Low dose compared to variable dose Warfarin and to Fondaparinux as prophylaxis for thromboembolism after elective hip or knee replacement surgery; a randomized, prospective study.

BACKGROUND: Deep vein thrombosis (DVT) and pulmonary emboli (PE), known together as venous thromboembolic (VTE) disease remain major complications following elective hip and knee surgery. This study compares three chemoprophylactic regimens for VTE following elective primary unilateral hip or knee replacement, one of which was designed to minimize risk of post-operative bleeding. METHODS: Patients were randomized and stratified for hip vs. knee to receive A: variable dose warfarin (first dose on the night preceding surgery with subsequent target INR 2.0-2.5), B: 2.5 mg fondaparinux daily starting 6-18 h postoperatively, or C: fixed 1.0 mg dose warfarin daily starting 7 days preoperatively. All treatments continued until bilateral leg venous ultrasound day 28 ± 2 or earlier upon a VTE event. The study examined primary endpoints including leg DVT, PE or death due to VTE and secondary endpoints including effects on D-dimer, estimated blood loss (EBL) at surgery and hemorrhagic complications. RESULTS: Three hundred fifty-five patients were randomized. None was lost to follow-up. Taking 1.0 mg warfarin for seven days preoperatively did not prolong the prothrombin time (PT). Two patients in Arm C had asymptomatic distal DVT. One major bleed occurred in Arm B and one in Arm C (ischemic colitis). Elevated d-dimer did not predict delayed VTE for one year. CONCLUSIONS: Fixed low dose warfarin started preoperatively is equivalent to two other standards of care under study (95 % CI: -0.0428, 0.0067 for both) as VTE prophylaxis for the patients having elective major joint replacement surgery. TRIAL REGISTRATION: ClinicalTrials.gov identifier # NCT00767559 FDA IND: 103,716.

Ceramic-on-ceramic hip outcome at a 5- to 10-year interval: has it lived up to its expectations?

This study reports revision and complication rates of a single cementless double-wedged tapered stem with an alumina-alumina bearing over 10 years since the beginning of premarket clinical trials. Of 930 hips (848 patients) implanted by 9 surgeons, there were 19 revisions at mean follow-up of 5.9 years compared to 10 revisions in the 123 hips implanted with the polyethylene control group at mean 7.8 years. The ongoing safety of alumina-alumina bearings is demonstrated through excellent (96.8%) survivorship at 10 years. Twenty-one patients reported 23 incidences of noise described as clicking, squeaking, popping, or creaking. Eight patients with 9 hips described the noise as squeaking, most occurring rarely and only 1 occurring frequently in a patient subsequently revised for a reason aside from the squeaking.

Administration of olanzapine to prevent postoperative delirium in elderly joint-replacement patients: a randomized, controlled trial.

BACKGROUND: Delirium is a serious postoperative condition for which few pharmacologic prevention trials have been conducted. OBJECTIVE: The authors tested the efficacy of perioperative olanzapine administration to prevent postoperative delirium in elderly patients after joint-replacement surgery. METHOD: The authors conducted a randomized, double-blind, placebo-controlled, prophylaxis trial at an orthopedic teaching hospital, enrolling 495 elderly patients age ≥65 years, who were undergoing elective knee- or hip-replacement surgery; 400 patients received either 5 mg of orally-disintegrating olanzapine or placebo just before and after surgery. The primary efficacy outcome was the incidence of (DSM-III-R) delirium. RESULTS: The incidence of delirium was significantly lower in the olanzapine group than in the placebo group; this held true for both knee- and hip-replacement surgery. However, delirium lasted longer and was more severe in the olanzapine group. Advanced age, a high level of medical comorbidity, an abnormal albumin level, and having knee-replacement surgery were independent risk factors for postoperative delirium (Clinicaltrials.gov Identifier: NCT000699946). CONCLUSION: Administration of 10 mg of oral olanzapine perioperatively, versus placebo, was associated with a significantly lower incidence of delirium. These findings suggest that olanzapine prophylaxis of postoperative delirium may be an effective strategy.

