Acute Renal Effects of Intravenous Bisphosphonates in the Rat

Abstract

Bisphosphonates are potent osteoclast inhibitors that have been associated with renal toxicity following rapid intravenous administration of high doses, which was hypothesised to be due to precipitation of bisphosphonate aggregates or complexes in the kidney. Five studies were conducted in rats investigating the characteristics of bisphosphonate-related acute renal effects. These studies included single intravenous injections of the nitrogen-containing bisphosphonates (1) ibandronate (1-20 mg/kg), or (2) zoledronate (1-10 mg/kg); (3) a single nephrotoxic dose of the non-nitrogen-containing bisphosphonate, clodronate (2¿200 mg/kg intraperitoneal injection); (4) a single low dose of ibandronate (1 mg/kg); (5) a single high dose of zoledronate (10 mg/kg). Clinical biochemistry and kidney histopathology were performed 1 and/or 4 days after bisphosphonate dosing. The proximal convoluted tubules were the primary target for renal injury. Tubular degeneration and single cell necrosis of the these tubules were observed with all three bisphosphonates on the fourth, but not the first day after dosing. Differences between the bisphosphonates in the type and/or localisation of the lesions were apparent. Granular deposits in the lumen of distal tubules were apparent with the highest dose of zoledronate (10 mg/kg). However, intraluminal debris was proteinaceous with no evidence of any precipitation of bisphosphonate, or formation of aggregates or complexes in the kidney. Generally, biochemical parameters of renal safety and urinary enzymes did not differ significantly from controls. In summary, bisphosphonate-related renal changes did not appear to be due to the precipitation, aggregation or complexation of bisphosphonate, and biochemical parameters of renal safety did not reliably detect this renal injury.

Risk of renal impairment after treatment with ibandronate versus zoledronic acid: a retrospective medical records review

“…Preclinical studies have shown significant differences in renal toxicity between agents, possibly related to different degrees of accumulation and retention in the kidney [26,27]. In clinical trials of intravenous ibandronate, the renal safety profile has consistently been shown to be similar to placebo, even after long-term treatment [3,5].…”

The Effect of Alendronate, Risedronate, and Raloxifene on Renal Functions, Based on the Cockcroft and Gault Method, in Postmenopausal Women

“…[15,21] However, no corpuscular precipitations were reported during kidney histopathological analysis in animals. [22][23][24][25][26][27][28] Therefore, it has been postulated that bisphosphonates induce cell death in renal cells in a manner similar to their apoptotic effects in osteoclasts and possibly even cancer cells. [24,25] Although oral treatment with bisphosphonates in cancer treatment has been available for many years, clinical experience has indicated that it was less effective than intravenous bisphosphonates.…”

A Case of Acquired Fanconi Syndrome Induced by Zoledronic Acid

“…It is effective in the treatment of hypercalcemia and bone metastasis, and widely used for various malignancies (2). However, it has been reported to be nephrotoxic (3)(4)(5), and several cases of acute tubular necrosis due to zoledronic acid have been reported (3). We encountered a breast cancer patient who developed Fanconi syndrome due to zoledronic acid.…”