Radiostereometric analysis in total hip arthroplasty and hip fracture patients

Complications related to primary total hip arthroplasty (THA) are relatively rare but still impose a significant burden on the recovery of individual patients and incur significant costs to the healthcare system. Research aimed at improving the results of THA is challenging as complications can take up to decades to manifest clinically. However, radiostereometric analysis (RSA) can, in some cases, be used to predict the long-term revision rates of THA with only a two-year follow-up. The purpose of this doctoral thesis was to examine the causes of RSA-measured micromotion and to further develop the methodology for the research of THA and hip fracture patients. The first study examined whether preoperative systemic bone mineral density (BMD) had an effect on the early RSA-measured micromotion of a cementless acetabular cup in female patients with osteoarthritis. The second study considered tha suitability of model-based RSA (MBRSA) for the analysis of a cementless femoral stem using both a phantom model and a clinical cohort. The third study validated differentially-loaded RSA (DLRSA) for the study of internally-fixated femoral neck fractures in a clinical cohort of 16 patients. The final study examined if RSA data analysis would benefit from the use of a multivariate three-dimensional analytical method. Low systemic BMD was associated with increased proximal migration of the cementless acetabular cups. The MBRSA proved to have comparable accuracy and precision compared to conventional RSA thereby validating the method for future clinical studies using the examined femoral stem. The deployed DLRSA methodology could be used to detect inducibile micromotion of femoral neck fractures. A multivariate linear mixed-effects model could provide a more robust and sensitive method for the analysis of three-dimensional RSA data.   Radiostereometrinen analyysi lonkan kokotekonivelen ja lonkkamurtumien tutkimuksessa Lonkan kokotekonivelleikkauksen komplikaatiot ovat harvinaisia mutta aiheuttavat merkittävää haittaa yksittäisille potilaille sekä merkittäviä taloudellisia kustannuksia terveydenhuollolle. Tutkimustyö lonkan kokotekonivelleikkauksien tuloksien parantamiseksi on haastavaa, koska komplikaatioiden ilmenemiseen voi kulua jopa vuosikymmeniä ja silloinkin harvinaisten komplikaatioiden todentamiseksi tarvittaisiin suuria potilasjoukkoja. Radiostereometrisellä analyysillä (RSA) voidaan tietyissä tapauksissa kuitenkin ennakoida uusintaleikkauksen riskiä jo kahden vuoden seuranta-ajalla. Tämän väitöskirjan tavoitteena oli laajentaa nykyistä tietoa RSA:lla mitattavan mikroliikkeen syistä ja merkityksestä sekä kehittää RSAmenetelmää lonkan kokotekonivel- ja lonkkamurtumapotilailla. Ensimmäisessä osatyössä tutkittiin, onko luuntiheydellä merkitystä sementittömän lonkan kokotekonivelen kuppiosan RSA:lla mitattuun mikroliikkeeseen nivelrikkoa sairastaneilla naispotilailla. Toisessa osatyössä tutkittiin kolmiulotteiseen mallinnukseen perustuvan RSA-menetelmän (MBRSA) soveltuvuutta sementittömän lonkan tekonivelen varren tutkimukseen. MBRSA menetelmää tutkittiin ensin fantomia käyttäen ja myöhemmin tulokset varmistettiin lonkan kokotekoniveltutkimukseen osallistuneilla potilailla. Kolmannessa osatyössä selvitettiin kuormituksen aiheuttaman RSA-mikroliikkeen (DLRSA) käyttöä reisiluun kaulan murtumien tutkimuksessa. Neljännessä osatyössä selvitettiin, hyötyisivätkö RSA-tutkimukset moniulotteisesta tilastollisesta menetelmästä. Sementittömän lonkan kokotekonivelen kuppiosan varhainen mikroliike olisuurentunutta potilailla, joiden luuntiheys oli alentunut. MBRSA menetelmä soveltuu tutkitun tekonivelen varren seurantaan ja käyttöön tulevissa tutkimuksissa. Kehitettyä DLRSA-menetelmää voidaan käyttää reisiluun kaulan murtumien tutkimuksessa. Kolmiulotteisella tilastollisella mallintamisella voidaan havaita yksiulotteisia menetelmiä herkemmin ja spesifisemmin eroja RSA-mikroliikkeessä

