Relationships between the Bone Expression of Alzheimer's Disease-Related Genes, Bone Remodelling Genes and Cortical Bone Structure in Neck of Femur Fracture.

Neck of femur (NOF) fracture is a prevalent fracture type amongst the ageing and osteoporotic populations, commonly requiring total hip replacement (THR) surgery. Increased fracture risk has also been associated with Alzheimer's disease (AD) in the aged. Here, we sought to identify possible relationships between the pathologies of osteoporosis and dementia by analysing bone expression of neurotropic or dementia-related genes in patients undergoing THR surgery for NOF fracture. Femoral bone samples from 66 NOF patients were examined for expression of the neurotropic genes amyloid precursor protein (APP), APP-like protein-2 (APLP2), Beta-Secretase Cleaving Enzyme-1 (BACE1) and nerve growth factor (NGF). Relationships were examined between the expression of these and of bone regulatory genes, systemic factors and bone structural parameters ascertained from plain radiographs. We found strong relative levels of expression and positive correlations between APP, APLP2, BACE1 and NGF levels in NOF bone. Significant correlations were found between APP, APLP2, BACE1 mRNA levels and bone remodelling genes TRAP, RANKL, and the RANKL:OPG mRNA ratio, indicative of potential functional relationships at the time of fracture. Analysis of the whole cohort, as well as non-dementia (n = 53) and dementia (n = 13) subgroups, revealed structural relationships between APP and APLP2 mRNA expression and lateral femoral cortical thickness. These findings suggest that osteoporosis and AD may share common molecular pathways of disease progression, perhaps explaining the common risk factors associated with these diseases. The observation of a potential pathologic role for AD-related genes in bone may also provide alternative treatment strategies for osteoporosis and fracture prevention.

Does cup-cage reconstruction with oversized cups provide initial stability in THA for osteoporotic acetabular fractures?

BACKGROUND: The incidence of acetabular fractures in osteoporotic patients is increasing. Immediate total hip arthroplasty (THA) has potential advantages, but achieving acetabular component stability is challenging and, at early followup, reported revision rates for loosening are high. QUESTIONS/PURPOSES: This study measured acetabular component stability and the initial surface contact achieved between the acetabular component and unfractured region of the pelvis after THA using an oversized acetabular component and cup-cage reconstruction. METHODS: Between November 2011 and November 2013, we treated 40 acute acetabular fractures in patients older than 70 years of age. Of these, 12 (30%) underwent immediate THA using an oversized acetabular component with screws inserted only into the ilium and a cup-cage construct. Postoperatively all patients were mobilized without weightbearing restrictions. Indications for immediate THA after acetabular fractures were displaced articular comminution deemed unreducible. Eleven of the 12 were prospectively studied to evaluate the initial stability of the reconstructions using radiostereometric analysis. One of the patients died of a pulmonary embolism after surgery, and the remaining 10 (median age, 81 years; range, 72-86 years) were studied. Of these, five were analyzed at 1 year and five were analyzed at 2 years. Acetabular component migration was defined as acceptable if less than the limits for primary THA that predict later loosening (1.76 mm of proximal migration and 2.53° of sagittal rotation). The contact surface between the acetabular component and ilium in direct continuity with the sacroiliac joint, and the ischium and pubis in direct continuity with the symphysis pubis, was measured on postoperative CT scans. RESULTS: At 1 year the median proximal migration was 0.83 mm (range, 0.09-5.13 mm) and sagittal rotation was 1.3° (range, 0.1°-7.4°). Three of the 10 components had migration above the suggested limits for primary THA at 1 year postoperatively. The contact surface achieved at surgery between the acetabular component and pelvis ranged from 11 to 17 cm(2) (15%-27% of each component). CONCLUSIONS: The majority of acetabular components in this cohort were stable despite the small contact surface achieved between the component and pelvic bone. Three of 10 migrated in excess of the limits that predict later loosening in primary THA but it remains to be seen whether these limits apply to this selected group of frail osteoporotic patients. We continue to use this technique routinely to treat patients with the same indications, but since the analysis of these data we have added screw fixation of the acetabular component to the ischial tuberosity and the superior pubic ramus. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Cemented liner exchange with bone grafting halts the progression of periacetabular osteolysis.

