Impact of Prior Radiation Therapy on Bone Mineral Density Change Over Time: Secondary Analysis of the Control Arm of a Phase III Randomized Trial

Abstract

Retrospective studies have demonstrated that pelvic radiation therapy (RT) can lead to decreased bone mineral density (BMD) and increased risk of fracture. This is more relevant for men with prostate cancer (PCa) who often receive androgen deprivation therapy (ADT) in conjunction with RT. We performed a post-hoc secondary analysis of publicly available data of the control arm of a phase III randomized controlled study (NCT00089674) to determine if history of prior pelvic RT affects change in BMD over time in non-metastatic PCa patients treated with ADT. In this study, PCa patients with age ≥70 years or <70 years with low BMD (T-score <-1) or history of osteoporotic fracture, on ADT for at least 12 months were randomized to receive densoumab vs. placebo every 6 months for 3 years. Additionally, all patients received daily vitamin D and calcium supplementation. Randomization was stratified by duration of prior ADT (≤6 months vs >6 months) and age (<70 vs ≥70 years). BMD was measured at baseline, and at months 1, 3, 6, 12, 24, and 36 with blind reading by central reviewer. To model the effect of prior pelvic RT on dynamic change in BMD in the hip, lumbar spine, and femoral neck, we applied separate multivariate linear mixed effect models for each site. Age, ECOG performance score, history and number of prior fractures, smoking history, and years from initial cancer diagnosis were included as fixed covariates while patients were included as random intercepts. Among 734 patients who were randomized to the control arm, 563 participants with baseline and at least one post baseline assessment of BMD were eligible for this analysis. Overall, 34.4% (n = 194) received prior RT. We did not find any significant association of dynamic change in BMD with receipt of prior pelvic RT for left femoral neck (p = 0.7), total hip (p = 0.8), and lumbar spine (p = 0.5), respectively. At 36 months, there was no significant association of prior RT with percent change in BMD in femoral neck (odds ratio [OR]: 0.85; 95% confidence interval [CI]: 0.30-2.41), total hip (OR: 0.96; 95% CI: 0.43-2.15), and lumbar spine (OR: 2.01; 95% CI: 0.63-6.45). However, note should be made of the opposite direction of association of prior RT with percent BMD change at 36 months for femoral neck and hip versus lumbar spine. In this exploratory analysis of the control arm of a phase III randomized trial, we did not find sufficient evidence of an association between prior pelvic RT and dynamic changes in BMD in femoral neck, hip, and lumbar spine over time in men with non-metastatic PCa and low BMD at baseline. This analysis should be interpreted cautiously considering its post-hoc nature with likely inadequate power, the possibility of selection bias, lack of information on receipt of prior ADT, and missing data in longitudinal assessments.