Vitamin D plays a protective role in osteoarthritis by regulating AMPK/mTOR signalling pathway to activate chondrocyte autophagy.

OBJECTIVES: The deletion of chondrocyte autophagy seems to play a key role in the pathogenesis of osteoarthritis (OA). Patients with OA often have vitamin D (VD) deficiency, and VD supplementation can improve pain and alleviate the progression of joint structures in patients. In this study, we aimed to investigate whether VD could enhance autophagy by activating the adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signalling pathway and protect against OA. METHODS: In this study, the levels of target proteins and genes were examined by western blot and qRT-PCR. Apoptotic cells were detected using TUNEL staining. Characteristics of autophagy were observed by LysoTracker red staining, mRFP-GFP-LC3 adenovirus transfection, and transmission electron microscopy. siRNA-mediated AMPK and mTOR knockdown were used to investigate the role of the AMPK/ mTOR signalling pathway in VD-induced autophagy. Haematoxylin and eosin and safranin-O/fast green staining were used detect cartilage alterations. RESULTS: We suggested that VD significantly reduced chondrocyte death and alleviated extracellular matrix degradation. Further studies showed that VD promoted the expression of the autophagy-related protein LC3II through the AMPK/mTOR signalling pathway in chondrocytes, activated lysosome activity, promoted the formation of autophagy-associated lysosomes, which played a crucial role in the degradation of intracellular organelles and maintained homeostasis. The anti-apoptotic effect of VD on chondrocytes was associated with the activation of autophagy. The group of AMPK-normal and mTOR-knockdown in the presence of VD inhibited chondrocyte apoptosis by promoting autophagy. CONCLUSIONS: This study highlights that VD can activate chondrocyte autophagy through the AMPK/mTOR signalling pathway.

Long-term effects of vitamin D supplementation and maintaining sufficient vitamin D on knee osteoarthritis over 5 years.

OBJECTIVES: This study aimed to investigate the long-term effect of vitamin D supplementation compared to placebo over 5 years in participants with knee osteoarthritis (OA). We also aimed to describe the effect of maintaining sufficient serum vitamin D levels over five years in knee OA. METHODS: Participants (n = 173) from the Hobart centre of the Vitamin D Effects on Osteoarthritis (VIDEO) trial were extensively followed up 3 years after the cessation of 2-year investigational treatment. Participants were classified as maintaining sufficient vitamin D (n = 79) and not maintaining sufficient vitamin D (n = 61) groups. RESULTS: There was no significant difference in change in the knee symptoms, depression, and serum levels of IL6 and hs-CRP between both comparisons after 3 years of cessation of the clinical trial. However, among participants who reported no knee surgery (KS), there was a significant improvement in WOMAC function (ß: - 83.7, 95% CI: - 167.3, 0) and depression scores (ß: - 1.3, 95% CI: - 2.3, - 0.2) in vitamin D group compared to the placebo group. Similarly, those who maintained adequate vitamin D levels over 5 years had significantly less WOMAC knee pain (ß: - 33.9, 95% CI: - 65.7, - 2) and physical dysfunction (ß: - 105.5, 95% CI: - 198.2, - 12.8) than participants with vitamin D deficiency over 5 years. CONCLUSION: Vitamin D supplementation over 2 years or maintaining vitamin D sufficiency for 5 years was not associated with statistically significant differences in change in knee symptom scores over 5 years. However, among participants who did not report KS, 2-year vitamin D supplementation and maintaining sufficient vitamin D was linked to modest improvements in knee symptoms and depression scores in knee OA.

Treatment with FAP-targeted zinc ferrite nanoparticles for rheumatoid arthritis by inducing endoplasmic reticulum stress and mitochondrial damage.

