The aetiology and pathophysiology of non-union is still unclear, but in this condition there is an abnormal bone metabolism. The paracrine matrix RAS has been implicated in the regulation of bone remodeling and injury responses, possibly via its effects on kinins. The influence of the local RAS or the genetic influence of the ACE/ BK2R genes to bone remodelling may thus be central to the disorder, or augmented in these conditions. We thus compared the distribution of the ACE I/D and BK2R “+9/-9” functional polymorphisms in patients with non-union and compared them to appropriate control.

Gene analysis was performed on buccal cells collected from all subjects and the data was analysed for 59 patients (46 males, 13 females; mean age 40.1±15.7 years) with non-union and 81 control subjects (49 males, 32 females; mean age 51.4±22.81 years. The overall genotype distribution was consistent with Hardy-Wein-berg equilibrium for the overall and individual groups for ACE (p0.16), B1BKR (p0.68) and B2BKR genotypes (p0.12)

As the -9 allele is associated with greater gene transcription and higher mRNA expression of the receptor we combined the -9/-9 homozygous and -9/+9 heterozygous groups and compared them with the homozygous +9/+9 groups. This showed a significant difference between the non-union and control groups, with the +9/+9 homozygous being less prominent in the former (p=0.03)

The B2BKR -9 allele is associated with the incidence of non-union in fracture healing, in this first study to address this question. We found no association with either the ACE I/D or B1BKR genotypes.

In conclusion, with previous findings that the absence of the -9 allele of the B2BKR +9/-9 polymorphism is associated with greater gene transcription and higher mRNA expression of the receptor our findings are suggestive that increased BK activity via the B2BKR may predispose to the development of non-union.

Introduction: Bradykinin (BK) exerts its effects directly via B2 receptors but also indirectly through release of factors such as prostaglandins, cytokines, or histamine. During in vitro and preclinical in vivo studies, the B2 receptor inhibitor icatibant (ITB) has been shown to be a potent inhibitor of BK effects. Recently it has been found that a single injection of 90 μg of ITB significantly reduced pain in patients with knee OA, and this effect lasted for about 1 week. The aim of the present study was to determine whether ITB, by multiple dosing, may exert long-lasting clinically relevant effects on OA pain. Objectives:. To compare the onset, extent and duration of pain relief (pain during activity, at rest and at night) in the affected knee between 2 dose groups of ITB and placebo by using a visual analogue scale (VAS). To compare ITB and placebo for safety and the efficacy variables: Western Ontario McMaster Universities OA index (WOMAC), and time until need of rescue medication. Study design: Randomised, double-blind, placebo-controlled, 3-arm, parallel-group, 12-week multi-centre study to compare the effect of intra-articular injections of 2 doses of ITB (500 μg and 2000 μg) and placebo in patients with symptomatic unilateral knee OA. Subjects were treated 3 times in weekly intervals and then followed-up for 10 weeks. Assessments of pain and intake of rescue medication was followed with an electronic patient diary on a daily basis. Functional assessment of the affected knee joint was performed by answering the WOMAC questionnaire at several visits following the last injection. Statistical analysis included the Chi-square test, differences in means, Wilcoxon-test, the trapezoid rule and Kaplan-Meier curves, using analysis of variance without and with covariates (ANOVA, ANCOVA). Results: 340 subjects were screened, and 266 were randomised and treated: 90 with placebo, 86 with 500 μg and 90 with 2000 μg ITB. Treatment-emergent adverse events were experienced by 13 subjects treated with placebo, 8 with 500 μg and 17 treated with 2000 μg ITB. After 3 injections, long-lasting reduction in pain up to 12 weeks after start of treatment could be observed in all treatment groups. Onset of pain relief by _ 10 units was fast and had been reported already 4 hours after start of injection. Both ITB groups consistently demonstrated greater effects on pain when compared to the placebo group; however, there was no difference between the 500 μg and 2000 μg dose groups. Conclusion: The outcome of the present study demonstrates ITB as an analgesic with fast onset and long-lasting pain relief, which could be differentiated against placebo. Its extent of pain relief, together with its excellent safety profile, qualifies ITB as a promising alternative for intervention in acute and chronic pain

Introduction: In the pathogenesis of steroid-associated femoral head necrosis only intra- and extravascular factors have been discussed. This study investigated the effect of long term glucocorticoid treatment on contraction of intraosseous femoral head arteries in a porcine model. Materials and Methods: From 24 immature female Danish Landrace pigs from 12 litters, 12 animals received 100 mg methylprednisolone daily for 3 months. Their 12 sister pigs served as controls and received no steroids. Resistance arteries (diameter approximately 250 μm) were isolated from the femoral head epiphyseal cancellous bone and mounted as ring preparations on a small vessel myograph for measurement of isometric force development. Results: Increasing doses of endothelin-1 evoked significantly stronger vasoconstriction after 3 months of methylprednisolone treatment. The vasocontractory response to increasing doses of noradrenaline was not altered by the previous methylprednisolone treatment. After submaximal precontraction by noradrenaline, vasorelaxation by bradykinin was not altered by methylprednisolone treatment. Discussion: The vasocontractory response of isolated intraosseous femoral head epiphyseal arteries to endothelin-1 after long term glucocorticoid treatment in the pig was enhanced. Enhanced contraction of FH lateral epiphyseal arteries can diminish femoral head blood flow as vessel diameter decreases. This may be a relevant cofactor in the early pathogenesis of steroid-associated femoral head necrosis