Commentary (Hillner): Bisphosphonates in the Prevention and Treatment of Bone Metastases

In this issue, Ramaswamy and Shapiro provide another excellent review of the recent literature on the role of bisphosphonates in the management of bone metastases from breast cancer and selected other cancers. Bisphosphonates and bone metastases have been the subject of numerous similar publications. In a quick Medline search of papers published since January 2002, I found 12 different review articles including a similar manuscript in this journal.[1]

Worldwide to date, four bisphosphonates have been approved for use in cancer: clodronate, ibandronate, pamidronate, and zoledronic acid (Zometa). The only oral bisphosphonate with any known activity in cancer is clodronate, which is used extensively by physicians in Canada and Western Europe but has not been approved for use in the United States. Only intravenous pamidronate or zoledronic acid have received US Food and Drug Administration approval.

Given their use as the mainstay of therapy for cancer-related hypercalcemia and bone metastases (as well as their price), bisphosphonates are major generators of revenue for their manufacturers and, conversely, of costs for cancer centers. In 2001, just prior to the availability of a generic form, worldwide sales of pamidronate were $756 million. In the first quarter of 2003 alone, sales of zoledronic acid totalled $207 million.[2]

Conflict of Interest

The typical review article of any subject generally concludes that the future is bright for the subject of interest, but areas for improvement and future research remain. Ramaswamy and Shapiro have highlighted a common set of unanswered questions about the use of bisphosphonates in cancer. In this commentary, I wish to focus on my concerns about these questions in metastatic breast cancer. Most of these concerns also apply to multiple myeloma. Specifically, I foresee that, in the near term, minimal new data will be generated to address these key clinical issues. This failure to refine our knowledge base on the use of these agents should be a cause of concern to oncologists and should make the oncology community wonder about who is setting the scientific agenda.

The primary source of my concern is the absence, since 2000, of any new major randomized controlled trials of currently approved bisphosphonates in metastatic breast cancer. In addition, I suspect that there are few prospective data or phase II data on the approved agents. All but one of the key questions (listed below) entail more targeted use or shorter duration of bisphosphonate therapy. Obviously, the manufacturers of currently approved bisphosphonates would not benefit from such investigations. My overarching goal is to highlight the conflict between the practitioner's evidence-based needs and the pharmaceutical industry's reluctance to address these questions. Unfortunately, interest in governmentsponsored cancer research groups that are independent of direct pharmaceutical support appears to be low.

Unanswered Questions

Key questions include:

(1) What is the relative efficacy of oral clodronate vs either intravenous pamidronate or zoledronic acid? Although this question has been identified for many years including in the initial 2000 American Society of Clinical Oncology guidelines, to my knowledge no country or multicenter research group has initiated this comparison.

(2) Could women with metastatic breast cancer but without known osteolytic lesions benefit from bisphosphonates? This would be an expansion of the current approved indications. Such a trial could use high levels of bone resorption (eg, > 100 nmol/mmol of urine N-telopeptide) as its indicator for high risk of skeletal-related complications.

(3) What is the efficacy of alternative doses or schedules?

(4) Is the bisphosphonate working? Current approaches of indefinite therapy are scientifically crude, expensive, and inconvenient. Using serum and urine makers of bone resorption as intermediate end points to guide therapy are intuitively attractive, convenient, and likely to be cost saving. Prospective studies that include discontinuing bisphosphonates in patients who fail to suppress their biomarkers are needed.

(5) When should bisphosphonate therapy be stopped? The benefit of continuing bisphosphonates after a skeletal-related event has never been addressed.

(6) How should bisphosphonates be integrated into other therapies for bone pain, especially irradiation? Are bisphosphonates needed at all after radiation therapy? (Is the horse already out of the barn?)

Conclusions

While scientific attention should continue to focus on other promising compounds and molecules to prevent or reduce bone complications, further immediate attention is needed to address issues surrounding existing agents. In contrast to the hundreds of studies examining different doses, schedules, and combinations of common cytotoxic chemotherapy agents, it appears that our knowledge of bisphosphonates in current approved indications will not advance in this decade unless the oncologist becomes more proactive.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Blum RH, Novetsky D, Shasha D, et al:The multidisciplinary approach to bone metastases.Oncology 17:845-857, 2003.

2.

Novartis: Investor relations release.Available at www.novartis.com/downloads/fresco07feb02fyr_e.pdf. Accessed July 31,2003.

3.

Novartis quarterly results. Available atwww.novartis.com/downloads/q1_2003_e.pdf.Accessed July 31, 2003.