Ibandronic acid (Bondronat®) is a third generation bisphosphonate, which acts mainly by inhibiting osteoclast activity. Both the intravenous and the oral formulation are indicated for prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases, and for the treatment of tumourinduced hypercalcaemia with or without metastases. This review focuses on the evidence for the use of ibandronic acid in patients with breast cancer and bone metastases, with a brief summary of evidence for its use in multiple myeloma and prostate cancer (both unlicensed indications).

Three Phase III trials of ibandronic acid in the treatment of women (aged ≥18 years) with breast cancer and bone metastases have been fully published to date; two involved oral ibandronate and one the intravenous formulation. In summary the findings were as follows:

Oral (2 studies): The licence for oral ibandronic acid is based on pooled data from two multicentre, placebo-controlled, double-blind phase III trials, where patients were randomised to placebo (n= 277) or oral ibandronic acid 50mg once daily (n=287) for up to 96 weeks. The primary endpoint was the skeletal morbidity period rate (SMPR; number of 12-week periods during which new skeletal complications - vertebral fractures, pathological non-vertebral fractures, radiotherapy or surgery for bone complications -occurred). This was lower with ibandronic acid (0.99 vs. 1.15, p= 0.004). When the individual components of the primary endpoint were analysed separately, this improvement was found to be primarily due to a reduction in bone events requiring radiotherapy (p<0.001) or surgery (p=0.037) (both secondary endpoints). Ibandronic acid was not found to reduce the incidence of either vertebral or non-vertebral fractures (secondary endpoints).

IV (one study): 466 patients were randomised to receive 2mg bolus ibandronic acid (n=154) 6mg by infusion (n=154), or placebo (n=158) every 3-4 weeks (maximum of 24 treatments). The primary end point was the SMPR; this was lower in the 6mg ibandronic acid group versus placebo (1.19 versus 1.48 periods with events per patient year; p = 0.004). Ibandronic acid 2mg was not statistically significantly different to placebo.

There has been only one direct comparison published to date; this compared oral ibandronate (50mg/day; n=137) and intravenous zoledronic acid (4mg every four weeks; n=138) for up to 12 weeks in women with breast cancer and at least one bone lesion. The primary endpoint was however a surrogate - mean percentage change in serum levels of the bone resorption marker cross-linked C-terminal telopeptide of type I collagen (S-CTX). The pre-defined equivalence criteria were met but this does not look at clinical outcomes.

A Cochrane review found that use of ibandronic acid in women with advanced breast cancer and clinically evident metastases reduced the risk of developing a skeletal event by 14% (RR 0.86; 95% CI 0.73-1.02) for 50mg oral ibandronic acid (p=0.08) and 18% (RR 0.82; 95% CI 0.67-1.00) for 6mg IV ibandronic acid (p=0.04). The authors concluded that oral ibandronate (in addition to chemotherapy or hormone therapy) is effective in reducing bone pain, the rate of skeletal events and improving global quality of life. It may also delay the time to skeletal events and may lower the risk of developing a skeletal event.

Current guidelines from the South West London Tumour Working Group recommend that women with metastatic breast cancer who require bisphosphonate treatment should receive at least 6 months of IV therapy, after which those with a stable clinical condition (according to set criteria) may be considered for a switch to oral therapy. A 2-year retrospective audit conducted by a specialist oncology breast unit in London estimated that up to 25% of patients seen would have been eligible for such a switch according to these criteria. The use of six months of IV bisphosphonate followed by 18 months of oral ibandronate may result in an overall saving to the NHS (estimate of between £4,200 and £13,500 per patient; please see full review for details) however this is largely dependent on which IV bisphosphonate is currently being used, and the locally negotiated cost of admission to a day care unit for an IV administration. Unless shared care arrangements are in place, the acute trust will bear both the increased cost of the drug and the loss of income from decreased clinical activity, and therefore will have little incentive to do implement this change.