Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

Abstract

We recently showed that zoledronate prevented fractures in older women with osteopenia (hip T-scores between −1.0 and −2.5). In addition to fewer fractures, this study also suggested that women randomized to zoledronate had fewer vascular events, a lower incidence of cancer, and a trend to lower mortality. The present analysis provides a more detailed presentation of the adverse event data from that study, a 6-year, double-blind trial of 2000 women aged >65 years recruited using electoral rolls. They were randomly assigned to receive four infusions of either zoledronate 5 mg or normal saline at 18-month intervals. Supplements of vitamin D, but not calcium, were provided. There were 1017 serious adverse events in 443 participants in the placebo group, and 820 events in 400 participants in those randomized to zoledronate (relative risk = 0.90; 95% CI, 0.81 to 1.00). These events included fractures resulting in hospital admission. Myocardial infarction occurred in 39 women (43 events) in the placebo group and in 24 women (25 events) in the zoledronate group (hazard ratio 0.60 [95% CI, 0.36 to 1.00]; rate ratio 0.58 [95% CI, 0.35 to 0.94]). For a prespecified composite cardiovascular endpoint (sudden death, myocardial infarction, coronary artery revascularization, or stroke) 69 women had 98 events in the placebo group, and 53 women had 71 events in the zoledronate group (hazard ratio 0.76 [95% CI, 0.53 to 1.08]; rate ratio 0.72 [95% CI, 0.53 to 0.98]). Total cancers were significantly reduced with zoledronate (hazard ratio 0.67 [95% CI, 0.51 to 0.89]; rate ratio 0.68 [95% CI, 0.52 to 0.89]), and this was significant for both breast cancers and for non-breast cancers. Eleven women had recurrent or second breast cancers during the study, all in the placebo group. The hazard ratio for death was 0.65 (95% CI, 0.40 to 1.06; p = 0.08), and 0.51 (95% CI, 0.30 to 0.87) in those without incident fragility fracture. These apparent beneficial effects justify further appropriately powered trials of zoledronate with these nonskeletal conditions as primary endpoints.

What Else Do We Need? A Commentary on Zoledronate Effects on Cancer and Cardiac Events

“…Notably, for all of these endpoints, the pattern of events suggested that the protective effects begin within the first year of treatment and then were progressive during the remaining 6‐year study period. Although Reid and colleagues are careful to point out the limitations of their analysis, including the fact that their study was not specifically powered to show differences in these safety endpoints and they did not correct for multiple comparisons, they also point out that their findings are generally consistent with prior observation studies and meta‐analyses in terms of overall death, cancer incidence (and breast cancer specifically), and vascular events. Moreover, as the authors discuss, physiologically plausible mechanistic explanations for these protective effects continue to be actively investigated.…”

“…But in the interim, the fact that there is more work to do cannot discourage us from clearly presenting the positive balance between the benefits and risks of osteoporosis medications. The results presented in Reid and colleagues should now be a significant part of that discussion.…”

“…And although these concerns are legitimate in certain circumstances, in appropriately selected patients in whom the necessity of continuing treatment is continually reassessed, they are not only misplaced but also detrimental to public health. In this setting, the article published in the current edition of the Journal of Bone and Mineral Research ( JBMR ), entitled Effects of Zoledronic Acid on Cancer , Cardiac Events and Mortality in Osteopenic Women , has the potential to provide us with additional tools as we work to close the osteoporosis treatment gap and reverse current negative trends.…”

“…In this issue of the JBMR , Reid and colleagues now provide a critical in‐depth analysis of the adverse events experienced by patients in their previous study . Specifically, study subjects recorded events in a questionnaire every 3 months and hospital admissions were reviewed by a study physician.…”

“…So now, considering the studies by Reid and colleagues and all the work that has come before it, the question remains: What additional information do we need to forcefully educate our patients and colleagues, reverse current trends, and make osteoporosis treatment a greater priority in our healthcare system? To answer this question, we must first recognize a few truths about clinical research: (i) there will often be clinical trial findings that conflict in some details because of variations in study design or differing patient populations; (ii) randomized placebo‐controlled trials will rarely address all patient subgroups of interest; and (iii) after the introduction of a new medication or class of medication, new data will continue to emerge that may alter our calculations in terms of risks and benefits.…”