Phenotype and energy metabolism differ between osteoarthritic chondrocytes from male compared to female patients: Implications for sexual dimorphism in osteoarthritis development?

OBJECTIVES: The prevalence and severity of knee osteoarthritis (OA) are greater in females than males. The purpose of this study was to determine whether there is an underlying difference in the biology of OA chondrocytes between males and females. METHODS: Chondrocytes were obtained following knee arthroplasty from male and female patients with primary OA. Phenotype marker expression, glucose and fat consumption, and rates of glycolysis and oxidative phosphorylation were compared between females and males. RNAi was used to determine the consequences of differential expression of Sry-box transcription factor 9 (SOX9) and PGC1α between males and females. RESULTS: OA chondrocytes from male donors showed elevated ribonucleic acid (RNA) and protein levels of SOX9, elevated COL2A1 protein synthesis, higher glucose consumption, and higher usage of glycolysis compared to females. OA chondrocytes from females had higher PGC1α protein levels, higher fat consumption, and higher oxidative energy metabolism than males. Knockdown of SOX9 reduced expression of COL2A1 to a greater extent in male OA chondrocytes than females whereas knockdown of PGC1α reduced COL2A1 expression in females but not males. Expression of ACAN and the glycolytic enzyme PGK1 was also reduced in males but not females following SOX9 knockdown. CONCLUSIONS: OA chondrocyte phenotype and energy metabolism differ between males and females. Our results indicate transcriptional control of COL2A1 differs between the two. Differences in chondrocyte biology between males and females imply the underlying mechanisms involved in OA may also differ, highlighting the need to consider sex and gender when investigating pathogenesis and potential treatments for OA.

The John N. Insall Award: Higher Tissue Concentrations of Vancomycin Achieved With Intraosseous Regional Prophylaxis in Revision TKA: A Randomized Controlled Trial.

BACKGROUND: In primary TKA, prophylaxis with low-dose vancomycin through intraosseous regional administration (IORA) achieves tissue concentrations six to 10 times higher than systemic administration and was shown to provide more effective prophylaxis in an animal model. However, in revision TKA, the presence of a tibial implant may compromise IORA injection, and tourniquet deflation during a prolonged procedure may lower tissue concentrations. QUESTIONS/PURPOSES: (1) Does low-dose IORA reliably provide equal or higher tissue concentrations of vancomycin compared with systemic IV administration in revision TKA? (2) Are tissue concentrations of vancomycin after IORA maintained for the duration of the revision TKA despite a period of tourniquet deflation? (3) Is there any difference in early postoperative (< 6 weeks) complications between IORA and systemic IV administration in revision TKA? METHODS: Twenty patients undergoing aseptic revision TKA were randomized to two groups. The IV group received 1 g systemic IV prophylactic vancomycin. The IORA group received 500 mg vancomycin as a bolus injection into a tibial intraosseous cannula below an inflated thigh tourniquet before skin incision. In all patients receiving IORA, intraosseous tibial injection was technically possible despite the presence of a tibial implant. Mean procedure length was 3.5 hours in both groups. Mean initial tourniquet inflation was 1.5 hours with a second inflation for a mean of 35 minutes during cementation. During the procedure, subcutaneous fat and bone samples were taken at regular intervals. Tissue vancomycin concentrations were measured using high-performance liquid chromatography. RESULTS: Overall geometric mean tissue concentration of vancomycin in fat samples was 3.7 µg/g (95% confidence interval [CI], 2.6-5.2) in the IV group versus 49.3 µg/g in the IORA group (95% CI, 33.2-73.4; ratio between means 13.5; 95% CI, 8.2-22.0; p < 0.001); mean tissue concentrations in femoral bone were 6.4 µg/g (95% CI, 4.5-9.2) in the IV group versus 77.1 µg/g (95% CI, 42.4-140) in the IORA group (ratio between means 12.0; 95% CI, 6.2-23.2; p < 0.001). Vancomycin concentrations in the final subcutaneous fat sample taken before closure were 5.3 times higher in the IORA group versus the IV group (mean ± SD, 18.2 ± 11.6 µg/g IORA versus 3.6 ± 2.5 µg/g; p < 0.001). The intraarticular concentration of vancomycin on postoperative Day 1 drain samples was not different between the two groups with the numbers available (mean 4.6 µg/L in the IV group versus 6.6 µg/g in the IORA group; mean difference 2.0 µg/g; 95% CI, 6.2-23.2; p = 0.08). CONCLUSIONS: IORA administration of vancomycin in patients undergoing revision TKA resulted in tissue concentrations of vancomycin five to 20 times higher than systemic IV administration despite the lower dose. High tissue concentrations were maintained throughout the procedure despite a period of tourniquet deflation. These preliminary results justify prospective cohort studies, which might focus on broader safety endpoints in more diverse patient populations. We believe that these studies should evaluate patients undergoing revision TKA in particular, because the risk of infection is greater than in patients undergoing primary TKA. LEVEL OF EVIDENCE: Level I, therapeutic study.

