Delmas P D, Li Zhengqing, Cooper Cyrus
INSERM Research Unit 403, Claude Bernard University of Lyon, Lyon, France.
J Bone Miner Res. 2004 Feb;19(2):330-7. doi: 10.1359/JBMR.0301228. Epub 2003 Dec 16.
Published meta-analyses have investigated the relationship between changes in BMD and fracture risk reduction observed with antiresorptive agents, with inconsistent results. Many factors may affect the outcome of such analyses. Our work explores some of these factors and illustrates the need for caution in interpreting the results of meta-analyses.
The role of the increase in bone mineral density (BMD) in fracture risk reduction observed in osteoporotic patients treated with antiresorptive drugs is unclear. We examined the effects of study selection, the use of summary statistics or individual patient data (IPD) as the basis for the analyses, and the choice of BMD values used on the outcome of meta-analyses.
To evaluate the effects of study selection, we performed Poisson regression analyses using the results from a number of published studies. To evaluate the effects of using individual patient data instead of summary statistics, we simulated the IPD for vertebral fracture to match the summary statistics for published trials and compared these results with those based on meta-regression using summary statistics. We also evaluated the effect of varying the BMD increase with treatment (3-8%) used in predicting the fracture risk reductions in these simulations.
The Poisson regression, which found a statistically significant relationship between nonvertebral fracture risk and spinal BMD when 18 trials of varying designs, duration, and sample size were included in the analysis (p = 0.02), was no longer significant when the analysis was based on the 7 large studies that were placebo-controlled, at least 3 years in duration (at least 1000 patient-years). Meta-analyses of simulated IPD from 12 trials of six antiresorptive agents gave accurate results regardless of the proportion of vertebral risk reduction assumed to be related to BMD change, whereas meta-regression based on summary statistics always produced an estimate around 50%. When the actual data from two risedronate studies were analyzed, the meta-regression based on summary statistics demonstrated a stronger correlation between BMD change and fracture risk reduction than the results based on the IPD analysis. In predicting the fracture risk reduction, the use of the average BMD gain (3%) observed in all studies in the calculations produced an overall fracture risk reduction very similar to the one observed clinically. In contrast, the use of a large BMD gain (8%) produced a substantially higher estimated fracture risk reduction and resulted in a high proportion of fracture risk reduction being attributed to BMD change.
Many factors may influence the outcome of meta-analyses, and caution should be used in interpreting the results of such analyses when exploring the relationship between BMD changes and fracture risk reduction with antiresorptive therapy of osteoporosis.
已发表的荟萃分析研究了抗吸收药物治疗后骨密度（BMD）变化与骨折风险降低之间的关系，但结果并不一致。许多因素可能会影响此类分析的结果。我们的研究探讨了其中一些因素，并说明了在解释荟萃分析结果时需要谨慎。
在接受抗吸收药物治疗的骨质疏松症患者中，骨密度增加在降低骨折风险方面的作用尚不清楚。我们研究了研究选择、使用汇总统计数据或个体患者数据（IPD）作为分析基础以及所使用的BMD值的选择对荟萃分析结果的影响。
为评估研究选择的影响，我们使用多项已发表研究的结果进行了泊松回归分析。为评估使用个体患者数据而非汇总统计数据的影响，我们模拟了椎体骨折的IPD以匹配已发表试验的汇总统计数据，并将这些结果与基于汇总统计数据的荟萃回归结果进行比较。我们还评估了在这些模拟中用于预测骨折风险降低的治疗后BMD增加幅度（3%-8%）变化的影响。
当分析中纳入18项设计、持续时间和样本量各异的试验时，泊松回归发现非椎体骨折风险与脊柱BMD之间存在统计学显著关系（p = 0.02），但当分析基于7项大型安慰剂对照、持续时间至少3年（至少1000患者年）的研究时，该关系不再显著。对来自六项抗吸收药物的12项试验的模拟IPD进行的荟萃分析得出了准确结果，无论假定与BMD变化相关的椎体风险降低比例如何，而基于汇总统计数据的荟萃回归始终得出约50%的估计值。当分析利塞膦酸盐两项研究的实际数据时，基于汇总统计数据的荟萃回归显示BMD变化与骨折风险降低之间的相关性比基于IPD分析的结果更强。在预测骨折风险降低时，计算中使用所有研究中观察到的平均BMD增加幅度（3%）得出的总体骨折风险降低与临床观察到的非常相似。相比之下，使用较大的BMD增加幅度（8%）会得出明显更高的估计骨折风险降低值，并导致很大比例的骨折风险降低归因于BMD变化。
许多因素可能影响荟萃分析的结果，在探讨骨质疏松症抗吸收治疗中BMD变化与骨折风险降低之间的关系时，解释此类分析结果时应谨慎。
