AS could adversely affect the HRQoL of patients. Measuring HRQoL should be considered as an essential part of the overall assessment of health status of AS patients, which would provide valuable clues for improving the management of disease and making decisions regarding treatment.

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IMPORTANCE A proof-of-principle study suggested that intravenous zoledronic acid may reduce knee pain and the size of bone marrow lesions in people with knee osteoarthritis, but data from large trials are lacking.OBJECTIVE To determine the effects of intravenous zoledronic acid on knee cartilage volume loss in patients with symptomatic knee osteoarthritis and bone marrow lesions. DESIGN, SETTING, AND PARTICIPANTSA 24-month multicenter, double-blind placebo-controlled randomized clinical trial conducted at 4 sites in Australia (1 research center and 3 hospitals). Adults aged 50 years or older with symptomatic knee osteoarthritis and subchondral bone marrow lesions detected by magnetic resonance imaging (MRI) were enrolled from November 2013 through September 2015. The final date of follow-up was October 9, 2017.INTERVENTIONS Intravenous infusion with either 5 mg of zoledronic acid in a 100-mL saline solution (n = 113) or a placebo saline solution (n = 110) at baseline and 12 months. MAIN OUTCOMES AND MEASURESThe primary outcome was absolute change in tibiofemoral cartilage volume assessed using MRI over 24 months (the minimum clinically important difference [MCID] has not been established). Three prespecified secondary outcomes were change in knee pain assessed by a visual analog scale (0 [no pain] to 100 [unbearable pain]; MCID, 15) and the Western Ontario and McMaster Universities Osteoarthritis Index (0 [no pain] to 500 [unbearable pain]; MCID, 75) over 3, 6, 12, 18, and 24 months and change in bone marrow lesion size over 6 and 24 months (the MCID has not been established). RESULTSOf 223 participants enrolled (mean age, 62.0 years [SD, 8.0 years]; 52% were female), 190 (85%) completed the trial. Change in tibiofemoral cartilage volume was not significantly different between the zoledronic acid group and the placebo group over 24 months (−878 mm 3 vs −919 mm 3 ; between-group difference, 41 mm 3 [95% CI, −79 to 161 mm 3 ]; P = .50). No significant between-group differences were found for any of the prespecified secondary outcomes, including changes in knee pain assessed by a visual analog scale (−11.5 in the zoledronic acid group vs −16.8 in the placebo group; between-group difference, 5.2 [95% CI, −2.3 to 12.8]; P = .17), changes in knee pain assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (−37.5 vs −58.0, respectively; between-group difference, 20.5 [95% CI, −11.2 to 52.2]; P = .21), and changes in bone marrow lesion size (−33 mm 2 vs −6 mm 2 ; between-group difference, −27 mm 2 [95% CI, −127 to 73 mm 2 ]; P = .60) over 24 months. Adverse events were more common with zoledronic acid than with placebo (96% vs 83%, respectively) and consisted mainly of acute reactions (defined as symptoms within 3 days of administration of infusion; 87% vs 56%).CONCLUSIONS AND RELEVANCE Among patients with symptomatic knee osteoarthritis and bone marrow lesions, yearly zoledronic acid infusions, compared with placebo, did not significantly reduce cartilage volume loss over 24 months. These finding...

Many publications with conflicting results have evaluated serum levels of copper (Cu) and zinc (Zn) in patients with rheumatoid arthritis (RA). To derive a more precise estimation of the relationship, a meta-analysis was conducted. Relevant published data were retrieved through PubMed, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Database (CBM) before September 20, 2014. Weighted mean difference (WMD) with a 95 % confidence interval (95 % CI) was calculated using STATA 11.0. A total of 26 studies, including 1444 RA cases and 1241 healthy controls, were collected in this meta-analysis. Pooled analysis found that patients with RA had a higher serum level of Cu and a lower serum Zn level than the healthy controls (Cu (μg/dl), WMD = 31.824, 95 % CI = 20.334, 43.314; Zn (μg/dl), WMD = -12.683, 95 % CI = -19.783, -5.584). Subgroup analysis showed that ethnicity had influence on the serum level of Cu (μg/dl) (Caucasian, WMD = 43.907, 95 % CI = 35.090, 52.723, P < 0.001; Asian, WMD = 14.545, 95 % CI = -12.365, 41.455, P = 0.289) and Zn (μg/dl) (Caucasian, WMD = -11.038, 95 % CI = -23.420, 1.344, P = 0.081; Asian, WMD = -14.179, 95 % CI = -18.963, -9.394, P < 0.001) in RA and healthy controls. No evidence of publication bias was observed. This meta-analysis suggests that increased serum level of Cu and decreased serum level of Zn are generally present in RA patients.

