To date there is no medical treatment alternative to surgery for osteolysis after THA. In this proof-of-concept clinical trial we examined the effect of a human monoclonal antibody against osteoclasts versus placebo on osteolytic lesion activity in patients undergoing revision surgery. Patients scheduled for revision for symptomatic osteolysis were randomised (1:1) to receive either denosumab 60mg or placebo subcutaneously eight weeks prior to operation. At surgery, biopsies from the osteolytic membrane-bone interface were taken for histomorphometric analysis of osteoclast number. Secondary outcome measures included systemic bone turnover markers. 22 subjects completed the study (10 denosumab). The denosumab group had 83% (−63 to −97), P=0.011 fewer osteoclasts at osteolytic lesion sites, 87% lower osteoclast surface (−65 to −95, P=0.009), and 72% lower eroded surface (−35 to −93, P=0.020) versus the placebo group. At surgery, serum CTX-I, TRAP5b and PINP were 80% (−65 to −95, p<0.001), 57% (−40 to −90, p<0.001), and 44% (−41 to −65, p<0.001) lower in the denosumab versus placebo groups, respectively. The rate of adverse events (denosumab 6, placebo 7) were similar between groups (P>0.05). These data provide a biological basis for a definitive clinical trial using pain, function and prosthesis survival as the study endpoints. As osteolysis/ aseptic loosening is the leading cause of prosthesis failure world-wide, the establishment of a non-surgical solution would reduce patient suffering and dramatically reducing the cost to healthcare economies.
A recent French report suggested that cobalt metal ions released from total hip replacements (THRs) were associated with an increased risk of dilated cardiomyopathy and heart failure. If the association is causal the consequences would be significant given the millions of Orthopaedic procedures in which cobalt-chrome is used annually. We examined whether cobalt-chrome containing THRs were associated with an increased risk of all-cause mortality, heart failure, cancer, and neurodegenerative disorders. Data from the National Joint Registry was linked to NHS English hospital inpatient episodes for 375,067 primary THRs with up to 14·5 years follow-up. Implants were grouped as either containing cobalt-chrome or not containing cobalt-chrome. The association between implant construct and the risk of all-cause mortality and incident heart failure, cancer, and neurodegenerative disorders was examined. There were 132,119 individuals (35·2%) with an implant containing cobalt-chrome. There were 48,106 deaths, 27,406 heart outcomes, 35,823 cancers, and 22,097 neurodegenerative disorders. There was no evidence of an association that patients with cobalt-chrome implants had higher rates of any of the outcomes. For all-cause mortality there was a very small survival advantage for patients having a cobalt-chrome implant (restricted mean survival time 13·8=days, 95% CI=6·8-20·9). Cobalt-chrome containing THRs did not have an increased risk of all-cause mortality, heart failure, cancer, and neurodegenerative disorders into the second decade post-implantation. Our findings will reassure clinicians and patients that primary THR is not associated with systemic implant effects.
The development of an algorithm that provides accurate individualised estimates of revision risk could help patients make informed surgical treatment choices. This requires building a survival model based on fixed and modifiable risk factors that predict outcome at the individual level. Here we compare different survival models for predicting prosthesis survivorship after hip replacement for osteoarthritis using data from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR). In this comparative study we implemented parametric and flexible parametric (FP) methods and random survival forests (RSF). The overall performance of the parametric models was compared using Akaike information criterion (AIC). The preferred parametric model and the RSF algorithm were further compared in terms of the Brier score, concordance index and calibration via repeated five-fold cross-validation.Introduction
Methods
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. 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.Introduction
Patients/Materials & Methods
Heterotopic ossification (HO) is lamellar bone formation in the soft tissues following trauma or joint replacement for osteoarthritis (OA). A genome wide association study of HO patients after total hip arthroplasty for OA has identified Kinesin Family Member 26B (KIF26B) as a gene associated with HO severity. KIF26B has previously been associated with HO in mice. Hypothesis and aims: We hypothesised that Kif26b regulates the osteogenic trans-differentiation of myoblasts; a possible mechanism of HO. Using an We developed CRISPR/Cas9 mediated Kif26b knockout (KO) C2C12 myoblasts. Wild type (WT) and KO cells were transdifferentiated towards an osteogenic lineage using BMP-2 for 24 days. The effect of Kif26b KO on mineralisation was quantified by calcium staining. The mean difference (±SEM) in gene expression between WT and KO lines was compared with ANOVA.Background
Methods
With the increasing demand for hip and knee replacement and move towards seven-day services, we examined whether this planned, elective surgery performed at the weekend is associated with a different 30-day mortality versus that performed between Monday and Friday. The study dataset comprised 118,096 joint replacement episodes performed at the weekend and 1,233,882 episodes done on a weekday. We used a Kaplan-Meier framework to examine the 30-day cumulative mortality rate for all elective hip and knee replacements performed in England and Wales and recorded in the NJR between 1st April 2003 and 31st December 2014, with Cox proportional-hazards regression models to assess for time-dependent variation and adjust for identified risk factors for mortality. For hip replacement the cumulative 30-day mortality was 0.15% (95%CI: 0.12–0.19) for patients operated on at the weekend versus 0.20% (0.19–0.21) for patients undergoing surgery during the normal working week. For knee replacement the cumulative 30-day mortality was 0.14% (0.11–0.17) for patients operated on at the weekend versus 0.18% (0.17–0.19) for patients undergoing surgery during the normal working week. The lower mortality associated with weekend operating was most apparent in the later years of the audit (2009 to 2014) and remained after adjustment for any differences in patient age, gender, American Society of Anaesthesiologist grade, surgeon seniority, surgical and anaesthetic practices, and thrombo-prophylaxis choice in weekend versus weekday operated patients. Routine hip and knee replacements performed at the weekend in England and Wales and are not associated with an increased risk of post-operative mortality.
