Browsing by Subject "zoledronic acid"

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    A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America
    (Taylor & Francis, 2018) Raje, Noopur; Roodman, Garson David; Willenbacher, Wolfgang; Shimizu, Kazuyuki; García- Sanz, Ramón; Terpos, Evangelos; Kennedy, Lisa; Sabatelli, Lorenzo; Intorcia, Michele; Hechmati, Guy; Medicine, School of Medicine
    Objective: A large, pivotal, phase 3 trial in patients with newly diagnosed multiple myeloma (MM) demonstrated that denosumab, compared with zoledronic acid, was non-inferior for the prevention of skeletal-related events (SREs), extended the observed median progression-free survival (PFS) by 10.7 months, and showed significantly less renal toxicity. The cost-effectiveness of denosumab vs zoledronic acid in MM in the US was assessed from societal and payer perspectives. Methods: The XGEVA Global Economic Model was developed by integrating data from the phase 3 trial comparing the efficacy of denosumab with zoledronic acid for the prevention of SREs in MM. SRE rates were adjusted to reflect the real-world incidence. The model included utility decrements for SREs, administration, serious adverse events (SAEs), and disease progression. Drug, administration, SRE management, SAEs, and anti-MM treatment costs were based on data from published studies. For the societal perspective, the model additionally included SRE-related direct non-medical costs and indirect costs. The net monetary benefit (NMB) was calculated using a willingness-to-pay threshold of US$150,000. One-way deterministic and probabilistic sensitivity analyses were conducted. Results: From a societal perspective, compared with zoledronic acid, the use of denosumab resulted in an incremental cost of US$26,329 and an incremental quality-adjusted life-year (QALY) of 0.2439, translating into a cost per QALY gained of US$107,939 and a NMB of US$10,259 in favor of denosumab. Results were sensitive to SRE rates and PFS parameters. Limitations: Costs were estimated from multiple sources, which varied by tumor type, patient population, country, and other parameters. PFS and overall survival were extrapolated beyond the follow-up of the primary analysis using fitted parametric curves. Conclusion: Denosumab’s efficacy in delaying or preventing SREs, potential to improve PFS, and lack of renal toxicity make it a cost-effective option for the prevention of SREs in MM compared with zoledronic acid.
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    Halofuginone inhibits TGF-β/BMP signaling and in combination with zoledronic acid enhances inhibition of breast cancer bone metastasis
    (Impact Journals, 2017-09-23) Juárez, Patricia; Fournier, Pierrick G.J.; Mohammad, Khalid S.; McKenna, Ryan C.; Davis, Holly W.; Peng, Xiang H.; Niewolna, Maria; Mauviel, Alain; Chirgwin, John M.; Guise, Theresa A.; Medicine, School of Medicine
    More efficient therapies that target multiple molecular mechanisms are needed for the treatment of incurable bone metastases. Halofuginone is a plant alkaloid-derivative with antiangiogenic and antiproliferative effects. Here we demonstrate that halofuginone is an effective therapy for the treatment of bone metastases, through multiple actions that include inhibition of TGFβ and BMP-signaling., Halofuginone blocked TGF-β-signaling in MDA-MB-231 and PC3 cells showed by inhibition of TGF-β–induced Smad-reporter, phosphorylation of Smad-proteins, and expression of TGF-β-regulated metastatic genes. Halofuginone increased inhibitory Smad7-mRNA and reduced TGF-β-receptor II protein. Proline supplementation but not Smad7-knockdown reversed halofuginone-inhibition of TGF-β-signaling. Halofuginone also decreased BMP-signaling. Treatment of MDA-MB-231 and PC3 cells with halofuginone reduced the BMP-Smad-reporter (BRE)4, Smad1/5/8-phosphorylation and mRNA of the BMP-regulated gene Id-1. Halofuginone decreased immunostaining of phospho-Smad2/3 and phospho-Smad1/5/8 in cancer cells in vivo., Furthermore, halofuginone decreased tumor-take and growth of orthotopic-tumors. Mice with breast or prostate bone metastases treated with halofuginone had significantly less osteolysis than control mice. Combined treatment with halofuginone and zoledronic-acid significantly reduced osteolytic area more than either treatment alone. Thus, halofuginone reduces breast and prostate cancer bone metastases in mice and combined with treatment currently approved by the FDA is an effective treatment for this devastating complication of breast and prostate-cancer.
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    Short-courses of dexamethasone abolish bisphosphonate-induced reductions in bone toughness.
    (doi: 10.1016/j.bone.2013.06.004 Final article can be found at: http://www.sciencedirect.com/science/article/pii/S8756328213002226, 2013) Luo, Tianyi D.; Allen, Matthew R.
    Atypical femoral fractures, which display characteristics of brittle material failure, have been associated with potent remodeling suppression drugs. Given the millions of individuals treated with this class of drugs it is likely that other factors play a role in these fractures. Some evidence suggests concomitant use of corticosteroids may contribute to the pathogenesis although data in this area is lacking. The goal of this study was to assess the combined role of bisphosphonates and examethasone on bone mechanical properties. Skeletally mature beagle dogs were either untreated controls, or treated with zoledronic acid (ZOL), dexamethasone (DEX), or ZOL + DEX. Zoledronic acid (0.06 mg/kg) was given monthly via IV infusion for 9 months. DEX (5 mg) was administered daily for one week during each of the last three months of the 9 month experiment. Ribs were harvested and assessed for bone geometry, mechanical properties, and remodeling rate (n=3-6 specimens per group). DEX significantly suppressed intracortical remodeling compared to vehicle controls while both ZOL and the combination of DEX+ZOL nearly abolished intracortical remodeling. ZOL treatment resulted in significantly lower bone toughness, determined from 3-point bending tests, compared to all other treatment groups while the toughness in ZOL+DEX animals was identical to those of untreated controls. These findings suggest not only that short-courses of dexamethasone do not adversely affect toughness in the setting of bisphosphonates, they actually reverse the adverse effects of its treatment. Understanding the mechanism for this tissue-level effect could lead to novels approaches for reducing the risk of atypical femoral fractures.