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      Use of ibandronate in the prevention of skeletal events in metastatic breast cancer

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          Abstract

          Bone metastasis from breast cancer often cause significant morbidity including pain, impaired mobility, pathological fracture, and spinal cord compression. Bisphosphonates play an important role in preventing these skeletal related events and are the standard of care for patients with bone metastasis from breast cancer. Ibandronate is a highly potent bisphosphonate available in both intravenous and oral preparations. It has been shown in clinical trials to be effective in reducing skeletal complications and also significantly improve quality of life up to 96 weeks. Unlike other intravenous bisphosphonates, ibandronate has minimal renal toxicity, allowing safe outpatient administration, reducing the need for hospital attendance and safety monitoring. Early trials have shown ibandronate may also be effective in high doses for palliation of opioid-resistant pain from bone metastasis, and as a second-line agent in patients developing a skeletal complication whilst receiving another bisphosphonate.

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          Most cited references 54

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          Protein prenylation: molecular mechanisms and functional consequences.

          Prenylation is a class of lipid modification involving covalent addition of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoids to conserved cysteine residues at or near the C-terminus of proteins. Known prenylated proteins include fungal mating factors, nuclear lamins, Ras and Ras-related GTP-binding proteins (G proteins), the subunits of trimeric G proteins, protein kinases, and at least one viral protein. Prenylation promotes membrane interactions of most of these proteins, which is not surprising given the hydrophobicity of the lipids involved. In addition, however, prenylation appears to play a major role in several protein-protein interactions involving these species. The emphasis in this review is on the enzymology of prenyl protein processing and the functional significance of prenylation in cellular events. Several other recent reviews provide more detailed coverage of aspects of prenylation that receive limited attention here owing to length restrictions (1-4).
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            Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras.

            Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of metabolic bone diseases. Although the molecular targets of bisphosphonates have not been identified, these compounds inhibit bone resorption by mechanisms that can lead to osteoclast apoptosis. Bisphosphonates also induce apoptosis in mouse J774 macrophages in vitro, probably by the same mechanisms that lead to osteoclast apoptosis. We have found that, in J774 macrophages, nitrogen-containing bisphosphonates (such as alendronate, ibandronate, and risedronate) inhibit post-translational modification (prenylation) of proteins, including the GTP-binding protein Ras, with farnesyl or geranylgeranyl isoprenoid groups. Clodronate did not inhibit protein prenylation. Mevastatin, an inhibitor of 3-hydroxy-3-methylglutatyl (HMG)-CoA reductase and hence the biosynthetic pathway required for the production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, also caused apoptosis in J774 macrophages and murine osteoclasts in vitro. Furthermore, alendronate-induced apoptosis, like mevastatin-induced apoptosis, could be suppressed in J774 cells by the addition of farnesyl pyrophosphate or geranylgeranyl pyrophosphate, while the effect of alendronate on osteoclast number and bone resorption in murine calvariae in vitro could be overcome by the addition of mevalonic acid. These observations suggest that nitrogen-containing bisphosphonate drugs cause apoptosis following inhibition of post-translational prenylation of proteins such as Ras. It is likely that these potent antiresorptive bisphosphonates also inhibit bone resorption by preventing protein prenylation in osteoclasts and that enzymes of the mevalonate pathway or prenyl protein transferases are the molecular targets of the nitrogen-containing bisphosphonates. Furthermore, the data support the view that clodronate acts by a different mechanism.
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              Osteonecrosis of the jaw and bisphosphonates.

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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                April 2008
                April 2008
                : 4
                : 2
                : 453-458
                Affiliations
                St Vincent’s Hospital Melbourne, Victoria, Australia
                Author notes
                Correspondence: Sue-Anne McLachlan St Vincent’s Hospital, Melbourne, Australia Tel +161 3928 83156 Fax +161 3928 83172 Email sue-anne.mclachlan@ 123456svhm.org.au
                Article
                2504065
                18728841
                © 2008 Dove Medical Press Limited. All rights reserved
                Categories
                Review

                Medicine

                ibandronate, bone metastasis, breast cancer, oral bisphosphonate, skeletal complications

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