Intravenous (i.v.) bisphosphonates are the standard of care for patients with metastatic
bone disease, with proven efficacy in reducing skeletal complications (Hortobagyi
et al, 1998; Theriault et al, 1999; Hillner et al, 2000; Lipton et al, 2000; Rosen
et al, 2001; Pavlakis and Stockler, 2002; Body et al, 2003c). Yet, for many patients,
i.v. bisphosphonate therapy is less than ideal. The risk of infusion-related adverse
events (AEs) and the possibility of renal toxicity adds to the treatment burden already
faced by patients with advanced cancer. The need for frequent hospital visits and
lengthy infusion duration (2 h for pamidronate) can make treatment cumbersome and
inconvenient for the patient, particularly as a long-term therapy.
Bisphosphonates administered via the oral route would allow the convenience of self-administration
at home. However, oral clodronate has been shown to be less effective than i.v. pamidronate
at reducing the risk of skeletal-related events (SREs) (Pavlakis and Stockler, 2002),
and its use can be associated with unpleasant gastrointestinal (GI) AEs, especially
diarrhoea (Kristensen et al, 1999; Powles et al, 2002). Owing to its relatively low
potency (Green et al, 1994), high doses are required and at least two large tablets
that are difficult for some patients to swallow have to be taken daily (Paterson et
al, 1993; Robertson et al, 1995). These factors, coupled with a recommended 1-h prefood
fasting period, may affect patient adherence to treatment.
Ibandronate, a highly potent, third-generation aminobisphosphonate, has been developed
in both i.v. and oral formulations for the management of metastatic bone disease.
As reported elsewhere, the i.v. formulation of ibandronate (6 mg infused every 3–4
weeks) has been shown to reduce significantly the risk of skeletal complications,
alleviate bone pain and improve quality of life in patients with metastatic breast
cancer, in the absence of renal safety concerns (Body et al, 2003a, 2003b; Diel et
al, 2003; Tripathy et al, 2003). This paper presents the results of a pooled analysis
of two phase III clinical trials that assessed the efficacy and safety of oral ibandronate
(50 mg day−1) in the treatment of women with breast cancer and bone metastases.
PATIENTS AND METHODS
Study population
Two randomised, parallel-group, double-blind, placebo-controlled studies were conducted
by centres across Europe and other countries, including Australia and the United States
of America. Women with histologically confirmed breast cancer and radiologically confirmed
bone metastases were recruited into the studies. Patients were required to have a
WHO performance status of 0, 1 or 2, be at least 18 years of age, and to provide written
informed consent. The exclusion criteria included previous treatment with bisphosphonates
or gallium nitrate within the last 6 months, life expectancy <60 weeks, hypercalcaemia
(serum calcium, albumin corrected, ⩾2.7 mmol l−1), hypocalcaemia (serum calcium, albumin
corrected, ⩽2.0 mmol l−1), severely impaired renal function (serum creatinine >3.0 mg dl−1),
Paget's disease of the bone, primary hyperparathyroidism, known liver/brain metastases,
receiving a high-dose chemotherapy (i.e. dose intensity >3 times standard therapy),
having a medical history of aspirin-sensitive asthma, or receiving treatment with
aminoglycoside antibiotics within 4 weeks prior to the start of study medication.
In the two studies, patients were randomised to treatment with oral ibandronate 20 mg,
50 mg or placebo once daily for up to 96 weeks. Only the ibandronate 50 mg data (vs
placebo) are reported in this pooled analysis, as 50 mg will be the recommended dose
for clinical use. Patients were instructed to take one tablet in the morning 1 h before
breakfast with a glass of water, but not with milk, milk products or calcium tablets.
To assess compliance with therapy, patients were required to return their oral medication
to the investigator every 12 weeks for checking. Concomitant treatments were allowed
during the study, except those specified as the exclusion criteria.
Efficacy and safety assessments
Efficacy and safety data from the two studies were pooled for analysis, as predefined
in the study protocols. Fractures, bone pain, analgesic consumption, episodes of radiotherapy
and surgical interventions were assessed at 4-weekly clinic visits. Urine samples
were collected at weeks 4, 12, 24, 48, 72 and 96 for the assessment of c-telopeptide
(CTx), a marker of bone turnover, using Crosslaps™ CTx assay. AEs were recorded continuously
throughout the study.
To allow for the possibility of nonrandom withdrawal from study groups, postwithdrawal
follow-up (PWFU) efficacy and safety data (i.e. for the period from study withdrawal
until death or the last scheduled study visit) were also collected. Postwithdrawal
follow-up data collection were discontinued when treatment with another bisphosphonate
began.