Rheumatoid arthritis (RA) is a common chronic inflammatory disease characterized by the proliferation of fibroblast-like synoviocytes (FLS), pannus development, cartilage, and bone degradation, and, eventually, loss of joint function. Fibroblast activating protein (FAP) is a particular product of activated FLS and is highly prevalent in RA-derived fibroblast-like synoviocytes (RA-FLS). In this study, zinc ferrite nanoparticles (ZF-NPs) were engineered to target FAP+ (FAP positive) FLS. ZF-NPswere discovered to better target FAP+ FLS due to the surface alteration of FAP peptide and to enhance RA-FLS apoptosis by activating the endoplasmic reticulum stress (ERS) system via the PERK-ATF4-CHOP, IRE1-XBP1 pathway, and mitochondrial damage of RA-FLS. Treatment with ZF-NPs under the influence of an alternating magnetic field (AMF) can significantly amplify ERS and mitochondrial damage via the magnetocaloric effect. It was also observed in adjuvant-induced arthritis (AIA) mice that FAP-targeted ZF-NPs (FAP-ZF-NPs) could significantly suppress synovitis in vivo, inhibit synovial tissue angiogenesis, protect articular cartilage, and reduce M1 macrophage infiltration in synovium in AIA mice. Furthermore, treatment of AIA mice with FAP-ZF-NPs was found to be more promising in the presence of an AMF. These findings demonstrate the potential utility of FAP-ZF-NPs in the treatment of RA.

How can we design a proper trial for vitamin D treatment of diseases? Facts and numbers.

Vitamin D deficiency is a globally common situation and closely related with many chronic diseases. It is a hot topic to examine if vitamin D supplementation is effective for the treatment of diseases, and there have been dozens of clinical trials published in recent years. However, most studies have not proved the extra-skeletal benefits of vitamin D supplementation on these diseases. Some inherent shortcomings of these trials, such as inclusion with vitamin D-sufficient and obese participants, low response rate from participants and the insensitive changes in chosen outcomes over a shorter period, may be main reasons why most studies have yet to demonstrate effects of vitamin D supplementation. In this editorial, we aim to discuss the perspectives on how can we design a proper trial for vitamin D treatment of diseases based on the evidence-based practice framework PICOS (participants, intervention, control, outcomes and study design) in the future. First, right participants should be chosen, which is crucial for the success of vitamin D clinical trials. Participants with vitamin D sufficiency (e.g., baseline 25(OH)D of >50 nmol/L), obesity (e.g., body mass index > 30 kg/m2 ) and/or high vitamin D response index could be excluded from the trials. Second, intervention with vitamin D in right forms or dosages should be used. Vitamin D3 supplementation with appropriate dosages that keep 25(OH)D levels between 75 and 100 nmol/L is recommended. Third, 'contamination' in the control groups needs to pay attention. To diminish this, it is ideal to include participants less interfered by sun exposure (such as living in places at a high latitude) or with greater compliance (less interference by supplemental vitamin D-containing nutrients). Fourth, the outcome measures should be sensitive to change to avoid type II error. For outcomes such as bone density, radiographic osteoarthritis and cardiovascular diseases, follow-up period of 3-5 years may be required to observe the changes. Last, precision clinical trials may be the only way to prove the benefits of vitamin D supplementation.

Effect of Curcuma longa extract on serum inflammatory markers and MRI-based synovitis in knee osteoarthritis: secondary analyses from the CurKOA randomised trial.

