Genomes and Genes
Summary: A diphosphonate which affects calcium metabolism. It inhibits bone resorption and soft tissue calcification.
- Morgan G, Child J, Gregory W, Szubert A, Cocks K, Bell S, et al. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol. 2011;12:743-52 pubmed publisher..The MRC Myeloma IX study was designed to compare the effects of zoledronic acid versus clodronic acid in newly diagnosed patients with multiple myeloma...
- Dearnaley D, Mason M, Parmar M, Sanders K, Sydes M. Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol. 2009;10:872-6 pubmed publisher..UK MRC; and an education grant and free drug from Roche Products Ltd. ..
- Day Y, Huang L, Ye H, Linden J, Okusa M. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages. Am J Physiol Renal Physiol. 2005;288:F722-31 pubmed..We conclude that the full extent of IRI requires macrophages and that A(2A) agonist-mediated tissue protection is independent of activation of macrophage A(2A)Rs. ..
- Rossini M, Viapiana O, Ramonda R, Bianchi G, Olivieri I, Lapadula G, et al. Intra-articular clodronate for the treatment of knee osteoarthritis: dose ranging study vs hyaluronic acid. Rheumatology (Oxford). 2009;48:773-8 pubmed publisher..Trial Registration. Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali - Agenzia Italiana del Farmaco. Comitato Etico Azienda Ospedaliera Universitaria Senese number CLIO 22/02 http://oss-sper-clin.agenziafarmaco.it. ..
- Van Rooijen N, Hendrikx E. Liposomes for specific depletion of macrophages from organs and tissues. Methods Mol Biol. 2010;605:189-203 pubmed publisher..In several cases, organ specific depletion can be obtained by choosing the right administration route for the clodronate liposomes. ..
- Powles T, Paterson A, McCloskey E, Schein P, Scheffler B, Tidy A, et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res. 2006;8:R13 pubmed..These results confirm that oral clodronate will significantly improve the 5 year bone relapse free survival when used as a supplementary adjuvant treatment for patients receiving standard treatment for primary operable breast cancer. ..
- Muratore M, Quarta L, Calcagnile F, Quarta E. "Twice-a-month" clodronate 200 mg IM: a new dosing regimen and improved therapy adherence in the treatment of postmenopausal osteoporosis. Adv Ther. 2010;27:314-20 pubmed publisher..Secondary aims were the assessments of bone resorption markers, safety, tolerability, pain, and patient compliance...
- Zeisberger S, Odermatt B, Marty C, Zehnder Fjällman A, Ballmer Hofer K, Schwendener R. Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer. 2006;95:272-81 pubmed
- Leppa S, Saarto T, Vehmanen L, Blomqvist C, Elomaa I. Clodronate treatment influences MMP-2 associated outcome in node positive breast cancer. Breast Cancer Res Treat. 2005;90:117-25 pubmed..Clodronate has a negative impact on outcome among patients with low serum MMP-2 and MMP-9 levels, while no such influence is observed among patients with high MMP-2 and MMP-9 levels. ..
- Clementi A, Gaudy A, Van Rooijen N, Pierce R, Mooney R. Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling. Biochim Biophys Acta. 2009;1792:1062-72 pubmed publisher..One or more additional factors appear to be required, however, for the Kupffer cell-dependent protective effect on insulin receptor signaling in DIO mice. ..
- Dehghani F, Conrad A, Kohl A, Korf H, Hailer N. Clodronate inhibits the secretion of proinflammatory cytokines and NO by isolated microglial cells and reduces the number of proliferating glial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp Neurol. 2004;189:241-51 pubmed..Furthermore, clodronate inhibits microglial secretion of proinflammatory cytokines and NO. Clodronate could therefore prove to be a useful tool in the investigation of interactions between damaged neurons and microglial cells. ..
- Banciu M, Metselaar J, Schiffelers R, Storm G. Antitumor activity of liposomal prednisolone phosphate depends on the presence of functional tumor-associated macrophages in tumor tissue. Neoplasia. 2008;10:108-17 pubmed..One of the major inhibitory actions of LCL-PLP on tumor growth is the reduction of the TAM-mediated production of pro-angiogenic factors, whereas production of anti-angiogenic factors by these cells is hardly affected. ..
