a Patient with Hypercalcemia
Initial Diagnostic Workup
Measure ionized calcium first to avoid pseudo-hypercalcemia from hemolysis or improper sampling, then obtain intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, phosphorus, magnesium, creatinine, and BUN simultaneously. 1, 2
Severity Classification
- Mild: 10-11 mg/dL 1
- Moderate: 11-12 mg/dL (polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain) 1
- Severe: >14 mg/dL (mental status changes, bradycardia, hypotension, dehydration, acute renal failure) 3, 1
Calculate Corrected Calcium
Use the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 1
Diagnostic Algorithm Based on PTH Level
PTH Elevated or Inappropriately Normal (PTH-Mediated)
Primary hyperparathyroidism is the diagnosis. 3
Key features:
- Hypophosphatemia 1
- Hyperchloremic metabolic acidosis 1
- Kidney stones may be present 4
- Calcium typically <12 mg/dL 4
- Duration >6 months 4
PTH Suppressed (<20 pg/mL) (Non-PTH-Mediated)
Proceed to PTHrP and vitamin D metabolites. 1
If PTHrP Elevated:
Malignancy-associated hypercalcemia (squamous cell carcinoma, renal cell carcinoma) 3, 1
Key features:
- Rapid onset (days to weeks) 1, 4
- Calcium often >12 mg/dL 4
- Marked anemia present 4
- No kidney stones or metabolic acidosis 4
If 1,25-dihydroxyvitamin D Elevated:
Granulomatous disease (sarcoidosis, lymphoma) or Williams syndrome (in infants) 3, 1
If 25-hydroxyvitamin D Elevated:
Vitamin D intoxication from excessive supplementation 3, 1
Medication History (Critical to Obtain)
Specifically ask about:
- Thiazide diuretics 3
- Lithium 2
- Calcium supplements >500 mg/day 2
- Vitamin D supplements >400 IU/day 2
- Calcitriol or vitamin D analogs (paricalcitol) - cause hypercalcemia in 22.6-43.3% of patients 2
- Calcium-based phosphate binders in CKD patients 3, 2
Treatment Algorithm
Step 1: Immediate Hydration (All Patients with Moderate-Severe Hypercalcemia)
Administer IV normal saline aggressively targeting urine output ≥100 mL/hour. 1, 2
- Give 250-500 mL boluses every 15 minutes until rehydration achieved 2
- Do NOT use loop diuretics until volume repletion is complete 1, 2, 5
- Loop diuretics only for patients with renal or cardiac insufficiency to prevent fluid overload 1, 2
Step 2: Bisphosphonate Therapy (First-Line for Moderate-Severe Hypercalcemia)
Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate. 1, 2, 5, 6
Key points:
- Superior efficacy compared to pamidronate 1, 2
- Normalizes calcium in 50% of patients by day 4 2
- Start immediately after hydration begins - do not wait for complete rehydration 2
- Never exceed 4 mg dose or infuse faster than 15 minutes (risk of renal toxicity) 5
Dose adjustments for renal impairment (CrCl <60 mL/min): 5
- CrCl 50-60: 3.5 mg
- CrCl 40-49: 3.3 mg
- CrCl 30-39: 3.0 mg
- CrCl <30 mL/min: NOT recommended 5
Mandatory co-administration:
Step 3: Calcitonin (For Severe Symptomatic Cases Only)
Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid onset (within hours) while waiting for bisphosphonates to take effect. 1, 2, 6
Cause-Specific Treatment
Primary Hyperparathyroidism
Parathyroidectomy is indicated if ANY of the following: 3, 1
- Symptomatic disease
- Osteoporosis
- Impaired kidney function
- Kidney stones
- Hypercalciuria
- Age <50 years
- Calcium >0.25 mmol/L (>1 mg/dL) above upper normal limit
If none of the above criteria met (age >50, calcium <1 mg/dL above normal, no organ involvement): Observation with monitoring is appropriate. 6
Malignancy-Associated Hypercalcemia
Treatment algorithm:
- Hydration + zoledronic acid 4 mg IV 1, 2
- Treat underlying malignancy (essential for long-term control) 3, 1
- If refractory: Denosumab 120 mg subcutaneously (lowers calcium in 64% within 10 days) 2
- If severe with renal failure: Dialysis with calcium-free or low-calcium dialysate 1, 2
For multiple myeloma specifically:
- Hydration + zoledronic acid + steroids ± calcitonin 2
- Continue bisphosphonates for up to 2 years 2
- Plasmapheresis for symptomatic hyperviscosity 2