Analysis of efficacy
The primary efficacy parameter was the skeletal morbidity period rate (SMPR) defined
as the number of 12-week periods with new skeletal complications, divided by the total
observation time. Skeletal complications included vertebral fractures, pathological
nonvertebral fractures, radiotherapy for bone complications (uncontrolled bone pain
or impending fractures) and surgery for bone complications (fractures or impending
fractures). To allow for the time spent in the study, SMPR was calculated using a
revised event ratio method, as follows (Scott et al, 2003):
As prespecified in the data analysis plan, analyses of the primary end point excluded
data collected in the first 12-week period. Exclusion of early events avoids the loss
of power associated with events occurring too early to have been prevented by bisphosphonates.
It was anticipated that effects on bone events of ibandronate vs placebo would begin
to appear 6–8 weeks after drug initiation. The first 12 weeks were selected for exclusion
as study visits were on a 3-month basis.
Supportive analyses of the SMPR included the mean number of skeletal events per patient,
the mean number of 12-week measurement periods with events per patient, the percentage
of patients with skeletal events and time to first new bone event. A multivariate
Poisson's regression analysis was performed to assess the risk of developing a skeletal
event over the entire 96 weeks of treatment, while controlling for any differences
in baseline characteristics between the oral ibandronate 50 mg group and the placebo
group. The input variables for the Poisson's regression analysis were country, age,
estrogen/progesterone receptor status, performance status, time from breast cancer
and metastatic bone disease diagnoses to study initiation, extraosseous metastases,
prior hormone and chemotherapy, pathological fractures at baseline, pain score, analgesic
score and baseline laboratory measures (e.g. haemoglobin, alkaline phosphatase, aspartate
transaminase, white blood cell counts).
Statistics
The global null hypothesis (no difference in SMPR between ibandronate and placebo)
was tested at the two-sided α-level of 5% using the nonparametric Jonckheere–Terpstra
method (Terpstra, 1952; Jonckheere, 1954). If the global hypothesis was rejected,
pairwise comparisons between treatments were performed using the Wilcoxon's rank-sum
method, maintaining an overall two-sided α-level of 5% and following a closed-test
procedure. The trial was designed such that the statistical analysis of the study
was powered for the composite end point SMPR, but not for the components of the composite.
Efficacy analyses were conducted on the intent-to-treat (ITT) population (all patients
randomised) and included PWFU data. Evaluation of safety was based on all randomised
patients who had received at least one dose of study drug and had at least one follow-up
assessment.
Ethics
The study was performed in accordance with the principles of the Declaration of Helsinki,
the Guidelines on Good Clinical Practice and local medicines legislation in place
at the time of study initiation.
RESULTS
Patients
A total of 564 patients were randomised to treatment with oral ibandronate 50 mg (n=287)
or placebo (n=277) and were included in the ITT analysis. Patient demographics and
baseline characteristics are shown in Table 1
Table 1
Patient demographics and baseline characteristics
Placebo (n=277)
Ibandronate, 50 mg (n=287)
Age (years)
Median (range)
56 (26–87)
57 (27–92)
Race, Caucasian (%)
94
93
Median time from diagnosis to first drug intake (years)
3.87
3.44
Median time from bone metastases diagnosis to study entry (years)
0.48
0.46
Performance status (%)
WHO grade 0 or 1
85
84
WHO grade 2
15
16
Mean pain score
1.13
1.33
Mean analgesic score
0.98
1.09
Prior fractures at baseline (%)
43
52
. Although the study groups were generally comparable at baseline, the oral ibandronate
50 mg group contained a higher percentage of patients receiving ongoing cytotoxic
therapy, with a higher mean bone pain score and a higher percentage of patients with
pre-existing fractures than in the placebo group (differences between groups nonsignificant).
The percentage of patients completing the 96-week treatment period was 42% in the
ibandronate group and 38% in the placebo group. The median time on study (from randomisation
to study end) was 79 weeks with ibandronate compared with 69 weeks with placebo (NS).
The most frequent reasons for withdrawal were malignancy progression (affecting 12%
of patients receiving ibandronate vs 19% of patients receiving placebo), death (15
vs 12%) and other AEs (10 vs 12%).
Efficacy
The mean SMPR for all new bone events was significantly reduced with oral ibandronate
50 mg compared with placebo (P=0.004) (Figure 1
Figure 1
Summary of the mean SMPR, weighted for observation time (*
P<0.05, **
P<0.01 and ***
P<0.001).
