Do Bisphosphonates Reduce Cardiovascular-Related Mortality?

It is well known that hip fractures are associated with significant morbidity and mortality: Mortality increases 15–25% in the year following a hip fracture.^1–5 We know that treating osteo­porosis prevents fractures and improves patient survival. But is there a relationship beyond this?

Several studies have found that bisphosphonate therapy is associated with a reduction in both all-cause and cardiovascular (CV) related mortality beyond what would be expected by preventing the next fracture. However, the data are not conclusive. What do the data say, and how should we advise our patients?

Bisphosphonate Use & Mortality

Prospective cohort studies, meta-analyses and randomized, controlled trials have demonstrated that bisphosphonate use is associated with a reduction in all-cause mortality.^1,6,7–15 Although the majority of studies are observational, data from a variety of studies in different clinical settings demonstrate reduced all-cause mortality among patients taking bisphos­phonate therapy. Before discussing the more focused question of CV-related morbidity and mortality, we briefly review the most compelling data demonstrating a connection between bisphosphonate use and all-cause mortality.

A large systematic review and meta-analysis conducted by Cummings et al. in 2019 investigated a bold question: If bisphosphonates are associated with decreased mortality, then should they be administered to patients for the mortality benefit alone?¹⁶ This study examined 21 clinical trials of bisphosphonate use and did not find an overall association between bisphosphonate use and all-cause mortality.¹⁶ However, a trend toward lower mortality associated with nitrogen-containing bisphosphonate use was seen in 20 trials.

Six trials of zoledronic acid showed marked heterogeneity. Some studies, such as the Health Outcomes and Reduced Inci­dence with Zoledronic Acid Once Yearly-Recurrent Fracture Trial (HORIZON-RFT), observed a substantial reduction in the risk of death, but others did not.¹ Ultimately, Cummings et al. concluded that bisphos­phonate use may not be associated with reduced overall mortality rates, but additional trials are needed to clarify mortality rates associated with zoledronic acid use.

One of several limitations to this study was the exclusion of patients on glucocorticoids and patients with cancer. Even though a discussion of all clinical trials addressed in the Cummings study is beyond the scope of this article, we address some of the more compelling trials below.

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Bisphosphonate Use Is Associated with a Reduction in All-Cause Mortality

A representation of pamidronic acid, a bisphosphonate used to treat osteoporosis.

The HORIZON-RFT trial demonstrated that zoledronic acid use was associated with an absolute fracture reduction of 5.3% and a relative reduction of 35% compared with the placebo group (primary endpoint). Beyond this, zoledronic acid use was associated with a 28% relative reduction in the risk of death among patients with recent surgical repair of a hip fracture, a mortality benefit that persisted after controlling for baseline factors between individuals who received zoledronic acid and those who did not (secondary endpoint).¹

Interestingly, as we discuss below, only 8% of the 28% reduction in risk of death was related to a reduction in hip fracture, implying that prevention of secondary fracture does not entirely explain the reduction in mortality risk.¹² The mortality benefit seen with zoledronic acid use in HORIZON-RFT was unexpected and launched efforts to confirm and explain this finding. Of note, the number of CV events was similar between the two groups.¹

Additional studies have likewise shown an improvement in all-cause mortality among bisphosphonate users. A smaller Canadian trial, drawing on patients previously randomized to either care manager intervention (i.e., arrangement for bone mineral density testing and oral bisphosphonate prescription) or usual care, demonstrated a significant reduction in mortality among patients on bisphosphonates.⁸

Using data from the West Glasgow health service between 1999 and 2007, a prospective cohort study demonstrated a decreased risk of mortality among patients receiving oral bisphosphonates compared with those taking just calcium and vitamin D.¹⁵ Interestingly, this study was conducted among patients who were referred to a fracture liaison service following a fragility fracture, arguably a more generalizable and real-world population than that represented by a randomized, controlled trial.¹⁵

A meta-analysis of eight studies pub­lished in 2010 found that treatment with osteoporosis therapy among 40,000 subjects—including oral and intravenous bisphosphonates—resulted in a 10% reduction in mortality.⁹ This observation was most prominent among patients at highest risk of fracture.⁹

The association between reduced mortality & bisphosphonate use seems most persuasive in the case of zoledronic acid, a medication that has demonstrated significant prevention rates for fragility fractures.

