Osteoarthritis (OA) is the most common form of arthritis and one of the ten most disabling diseases in developed countries. Total joint replacement (TJR) is considered by far as the most effective treatment for end-stage OA patients. The majority of patients achieve symptomatic improvement following TJR. However, about 22% of the TJR patients either do not improve or deteriorate after surgery. Several potential non-genetic predictors for the TJR outcome have been investigated. However, the results were either inconclusive or had very limited predictive power. The aim of this study was to identify genetic variants for the poor outcome of TJR in primary OA patients by a genome-wide association study (GWAS).

Study participants were total knee or hip replacement patients due to primary OA who were recruited to the Newfoundland Osteoarthritis Study (NFOAS) before 2017. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to assess pain and functional impairment pre- and 3.99±1.38 years post-surgery. Two non-responder classification criteria were used in our study. One was defined by an absolute WOMAC change score. Participants with a change score less than 7/20 points for pain were considered as pain non-responders; and those with less than 22/68 points for function were classified as function non-responders. The second one was the Outcome Measures in Arthritis Clinical Trials and the Osteoarthritis Research Society International (OMERACT-OARSI) criteria. Blood DNA samples were genotyped using the Illumina GWAS microarrays genotyping platform. The quality control (QC) filtering was performed on GWAS data before the association of the genetic variants with non-responders to TJR was tested using the GenABEL package in R with adjustment for the relatedness of the study population and using the commonly accepted GWAS significance threshold p < 5*10⁻⁸ to control multiple testing.

In total, 316 knee and 122 hip OA patients (mean age 65.45±7.62 years, and 58% females) passed the QC check. These study participants included 368 responders and 56 non-responders to pain, and 364 responders and 68 non-responders to function based on the absolute WOMAC point score change classification. While 377 responders and 56 non-responders to pain, and 366 responders and 71 non-responders to function were identified by the OMERACT-OARSI classification criteria. Interestingly, the same results were obtained by both classification methods, and we found that the G allele of rs4797006 was significantly associated with pain non-responders with odds ratio (OR) of 5.12 (p<7.27×10^-10). This SNP is in intron one of the melanocortin receptor 5 (MC5R) gene on chr18. This gene plays central roles in immune response, pain sensitivity, and negative regulation of inflammatory response to antigenic stimulus. The A allele of rs200752023 was associated with function non-responders with OR of 4.41 (p<3.29×10^-8). The SNP is located in intron three of the RNA Binding Fox-1 Homolog 3 (RBFOX3) gene on chr17 which has been associated with numerous neurological disorders.

Our data suggested that two chromosomal regions are associated with TJR poor outcomes and could be the novel targets for developing strategies to improve the outcome of the TJR.

Total joint replacement (TJR) is by far the most effective therapy for end-stage OA patients. Most of patients achieve joint pain reduction and function improvement following to TJR, however up to 22% of them either do not improve or deteriorate after surgery. The aim of this study was to identify genetic variants to be associated with poor outcome of TJR in primary OA patients by a genome-wide association approach (GWAS).

Study participants were primary OA patients from the Newfoundland Osteoarthritis Study (NFOAS) that comprised total knee or hip replacement and recruited before 2016 in St. John's, NL. DNA samples were extracted from patients' blood. Study participants completed their pre-operation and 3.99±1.38 years post-surgery outcome assessment using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). DNA samples were genotyped using the genome-wide Illumina HumanOmni2.58 genotyping microarray containing 2.4 million SNPs. Pre-association quality control filtering was conducted for the raw genotyping data using PLINK 1.7 program, and genotype imputation was performed using the IMPUTE2 algorithm with multiple population reference data from 1000 Genome Project. The imputed data with ∼3.1 million variants was used to test the association with non-responders to TJR using the additive genetic model.

