Surgical treatment and management of hip fracture patients.

INTRODUCTION: Osteoporosis-related hip fractures are associated with high mortality and costs. The optimum type of treatment for such fractures is controversial. To shed some light on this issue, the surgical treatment and management of osteoporotic hip fractures were discussed during a hip fracture surgical working group at the 2009 International Society For Fracture Repair Annual Meeting comprising leading experts in the field. MATERIALS AND METHODS: The working group consisted of eight orthopaedic surgeons, six industry representatives and one research scientist. Eleven participants were from Europe and four were from the USA and Canada. Two chairmen posed 12 questions relating to the surgical treatment and management of osteoporotic hip fractures. Each question was discussed and key points were noted. RESULTS: Surgery should commence within 24-48 h but the patient should be optimized if presenting with ≥3 comorbidities. Specialized centres integrating orthopaedics, geriatricians and rheumatologists could be a solution for the lack of specialist care post-surgery. Surgical technique is important in fracture fixation, as is the implant, but there has been no improvement in implant design in the past 50 years. As a consequence, malunion has become unjustifiably accepted. Fracture healing can be accelerated using pharmaceuticals which are also important in secondary prophylaxis. All displaced femoral neck fractures in geriatric patients should be treated with hip replacement, the choice between using cemented or uncemented fixation being at the surgeon's discretion. DISCUSSION AND CONCLUSION: This working group discussion highlighted several important issues which could be of interest to the orthopaedic community.

Cushion bearings versus large diameter head metal-on-metal bearings in total hip arthroplasty: a short-term metal ion study.

INTRODUCTION: Metal-on-metal total hip arthroplasty (MOM THA) has the advantage of replicating the femoral head size, but the postoperative elevation of serum metal ion levels is a cause for concern. Metal-on-polycarbonate-urethane is a new cushion bearing featuring a large diameter metal head coupled with a polycarbonate-urethane liner. AIM: The aim of this study was to assess and compare serum cobalt (Co) and chromium (Cr) levels in a group of 15 patients treated with a cushion bearing THA system (Group A) and a group of 15 patients treated with a MOM THA system (Group B) at short-term. At a mean follow-up of 27.3 months (18-35 months), in Group A the median Cr and Co serum levels were significantly lower than in Group B, measuring 0.24 µg/L (0.1-2.1 µg/L) and 0.6 µg/L (0.29-2.3 µg/L) compared to 1.3 µg/L (0.1-9 µg/L, p < 0.001) and 2.9 µg/L (0.85-13.8 µg/L, p < 0.001) respectively. RESULTS: All patients demonstrated an excellent clinical result, as shown by the Harris and Oxford hip scores. The cushion bearing THA studied in this paper showed clinical outcomes similar to the MOM THA bearing, with the advantage of no significant metal ion elevation in the serum. CONCLUSION: These findings warrant the continued clinical study of compliant bearing options.

Conservative versus surgical treatment of osteogenesis imperfecta: a retrospective analysis of 29 patients.

The aim of our study was to compare the surgical and conservative treatment of patients affected by fragility fractures and deformities of long bones in osteogenesis imperfecta (OI).Our series consisted of 29 consecutive OI patients treated at our Institute. The series comprised 14 females and 15 males of different ages. The mean age at the time of the first treatment was 8 years (median 6 years; SD ± 15; range 1 to 75). The mean follow-up was 88 months. The Sillence classification was used to classify OI. Fifteen patients were classified as Type I; five as Type III and nine as Type IV.A total number of 245 procedures were recorded. Of these, 147 were surgical (pinning; intramedullary nailing and plating) while 98 were conservative (cast, braces and bandages). Bisphosphonate use was a major variable in the study. Clinical charts and radiographic films were analyzed for complications (delayed union, nonunion, malunion, hardware loosening). We recorded 58 complications: 13 in Type I; 28 in Type III and 17 in Type IV OI. The rate of each complication was: 15/245 nonunions (6.1%), 14/245 delayed unions (5.7%), 14/245 malunions (5.7%) and 15/245 hardware loosenings (6.1%).We found no statistically significant differences between surgical and conservative treatments. Type III OI, which is a very crippling form of the disease, was associated with radiographically poorer results than the other types. In our analysis, the two groups were unbalanced and only five patients were treated with bisphosphonates. Nevertheless, bisphosphonate use can be considered a good adjuvant to both the conservative and surgical treatment of OI in order to reduce the rate of complications.