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Bisphosphonate Use Is Associated with a Reduction in CV-Related Mortality

Starting from the premise that bisphosphonates may be associated with a reduction in all-cause mortality, to what is this survival benefit attributed? A compelling question: What proportion of post-fragility fracture mortality is related directly to the fracture itself vs. what portion is due to comorbidities, preexisting conditions and frailty?

Several studies have sought to answer this question.^17,18 It may be that the decreased risk in all-cause mortality is due to more than secondary fracture prevention alone.

An analysis of HORIZON-RFT data by Colón-Emeric et al. sought to answer the above question.¹² This study examined cause of death among the 242 subjects whose cause of death was captured by the HORIZON-RFT. The cumulative mortality rates were 13.3% in the placebo group and 9.6% in the zoledronic acid group (P=0.01). After adjusting for baseline risk and new clinical fractures, the study authors concluded that only 8% of the mortality benefit associated with zoledronic acid use was due to a reduction in secondary fractures, thereby invoking the presence of an additional mediator to explain the reduction in all-cause mortality.^1,12

A trend was seen toward increased incidence of cardiac death among patients in the placebo group compared with those in the zoledronic acid group.^1,12 Two of the study limitations were that baseline charac­teristics and comorbidities were investigator reported and could not be confirmed, and that cause of death could not be adjudicated for a large number of subjects.¹²

Several other studies also found a protective benefit of bisphosphonate use for cardiovascular disease. A retrospective cohort study using data pooled from three North American risedronate osteoporosis trials demonstrated a trend toward lower CV-related mortality in the risedronate groups compared with placebo groups.¹⁹

A Danish prospective cohort study using propensity score matching observed a 33% reduction in any CV event among patients taking oral bisphosphonates compared with those who were not.¹¹ Adjusted analyses for baseline bone mineral density did not materially alter results, suggesting CV protection may be independent of bone density. Importantly, registry data in this study did not include information on lifestyle factors, such as smoking and alcohol use.

Other studies have found a similar association between bisphosphonate use and decreased risk of CV-related morbidity and mortality; however, no clear mechanism has been identified. One hypothesis is that the survival benefit may be due to decreased risk of myocardial infarction (MI) among patients on bisphosphonate therapy. Several observational studies have demonstrated this association, including three studies we discuss in more detail below.^6,13,14,20

Wolfe et al. conducted a prospective cohort study among patients with rheumatoid arthritis (RA), a population enriched for CV disease and osteoporosis, utilizing data from the National Data Bank for Rheumatic Diseases.⁶ Patients with RA on bisphosphonate therapy had a decreased risk of MI compared with those who were not.⁶

Kang et al. conducted a matched cohort analysis of 1,548 subjects who received alendronate for fragility fractures compared with 4,644 subjects who did not receive bisphosphonate therapy for fracture.²⁰ During a follow-up time of two years, fewer MIs occurred among patients on bisphosphonates compared to those who were not on bisphosphonates.²⁰

Lastly, Sing et al. observed that alendronate use was associated with reduced risk of CV mortality and incident MI at one year.¹³ This risk reduction decreased over time, but was still evident at 10 years of follow-up.¹³ This data supports reduced risk of CV disease as a potential mechanism of action for mortality reduction.

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Bisphosphonate Use Is Not Associated with a Reduction in All-Cause Mortality or a Reduction in CV-Related Mortality

Numerous studies have failed to demonstrate a protective benefit of bisphosphonates either for all-cause mortality or for CV-related mortality. The HORIZON Pivotal Fracture Trial (HORIZON-PFT) was a landmark randomized, controlled trial that established, along with the HORIZON-RFT, that once yearly infusions of zoledronic acid significantly decreased incidence of clinical fractures.²¹ Interestingly, this study did not demonstrate a survival benefit, in stark contrast to the results of HORIZON-RFT.

