Bone is the most common site of metastasis in breast cancer patients, but bisphosphonate use has been shown to cut incidence and delay onset. This article reviews subgroups that may gain from adjuvant treatment and ongoing trials
BHB MBChB FRACP
MB MD FRCP(UK)
Head, Breast Medical Oncology
Department of Medical Oncology
Princess Margaret Hospital
Some 80% of patients with metastatic breast cancer (MBC) develop bone disease. Bone metastases cause considerable morbidity through pain and skeletal-related events (SREs). SREs
can be defined as pathological fractures, need for surgery and/or radiotherapy to bone, hypercalcaemia or spinal-cord compression. While MBC patients with bone-predominant disease tend to live longer than those with significant visceral disease, the occurrence of an SRE portends a poorer prognosis. Bisphosphonates are compounds that bind preferentially to sites of bone turnover and inhibit osteoclast-mediated bone resorption. The bisphosphonates commonly used in oncology are oral clodronate (first-generation), intravenous pamidronate (second-generation), intravenous zoledronic acid (third-generation), and oral or intravenous ibandronate (also third-generation).
There is substantial preclinical evidence suggesting that bisphosphonates have both direct antitumour effects (such as inhibiting tumour-cell adhesion to bone, inducing tumour-cell apoptosis, antagonising growth factors and exhibiting antiangiogenic effects),[3-5] as well as the ability to reduce osteoclast-mediated bone resorption,[6-9] an important early step in the development of bone metastases. Randomised trials performed on patients with MBC and bone metastases
consistently demonstrate that bisphosphonate treatment significantly reduces both the incidence of SREs and delays the onset of SREs.[10-16] Three studies have demonstrated that oral clodronate could also prevent and delay SREs in patients with known bone metastases.[17-19] This research prompted the evaluation of oral clodronate in the adjuvant setting with the aim of preventing skeletal metastases and improving patient
survival. The purpose of this review is to evaluate the current adjuvant role of bisphosphonate treatment.
A number of trials have investigated the role of clodronate in the adjuvant setting[20-25] in order to evaluate whether treatment with clodronate:
- Delays onset of skeletal metastases.
- Delays onset of nonskeletal metastases.
- Prolongs survival.
In addition, one small trial has examined the role of adjuvant pamidronate (see Table 1).
These trials yielded conflicting results, and, as such, a meta-analysis of the clodronate trials was performed in 2007 in a bid to answer these questions. The analysis included three studies in patients with early and five in patients with advanced breast cancer. The authors concluded that there was ‘no evidence of any statistically significant difference in overall survival, bone metastasis-free survival or nonskeletal metastasis-free survival’ in either patients with early breast
cancer or those with metastatic breast cancer from therapy with adjuvant clodronate.
Are there subgroups of patients that may benefit from treatment with oral clodronate?
Clodronate in early breast cancer
In the early breast cancer setting, three trials examined use of clodronate in preventing skeletal (and nonskeletal) metastases and prolonging overall survival. Diel et al randomised 302 patients with early-stage breast cancer who had no overt bone metastases, but at least one tumour cell detected in a bone-marrow aspirate, either to receive 1,600mg of oral clodronate daily for two years or to a control arm. The presence of such cells in the marrow correlates with an increased risk of relapse. At a median follow-up of 36 months, more than twice as many patients in the control compared
with the clodronate group developed distant metastases (29% vs 13%, p<0.001), bony metastases (17% vs 8%, p=0.003) and visceral metastases (19% vs 8%, p=0.003). Furthermore, almost four times as many patients died in the control arm compared with the clodronate arm (15% vs 4%, p=0.001). The data were updated at a follow-up of 8.6 years, and there was no longer a significant difference in the incidence of osseous and visceral metastases between the groups; however, a significant overall survival advantage persisted for the clodronate arm.
In the largest reported adjuvant clodronate trial, Powles et al randomised 1,069 patients with operable, breast cancer to receive either oral clodronate (1,600mg daily) or placebo for two years. In the final analysis (after a median follow-up of 5.6 years), the risk of bone metastases was significantly decreased in the clodronate compared with the placebo arms (9.6 vs 13.5%, p=0.043), equating to a risk reduction of 31%. Despite most patients receiving bisphosphonates upon osseous relapse, those patients who received adjuvant clodronate had significantly fewer SREs compared with those who received placebo. There was a trend towards adjuvant clodronate conferring an overall survival advantage, with the risk of death being reduced by 23% (p=0.048). A substudy done as part
of the aforementioned trial showed that clodronate, compared with placebo, could also reduce the bone loss caused by adjuvant therapy. This finding is particularly important given the increased use of aromatase inhibitors in treating early breast cancer.
The findings of the above two trials are somewhat contrary to those of Saarto et al.[23,24] This trial randomised 299 patients with lymph-node-positive early-stage breast cancer to either receive or not receive the same daily dose of clodronate for three years. Premenopausal patients also received adjuvant three-weekly intravenous CMF chemotherapy, and postmenopausal patients were further randomised to either tamoxifen or toremifene for three years. Therefore, postmenopausal hormone-receptor-negative patients received
endocrine therapy as opposed to chemotherapy. There were more hormone-receptor-negative patients in the clodronate group.
