Renal Safety of Intravenous Ibandronic Acid in Breast Cancer
Renal Safety of Intravenous Ibandronic Acid in Breast Cancer
Introduction: Renal adverse events are a troublesome complication of bisphosphonate therapy. This study investigated the effect of intravenous ibandronic acid (ibandronate) treatment on renal function in breast cancer patients with metastatic bone disease.
Methods: 74 patients were randomised to double-blind (but not dose-blind) treatment with bolus injections of ibandronic acid 2mg (n = 23), 1-hour infusions of ibandronic acid 6mg (n = 28), or placebo injections or infusions (n = 23). According to randomisation, patients received either three injections or three infusions over the 3-month period, one at the start and two subsequent doses at 4-weekly intervals. Measurements of urinary excretion of total protein, albumin, α1-microglobulin, N-acetyl-β-D-glucosaminidase, haematuria and serum creatinine were performed before, during and after treatment.
Results: Treatment with ibandronic acid was not associated with impairment of renal function; the renal safety profiles of ibandronic acid 2 and 6mg were similar to that of placebo. Assessments of proteinuria, haematuria, enzymuria and serum creatinine indicated that there were no statistically significant changes between pre- and post-treatment levels in patients receiving ibandronic acid 2 or 6mg or between patients receiving ibandronic acid or placebo. Urine parameters varied during treatment in the same range with approximately similar frequency in the ibandronic acid and placebo groups.
Conclusions: Short-term administration of intravenous ibandronic acid did not impair renal function in breast cancer patients with metastatic bone disease. Because tolerability profiles vary between bisphosphonates, the lack of renal toxicity with ibandronic acid makes the drug an attractive treatment option for metastatic bone disease.
Bisphosphonates are a class of antiresorptive drugs used in the management of hypercalcaemia of malignancy and other diseases affecting the skeleton. The increasingly important role of these agents in the treatment and prevention of metastatic bone disease has recently been emphasised. The investigation of not only antiresorptive effects but also adverse events is very important for the clinical use of bisphosphonates. Very few adverse effects from treatment with clodronic acid and other bisphosphonates have been reported. The most frequently observed adverse effect for oral alendronic acid, pamidronic acid and clodronic acid is gastrointestinal disturbance. Following administration of intravenous bisphosphonates such as pamidronic acid, the main adverse effects are injection site reactions and 'flu-like syndrome.
Renal adverse events are a troublesome complication of bisphosphonate therapy. Renal toxicity normally manifests as deterioration of renal function, which may progress to renal failure. Risk factors for this deterioration include elevated baseline serum creatinine, multiple cycles of treatment with the bisphosphonate, and time on study. Clodronic acid, pamidronic acid and zoledronic acid are associated with similar nephrotoxic potentials. Transient mild proteinuria has been reported in 20% of patients treated with clodronic acid. Furthermore, rapid bolus injection of clodronic acid has been reported to lead to renal failure, probably because of the formation of a solid drug phase in the blood, which is then retained in the kidney. However, this type of nephrotoxicity can be avoided by use of a slow intravenous infusion. Pamidronic acid has also been associated with nephrotoxicity at high doses, although renal damage is rarely seen when pamidronic acid is administered via 2-hour intra-venous infusion at the commonly used dose of 60-90mg. In a comparative phase III trial of zoledronic acid and pamidronic acid in patients with bone metastases from breast cancer, the study protocol was amended to increase the 5-min infusion time for zoledronic acid 4mg to 15 min because of concerns over renal safety. Before the amendment, 13% of patients experienced renal impairment, whereas 9% of patients still experienced deterioration of renal function when the infusion time was increased.
The evaluation of renal function is usually based on the determination of serum creatinine, but this test is neither sensitive nor specific enough to detect nephropathy at an early stage. Recently, urinary proteins and enzymes have been proposed as sensitive indicators for the diagnosis of toxic effects of drugs on the kidney. Albuminuria has been defined as an early marker of glomerular lesions. The determination of α1-microglobulin (MG) and N-acetyl-β-D-glucosaminidase (NAG) has been proposed for the evaluation of tubular nephrotoxicity. Quantitative measurement of urinary proteins and enzymes thus gives additional information about the degree of tubular and glomerular dysfunction, in addition to the standard urinalysis including haematuria and leucocyturia.
Ibandronic acid (ibandronate), one of the most potent bisphosphonates, has demonstrated efficacy in hypercalcaemia of malignancy. A recent multicentre phase III trial has shown that ibandronic acid can also significantly reduce the occurrence of skeletal complications, minimise bone pain, and improve quality of life in metastatic bone disease caused by breast cancer. Because of interest in the renal toxicity of bisphosphonates, we report here a subset analysis of the data from those patients recruited by the Russian study centre to investigate the effect of intravenous ibandronic acid treatment on renal function.
