Abstract
Background: More than 50% of patients with advanced breast cancer develop bone metastases that may lead to multiple complications such as pathological fractures, bone pain or hypercalcaemia. The standard treatment, besides endocrine, targeted-therapy or chemotherapy, is the use of bisphosphonates. However, one of their main adverse side-effects is bisphosphonate-induced nephrotoxicity. The mechanism by which the latter occurs is not well-understood, although emerging evidence suggests that the effect of bisphosphonates on the kidney may differ between agents. Patients and Methods: The aim of this evaluation was to compare the renal toxicity of 6 mg ibandronate i.v. versus 4 mg zoledronic acid i.v. over a period of six months in women with breast cancer and bone metastases. A prospective randomized trial was carried out to examine specific kidney and other parameters (α1- and β2-microglobulin, albumin, α2-macroglobulin, IgG and C-reactive protein (CRP) generated from spontaneous urine samples from 17 patients of each group. Results: We were unable to find any significant difference between the two treatment groups with regard to renal toxicity. All patients, independently of the applied bisphosphonate, experienced only temporary renal dysfunction without any evidence of irreversible damage in terms of acute nephrotoxicity during the study period. α1-Microglobulin, a marker for proximal tubular damage, in particular, was not differently elevated in either group. Conclusion: Both applied bisphosphonates were found to be well-tolerated and safe with regard to renal toxicity during a six-month treatment period in patients with otherwise healthy kidneys having advanced breast cancer and bone metastases.
More than 50% of patients with advanced breast cancer develop bone metastases that may lead to multiple complications such as pathological fractures, bone pain or hypercalcaemia. These complications develop from an abnormal homeostasis with a loss of bone integrity, resulting in increased resorption and lytic lesions (1).
Intravenous bisphosphonates have become the gold-standard for the prevention of skeletal complication. All bisphosphonates are pyrophosphate analogues, characterized by a P-C-P-containing central structure. Each bisphosphonate has two unique side chains (R1 and R2) attached to the central carbon atom. The central structure and the R1 chain bind to mineralised bone matrix (2). Bisphosphonates with R2 side chain containing a primary nitrogen are more potent than their non-nitrogen counterparts and can inhibit farnesyl diphosphatase and other enzymes of the mevalonate pathway. The latter are regarded as critical for osteoclast function and survival (3, 4). Ibandronate and zoledronic acid are third-generation amino-bisphosphonates. Both are generally well-tolerated, with transient side-effects such as mild flu-like symptoms. However, all bisphosphonates have a potential for side-effects such as osteonecrosis of the jaw, and renal toxicity. The mechanism by which the latter occurs is not well-understood; emerging evidence suggests that the effect of bisphosphonates on the kidney may differ between agents (5, 6).
Clinical data show that zoledronic acid can be associated with renal impairment (7, 8). In contrast, other data suggest that Ibandronate is a bisphosphonate with a renal safety profile comparable with that of placebo (6, 9). Bisphosphonates have been linked to the development of renal cell apoptosis, with renal impairment related to the dose applied, its infusion time, and the total number of infusions (10). The severity of renal insufficiency can be deduced from the elevation of creatinine serum. A clinical problem in the detection of subacute renal toxicity is the so-called ‘creati nine-blind’ range (60-100 ml/min) of the glomerular filtration rate. In this range, no predictive data are available. More sensitive indicators of renal insufficiency include the measu rement of low-molecular-weight proteins in urine such α1- and β2-microglobulin. Both markers can identify high-risk patients at an early stage of tubulo-interstitial injury. α1-Microglobulin and β2-microglobulin are regarded as specific markers for tubular damage, whereas albumin and IgG are markers for glomerular damage (11). Additionally to these parameters, α2-macroglobulin can be measured to exclude post-renal damage and to detect post-renal blood. C-Reactive protein (CRP) is a parameter used to detect infection.
Reference values for urine proteins, data from (11).
The best-proven predictor of renal outcome, with early detection of functional problems, is α1-microglobulin because of its lower pre-renal variability and higher stability in urine during storage in the bladder and urinary vessels. Another advantage is its easy inclusion in routine analytical programmes (12-13).
The aim of this evaluation was to compare the renal toxicity of 6 mg ibandronate i.v. versus 4 mg zoledronic acid i.v. over a treatment period of six months.
