Fred Saad, Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, 1560 Rue Sherbrooke East, Montréal, PQ H2L 4M1 Québec, Canada. e-mail: firstname.lastname@example.org
Patients with metastatic bone disease often have severe bone pain and debilitating skeletal complications. Zoledronic acid is the only bisphosphonate shown to be safe and effective in reducing skeletal-related events (SREs), including pathological fractures, spinal cord compression, and radiation or surgery to bone in patients with bone metastases from advanced prostate cancer or renal cell carcinoma (RCC). In both tumour types, zoledronic acid significantly decreased the overall risk of developing an SRE, delayed their onset and significantly reduced the incidence of SREs compared with placebo. In patients with RCC, zoledronic acid also significantly delayed the time to progression of bone lesions by 5 months compared with placebo. Zoledronic acid is safe and well tolerated with long-term use.
Prostate cancer is the most commonly diagnosed cancer among men in the USA and the second most common cause of cancer-related deaths in men . Patients with prostate cancer are at high risk of developing bone metastases and developing compromised bone integrity induced by hormonal antineoplastic therapy; thus, skeletal morbidity is a significant clinical problem in these patients. Androgen-deprivation therapy is effective for treating prostate cancer, but hormonal ablation interferes with normal bone metabolism and causes loss of bone mineral density . Recently, it was proposed that treatment-induced bone resorption may promote the development of bone metastases (‘seed and soil’ theory) by releasing bone-derived growth factors and creating a favourable environment for invading tumour cells .
Unlike bone metastases from breast cancer, most bone lesions in prostate cancer are osteoblastic. However, recent studies show that osteoblastic lesions not only have up-regulated bone growth, but also concomitant increased osteolysis [2,4]. The new bone created by tumour-stimulated osteoblasts is weak and poorly mineralized, and the osteopenia secondary to the increased osteolysis results in a bone matrix with severely compromised integrity. The risk of developing a skeletal complication is thus increased.
Current treatments for prostate cancer do not address the skeletal complications that can arise from bone metastases. A hallmark symptom of bone metastases is severe, debilitating bone pain that often requires strong narcotic therapy or radiation therapy to palliate. Additional complications include pathological fracture that may require surgery, and spinal cord compression. These skeletal complications can have a negative effect on health-related quality of life.
Data from the placebo arms of double-blind trials of patients with prostate cancer and bone metastases show that about half had one or more skeletal-related event (SRE) at 2 years of follow-up; most of these events were radiation to bone, and fractures . These complications compromise health-related quality of life, leading to significant decreases in the functional, emotional, and physical subscales of the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire . Skeletal complications are also associated with significant costs. A recent analysis of a USA healthcare insurance-claims database from July 1994 to June 2002 revealed that total medical costs for patients with prostate cancer who had skeletal complications were >$20 000 more than for patients who had none ($59 522 vs $39 038) . Therefore, preventing skeletal complications secondary to bone metastases provides significant benefit to both patients and healthcare providers.
Although only ≈ 30% of patients with advanced RCC develop bone metastases, once developed the patients have a short median survival (≈ 12 months) and their 2-year survival rate is only 10–20%[8,9]. Bone lesions associated with RCC are predominantly osteolytic (65%) and patients are at high risk of skeletal complications . In a placebo-controlled, double-blind trial, almost 75% of patients in the placebo arm had one or more SRE . Most patients required radiotherapy to palliate bone pain, about half had long-bone fractures, and nearly a third required surgery over the 21 months of follow-up . In addition, almost a third of patients develop hypercalcaemia of malignancy (HCM) . As with prostate cancer, current treatment options for RCC do not treat bone metastases. Therefore, for patients with bone metastases from prostate cancer or RCC, new treatment options are needed.
Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and are widely used for treating malignant bone disease. Intravenous bisphosphonates, which have been shown to significantly reduce the incidence and to delay the onset of skeletal complications, are the current standard of care for patients with stage III multiple myeloma or bone metastases from advanced breast cancer. The incidence of skeletal complications in patients with prostate cancer is similar to that observed in clinical trials of patients with advanced multiple myeloma ; however, until recently, no bisphosphonate had shown significant clinical benefit in patients with bone metastases from advanced prostate cancer. Bisphosphonates have also not been widely investigated in patients with bone metastases from solid tumours such as RCC. Zoledronic acid is the first bisphosphonate to have significant clinical benefit in patients with bone metastases from advanced prostate cancer or RCC. The purpose of this review is to discuss the efficacy and safety of zoledronic acid for preventing skeletal complications in these patients.
EFFICACY OF ZOLEDRONIC ACID FOR TREATING BONE METASTASES FROM PROSTATE AND RENAL CANCERS
The efficacy and safety of zoledronic acid for preventing skeletal complications in patients with prostate cancer or RCC metastatic to bone was shown in two large, international, placebo-controlled, phase III trials. Study 039 randomized 643 men with advanced, hormone-refractory prostate cancer (Table 1)  and study 011 randomized 773 patients with lung cancer or solid tumours including RCC . Among patients with prostate cancer, about two-thirds had no SRE before study entry. For study 011, the subset of 46 patients with RCC was analysed retrospectively (Table 1) . The treatment groups were well balanced in this subset. Most patients (≈ 80%) were men with a good performance status and normal kidney function as determined by baseline serum creatinine levels. Most patients had already had a SRE before study entry.
Table 1. Patient demographics and baseline disease characteristics of patients with advanced prostate cancer and bone metastases in study 039, or with RCC and bone metastases in study 011
Median time from initial diagnosis to study entry, months§
ECOG performance status, n (%)
No. of lesions at study entry, n (%)
Previous SRE, n (%)
Baseline serum creatinine, n (%)
Normal (<1.4 mg/dL)
Abnormal (≥ 1.4 mg/dL)
The study design for both trials was similar. Patients were randomized to receive either placebo or zoledronic acid 4 mg by a 15-min infusion every 3 weeks, for up to 2 years for patients with prostate cancer, and up to 21 months for patients with RCC [5,12]. Results for the subset analysis of patients with RCC after 1 year of treatment were reported previously ; updated results from 21 months of treatment are presented here.
For both trials, the primary efficacy endpoint was the proportion of patients with a SRE, prospectively defined as pathological fracture, spinal cord compression, radiation therapy to treat bone pain or to prevent fractures/spinal cord compression, surgery to bone, or (for the prostate cancer trial only) change of antineoplastic therapy to treat bone pain. Because of the previously reported efficacy of zoledronic acid for treating HCM in patients with metastatic bone disease, HCM was not included as a SRE in analyses of primary endpoints in either trial. However, as HCM represents a serious, potentially life-threatening skeletal complication, it was included as a SRE in analyses of secondary endpoints across the phase III clinical trial programme of zoledronic acid.
Secondary endpoints in these trials included the skeletal morbidity rate (SMR, defined as the number of SREs that occurred on study divided by time on study, in years), the time to first SRE (by Kaplan–Meier analysis) and Andersen–Gill multiple-event analysis. In general, each of these secondary endpoints captures different aspects of the clinical benefit of zoledronic acid for preventing SREs. The time to first event is a conservative endpoint that assesses only the first event experienced by a patient while on study, but it also accounts for the discontinuation rate among patients. The SMR accounts for all events experienced by a patient over the course of the study but assumes a constant event rate. However, examinations of the clinical course of advanced cancer show that there can be considerable variations among patients in the rate at which skeletal events occur . Andersen–Gill multiple-event analysis uses regression methods to account for both the number of SREs and the timing of SREs, to provide a statistically robust, comprehensive assessment of the clinical benefit of zoledronic acid. This analysis is expressed as a hazard ratio (HR), wherein an HR of <1 indicates a favourable risk reduction for patients treated with zoledronic acid.
