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Bisphosphonates: Clinical Experience

Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, England, United Kingdom

Correspondence: Robert E. Coleman, M.D., Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Whitham Road, Sheffield, England S10 2SJ, United Kingdom. Telephone: 44-114-226-5213; Fax: 44-114-226-5678; e-mail: r.e.coleman{at}sheffield.ac.uk

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Treatment and Management of... Bisphosphonates in Breast Cancer Bisphosphonates in Prostate... Bisphosphonates in Other Solid... Conclusions References

 
After completing this course, the reader will be able to:

1. Explain the importance of bone disease in the common solid tumors of adulthood.
   
2. Describe the pathophysiology of bone metastasis.
   
3. List the specialized end points used in clinical trials assessing treatment of bone disease.
   
4. Discuss the current standard for the treatment and prevention of bone complications that may arise in cancer and its treatment.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Treatment and Management of... Bisphosphonates in Breast Cancer Bisphosphonates in Prostate... Bisphosphonates in Other Solid... Conclusions References

 
Bone is a preferred site of metastasis for many solid tumors, and the complications associated with bone metastases can result in significant skeletal morbidity including severe bone pain, pathologic fracture, spinal cord compression, and hypercalcemia of malignancy (HCM). Bisphosphonates are the current standard of care for preventing skeletal complications associated with bone metastases. Clinical trials investigating the benefit of bisphosphonate therapy have used a composite end point defined as a skeletal-related event (SRE) or bone event, which typically includes pathologic fracture, spinal cord compression, radiation or surgery to bone, and HCM. Bisphosphonates have been shown to significantly reduce the incidence of these events in patients with bone metastases. Zoledronic acid (Zometa^®; Novartis Pharmaceuticals Corp.; East Hanover, NJ), pamidronate (Aredia^®; Novartis Pharmaceuticals Corp.), clodronate (Bonefos^®; Anthra Pharmaceuticals; Princeton, NJ), and ibandronate (Bondronat^®; Hoffmann-La Roche Inc.; Nutley, NJ) all have demonstrated efficacy superior to that of placebo in patients with breast cancer. Zoledronic acid is the only bisphosphonate that has been compared directly with pamidronate, and it was shown by multiple event analysis to be significantly more effective at reducing the risk of an SRE. In patients with prostate cancer, clodronate, etidronate (Didronel^®; Procter and Gamble Pharmaceuticals, Inc.; Cincinnati, OH), and pamidronate have demonstrated transient palliation of bone pain. However, zoledronic acid is the only bisphosphonate to demonstrate both significant and sustained pain reduction and a significantly lower incidence and longer time to onset of SREs compared with placebo. Zoledronic acid is also the only bisphosphonate to demonstrate efficacy in patients with bone metastases from a variety of other solid tumors, including lung cancer and renal cell carcinoma. In conclusion, bisphosphonates effectively reduce skeletal complications in patients with bone metastases from breast cancer, and zoledronic acid has demonstrated the broadest clinical activity in patients with a wide variety of tumor types.

Key Words. Bone metastases • Phase III • Zoledronic acid • Pamidronate • Skeletal complications

	INTRODUCTION

Top Learning Objectives Abstract Introduction Treatment and Management of... Bisphosphonates in Breast Cancer Bisphosphonates in Prostate... Bisphosphonates in Other Solid... Conclusions References

 
Bone metastases are common in patients with many types of cancer (Table 1) [1–4], especially breast and prostate cancer, in which the incidence is approximately 70% among patients with advanced metastatic disease [2, 3]. Because patients with breast or prostate cancer have a relatively long median survival time after diagnosis of bone metastases, the prevalence of bone metastases is high. These two cancer types probably account for more than 80% of cases of metastatic bone disease. In addition, approximately 40% of patients with advanced lung cancer develop bone metastases.

