Numerous animal studies have demonstrated beyond doubt that
Numerous animal studies have demonstrated beyond doubt that effective inhibition of osteoclastogenesis or osteoclast function significantly reduces metastatic tumour growth in bone [13–20]. Likewise, clinical trials in patients with non-metastatic or metastatic cancers established that treatment with “anti-resorptive” agents such as bisphosphonates or the anti-RANKL antibody, denosumab, resulted in significant reductions in the incidence, progress or complications of bone metastases [21–23]. Despite these significant developments, complications of bone metastases still occur in up to 50% of patients even whilst receiving anti-resorptive therapy [1,4], indicating that there are still significant unmet needs in the prevention and treatment of metastatic bone disease.
Types of bone metastasis Bone metastases have generally been characterized as osteolytic or osteoblastic based on their radiographic appearance . Osteolytic lesions are caused by increased osteoclast activity accompanied by a concomitant absolute or relative decrease in osteoblast number or activity. This results in net bone resorption [7,24] with little or no associated bone repair. In contrast, osteoblastic lesions are characterized by abnormal bone formation around tumour cell foci, but this typically also co-exists with increased osteoclast activity. Thus, both types of cancer metastasis to bone are characterised by significantly accelerated bone resorption with the radiographic appearance depending on the concurrent levels of bone formation. These tumour-induced changes in bone thiostrepton can clinically be identified and monitored through the measurement of bone turnover markers, which correlate with both tumour burden and therapy-induced reductions in skeletal related events [1,25–35]. Thus, the classification of metastatic bone lesions into osteolytic and osteoblastic represent no less than the two extremes of a continuum in which the normal bone remodelling process becomes dysfunctional. Furthermore, patients can present with both osteolytic and osteoblastic lesions, and in fact, many bone metastases are mixed in nature, containing both lytic and blastic elements . For example, breast cancer predominantly causes osteolytic metastases but at least 20% of patients present with mixed osteolytic-osteosclerotic lesions . Conversely, prostate cancer presents mostly with osteoblastic lesions although a concurrent increase in bone resorption invariably occurs [2,4,36]. In patients with advanced bone metastases, high circulating levels of bone resorption markers, such as the aminoterminal telopeptide of type I collagen (NTX), were seen regardless of whether the lesions were radiographically lytic, blastic or “mixed” [30,37,38]. This indicates that all types of bone metastases contain an element of osteoclast activation, and this has been confirmed histologically. The role of osteoclasts in the spectrum of metastatic bone lesions is also supported by the fact that anti-resorptive therapy effectively reduces skeletal related events independent of whether there is predominantly lytic or blastic metastatic bone disease [23,39,40].
The bone microenvironment
The ‘vicious cycle’ of metastatic tumour growth in bone The concept of a ‘vicious cycle’ supporting and maintaining metastatic tumour growth in bone was first introduced by Mundy and Guise in 1997 . The model successfully explains how bone and cancer cells interact in a feed-forward loop to allow and perpetuate cancer cell growth within the bone microenvironment. In its essence, the model describes how tumour cells communicate with osteoblasts, which ultimately leads to osteoclast activation and accelerated bone resorption. This not only makes room for the cancer to grow, but also triggers the release of growth factors embedded into the degraded bone matrix. These growth factors then promote further tumour growth, resulting in the production of more pro-resorptive signals by the cancer (Fig. 1).