With the increasing demand for hip and knee replacement, and the increasing pressure to move towards routine seven-day services within the National Health Service, the trend towards weekend operating is set to increase. We aimed to determine whether planned, elective total hip and total knee replacement performed at the weekend is associated with a different 30-day mortality versus those performed between Monday and Friday. We used National Joint Registry of England, Wales, Northern Ireland and Isle of Man (NJR) linked to Office for National Statistics (ONS) data. The study dataset comprised 118,096 joint replacement episodes performed at the weekend and 1,233,882 episodes done on a weekday. The main outcome measure was 30-day all-causes mortality. We applied a survivorship analysis using a Kaplan-Meier framework to examine the 30-day cumulative mortality rate for all elective hip and knee replacements performed in England and Wales between 1st April 2003 and 31st December 2014, with Cox proportional-hazards regression models to assess for time-dependent variation and adjust for identified risk factors for mortality. For hip replacement the cumulative 30-day mortality was 0.15% (95%CI: 0.12–0.19) for patients operated on at the weekend versus 0.20% (0.19–0.21) for patients undergoing surgery during the normal working week. For knee replacement the cumulative 30-day mortality was 0.14% (0.11–0.17) for patients operated on at the weekend versus 0.18% (0.17–0.19) for patients undergoing surgery during the normal working week. The lower mortality associated with weekend operating was most apparent in the later years of the audit (2009 to 2014) and remained after adjustment for any differences in patient age, gender, American Society of Anaesthesiologist grade, surgeon seniority, surgical and anaesthetic practices, and thrombo-prophylaxis choice in weekend versus weekday operated patients. Hip and knee replacements are routinely performed on Saturdays, and to a lesser extent on Sundays, in England and Wales and are not associated with an increased risk of post-operative mortality.
We have previously observed an increase in total bone mineral density and reduced bone turnover (TRAP5b and osteocalcin) in patients with well-functioning metal-on-metal hip resurfacing (MOMHR). Here, we provide data to support the hypothesis that osteoclast differentiation and function is altered in this patient population, and that this effect is transferrable through their serum. Patients with well-functioning MOMHR (cases, n=18) at a median follow-up of 8 years were individually matched for gender, age and time-since-surgery to a low-exposure group consisting of patients with THA (controls, n=18). The monocyte fraction of patient peripheral blood was isolated and differentiated into osteoclasts on dentine wafers using RANKL and M-CSF supplemented media (osteoclastogenic media, OM). Cultures were monitored for the onset of resorption, at which point the cells were treated with OM, autologous serum or serum from matched MOMHR/THA donors, all supplemented with RANKL and M-CSF. At the end of the culture, cells were TRAP-stained and quantified using CellD Software Package, Olympus. When cells were differentiated in standard osteoclastogenic media, the resorbing ability of osteoclasts derived from MOMHR patients was reduced 22%(p<0.0079) compared to THA. The resorbing ability of osteoclasts generated from MOMHR patients and differentiated in autologous serum was reduced 33%(p<0.0001), whilst matched THA serum caused a smaller reduction of 14%(p<0.01). When cells derived from THA patients were differentiated in autologous serum, the resorbing ability of osteoclasts was similarly reduced by 35%(p<0.0001), whilst the matched MOMHR serum also caused a reduction of 21%(p<0.0001). This data suggests that prior exposure to higher circulating Co and Cr in patients with MOMHR reduces osteoclastogenesis, and that the detrimental effect on the functionality of mature osteoclasts is transferable through the serum. This has implications for systemic bone health of patients with MOMHR or modular taper junctions.
