Comparison of the efficacy and safety of denosumab versus bisphosphonates in breast cancer and bone metastases treatment: A meta-analysis of randomized controlled trials

Abstract

Breast cancer is the most common type of cancer in females worldwide. Patients with breast cancer and bone metastases may experience increased osteoclast activity, resulting in local bone destruction and skeletal complications, including pain, hypercalcemia and skeletal-related events. Intravenous bisphosphonates (BPs) are the standard treatment administered to patients with breast cancer and bone metastases to prevent skeletal-related events. However, in certain patients, BPs may cause renal toxicity, acute-phase reactions and osteonecrosis of the jaw. More effective, safer and more tolerable therapies, which prevent bone destruction and skeletal complications, are required in order to improve patient quality of life. Denosumab is a fully human monoclonal antibody that binds to and neutralizes receptor activator of nuclear factor-κB ligand, which is a key mediator in the pathogenesis of a broad range of skeletal diseases, thereby inhibiting osteoclast function and bone resorption. Therefore, we conducted a meta-analysis to compare both the safety and efficacy of denosumab and BPs in the treatment of breast cancer and bone metastases. Five databases, two clinical trial registry platforms and reference lists of relevant papers were analyzed. The meta-analysis concluded that denosumab was more effective at preventing pain and skeletal-related events than BPs, in patients with breast cancer and bone metastases. Patients receiving denosumab demonstrated a higher level of clinical improvement in terms of health-related quality of life than patients receiving BPs. Compared with BPs, denosumab reduced the incidence of certain indicators of adverse events, including pyrexia, bone pain, edema and renal failure.

Side Effects of Bone-Targeted Therapies in Advanced Breast Cancer

“…In large meta-analyses of comparative trials in metastatic breast cancer patients, within 2 years of treatment no statistically significant difference in the incidence of ONJ could be detected between denosumab (2.0% of cases) and zoledronate (1.4%) [41,55,56,57]. Among nitrogen-containing bisphosphonates, there may be a higher risk of ONJ with zoledronate compared with pamidronate or ibandronate [12].…”

Pain management of the cancer patient

“…Positive outcome has been seen in early studies on patients with bone metastases, who have been treated with denosumab. Compared to bisphosphonates, denosumab has better analgesic profile, prevents skeletal-related events and less adverse effects [89].…”

Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis

“…Findings from these studies suggest that bisphosphonates accumulate in bone but the effect on resorption is not well understood (54). Distinct cellular distribution and action could explain the difference in the degree, speed and action of anti-resorptive effects between DMab and bisphosphonate (18, 31, 58). In contrast to bisphosphonate, DMab significantly reduced bone-specific alkaline phosphatase at 6 and 12 months compared with pretreatment, but had no effect on tartrate-resistant acid phosphatase 5b levels, emphasizing the effect of DMab more on bone formation than resorption rate(58).…”

“…DMab was approved by the FDA for 1) postmenopausal women with osteoporosis at high risk for fracture; 2) fractures arising from metastastic bone cancer; and 3) prevention of skeletal-related events in patients with bone metastases from solid tumors 4) adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity (13-18). Elevated OC activity coupled with increased OC in bone are shared features of disorders that respond to DMab.…”

“…Based on its ability to enhance bone quality and limit the progression of inflammatory bone diseases and cancer metastasis, the efficacy and safety of DMab has been examined in ongoing and completed trials. Thus, despite divergent molecular mechanisms, DMab exerts beneficial effects in cancer, inflammatory arthritis and osteoporosis that far outweigh the rare and often minor side effects including hypocalcemia and local infection (18, 21, 22). Herein we provide an update on the role of DMab in RA from the molecular, cellular and clinical perspective.…”