Patients and Methods
Study design and treatment. We conducted a prospective, randomized, monocentric trial to examine specific kidney and other parameters (α1- and β2-microglobulin, albumin, α2-macroglobulin, IgG and CRP) after treatment with 6 mg ibandronate i.v versus 4 mg zoledronic acid i.v. (both for 15 min for 28 days) over a period of six months. All included patients (n=34) had healthy kidneys, breast cancer with bone metastases and had not previously been treated with bisphosphonate. Any parallel non-experimental type of chemotherapy, endocrine therapy or radiation was allowed. Approval of the study according to the principles set out in the Declaration of Helsinki was obtained from the local ethics committee before the beginning of the study (approval number 04-035). Written informed consent from each patient was obtained after the purpose of the study had been fully explained.
Inclusion and exclusion criteria. Women aged 18 years or more with histologically confirmed breast cancer and bone metastases demonstrated by X-ray, computed tomography, nuclear magnetic resonance imaging or magnetic resonance imaging were included. Patients were excluded if they had a life expectancy of less than 12 months, were pregnant or breast-feeding, or were pre-treated with bisphosphonates or with aminoglycoside antibiotic four weeks before and during treatment with bisphosphonates. Other exclusion criteria were hyper- or hypocalcaemia (≥2.7 mmol/l and ≤2.0 mmol/l, respectively), brain metastases, serum creatinine >120 mol/l, diabetes mellitus, and pre-existing heart-insufficiency, or liver or kidney damage.
Urine collection and analysis. Specific kidney and other parameters (α1- and β2-microglobulin, albumin, α2-macroglobulin, IgG and CRP) were analyzed in spontaneous urine samples before treatment and after days 2, 4 and 6 of each cycle for both groups. The 10 ml urine sample was analysed on the day following collection. In case of intervening weekends, the samples were stored at 4°C to be analysed on the following Monday. Previous studies have demonstrated sufficient protein stability under these conditions (14).
Quantitative analysis of urinary proteins was performed by immuno-luminometric assays. The basic principle is a sandwich method, consisting of an antibody bound to a stationary matrix and a second antibody labelled with luminescent substrate. Light emission was evaluated by a luminometer (AutiCliniLumat, Berthold LB 952/16T; EG&G, Wildbad, Germany) as previously described in detail (11).
Low-molecular-mass proteinuria was indicated by the presence of α1- and β2-microglobulin and α2-macroglobulin. The presence of α2-macroglobulin was interpreted as a sign of post-renal blood. Urinary albumin and IgG served as markers of high-molecular-mass proteinuria, the latter suggesting low selectivity. CRP was used as parameter to detect possible infection. Reference values for these parameters are shown in Table I.
The mean of the three measurements of urinary parameters of each cycle was taken as reference for further calculation. Furthermore, the parameters before the first cycle were compared against those at the end of the observation period and the difference calculated. Other possible side-effects such as bone pain, fever, uveitis and jaw necrosis were also to be recorded in case of occurrence.
Statistical analysis. Data are presented as means±standard deviation or proportions. Laboratory parameters and their differences were compared between treatment groups by the Wilcoxon-Mann-Whitney U-test, with the two pre-defined primary endpoints (α1-microglobulin and β2-microglobolin) analysed confirmatively at a one-sided p-value of 0.05. All other p-values are exploratory, two-sided and no adjustment for multiplicity was performed. Within-group comparisons between baseline and end of therapy measurements were performed using the paired Wilcoxon test. Statistical analyses were performed with SPlus for Windows (Insightful Corp., Seattle, WA, USA). A sample size of 17 patients in each arm of the study was needed in order to significantly detect a stochastic superiority of ibandronate vs. zoledronic acid of p1=P(x<y)=0.75 (i.e. a probability of 75% that the protein difference is larger on treatment with zoledronic acid) with a power of 80% (NQuery Advisor V.6, Statistical Solutions Ltd., Cork, Ireland). The basis for this assumption was the historical clinical observation that ibandronate was likely to lead to lower rates of renal toxicity compared to zoledronic acid.
Clinical parameters.
Number of applications of the respective bisphosphonate.
Results
Patients' demographics. Thirty-four patients were randomized in this study. Baseline characteristics, except for age, were comparable between the two groups, with no relevant differences in concomitant medications and tumor histology (Table II).