Systemic concentrations of metal ions (cobalt and chromium) are persistently elevated in patients with metal-on-metal hip resurfacing (MOMHR) compared to conventional total hip arthroplasty (THA). Several studies by us and others have described the detrimental effects of metal exposure on survival and function of various cell types The cohort consisted of 34 patients with a well-functioning MOMHR at a median follow-up of 9.75 years. These were individually matched for gender, age and time-since-surgery to a non-exposure group consisting of patients with THA. Genomic DNA was isolated from blood samples and cell composition estimated using the ‘estimateCellCounts’ function in ‘minfi R-package’. Methylation was assessed using the Illumina 450k BeadChip array analysing 426,225 probes. Logit model was fitted at each probe with case/control status as independent variable and covariates of gender, age, time-since-surgery, smoking, non-arthroplasty metal exposure, and cell composition. DNA methylation age was assessed using an online calculator ( Cell distributions did not differ between the cases and controls (Wilcoxon test In summary, large methylation changes following MOMHR seem to be absent, compared to THA. Future research with larger samples will be needed to clarify the presence and extent of small methylation changes.
An extended trochanteric osteotomy (ETO) is a widely used approach for revision hip arthroplasty. Following an ETO it is common practice to use a long stemmed femoral prosthesis at the second stage to bypass the osteotomy. We propose that at the second stage, if the osteotomy has united, it is appropriate to use a standard length prosthesis, which preserves bone stock for any future revisions. We performed a retrospective review of our institution's prospective arthroplasty database, identifying all patients who had undergone an ETO at the first stage revision. A radiograph review was then performed and any subsequent complications recorded. A selection of patients radiographs were individually reviewed by three reviewers and intra-class correlation (ICC) was performed to assess intra-observer reliability.Background
Methods
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. 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.Introduction
Methods
In rheumatoid (RA) patients undergoing total joint arthroplasty, evidence suggests methotrexate should be continued without increase in post-operative infection. Prednisolone increases post-operative infection risk, but cannot be stopped without risk of Addisonian events. Insufficient evidence exists to clarify perioperative biologic agent management. We currently stop biologics 2 weeks prior to operation and reintroduced following wound healing. This service evaluation reviewed infection rates and length of stay in RA patients following lower-limb arthroplasty, on various anti-rheumatoid therapies across a 28-month period.Introduction
Patients/Materials & Methods
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. 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.Introduction
Methods
Subtle variations in hip morphology associate with risk of hip osteoarthritis (OA). However, validated accurate methods to quantitate hip morphology using plain radiography are lacking. We have developed a Matlab-based software-tool (SHIPs) that measures 19 OA-associated morphological-parameters of the hip using a PACS pelvic radiograph. In this study we evaluated the accuracy and repeatability of the method. Software accuracy was assessed by firstly measuring the linear ratio of 2 fixed distances and several angles against a gold-standard test radiograph, and secondly by repeated measurements on a simulated AP radiograph of the pelvis (reformatted from CT-data) that was digitally rotated about 3-axes to determine the error associated with pelvic mal-positioning. Repeatability was assessed using 30-AP Pelvic radiographs analysed twice (intra-observer), by 2 readers (inter-observer), and finally, using 2 pelvic radiographs taken in 23 subjects (n=46 radiographs) taken same day after re-positioning (short-term clinical-practice variability), and was expressed as coefficient of variation (CV%).Introduction
Methods
Local bone-related adverse events occur more frequently following metal-on metal hip resurfacing (MOMHR) versus convention total hip arthroplasty (THA). High local tissue levels of cobalt and chromium may contribute to impaired bone health, however the systemic effects on bone of exposure to elevated metal levels after MOMHR are unknown. In this cross-sectional study we compared whole body bone mineral density (WB-BMD) and biochemical markers of bone turnover in 31 healthy male subjects at a mean of 8 years after MOMHR versus 31 individually age and time since surgery matched male subjects after conventional THA. All subjects had well-functioning prostheses and were in good self-reported health as assessed by Oxford Hip Score and EQ-5D questionnaire. WB-BMD was measured by dual energy x-ray absorptiometry and adjusted for pre-morbid osteoporosis risk factors using the FRAX tool, and for the presence of the metal prostheses using identical exclusion regions. Bone turnover markers were measured on fasting morning serum or 24hr urine collection by electro-chemiluminescent assay. Cobalt and chromium were measured by ICP-MS.Background and objectives
Methods
