Time to Update "Routine, Repeated" Use of Bone Metastasis Drugs

Mark G. Kris, MD


May 02, 2019

This transcript has been edited for clarity.

Hello. It's Mark Kris from Memorial Sloan Kettering, talking today about the treatment of bone metastases, particularly the use of zoledronic acid and denosumab in preventing problems brought on by bone metastases.

My practice group had a lecture from one of our endocrinology colleagues a few days ago, where we reviewed bone issues in the setting of our patients with lung cancers. Clearly, these drugs are very important in the treatment of osteoporosis and are a mark of real advancement in care. There is no issue there, and I am no expert in the treatment of osteoporosis. I am lucky to have really great endocrinologists I work with who can advise me and handle those issues.

I asked my endocrinologist about the data behind how effective these drugs are for the treatment of bone metastasis, and he gave me two papers. One paper from 2003 compared zoledronic acid with placebo,[1] and the second paper from 2011 compared denosumab with zoledronic acid.[2]

I spent a little time going through those papers, and I must say I was a little disappointed by the magnitude of benefit that we saw. For the zoledronic acid paper, there was a 9% decrease in the percentage of people with skeletal events. The best arm had 44 events, and the placebo arm had 35 events.

In the denosumab experience, they did not report—at least that I could find—the number of skeletal events that were prevented. They talked about the time to the first skeletal event, and they found a 5-month difference, from 16 to 21 months, in the time to the first skeletal event. The denosumab versus zoledronic acid trial was a noninferiority trial, and it did not show any substantial improvement.

I should also say that neither trial showed any clear improvement in pain, improvement in quality of life, or in harder endpoints of overall or disease-free survival.

Taking all that into account, you have to wonder what we are gaining through the use of repeated doses of zoledronic acid or denosumab. Again, I'm not talking about the treatment of osteoporosis—different disease, different set of issues.

I think that we have to look at these papers again, as I did. First, I think the data are hard to interpret. One paper talked about skeletal events—frankly, a term I had not heard of until that paper. The second compared time with a skeletal event, and we really don't have a clear apples-to-apples comparison there. Again, I will mention that the denosumab versus zoledronic acid study was designed as a noninferiority trial, and that's exactly what it was.

The second thing is that I think there is little disagreement in the treatment of lung cancers—that things have changed substantially since these papers were published. Please remember that the zoledronic acid paper was published in 2003, so these patients were treated more than 16 years ago. The denosumab paper was published in 2011, and those patients actually started treatment in 2003.

I think so much has changed since then, specifically regarding two things. First, consider the improvements in systemic therapy. Remember, there was no alectinib, osimertinib, or up-front treatment with checkpoint inhibitors and chemotherapy for all histologies. I think all of us agree that that has changed the landscape and really brings into question the degree of benefit brought on by these agents.

The second thing is this movement with oligoprogression and oligometastases. Nowadays, when we have a small number of bone metastases, they are treated either up front as part of an oligometastasis strategy or at the time of progression in an oligoprogression strategy.

I think the advancements in our systemic therapies and the ability of focused radiation to effectively control oligoprogression and oligometastases has really changed the landscape here. I would question the one-size-fits-all use of either zoledronic acid or denosumab in patients who have a skeletal metastasis.

In short, what to do? I would try to individualize treatment from patient to patient and carefully look at prognosis. I would carefully look at the ability of our systemic therapies to help those patients, and I would very quickly use the strategies of treating oligometastases or oligoprogression.

I think those strategies are probably better than the routine, repeated use of either of these agents to prevent skeletal-related events.

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