In a recent phase 2 superiority clinical trial we demonstrated that a single dose of 60mg of the human monoclonal antibody denosumab inhibits osteolytic lesion activity in patients undergoing revision total hip arthroplasty (THA), demonstrating proof of biological efficacy for this clinical application. Here, we examined the effect that denosumab has on disease biology at the osteolysis tissue level. Osteolytic tissue taken from the prosthesis-bone lesion interface at revision surgery in patients with osteolysis (n=10 participants that had received a single 60 mg dose of denosumab 8 weeks prior to revision surgery and n=10 that had received placebo) was examined for total genetic message activity and protein levels using whole genome sequencing and mass spectrometry, respectively. The top five upregulated enriched pathways with denosumab treatment included inflammatory response, myeloid cell activation, myeloid leukocyte migration, neutrophil and granulocyte activation (p<6.26 × 10. −28. ). Cell morphogenesis was amongst the most downregulated pathways (p<3.42 ×10. −23. ). Finally, comparison of the trial mRNA and protein data versus mouse single cell RNA sequencing data of the same pathway blockade in mouse tibia showed the same direction of effect, suggesting that giving the drug causes then cells responsible for osteolysis to disperse into a more immature form (128 of 189 genes (z=4.87, P<0.0001) disease and functional pathways at the mRNA level and 10 of 11 (z=2.72, P=0.0065) at the protein level). In this first-in-man study we identify multiple genes and pathways within periprosthetic osteolysis tissue that are affected by denosumab treatment. The dominant pathways involved upregulation of innate inflammatory signaling and downregulation of cell morphogenesis. We also found enrichment of similar disease and functional pathways at both the mRNA and protein levels versus mRNA pathway enrichment found in mouse osteomorphs. These data provide the first human data of the mechanistic effect of denosumab treatment on inflammatory osteolytic lesion activity after joint replacement that is necessary to support its clinical application. ∗Winner of The Bone & Joint Journal prize∗

Now that periprosthetic osteolysis is under control, analyzing how it was overcome has substantial value. What can we learn about how to attack the next enigma? There were six important generic drivers leading to that success:. Surmounting the failure to recognize its full nature. Why was it that the lapse between the first case and the publication of the article called “cement disease” was three decades? In part, because the concept of “cement disease” was simultaneously ingenious, essential, incomplete and misleading. Understanding “biology beyond the histology.” Histology assured us that this destruction process was not malignant but well beyond that was discovery of the novel and exquisite understanding of the molecular biology. The importance of multiple parallel approaches. The detailed molecular biology suggested that a pharmacologic prophylaxis should exist, but none was ever found. Of the three possible alternate bearings, the most likely (metal-on-metal) failed badly and the least likely (metal-on-polyethylene) succeeded. The critical role of “beyond luck.” It is essential to understand more fully that serendipity nearly always follows Pasteur's motto that “chance favors only the prepared mind.”. The irreplaceable role of persistence. This is almost a homily. The unavoidable requirement of risk-taking. Forty years of metal-on-metal THA without pseudotumors provided no protection against its current ravages

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

There are numerous studies in the current literature that have demonstrated altered levels of various biomarkers in the serum of patients with implant loosening. Despite increasing interest in the biology of implant incorporation there are no studies investigating the changes in biological marker (of either osteoblastic or osteoclastic activity) levels during the integration of the bone-implant interface. Such a study would provide data about the biological profile of normal integration and would be helpful for future monitoring of implant prosthetic performance (either normal or abnormal). We present data from a study performed on 100 osteoarthritic patients, who underwent cementless THA (Synergy, Reflexion Interfit, Smith & Nephew) and 100 non arthritic volunteers. Serial measurements of serum biochemical markers (bone formation and resorption), of cytokines and of other biological mediators and growth factors were evaluated at regular intervals over the course of six years. Curves of per cent changes from baseline and marker variability curves have been created for each marker which are indicative of the incorporation process. Evaluating markers of osteoblastic activity, a first response, with average values below baseline, was observed at the level of the seventh day (perhaps as a response to local trauma). A second osteo-productive response was observed between the third week and 9 months (peak average values at the level of the 6. th. month). At the 1st year time interval, average values reached baseline and remained at this level up to the 6th postoperative year. Evaluating markers of osteoclastic activity, a first response, with average values above baseline, was observed at the level of the seventh day (perhaps as a response to local trauma). A second osteoclastic response was observed between the third week and 3 months (perhaps a coupling response to enhanced osteoblastic activity). At 6 months, average values reached baseline and remained at this level up to the 6th postoperative year. It seems that bone implant interface in cementless total hip arthroplasty remains active up to the 9. th. postoperative month. Possible future deviation from such ‘individual normal’ curves will be indicative of the initiation of the osteolysis process and loss of fixation

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

Aims

The aim of this study was to evaluate blood metal ion levels, leucocyte profiles, and serum cytokines in patients with a total hip arthroplasty (THA) involving modular dual-mobility components.

Aims

The aim of this study was to examine the results of the acetabular distraction technique in achieving implantation of a stable construct, obtaining biological fixation, and producing healing of chronic pelvic discontinuity at revision total hip arthroplasty.

