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

“skeletal-related events ” in patients with hormone-refractory metastatic prostate cancer who received zoledronic acid ev-ery 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 pos-sibility that asymptomatic fractures of limited clinical relevance were counted as skeletal events. The authors noted that nonvertebral fractures are generally accompanied by acute clinical symp-toms (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 skel-etal 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 frac-ture 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 inap-propriate count of two events for one clinically insignificant episode? Because the authors showed no sta-tistically 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 hor-mone-refractory prostate cancer meta-static 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 wheth-er the requirement for surgery or radia-tion therapy to bone for 7.5 % fewer pa-tients is sufficient justification for the administration of zoledronic acid intra-venously every 3 weeks to all patients with prostate cancer metastatic to bone