The aims of this were to examine the effect of acetabular liner exchange and intra-operative bone grafting surgery on peri-prosthetic osteolysis. Seven patients with well-fixed Harris-Galante-1 acetabular components received cemented exchange liners for worn liners associated with pre-operatively CT-quantified osteolysis. During surgery, accessible osteolytic lesions were debrided and bone-grafted. Except for one patient with recurrent dislocation and acetabular component revision, the other patients had CT scans at a median of 4 months and at approximately 4 years after surgery. None of the pre-operative lesions increased in volume during the post-operative reporting period and no new lesions were detected. These results show that cemented liner exchange surgery can halt the progression of osteolysis and that bone grafting has the potential to restore bone.

Imaging periprosthetic osteolysis around total knee arthroplasties using a human cadaver model.

We examined the sensitivity and accuracy of measuring osteolysis around total knee arthroplasty (TKA) on radiographs, computed tomography (CT), and magnetic resonance imaging (MRI) in a cadaver model. Fifty-four simulated osteolytic defects ranging from 0.7 to 14 cm(3) were created in 6 cadaver knees implanted with either a cemented or an uncemented TKA. Three blinded investigators assessed the presence, location, and volume of defects on radiographs and CT and MRI scans with metal reduction protocols. Both CT and MRI had significantly higher sensitivities and specificities than did plain radiographs (P < .005). Overall, there was no difference in the accuracy of defect volume measurements between CT and MRI (P = .574). This study demonstrates the limitations of radiographs and the high sensitivity and specificity of both CT and MRI in assessing osteolysis around TKA.

A preclinical study of stem subsidence and graft incorporation after femoral impaction grafting using porous hydroxyapatite as a bone graft extender.

This preclinical in vivo screening study compared bone graft incorporation and stem subsidence in cemented hemiarthroplasty after femoral impaction bone grafting with either morselized allograft bone (n = 5, control group) or a 1:1 mix of allograft and porous hydroxyapatite ceramics (HA) granules (n = 5, HA group). At 14 weeks, there was excellent bone graft incorporation by bone, and the stems were well fixed in both groups. The median subsidence at the cement-bone interface, measured using radiostereometric analysis, was 0.14 and 0.93 mm in the control and HA groups, respectively. The comparable histologic results between groups and good stem fixation in this study support the conduct of a larger scale investigation of the use of porous HA in femoral impaction bone grafting at revision hip arthroplasty.

Cemented Revision Hip Arthroplasty With Femoral Impaction Bone Grafting.

Long-stemmed uncemented implants are commonly used during revision hip arthroplasty but may be difficult to re-revise. Impaction bone grafting allows for the use of a shorter cemented stem during revision hip arthroplasty and may restore bone stock in patients with substantial femoral defects. Femoral impaction bone grafting is particularly beneficial in younger patients, who are more likely to require additional revision procedures in the future. The surgical technique used at our institution includes improvements to previous methods including the use of modular tamps and nonirradiated, size-profiled bone graft.

Distribution of periacetabular osteolytic lesions varies according to component design.

Using computed tomography, the volume, location, and number of osteolytic lesions were determined adjacent to 38 Harris-Galante 1 (HG-1) acetabular components fixed with screws and 19 porous-coated anatomic (PCA) acetabular components press-fitted without screws. The median implantation times were 16 and 15 years, respectively. The mean total lesion volumes were similar: 11.1 cm(3) (range, 0.7-49 cm(3)) and 9.8 cm(3) (range, 0.4-52 cm(3)), respectively, for hips with HG-1 and PCA components (P = .32). There was a significant difference in the proportion of rim-related, screw or screw hole-related, and combined lesions between the 2 component designs (P < .0001). HG-1 components had more screw and screw hole-related lesions, and PCA components had more rim-related lesions. Although there are concerns regarding screw and screw hole-associated osteolysis, these findings suggest that peripheral fixation may be well maintained in the long term with the use of multiple-hole acetabular components with screw fixation.

Evidence for Gender-Specific Bone Loss Mechanisms in Periprosthetic Osteolysis.

