Aims. Hip resurfacing remains a potentially valuable surgical procedure for appropriately-selected patients with optimised implant choices. However, concern regarding high early failure rates continues to undermine confidence in use. A large contributor to failure is adverse local tissue reactions around metal-on-metal (MoM) bearing surfaces. Such phenomena have been well-explored around MoM total hip arthroplasties, but comparable data in equivalent hip resurfacing procedures is lacking. In order to define genetic predisposition, we performed a case-control study investigating the role of human leucocyte antigen (HLA) genotype in the development of pseudotumours around MoM hip resurfacings. Methods. A matched case-control study was performed using the prospectively-collected database at the host institution. In all, 16 MoM hip resurfacing 'cases' were identified as having symptomatic periprosthetic pseudotumours on preoperative metal artefact reduction sequence (MARS) MRI, and were subsequently histologically confirmed as high-grade aseptic lymphocyte-dominated vasculitis-associated lesions (ALVALs) at revision surgery. ‘Controls’ were matched by implant type in the absence of evidence of pseudotumour. Blood samples from all cases and controls were collected prospectively for high resolution genetic a nalysis targeting 11 separate HLA loci. Statistical significance was set at 0.10 a priori to determine the association between HLA genotype and pseudotumour formation, given the small sample size. Results. Using a previously-reported ALVAL classification, the majority of pseudotumour-positive caseswere found to have intermediate-grade group 2 (n = 10; 63%) or group 3 (n = 4; 25%) histological findings. Two further patients (13%) had high-grade group 4 lesions. HLA-DQB1*05:03:01 (p = 0.0676) and HLA-DRB1*14:54:01 (p = 0.0676) alleles were significantly associated with a higher risk of pseudotumour formation, while HLA-DQA1*03:01:01 (p = 0.0240), HLA-DRB1*04:04:01 (p = 0.0453), HLA-C*01:02:01 (p = 0.0453), and HLA-B*27:05:02 (p = 0.0855) were noted to confer risk reduction. Conclusion. These findings confirm the association between specific HLA genotypes and the risk of pseudotumour development around MoM hip resurfacings. Specifically, the two ‘at risk’ alleles (DQB1*05:03:01 and DRB1*14:54:01) may hold clinical value in preoperative screening and prospective surgical decision-making. Cite this article: Bone Jt Open 2023;4(3):182–187

Cobalt chrome alloy is commonly used in joint replacement surgery. However, it is recognised that some patients develop lymphocyte mediated delayed type hypersensitivity (DTH) responses to this material, which may result in extensive bone and soft tissue destruction. Phase 1. United Kingdom: From an existing database, we identified extreme phenotype patient groups following metal on metal (MoM) hip resurfacing or THR: ALVAL with low wearing prostheses; ALVAL with high wear; no ALVAL with high wear; and asymptomatic patients with implants in situ for longer than ten years. Class I and II HLA genotype frequency distributions were compared between these patients’ groups, and in silico peptide binding studies were carried out using validated methodology. Phase 2. United Kingdom: We expanded the study to include more patients, including those with intermediary phenotypes to test whether an algorithm could be developed incorporating “risk genotypes”, patient age, sex and metal exposure. This model was trained in phase 3. Phase 3. United Kingdom, Australia, United States. Patients from other centres were invited to give DNA samples. The data set was split in two. 70% was used to develop machine learning models to predict failure secondary to DTH. The predictions were tested using the remaining blinded 30% of data, using time-dependent AUROCs, and integrated calibration index performance statistics. A total of 606 DNA samples, from 397 males and 209 female patients, were typed. This included 176 from patients with failed prostheses, and 430 from asymptomatic patients at a mean of >10 years follow up. C-index and ROC(t) scores suggested a high degree of discrimination, whilst the IBS indicated good calibration and further backed up the indication of high discriminatory ability. At ten years, the weighted mean survival probability error was < 4%. At present, there are no tests in widespread clinical use which use a patient's genetic profile to guide implant selection or inform post-operative management. The algorithm described herein may address this issue and we suggest that the application may not be restricted to the field of MoM hip arthroplasty

Introduction. We aimed to identify genes associated with the development of ALVAL at relatively low levels of wear. Methods. At our unit all patients undergoing revision of a MoM hip prosthesis have periprosthetic tissue samples graded for ALVAL. Explants undergo volumetric wear testing of the bearing and taper surfaces. We identified patients with moderate/severe ALVAL who had been exposed to lower than the median wear rate of all recorded patients who had developed ALVAL (<3mm. 3. /year). This was termed the “ALVAL” group. We then identified all patients whose tissues had shown no signs of ALVAL. The patients in the two groups were sent buccal DNA collection kits. DNA was examined using next generation sequencing. Alleleic frequencies in the two groups were compared using Fisher's test and compared to a background UK population group (n=8514). We then conducted binary logistic regression with patient age, sex, primary source of debris (taper/bearing) and HLA genotype as the predictors. With the hypothesis that a cobalt/albumin metalloprotein acts as the epitope, we used validated binding prediction software to determine the relative affinities of the binding grooves created by different DQA1/DQB1 genetic combinations for albumin derived peptides. Given the protection that male sex and younger age appears to confer against ALVAL, we hypothesized that testosterone peptides may compete for these binding sites. Results. 28 ALVAL and 37 non ALVAL patients returned their samples for testing. The frequencies of DQA1∗05:05 and DQB1∗03:01 were significantly greater in the ALVAL groups(p=0.018). The variables positively associated with ALVAL were female sex(0.021), increasing age(0.003) and DQA1/DQB1 combinations with greater binding affinity for albumin fragments(0.03). Greater binding affinities for testosterone peptides were inversely related to ALVAL(0.05). Discussion. Common immune genotypes are associated with a greater risk of ALVAL. Conclusion. The evidence base on which MoM follow up protocols are based should be re-evaluated in light of these findings and future studies designed accordingly

