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Optimizing bisphosphonate therapy in patients with breast cancer on endocrine therapy
Optimizing Bisphosphonate Therapy in Patients With Breast Cancer on Endocrine Therapy Harold A. Harvey Deterioration of bone health is a major concern during progression and treatment of patients with breast cancer, especially in postmenopausal women. Disease- and treatmentassociated skeletal-related events include fractures, spinal compression, bone pain, and hypercalcemia of malignancy. Bisphosphonates, which inhibit osteoclastic bone resorption, are important new agents in the management of skeletal-related events, and their impact on breast cancer-related bone metastases and on bone loss during long-term estrogen deprivation therapies such as aromatase inhibitors is reviewed. Intravenous pamidronate has become the standard bisphosphonate to reduce or delay skeletal complications of advanced breast cancer bone metastases, but the more potent agent, zoledronic acid, appears to be at least as effective. Another agent, ibandronate, is also active but has not been investigated in comparison with the other intravenous bisphosphonates. Zoledronic acid is the most convenient to administer, requiring only a short infusion. The effects of bisphosphonates on bone health in women with early breast cancer are also being investigated. A single yearly infusion of zoledronic acid has been shown to significantly increase bone mineral density in osteoporotic postmenopausal women and to reduce biochemical markers of bone turnover. The possibility of such treatment-reversing aromatase inhibitor–associated bone loss during adjuvant therapy of breast cancer is being evaluated in a trial of letrozole, with zoledronic acid added initially or after the onset of bone loss or fracture. Semin Oncol 31(suppl 12):23-30 © 2004 Elsevier Inc. All rights reserved.
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omen with breast cancer are highly susceptible to bone complications during the course of disease progression and treatment. During treatment of early breast cancer, long-term chemotherapy-induced ovarian failure or long-term estrogen deprivation can reduce bone mineral density (BMD) and potentially lead to osteoporosis.1 In patients with advanced disease, bone metastases are a common occurrence since breast cancer is highly osteotropic.2 Thus, patients with early breast cancer are at high risk of developing treatment-related bone loss, while those with advanced disease and bone involvement often experience disease-associated skeletal-related events (SREs; eg, fractures, spinal compression, bone pain, or hypercalcemia of malignancy [HCM]) which compromise quality of life and require management
Penn State Milton S. Hershey Medical Center, Hershey, PA. Dr Harvey has received honoraria from AstraZeneca. He has received research grant support and honoraria from and has served as a consultant to Novartis. Address reprint requests to Harold A. Harvey, MD, Penn State Milton S. Hershey Medical Center, 500 University Dr, P.O. Box 850, H046, C6830, Hershey, PA 17033.
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.09.023
with surgery, radiation therapy, or other medical interventions.1,3 Treatment of breast cancer with adjuvant chemotherapy, especially cyclophosphamide, is associated with high rates of amenorrhea, which may contribute to the overall antitumor effects of chemotherapy.4,5 Furthermore, in premenopausal women with estrogen receptor–positive and/or progesterone receptor–positive breast cancer, ovarian ablation is routinely used to suppress estrogen production. Finally, in the therapy of hormone-sensitive breast cancer in postmenopausal women, the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, which act with high specificity to potently suppress estrogen synthesis in this population, are increasingly being used because of favorable results in the advanced disease and adjuvant settings.6-9 Clinical trials have shown that bisphosphonates, which inhibit osteoclastic bone resorption,10 can substantially reduce SREs in patients with advanced breast cancer.3 The new nitrogen-containing bisphosphonates, including zoledronic acid, the most potent of these drugs in preclinical studies,11 as well as pamidronate and ibandronate, are highly effective treatments for reducing the impact of bone complications.12-15 23
24 This article will review the clinical trials using the newer bisphosphonates to treat bone metastases in patients with breast cancer. Data from large trials comparing pamidronate with placebo, zoledronic acid with pamidronate, and ibandronate with placebo will be discussed. Also, the effect of endocrine therapies for breast cancer on the health of the bony skeleton will be discussed in the context of ongoing trials. To address the efficacy of bisphosphonates as therapy to prevent the occurrence of SREs in patients with early breast cancer, clinical studies of zoledronic acid and other bisphosphonates in the adjuvant setting are currently under way.
Bone Metastases in Breast Cancer Bone metastases occur in as many as 75% of patients with advanced breast cancer; in 45% to 50% of patients, bone is the first site of clinically evident metastasis.16 Clinical dictum has taught that hormone-dependent breast cancer is especially prone to metastasize to bone. Although supporting data are somewhat lacking, it is generally agreed that patients with hormone receptor–positive tumors live longer than patients with receptor-negative tumors. Thus, patients with hormone receptor–positive tumors may suffer more, or longer-lasting, bone complications as metastatic disease has longer to progress. Overall, patients with advanced breast cancer have a median survival of approximately 2 to 3 years.17 Metastatic bone lesions are traditionally described, based on radiographic appearance, as lytic, blastic, or mixed.1,18 In breast cancer metastases, lytic lesions that exhibit a preponderance of osteoclastic bone resorption and very little new osteoblastic bone formation are the most common type. However, even in bone metastases that appear to be predominantly blastic, both osteoblastic and osteoclastic processes are typically accelerated.1 Because bone is a dynamic structure and is continually undergoing new formation as well as resorption, it can be subject to periods of especially high or low turnover. Menopause and estrogen deprivation create a state of relatively high turnover, resulting in bone loss. However, replenishment of estrogens, use of antiresorptive therapies such as intravenous bisphosphonates, or use of antibodies to parathyroid hormone, can all reduce bone resorption rates and favor bone formation. These approaches can therefore be used to reduce the osteoclastic activity induced by treatment with aromatase inhibitors, ovarian ablation, and chemotherapy, and they can be critical to reducing skeletal morbidity in patients with breast cancer.1,18
