Dr Rick de Boer, Oncologist at Royal Melbourne Hospital, produced data he had presented at the San Antonia Breast Cancer Conference on behalf of the ZO-FAST’s trialists’ group.
He gave an overview of the protective effect of oestrogen on bone mineral density (BMD) and explained how aromatase inhibitors (AIs) had been shown to significantly reduce BMD to the extent of causing osteoporosis. He reviewed the ATAC data which showed a mean change of -2% in BMD compared to a 1% gained in BMD in those treated with tamoxifen. After 100 months follow-up, 13.8% of those treated with anastrazole had suffered fractures, compares to 10.1% for tamoxifen. A similar pattern was seen in the trials BIG-1-98, ies, ARNO and MA17.
The drug zoledronic acid, increased bone mineral density in post-menopausal women (Reid IR et al, NEJM 2002; 346:653-661) and hence the drug was trialed at a dose of 4mg given 6-monthly in those being treated with letrozole 2.5mg daily. All in all, 1065 patients in 128 centres worldwide were randomised to either letrolozole with zoledronic acid 4mg 4-monthly, vs. letrolezole alone with zoledronic acid only being given once osteoporosis was established.
Two years into therapy, those treated with zoledronic acid had increased BMD by 2 to 3.5% whereas those without had lost between 3 and 4.5% BMD. The study found an accelerated rate of bone loss in those who were recently menopausal with a 7.8% reduction in BMD at 24 months in this group.
Those who started off with healthy bones maintained their bone health, with a T-score of greater than -1. Of those not given zoledronic acid, 15.5% had a decrease in T-score to less than -2 (i.e. developed frank osteoporosis). Likewise, those with borderline osteopaenia, maintained osteopaenia with zoledronic acid therapy whereas of those not given zoledronic acid, 15.5% became frankly osteoporotic and 60% became osteopaenic.
The potential for bisphosphonates to reduce disease recurrence was also mentioned with a non-significant reduction in recurrence being 3.9% at 2 years in the zoledronic acid upfront group and 6% in those not treated with zoledronic acid.
Dr de Boer concluded that upfront zoledronic acid 4mg 6-monthly given during AI treatment effectively minimises bone loss. There is a suggestion of an impact on disease relapse and this effect may become more obvious and statistically significant as follow-up continues.
These findings were discussed by Dr Vernon Harvey who commented on the findings of studies that have demonstrated a reduction in colorectal cancer in patients taking tamoxifen. This finding was not seen with AIs.
It is known that oestrogen receptors inhibit development of colonic polyps in mice and he cautioned that prolonged hormonal therapy may have unwanted effects on malignancies other than breast cancer.
He also addressed the so-called ‘switch debate’ where tamoxifen is given initially followed by AI later and he reviewed a number of studies which suggest that this may be the most efficacious hormonal therapy.
The big 198 study should clarify whether this is the correct approach. He suggested that the optimal duration of tamoxifen therapy was not established yet and he agreed with Professor Coates’ conclusions that 10 years therapy was not worse than 5 and may be better although the effect in premenopausal women was likely to be small.
He cautioned against widespread adoption of zoledronic acid therapy as the natural history of osteopaenia was not yet clearly established and bisphosphonates, especially zoledronic acid were not without their toxicities. All of the bisphosphonates improve bone density and clodrontate (Bonefos) and pamidronate (Pamisol) may represent less toxic alternatives to zoledronic acid. Certainly zoledronic acid appears to have a higher incidence of osteonecrosis of the jaw (Durie et al NEJM 2005:353;99-102). Dr Vernon Harvey showed an excerpt from an American law firm encouraging legal action for patients experiencing this side effect.