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      Letter to the Editor: Acute Effects of Intravenous Administration of Pamidronate in Patients with Osteoporosis

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          Abstract

          To the Editor: We read the interesting article "Acute Effects of Intravenous Administration of Pamidronate in Patients with Osteoporosis" in the Journal of Korean Medical Science by Lim et al. (1). We would like to comment and compare these data to a study recently published by our research group (2). The two studies had different initial aims, but still they share the same results in determining the modulatory effect of inflammation of aminobisphosphonates, such as pamidronate. The pamidronate belongs to the family of aminobisphosphonates (N-BPs), currently the major class of drugs used for the treatment of osteoporosis and other diseases characterized by increased bone resorption. The immune modulation exerted by pamidronate has not yet fully been understood (3). In vitro experiments have shown an anti-inflammatory effect of this N-BP; (4, 5) as well as a pro-inflammatory one (6, 7). Moreover contrasting results were obtained when pamidronate was used for the treatment of different inflammatory or immunologic diseases, such as rheumatoid arthritis (8, 9) or systemic sclerosis. The aminobiphosphonates act on farnesylpyrophosphate synthase (FPPS) and inhibit the mevalonate pathway, the latter being responsible for production of cholesterol and isoprenoid lipids. In particular we can hypothesize that the inflammatory phenotype is due to lack of enzymes downstream the FPPS, and in particular the lack of geranylgeranyl-pyrophosphate (GGPP) could be associated to the activation of caspase-1 and the high IL-1β release. Lim et al. (1) emphasized that in vivo infusion of pamidronate at a therapeutic dose of 30 mg increased production of two inflammatory cytokines, IL-6 and TNF-α in serum. The increase is an acute effect after intravenous injection (1). Recently, our group demonstrated that pamidronate is able to increase the sensitivity to bacterial compounds both in the murine macrophagic cell line (Raw 264.7) and in Balb/c mice, by an incremental release of IL1β. These findings are in agreement with published data concerning inflammatory modulation in alendronate treated-mice (2). Moreover the effect of pamidronate does not depend on its concentration, whereas it may be involved in the increase of susceptibility to pro-inflammatory compounds such as muramildipeptide or lipopolysaccaride (2). In summary, we agree with the study by Lim et al. (1) and we emphasize the pivotal role of pamidronate in the modulation of inflammatory response. Sincerely.

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          Most cited references 9

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          A role for geranylgeranylation in interleukin-1beta secretion.

          Mevalonate kinase deficiency (MKD) is an autosomal-recessive disorder characterized by recurring episodes of inflammation. MK catalyzes the phosphorylation of mevalonic acid, which is an early step in isoprenoid biosynthesis. The goal of our study was to determine whether a temporary shortage of certain isoprenoid end products and/or the accumulation of mevalonic acid is the cause of interleukin-1beta (IL-1beta) secretion in MKD. We studied the effect of the addition of intermediate metabolites and inhibitors of the isoprenoid biosynthesis pathway on IL-1beta secretion by peripheral blood mononuclear cells (PBMCs) of patients with MKD and healthy controls. Inhibition of enzymes involved in geranylgeranyl pyrophosphate (GGPP) synthesis or geranylgeranylation of proteins led to a marked increase of lipopolysaccharide-stimulated IL-1beta secretion in PBMCs of control subjects. Furthermore, the increased IL-1beta secretion by PBMCs of patients with MKD was reversed by supplementation with GGPP as well as with mevalonic acid. IL-1beta secretion was increased only when control PBMCs were incubated with excessive amounts of mevalonic acid. Finally, a reduction in IL-1beta secretion by MKD PBMCs was also observed when sterol biosynthesis was inhibited, favoring nonsterol isoprenoid biosynthesis. Our results indicate that a shortage of geranylgeranylated proteins, rather than an excess of mevalonate, is likely to cause increased IL-1beta secretion by PBMCs of patients with MKD.
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            An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates.

