Review Minimizing cancer’s impact on bone with denosumab: current and future perspectives William Gradishar, MD,1 Julie Gralow, MD,2 Stephen Jones, MD,3 and Helen Collins, MD4 1 Northwestern University Feinberg School of Medicine, Chicago, Illinois; 2 University of Washington School of Medicine, Seattle, Washington; 3 US Oncology Research Inc, The Woodlands, Texas; 4 Amgen Inc, Thousand Oaks, California Bone metastasis is a serious complication of advanced cancer. It is most commonly observed in patients with metastatic breast and prostate cancers, but also occurs in most other metastatic solid cancers. Without treatment, patients may experience complications including intractable bone pain, hypercalcemia, fracture, spinal cord compression and/or a requirement for surgical or radiotherapeutic intervention. In 2010, denosumab, a fully human monoclonal antibody that inhibits RANK ligand (RANKL) and subsequent osteoclast-mediated bone destruction, was approved by the Food and Drug Administration for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. This article reviews the role of denosumab in preventing SREs due to bone metastases, treating bone loss due to hormone-ablative cancer therapies, and describes denosumab’s safety profile and potential future indications under investigation. mprovements in cancer treatment have allowed breast and prostate cancers.5-7 This review dis- patients with common cancers, such as breast cusses the burden of bone metastases and the role and prostate cancers, to live longer with their of denosumab in preventing complications of I 1-3 disease. In addition to extending life, an impor- bone metastases in patients with advanced cancer tant goal of therapy is to minimize cancer’s impact and bone loss in patients receiving hormone ab- on functional status. Bone metastasis is a common lative therapies. The safety profile of denosumab complication of advanced cancer, occurring in a ma- and current trials are also described. jority of patients with solid tumors, particularly breast and prostate cancers.4 Bone metastases often Bone metastases impact quality of life, causing pain, fractures, cord Bone metastases develop via a multistep process compression, and secondary hypercalcemia. These that begins with primary tumor cells entering sys- complications may require therapeutic interven- temic circulation, avoiding detection by the im- tions such as radiation and surgery, which can mune system, adhering to the vascular endothe- further impact the patient’s functional status.4 lium, and invading the skeletal stroma.8 Under Recognizing the importance of maintaining skel- normal conditions, skeletal integrity is maintained etal integrity in these populations, the National through a continuous process of bone remodeling, Comprehensive Cancer Network (NCCN) and in which old bone is resorbed by osteoclasts and the American Society of Clinical Oncology (ASCO) replaced by new bone formed by osteoblasts.9 recommend bone-modifying agents such as deno- These bone remodeling processes and the ana- sumab or bisphosphonates as standard treatment tomic features of bone render it a favorable envi- for patients with bone metastases secondary to ronment for tumor cell survival and growth.10 Growth factors, cytokines, and calcium released Manuscript received October 8, 2012; accepted January 23, 2013. by bone during the resorption process support the Correspondence William Gradishar, MD, Northwestern survival and proliferation of infiltrating cancer University Feinberg School of Medicine, Suite 850, 676 N Saint cells.11,12 Cancer cells, in turn, secrete growth Clair, Chicago, IL 60611 ([email protected]). Disclosures Dr Gradishar has been an advisory board member factors and cytokines that increase the synthesis for Amgen Inc; Julie Gralow receives research funding from and maturation of osteoblasts, leading to an in- Amgen, Novartis, Roche and Genentech; Stephen Jones has crease in RANK ligand (RANKL). Increases in been a consultant for Novartis and a consultant and speaker’s bureau participant for Amgen; and Helen Collins is an em- Commun Oncol 2013;10:235-243 © 2013 Frontline Medical Communications ployee of Amgen and has stock ownership in Amgen. DOI: 10.12788/j.cmonc.0024 Volume 10/Number 8 August 2013 Ⅲ COMMUNITY ONCOLOGY 235 Review term care requirements. An estimated 12,700 cancer pa- tients in the United States develop spinal cord compres- sion each year, with breast, prostate, and lung cancer each accounting for 15%-20% of cases.17 Clinical trials evaluating bone metastases have used skeletal-related events (SREs) to specify study endpoints, defined as a composite of cord compression, fracture, radiation therapy to the bone, and surgical stabilization of bone. Other