背景:骨质疏松症是骨量减少和骨退化的异常,导致骨折风险增加。依替膦酸盐属于双膦酸盐类药物,通过干扰破骨细胞(分解骨组织的骨细胞)的活性来抑制骨吸收。这是对2008年首次发布的Cochrane评论的更新。为了临床相关性,我们调查了依替膦酸钠对绝经后女性骨折风险分层(低与高)的影响.
目的:评估间歇性/环状依替膦酸盐在低和高骨折风险绝经后妇女骨质疏松性骨折的一级和二级预防中的益处和危害。分别。
方法:我们搜索了Cochrane中央对照试验登记册(CENTRAL),MEDLINE,Embase,两份临床试验登记簿,药品审批机构的网站,以及相关系统评价的参考书目。我们确定了1966年至2023年2月之间发表的合格试验。
方法:我们纳入了随机对照试验,评估了依替膦酸钠预防绝经后妇女骨折的益处和危害。实验武器中的妇女必须接受至少一年的依替膦酸盐治疗,有或没有其他抗骨质疏松药物和钙/维生素D。合格的比较者是安慰剂(即不治疗;或钙,维生素D,或两者)或另一种抗骨质疏松药物。主要结果是临床椎体,非椎骨,臀部,和手腕骨折,由于不良事件而退出,和严重不良事件。我们将一项研究归类为二级预防,如果其人群满足以下一个或多个分级标准:骨质疏松症的诊断,有椎骨骨折史,低骨密度T评分(≤-2.5),或75岁以上。如果这些标准都不符合,我们认为这项研究是一级预防。
方法:我们使用了Cochrane预期的标准方法学程序。该综述有三个主要比较:(1)依替膦酸盐400mg/天与安慰剂;(2)依替膦酸盐200mg/天与安慰剂;(3)任何剂量的依替膦酸盐与另一种抗骨质疏松剂。我们将每个比较的分析分为一级和二级预防研究。对于依替膦酸盐400毫克/天的安慰剂对照研究中的主要结果,我们遵循最初的回顾,将大于15%的相对变化定义为临床重要.对于所有感兴趣的结果,我们提取了研究中最长时间点的结局测量值.
结果:30项研究符合审查的资格标准。其中,26项研究,共有2770名女性,报告了我们可以提取和定量合成的数据。有9项一级预防研究和17项二级预防研究。我们担心在每项研究中至少有一个偏倚领域的风险。没有一项研究描述了适当的分配隐藏方法,尽管27%描述了适当的随机序列生成方法。我们判断,只有8%的研究避免了性能偏差,并提供了适当的盲法的充分描述。报告疗效结果的研究中有四分之一存在减员偏倚的高风险,而23%的报告安全性结局的研究在该领域处于高风险.纳入的30项研究比较了(1)依替膦酸盐400mg/天与安慰剂(13项研究:9项一级预防和4项二级预防);(2)依替膦酸盐200mg/天与安慰剂(三项研究,所有二级预防);或(3)依替膦酸盐(两种给药方案)与另一种抗骨质疏松药(14项研究:1项一级预防和13项二级预防)。我们仅讨论依替膦酸盐400毫克/天与安慰剂的比较。对于一级预防,我们从9项研究(1~4年)中收集了中度至极低确定性的证据,其中包括740名骨折风险较低的绝经后女性.与安慰剂相比,依替膦酸钠400mg/d可能导致非椎骨骨折的差异很小或没有差异(风险比(RR)0.56,95%置信区间(CI)0.20至1.61);绝对风险降低(ARR)减少4.8%,95%CI8.9%减少至6.1%增加)和严重不良事件(RR0.90,95%CI0.52至1.54;ARR1.1%减少,95%CI4.9%减少到5.3%增加),基于中度确定性证据。依替膦酸钠400mg/天可能导致临床椎骨骨折几乎没有差异(RR3.03,95%CI0.32至28.44;ARR0.02%以上,95%CI0%以下至0%以上)和因不良事件而退出(RR1.41,95%CI0.81至2.47;ARR2.3%以上,95%CI减少1.1%至8.4%),基于低确定性证据。我们不知道依替膦酸钠对髋部骨折的影响,因为证据非常不确定(基于非常低的确定性证据,RR无法估计)。在纳入的研究中未报告腕部骨折。二级预防,包括667名骨折风险较高的绝经后女性在内的4项研究(长度为2~4年)提供了证据.与安慰剂相比,依替膦酸钠400mg/天可能对非椎骨骨折影响很小或没有影响(RR1.07,95%CI0.72~1.58;ARR多0.9%,95%CI减少3.8%,增加8.1%),基于低确定性证据。关于依替膦酸钠对髋部骨折的影响的证据非常不确定(RR0.93,95%CI0.17至5.19;ARR少0.0%,95%CI减少1.2%至增加6.3%),腕部骨折(RR0.90,95%CI0.13~6.04;ARR少0.0%,95%CI减少2.5%至15.9%),因不良事件而退出(RR1.09,95%CI0.54至2.18;ARR多0.4%,95%CI少1.9%多4.9%),和严重不良事件(RR不可估计),与安慰剂相比。在纳入的研究中未报告临床椎骨骨折。
结论:此更新呼应了我们先前的综述的主要发现,即依替膦酸钠在一级和二级预防方面可能对椎体和非椎体骨折产生或可能几乎没有影响。
Osteoporosis is an abnormal reduction in bone mass and bone deterioration, leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts - bone cells that break down bone tissue. This is an update of a Cochrane review first published in 2008. For clinical relevance, we investigated etidronate\'s effects on postmenopausal women stratified by fracture risk (low versus high).