According to HORIZON-PFT, 112 patients (2.9%) in the placebo group died during the three-year study period, compared with 130 patients (3.4%) in the zoledronic acid group.²¹ Further, no statistically significant difference was observed in death from CV causes or MI between the two groups.²¹ In fact, an increased incidence of serious atrial fibrillation was observed in the zoledronic acid group.²¹

A full discussion of the relationship between bisphosphonates and atrial fibrillation is outside the scope of this article; however, a recent study seeks to add clarity.²² It is not clear why the two HORIZON studies did not reach the same conclusion.

Turning to CV-related morality, it should be noted that many studies failed to detect a difference.

Several systematic reviews similarly failed to find an association between CV mortality and bisphosphonate use. One review conducted by Kranenburg et al. examined the pooled relative risk (RR) of 20 studies (published up to 2016) and did not find a benefit of bisphosphonate treatment on CV events.²³ As demonstrated in other studies, a non-significant trend toward lower risk for all-cause mortality and CV mortality was observed in patients treated with bisphosphonates.²³

A systematic review from Kim et al. found that bisphosphonate treatment for up to 36 months did not have a significant effect on total CV events (14 trials; absolute risk 6.5% in bisphosphonate treated patients vs. 6.2% in patients not treated).²⁴ Likewise, no effect was observed of bisphosphonate use on MI, stroke and CV death, because pooled odds ratios were not significantly different between the groups.²⁴

In contrast, a randomized, controlled trial conducted by Reid et al. demonstrated a trend toward fewer vascular events (including MI), as well as lower mortality rates among 1,000 women with osteopenia who were treated with zoledronic acid.²⁵

A follow-up safety study, examining detailed adverse event data from the trial, found a lower risk of MI and CV events in the treatment group.¹⁴ Study authors concluded that zoledronic acid use may result in fewer vascular events, as well as less cancer; however, these events were not primary endpoints of the original study, and the study was not powered to detect a difference.

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.

