**9.7 Upcoming agents: Toremifene citrate and denosumab**

The effects on BMD of toremifene citrate, a new SERM, were tested in a 6-month, placebocontrolled dose-finding study with 46 men with prostate cancer receiving ADT. An oral dose of 60 mg daily significantly improved BMD and decreased hot flushes (Steiner MS, et al., 2004). A 2-year, double blind, placebo- controlled phase-III multicentre study of oral toremifene 80 mg has been completed in 1389 ADT patients with advanced prostate cancer; this compound reduced new morphometric vertebral fractures (the primary endpoint) by 53% (p = 0.034). Bone mineral density at lumbar spine, hip, and femur was also increased significantly (p < 0.0001), and lipid profiles were improved compared with placebo (Smith MR, et al., 2004; Schwarz EM & Ritchlin CT, 2006).

In advanced prostate cancer, metastasis is sadly inevitable. Although bone metastases from prostate cancer have a predominantly osteoblastic appearance, histological findings (Roudier MP, et al., 2008) and analysis of bone turnover markers (Brown JE, et al., 2005; Demers LM, 2003), support the view that excess osteoclastic activity induces bone destruction in these metastases. The Receptor Activator of NF-B Ligand (RANKL) is the main driver of osteoclast formation, function, and survival (Boyle WJ, et al., 2003). Lymphocytes infiltrate the tumour, causing upregulation of nuclear factor-Kappa B (RANK) ligand (RANKL) and lymphotoxin (Luo et al., 2007). Denosumab is a fully human monoclonal antibody that specifically targets RANKL and is delivered by subcutaneous injection twice a year (Schwarz EM & Ritchlin CT, 2006). This therapy was found to be very effective in reducing fractures and was well-tolerated in the clinical settings of osteoporotic postmenopausal women (McClung MR, et al., 2006; Cummings SR, et al., 2009) and protecting BMD in osteopenic postmenopausal women receiving adjuvant aromatase inhibitors for breast cancer (Ellis GK, et al., 2008). More recently, denosumab (60 mg subcutaneously, every 6 months) was evaluated in a 36-month, phase-III, placebocontrolled randomized clinical trial involving 1468 men with non-metastatic prostate cancer who were receiving ADT.48 Compared with placebo, denosumab significantly improved BMD at all sites measured, including lumbar spine (the primary endpoint) by 6.7% (p < 0.001), total hip by 4.8% (p < 0.001), femoral neck by 3.9% (p < 0.001), and distal radius by 5.5% (p < 0.001) at 24 months; by the end of the trial (36 months), denosumab dramatically reduced the risk of new vertebral fractures (a secondary endpoint) by 62% (p = 0.006), but not overall survival in prostate cancer (Fizzazi et al., 2011).

A recent phase-III study comparing denosumab versus zoledronic acid (Fizazi K, et al., 2011) showed that denosumab was better than the established therapy, zoledronic acid, for the delay or prevention of skeletal-related events in patients with advanced prostate cancer, while there was no difference in overall survival or disease progression.