Eighty three primary OA patients (44 responders and 39 non-responders) were included in the analysis. Association analysis detected three chromosomal regions on chr5, 7, and 8 to be significantly associated with non-responding to pain. The top SNPs at these loci are intergenic variants that include SNP (rs17118094, p=4.4×10-5) on chr5. This SNP is adjacent to SGCD gene that plays an important role in muscular strength and maintenance. Another associated SNP (rs71572810, p=4.7×10-5) is nearby IMMP2L gene on chr7. This gene is reported to be associated with behavioral abnormalities. Finally, SNP (rs6992938, p=5.8×10-5) on chr8 is located downstream of TRPA1 gene that is known to have a central role in the pain response to endogenous inflammatory mediators. Three loci were also found to be significantly associated with non-responding to function. The lead variant in the locus on chr1 is an intergenic SNP (rs9729377, p=1.7×10-5) falling between CTBS and MCOLN2 genes. CTBS gene is associated with TNF-α, a cytokine that stimulate the inflammation acute phase reaction, and MCOLN2 gene plays a role in the chemokine secretion and macrophage migration in the innate immune response. Other top SNPs in loci on chr2 and 10 harbor CCDC93, INSIG2, and KLF6 genes that are associated with heel bone mineral density, hypercholesterolemia, obesity and BMI.

To our knowledge, this project is the first study that investigated the association between genetic factors and TJR non-responders. Our results demonstrated that genes related to muscle strength, behavioral trait, pain response, and inflammation play a significant role in poor outcome of TJR, warranting further investigation.

While total joint replacement (TJR) is considered as an effective intervention to relieve pain and restore joint function for end-stage osteoarthritis (OA) patients, a significant proportion of the patients are dissatisfied with their surgery outcomes. The aim of this study was to identify genetic factors that can predict patients who do or do not benefit from these surgical procedures by a genome-wide association study (GWAS).

Study participants were derived from the Newfoundland Osteoarthritis Study (NFOAS) which consisted of 1086 TJR patients. Non-responders to TJR was defined as patients who did not reach the minimum clinically important difference (MCID) based on the self administered Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in terms of pain reduction or function improvment. DNA was extracted from the blood samples of the study participants and genotyped by Illumina GWAS genotyping platform. Over two million single nucleotide polymorphisms (SNPs) across the genome were genotyped and tested for assocition with non-responders.

39 non-responders and 44 age, sex, and BMI matched responders were included in this study. Four chromosome regions on chromosomes 5, 7, 8, and 12 were suggested to be associated with non-responders with p < 1 0–5. The most promising one was on chromosome 5 with the lead SNP rs17118094 (p=1.7×10–6) which can classify 72% of non-responders accurately. The discriminatory power of this SNP alone is very promising as indicated by an area under the curve (AUC) of 0.72 with 95% confidence interval of 0.63 to 0.81, which is much better than any previously studied predictors mentioned above. All the patients who carry two copies of the G allele (minor allele) of rs17118094 were non-responders and 75% of those who carry one copy of the G allele were non-responders. The discriminatory ability of the lead SNPs on chromosomes 7 and 12 were comparable to the one on chromosome 5 with an AUC of 0.74, and 88% of patients who carry two copies of the A allele of rs10244798 on chromosome 7 were non-responders. Similarly, 88% of patients who carry two copies of the C allele of rs10773476 on chromosome 12 were non-responders. While the discriminatory ability of rs9643244 on chromosome 8 was poor with an AUC of 0.26, its strong association with non-responders warrants a further investigation in the region.

The study identified four genomic regions harboring genetic factors for non-responders to TJR. The lead SNPs in those regions have great discriminatory ability to predict non-responders and could be used to create a genetic prediction model for clinical unitilty and application.

Objectives

Osteoporosis is a systemic bone metabolic disease, which often occurs among the elderly. Angelica polysaccharide (AP) is the main component of angelica sinensis, and is widely used for treating various diseases. However, the effects of AP on osteoporosis have not been investigated. This study aimed to uncover the functions of AP in mesenchymal stem cell (MSC) proliferation and osteoblast differentiation.

Sclerostin is a negative regulator of osteoblast differentiation and bone formation. Expressed by osteocytes, it acts through antagonising the Wnt/â-catenin pathway and/or BMP activity. Distraction osteogenesis, used for limb lengthening and reconstruction, can be complicated by disuse osteopenia and poor healing response, both of which would benefit from pro anabolic therapy.

