Two major concerns of idiopathic hipercalciuria are renal stone formation and its urinary tract complications as the third cause of renal pathology, as well as bone fragility [11-17].
Tannenbaum et al found 9.8% of IH in postmenopausal osteoporosis . Our group found IH in 34.1% of 1000 patients with osteopenia or osteoporosis, (not published).
Idiopathic hypercalciuria is present in 40-60% of renal lithiasis [1,19,20] and is considered a risk factor for bone loss throughout life with fragility fractures increased risk [17,21,22]. Giannini and colleagues found that up to19% of postmenopausal women with osteoporosis, referred for the first time to their Metabolic Bone Diseases Unit, had hypercalciuria in their bone metabolic evaluation .
Thiazide diuretics and their analogs are commonly used for lowering calcium excretion in hypercalciuric, recurrent calcium stone formers . Four randomized controlled trials (RCTs), which evaluated 408 patients over periods of 26 to 36 months, demonstrated significant reductions in recurrent kidney stones with thiazides and the thiazide analog, indapamide [12,13,14]. Thiazide administration along with dietary sodium restriction to maximize the hypocalciuric effect of thiazide is the treatment of choice in hypercalciuric, calcium stone-forming subjects. The incidence of thiazide diuretic adverse effects is about 30%, although adverse effects requiring discontinuation of the drug are rare . Indapamine is a diuretic agent that was developed to be administered alone or combined for the treatment of hypertension [24,25] with similar effect as hydrochlorothiazide that has been reported in many studies to have 50% reduction in hypercalciuria even in patients followed for 3 years [7,26,27].
In our cohort of 88 IH patients we observed 12.5% non-responders that were prescribed other drug to control urine calcium. This lack of response percentage to indamine 1.5 mg fixed dose was also published by Martins et al. that found in a double blind randomized crossover protocol with indapamine 2.5 mg versus hydrochlorothiazide 50 mg a lack of response in the indapamine group of 16.6% after 3 months of treatment .
Significant reduction in hypercalciuria and no bone loss with few adverse events along 2 years under indamine 1.5mg/day, resulted in 77 patients participating in our study. We also observed a significant reduction in bone turn-over markers, (CTX, ALP, Bone ALP and BGP) different to Lalande et al. that reported that IDP, decreased bone resorption but increased bone formation without significant variation of PTH level in vivo, as assessed by bone histomorphometry .
Urine calcium in IH and stone forming patients was significantly reduced at first and second year of follow-up with no urine sodium changes nor bone turn-over markers changes in this group. Urine calcium had a 36.8% reduction at year one and 44% at year 2, similar to the 48% reported by Alonso et al in 12 IH stone forming patients followed for 18 months. Kadir et al.  reported similar reductions, 43% and 50% in IH patients with and without stone formation respectively .
Urine calcium also decreased significantly in 34 IH and osteoporotic patients, 32% reduction at both year 1 and 2 with a small reduction in ALP and CTX.
In a small group of 9 IH patients with both conditions stone formation and osteoporosis, there was a 44% reduction in urine calcium at both years of follow-up.
Bone densitometry showed no changes in lumbar spine and femoral neck in IH stone formers during the two year follow-up while IH osteoporotic patients had a significant increase in lumbar spine at year 2 of follow-up. Those IH with both conditions had an increase in femoral neck since year 1 that stayed stable at year 2.
Our 77 patients showed a significant reduction in urine calcium in all IH groups.
Bone turn-over markers changed with reduction in CTX (resorption) and in ALP and BGP (formation) different as it was observed in the experimental study with spontaneously hypertensive rats supplemented with sodium .
These changes were present in all IH and osteoporotic patients with or without renal stones. No changes were present in IH and stone formers.
The lack of changes in bone density in IH and stone formers suggests that IDP keeps stable bone mass by correcting urine calcium and increasing calcium balance .
There was a significant increase in lumbar spine at year 2 follow-up in IH and osteoporotic patients with small but not significant increase in femoral neck. In IH with both conditions the increase was seen in femoral neck since year 1 with a tendency of increase not significant in lumbar spine at year 2, but this group included low number of patients to withdraw evidence.
Changes in bone turn-over markers and bone density could be influenced by bisphosphonates. Giusti et al have demonstrated that combination of IDP and alendronate in IH has a superior result in controlling urine calcium and increasing bone density than alendronate alone .
Adverse effects were not significant, no changes in blood pressure, glycaemia, cholesterol, serum uric acid, sodium and potassium were found. Only 2 patients needed potassium supplementation for mild hypokalemia and did not stop IDP.
The limitations of our study is that women are superior in number, bisphosphonates were not excluded, and new stone or fracture events were not registered. Future prospective studies are needed. The strength is to show the use of an alternative diuretic that controls in the majority of cases urine calcium with very few adverse events.
In conclusion fixed dose of Indamine is an effective alternative treatment to Idiopathic Hypercalciuria, controlling urine calcium loss and bone mineral density for at least two years. Association with bisphosphonates not only controls urine calcium but has a positive effect in bone mass. No significant adverse events were present and only 12.5% of patients were prescribed other thiazide to treat urine calcium loss.