Estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid in hormone sensitive breast cancer cells in vitro.

BACKGROUND: Zoledronic acid (ZA) has antiresorptive effects and protects from bone metastasis in women with early breast cancer. In addition, in postmenopausal women with endocrine responsive breast cancer ZA prolongs DFS. The exact mechanism is still unclear. We have therefore investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro. MATERIALS AND METHODS: Using assays for cell proliferation (EZ4U, BrdU) and cell death (Annexin/PI), we have analyzed the dose-dependent antiproliferative and pro-apoptotic effects of ZA in two hormone sensitive cell lines (MCF-7 and T47D) and a hormone insensitive, triple negative cell line (MDA-MB-231) in the presence of 0, 1 and 10 nM estradiol. RESULTS: In the absence of estradiol, ZA exerts dose-dependent antiproliferative and pro-apoptotic antitumor effects in both, hormone sensitive (MCF-7, T47D) and -insensitive (MDA-MB-231) breast cancer cell lines (p<0.0001). In the presence of estradiol, the antitumoral effect of ZA was significantly decreased only in the hormone sensitive MCF-7 and T47D cell lines (p = 0.0008 and p = 0.0008, respectively). CONCLUSION: We have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of ZA in hormone sensitive, but not in hormone insensitive breast cancer cell lines. Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal patients with hormone sensitive early breast cancer, which has been demonstrated clinically. We further hypothesize that endocrine insensitive tumors such as triple negative breast cancer (TNBC) should benefit from ZA irrespective of their menopausal status.

The influence of geranylgeraniol on human oral keratinocytes after bisphosphonate treatment: An in vitro study.

This in vitro study analyzed the influence of geranylgeraniol (GGOH) on human oral keratinocytes (HOK) after exposure to bisphosphonates. HOK were incubated with four different bisphosphonates (clodronate, ibandronate, pamidronate, zoledronate) in two experimental set-ups: with and without GGOH. MTT and PrestoBlue assays were used to analyze HOK cell viability. HOK migration ability was examined with Boyden and Scratch assays, and Tunel and ToxiLight assays were used to detect the HOK apoptosis rate. No significant differences between the experimental set-ups, with and without GGOH, could be found for clodronate (p each >0.3). For the nitrogen-containing bisphosphonates, negative effects could be shown in the experimental set-ups without GGOH in all assays. In the GGOH experimental set-ups, the levels of HOK cell viability were significantly increased (MTT: p each ≤0.001; PrestoBlue: p each ≤0.012). The HOK migration ability was also greater (Boyden: p each <0.001; Scratch: p each ≤0.015). Regarding the apoptosis rate, reduced numbers of apoptotic HOK in the Tunel assay (p each <0.001) and decreased adenylate kinase release in the ToxiLight assay (p each ≤0.002) were observed. GGOH reversed the negative effects of bisphosphonates on HOK. These findings provide evidence that GGOH could be a promising treatment option for BP-ONJ.

Zoledronic acid induces apoptosis and S-phase arrest in mesothelioma through inhibiting Rab family proteins and topoisomerase II actions.

Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, produced anti-tumor effects through apoptosis induction or S-phase arrest depending on human mesothelioma cells tested. An addition of isoprenoid, geranylgeraniol but not farnesol, negated these ZOL-induced effects, indicating that the ZOL-mediated effects were attributable to depletion of geranylgeranyl pyrophosphates which were substrates for prenylation processes of small guanine-nucleotide-binding regulatory proteins (small G proteins). ZOL-treated cells decreased a ratio of membrane to cytoplasmic fractions in RhoA, Cdc42 and Rab6 but less significantly Rac1 proteins, indicating that these proteins were possible targets for ZOL-induced actions. We further analyzed which small G proteins were responsible for the three ZOL-induced effects, caspase-mediated apoptosis, S-phase arrest and morphological changes, using inhibitors for respective small G proteins and siRNA for Cdc42. ZOL-induced apoptosis is due to insufficient prenylation of Rab proteins because an inhibitor of geranlygeranyl transferase II that was specific for Rab family proteins prenylation, but not others inhibitors, activated the same apoptotic pathways that ZOL did. ZOL suppressed an endogenous topoisomerase II activity, which was associated with apoptosis and S-phase arrest in respective cells because we detected the same cell cycle changes in etoposide-treated cells. Inhibitors for geranlygeranyl transferase I and for RhoA produced morphological changes and disrupted actin fiber structures, both of which were similar to those by ZOL treatments. These data demonstrated that anti-tumor effects by ZOL were attributable to inhibited functions of respective small G proteins and topoisomerase II activity, and suggested that cellular factors were involved in the differential cell cycle changes.

