Treatment of primary hypercalciuria: Thiazide diuretics
The drugs of this class have been widely used in patients with calcium nephrolithiasis, more so in those presenting with idiopathic hypercalciuria. Hydrochlorothiazide, chlortalidone or trichlormethiazide, alone or in association with amiloride, induce a significant reduction of calcium excretion, revert external balance of calcium to positive, and protect bone from demineralisation. Thiazides are able to reduce calcium excretion by acting at the cortical segment of the distal tubule, where they increase calcium reabsorption. This mechanism is thought to ensue from contraction of extra-cellular fluids induced by these drugs. Prostaglandin E2, which is likely involved in the pathogenesis of hypercalciuria, was suggested to be inhibited by thiazides. It has also been hypothesised that, over long-term therapy, they reduce both intestinal absorption and bone resorption of calcium. Zerwekh et al. found that 50 mg of hydrochlorothiazide twice daily reduced fractional intestinal absorption of calcium from 0.68 to 0.56 in patients with renal leak hypercalciuria, but not in those with absorptive hypercalciuria, and this effect was attributed to a reduction of serum levels of calcitriol. 1 Internet Online Drugstore
Reduction of calcium intestinal absorption was also observed by Coe et al. in 7 patients with severe hypercalciuria after 3 and 6 months of either chlortalidone or trichlormethiazide: despite this, calcium retention improved because calcium loss decreased even more. No changes were seen in calcitriol and parathormone serum concentrations. Favus et al. carried out an experimental study on rats in which secondary hyperparathyroidism was induced by a low-calcium diet. They found that thiazides prevented the increase in PTH induced by low-calcium diet but not the increase in calcitriol nor intestinal calcium transport, and the drug caused no change in rats fed normal chow. Furthermore, in rats given exogenous calcitriol to stimulate intestinal calcium absorption, thiazides greatly reduced urine calcium excretion but did not alter intestinal calcium absorption. The issue of calcium absorption and thiazides is important for the potential effect on intestinal absorption of oxalate, in that intestinal transport of the former influences the latter. Earlier reports of the effects of thiazides found a decrease in oxalate excretion, whereas others failed to confirm it. This topic has not so far been studied in more depth.
The positive calcium balance induced by long-term therapy with thiazides may have a favourable impact on bone. A number of epidemiology studies have addressed this issue, and found that the risk of hip fractures reduced by 20% and 50% over more than 2.5 and 6 years of therapy, respectively. A rapid recovery of bone mass occurred in osteoporotic hypercalciuric men given thiazides. In a meta-analysis on 13 observational studies in which 29,600 subjects had ex- tractable data on thiazides and fracture occurrence, current thiazide users of long duration were protected against hip fracture with a 20% reduction in risk, whereas short duration use did not. In a large survey conducted by U.S. on 83,728 women aged 36-61 at baseline and followed for 10 years, there was 22% reduction in the risk of forearm fractures among current thiazide users, reaching 37% among women who had been using thiazides for 8 or more years. For hip fractures, thiazide use yielded a 31% reduction in the relative risk. In a recent 2-year prospective follow-up conducted on 138 women given hydrochlorothiazide 50 mg per day, urine calcium excretion and indices of bone turnover decreased in the thiazide group. DEXA bone mineral density improved in total body, mid- and ultradistal forearm and legs, but no effect was seen in the lumbar spine or femoral neck, leading Authors to conclude that thiazides are not an appropriate monotherapy for treating osteoporosis. In a prospective population- based cohort study, on 7,891 individuals 55 years of age, current use of thiazides for more than 1 year was associated with a lower risk for hip fracture, but this protective effect disappeared within 4 months after use was discontinued. The mechanisms of the beneficial effects of thiazides on bone may be not merely related to their ability to reduce urinary calcium, and direct effects on bone resorption were postulated. This effect is partly due to a reduction in PGE2 synthesis. Thiazides have specific effects on osteoblasts, because they reduce serum osteocalcin. In vitro studies on human osteoblast- like cell line showed hydrochlorothiazide dose-dependently inhibited 1,25-dihydroxyvitamin D3-induced osteocalcin release and mRNA expression, independently of VDR or extracellular Ca2+ levels, and TNF-a induced production con macrophage CSF as well. This may explain its preventive role in bone loss rate.
The majority of the aforementioned studies support indications to thiazide use especially in the setting of hypercalciuria associated with negative calcium balance and enhanced bone resorption. Anyway, the former limitation of thiazides use to renal hypercalciuria was subsequently extended to any type of hypercalciuria, in both adults and children. The favourable effects on stone recurrences obtained by using higher dosages, i.e. hydrochlorothiazide 50 mg twice daily or chlortalidone 50 mg/day, were also confirmed with lower doses and even in the absence of a marked reduction of calcium excretion. The rationale for the use of lower dosages is to reduce the impact of side-effects, including hypotension, potassium wasting and hypopotassiemia, increase of plasma bicarbonate (and urate), and a consequent decrease in citrate excretion. The latter event may be as important as to offset the benefits related to the reduction of calcium excretion. It is agreed that some of these side-effects can be lessened by giving thiazides with amiloride, and by supplementing potassium citrate in the presence of hypocitraturia. Hypercalciuric patients presenting with hypertension may be especially eligible for thiazides.