Introduction. Periprosthetic osteolysis resulting in aseptic loosening is a leading cause for total hip arthroplasty (THA) failure. Individuals vary in their susceptibility to osteolysis, and it is thought that heritable factors contribute to this variation. We conducted two genome-wide association studies to identify genetic risk loci associated with osteolysis and genetic risk loci associated with time to prosthesis failure due to osteolysis. Patients/Materials & Methods. The Norway cohort comprised 2,624 subjects after THA recruited from the Norwegian Arthroplasty Registry, 779 with revision surgery for osteolysis. The UK cohort comprised 890 subjects recruited from hospitals in the north of England, 317 with radiographic evidence or revision surgery for osteolysis. All subjects had received a fully cemented or hybrid THA using small-diameter metal or ceramic-on-conventional polyethylene bearing. Osteolysis susceptibility case-control analyses and quantitative trait analyses for time to prosthesis failure were undertaken after genome-wide genotyping. Finally, a meta-analysis of the discovery datasets was undertaken. Results. Genome-wide association analysis identified 4 and 11 independent suggestive genetic signals for osteolysis susceptibility at P≤5×10. −6. in the Norwegian and UK cohorts, respectively. Following meta-analysis, 5 independent genetic signals showed suggestive association with osteolysis at P≤5×10. −6. , with the strongest comprising 18 correlated variants on chromosome 7 (lead signal rs850092, Figure 1, p=1.13×10. −6. ). Genome-wide quantitative trait analysis in cases only showed a total of 5 and 9 independent genetic signals for time to prosthesis failure at P≤5×10. −6. , respectively. Following meta-analysis, 11 independent genetic signals showed suggestive evidence of association with time to failure at P≤5×10. −6. , with the largest association block comprising 174 correlated variants in chromosome 15 (lead signal rs10507055, Figure 2, p=1.40×10. −7. ). Discussion. These studies provide the first genome-wide insights into the heritable biology of osteolysis, a major complication of joint replacement surgery. Although there were no dominant signals of genome-wide significance, we find replicating evidence for several independent genetic loci both for osteolysis susceptibility and time to prosthesis failure at P≤5×10. −6. , consistent with the complex aetiology of the disease. Conclusion. The heritable contribution to osteolysis is modest. The identified genetic loci may however provide novel avenues for therapy development in this condition. For any figures and tables, please contact the authors directly

Introduction. Although DDH is one of the most common skeletal dysplasias (incidence 1.5 cases per 1000 births), it remains slow and costly to recruit large-scale patient cohorts for powerful genetic association studies. In this work we have successfully used the NJR as a platform to generate a DDH biobank of 907 individuals, upon which we have conducted the first ever genome-wide association study (GWAS) for DDH. Methods. 5411 patients recorded as having a hip replacement for ‘hip dysplasia’ between March 2003 and December 2013 were approached to participate in the study. Following filtering by questionnaire for non-DDH cases and non-European Caucasians, 907 patients returned a completed saliva sample. A randomly selected sample of individuals participating on the UK Household Longitudinal Study that had been previously genotyped using the same platform were used as controls at a case:control ratio of 1:4. A further data set consisting of 332 cases, 1375 controls and 26 variants was used to replicate the top signals. Results. Of 256833 variants that passed QC, 11 variants reached genome-wide significance. All these variants came from the same signal, with rs143384 as the index SNP (allele A, allele frequency 0.60, OR [95% CI] 1.58[1.40–1.77], P=1.1×10. −14. ). Twenty-six independent variants were prioritized to follow up through de novo replication. Variant rs143384 was found to be significantly associated with DDH after meta-analysing discovery and replication datasets (allele A, allele frequency 0.60, OR [95% CI] 1.50[1.36–1.66], P=2.81×10. −16. ). Discussion. Using eHR case-ascertainment and distance recruitment strategies we conducted the first GWAS for DDH and confirmed association of the GDF5 variant rs143384 with DDH (P=2.81×10. −16. ). We establish the first genome-wide significant locus for DDH, discovered through linking EHRs with genomics as a proof of principle in enabling powerful genetic association studies of relatively rare but complex diseases