bone-related events such as pain are not included in the definition of SRE. The rate of SREs varies according to tumor type. For example, prior to the advent of bone-targeted treatments, breast cancer patients with bone metastases experienced a mean 3.7 SREs per patient per year, or 1 every 3-4 months.18 As patients with bone-only metastatic breast cancer now have an ex- pected median overall survival (OS) of about 5 years,19 the prevention of SREs becomes greatly important. Furthermore, both breast and prostate cancer patients who experience 1 SRE are at higher risk for developing 20,21 FIGURE 1 Cycle of cancer-induced osteolytic bone disease. Tumor- subsequent SREs. induced bone resorption leads to the release of growth factors and All SREs can impact patients beyond the acute event. cytokines that support tumor survival and growth. In a recent evaluation of more than 2,000 patients with Abbreviations: BMP, bone morphogenetic protein; FGF, fibroblast growth factor; IGF, insulin-like growth factor; IL-6, interleukin-6; breast and prostate cancers admitted to the hospital for an M-CSF, macrophage colony-stimulating factor; PDGF, platelet- SRE, 41.6% of prostate cancer patients and 34.4% of derived growth factor; PGE2, prostaglandin E2; PTHrP, parathyroid breast cancer patients were not discharged to their homes hormone-related peptide; TGF-␤, transforming growth factor-␤; TNF, tumor necrosis factor. after acute hospitalization, but rather went to a skilled nursing or other facility, or died.22 The impact of bone metastases and its complications can reduce quality of life RANKL contribute to increased osteoclast formation, and be devastating to patients who are already facing a limited life expectancy. function, and survival that ultimately enhance bone re- sorption, causing a vicious cycle of cancer-induced bone Bisphosphonates destruction and tumor cell growth (Figure 1).11,12 Bisphosphonates have been used to treat bone metastases Burden of bone metastases since the initial approval of pamidronate for breast cancer and multiple myeloma in 1998. They bind with high Bone metastases are the most common cause of chronic affinity to bone minerals such as calcium and reduce pain in cancer patients. However, the pathophysiological osteoclast-mediated bone resorption (Table 1). Zole- mechanisms underlying bone pain are unclear. Possible dronic acid (ZA) was approved in the US in 2002 based mechanisms include stretching of the periosteum or nerve on randomized clinical trials showing that over a median entrapment due to the growing tumor, fractures caused by duration of 10.5 months, fewer metastatic prostate cancer osteolytic bone destruction, and acidification of the local patients who received the 4 mg dose of ZA had an SRE microenvironment, which may activate nociceptive sig- compared with placebo (33% vs 44%, respectively; P ϭ 13-16 naling pathways. Approximately 35%-70% of pa- .021; 422 patients) and over a median 3.8 months, fewer tients with stage IV solid tumors eventually develop bone patients with metastatic solid tumors other than breast metastases depending upon the tumor type. In addition to and prostate cancer had an SRE (38% with ZA vs 44% pain medications, radiation therapy and/or surgical pro- with placebo; P ϭ not statistically significant; 507 cedures may be required to relieve pain, preserve function patients).23-25 Also, in a secondary analysis, the 4 mg ZA and/or maintain skeletal integrity. Potentially the most dosing group demonstrated an improvement in the time catastrophic outcome for patients with metastatic bone to first SRE for prostate cancer (HR, 0.67; 95% CI, cancer is spinal cord compression due to collapse of ver- 0.49-0.91; P ϭ .011; and for other solid tumors (HR, tebrae or extension of bone metastases into the epidural 0.73; 95% CI, 0.55-0.96; P ϭ .023; P-values not adjusted space which can lead to incontinence, paralysis, and long- for multiple significance testing).25 In a study of patients 236 COMMUNITY ONCOLOGY Ⅲ August 2013 www.CommunityOncology.net Gradishar & Gralow et al TABLE 1 Mechanisms of action for antiresorptive agents Agent Name (administration) Mechanism of action Bisphosphonates Clodronate (oral)a Metabolized inside of osteoclasts into nonhydrolyzable (non–nitrogen-containing) ATP causing apoptosis72,73 Bisphosphonates (nitrogen-containing) Zoledronic acid (IV) Bind to bone mineral and are incorporated into bone, then Pamidronate (IV) internalized by osteoclasts to cause apoptosis by Ibandronate (IV or PO) inhibiting farnesyl pyrophosphate synthase (FPP) in the Alendronate (PO) mevalonate pathway, preventing the formation of two Risedronate (PO) metabolites (farnesol and geranylgeraniol) that are involved in protein attachment to cell membranes and