Early inhibitory effects of zoledronic acid in tooth extraction sockets in dogs are negated by recombinant human bone morphogenetic protein.

PURPOSE: This study was conducted with 2 purposes. The first was to determine the effect of a single dose of zoledronic acid (ZA) on the healing of a tooth extraction socket in dogs. The second was to determine if placement of recombinant human bone morphogenetic protein-2 (rhBMP-2)/absorbable collagen sponge (ACS) - INFUSE, (Medtronic, Memphis, TN) into these extraction sockets would inhibit the inhibition on bone healing and remodeling by ZA. MATERIALS AND METHODS: Nine adult female beagle dogs (2 to 3 yr old) were placed into 3 groups of 3 dogs each. Group I received 15 mL of sterile saline intravenously; group II received 2.5 mg of ZA intravenously; and group III received 5 mg of ZA intravenously. Forty-five days after treatment, all dogs underwent extraction of noncontiguous right and left mandibular first molars and second premolars. In group I, the right mandibular extraction sockets had nothing placed in them, whereas the left mandibular sockets had only ACS placed in them. In groups II and III, the right mandibular sockets had rhBMP-2/ACS placed in them, whereas the left mandibular sockets had only ACS placed. All extraction sockets were surgically closed. Tetracycline was given intravenously 5 and 12 days later, and all animals were euthanized 15 days after tooth extraction. The extraction sockets and rib and femur samples were harvested immediately after euthanasia, processed, and studied microscopically. RESULTS: A single dose of ZA significantly inhibited healing and bone remodeling in the area of the tooth extractions. The combination of rhBMP-2/ACS appeared to over-ride some of the bone remodeling inhibition of the ZA and increased bone fill in the extraction sites, and remodeling activity in the area was noted. The effects of rhBMP-2/ACS were confined to the area of the extraction sockets because bone activity at distant sites was not influenced. CONCLUSIONS: A single dose of ZA administered intravenously inhibits early healing of tooth extraction sockets and bone remodeling in this animal model. The combination of rhBMP-2/ACS significantly increased bone fill and bone remodeling in these areas, negating much of the effect of the ZA.

Eficácia e segurança de ácido zoledrônico para o tratamento de osteoporose / Efficacy and safety of zoledronic acid for the treatment of osteoporosis / Eficacia y seguridad de acido zoledrónico para el tratamiento de la osteoporosis