- Coleman R. Adjuvant bisphosphonates in breast cancer: are we witnessing the emergence of a new therapeutic strategy?. Eur J Cancer. 2009;45:1909-15 pubmed publisher..The results of ongoing large metastasis prevention trials are however, required before routine use of adjuvant bisphosphonates can be recommended. ..
- Diel I, Jaschke A, Solomayer E, Gollan C, Bastert G, Sohn C, et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol. 2008;19:2007-11 pubmed publisher..These long-term survival data extend the survival advantage reported in previous studies with oral clodronate in breast cancer. ..
- Dominguez L, Galioto A, Ferlisi A, Alessi M, Belvedere M, Putignano E, et al. Intermittent intramuscular clodronate therapy: a valuable option for older osteoporotic women. Age Ageing. 2005;34:633-6 pubmed
- Giuliani A, Graldi G, Veronesi M, Unis L, Previato A, Lorenzini F, et al. Aging of red blood cells and impaired erythropoiesis following prolonged administration of dichloromethylene diphosphonate containing liposomes in rats. Eur J Haematol. 2005;75:406-16 pubmed..They also showed impaired erythropoiesis, presumably related to a reduction in BM macrophages and increased production of proinflammatory cytokines by residual activated marrow macrophages and other cells. ..
- Reszka A, Rodan G. Mechanism of action of bisphosphonates. Curr Osteoporos Rep. 2003;1:45-52 pubmed..Although nitrogen-containing bisphosphonates can induce osteoclast apoptosis, this is not necessary for their inhibition of bone resorption. ..
- Dando T, Wiseman L. Clodronate : a review of its use in the prevention of bone metastases and the management of skeletal complications associated with bone metastases in patients with breast cancer. Drugs Aging. 2004;21:949-62 pubmed..In the meantime, clodronate is a well established bisphosphonate which has shown beneficial effects in the prevention of bone metastases and on survival in patients with primary breast cancer. ..
- Markovic D, Glass R, Synowitz M, Rooijen N, Kettenmann H. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J Neuropathol Exp Neurol. 2005;64:754-62 pubmed..Our data indicate that glioma cells stimulate microglial cells to increase breakdown of extracellular matrix and thereby promote tumor invasiveness. ..
- Van Rooijen N. Liposomes for targeting of antigens and drugs: immunoadjuvant activity and liposome-mediated depletion of macrophages. J Drug Target. 2008;16:529-34 pubmed publisher..In several cases, organ-specific depletion can be obtained by choosing the right administration route for the clodronate liposomes. ..
- Mason M, Sydes M, Glaholm J, Langley R, Huddart R, Sokal M, et al. Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst. 2007;99:765-76 pubmed..Modification of trial drug dose was more frequent in the clodronate group than the placebo group (HR = 1.63, 95% CI = 1.21 to 2.19). Adjuvant sodium clodronate does not modify the natural history of nonmetastatic prostate cancer. ..
- Daubiné F, Le Gall C, Gasser J, Green J, Clezardin P. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst. 2007;99:322-30 pubmed..2 cell tumor burden compared with vehicle, whereas a single preventive dose of zoledronic acid had no effect. Daily or repeated intermittent therapy with clinical doses of bisphosphonates inhibits skeletal tumor growth in a mouse model. ..
- McCloskey E, Beneton M, Charlesworth D, Kayan K, deTakats D, Dey A, et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res. 2007;22:135-41 pubmed..This study suggests that antiresorptive therapies can reduce fracture incidence in high-risk individuals even in the presence of a normal or osteopenic BMD. ..
