Adachi Jonathan D, Bone Henry G, Daizadeh Nadia S, Dakin Paula, Papapoulos Socrates, Hadji Peyman, Recknor Chris, Bolognese Michael A, Wang Andrea, Lin Celia J F, Wagman Rachel B, Ferrari Serge
McMaster University, 501-25 Charlton Ave E., Hamilton, ON, L8N 1Y2, Canada.
Michigan Bone and Mineral Clinic, 22201 Moross Rd, Detroit, MI, 48236, USA.
BMC Musculoskelet Disord. 2017 Apr 27;18(1):174. doi: 10.1186/s12891-017-1520-6.
Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study.
To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study.
Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (-1.9 and -2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively).
The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects.
ClincalTrials.gov registration number NCT00523341 ; registered August 30, 2007.
在FREEDOM研究及扩展研究中，地诺单抗治疗长达8年与低骨折发生率相关。尚不清楚在研究过程中停药的受试者骨折风险是否高于仍参与研究的受试者，从而低估了整个试验队列的真实骨折风险。因此，我们在扩展研究中探讨了早期退出对非椎体骨折发生率的影响。
为了解易感受试者减少对骨折发生率的潜在影响，我们首先评估了参与扩展研究的患者与未参与患者的特征。随后，我们采用Kaplan-Meier多重插补（KMMI）方法，将停药受试者视为仍参与研究，假设其骨折风险比继续参与研究的受试者分别增加0%、20%、50%和100%。
扩展研究的受试者与未参与者在中位年龄（分别为71.9岁和73.1岁）、平均全髋骨密度T值（分别为-1.9和-2.0）以及在FREEDOM基线时通过骨折风险评估工具（FRAX）评估的骨折风险概率方面总体相似（主要骨质疏松性骨折分别为16.9%和17.7%，髋部骨折分别为6.7%和7.4%）。在KMMI分析中，当我们假设停药后骨折风险加倍（增加100%）时，非椎体骨折率估计值仅略高于交叉组（分别为10.32%和9.16%）和长期组（分别为7.63%和6.63%）的观察率。
地诺单抗治疗8年持续有效的观察结果是可靠的，似乎不能用易感受试者减少来解释。
ClinicalTrials.gov注册号NCT00523341；于2007年8月30日注册。