Periprosthetic Joint Infection in Hip Arthroplasty: Is There an Association Between Infection and Bearing Surface Type?

BACKGROUND: Preliminary studies have raised the question of whether certain prosthetic biomaterials used in total hip arthroplasty (THA) bearings are associated with increased risk of periprosthetic joint infection (PJI). For example, some observational data suggest the risk of PJI is higher with metal-on-metal bearings. However, it is not known whether other bearings-including ceramic bearings or metal-on-polyethylene bearings-may be associated with a higher or lower risk of PJI. QUESTIONS/PURPOSES: The objective of this study was to use a national arthroplasty registry to assess whether the choice of bearings-metal-on-polyethylene (MoP), ceramic-on-polyethylene (CoP), ceramic-on-ceramic (CoC), or metal-on-metal (MoM)-is associated with differences in the risk of revision for deep infection, either (1) within 6 months or (2) over the entire period of observation, which spanned 15 years. METHODS: Data from primary THAs were extracted from the New Zealand Joint Registry over a 15-year period. A total of 97,889 hips were available for analysis. Inclusion criterion was degenerative joint disease; exclusion criteria were previous surgery, trauma, and any other diagnosis (12,566 hips). We also excluded a small group of ceramic-on-metal THAs (429) with short followup. The median observation period of the selected group of hips (84,894) was 9 years (range, 1-15 years). The mean age of patients was 68 years (SD ± 11 years), and 52% were women. There were 54,409 (64%) MoP, 16,503 (19%) CoP, 9051 (11%) CoC, and 4931 (6%) MoM hip arthroplasties. Four hundred one hips were revised for deep infection. A multivariate assessment was carried out including the following risks factors available for analysis: age, sex, operating room type, use of body exhaust suits, THA fixation mode, and surgeon volume. Because of late introduction of data collection in the Registry, we were unable to include body mass index (BMI, recording started 2010) and medical comorbidities according to the American Society of Anesthesiologists class (ASA, recording started 2005) in the multivariate analysis. RESULTS: The rate of early PJI (< 6 months) did not differ by bearing surface. In contrast, we observed a difference over the total observation period. Within the first 6 months after the index surgery, CoC THAs were not associated with a lower risk of revision for PJI (p = 0.118) when compared with CoP (hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.50-3.41), MoP (HR, 2.10; CI, 0.91-4.82), and MoM (HR, 2.04; CI, 0.69-6.09). When the whole observation period was considered, CoC hips were associated with a lower risk of revision for deep infection when compared with CoP (HR, 1.30; CI, 0.78-2.18; p = 0.01), MoP (HR, 1.75; CI, 1.07-2.86; p = 0.02), and MoM (HR, 2.12; CI, 1.23-3.65; p = 0.008). CONCLUSIONS: Our finding associating CoC THA bearings with a lower risk of infection after THA must be considered very preliminary, and we caution readers against attributing all of the observed difference to the bearing surface. It is possible that some or all of the observed difference associated with bearing type may have been driven by other factors such as ASA and BMI, which could not be included in our multivariate analysis, and so future registry studies on this topic must assess those variables carefully. LEVEL OF EVIDENCE: Level III, therapeutic study.

