Are Bisphosphonates Ready for the Adjuvant Setting?

A majority of the more than 190,000 women diagnosed with breast cancer each year in the US[1] will receive some form of adjuvant therapy. Many breast cancer treatments cause decreases in circulating estrogen levels, which in turn can have a significant effect on bone mineral density; this condition is known as cancer treatment-induced bone loss (CTIBL). In this issue of ONCOLOGY, Reeder and Brufsky review the role of bisphosphonates in the setting of adjuvant breast cancer treatment. Both oral and intravenous bisphosphonates are effective in the prevention and treatment of CTIBL, and emerging data suggest that adjuvant bisphosphonate therapy may also affect breast cancer recurrence and survival. In considering the role of these medicines in early stage breast cancer, however, a number of important questions remain.

In a majority of studies of adjuvant bisphosphonate therapy, the primary endpoint is change in bone mineral density rather than rate of fracture, which is the more clinically significant outcome. In large adjuvant trials comparing tamoxifen with aromatase inhibitors (AIs), absolute rates of fracture are 1%–3% higher in AI-treated patients,[2-4] but data suggest that this increase may be transient. In the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, fracture rates after discontinuation of therapy were similar.[3] Additionally, in a substudy of ATAC designed to evaluate effects on bone density, none of the women in either the tamoxifen or anastrozole (Arimidex) arms with normal baseline bone density developed osteoporosis at 5 years, and only 5% of those with baseline osteopenia become osteoporotic.[5] Data also suggest that the observed difference in fracture rates in adjuvant AI trials may be more related to a bone-protective effect of tamoxifen than a detrimental effect of AIs. In the MA.17 trial, in which treatment with 5 years of letrozole (Femara) was compared with placebo in women who had completed 5 years of adjuvant tamoxifen, fracture rates were similar in the two study arms.[6] If, as these data suggest, fracture risk with AI therapy is less of an issue than previously suspected, then the role of adjuvant bisphosphonate therapy becomes less clear. In addition, the appropriate duration of bisphosphonate therapy for CTIBL has yet to be determined.

When evaluating the overall clinical utility of any new therapy, both the potential benefits and risks must be considered. Emerging data from large studies of IV bisphosphonate therapy suggest a possible increase in incidence of atrial fibrillation,[7] and a small but significant number of subtrochanteric hip fractures appear to have developed in patients on long-term bisphosphonate therapy.[8,9] Osteonecrosis of the jaw (ONJ) is a highly publicized complication of bisphosphonate use. The incidence of ONJ among patients receiving intravenous bisphosphonate therapy in the setting of metastatic disease is estimated to be on the order of 1%–10%,[10] and the risk is related to both dose and duration of use. Fortunately, ONJ appears to be rare in the context of both oral bisphosphonate use and the less frequent IV dosing schedule studied for CTIBL.

Dr. Reeder and Dr. Brufsky point out that a growing body of evidence suggests that bisphosphonate therapy may have an effect on breast cancer recurrence when used in the adjuvant setting. Three recently completed trials are evaluating the effects of oral and IV bisphosphonates on disease-free and overall survival, and it is hoped that they will provide a definitive answer to this important question in the next several years. The National Surgical Adjuvant Breast and Bowel Project NSABP B34 trial and the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial are comparing oral (clodronate) and IV (zoledronic acid [Zometa]) bisphosphonates, respectively, to placebo. The Southwest Oncology Group study S0307 is a three-arm trial comparing two oral bisphosphonates (clodronate and ibandronate [Boniva]) with IV zoledronic acid. It will provide important additional data regarding comparative toxicities and efficacy of oral vs intravenous therapy.

Although the results of these trials will help to clarify the role of bisphosphonates in the treatment of early-stage breast cancer, questions of dose scheduling and duration of therapy persist. The Austrian Breast and Colorectal Cancer Study Group ABSCG-12 trial, which suggested that IV zoledronic acid improves disease-free survival in premenopausal women treated with hormonal therapy, utilized an every-6-month dosing schedule of zoledronic acid, given for a total of 3 years. The two recently completed adjuvant zoledronic acid trials with disease-free-survival endpoints employed a more intensive dosing schedule. Given the known toxicities and cost of these medications, the issue of whether a less-intensive dosing schedule is sufficient for affecting breast cancer outcomes, or whether more intensive dosing is needed, is an important clinical question and should be addressed in the next generation of clinical trials.

Lastly, these data raise the question of whether bisphosphonates have specific antitumor properties, or whether bone-targeted agents in general might have a biologic effect on breast cancer recurrence. Recent data suggest that denosumab (Prolia) is at least equivalent to zoledronic acid in terms of preventing skeletal related events in the setting of metastatic disease,[11] and may also be a viable alternative to bisphosphonate therapy for CTIBL,[12] raising the important question of whether denosumab might have a role in the adjuvant setting. This drug is administered subcutaneously, eliminating the need for an infusion visit for treatment. While the overall side-effect profile for denosumab appears quite favorable, it is important to note that in metastatic trials, the incidence of ONJ appears similar to that seen with zoledronic acid,[11] therefore additional data are needed on both the efficacy and toxicity of this drug in the adjuvant setting. Studies investigating the impact of denosumab on disease recurrence in the adjuvant breast cancer setting are in the planning stages.

In conclusion, current data support the use of oral or IV bisphosphonate therapy for CTIBL, but risk of fracture needs to be individualized and toxicities need to be considered. All patients being treated with bisphosphonates in this setting should receive adequate calcium and vitamin D supplementation and undergo periodic monitoring of bone mineral density, but the majority will not require addition of antiosteoclast therapy. Data expected in the near future regarding the ability of bisphosphonates to affect the incidence of disease recurrence will help to establish the role of these drugs in the treatment of early stage breast cancer; however, additional trials are needed to determine the optimal dosing schedule and duration of treatment, and to evaluate newer bone-targeted agents in this setting.

-Larissa A. Korde, MD, MPH -Julie R. Gralow, MD

Financial Disclosure:Dr. Korde has no relationships to disclose. Dr. Gralow receives research funding from Novartis, Amgen, and Roche.

References:

References

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