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

Atkins and Rosenthal suggest that the reductions in skeletal-related events and in clinical interventions for the events observed in patients who received zoledronic acid in our study (1) are of limited clinical meaning. They questioned why quality of life, bone pain, analgesic use, progression-free survival, and survival were not improved in patients who received zoledronic acid compared with those who received placebo. The types of skeletal-related events evaluated in our study can cause serious morbidity and may affect survival. Indeed, Oefelein et al. (2) suggest that there is a negative correlation between fractures and overall survival in a similar patient population. Atkins and Rosenthal also question how many of the bone fractures had a significant clinical impact. We determined that approximately 3% and 10% of patients who received 4 mg of zoledronic acid and placebo, respectively, had a bone fracture that required medical intervention. When only these bone fractures are included in the analysis of the proportion of patients having at least one skeletal-related event, the benefit of 4 mg of zoledronic acid remains statistically significant (P = .029). Dr. Atkins expressed a concern that there might be double counting of the skeletal events in the efficacy analysis. For analyses of the proportion of patients having at least one skeletal-related event and for the time to the first skeletal-related event, only information pertaining to the first event was used. Thus, additional events had no impact on the results of these two analyses. For subsequent events, we counted all events occurring in close proximity in a patient as a single event to prevent “double counting.” Two additional multiple events analyses to address Dr. Atkins's concern on the double counting of the skeletal-related events were done. Each analysis excludes one of the two most frequently occurring types of skeletal-related events (i.e., pathologic fractures and radiation therapy to bone). The comparisons of treatment effect in reducing the skeletal-related event occurrences between the 4 mg of zoledronic acid and placebo groups remain statistically significant in both analyses (P = .026 and P = .004, respectively). No conclusive evidence on spinal cord compression and surgery to bone was available from the study because of the low incidences of these events. The incremental benefits of each component of the skeletal-related event contributed to the aggregate statistically significant clinical benefits observed with zoledronic acid. There were no statistically significant differences in quality-of-life assessments between the groups. These assessment instruments, however, have not been validated for the purpose of detecting the quality-of-life benefits associated with the prevention of skeletal-related events. Survival was also similar in the groups. We note that no clinical study to date has provided evidence of improved survival with any medical intervention in this patient population. Better control of pain without a higher level of analgesic use, as observed in our study, is one criterion of treatment benefit when palliating bone pain. Management of bone pain in our study also included use of radiation therapy, which was used more frequently in the placebo group and could have partially obfuscated differences in analgesic scores between those in the zoledronic and placebo groups. In summary, zoledronic acid statistically significantly reduced the incidence of clinically relevant skeletal-related complications, delayed the onset of all skeletal-related events, and helped reduce the inevitable increase in bone pain. We therefore believe that zoledronic acid provides a clinically meaningful benefit to patients with metastatic prostate cancer. Berruti et al. raised interesting questions regarding the levels of bone alkaline phosphates (BALP) and parathyroid hormone (PTH) in patients in our study. We found that 73% of patients in the placebo arm and 48% of patients in the zoledronic acid-treated group (4 mg and 8/4 mg groups) had a transient rise in BALP over 15 months. However, the effects of zoledronic acid did not appear to be different in patients with a transient rise in BALP (proportion of patients with any skeletal-related event was 40%, 34%, and 40%, in placebo, 4 mg zoledronic acid, and 8/4 mg zoledronic acid groups, respectively) compared with those without a transient rise in BALP (proportion of patients with any skeletal-related event was 44%, 35%, and 44%, in placebo, 4 mg zoledronic acid, and 8/4 mg zoledronic acid groups, respectively). However, the sample size for each subgroup is small, and no definitive conclusions should be drawn on the basis of this analysis. With regard to baseline PTH levels, there was no statistically significant difference in response to zoledronic acid between patients with normal PTH levels and those with elevated PTH levels. The response to 4 mg zoledronic acid was better than that to placebo in both PTH groups but may favor patients with normal baseline PTH levels. For patients with normal baseline PTH levels, the proportion of patients with any skeletal-related event was 43% and 33% for placebo and 4 mg zoledronic acid groups, respectively. For patients with elevated PTH levels, the proportion of patients with any skeletal-related event was 41% and 35% for placebo and 4 mg zoledronic acid, respectively. However, the sample size for each subgroup is small, with only 32 patients in the placebo group and 40 patients in the zoledronic acid-treated group having elevated baseline PTH levels.

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