- Muscoso E, Puglisi N, Mamazza C, Lo Giudice F, Testai M, Abbate S, et al. Antiresorption therapy and reduction in fracture susceptibility in the osteoporotic elderly patient: open study. Eur Rev Med Pharmacol Sci. 2004;8:97-102 pubmed
- Liu L, Igarashi K, Kanzaki H, Chiba M, Shinoda H, Mitani H. Clodronate inhibits PGE(2) production in compressed periodontal ligament cells. J Dent Res. 2006;85:757-60 pubmed..These results suggest that the inhibitory effects of clodronate on tooth movement and osteoclasts may be due, at least in part, to the inhibition of COX-2-dependent PGE(2) production and RANKL expression in PDL cells. ..
- Itoh F, Aoyagi S, Kusama H, Kojima M, Kogo H. Effects of clodronate and alendronate on local and systemic changes in bone metabolism in rats with adjuvant arthritis. Inflammation. 2004;28:15-21 pubmed..Clodronate would be useful in the treatment of inflammation-induced bone deformation and osteopenia. ..
- Rozemuller H, Knaän Shanzer S, Hagenbeek A, van Bloois L, Storm G, Martens A. Enhanced engraftment of human cells in RAG2/gammac double-knockout mice after treatment with CL2MDP liposomes. Exp Hematol. 2004;32:1118-25 pubmed..Our findings indicate that macrophage-depleted RAG2(-/-)gammac(-/-) are a suitable model for studying human hematopoiesis including multipotential stem cells, and long-term repopulation. ..
- Morgan G, Davies F, Gregory W, Cocks K, Bell S, Szubert A, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010;376:1989-99 pubmed publisher..an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3-4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy...
- van Neerven S, Nemes A, Imholz P, Regen T, Denecke B, Johann S, et al. Inflammatory cytokine release of astrocytes in vitro is reduced by all-trans retinoic acid. J Neuroimmunol. 2010;229:169-79 pubmed publisher..01). The data are consistent with the hypothesis that all-trans RA takes part in endogenous anti-inflammatory feedback loops in the CNS. ..
- McCloskey E, Selby P, Davies M, Robinson J, Francis R, Adams J, et al. Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res. 2004;19:728-36 pubmed..We conclude that clodronate 800 mg daily is a safe and effective treatment to reduce fracture risk in women with osteoporosis, regardless of causation. ..
- van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S. Nitrogen-containing bisphosphonates inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo. Biochem Biophys Res Commun. 1999;255:491-4 pubmed..Our study reveals for the first time the intracellular target of N-containing bisphosphonates and supports the view that all bisphosphonates do not share the same molecular mechanism of action. ..
- Powles T, Paterson S, Kanis J, McCloskey E, Ashley S, Tidy A, et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol. 2002;20:3219-24 pubmed..Clodronate, given to patients with primary operable breast cancer, may reduce the occurrence of bone metastases, although this reduction was only significant during this medication period. There was a significant reduction in mortality. ..
- O Rourke N, McCloskey E, Vasikaran S, Eyres K, Fern D, Kanis J. Effective treatment of malignant hypercalcaemia with a single intravenous infusion of clodronate. Br J Cancer. 1993;67:560-3 pubmed..The single infusion has a more rapid onset of effect, is more convenient than multiple infusions, and has no adverse effect on renal function. ..
- Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino F, Colombel M, et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res. 2000;60:2949-54 pubmed..These results suggest, therefore, that BPs may be useful agents for the prophylactic treatment of patients with cancers that are known to preferentially metastasize to bone. ..
- Giuliani A, Wiener E, Lee M, Brown I, Berti G, Wickramasinghe S. Changes in murine bone marrow macrophages and erythroid burst-forming cells following the intravenous injection of liposome-encapsulated dichloromethylene diphosphonate (Cl2MDP). Eur J Haematol. 2001;66:221-9 pubmed..The results suggest that mice treated with liposome-encapsulated Cl2MDP are a model for studying the role of macrophages in erythropoiesis. ..
- Sonnemann J, Eckervogt V, Truckenbrod B, Boos J, Winkelmann W, van Valen F. The bisphosphonate pamidronate is a potent inhibitor of human osteosarcoma cell growth in vitro. Anticancer Drugs. 2001;12:459-65 pubmed..Importantly, cell growth of fibroblasts was only very weakly affected by treatment with pamidronate. These results suggest that pamidronate may be a useful agent for the treatment of patients with osteosarcoma. ..
