Bone pain reduction in patients with metastatic breast cancer treated with ibandronate–results from a post-marketing surveillance study
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- Diel, I.J., Kurth, A.H.A., Sittig, H. et al. Support Care Cancer (2010) 18: 1305. doi:10.1007/s00520-009-0749-5
Pain relief is an important treatment goal for breast cancer patients with metastatic bone disease and treatment should be associated with a low rate of side effects. This interim analysis of a prospective non-interventional study documents the efficacy and safety of the amino-bisphosphonate ibandronate in the treatment of metastatic bone disease under real-life conditions.
Patients and methods
For up to 24 weeks 913 breast cancer patients received IV infusions of 6 mg ibandronate every 3–4 weeks or 50 mg of oral ibandronate once daily. Efficacy variables included pain severity, analgesic use, and skeletal-related events; the major safety parameter was renal function, assessed by serum creatinine levels. Subgroup analyses were performed according to pretreatment with bisphosphonates (none, ibandronate, or other bisphosphonates).
At baseline, patients with ibandronate pretreatment tended to have lower mean pain scores and lower serum creatinine levels than those pre-treated with other bisphosphonates. Over the observation period, analgesic use did not increase. Among the 712 patients reporting pain at baseline, 70% achieved an improvement in pain severity during treatment with ibandronate, and there was no evidence to suggest relevant differences in mean pain reductions with IV or oral administration of ibandronate or according to prior bisphosphonate treatment. Skeletal-related events were rare (7%). Changes in serum creatinine levels during ibandronate treatment were small and both formulations of ibandronate were rated as well tolerated by physicians and patients.
Data from this non-interventional study confirm the analgesic efficacy and safety profile of IV and oral ibandronate under real-life conditions.
KeywordsBreast cancerBone metastasesBisphosphonatesIbandronatePainRenal safety
Metastatic bone disease affects many patients with cancer and while bone metastases often indicate terminal illness, patients with advanced breast cancer may now expect a median survival time of 3 years or more after the diagnosis of bone metastases . The symptoms of metastatic bone disease such as severe bone pain, pathologic fractures, and the ensuing disability and immobility have a strong negative impact on the quality of life of affected patients . It is therefore a major treatment goal to alleviate these symptoms and enable patients to continue with a normal life for as long as possible.
Metastatic bone disease is a consequence of a tumor-induced imbalance of the activities of osteoclasts and osteoblasts. As the inhibition of bone resorption by bisphosphonates has been shown to be highly effective in the prevention of skeletal-related events (SREs), the reduction of bone pain, and the improvement of quality of life  and as toxicity associated with bisphosphonate treatment in general is mild and infrequent , bisphosphonates are the currently recommended standard of care for patients with metastatic bone disease from breast cancer [2, 12].
Ibandronate, a third-generation, single-nitrogen amino-bisphosphonate available in IV and oral formulations, was approved for the treatment of breast cancer patients with metastatic bone disease in the European Union in 2003. Both formulations demonstrated equivalent efficacy in reducing the incidence of skeletal complications associated with metastatic bone disease in breast cancer [4, 5] and had closely similar significant and sustained effects on bone pain and patient quality of life [3, 10]. The safety profile is favorable with a low incidence of renal adverse events, comparable with that for placebo in a study with IV ibandronate .
In order to confirm the results of clinical trials without experimental bias, standardized observational studies on the use of medicinal products administered in accordance with the terms of the marketing authorization under routine conditions are a valuable tool. The aim of this prospective non-interventional study was to document and quantify the efficacy and safety of ibandronate, (Bondronat®; Roche Pharma AG, Grenzach-Wyhlen, Germany), administered as oral or IV formulation, when used to treat metastatic bone disease in breast cancer patients over a period of up to 24 weeks under real-life conditions. So as to obtain reliable results about the incidence of relatively rare adverse effects, 3,000 patients are to be observed and documented. The results of an interim analysis of the effects of ibandronate on bone pain, skeletal-related events, and renal safety in 913 patients documented and analyzed so far are presented in this paper.
Patients and methods
This prospective, observational non-interventional study1 was started on January 1, 2004. German hospital- and office-based physicians were asked to document female breast cancer patients for whom they had decided to treat metastatic bone disease with IV or oral formulations of ibandronate. Data on the efficacy and safety of ibandronate were to be documented during routine practice, i.e. there was no intervention concerning either the choice of treatment or the selection and timing of diagnostic or monitoring procedures either during or after the study.