Clinical Trials of Bisphosphonates for Bone Metastases of Advanced Breast Cancer Pamidronate Versus Placebo The results of two trials showing efficacy of pamidronate in reducing the incidence of SREs in patients undergoing chemo-
H.A. Harvey therapy for advanced breast cancer have changed clinical practice for managing these complications.3,19-21 Compared with patients in the placebo group (total, n ⫽ 384), those receiving intravenous infusions of pamidronate for 2 years (n ⫽ 367) had a significantly longer time to first skeletal complication (12.7 months for pamidronate v 7 months for placebo; P ⬍ .001). The proportion of patients in whom any skeletal complication occurred was significantly lower with pamidronate than with placebo (51% v 64%, respectively; P ⬍ .001), and skeletal morbidity rate was similarly lower (2.4 v 3.7 skeletal complications/ year, respectively; P ⬍ .001). Progression of pain-related symptoms, and deterioration of pain scores and performance status, were also significantly reduced by pamidronate treatment.3,19-21 As a result, bisphosphonates are recommended for the treatment of breast cancer bone metastases of the osteolytic type.22 Pamidronate has become widely accepted as standard therapy to reduce or delay skeletal complications, particularly in breast cancer, and is the standard for comparing the benefits of new bone resorption therapies.12 Zoledronic Acid Versus Pamidronate Zoledronic acid has been shown to be the most potent of the available bisphosphonates in inhibiting bone resorption in vitro and in vivo.11 In these models, zoledronic acid was approximately two to three orders of magnitude more potent than pamidronate.11 To determine whether these preclinical observations translate into improved clinical efficacy, the effects of treatment with intravenous zoledronic acid have been compared with pamidronate in patients with metastatic bone lesions in two identical and concurrent randomized, doubleblind, multicenter trials focusing on HCM. This common, life-threatening complication affects approximately 40% of patients with breast cancer.23 Combined analysis of data from these two trials in patients with cancer-related HCM (n ⫽ 275 for efficacy, n ⫽ 287 for safety) showed that a single dose of either zoledronic acid 4 mg or 8 mg (by 5-minute infusion) was significantly more effective than single-dose pamidronate 90 mg (2-hour infusion) in achieving HCM complete responses by day 10 (88.4%, 86.7%, and 69.7% for zoledronic acid 4 mg and 8 mg, and for pamidronate, respectively; P ⱕ .015 for both doses v pamidronate), and median duration of complete response favored both doses of
Figure 1 Trial comparing zoledronic acid versus pamidronate in patients with advanced breast cancer or multiple myeloma: Study design. *Plus daily oral vitamin D 400 IU and calcium 500 mg supplements.13
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Figure 2 Trial comparing zoledronic acid versus pamidronate in patients with advanced breast cancer or multiple myeloma: Time to first SRE. Hypercalcemia of malignancy is included as an SRE. ZA, zoledronic acid; Pam, pamidronate. (From Rosen et al: Cancer. 98:1735. ©2003, American Cancer Society. Reproduced with permission of John Wiley & Sons, Inc.13)
zoledronic acid (32, 43, and 18 days for zoledronic acid 4 mg and 8 mg, and for pamidronate, respectively). The main adverse events occurred with similar frequency in all three treatment groups: fever, anemia, nausea, constipation, and dyspnea. Renal toxicity was reported with somewhat greater frequency in patients who received zoledronic acid than in those on pamidronate, mainly with the higher dose.24 Another randomized, double-blind, multicenter trial compared zoledronic acid, either 4 mg or 8 mg (initially by 5-minute infusion, but amended to 15 minutes), with pamidronate 90 mg infused over 2 hours, in patients with either advanced breast cancer or multiple myeloma. Both drugs were administered every 3 to 4 weeks for 24 months (Fig 1).13 Early in the trial, the higher dose of zoledronic acid was reduced to 4 mg because of renal toxicity. The core data analysis was performed after 13 months’ follow-up, with the final analysis 12 months later.13,25 Breast cancer was the primary diagnosis in 377 of 564 patients randomized to receive zoledronic acid 4 mg, and in 389 of 558 patients in the pamidronate group. Of those patients with breast cancer, more than 50% were receiving concurrent endocrine therapy (201 and 210 in the zoledronic acid 4 mg and pamidronate groups, respectively).13
Considering only those patients with breast cancer in this trial, zoledronic acid achieved a 16% reduction in risk of SRE compared with pamidronate (hazard ratio 0.84, P ⫽ .030), and also a significantly lower skeletal morbidity rate (0.83 v 1.37 SREs per year, respectively; P ⫽ .039). In the subgroup that also received endocrine therapy, zoledronic acid also significantly prolonged the time to first SRE compared with pamidronate (415 v 370 days, respectively; P ⫽ .047), but there was no significant difference when all patients with breast cancer were included (Fig 2).13 Multiple event analysis showed that zoledronic acid significantly reduced the risk of any SRE in the overall population compared with pamidronate. In the subset of patients with breast cancer, the risk was reduced by an additional 20% compared with pamidronate after 24 months’ treatment (evaluated at 25 months; P ⫽ .042) (Fig 3).13 That difference was maintained whether or not HCM was included in the analysis (Table 1).13 In the subgroup of patients with breast cancer and at least one osteolytic lesion, zoledronic acid was significantly better than pamidronate in increasing time to first SRE (310 v 174 days, respectively; P ⫽ .013), with a strong trend also in reducing the rate of SREs (48% v 58%, respectively; P ⫽ .058).26 Multiple-event analysis showed significantly
Figure 3 Trial comparing zoledronic acid versus pamidronate in patients with advanced breast cancer or multiple myeloma: Survival-adjusted multiple-event analysis of cumulative expected SREs in patients with breast cancer treated with zoledronic acid 4 mg or pamidronate 90 mg after 24 months of treatment. (Cook and Lawless approach, pooled stratified analysis.) SRE, skeletal-related event.13
H.A. Harvey
26 Table 1 Trial Comparing Zoledronic Acid Versus Pamidronate in Patients With Advanced Breast Cancer or Multiple Myeloma: Multiple-Event Analysis Comparing the Effects of Zoledronic Acid and Pamidronate on Risk of Developing at Least 1 SRE in Patients With Breast Cancer13
Including HCM Not including HCM
Hazard Ratio*
P Value
0.80 0.82
.025 .042
*A hazard ratio of < 1 favors zoledronic acid over pamidronate. Abbreviations: SRE, skeletal-related event; HCM, hypercalcemia of malignancy.