A total of 59% (n=10) of the patients in the ibandronate-treated group and 71% (n=12) of the patients in the zoledronic acid-treated group completed the full six-month treatment period. The median number of cycles was 5.5±1.2 in the zoledronic acid-treated group and 4.9±2 in the ibandronate-treated group (Table III). No patients were excluded due to grade IV toxicity. In most cases (n=8), the patients requested to discontinue the study due to home-collection of urine samples. Two patients died during the study period. Two patients left the study because of other necessary medical treatment, which was not in line with the treatment of breast cancer.
Results for the pre-defined primary end-points. The two pre-defined primary endpoints were the progression of α1-microglobulin and β2-microglobulin in urine during the six-month study period.
Independently of the applied bisphosphonate, no patient exhibited evidence of renal damage in terms of acute nephrotoxicity during the study period. The rate of elevation of α1-microglobulin as a marker of proximal tubular damage and β2-microglobulin as a marker of glomerular damage were not significantly different between the two groups (Tables IV and V). We did not find any significant difference between the two treatment groups with regard to renal toxicity by these parameters.
Results for the other parameters. All the other measured parameters (albumin, α2-macroglobulin, IgG and CRP) were also within the normal range, showing no difference between the two medications (data not shown). No other possible side-effects such as bone pain, fever, uveitis and jaw necrosis were detected in either group.
Discussion
Intravenous bisphosphonates are valuable agents for the treatment of bone metastases. Nephrotoxicity is a potential limiting factor of the use of intravenous bisphosphonates. Patterns of nephrotoxicity described, especially during use of zoledronic acid, include toxic acute tubular necrosis and collapsing focal segmental glomerulosclerosis.
Change in urinary α1-microglobulin between the end of and the beginning of the study period (normal value <14 mg/g creatinine).
Zoledronic acid appears to be mainly associated with injury to renal tubules, resulting in a toxic acute tubular necrosis without evidence of collapsing focal segmental glomerulosclerosis (15). Toxic acute tubular necrosis in six patients was reported after treatment with zoledronic acid (4 mg/month i.v. over 15 min over a mean treatment period of 4.7 months) (15). In one case report from Bodmer et al., collapsing focal segmental glomerulosclerosis following treatment with zoledronic acid was reported (16). According to the literature, intravenous ibandronate appears to have less nephrotoxic potential compared with zoledronic acid. Body et al. in their phase III trial reported that ibandronate (6 mg/3-4 weeks over 1-2 h over two years) compared with placebo had no effect on time to deterioration of renal function in patients with metastatic breast cancer (17). In line with these results, Heidenreich et al. described that 6 mg ibandronate given i.v. during 1 h on three consecutive days followed by a single 6-mg infusion every four weeks was not associated with nephrotoxicity in patients with bone-metastatic prostate cancer (18).
The different renal safety of these two agents is not well-understood but may possibly be due to the difference in protein binding, elimination half-life in renal tissue, infusion time and infusion period, because bisphosphonates are not metabolized and are excreted unchanged by the kidney by glomerular filtration without a significant component of tubular secretion.
Therefore, impaired renal function with reduced bisphosphonate excretion can lead to excessive serum and bone concentrations of the agent, with the result of renal toxicity (19-21). Intravenous ibandronate is the bisphosphonate with the highest percentage of protein binding (87%), whereas zoledronic acid is described as having a lower protein-binding percentage (56%). In addition to these differences, zoledronic acid has a longer terminal renal tissue half-life of 150-200 days compared with 24 days for ibandronate, which may possibly allow patients treated with ibandronate for an adequate time period to repair any renal effects prior to re-treatment (6, 22).
Change in β2-microglobulin between the end of and the beginning of the study period (normal value <14 mg/g creatinine).
Differences in bisphosphonate-induced nephrotoxicity may also depend on both dosage and infusion time. Rosen et al. reported that in patients with advanced breast cancer or with multiple myeloma, renal insufficiency was significantly reduced after increasing the infusion time from 5 to 15 min and reducing the dose of zoledronic acid from 8 mg to 4 mg (23). These findings underline the assumption that a dose reduction and prolongation of the infusion time may reduce nephrotoxicity without any reduction in drug efficacy (23).
Due to these basic findings, the current recommendation in the U.S. and Europe for dosing of zoledronic acid is 4 mg i.v. once a month with an infusion time of at least 15 min (24-25).