	TREATMENT AND MANAGEMENT OF BONE METASTASES

Top Learning Objectives Abstract Introduction Treatment and Management of... Bisphosphonates in Breast Cancer Bisphosphonates in Prostate... Bisphosphonates in Other Solid... Conclusions References

 
Traditional approaches for treating patients with bone metastases include standard antineoplastic therapies (chemotherapy or biologic therapies), which may be administered in conjunction with additional supportive or palliative therapies. Severe bone pain is treated with radiotherapy and/or radionuclides, and many patients also receive systemic analgesic therapy with nonsteroidal anti-inflammatory drugs or opioids. Radiotherapy is also used to stabilize bone lesions and may prevent impending fractures. Orthopedic surgery is used to treat existing fractures or to prevent impending fractures or spinal cord compression.

Bisphosphonates
In addition to these strictly palliative interventions, bisphosphonates have emerged in recent years as a highly effective therapeutic option for the prevention of skeletal complications secondary to bone metastases. Bisphosphonates bind preferentially to bone at sites of active bone metabolism, are released from the bone matrix during bone resorption, and potently inhibit osteoclast activity and survival, thereby reducing osteoclast-mediated bone resorption [13]. Newer nitrogen-containing bisphosphonates, such as zoledronic acid (Zometa^®; Novartis Pharmaceuticals Corp.; East Hanover, NJ), pamidronate (Aredia^®; Novartis Pharmaceuticals Corp.), and ibandronate (Bondronat^®; Hoffmann-La Roche Inc.; Nutley, NJ), have a unique mechanism of action and greater clinical activity than first-generation bisphosphonates such as etidronate (Didronel^®; Procter and Gamble Pharmaceuticals, Inc.; Cincinnati, OH) and clodronate (Bonefos^®; Anthra Pharmaceuticals; Princeton, NJ) [14]. These newer agents are orders of magnitude more potent than the first-generation compounds. Consequently, they can inhibit bone resorption at micromolar concentrations.

Evaluating the Clinical Benefit of Bisphosphonates
The clinical benefits of bisphosphonate therapy have been evaluated in many clinical trials designed to capture data on skeletal complications. The majority of these trials used a composite end point defined as a skeletal-related event (SRE) or bone event, which generally includes events such as pathologic fracture, radiation to bone, surgery to bone, spinal cord compression, and HCM. Such composite end points capture data on all clinically relevant events and are more likely to detect therapeutic benefits when treatment effects and disease morbidity are multifaceted [15].

Using a composite definition of skeletal events, it is possible to assess treatment effect using a variety of outcome analyses. First-event descriptors such as proportion of patients with 1 SRE or time to first SRE are objective and conservative end points that provide readily assessable estimations of treatment effect. Of these, the U.S. Food and Drug Administration has suggested that time to first event is the preferred end point because it also accounts for the patient’s time on study [16]. However, first-event analyses only capture information about the first event and ignore data on all subsequent events that occur in any given patient. Skeletal morbidity rates (SMRs) or skeletal morbidity period rates (SMPRs) assess the number of events that occur during a designated time period (e.g., events/year). These analyses account for the occurrence of multiple skeletal events but assume that these events occur at a constant rate. However, clinical evidence suggests that patients with bone metastases exhibit considerable variation in both the number of skeletal events they experience and the rate at which these events occur [17]. Moreover, skeletal events do not demonstrate random distribution but often occur in clusters. Therefore, analyses that assume a linear event rate tend to overestimate the differences between study groups and may unduly overestimate treatment effects [18].

Regression analyses such as a Poisson analysis or the Andersen-Gill multiple event analysis are able to model all events, as well as the time between events, and are able to account for inter- and intrapatient variations in event rates [19]. However, Poisson analyses that do not account for nonconstant event rates are subject to the same limitations as those of other analyses, such as analyses using SMR, that do not account for variability in event rate. Therefore, multiple event analysis provides a statistically robust and comprehensive assessment of skeletal morbidity throughout the entire length of follow-up. Andersen-Gill multiple event analysis calculates a hazard ratio (HR) that indicates the extent to which the risk of skeletal events is affected by one specific treatment relative to another. A hazard ratio <1 indicates a favorable treatment effect. Recently, nonparametric methods for multiple event analysis have been described by Ghosh and Lin [20] and by Cook and Lawless [21]. These models calculate the cumulative incidence of skeletal complications and allow for right-censored data, thus accounting for death or study discontinuation for other reasons. Together, all these statistical analyses provide both conservative and comprehensive assessments of the clinical benefit of bisphosphonates in patients with bone metastases.