greater reductions in risk of developing SREs with zoledronic acid versus pamidronate in that patient subgroup (30% greater; P ⫽ .010) and in all patients with breast cancer (20% greater; P ⫽ .037). In that trial, zoledronic acid 4 mg and pamidronate 90 mg were equally well tolerated. However, because of renal toxicity in the 8-mg zoledronic acid group, two protocol amendments were introduced: the 8-mg dose was reduced to 4 mg, and the infusion time for zoledronic acid was lengthened from 5 minutes to 15 minutes. After implementation of these amendments, the incidence of renal insufficiency was similar in both treatment groups (Fig 4).13,25 This study was powered to assess whether zoledronic acid treatment met the stringent statistical criteria for noninferiority to pamidronate. Zoledronic acid was not inferior to pamidronate in affecting the incidence of SREs, nor in individual outcomes such as fractures, need for palliative radiation or surgery, or spinal cord compression. In fact, all outcomes with zoledronic acid, including time to first SRE, were somewhat improved with zoledronic acid compared with pamidronate, especially in the subgroup of patients with breast cancer and at least one osteolytic lesion.26 The study investigators caution, however, against drawing firm conclusions about the significance of the observed differences.13 Ibandronate Versus Placebo Ibandronate is another intravenous bisphosphonate that has been evaluated in patients with bone lesions secondary to breast cancer. In a phase III trial, patients were randomized to receive either ibandronate 2 mg as a bolus injection, ibandronate 6 mg infused over 1 to 2 hours, or infused placebo.14 Of the 466 patients randomized, more than 60% (283) were also receiving endocrine treatment, 24% (110) were receiving chemotherapy, and the remaining 16% (69) received neither endocrine therapy nor chemotherapy. Treatments were administered at 3- to 4-week intervals for between 60 and 96 weeks. The primary efficacy end point was the number of 12-week periods with new bone complications, expressed as skeletal morbidity period rate. Ibandronate 6 mg compared with placebo significantly reduced the mean skeletal morbidity period rate overall (P ⫽ .004) and for vertebral fractures (P ⫽ .023), as well as the mean number of events per patient (P ⫽ .025) (Table 2). However, nonvertebral fractures and the percentage of patients experiencing one or more events were not significantly affected. The median time from randomiza-
tion to a first new bone event was also significantly longer for patients receiving ibandronate 6 mg compared with placebo (50.6 v 33.1 weeks, respectively; P ⫽ .018) (Fig 5).14 Bolus ibandronate 2 mg was similar to placebo in efficacy.14 Treatment with ibandronate was well tolerated, based on adverse events likely to be associated with treatment rather than related to the underlying disease. The incidences of flu-like syndrome and arthralgia were slightly higher with ibandronate, whereas leukopenia was more frequent with placebo. The ibandronate 6 mg group had significantly improved bone pain scores compared with the other groups, and analgesic use was lower in both ibandronate groups than in the placebo group.14 In contrast to studies with zoledronic acid, which evaluated efficacy in comparison with standard pamidronate, this study compared ibandronate with placebo. As a consequence, how efficacy with ibandronate compares with that of the other intravenous bisphosphonates cannot be determined.27 Furthermore, skeletal morbidity period rate includes nonfracture bone events (radiotherapy and surgery for bone complications), and although intravenous ibandronate significantly improved skeletal morbidity period rate overall and for vertebral fractures, there was no significant improvement in nonvertebral fractures.14 Summary of Clinical Trials in Advanced Breast Cancer Intravenous bisphosphonates clearly reduce the skeletal morbidity associated with metastatic breast cancer bone lesions. In clinical trials, zoledronic acid has been shown to provide skeletal benefits that are at least equivalent to the standard, pamidronate.13,24 For zoledronic acid 4 mg delivered as a 15-minute infusion, renal effects were similar to those associated with pamidronate. Ibandronate is another potent bisphosphonate that significantly reduces skeletal complications of malignancy compared with placebo.14 In practice, although all three of these intravenous bisphosphonates are effective in patients with advanced breast cancer and bone involvement, zoledronic acid is the most conve-
Figure 4 Trial comparing zoledronic acid versus pamidronate in patients with advanced breast cancer or multiple myeloma: percentage of patients with serum creatinine ⱖ 1.4 mg/dL before and after implementation of protocol amendment to reduce zoledronic acid from 8 mg to 4 mg, and increase infusion time from 5 minutes to 15 minutes. (Modified and reprinted, with permission, from Rosen et al. Cancer J 7:377, 2001, Jones and Bartlett.25)
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Table 2 Effects of Ibandronate 2 mg or 6 mg Versus Placebo on Mean SMPR, Mean Number of Events Per Patient, and Percentage of Patients With 1 or More Events14 Placebo (n ⴝ 158)
Ibandronate 2 mg (n ⴝ 154)
Ibandronate 6 mg (n ⴝ 154)
Mean SMPR All new bone events
1.48
Vertebral fractures
0.82
Nonvertebral fractures
0.81
Mean events per patient (n)
3.64
1.31 P ⴝ .152* 0.70 P ⴝ .028* 0.70 P ⴝ .235* 4.24 P ⴝ .905* 62.3 P ⴝ 1.000†
1.19 P ⴝ .004* 0.71 P ⴝ .023* 0.72 P ⴝ .396* 2.65 P ⴝ .025* 50.6 P ⴝ .052†
Parameter
Patients with events (%)
62.0
*Pairwise comparisons versus placebo using the Wilcoxon rank sum test. †Pairwise comparisons versus placebo using exact Pearson 2 -test for 2 ⴛ 3 table. Abbreviation: SMPR, skeletal morbidity period rate. Adapted with permission, from Body et al. Ann Oncol. 14:1399, 2003, European Society for Medical Oncology.
nient to use. Because zoledronic acid can be administered safely as an infusion over 15 minutes rather than over the 1 to 2 hours required for pamidronate and ibandronate, less clinic time is needed, an advantage that has been reported to be preferred by patients.28 Recent reports indicated an increased rate of osteonecrosis of the jaw in patients receiving chronic bisphosphonate therapy.29 It is unclear at this point if osteonecrosis can be solely attributed to bisphosphonate therapy; however, monitoring patients receiving chronic bisphosphonate therapy is advised.
