Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Lancet Diabetes Endocrinol. 2020 Aug;8(8):672-682. doi: 10.1016/S2213-8587(20)30159-5.
The validation of bone mineral density (BMD) as a surrogate outcome for fracture would allow the size of future randomised controlled osteoporosis registration trials to be reduced. We aimed to determine the association between treatment-related changes in BMD, assessed by dual-energy x-ray absorptiometry, and fracture outcomes, including the proportion of treatment effect explained by BMD changes.
We did a pooled analysis of individual patient data from multiple randomised placebo-controlled clinical trials. We included data from multicentre, randomised, placebo-controlled, double-blind trials of osteoporosis medications that included women and men at increased osteoporotic fracture risk. Using individual patient data for each trial we calculated mean 24-month BMD percent change together with fracture reductions and did a meta-regression of the association between treatment-related differences in BMD changes (percentage difference, active minus placebo) and fracture risk reduction. We also used individual patient data to determine the proportion of anti-fracture treatment effect explained by BMD changes and the BMD change needed in future trials to ensure fracture reduction efficacy.
Individual patient data from 91 779 participants of 23 randomised, placebo-controlled trials were included. The trials had 1-9 years of follow-up and included 12 trials of bisphosphonate, one of odanacatib, two of hormone therapy (one of conjugated equine oestrogen and one of conjugated equine oestrogen plus medroxyprogesterone acetate), three of PTH receptor agonists, one of denosumab, and four of selective oestrogen receptor modulator trials. The meta-regression revealed significant associations between treatment-related changes in hip, femoral neck, and spine BMD and reductions in vertebral (r 0·73, p<0·0001; 0·59, p=0·0005; 0·61, p=0·0003), hip (0·41, p=0·014; 0·41, p=0·0074; 0·34, p=0·023) and non-vertebral fractures (0·53, p=0·0021; 0·65, p<0·0001; 0·51, p=0·0019). Minimum 24-month percentage changes in total hip BMD providing almost certain fracture reductions in future trials ranged from 1·42% to 3·18%, depending on fracture site. Hip BMD changes explained substantial proportions (44-67%) of treatment-related fracture risk reduction.
Treatment-related BMD changes are strongly associated with fracture reductions across randomised trials of osteoporosis therapies with differing mechanisms of action. These analyses support BMD as a surrogate outcome for fracture outcomes in future randomised trials of new osteoporosis therapies and provide an important demonstration of the value of public access to individual patient data from multiple trials.
Foundation for National Institutes of Health.
骨密度（BMD）作为骨折替代终点的验证，将允许减少未来骨质疏松症注册试验的规模。我们旨在确定双能 X 射线吸收法评估的治疗相关 BMD 变化与骨折结局之间的关联，包括 BMD 变化解释的治疗效果比例。
我们对来自多个随机安慰剂对照临床试验的个体患者数据进行了汇总分析。我们纳入了多中心、随机、安慰剂对照、双盲骨质疏松症药物临床试验的数据，这些试验纳入了处于增加的骨质疏松性骨折风险的女性和男性。使用每个试验的个体患者数据，我们计算了 24 个月时 BMD 的平均百分比变化，以及骨折减少情况，并对 BMD 变化（活性药物与安慰剂的差异百分比）与骨折风险降低之间的关联进行了荟萃回归分析。我们还使用个体患者数据确定了 BMD 变化对抗骨折治疗效果的解释比例，以及未来试验中需要的 BMD 变化以确保骨折减少疗效。
纳入了 23 项随机、安慰剂对照试验的 91779 名个体患者的数据。这些试验的随访时间为 1-9 年，包括 12 项双磷酸盐试验、1 项odanacatib 试验、2 项激素治疗试验（1 项共轭马雌激素，1 项共轭马雌激素加醋酸甲羟孕酮）、3 项甲状旁腺激素受体激动剂试验、1 项 denosumab 试验和 4 项选择性雌激素受体调节剂试验。荟萃回归显示，髋部、股骨颈和脊柱 BMD 的治疗相关变化与椎体（r 0·73，p<0·0001；0·59，p=0·0005；0·61，p=0·0003）、髋部（0·41，p=0·014；0·41，p=0·0074；0·34，p=0·023）和非椎体骨折（0·53，p=0·0021；0·65，p<0·0001；0·51，p=0·0019）减少之间存在显著关联。未来试验中，总髋部 BMD 至少 24 个月的百分比变化提供了几乎确定的骨折减少，范围从 1·42%到 3·18%，取决于骨折部位。髋部 BMD 变化解释了治疗相关骨折风险降低的大部分（44-67%）。
在具有不同作用机制的骨质疏松症治疗的随机试验中，治疗相关的 BMD 变化与骨折减少有很强的相关性。这些分析支持 BMD 作为未来新骨质疏松症治疗随机试验中骨折结局的替代终点，并提供了对公共获取多个试验个体患者数据的重要证明。
美国国立卫生研究院基金会。