TECNOLOGIA: Ácido Zoledrônico. INDICAÇÃO: Tratamento da osteoporose. CARACTERIZAÇÃO DA TECNOLOGIA: O ácido zoledrônico pertence a uma nova classe de bisfosfonatos altamente potentes que atuam especificamente no osso. É um inibidor da reabsorção óssea osteoclástica. PERGUNTA: O ácido zoledrônico é mais eficaz e seguro no tratamento da osteoporose do que os medicamentos fornecidos pelo SUS ou demais alternativas terapêuticas? BUSCA E ANÁLISE DAS EVIDÊNCIAS CIENTÍFICAS: Foram pesquisadas as bases de dados The Cochrane Library (via Bireme), Medline (via Pubmed), LILACS e Centre for ReviewsandDissemination (CRD). Foram incluídas revisões sistemáticas (RS) com metanálise de ensaios clínicos que avaliassem a eficácia do acido zoledrônico no tratamento da osteoporose comparado aos medicamentos raloxifeno; calcitonina sintética de salmão; ibandronato; denumabe e estrógenos conjugados. Foram selecionadas também avaliações de tecnologias em saúde (ATS) em sites de agências internacionais. RESUMO DOS RESULTADOS DOS ESTUDOS SELECIONADOS: Foram incluídos seis estudos com metanálise: quatro RS e duas publicações em ATS. Os resultados apresentados mostraram que apesar do ácido zoledrônico ter apresentado resultados benéficos para os desfechos analisados (densidade óssea, fratura vertebral e não vertebral), esse efeito não foi estatisticamente significante quando comparado a outros bisfosfonato disponíveis pelo Sistema Único de Saúde. Foram incluídas duas ATS. A primeira relatou que não foram encontrados dados de eficácia do uso dos bisfosfonatos por períodos superiores a cinco anos abrangendo desfechos de interesse, como fraturas. A outra relatou que o ácido zoledrônico apresentou um efeito similar aos demais bisfosfonatos, inclusive apresentando uma atividade ligeiramente reduzida em pacientes que já faziam uso de alendronato previamente, fator atribuído a um efeito residual do bisfosfonato anterior. RECOMENDAÇÕES: Os resultados apresentados não mostraram diferenças entre o ácido zoledrônico e os demais bisfosfonatos já utilizados como tratamento na prática clínica. Das quatro RS avaliadas somente uma apresentou uma indicação forte a favor da tecnologia, que pode estar relacionada ao fato de que o ácido zoledrônico foi comparado a placebo, bem como foi considerado fator determinante a melhor adesão ao tratamento. Os demais estudos apresentaram uma indicação fraca a favor do medicamento, uma vez que o efeito sobre a densidade óssea não foi estatisticamente significante comparado aos demais medicamentos. Com isso, faz-se necessário realizar uma avaliação individualizada nos casos especiais sobre qual das opções se adequa melhor as suas necessidades. Os resultados apontam para a não utilização do ácido zoledrônico para o tratamento da osteoporose, uma vez que as evidencias disponíveis até o momento mostram que os medicamentos disponíveis no SUS apresentam eficácia semelhante, e custo menor.(AU)

STRENGTH OF RECOMMENDATIONS: Recommendation strength is weak in favor of using the technology. TECHNOLOGIES: Zoledronic acid. INDICATION: Osteoporosis treatment. CHARACTERIZATION OF THE TECHNOLOGY: Zoledronic acid belongs to a new class of highly potent bisphosphonate which specifically act on the bone. It is an inhibitor of osteoclastic bone resorption. QUESTION: Zoledronic acid is effective in the osteoporosis treatment? SEARCH AND ANALYSIS OF SCIENTIFIC EVIDENCE: Search and quality of scientific evidence: the databases The Cochrane Library (via Bireme), Medline (via Pubmed), LILACS and Centre for Reviews and Dissemination (CRD) were investigated. We included systematic reviews (SR) and meta-analyzes of clinical trials that assessed the effectiveness of zoledronic acid in the treatment of osteoporosis. Reviews of health technologies (HTS) in agencies of international sites were also selected. The studies showed quality between high and low. SUMMARY OF RESULTS OF SELECTED STUDIES: Six studies were included: four systematic review (SR) and two publications in Health Technology Assessment (HTS). The results showed that in spite of zoledronic acid have showed beneficial for the outcomes analyzed (bone density, vertebral fracture and nonvertebral), this effect is not statistically different from that reached with other bisphosphonates available by the health care system. Two HTS were included. The first related that no efficacy data from the bisphosphonates use of for longer than five years encompassing outcomes of interest to patients, such as fractures were found. The other reported that zoledronic acid had a similar effect to other bisphosphonates, including presenting a slightly reduced activity in patients who were already taking alendronate previously, a factor assigned to a residual effect of prior bisphosphonate. RECOMMENDATIONS: The results showed no differences between the zoledronic acid and other bisphosphonates already used as a treatment in clinical practice. The four SR evaluated only one showed a strong statement in support of the technology, this was probably due to the fact that in this study, zoledronic acid was compared to placebo and was regarded the best determinant of patient compliance with treatment. While other studies showed a weak indication for the drug, since the effect on bone mineral density was not statistically different from reached with other drugs. We should make an individualized assessment for each patient on which option is best suited to your needs. Therefore the use of zoledronic acid for the osteoporosis treatment is weakly recommended, since the evidence available so far shows that the drugs available in Brazilian system (SUS) have similar efficacy and lowest cost.(AU)