	BISPHOSPHONATES IN BREAST CANCER

Top Learning Objectives Abstract Introduction Treatment and Management of... Bisphosphonates in Breast Cancer Bisphosphonates in Prostate... Bisphosphonates in Other Solid... Conclusions References

 
Several bisphosphonates have been approved in the U.S. and/or Europe for the treatment of breast cancer patients with bone metastases (Table 3) [22]. Oral clodronate, at a daily dose of 1,600 mg, is approved in Europe. The more potent nitrogen-containing bisphosphonates are administered via i.v. infusions, over 2 hours for 90-mg pamidronate, 1 hour for 6-mg ibandronate, and 15 minutes for 4-mg zoledronic acid. An oral formulation of ibandronate (50 mg/day) has also been investigated in patients with breast cancer. Only i.v. pamidronate and zoledronic acid have been approved in the U.S., and they are recommended by the American Society of Clinical Oncology for the treatment of breast cancer patients with bone metastases [23].

Clodronate
The safety and efficacy of oral clodronate (1,600 mg/day) were evaluated more than a decade ago in a double-blind, placebo-controlled trial enrolling 173 patients [24]. That study assessed the number of HCM episodes, courses of radiotherapy to bone, and pathologic fractures (expressed as events per 100 patient-years). After a median follow-up of approximately 14 months, there was no difference between treatment groups in terms of the percentage of patients with HCM, requiring radiotherapy to bone, or sustaining fractures, and there was no difference in terms of median time to first event. However, treatment with clodronate produced significantly lower event rates for HCM (p < 0.01), vertebral fractures (p < 0.025), and vertebral deformity (p < 0.001) and combined event rate for all events (218.6 versus 304.8 events per 100 patient-years; p < 0.001). However, the statistical methodology used in that trial (events per 100 patient-years) has been criticized because of the potential for overestimation of treatment effects [25]. This is a particular concern given that the majority of patients died before they completed the 18-month study. Results of time to first SRE and survival were later updated by Pavlakis et al. [26] based on an analysis of 185 patients treated on this protocol. In the updated analysis, time to first skeletal event was significantly longer for the clodronate group (9.9 months versus 4.9 months for placebo; p = 0.022), and survival times were similar in the two treatment groups.

Two other large placebo-controlled trials of the efficacy of oral clodronate in preventing SREs have also been published. In a study reported by Kristensen et al. [27], 100 patients with breast cancer metastatic to bone who were receiving first-line antineoplastic therapy were randomized to receive either placebo or two 400-mg clodronate capsules twice a day for 2 years. Among 99 evaluable patients, treatment with 800 mg/day of clodronate resulted in fewer bone events (defined as HCM, fractures, or radiotherapy) than treatment with placebo and a significantly longer time to first bone event than placebo (p = 0.015). There were significantly fewer fractures among patients treated with clodronate versus patients treated with placebo (p = 0.023). However, these effects of clodronate were transient, as the need for radiation therapy was greater after 15 months in the clodronate treatment group than in the placebo group (p = 0.069). There was no effect on progression of bone disease or survival. The most common adverse events leading to discontinuation of clodronate were nausea and diarrhea.

Tubiana-Hulin et al. [28] reported the results from a placebo-controlled study in which 144 patients with breast cancer and osteolytic bone metastases being treated with either chemotherapy or hormonal therapy were randomized to also receive either 1,600 mg/day oral clodronate (n = 73) or placebo (n = 71) for up to 12 months. In that study, SREs were defined as HCM, radiotherapy to bone, pathologic fractures (including spinal cord compression), increase or onset of bone pain, or death due to bone metastases. Among 137 evaluable patients, the median time to first bone event was significantly longer with clodronate treatment (244 days versus 180 days for placebo; p = 0.05) and patients treated with clodronate had significantly lower pain intensities and analgesic use than patients treated with placebo (p = 0.01 and p = 0.02, respectively). There were no significant differences in adverse event incidences between the clodronate and placebo treatment groups.