Introduction: Renal adverse events are a troublesome complication of bisphosphonate therapy. This study investigated the effect of intravenous ibandronic acid (ibandronate) treatment on renal function in breast cancer patients with metastatic bone disease.
Methods: 74 patients were randomised to double-blind (but not dose-blind) treatment with bolus injections of ibandronic acid 2mg (n = 23), 1-hour infusions of ibandronic acid 6mg (n = 28), or placebo injections or infusions (n = 23). According to randomisation, patients received either three injections or three infusions over the 3-month period, one at the start and two subsequent doses at 4-weekly intervals. Measurements of urinary excretion of total protein, albumin, α1-microglobulin, N-acetyl-β-D-glucosaminidase, haematuria and serum creatinine were performed before, during and after treatment.
Results: Treatment with ibandronic acid was not associated with impairment of renal function; the renal safety profiles of ibandronic acid 2 and 6mg were similar to that of placebo. Assessments of proteinuria, haematuria, enzymuria and serum creatinine indicated that there were no statistically significant changes between pre- and post-treatment levels in patients receiving ibandronic acid 2 or 6mg or between patients receiving ibandronic acid or placebo. Urine parameters varied during treatment in the same range with approximately similar frequency in the ibandronic acid and placebo groups.
Conclusions: Short-term administration of intravenous ibandronic acid did not impair renal function in breast cancer patients with metastatic bone disease. Because tolerability profiles vary between bisphosphonates, the lack of renal toxicity with ibandronic acid makes the drug an attractive treatment option for metastatic bone disease.
Bisphosphonates are a class of antiresorptive drugs used in the management of hypercalcaemia of malignancy and other diseases affecting the skeleton. The increasingly important role of these agents in the treatment and prevention of metastatic bone disease has recently been emphasised. The investigation of not only antiresorptive effects but also adverse events is very important for the clinical use of bisphosphonates. Very few adverse effects from treatment with clodronic acid and other bisphosphonates have been reported. The most frequently observed adverse effect for oral alendronic acid, pamidronic acid and clodronic acid is gastrointestinal disturbance. Following administration of intravenous bisphosphonates such as pamidronic acid, the main adverse effects are injection site reactions and 'flu-like syndrome.
Renal adverse events are a troublesome complication of bisphosphonate therapy. Renal toxicity normally manifests as deterioration of renal function, which may progress to renal failure. Risk factors for this deterioration include elevated baseline serum creatinine, multiple cycles of treatment with the bisphosphonate, and time on study. Clodronic acid, pamidronic acid and zoledronic acid are associated with similar nephrotoxic potentials. Transient mild proteinuria has been reported in 20% of patients treated with clodronic acid. Furthermore, rapid bolus injection of clodronic acid has been reported to lead to renal failure, probably because of the formation of a solid drug phase in the blood, which is then retained in the kidney. However, this type of nephrotoxicity can be avoided by use of a slow intravenous infusion. Pamidronic acid has also been associated with nephrotoxicity at high doses, although renal damage is rarely seen when pamidronic acid is administered via 2-hour intra-venous infusion at the commonly used dose of 60-90mg. In a comparative phase III trial of zoledronic acid and pamidronic acid in patients with bone metastases from breast cancer, the study protocol was amended to increase the 5-min infusion time for zoledronic acid 4mg to 15 min because of concerns over renal safety. Before the amendment, 13% of patients experienced renal impairment, whereas 9% of patients still experienced deterioration of renal function when the infusion time was increased.
The evaluation of renal function is usually based on the determination of serum creatinine, but this test is neither sensitive nor specific enough to detect nephropathy at an early stage. Recently, urinary proteins and enzymes have been proposed as sensitive indicators for the diagnosis of toxic effects of drugs on the kidney. Albuminuria has been defined as an early marker of glomerular lesions. The determination of α1-microglobulin (MG) and N-acetyl-β-D-glucosaminidase (NAG) has been proposed for the evaluation of tubular nephrotoxicity. Quantitative measurement of urinary proteins and enzymes thus gives additional information about the degree of tubular and glomerular dysfunction, in addition to the standard urinalysis including haematuria and leucocyturia.
Ibandronic acid (ibandronate), one of the most potent bisphosphonates, has demonstrated efficacy in hypercalcaemia of malignancy. A recent multicentre phase III trial has shown that ibandronic acid can also significantly reduce the occurrence of skeletal complications, minimise bone pain, and improve quality of life in metastatic bone disease caused by breast cancer. Because of interest in the renal toxicity of bisphosphonates, we report here a subset analysis of the data from those patients recruited by the Russian study centre to investigate the effect of intravenous ibandronic acid treatment on renal function.
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