Hydrochlorothiazide and Hypercalcemia
Yes, hydrochlorothiazide can cause hypercalcemia, particularly in patients with underlying conditions that increase calcium absorption or bone resorption, such as hyperparathyroidism, vitamin D therapy, or malignancy.
Mechanism of Thiazide-Induced Hypercalcemia
Hydrochlorothiazide decreases urinary calcium excretion through direct tubular effects on the distal nephron, leading to calcium retention 1. The FDA label explicitly states that "hydrochlorothiazide also decreases the excretion of calcium" 1. This calcium-retaining effect occurs through:
- Direct tubular reabsorption: HCTZ increases calcium reabsorption in the distal tubule independent of parathyroid hormone (PTH) effects 2
- Volume depletion-mediated effects: Both extracellular fluid volume depletion and intact parathyroid function are necessary for the hypocalciuric response 3
- Potentiation of PTH action: Thiazides may enhance PTH effects on the nephron, though this is not the sole mechanism 3
High-Risk Populations for Thiazide-Induced Hypercalcemia
Patients with hyperparathyroidism are at particularly high risk, as the combination of increased PTH-mediated bone resorption and thiazide-induced calcium retention can significantly elevate serum calcium 3. Research demonstrates that after correcting for thiazide-induced hemoconcentration, serum calcium levels increased significantly only in patients with hyperparathyroidism and vitamin D-treated hypoparathyroid patients 3.
Patients receiving vitamin D therapy also face elevated risk, as the rise in serum calcium may be due to thiazide-induced release of calcium from bone into extracellular fluid, particularly in states where bone resorption is augmented 3.
Patients with malignancy-associated hypercalcemia should avoid thiazides entirely, as the medication history assessment for hypercalcemia specifically includes thiazide diuretics as a causative factor 4.
Clinical Monitoring Requirements
The FDA label warns that "pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy" 1. Therefore:
- Monitor serum calcium and potassium levels as recommended by hypertension guidelines 5
- Discontinue thiazides before parathyroid function testing, as they interfere with accurate assessment 1
- Assess for symptoms of hypercalcemia: dryness of mouth, thirst, weakness, lethargy, drowsiness, muscle pains or cramps, and gastrointestinal disturbances 1
Critical Clinical Distinction
The hypocalciuric effect is therapeutic in specific conditions but becomes problematic when it causes hypercalcemia. HCTZ is intentionally used to reduce urinary calcium in:
- Idiopathic hypercalciuria 5
- Dent disease 5
- Hypocalcemia with hypercalciuria from calcium-sensing receptor mutations 5, 6
In these conditions, the goal is calcium retention to prevent kidney stones or maintain serum calcium, not to cause hypercalcemia.
Management When Hypercalcemia Develops
Immediately discontinue hydrochlorothiazide if hypercalcemia develops, as medication history including thiazide use is crucial in hypercalcemia assessment 4. The National Comprehensive Cancer Network recommends aggressive IV normal saline hydration and bisphosphonates (zoledronic acid preferred) as cornerstone treatment for moderate to severe hypercalcemia 4.
Avoid thiazides in patients with known hyperparathyroidism unless specifically treating concurrent hypercalciuria under close monitoring, as the combination significantly increases hypercalcemia risk 3.