Of these, pamidronate and zoledronic acid are indicated for the management of bone metastases. Although the mechanism of bisphosphonates' role in bone metastases is unclear, it is thought that bisphosphonates may affect the bone microenvironment to decrease the invasion of cancer cells. Other possible beneficial mechanisms of bisphosphonates in bone metastases include antiangiogenic and antitumor activity, prevention of proliferation of cancer cells, retardation of bone resorption, and cytotoxic effects on osteoclasts.
To help provide further information on this topic, researchers conducted a meta-analysis and trial sequential analysis (a method for improving the quality of information from traditional meta-analyses while simultaneously determining if the evidence is reliable and conclusive) to determine and quantify the impact of bisphosphonates on survival in women with early-stage BC.
Studies were included in these analyses if they were prospective epidemiological trials that addressed the effects of bisphosphonates on BC survival among women with no evidence of relapse or metastasis; if they reported (or the investigator was able to calculate) effect estimates; and if bisphosphonates were administered only before the occurrence of BC relapses or metastases. If duplicate studies were present, the one with the longest follow-up was included, while also including all datasets at different follow-up time points in other analyses; if no-event trials were identified, an empirical constant continuity correction factor of 1 was used to include no-event trials in the main analysis. (A continuity correction factor is used to approximate a discrete probability distribution when a continuous probability distribution was used.)
The analyses included 25 studies—17 randomized, controlled trials and eight cohort trials—with a total of 81,508 BC patients. Among the bisphosphonates included in the study were zoledronic acid, clodronate (not available in the U.S.), oral pamidronate (not available in the U.S.), ibandronate, and risedronate.
The researchers found that bisphosphonates significantly improved survival in women with early BC, with a risk reduction of 27.5% (relative risk reduction [RR] 0.725, P <.001). The antiresorptive drugs improved BC patient survival, and this beneficial effect was maintained for more than 4 years after treatment discontinuation (22% risk reduction; RR 0.780, P = .016). These agents also had a protective effect against bone metastases (28.7% risk reduction; RR 0.713, P <.001). Bisphosphonate use was associated with a significant survival benefit in postmenopausal patients with BC, but not premenopausal BC patients (26.3% risk reduction; RR 0.737, P <.001).
A sensitivity analysis revealed that the data were robust and there was no evidence of publication bias; however, there was between-study heterogeneity, which was due primarily to the inclusion of the cohort studies.
This study did not account for various dosages and durations of bisphosphonate treatment. Multiple testing, such as performing post hoc subgroup analyses by follow-up duration and menopausal status, could have affected the results. The authors called for a large sample–sized, randomized, controlled trial to confirm their findings.
Nonetheless, this study offers encouraging evidence for pharmacists about the benefits of bisphosphonates in patients with early BC.
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