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.

Most cited references 62

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Protein prenylation: molecular mechanisms and functional consequences.

F. Zhang, P J Casey (1996)

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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Metastatic bone disease: clinical features, pathophysiology and treatment strategies.

Denis Coleman (2001)

Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumour types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anticancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases. Copyright 2001 Harcourt Publishers Ltd.

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Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras.

S Luckman, D E Hughes, F. Coxon … (1998)

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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Journal

Journal ID (nlm-ta): Ther Clin Risk Manag

Journal ID (publisher-id): Therapeutics and Clinical Risk Management

Title: Therapeutics and Clinical Risk Management

Publisher: Dove Medical Press

ISSN (Print): 1176-6336

ISSN (Electronic): 1178-203X

Publication date (Print): April 2008

Publication date (Electronic): April 2008

Volume: 4

Issue: 2

Pages: 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

PMC ID: 2504065

PubMed ID: 18728841

SO-VID: 1e434bd5-2e72-4916-81f1-029895d2ab09

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

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Abstract

Most cited references 62

Protein prenylation: molecular mechanisms and functional consequences.

Metastatic bone disease: clinical features, pathophysiology and treatment strategies.

Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras.

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