To assess the benefits and harms of intermittent/cyclic etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture, respectively.
We searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE, Embase, two clinical trial registers, the websites of drug approval agencies, and the bibliographies of relevant systematic reviews. We identified eligible trials published between 1966 and February 2023.
We included randomized controlled trials that assessed the benefits and harms of etidronate in the prevention of fractures for postmenopausal women. Women in the experimental arms must have received at least one year of etidronate, with or without other anti-osteoporotic drugs and concurrent calcium/vitamin D. Eligible comparators were placebo (i.e. no treatment; or calcium, vitamin D, or both) or another anti-osteoporotic drug. Major outcomes were clinical vertebral, non-vertebral, hip, and wrist fractures, withdrawals due to adverse events, and serious adverse events. We classified a study as secondary prevention if its population fulfilled one or more of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, a low bone mineral density T-score (≤ -2.5), or aged 75 years or older. If none of these criteria were met, we considered the study to be primary prevention.
We used standard methodological procedures expected by Cochrane. The review has three main comparisons: (1) etidronate 400 mg/day versus placebo; (2) etidronate 200 mg/day versus placebo; (3) etidronate at any dosage versus another anti-osteoporotic agent. We stratified the analyses for each comparison into primary and secondary prevention studies. For major outcomes in the placebo-controlled studies of etidronate 400 mg/day, we followed our original review by defining a greater than 15% relative change as clinically important. For all outcomes of interest, we extracted outcome measurements at the longest time point in the study.
Thirty studies met the review\'s eligibility criteria. Of these, 26 studies, with a total of 2770 women, reported data that we could extract and quantitatively synthesize. There were nine primary and 17 secondary prevention studies. We had concerns about at least one risk of bias domain in each study. None of the studies described appropriate methods for allocation concealment, although 27% described adequate methods of random sequence generation. We judged that only 8% of the studies avoided performance bias, and provided adequate descriptions of appropriate blinding methods. One-quarter of studies that reported efficacy outcomes were at high risk of attrition bias, whilst 23% of studies reporting safety outcomes were at high risk in this domain. The 30 included studies compared (1) etidronate 400 mg/day to placebo (13 studies: nine primary and four secondary prevention); (2) etidronate 200 mg/day to placebo (three studies, all secondary prevention); or (3) etidronate (both dosing regimens) to another anti-osteoporotic agent (14 studies: one primary and 13 secondary prevention). We discuss only the etidronate 400 mg/day versus placebo comparison here. For primary prevention, we collected moderate- to very low-certainty evidence from nine studies (one to four years in length) including 740 postmenopausal women at lower risk of fractures. Compared to placebo, etidronate 400 mg/day probably results in little to no difference in non-vertebral fractures (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.20 to 1.61); absolute risk reduction (ARR) 4.8% fewer, 95% CI 8.9% fewer to 6.1% more) and serious adverse events (RR 0.90, 95% CI 0.52 to 1.54; ARR 1.1% fewer, 95% CI 4.9% fewer to 5.3% more), based on moderate-certainty evidence. Etidronate 400 mg/day may result in little to no difference in clinical vertebral fractures (RR 3.03, 95% CI 0.32 to 28.44; ARR 0.02% more, 95% CI 0% fewer to 0% more) and withdrawals due to adverse events (RR 1.41, 95% CI 0.81 to 2.47; ARR 2.3% more, 95% CI 1.1% fewer to 8.4% more), based on low-certainty evidence. We do not know the effect of etidronate on hip fractures because the evidence is very uncertain (RR not estimable based on very low-certainty evidence). Wrist fractures were not reported in the included studies. For secondary prevention, four studies (two to four years in length) including 667 postmenopausal women at higher risk of fractures provided the evidence. Compared to placebo, etidronate 400 mg/day may make little or no difference to non-vertebral fractures (RR 1.07, 95% CI 0.72 to 1.58; ARR 0.9% more, 95% CI 3.8% fewer to 8.1% more), based on low-certainty evidence. The evidence is very uncertain about etidronate\'s effects on hip fractures (RR 0.93, 95% CI 0.17 to 5.19; ARR 0.0% fewer, 95% CI 1.2% fewer to 6.3% more), wrist fractures (RR 0.90, 95% CI 0.13 to 6.04; ARR 0.0% fewer, 95% CI 2.5% fewer to 15.9% more), withdrawals due to adverse events (RR 1.09, 95% CI 0.54 to 2.18; ARR 0.4% more, 95% CI 1.9% fewer to 4.9% more), and serious adverse events (RR not estimable), compared to placebo. Clinical vertebral fractures were not reported in the included studies.
This update echoes the key findings of our previous review that etidronate probably makes or may make little to no difference to vertebral and non-vertebral fractures for both primary and secondary prevention.