RESULTS FROM PHASE III TRIALS OF ZOLEDRONIC ACID IN PATIENTS WITH PROSTATE CANCER OR RCC
Zoledronic acid significantly reduced the incidence of SREs in patients with prostate cancer and RCC. Significantly fewer patients had at least one SRE when treated with zoledronic acid compared with placebo (Table 2) [5,16]. Zoledronic acid also significantly delayed the onset of SREs. In patients with advanced prostate cancer, the time to first SRE was delayed by >5.5 months compared with placebo (Fig. 1A) . This finding has particular clinical relevance for long-term health-related quality of life in patients with prostate cancer, given the relatively long median survival of these patients after developing bone metastases. In RCC, the treatment benefit provided by zoledronic acid was even more notable; it significantly delayed the time to first SRE by almost 1 year compared with placebo (Fig. 1B) . Similarly, the time to first pathological fracture was significantly delayed in patients with prostate cancer (Fig. 2A)  or RCC (Fig. 2B) .
Table 2. Proportion of patients with one or more SRE and mean SMR for patients with bone metastases and advanced prostate cancer or RCC
Treatment with 4 mg zoledronic acid significantly reduced the overall risk of developing an SRE in patients with bone metastases from either advanced prostate cancer or RCC (Fig. 3) [5,16]. In patients with prostate cancer, the risk decreased by 36% compared with placebo, whereas in patients with RCC, the risk decreased by 58% compared with placebo. The mean SMR was also significantly lower in patients treated with zoledronic acid compared with placebo (Table 2).
Secondary efficacy endpoints also showed significant clinical benefits in patients treated with zoledronic acid. Patients with prostate cancer who were treated with zoledronic acid reported less bone pain than those who received placebo. These results have particular clinical relevance because severe, debilitating pain is a hallmark of bone metastases from prostate cancer. Therefore, decreases in bone pain may improve patient health-related quality of life. In patients with prostate cancer, although pain scores increased from baseline throughout the study period in both treatment groups, those who were treated with zoledronic acid had consistently smaller increases in pain than patients receiving placebo (Fig. 4) . These differences were statistically significant at 3, 9, 21 and 24 months.
In patients with RCC, treatment with zoledronic acid significantly delayed bone lesion progression by >5.5 months compared with placebo (Fig. 5) . Notably, this analysis was done centrally by radiographic experts who were blinded to treatment conditions. This result is consistent with evidence from animal models showing that zoledronic acid can inhibit the growth of established bone lesions and reduce skeletal tumour burden . Zoledronic acid has also shown anti-angiogenic activity in preclinical models [18–20]. RCC is a highly vascularized tumour, and increased angiogenesis has been correlated with poor prognosis . Therefore, the clinical activity of zoledronic acid in patients with RCC may be due, at least in part, to the antitumour and anti-angiogenic effects of zoledronic acid.
Kaplan–Meier analysis of overall survival showed an early and consistent separation of event curves in both studies in favour of the zoledronic acid group (data not shown). Among patients with RCC, zoledronic acid improved the median survival by 131 days compared with placebo (11.5 vs 7.2 months). For patients with prostate cancer, the median survival was improved by 77 days for patients treated with zoledronic acid compared with placebo (18.2 vs 15.6 months). However, these differences were not significant (P = 0.104 for RCC and 0.103 for prostate cancer).
These results in patients with prostate cancer and RCC show the broad efficacy of zoledronic acid across the spectrum of osteolytic and osteoblastic lesions. Zoledronic acid can be safely and effectively administered to patients with bone metastasis, regardless of their underlying disease. Zoledronic acid is also currently being evaluated for preventing bone metastases in the adjuvant setting for patients with high-risk prostate cancer .
