Division of Cardiac and Vascular Sciences, St. George's University of London, London, UK.
Clin Ther. 2010 Mar;32(3):426-36. doi: 10.1016/j.clinthera.2010.03.014.
In 2 large, randomized, placebocontrolled trials, yearly 5-mg infusions of the bisphosphonate zoledronic acid were associated with increased bone mineral density and reduced fracture incidence in patients with osteoporosis, previous fracture, or both.
This review evaluated the cardiovascular risks of bisphosphonates (with a focus on zoledronic acid) for the treatment of osteoporosis and put these potential risks into perspective, summarizing available evidence from randomized clinical trials.
A search of PubMed (1991-September 2009) for preclinical and clinical trials was conducted using the following search terms: arrhythmia, atrial fibrillation, bisphosphonate, osteoporosis, cardiovascular adverse events, bone mineral density, fracture incidence, stroke, alendronate, etidronate, ibandronate, risedronate, and zoledronic acid. New analyses using unpublished data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) and Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Recurrent Fracture Trial (HORIZON-RFT) were also performed to evaluate the cardiovascular risk of zoledronic acid using stepwise Cox proportional hazards regression and risk modeling. After selection of risk factors for the model, treatment-by-factor interactions were evaluated at the 0.10 level of significance.
Atrial fibrillation (AF) serious adverse events (SAEs) were observed among more patients receiving zoledronic acid (1.3%) than placebo (0.5%) over 36 months in HORIZON-PFT (P < 0.001), but the overall incidence of AF events was not significantly different between groups. The timing of AF SAEs did not correspond with drug administration or the pharmacokinetic profile of the drug. Nearly all women with sick sinus syndrome had predisposing conditions. An electrocardiography study after the third yearly infusion found no differences between those who received zoledronic acid versus placebo. Cardiovascular deaths, stroke, and other nonarrhythmia cardiovascular adverse events (AEs) were not significantly different between groups, but arrhythmia was more common in the zoledronic acid group than in the placebo group (6.9% vs 5.3%; P = 0.003). In analyses of pooled data from HORIZON-PFT and HORIZON-RFT to determine risk factors associated with the likelihood of experiencing AF, atrial flutter, or stroke, the only treatment-by-factor interaction was age (hazard ratio = 0.963; P < 0.067), which may be attributable to the fact that, among those aged > or =85 years, AF AEs occurred in 5.9% of the placebo group and 5.3% of the zoledronic acid group. Preclinical and other clinical trials of zoledronic acid for the treatment of osteoporosis or other indications did not identify an effect on AF AEs. A reanalysis of risedronate controlled clinical trials found no difference in the incidence of AF among active-treatment or placebo groups. In alendronate trials, AF SAEs occurred in 1.5% of the alendronate group and 1.0% of the placebo group (P = 0.07); the overall incidence of AF AEs was similar.
Despite the greater incidence of AF SAEs among zoledronic acid recipients versus placebo recipients in one study (not observed in other trials of this agent), clinical data for zoledronic acid, risedronate, and alendronate indicate no significant differences from placebo in overall incidence of AF AEs.
在两项大型、随机、安慰剂对照试验中，每年一次给予 5mg 唑来膦酸治疗骨质疏松症、既往骨折或两者兼有的患者，可增加骨矿物质密度并降低骨折发生率。
本综述评估了双膦酸盐（重点为唑来膦酸）治疗骨质疏松症的心血管风险，并从随机临床试验的角度对这些潜在风险进行了分析。
使用以下搜索词在 PubMed（1991 年至 2009 年 9 月）中对临床前和临床试验进行了搜索：心律失常、心房颤动、双膦酸盐、骨质疏松症、心血管不良事件、骨矿物质密度、骨折发生率、中风、阿仑膦酸钠、依替膦酸二钠、伊班膦酸钠、利塞膦酸钠和唑来膦酸。还使用 Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial（HORIZON-PFT）和 Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Recurrent Fracture Trial（HORIZON-RFT）的未发表数据进行了新的分析，以使用逐步 Cox 比例风险回归和风险建模评估唑来膦酸的心血管风险。在选择模型的风险因素后，以 0.10 的显著性水平评估治疗与因素之间的相互作用。
在 HORIZON-PFT 中，36 个月时，接受唑来膦酸治疗的患者（1.3%）比安慰剂组（0.5%）发生心房颤动（AF）严重不良事件（SAE）的患者更多（P < 0.001），但两组之间的 AF 事件总体发生率无显著差异。AF SAE 的发生时间与药物给药或药物的药代动力学特征不对应。几乎所有窦性心动过缓综合征的女性都有潜在的疾病。第三次每年输注后的心电图研究发现，唑来膦酸组与安慰剂组之间没有差异。心血管死亡、中风和其他非心律失常心血管不良事件（AE）在两组之间无显著差异，但唑来膦酸组的心律失常比安慰剂组更常见（6.9%比 5.3%；P = 0.003）。在 HORIZON-PFT 和 HORIZON-RFT 的汇总数据中分析确定与发生 AF、心房扑动或中风可能性相关的风险因素，唯一的治疗与因素之间的相互作用是年龄（风险比=0.963；P < 0.067），这可能归因于这样一个事实，即在年龄≥85 岁的患者中，安慰剂组中有 5.9%发生了 AF AEs，唑来膦酸组中有 5.3%发生了 AF AEs。唑来膦酸治疗骨质疏松症或其他适应症的临床前和其他临床试验并未发现对 AF AEs 有影响。对利塞膦酸钠对照临床试验的重新分析发现，在活性治疗组或安慰剂组中，AF 的发生率没有差异。在阿仑膦酸钠试验中，阿仑膦酸钠组发生 1.5%的 AF SAE，安慰剂组发生 1.0%（P = 0.07）；AF AEs 的总体发生率相似。
尽管一项研究中唑来膦酸组与安慰剂组相比发生 AF SAE 的发生率更高（在该药物的其他试验中未观察到），但唑来膦酸、利塞膦酸钠和阿仑膦酸钠的临床数据表明，在 AF AEs 的总体发生率方面，与安慰剂无显著差异。
