Nephrolithiasis is an increasingly common health problem and the current treatment modalities are unsatisfactory. Consequently, new management strategies are imperative. There is a well-established association of kidney stone disease with both osteoporosis and greater risk of osteoporotic fracture.¹ While the exact mechanisms connecting osteoporosis and nephrolithiasis are incompletely understood, hypercalciuria is a shared and modifiable risk factor between both conditions.¹ Bisphosphonates are effective agents widely used for the management of osteoporosis and represent a class of agents that may also reduce the risk of stone formation. Thus, evaluating the impact of this commonly used antiosteoporosis therapy in patients with nephrolithiasis is essential.

Bisphosphonates were first synthesized in the 19th century and were initially used as corrosion inhibitors due to their ability to act as sequestering agents for calcium and to inhibit calcium carbonate precipitation.² From there, the biologic effects of bisphosphonate on biologic calcification mechanisms became of interest. Over the past 50 years, bisphosphonates have become the primary therapy for management of skeletal disorders characterized by increased bone resorption, including osteoporosis, Paget’s disease of bone, hypercalcemia of malignancy, bone metastasis, and several childhood inherited disorders.² Bisphosphonates may also conceivably reduce kidney stone recurrence through at least 2 separate mechanisms:

1. Bisphosphonates are structurally related to pyrophosphate, an endogenous molecule that inhibits mineralization and enhances dissolution of calcium phosphate and calcium oxalate in vitro. Similar to pyrophosphate, bisphosphonates have been shown in several studies to be powerful inhibitors of calcium phosphate and calcium oxalate crystallization in solutions^2,3 and in synthetic urine (Figure).⁴ However, it is not clear if the concentrations required to achieve such inhibitory activity are achieved in the urine of patients receiving these agents. Furthermore, the development of the more potent second generation (alendronate and ibandronate) and third generation (risedronate and zoledronate) bisphosphonates has allowed for their use on a more intermittent basis (weekly or monthly for oral agents and quarterly or yearly for intravenous agents). While the reduced frequency of administration has improved patient adherence to bisphosphonates, it also results in less frequent postadministration excretion in urine, potentially limiting their exposure to calcium crystals and/or Randall’s plaques in the urine space. This in turn could reduce the effectiveness of currently used bisphosphonates as crystallization inhibitors.
2. Separate from their direct inhibitory effects on calcium crystals, bisphosphonates may also reduce stone recurrence by significantly lowering 24-hour urine calcium excretion through their inhibition of osteoclastic bone resorption (Figure). When tested in the genetic hypercalciuric stone-forming rats, the bisphosphonate alendronate significantly reduced calcium excretion and consequently urine supersaturation with respect to calcium oxalate and calcium phosphate.⁵ In human studies, bisphosphonates have similarly been shown to significantly reduce urinary calcium excretion in hypercalciuric patients with or without nephrolithiasis. One study randomized 77 postmenopausal women with hypercalciuria and low bone density to the thiazide-like diuretic indapamide, the bisphosphonate alendronate, or indapamide and alendronate in combination therapy.⁶ After 1 year, 24-hour urine calcium excretion was significantly decreased in all groups. The mean percentage decrease of 24-hour urine calcium in the combination group (−50%, P < .001) was significantly greater compared to alendronate alone (−24%, P < .001) and indapamide alone (−35%, P = .012).⁶ Another study evaluated 18 hypercalciuric stone-forming patients and 8 normocalciuric stone-forming patients.⁷ After 1 year of alendronate therapy, calcium excretion decreased significantly in hypercalciuric patients (from 277 ± 28 to 202 ± 26 mg calcium/g creatinine, P < .01), whereas normocalciuric patients experienced no significant change in urinary calcium.⁷ These short-term studies raise a new potential role for bisphosphonates in the management of hypercalciuria with associated bone loss.

Figure. Bisphosphonates: mechanism of action and potential impact on calcium stone formation. Serum calcium is maintained within a tight range through regulation of intestinal absorption, flux to and from bone (through bone formation and resorption, respectively), and filtration and reabsorption by the kidneys. Urine calcium excretion, a major determinant of calcium stones, integrates fluxes across these organs. Bisphosphonates act directly on the bones to inhibit resorption. By doing so, bisphosphonates decrease urinary calcium. Bisphosphonates, which are renally excreted, can directly inhibit the formation and aggregation of calcium crystals in urine.

Although bisphosphonates have the potential to reduce calcium stone formation, there is still very limited information on their impact on kidney stone incidence or recurrence rate. In the large prospective observational Nurses’ Health Study II, bisphosphonate use was independently associated with a 32% lower incidence of kidney stones among participants with low bone density.⁸ However, due to the observational design of this study, residual confounding cannot be ruled out. Bisphosphonate use was also shown to reduce stone incidence in participants evaluated during prolonged bed rest, a setting characterized by accelerated bone resorption resulting in a significant increase in urine calcium excretion and a higher risk of stone formation. In 1 prospective study of healthy males studied during a 90-day bed rest period, 25 participants were randomly assigned to 3 groups: control, resistive exercise, or a single intravenous infusion of the second generation bisphosphonate pamidronate.⁹ In the control and exercise groups, bone mineral density decreased and urinary calcium increased, with 6 men developing new kidney stones on kidney, ureter, and bladder X-ray. On the other hand, pamidronate maintained femoral bone mineral density, reduced bone resorption markers and urinary calcium excretion, and completely prevented renal stone formation.⁹ This small study raises the possibility that bisphosphonates may reduce the risk of urolithiasis in conditions of weightlessness, including possibly astronauts on long-term spaceflights.

In summary, in addition to inhibiting bone resorption, bisphosphonates may reduce the risk of incident or recurrent kidney stones by preventing calcium oxalate and phosphate crystallization and reducing urinary calcium. The use of bisphosphates is currently indicated in patients with osteoporosis to reduce the risk of fractures. Stone-forming patients are at a higher risk for osteoporotic fractures compared to the nonstone-forming population, and a sizable subset of kidney stone formers have concurrent osteoporosis¹⁰ and thus meet indications for use of bisphosphate therapy. Therefore, at this time the use of bisphosphonates should be strongly considered in stone formers with low bone mass, particularly those with hypercalciuria. Contraindications to bisphosphonate use (creatinine clearance <35 mL/min, esophageal disease in the case of oral bisphosphonates) and infrequent side effects with very long-term use (eg, atypical femoral fracture and osteonecrosis of the jaw)² should be kept in mind. Additional prospective placebo-controlled studies assessing the impact of bisphosphonate use on stone recurrence should also be considered in larger populations of stone formers.