Introduction. Hip Osteoarthritis (HOA) is a highly heterogeneous disease with potentially different genetic aetiologies. Thus far, few genetic variants have been robustly associated with broad definitions of HOA. We aimed to identify novel HOA susceptibility variants by examining a set of more homogeneous, radiographically-derived endophenotypes relating to anatomic pattern of joint involvement and bone remodelling response in HOA. Materials, Methods and Results. Individuals with HOA and AP-hip radiographs (n=2,109) were selected from the arcOGEN study, genotyped on 2 platforms. The most arthritic hip per patient was categorised using Bombelli's classification (atrophic/normotrophic/hypertrophic), and for pattern of joint space narrowing (superior/medial-axial/concentric). Following 1000-Genomes-Project-based imputation and stringent quality control over 7 million variants were tested for association with each phenotype under the additive model. Fixed-effects meta-analysis was used to combine the results from the two GWA studies. In the discovery GWAS of atrophic HOA vs cases with non-atrophic HOA a strong signal (rs16869403, OR[95% CI]=2.47[1.81–3.38], p=1.53×10. −8. ) was detected in the G protein-coupled receptor, GPR98. Polymorphisms in GPR98 have been associated with osteoporotic fracture and low bone mineral density and GPR98 knockout mice have a low bone mass phenotype. The meta-analysis of medial joint space narrowing showed strong association with variants in LRCH1 (rs754106, OR[95% CI]=1.46[1.26–1.68], P=2.85×10. −7. ) previously associated with OA but with conflicting replication evidence, and BMP1 (chr8:22065846, OR[95% CI]=3.36[2.12–5.33], P=2.6×10. −7. ) which induces bone and cartilage development. None of these variants showed significant evidence for association when broadly classified HOA cases were compared to population-based controls from the arcOGEN GWAS. Conclusion. Through comprehensive examination of radiographically-derived, HOA-related phenotypes we have identified several promising signals that point to novel biologically plausible genes for HOA. Our results indicate that, in a heterogeneous disease like OA the study of narrower phenotype definitions closer to the biology of the disease has the potential to enhance power to detect OA-relevant associations

Introduction. Aseptic loosening, the clinical endpoint of osteolysis, remains the leading cause of total hip arthroplasty (THA) failure, and is caused by a host response to wear debris that varies between individuals. Although several candidate gene studies have identified loci associated with osteolysis susceptibility, there have been no systematic studies at genome-wide level. We aimed to identify risk loci associated with osteolysis by conducting a genome-wide association study. Methods. 3,706 Caucasian European patients following THA were studied. The discovery cohort comprising 894 patients (317 with osteolysis) were genotyped using the Illumina-610 beadchip followed by 1000 Genome-based imputation covering 10 million single nucleotide polymorphisms (SNPs). Phenotypes were transformed to normality where required, regressed on important covariates and z-standardised. Following quality control, osteolysis case-control analysis and a quantitative trait association analysis for time to prosthesis failure were undertaken. Index SNPs p<9×10. −4. were taken forward for replication in a second cohort comprising 2,812 subjects (834 osteolysis cases) recruited from the Norwegian arthroplasty registry. Genotyping was undertaken using Sequenom MassARRAY iPLEX Gold assay and association analyses undertaken using logistic and linear regression. Summary statistics were combined in a fixed-effects meta-analysis framework. Results. The strongest signal associated with time to prosthesis failure lay within DEFB129 gene. The signal index SNP, rs6105394, approached genome wide significance at p=5.75×10. −7. Two signals in the susceptibility analysis also approached genome-wide significance, 1 within CAMK4 (rs306105, OR 0.41, p=6.54×10. −7. ) and 1 upstream of PLNXA2 (rs11119057, OR 0.96, p=6.44×10. −7. ). Following meta-analysis, the strongest signal in the susceptibility analysis remained that within CAMK4 (rs306105, p=3.79×10. −4. ). The strongest signal associated with time to failure was just upstream of CNTN3 (rs1374879, p=2.15×10. −5. ). Discussion. We have identified promising loci associated with osteolysis and time to prosthesis failure although not at genome-wide significance (p<5×10. −8. ). In order to further validate these loci, larger genome wide association analysis is required

Aims

The processes linking long-term bisphosphonate treatment to atypical fracture remain elusive. To establish a means of exploring this link, we have examined how long-term bisphosphonate treatment with prior ovariectomy modifies femur fracture behaviour and tibia mass and shape in murine bones.

We measured the plasma 25-hydroxyvitamin D₃ (25(OH)D₃) levels in 62 consecutive Caucasian patients undergoing total hip replacement for osteoarthritis. The patients were divided into two groups based on whether they were vitamin D sufficient or deficient. The groups were matched for age, gender and the American Society of Anaesthesiologists (ASA) grade. The prevalence of vitamin D deficiency in our patients was comparable with recent population-based studies performed in the United Kingdom. Patients with vitamin D deficiency had lower pre-operative Harris hip scores (Mann-Whitney test, p = 0.018) and were significantly less likely to attain an excellent outcome from total hip replacement (chi-squared test, p = 0.038). Vitamin D levels were found to positively correlate with both pre- and post-operative Harris hip scores.

These results warrant further study of vitamin D deficiency in patients undergoing joint replacement as it is a risk factor for a suboptimal outcome which is relatively simple and cheap to correct.