The effect of paraformaldehyde fixation on the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) measurement.

The delayed Gadolinium-Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC) method allows for both qualitative and quantitative measurement of the spatial distribution of glycosaminoglycan [GAG] in excised cartilage. The objective of this study was to determine the effect of paraformaldehyde fixation on dGEMRIC measurements. Five bovine and seven human cartilage pieces were punched into 5-mm plugs, fixed for 18 h in 4% paraformaldehyde solution, and washed. The magnetic resonance imaging (MRI) parameter T1 was measured prior and post fixation in cartilage without (T1(0)) and with (T1(Gd)), the ionically charged MRI contrast agent Gd(DTPA)(2-). Images of tissue before and after fixation were qualitatively very similar. The ratios of T1(0), T1(Gd), and calculated [GAG] after fixation, relative to before fixation, were near or slightly higher than 1 for both bovine cartilage (1.01 +/- 0.01, 1.04 +/- 0.02, 1.05 +/- 0.03, respectively) and for human cartilage (0.96 +/- 0.11, 1.03 +/- 0.05, 1.09 +/- 0.13). Thus, these data suggest that dGEMRIC can be used on previously fixed samples to assess the three dimensional spatial distribution of GAG.

Hemostasis using a bipolar sealer in primary unilateral total knee arthroplasty.

Previous studies have shown that, compared with standard electrocautery, a bipolar sealer reduces tissue damage and smoke production during surgery. We conducted a multicenter, prospective, randomized study to compare a bipolar sealer with standard electrocautery for hemostasis. Sixty-nine primary total knee arthroplasties were performed. Cohorts were evaluated for intraoperative and postoperative blood loss, blood transfusion requirements, postoperative hemoglobin and pain levels, length of hospital stay, range of motion, and Knee Society scores. Amount of blood loss and decrease in postoperative hemoglobin were significantly lower in the bipolar sealer group than in the standard electrocautery group. Need for autologous blood transfusions was decreased in the bipolar sealer group compared with the electrocautery group. There were no between-groups differences in clinical knee scores. The bipolar sealer was an effective coagulation alternative for total knee arthroplasties in reducing blood loss and transfusion requirements without affecting clinical outcome.

Differential expression of GADD45beta in normal and osteoarthritic cartilage: potential role in homeostasis of articular chondrocytes.

OBJECTIVE: Our previous study suggested that growth arrest and DNA damage-inducible protein 45beta (GADD45beta) prolonged the survival of hypertrophic chondrocytes in the developing mouse embryo. This study was undertaken, therefore, to investigate whether GADD45beta plays a role in adult articular cartilage. METHODS: Gene expression profiles of cartilage from patients with late-stage osteoarthritis (OA) were compared with those from patients with early OA and normal controls in 2 separate microarray analyses. Histologic features of cartilage were graded using the Mankin scale, and GADD45beta was localized by immunohistochemistry. Human chondrocytes were transduced with small interfering RNA (siRNA)-GADD45beta or GADD45beta-FLAG. GADD45beta and COL2A1 messenger RNA (mRNA) levels were analyzed by real-time reverse transcriptase-polymerase chain reaction, and promoter activities were analyzed by transient transfection. Cell death was detected by Hoechst 33342 staining of condensed chromatin. RESULTS: GADD45beta was expressed at higher levels in cartilage from normal donors and patients with early OA than in cartilage from patients with late-stage OA. All chondrocyte nuclei in normal cartilage immunostained for GADD45beta. In early OA cartilage, GADD45beta was distributed variably in chondrocyte clusters, in middle and deep zone cells, and in osteophytes. In contrast, COL2A1, other collagen genes, and factors associated with skeletal development were up-regulated in late OA, compared with early OA or normal cartilage. In overexpression and knockdown experiments, GADD45beta down-regulated COL2A1 mRNA and promoter activity. NF-kappaB overexpression increased GADD45beta promoter activity, and siRNA-GADD45beta decreased cell survival per se and enhanced tumor necrosis factor alpha-induced cell death in human articular chondrocytes. CONCLUSION: These observations suggest that GADD45beta might play an important role in regulating chondrocyte homeostasis by modulating collagen gene expression and promoting cell survival in normal adult cartilage and in early OA.