Denosumab in Cementless Total Hip Arthroplasty: Multivariate Reanalysis of 3D Femoral Stem Migration and the Influence on Outliers

In cementless total hip arthroplasty, adequate implant stability is necessary for the success of osseointegration and rapid clinical recovery. Postoperative femoral stem migration, measured by radiostereometric analysis (RSA), defines the initial stability achieved during surgical implantation. In a recent trial of 65 postmenopausal women randomized 1:1 denosumab:placebo, denosumab failed to reduce the initial migration of a cementless femoral stem despite the successful prevention of periprosthetic bone loss. The trial applied the current RSA standard, which examined stem migration on an axis-by-axis basis and did not consider more complex three-dimensional (3D) migration. Therefore, we performed a reanalysis of the trial data using a multivariate hierarchical linear mixed model (LMM). As an additional limitation, the data included influential outliers. Women with normal bone mineral density exhibited significantly (p = 0.036) less stem subsidence compared with osteopenic and osteoporotic women. Denosumab significantly decreased the variance of stem migration in osteopenic and osteoporotic women. The mean magnitude of 3D stem migration did not differ between denosumab-treated and placebo-treated women (p = 0.820). After application of a common statistical definition for RSA outlier identification, there were eight (12%) outliers, six in the placebo group and two in the denosumab group (p = 0.149). After exclusion of the outliers, the repeated LMM analysis demonstrated a trending difference in 3D stem migration (p = 0.086), with a significant difference of z-axis rotation (valgus-varus tilt) of the femoral stem (p = 0.029). The observed effect size was small and without clinically important differences in postoperative recovery. Based on a Monte Carlo simulation with random-generated 3D migration data, multivariate LMM showed greater statistical power than univariate analyses. The application of hierarchical LMM facilitated the analysis of implant migration as a factual 3D event. The observed trend in the lower number of RSA outliers in denosumab-treated subjects warrants powered large-scale trials. </p

Radiostereometric analysis of the initial stability of internally fixed femoral neck fractures under differential loading

We examined the feasibility of radiostereometric analysis (RSA) in the assessment of the initial stability of internally fixed femoral neck fractures. The study included 16 patients (mean age 73 years). During surgery, multiple RSA‐beads were inserted on both sides of the fracture. Radiographs for RSA were taken in the supine position within the first 3 days and 6, 12, 24, and 52 weeks after surgery. To detect any inducible motion at the fracture‐site, radiographs for RSA were taken with the patient resting or applying a load through the fracture. Fracture loading was achieved by the patient pressing the ipsilateral foot as much as tolerated on a force plate while providing a counterforce through both hands. Micromotion exceeding the precision values of RSA (≥0.3 mm for the translation vector and/or ≥1.2 degrees for the rotation vector) was considered significant. Permanent three‐dimensional fracture‐site displacement was also recorded. Voluntary loading induced fracture‐site micromotion, which exhibited a dichotomous distribution. In patients with uncomplicated fracture union, inducible micromotion was detectable only at baseline—if at all. Conversely, fractures that developed a nonunion were characterized by the continuation of inducible micromotion beyond baseline. Permanent fracture‐site displacement was, on average, nearly an order of magnitude greater than the inducible micromotion. Fracture unions were characterized by the cessation of permanent fracture‐site displacement by 12 weeks. Nonunions presented as outliers in permanent fracture‐site displacement. Large‐scale studies are warranted to evaluate whether the detection of inducible micromotion beyond baseline could serve as an indicator of insufficient fixation stability.</p

Effects of Articular Cartilage Constituents on Phosphotungstic Acid Enhanced Micro-Computed Tomography