Bisphosphonate Therapy in Breast Cancer: New Directions Recently, bisphosphonate therapy has been assessed in patients with early breast cancer as a means to improve skeletal health before bone lesions develop. It is well established that bone loss is a natural consequence of aging even in healthy women, and this shift in skeletal health, which starts at about 35 years of age, is related to decreasing estrogen production. This process is accelerated by any form of estrogen deprivation, whether it is a result of menopause or treatment for
Figure 5 Phase III trial of ibandronate in patients with advanced breast cancer and bone metastases: time to first new SRE. The dashed line at 96 weeks indicates maximum total treatment period. (Reprinted with permission, from Body et al: Ann Oncol. 14:1399. © 2003 European Society for Medical Oncology.14)
breast cancer.30 In premenopausal women, luteinizing hormone-releasing hormone analogs result in significant loss of BMD. Postmenopausal women treated with aromatase inhibitors such as letrozole and anastrozole also experience considerable estrogen suppression that may lead to loss of BMD.31,32 The osteoporosis literature has shown that bisphosphonates can preserve BMD. Intriguing results from a study of the effects of zoledronic acid on bone turnover and density in postmenopausal women with low BMD suggests that a single annual intravenous infusion of zoledronic acid may be as effective as oral forms taken daily. Compared with placebo, a single infusion of zoledronic acid 4 mg significantly increased BMD in these women (Fig 6).33 Furthermore, a single dose of zoledronic acid stably and significantly reduced the levels of biochemical markers of bone turnover, including serum Ctelopeptide and ratio of urinary N-telopeptide to serum creatinine, throughout the study (P ⬍ .01 for all comparisons). This improvement was similar to those observed in studies comparing oral bisphosphonate treatments in postmenopausal women with low BMD.34-37 The dramatic effects of zoledronic acid in women with low BMD are important because a once-yearly treatment may eliminate the problem of
28
H.A. Harvey
Figure 6 Effects of annual infusion of zoledronic acid 4 mg on BMD in postmenopausal women with low BMD. Left, lumbar spine; right, femoral neck. BMD, bone mineral density; ZA, zoledronic acid. (Modified and reprinted with permission, from Reid et al: N Engl J Med. 346:653. © 2002 Massachusetts Medical Society. All rights reserved.33)
long-term compliance with daily dosing of an oral bisphosphonate. In a recent study, ibandronate appeared to be less effective in this setting: Intravenous injections of 0.5 mg and 1 mg every 3 months in women with postmenopausal osteoporosis resulted in increases in lumbar spine BMD and comparatively small decreases in bone resorption markers. As a consequence, the occurrence of fractures was not significantly reduced.38 These findings in women with osteoporosis who are otherwise healthy suggest that there may be a therapeutic advantage to similarly treating women who are receiving estrogen deprivation therapy for early breast cancer. This question has been addressed in a large phase III study of premenopausal
Figure 7 Effects of zoledronic acid on bone mineral regression associated with adjuvant treatment of early breast cancer with ovarian ablation (goserelin) plus tamoxifen or anastrozole. (A) Lumbar spine. (B) Trochanter. BMD, bone mineral density; ZA, zoledronic acid.39
women with stage I or II hormone receptor–positive breast cancer who were treated with the luteinizing hormone-releasing hormone analog goserelin during adjuvant therapy.39 All patients received goserelin and were randomized to receive standard doses of either tamoxifen or anastrozole. Both of these two treatment groups were further randomized to receive either zoledronic acid 4 mg or placebo every 6 months. Bone loss attributable to ovarian ablation was noted in all patients without zoledronic acid. This effect was somewhat more pronounced for anastrozole than for tamoxifen. The results clearly showed that zoledronic acid prevented treatment-related bone loss (Fig 7).39 These findings have led to the ongoing Zometa Femara
Optimizing bisphosphonate therapy
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Figure 8 Study design for the ongoing ZO/Z-FAST trial. ER/PgR, estrogen receptor/progesterone receptor; BMD, bone mineral density; SD, standard deviations.
Adjuvant Synergy Trial (ZO-FAST outside North America, and Z-FAST in the United States and Canada), which is evaluating the addition of zoledronic acid to adjuvant therapy with letrozole. In this trial, all postmenopausal women with hormone receptor–positive early breast cancer receive adjuvant letrozole, and they are randomized to receive zoledronic acid 4 mg as a 15-minute infusion once every 6 months starting either at the initiation of letrozole therapy (“upfront”) or when either a postbaseline BMD T-score falls more than ⫺2.0 standard deviations below the average score for a healthy young woman, or a symptomatic or asymptomatic fracture occurs (Fig 8; data on file, Novartis Pharmaceuticals Corp, East Hanover, NJ). Zoledronic acid has also been shown to be effective in the treatment of bone complications associated with other cancer types. Treatment has reduced SREs in patients with multiple myeloma or bone metastases secondary to prostate, lung, and other cancers.15
Summary The third-generation aromatase inhibitors may improve the survival of postmenopausal women with hormone receptor– positive breast cancer, when used as therapy in the adjuvant setting or for advanced disease.6 However, long-term estrogen deprivation resulting from those treatments may lead to loss of BMD and the occurrence of SREs. Intravenous bisphosphonates have been shown to reduce skeletal morbidity in postmenopausal osteoporotic women who are otherwise healthy, as well as in patients with metastatic bone lesions secondary to breast cancer.13,26,33 These results have prompted ongoing studies to investigate whether, in patients receiving estrogen-deprivation therapy for early breast cancer, treatment with bisphosphonates also improves skeletal health and prevents or delays SRE occurrence. Recently, zoledronic acid has been shown to be superior in activity to the standard, pamidronate, in patients with breast cancer and osteolytic lesions.13,26 Furthermore, the considerably shorter infusion period of 15 minutes for zoledronic acid compared with 1 to 2 hours for pamidronate and ibandronate is an important consideration in choosing the most appropriate bisphosphonate.