Case mix and outcomes of total knee replacement in orthopaedic specialty hospitals.

OBJECTIVES: To examine patient characteristics and outcomes of total knee replacement (TKR) in orthopaedic specialty hospitals. METHODS: We performed a retrospective cohort study in the US Medicare population. We defined specialty hospitals for TKR as centers: (1) that performed >75 TKRs in Medicare recipients in 2000; (2) in which TKR accounted for >7% of all Medicare discharges; and (3) that had <300 beds. We divided specialty hospitals into those with

Ceramic-on-ceramic total hip arthroplasty early dislocation rate.

Wear debris from metal-on-polyethylene articulation in conventional total hip arthroplasty can limit the implant's longevity. Modern ceramic material with high wear resistance and low fracture risk has the potential to extend the lifetime of total hip arthroplasty, which makes the procedure potentially more suitable for young, active patients. Concerns with brittle ceramic material include fracture risk, the "squeak" phenomenon, and potentially a higher dislocation rate secondary to limited neck lengths and liner options. We therefore determined the early dislocation rate in modern ceramic-on-ceramic total hip arthroplasty. In 1635 total hip arthroplasties performed over the 9-year period (1996-2005), we observed three anterior and 15 posterior dislocations (1.1%). All were treated successfully, one with a revision and 17 with closed reduction under general anesthesia. Ceramic-on-ceramic total hip arthroplasty can be a good alternative bearing surface with a low dislocation rate.

Use of a hydroxyapatite-coated stem in patients with Dorr Type C femoral bone.

Type C bone, as described by Dorr, exhibits both cellular and structural compromise, which presents a challenge for fixation of a total hip arthroplasty (THA). We evaluated the performance of the Omnifit HA stem, a hydroxyapatite-coated titanium alloy stem, by retrospectively reviewing the clinical and radiographic data of 15 patients with femoral Type C bone who received the stem during primary THA between 1991 and 1994. The patients were followed a minimum of 9 years (mean, 11.5 years; range, 9-14 years). The average age at surgery was 54 years and the average body mass index was 28. Eight of the patients were men. The median Harris hip score was 94.5 points. Radiographically, two independent reviewers identified all patients as Type C bone. The average canal to calcar isthmus ratio was 0.74 (range, 0.65-0.95). At most recent followup, four patients demonstrated proximal osteolysis. Using plain radiography we detected no patients with distal osteolysis or subsidence. At 9 to 14 years, the stem has performed well in a selected series of patients with poor bone quality and the outcomes compare favorably with previously reported findings using this design of stem in other bone types. These results support the decision to use a hydroxyapatite-coated stem in patients with Type C bone.

Relationship between cartilage stiffness and dGEMRIC index: correlation and prediction.

We sought to determine if a generalized relationship between the dGEMRIC index (T1Gd relaxation time) and compressive stiffness of articular cartilage could be defined across multiple samples. Osteochondral blocks were cut from 12 human tibial plateaus, six from cadaveric sources and six from total knee replacement surgeries. Each block contained submeniscal ("covered") and extrameniscal ("uncovered") cartilage regions. At approximately 18 sites per block, a pulse indentation was applied and local dGEMRIC index was determined using dGEMRIC MRI. No correlation was found between stiffness and full cartilage depth dGEMRIC index. When averaged over the depth comparable to the indentation, good correlations were found between stiffness and the dGEMRIC index whether all data were combined, or whether each sample/region was considered independently. However, the standard error of the estimate for predicting stiffness from the local dGEMRIC index was improved when the uncovered and covered regions were considered separately. Further improvement in predictive capacity was obtained if, rather than predict absolute stiffness, differences in the dGEMRIC index across a region were used to predict difference in stiffness. The dGEMRIC index is highly correlated to mechanical stiffness. A generalized relationship was found to provide good correspondence across sources and regions. Use of the dGEMRIC index as a predictive measure of stiffness is possible, depending on the application's acceptable error.

