Association of denosumab with serum cytokines, chemokines, and bone-related factors in patients with rheumatoid arthritis: A post hoc analysis of a multicentre, open-label, randomised, parallel-group study.

OBJECTIVES: To clarify changes in serum cytokines, chemokines, and bone-related factors during denosumab treatment in rheumatoid arthritis (RA) patients. METHODS: This was a post hoc analysis of a multicentre, open-label, randomised, parallel-group study. Patients were randomly assigned to continue treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) plus receive treatment with denosumab (csDMARDs plus denosumab group) or to continue treatment with csDMARD therapy alone for 12 months. Serum biomarker levels were measured at baseline and 6 and 12 months. RESULTS: Baseline and 6-month data from the csDMARDs plus denosumab (n = 22) and csDMARD therapy alone (n = 22) groups were analysed. Statistically significant changes from baseline were seen: dickkopf-related protein 1 decreased at 6 and 12 months (both groups); osteopontin decreased at 6 months in the csDMARDs plus denosumab group; osteopontin and soluble CD40 ligand increased at 6 and 12 months in the csDMARD therapy alone group; osteocalcin decreased at 6 and 12 months, epidermal growth factor decreased at 12 months, and macrophage-derived chemokine decreased at 6 months in the csDMARDs plus denosumab group; and interferon gamma-induced protein-10 increased at 12 months in the csDMARD therapy alone group. CONCLUSIONS: Denosumab may inhibit bone destruction by suppressing bone-related factors/chemokines.

Denosumab improves bone mineral density and microarchitecture in rheumatoid arthritis: randomized controlled trial by HR-pQCT.

INTRODUCTION: This pre-specified exploratory analysis investigated the effect of denosumab on bone mineral density (BMD) and bone microarchitecture in patients with rheumatoid arthritis (RA) treated with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). MATERIALS AND METHODS: In this open-label, parallel-group study, patients were randomly assigned (1:1) to continuous treatment with csDMARDs plus denosumab or continuous treatment with csDMARD therapy alone for 12 months. BMD and bone microarchitecture were measured by dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT). RESULTS: Of 46 patients enrolled in the primary study, 43 were included in the full analysis set. The mean age was 65.3 years, 88.4% were female, and 60.5% had osteoporosis. Areal BMD of the lumbar spine increased from baseline to 6 and 12 months in both groups, but the increase was higher in the csDMARDs plus denosumab group. Areal BMD of the total hip and femoral neck increased from baseline to 6 and 12 months only in the csDMARDs plus denosumab group. Cortical volumetric BMD and cortical thickness of the distal tibia increased in the csDMARDs plus denosumab group at 6 and 12 months but decreased in the csDMARD therapy alone group. Trabecular bone parameters of the distal tibia improved only in the csDMARDs plus denosumab group at 12 months. CONCLUSION: Denosumab may be recommended for patients with RA treated with csDMARDs to increase BMD and improve bone microarchitecture.

The Anterior Position of the Hip Center of Rotation Is Related to Anterior Cup Protrusion Length and Symptomatic Iliopsoas Impingement in Primary Total Hip Arthroplasty.

BACKGROUND: Iliopsoas impingement (IPI) is an important complication after total hip arthroplasty (THA), and anterior cup protrusion is believed to be its main cause; however, the relationship between the hip center of rotation (COR) and symptomatic IPI or cup protrusion remains poorly understood. Therefore, the present study investigated these relationships. METHODS: The medical records of 138 patients who underwent unilateral primary THA were retrospectively reviewed. There were 8 patients (5.8%) who had symptomatic IPI. The COR and cup protrusion length measured with 2 methods were assessed on computed tomography. Risk factors for symptomatic IPI and the relationship between the COR and protrusion length were evaluated. RESULTS: Logistic regression analyses showed that anteroposterior position of the COR, sagittal cup protrusion length (SCPL) at the COR, and both axial and SCPLs at the most anterior margin of the cup were related to symptomatic IPI. Multivariable regression analyses showed that acetabular offset was related to axial protrusion length at the COR, and anteroposterior position of the COR was related to both axial and sagittal protrusion lengths at the most anterior margin of the cup. CONCLUSION: Anterior position of the cup was related to symptomatic IPI and both axial and sagittal protrusion lengths at the most anterior margin of the cup. Anterior reaming and cup protrusion should be avoided as much as possible to prevent symptomatic IPI.

