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.

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.

Adjuvant endocrine therapy effects on bone mineral density and microstructure in women with breast cancer.

INTRODUCTION: Although aromatase inhibitors (AIs) are typical drugs for cancer treatment-induced bone loss, their effects on the bone microstructure remain unclear. In this study, we evaluated changes in the bone mineral density (BMD) and bone microstructure associated with AI treatment using high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with early breast cancer. MATERIALS AND METHODS: This prospective, single-arm, observational study included non-osteoporotic, postmenopausal women with hormone receptor-positive breast cancer. Patients underwent dual-energy X-ray absorptiometry (DXA), HR-pQCT, and tartrate-resistant acid phosphatase-5b (TRACP-5b) or procollagen type-I N-terminal propeptide measurements at baseline and 6 and 12 months after AI therapy. The primary endpoint was changes in the total volumetric BMD (Tt.vBMD), trabecular vBMD (Tb.vBMD), and cortical vBMD (Ct.vBMD) longitudinally at the distal radius and tibia. RESULTS: Twenty women were included (median age 57.5 years; range 55-72 years). At 12 months, HR-pQCT indicated a significant decrease in the Tt.vBMD (median distal radius - 5.3%, p < 0.01; distal tibia - 3.2%, p < 0.01), Tb.vBMD (- 3.2%, p < 0.01; - 1.0%, p < 0.05, respectively), and Ct.vBMD (- 3.2%, p < 0.01; - 2.7%, p < 0.01, respectively). Estimated bone strength was also significantly decreased. The DXA BMD value in the total hip (p < 0.01) and femoral neck (p = 0.03), but not in the lumbar spine, was significantly decreased. The TRACP-5b levels was significantly negatively associated with changes in the Tt.vBMD in both the distal radius and tibia (r =  - 0.53, r =  - 0.47, respectively) CONCLUSION: Postmenopausal women who received AIs for early breast cancer experienced significant trabecular and cortical bone deterioration and a decrease in estimated bone strength within only 1 year.

High cervical arteriovenous fistulas fed by dural and spinal arteries and draining into a single medullary vein: report of 3 cases.

OBJECT: The authors previously reported a case of complex arteriovenous fistula (AVF) at C-1 with multiple dural and spinal feeders that were linked with a common medullary venous channel. The purpose of the present study was to collect similar cases and analyze their angioarchitecture to gain a better understanding of this malformation. METHODS: Three such cases, affecting 2 males and 1 female in their 60s who had presented with hematomyelia (2) or progressive myelopathy (1), were treated surgically, and the operative findings from all 3 cases were compared using digital subtraction angiography (DSA) to determine the angioarchitecture. RESULTS: The C-1 and C-2 radicular arteries and anterior and posterior spinal arteries supplied feeders to a single medullary draining vein in various combinations and via various routes. The drainage veins ran along the affected ventral nerve roots and lay ventral to the spinal cord. The sites of shunting to the vein were multiple: dural, along the ventral nerve root in the subarachnoid space, and on the spinal cord, showing a vascular structure typical of dural AVF, that is, a direct arteriovenous shunt near the spinal root sleeve fed by one or more dural arteries and ending in a single draining vein, except for intradural shunts fed by feeders from the spinal arteries. In 2 cases with hemorrhagic onset the drainer flowed rostrally, and in 1 case associated with congestive myelopathy the drainer flowed both rostrally and caudally. Preoperative determination of the shunt sites and feeding arteries was difficult because of complex recruitment of the feeders and multiple shunt sites. The angioarchitecture in these cases was clarified postoperatively by meticulous comparison of the DSA images and operative video. Direct surgical intervention led to a favorable outcome in all 3 cases. CONCLUSIONS: A high cervical complex AVF has unique angioarchitectural characteristics different from those seen in the other spinal regions.