SAFETY AND TOLERABILITY OF LONG-TERM ZOLEDRONIC ACID (4 mg) IN PATIENTS WITH RCC OR PROSTATE CANCER
In general, zoledronic acid was well tolerated in patients with prostate cancer or RCC. Adverse events (AEs) more commonly reported by patients treated with 4 mg zoledronic acid (compared with those receiving placebo) included transient, infusion-related nausea, fatigue, pyrexia, vomiting, and arthralgia. These AEs were mild to moderate, were easily managed with supportive care, and tended to be limited to the first few treatment cycles.
It is widely known that all i.v. bisphosphonates have the potential to affect renal function. In these trials, renal function was prospectively assessed using the increase from baseline in serum creatinine, which was monitored before administration of each dose of study drug. A notable increase in serum creatinine was defined as ≥ 0.5 mg/dL if baseline serum creatinine was normal (<1.4 mg/dL, ≥1 mg/dL) if baseline serum creatinine was abnormal (>1.4 mg/dL), or any doubling of the baseline serum creatinine level.
This analysis showed that for patients with prostate cancer, the risk of increased serum creatinine level was similar between the zoledronic acid and placebo groups over 24 months. Kaplan-Meier analysis of the time to first notable serum creatinine increase showed an HR of 1.137 (95% CI 0.514–2.514; P = 0.75), indicating a minimal nonsignificant increased risk for patients treated with 4 mg zoledronic acid (by 15-min infusion). For patients with metastatic RCC, renal AEs were also minimal. These results are particularly important, as patients with RCC may be considered to be at higher risk of renal-related AEs. After 21 months of treatment, four of 27 patients who received 4 mg zoledronic acid via a 15-min infusion had a renal-related AE, whereas three of 19 treated with placebo had a renal-related AE (Table 3) . Therefore, based on this subset analysis, zoledronic acid does not appear to impair renal function in these high-risk patients.
Table 3. Incidence of renal-related AEs, regardless of causality, for patients with bone metastases and RCC
Zoledronic acid 4 mg
NOS, not otherwise specified. Reproduced with permission from Lipton et al..
Patients, n (%)
Renal failure NOS
Difficulty in micturition
Zoledronic acid is the only bisphosphonate confirmed to be effective in reducing skeletal complications associated with bone metastases from advanced prostate cancer or RCC, with an acceptable safety profile. In both tumour types, zoledronic acid significantly decreased the overall risk of developing an SRE, significantly delayed the onset of SREs, and significantly reduced the incidence of SREs compared with placebo.
Patients with RCC have clinically aggressive osteolytic lesions and benefit greatly from treatment with zoledronic acid, which resulted in a nearly 60% lower risk of developing an SRE and a delay of nearly 1 year in the onset of SREs compared with placebo. Moreover, the time to progression of bone lesions was significantly delayed compared with placebo. Further assessment of the effects of zoledronic acid on bone disease progression and survival in RCC is warranted. The delay in progression of bone lesions may potentially reflect some antitumour effects in vivo.
Zoledronic acid is the most broadly active i.v. bisphosphonate, and is the only one approved for preventing skeletal complications of malignancy in patients with bone metastases from all solid tumour types. When administered using the recommended dose and schedule, zoledronic acid is safe and well tolerated with long-term use. It has an overall safety profile similar to other i.v. bisphosphonates and a renal safety profile that is comparable with pamidronate. As with all i.v. bisphosphonates, renal monitoring during bisphosphonate therapy is recommended to maintain renal safety. When administered in accordance with treatment guidelines, zoledronic acid is associated with a minimal risk of increased serum creatinine in patients with advanced prostate cancer or RCC. In conclusion, zoledronic acid represents an effective treatment option for preventing skeletal complications in patients with advanced prostate or RCC metastatic to bone.
CONFLICT OF INTEREST
F. Saad is a study investigator funded by sponsor, and an advisory board member. A. Lipton has 200 shares in Novartis in a retirement account and is a speaker for the Bureau of Novartis.