- Polfliet M, Goede P, van Kesteren Hendrikx E, van Rooijen N, Dijkstra C, van den Berg T. A method for the selective depletion of perivascular and meningeal macrophages in the central nervous system. J Neuroimmunol. 2001;116:188-95 pubmed..This selective depletion method of the PVM and MM will enable us to get direct insight in their functions during normal and pathologic conditions of the CNS. ..
- Diel I. Bisphosphonates in the prevention of bone metastases: current evidence. Semin Oncol. 2001;28:75-80 pubmed..This article evaluates and presents the results of these studies, and reviews current evidence surrounding the prophylactic use of bisphosphonates for skeletal progression of breast cancer. ..
- Ghinoi V, Brandi M. Clodronate: mechanisms of action on bone remodelling and clinical use in osteometabolic disorders. Expert Opin Pharmacother. 2002;3:1643-56 pubmed..However, studies that demonstrate an effect on the rate of fractures are needed before any recommendation can be made. ..
- Kohl A, Dehghani F, Korf H, Hailer N. The bisphosphonate clodronate depletes microglial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp Neurol. 2003;181:1-11 pubmed..Our results demonstrate that clodronate is a useful tool in the investigation of neuron-glia interactions because it induces an efficient depletion of microglial cells that are activated after excitotoxic CNS injury. ..
- Dearnaley D, Sydes M, Mason M, Stott M, Powell C, Robinson A, et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst. 2003;95:1300-11 pubmed..These results suggest that further studies of the effect of newer generation bisphosphonates on BPFS in men with metastatic prostate cancer are warranted. ..
- Perugini P, Genta I, Conti B, Modena T, Pavanetto F. Long-term release of clodronate from biodegradable microspheres. AAPS PharmSciTech. 2001;2:E10 pubmed..Clodronate was successfully entrapped in PLGA and PDLLA microspheres, and drug release could be modulated from 48 hours up to 3 months by suitable selection of polymer, composition, additives, and manufacturing conditions. ..
- Mönkkönen H, Rogers M, Makkonen N, Niva S, Auriola S, Monkkonen J. The cellular uptake and metabolism of clodronate in RAW 264 macrophages. Pharm Res. 2001;18:1550-5 pubmed..These results strongly support the idea that clodronate acts as a prodrug, the active form being its intracellular AppCCl2p metabolite. ..
- Mundy G. Bisphosphonates and tumor burden. J Clin Oncol. 2002;20:3191-2 pubmed
- Villikka K, Perttunen K, Rosnell J, Ikävalko H, Vaho H, Pylkkanen L. The absolute bioavailability of clodronate from two different oral doses. Bone. 2002;31:418-21 pubmed..All treatments were well tolerated, and the AE profiles were similar in the different treatment groups. There were no serious adverse events during the study. ..
- Sadahira Y, Yasuda T, Yoshino T, Manabe T, Takeishi T, Kobayashi Y, et al. Impaired splenic erythropoiesis in phlebotomized mice injected with CL2MDP-liposome: an experimental model for studying the role of stromal macrophages in erythropoiesis. J Leukoc Biol. 2000;68:464-70 pubmed
- Reszka A, Halasy Nagy J, Masarachia P, Rodan G. Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase. J Biol Chem. 1999;274:34967-73 pubmed..For alendronate and risedronate, these events seem to be downstream of inhibition of geranylgeranylation. ..
- Van Rooijen N, van Kesteren Hendrikx E. "In vivo" depletion of macrophages by liposome-mediated "suicide". Methods Enzymol. 2003;373:3-16 pubmed
- Luckman S, Hughes D, Coxon F, Graham R, Russell G, Rogers M. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 1998;13:581-9 pubmed..Furthermore, the data support the view that clodronate acts by a different mechanism. ..
- van Rooijen N, Sanders A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods. 1994;174:83-93 pubmed..In the present review, the preparation of Cl2MBP-liposomes has been described in detail. Furthermore, the mechanism of action of the new approach and its applicabilities are discussed. ..