High risk of elevated metal concentrations with 9/10-mm stem trunnions and highly cross-linked polyethylene grafted with poly(2-methacryloyloxyethyl phosphorylcholine) in total hip arthroplasty.

BACKGROUND: The risks of metal release due to fretting and corrosion at the head-neck junction and consequent adverse local tissue reaction (ALTR) have concerns in metal-on-polyethylene (MoP) total hip arthroplasty (THA). Although trunnions have become thinner in diameter to increase the range of motion, it has remained unclear whether this change affects metal release and ALTR in vivo. This study aimed to investigate serum metal concentrations and the prevalence of ALTR in MoP THA with a 9/10-mm stem trunnion. PATIENTS AND METHODS: A consecutive series of 37 hips that underwent THA using MoP grafted with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) with a 9/10-mm trunnion stem were retrospectively reviewed. Serum metal levels were assessed and compared with those in MoP THA with a 10/12-mm trunnion stem. ALTR was diagnosed with serum metal levels and cross-sectional images. The factors associated with serum metal levels were also assessed. RESULTS: The median serum cobalt and chromium levels were 1.5 µg/L and 1.0 µg/L in the 9/10-mm group and 0.2 µg/L and 0.4 µg/L in the 10/12-mm group, respectively. ALTR was found in 5 hips of 3 patients. Revision surgery was performed in 4 hips, and all stem trunnions and femoral heads showed severe corrosion. Postoperative walking ability was associated with serum metal levels. CONCLUSION: It was found that a 9/10-mm stem trunnion with MoP grafted with PMPC had high risks of metal release in primary THA. Careful follow-up and cross-sectional imaging are needed to detect ALTR for early revision.

Inhibition of bone erosion, determined by high-resolution peripheral quantitative computed tomography (HR-pQCT), in rheumatoid arthritis patients receiving a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) plus denosumab vs csDMARD therapy alone: an open-label, randomized, parallel-group study.

BACKGROUND: This exploratory study compared the inhibition of bone erosion progression in rheumatoid arthritis (RA) patients treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) plus denosumab versus csDMARD therapy alone and investigated the effects of denosumab on bone micro-architecture and other bone-related parameters using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: In this open-label, randomized, parallel-group study, patients with RA undergoing treatment with a csDMARD were randomly assigned (1:1) to continue csDMARD therapy alone or to continue csDMARDs with denosumab (60-mg subcutaneous injection once every 6 months) for 12 months. The primary endpoint was the change from baseline in the depth of bone erosion, measured by HR-pQCT, in the second and third metacarpal heads at 6 months after starting treatment. Exploratory endpoints were also evaluated, and adverse events (AEs) were monitored for safety. RESULTS: In total, 46 patients were enrolled, and 43 were included in the full analysis set (csDMARDs plus denosumab, N = 21; csDMARD therapy alone, N = 22). Most patients were female (88.4%), and the mean age was 65.3 years. The adjusted mean (95% confidence interval) change from baseline in the depth of bone erosion, measured by HR-pQCT, in the 2-3 metacarpal heads at 6 months was - 0.57 mm (- 1.52, 0.39 mm) in the csDMARDs plus denosumab group vs - 0.22 mm (- 0.97, 0.53 mm) in the csDMARD therapy alone group (between-group difference: - 0.35 mm [- 1.00, 0.31]; P = 0.2716). Similar results were shown for the adjusted mean between-group difference in the width and volume of bone erosion of the 2-3 metacarpal heads. Significant improvements in bone micro-architecture parameters were shown. The incidence of AEs and serious AEs was similar between the csDMARDs plus denosumab and the csDMARD therapy alone groups (AEs: 52.2% vs 56.5%; serious AEs: 4.3% vs 8.7%). CONCLUSIONS: Although the addition of denosumab to csDMARDs did not find statistically significant improvements in bone erosion after 6 months of treatment, numerical improvements in these parameters suggest that the addition of denosumab to csDMARDs may be effective in inhibiting the progression of bone erosion and improving bone micro-architecture. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, UMIN000030575. Japan Registry for Clinical Trials, jRCTs071180018.

