Answer: Bone metastasis is an enormous problem. It's been estimated that 400,000 new patients in the United States will be diagnosed with bone metastasis annually.² Patients with metastatic breast or prostate cancer are most likely to develop bone metastasis; as many as two-thirds to three-fourths of these patients will be diagnosed with bone metastasis. About one-third of patients with lung and renal cell cancers will have bone metastasis. It's been estimated that of the patients with bone metastasis in a 2-year period, approximately half will have a skeletal-related event (Figure 1).³

The clinical and economic impact of metastatic bone disease is substantial. Patients who develop bone metastasis experience many complications: They have severe pain that frequently requires narcotics and radiation therapy. They are prone to develop fractures that can be debilitating and disabling. They may be prone to spinal cord compression due to metastasis in the spine. Furthermore, patients with bone metastases may need surgery to treat or prevent a fracture. That is what we need to prevent.

Pamidronate was the first drug approved in the United States for delaying skeletal-related events in patients with breast cancer or multiple myeloma who had bone metastasis. It was the standard of care until 2001, when zoledronic acid was approved to treat hypercalcemia and to delay or prevent skeletal-related events in 2002.^4-8 Pamidronate decreased the percentage of patients with a skeletal event by about 20%. Zoledronic acid was shown to be about 20% more effective than pamidronate. Zoledronic acid was the standard of care until this past year, when results of head-to-head trials with a new agent, denosumab, became available.^9.10 Denosumab was studied in patients with breast, prostate, and other solid tumors, as well as myeloma, and was shown to be 20% more effective than zoledronic acid in delaying skeletal-related events.

Denosumab is a fully human monoclonal antibody to a molecule called RANK ligand. RANK ligand is the molecule that has been shown to turn on osteoclasts, which is the cell that destroys bone; so, it's a specific osteoclast inhibitor. At this point, however, denosumab is not approved for the treatment of bone metastasis in patients with multiple myeloma. Myeloma was a subset of the solid tumor study; so, there was not enough data to show whether denosumab was effective. A large myeloma-only trial of denosumab versus zoledronic acid is underway.

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Answer: We don't have a definitive answer to the question of how long to continue bone-targeted therapy in patients with good life expectancy. The studies of zoledronic acid were conducted over a period of 2 years, and treatment was beneficial over that period. The median time with denosumab in clinical trials was about 41 months, or about 3 1/2 years. Many of us continue zoledronic acid beyond 2 years, because the risk of skeletal-related events does not abate in most patients with cancer. However, there is a lot of debate within the community as to whether to continue with monthly treatment after 2 years or move to treatment every 3 months.

A couple of studies are looking at that question. One is the OPTIMIZE trial in the United States, as well as worldwide.¹¹ The other one was a study that was planned in England, but I'm told that it's been abandoned, called the BISMARK trial.¹²

Looking at the curves for multiple events—not just the first skeletal-related event, but events over time—the benefit of denosumab over zoledronic acid is greater in the second year and beyond (Figure 2).¹³ Even though we don't have really definitive evidence, my opinion is that if a patient is at risk for continuing skeletal events, if the disease is active, if they had one skeletal event, I would continue each drug beyond 2 years, being aware that there is an incidence of osteonecrosis of the jaw that's related to bone-targeted therapies over time. It’s important to remember that the risk of a devastating skeletal-related event may be as high as 50%, versus the 1.5% risk of osteonecrosis of the jaw. In my mind, the benefit outweighs this associated risk.

Now this may not be the case for patients with multiple myeloma. With newer and better therapies for myeloma, patients are achieving complete responses in which bone disease becomes totally inactive. I think the feeling in the myeloma community is that you might be able to stop the bone-directed therapy after a period of 2 or 3 years, especially if the patient has had a good response on x-ray.

Fortunately, our patients are living longer; so, this question will keep coming up more and more in future years, as our patients live beyond 2 years. But, my feeling is if they are doing well and not having any side effects, if they are not having skeletal events, I would continue the therapy indefinitely.

