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Background Data on the effect of oral bisphosphonates (BPs) on risk of upper gastrointestinal complications (UGIC) are conflicting. We conducted a large population-based study from a network of Italian healthcare utilization databases aimed to assess the UGIC risk associated with use of BPs in the setting of secondary prevention of osteoporotic fractures. Methods A nested case–control study was carried out within a cohort of 68,970 patients aged 45 years or older, who have been hospitalized for osteoporotic fracture from 2003 until 2005. Cases were the 804 patients who experienced hospitalization for UGIC until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio (OR) associated with current and past use of BPs (i.e. for drug dispensation within 30 days and over 31 days prior the outcome onset, respectively) after adjusting for several covariates. Results Compared with patients who did not use BPs, current and past users had OR (and 95% confidence interval) of 0.86 (0.60 to 1.22) and 1.07 (0.80 to 1.44) respectively. There was no difference in the ORs estimated according with BPs type (alendronate or risedronate) and regimen (daily or weekly), nor with co-therapies and comorbidities. Conclusions Further evidence that BPs dispensed for secondary prevention of osteoporotic fractures are not associated with increased risk of severe gastrointestinal complications is supplied from this study. Further research is required to clarify the role BPs and other drugs of co-medication in inducing UGIC.

1. Peroxynitrite is a strong oxidant that results from reaction between NO and superoxide. It has been recently proposed that peroxynitrite plays a pathogenetic role in inflammatory processes. Here we have investigated the therapeutic efficacy of raxofelast, a new hydrophilic vitamin E-like antioxidant agent, in rats subjected to carrageenan-induced pleurisy. 2. In vivo treatment with raxofelast (5, 10, 20 mg kg(-1) intraperitoneally 5 min before carrageenan) prevented in a dose dependent manner carrageenan-induced pleural exudation and polymorphonuclear migration in rats subjected to carrageenan-induced pleurisy. Lung myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, as well as histological organ injury were significantly reduced by raxofelast. 3. Immunohistochemical analysis for nitrotyrosine, a footprint of peroxynitrite, revealed a positive staining in lungs from carrageenan-treated rats. No positive nitrotyrosine staining was found in the lungs of the carrageenan-treated rats, which received raxofelast (20 mg kg 1) treatment. 4. Furthermore, in vivo raxofelast (5, 10, 20 mg kg(-1)) treatment significantly reduced peroxynitrite formation as measured by the oxidation of the fluorescent dihydrorhodamine 123, prevented the appearance of DNA damage, the decrease in mitochondrial respiration and partially restored the cellular level of NAD+ in ex vivo macrophages harvested from the pleural cavity of rats subjected to carrageenan-induced pleurisy. 5. In conclusion, our study demonstrates that raxofelast, a new hydrophilic vitamin E-like antioxidant agent, exerts multiple protective effects in carrageenan-induced acute inflammation.

1. Antioxidants can exert protective effects in endotoxic shock by either a reduction of the oxidant damage or attenuation of Tumour Necrosis Factor (TNF-alpha) production. 2. Lazaroids are a family of compounds that inhibit lipid peroxidation. Besides, they can also reduce TNF-alpha. U-83836E is a new lazaroid lacking the glucocorticoid ring. 3. Aim of our study was to investigate the effect of U-83836E on TNF-alpha production either in vivo or in vitro. Endotoxic shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg kg(-1) of S. enteritidis lipopolysaccharide (LPS). LPS administration reduced survival rate (0% survival, 72 h after endotoxin administration), decreased mean arterial blood pressure, increased serum and macrophage TNF-alpha and enhanced plasma malonylaldehyde (MAL) levels. Furthermore aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE 1 nM-10 microM). 4. Treatment with U-83836E (7.5, 15 and 30 mg kg(-1), i.v.) 5 min after endotoxin challenge significantly protected against LPS induced lethality (90% survival rate and 80% survival rate 24 h and 72 h after LPS injection respectively, following the highest dose of the drug), reduced hypotension, blunted plasma MAL, decreased serum and macrophage TNF-alpha and restored the hyporeactivity of aortic rings to control values. In vitro LPS stimulation (50 microg ml(-1) for 4 h) significantly increased cytokine production in macrophages (Mphi) harvested from untreated normal rats. Pretreatment with pertussis toxin (PT; 0.1, 1 and 10 ng ml(-1) 4 h before LPS) significantly increased TNF-alpha production. PT effects on these LPS responses were correlated with a PT mediated ADP ribosylation of a 41 kDa protein. U-83836E (50 microM) reduced, in a dose dependent manner, LPS induced TNF-alpha production and inhibited the PT effects on cytokine production and on ADP ribosylation of the protein. 5. Our data suggest that lazaroids may affect the early events associated with LPS receptor mediated activation of a G protein in LPS induced TNF-alpha production. These molecular events may explain, at least in part, the in vivo inhibition of cytokine production and reversal of endotoxic shock.