In patients with solid tumors, including those with advanced breast and prostate cancer, metastasis to bone is common.1,2 Bone metastases undermine the structural integrity of bone by upsetting the balance between osteoblast (bone rebuilding) and osteoclast (bone breakdown) activity.
Additionally, growth factors released during upregulated osteoclast activity further contribute to tumor growth in what is termed a “vicious cycle.”3 Skeletal-related events (SREs) are complications associated with bone metastases and may include fractures, spinal cord compression, bone pain, and frequently hypercalcemia.1,3,4
Frequency of SREs Occurring with Solid Tumors
For patients with bone metastases, SREs are distressingly common. Approximately 75% of women with advanced breast cancer will develop bone metastases and of that group, most will develop at least one SRE within 24 months of follow-up.1,5 More than 80% of men with castration-resistant prostate cancer develop bone metastases; about half of them develop SREs.6,7
A recent analysis of health databases in the United States found the cumulative incidence of SREs at 24 months to be 54.2% among patients with breast cancer, 41.9% among patients with prostate cancer, and 47.7% among those with lung cancer (Table 1).5
Table 1. Cumulative Incidence of SREs in US Health Databases5
|Cancer Type||6 months||12 months
|Abbreviations: SRE, skeletal-related event.|
Options in the Management of SREs
SREs have a deleterious effect on patients. They are associated with intractable bone pain, fractures, bladder and bowel disturbances, anxiety, depression, and decreased survival. SREs can negatively impact patients’ overall quality of life and often lead to decreased mobility, loss of independence, and higher medical costs.1,3,7
The prevention or delay of SRE development is an integrated part of caring for patients with bone metastases. At present, denosumab and the bisphosphonates pamidronate (Aredia®) and zoledronic acid (Zometa®) are the treatment options approved in the United States for supportive care of patients at risk for SREs related to solid tumors.
Among the bisphosphonates, pamidronate and zoledronic acid are indicated for treatment of bone metastases in all solid tumors, as is the case for zoledronic acid; or for bone metastases associated specifically with breast cancer, as with pamidronate. Both are administered intravenously on a 3-to-4 week schedule.3
As a class, bisphosphonates chemically bind to the mineral bone matrix and inhibit osteoclast function and viability through inhibition of the mevalonate pathway.3 These well-established drugs have been shown to significantly reduce SREs and are considered part of the standard of care for patients with solid tumor bone metastases.3,7,8
In patients with breast cancer, bisphosphonate use in general appears to improve overall survival (but not disease-free survival) and to have no effect on SREs in women without bone metastases.1,9 In a large trial comparing zoledronic acid and pamidronate, zoledronic acid reduced SRE risk by 20% over pamidronate. The effect was greater in women treated with hormonal therapy compared with those who received chemotherapy.1
Denosumab, on the other hand, is a monoclonal antibody specifically designed to inhibit growth-stimulating RANK (a protein that acts as the primary signal for bone removal) from binding with its ligand (RANKL) on osteoclasts, thus blocking osteoclast formation and signaling, thereby inhibiting osteoclast-mediated bone resorption.6 Denosumab is administered via subcutaneous injection every 4 weeks. Studied for treatment of bone metastases, denosumab is indicated for prevention of SREs in patients with bone metastases from solid tumors.
In a systematic review of comparative trials, denosumab was superior to zoledronic acid in delaying SREs in patients with breast or prostate cancer who had bone metastases (Table 2).1,3,4 In a review of treatments for bone metastases related to non-small cell lung cancer (NSCLC), the difference between denosumab and zoledronic acid was not significant.4
Table 2. Time to First On-Study SRE: Hazard Ratio (HR) for Denosumab vs. Zoledronic Acid4
|Cancer Type||Median Time||HR (95% CI)
|Breast||Not reached vs. 26.4 months||0.82 (0.71-0.95)||< 0.01|
|Prostate||20.7 vs 17.1 months||0.82 (0.71-0.95)||0.0002|
Overall survival was similar in groups treated with denosumab or zoledronic acid. Denosumab also produces clinically meaningful improvements in pain and quality-of-life measures.1,4
Safety concerns with bisphosphonates include nephrotoxicity and acute-phase reactions; the latter are reported in 15% to 27% of patients, but generally are manageable and rarely lead to discontinuation. While denosumab has no renal effects, it has been associated with mild and transient hypocalcemia in up to 5.5% of patients; this adverse effect occurs more commonly in patients with renal impairment. Although no related safety signals have been noted in denosumab clinical trials, the potential for non-bone effects, including increased infection risk, must be considered.1,3
Use of either bisphosphonates or denosumab is associated with a risk for osteonecrosis of the jaw (ONJ), a rare outcome that has been reported in about 1% to 2% of patients being treated for bone metastases. In a head-to-head trial, ONJ was seen in 2% of patients treated with denosumab versus 1.4% of those treated with zoledronic acid. Other factors that may increase the risk for ONJ development include high drug doses, poor dental hygiene, and concomitant chemotherapy.1,3
Bone-modifying agents have beneficial effects, supporting their use in the management SREs. American Society of Clinical Oncology (ASCO) guidelines for patients with breast cancer who have bone metastases recommend use of bone-modifying agents as supportive care.7
However, 15-year study of US health systems found that routine use of bisphosphonates to treat bone metastases was relatively low in patients with lung (14.8%) or prostate cancer (20.2%), compared with breast cancer (55.8%), where use was still suboptimal.5 Some of the available data indicates that denosumab may be more effective than zoledronic acid in key outcomes related to SREs; however, at present, the choice between zoledronic acid and denosumab rests largely on factors such as patients’ renal status, side effect burden, and cost.
1. Clemons M, Gelman KA, Pritchard KI, Paterson AHG. Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases: state of the art. Curr Oncol. 2012;19:259-268.
2. Smith MR, Saad F, Coleman R, et al. Denosumab and bone metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomized, placebo-controlled trial. Lancet. 2012;379(9810):39-46.
3. Talreja DB. Importance of anti-resorptive therapies for patients with bone metastases from solid tumors. Cancer Manag Res. 2012;4:287-297.
4. Ford J, Cummins E, Sharma P, et al. Systematic review of the clinical effectiveness and cost-effectiveness, and economic evaluation, of denosumab for the treatment of bone metastases from solid tumors. Health Technol Assess. 2012;17(29).
5. Oster G, Lamerato L, Glass AG, et al. Natural history of skeletal-related event in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems. Support Care Cancer. 2013;July 25[e pub ahead of print].
6. Paller CJ, Carducci MA, Philips GK. Management of bone metastases in refractory prostate cancer—role of denosumab. Clin Intervent Aging. 2012;7:363-372.
7. So A, Chin J, Fleshner N, Saad F. Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: incorporating new agents into clinical practice. Can Urol Assoc J. 2012;6(6):465-470.
8. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncologists Clinical Practice Guideline Update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29(9):1221-1227.
9. Valachis A, Polyzos NP, Coleman RE, et al. Adjuvant therapy with zoledronic acid in patients with breast cancer: a systematic review and meta-analysis. Oncologist. 2012;18(4):353-361.