Tyler Sheetz, MD, was one of the recipients of the 2024 Urology Care Foundation™ Research Scholar Awards. These awards provide $40,000 annually for mentored research training for clinical and postdoctoral fellows or early-career faculty. The Endourological Society Raju Thomas Award sponsored Dr Sheetz’s award.

Barriers to the adoption of preventative pharmacologic treatment for kidney stones include cumbersome metabolic evaluations, poor patient compliance (due to inconvenient dosing schedules), and medication side effects (Table). Thiazides, the only currently recommended medical treatment of hypercalciuria in the AUA Guidelines for Medical Management of Kidney Stones,¹ has an intolerance rate of up to 65% due to side effects.² Furthermore, the clinical efficacy of thiazides has recently been called into question.³

Table. Medical Therapies and Limitations

One promising alternative is the off-label use of bisphosphonates (BPs), which are affordable, conveniently dosed weekly, and have already been utilized in the treatment of osteoporosis. BPs have been studied for the prevention of nephrolithiasis via reduction of hypercalciuria, inhibition of calcium-based stone crystallization, and other emerging mechanisms (Figure 1),⁴ although clinical data are limited.

We first aimed to evaluate BPs in the preventative treatment of nephrolithiasis via a novel large population study. Using a de-identified retrospective database, we selected patients with an osteoporosis diagnosis who had taken BPs. We compared kidney stone outcomes to a cohort of osteoporosis patients not on the medication (Figure 2). We found significant reductions in the incidence of a urology encounter, kidney stone diagnosis, and kidney stone procedures in BP-treated groups (unpublished data).

Given this initial data and a recent AUANews article calling for the need for high-level evidence on this topic,⁵ we received funding from an AUA/UCF Research Scholar Grant to design a trial at our institution. With a multidisciplinary team of urologists and endocrinologists, we now aim to complete a randomized controlled trial with a cohort of 100 hypercalciuric recurrent calcium stone formers with at least one stone > 500 HU on their most recent CT imaging.⁶ All patients will receive concurrent dietary counseling as recommended in the AUA Guidelines,¹ and if high urine sodium is present, they will have the opportunity to modulate with diet before entering the trial. Eligible patients will be randomized to a 70 mg weekly dose of alendronate plus dietary counseling or dietary counseling alone for an intervention period of 24 months.

The 70 mg weekly dosing was chosen for several reasons. First, a weekly dose will likely improve study compliance. Second, part of the appeal of BPs for treating metabolic stone disease is their weekly dosing; thus, a trial should be designed to reflect this dosing and translate it into clinical practice. Third, though concerns have been raised about inadequate urine concentrations of BPs with weekly compared to daily dosing,⁵ there is evidence of high concentrations in the renal tissues at least 96 hours post administration.⁷ Additionally, BPs have been shown to inhibit all 3 phases of calcium oxalate and calcium phosphate crystallization: nucleation, growth, and aggregation. This inhibition by BP complexes persisted despite a week of continual rinsing with a solution of sodium chloride and calcium.⁸ Thus, we feel that even transient, weekly surges in urine concentration are likely adequate to inhibit stone crystallization, given strong BP binding to calcium-based crystals.

Though similar trials have been conducted examining the effect of BPs on urine calcium and bone turnover rates,^9,10 the study’s novelty lies in our aims to examine radiographic and clinical outcomes, including the number of stone episodes, emergency room visits, and required procedures. We hypothesize that the BP-treated group will have lower urine calcium and bone turnover markers, a lower increase in stone volume and number of new stones, and protection from stone-related clinical events.

The results of this single institution trial will help us to justify further studies on BPs for nephrolithiasis treatment. We hope to perform a larger double-blind, placebo-controlled trial to solidify these results. Additionally, we hope to perform translational studies to help us investigate other mechanisms of action of BPs in the kidney (Figure 1) as well as determine clinical and biological markers of optimal candidates for BPs moving forward.

Funding

AUA/UCF Research Scholar Grant: Endourological Society Raju Thomas, MD Award, Boston Scientific Fellowship Grant, Calyxo Fellowship Grant