Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK.
Faculty of Epidemiology and Population Health, Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
Health Technol Assess. 2021 Mar;25(17):1-106. doi: 10.3310/hta25170.
Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects.
The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time.
This was a new-user cohort study design with propensity score matching.
Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1-3 and from the Danish Odense University Hospital Databases for work package 4.
Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of < 45 ml/minute/1.73 m were eligible. A second estimated glomerular filtration rate value of < 45 ml/minute/1.73 m within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1-3. Patients with < 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1-4.
INTERVENTIONS/EXPOSURE: Bisphosphonate use, identified from primary care prescriptions (for work packages 1-3) or pharmacy dispensations (for work package 4), was the main exposure.
Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change.
Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users.
Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively.
Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness.
Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data.
This study is registered as EUPAS10029.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 17. See the NIHR Journals Library website for further project information. The project was also supported by the National Institute for Health Research Biomedical Research Centre, Oxford.
对于处于 4 期及以上慢性肾脏病的患者，双膦酸盐类药物是禁忌使用的。然而，尽管缺乏高质量的数据来证明其疗效，双膦酸盐类药物仍被广泛用于预防 3 期慢性肾脏病患者的脆性骨折。
各工作包的目标如下。工作包 1：研究双膦酸盐类药物使用与慢性肾脏病进展之间的关系。工作包 2：研究使用双膦酸盐类药物与骨折风险之间的关联。工作包 3：确定与使用双膦酸盐类药物相关的低钙血症、低磷血症、急性肾损伤和上消化道事件的风险。工作包 4：调查使用双膦酸盐类药物与随时间变化的骨密度变化之间的关系。
这是一项新用户队列研究设计，采用倾向评分匹配。
数据来自英国国民保健署（NHS）初级保健（临床实践研究数据链接 GOLD 数据库）和医院住院记录（医院发病统计），用于工作包 1-3，以及丹麦奥胡斯大学医院数据库，用于工作包 4。
符合以下条件的数据源患者有资格入选：至少有一次估计肾小球滤过率（eGFR）<45ml/min/1.73m2，且在第一次测量后 1 年内有第二次 eGFR<45ml/min/1.73m2 的记录。工作包 1-3 排除了没有医院发病统计数据链接的患者。在指数 eGFR 之前的 1 年内没有运行数据的患者和之前使用过抗骨质疏松药物的患者被排除在工作包 1-4 之外。
干预/暴露：双膦酸盐类药物的使用是通过初级保健处方（用于工作包 1-3）或药房配药（用于工作包 4）确定的，这是主要暴露因素。
工作包 1：慢性肾脏病进展，定义为病情恶化或开始进行肾脏替代治疗。工作包 2：髋部骨折。工作包 3：急性肾损伤、低钙血症和低磷血症通过医院发病统计数据识别，胃肠道事件通过临床实践研究数据链接或医院发病统计数据识别。工作包 4：每年股骨颈骨密度百分比变化。
在工作包 1 中，双膦酸盐类药物的使用与慢性肾脏病进展的风险增加相关（亚分布风险比 1.12，95%置信区间 1.02-1.24），但在工作包 3 中并未增加其他安全性结局的发生风险。工作包 2 的结果表明，双膦酸盐类药物的使用增加了髋部骨折的骨折风险（风险比 1.25，95%置信区间 1.13-1.39），但敏感性分析表明，这与未解决的混杂因素有关。相反，工作包 4 表明双膦酸盐类药物改善了骨密度，与匹配的非使用者相比，每年股骨颈骨密度的平均增益为 2.65%（95%置信区间 1.32%-3.99%）。
临床疗效（即工作包 2）数据存在混杂偏倚的问题。偏倚分析表明，这些发现归因于对治疗前风险的不适当调整。工作包 3 和 4 分别基于小数量的事件和参与者。
在 3B+期慢性肾脏病患者中，双膦酸盐类药物的使用与慢性肾脏病进展风险增加 12%相关。没有发现其他安全性问题。双膦酸盐类药物治疗增加了骨密度，但研究小组未能证明其在 3B+期慢性肾脏病患者中的抗骨折疗效。
需要随机对照试验数据来证明在 3B+期慢性肾脏病患者中双膦酸盐类药物的抗骨折疗效。需要进行更多的安全性分析，以描述双膦酸盐类药物在 3A 期慢性肾脏病中的肾毒性，可能需要使用观察性数据。
本研究在英国国家卫生与保健优化研究所（NIHR）健康技术评估计划中注册，将在；第 25 卷，第 17 期。请访问 NIHR 期刊库网站以获取更多项目信息。该项目还得到了英国牛津国家卫生研究院生物医学研究中心的支持。