We examined the effects of Sclerostin Antibody (Scl-AbIII, Amgen Inc.,) in a rat model of distraction osteogenesis. A femoral osteotomy was stabilized with an external fixator in male Sprague Dawley rats. After a week of latency, the gap was distracted twice daily for 14 days to a total of 7 mm. Saline or Scl-Ab was administered twice weekly throughout the distraction period and up to 4, 6 or 8 weeks post commencement of distraction. Three groups were examined: Saline, Continuous Scl-Ab throughout the study (C Scl-Ab), and Delayed Scl-Ab with commencement of Scl-Ab after distraction (D Scl-Ab).

Regenerate bone mineral content (BMC), determined by DEXA, was increased 36% at 4 weeks and 86% at 6 weeks with C Scl-Ab, resulting in a 65% increase in bone mineral density (BMD) at 6 weeks, compared with Saline (p<0.01). D Scl-Ab treatment showed a 41% increase in BMC and a 31% increase in BMD compared with Saline at 6 weeks (p<0.05). At 8 weeks, C Scl-Ab remained significantly increased over Saline (72% in BMC; 60% in BMD).

Micro-CT scans of the regenerate revealed increases in bone volume of 88% with C Scl Ab and 65% with D Scl-Ab compared with Saline at 6 weeks (p<0.05). By 8 weeks, these increases were 36% for C Scl-Ab (p<0.05) and 37% for D Scl-Ab compared with Saline (p<0.01). Importantly, mean moment of inertia was increased over two-fold in both Scl-Ab groups at 6 weeks compared with Saline (p<0.05). Histology at 6 weeks confirmed micro-CT data with 85–88% increases in bone volume/tissue volume (BV/TV) in the regenerate with both C Scl-Ab and D Scl-Ab compared with Saline (p<0.05). Analysis of bone formation at 6 weeks revealed increases in mineral apposition rate of 56% in C Scl-Ab and 52% in D Scl-Ab compared with Saline (p<0.05).

Scl-Ab treatment increased bone formation in this model of distraction osteogenesis, resulting in a larger regenerate callus (increased BMC and BV/TV). We expect further studies to reveal increases in mechanical strength. Scl-Ab may hold promise as a therapeutic to accelerate regenerate formation and consolidation in distraction osteogenesis for limb reconstruction.

Introduction: The diagnosis of acetabular retroversion has traditionally been established by the presence of a cross-over sign on a plain pelvic radiograph. This however can be greatly influenced by the radiograph’s quality and degree of pelvic tilt. The aim of this study was to look at the relationship between cross-over and true anatomical version as measured in relation to an anatomical reference plane. The secondary aim was to determine whether in true retroversion there was excess coverage of the femoral head anteriorly.

Materials and Methods: Radiographs of 33 patients (64 hips) being investigated for symptoms of femoro-acetabular impingement were analysed. The presence of a cross-over sign was documented and the extent of cross-over was measured by noting the point on the rim where the cross-over occurs. CT scans of the same hips were analysed to determine anatomical version, and to calculate total, anterior and posterior coverage of the femoral head. This was done in relation to the anterior pelvic plane after correcting for pelvic tilt.

Results: The sensitivity, specificity and positive and negative predictive values for the cross-over sign were 92%, 55%, 59% and 91% respectively. The cross-over distance was correlated with 3D version (p=0.01). There was no significant difference in total cover of the femoral head between the anteverted and retroverted subgroups (71% vs. 72% respectively; p=0.55). Anterior cover was higher in the retroverted subgroup (35% vs. 32%; p = 0.0001), and posterior cover was significantly lower in this subgroup (37% vs. 39%; p = 0.002).

Discussion: Although the cross-over sign was sensitive enough to identify 92% of the retroverted cases, its specificity was low with just under half of the anteverted cases being labelled as retroverted. The findings for femoral head cover suggest that retroversion is characterised by posterior deficiency and increased cover anteriorly.

This study examined the relationship between the cross-over sign and the true three-dimensional anatomical version of the acetabulum. We also investigated whether in true retroversion there is excessive femoral head cover anteriorly. Radiographs of 64 hips in patients being investigated for symptoms of femoro-acetabular impingement were analysed and the presence of a cross-over sign was documented. CT scans of the same hips were analysed to determine anatomical version and femoral head cover in relation to the anterior pelvic plane after correcting for pelvic tilt. The sensitivity and specificity of the cross-over sign were 92% and 55%, respectively for identifying true acetabular retroversion. There was no significant difference in total cover between normal and retroverted cases. Anterior and posterior cover were, however, significantly different (p < 0.001 and 0.002). The cross-over sign was found to be sensitive but not specific. The results for femoral head cover suggest that retroversion is characterised by posterior deficiency but increased cover anteriorly.

