What medications can cause hypercalcemia?

Medications That Can Cause Hypercalcemia

Several medications can cause hypercalcemia, with thiazide diuretics, vitamin D supplements, and calcium supplements being the most common culprits. Understanding which drugs elevate calcium levels is crucial for proper diagnosis and management of hypercalcemia.

Common Medications That Cause Hypercalcemia

Vitamin D and Analogs

• Active vitamin D (calcitriol) and vitamin D analogs can cause hypercalcemia by increasing intestinal calcium absorption, renal calcium reabsorption, and bone resorption 1
• Calcitriol therapy requires careful monitoring of serum calcium levels, as hypercalcemia may develop rapidly and lead to cardiac arrhythmias, especially in patients on digitalis 2
• Vitamin D ointments (tacalcitol, calcipotriol) used for psoriasis can cause severe hypercalcemia when absorbed through damaged skin 3

Thiazide Diuretics

• Thiazide diuretics cause hypercalcemia primarily by enhancing renal proximal calcium reabsorption 1, 4
• They can unmask previously asymptomatic primary hyperparathyroidism, converting normocalcemic or intermittently hypercalcemic hyperparathyroidism into classic hypercalcemic hyperparathyroidism 1, 4
• Cases of severe hypercalcemia (up to 19.8 mg/dL) have been reported with thiazide use, particularly in patients also taking calcium supplements 5

Calcium Supplements

• Uncontrolled intake of calcium-containing preparations can trigger hypercalcemia, especially when combined with other calcium-raising medications 2, 3
• Patients on calcitriol or other vitamin D analogs should avoid excessive calcium intake to prevent hypercalcemia 2

Other Medications

Lithium

• Lithium causes hypercalcemia primarily through drug-induced hyperparathyroidism 1
• It can lead to persistent elevations in parathyroid hormone levels with chronic use

Recombinant Parathyroid Hormone

• In patients with hypoparathyroidism receiving recombinant human PTH, transient hypercalcemia can occur due to overtreatment, particularly during acute illness 1

Newer Agents

• Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been associated with hypercalcemia 6
• Immune checkpoint inhibitors can cause hypercalcemia 6
• Discontinuation of denosumab (a RANKL inhibitor) can lead to rebound hypercalcemia 6

Clinical Implications and Management

Monitoring Recommendations

• For patients on thiazide diuretics, regular monitoring of serum calcium is recommended 5
• For patients on calcitriol, serum calcium, phosphorus, magnesium, and alkaline phosphatase should be monitored periodically 2
• During titration of calcitriol therapy, serum calcium levels should be checked at least twice weekly 2

Management of Drug-Induced Hypercalcemia

• Discontinue the offending medication when hypercalcemia develops 2, 5
• Provide adequate hydration to promote calcium excretion 5
• For severe hypercalcemia (≥14 mg/dL), intravenous bisphosphonates such as zoledronic acid or pamidronate may be necessary 7, 6
• For hypercalcemia due to malignancy, bisphosphonates can effectively control calcium levels in approximately 50% of cases 7

Special Considerations

• In patients with kidney failure, denosumab and dialysis may be indicated for hypercalcemia management 6
• Glucocorticoids may be used when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders) 6
• Patients on calcitriol should avoid dehydration and maintain adequate fluid intake 2

Prevention Strategies

• Estimate daily dietary calcium intake in patients on calcium-raising medications and adjust intake when indicated 2
• Use the lowest possible dose of calcitriol and increase dosage only with careful monitoring 2
• Avoid combining multiple medications that can raise calcium levels (e.g., thiazides plus calcium supplements) 5
• Educate patients about symptoms of hypercalcemia (fatigue, nausea, vomiting, confusion) to enable early recognition 6

Remember that mild hypercalcemia (total calcium <12 mg/dL) is often asymptomatic, while severe hypercalcemia can cause significant symptoms including confusion, somnolence, and even coma 6.