Abstract
Over the past decade, osteoclast-directed therapies have been increasingly applied in patients with cancer bone disease. The bone is a common metastatic site for many malignancies, notably carcinomas. It is held that complex bidirectional communication between bone cells and cancer cells activates a vicious circle that eventually leads to the clinical appearance of metastases and relevant morbidity. Excess osteoclast-mediated bone resorption plays an important pathogenetic role, even in metastases referred to as osteoblastic in nature (typically those from prostate cancer). As a consequence, bone architecture is altered, resistance to mechanical stress is lowered, and fractures may occur. Besides degrading the bone matrix, osteoclasts might also play a role in releasing dormant cancer cells from bone. Such a pro-metastatic function would fit well with the observations of reduced presence of disseminated tumour cells in bone marrow of breast cancer patients treated with the aminobisphosphonate zoledronic acid, a potent anti-osteoclastic agent. Pertinently too, much attention has been paid to the results of the ABCSG-12 study, which showed an increased disease-free survival in premenopausal women with oestrogen receptor-positive early breast cancer who received zoledronic acid additive to their adjuvant endocrine therapy. Bisphosphonates (BPs) are synthetic derivatives of inorganic pyrophosphate. After administration, BPs concentrate at skeletal sites where active remodelling takes place. They are incorporated into osteoclasts under the acidic conditions of the resorbing lacunae. Nitrogen-containing BPs interfere with the mevalonate pathway and hence disrupt the protein trafficking essential for cytoskeleton integrity, cell function and survival. The action on the mevalonate pathway has also been credited, together with other mechanisms, with a role in subserving anti-proliferative, pro-apoptotic effects of amino-BPs directly on cancer cells. Such effects could complement those of chemotherapeutic agents. Interestingly, the results of the neo-adjuvant chemotherapy subset of the AZURE study have shown that adding zoledronic acid has a significant beneficial effect on the residual tumour size at surgery and on the pathological response. The anti-resorptive, anti-osteoporotic effects of BPs across a broad spectrum of bone diseases, first of all primary osteoporosis, provide the rationale for their use in preventing and treating cancer treatment-induced bone loss. The same holds true for SERMs in postmenopausal patients with breast cancer given aromatase inhibitors, and for de-nosumab in patients with prostate cancer given androgen-deprivation medication. The basic concept of SERMs is that they act as oestrogen agonists on bone cells, but have an antagonist or neutral action on oestrogen-sensitive reproductive tissues, including breast. Indeed, the first-generation SERM tamoxifen is used worldwide for its anti-oestrogenic properties in breast cancer. The second-generation SERM raloxifene and the third-generation SERM bazodoxifene, on the other hand, have as a primary (and approved) application the prevention and treatment of post-menopausal osteoporosis. SERMs display a structural heterogeneity, variable interactions with the oestrogen receptors (ER-α, ER-β) and subsequent conformational changes, and may have differential effects depending on the microenvironment in which they act. Therefore, the efficacy and safety of SERMs in any oncological setting need to be evaluated individually. Since a vast body of literature supports the concept that RANKL, a member of TNF family, functions as a major effector molecule of osteoclast-mediated bone resorption, there is a rationale for developing RANKL inhibition as a targeted therapy in bone diseases. Denosumab is a fully human monoclonal Ig G2 antibody which mimics the natural bone-protecting action of the decoy receptor of RANKL, osteoprotegerin. Importantly, denosumab binds RANKL with high affinity, but not other ligands of the TNF family, such as TRAIL. To date, denosumab administered subcutaneously at 6-month intervals has been found to be beneficial in postmenopausal women with osteoporosis, as well as in men with androgen deprivation-induced low bone mass. Denosumab was well tolerated; its rapid yet sustained anti-resorptive action has been consistently documented. This action has already been confirmed in patients with neoplastic bone involvement, including lytic metastases from carcinomas and multiple myeloma. Accumulating evidence supports the view that denosumab will be an important additional option for individualising therapy in patients with cancer bone disease.