Purpose: The objective of this study was to examine the shock absorption capacity of two currently marketed lumbar disc prostheses, a metal-polyethylene prosthesis and a metal-metal prosthesis. Shock absorption capacity, which could be a useful parameter for choosing between implants, has not been examined in the literature.

Material and methods: Two types of implants were tested: the Maverick prosthesis marketed by Medtronic, and the Prodic proposed by Spine Solution. Five implants of each type were tested. The disc prostheses were mounted on a testing device designed to analyse shock transmission by application of a constant force. Force captors were positioned on the upper and lower parts of the implant being tested. The force delivered and the force perceived on the opposite side of the implant were recorded simultaneously. The implant was submitted to a static loading force of 350 N to which was added a 100 N oscillating vibration force delivered at a frequency varying from 0 to 100 Hz. A supplementary 250 N shock was also applied every 10 s. The spectrum and frequency of each input and output were recorded. Vibration and transmission of the shock though the implant were defined as the ratio of the output over input spectra. Measurements were taken for all frequencies between 0 and 100 Hz. Phase deviation was calculated to characterise the shock absorption effect.

Results: The phase deviation between the input and the output signal was less than 10 for both prostheses. Under loaded oscillating vibration, shock transmission was greater than 99.8% for both implants. In the 1–100 Hz frequency interval, the difference in shock transmission was less than 0.3±0.1% between the two implants. More than 98% of the supplementary 250 N shocks were transmitted by both implants. The difference between the two implants was thus less than 0.8% and can be considered negligible since the machine’s test sensitivity was 0.5%.

Conclusion: The two implants tested exhibited the same capacity to absorb and transmit vibration and shocks. Shock absorption capacity was close to zero or at least less than the sensitivity threshold of the testing device. This degree of freedom is not sufficient to use shock absorption capacity as an argument for choosing between the two implants currently available.

Purpose: Cage fusion of the L5–S1 segment is a controversial issue due to the weak stabilisation of the spine during extension and axial rotation. Complementary fixation appears to be needed to improve stability, but the presence of the bifurcation of the great vessels is an anatomic limitation. We studied the anatomy of this area to examine the feasibility of anterior plate fixation.

Material and methods: According to the recognised anatomic references (Rouvière, Bouchet and Cuilleret, Louis), a 33-mm safety zone was described at the aortoiliac and iliocaval bifurcation. This space free from contact with the greater vessels lies in front of the L5–S1 disc. Pre-operative angio-MRI was used to assess the size of this safety zone. A triangular anterior plate was designed for arthrodesis (Pyramid Sofamor Danek, USA). An L5–S1 arthrodesis was performed in 15 consecutive patients using this plate. Follow-up was one year. A video-assisted anterior retroperitoneal approach was used in all cases. The Prolo and Oswestry scores were used for the preoperative and last follow-up evaluations.

Results: According to the anatomic study and the MRI views, 89% of the patients had a sufficient safety zone for plate fixation. The method was contraindicated in two patients who had a low bifurcation. Angio-MRI was found to be simple and reproducible. The MRI analysis was confirmed at surgery (no false negatives). The plate was successfully implanted in 15 patients with no contact with the great vessels. There were no serious complications (vascular, neurological, urological, digestive). The economic Prolo score was improved from 2.7 to 4.2 and the functional score from 2.6 to 4.3. The Oswestry score improved 33%. The rate of clinical success was 93% (14/15 patients).

Discussion and conclusion: Implantation of an anterior plate for L5-S1 fusion is feasible. The key points are: 1) rigorous preoperative evaluation of the greater vessel bifurcation; 2) anatomic plate design; 3) appropriate surgical technique. The risk of retrograde ejaculation is related to retraction of the hypogastric plexus and should be investigated with a prospective study. This osteosynthesis technique can avoid secondary operations for fixation with pedicular or transarticular screwing.