Joint unloading implant modifies subchondral bone trabecular structure in medial knee osteoarthritis: 2-year outcomes of a pilot study using fractal signature analysis.

BACKGROUND: Knee osteoarthritis (OA) is largely attributable to chronic excessive and aberrant joint loading. The purpose of this pilot study was to quantify radiographic changes in subchondral bone after treatment with a minimally invasive joint unloading implant (KineSpring(®) Knee Implant System). METHODS: Nine patients with unilateral medial knee OA resistant to nonsurgical therapy were treated with the KineSpring System and followed for 2 years. Main outcomes included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function, and stiffness subscores and independent core laboratory determinations of joint space width and fractal signature of the tibial cortex. RESULTS: WOMAC scores, on average, improved by 92% for pain, 91% for function, and 79% for stiffness over the 2-year follow-up period. Joint space width in the medial compartment of the treated knee significantly increased from 0.9 mm at baseline to 3.1 mm at 2 years; joint space width in the medial compartment of the untreated knee was unchanged. Fractal signatures of the vertically oriented trabeculae in the medial compartment decreased by 2.8% in the treated knee and increased by 2.1% in the untreated knee over 2 years. No statistically significant fractal signature changes were observed in the horizontally oriented trabeculae in the medial compartment or in the horizontal or vertical trabeculae of the lateral compartment in the treated knee. CONCLUSION: Preliminary evidence suggests that the KineSpring System may modify knee OA disease progression by increasing joint space width and improving subchondral bone trabecular integrity, thereby reducing pain and improving joint function.

Age- and gender-related differences in cortical geometry and microstructure: Improved sensitivity by regional analysis.

OBJECTIVE: While the importance of cortical structure quantification is increasingly underscored by recent literature, conventional analysis techniques obscure potentially important regional variations in cortical structure. The objective of this study was to characterize the spatial variability in cortical geometry and microstructure at the distal radius and tibia using high resolution peripheral quantitative computed tomography (HR-pQCT). We show that spatially-resolved analysis is able to identify cortical sub-regions with increased sensitivity to the effects of gender and aging. METHODS: HR-pQCT scans of 146 volunteers (92 female/54 male) spanning a wide range of ages (20-78years) were analyzed. For each subject, radius and tibia scans were obtained using a clinical HR-pQCT system. Measures describing geometry (cortical bone thickness (Ct.Th)), microstructure (porosity (Ct.Po), pore diameter (Ct.Po.Dm), and pore size heterogeneity (Ct.Po.Dm SD)), and cortical bone density were calculated from the image data. Biomechanical parameters describing load and stress distribution were calculated using linear finite element analysis. Cortical quadrants were defined based on anatomic axes to quantify regional parameter variation. Subjects were categorized by gender, and age, and menopausal status for analysis. RESULTS: Significant regional variation was found in all geometric and microstructural parameters in both the radius and tibia. In general, the radius showed more pronounced and significant variations in all parameters as compared with the tibia. At both sites, Ct.Po displayed the greatest regional variations. Correlation coefficients for Ct.Po and Ct.Th with respect to load and stress distribution provided evidence of an association between regional cortical structure and biomechanics in the tibia. Comparing women to men, differences in Ct.Po were most pronounced in the anterior quadrant of the radius (36% lower in women (p<0.01)) and the posterior quadrant of the tibia (27% lower in women (p<0.01)). Comparing elderly to young women, differences in Ct.Po were most pronounced in the lateral quadrant of the radius (328% higher in elderly women (p<0.001)) and the anterior quadrant of the tibia (433% higher in elderly women (p<0.001)). Comparing elderly to young men, the most pronounced age differences were found in the anterior radius (205% higher in elderly men, (p<0.001)) and the anterior tibia (190% higher in elderly men (p<0.01)). All subregional Ct.Po differences provided greater sensitivity to gender and age effects than those based on the global means. CONCLUSION: These results show significant regional variation in all geometric and microarchitectural parameters studied in both the radius and tibia. Quantification of region-specific parameters provided increased sensitivity in the analysis of age- and gender-related differences, in many cases providing statistically significant differentiation of groups where conventional global analysis failed to detect differences. These results suggest that regional analysis may be important in studies of disease and therapeutic effects, particularly where microstructural parameters based on global analyses have thus far failed to identify a response in bone quality.

Quantitative characterization of subject motion in HR-pQCT images of the distal radius and tibia.

