Defining the role of exercise in prostate cancer bone metastasis

Prostate cancer (PCa) is one of the most common cancers diagnosed in men of western countries. It is estimated that ~70% of patients with PCa will develop bone metastasis, in which the disease is considered to be incurable. Therefore, alternative therapies are in need to be evaluated. Exercise has been shown to be safe and tolerable for patients with PCa, and have positive outcomes, such as reduced cancer�related fatigue, improvement in quality of life, and increased strength and bone mass. However, there are no evidence related to the effect of exercise in patients with PCa bone metastasis. As exercise is a known factor to induce an osteogenic response and improve the bone health, we hypothesize that physical exercise interferes in the development of PCa skeletal metastases through promoting osteogenic response. To test this overarching hypothesis and examine the effect of exercise in PCa bone metastasis, we used PCa xenograft and syngeneic murine models and applied three different exercise regimens: tibial mechanical loading which mimics load-bearing exercise, treadmill running and whole-body high frequency low magnitude vibration platform. Firstly, the tibial mechanical loading not only effectively induced an osteogenic response within the first week of loading (3 loads) but also caused the spatial re-distribution of osteoblasts and osteoclasts cells in the loaded tibias. The arrival of PCa cells into bone was not enhanced by the osteogenic response induced by mechanical loading examined using quantitative multiphoton microscopy ex vivo. Furthermore, continuous tibial mechanical loading reduced the PCa bone metastasis incidence and tumour burden and preserved the bone structure parameters in the intracardiac injected xenograft and syngeneic PCa models and in the intra-tail artery injected xenograft model. This effect might be mediated by breakage of the vicious cycle due to the osteoclast’s inhibition, and the alteration of the profile of pro�metastatic cytokines such as DKK1 and RANTES. Interestingly, treadmill running and whole-body vibration platform stimulus did not affect the development of PCa bone metastasis, a result possibly caused by these exercise regimens being insufficient to generate an osteogenic response. These findings support our original hypothesis and provide invaluable information for future research and clinical trials in applying appropriate exercise regimens as an alternative therapeutic strategy in patients already with or in risk of developing PCa bone metastasis.