At the baseline visit demographic data, medical history, concomitant treatment (radio-, hormone-, and chemotherapy and analgesic treatment), and Eastern Cooperative Oncology Group (ECOG) performance status  were documented; breast cancer receptor status, type and location of metastases, and previous SREs were recorded and the patient was asked to rate the severity of bone pain by means of a visual analog scale (VAS) . Laboratory parameters reflecting the renal function and serum calcium levels were measured and recorded as well.
Based on the dosage recommendations for IV ibandronate, visits and collection of data during treatment were scheduled every 4 weeks. Documentation of the patient status during ibandronate treatment included ECOG performance status, SREs, pain severity, treatment with ibandronate and concomitant therapies, and adverse effects. Measurement of the aforementioned laboratory parameters throughout the study was optional.
At the final visit, 24 weeks after the start or on premature discontinuation of ibandronate treatment, physicians also rated the tolerability of ibandronate.
Female patients aged 18 years or more were included if they presented with histologically proven breast cancer, the physician had decided to prescribe ibandronate for IV or oral administration for the treatment of bone metastases confirmed by X-ray or radionuclide bone scans, and the patient’s expected survival time was at least 3 months.
According to the contraindications listed in the prescribing information, patients with known hypersensitivity to bisphosphonates were excluded; other exclusion criteria were hypocalcaemia (albumin-corrected serum calcium levels <2.0 mmol/L) and an estimated creatinine clearance of ≤30 mL/min (Cockcroft–Gault equation).
In accordance with the terms of the marketing authorization, patients generally received 6 mg ibandronate IV, infused over 1 h every 3–4 weeks, or 50 mg of oral ibandronate once daily, taken at least 30 min before breakfast.
Efficacy variables included pain severity (VAS, 0–10), the use of analgesics, and SREs. Changes in pain severity during treatment with ibandronate were rated as improvement when the sum of decreases in pain scores between visits outweighed the sum of increases. Analgesic treatment was characterized according to the steps of the analgesic ladder developed by the World Health Organization (WHO) . Fractures and bone surgery or radiotherapy for the treatment of pain or impending fractures were documented at every visit.
Renal function was assessed by serum creatinine levels throughout the study. Other safety endpoints included premature discontinuations and physician and patient assessments of tolerability, rated by means of a four-step scale at the final visit.
The set of patients to be analyzed was defined as all patients prospectively documented who presented with histologically proven breast cancer and bone metastases diagnosed by X-ray or bone scans at baseline, did not fulfill any of the exclusion criteria, and received at least one dose of ibandronate during the observation period. For this interim analysis, only case report forms completed and entered in the database without pending queries before August 4, 2006 were included.
All analyses were descriptive and exploratory. Summary measures are reported as proportions or as mean values ± SD. For some of the analyses, patients were divided into subgroups according to bisphosphonate pretreatment: (bisphosphonate-naïve, prior treatment with ibandronate, or other bisphosphonates) and ibandronate administration (IV or oral).
Subgroup differences with respect to continuous variables such as VAS pain scores were statistically assessed by the Wilcoxon–Mann–Whitney procedure for between-group comparisons, while the paired version of the Wilcoxon test was applied to compare data observed at different timepoints. Nominal parameters such as use of analgesics were compared between subgroups using Fisher’s exact test and McNemar’s test for changes within groups, respectively.
Case report forms for 1,428 patients were collected between June 2, 2004 and August 4, 2006. Among these, 32 patients were excluded due to retrospective documentation, for six patients the participating physicians withdrew their consent for the study and one patient had received another bisphosphonate instead of ibandronate. Three hundred sixty-two patients were not included into the interim analysis because of pending queries, for another 49 patients data entry into the database had not been completed by the cut-off date. Fifty-five patients were excluded because they had other tumors instead of breast cancer and ten patients did not have metastatic bone disease.
The remaining 913 patients, documented by 157 participating physicians or centers (1–32 patients per site), were evaluable for medical history, previous therapies, and SREs. Laboratory values were available for 813 patients.
