J M Wilkinson

Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study

Objectives The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. Methods The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44 449 individuals), and de novo in 14 534 independent samples, all of European descent. Results None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. Conclusions Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Long-term outcome of a cementless, hemispherical, press-fit acetabular component: SURVIVORSHIP ANALYSIS AND DOSE-RESPONSE RELATIONSHIP TO LINEAR POLYETHYLENE WEAR

Between 1988 and 1998 we implanted 318 total hip replacements (THRs) in 287 patients using the Plasmacup (B. Braun Ltd, Sheffield, United Kingdom) and a conventional metal-on-polyethylene articulation. The main indications for THR were primary or secondary osteoarthritis. At follow-up after a mean 11.6 years (7.6 to 18.4) 17 patients had died and 20 could not be traced leaving a final series of 280 THRs in 250 patients. There were 62 revisions (22.1%) in 59 patients. A total of 43 acetabular shells (15.4%) had been revised and 13 (4.6%) had undergone exchange of the liner. The most frequent indications for revision were osteolysis and aseptic loosening, followed by polyethylene wear. The mean Kaplan-Meier survival of the Plasmacup was 91% at ten years and 58% at 14 years. Osteolysis was found around 36 (17.1%) of the 211 surviving shells. The median annual rate of linear wear in the surviving shells was 0.12 mm/year and 0.25 mm/year in those which had been revised (p < 0.001). Polyethylene wear was a strong independent risk factor for osteolysis and aseptic loosening. The percentage of patients with osteolysis increased proportionately with each quintile of wear-rate. There is a high late rate of failure of the Plasmacup. Patients with the combination of this prosthesis and bearing should be closely monitored after ten years.

Bone remodelling around a cemented polyethylene cup: A LONGITUDINAL DENSITOMETRY STUDY

The aims of this study were to examine the repeatability of measurements of bone mineral density (BMD) around a cemented polyethylene Charnley acetabular component using dual-energy x-ray absorptiometry and to determine the longitudinal pattern of change in BMD during the first 24 months after surgery. The precision of measurements of BMD in 19 subjects ranged from 7.7% to 10.8% between regions, using a four-region-of-interest model. A longitudinal study of 27 patients demonstrated a transient decrease in net pelvic BMD during the first 12 months, which recovered to baseline at 24 months. The BMD in the region medial to the dome of the component reduced by between 7% and 10% during the first three months, but recovered to approximately baseline values by two years. Changes in BMD in the pelvis around cemented acetabular components may be measured using dual-energy x-ray absorptiometry. Bone loss after insertion of a cemented Charnley acetabular component is small, transient and occurs mainly at the medial wall of the acetabulum. After two years, bone mass returns to baseline values, with a pattern suggesting a uniform transmission of load to the acetabulum.

Individual Susceptibility to Periprosthetic Osteolysis Is Associated with Altered Patterns of Innate Immune Gene Expression in Response to Pro-Inflammatory Stimuli

Susceptibility to osteolysis after total hip arthroplasty (THA) varies between individuals. We examined whether patients susceptible to osteolysis (group I, nu2009=u200934 subjects) after cemented Charnley THA have quantitatively different innate immune responses to pro‐inflammatory stimuli versus patients without this susceptibility (group II, nu2009=u200928 subjects) at a mean of 14 years after primary surgery. Extracted peripheral blood mononuclear cells were stimulated for 3u2009h using endotoxin (lipopolysaccharide—LPS, 100u2009ng/mL), endotoxin‐stripped titanium particles (Ti) or endotoxin‐stripped particles with adherent LPS added‐back (TIu2009+u2009LPS). Subjects returned 1 week later and the experimental protocol was repeated. Assays for mRNA induction for interleukin (IL)‐1α, IL‐1β, IL‐1Ra, IL‐6, IL‐10, IL‐18, and tumor necrosis factor (TNF) were made using quantitative real‐time PCR. Although baseline levels of mRNA expression were slightly lower in group I, inducibility of mRNA expression was markedly greater in group I versus group II for all cytokines in response to LPS or Tiu2009+u2009LPS, and for IL‐1α in response to Ti (Pu2009<u20090.05). LPS or Tiu2009+u2009LPS stimulation also resulted in an increase in the IL‐1/IL‐1Ra mRNA ratio in group I versus group II (Pu2009<u20090.05). mRNA induction was highly reproducible between subject visits (ru2009>u20090.7, Pu2009<u20090.001). Osteolysis‐susceptible patients show repeatable, quantitatively different patterns of innate cytokine gene expression in response to pro‐inflammatory stimuli versus THA patients who do not display this susceptibility. These innate immune differences may contribute to the variation in osteolysis‐susceptibility observed clinically between individuals.

Quantitating the effect of prosthesis design on femoral remodeling using high-resolution region-free densitometric analysis (DXA-RFA)

Dual energy X‐ray absorptiometry (DXA) is the reference standard method used to study bone mineral density (BMD) after total hip arthroplasty (THA). However, the subtle, spatially complex changes in bone mass due to strain‐adaptive bone remodeling relevant to different prosthesis designs are not readily resolved using conventional DXA analysis. DXA region free analysis (DXA RFA) is a novel computational image analysis technique that provides a high‐resolution quantitation of periprosthetic BMD. Here, we applied the technique to quantitate the magnitude and areal size of periprosthetic BMD changes using scans acquired during two previous randomized clinical trials (2004 to 2009); one comparing three cemented prosthesis design geometries, and the other comparing a hip resurfacing versus a conventional cementless prosthesis. DXA RFA resolved subtle differences in magnitude and area of bone remodeling between prosthesis designs not previously identified in conventional DXA analyses. A mean bone loss of 10.3%, 12.1%, and 11.1% occurred for the three cemented prostheses within a bone area fraction of 14.8%, 14.4%, and 6.2%, mostly within the lesser trochanter (pu2009<u20090.001). For the cementless prosthesis, a diffuse pattern of bone loss (−14.3%) was observed at the shaft of femur in a small area fraction of 0.6% versus no significant bone loss for the hip resurfacing prosthesis (pu2009<u20090.001). BMD increases were observed consistently at the greater trochanter for all prostheses except the hip‐resurfacing prosthesis, where BMD increase was widespread across the metaphysis (pu2009<u20090.001). DXA RFA provides high‐resolution insights into the effect of prosthesis design on the local strain environment in bone.