Are ceramic-on-ceramic bearings in total hip arthroplasty associated with reduced revision risk for late dislocation?

BACKGROUND: Dislocation is a major complication after primary total hip arthroplasty (THA), but little is known about the potential relationships between bearing materials and risk of dislocation. Dislocation within the first year after surgery is typically related to either surgical error or patient inattention to precautions, but the reasons for dislocation after the first year are often unclear, and whether ceramic bearings are associated with an increased or decreased likelihood of late dislocation is controversial. QUESTIONS/PURPOSES: The purpose of this study was to use a national registry to assess whether the choice of bearings-metal-on-polyethylene (MoP), ceramic-on-polyethylene (CoP), ceramic-on-ceramic (CoC), or metal-on-metal (MoM)-is associated with differences in the risk of late dislocation. METHODS: Data from primary THAs were extracted from the New Zealand Joint Registry over a 10-year period. The mean age of patients was 69 years (SD ± 12 years), and 53% were women. The median followup in this population was 7 years (range, 1-13 years). The surgical approach used was posterior in 66% of THAs, lateral in 29%, and anterior in 5%. The primary endpoint was late revision for dislocation with "late" defined as greater than 1 year postoperatively. A total of 73,386 hips were available for analysis: 65% MoP, 17% CoP, 10% CoC, and 7% MoM. In general, patients receiving CoC and MoM bearings were younger compared with patients receiving CoP and MoP bearings. RESULTS: Four percent of the hips were revised (3130 THAs); 867 THAs were revised for dislocation. Four hundred seventy THAs were revised for dislocation after the first postoperative year. After adjusting for head size, age, and surgical approach, only CoP (hazard ratio [HR], 2.10; p = 0.021) demonstrated a higher proportion of revision, whereas MoP did not (HR, 1.76; 95% p = 0.075). There were no differences of revisions for dislocation in the CoC (HR, 1.60; p = 0.092) and MoM cohorts (HR, 1.54; p = 0.081). CONCLUSIONS: Dislocation is a common reason for revision after THA. The relationships between bearing materials and risk of revision for late dislocation remain controversial. This large registry study demonstrated that bearing surface had little association with the incidence of late dislocation. Future studies with longer followups should continue to investigate this question. LEVEL OF EVIDENCE: Level III, therapeutic study.

CORR Insights™: Is limited incision better than standard total hip arthroplasty? A meta-analysis.

This CORR Insights™ is a commentary on the article "Is Limited Incision Better Than Standard Total Hip Arthroplasty? A Meta-analysis" by Joseph T. Moskal MD and Susan G. Capps PhD available at DOI 10.1007/s11999-012-2717-5 .

Quantitative CT with finite element analysis: towards a predictive tool for bone remodelling around an uncemented tapered stem.

PURPOSE: We used quantitative CT in conjunction with finite element analysis to provide a new tool for assessment of bone quality after total hip arthroplasty in vivo. The hypothesis of this prospective five-year study is that the combination of the two modalities allows 3D patient-specific imaging of cortical and cancellous bone changes and stress shielding. METHOD: We tested quantitative CT in conjunction with finite elements on a cohort of 29 patients (31 hips) who have been scanned postoperatively and at one year, two years and five years follow-up. The method uses cubic Hermite finite element interpolation for efficient mesh generation directly from qCT datasets. The element Gauss points that are used for the geometric interpolation functions are also used for interpolation of osteodensitometry data. RESULTS: The study showed changes of bone density suggestive of proximal femur diaphysis load transfer with osteointegration and moderate metaphyseal stress shielding. Our model revealed that cortical bone initially became porous in the greater trochanter, but this phenomenon progressed to the cortex of the lesser trochanter and the posterior aspect of the metaphysis. The diaphyseal area did not experience major change in bone density for either cortical or cancellous bone. CONCLUSION: The combination of quantitative CT with finite element analysis allows visualization of changes to bone density and architecture. It also provides correlation of bone density/architectural changes with stress patterns enabling the study of the effects of stress shielding on bone remodelling in vivo. This technology can be useful in predicting bone remodeling and the quality of implant fixation using prostheses with different design and/or biomaterials.