Demographic data, medical history, and previous treatments
Baseline patient characteristics in subgroups according to prior bisphosphonate treatment
Prior treatment with ibandronate
Prior treatment with other bisphosphonates
Age (mean ± SD; years)
63.4 ± 12.3
61.8 ± 11.3
63.6 ± 11.9
63.3 ± 12.1
Time since diagnosis of breast cancer (mean ± SD, range; years)
5.2 ± 5.3 (0–39.8)
6.9 ± 5.9 (0.1–24.1)
7 ± 5.5 (0.1–31.9)
5.9 ± 5.5 (0–39.8)
Time since diagnosis of met. bone disease (mean ± SD, range; years)
0.4 ± 1.3 (0–14.8)
1.8 ± 1.6 (0–7.6)
2.2 ± 2.1 (0–13.1)
1.1 ± 1.8 (0–14.8)
Time since diagnosis of met. bone disease (median; years)
SRE prior to start of study (n; %)
The mean time since diagnosis of bone metastases was 1.1 years. Forty-four percent of patients presented with bone metastases only, 33% had additional distant metastases, and 10% had additional locoregional relapse. Thirteen percent of patients had local relapse, bone, and distant metastases. Eighty-nine percent of patients had not experienced SREs before enrollment in the study; most documented SREs were pathological fractures, spinal cord compression was rare (2% of patients).
At baseline, 94% of patients had undergone surgery and 72% had received radiotherapy. Hormone therapy, chemotherapy, or treatment with trastuzumab was documented for 75%, 69%, and 11% of patients, respectively. Five hundred forty-nine patients (60%) had not received treatment with bisphosphonates before, 93 patients (10%) were enrolled after prior treatment with ibandronate, and 271 patients (30%) had been treated with other bisphosphonates. In this subgroup, 59% received zoledronic acid, 37% pamidronate, 12% clodronate, and 2% other bisphosphonates (alendronate or unspecified).
Previous treatments in subgroups according to prior bisphosphonate treatment
Prior treatment with ibandronate
Prior treatment with other bisphosphonates
Primary tumor/local (%)
Bone metastases (%)
Hormone therapy (%)
Eighty-eight percent of patients received intravenous ibandronate. In accordance with the terms of the marketing authorization, doses of 6 mg and intervals of 4 weeks between injections were used for most patients (90% and 87%, respectively); for 12% of patients, physicians chose dosing intervals of 3 weeks. Daily oral ibandronate 50 mg was given to 10% of patients, especially to those who had been treated with bisphosphonates for a longer period of time (Fisher's exact test, p = 0.14); only 2% switched from IV to oral or vice versa. The mean duration of observation under treatment in this 24-week-study was 5.4 ± 1.7 months. Treatment interruptions were rare (4%) and mostly related to vacations or similar reasons.
Sixteen percent of patients underwent radiotherapy during the study, mostly targeted at the bone metastases. Seventy-one percent and 39% received hormone therapy and chemotherapy, respectively.
Bone pain, ECOG performance status, and skeletal-related events
At baseline, 14% of patients were pain-free. The mean pain score of patients reporting pain at baseline was 3.4 ± 2.5. Analgesic use was reported in 50% of all patients. Characterized according to the steps of the WHO analgesic ladder, 50% of analgesics were step I, 32% were step II (weak opioids), and 18% were step III (strong opioids).
More patients pretreated with ibandronate were pain-free at baseline. Mean pain scores were lower in patients with ibandronate pretreatment (2.6 ± 2.3) than in patients who were bisphosphonate-naïve (3.6 ± 2.5; p = 0.0006) or were previously treated with other bisphosphonates (3.4 ± 2.5; p = 0.019). Analgesic use at baseline was also lower in the subgroup with ibandronate pretreatment (37% vs. 52% and 49% for bisphosphonate-naïve and other bisphosphonates; p = 0.0093 and p = 0.052, respectively). Five of 92 patients pretreated with ibandronate required step III analgesics compared to 11.1% in the subgroup with prior treatment with other bisphosphonates (p = 0.15).
Mean pain scores (VAS) at baseline and study end in subgroups according to prior bisphosphonate treatment and administration of study drug (n = 712 patients reporting pain at baseline and evaluable for changes in pain throughout the study)
Prior treatment with ibandronate
Prior treatment with other bisphosphonates
Administration of study drug
Mean pain score at baseline (VAS)
4.1 ± 2.1
4.4 ± 2.4
3.4 ± 2.1
3.2 ± 2.3
4 ± 2.3
3.4 ± 1.9
4 ± 2.2
4 ± 2.3
Last mean pain score (VAS)
2.6 ± 1.9
2.4 ± 2.2
3 ± 2
2.6 ± 2.9
3 ± 2
3 ± 2
2.7 ± 2
2.6 ± 2.2
Change in mean pain score (last–baseline)
−1.5 ± 2
−2.1 ± 1.9
−0.4 ± 1.5
−0.7 ± 1.9
−1.1 ± 2
−0.4 ± 1.4
−1.3 ± 2
−1.5 ± 1.9
Analgesic use decreased significantly over the observation period with more patients not taking analgesics at study end (57%) than at enrolment (50%; p < 0.0001). Overall there were more patients being switched to less potent or no analgesic treatment than patients requiring more analgesia: in the subgroup of patients receiving step I analgesics at baseline, for example, 36% did not need analgesia at study end vs. only 6% and 3% being switched to step II and step III analgesics during the observation period.
