Management with thiazides
Prevention of stones in patients with hypercalciuria has not significantly advanced in recent years. RCTs have consistently shown that thiazides prevent recurrent stones.11 The AHRQ review stated that treatment with thiazides did not necessarily require the presence of hypercalciuria, as some studies had not indicated specific levels of calcium excretion as an inclusion criterion and because successful studies did not demonstrate that efficacy was clearly associated with the expected reduction in urinary calcium excretion.2
This is consistent with the idea that there is no clear demarcation useful in defining hypercalciuria. Observational studies indicate no clear threshold at which higher calcium excretion suddenly becomes associated with higher relative risk for stones.12 The use of thiazides may, therefore, be appropriate when fluid and diet therapy (particularly reduction of dietary sodium intake) is not sufficient, regardless of whether urinary calcium excretion meets the traditional definition of hypercalciuria.
Thiazides are commonly used in the management of hypertension, where they are considered a first-line agent. However, the trend toward using lower doses has recently been criticized as not being evidence based.13 The use of the shorter-acting hydrochlorothiazide (HCTZ) rather than the longer-acting chlorthalidone has not been associated with the same cardiovascular benefits.
In addition, when HCTZ has been successful in reducing hypertension-associated outcomes, it was with a twice-a-day dosage. Similarly, the doses used to manage hypercalciuria have also decreased despite a lack of supportive evidence. Studies showing efficacy of thiazides to reduce stone recurrence have used either chlorthalidone or indapamide, or HCTZ twice a day. One survey of prescriptions demonstrated that HCTZ once a day was prescribed most commonly, often at doses that would not be expected to provide satisfactory reductions in urinary calcium excretion.14
A retrospective study (Figure 1) showed that patients with hypercalciuria treated with 25 mg chlorthalidone had a greater reduction in urinary calcium excretion (164 mg, 41 %) than those on HCTZ (85 mg, 21 %).15 When given at 12.5 mg once a day, neither drug significantly lowered urinary calcium excretion.
The significant benefit of thiazides to increase BMD is, perhaps, not sufficiently heralded.16 Hypercalciuria has consistently been associated with reductions in BMD and increased rates of osteoporotic fractures in both men and women.17 In fact, some studies have suggested that hypercalciuria represents the result of a primary disorder of bone turnover.18
As the result of the reduction in urine calcium, or perhaps due to a direct effect on bone turnover, thiazides lead to improvements in BMD. No RCTs have been performed, but the actions of the drug support the observational studies that demonstrate reduced fractures. Measuring BMD may often be appropriate in patients with hypercalciuria, especially in older patients. Describing the association of lower BMD and stones may be helpful in motivating even younger patients to reduce dietary sodium intake. (See the section on bisphosphonates below.)
A note of caution must be put forth about the use of thiazides. While this class of drugs, when prescribed at appropriate doses, has clear cardiovascular benefits for hypertensives, that effect has not been demonstrated in stone formers, who are often younger and normotensive.19 Available data have not provided sufficient monitoring of long-term adverse effects in stone formers. Supplementation of potassium is always appropriate, as it avoids the hypocitraturia that occurs with potassium depletion (even without hypokalemia) and probably prevents reduced glucose tolerance as well. Triamterene should be avoided because it is poorly soluble and may promote calcium stone formation. Amiloride or spironolactone are acceptable alternatives as “K-sparing” diuretics.