Pamidronate
The efficacy and safety of i.v. pamidronate (90 mg via a 2-hour infusion every 3–4 weeks) for the treatment of bone metastases secondary to breast cancer were established in the mid-1990s based on two multicenter, randomized, placebo-controlled trials involving 754 patients [29, 30]. Those trials showed that treatment with pamidronate resulted in a significantly lower incidence and longer time to onset of skeletal complications compared with placebo in patients receiving chemotherapy or hormonal therapy.

In the study by Hortobágyi et al. [29], 382 women with breast cancer and metastatic osteolytic bone lesions who were receiving chemotherapy were randomized to receive either 90 mg of pamidronate (via a 2-hour infusion) or placebo every 3–4 weeks for 2 years. The primary end point of that trial was the proportion of patients who had any SRE, defined as hypercalcemia, pathologic fracture, radiation to bone for pain relief, surgery to bone, or spinal cord compression. After 2 years of treatment, the proportion of patients with any SRE was significantly lower at months 15, 18, 21, and 24 for patients treated with pamidronate than for patients treated with placebo (p < 0.001). The median time to first SRE was more than 6 months longer for patients treated with pamidronate than for those treated with placebo (median 13.9 months for pamidronate versus 7.0 months for placebo; p < 0.001).

Similarly, Theriault et al. [30] assessed the efficacy of pamidronate in reducing skeletal morbidity in 372 patients with osteolytic bone metastases and breast cancer who were receiving hormonal therapy. Patients were randomized to receive double-blinded treatment with either 90 mg of pamidronate (via a 2-hour infusion) or placebo every 4 weeks for 24 treatment cycles. Among 371 evaluable patients, the SMR was significantly lower in patients treated with pamidronate than in patients treated with placebo at 12 (p = 0.028), 18 (p = 0.023), and 24 (p = 0.008) months. After 2 years of treatment, the proportion of patients with any SRE was a relative 16% lower in the pamidronate group than in the placebo group (56% versus 67% for placebo; p = 0.027), and the median time to first SRE was approximately 4 months longer than in the placebo group (p = 0.049). In both the Hortobágyi et al. [29] and Theriault et al. [30] trials, pamidronate was well tolerated and had no effect on survival.

An updated pooled analysis of these trials at 2 years’ follow-up demonstrated that treatment with pamidronate resulted in a significantly lower percentage of patients with 1 SRE (51% versus 64% for placebo; p < 0.001), a nearly 6 months longer median time to first SRE (12.7 versus 7.0 months for placebo; p < 0.001), and a significantly lower mean SMR (2.5 versus 4.0 SREs/year for placebo; p < 0.001) [5]. Pamidronate also resulted in a significantly higher bone lesion response (32% versus 22% for placebo; p = 0.002) and significantly lower pain scores (p = 0.015) than placebo. In those trials, pamidronate had an acceptable safety profile.

These results were confirmed in a study reported by Hultborn et al. [31]. Among 404 women with skeletal metastases from breast cancer, patients who were administered 60 mg of pamidronate i.v. every 4 weeks had significantly fewer SREs—defined as increased pain, HCM, pathologic fracture of long bones or pelvis, paralysis secondary to vertebral compression, palliative radiotherapy or surgery to bone, or change of antineoplastic therapy—than patients given placebo (p < 0.01). There were no significant differences between treatment groups in the incidences of pathologic fractures of long bone or pelvis, paralysis due to vertebral compression, radiotherapy, or surgery. However, patients treated with pamidronate did have a significantly longer time to increase of pain (p < 0.01), lower incidence of HCM (p < 0.05), and higher performance status scores than patients given placebo (p < 0.05).

Pamidronate was also shown to be effective in delaying the time to progression of bone lesions in 297 women with breast cancer and bone metastases treated with either placebo or 45 mg pamidronate via a 1-hour infusion every 3 weeks (median 249 days versus 168 days for placebo; p = 0.02) [32]. That study also showed that significantly more patients treated with pamidronate reported decreased pain than those treated with placebo (44% for pamidronate versus 30% for placebo; p = 0.025). No major toxicities were reported in either treatment group. SREs were not assessed in that study. It is important to note that both the Hultborn et al. [31] and Conte et al. [32] studies did not evaluate the currently recommended dose of 90 mg pamidronate.