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associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527-534, 2004 Goss PE, Strasser-Weippl K: Prevention strategies with aromatase inhibitors. Clin Cancer Res 10:372s-379s, 2004 (suppl) Howell A: Effect of anastrozole on bone mineral density: 2-year results of the ‘Arimidex’ (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial. Breast Cancer Res Treat 82:S27, 2003 (suppl 1) (abstr 129) Harper-Wynne C, Ross G, Sacks N, et al: A pilot prevention study of the aromatase inhibitor letrozole: Effects on breast cell proliferation and bone/lipid indices in healthy postmenopausal women. Breast Cancer Res Treat 69:225, 2001 (abstr 136) Reid IR, Brown JP, Burckhardt P, et al: Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 346:653-661, 2002 Harris ST, Watts NB, Genant HK, et al: Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. JAMA 282:13441352, 1999 Fogelman I, Ribot C, Smith R, et al: Risedronate reverses bone loss in postmenopausal women with low bone mass: Results from a multinational, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 85:1895-1900, 2000 Ravn P, Clemmesen B, Riis BJ, et al: The effect on bone mass and bone markers of different doses of ibandronate: A new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: A 1-year, randomized, double-blind, placebo-controlled dose-finding study. Bone 19:527-533, 1996 Garnero P, Shih WJ, Gineyts E, et al: Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab 79: 1693-1700, 1994 Recker R, Stakkestad JA, Chesnut CH 3rd, et al: Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone 34:890-899, 2004 Gnant M, Hausmaninger H, Samonigg H, et al: Changes in bone mineral density caused by anastrozole or tamoxifen in combination with goserelin (⫹/⫺ zoledronate) as adjuvant treatment for hormone receptor-positive premenopausal breast cancer: Results of a randomized multicenter trial. Breast Cancer Res Treat 76:S31, 2002 (suppl 1) (abstr 12)
W
omen with breast cancer are highly susceptible to bone complications during the course of disease progression and treatment. During treatment of early breast cancer, long-term chemotherapy-induced ovarian failure or long-term estrogen deprivation can reduce bone mineral density (BMD) and potentially lead to osteoporosis.1 In patients with advanced disease, bone metastases are a common occurrence since breast cancer is highly osteotropic.2 Thus, patients with early breast cancer are at high risk of developing treatment-related bone loss, while those with advanced disease and bone involvement often experience disease-associated skeletal-related events (SREs; eg, fractures, spinal compression, bone pain, or hypercalcemia of malignancy [HCM]) which compromise quality of life and require management
Penn State Milton S. Hershey Medical Center, Hershey, PA. Dr Harvey has received honoraria from AstraZeneca. He has received research grant support and honoraria from and has served as a consultant to Novartis. Address reprint requests to Harold A. Harvey, MD, Penn State Milton S. Hershey Medical Center, 500 University Dr, P.O. Box 850, H046, C6830, Hershey, PA 17033.
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.09.023
with surgery, radiation therapy, or other medical interventions.1,3 Treatment of breast cancer with adjuvant chemotherapy, especially cyclophosphamide, is associated with high rates of amenorrhea, which may contribute to the overall antitumor effects of chemotherapy.4,5 Furthermore, in premenopausal women with estrogen receptor–positive and/or progesterone receptor–positive breast cancer, ovarian ablation is routinely used to suppress estrogen production. Finally, in the therapy of hormone-sensitive breast cancer in postmenopausal women, the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, which act with high specificity to potently suppress estrogen synthesis in this population, are increasingly being used because of favorable results in the advanced disease and adjuvant settings.6-9 Clinical trials have shown that bisphosphonates, which inhibit osteoclastic bone resorption,10 can substantially reduce SREs in patients with advanced breast cancer.3 The new nitrogen-containing bisphosphonates, including zoledronic acid, the most potent of these drugs in preclinical studies,11 as well as pamidronate and ibandronate, are highly effective treatments for reducing the impact of bone complications.12-15 23
24 This article will review the clinical trials using the newer bisphosphonates to treat bone metastases in patients with breast cancer. Data from large trials comparing pamidronate with placebo, zoledronic acid with pamidronate, and ibandronate with placebo will be discussed. Also, the effect of endocrine therapies for breast cancer on the health of the bony skeleton will be discussed in the context of ongoing trials. To address the efficacy of bisphosphonates as therapy to prevent the occurrence of SREs in patients with early breast cancer, clinical studies of zoledronic acid and other bisphosphonates in the adjuvant setting are currently under way.
Bone Metastases in Breast Cancer Bone metastases occur in as many as 75% of patients with advanced breast cancer; in 45% to 50% of patients, bone is the first site of clinically evident metastasis.16 Clinical dictum has taught that hormone-dependent breast cancer is especially prone to metastasize to bone. Although supporting data are somewhat lacking, it is generally agreed that patients with hormone receptor–positive tumors live longer than patients with receptor-negative tumors. Thus, patients with hormone receptor–positive tumors may suffer more, or longer-lasting, bone complications as metastatic disease has longer to progress. Overall, patients with advanced breast cancer have a median survival of approximately 2 to 3 years.17 Metastatic bone lesions are traditionally described, based on radiographic appearance, as lytic, blastic, or mixed.1,18 In breast cancer metastases, lytic lesions that exhibit a preponderance of osteoclastic bone resorption and very little new osteoblastic bone formation are the most common type. However, even in bone metastases that appear to be predominantly blastic, both osteoblastic and osteoclastic processes are typically accelerated.1 Because bone is a dynamic structure and is continually undergoing new formation as well as resorption, it can be subject to periods of especially high or low turnover. Menopause and estrogen deprivation create a state of relatively high turnover, resulting in bone loss. However, replenishment of estrogens, use of antiresorptive therapies such as intravenous bisphosphonates, or use of antibodies to parathyroid hormone, can all reduce bone resorption rates and favor bone formation. These approaches can therefore be used to reduce the osteoclastic activity induced by treatment with aromatase inhibitors, ovarian ablation, and chemotherapy, and they can be critical to reducing skeletal morbidity in patients with breast cancer.1,18