What about the patient with a short life expectancy, such as the patient with lung cancer who presents with widespread metastatic disease? Even then, I think it's terribly important to continue the bone-directed therapy as long as they live. I had a patient who was referred to me with a diagnosis of metastatic bladder cancer, who had widespread disease including bony metastasis. I referred him to a tertiary cancer center, where he was placed on a new targeted experimental drug. About 4 months later, I saw him in the emergency department here. He had a fractured pelvis. They didn't put him on bone-targeted therapy, even though he had known bone metastasis. He lived 3 more months in a wheelchair and in great pain before he died. The lesson here is that we can avoid this pain and misery in our patients—even those with advanced disease. It's just one example of how important bone treatment is to prevent skeletal events and keep patients as functional as possible for as long as possible.

There are safety concerns with the use of bone-targeted therapy. In initial clinical trials of denosumab, there were questions about the increased risk of infection as well as long-term cardiac safety. Finally, there was a concern about the risk of second malignancies. So far, in a combined analysis of 5,600 patients in three metastatic disease studies with denosumab or zoledronic acid, no significant increases in second cancers and no detrimental effects on survival have been observed.¹⁴ These data will be presented at the upcoming European Multidisciplinary Cancer Congress in September 2011 in Stockholm, Sweden.

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Answer: We’ve made good strides in the past 20 years in reducing the risk of skeletal-related events in patients with metastatic bone disease. There are a number of new bone potential therapies out there. One focus of new research is inhibiting a protein called dickkopf-1, or DKK-1, that is overexpressed in myeloma cells. Agents that block DKK-1 could restore osteoblast function and counteract the increased osteoclastogenesis observed in multiple myeloma. BHQ880, an IgG antibody, is the first fully human anti-DKK-1 neutralizing antibody. It seems to promote bone formation and, thus, inhibits tumor-induced osteolytic disease in preclinical studies.¹⁵ Clinical trials of this agent in combination with zoledronic acid and in patients with untreated multiple myeloma are getting underway.^15,16

AMG 785/CDP7851 is another humanized monoclonal antibody that binds to and inhibits sclerostin, a protein secreted by bone cells that inhibits bone formation. This agent can potentially turn on osteoblasts to heal destructive lesions in bone. Studies are just getting underway in patients with low bone density.

But, prevention of metastatic disease may be the most exciting development in bone health. Results of the Austrian ABCSG-12 trial demonstrated that zoledronic acid could prevent metastatic bone disease in about one-third of women with early breast cancer.¹⁸ This study included premenopausal women in whom menopause had been induced. Results of the AZURE trial failed to reproduce these findings.¹⁹ AZURE included 3,300 pre- and postmenopausal patients and compared the use of zoledronic acid in addition to chemotherapy or hormone therapy versus placebo, in addition to chemotherapy or hormone therapy. Despite great hopes for this study, it missed its primary endpoint in the total patient population of preventing distant metastasis affecting survival. Only a subset of patients seemed to benefit, and that was women who were more than 5 years postmenopausal.

At the 2011 American Urologic Association Meeting, we saw results of a large, randomized clinical trial demonstrating that targeting the bone microenvironment with denosumab therapy prevented bone metastasis in men with prostate cancer.²⁰ In this study, 1,412 patients with nonmetastatic, castration-resistant prostate cancer were randomized to denosumab or placebo. These men had a high risk for bone metastasis, as defined by a PSA level ≥8 ng/mL within 3 months of randomization or a PSA doubling time of ≤10 months. The primary endpoint was bone metastasis-free survival. Treatment with denosumab increased bone metastases-free survival by 4 months compared with placebo, although progression-free and overall survival were not increased.

We're going to see a lot more data in the next 2 to 3 years. There's a study of zoledronic acid in patients with prostate cancer looking at prevention of metastatic disease.²¹ There’s a study of zoledronic acid in patients with lung cancer to prevent metastatic disease.²² And, just starting up now, is the study of denosumab for delaying or preventing metastatic bone disease patients in with early stage breast cancer.²³

So, there's a lot of activity with these bone treatments—not only to treat or prevent skeletal events in metastatic disease, but as prevention of metastatic disease.

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