Analysis of bone erosions in rheumatoid arthritis using HR-pQCT: Development of a measurement algorithm and assessment of longitudinal changes.

PURPOSE: The purpose of this study was to establish an algorithm for measuring bone erosions at metacarpophalangeal (MCP) joints using high-resolution peripheral quantitative computed tomography (HR-pQCT), to investigate the precision of measurements, and to assess longitudinal changes in bone erosions among patients with rheumatoid arthritis (RA). METHODS: The 2nd and 3rd MCP joints were scanned at a voxel size of 60.7 µm using second-generation HR-pQCT. Bone erosions on MCP joints were identified using a semi-automated algorithm we developed, and each erosion parameter was measured. Measurement reproducibility was evaluated in 19 healthy subjects using intraclass correlation coefficients (ICCs) and root mean square percent coefficient of variance (RMS%CV). Finally, longitudinal changes in bone erosions over a period of 12 months were assessed in 26 patients with RA based on the calculated least significant change (LSC). RESULTS: Reproducibilities for measurement parameters regarding bone erosions with our algorithm were good (all ICCs ≥ 0.98; all RMS%CVs < 5%). No erosion parameters showed significant changes after 12 months of treatment in terms of median values in all erosions, while both progression and repair of erosions were observed individually (e.g., erosion volume: progression, 26% (+0.62 mm3); repair, 34% (-0.85 mm3); no change, 40%). CONCLUSIONS: The measurement algorithm developed for bone erosions at MCP joints showed good reproducibility. Both progression and repair of bone erosions were observed in patients with RA even after 12 months of appropriate treatment. Our algorithm may be useful to investigate the etiology of RA and assess drug efficacy.

Global and Spatial Compartmental Interrelationships of Bone Density, Microstructure, Geometry and Biomechanics in the Distal Radius in a Colles' Fracture Study Using HR-pQCT.

Background: Bone parameters derived from HR-pQCT have been investigated on a parameter-by-parameter basis for different clinical conditions. However, little is known regarding the interrelationships of bone parameters and the spatial distribution of these interrelationships. In this work: 1) we investigate compartmental interrelationships of bone parameters; 2) assess the spatial distribution of interrelationships of bone parameters; and 3) compare interrelationships of bone parameters between postmenopausal women with and without a recent Colles' fracture. Methods: Images from the unaffected radius in fracture cases (n=84), and from the non-dominant radius of controls (n=98) were obtained using HR-pQCT. Trabecular voxel-based maps of local bone volume fraction (L.Tb.BV/TV), homogenized volumetric bone mineral density (H.Tb.BMD), homogenized µFEA-derived strain energy density (H.Tb.SED), and homogenized inter-trabecular distances (H.Tb.1/N) were generated; as well as surface-based maps of apparent cortical bone thickness (Surf.app.Ct.Th), porosity-weighted cortical bone thickness (Surf.Ct.SIT), mean cortical BMD (Surf.Ct.BMD), and mean cortical SED (Surf.Ct.SED). Anatomical correspondences across the parametric maps in the study were established via spatial normalization to a common template. Mean values of the parametric maps before spatial normalization were used to assess compartmental Spearman's rank partial correlations of bone parameters (e.g., between H.Tb.BMD and L.Tb.BV/TV or between Surf.Ct.BMD and Surf.app.Ct.Th). Spearman's rank partial correlations were also assessed for each voxel and vertex of the spatially normalized parametric maps, thus generating maps of Spearman's rank partial correlation coefficients. Correlations were performed independently within each group, and compared between groups using the Fisher's Z transformation. Results: All within-group global trabecular and cortical Spearman's rank partial correlations were significant; and the correlations of H.Tb.BMD-L.Tb.BV/TV, H.Tb.BMD-H.Tb.1/N, L.Tb.BV/TV-H.Tb.1/N, Surf.Ct.BMD-Surf.Ct.SED and Surf.Ct.SIT-Surf.Ct.SED were significantly different between controls and fracture cases. The spatial analyses revealed significant heterogeneous voxel- and surface-based correlation coefficient maps across the distal radius for both groups; and the correlation maps of H.Tb.BMD-L.Tb.BV/TV, H.Tb.BMD-H.Tb.1/N, L.Tb.BV/TV-H.Tb.1/N, H.Tb.1/N-H.Tb.SED and Surf.app.Ct.Th - Surf.Ct.SIT yielded small clusters of significant correlation differences between groups. Discussion: The heterogeneous spatial distribution of interrelationships of bone parameters assessing density, microstructure, geometry and biomechanics, along with their global and local differences between controls and fracture cases, may help us further understand different bone mechanisms of bone fracture.