Effect of preoperative exercise on measures of functional status in men and women undergoing total hip and knee arthroplasty.

OBJECTIVE: To evaluate the effect of a short preoperative exercise intervention on the functional status, pain, and muscle strength of patients before and after total joint arthroplasty. METHODS: A total of 108 men and women scheduled for total hip arthroplasty (THA) or total knee arthroplasty (TKA) were randomized to a 6-week exercise or education (control) intervention immediately prior to surgery. We assessed outcomes through questionnaires and performance measures. Analyses examined differences between groups over the preoperative and immediate postoperative periods and at 8 and 26 weeks postsurgery. RESULTS: Among THA patients, the exercise intervention was associated with improvements in preoperative Western Ontario and McMaster Universities Osteoarthritis Index function score (improvement of 2.2 in exercisers versus decline of 3.9 in controls; P = 0.02) and Short Form 36 physical function score (decline of 0.4 in exercisers versus decline of 14.3 in controls; P = 0.003). No significant differences were seen in TKA patients. Exercise participation increased muscle strength preoperatively (18% in THA patients and 20% in TKA patients), whereas the control patients had essentially no change in strength (P > 0.05 for exercise versus education in both THA and TKA groups). Exercise participation prior to total joint arthroplasty substantially reduced the risk of discharge to a rehabilitation facility in THA and TKA patients (adjusted odds ratio 0.27, 95% confidence interval 0.074-0.998). The intervention had no effects on outcomes 8 and 26 weeks postoperatively. CONCLUSION: A 6-week presurgical exercise program can safely improve preoperative functional status and muscle strength levels in persons undergoing THA. Additionally, exercise participation prior to total joint arthroplasty dramatically reduces the odds of inpatient rehabilitation.

The role played by cell-substrate interactions in the pathogenesis of osteoclast-mediated peri-implant osteolysis.

Prosthetic wear debris-induced peri-implant osteolysis is a major cause of aseptic loosening after total joint replacement. In this condition, wear particles released from the implant components induce a granulomatous inflammatory reaction at the interface between implant and adjacent bone, leading to progressive bone resorption and loss of fixation. The present study was undertaken to characterize definitively the phenotype of osteoclast-like cells associated with regions of peri-implant focal bone resorption and to compare the phenotypic features of these cells with those of mononucleated and multinucleated cells associated with polyethylene wear particles. Peri-implant tissues were obtained from patients undergoing hip revision surgery for aseptic loosening after total joint replacement. Cells were examined for the expression of several markers associated with the osteoclast phenotype using immunohistochemistry, histochemistry, and/or in situ hybridization. CD68 protein, a marker expressed by multiple macrophage lineage cell types, was detected in mononucleated and multinucleated cells associated with polyethylene particles and the bone surface. Cathepsin K and tartrate-resistant acid phosphatase were expressed highly in both mononucleated and multinucleated cells associated with the bone surface. Levels of expression were much lower in cells associated with polyethylene particles. High levels of beta3 integrin protein were detected in cells in contact with bone. Multinucleated cells associated with polyethylene particles exhibited faint positive staining. Calcitonin receptor mRNA expression was detected solely in multinucleated cells present in resorption lacunae on the bone surface and was absent in cells associated with polyethylene particles. Our findings provide further evidence that cells expressing the full repertoire of osteoclast phenotypic markers are involved in the pathogenesis of peri-implant osteolysis after total joint replacement. They also demonstrate that foreign body giant cells, although believed to be phenotypically and functionally distinct from osteoclasts, express many osteoclast-associated genes and gene products. However, the levels and patterns of expression of these genes in the two cell types differ. We speculate that, in addition to the role of cytokines and growth factors, the substrate with which these cells interact plays a critical role in their differential phenotypic and functional properties.

