How do loop diuretics cause hypocalcemia (low calcium levels)?

From the Guidelines

Loop diuretics cause calcium loss by inhibiting the sodium-potassium-chloride cotransporter in the thick ascending limb of the loop of Henle in the kidneys, leading to increased calcium excretion in the urine (hypercalciuria) 1. This mechanism directly affects calcium reabsorption in the kidneys. Normally, about 65% of filtered calcium is reabsorbed in the proximal tubule and 25-30% in the thick ascending limb. When loop diuretics like furosemide block this cotransporter, they prevent the creation of the positive electrical gradient needed for paracellular calcium reabsorption. Some key points to consider:

• Loop diuretics increase calcium excretion in the urine, which can lead to negative calcium balance and potentially contribute to bone demineralization and increased risk of osteoporosis or fractures 1.
• Thiazide diuretics, by contrast, actually decrease urinary calcium excretion and may be preferred in patients with conditions like osteoporosis or hypercalciuria.
• The use of loop diuretics can lead to hypokalemia and metabolic alkalosis, which can exacerbate CO2 retention in patients with chronic lung disease 1.
• It is essential to monitor serum electrolytes periodically in patients treated with chronic diuretic therapy to prevent and treat potential side effects 1.
• Net calcium absorption is reduced in chronic renal failure, and dietary calcium intake is often low in patients with chronic kidney disease (CKD) 1.
• Increasing dietary calcium intake can help achieve neutral calcium balance in patients with CKD 1.

From the Research

Mechanism of Calcium Loss

• Loop diuretics cause calcium loss by increasing renal calcium excretion, as seen in studies 2, 3, 4, 5.
• This is due to the inhibition of the Na-K-2Cl transporter in the thick ascending limb of the loop of Henle, leading to increased calcium delivery to the distal tubules 3, 5.
• The increased calcium delivery to the distal tubules results in an upregulation of calcium transport molecules, such as TRPV5 and TRPV6, leading to increased urinary calcium excretion 2.

Effects on Calcium Homeostasis

• Loop diuretics can lead to hypercalciuria, which may cause secondary hyperparathyroidism and bone disease 3, 6.
• However, the increased renal calcium losses can be compensated for by a parathyroid hormone (PTH)-dependent increase in 1,25-dihydroxyvitamin D levels, maintaining calcium balance 6.
• Thiazide diuretics, on the other hand, can decrease calcium excretion and provide protection against hypercalciuria 3, 4, 5.

Clinical Implications

• Loop diuretics are useful in treating hypercalcemia due to their ability to increase renal calcium excretion 2, 3, 5.
• However, long-term treatment with loop diuretics may affect bone mineral density, with some studies suggesting a positive association between duration of treatment and bone mineral density 6.
• The use of diuretics should be carefully considered in patients with disorders of calcium homeostasis, taking into account their potential effects on renal calcium excretion and bone metabolism 3, 4, 5.