Clinical Trials of Bisphosphonates for Bone Metastases of Advanced Breast Cancer Pamidronate Versus Placebo The results of two trials showing efficacy of pamidronate in reducing the incidence of SREs in patients undergoing chemo-
H.A. Harvey therapy for advanced breast cancer have changed clinical practice for managing these complications.3,19-21 Compared with patients in the placebo group (total, n ⫽ 384), those receiving intravenous infusions of pamidronate for 2 years (n ⫽ 367) had a significantly longer time to first skeletal complication (12.7 months for pamidronate v 7 months for placebo; P ⬍ .001). The proportion of patients in whom any skeletal complication occurred was significantly lower with pamidronate than with placebo (51% v 64%, respectively; P ⬍ .001), and skeletal morbidity rate was similarly lower (2.4 v 3.7 skeletal complications/ year, respectively; P ⬍ .001). Progression of pain-related symptoms, and deterioration of pain scores and performance status, were also significantly reduced by pamidronate treatment.3,19-21 As a result, bisphosphonates are recommended for the treatment of breast cancer bone metastases of the osteolytic type.22 Pamidronate has become widely accepted as standard therapy to reduce or delay skeletal complications, particularly in breast cancer, and is the standard for comparing the benefits of new bone resorption therapies.12 Zoledronic Acid Versus Pamidronate Zoledronic acid has been shown to be the most potent of the available bisphosphonates in inhibiting bone resorption in vitro and in vivo.11 In these models, zoledronic acid was approximately two to three orders of magnitude more potent than pamidronate.11 To determine whether these preclinical observations translate into improved clinical efficacy, the effects of treatment with intravenous zoledronic acid have been compared with pamidronate in patients with metastatic bone lesions in two identical and concurrent randomized, doubleblind, multicenter trials focusing on HCM. This common, life-threatening complication affects approximately 40% of patients with breast cancer.23 Combined analysis of data from these two trials in patients with cancer-related HCM (n ⫽ 275 for efficacy, n ⫽ 287 for safety) showed that a single dose of either zoledronic acid 4 mg or 8 mg (by 5-minute infusion) was significantly more effective than single-dose pamidronate 90 mg (2-hour infusion) in achieving HCM complete responses by day 10 (88.4%, 86.7%, and 69.7% for zoledronic acid 4 mg and 8 mg, and for pamidronate, respectively; P ⱕ .015 for both doses v pamidronate), and median duration of complete response favored both doses of
Figure 1 Trial comparing zoledronic acid versus pamidronate in patients with advanced breast cancer or multiple myeloma: Study design. *Plus daily oral vitamin D 400 IU and calcium 500 mg supplements.13
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25
Figure 2 Trial comparing zoledronic acid versus pamidronate in patients with advanced breast cancer or multiple myeloma: Time to first SRE. Hypercalcemia of malignancy is included as an SRE. ZA, zoledronic acid; Pam, pamidronate. (From Rosen et al: Cancer. 98:1735. ©2003, American Cancer Society. Reproduced with permission of John Wiley & Sons, Inc.13)
zoledronic acid (32, 43, and 18 days for zoledronic acid 4 mg and 8 mg, and for pamidronate, respectively). The main adverse events occurred with similar frequency in all three treatment groups: fever, anemia, nausea, constipation, and dyspnea. Renal toxicity was reported with somewhat greater frequency in patients who received zoledronic acid than in those on pamidronate, mainly with the higher dose.24 Another randomized, double-blind, multicenter trial compared zoledronic acid, either 4 mg or 8 mg (initially by 5-minute infusion, but amended to 15 minutes), with pamidronate 90 mg infused over 2 hours, in patients with either advanced breast cancer or multiple myeloma. Both drugs were administered every 3 to 4 weeks for 24 months (Fig 1).13 Early in the trial, the higher dose of zoledronic acid was reduced to 4 mg because of renal toxicity. The core data analysis was performed after 13 months’ follow-up, with the final analysis 12 months later.13,25 Breast cancer was the primary diagnosis in 377 of 564 patients randomized to receive zoledronic acid 4 mg, and in 389 of 558 patients in the pamidronate group. Of those patients with breast cancer, more than 50% were receiving concurrent endocrine therapy (201 and 210 in the zoledronic acid 4 mg and pamidronate groups, respectively).13
Considering only those patients with breast cancer in this trial, zoledronic acid achieved a 16% reduction in risk of SRE compared with pamidronate (hazard ratio 0.84, P ⫽ .030), and also a significantly lower skeletal morbidity rate (0.83 v 1.37 SREs per year, respectively; P ⫽ .039). In the subgroup that also received endocrine therapy, zoledronic acid also significantly prolonged the time to first SRE compared with pamidronate (415 v 370 days, respectively; P ⫽ .047), but there was no significant difference when all patients with breast cancer were included (Fig 2).13 Multiple event analysis showed that zoledronic acid significantly reduced the risk of any SRE in the overall population compared with pamidronate. In the subset of patients with breast cancer, the risk was reduced by an additional 20% compared with pamidronate after 24 months’ treatment (evaluated at 25 months; P ⫽ .042) (Fig 3).13 That difference was maintained whether or not HCM was included in the analysis (Table 1).13 In the subgroup of patients with breast cancer and at least one osteolytic lesion, zoledronic acid was significantly better than pamidronate in increasing time to first SRE (310 v 174 days, respectively; P ⫽ .013), with a strong trend also in reducing the rate of SREs (48% v 58%, respectively; P ⫽ .058).26 Multiple-event analysis showed significantly
Figure 3 Trial comparing zoledronic acid versus pamidronate in patients with advanced breast cancer or multiple myeloma: Survival-adjusted multiple-event analysis of cumulative expected SREs in patients with breast cancer treated with zoledronic acid 4 mg or pamidronate 90 mg after 24 months of treatment. (Cook and Lawless approach, pooled stratified analysis.) SRE, skeletal-related event.13
H.A. Harvey
26 Table 1 Trial Comparing Zoledronic Acid Versus Pamidronate in Patients With Advanced Breast Cancer or Multiple Myeloma: Multiple-Event Analysis Comparing the Effects of Zoledronic Acid and Pamidronate on Risk of Developing at Least 1 SRE in Patients With Breast Cancer13
Including HCM Not including HCM
Hazard Ratio*
P Value
0.80 0.82
.025 .042
*A hazard ratio of < 1 favors zoledronic acid over pamidronate. Abbreviations: SRE, skeletal-related event; HCM, hypercalcemia of malignancy.
