Do Bisphosphonates Reduce Cardiovascular-Related Mortality?

What Can We Conclude?

What then is the relationship between bisphosphonate use and all-cause and CV-related mortality? The issue at heart in answering these questions centers on the large amount of data derived from observational trials rather than randomized clinical trials designed specifically to answer these questions. We are all keenly aware that potential confounding in the studies cited above, as well as others not cited here that have contributed to this body of literature, can pose an existential threat to the work as a whole.²⁶

Although there certainly are clinical trials in this realm—such as those examined by Cummings et al.—many were not powered to detect a survival benefit and were not intended to examine these relationships as primary endpoints. Still, the association between reduced mortality and bisphos­phonate use seems most persuasive in the case of zoledronic acid, a medication that has demonstrated significant prevention rates for fragility fractures. In the most comprehensive study discussed above, Cummings et al. conclude additional trials are needed to investigate the effect of zoledronic acid on mortality.

Even though the precise mechanism by which mortality may be affected is not yet clear, hypotheses abound and are ripe for areas of future study.^27–29 As many of the studies examined above echoed, to answer these questions, randomized, controlled trials are required to specifically address these relationships as primary endpoints.

At the end of the day, the insight of Benjamin Leder, MD, is compelling and should serve as a guiding principle for all who are committed to fragility fracture prevention: “Specifically, we know that treating osteoporosis reduces fractures and saves lives … . The fact that there is more work to do cannot discourage us from clearly presenting the positive balance between the benefits and the risks of osteoporosis medications.”³⁰

Sarah F. Keller, MD, graduated from the Massachusetts General Hospital Rheumatology Fellowship Training Program in 2018. She is a staff rheumatologist in the Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Ohio.

Marcy B. Bolster, MD, is associate professor of medicine at Harvard Medical School and director of the Rheumatology Fellowship Training Program at Massachusetts General Hospital, Boston.

Disclosures

Dr. Bolster owns stock and is an investor in Johnson & Johnson. She is a co-investigator in clinical trials sponsored by Genentech, Cumberland and Corbus, and has received an honorarium from Merck Manual.

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