Reviewing the effects of bisphosphonates or RANKL-inhibitors for men with prostate cancer and bone metastases

The study summarized the outcomes of bisphosphonates and RANKL-inhibitors as supportive treatment in men with prostate cancer (PC) and bone metastases (BM). The authors recommended that a balance between the efficacy and safety of such therapies must be considered for preventing skeletal events in such patients.

Men whose PC spread (metastasized) to the bones can experience skeletal-related events (SREs). SREs include bone fractures (breaks) or pain, spinal cord compression, and a need for bone surgery or radiation. These lead to more illness and poor quality of life (QoL).

Bone-modifying agents treat damage from BM and prevent SREs. Bone-modifying agents include bisphosphonates such as zoledronic acid (Zometa), risedronate (Actonel), pamidronate (Aredia), alendronate (Fosamax), etidronate (Didronel), or clodronate (Bonefos) and RANKL-inhibitors such as denosumab (Prolia, Xgeva). However, clear ranking and guidance about the effectiveness and safety of such agents are lacking.

The authors analyzed 25 clinical trials comparing different bone-modifying agents in men with PC and BM. 

There was not enough good quality evidence to show that any of the bisphosphonates improve pain in these patients. Patients receiving zoledronic acid (ZA) had a 16% lower risk of experiencing SREs. Those receiving denosumab had a 28% lower risk of experiencing SREs compared to no treatment/placebo. Both ZA and denosumab had no influence on mortality rate compared to no treatment/placebo. One trial with 1904 patients showed that more patients on ZA had deterioration of cancer-related QoL compared to denosumab.

Patients receiving ZA had a 63% higher risk of experiencing kidney-related side effects compared to no treatment/placebo. Denosumab possibly increased the occurrence of osteonecrosis of the jaw (ONJ) compared to no treatment/placebo. ONJ happens when the jaw bone degenerates due to starving from a lack of blood. ZA was found to probably neither increase nor reduce ONJ.

The study suggested that the balance between the effectiveness and safety of bisphosphonates and RANKL-inhibitors should be considered for supportive treatment in men with PC and BM. Among bisphosphonates, ZA likely reduces SREs, while increasing the risk of side effects.

This analysis compared multiple trials with different therapies and patient characteristics. More trials with direct comparisons of bone modifying agents are needed to support the results of this analysis.