Bisphosphonates: Game Changers?

Table: Clinical Settings in Which Use of Bone-Modifying Agents Is Appropriate

Bone was once considered a destination for metastases. Now it appears to be a critical part of the process. For years I taught that breast cancer could metastasize to almost any organ in the body, in contrast to cancers such as sarcoma that have a primary destination-eg, the lungs-where metastases almost invariably first appear. It is commonly stated that 70% to 80% of patients with breast cancer metastases will eventually have tumor in the bone, but the bone is a very large organ, and small metastases can be easily overlooked unless bone is decalcified. It is plausible that all-or almost all-breast cancers first metastasize to the bone and from there to other parts of the body.

Circulating tumor cells, often released from breast cancers before they can be detected within breast, have a predilection for bone and lodge there as disseminated tumor cells (DTCs).[1] Only a small percentage of these DTCs become overt tumor metastases; they have been found in metastasis-free patients as long as 22 years after diagnosis. However, bone may profoundly affect the behavior of DTCs and determine which will progress to clinically important metastases-even determining which organs they will eventually populate. Breast cancer cells in bone marrow secrete factors-such as parathyroid hormone–related peptide, prostaglandin E, tumor necrosis factor, interleukins, and 1,25-dihydroxyvitamin D₃-that stimulate osteoblasts to release receptor activator of nuclear factor kappa-B ligand (RANKL), which in turn activates osteoclasts. The activated osteoclasts induce bone resorption and release tumor growth factors (including platelet-derived growth factor, insulin-like growth factor, and fibroblast growth factor, bone morphogenetic proteins, and extracellular Ca²⁺). Thus, a vicious cycle is set up in which tumor cells stimulate bone resorption, which in turn stimulates further tumor cell growth.[2] This chain of interactions may be key to determining whether breast cancer DTCs thrive and metastasize further. Agents that break this cycle, such as bisphosphonates (which cause osteoclast apoptosis) or the monoclonal antibody denosumab (which blocks binding of RANKL to RANK on osteoclasts), have the potential to profoundly affect the entire metastatic process, not just the growth of bone metastases.

Thus far, however, we have not reproducibly demonstrated in clinical trials that these agents have broader effects.[3] In patients with known bone metastases, the addition of these agents to conventional endocrine therapy or chemotherapy reduces the incidence or delays the onset of fractures, bone pain, and other skeletal-related events, but they do not improve survival.[3] Nor do these agents appear to benefit patients who do not already have bone metastases. (However, the number of patients in the relevant trials is small.)

A meta-analysis has shown that bisphosphonates administered with adjuvant endocrine therapy or chemotherapy significantly reduced bone recurrences and improved disease-free, breast cancer–specific, and overall survival.[3] However, in this setting, bisphosphonates had no effect on distant recurrence at sites other than bone, thus providing no support for the hypothesis that these agents may more broadly interrupt the metastatic process. (This meta-analysis was presented at the San Antonio Breast Cancer Symposium [SABCS] in 2013 but has not yet been published. The SABCS presentation did not provide data on the contributions of individual trials or on possible heterogeneity among studies; thus for now, the results should be accepted cautiously.)

Bisphosphonates are generally considered cost-effective, but analyses comparing a bisphosphonate with no bone agent have used costs in countries other than the United States. Blanchette and Pritchard, in their review in this issue of ONCOLOGY,[3] quote Canadian prices for these drugs, but this may seriously underestimate costs in the United States, which are 2.5- to 3-fold greater. In an American cost-effectiveness analysis, the cost used for a month of zoledronic acid was $965, and that for denosumab, $1,673.[4] There is considerable variability in the results of cost-effectiveness studies and contention about the proper way to conduct these analyses.[5,6] This may be due to the fact that all the studies have been sponsored by one of the two manufacturers of these products![5] Since it is not clear which patients might benefit from using these agents adjuvantly, all patients (or at a minimum, postmenopausal women with a risk of recurrence greater than 10% to 20%) might receive treatment. At the prices used in the Xie et al analysis, the cost to the medical system is likely to be quite high and cost-effectiveness low. Blanchette and Pritchard note that the use of generic zoledronic acid on an every-12-weeks schedule will lower costs substantially, but cost-effectiveness in the adjuvant setting should be determined before recommending bisphosphonates as adjuvant treatment. In addition, serious long-term toxicities, even though infrequent-eg, osteonecrosis of the jaw and subtrochanteric and femoral shaft fractures-will be more important considerations in the adjuvant setting, where the drugs are likely to be given for longer durations and the absolute number of patients who benefit is smaller.

For the present, then, bisphosphonates and denosumab should be used only in the setting of advanced breast cancer with bone metastases (Table).

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Redig AJ, McAllister SS. Breast cancer as a systemic disease: a view of metastasis. J Intern Med. 2013;274:113-26.

2. Green J, Clezardin P. The molecular basis of bisphosphonate activity: a preclinical perspective. Sem Oncol. 2010;37(suppl 1):S3-11.

3. Blanchette PS, Pritchard KI. The role of bisphosphonates in early and advanced stage breast cancer: Have we finally optimized care? Oncology (Williston Park). 2015;29:16,42.

4. Xie J, Diener M, Sorg R, et al. Cost-effectiveness of denosumab compared with zoledronic acid in patients with breast cancer and bone metastases. Clin Breast Cancer. 2012;12:247-58.

5. Koo K, Lam K, Mittmann N, et al. Comparing cost-effectiveness analyses of denosumab versus zoledronic acid for the treatment of bone metastases. Support Care Cancer. 2013;21:1785-91.

6. Rader M, Goessl C, Cong Z. Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases. J Manag Care Pharm. 2012;18:74-5; author reply 75-6.