Aims

The objective of this study was to investigate bone healing after internal fixation of displaced femoral neck fractures (FNFs) with the Dynamic Locking Blade Plate (DLBP) in a young patient population treated by various orthopaedic (trauma) surgeons.

Acetabular bone loss is a challenging problem facing the revision total hip replacement surgeon. Reconstruction of the acetabulum depends on the presence of anterosuperior and posteroinferior pelvic column support for component fixation and stability. The Paprosky classification is most commonly used when determining the location and degree of acetabular bone loss. Augments serve the function of either providing primary construct stability or supplementary fixation.

When a pelvic discontinuity is encountered we advocate the use of an acetabular distraction technique with a jumbo cup and modular porous metal acetabular augments for the treatment of severe acetabular bone loss and associated chronic pelvic discontinuity.

Cite this article: Bone Joint J 2014;96-B(11 Suppl A):36–42.

Objectives

Sagittal alignment of the lumbosacral spine, and specifically pelvic incidence (PI), has been implicated in the development of spine pathology, but generally ignored with regards to diseases of the hip. We aimed to determine if increased PI is correlated with higher rates of hip osteoarthritis (HOA). The effect of PI on the development of knee osteoarthritis (KOA) was used as a negative control.

An 81-year-old woman presented with a fracture in the left femur. She had well-fixed bilateral hip replacements and had received long-term bisphosphonate treatment. Prolonged bisphosphonate use has been recently linked with atypical subtrochanteric and diaphyseal femoral fractures. While the current definition of an atypical fracture of the femur excludes peri-prosthetic fractures, this case suggests that they do occur and should be considered in patients with severe osteopenia. Union of the fracture followed cessation of bisphosphonates and treatment with teriparatide. Thus, this case calls into question whether prophylactic intramedullary nailing is sufficient alone to treat early or completed atypical femoral fractures.

Femoroacetabular impingement causes pain in the hip in young adults and may predispose to the development of osteoarthritis. Genetic factors are important in the aetiology of osteoarthritis of the hip and may have a role in that of femoroacetabular impingement. We compared 96 siblings of 64 patients treated for primary impingement with a spouse control group of 77 individuals. All the subjects were screened clinically and radiologically using a standardised protocol for the presence of cam and pincer deformities and osteoarthritis.

The siblings of those patients with a cam deformity had a relative risk of 2.8 of having the same deformity (66 of 160 siblings hips versus 23 of 154 control hips, p < 0.00001). The siblings of those patients with a pincer deformity had a relative risk of 2.0 of having the same deformity (43 of 116 sibling hips versus 29 of 154 control hips, p = 0.001). Bilateral deformity occurred more often in the siblings (42 of 96 siblings versus 13 of 77 control subjects, relative risk 2.6, p = 0.0002). The prevalence of clinical features in those hips with abnormal morphology was also greater in the sibling group compared with the control group (41 of 109 sibling hips versus 7 of 46 control hips, relative risk 2.5, p = 0.007). In 11 sibling hips there was grade-2 osteoarthritis according to Kellgren and Lawrence versus none in the control group (p = 0.002).

Genetic influences are important in the aetiology of primary femoroacetabular impingement. This risk appears to be manifested through not only abnormal joint morphology, but also through other factors which may modulate progression of the disease.

We examined the relationships between the serum levels of chromium and cobalt ions and the inclination angle of the acetabular component and the level of activity in 214 patients implanted with a metal-on-metal resurfacing hip replacement. Each patient had a single resurfacing and no other metal in their body. All serum measurements were performed at a minimum of one year after operation. The inclination of the acetabular component was considered to be steep if the abduction angle was greater than 55°.

There were significantly higher levels of metal ions in patients with steeply-inclined components (p = 0.002 for chromium, p = 0.003 for cobalt), but no correlation was found between the level of activity and the concentration of metal ions. A highly significant (p < 0.001) correlation with the arc of cover was found. Arcs of cover of less than 10 mm were correlated with a greater risk of high concentrations of serum metal ions. The arc of coverage was also related to the design of the component and to size as well as to the abduction angle of the acetabular component. Steeply-inclined acetabular components, with abduction angles greater than 55°, combined with a small size of component are likely to give rise to higher serum levels of cobalt and chromium ions. This is probably due to a greater risk of edge-loading.

Deficiencies of acetabular bone stock at revision hip replacement were reconstructed with two different types of allograft using impaction bone grafting and a Burch-Schneider reinforcement ring. We compared a standard frozen non-irradiated bone bank allograft (group A) with a freeze-dried irradiated bone allograft, vitalised with autologous marrow (group B). We studied 78 patients (79 hips), of whom 87% (69 hips) had type III acetabular defects according to the American Academy of Orthopaedic Surgeons classification at a mean of 31.4 months (14 to 51) after surgery. At the latest follow-up, the mean Harris hip score was 69.9 points (13.5 to 97.1) in group A and 71.0 points (11.5 to 96.5) in group B. Each hip showed evidence of trabeculation and incorporation of the allograft with no acetabular loosening.

These results suggest that the use of an acetabular reinforcement ring and a living composite of sterile allograft and autologous marrow appears to be a method of reconstructing acetabular deficiencies which gives comparable results to current forms of treatment.