Alendronate significantly reduces the risk of cardiovascular events in patients treated with the bisphosphonate following a hip fracture, the first population-based study of its kind indicates.
“One of the consequences of hip fracture is an increased risk of cardiovascular events such as myocardial infarction (MI), stroke, and cardiovascular mortality,” Chor-Wing Sing, PhD, University of Hong Kong, and colleagues write in their article, published online May 9 in the Journal of Bone and Mineral Research.
“Thus, there is a clinical need to be aware of this increased risk of cardiovascular events among patients who sustain a hip fracture and intervene to reduce these life-threatening outcomes,” they add.
“Notably, we showed that post-hip fracture use of alendronate [significantly] reduced cardiovascular mortality [and] this highlights the importance of initiating alendronate treatment after hip fracture,” they emphasize.
Alendronate Reduced CV Mortality by 67%, MI Risk by 45%
Nitrogen-containing bisphosphonates are recommended for the secondary prevention of fractures in patients who have sustained a fragility fracture, Sing and colleagues explain. However, bisphosphonates are underused worldwide because of patients’ concerns about potential side effects.
They note that emerging evidence suggests bisphosphonates may be cardioprotective, so in this analysis, using a large, territory-wide healthcare database in Hong Kong, they set out to determine the risk of cardiovascular events in patients who had sustained a hip fracture. The primary drug of interest was alendronate, the first-line therapy for osteoporosis there, following hospital discharge after a hip fracture.
In total, 34,991 patients were included in the final analysis; 8.2% received a drug to treat osteoporosis in the first year following discharge, and 13.2% received treatment by study end.
Mean age of the cohort was 82 years and slightly over two thirds were women.
A smaller group of 4594 patients exposed to osteoporosis treatment were propensity-score matched with 123,568 patients not exposed to treatment. Median follow-up was slightly shorter, at 1349 days, in those who had not been treated, compared with 1371 days in those who had been treated.
Two thirds of the treated group received alendronate (67%), and almost all were treated weekly rather than daily.
At 1-year post-discharge, the risk of cardiovascular mortality was 67% lower among patients treated with alendronate compared with untreated controls (hazard ratio [HR], 0.33; P = .001), the investigators report.
Similarly, the risk of MI was 45% lower among patients treated with alendronate vs controls (HR, 0.55; P = .014), they add.
“For incident stroke, a marginally significant reduction in risk was observed at 5 years…and 10 years follow-up,” the researchers observe. At 5 years, the risk of stroke was 18% lower, and at 10 years, it was 17% lower among those who had received alendronate compared with those who had not.
In contrast, there was no difference in physical functioning or survival between those treated or not treated with alendronate.
As Sing and colleagues point out, the protective effect alendronate had on cardiovascular event risk declined over time but remained statistically significant.
In a secondary analysis, researchers looked at use of other bisphosphonates, including ibandronate, risedronate, and zoledronate, and found similar significant findings.
Two nonbisphosphonates commonly prescribed for osteoporosis in Hong Kong, salcatonin and strontium (neither of which are approved for osteoporosis in North America) were also analyzed to see if they, too, protected patients against cardiovascular events.
There was no association between salcatonin and cardiovascular risk at 1-year follow-up. However, the drug doubled the risk of MI at both 5 and 10 years, at an HR of 2.0 (P = .013 and P = .011, for 5 and 10 years, respectively).
In contrast, investigators found no association between strontium and cardiovascular event risk at any time point.
Alendronate Protects Against CV Death, but Not Heart Attack, in Men
Researchers also performed a subgroup analysis of women only, and trends towards reduced risk in cardiovascular mortality and MI with alendronate were similar to what was seen in the overall cohort.
In contrast, although alendronate proved protective against cardiovascular mortality in men, it didn’t seem to protect against MI, they note.
They suggest that bisphosphonates might lower cardiovascular event risk by indirectly targeting the mevalonate pathway — the same pathway statins target — suggesting bisphosphonates may have a cholesterol-lowering effect.
“Hip fracture is often under-treated with anti-osteoporosis medication, which is the worldwide experience,” Sing and colleagues observe. “If the results are further validated, the initiation of alendronate treatment in patients with hip fracture is encouraged,” they urge.
Could Findings Shed Light on Romosozumab Study Findings?
The investigators say that their study also “has important implications” for the design of randomized controlled trials for new osteoporosis agents, which often use alendronate as a comparator.
They note that the US Food and Drug Administration (FDA) has requested more data before reaching a decision on whether to approve the investigational osteoporosis agent romosozumab (Amgen), because of the excess cardiovascular adverse events in the romosozumab arm compared with the alendronate arm in the ARCH trial.
“In light of these important deliberations, our results provide evidence that such differences in cardiovascular adverse events could be potentially related to protective association of alendronate, rather than an increase in cardiovascular adverse events related to romosozumab use,” they observe.
Sing reported no relevant financial relationships. Douglas Kiel, MD, study author, reports serving as a scientific advisory board member for Merck Sharp & Dohme, Amgen, and Novartis, and has received grants from Merck Sharp & Dohme, Policy Analysis, and Eli Lilly.
J Bone Miner Res. Published online May 9, 2018. Abstract
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