Infection in total hip replacement: meta-analysis.

While total hip arthroplasty has progressed to become one of the most successful surgical procedures ever developed, infection remains a serious complication. We have conducted a review of the literature pertaining to management of deep infection in total hip arthroplasty, specifically focusing on clinically relevant articles published in the last five years. A search was conducted using MEDLINE and PubMed, as well as a review of the Cochrane database, using the terms "total hip arthroplasty", "total hip replacement" and "infection". References for all selected articles were cross-checked. While the so-called two-stage revision is generally considered to be the gold standard for management, numerous studies now report outcomes for implant retention and reassessing one-stage revision strategies. There are encouraging reports for complex reconstruction options in patients with associated severe bone stock loss. The duration of antibiotic therapy remains controversial. There is concern about increasing bacterial resistance especially with the widespread use of vancomycin and ertapenem (carbapenem).

Molecular characterisation of osteoblasts from bone obtained from people of Polynesian and European ancestry undergoing joint replacement surgery.

Population studies in Aotearoa New Zealand found higher bone mineral density and lower rate of hip fracture in people of Polynesian ancestry compared to Europeans. We hypothesised that differences in osteoblast proliferation and differentiation contribute to the differences in bone properties between the two groups. Osteoblasts were cultured from bone samples obtained from 30 people of Polynesian ancestry and 25 Europeans who had joint replacement surgeries for osteoarthritis. The fraction of cells in S-phase was determined by flow cytometry, and gene expression was analysed by microarray and real-time PCR. We found no differences in the fraction of osteoblasts in S-phase between the groups. Global gene expression analysis identified 79 differentially expressed genes (fold change > 2, FDR P < 0.1). Analysis of selected genes by real-time PCR found higher expression of COL1A1 and KRT34 in Polynesians, whereas BGLAP, DKK1, NOV, CDH13, EFHD1 and EFNB2 were higher in Europeans (P ≤ 0.01). Osteoblasts from European donors had higher levels of late differentiation markers and genes encoding proteins that inhibit the Wnt signalling pathway. This variability may contribute to the differences in bone properties between people of Polynesian and European ancestry that had been determined in previous studies.

Loss of tibial bone density in patients with rotating- or fixed-platform TKA.

Little is known about tibial bone remodeling with TKA and its clinical relevance. We performed a randomized clinical trial to compare tibial bone density changes in cemented components with different bearing designs. Bone density changes were assessed using quantitative computed tomography (qCT)-assisted osteodensitometry. Twenty-eight rotating-platform and 26 fixed-platform cemented TKAs were included. The nonoperated contralateral side was used as a control. CT scans were performed postoperatively and 1 year and 2 years after the index operation. Cancellous bone density loss (up to 12.6% at 2 years) was observed in all proximal tibial regions in both cohorts. In contrast, we found lower cortical bone density loss (up to 3.6% at 2 years). We found no differences in bone loss between fixed- and rotating-platform implants. The decrease of cancellous bone density after TKA suggests stress transfer to the cortical bone.

Femoral bone density changes after total hip arthroplasty with uncemented taper-design stem: a five year follow-up study.