greater reductions in risk of developing SREs with zoledronic acid versus pamidronate in that patient subgroup (30% greater; P ⫽ .010) and in all patients with breast cancer (20% greater; P ⫽ .037). In that trial, zoledronic acid 4 mg and pamidronate 90 mg were equally well tolerated. However, because of renal toxicity in the 8-mg zoledronic acid group, two protocol amendments were introduced: the 8-mg dose was reduced to 4 mg, and the infusion time for zoledronic acid was lengthened from 5 minutes to 15 minutes. After implementation of these amendments, the incidence of renal insufficiency was similar in both treatment groups (Fig 4).13,25 This study was powered to assess whether zoledronic acid treatment met the stringent statistical criteria for noninferiority to pamidronate. Zoledronic acid was not inferior to pamidronate in affecting the incidence of SREs, nor in individual outcomes such as fractures, need for palliative radiation or surgery, or spinal cord compression. In fact, all outcomes with zoledronic acid, including time to first SRE, were somewhat improved with zoledronic acid compared with pamidronate, especially in the subgroup of patients with breast cancer and at least one osteolytic lesion.26 The study investigators caution, however, against drawing firm conclusions about the significance of the observed differences.13 Ibandronate Versus Placebo Ibandronate is another intravenous bisphosphonate that has been evaluated in patients with bone lesions secondary to breast cancer. In a phase III trial, patients were randomized to receive either ibandronate 2 mg as a bolus injection, ibandronate 6 mg infused over 1 to 2 hours, or infused placebo.14 Of the 466 patients randomized, more than 60% (283) were also receiving endocrine treatment, 24% (110) were receiving chemotherapy, and the remaining 16% (69) received neither endocrine therapy nor chemotherapy. Treatments were administered at 3- to 4-week intervals for between 60 and 96 weeks. The primary efficacy end point was the number of 12-week periods with new bone complications, expressed as skeletal morbidity period rate. Ibandronate 6 mg compared with placebo significantly reduced the mean skeletal morbidity period rate overall (P ⫽ .004) and for vertebral fractures (P ⫽ .023), as well as the mean number of events per patient (P ⫽ .025) (Table 2). However, nonvertebral fractures and the percentage of patients experiencing one or more events were not significantly affected. The median time from randomiza-
tion to a first new bone event was also significantly longer for patients receiving ibandronate 6 mg compared with placebo (50.6 v 33.1 weeks, respectively; P ⫽ .018) (Fig 5).14 Bolus ibandronate 2 mg was similar to placebo in efficacy.14 Treatment with ibandronate was well tolerated, based on adverse events likely to be associated with treatment rather than related to the underlying disease. The incidences of flu-like syndrome and arthralgia were slightly higher with ibandronate, whereas leukopenia was more frequent with placebo. The ibandronate 6 mg group had significantly improved bone pain scores compared with the other groups, and analgesic use was lower in both ibandronate groups than in the placebo group.14 In contrast to studies with zoledronic acid, which evaluated efficacy in comparison with standard pamidronate, this study compared ibandronate with placebo. As a consequence, how efficacy with ibandronate compares with that of the other intravenous bisphosphonates cannot be determined.27 Furthermore, skeletal morbidity period rate includes nonfracture bone events (radiotherapy and surgery for bone complications), and although intravenous ibandronate significantly improved skeletal morbidity period rate overall and for vertebral fractures, there was no significant improvement in nonvertebral fractures.14 Summary of Clinical Trials in Advanced Breast Cancer Intravenous bisphosphonates clearly reduce the skeletal morbidity associated with metastatic breast cancer bone lesions. In clinical trials, zoledronic acid has been shown to provide skeletal benefits that are at least equivalent to the standard, pamidronate.13,24 For zoledronic acid 4 mg delivered as a 15-minute infusion, renal effects were similar to those associated with pamidronate. Ibandronate is another potent bisphosphonate that significantly reduces skeletal complications of malignancy compared with placebo.14 In practice, although all three of these intravenous bisphosphonates are effective in patients with advanced breast cancer and bone involvement, zoledronic acid is the most conve-
Figure 4 Trial comparing zoledronic acid versus pamidronate in patients with advanced breast cancer or multiple myeloma: percentage of patients with serum creatinine ⱖ 1.4 mg/dL before and after implementation of protocol amendment to reduce zoledronic acid from 8 mg to 4 mg, and increase infusion time from 5 minutes to 15 minutes. (Modified and reprinted, with permission, from Rosen et al. Cancer J 7:377, 2001, Jones and Bartlett.25)
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Table 2 Effects of Ibandronate 2 mg or 6 mg Versus Placebo on Mean SMPR, Mean Number of Events Per Patient, and Percentage of Patients With 1 or More Events14 Placebo (n ⴝ 158)
Ibandronate 2 mg (n ⴝ 154)
Ibandronate 6 mg (n ⴝ 154)
Mean SMPR All new bone events
1.48
Vertebral fractures
0.82
Nonvertebral fractures
0.81
Mean events per patient (n)
3.64
1.31 P ⴝ .152* 0.70 P ⴝ .028* 0.70 P ⴝ .235* 4.24 P ⴝ .905* 62.3 P ⴝ 1.000†
1.19 P ⴝ .004* 0.71 P ⴝ .023* 0.72 P ⴝ .396* 2.65 P ⴝ .025* 50.6 P ⴝ .052†
Parameter
Patients with events (%)
62.0
*Pairwise comparisons versus placebo using the Wilcoxon rank sum test. †Pairwise comparisons versus placebo using exact Pearson 2 -test for 2 ⴛ 3 table. Abbreviation: SMPR, skeletal morbidity period rate. Adapted with permission, from Body et al. Ann Oncol. 14:1399, 2003, European Society for Medical Oncology.
nient to use. Because zoledronic acid can be administered safely as an infusion over 15 minutes rather than over the 1 to 2 hours required for pamidronate and ibandronate, less clinic time is needed, an advantage that has been reported to be preferred by patients.28 Recent reports indicated an increased rate of osteonecrosis of the jaw in patients receiving chronic bisphosphonate therapy.29 It is unclear at this point if osteonecrosis can be solely attributed to bisphosphonate therapy; however, monitoring patients receiving chronic bisphosphonate therapy is advised.
