There is conflicting evidence regarding efficacy of bisphosphonates on reducing skeletal related events (SRE: pathological fracture, cord compression or requirement for surgery or radiation of bony metastases, or hypercalcemia) or bone pain in prostate cancer.
A randomised study of 8 mg and 4 mg of zoledronic acid compared to placebo demonstrated a reduction in number of SRE’s and prolongation of time to first SRE.r There was little impact on quality of life or analgesic score. Because of a higher incidence of elevated creatinine, the protocol was amended to reduce the 8 mg dose to 4mg. This trial used routine imaging rather than symptomatic investigation to document SRE, and radiation to bone was counted as an SRE.
These results contrast that of a study of pamidronate disodium (APD), where no effect was seen on bone pain or reduction in SRE using clinical endpoints.r In this study, radiation to symptomatic bone metastases was seen as ‘routine care’ and not counted as an SRE.
Evidence for the dosing interval is from CALGB (Alliance) 70604,r a phase III randomised, open-label, non-inferiority trial. 1822 bisphosphonate-naïve cancer patients with at least one site of bone involvement (breast n = 855, prostate n = 689, multiple myeloma n = 278) were enrolled. In the prostate cancer subgroup, 345 patients were randomised to the 4 weekly treatment group and 344 patients to the 12 weekly treatment group. The primary end point was the proportion of patients with at least one SRE at 2 years. Secondary end points included the proportion of patients with at least one SRE by disease type.
The CALGB 70604 study showed non-inferiority for the 12 weekly interval arm compared with the 4 weekly arm for SRE within 2 years. The prostate cancer between-group proportion difference was 0.02 (99.9% CI, −0.10 to 0.14); P = .59)). There was no difference in serum bone turnover marker profiles.r
Summary of efficacyr
© The Journal of the American Medical Association 2017
The rate of adverse events in the CALGB 70604 study were comparable between the two dosing interval arms and between the breast, prostate and multiple myeloma groups. Osteonecrosis of the jaw occurred in 2% of patients in the 4 weekly arm and 1% of patients in the 12 weekly arm. Renal adverse events (grade 3 or 4 increase in creatinine level) occurred in 1.2% of patients in the 4 weekly arm and 0.5% of patients in the 12 weekly arm.r