INTENSIDAD DE LAS RECOMENDACIONES: La fuerza de la recomendación es débil en favor del uso de la tecnologia. TECNOLOGÍAS: Ácido zoledrónico. INDICACIÓN: El tratamiento para la osteoporosis. CARACTERIZACIÓN DE LA TECNOLOGÍA:El ácido zoledrónico pertenece a una nueva clase de bisfosfonato muy potente que actúan específicamente sobre el hueso. Es un inhibidor de la resorción ósea osteoclástica. PREGUNTA: ¿El ácido zoledrónico es más eficaz y seguro en el tratamiento de la osteoporosis que las proporcionadas por las drogas SUS u otras alternativas terapéuticas? BÚSQUEDA Y ANÁLISIS DE LA EVIDENCIA CIENTÍFICA: Se hicieron búsqueda y calidad de la evidencia científica: las bases de datos de la Cochrane Library (vía Bireme), MEDLINE (vía PubMed), LILACS y Centro de Revisiones y Difusión (CRD) fueron investigados. Se incluyeron revisiones sistemáticas (SR) y meta-análisis de los ensayos clínicos que evaluaron la eficacia del ácido zoledrónico en el tratamiento de la osteoporosis. También fueron seleccionados comentarios de tecnologías sanitarias (ATS) en las agencias de sitios internacionales. Los estudios demostraron la calidad entre alta y baja. RESUMEN DE LOS RESULTADOS DE LOS ESTUDIOS SELECCIONADOS: Se incluyeron seis estudios: cuatro RS y dos publicaciones en ATS. Los resultados mostraron que a pesar de ácido zoledrónico han mostrado beneficioso para los resultados analizados (la densidad ósea, fractura vertebral y no vertebrales) resultados, este efecto no es estadísticamente diferente de la que se consigue con otros bisfosfonatos disponibles por el sistema de cuidado de la salud. Dos ATS fueron incluidos. El primero informó que no se encontraron datos sobre la eficacia del uso de los bifosfonatos durante más de cinco años, cubriendo los resultados de interés para los pacientes, como las fracturas. El otro reportado que el ácido zoledrónico tenían un efecto similar al de otros bisfosfonatos, incluyendo la presentación de una actividad ligeramente reducido en pacientes que ya tomaban alendronato anteriormente, un factor atribuido a un efecto residual de bisfosfonato antes. RECOMENDACIONES: Los resultados no mostraron diferencias entre el ácido zoledrónico y otros bisfosfonatos ya utilizan como tratamiento en la práctica clínica. Los cuatro RS evaluados sólo uno mostró una fuerte declaración en apoyo de la tecnología, esto era probablemente debido al hecho de que este ácido zoledrónico estudio se comparó con placebo y se consideró el mejor determinante de la adhesión del paciente al tratamiento. Mientras que otros estudios mostraron un débil indicación para el fármaco, ya que el efecto sobre la densidad mineral ósea no fue estadísticamente diferente de la lograda con otras drogas. A continuación, debe hacer una valoración individualizada para cada paciente de la opción que mejor se adapte a sus necesidades. Por lo tanto se recomienda el uso de ácido zoledrónico débilmente para el tratamiento de la osteoporosis, ya que la evidencia disponible hasta ahora muestran que los medicamentos disponibles en el SUS tienen una eficacia similar, con el costo más bajo.(AU)

In vitro cytotoxicity of zoledronate (nitrogen-containing bisphosphonate: NBP) and/or etidronate (non-NBP) in tumour cells and periodontal cells.