Contrast-enhanced micro-computed tomography (CE mu CT) with phosphotungstic acid (PTA) has shown potential for detecting collagen distribution of articular cartilage. However, the selectivity of the PTA staining to articular cartilage constituents remains to be elucidated. The aim of this study was to investigate the dependence of PTA for the collagen content in bovine articular cartilage. Adjacent bovine articular cartilage samples were treated with chondroitinase ABC and collagenase to degrade the proteoglycan and the collagen constituents in articular cartilage, respectively. Enzymatically degraded samples were compared to the untreated samples using CE mu CT and reference methods, such as Fourier-transform infrared imaging. Decrease in the X-ray attenuation of PTA in articular cartilage and collagen content was observed in cartilage depth of 0-13% and deeper in tissue after collagen degradation. Increase in the X-ray attenuation of PTA was observed in the cartilage depth of 13- 39% after proteoglycan degradation. The X-ray attenuation of PTA-labelled articular cartilage in CE mu CT is associated mainly with collagen content but the proteoglycans have a minor effect on the X-ray attenuation of the PTA-labelled articular cartilage. In conclusion, the PTA labeling provides a feasible CE mu CT method for 3D characterization of articular cartilage.Peer reviewe

Micro-Scale Distribution of CA4+ in Ex vivo Human Articular Cartilage Detected with Contrast-Enhanced Micro-Computed Tomography Imaging

Contrast-enhanced micro-computed tomography (CE mu CT) with cationic and anionic contrast agents reveals glycosaminoglycan (GAG) content and distribution in articular cartilage (AC). The advantage of using cationic stains (e.g., CA4+) compared to anionic stains (e.g., Hexabrix (R)), is that it distributes proportionally with GAGs, while anionic stain distribution in AC is inversely proportional to the GAG content. To date, studies using cationic stains have been conducted with sufficient resolution to study its distributions on the macro-scale, but with insufficient resolution to study its distributions on the micro-scale. Therefore, it is not known whether the cationic contrast agents accumulate in extra/pericellular matrix and if they interact with chondrocytes. The insufficient resolution has also prevented to answer the question whether CA4+ accumulation in chondrons could lead to an erroneous quantification of GAG distribution with low-resolution mu CT setups. In this study, we use high-resolution mu CT to investigate whether CA4+ accumulates in chondrocytes, and further, to determine whether it affects the low-resolution ex vivo mu CT studies of CA4+ stained human AC with varying degree of osteoarthritis. Human osteochondral samples were immersed in three different concentrations of CA4+ (3 mgI/ml, 6 mgI/ml, and 24 mgI/ml) and imaged with high-resolution mu CT at several timepoints. Different uptake diffusion profiles of CA4+ were observed between the segmented chondrons and the rest of the tissue. While the X-ray -detected CA4+ concentration in chondrons was greater than in the rest of the AC, its contribution to the uptake into the whole tissue was negligible and in line with macro-scale GAG content detected from histology. The efficient uptake of CA4+ into chondrons and surrounding territorial matrix can be explained by the micro-scale distribution of GAG content. CA4+ uptake in chondrons occurred regardless of the progression stage of osteoarthritis in the samples and the relative difference between the interterritorial matrix and segmented chondron area was less than 4%. To conclude, our results suggest that GAG quantification with CE mu CT is not affected by the chondron uptake of CA4+. This further confirms the use of CA4+ for macro-scale assessment of GAG throughout the AC, and highlight the capability of studying chondron properties in 3D at the micro scale.Peer reviewe

Increased migration of uncemented acetabular cups in female total hip arthroplasty patients with low systemic bone mineral density - A 2-year RSA and 8-year radiographic follow-up study of 34 patients

Siirretty Doriast

Increased migration of uncemented acetabular cups in female total hip arthroplasty patients with low systemic bone mineral density: A 2-year RSA and 8-year radiographic follow-up study of 34 patients

Background and purpose — Low bone mineral density (BMD) may jeopardize the initial component stability and delay osseointegration of uncemented acetabular cups in total hip arthroplasty (THA). We measured the migration of uncemented cups in women with low or normal BMD. Patients and methods — We used radiostereometric analysis (RSA) to measure the migration of hydroxyapatite-coated titanium alloy cups with alumina-on-alumina bearings in THA of 34 female patients with a median age of 64 (41–78) years. 10 patients had normal BMD and 24 patients had low systemic BMD (T-score ≤ −1) based on dual-energy X-ray absorptiometry (DXA). Cup migration was followed with RSA for 2 years. Radiographic follow-up was done at a median of 8 (2–10) years. Results — Patients with normal BMD did not show a statistically significant cup migration after the settling period of 3 months, while patients with low BMD had a continuous proximal migration between 3 and 12 months (p = 0.03). These differences in cup migration persisted at 24 months. Based on the perceived risk of cup revision, 14 of the 24 cases were “at risk” (proximal translation of 0.2 to 1.0 mm) in the low-BMD group and 2 of the10 cases were “at risk” in the normal-BMD group (odds ratio (OR) = 8.0, 95% CI: 1.3–48). The radiographic follow-up showed no radiolucent lines or osteolysis. 2 cups have been revised for fractures of the ceramic bearings, but none for loosening. Interpretation — Low BMD contributed to cup migration beyond the settling period of 3 months, but the migrating cups appeared to osseointegrate eventually