The 90-mg dose of pamidronate was significantly superior to placebo in reducing skeletal complications of bone metastases across all end points in women with breast cancer [29, 30]. Given these results, based on conservative clinical end points, the 90-mg dose of pamidronate via a 2-hour infusion was approved in the U.S. and quickly became established as the international standard of care for women with bone metastases from breast cancer.

Ibandronate
More recently, ibandronate (both oral and i.v.) has been evaluated for the prevention of skeletal complications in breast cancer patients with bone metastases using placebo as the comparator. A randomized, placebo-controlled trial of 2 or 6 mg i.v. ibandronate (via 1- to 2-hour infusions every 3–4 weeks for 2 years) was recently conducted in 466 patients [33]. The primary efficacy end point was the SMPR, defined as the number of 12-week periods on study in which a patient experienced a new bone event divided by the number of periods on study. Bone events were defined as pathologic fracture, radiotherapy to treat bone pain or impending fracture, or surgery for bone complications. At 2 years, patients treated with 6-mg ibandronate had a significantly lower SMPR by 20% (1.19 versus 1.48 events per patient-year for placebo; p = 0.004) and a significantly longer time to first SRE (median 51 versus 33 weeks for placebo; p = 0.018) than patients treated with placebo. Ibandronate (6 mg) demonstrated a trend toward a lower percentage of patients with 1 new bone event, but this difference did not quite reach statistical significance (p = 0.052). Ibandronate (2 mg) demonstrated no significant clinical benefit.

Treatment with oral ibandronate (50 mg/day for up to 96 weeks) was also shown to produce a significantly lower SMPR than placebo (0.95 versus 1.18 events per patient-year; p = 0.004) in a combined analysis of two trials involving 564 patients with bone metastases [34]. However, that analysis excluded SREs that occurred during the first 3 months on study and included SREs that occurred after completing/withdrawing from the study. In addition, Poisson’s regression analysis demonstrated a 38% reduction in the risk of new bone events (HR = 0.62; p = 0.0001). It was not reported whether the Poisson analysis was adjusted to account for nonconstant event rates in order to address potential overestimation of treatment effects [18]. However, oral ibandronate did not result in a significantly lower percentage of patients with a new bone event (45% versus 52% for placebo; p = 0.122) or a significantly longer time to first new bone event (median 21 months versus 15 months for placebo; p = 0.089) compared with placebo. It is also important to note that patients in that trial appear to have had a low event rate (i.e., SMPR), compared with that of the i.v. ibandronate trial described above, and a long median time to first event compared with those of other bisphosphonate trials in breast cancer patients (median time to first event was typically ~7 months in the placebo group). This suggests that patients in that trial had less advanced disease than those in other bisphosphonate trials in breast cancer. Nevertheless, based on these placebo-controlled trials, both the oral and i.v. formulations of ibandronate (50 mg/day oral and 6 mg i.v.) have been approved in Europe for the treatment of breast cancer patients with bone metastases.

Zoledronic Acid
Zoledronic acid (4 mg via 15-minute infusions every 4 weeks for 1 year) was also recently compared with placebo in 227 Japanese women with bone metastases from breast cancer [35]. In that trial, the primary end point was the SRE rate ratio adjusted for history of pathologic fractures before study entry, which showed a significant 39% lower rate of SREs in the zoledronic acid group (ratio = 0.61; p = 0.027). In addition, secondary efficacy analyses showed that zoledronic acid produced a significantly lower percentage of patients with an SRE (31% versus 52% for placebo; p = 0.001) and significantly longer time to first SRE (median not reached versus 360 days for placebo; p = 0.004) than placebo. Multiple event analysis demonstrated a 44% lower risk of developing an SRE (HR = 0.56; p = 0.009) in the zoledronic acid group. Of note, the magnitude of the clinical benefit of zoledronic acid observed in that trial appears to be greater than that achieved with pamidronate or ibandronate in similar patient populations after 1 year of treatment [30, 36]. Similar to the pamidronate trials, patients enrolled in this trial had predominantly osteolytic lesions. Zoledronic acid was well tolerated; the adverse events that occurred more often with zoledronic acid than with placebo included the acute-phase, infusion-related symptoms of pyrexia (55% versus 33% for placebo), fatigue (44.5% versus 31.9% for placebo), and arthralgia (21.1% versus 15.9% for placebo). Only 1 of 114 patients experienced an elevated serum creatinine level with zoledronic acid treatment in that study [35].

