Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases

Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 54.37.117.73 on 13-Jul-2018 For personal use only. REVIEW Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases Thomas J Polascik Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC, USA Abstract: Bone metastases frequently occur in patients with advanced solid tumors, particularly breast and prostate cancers, and nearly all patients with multiple myeloma have some degree of skeletal involvement. The strides made in treating these primary tumors have extended median survival times and thereby increased patient risk for skeletal-related events (SREs), including pathologic fractures, spinal cord compression, need for palliative radiation therapy or surgery to bone, and hypercalcemia. Bisphosphonates, inhibitors of osteoclastic bone resorption that were first established as treatment of osteoporosis, have been shown to prevent and/or delay SREs related to malignancy. The results of a large, randomized phase 3 study comparing zoledronic acid and pamidronate in breast cancer or multiple myeloma patients with osteolytic lesions showed that the incidence of SREs, time to first SRE, and risk of developing a SRE were similar between treatment groups. However, in patients with solid tumors (excluding breast or prostate cancer) metastatic to the bone, only zoledronic acid has demonstrated clinical efficacy. Although bone turnover marker levels, such as N-telopeptide of type I collagen, have been shown to correlate with clinical response, additional studies are needed to validate their ability to predict response to bisphosphonate therapy. Keywords: bisphosphonates, prevention, skeletal-related events, bone metastases, cancer Introduction Correspondence: Thomas J Polascik Division of Urology, Department of Surgery, Duke University, Box 2804, Yellow Zone, Durham, NC 27710, USA Tel +1 919 684 4946 Fax +1 919 684 5220 Email Osteoporosis, a skeletal condition common in postmenopausal women and aging men, is characterized by low bone mass, destruction of bone microarchitecture, and increased bone turnover resulting in decreased bone strength and consequent susceptibility to fractures.1,2 Osteoporotic fractures, such as fractures of the hip, vertebral body, and distal forearm, may lead to decreased quality of life (QOL), disability, and possibly death. In the last decade, bisphosphonates, compounds that inhibit osteoclastic bone resorption, have been the most significant contribution to the advancement in osteoporosis treatment; clinical trials have demonstrated a reduction in vertebral fractures of 40% to 50% and nonvertebral fractures (including hip fractures) of 20% to 40%.1,3 Bisphosphonates approved by the United States Food and Drug Administration (FDA) for the prevention and/or treatment of osteoporosis include alendronate, alendronate plus vitamin D, ibandronate, risedronate, risedronate with calcium, and zoledronic acid.4–10 Because their bioavailability is quite low, oral agents usually require daily or weekly administration (with the exception of ibandronate, which may be administered monthly) that can contribute to low patient compliance rates.6–9 Intravenous (IV) bisphosphonates may be administered less frequently (eg, on a monthly, quarterly, or yearly basis).6,10–12 In general, patient compliance rates with prescribed IV bisphosphonate regimens are higher than with oral bisphosphonates. Drug Design, Development and Therapy 2009:3 27–40 © 2009 Polascik, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) 27 Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 54.37.117.73 on 13-Jul-2018 For personal use only. Polascik In addition to osteoporosis, bisphosphonates have been used to prevent and/or treat cancer-related bone complications.3,13 Patients who develop bone metastases are at increased risk for developing skeletal-related events (SREs), such as intractable bone pain requiring opioid analgesics or palliative radiation therapy, pathologic fractures, spinal cord compression, a need for surgery, and hypercalcemia of malignancy (HCM).14 SREs are a consequence of excessive bone metabolism, primarily bone resorption, which characterizes malignant bone lesions.3 Local bone pain requiring radiation therapy and pathologic fractures are the most commonly reported SREs.3 As a result of advancements in the primary treatment of several solid tumors and hematologic malignancies, patients are surviving longer, placing them at an increased risk for developing bone metastasis and SREs that may complicate their clinical course, adversely affect QOL, and increase medical costs.14–16 Bone metastases are particularly prevalent in patients with advanced metastatic breast or prostate cancers, affecting approximately 70% of patients.3 Although observed less frequently, bone metastases also occur in patients with lung, kidney, and thyroid tumors.17 Nearly all patients with advanced multiple myeloma (MM) develop bone involvement during the course of their disease since this malignancy colonizes in the bone marrow.14,18 Metastatic bone disease Under normal circumstances, bone homeostasis is achieved through balanced resorption of old bone by osteoclasts and formation of new bone by osteoblasts.19 Metastatic bone disease alters the normal bone remodeling process by causing osteolytic bone destruction and abnormal osteoblastic bone formation, often with one process more dominant than the other, resulting in an imbalance in normal bone homeostasis.18–20 Although historically bone metastases from breast cancer or MM have been characterized as osteolytic lesions and prostate cancer bone metastases have been primarily osteoblastic in nature, recent evidence suggest that both bone processes are present in many patients.18,20 Without bisphosphonate treatment, it is estimated that patients with bone metastases from advanced cancer will experience, on average, 2 to 4 SREs per year.17 Thus, bone complications of cancer are a considerable clinical concern, and preventing or delaying the occurrence of such events is an important treatment objective. Although palliation has traditionally been the primary goal of therapy, the introduction of bisphosphonates has afforded oncologists with an effective therapeutic option for preventing and/or treating SREs associated with bone metastases. 28 Powered by TCPDF (www.tcpdf.org) Mechanism of action of bisphosphonates Because of their ability to diminish bone resorption and subsequently normalize calcium levels, prevent development of new osteolytic lesions, and reduce the risk of fractures, bisphosphonates are the treatment of choice for skeletal complications of malignancy.21 Bisphosphonates are pyrophosp (...truncated)