Effects of articular cartilage constituents on phosphotungstic acid enhanced micro-computed tomography

Contrast-enhanced micro-computed tomography (CEμCT) with phosphotungstic acid (PTA) has shown potential for detecting collagen distribution of articular cartilage. However, the selectivity of the PTA staining to articular cartilage constituents remains to be elucidated. The aim of this study was to investigate the dependence of PTA for the collagen content in bovine articular cartilage. Adjacent bovine articular cartilage samples were treated with chondroitinase ABC and collagenase to degrade the proteoglycan and the collagen constituents in articular cartilage, respectively. Enzymatically degraded samples were compared to the untreated samples using CEμCT and reference methods, such as Fourier-transform infrared imaging. Decrease in the X-ray attenuation of PTA in articular cartilage and collagen content was observed in cartilage depth of 0-13% and deeper in tissue after collagen degradation. Increase in the X-ray attenuation of PTA was observed in the cartilage depth of 13-39% after proteoglycan degradation. The X-ray attenuation of PTA-labelled articular cartilage in CEμCT is associated mainly with collagen content but the proteoglycans have a minor effect on the X-ray attenuation of the PTA-labelled articular cartilage. In conclusion, the PTA labeling provides a feasible CEμCT method for 3D characterization of articular cartilage

Micro-Scale Distribution of CA4+ in Ex vivo Human Articular Cartilage Detected with Contrast-Enhanced Micro-Computed Tomography Imaging

Contrast-enhanced micro-computed tomography (CEμCT) with cationic and anionic contrast agents reveals glycosaminoglycan (GAG) content and distribution in articular cartilage (AC). The advantage of using cationic stains (e.g., CA4+) compared to anionic stains (e.g., Hexabrix®), is that it distributes proportionally with GAGs, while anionic stain distribution in AC is inversely proportional to the GAG content. To date, studies using cationic stains have been conducted with sufficient resolution to study its distributions on the macro-scale, but with insufficient resolution to study its distributions on the micro-scale. Therefore, it is not known whether the cationic contrast agents accumulate in extra/pericellular matrix and if they interact with chondrocytes. The insufficient resolution has also prevented to answer the question whether CA4+ accumulation in chondrons could lead to an erroneous quantification of GAG distribution with low-resolution μCT setups. In this study, we use high-resolution μCT to investigate whether CA4+ accumulates in chondrocytes, and further, to determine whether it affects the low-resolution ex vivo μCT studies of CA4+ stained human AC with varying degree of osteoarthritis. Human osteochondral samples were immersed in three different concentrations of CA4+ (3 mgI/ml, 6 mgI/ml, and 24 mgI/ml) and imaged with high-resolution μCT at several timepoints. Different uptake diffusion profiles of CA4+ were observed between the segmented chondrons and the rest of the tissue. While the X-ray -detected CA4+ concentration in chondrons was greater than in the rest of the AC, its contribution to the uptake into the whole tissue was negligible and in line with macro-scale GAG content detected from histology. The efficient uptake of CA4+ into chondrons and surrounding territorial matrix can be explained by the micro-scale distribution of GAG content. CA4+ uptake in chondrons occurred regardless of the progression stage of osteoarthritis in the samples and the relative difference between the interterritorial matrix and segmented chondron area was less than 4%. To conclude, our results suggest that GAG quantification with CEμCT is not affected by the chondron uptake of CA4+. This further confirms the use of CA4+ for macro-scale assessment of GAG throughout the AC, and highlight the capability of studying chondron properties in 3D at the micro scale