Bone remodeling is a process in which bone is broken down by osteoclasts and then replaced with new bone by osteoblasts During the development of skeletal related diseases such as osteoporosis, rheumatoid arthritis, multiple myeloma, and metastatic cancers, there is an imbalance between osteoclast and osteoblast activity, where there is more osteoclast resorption and less bone formation, causing bones to become brittle and more likely to fracture. (2) Complications of these skeletal related events (SREs) include reduced mobility, increased pain, fractures, and spinal cord compressions, surgical/radiologic procedures for bone lesions, and hypercalcemia. (3) It is estimated that 50-70% of patients with bone metastases will experience one of these SREs.(4, 5) Osteoclast function is controlled by osteoclast osteoprotegerin (OPG) and receptor activator of NFÎºB (RANK), and its ligand (RANKL)(6). RANKL binds to RANK on immature osteoclast cells and signal osteoclast formation, activation, proliferation and survival by activating the NFÎºB transcription factor (7). At the same time, Osteoblasts produce OPG, which suppresses bone turnover by binding to RANKL, preventing it from interacting with RANK. (8) Because of this mechanism, RANKL-RANK signaling was identified as a target to reduce the activity of osteoclasts and restore the balance between bone resorption and formation. (1) Denosumab, a human monoclonal antibody, was designed to bind to RANKL on the surface of both immature and mature osteoclasts and reduce osteoclast formation and activity, leading to increased bone mass and strength. (9, 10) The aim of this paper is to discuss the indications, recent evidence and safety surrounding denosumab use in patients with skeletal related events.
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Indication and Efficacy
Denosumab is currently available under two different brand names, Prolia and Xgeva. It is a given as a single 60 mg SC injection, either monthly or every 6 months depending on the indication, in the upper arm, upper thigh or abdomen, with no dose adjustments necessary for those with renal impairment.lexi Its half-life of approximately 26 days, and it does not appear to induce the formation of neutralizing antibodies.(8)
Prolia (dosed every 6 monthslexi) is used for the treatment of men and postmenopausal women with osteoporosis that are at a high risk for fracture, including "patients who have failed or are intolerant to other available osteoporosis therapy" mono. In the FREEDOM trial, denosumab demonstrated a 4.9% absolute risk reduction (ARR) in the incidence of vertebral fractures over 36 months, and also .showed a reduction in non-vertebral fracture and hip fractures. (10) When compared to alendronate, the DECIDE trial showed greater improvements in hip, femoral neck , and lumbar spine bone mineral density (BMD) scores after 12 months, demonstrating non-inferiority. (11) Prolia has also been used to treat androgen deprivation-induced bone loss in men with prostrate cancer and aromatase inhibitor induced bone loss in women with breast cancer.
Xgeva (dosed monthlylexi) is indicated to prevent skeletal related events (SREs) in patients with bone metastases from solid tumours. Unlike Prolia, it is indicated to reduce bone loss in patients not being treated with androgen depriving or aromatase inhibiting drugs. Bone metastases are very common in cancers, especially breast, prostrate, lung and multiple myeloma.(12) The incidence of bone metastasis is estimated to be 65% to 75% in patients with metastatic breast or metastatic prostrate cancer.(13, 14) Osteolytic bone lesions are thought to occur because tumor cells are able to independently secrete cytokines that activate the RANK system (14). Zolendronic acid, a bisphophonate currently being used for the prevention and treatment of SREs, has a number of issues such as reducing of SREs by only 30%, requiring intravenous administration, causing infusion reactions, and it is contraindicated in patients with severe renal impairment.(15)
A meta-analysis showed that denosumab, when compared to zoledronic acid or placebo, was more effective in delaying first and first-and-subsequent SREs, but concluded that more long term studies are needed in this area (3). The efficacy of denosumab was also shown in three large, randomized, double-blind phase III studies in patients with metastatic prostrate cancer, breast cancer, or multiple myeloma. These trials compared denosumab and zoledronic acid in their abilities to prevent and delay SREs from occurring. In patients with prostrate cancer, denosumab was shown to be superior to zoledronic acid at delay the first appearance of SREs (HR=0.82, p=0.008) (16). However,Â there was no significant difference between the two treatments in overall survival or disease progression.