Bisphosphonates for cardiovascular risk reduction: A systematic review and meta-analysis
Introduction
Despite improvements in treatment of cardiovascular risk factors cardiovascular disease still results in an immense disease burden [1]. New treatment targets could further reduce the risk for first and subsequent cardiovascular events. As vascular calcifications are related to an increased cardiovascular risk, preventing or reducing arterial calcification might be an important target for further cardiovascular risk reduction [2]. Arterial calcifications are observed in several common conditions such as diabetes mellitus, renal failure and aging, all conditions known to be related to a high cardiovascular risk [3].
Osteoporosis is related to a 2-fold increased risk of cardiovascular mortality, also known as the ‘bone-vascular axis’ [4], [5], [6], [7], [8]. The process of arterial calcification might play an important role in this relation [9]. Arterial calcification is regulated through a network of inhibitory (and promoting) pathways, such as vitamin K dependent pathways, the Klotho protein, Fetuin-A and pyrophosphate [10]. Pyrophosphate is a strong inhibitor of arterial calcification [11], [12] and bisphosphonates, well-established drugs for the treatment of bone diseases associated with excessive bone resorption including osteoporosis and bone metastasis, are pyrophosphate analogues and could thus stimulate the inhibitory effects of pyrophosphate on arterial calcification [13], [14]. In fact, bisphosphonates were first shown to reduce arterial calcification and soft tissues calcification in rats [15].
Therefore it is conceivable that bisphosphonates interfere in the arterial calcification process and might be able to reduce the risk of cardiovascular disease [16]. Support for this hypothesis is growing as cohort studies show that the use of bisphosphonates in patients with maximum adherence is associated with a 20% lower risk of acute myocardial infarction [17] and randomized controlled trials such as the Health Outcomes and Reduced Incidence with Zolendronic Acid Once Yearly (HORIZON) trial show an 11% reduction of risk of cardiovascular events and a 31% reduction of cardiovascular deaths was found after treatment with bisphosphonates compared to placebo [18].
To investigate the effects of treatment with bisphosphonates on arterial wall calcification and stiffness, cardiovascular events, cardiovascular mortality and all-cause mortality, we performed a systematic review of randomized controlled trials with no restrictions on populations and summarized the results in a meta-analysis.
Section snippets
Search strategy
A systematic literature search of Medline, Embase and the Cochrane Library was performed reviewing articles published up to January 2016. A search filter was designed using synonyms for the determinant (bisphosphonates) and outcome (surrogate markers of cardiovascular disease such as arterial stiffness and arterial calcification, cardiovascular events, cardiovascular mortality, survival and mortality) and using synonyms for determinant (bisphosphonates) and randomized controlled trials. A full
Results
The search strategy identified 6573 unique articles. Initial screening on title and abstract decreased this number to 353 potentially relevant studies. After evaluation of these articles in more detail using the full-text, 292 articles were excluded for reasons shown in Fig. 1. No additional articles were identified through manual reference check, resulting in a total number of 61 articles for meta-analysis [18], [19], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]
Discussion
This systematic review and meta-analysis included 61 randomized controlled trials using various patient groups including osteoporosis patients and cancer patients. 45 studies were placebo-controlled, while the other 16 trials used standard of care without bisphosphonates as the control group. Two studies reported on surrogate markers of cardiovascular disease and showed that bisphosphonates reduce arterial wall calcification, but have no effect on arterial stiffness. Also, no effects of
Conflict of interest
The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.
Acknowledgments
All authors have made substantial contributions to all of the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted.
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