            We studied the acute phase response, including specific cytokine production, [interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha(TNF alpha)] following a single dose of Aredia (disodium pamidronate) in patients with increased bone turnover and, in vitro, the role played by specific cytokines in the acute-phase reaction which may follow the administration of aminobisphosphonates. An in vivo exploratory study was done on 24 in- and outpatients with increased bone turnover given a single intravenous dose of pamidronate 60 mg. Measurements were taken at baseline and at 24, 48, and 72 hours. The main outcome measures were changes from baseline in serum IL-1, IL-6, and TNF alpha. In addition, C-reactive protein (CRP), white blood cell count (WCC), lymphocyte count, and elastase concentration were measured. Symptomatic evaluation was made of fever, bone pain, and rigors. In vitro, whole blood from eight healthy volunteers was exposed to various concentrations of the three bisphosphonates--pamidronate, clodronate, and zoledronate. Measurements were taken immediately before and at 3, 6, and 10 hours after exposure to drugs. The main outcome measures were changes in serum IL-1, IL-6, and TNF alpha. In vivo, there was a statistically significant (P < 0.001) increase in median values of TNF alpha in all post-baseline measurements. Median values for IL-6 also showed a significant (P < 0.001) increase at 24 hours after dosing. There were no statistically significant changes in median IL-1 values. Few patients showed any change from baseline in total WCC or in lymphocyte count, but 62.5% of patients with normal range baseline values for CRP increased to above normal levels after treatment. Fourteen patients experienced fever; 2 reported rigors. There was no correlation between fever and changes in cytokines. There were no serious adverse experiences or premature discontinuations due to poor tolerability, and 91% of the patients expressed willingness to receive pamidronate again. In vitro, an increase in TNF alpha and a mild increase in IL-6 was seen with all bisphosphonates, with the greatest effects seen with the highest concentration of both pamidronate and zoledronate. No changes were observed in IL-1 with any agent. Significant changes in both TNF alpha and IL-6 were observed within 3 days of a single dose of pamidronate in patients treated for the first time confirming previous findings. However, the lack of change in IL-1 in vivo and in vitro does not support the hypothesis that this cytokine plays a major role in the acute phase reaction. The cellular mechanism of the interaction among aminobisphosphonates, IL-6, and TNF alpha requires further investigations. The results of the in vitro study are consistent with the in vivo findings.
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              Effect of liposomal and free bisphosphonates on the IL-1 beta, IL-6 and TNF alpha secretion from RAW 264 cells in vitro.

              In order to evaluate the possible antiinflammatory action of bisphosphonates, the effect of the drugs on the secretion of proinflammatory cytokines (IL-1 beta, IL-6 and TNF alpha) from macrophages was studied. Liposomes or high concentration of extracellular calcium was used to enhance the intracellular delivery of bisphosphonates. RAW 264 cells were used as macrophage model, and they were induced with lipopolysaccharide to produce the cytokines. The cytokine concentrations in the culture supernatants were measured with time-resolved fluoroimmunoassay. As a free drug, clodronate and pamidronate, but not etidronate, inhibited LPS-stimulated secretion of the cytokines from macrophage-like RAW 264 cells. Low concentrations of pamidronate, however, induced the IL-6 secretion, and the cytokine inhibitory action at the higher concentrations of pamidronate was attributed to cytotoxicity of the compound. The cytokine induction or toxic effects were not observed with clodronate or etidronate. When the drugs were encapsulated in negatively charged unilamellar liposomes, the inhibitory potency of both clodronate and etidronate enhanced by a factor of 10-20, while that of pamidronate was not increased. The complex formation of bisphosphonates with extracellular calcium, although enhancing the uptake of the compounds by macrophages, did not considerably increase their cytokine inhibitory potency. Bisphosphonates have inhibitory action on cytokine secretion by macrophages. The non-cytotoxic cytokine inhibition by liposome encapsulated clodronate could be beneficial in local inflammatory diseases, where the inflammation is sustained by the excessive amounts of inflammatory cytokines produced by activated macrophages.
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                Author and article information

                Affiliations
                [1]Medical Genetic Service, Institute for Maternal and Child Health "Burlo Garofolo", Trieste, Italy.
                [2]Department of Reproductive and Developmental Sciences and Public Health Care, University of Trieste, Italy.
                [3]Department of Genetics, Federal University of Pernambuco, Av. Academico H Ramos, Cidade Universitaria, 50.740-530 Recife, Brazil.
                Author notes
                Address for Correspondence: Annalisa Marcuzzi. Department of Reproductive and Developmental Sciences Via dell'Istria, 65/1 - 34134 Trieste, Italy. Tel: +39-040-3785422, Fax: +39-040-3785210, marcuzzi@123456burlo.trieste.it
                Journal
                J Korean Med Sci
                JKMS
                Journal of Korean Medical Science
                The Korean Academy of Medical Sciences
                1011-8934
                1598-6357
                June 2011
                18 May 2011
                : 26
                : 6
                : 848-849
                3102885
                21655077
                10.3346/jkms.2011.26.6.848
                © 2011 The Korean Academy of Medical Sciences.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Medicine

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