Pharmerit North America
Bisphosphonates have become the standard of care for preventing painful and expensive skeletal complications occurring in breast cancer patients with bone metastases.(1) The approval of newer-generation bisphosphonates and the availability of generic intravenous (IV) pamidronate provide decision makers with increased flexibility in designing rational and cost-effective formularies. However, along with increased flexibility come difficult choices, as the profiles of these agents vary in many respects.
Bisphosphonates are not equally efficacious in the prevention, delay or reduction in the risk of skeletal complications (see Table 1). For instance, pamidronate and zoledronic acid are the only bisphosphonates to statistically significantly reduce the proportion of patients developing new bone complications, the most stringent endpoint now required for approval by the US Food and Drug Administration.(2−6)
Oral clodronate (an older-generation bisphosphonate) was only effective using this endpoint when three separate trials (each showing statistically insignificant results) were pooled together in a meta-analysis.(7) Furthermore, oral ibandronate was not significantly better than placebo in delaying the time to the first new skeletal-related event (SRE).(8)
Interestingly, a direct comparative trial has shown, via multiple-event analysis using the Anderson-Gill method, that zoledronic acid reduces the risk of SRE by an additional 20% relative to pamidronate.(9) In contrast, decreases in the occurrence of SREs and reductions in pain scores have been reported for all agents, albeit with various degrees of success (eg, at least three placebo-controlled trials of pamidronate have demonstrated a pain benefit whereas a comparable benefit for clodronate has been reported in only one trial).(2,3,5,8,10–15) In at least one study a trend towards greater pain reduction has been shown with pamidronate over oral clodronate.(16)
A more recent study also demonstrated that patients with either progressive bone metastases or SREs while receiving oral clodronate or IV pamidronate can experience meaningful pain control benefits when switched to zoledronic acid.(17) Less is known regarding the ultimate impact these agents have on patient’s functional status and quality of life (QoL), as few rigorous studies have assessed these endpoints. When validated instruments have been used, placebo-controlled studies have shown that QoL improves with ibandronate (oral or IV) but not with oral clodronate or pamidronate.(2,3,11,13,14,18)
No placebo-controlled study of zoledronic acid in breast cancer has included a validated QoL instrument. However, in uncontrolled studies zoledronic acid improved or maintained QoL relative to baseline.(19,20)
Although bisphosphonates are generally well tolerated, important differences exist across agents in this respect. Oral administration is associated with high incidence of gastrointestinal (GI) adverse events (especially oral clodronate). IV bisphosphonates are associated with mild to moderate flu-like symptoms following infusion and pamidronate and zoledronic acid can cause mild to moderate renal function impairments.(21,22) However, these impairments are generally manageable, which may explain why severe renal complications are rare. Nevertheless, serum creatinine monitoring is recommended for pamidronate and zoledronic acid and is advised by the manufacturers of ibandronate (depending on the clinical assessment of the individual patient) and oral clodronate.(1,21–24)
Since 2003, cases of osteonecrosis of the jaw – a clinically significant, albeit uncommon complication – have been reported in association with the administration of (typically long-term and/or high-dose IV) amino-bisphosphonates in cancer patients.(25,26) Because the risk of developing osteonecrosis is already significantly elevated in cancer patients relative to the noncancer populations, and because multiple factors, including previous/concomitant chemotherapy, steroid therapy or radiation therapy, as well as trauma, infection and a history of dental procedures, contribute to the risk of developing osteonecrosis, it is unclear whether a causal relationship exists between bisphosphonate use and jaw osteonecrosis.(27)
Although it has been claimed that no case has implicated the non-amino bisphosphonate
clodronate in its worldwide database on spontaneous adverse event reporting, several cases directly or indirectly implicating this agent have been reported.(28–30) In fact, even the summary of product characteristics for Bonefos® (clodronate sodium; Schering) includes information regarding the risk of osteonecrosis of the jaw in patients receiving bisphosphonates.(24)
As we refine our understanding of the incidence, aetiology and pathogenesis of this complication, routine precautionary measures include careful assessment of patients’ dental status, avoidance of invasive dental procedures while on bisphosphonate therapy, maintenance of good dental hygiene and monitoring for the occurrence of osteonecrosis of the jaw.