OBJECTIVE: Nitrogen-containing bisphosphonates (NBPs), the first-choice drugs for diseases that cause enhanced bone resorption, may injure jawbones and gastrointestinal tissues. In rodents, NBPs cause necrosis at injection sites. Bisphosphonates accumulate within bones, especially where there is inflammation. We hypothesized that if jawbone-accumulated NBPs are released, they may directly injure cells around the jawbones. To examine this hypothesis, we compared the direct effects of zoledronate (NBP) and/or etidronate (non-NBP) on various cells, including periodontal cells. DESIGN: Various human tumour cells (such as squamous carcinoma cells and prostate adenocarcinoma cells) and periodontal cells (such as gingival fibroblasts and periodontal ligament cells) were incubated with or without zoledronate and/or etidronate. Cell viability and cytotoxicity were determined by tetrazolium dye assay and by FITC-Annexin V/propidium iodide assay, respectively. RESULTS: Zoledronate, at 100µM, was toxic to all types of cells tested, while its toxicity varied among cells at both 1 and 10µM. There was no clear difference between tumour cells and non-tumour cells in sensitivity to the cytotoxicity of zoledronate. In contrast, etidronate was not toxic at 1-100µM in any of the cells tested. Interestingly, etidronate reduced the cytotoxicity of zoledronate in many cell-types, including gingival fibroblasts. CONCLUSIONS: These results, together with those reported by others and those from our previous in vivo experiments, suggest that NBPs, upon release from jawbones (e.g., during dental surgery or bone infection), may directly injure various cells located around the jawbones, and that etidronate may be protective against the cytotoxicity of NBPs in periodontal tissues.

Zoledronic acid induces cell-cycle prolongation in murine lung cancer cells by perturbing cyclin and Ras expression.

Zoledronic acid (ZOL) was shown earlier to prolong survival in animal models of lung cancer. The aim of this study was to examine whether alteration of intracellular cyclins, cyclin-dependent kinases, cyclin-dependent kinase inhibitors, retinoblastoma, and Ras protein expression and E2F localization are among the possible antilung cancer mechanisms driven by ZOL. Furthermore, we used geranylgeraniol to test whether the mevalonate pathway is involved in the antitumor effects of ZOL against lung cancer. Line-1 cells, a murine lung adenocarcinoma cell line, were examined. ZOL significantly slowed the growth of these cells both in vitro and in vivo. The ZOL-treated cells typically arrested at the S/G2/M phase of the cell cycle, accompanied by increased intracellular levels of cyclin A, B1, and CDC2 and decreased levels of cyclin D, p21, p27, phosphorylated retinoblastoma, and Ras. In addition, ZOL affected the distribution of E2F. When geranylgeraniol was added to the ZOL-treated cells, either in vitro or in vivo, tumor growth, cell-cycle progression, the expression of certain cyclins, and cyclin-related regulatory proteins were partially returned to that of untreated controls. Therefore, ZOL elicits cell-cycle prolongation that seems to be associated with alterations in the levels of certain cyclins and cyclin-related regulatory proteins. Furthermore, the mevalonate pathway regulates ZOL-induced murine lung cancer inhibition both in vitro and in vivo.

Inhibition of necrotic actions of nitrogen-containing bisphosphonates (NBPs) and their elimination from bone by etidronate (a non-NBP): a proposal for possible utilization of etidronate as a substitution drug for NBPs.

PURPOSE: Nitrogen-containing bisphosphonates (NBPs) have powerful anti-bone-resorptive effects (ABREs). However, recent clinical applications have disclosed an unexpected side effect, osteonecrosis of the jaw. We previously found in mice that etidronate (a non-NBP), when coadministered with alendronate (an NBP), inhibited the latter's inflammatory effects. However, etidronate also reduced the ABRE of alendronate. The present study examined in mice the modulating effects of etidronate on the inflammatory and necrotic actions of zoledronate (the NBP with the strongest anti-bone-resorptive activity and the highest incidence of osteonecrosis of the jaw) and on ABREs of various NBPs including zoledronate. MATERIALS AND METHODS: NBPs were subcutaneously injected into ear pinnas of mice and ensuing inflammation and necrosis at the site of the injection were evaluated. ABREs of NBPs were evaluated by analyzing sclerotic bands induced in mouse tibias. RESULTS: Coinjection of etidronate reduced inflammatory and necrotic reactions induced by zoledronate, and also reduced the amount of zoledronate retained within the ear tissue. When both agents were intraperitoneally injected, etidronate reduced the ABRE of zoledronate and those of other NBPs. Notably, etidronate reduced the ABRE of zoledronate even when this non-NBP was injected 16 hours after the injection of zoledronate. Bone scintigram indicated that etidronate reduced the amount of zoledronate that had already bound to bone. CONCLUSIONS: These results suggest that etidronate may 1) inhibit the entry of NBPs into cells related to inflammation and/or necrosis, 2) inhibit the binding of NBPs to bone hydroxyapatite, 3) at least partly eliminate (or substitute for) NBPs that have already accumulated within bones, and thus 4) if used as a substitution drug for NBPs, be effective at treating or preventing NBP-associated osteonecrosis of the jaw.

Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: a QSAR investigation.

We report the results of an investigation of the inhibition of the ATP-mediated HIV-1 reverse transcriptase catalyzed phosphorolysis in vitro of AZT from AZT-terminated DNA primers by a series of 42 bisphosphonates. The four most active compounds possess neutral, halogen-substituted phenyl or biphenyl sidechains and have IC(50) values < 1 microM in excision inhibition assays. Use of two comparative molecular similarity analysis methods to analyze these inhibition results yielded a classification model with an overall accuracy of 94%, and a regression model having good accord with experiment (q(2)=0.63, r(2)=0.91), with the experimental activities being predicted within, on average, a factor of 2. The most active species had little or no toxicity against three human cell lines (IC(50)(avg) > 200 microM). These results are of general interest since they suggest that it may be possible to develop potent bisphosphonate-based AZT-excision inhibitors with little cellular toxicity, opening up a new route to restoring AZT sensitivity in otherwise resistant HIV-1 strains.

Mechanisms of the action of zoledronic acid on human MG-63 osteosarcoma cells.

The aim of our study was to analyze the action of zoledronic acid on MG-63 human osteosarcoma cells. The proliferation of MG-63 cells was inhibited by either continuous or pulsatile exposures of zoledronic acid in a dose-dependent manner (10-250 microM). Zoledronic acid did not produce evidence of MG-63 cell death when administered at 100 mM for 48 hours, but only after exposure of 96 hours. Zoledronic acid (100 microM) increased the distribution of MG-63 cells in G0/G1 phase, however, it did not increase the adriamycin-induced apoptosis. In addition, zoledronic acid action was partially neutralized by exogenous administration of geranylgeranyl pyrophosphate (GGPP), but not by farnesyl pyrophosphate (FPP). Furthermore, zoledronic acid resulted in the attenuation of the prenylated form of Ras. Zoledronic acid and EDTA increased fluorescence of Fluo-3 loaded MG-63 cells in a similar pattern. This increase was owing to the release of Ca2+ from intracellular stores since zoledronic acid failed to reveal such a change to intracellular Ca2+ when cells were previously treated with 1 mM caffeine. Moreover, zoledronic acid significantly decreased the expression of estrogen receptor alpha (ERalpha) whereas it did not change significantly the expression of estrogen receptor beta (ERbeta) in MG-63 cells. These data suggest that zoledronic acid can control the proliferation and the differentiation of osteosarcoma-like cells.

Zoledronate has an antitumor effect and induces actin rearrangement in dexamethasone-resistant myeloma cells.

New strategies are needed to overcome the resistance of multiple myeloma (MM) to dexamethasone (Dex). Several recent in vitro studies demonstrated the antitumor effect of nitrogen-containing amino-bisphosphonates (N-BPs) in various tumor cell lines. Inhibition of the prenylation of small G proteins is assumed to be one of the principal mechanisms by which N-BPs exert their effects. There have been few reports on N-BP treatment of MM cells that are resistant to Dex. Additionally, it is not known how small G proteins are altered in N-BP-treated MM cells. In this study, we evaluated the effect of the most potent N-BP, zoledronate (ZOL), on a Dex-resistant human MM cell subline (Dex-R) that we established from the well-documented RPMI8226 cell line. ZOL reduced the viability and induced apoptosis of Dex-R cells. Some of the ZOL-treated RPMI8226 cells and ZOL-treated Dex-R cells were elongated; however, elongated cells were not seen among the Dex-treated RPMI8226 cells. Furthermore, we found that portions of the small G proteins, Rho and Rap1A, were unprenylated in the ZOL-treated MM cells. Geranylgeraniol reduced the above-mentioned ZOL-induced effects. These findings suggest that ZOL may be beneficial for the treatment of Dex-resistant MM by suppressing the processing of RhoA and Rap1A.