For the majority of patients (79%), ECOG status did not change during the observation period; improvement (11%) and deterioration (10%) of performance status occurred in a similar number of patients.
By study end only 7% of patients had experienced a skeletal-related event. Two thirds of reported SREs were need for radiotherapy; fractures accounted for close to one third of SREs. The mean time until the visit when the first SRE was documented was 13.4 weeks with SREs occurring slightly earlier in bisphosphonate-naïve patients (11.3 weeks) than in those pretreated with ibandronate (17.3 weeks) or other bisphosphonates (14.9 weeks).
Thirteen percent of patients withdrew before the end of the 24-week observation period. Reasons for discontinuation included mainly tumor-related death and disease progression (33% and 35% of discontinuations, respectively); 17% of discontinuations were due to patients being lost to follow-up and 3% to non-tumor-related death. Refusal to continue in the study and adverse clinical effects accounted for 15% and 9% of withdrawals, respectively. Adverse effects resulting in premature withdrawal from the study included bone pain, gastrointestinal side effects (dyspepsia, nausea), and fatigue.
Physician and patient assessment of tolerability was very good in 65% and 59% of cases and good in 33% and 37% of cases.
At baseline, mean serum creatinine levels were 0.9 mg/dL; 12% of patients presented with initial creatinine levels above 1.2 mg/dL. Patients pretreated with other bisphosphonates had marginally (non-significant) higher baseline creatinine levels (1.0 ± 0.4 mg/dL) than bisphosphonate-naïve patients and patients pretreated with ibandronate (0.9 ± 0.3 mg/dL for both groups); the percentage of patients with initial creatinine levels above 1.2 mg/dL was also numerically higher in patients pretreated with other bisphosphonates.
Serum creatinine levels generally remained stable during ibandronate treatment. The mean of maximum decreases as well as increases during the study was 0.1 mg/dL except for patients previously treated with other bisphosphonates who had a mean maximum increase of 0.2 mg/dL during treatment. In patients with baseline serum creatinine levels >1.2 mg/dL, mean maximum decreases during ibandronate treatment were larger than mean maximum increases, in the total population (0.3 ± 0.3 mg/dL vs 0.1 ± 0.2 mg/dL) and in all subgroups.
Bisphosphonates have become the standard of care for symptoms of metastatic bone disease in breast cancer patients. In this non-interventional study the effects of the third-generation amino-bisphosphonate ibandronate, administered as oral or IV formulation, were documented in a large number of patients under real-life conditions over a period of up to 24 weeks.
The patient population in this study represents breast cancer patients with metastatic bone disease treated by hospital- and office-based oncologists in Germany. Compared to the phase III trials on the efficacy of IV and oral ibandronate [3–5], patients in this observational study were older. While the pivotal trials on IV and oral ibandronate excluded patients with bisphosphonate treatment in the 6 months before study entry, only 60% of patients in this study were bisphosphonate-naïve; 10% and 30% of patients had received prior treatment with ibandronate or other bisphosphonates.
Regarding some aspects of medical history, the population in this observational study was thus heterogeneous: for the subgroup of bisphosphonate-naïve patients, the time since diagnosis of metastatic bone disease was shorter than for the patients treated in the clinical trials on oral ibandronate [3–5] while for those patients enrolled after prior treatment with ibandronate or other bisphosphonates it was considerably longer. This difference in duration of disease is also reflected in the percentage of patients with SREs at baseline, with only 7% of bisphosphonate-naïve patients presenting with previous SREs compared to 13% and 19% for the subgroups with prior ibandronate or other bisphosphonates treatment.
Beneficial effects on bone pain in breast cancer patients with metastatic bone disease have previously been documented for IV infusions of clodronate, pamidronate, and zoledronic acid [8, 11, 13, 21], while the effects of early-generation oral bisphosphonates were disappointing . In clinical trials with the third-generation bisphosphonate ibandronate, administration of both 6 mg IV every 3–4 weeks and 50 mg oral per day has been shown to reduce bone pain scores in bisphosphonate-naïve patients with metastatic bone disease for up to 96 weeks [3, 5].