Image quality degradation due to subject motion is a common artifact affecting in vivo high-resolution peripheral quantitative computed tomography (HR-pQCT) of bones. These artifacts confound the accuracy and reproducibility of bone density, geometry, and cortical and trabecular structure measurements. Observer-based systems for grading image quality and criteria for deciding when to repeat an acquisition and post hoc data quality control remain highly subjective and non-standardized. This study proposes an objective, quantitative technique for measuring subject motion in HR-pQCT acquisitions from raw projection data, using image similarity measures applied to parallelized projections at 0° and 180°. A total of 88 HR-pQCT exams with repeated acquisitions of the distal radius (N = 54) or distal tibia (N = 34) of 49 women (age = 59 ± 14 year) and 3 men (46 ± 2 year) were retrospectively evaluated. All images were graded from 1 (no visible motion artifacts) to 5 (severe motion artifacts) according to the manufacturer-suggested image quality grading system. In addition, to serve as the reference case without motion artifacts, two cadaveric wrist and two ankle specimens were imaged twice with repositioning. The motion-induced error was calculated as the percent difference in each bone parameter for the paired scans with and without visually apparent motion artifacts. Quantitative motion estimates (QMEs) for each motion-degraded scan were calculated using two different image similarity measures: sum of squared differences (SSD) and normalized cross-correlation (NCC). The mean values of QME(SSD) and QME(NCC) increased with the image quality grade for both radius and tibia. Quality grades were differentiated between grades 2 and 3 using QME(SSD), but not with QME(NCC), in addition to between grades 4 and 5. Both QMEs correlated significantly to the motion-induced errors in the measurements and their empirical relationship was derived. Subject motion had greater impact on the precision of trabecular structure indices than on the densitometric indices. The results of this study may provide a basis for establishing a threshold for motion artifacts in accordance to the study design as well as a standardized quality control protocol across operators and imaging centers.

A longitudinal HR-pQCT study of alendronate treatment in postmenopausal women with low bone density: Relations among density, cortical and trabecular microarchitecture, biomechanics, and bone turnover.

The goal of this study was to characterize longitudinal changes in bone microarchitecture and function in women treated with an established antifracture therapeutic. In this double-blind, placebo-controlled pilot study, 53 early postmenopausal women with low bone density (age = 56 ± 4 years; femoral neck T-score = -1.5 ± 0.6) were monitored by high-resolution peripheral quantitative computed tomography (HR-pQCT) for 24 months following randomization to alendronate (ALN) or placebo (PBO) treatment groups. Subjects underwent annual HR-pQCT imaging of the distal radius and tibia, dual-energy X-ray absorptiometry (DXA), and determination of biochemical markers of bone turnover (BSAP and uNTx). In addition to bone density and microarchitecture assessment, regional analysis, cortical porosity quantification, and micro-finite-element analysis were performed. After 24 months of treatment, at the distal tibia but not the radius, HR-pQCT measures showed significant improvements over baseline in the ALN group, particularly densitometric measures in the cortical and trabecular compartments and endocortical geometry (cortical thickness and area, medullary area) (p < .05). Cortical volumetric bone mineral density (vBMD) in the tibia alone showed a significant difference between treatment groups after 24 months (p < .05); however, regionally, significant differences in Tb.vBMD, Tb.N, and Ct.Th were found for the lateral quadrant of the radius (p < .05). Spearman correlation analysis revealed that the biomechanical response to ALN in the radius and tibia was specifically associated with changes in trabecular microarchitecture (|ρ| = 0.51 to 0.80, p < .05), whereas PBO progression of bone loss was associated with a broad range of changes in density, geometry, and microarchitecture (|ρ| = 0.56 to 0.89, p < .05). Baseline cortical geometry and porosity measures best predicted ALN-induced change in biomechanics at both sites (ρ > 0.48, p < .05). These findings suggest a more pronounced response to ALN in the tibia than in the radius, driven by trabecular and endocortical changes.

Regional variations of gender-specific and age-related differences in trabecular bone structure of the distal radius and tibia.