). Analysis of the individual components revealed that this effect was due primarily
to significant reductions in bone events requiring radiotherapy (P<0.001) or surgery
(P=0.037) (Figure 1). There was no significant difference in the number of skeletal
fractures with ibandronate compared with placebo (P=0.195). When bone events occurring
during the first 12-week period were included in the SMPR calculation, the impact
of ibandronate on the incidence of skeletal events was reduced, but remained significant
for overall SMPR and for events requiring radiotherapy (Table 2
Table 2
Supportive analysis of SMPR, including events occurring during the first 12 weeks
of treatment
Mean SMPR
Placebo
Ibandronate, 50 mg
All new bone events
1.15
0.99, P=0.041*
Vertebral fractures
0.52
0.49, P=0.145*
Nonvertebral fractures
0.52
0.51, P=0.330*
Need for radiotherapy
0.98
0.80, P<0.004*
Need for surgery
0.44
0.40, P=0.098*
SMPR=skeletal morbidity period rate.
*
Wilcoxon's rank-sum test, pairwise comparisons vs placebo.
). Supportive analyses of new bone events demonstrated that the mean number of events
and the mean number of measurement periods with events per patient were significantly
reduced in the ibandronate group compared with placebo (P=0.008 and 0.015, respectively,
Table 3
Table 3
Supportive analyses of new bone events
Placebo
Ibandronate, 50 mg
No. of events per patient
1.85
1.15, P=0.008*
No. of 12-week periods with events per patient
0.99
0.71, P=0.015*
% of patients with events
52.2
45.3, P=0.122*
*
Wilcoxon's rank-sum test, pairwise comparisons vs placebo.
). The median time to first bone event was 90.3 weeks with oral ibandronate 50 mg
and 64.9 weeks with placebo (P=0.089).
Multivariate Poisson's regression analysis showed that the risk reduction for a skeletal
event in the ibandronate 50 mg group was significantly lower than in the placebo group
(hazard ratio 0.62, 95% CI=0.48, 0.79, P<0.0001), translating to a 38% risk reduction
for ibandronate vs placebo.
Patients receiving oral ibandronate 50 mg showed a significant decrease from baseline
in the bone marker urinary CTx over the 96-week study period compared with placebo
(median change −77.3% and +11.0%, P<0.001) (Figure 2
Figure 2
Change in urinary CTx during study period (*
P<0.001).
).
Safety
A total of 563 patients were included in the safety analysis. As would be expected
with skeletal metastases due to advanced cancer, almost all patients reported AEs
during the course of the study. The percentage of patients experiencing any AE was
similar between the oral ibandronate 50 mg and placebo groups (94.4 vs 95.3%). The
most frequently recorded AE was malignancy progression (affecting 67.5 and 70.8% of
patients, respectively). There was a slightly higher incidence of drug-related AEs
with ibandronate (26.6%) than with placebo (17.7%), primarily due to more reports
of hypocalcaemia in the ibandronate group (Table 4
Table 4
Treatment-related AEs (reported by ⩾2% of patients in any treatment group)
AEs
Placebo (n (%))
Ibandronate, 50 mg (n (%))
Abdominal pain
2 (0.7%)
6 (2.1%)
Dyspepsia
13 (4.7%)
20 (7.0)
Nausea
4 (1.4%)
10 (3.5%)
Oesophagitis
2 (0.7%)
6 (2.1)
Hypocalcaemia
14 (5.1%)
27 (9.4%)
AEs=adverse events.
), a side effect associated with the use of any bisphosphonate. Serious AEs that were
considered to be drug related were experienced by 1.0% of patients receiving ibandronate,
compared with 1.4% of patients in the placebo group.
The incidence of mild treatment-related upper GI AEs (dyspepsia, nausea and oesophagitis)
was slightly higher in the oral ibandronate 50 mg group compared with placebo (Table
4). The incidence of drug-related upper GI AEs known to be associated with oral bisphosphonate
administration was similar in the placebo and 50 mg oral ibandronate groups (Table
4). Only two serious upper GI AEs (duodenal ulcer haemorrhage and nausea, each recorded
by one patient) were considered related to ibandronate treatment.
The incidence of renal AEs was comparable between ibandronate (5.2%) and placebo (4.7%),
and there were no reports of serious AEs (renal failure) in the active treatment group.
During the course of the study, 20% of patients (n=57) in the ibandronate 50 mg group
and 15% of patients (n=42) in the placebo group died as a result of an AE. Death was
most commonly due to malignancy progression, and no deaths were considered to be related
to study treatment.
DISCUSSION
The primary efficacy measure used in these two phase III trials of oral ibandronate
was the SMPR, defined as the number of 12-week periods with new bone events, weighted
for observation time. By assessing 12-week time periods where all complications are
considered as a single occurrence, the SMPR avoids multiple counting of events, and
therefore represents a conservative measure of efficacy. Clinical trials of other
bisphosphonates in patients with metastatic bone disease have used the SRE or skeletal
morbidity rate to assess the impact of treatment on skeletal complications. By counting
all occurrences of new bone events, these measures may overestimate the effect of
treatment, as many skeletal events (e.g. radiotherapy, fracture and bone surgery)
are likely to be related in many cases.