Summary of Placebo-Controlled Trials
The efficacy of bisphosphonates based on placebo-controlled trials in patients with breast cancer is summarized in Table 4 [5, 24, 26–30, 31–35]. Although all i.v. bisphosphonates have been shown to reduce skeletal complications compared with placebo, i.v. pamidronate and i.v. zoledronic acid have demonstrated the most consistent clinical benefit across multiple end points, particularly the more conservative first-event analyses. A comparison of the overall and renal safety of i.v. and oral bisphosphonates is addressed in detail elsewhere [37].

View larger version (17K): [in this window] [in a new window]   Figure 1. Shown are the proportions of breast cancer patients who experienced 1 SRE in the pivotal trials of pamidronate and zoledronic acid for the prevention of skeletal complications secondary to bone metastases and breast cancer. Data from Rosen et al. [39] and Lipton et al. [5].

	BISPHOSPHONATES IN PROSTATE CANCER

Top Learning Objectives Abstract Introduction Treatment and Management of... Bisphosphonates in Breast Cancer Bisphosphonates in Prostate... Bisphosphonates in Other Solid... Conclusions References

Clodronate
Recent randomized, placebo-controlled trials of i.v. clodronate have failed to demonstrate statistically significant or durable clinical benefits in patients with advanced prostate cancer. Intravenous clodronate (1,500 mg every 3 weeks in combination with mitoxantrone plus prednisone) was investigated in 209 patients with hormone-refractory prostate cancer (HRPC). The primary end point was a subjective measurement of palliative response, defined as a decrease in the present pain intensity index or a 50% decrease in analgesic use [45]. However, clodronate did not significantly improve palliative response over placebo or result in any significant decrease in serum prostate-specific antigen (PSA) levels or quality-of-life scores.

A second randomized trial used a more objective measure of skeletal morbidity. That trial assessed the effect of oral clodronate (2,080 mg/day) on symptomatic bone progression and survival in 311 men with prostate cancer who were either commencing or responding to standard hormonal therapy [46]. At a median follow-up of 59 months, oral clodronate demonstrated a nonsignificant 20% lower risk for symptomatic bone progression or prostate cancer-specific death compared with placebo. The median time to event was 23.6 months for patients receiving clodronate versus 19.3 months for the placebo group (HR = 0.79; p = 0.066). A secondary analysis of overall survival demonstrated similar results. The authors noted that patients who were treated with oral clodronate had a significantly lower risk of a worsened World Health Organization performance status score (HR = 0.71; p = 0.008), but analgesic use was not affected. Importantly, patients who received oral clodronate had a significantly greater risk for adverse events, primarily gastrointestinal problems (HR = 1.71; p = 0.002), and required more frequent dose modifications as a result of adverse events (HR = 2.81; p < 0.0001).

In early 2004, Mason reported the first results from an adjunct trial of clodronate in patients with nonmetastatic prostate cancer [47]. A total of 508 patients receiving standard treatment for stage T2 to T4 prostate cancer with no symptomatic bone metastases was randomized to receive either 2,080 mg of clodronate or placebo daily for 5 years. After a median of 7 years’ follow-up, there was no difference in the development of symptomatic bone metastases (HR = 1.29; p = 0.13) or survival (HR = 1.03; p = 0.86) between the clodronate and placebo treatment groups. The most commonly reported adverse events among patients administered clodronate were gastrointestinal problems and elevated lactate dehydrogenase. One weakness of that study is the use of symptoms rather than bone scans for the detection of bone metastases; nevertheless, the lack of efficacy of clodronate for the prevention of skeletal complications of malignancy in patients with prostate cancer has been consistent across published trials.

