Over recent years the introduction of bone-targeted treatments has transformed the clinical care of patients with metastatic bone disease. Both bisphosphonates (BP) and denosumab have a major beneficial impact on skeletal morbidity, leading to improved quality of life and physical functioning and reduced demands on expensive interventions and hospital care. Improvements have also been seen in radiation based therapies with the widespread use of single large (8Gy) treatment fractions for bone pain, improved delivery of high dose radical radiation treatment to oligo-metastatic disease through the use of stereotactic ablative radiation (SABR) and the introduction of highly effective and safe, novel radiopharmaceuticals such as radium-223. Coupled with these improvements in bone-targeted treatments, are rapid developments in both cytotoxic therapy and molecularly targeted treatments for cancer. These can now provide disease control, albeit only temporary at present, to most patients and are resulting in steadily improved survival and ever increasing treatment options such that, for many, advanced cancer is becoming a chronic disease and no longer the rapid death sentence of yesteryear. Some of these targeted cancer treatments also have important effects on bone metabolism that are of importance to bone specialists. Finally, improved surgical and interventional radiologic options are contributing to the multidisciplinary care of >1 million patients with metastatic disease worldwide.
Through their profound effects on bone physiology, bone targeted treatments can potentially modify the process of metastasis and have important effects on disease outcomes as well as bone health. Metastasis prevention trials have reported variable outcomes in terms of disease recurrence with efficacy apparently influenced by tumour type and, at least in breast cancer, by levels of reproductive hormones. At least in breast cancer we now understand better the potential of BP to influence relapse and survival rates. In a recent initiative with the Early Breast Cancer Clinical Trials Group, we sought individual patient data for meta-analysis from 36 randomised trials that compared BP to no BP (placebo or open control) and evaluated the effect of adjuvant BP on disease outcomes. Data on 18 766 women were received, with 3453 and 2.106 breast cancer recurrences and deaths respectively. BPs reduced first distant recurrence in bone (RR=0.83; 95% CI 0.730.94, 2P=0.004) but not recurrence at other distant sites, or local or contralateral breast cancer recurrence. Importantly, there was a significant interaction between treatment efficacy and menopausal status with no apparent benefit for premenopausal women but highly significant reductions for postmenopausal women in bone recurrence (RR=0.72; 95% CI 0.600.86, 2P=0.0002) and breast cancer mortality (0.82; 95% CI 0.730.93, 2P=0.002). These findings are changing clinical practice and are being followed by adjuvant trials of other agents such as denosumab and in other disease settings such as prostate and lung cancers to see if we can build further on these exciting clinical observations and fulfill the preclinical promise of the past 25 years.