Quantifying the characteristics of the acetabulum and proximal femur using a semi-automated hip morphology software programme (SHIPS)

Background Hip-joint shape is an important factor that affects an individuals risk of developing osteoarthritis (OA). However, validated tools to quantify these morphological characteristics on clinical plain radiographs are few. We developed a Matlab-based Semi-automated HIP Software programme (SHIPS) that measures 10 morphologic characteristics of the hip that are risk factors for OA using a plain digitised antero-posterior pelvic radiograph. In this study we validated the accuracy and repeatability of this freeware-tool. Methods Software accuracy was assessed using a test pelvic radiograph, and by repeated measurements of an AP-pelvic radiograph digitally recreated from pelvis computed-tomography images reformatted to create images rotated in 2-dimensions (2.5° increments, range −15° to +15°). Intra- and inter-observer repeatability was assessed using pelvic radiographs from 30 subjects analysed twice using the software by two readers, and expressed as coefficient of variation (CV). Clinical-repeatability was assessed by measuring sequential pelvic radiographs taken on the same day after re-positioning in 23 subjects. Results Software accuracy was within 0.1% for linear-ratios and 0.4° for angular-measurements. Changes in pelvic inclination and rotation of ±15° resulted in <14% change in linear-measurement ratios and <7° change in angular-measurements. The intra-observer CV was between 0.3 to 4.1%, and inter-observer CV 0.7 to 9.7% with the exception of horizontal-toit-externa (HTE, 14.6 and 24.2% respectively). Short-term clinical-repeatability varied from 0.4 to 6.1%, with the exception of HTE (37.4%). Conclusion The software showed good accuracy and repeatability for measurement of most hip-joint morphologic risk factors for OA apart from HTE. This tool has particular value in studying large or retrospective datasets where cross-sectional imaging is not feasible or available.

Midterm outcome of the plasma cup in total hip arthroplasty

One hundred and twenty eight primary total hip arthroplasties (THA) in 104 patients were reviewed to assess mid-term survivorship and clinical outcome of the Plasma cup. Outcome was evaluated clinically, radiographically, and by self-administered questionnaires. Patient mean age at surgery was 51 years, and 52 THAs (41%) were performed for secondary arthritis. Prior to surgery the median Merle DAubigne score was 8. At 59 (standard deviation 18) months this score had improved to 17, and the median Harris hip score was 85. The mean annual polyethylene wear rate was 0.14mm/year. There were no instances of aseptic loosening but 2 cups had small, focal osteolytic lesions at the site of screw holes. Three cups were revised, two for recurrent dislocations, and one for infection. Cup survivorship at 5 years was 97% (Kaplan-Meier).This data suggests that the Plasma cup performs well in the mid-term and may be used safely in a young population with a high incidence of secondary osteoarthritis. (Hip International 2002; 2: 119-25).

EBRA-Digital release 2003 versus 1998: A comparison of instrument repeatability for measuring implant migration and wear

EBRA-Digital is an established method for measuring implant migration after total hip arthroplasty using digitized radiographs that has recently undergone a change in the software platform that may influence its precision. We assessed the precision of EBRA-Digital 2003 release and compared it to the previous 1998 release using consecutive, standardized, plain radiographic examinations made on the same day after repositioning in 29 patients. The precision of implant migration and wear measurements was similar between the two software releases, although analysis times were quicker using the 2003 release (p<0.01). Image file compression at a ratio of 30 resulted in poorer measurement precision for some variables. The EBRA 2003 software platform has similar precision to the previous release and allows faster measurement of implant migration and wear. The level of image file compression that is used affects the precision of these measurements. (Hip International 2005; 15: 226-9).

Abstracts from the 5TH EBRA Meeting: Migration and Wear after Total Hip Arthroplasty

The aim of the biennial EBRA meetings is to bring together clinicians and non-clinical scientists with an interest in implant migration and wear after total hip arthroplasty to discuss topics and developments of mutual interest. The 5th (10th Anniversary) meeting was attended by delegates from several European countries. Presentations were given that encompassed research into aspects of migration and wear in primary and revision arthroplasty using both the EBRA method and other systems for measuring these endpoints. We were also delighted to welcome Professor John Paul from The University of Strathclyde who gave a timely and clear account of the progress made by the European Standards Organisation in issuing guidance on the pre-clinical testing of joint replacement implants. The abstracts for the meeting presentations together with a summary of the plenary lecture given by Professor Paul are given below. Finally we would like to extend our thanks to B.Braun Ltd and Aesculap Academia for sponsoring this meeting. Details of the next EBRA meeting in 2004 will be posted on the EBRA website: www.techmath.uibk.ac.at/ geometrie/forschung.htm, or www.orthopaedie.uibk.ac.at in due course. PRE-CLINICAL TESTING OF JOINT REPLACEMENT IMPLANTS J.P. Paul Bioengineering Unit, University of Strathclyde, Glasgow, Scotland UK