Pamidronate
A combined analysis of two parallel, multicenter, randomized, placebo-controlled trials of i.v. pamidronate (90 mg via a 2-hour i.v. infusion every 3 weeks for 27 weeks) for the treatment of bone metastases in patients with HRPC has also been reported [48]. A total of 378 men were randomized to receive either 90 mg of pamidronate or placebo, and the primary efficacy end point was change from baseline pain scores, as assessed by the Brief Pain Inventory (BPI). Secondary end points included the proportion of patients who experienced 1 SRE and the SMR. Similar to i.v. clodronate, pamidronate failed to demonstrate a statistically or clinically significant effect on baseline pain scores (least, average, or worst) compared with placebo at either 9 or 27 weeks. In the subset of patients with stable or decreasing analgesic use, pamidronate produced statistically significant changes from baseline pain scores at 9 weeks (p = 0.008 for worst pain and p = 0.011 for average pain), but these differences were not sustained at 27 weeks. Pamidronate also did not reduce the proportion of patients with an SRE or the mean SMR at 9 or 27 weeks. The results at 27 weeks are shown in Figure 2 [48]. The percentage of patients who experienced an SRE was 25% in both treatment groups, and the mean SMRs were 1.56 for pamidronate and 1.51 for placebo (p = 0.942). Unlike oral clodronate, i.v. pamidronate was generally well tolerated, with no significant differences between treatment groups in terms of the incidence of adverse events or study discontinuation due to adverse events. The most frequently reported adverse events in both treatment groups were mild to moderate in severity and included bone pain, nausea, anorexia, and fatigue.

View larger version (11K): [in this window] [in a new window]   Figure 2. Intravenous pamidronate (90 mg via a 2-hour infusion every 3 weeks for 27 weeks) administered to men with advanced metastatic prostate cancer had no effect on either: A) the proportion of patients with 1 SRE or B) the mean SMR (defined as the number of SREs per year). Data from Small et al. [48].

View larger version (13K): [in this window] [in a new window]   Figure 3. Treatment with zoledronic acid (4 mg) resulted in a significantly longer time to onset of skeletal complications by approximately 6 months compared with placebo in men with bone metastases and prostate cancer. Reproduced with permission from Coleman et al. [52].

View larger version (15K): [in this window] [in a new window]   Figure 4. Men with bone metastases and prostate cancer treated with 4 mg zoledronic acid had consistently less bone pain than those treated with placebo. *p = 0.003 at 3 months; p = 0.03 at 9 months; p = 0.014 at 21 months; p = 0.024 at 24 months. Reproduced with permission from Saad et al. [53]

That trial demonstrated for the first time that a potent i.v. bisphosphonate can provide significant clinical benefit to patients with bone metastases from advanced prostate cancer. Zoledronic acid not only provided durable pain palliation but also produced a significantly lower incidence of skeletal complications, such as fractures, that can have devastating effects on quality of life in these patients [53]. The results from this trial have also been compared with those of the pamidronate trials (described above) based on an analysis of the clinical benefit of zoledronic acid after 6 months (i.e., 27 weeks), which matches the duration of the pamidronate trials. That analysis showed that zoledronic acid produced a significantly lower percentage of patients with an SRE at 6 months than placebo (21% versus 31% for placebo; p = 0.025) [54]. A significantly lower incidence of SREs was also observed at 3 months (p = 0.003). Therefore, despite some minor differences in the patient populations enrolled in those trials, the overall incidence of SREs was similar at 6 months, and, unlike pamidronate, zoledronic acid resulted in significantly fewer skeletal complications than placebo.

	BISPHOSPHONATES IN OTHER SOLID TUMORS

Top Learning Objectives Abstract Introduction Treatment and Management of... Bisphosphonates in Breast Cancer Bisphosphonates in Prostate... Bisphosphonates in Other Solid... Conclusions References

 
To date, zoledronic acid is the only bisphosphonate to be evaluated for the prevention of skeletal complications in patients with bone metastases secondary to solid tumors other than breast or prostate cancer. In the first trial of its kind, 773 patients with bone metastases from non-small cell lung cancer (NSCLC) or other advanced-stage solid tumors were randomized to receive either zoledronic acid (4 mg via a 15-minute infusion) or placebo every 3 weeks for 21 months [8]. That trial enrolled a diverse patient population composed of patients with NSCLC (49% of patients) and more than 20 other tumor types including renal cell carcinoma (RCC), colorectal cancer, small cell lung cancer, and bladder cancer. However, this was a poor-prognosis group of patients with a median survival of only 6 months, and patients received a median of only four infusions of zoledronic acid. Nevertheless, Andersen-Gill multiple event analysis demonstrated that treatment with zoledronic acid resulted in a 31% significantly lower risk for developing an SRE compared with placebo (HR = 0.693; p = 0.003), and zoledronic acid produced a significantly longer median time to first SRE (236 days versus 155 days for placebo; p = 0.009).

