Denosumab is a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa B ligand (RANKL).13 RANKL is a cytokine member of the tumor necrosis factor family and is an important mediator of osteoclast formation, function, and survival.14 Denosumab has been shown to increase bone mineral density (BMD) and suppress bone resorption in postmenopausal women with low BMD. When administered every six months via the subcutaneous (SC) route, denosumab reduced the risk of vertebral, hip, and nonvertebral fractures in postmenopausal women compared with placebo-treated women.15 When compared with alendronate, denosumab provided a greater BMD increase with greater decreases in bone turnover markers.
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Explore This IssueJanuary 2010
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A major concern about long-term use of denosumab relates to its possible effects on the immune system, because RANKL is expressed not just in bone cells but also in immune cells.16 Neither Cummings et al nor Smith et al. observed an increased rate of serious infections related to denosumab.15,17 However, Cummings et al reported significant increases in rates of eczema and hospitalizations for cellulitus in denosumab when compared with placebo. A previous study of 314 patients treated with denosumab reported that six patients developed neoplasms and three developed serious infections, whereas none of the 46 patients in the placebo group had such complications.18 Although not statistically significant, these findings support ongoing surveillance of patients receiving denosumab, particularly when the drug is used in the community setting in patients with coexisting illnesses that might have excluded them from participating in clinical trials. Finally, cost is increasingly relevant. The average wholesale price for the most direct competitor for denosumab, zoledronic acid, is approximately $1,300 per year. Given the relatively marginal clinical differences between these two drugs, a higher cost of denosumab would considerably limit its use. Denosumab is currently in clinical trials for the treatment of RA.
Compared with agents already approved for osteoporosis, denosumab may enhance compliance because in clinical trials, it was administered as a SC injection every six months. Most current treatments are administered daily, weekly, or monthly. The bisphosphonates are quite effective, but can lead to gastrointestinal toxicity or osteonecrosis of the jaw, with some studies showing decreased medication adherence due to these potential adverse events.19 The use of hormone therapies has decreased, likely reflecting concerns over data from the Women’s Health Initiative, indicating an increased risk of stroke and venous thromboembolism with estrogen use. Selective estrogen receptor modifiers (SERMs), of which raloxifene is currently the only agent FDA-approved for osteoporosis, can also increase thromboembolic events; therefore, SERMs are contraindicated in certain patient populations. Raloxifene can also increase vasomotor symptoms, such as hot flashes and leg cramping. According to the Wyeth/Pfizer pipeline, their SERM bazedoxifene has been filed for FDA approval.20 A bazedoxifene/conjugated estrogen combination product is currently in phase III clinical trials. However, if approved, the use of this combination product may also be limited, because it combines estrogen and a SERM. Salmon calcitonin (Miaclacin) is administered intranasally and is a relatively low-potency agent. It is often reserved for osteoporosis patients who are unable to take other agents. Teriparatide (Forteo), a human recombinant parathyroid hormone administered as a daily SC injection, is an effective treatment modality as well. However, it is not recommended for use beyond two years because it has not been studied beyond two years. Teripartide must also be given by injection, which may decrease adherence. Dose-limiting side effects include dizziness, nausea, and leg cramps. Eli Lilly and TransPharma Medical are studying transdermal teriparatide, which is in phase II clinical trials.21 Use of the transdermal route will likely enhance adherence, yet there are many individuals who have difficulty tolerating adhesives in transdermal products.