Finally, more obvious differences exist regarding the administration of these agents. Oral clodronate and ibandronate provide an important convenience advantage to patients who find receiving repeat IV infusions burdensome.(31) However, in a German study, discontinuation rates for oral bisphosphonates in patients with bone metastases were high (36.4% vs 92%) relative to those receiving IV therapy, due in part to high rates of GI side-effects and complex daily regimens (note that oral ibandronate was not included in this study because it was not available in Germany at the time the study was conducted). Differences also exist in terms of duration of administration and related cost (see Table 1).(32−34)
In the above context, decision makers are faced with increasingly difficult trade-offs between considerations of efficacy, safety, convenience, persistence and costs. In an attempt to systematically and quantitatively evaluate these trade-offs, my colleagues and I assessed the relative cost-effectiveness of commonly used bisphosphonates relative to no therapy for the prevention of SREs in breast cancer patients with bone metastases.(35)
This study adopted the UK National Health Service viewpoint. It took into consideration differences in acquisition price, route and cost of administration, SRE and quality of life, efficacy, compliance, and gastrointestinal and renal side-effects. Because efficacy measures differed across agents, two separate analyses were conducted. The primary analysis used the Anderson-Gill multiple-event hazard ratio and compared oral ibandronate, IV ibandronate, zoledronic acid and pamidronate (no data were available on oral clodronate). To allow comparisons with oral clodronate, a secondary analysis relied on skeletal morbidity rate, which has been reported for all bisphosphonates except oral ibandronate.
From these data, we predicted that patients receiving bisphosphonate therapy would experience reduction in SREs over their lifetime (see Table 2) and gains in quality-adjusted life-years (QALYs). Bisphosphonates cut the total costs of SREs and pain care, but drug acquisition and administration costs partially offset these savings. Overall, compared with no therapy, bisphosphonate therapy was cost saving with both zoledronic acid and oral ibandronate but not with pamidronate and IV ibandronate (in the primary analysis), and with zoledronic acid, pamidronate and clodronate but not with IV ibandronate (in the secondary analysis).
Even if not strictly cost-saving, all bisphosphonates were cost-effective vs no therapy (ie, with a cost per QALY gained of ≤ £6,126 (see Table 2).
Our understanding of the economic value of bisphosphonates for managing bone metastases secondary to breast cancer continues to evolve. Current knowledge indicates that as a class, bisphosphonates can broadly be considered cost-effective.
Our analysis suggests that, based on the data and the assumptions we used, zoledronic acid was the most cost-effective therapy.
This analysis also shows that one cannot readily conclude that the least expensive options (ie, generic oral clodronate and IV pamidronate) are de facto the most cost-effective options. Decision makers are therefore encouraged to consider all the relevant aspects of these agents’ profile before selecting bisphosphonates for inclusion in their formularies.
1. J Clin Oncol 2003;21(21):4042-57.
2. N Engl J Med 1996;335(24):1785-91.
3. J Clin Oncol 1999;17(3):846-54.
4. Cancer 2000;88(5):1082-90.
5. J Clin Oncol 2005;23(15):3314-21.
6. J Biopharm Stat 2004;14:5-21.
7. Cochrane Database Syst Rev 2005;3.
8. Br J Cancer 2004;90(6):1133-7.
9. Cancer 2003;98(8):1735-44.
10. Bull Cancer 2001;88(7):701-7.
11. J Intern Med 1999;246: 67-74.
12. Support Care Cancer 1998;6:139-43.
13. J Clin Oncol 1998;16:2038-44.
14. Pain 2004;111(3):306-12.
15. Ann Oncol 2003;14(9):1399-405.
16. Proc Ann Meet ASCO 1999:Abstract 488.
17. J Clin Oncol 2006;24(30):4895-900.
18. Eur J Cancer 2004;40(11):1704-12.
19. Br J Cancer 2005;92(10):1869-76.
20. Oncologist 2006;11(7):841-8.
21. Ann Oncol 2005;16:687-95.
22. Oncologist 2004;9 (suppl 4):28-37.
23. Roche. Summary of product characteristics: Bondronat®. 2007.
24. Schering. Summary of product characteristics: Bonefos®. 2007.
25. Cancer Invest 2004;24:110-2.
26. Ann Intern Med 2006;144:753-61.
27. J Oral Maxillofac Surg 2003;61:1238-9.
28. Jones GR, et al. Paper presented at ASCO Annual Meeting, 2005. Abstract 799.
29. Mund Kiefer Gesichtschir 2005;9(4):239-45.
30. Deutsches Ärzteblatt 2006;103(46):3078,3080.
31. J Clin Oncol 2005;23 (S16);1:558.
32. ASCO Ann Meet Procs 2006;1;24;18S:18623.
33. Support Care Cancer 2001;9(7):545-51.
34. Support Care Cancer 2004;12(6):463-6.
35. Ann Oncol 2006;17:1072-82.
36. J Clin Oncol 1993;11:59-65.