In vivo analysis of subchondral trabecular bone in patients with osteoarthritis of the knee using second-generation high-resolution peripheral quantitative computed tomography (HR-pQCT).

OBJECTIVE: Subchondral bone plays an important role in the pathological mechanisms of knee osteoarthritis (OA). High-resolution peripheral quantitative computed tomography (HR-pQCT) is an imaging modality allowing noninvasive microstructural analysis of human bone, and the second generation enables scanning of the knee. The purpose of this study was to perform in vivo analysis of subchondral trabecular bone in patients with medial knee OA, to elucidate features of bone microstructure in medial knee OA, and to investigate relationships between bone microstructure and both stage of disease and lower limb alignment. METHODS: Subjects were 20 women, including both patients with medial knee OA (Kellgren-Lawrence (KL) grade 2, n = 5, KL grade 3, n = 7, and KL grade 4, n = 4; mean age: 63.0 years; body mass index (BMI): 23.8 kg/m2) and volunteers without knee OA (KL grade 1, n = 4, mean age: 66.0 years; BMI: 23.8 kg/m2). The proximal tibia (20-mm length) was scanned by second-generation HR-pQCT at a voxel size of 60.7 µm. A subchondral trabecular bone volume of 5 mm length was extracted from the medial and lateral plateaus. They were then divided into 4 regions: anterior, central, medial or lateral, and posterior. Finally, subchondral bone microstructure parameters were analyzed and compared, between each plateau and region. Relationships between microstructural parameters and disease stage (KL grade, minimum joint space width), and between those parameters and lower limb alignment (femorotibial angle: FTA, mechanical axis deviation: MAD) were also investigated. RESULTS: In the medial plateau, volumetric bone mineral density (vBMD), bone volume fraction (BV/TV), and trabecular thickness were significantly higher and structure model index (SMI) was significantly lower than in the lateral plateau, particularly in the anterior, central, and medial regions (p < .01 each). In the anterior region of the medial plateau, vBMD, BV/TV, and connectivity density showed strong positive correlations with KL grade, FTA, and MAD (r-range: 0.61 to 0.83), while trabecular separation and SMI exhibited strong negative correlations with KL grade, FTA, and MAD (r-range: -0.60 to -0.83). CONCLUSIONS: Higher bone volume, trabecular thickness, and a more plate-like structure were observed in the medial tibial plateau than in the lateral. Subchondral bone microstructure at the anterior region in the medial plateau showed strong relationships with KL grade and lower limb alignment. These results indicate that subchondral bone microstructure in this region may provide representative indices, particularly in medial knee OA. Although this study involved a specifically Asian cohort with a lower BMI distribution than other ethnic groups, the technique presented may be useful in studying the pathogenesis of OA or evaluating treatment effects.