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Overview of Bone Metastases and Bisphosphonate Treatment

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A query was recently raised about the use of denosumab for the treatment of bony metastases from lung cancer. We’ll cover what is known about that newer agent for bone metastases, but first let’s set the stage with a general discussion of the topic and the management options we’ve generally pursued over the past few years.

To put things into context, when a cancer spreads to bones, the chief concerns are that the tumors can cause pain, as well as a risk of fracture in those bones. Depending on the location of the bones involved, fractures can have consequences beyond just the pain. For example, a break in a hip bone may require surgery in order to help a patient maintain the ability to walk, etc.

With lung cancer, for large bone metastases that are already symptomatic or at risk of breaking, generally the first treatment of choice is radiation to that area. This can help to relieve pain, and to strengthen the bone and decrease the risk of the bone breaking. If a bone in a weight-bearing area (the upper arms and legs in particular) has broken or is at too high of a risk for breaking, surgery may be required to stabilize that region.

Chemotherapy can also help to decrease the symptoms from bone metastases by treating the cancer cells directly, while at the same time treating cancer cells wherever else they may be located in the body.

Questions have been raised however about what to do with cancers that have spread to many different bone locations, or who have small bone metastases that do not require radiation. These patients may be at risk for pain or fracture in the future, but not necessarily immediately. Is there anything that can be done to decrease that risk of developing pain? Can the risk of fracture (which by the nature of a risk, may or may not happen), be reduced or delayed?

Such an event (pain or bone fracture) in the medical literature is termed a skeletal-related event, or SRE for short.

One of the ways that tumors cause bone pain or breakage is by stimulating osteoclasts. Osteoclasts are normal cells in the bones that are in charge of “remodeling” and reabsorbing excess bone formation that occurs as part of the basic housekeeping of bone strength. Cancers can release “osteoclast-activating factors” (OAFs) that essentially turn on perpetual osteoclast function, thereby thinning and weakening the bones.

Bisphosphonate drugs are agents that inhibit osteoclasts. Used initially to treat high blood calcium levels due to cancer, they then were found to decrease the incidence of SREs. Pamidronate (Aredia) was the first of these agents to show a decrease in SREs compared with placebo in women who were receiving chemotherapy for metastatic breast cancer.

The downsides of this medication include the requirements of a 2-hour infusion once a month, risk of low blood calcium levels, stress on the kidneys, nausea or vomiting, and joint or body aches. Despite this, quality of life was better than for patients who did not receive pamidronate.

The next agent to gain widespread usage was Zometa (zoledronic acid, also sometime referred to as zoledronate). This is a similar bisphosphonate, but requires a shorter infusion time (a few minutes). In a randomized trial involving patients with lung cancer or other solid tumors (this was the first bisphosphonate study that particularly included lung cancer) who were also receiving chemotherapy, Zometa decreased SREs. Of 773 patients enrolled, half had NSCLC. In this study, 38% of patients receiving Zometa developed an SRE, compared with 47% of patients receiving placebo. The most common side effects were bony pain from the infusion, as well as nausea and vomiting.

Of note, an important side effect of the bisphosphonates (thereby both pamidronate and Zometa) is a condition called osteonecrosis of the jaw (ONJ). This is a rare but devastating event where a part of the jawbone essentially dies, which can lead to chronic pain, nonhealing wounds, or risk of infection in the area which can be quite detrimental to quality of life. While doctors cannot reliably predict those patients who will develop ONJ, the risk is higher in patients who have bad teeth, chronic mouth infections, or who may require dental work while receiving the drug. The risk also increases the longer a person has been on the drug.

Although quality of life can be improved and the risk of SREs can be decreased, the potential benefits must be weighed against the side effects and risks for every individual patient. These drugs are definitely not for everyone, and particularly as the goal of treatment is reduction of SREs and not for improvement in survival, use of the medication has not been universally adopted as a rule for all patients with tumors spread to the bone.

Recently though, the New England Journal of Medicine published a randomized trial of patients with surgically-removed breast cancer who received endocrine therapy with or without Zometa. For the 1803 patients enrolled in this study, the addition of Zometa (given every 6 months for 3 years) improved disease-free survival (the time until cancer recurs) by 3.2%.

It is important to keep in mind that this was a trial of patients with resected breast cancer, and the results cannot be extrapolated to other cancers. These results help to support the rationale for further study in other tumor types and ongoing research and raises the question of whether bisphosphonates may improve outcomes beyond the risk of skeletal complications.

While the bisphosphonates have been the primary systemic treatment option specifically targeting bone metastases in cancer, a new agent called denosumab with a somewhat different mechanism has emerged as an interesting approach, and we’ll focus on that in my next post.

4 Responses to Overview of Bone Metastases and Bisphosphonate Treatment

  • mo wanchuk says:

    Dr. Sanborn:

    Thanks for an informative article. I have taken zometa for a year now without any side-effects or SRE’s. My doctor wants me to continue taking it indefinitely.

  • Dr Sanborn says:

    Hello Mo–

    Thank you. I am glad that it is working for you. It is always good to hear about things going well!

  • Catharine says:

    Dr. Sanborn –

    Thank you. It’s good to know about the treatments for bone mets. I’m also taking zometa (like mo wanchuk) and have been since February, so guess it’s too early to tell much about the effects. It’s encouraging to read mo’s post because the zometa seems to be working for mo. I take it for a “lytic lesion” in my right sacrum, per the oncologist. Zometa forms part of my chemotherapy “triad” along with taxol and carboplatin. I’ll have my third session (of six planned sessions) late this week. Am looking forward to your post on denosumab.


  • Pingback: GRACE :: Cancer 101» Blog Archive » Update on Denosumab for Prevention of SREs

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