Osteolysis adjacent to total hip replacement (THR) prostheses is a major cause of their eventual failure. Periprosthetic osteolysis is associated with the production of bioactive particles, produced by the wear of articulating prosthesis surfaces. Wear particles invade the periprosthetic tissue, inducing inflammation and bone resorption. Previous studies have shown that osteocytes, the most numerous cell type in mineralised bone, can respond to wear particles of multiple orthopaedic material types. Osteocytes play important roles in bone resorption, regulating bone resorption by osteoclasts and directly through osteocytic osteolysis, also known as perilacunar remodelling. In this study, we perform a histological analysis of bone biopsies obtained from cohorts of male and female patients undergoing either primary THR surgery or revision THR surgery for aseptic loosening. The osteocyte lacunae area (Ot.Lac.Ar) and percentage lacunar area/bone area (%Ot.Lac.Ar/B.Ar) were significantly larger overall in revision THR bone than bone from similar sites in primary THR. Analysis by patient gender showed that increased Ot.Lac.Ar, indicative of increased perilacunar remodelling, was restricted to female revision samples. No significant differences in osteoclast parameters were detectable between the cohorts. These findings suggest previously unrecognised gender-specific mechanisms of bone loss in orthopaedic wear particle-induced osteolysis in humans.

Elevated Serum 25-Hydroxyvitamin D Levels Are Associated with Improved Bone Formation and Micro-Structural Measures in Elderly Hip Fracture Patients.

Vitamin D, along with calcium, is generally considered necessary for bone health and reduction of fractures. However, he effects of improving vitamin D status have not always been observed to improve bone mineral density (BMD). We have investigated whether varying vitamin D status in humans, as measured by serum 25(OH)D levels, relate to micro-structural and histomorphetric measures of bone quality and quantity, rather than density. Intertrochanteric trabecular bone biopsies and serum samples were collected from patients undergoing hip arthroplasty (65 females, 38 males, mean age 84.8 ± 8.3 years) at Royal Adelaide Hospital. Estimated GFR, serum ionized calcium, alkaline phosphatase, albumin, supplement and medication intake prior to surgery were taken from patient case records. Serum 25(OH)D, 1,25(OH)2D, and parathyroid hormone (PTH) levels were measured by immunoassays. Trabecular bone structural indices were determined by high-resolution micro-CT. Mean wall thickness (MWT) was measured on toluidine blue-stained histological sections. Bone mRNA levels for vitamin D metabolising enzymes CYP27B1 and CYP24A1 were measured by qRT-PCR. While serum 25(OH)D levels did not associate with bone volume/tissue volume (BV/TV%), serum 25(OH)D levels were strongly and independently associated with MWT (r = 0.81 p < 0.0001) with values significantly greater in patients with higher serum 25(OH)D levels. Furthermore, serum 25(OH)D levels were negatively associated with Bone Surface/Bone Volume (BS/BV) (r = -0.206, p < 0.05) and together with bone CYP27B1 and CYP24A1 mRNA accounted for 10% of the variability of BS/BV (p = 0.001). These data demonstrate that serum 25(OH)D is an independent positive predictor of micro-structural and bone formation measures and may be dependent, in part, on its metabolism within the bone.

Progression of acetabular periprosthetic osteolytic lesions measured with computed tomography.

BACKGROUND: A better understanding of the factors associated with the size and/or progression of osteolytic lesions has been hampered by a lack of sensitivity of radiographic measurement techniques. METHODS: We retrospectively analyzed quantitative computed tomography scans that had been made with use of a high-resolution multi-slice scanner with a metal artifact-suppression protocol. The scans had been made to determine the volume of osteolytic lesions around thirty-five cementless Harris-Galante acetabular components that had been in situ for at least ten years. Repeat scans of thirty hips allowed for the measurement of progression in the size of osteolytic lesions over a one-year period. Associations between the volume of osteolytic lesions, progression in the size of the lesions, polyethylene wear since the time of implantation, change in component position, and patient-related variables (age, gender, body mass index, activity level, walking limitations, joint pain, and function) were determined. RESULTS: In sixteen of the thirty hips that had repeat computed tomography scans, the lesions progressed in size during the study period. The median size of the lesions in these sixteen hips was 10.3 cm(3) at the time of the initial scan, compared with 13.3 cm(3) at a median of fifteen months later (p = 0.001). Osteolytic lesions measuring >10 cm(3) in volume on the initial scan were 2.5 times (95% confidence interval 1.3 to 4.8 times) more likely to progress in size over one year than smaller lesions were. Patients with greater polyethylene wear rates, higher activity levels, no walking limitations, and larger prosthetic femoral head dimensions (26 or 28 mm) had significantly larger osteolytic lesions (p < 0.0001, p = 0.009, p = 0.006, and p = 0.028, respectively). Progression in the size of the osteolytic lesions over one year was significantly associated with larger initial osteolytic lesions (p = 0.002), greater polyethylene wear rates (p = 0.009), and larger (26 or 28-mm) prosthetic femoral head dimensions (p = 0.019). CONCLUSIONS: There is considerable variation in the rates of progression of the size of osteolytic lesions around stable acetabular components. Lesion size and the progression of lesion size are generally related to polyethylene wear rates, higher patient activity levels, and larger-diameter femoral heads. Osteolytic lesions measuring >10 cm(3) in volume are associated with a high rate of progression.