There was no difference in the occurrence of bone metastases between groups with a similar 10-year skeletal disease-free survival (DFS). Bone was less commonly the first site of relapse in the clodronate group (11% vs 18%, p=0.03). However, extraskeletal metastases developed more often in the clodronate group (50% vs 36%, p=0.004). The deleterious effect of clodronate was most pronounced in the oestrogen
receptor-negative patients, with 10-year DFS being 58% vs 25% (p=0.004), respectively. Despite initial concern, with longer follow-up it has transpired that overall survival was not significantly affected by clodronate in this study.
The Saarto trial has been criticised for lack of balance. Given that there were more hormone-receptor-negative patients in the clodronate arm and that overall survival was not significantly different in the two arms, some authors have contended this actually lends credence to the claim that clodronate may have a protective effect on survival.
If we exclude the Saarto trial due to the confounding effects of unbalanced randomisation, we are left with two positive trials, with the largest-effect size seen in the Diel trial. One possible explanation for this discrepancy lies in the inclusion criteria of the two trials. Diel’s study enrolled high-risk women who had at least one tumour cell in their bone-marrow aspirate, while Powles’ trial included both low- and high-risk women. Indeed, the reduction in risk of bone metastases in Powles’ trial was most pronounced in those with stage II and III disease. It is possible, therefore, that clodronate has significant benefit in high-risk women, yet that this benefit is less pronounced in those at lower risk. Indeed, two trials presented in abstract form[29,30] have demonstrated a decrease in the number of isolated tumour cells in the bone marrow following treatment with a third-generation bisphosphonate, zoledronic acid.
Pamidronate in early breast cancer
One small nonrandomised trial by Kokofu et al investigated
using adjuvant intravenous pamidronate therapy in breast cancer patients with high-risk disease. Breast cancer patients with four or more positive lymph nodes were assigned to either pamidronate 45mg (n=33) every two weeks for a total of four infusions, or to a control group (n=57), according to patient preference. After a median follow-up of five years, the incidence
of bone metastases was significantly lower in the pamidronate group (p=0.008). Overall survival was comparable between groups.
A number of researchers have commented on the need for large, pragmatic trials when results of a meta-analysis are inconclusive (and even in the face of a negative meta-analysis). We are eagerly awaiting the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B34 trial. Accrual is complete for this fourth adjuvant clodronate trial, which is double-blinded and which randomised 3,323 patients to either 1,600mg of clodronate or placebo for three
Several other trials are also underway that aim to evaluate the adjuvant benefit of more potent bisphosphonates. Accrual for the 3,300-patient AZURE trial is complete; this randomises patients to receive either intravenous zoledronic acid or control in patients with lymph-node-positive disease. Ibandronate has the advantages of being less nephrotoxic than zoledronic
acid and is available in a smaller-sized oral preparation than clodronate. Additionally, the 6,000-patient SWOG/Intergroup/ NSABP S0307 trial is accruing to evaluate its adjuvant role compared with intravenous zoledronic acid and oral clodronate. And finally, the GAIN trial, evaluating two chemotherapy regimens in node-positive breast cancer, is further randomising patients to either receive or not receive oral ibandronate.
Compared with other agents, clodronate has the advantage of oral delivery: one BP trial of ibandronate found patients preferred the oral route. Oral therapy also necessitates fewer visits to a hospital or infusion centre – an important factor in adjuvant treatment, as these patients would generally be seen relatively infrequently (one to four times a year) in follow-up.
Oral clodronate is generally very well tolerated. The most common side-effects are gastrointestinal. However, in the largest of the above-mentioned trials, the only adverse effect significantly increased by clodronate administration was diarrhoea (19.9% vs 10.0%). These trials yielded no cases of the more serious toxicities associated with some other bisphosphonates, such as oesophageal ulceration/perforation or osteonecrosis of the jaw (ONJ). Reports of ONJ in patients undergoing therapy with clodronate are extremely rare, particularly in light of the fact that this agent has been used extensively for over 20 years. Rates of ONJ with other agents are still being elucidated but are 4-13% with pamidronate, are at 7% with ibandronate, and 7-10% with zoledronic acid.
Altering treatment-induced bone loss
Aromatase inhibitors are increasingly used in the adjuvant setting in postmenopausal women and are known to cause bone mineral loss. In addition, bone loss is often caused by chemotherapy-induced premature menopause or intentional ovarian ablation. Currently there is a wave of adjuvant hormone therapy trials with arms having different bisphosphonate schedules.[36-38] While these trials give an insight into how bisphosphonates can mitigate against hormone-therapy-induced
bone loss and consequent fractures, they may also provide further information about bisphosphonates’ adjuvant benefit.
