Departments of Medicine and Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
J Bone Miner Res. 2018 Apr;33(4):634-642. doi: 10.1002/jbmr.3355. Epub 2018 Jan 10.
Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. Such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from 28,000 participants enrolled in 11 bisphosphonate (BP) and three selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo % difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of follow-up. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r = 0.82 [p < 0.001] and r = 0.75 [p = 0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r = 0.33 [p = 0.053] and r = 0.53 [p = 0.065], respectively) and hip fracture (r = 0.17 [p = 0.24] and r = 0.43 [p = 0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2017 American Society for Bone and Mineral Research.
很少有关于抗吸收（AR）治疗试验的汇总分析将骨转换标志物（BTM）的短期变化与随后的骨折减少联系起来。这种信息对于评估新的 AR 或新的给药方案很有用。在国立卫生研究院（NIH）基金会骨质量项目中，我们分析了来自 11 项双膦酸盐（BP）和 3 项选择性雌激素受体调节剂（SERM）安慰剂对照骨折终点试验的 28,000 名参与者的个体水平数据。使用两种骨形成标志物（骨碱性磷酸酶[骨 ALP]和前胶原 I N-端肽[PINP]）和两种骨吸收标志物（I 型胶原 N-末端和 C-末端肽）的 BTM 结果以及事件性骨折结果数据，我们进行了一项元回归分析，将治疗对骨转换变化的平均净效应（3 至 12 个月时治疗与安慰剂的活性差异%）与研究范围骨折风险降低的对数相关联，并使用线性回归绘制最佳拟合线。分别对 1 至 4 年随访期间发生的形态计量性椎体、非椎体和髋部骨折进行了分析。有超过 16,000 名和 10,000 名参与者分别获得了骨 ALP 和 PINP 的变化。对于椎体骨折，结果表明，治疗相关的骨 ALP 或 PINP 变化与椎体骨折风险降低之间存在很强的关系（r = 0.82 [p <0.001] 和 r = 0.75 [p = 0.011]），对于非椎体骨折（r = 0.33 [p = 0.053] 和 r = 0.53 [p = 0.065]）和髋部骨折（r = 0.17 [p = 0.24] 和 r = 0.43 [p = 0.11]）的关系较弱，且不再具有统计学意义。仅限于 BP 试验的分析得出了类似的结果。对于所有骨折类型，骨吸收标志物的相关性较弱且无统计学意义。我们得出结论，AR 治疗的短期治疗相关的骨 ALP 和 PINP 变化强烈预测椎体骨折治疗效果，但不能预测非椎体或髋部骨折治疗效果。骨形成标志物的变化可能有助于预测新的 AR 化合物或经批准的 AR 药物的新型给药方案的抗椎体骨折疗效。
