Fractures and the Use of Bisphosphonates in Patients With Breast Cancer

In Clinical Studies News by Barbara Jacoby


In an interview with Oncology Learning Network, Julie R. Gralow, MD, Clinical Director, Breast Medical Oncology, Seattle Cancer Care Alliance, Washington, discussed findings from the SWOG S0307 trial, which looked at the occurrence of fractures in patients with breast cancer receiving high-dose bisphosphonates to prevent metastases.


I’m Dr Julie Gralow. I’m a Professor of Breast Medical Oncology at the University of Washington and the Seattle Cancer Care Alliance. First, I’d like to discuss an abstract and poster presented at the San Antonio Breast Cancer Symposium in 2019 related to fractures on the SWOG S0307 trial. This was presented by my colleague and first author, Dr Rachel Yung.

S0307 is a trial that I led for SWOG that was looking at a comparison between 3 different bisphosphonates with the end point being disease‑free and overall survival. The background is that we had had many trials comparing a placebo or a control group to a high‑dose bisphosphonate over the years.

In a meta‑analysis, we showed that in a post‑menopausal population that adding bisphosphonate after a diagnosis of breast cancer to post‑menopausal women with stage 1 to 3 breast cancer, we could reduce bone recurrence, overall recurrence, and death due to breast cancer.

So we’ve now incorporated at least a strong consideration for the use of high‑dose bisphosphonate in post‑menopausal, early‑stage breast cancer into our guidelines—that occurred several years ago. The idea behind the SWOG S0307 trial was that we had never head on compared different bisphosphonates, and we know they have different potencies, different routes of administration.

So SWOG S0307 compared zoledronic acid in intravenous form, a potent aminobisphosphonate, with clodronate, an oral and non‑aminobisphosphonate given daily. Then a third arm was ibandronate given at a full bone metastasis treatment dose orally daily. Six thousand patients enrolled in this study, stage 1 through 3 breast cancer, pre or post‑menopausal, and they were treated for 3 years in this study.

We’ve previously shown and recently published that there was no difference in 5‑year disease‑free or overall survival between the 3 different bisphosphonates.

Our conclusion was, all 3 could be considered. The current ASCO guideline recommends clodronate or zoledronic acid. Of course, clodronate is not available in the United States, so we predominantly use zoledronic acid in the United States.

The purpose of this poster at San Antonio was to start looking at some of the toxicities between the 3 drugs, because if efficacy is the same, maybe toxicity should distinguish between them. This particular poster looked at the fracture rates that we saw on S0307.

We know that bisphosphonate, in addition to reducing bone recurrences, also reduce bone loss in our breast cancer patient. They reduce fractures. So we wanted to compare the fracture rate between the 3 arms of this study, and at 7.6 years of follow‑up, we showed that the overall fracture rate across all 3 arms was about 8%. So 8% of patients receiving 3 years of high‑dose bisphosphonate had fractures. Statistically, the fracture rate was slightly higher in the clodronate arm, 9.3% versus 7.1% in the zoledronic acid arm.

We were particularly interested in the phenomenon that we call atypical femur fractures. We’ve seen in patients who were on bisphosphonates for long‑term use when we are treating or preventing osteoporosis that, rarely, atypical femur fractures have been reported.

So, ironically, even though bisphosphonates prevent bone breakdown, they also can result in bone that is less spongy because you’re inhibiting the normal balance between bone breakdown and bone formation. You don’t get the scaffolding that occurs. Bones can look denser, but they can be a little bit more brittle. We wanted to see if we saw more of these atypical femur fractures on S0307.

What we saw was, we asked at various intervals when a fracture occurred, “Was it related to trauma or was it atraumatic?” The traumatic fractures were about 2% across the board. The atraumatic fractures were about 6%. Remember, overall fractures were about 8%.

Atraumatic fractures were just ones that were reported to be more spontaneous, not related to a fall or some kind of event. With respect to the atraumatic fractures, they were about 5.2% for zoledronic acid, but 7.2% in the clodronate arm, and that was also statistically significantly different.

Interestingly, we showed where the fractures were occurring. The most common site of fracture was the ankle at 35% of all fractures. The wrist, the leg, the spine, and the arm ranged between 15% and 20% of all fractures. Hip fractures were about 6% of all fractures. Pelvic fractures were about 4%.

We saw a low rate in this trial of hip fractures and leg fractures. Overall, femur fractures were about 1.5%. We didn’t see an increase in atypical femur fractures, but we were unable to sort out within those fractures of a leg exactly where they occurred.

In any event, the fractures of the femur were rare. We didn’t see any significant differences between the arms.

Our conclusion was that fractures at 7.6 years were still moderately high at 8% in patients who’ve got a good 3 years of potent bisphosphonate. We need to do better and understand who is at risk of developing fractures despite getting good bisphosphonate.

We collected serum, we collected tissue in this study, so with bone turnover at the time of enrollment in the study or the starting of bisphosphonate to predict who’s at increased risk, we recommended and reinforced calcium and vitamin D to be given with the bisphosphonates in all women. We hope that they were taking it, but that would be something to encourage.

Our next steps are going to be not just to further investigate the fractures and who’s at the risk for fracture, but also we’re going to be doing lots of studies with the tissue that we’ve collected on who is at risk of developing bone metastasis and who is going to get most benefit from bisphosphonate.

We have a lot of important work to do there with respect to further defining populations of early‑stage patients with breast cancer who benefit from bisphosphonate and those who don’t.