The correlation of RANK, RANKL and TNFalpha expression with bone loss volume and polyethylene wear debris around hip implants.

This study investigates receptor activator NF-kappaB (RANK), RANK ligand (RANKL) and tumour necrosis factor (TNFalpha), key factors regulating bone turnover, present in the tissues near peri-prosthetic osteolysis. Tissue was obtained from zones of peri-prosthetic osteolysis from 11 patients undergoing revision of total hip prostheses, analysed preoperatively by high-resolution spiral multislice CT using a metal artefact suppression protocol. Synovial tissue from 10 patients with osteoarthritis undergoing primary hip replacement was used as control tissue. Immunohistochemical analysis of formalin fixed tissue sections demonstrated that RANK, RANKL and TNFalpha were strongly expressed by large multinucleated cells containing polyethylene wear debris in revision tissues. Control tissue stained weakly for RANK, RANKL and TNFalpha. A strong statistical correlation (p<0.02) was found between the five parameters, volume of bone loss, polyethylene wear debris, RANK, RANKL and TNFalpha expression. Importantly, in vitro studies revealed that RANKL and TNFalpha synergise to increase the volume of bone resorbed, by more than seven fold, when compared to the effect of either cytokine treatment alone. This suggests that the interaction of TNFalpha and RANKL promotes osteoclast activity associated with polyethylene wear and therapies targeting TNF activity may be useful to treat peri-implant osteolysis.

Early acetabular cartilage wear following hemiarthroplasty: An ovine model.

OBJECTIVES: Hemiarthroplasty induces degenerative changes in the hip joint, which are difficult to evaluate in vivo. Radiostereometric analysis (RSA) is a radiographic measurement technique that has recently been used to measure acetabular cartilage wear in vivo. The aim of the study was to measure acetabular cartilage wear, using this technique, in an ovine model during the first 14 weeks post-implantation. METHODS: Measurements of three-dimensional femoral head migration, combined with visual assessments at necropsy and safranin O staining for cartilage integrity, were undertaken. RESULTS: Mean femoral head migration during the first six weeks was 0.525 mm in the medial, 0.144 mm in the cranial, and 0.517 mm in the dorsal direction. The majority of this migration was confirmed to be cartilage wear in the medial and dorsal aspects of the acetabulum at necropsy and with subsequent histological evaluation depicting significant cartilage degeneration. CLINICAL SIGNIFICANCE: Radiostereometric analysis is the current gold standard technique for in vivo assessment of implant migration following total hip replacement. This study has utilized RSA to quantify the amount of early cartilage wear in vivo, which was supported by ex vivo evaluations. Accurately measuring the amount of cartilage wear will allow future studies to compare component material and design characteristics prior to clinical use.

The use of OP-1 in femoral impaction grafting in a sheep model.

The aim of this pilot study was to examine bone graft incorporation in femurs impacted with allograft bone alone (control group) or with allograft containing the bone morphogenetic protein OP-1 (BMP-7) (OP-1 group) in a sheep model of cemented hemiarthroplasty. Two sheep in each group were sacrificed at 6, 18 and 26 weeks. Successful bone graft incorporation was evident in both groups by six weeks but in the OP-1 group, there had been more extensive resorption of the graft. There was one case of excessive stem subsidence in the OP-1 group at six weeks. By 18 weeks, there was remodelling and trabeculation of the new bone in the OP-1 group, but this appeared less advanced in the control group. By 26 weeks, there was remodelling of bone in the graft bed. The results of this small study suggest that OP-1 promotes initial graft resorption, thus hastening bone graft incorporation and remodelling in femoral impaction grafting. The one case of stem subsidence may be associated with the early resorption seen in the OP-1 group and reinforces the need for further studies, examining dose response and using precise measures of stem movement, before this BMP is used in femoral impaction grafting at revision hip arthroplasty.

