Given the association of hypercalciuria with low BMD, interest in the use of bisphosphonates for treatment of idiopathic hypercalciuria has grown. No RCT has been performed to demonstrate reduction of stone recurrence, but with bisphosphonate use urinary calcium excretion falls and BMD increases.
This drug class is effective in genetic hypercalciuric stone-forming rats; alendronate reduced urinary calcium excretion and urinary calcium oxalate and brushite supersaturation.20 Similar data have been acquired in an RCT with humans.21 Post-menopausal osteoporotic female patients with idiopathic hypercalciuria were randomly assigned to receive either 70 mg alendronate once weekly, 2.5 mg indapamide daily, or a combination of alendronate plus indapamide at the same doses.
After 12 months of therapy, there was no significant change in BMD from baseline in the indapamide group, but BMD was significantly increased in the alendronate and combination groups. All treatment groups experienced a reduction in urinary calcium excretion, with the greatest effect for both endpoints observed in the combination arm. Whether the findings can be generalized to hypercalciuric men is not known. In another study that included men, the combination of 50 mg HCTZ daily and 70 mg alendronate each week was more effective than alendronate alone in reducing urine calcium excretion and increasing BMD in hypercalciuric stone-formers with osteopenia or osteoporosis.22 From these data, one can conclude that bisphosphonates are likely beneficial in hypercalciuric patients with maximal benefit when used in combination with thiazides. These data are particularly important given that the Women’s Health Initiative demonstrated a small absolute increased risk of kidney stones without significant increases in BMD as the result of calcium and vitamin D supplementation.23
Hyperuricosuria and calculi formation
Hyperuricosuria has long been thought to be a risk factor promoting calcium stone formation. While the original hypothesis was that monosodium urate crystals served as a nucleus for calcium oxalate crystal formation, the rarity of urate crystals in urine and the failure to identify them in calcium oxalate stones led to the current hypothesis that uric acid instead “salts out,” or reduces the solubility of, calcium oxalate.15
Whatever the chemical interaction, the association was supported by an RCT in which 100 mg allopurinol three times a day reduced stone recurrence at three years compared with placebo.16 Participants were calcium stone formers with 24-hour uric acid excretion of 800 mg/day in men and 750 mg/day in women; patients with hypercalciuria were excluded.
The epidemiologic data have not been entirely supportive of the effect. In the Nurses’ Health Study (NHS) 1 and 2, and the Health Professionals Follow-Up Study (HPFS), higher 24-hour uric acid excretion was not associated with a greater risk for stone formation. In fact, the relative risk for stones was inversely associated with 24-hour uric acid in HPFS.17
Earlier smaller studies that first suggested that uricosuria was a risk factor for calcium stones were not prospective. It has been suggested that allopurinol’s ability to prevent calcium stones could be related to some other effect not directly related to the lowering of uric acid excretion.17 For instance, allopurinol has antioxidant properties and promotes endothelial function.18
Despite the uncertainty about how, or if, uric acid promotes calcium stones, there is a further need for studies, and we designed a trial of febuxostat, analogous to the earlier study of allopurinol.24 Febuxostat is a non-purine analog that also inhibits xanthine oxidoreductase and predominantly undergoes hepatic metabolism.
In recurrent stone formers with hyperuricosuria (>700 mg/day) and a radio-opaque stone seen on computed tomography scans, we randomized patients to 300 mg allopurinol once a day, 80 mg febuxostat once a day, or placebo. Patients with hypercalciuria were not excluded. The primary outcome is reduction in 24-hour urinary uric acid excretion after six months of therapy. The duration of follow up will be too short to demonstrate an effect of the drugs on stone growth or recurrence.
Although higher doses of allopurinol would probably further reduce 24-hour uric acid excretion, we used the dose previously shown to be effective and the one most commonly prescribed for stones or gout. We hope to replicate this study design for a longer duration to test for effects on stone recurrence.