Five-year experience with Crossfire highly cross-linked polyethylene.

UNLABELLED: Our purpose was to compare the clinical wear performance of highly cross-linked (Crossfire) polyethylene with conventional (N2Vac) polyethylene total hip bearings. We implanted 56 hips (47 patients) with Crossfire acetabular bearing liners and compared their wear performance with 53 conventional polyethylene inserts. Wear and clinical data were collected retrospectively at a minimum 4-year and average 5-year followup. The linear femoral head penetration rate measured from plain radiographs was 0.055 mm/year +/- 0.022 mm/year for the Crossfire polyethylene and 0.138 mm/year +/- 0.073 mm/year for the control, a reduction of 60% for the Crossfire components. Calculated annual wear was 0.036 mm/year for the Crossfire components and 0.131 mm/year for the controls, a reduction of 72%. Radiographic review at most recent followup showed a reduction in erosive osteolytic lesions of the proximal femur for the Crossfire components compared with controls, also suggesting a reduction in debris release for the Crossfire components. Complications leading to revision were not seen in the Crossfire or control groups. These clinical findings suggest that this particular highly cross-linked polyethylene can provide wear reduction and an alternate bearing surface for active patient populations. LEVEL OF EVIDENCE: Therapeutic study, Level III (retrospective comparative study). See the Guidelines for Authors for a complete description of levels of evidence.

A mouse model of human breast cancer metastasis to human bone.

Currently, an in vivo model of human breast cancer metastasizing from the orthotopic site to bone does not exist, making it difficult to study the many steps of skeletal metastasis. Moreover, models used to identify the mechanisms by which breast cancer metastasizes to bone are limited to intracardiac injection, which seeds the cancer cells directly into the circulation, thus bypassing the early steps in the metastatic process. Such models do not reflect the full process of metastasis occurring in patients. We have developed an animal model of breast cancer metastasis in which the breast cancer cells and the bone target of osteotropic metastasis are both of human origin. The engrafted human bone is functional, based on finding human IgG in the mouse bloodstream, human B cells in the mouse spleen, and normal bone histology. Furthermore, orthotopic injection of a specific human breast cancer cell line, SUM1315 (derived from a metastatic nodule in a patient), later resulted in both bone and lung metastases. In the case of bone, metastasis was to the human implant and not the mouse skeleton, indicating a species-specific osteotropism. This model replicates the events observed in patients with breast cancer skeletal metastases and serves as a useful and relevant model for studying the disease.

Ceramic-on-ceramic bearings in total hip arthroplasty.

The ideal bearing surface for total hip arthroplasty still is being sought. This bearing would be durable, cost-effective, easy to implant, inert, and produce minimal wear debris. Ceramic-on-ceramic bearings have continued to evolve and have enjoyed success in many European centers throughout the past 3 decades. A limited number of early reports from the United States discouraged widespread acceptance and use of ceramic-on-ceramic total hip arthroplasty. Once critically analyzed most of the failures from the early reports are attributable to design and material specific flaws. Vast improvements have been made in ceramic manufacturing leading to even more superior wear characteristics and higher burst strengths. The case for alumina-on-alumina ceramic bearings is becoming stronger as data accumulate clinically and in vitro. In a multicenter, prospective and randomized study, an alumina-on-alumina ceramic bearing is compared with a cobalt chrome-on-polyethylene bearing. After as many as 48 months there has been no significant difference in clinical performance between the two study groups. No ceramic head fracture or ceramic bearing failure has occurred. Therefore, this new alumina-on-alumina ceramic bearing is a safe option for total hip arthroplasty and may provide a more durable prosthesis especially in young and active patients.