Change in inclusion criterium; instead of only hormone naive patients, also patients receiving androgen deprivation therapy were allowed. The definition of abnormal renal function was changed. Change in bone turnover parameters.

Originally, for the sample size calculation, an event rate in high risk prostate cancer patients not treated with Zometa of 25%, which was based on expert opinion, was assumed. However, with the adoption of new inclusion criteria a reduced proportion of events was expected and concerns were raised regarding the fact that the sample size calculation in the current study was based on a very large treatment effect of Zometa on time to symptomatic bone metastases and there was certainly a risk of the study being underpowered. Introduction of review of the safety data at 12 months from study starting, by an Independent Data Monitoring Committee.

During the Steering Committee that took place in Munich on March 31st 2004 it was decided to re-introduce the sub-study on bone mineral density, that was erroneously cancelled with the Amendment 1. Therefore, Amendment 4 re-introduced all the parts that were deleted with Amendment 1 as far as the sub-study on bone mineral density was concerned. Since in the original protocol no limitation of the time-window between two infusions of the experimental drug was reported, it was decided that the maximum time for Zometa discontinuation should be 16 weeks. Administration of the drug beyond 16 weeks after the last Zometa infusion would be considered as a major protocol deviation. Due to changes made, at that time, to Zometa prescribing information, an amendment to clinical study protocols with Zometa was required. These changes involved two areas: - Dose reduction for patients with renal impairment: - Osteonecrosis of the jaw (ONJ): The instructions for rapid notification of serious adverse events were revised according to local internal procedure of Novartis subsidiaries of the countries involved in the trial. It was specified that the FDA form 1572 was not needed as one of the essential documents of the study. Therefore, the document was not collected anymore. Staging of Prostate Cancer in protocol Appendix 3 was replaced by the latest TNM Classification (American Joint Committee on Cancer, 2002).

1) to introduce an expedited report in case of occurrence of osteonecrosis of the jaw (ONJ) and in cases of osteomyelitis. While ONJ was reported in cancer patients receiving bisphosphonates as a component of their therapy, the etiology and pathogenesis of ONJ are not clear. In order to better understand and assess ONJ, all cases of ONJ and osteomyelitis were to be expedited as 15-day reports. 2) Planning of an interim analysis In the presence of strong evidence of treatment effect with Zometa in preventing bone metastases, the total study duration would be shortened.

1) The change of the study statistician. 2) The change of Steering Committee (SC) membership. 3) The inclusion of a mandatory bone scan in ALL patients still on-study and a second interim analysis, as a consequence of the first interim analysis results. 4) The inclusion of a blind central imaging review.

During the Steering Committee and National Coordinators Meeting in March 2011, interim results relating to the development of bone metastases were evaluated. Analyses in December 2010 showed that 9% of patients developed bone metastases. At the end of the study (December 2011), when, at that time, looking at the status of patients who developed metastases, it was clear that it was unlikely that the 18% event rate as assumed in the protocol would be reached. With a prolonged follow up of another 2 years, it was very likely that we would have sufficient events for a powerful analysis. Therefore a 2 years longer follow up then anticipated originally in the protocol was proposed. During this period follow up information on the development of bone metastases and survival was collected yearly for each patient that was, at that time, followed for progression or survival in the ZEUS study. Only information on progression and survival was collected.