Bisphosphonate Therapy in Breast Cancer: New Directions Recently, bisphosphonate therapy has been assessed in patients with early breast cancer as a means to improve skeletal health before bone lesions develop. It is well established that bone loss is a natural consequence of aging even in healthy women, and this shift in skeletal health, which starts at about 35 years of age, is related to decreasing estrogen production. This process is accelerated by any form of estrogen deprivation, whether it is a result of menopause or treatment for
Figure 5 Phase III trial of ibandronate in patients with advanced breast cancer and bone metastases: time to first new SRE. The dashed line at 96 weeks indicates maximum total treatment period. (Reprinted with permission, from Body et al: Ann Oncol. 14:1399. © 2003 European Society for Medical Oncology.14)
breast cancer.30 In premenopausal women, luteinizing hormone-releasing hormone analogs result in significant loss of BMD. Postmenopausal women treated with aromatase inhibitors such as letrozole and anastrozole also experience considerable estrogen suppression that may lead to loss of BMD.31,32 The osteoporosis literature has shown that bisphosphonates can preserve BMD. Intriguing results from a study of the effects of zoledronic acid on bone turnover and density in postmenopausal women with low BMD suggests that a single annual intravenous infusion of zoledronic acid may be as effective as oral forms taken daily. Compared with placebo, a single infusion of zoledronic acid 4 mg significantly increased BMD in these women (Fig 6).33 Furthermore, a single dose of zoledronic acid stably and significantly reduced the levels of biochemical markers of bone turnover, including serum Ctelopeptide and ratio of urinary N-telopeptide to serum creatinine, throughout the study (P ⬍ .01 for all comparisons). This improvement was similar to those observed in studies comparing oral bisphosphonate treatments in postmenopausal women with low BMD.34-37 The dramatic effects of zoledronic acid in women with low BMD are important because a once-yearly treatment may eliminate the problem of
28
H.A. Harvey
Figure 6 Effects of annual infusion of zoledronic acid 4 mg on BMD in postmenopausal women with low BMD. Left, lumbar spine; right, femoral neck. BMD, bone mineral density; ZA, zoledronic acid. (Modified and reprinted with permission, from Reid et al: N Engl J Med. 346:653. © 2002 Massachusetts Medical Society. All rights reserved.33)
long-term compliance with daily dosing of an oral bisphosphonate. In a recent study, ibandronate appeared to be less effective in this setting: Intravenous injections of 0.5 mg and 1 mg every 3 months in women with postmenopausal osteoporosis resulted in increases in lumbar spine BMD and comparatively small decreases in bone resorption markers. As a consequence, the occurrence of fractures was not significantly reduced.38 These findings in women with osteoporosis who are otherwise healthy suggest that there may be a therapeutic advantage to similarly treating women who are receiving estrogen deprivation therapy for early breast cancer. This question has been addressed in a large phase III study of premenopausal
Figure 7 Effects of zoledronic acid on bone mineral regression associated with adjuvant treatment of early breast cancer with ovarian ablation (goserelin) plus tamoxifen or anastrozole. (A) Lumbar spine. (B) Trochanter. BMD, bone mineral density; ZA, zoledronic acid.39
women with stage I or II hormone receptor–positive breast cancer who were treated with the luteinizing hormone-releasing hormone analog goserelin during adjuvant therapy.39 All patients received goserelin and were randomized to receive standard doses of either tamoxifen or anastrozole. Both of these two treatment groups were further randomized to receive either zoledronic acid 4 mg or placebo every 6 months. Bone loss attributable to ovarian ablation was noted in all patients without zoledronic acid. This effect was somewhat more pronounced for anastrozole than for tamoxifen. The results clearly showed that zoledronic acid prevented treatment-related bone loss (Fig 7).39 These findings have led to the ongoing Zometa Femara
Optimizing bisphosphonate therapy
29
Figure 8 Study design for the ongoing ZO/Z-FAST trial. ER/PgR, estrogen receptor/progesterone receptor; BMD, bone mineral density; SD, standard deviations.
Adjuvant Synergy Trial (ZO-FAST outside North America, and Z-FAST in the United States and Canada), which is evaluating the addition of zoledronic acid to adjuvant therapy with letrozole. In this trial, all postmenopausal women with hormone receptor–positive early breast cancer receive adjuvant letrozole, and they are randomized to receive zoledronic acid 4 mg as a 15-minute infusion once every 6 months starting either at the initiation of letrozole therapy (“upfront”) or when either a postbaseline BMD T-score falls more than ⫺2.0 standard deviations below the average score for a healthy young woman, or a symptomatic or asymptomatic fracture occurs (Fig 8; data on file, Novartis Pharmaceuticals Corp, East Hanover, NJ). Zoledronic acid has also been shown to be effective in the treatment of bone complications associated with other cancer types. Treatment has reduced SREs in patients with multiple myeloma or bone metastases secondary to prostate, lung, and other cancers.15
Summary The third-generation aromatase inhibitors may improve the survival of postmenopausal women with hormone receptor– positive breast cancer, when used as therapy in the adjuvant setting or for advanced disease.6 However, long-term estrogen deprivation resulting from those treatments may lead to loss of BMD and the occurrence of SREs. Intravenous bisphosphonates have been shown to reduce skeletal morbidity in postmenopausal osteoporotic women who are otherwise healthy, as well as in patients with metastatic bone lesions secondary to breast cancer.13,26,33 These results have prompted ongoing studies to investigate whether, in patients receiving estrogen-deprivation therapy for early breast cancer, treatment with bisphosphonates also improves skeletal health and prevents or delays SRE occurrence. Recently, zoledronic acid has been shown to be superior in activity to the standard, pamidronate, in patients with breast cancer and osteolytic lesions.13,26 Furthermore, the considerably shorter infusion period of 15 minutes for zoledronic acid compared with 1 to 2 hours for pamidronate and ibandronate is an important consideration in choosing the most appropriate bisphosphonate.
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30 17. Ferlay J, Bray F, Pisani P, et al: GLOBOCAN 2000. Lyon, France; IARC Press, 2001 18. Brown HK, Healey JH: Metastatic cancer to the bone, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 6). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 2713-2729 19. Hortobagyi GN, Theriault RL, Porter L, et al: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 335:1785-1791, 1996 20. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17:846-854, 1999 21. Hultborn R, Gundersen S, Ryden S, et al: Efficacy of pamidronate in breast cancer with bone metastases: A randomized, double-blind placebo-controlled multicenter study. Anticancer Res 19:33833392, 1999 22. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003 23. Warrell RP J: Metabolic emergencies, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 6). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 2633-2645 24. Major P, Lortholary A, Hon J, et al: Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 19:558-567, 2001 25. Rosen LS, Gordon D, Kaminski M, et al: Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: A phase III, doubleblind, comparative trial. Cancer J 7:377-387, 2001 26. Rosen LS, Gordon DH, Dugan W J, et al: Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100:36-43, 2004 27. Westermann AM: Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 15:537-538, 2004 28. Joseph D, Chern B, Pittman K, et al: An assessment of patient preferences for intravenous zoledronic acid or pamidronate in patients commencing bisphosphonate therapy for malignant disease in bone. Blood 100:388b, 2002 (abstr 5114) 29. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws
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