pde inhibitor Introduction Despite advances in breast

Introduction Despite advances in breast cancer treatment, bone remains the most common site of pde inhibitor [1,2] occurring in around 70% of patients with metastatic disease [3]. Bone metastases are incurable and associated with significant morbidity in terms of fractures, pain, and reduced quality of life. Bone destruction occurs from disruption of the finely controlled balance between bone resorption (by osteoclasts) and formation (by osteoblasts), resulting in net bone breakdown [4]. Increased understanding of the pathogenesis of bone disease has resulted in the development of a number of bone-targeted agents (BTAs), the most widely used clinically being inhibitors of osteoclastogenesis and osteoclast activation [i.e. bisphosphonates, or receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (e.g. denosumab)] [5]. However, despite the use of these increasingly potent BTAs, progress in terms of absolute reductions in the occurrence of skeletal related events (SREs) is modest, and further basic, translational, and clinical research is clearly needed [6–12]. The Bone and the Oncologist New Updates (BONUS) meeting is an annual Canadian multidisciplinary conference on the interaction of bone and cancer biology. Each year, clinical oncologists, basic scientists, and other health researchers gather to discuss the discoveries in bone research and their implications for cancer patients [13]. The most recent conference, BONUS 8, was held in Ottawa in April 2013 with featured speakers from across Canada and the United States. Topics of discussion were diverse, and ranged from prevention of skeletal metastases to the exploration of biomarkers as tools to guiding treatment. As part of this meeting׳s mandate is to ensure publication of findings to as broad an audience as possible this commentary was written to assimilate key presentations from a number of experts in the area and focus on where the field is moving, or needs to move, if we are to make further progress.
Bone specific therapy in metastatic disease—should we curb our enthusiasm? Quite simply the objectives of any therapy should be the prolongation of life and/or improvement of quality of life. All other endpoints are clinically relevant only if they are associated with these goals. We all recognize that bone metastases are common in breast cancer and cause significant morbidity. They may lead to SREs, including pathologic fractures, need for surgery or radiation to bone, spinal cord compression, and hypercalcemia [14]. These complications result in loss of autonomy, pain, and consumption of significant healthcare resources. Ultimately they may also lead to decreased survival [15]. Bone-targeted therapy with bisphosphonates and more recently, denosumab, has been seen as an important part of anti-cancer therapy. In the bone microenvironment, bisphosphonates may exert anti-tumor effects via attenuation of tumor adhesion and invasion, and induction of tumor cell apoptosis [16]. This class of drugs may also indirectly suppress tumor proliferation by virtue of their anti-angiogenic effects [17]. Denosumab is an inhibitor of the RANK ligand, a factor that promotes osteoclast differentiation and activation, and interruption of this interaction may lead to decreased bone resorption and destruction [12]. Both bisphosphonates and denosumab have been shown to be effective in reducing SREs [12,18,19]. However, while bisphosphonates and denosumab are effective in preventing and delaying SREs, none have yet shown a beneficial effect on overall or progression free survival [12,20,21]. Moreover, the benefit in terms quality of life for patients with metastatic cancer from the use of these bone-targeted agents is also unclear. While long term follow up of two large trials comparing pamidronate to placebo showed that patients in the pamidronate arm experienced less pain, the overall quality of life was not different between the arms [20]. Similarly, another trial comparing zoledronic acid to placebo showed that while zoledronic acid did improve pain control slightly compared to placebo, it did not improve the overall quality of life for patients on this drug [21]. Lastly, in a trial comparing denosumab to zoledronic acid in metastatic breast cancer, statistical improvements in quality of life was observed with denosumab only at a minority of time points during follow up and the analysis was compromised by the effects of multiplicity [19].