We measured bone density (BD) changes to assess adaptive bone remodelling five years after uncemented total hip arthroplasty with taper-design femoral component using quantitative computed-tomography-assisted osteodensitometry (qCT). Nineteen consecutive patients (21 hips) with degenerative joint disease were enrolled in the study. A press-fit cup and a tapered uncemented stem ceramic-ceramic pairing were used in all patients. Serial clinical, radiological and qCT osteodensitometry assessments were performed after the index operation and at the one, two and five year follow-ups. At the latest follow-up, the clinical outcome was rated satisfactory in all hips. The radiological assessment showed signs of osteointegration with stable fixation of all cups and stems. Overall, there was evidence of a BD loss at year five (p = 0.004). We estimate that BD loss was between 2.2% and 12.1% in comparison with baseline postoperative values. Progressive loss of BD in the metaphyseal region was observed in all hips. We found unremarkable BD changes of diaphyseal cortical BD throughout the five year follow-up period. qCT osteodensitometry technology allows differentiation of cortical and cancellous BD changes over time. Periprosthetic BD changes at the five year follow-up are suggestive of stable stem osteointegration with proximal femoral diaphysis load transfer and metaphyseal stress shielding.

The effect of age on the microarchitecture and profile of gene expression in femoral head and neck bone from patients with osteoarthritis.

Ageing of the skeleton is characterised by decreased bone mineral density, reduced strength, and increased risk of fracture. Although it is known that these changes are determined by the activities of bone cells through the processes of bone modelling and remodelling, details of the molecular mechanisms that underlie age-related changes in bone are still missing. Here, we analysed age-related changes in bone microarchitecture along with global gene expression in samples obtained from patients with osteoarthritis (OA). We hypothesised that changes would be evident in both microarchitecture and gene expression and aimed to identify novel molecular mechanisms that underlie ageing processes in bone. Samples of femoral head and neck were obtained from patients undergoing hip arthroplasty for OA, who were either ≤60 years or ≥70 years of age. Bone microarchitecture was analysed in cores of trabecular bone from the femoral head (17 from the younger group and 18 from the older), and cortical bone from the femoral neck (25 younger/22 older), using a Skyscan 1172 microCT scanner (Bruker). Gene expression was compared between the two age groups in 20 trabecular samples from each group, and 10 cortical samples from each group, using Clariom S Human microarrays (ThermoFisher Scientific). We found no significant changes between the two age groups in indices of trabecular or cortical bone microarchitecture. Gene expression analysis identified seven genes that had higher expression in the older group, including the transcription factor EGR1 and the glucose transporter SLC2A3 (GLUT3), and 21 differentially expressed genes in cortical bone samples (P<0.05, fold change>2). However, none of the comparisons of gene expression had false discovery rate-adjusted P<0.1. In contrast to our working hypothesis, we found only minor differences in gene expression and no differences in bone microarchitecture between the two age-groups. It is possible that pathological processes related to OA provide protection against age-related changes in bone. Our study suggests that in patients with OA, the bone properties measured here in femoral head and neck do not deteriorate significantly from the sixth to the eighth decade of life.

Absence of somatic SQSTM1 mutations in Paget's disease of bone.

BACKGROUND: Paget's disease is a common focal bone disorder that appears to be caused by a combination of genetic and environmental factors. Mutations in the SQSTM1 gene are found in about one third of families with Paget's disease and 8% of sporadic cases. Other potential loci linked to the disease have also been identified, and a number of environmental factors have been suggested to be involved in the disease. However, the focal nature of Paget's is still unexplained. Therefore, we examined the possibility that somatic mutations in the SQSTM1 gene are present in the local lesions, using RNA collected from primary osteoblast and bone marrow cell cultures of patients with this condition. METHODS: SQSTM1 was sequenced, and allelic discrimination for the common P392L mutation was performed in cDNA samples from 14 osteoblast cultures and from 14 cultures of bone marrow cells. RESULTS: In these 28 samples drawn from 23 patients, the wild-type sequence of SQSTM1 was found in all but one marrow sample, which was heterozygous for the P392L mutation. DNA from peripheral blood in this subject had an identical sequence of SQSTM1, indicating that this was a germline mutation. CONCLUSION: We conclude that somatic mutations for SQSTM1 are not commonly present in Paget's disease.