Problematic issues and conclusive remarks.

Since 2002, there has been a paradigm shift in the prevention and treatment of osteoporotic fractures. The focus now is on preventing fragility fractures and their associated complications rather than on treating low bone mineral density. Evidence shows that many patients with fractures do not undergo appropriate assessment or treatment. It is important to have an integrated approach in the overall patient management in order to address this care gap for high-risk patients.

Osteosynthetic improvement of osteoporotic bone: prevention surgery.

A prior osteoporotic femoral neck fracture (FNF) doubles the risk of a second, contralateral hip fracture. Pharmacological prevention of osteoporotic fractures is cost-effective but medication compliance and persistence rates are suboptimal.The aim of our study was to evaluate the safety and effectiveness of a device developed for the surgical prevention of an additional contralateral FNF in elderly osteoporotic patients.Only patients with a T score ≤ -2.5 were enrolled and randomized either to receive (Group A) or not receive (Group B) surgical prevention. Sixty-seven patients were enrolled. The mean follow-up was 16 months (range 1 to 22). To date, no contralateral FNF has been reported in either group. In Group A, no device-related complications were recorded. Twelve patients reported one or more falls and in four cases a non-femoral fragility fracture occurred.The main problem with pharmacological prevention is therapy adherence and the extensive period needed for only a slight improvement in bone strength.Surgical prevention is a potential solution for avoiding the occurrence of a second contralateral FNF. Nevertheless, a longer follow-up and a larger cohort of patients is necessary in order to verify the true effectiveness of the surgical prevention in elderly osteoporotic patients.

Differential activation of heme oxygenase-1 by chalcones and rosolic acid in endothelial cells.

The induction of heme oxygenase-1 (HO-1) is widely recognized as an effective cellular strategy to counteract a variety of stressful events. We have shown that curcumin and caffeic acid phenethyl ester, two naturally occurring phytochemicals that possess antioxidant, anti-inflammatory, and anticarcinogenic activities, induce HO-1 in many cell types. This suggests that stimulation of HO-1 could partly underlie the beneficial effects exerted by these plant-derived constituents. Here we examined the ability of additional plant constituents to up-regulate heme oxygenase activity and HO-1 in aortic endothelial cells. Incubation of endothelial cells with a series of polyphenolic chalcones (5-50 microM) resulted in increased heme oxygenase activity; interestingly, the chemical structure dictated the pattern of heme oxygenase induction, which was unique to each particular compound employed. We also found that rosolic acid, a constituent isolated from the rhizome of Plantago asiatica L. dramatically increased HO-1 in a concentration- and time-dependent manner. Severe cytotoxicity was observed after prolonged exposure (24 or 48 h) of cells to curcumin and caffeic acid phenethyl ester, whereas 2'-hydroxychalcone and rosolic acid did not affect cell viability. By using different mitogen-activated protein kinase inhibitors, we determined that the extracellular signal-regulated kinase, p38, and c-Jun NH(2)-terminal protein kinase pathways play only a minor role in the induction of HO-1 by rosolic acid and 2'-hydroxychalcone. On the other hand, increased intra- and extracellular thiols markedly reduced the rise in heme oxygenase activity elicited by rosolic acid. Thus, this study identified novel plant constituents that highly induce HO-1 in endothelial cells and investigated some of the mechanisms involved in this effect.

Haem and nitric oxide: synergism in the modulation of the endothelial haem oxygenase-1 pathway.

NO potently up-regulates vascular haem oxygenase-1 (HO-1), an inducible defensive protein that degrades haem to CO, iron and the antioxidant bilirubin. Since several pathological states are characterized by increased NO production and liberation of haem from haem-containing proteins, we examined how NO influences HO-1 induction mediated by haemin. Aortic endothelial cells treated with S-nitroso-N-acetylpenicillamine (SNAP), sodium nitroprusside (SNP) or diethylenetriamine-NONOate (DETA/NO) and haemin exhibited higher levels of haem oxygenase activity compared with cells exposed to NO donors or haemin alone. This was accompanied by a marked increase in bilirubin production and, notably, by a strong magnification of cellular haem uptake. A role for haem metabolites in modulating HO-1 expression by NO was assessed by exposing cells to SNAP, SNP or DETA/NO in medium derived from cells treated with haemin, which contained increased bilirubin levels. This treatment considerably potentiated HO-1 expression and haem oxygenase activity mediated by NO and the use of a haem oxygenase inhibitor abolished this effect. Both iron liberated during haem breakdown and the formation of nitroxyl anion from NO appeared to partially contribute to the amplifying phenomenon; in addition, medium from haemin-treated cells significantly augmented the release of NO by NO donors. Thus we have identified novel mechanisms related to the induction of HO-1 by NO indicating that the signalling actions of NO vary significantly in the presence of haem and haem metabolites, ultimately increasing the defensive abilities of the endothelium to counteract oxidative and nitrosative stress.

Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element.

The transcription factor Nrf2, which normally exists in an inactive state as a consequence of binding to a cytoskeleton-associated protein Keap1, can be activated by redox-dependent stimuli. Alteration of the Nrf2-Keap1 interaction enables Nrf2 to translocate to the nucleus, bind to the antioxidant-responsive element (ARE) and initiate the transcription of genes coding for detoxifying enzymes and cytoprotective proteins. This response is also triggered by a class of electrophilic compounds including polyphenols and plant-derived constituents. Recently, the natural antioxidants curcumin and caffeic acid phenethyl ester (CAPE) have been identified as potent inducers of haem oxygenase-1 (HO-1), a redox-sensitive inducible protein that provides protection against various forms of stress. Here, we show that in renal epithelial cells both curcumin and CAPE stimulate the expression of Nrf2 in a concentration- and time-dependent manner. This effect was associated with a significant increase in HO-1 protein expression and haem oxygenase activity. From several lines of investigation we also report that curcumin (and, by inference, CAPE) stimulates ho-1 gene activity by promoting inactivation of the Nrf2-Keap1 complex, leading to increased Nrf2 binding to the resident ho-1 AREs. Moreover, using antibodies and specific inhibitors of the mitogen-activated protein kinase (MAPK) pathways, we provide data implicating p38 MAPK in curcumin-mediated ho-1 induction. Taken together, these results demonstrate that induction of HO-1 by curcumin and CAPE requires the activation of the Nrf2/ARE pathway.

Induction of heme oxygenase 1 by nitrosative stress. A role for nitroxyl anion.

Nitric oxide and S-nitrosothiols modulate a variety of important physiological activities. In vascular cells, agents that release NO and donate nitrosonium cation (NO(+)), such as S-nitrosoglutathione, are potent inducers of the antioxidant protein heme oxygenase 1 (HO-1) (Foresti, R., Clark, J. E., Green, C. J., and Motterlini, R. (1997) J. Biol. Chem. 272, 18411-18417; Motterlini, R., Foresti, R., Bassi, R., Calabrese, V., Clark, J. E., and Green, C. J. (2000) J. Biol. Chem. 275, 13613-13620). Here, we report that Angeli's salt (AS) (0.25-2 mm), a compound that releases nitroxyl anion (NO(-)) at physiological pH, induces HO-1 mRNA and protein expression in a concentration- and time-dependent manner, resulting in increased heme oxygenase activity in rat H9c2 cells. A time course analysis revealed that NO(-)-mediated HO-1 expression is transient and gradually disappears within 24 h, in accordance with the short half-life of AS at 37 degrees C (t(12) = 2.3 min). Interestingly, multiple additions of AS at lower concentrations (50 or 100 microm) over a period of time still promoted a significant increase in heme oxygenase activity. Experiments performed using a NO scavenger and the NO electrode confirmed that NO(-), not NO, is the species involved in HO-1 induction by AS; however, the effect on heme oxygenase activity can be amplified by accelerating the rate of NO(-) oxidation. N-Acetylcysteine almost completely abolished AS-mediated induction of HO-1, whereas a glutathione synthesis inhibitor (buthionine sulfoximine) significantly decreased heme oxygenase activation by AS, indicating that sulfydryl groups are crucial targets in the regulation of HO-1 expression by NO(-). We conclude that NO(-), in analogy with other reactive nitrogen species, is a potent inducer of heme oxygenase activity and HO-1 protein expression. These findings indicate that heme oxygenase can act both as a sensor to and target of redox-based mechanisms involving NO and extend our knowledge on the biological function of HO-1 in response to nitrosative stress.