A long-term subset analysis of 46 patients with RCC enrolled in that trial has also been reported [55], showing that patients with bone metastases secondary to advanced RCC are at extremely high risk for skeletal complications. Among patients randomized to placebo, 79% had 1 SRE over 21 months of follow-up. Moreover, zoledronic acid provided highly significant clinical benefits in this subset. For example, patients treated with 4 mg zoledronic acid had a significantly lower SRE incidence of 41% (p = 0.011) and longer time to onset of SREs (by approximately 1 year) than patients treated with placebo (median 424 versus 72 days for placebo; p = 0.007). In addition, Andersen-Gill multiple event analysis showed that zoledronic acid produced a 58% lower risk for SREs (HR = 0.418; p = 0.010). Even more noteworthy is the observation that treatment with zoledronic acid resulted in greater bone lesion response and a significantly longer time to progression of bone lesions by approximately 6 months (median 256 days versus 89 days for placebo; p = 0.014). Zoledronic acid was well tolerated in patients with RCC; the most common adverse events reported by patients for both 4 mg zoledronic acid and placebo included bone pain, nausea, vomiting, anemia, and fatigue. There was no significant difference between treatment groups in the incidence of renal-related adverse events. These results indicate that the predominantly osteolytic bone metastases associated with RCC are clinically aggressive, and these patients are at high risk for skeletal complications, but this risk can be significantly reduced with zoledronic acid.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Treatment and Management of... Bisphosphonates in Breast Cancer Bisphosphonates in Prostate... Bisphosphonates in Other Solid... Conclusions References

 
Skeletal complications from bone metastases remain an important health care problem in patients with advanced cancer. However, bisphosphonates provide significant benefits to patients with bone metastases by decreasing skeletal complications and reducing bone pain. In patients with bone metastases from advanced breast cancer, several bisphosphonates, including oral clodronate, i.v. pamidronate, oral and i.v. ibandronate, and i.v. zoledronic acid, have demonstrated significant clinical benefits over placebo. In this setting, i.v. pamidronate and zoledronic acid have demonstrated the most consistent clinical benefits across multiple end points that provide both a conservative and comprehensive assessment of skeletal morbidity. Zoledronic acid has also been shown to be significantly more effective than pamidronate in patients with breast cancer. Consequently, i.v. zoledronic acid is the standard of care in patients with breast cancer. In patients with prostate cancer, lung cancer, RCC, and other solid tumors, the situation is quite different. In these tumor types, zoledronic acid is the only bisphosphonate that has demonstrated significant clinical benefit. Indeed, zoledronic acid has demonstrated the broadest clinical activity of any bisphosphonate across multiple tumor types. As shown in Figure 5, regardless of the underlying disease, zoledronic acid resulted in a consistently and significantly lower cumulative incidence of SREs compared with pamidronate (in patients with breast cancer) and placebo (in patients with prostate cancer or other solid tumors) [17]. Moreover, the overall safety profile of zoledronic acid was comparable with those of other i.v. bisphosphonates.

View larger version (10K): [in this window] [in a new window]   Figure 5. Treatment with zoledronic acid resulted in consistently lower cumulative incidences of SREs across all tumor types. Adapted with permission from Major et al. [17].

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Introduction Treatment and Management of... Bisphosphonates in Breast Cancer Bisphosphonates in Prostate... Bisphosphonates in Other Solid... Conclusions References

 
Robert Coleman receives a research grant from and is a member of the Speakers Bureau for Novartis and Roche.

	References

Top Learning Objectives Abstract Introduction Treatment and Management of... Bisphosphonates in Breast Cancer Bisphosphonates in Prostate... Bisphosphonates in Other Solid... Conclusions References

 

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