Lumbar spinal pain can be a consequence of discogenic pain. After failure of conservative management, lumbar fusions are popular and considered the gold standard. However, these techniques are associated with significant morbidity. A percutaneous trans-sacral technique may address these for L4/L5 and/or L5/S1 alone spinal fusions. Our unit has adopted this technique and presents our initial experience of 51 patients and preliminary results. Patients with a confirmed clinical and radiological evidence of degenerate intervertebral disc with or without prior surgical intervention were selected. Patients with a history of pelvic surgery/radiotherapy were excluded. Data was collected prospectively using the Global Patient Outcome Scoring System and Oswestry Disability Index (ODI) scores at clinical follow-up.Introduction
Method
One possible mechanism by which metal-on-metal hip resurfacing (MOMHR) may be associated with prosthesis loosening, periprosthetic fracture, and femoral neck narrowing is through an increase in bone resorption by osteoclast cells. Whilst it is known that metal ions such as cobalt (Co) and chromium (Cr) ions (that are elevated locally and systemically after MOMHR), may affect osteoblast and macrophage activity in-vitro, little is known about the effect of these ions on osteoclasts. We examined whether these ions have an adverse effect on human peripheral blood derived osteoclasts at levels that are clinically relevant after MOMHR. Peripheral blood mononuclear cells from healthy donors were seeded onto dentine wafers, and treated to transform them into osteoclasts using standard techniques in the presence of various clinically relevant concentrations of Co2+, Cr3+, and Cr6+. After 3 weeks of culture osteoclast number and resorption pit formation was quantified using histological techniques. All 3 metal ions had a dose-dependent effect on both osteoclast formation and resorption activity. At ion levels found in serum after MOMHR, an increase in osteoclast formation and bone resorption was found, but at higher levels found in synovial fluid, osteoclast cell proliferation and resorption activity was decreased, likely due to a direct toxic effect of the ions on the cells (Figure 1). Cr6+ was more toxic than the other ions at higher concentrations. Our data suggest that metal ion release following MOMHR may increase osteoclast activity systemically that might have a deleterious effect on general and local bone health, and may contribute to the observed bone related complications of MOMHR.
Measurements of biochemical markers of bone turnover have been explored as a diagnostic tool for the detection of osteolysis after THA, but their predictive value in individual subjects has been poor. One explanation for this low diagnostic utility is that the mechanism of bone resorption in osteolysis may be different to that occurring in other high bone turnover states, such as osteoporosis, where these markers were principally developed. The aim of this study was to examine the role of the biomarkers urinary ααCTX-I and serum CTX-MMP, that are released in pathological rather than physiological bone turnover states, for detecting periprosthetic osteolysis in a case control study of 23 subjects with osteolysis and 26 controls. All samples were collected between the hours of 0800 and 1000 following an overnight fast, and were assayed using standard techniques. The demographic characteristics of the subjects in both groups were similar. Serum CTX-MMP was greater in the osteolysis versus the control group (P=0.001). Urinary ααCTX-I was similar between osteolysis and control groups (P>
0.05). A cut-off value of 5.50ng/mL CTX-MMP had a sensitivity of 91% (95% CI: 72 to 99) and specificity of 69% (48 to 96) detecting osteolysis (P=0.001). The same cut-off had a sensitivity of 100% (100 to 100) and specificity of 63% (44 to 79) for detecting femoral osteolysis (P=0.0004), and a sensitivity of 89% (65 to 98) and specificity of 58% (39 to 75) for identifying pelvic osteolysis (P=0.014). Serum CTX-MMP shows promise for further investigation as a sensitive bio-marker for detecting periprosthetic osteolysis.
In this 2-year randomised clinical trial we examined whether cemented femoral prosthesis geometry affects the pattern of strain-adaptive bone remodelling in the proximal femur after THA. 128 patients undergoing primary THA were randomised to receive a Charnley (shape-closed, no taper), Exeter (force-closed, double-tapered) or C-stem (forced-closed, triple-tapered) prosthesis. All received a cemented Charnley cup. Proximal femoral BMD change over 2 years was measured by DXA. Urine and serum samples were collected at pre-operative baseline and over 1 year post-operatively. N-telopeptides of type-I-collagen (NTX) was measured in urine as a marker of osteoclast activity and Osteocalcin (OC) in serum as a maker of osteoblast activity. Clinical outcome using the Harris and Oxford hip scores, and prosthesis migration measured using digitised radiographs (EBRA-Digital) were measured over 2 years. The baseline characteristics of the subjects in each group were similar (P>
0.05). Decreases in femoral BMD were observed over the first year for all prosthesis designs. Bone loss was greatest (14%) in the proximal medial femur (region 7). The pattern and amount of bone loss observed was similar between all prosthesis designs (P>
0.05). Transient rises in both osteoclast (NTX) and osteoblast (OC) activity also occurred over year 1, and were similar in pattern in the 3 prosthesis groups (p>
0.05). All prostheses showed migration patterns that were true to their design type and similar improvements in clinical hip scores were observed over the 2 year study. Differences in the proposed mechanism of load transfer between prosthesis and host bone in force-closed versus shape-closed femoral prosthesis designs in THA are not major determinants of prosthesis-related remodelling.