The pooled results of the two oral trials demonstrated that ibandronate 50 mg once
daily effectively reduces the incidence of new bone events in women with breast cancer
and bone metastases. A statistically significant clinical benefit was observed for
overall SMPR compared with placebo. This effect was maintained when skeletal events
occurring in the first 12-week treatment period (including prescheduled radiotherapy
events, which may have reduced the observed effect of active treatment) was included
in the analysis. Ibandronate also significantly improved the need for bone radiotherapy
and the need for bone surgery, both of which are considered to be highly clinically
relevant indicators of disease outcomes. As the study was not powered to detect statistical
significance on individual components of the SMPR, these results strongly support
the clinical impact of ibandronate on the occurrence of new bone events. The results
for fractures did not reach statistical significance in contrast to the data for i.v.
ibandronate (Body et al, 2003a), and the patients had overall less fractures in the
oral studies. Since a large meta-analysis of clinical trials has shown that bisphosphonates
significantly decrease skeletal morbidity including fractures and need for radiotherapy
(Ross et al, 2003), the trend that was observed for oral ibandronate will need to
be confirmed in larger studies.
The percentage reduction in SMPR with oral ibandronate vs placebo in this pooled analysis
(19%) was comparable to that observed in a clinical trial of i.v. ibandronate 6 mg
(20%), which had a similar study design and was also conducted in patients with metastatic
breast cancer (Body et al, 2003a, 2003c). The Poisson's regression analysis conducted
on the pooled data set and the results of the i.v. trial also revealed comparable
reductions in the risk of SREs with oral and i.v. ibandronate compared with placebo
(hazard ratio 0.62, P=0.001 and hazard ratio 0.60, P=0.0033, respectively) (Body et
al, 2003a, 2003c). Comparisons between these trials are cautious, as patients in the
i.v. study had received a diagnosis of metastatic bone disease approximately 10 months
earlier prior to study entry than patients in the oral trials, indicating that they
had more severe disease. However, patients in the trials were similar in terms of
their clinical presentation (age, baseline fracture incidence, performance status
and bone-pain level), suggesting that the oral and i.v. formulations had broadly similar
efficacy. Supporting this, oral and i.v. ibandronate were shown to have similar effects
on secondary efficacy end points, with bone pain significantly reduced and maintained
below baseline over 2 years of treatment, and significantly less deterioration in
quality of life compared with placebo (Body et al, 2003b; Tripathy et al, 2003). This
would be expected given that a daily oral 50 mg dose and an i.v. 6 mg given every
3–4 weeks provide the same bone surface exposure to ibandronate (Leyland-Jones, in
press). Direct comparisons between bisphosphonates are difficult because of differences
in study methodology. A comparative trial is currently examining the effects of oral
ibandronate and i.v. zoledronate in patients with metastatic bone disease due to breast
cancer.
Long-term drug safety and tolerability is an important consideration in the selection
of treatment for skeletal metastases, due to the high disease-related morbidity burden
and the side effects associated with systemic cancer therapy. Oral ibandronate 50 mg day−1
for 2 years of treatment was well tolerated in these trials, with an AE profile quite
similar to placebo. As demonstrated for i.v. ibandronate (Body et al, 2003a; Lyubimova
et al, 2003), oral ibandronate was not associated with renal AEs. This contrasts with
the enhanced risk of renal AEs reported with i.v. zoledronate and pamidronate in a
phase III trial (Rosen et al, 2001). With its benign renal safety profile, oral ibandronate
may be used in patients with existing renal impairment. In addition, the results suggest
that serum creatinine monitoring can be made, depending on the assessment of the individual
patient, at the clinician's discretion. The associated reductions in renal monitoring
time and costs could help to relieve the burden of bisphosphonate care on nursing
staff and hospital budgets (Body, 2003).
As well as efficacy and safety, the availability of oral ibandronate could offer improved
treatment flexibility for physicians and convenience for patients. Oral ibandronate
may be prescribed alongside other oral agents (particularly hormonal treatment) for
at-home dosing (e.g. when hospital care is not being received). Patients would no
longer have to spend time travelling to and from the hospital solely for bisphosphonate
infusion, allowing them to maintain their lifestyle without unnecessary disruption.
The dosing regimen of oral ibandronate is convenient for patients. Adequate adherence
is important in real-life situations, where dosing instructions are not closely monitored,
unlike in clinical trials.
In conclusion, oral ibandronate 50 mg is an effective, well-tolerated and convenient
treatment for the skeletal complications of metastatic bone disease.