Effectiveness of pretreatment in decreasing adverse events associated with pamidronate in children and adolescents.

STUDY OBJECTIVES: To assess the effectiveness of pretreatment with ibuprofen or acetaminophen compared with no pretreatment in decreasing adverse events in children and adolescents receiving the first and second series of pamidronate therapy; and to compare the effectiveness of ibuprofen versus acetaminophen for prevention of adverse events associated with pamidronate infusion. DESIGN: Retrospective case review. SETTING: Children's hospital. PATIENTS: Twenty-seven children and adolescents aged 3-21 years receiving pamidronate therapy. MEASUREMENTS AND MAIN RESULTS: Data for patient demographics, medical history, genetic history of disease, pamidronate infusion dosage, and concurrent drug therapy were collected. Adverse drug events secondary to pamidronate infusion and subsequent drug therapies received were documented. Data were categorized by presence or absence of pretreatment and analyzed by cross-tabulation to determine whether the presence of adverse events differed between groups (no pretreatment, acetaminophen pretreatment, and ibuprofen pretreatment). Fewer adverse events were reported in patients receiving ibuprofen (17% of patients) versus acetaminophen (83%). Differences in presence of fever (chi2 = 10.5, p = 0.005) and bone pain (chi2 = 7.3, p = 0.027) among the three pretreatment groups were also statistically significant. CONCLUSION: Pretreatment with ibuprofen or acetaminophen appears to decrease the occurrence of adverse events from pamidronate therapy. However, adverse events seem less likely to occur with ibuprofen. Further study is necessary to determine the relationship between occurrence of adverse events, other possible treatment strategies, and patient adherence with pamidronate therapy.

Inhibition of inflammatory actions of aminobisphosphonates by dichloromethylene bisphosphonate, a non-aminobisphosphonate.

1. When injected intraperitoneally into mice in doses larger than those used clinically, all the amino derivatives of bisphosphonates (aminoBPs) tested induce a variety of inflammatory reactions such as induction of histidine decarboxylase (HDC, the histamine-forming enzyme), hypertrophy of the spleen, atrophy of the thymus, hypoglycaemia, ascites and accumulation of exudate in the thorax, and an increase in the number of macrophages and/or granulocytes in the peritoneal cavity of blood. On the other hand, dichloromethylene bisphosphonate (Cl2MBP) a typical non-aminoBP, has no such inflammatory actions. In the present study, we found that this agent can suppress the inflammatory actions of aminoBPs. 2. Cl2MBP, when injected into mice before or after injection of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (AHBuBP; a typical aminoBP), inhibited the induction of HDC activity by AHBuBP in a dose- and time-dependent manner. The increase in HDC activity induced by AHBuBP was largely suppressed by the injection of an equimolar dose of Cl2MBP. Cl2MBP also inhibited other AHBuBP-induced inflammatory reactions, as well as the inflammatory actions of two other aminoBPs. However, Cl2MBP did not inhibit the increase in HDC activity induced by lipopolysaccharide (LPS). 3. We have previously reported that AHBuBP augments the elevation of HDC activity and the production of interleukin-1beta (IL-1beta) that are induced by LPS. These actions of AHBuBP were also inhibited by Cl2MBP. 4. Based on these results and reported actions of bisphosphonates, the mechanisms underlying the contrasting effects of aminoBPs and Cl2MBP, a non-aminoBP are discussed. The results suggest that combined administration of Cl2MBP and an aminoBP in patients might be a useful way of suppressing the inflammatory side effects of aminoBPs.