Denosumab: a new agent in the management of hypercalcemia of malignancy.

Hypercalcemia of malignancy is an oncologic emergency due to tumoral factors that stimulate osteoclast-mediated bone resorption. It requires a combination of recommended treatments (i.e., hydration, bisphosphonate and calcitonin), which may be deleterious in patients with compromised cardiac or renal function or may not control serum calcium levels long term. Recurrent or refractory hypercalcemia may preclude the use of chemotherapeutic agents needed to effectively treat the underlying cancer, which is the cause of hypercalcemia. Denosumab, a fully human monoclonal antibody against RANKL, inhibits the maturation, function and survival of osteoclasts. An open-label, single-arm study of denosumab in patients with hypercalcemia of malignancy despite recent bisphosphonate treatment revealed positive results. Thus, the US FDA recently approved denosumab for the indication of hypercalcemia of malignancy, increasing the options available for patients with this debilitating and life-threatening condition.

Denosumab treatment and infection risks in patients with osteoporosis: propensity score matching analysis of a national-wide population-based cohort study.

Introduction: Denosumab demonstrates efficacy in reducing the incidence of hip, vertebral, and nonvertebral fractures in postmenopausal women with osteoporosis. We present a population-based national cohort study to evaluate the infection risks in patients with osteoporosis after long-term denosumab therapy. Methods: We used the Taiwan National Health Insurance Research Database (NHIRD) to identify patients with osteoporosis. The case cohort comprised patients treated with denosumab. Propensity score (PS) matching was used to select denosumab nonusers for the control cohort. The study period was between August 2011 and December 2017. Our study comprised 30,106 pairs of case and control patients. Results: Patients receiving denosumab therapy had high risks of the following infections: pneumonia and influenza (adjusted hazard ratio [aHR]: 1.33; 95% confidence interval [CI]: 1.27 -1.39), urinary tract infection (aHR: 1.36; 95% CI:1.32 -1.40), tuberculosis (aHR: 1.60; 95% CI: 1.36 -1.87), fungal infection (aHR: 1.67; 95% CI:1.46 -1.90), candidiasis (aHR: 1.68; 95% CI: 1.47 -1.93), herpes zoster infection (aHR: 1.27; 95% CI: 1.19 -1.35), sepsis (aHR: 1.54; 95% CI:1.43 -1.66), and death (aHR: 1.26; 95% CI: 1.20 -1.32). However, the longer the duration of denosumab treatment, the lower the risk patients had of developing infections. Discussion: Denosumab therapy is associated with a higher infection risk at the early periods of treatment. Nevertheless, the risk attenuates significantly after the 2nd year of therapy. Clinicians should closely monitor infection status in patients with osteoporosis during the initial stages of denosumab therapy.

RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives.

RANKL/RANK/OPG system consists of three essential signaling molecules: i) the receptor activator of nuclear factor (NF)-kB-ligand (RANKL), ii) the receptor activator of NF-kB (RANK), and iii) the soluble decoy receptor osteoprotegerin (OPG). Although this system is critical for the regulation of osteoclast differentiation/activation and calcium release from the skeleton, different studies have elucidated its specific role in mammary gland physiology and hormone-driven epithelial proliferation during pregnancy. Of note, several data suggest that progesterone induces mammary RANKL expression in mice and humans. In turn, RANKL controls cell proliferation in breast epithelium under physiological conditions typically associated with higher serum progesterone levels, such as luteal phase of the menstrual cycle and pregnancy. Hence, RANKL/RANK system can be regarded as a major downstream mediator of progesterone-driven mammary epithelial cells proliferation, potentially contributing to breast cancer initiation and progression. Expression of RANKL, RANK, and OPG has been detected in breast cancer cell lines and in human primary breast cancers. To date, dysregulation of RANKL/RANK/OPG system at the skeletal level has been widely documented in the context of metastatic bone disease. In fact, RANKL inhibition through the RANKL-blocking human monoclonal antibody denosumab represents a well-established therapeutic option to prevent skeletal-related events in metastatic bone disease and adjuvant therapy-induced bone loss in breast cancer. On the other hand, the exact role of OPG in breast tumorigenesis is still unclear. This review focuses on molecular mechanisms linking RANKL/RANK/OPG system to mammary tumorigenesis, highlighting pre-clinical and clinical evidence for the potential efficacy of RANKL inhibition as a prevention strategy and adjuvant therapy in breast cancer settings.

Receptor activator of NF-κB (RANK)-mediated induction of metastatic spread and association with poor prognosis in renal cell carcinoma.

BACKGROUND: Inhibition of the receptor activator of NF-κB ligand (RANKL) has become a standard of care supportive treatment to prevent skeletal related events in cancer patients. Moreover, RANKL inhibition has been implicated with better survival outcome in lung cancer, while RANKL expression induces tumor progression and metastatic spread in vivo in breast cancer. Whether RANK/RANKL may have an impact on the pathogenesis of clear cell renal cell carcinoma (ccRCC) is currently unknown. PATIENTS AND METHODS: A retrospective tissue micro array (TMA)-study was carried out determining the expression of RANK/RANKL in primary tumors of 306 ccRCC patients. Additionally, 24 ccRCC cell lines were employed for in vitro analyses of the RANK/RANKL axis including cell proliferation, migration and anchorage independent growth. RESULTS: RANK (+) vs. RANK (-) tumors had both worse cancer specific survival (CSS) (6.3 vs. 1.3 years; p < 0.001) and recurrence free survival (RFS) (9.9 vs. 5.8 years; p < 0.001). RANK (+) (HR 2.21; p < 0.001) was an independent prognostic factor for CSS and RFS (HR 4.98; p < 0.001). RANKL treatment resulted in increased proliferation, soft agar growth, and colony formation of RANK (+) RCC cell lines, which could be reversed by treatment with an NF-κB inhibitor and with a combination of osteoprotegrin and RANKL in vitro. CONCLUSIONS: RANK is expressed in ccRCC tissue, correlates with clinicopathological features, survival outcome, and when stimulated with RANKL can induce ccRCC progression in vitro. Consequently, RANKL inhibition combined with standard of care treatment may be a promising approach to improve ccRCC patient's survival.