Re: A Randomized, Placebo-Controlled Trial of Zoledronic Acid in Patients With Hormone-Refractory Metastatic Prostate Carcinoma

Saad et al. (1) report a reduction in “skeletal-related events” in patients with hormone-refractory metastatic prostate cancer who received zoledronic acid every 3 weeks. This included a reduction in pathologic fractures and radiation therapy to bone. However, the protocol required bone surveys every 3 months, and vertebral fractures were defined only as a 25% reduction in vertebral height, without any requirement for clinical correlation. This raises the possibility that asymptomatic fractures of limited clinical relevance were counted as skeletal events. The authors noted that nonvertebral fractures are generally accompanied by acute clinical symptoms (emphasis mine) and that such fractures were also reduced. However, the reduction in nonvertebral fractures was not statistically significant, and we may well question whether routine skeletal surveys would have demonstrated such fractures that were asymptomatic. Furthermore, although only one event was counted in any 3-week interval, is it not possible that an asymptomatic fracture was counted as an event during one interval and, because of this finding, the patient was then given radiation therapy in the next interval, leading to an inappropriate count of two events for one clinically insignificant episode? Because the authors showed no statistically significant changes in pain or quality of life among the treatment groups, I question whether zoledronic acid treatment results in any clinically relevant benefit for patients with hormone-refractory prostate cancer metastatic to bone. The authors should first assure us that radiation therapy to bone was not counted as an additional event in patients with a pathologic fracture within the treatment field. They must then show that treatment results in an overall reduction in clinically relevant skeletal-related events by excluding asymptomatic fractures. Assuming they can do so, we must still question whether the requirement for surgery or radiation therapy to bone for 7.5% fewer patients is sufficient justification for the administration of zoledronic acid intravenously every 3 weeks to all patients with prostate cancer metastatic to bone.