Despite the negative results of one meta-analysis, treatment with adjuvant clodronate shows promise in high-risk women with early breast cancer in preventing skeletal metastases and possibly prolonging survival. The results of four large randomised clinical trials are awaited in order to further clarify the role of bisphosphonates in adjuvant treatment. In addition, multiple trials are currently assessing use of bisphosphonates in the adjuvant setting for their bone-protective effect, and these trials may also elucidate the biological effect of early bisphosphonate treatment.
1. Theriault RL, et al. 1992;3:445-62.
2. Solomayer EF, et al. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 2000;59:271-8.
3. Van der Pluijm G, et al. Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 1996;98:698-705.
4. Neudert M, et al. Site-specific human breast cancer (MDA-MB-231) metastases in nude rats: model characterisation and in vivo effects of ibandronate on tumour growth. Int J Cancer 2003;107:468-77.
5. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002;302:1055-61.
6. Mundy G. Preclinical models of bone metastases. Semin Oncol 2001;28:2-8.
7. Diel IJ. Bisphosphonates in the prevention of bone metastases: current evidence. Semin Oncol 2001;28:75-80.
8. Padalecki SS, Guise TA. Actions of bisphosphonates in animal models of breast cancer. Breast Cancer Res 2002;4:35-41.
9. Neville-Webbe HL, et al. Coleman RF. The antitumor activity of bisphosphonates. Cancer Treat Rev 2002;28:305-19.
10. Hortobagyi GN, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 1998;16:2038-44.
11. Theriault RL, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. J Clin Oncol 1999;17:846-54.
12. Lipton A, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases. Cancer 2000;88:1082-90.
13. Hultborn R, et al. Efficacy of pamidronate in breast cancer with bone metastases: a randomized, doubleblind placebo-controlled multicenter study. Anticancer Res 1999;19:3383-92.
14. Kohno N, et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 2005;23:3314-21.
15. Body JJ, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004;90:1133-7.
16. Body JJ, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399-405.
17. Paterson AHG, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59-65.
18. Kristensen B, et al. Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 1999;246:67-74.
19. Tubiana-Hulin M, et al. Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases. Bull Cancer 2001;88:701-7.
20. Diel IJ, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357-63.
21. Jaschke A, et al. Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow: a longtime follow-up. Proc Am Soc Clin Oncol 2004;22:abs 529.
22. Powles T, et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20:3219-24.
23. Saarto T, et al. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 2001;19:10-17.
24. Saarto T, et al. Ten year follow up of a randomized controlled trial of adjuvant clodronate treatment. Proc Am Soc Clin Oncol 2004;23:abs 527.
25. Powles T, et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer (ISRCTN83688026). Breast Cancer Res 2006;8:R13.
26. Ha TC, et al. Meta-analysis of clodronate and breast cancer survival. Br J Cancer 2007;96:1796-1801.
27. Powles TJ, et al. Oral clodronate and reduction in loss of bone mineral density in women with operable primary breast cancer. J Natl Cancer Inst 1998;90:704-8.
28. Paterson AG. The role of bisphosphonates in early breast cancer. Oncologist 2006;11 Suppl 1:13-9.
29. Rack BK, et al. Effect of zoledronic acid on persisting isolated tumor cells in the bone marrow without recurrence in early breast cancer. J Clin Oncol 2004;23:834 (abs 9515).
30. Lin A, et al. Zoledronic acid as adjuvant therapy for women with early stage breast cancer and occult tumor cells in bone marrow. SABCS 2007:abs 510.
31. Kokufu I, et al. Adjuvant pamidronate (PMT) therapy for the prevention of bone metastasis in breast cancer (BC) patients (pts) with four or more positive nodes. J Clin Oncol: 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004;l22
32. Ioannidis JP, et al. J. Issues in comparisons between meta-analyses and large trials. JAMA 1998;279(14):1089-93.
33. Bergner R, et al. Differences in nephrotoxicity of intravenous bisphosphonates for the treatment of malignancy-related bone disease. Onkologie 2006;29:534-40.
34. Clemons M, et al. Oral ibandronate provides significant palliative benefit in metastatic breast cancer patients who have experienced bony progression or a skeletal related event (SRE) despite first-line bisphosphonate therapy. Breast Cancer Res
Treat 2007;Suppl 1.
35. Diel IJ, et al. Pathophysiology, risk factors and management of bisphosphonateassociated osteonecrosis of the jaw: is there a diverse relationship of amino- and nonaminobisphosphonates? Crit Rev Oncol-Hematol 2007;64(3):198-207.
36. Brufsky A, Harker WG, Beck JT, et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopaual women with early breast cancer J Clin Oncol 2007;25:829-36.
37. Gnant MFX, Mlineritsch B, Luschin-Ebengreuth G, et al. Zoledronic acid prevents cancer treatmentinduced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormoneresponsive breast cancer: a report from the Austrian
Breast and Colorectal Cancer Study Group. J Clin Oncol 2007;25:820-8.
38. Lester JE, Gutcher SA, Ellis SP, et al. The ARIBON study: reversal of anastrozole (Arimidex) induced bone loss with oral monthly ibandronate (Bondronate) treatment during adjuvant therapy for breast cancer. Cancer Treat Rev 2006;32:abs 12.