Regional variation in trabecular structure across axial sections is often obscured by the conventional global analysis, which takes an average value for the entire trabecular compartment. The objective of this study is to characterize spatial variability in trabecular structure within a cross-section at the distal radius and tibia, and gender and age effects using in vivo high-resolution peripheral quantitative computed tomography (HR-pQCT). HR-pQCT images of the distal radius and tibia were acquired from 146 healthy individuals aged 20-78 years. Trabecular bone volume fraction (BV/TV), number (Tb.N), thickness (Tb.Th), separation (Tb.Sp), and heterogeneity (Tb.1/N.SD) were obtained in a total of 11 regions-the entire trabecular compartment (the global means), inner, outer, and eight defined subregions. Regional variations were examined with respect to the global means, and compared between women and men, and between young (20-29 years old) and elderly (65-79 years old) adults. Substantial regional variations in trabecular bone structure at the distal radius and tibia were revealed (e.g. BV/TV varied -40% to +57% and -59% to +100% of the global means, respectively, for elderly women). The inner-lateral (IL) subregion had low BV/TV, Tb.N, and Tb.Th, and low Tb.Sp and Tb.1/N.SD at both sites; the opposite was true in the outer-anterior (OA) subregion at the distal radius and the outer-medial (OM) and -posterior (OP) subregions at the distal tibia. Gender differences were most pronounced in the inner-anterior (IA) subregion compared to the other regions or the global mean differences at both sites. Trabecular structure associated with age and differed between young and elderly adults predominantly in the inner-posterior (IP) subregion at the distal radius and in the IL and IA subregions at the distal tibia; on the other hand, it remained unchanged in the OA subregion at the distal radius and in the OM subregion at the distal tibia for both women and men. This study demonstrated that not only the conventional global analysis can obscure regional differences, but also assuming bone status from that of smaller subregion may introduce a confounding sampling error. Therefore, a combined approach of investigating the entire region, each subregion, and the cortical compartment may offer more complete information.

Resolution dependence of the non-metric trabecular structure indices.

Non-metric indices of topological features of trabecular bone structure, such as structure model index (SMI), connectivity density (Conn.D), and degree of anisotropy (DA), provide unique information relevant to bone quality. With recent technological advancement, in vivo assessment of these indices may be possible from images acquired using high-resolution imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT). However, more detailed investigation of the dependence of non-metric indices on spatial resolution is needed to determine their applicability. The purpose of this study was to determine whether these three non-metric indices are affected by the spatial resolution of CT images. First, the SMI, Conn.D, and DA were calculated for trabecular bone specimens with varying plate-like and rod-like structures from resampled muCT images across a range of spatial resolutions and compared to the reference values. To account for differences in size across different species and anatomical sites, the results are reported in normalized resolution units. Next, the impact of resolution on the non-metric indices for cores of human distal tibia trabecular bone from clinical HR-pQCT images was evaluated to determine the applicability of the non-metric indices to in vivo imaging. We found that the non-metric indices of trabecular bone structure were affected by spatial resolution of CT images. Particularly, the SMI deviated from the high-resolution muCT reference value depending on the structure type, whether plate-like or rod-like. Both Conn.D and DA were underestimated in the images obtained at an in vivo resolution. It is not trivial to determine absolute threshold for validity of these non-metric indices without considering a specific study design (e.g. relative resolution, the size of the treatment effect to detect, and specimen type). The results of this study provide an upper bound for the accuracy of the non-metric indices under limited resolution scenarios.

Automated registration of hip and spine for longitudinal QCT studies: integration with 3D densitometric and structural analysis.

To eliminate user interaction in longitudinal quantitative computed tomography (QCT) measurements of bone mineral density (BMD) and geometry, we have developed and optimized an automated registration algorithm for QCT images of the hip and spine and integrated it with a previously developed 3D densitometric and structural analysis program. With registration, the follow-up images are automatically aligned with respect to the baseline scans, and the bone quantification of the aligned follow-up scan is initiated based on the bone morphometric features defined on the baseline scan. To validate the algorithm, we analyzed 20 pairs of repeat QCT images (10 hip pairs and 10 spine pairs) acquired on a modern multi-slice CT scanner, with repositioning between each scan pair to simulate repeat visits. Bone measurements obtained with automatic registration achieved comparable or improved precision errors compared to those obtained by careful manual analysis of the follow-up scans. The algorithm we have developed was based on the mutual information approach, with simplex optimization under a multi-resolution scheme. The average registration time was 2.3 min for a hip pair and 1.1 min for a vertebra pair using a standard desktop computer. Based on the reduced user interaction, high degree of precision, and short execution time, this is a promising technique for monitoring therapy in patients and clinical trials.