References

1. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007 Nov;357(18):1799–1809.
2. Hannan EL, Magaziner J, Wang JJ, et al. Mortality and locomotion 6 months after hospitalization for hip fracture risk factors and risk-adjusted hospital outcomes. JAMA. 2001 Jun 6;285(21):2736–2742.
3. Davison CW, Merrilees MJ, Wilkinson TJ, et al. Hip fracture mortality and morbidity—Can we do better? N Z Med J. 2001 Jul 27;114(1136)329–332.
4. Magaziner J, Lydick E, Hawkes W, et al. Excess mortality attributable to hip fracture in white women aged 70 years and older. Am J Public Health. 1997 Oct;87(10):1630–1636.
5. Haleem S, Lutchman L, Mayahi R, et al. Mortality following hip fracture: Trends and geographical variations over the last 40 years. Injury. 2008 Oct;39(10):1157–1163.
6. Wolfe F, Bolster MB, O’Connor CM, et al. Bisphosphonate use is associated with reduced risk of myocardial infarction in patients with rheumatoid arthritis. J Bone Miner Res. 2013 May;28(5):984–991.
7. Sambrook PN, Cameron ID, Chen JS, et al. Oral bisphosphonates are associated with reduced mortality in frail older people: A prospective five-year study. Osteoporos Int. 2011 Sep;22(9):2551–2556.
8. Beaupre LA, Morrish DW, Hanley DA, et al. Oral bisphosphonates are associated with reduced mortality after hip fracture. Osteoporos Int. 2011 Mar;22(3):983–991.
9. Bolland MJ, Grey AB, Gamble GD, et al. Effect of osteoporosis treatment on mortality: A meta-analysis. J Clin Endocrinol Metab. 2010 Mar;95(3):1174–1181.
10. Center JR, Bliuc D, Nguyen ND, et al. Osteoporosis medication and reduced mortality risk in elderly women and men. J Clin Endocrinol Metab. 2011 Apr;96(4):1006–1014.
11. Rodríguez AJ, Ernst MT, Nybo M, et al. Oral bisphosphonate use reduces cardiovascular events in a cohort of Danish patients referred for bone mineral density. J Clin Endocrinol Metab. 2020 Oct 1;105(10):dgaa481.
12. Colón-Emeric CS, Mesenbrink P, Lyles KW, et al. Potential mediators of the mortality reduction with zoledronic acid after hip fracture. J Bone Miner Res. 2010 Jan;25(1):91–97.
13. Sing CW, Wong AYS, Kiel DP, et al. Association of alendronate and risk of cardiovascular events in patients with hip fracture. J Bone Miner Res. 2018 Aug;33(8):1422–1434.
14. Reid IR, Horne AM, Mihov B, et al. Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. J Bone Miner Res. 2020 Jan;35(1):20–27.
15. Van Geel TACM, Bliuc D, Geusens PPM, et al. Reduced mortality and subsequent fracture risk associated with oral bisphosphonate recommendation in a fracture liaison service setting: A prospective cohort study. PLoS One. 2018 Jun1;13(6): e0198006.
16. Cummings SR, Lui LY, Eastell R, et al. Association between drug treatments for patients with osteoporosis and overall mortality rates: A meta-analysis. JAMA Intern Med. 2019 Aug;179(11):1491–1500.
17. Schousboe JT. Mortality after osteoporotic fractures: What proportion is caused by fracture and is preventable? J Bone Miner Res. 2017 Sep;32(9):1783–1788.
18. Kanis JA, Oden A, Johnell O, et al. The components of excess mortality after hip fracture. Bone. 2003 May;32(5):468–473.
19. Steinbuch M, D’Agostino RB, Mandel JS, et al. Assessment of mortality in patients enrolled in a risedronate clinical trial program: A retrospective cohort study. Regul Toxicol Pharmacol. 2002 Jun;35(3):320–326.
20. Kang JH, Keller JJ, Lin HC. Bisphosphonates reduced the risk of acute myocardial infarction: A 2-year follow-up study. Osteoporos Int. 2013 Jan;24(1):271–277.
21. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007 May 3;356(18):1809–1822.
22. D’Silva KM, Cromer SJ, Yu EW, et al. Risk of incident atrial fibrillation with zoledronic acid versus denosumab: A propensity score–matched cohort study. J Bone Miner Res. 2021 Jan;36(1):52–60.
23. Kranenburg G, Bartstra JW, Weijmans M, et al. Bisphosphonates for cardiovascular risk reduction: A systematic review and meta-analysis. Atherosclerosis. 2016 Sep;252:106–115.
24. Kim DH, Rogers JR, Fulchino LA, et al. Bisphosphonates and risk of cardiovascular events: A meta-analysis. PLoS One. 2015 Apr 17;10(4):e0122646.
25. Reid IR, Horne AM, Mihov B, et al. Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med. 2018 Dec 20;379(25):2407–2416.
26. Bergman J, Nordström A, Hommel A, et al. Bisphosphonates and mortality: Confounding in observational studies? Osteoporos Int. 2019 Oct;30(10):1973–1982.
27. Guney E, Kisakol G, Ozgen AG, et al. Effects of bisphosphonates on lipid metabolism. Neuro Endocrinol Lett. 2008 Apr;29(2):252–255.
28. Cutini PH, Rauschemberger MB, Sandoval MJ, et al. Vascular action of bisphosphonates: In vitro effect of alendronate on the regulation of cellular events involved in vessel pathogenesis. J Mol Cell Cardiol. 2016 Nov;100:83–92.
29. Gonçalves AF, Congio LH, dos Santos PP, et al. Pamidronate attenuates diastolic dysfunction induced by myocardial infarction associated with changes in geometric patterning. Cell Physiol Biochem. 2015;35(1):259–269.
30. Leder BZ. What else do we need? A commentary on zoledronate effects on cancer and cardiac events. J Bone Miner Res. 2020 Jan;35(1):18–19.