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Long non-coding RNA (lncRNA) H19 is associated with inflammatory diseases, but the molecular mechanism of H19 in the inflammatory process of ankylosing spondylitis (AS) is unclear. Here, we investigated the role of H19 and its downstream molecules in the inflammation of AS by microarray analysis, qRT-PCR, western blot, and dual-luciferase reporter assay. H19 small interfering RNA (siRNA) (Si-H19) and adenovirus (AD-H19) were used to decrease and increase H19 expression, respectively. 42 annotated lncRNAs were identified, and H19 was overexpressed. H19, vitamin D receptor (VDR), and transforming growth factor β (TGF-β) can bind to microRNA22-5p (miR22-5p) and miR675-5p. Si-H19 significantly downregulated miR22-5p and upregulated miR675-5p expression; Si-H19 decreased the protein and mRNA expression of VDR and decreased the cytokine and mRNA levels of interleukin-17A (IL-17A) and IL-23. These results were verified by AD-H19. In addition, miR22-5p and miR675-5p inhibitors increased the protein and mRNA expression of VDR and increased the cytokine and mRNA levels of IL-17A and IL-23. These results were also confirmed by miRNA mimics. Furthermore, H19 directly interfered with miR22-5p and miR675-5p expression, whereas the two miRNAs directly inhibited VDR expression. Overall, the H19-miR22-5p/miR675-5p-VDR-IL-17A/IL-23 signaling pathways have important roles in the pathogenesis of AS.

The aim of this study was to evaluate the effect of zoledronic acid (ZA) and denosumab on low back pain (LBP) and Modic change (MC) over 6 months. Adults aged ≥40 years with significant LBP for at least 6 months duration and MC (type 1, 2, or mixed) were randomized to receive ZA (5 mg/100 mL), denosumab (60 mg), or placebo. LBP was measured monthly by visual analogue scale (VAS) and the LBP Rating Scale (RS). MC was measured from MRIs of T -S vertebrae at screening and 6 months. A total of 103 participants with moderate/severe LBP (mean VAS = 57 mm; mean RS = 18) and median total MC area 538 mm were enrolled. Compared to placebo, LBP reduced significantly at 6 months in the ZA group for RS (-3.3; 95% CI, -5.9 to -0.7) but not VAS (-8.2; 95% CI, -18.8 to +2.4) with similar findings for denosumab (RS, -3.0; 95% CI, -5.7 to -0.3; VAS, -10.7; 95% CI, -21.7 to +0.2). There was little change in areal MC size overall and no difference between groups with the exception of denosumab in those with type 1 Modic change (-22.1 mm ; 95% CI, -41.5 to -2.7). In post hoc analyses, both medications significantly reduced VAS LBP in participants with milder disc degeneration and non-neuropathic pain, and denosumab reduced VAS LBP in those with type 1 MC over 6 months, compared to placebo. Adverse events were more frequent in the ZA group. These results suggests a potential therapeutic role for ZA and denosumab in MC-associated LBP. © 2018 American Society for Bone and Mineral Research.

BackgroundBisphosphonates are a class of drugs that slow bone loss and are a promising candidate to treat knee osteoarthritis (OA) patients. In a pilot study, we demonstrated that zoledronic acid reduced knee pain and size of subchondral bone marrow lesions (BMLs) over 6 months in knee OA patients with significant knee pain and BMLs. A longer, larger study is required to assess whether decreases in BML size will translate to reductions in cartilage loss over time. We are currently conducting a multicentre, randomised, double-blind, placebo-controlled trial over 24 months that aims to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change (assessed using magnetic resonance imaging (MRI)) and knee pain in knee OA patients.MethodsTwo hundred sixty-four patients with clinical knee OA, significant knee pain and subchondral BMLs present on MRI will be recruited in Hobart, Melbourne, Sydney and Adelaide. They will be randomly allocated to the two arms of the study, receiving an annual identical intravenous infusion of either 100 mL of fluid containing zoledronic acid (5 mg/100 mL) or placebo (0.9% NaCl 100 mL), at baseline and 1 year later. MRI of the study knee will be performed at screening, month 6 and 24. Knee structure, symptoms and function will be assessed using validated methods. The primary outcome is absolute change in tibiofemoral cartilage volume (mm3) over 24 months. Secondary outcomes include improvement in knee pain over 3, 6, 12, 18, and 24 months and reductions in BML size over 6 and 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses will be performed as the secondary analyses.DiscussionThis study will provide high-quality evidence to assess whether zoledronic acid has a novel disease modifying effect in OA by slowing cartilage loss and reducing pain. If zoledronic acid proves effective, it suggests great potential for cost savings through a delay or reduced need for joint replacement surgery, and potential for great improvements in quality of life for OA suffers.Trial registrationAustralian New Zealand Clinical Trials Registry: ACTRN12613000039785, registered on 14 January 2013.