Vitamin D-Mediated Hypercalcemia (Granulomatous Disease, Lymphoma, Vitamin D Intoxication)
Glucocorticoids are the PRIMARY treatment, NOT bisphosphonates. 3, 1, 6
Dosing:
- Prednisone 20-40 mg/day orally OR methylprednisolone IV equivalent 2
- Allow 3-6 months to demonstrate response 2
- Target lowest effective dose ≤10 mg/day 2
- If unable to wean below 10 mg/day after 3-6 months: Add methotrexate as steroid-sparing agent 2
Mandatory monitoring:
- Pneumocystis pneumonia prophylaxis if ≥20 mg methylprednisolone equivalent for ≥4 weeks 2
- GI prophylaxis with proton pump inhibitor 2
- Tuberculosis screening before initiating steroids 2
CKD Patients with Hypercalcemia
Immediately discontinue: 2
- All calcium-based phosphate binders
- All vitamin D analogs (calcitriol, paricalcitol)
- All vitamin D supplements
Consider lower dialysate calcium (1.5-2.0 mEq/L) if PTH is suppressed to stimulate PTH and increase bone turnover. 2
For severe hypercalcemia with renal failure: Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L). 1, 2
Critical Pitfalls to Avoid
Do NOT:
- Use loop diuretics before complete volume repletion 1, 2, 5
- Exceed 4 mg zoledronic acid or infuse faster than 15 minutes 5
- Use bisphosphonates in CrCl <30 mL/min 5
- Use NSAIDs or IV contrast in patients with renal impairment 2
- Delay bisphosphonates in moderate-severe hypercalcemia 2
- Restrict calcium intake without medical supervision 2
- Give vitamin D supplements to hypercalcemic patients 3, 1, 2
- Rely on corrected calcium instead of ionized calcium 2
- Measure only 25-hydroxyvitamin D OR 1,25-dihydroxyvitamin D - measure BOTH together 2
Monitoring
Monitor every 6-12 hours during acute phase: 2
- Serum calcium
- Creatinine
- Electrolytes (potassium, magnesium, phosphorus)
Before each bisphosphonate dose: 2
- Serum creatinine (withhold if renal deterioration occurs)
Long-term bisphosphonate complications: 1
- Renal toxicity
- Osteonecrosis of the jaw (preventive dental exam before starting, avoid invasive dental procedures during treatment) 5
Prognosis
Primary hyperparathyroidism: Excellent prognosis with surgical or medical management 6
Malignancy-associated hypercalcemia: Poor survival (median survival approximately 1 month) 2, 6
Take-Home Messages for PowerPoint
PTH level is the single most important test - it immediately divides hypercalcemia into PTH-mediated (hyperparathyroidism) vs. non-PTH-mediated (everything else) 1
Hydration FIRST, bisphosphonates SECOND, loop diuretics LAST - this sequence is critical to avoid complications 1, 2, 5
Zoledronic acid 4 mg IV over ≥15 minutes is the gold standard bisphosphonate - never exceed this dose or infusion rate 1, 2, 5
Glucocorticoids, NOT bisphosphonates, for vitamin D-mediated hypercalcemia (sarcoidosis, lymphoma, vitamin D intoxication) 3, 1, 6
Parathyroidectomy criteria are specific - age <50, calcium >1 mg/dL above normal, or any organ involvement (bones, kidneys, stones) 3, 1, 6
Malignancy-associated hypercalcemia has dismal prognosis - treat the cancer, not just the calcium 3, 1, 2
Always co-administer calcium 500 mg + vitamin D 400 IU daily with bisphosphonates to prevent severe hypocalcemia 1, 2, 5
Preventive dental exam before bisphosphonates - osteonecrosis of the jaw is a serious complication 5
Difficult MCQ Topics to Include
- Differentiating primary hyperparathyroidism from familial hypocalciuric hypercalcemia (calcium/creatinine clearance ratio)
- Zoledronic acid dose adjustments for varying CrCl levels
- Distinguishing hypercalcemia of malignancy (rapid onset, anemia, no stones) from hyperparathyroidism (slow onset, stones, no anemia)
- When to use denosumab vs. bisphosphonates (refractory cases, renal impairment)
- Medication-induced hypercalcemia (thiazides, lithium, vitamin D, calcium supplements)
- Tertiary hyperparathyroidism in CKD (autonomous PTH secretion with hypercalcemia despite dialysis)
- Williams syndrome presentation in infants (extreme irritability, vomiting, constipation, muscle cramps)