In this study, over 24 weeks, ibandronate reduced bone pain for the majority of patients and there was no evidence to suggest relevant differences in mean pain reductions with IV or oral administration of ibandronate. The magnitude and the percentage of reductions in mean pain scores as documented for the subgroup of bisphosphonate-naïve patients and for patients with prior ibandronate in this study are also in line with the data from the abovementioned pivotal clinical trials. As the overall frequency and intensity of analgesic use did not increase during the observation period of this study, these effects on pain severity cannot be attributed to analgesic co-medication; rather, they reflect the analgesic properties of ibandronate in this setting.
Baseline data of patients previously treated with other bisphosphonates, presenting with more severe pain and more frequent as well as more potent analgesic use than patients with prior ibandronate treatment, may suggest an improved analgesic effect with ibandronate compared with other bisphosphonates. However, while physicians were not asked about their reasons for including patients pretreated with other bisphosphonates into this observational study with ibandronate, it may be assumed that some did so because they considered previous treatment less effective in these patients. Nevertheless, ibandronate reduced pain scores in patients previously treated with other bisphosphonates to scores comparable with those achieved in patients with prior ibandronate treatment and thus showed good efficacy in this presumably difficult-to-treat subgroup of patients.
The number of SREs occurring during the observation period was small. Due to the short duration of this study which amounted to a mean observation time of less than two 12-week periods, an evaluation of data for this parameter is difficult. As effects on skeletal events may not begin to appear before 6–8 weeks after initiation of drug treatment  this type of time lag may explain why the subgroup of bisphosphonate-naïve patients experienced (non-significantly) shorter times till the occurrence of SREs in this study than the subgroups with prior bisphosphonate treatment.
In this study changes in serum creatinine levels during ibandronate treatment were small; in patients presenting with serum creatinine levels >1.2 mg/dL at baseline, decreases were more prominent than increases. In 2-year clinical trials [3–5], renal safety comparable with that of placebo has been demonstrated for IV and oral ibandronate and for IV ibandronate an open-label safety extension study has confirmed long-term safety for up to 4 years . As expected from these clinical trials, there was no evidence of renal toxicity associated with ibandronate treatment in this observational study.
Baseline data showing (numerically) higher creatinine levels and percentages of patients with initial creatinine levels above 1.2 mg/dL in the subgroup pretreated with other bisphosphonates must be seen in the light of potential effects of zoledronic acid that had been given to 59% of patients in this group: treatment with zoledronic acid may be associated with deterioration of renal function that may progress to acute renal failure [6, 15, 21, 22]. The labeling for zoledronic acid thus contains renal safety precautions and a recommendation for monthly monitoring of renal function prior to each dose. Data from the final analysis with 3,000 patients may help to clarify the magnitude of the effects of pretreatment with zoledronic acid and how this may affect the further development of renal function under treatment with ibandronate.
The current analysis is based on the interim results of an observational study. Despite the limitations of this type of study (e. g. lack of a control group) that do not allow for statements regarding absolute efficacy or tolerability, it also has certain advantages such as the observation of populations with a broader spectrum of medical history. Most important, the large number of patients to be included will allow the evaluation of rare events in the final analysis. Moreover, in contrast to most other studies, treatment data were obtained under real-life conditions, which make these findings likely to be applicable to general practice.
In this observational study, ibandronate treatment over 24 weeks reduced bone pain in breast cancer patients with metastatic bone disease with and without prior bisphosphonate treatment. There was no evidence to suggest relevant differences in reductions of pain scores with IV and oral formulations of ibandronate or according to prior bisphosphonate treatment. SREs were rare.
Both formulations of ibandronate were rated as well tolerated by physicians and patients; renal function, as measured by serum creatinine levels, remained stable throughout the observation period with ibandronate treatment.
The data from this interim analysis suggest that the analgesic efficacy and safety profile of IV and oral formulations of ibandronate seen in phase III trials transfers to routine clinical practice under real-life conditions.
Funding for this study was provided by Roche Pharma AG, Grenzach, Germany.
We are indebted to the 157 investigators who documented the patients in this trial and thank Gisela Beyendorff-Hajda of Physicians World GmbH for medical writing assistance. The study was supported by Roche Pharma AG, Grenzach-Wyhlen, Germany, who also provided funding for medical writing support.