These recommendations (24-25) were confirmed by the findings of Major et al., who showed that zoledronic acid is superior to pamidronate in the reduction of hypercalcaemia (26). Treatment with 4 mg zoledronic acid has the same effect of reduction of hypercalcaemia as does treatment with 8 mg zoledronic acid both as a 5-min infusion, but renal adverse events such as grade IV increase in serum creatinine were reported more frequently in the zoledronic acid-treated group, especially when 8 mg were given (26).
Ralston et al. showed that 4 mg and 6 mg doses of ibandronate were equally effective in normalizing calcium levels of patients with bone metastases from lung or breast cancer, and haematological or other malignancies (27). Both treatment approaches with 4 or 6 mg proved to be more effective than treatment with 2 mg over a 2-h infusion time, without any relevant sign of renal failure (27). These results are in line with data from Pecherstorfer et al., who showed that 2 mg or 4 mg ibandronate over an infusion time of one hour is not associated with renal insufficiency (1). Furthermore, no renal adverse events were reported with single 15-min infusions of 6 mg ibandronate in healthy volunteers (28).
These results were confirmed in patients with metastases from breast cancer. In their study, Von Moos et al. showed that 6 mg ibandronate as a single 15-min infusion has the same renal safety profile as 6 mg given during an infusion time of 60 min (29). This results led to the European accreditation of 6 mg ibandronate as a 15-min infusion in patients with breast cancer metastatic to bone (30, 31). According to these historical clinical results, renal toxicity of ibandronate was assumed to be lower compared to zoledronic acid.
As far as we are aware of, the current study is the first to compare the two bisphosphonates zoledronic acid (4 mg) and ibandronate (6 mg) as a 15-min infusion in patients with healthy kidneys with breast cancer and bone metastases.
Up to now, the nephrotoxicity of these two third-generation bisphosphonates was only directly compared in rats. Pfister et al. found clear evidence of qualitative differences between the two agents with respect to the accumulation of renal damage when they were administered at their minimal nephrotoxic doses. Ibandronate appeared superior compared to zoledronic acid as renal damage did not accumulate following chronic intermittent administration (5).
In our study, we did not identify significant changes of any of the measured kidney parameters during the whole study period in either group. In particular, the two pre-defined primary end-points, levels of α-1-microglobulin and β-2-microglobulin in urine, which are both sensitive indicators of renal insufficiency and can therefore identify high-risk patients at an early stage of tubulo-interstitial injury, were not different between the two agents. These data underline the assumption that both medications given intravenously for 15 min have a high safety profile.
However, our study has certain limitations: the power analysis was based on the historical clinical observation that ibandronate was likely to have a lower associated rate of renal toxicity compared to zoledronic acid. As we did not find such results, a larger study with a longer study period may provide more evidence about the effects of bisphosphonates in patients with healthy kidneys. Furthermore, it has to be underlined that only women without diabetes, hypertension or a history of treatment with bisphosphonates were included in this study. Therefore, important risk factors for pre-existing kidney damage were ruled out. Balla came to the conclusion that patients with pre-existing chronic kidney disease are at greater risk for renal deterioration during long-term bisphosphonate therapy (32). Thus, the conclusion that the described bisphosphonates may also be applied with a comparable safety profile in patients with pre-existing kidney damage cannot be drawn from our trial.
The fact that only a relatively short study period of six months was chosen may have contributed to the lack of detectable renal damage when compared to longer treatment intervals. It is well established that patients with isolated bone metastases from breast cancer have the best median overall survival compared to those patients suffering from hepatic or pulmonary metastases. Therefore, an extended treatment with bisphosphonates, due to the patients' relatively good overall survival, may possibly lead to higher rates of renal damage as seen in retrospective studies, with renal toxicity grades 1-2 and 3 occurring in 3.9% and 0.7% of patients, respectively (33). In spite of their well-established preventative and supportive effects (34), however, the optimal duration of bisphosphonate treatment for patients with bone metastases from breast cancer remains unclear (35).
Acknowledgements
The study was supported by an unrestricted grant from Hoffmann-La Roche Pharmaceuticals, Basel, Switzerland.
- Received November 13, 2014.
- Revision received December 4, 2014.
- Accepted December 10, 2014.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