Stem micromotion after femoral impaction grafting using irradiated allograft bone: a time zero in vitro study.

BACKGROUND: A gamma irradiation dose of 15kGy has been shown to adequately sterilise allograft bone, commonly used in femoral impaction bone grafting to treat bone loss at revision hip replacement, without significantly affecting its mechanical properties. The objective of this study was to evaluate whether use of 15kGy irradiated bone affects the initial mechanical stability of the femoral stem prosthesis, as determined by micromotion in a comprehensive testing apparatus, in a clinically relevant time zero in vitro model of revision hip replacement. METHODS: Morselised ovine bone was nonirradiated (control), or irradiated at 15kGy or 60kGy. For each dose, six ovine femurs were implanted with a cemented polished taper stem following femoral impaction bone grafting. Using testing apparatus that reproduces stem loading, stems were cyclically loaded and triaxial micromotion of the stem relative to the bone was measured at the proximal and distal stem regions using non-contact laser transducers and linear variable differential transformers. FINDINGS: There were no significant differences in proximal or distal stem micromotion between groups for all directions (p≤0.80), apart for significantly greater distal stem medial-lateral micromotion in the 60kGy group compared to the 15kGy group (P=0.03), and near-significance in the anterior-posterior direction (P=0.08, power=0.85). INTERPRETATION: Using a clinically relevant model and loading apparatus, irradiation of bone at 15kGy does not affect initial femoral stem stability following femoral impaction bone grafting.

Progression of periacetabular osteolytic lesions.

BACKGROUND: The development of three-dimensional computed tomography (CT) imaging techniques has enabled the detection, accurate measurement, and monitoring of periprosthetic osteolytic lesions. The aim of this study was to track the progression in size of osteolytic lesions and to determine those factors that are associated with the risk of progression. A secondary aim was to investigate whether progression in size of osteolytic lesions could be monitored with use of radiographs. METHODS: We retrospectively determined, with use of sequential CT scans, the progression of periacetabular osteolysis over a period of as much as nine years in a cohort of twenty-six patients (thirty acetabular components) in whom the cementless acetabular component or components had been in place for longer than ten years at the time of the initial CT scan. High-resolution CT scans with metal-artifact suppression were used to determine the volume of osteolytic lesions. Progression in the size of osteolytic lesions per year was calculated as the change in the volume of osteolytic lesions between serial CT scans. Associations were determined between the progression in size of osteolytic lesions, osteolysis rate at the initial CT, patient age, sex, walking limitations, and activity level. Progression in size of osteolytic lesions as determined with use of CT was compared with that determined with use of radiographs. RESULTS: Mean progression in the size of osteolytic lesions, as determined with use of CT, was 1.5 cm(3)/yr (range, 0 to 7.5 cm(3)/yr). The amount of osteolysis at the initial CT scan and patient activity were good predictors of osteolytic lesion progression. The strongest predictor of osteolytic lesion progression occurred when these two risk factors were combined (p = 0.0019). The value of radiographs was limited to monitoring of larger lesions identified by CT. CONCLUSIONS: This is the first study to report on the progression of osteolysis adjacent to cementless acetabular components from medium to long-term follow-up. The data suggest that the osteolysis rate at the initial CT and patient activity can be useful factors in predicting the progression in size of periacetabular osteolytic lesions.

Measurement of bone defects adjacent to acetabular components of hip replacement.

Computed tomography can assist in the detection of periprosthetic osteolysis, but it has not been used to measure the actual volume of bone defects adjacent to hip replacement components because of the scanning artifact caused by metal. The aim of the current study was to develop a spiral computed tomography technique that provides precise and reliable volumetric measurement of bone defects adjacent to uncemented metal-backed acetabular components. Computed tomography scans were taken of small and large defects of known volume created in the ilium in a bovine hemipelvis and a pelvis from a cadaver. Scans were analyzed by two independent observers. The computed tomography operating conditions were determined that enabled volumetric measurements and that were accurate to within 96% for small and large defects and precise to greater than 98% for small and large defects. This computed tomography technique has the capability to measure accurately and precisely the volume of bone defects in the ilium adjacent to metal-backed acetabular components. This technique has clear advantages over plain radiographs. It will allow investigation of the natural history of osteolytic lesions, enhance preoperative planning, and improve monitoring of the outcomes of treatments of osteolysis.