(17) In a studies performed in patients with multiple myeloma, denosumab was shown to be non-inferior to zolendronic acid in one study and superior in another at preventing SREs (HR=0.83, p=0.0007). (18, 19) Since multiple myeloma is characterized by weak brittle bones related to increases in osteoclast formation and activity, these results are very promising and more studies are currently ongoing (20). In patients with breast cancer, denosumab was shown to be superior at preventing SREs (HR=0.82, p=0.01)(21). Importantly, breast cancer bone metastases secrete numerous cytokines and growth factors that cause RANKL secretion from osteoblasts, which in turn causes more osteoclast differentiation and survival. (22). This process creates a vicious cycle where the released cytokines and growth factors stimulate further tumour proliferation and cell survival(23). This mechanism has led many researchers to begin to evaluate whether denosumab may be not only be effective at preventing SREs in breast cancer patients, but it may also be used to prevent tumour growth. To support this, other studies have also shown that denosumab may reduce tumour size by activing apoptosis and decreasing tumour proliferation. (15)
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Common adverse effects of denosumab include arthralgia, back pain, pain in extremity, musculoskeletal pain, peripheral edemas, cough, and dizziness.(24) Denosumab has also be shown to cause more hypocalcemia compared to zolendric acid or placebo, but can be managed by ensuring patients are supplemented with calcium and vitamin D.(4, 10, 11, 16, 21)
Osteonecrosis of the jaw (ONJ) is a serious adverse effect associated with intravenous bisphophonates (5). The occurrence of ONJ was examined in the three trials involving patients with metastatic bone disease discussed above, and it was found that ONJ occurred in 1.8% of patients receiving denosumab and 1.3% of patients receiving zolendronic acid. (25) Given that ONJ in an infrequent but serious adverse event, caution should be used in patients with risk factors for its development such as poor oral hygiene, exisiting oral infections, or concurrent use of corticosteroids. (5)
There have also been a number of serious adverse effects associated with denosumab use in patients. In the FREEDOM and DECIDE trials, there were small but statistically non-significant increases in the rates of cancer and serious infection.(10, 11) A recent meta-analysis and subsequent follow-up of nine randomized controlled trials involving patients with either postmenopausal osteoporosis, breast cancer or rheumatoid arthritis treated with denosumab showed a significant increase in the risk of serious infection (odds ratio 4.45, p= 0.03) (26, 27) This is thought to be due to the fact that RANKL is expressed on T cells and B cells (12). In mouse models, eliminating the RANK signaling pathway causes them to develop without lymph nodes (14). Furthermore, denosumab may block the activation of dendritic cells and make patients more susceptible to infection. (28)Therefore it may potentially weaken the immune system of patients by inhibiting the activation, differentiation and proliferation of these immune cells.(29) Since denosumab is being used in elderly patients and patients already immune-compromised by chemotherapy, more research is needed to determine the long term safety prior to becoming a first line agent.
Denosumab It's effects on resorption and BMD are reversible and does not induce neutralizing antibodies
Denosumab offers the advantage of being administered by subcutaneous injection, eliminating the need for patients to have to receive intravenous infusions. This also eliminates the occurrence of infusion reactions, a serious side effect that occurs frequently with zolendronic acid(21) Given that the frequency of adverse events are similar between denosumab and zolendronic acid, denosumab offers the advantage of having reversible effects on resorption that allow treatment to be stopped in the event of a serious adverse event (ref).
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Although the direct cost of denosumab is higher than zoledronic acid for patients with bone metastases, but when you factor in the cost savings of delayed SREs, one study showed that denosumab was more cost-effective than zoledronic acid.(30).
Denosumab has been shown to reduce the rate of skeletal related events and ultimately improve control of bone metastases. Due to its mechanism of action, there is promising evidence that it can also be used as an adjunct treatment option to reduce the size of metastatic tumours. Despite this evidence, more long term safety date is required before it becomes a mainstay in therapy and it should only be used after weighing the potential risks with the perceived evidence of efficacy.