BACKGROUND: Curcuma longa (CL) extract is modestly effective for relieving knee symptoms in knee osteoarthritis (OA) patients; however, its mechanism of action is unclear. PURPOSE: We aimed to determine the effects of CL treatment on serum inflammatory markers over 12 weeks and to explore its potential effects on synovitis assessed by contrast-enhanced magnetic resonance imaging (CE-MRI) of the knee. METHODS: Secondary analyses were conducted on the CL for knee OA (CurKOA) trial, which compared CL (n = 36) and placebo (n = 34) over 12 weeks for the treatment of knee OA. Systemic inflammatory markers (TNFα, IL6, and hsCRP) and a cartilage extracellular matrix degradative enzyme (MMP-3) were measured. A subgroup of participants (CL, n = 7; placebo, n = 5) underwent CE-MRI at baseline and a 12-week follow-up. RESULTS: Over 12 weeks, there were no between-group differences in change in hsCRP, IL-6, and TNFα levels. MMP-3 levels decreased in both CL (-1.31 ng/ml [95%CI: -1.89 to -0.73]) and placebo (-2.34 ng/ml [95%CI: -2.95 to -1.73]) groups, with the placebo group having a slightly greater decrease (1.03 ng/ml [95%CI: 0.19 to 1.88]). Most (10 of 12) sub-study participants had normal synovial thickness scores at baseline. One participant had mild synovitis in each of the placebo and CL groups. Synovitis status was stable for all except two participants, one each in the CL and placebo group, whose synovitis score increased. CONCLUSION: This is the first study that explored the effect of CL treatment on local and systemic inflammation using biochemical markers and CE-MRI outcomes on knee OA patients. Secondary analyses from this pilot study suggest that CL is unlikely to have clinically significant effects on systemic (inflammatory and cartilage) or local synovitis (CE-MRI) biomarkers compared to placebo. The mechanism of action for CL effect on pain remains unclear.

Associations Between Dietary Intake of Vitamin K and Changes in Symptomatic and Structural Changes in Patients With Knee Osteoarthritis.

OBJECTIVE: To investigate associations of dietary vitamin K intake with changes in knee symptoms and structures in patients with knee osteoarthritis (OA). METHODS: Participants with symptomatic knee OA were enrolled (n = 259) and followed up for 2 years (n = 212). Baseline dietary vitamin K intake was calculated from a validated food frequency questionnaire. Knee symptoms were assessed by using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. Knee cartilage defects, bone marrow lesions, and effusion-synovitis volume were measured from magnetic resonance imaging (MRI) scans. Univariable and multivariable linear regressions were used for analyses. RESULTS: A higher vitamin K intake quartile was significantly associated with a greater decrease in the total WOMAC score and dysfunction score over 24 months. The subgroup analyses showed in patients with severe baseline visual analog scale (VAS) pain that a higher vitamin K intake quartile was associated with more improvement in all WOMAC scores. There were no overall significant associations between vitamin K intake and changes in MRI features. In subgroup analysis, vitamin K intake was negatively associated with changes in tibiofemoral, patellar, and total cartilage defects in participants with a severe baseline radiographic grade and was negatively associated with change in total and patellar cartilage defects in participants with severe baseline VAS pain and in female patients. CONCLUSION: The association of higher vitamin K intake with decreased knee symptoms over 24 months in patients with knee OA suggests that clinical trials examining the effect of vitamin K supplementation for knee OA symptoms are warranted. Whether there is an effect on knee structure is unclear.

A Randomised Controlled Trial of YOGa and Strengthening Exercise for Knee OsteoArthritis: Protocol for a Comparative Effectiveness Trial (YOGA Trial).

Osteoarthritis (OA) is a common joint disorder for which there is no cure. Current treatments are suboptimal. Exercise is a core treatment for knee OA, with muscle strengthening exercise commonly recommended. Yoga is a mind-body exercise intervention that can improve flexibility, muscle strength, balance, and fitness and potentially reduce symptoms of OA. However, there is a scarcity of robust, high-quality conclusive evidence on the efficacy of yoga in knee OA. We are currently conducting the first randomised comparative effectiveness and cost-effectiveness trial of a yoga program compared with a strengthening exercise program in patients with symptomatic knee OA. This study protocol describes the design and conduct of this trial. The YOGA study is a phase III, single-centre, parallel, superiority, randomised, active-controlled trial which will be conducted in Hobart, Australia. One hundred and twenty-six participants (63 in each arm) aged over 40 years with symptomatic knee OA will be recruited from the community and randomly allocated to receive either a 24-week yoga program (3×/week) or a strengthening exercise program (3×/week). The primary outcome will be change in knee pain over 12 weeks, assessed using a 100 mm visual analogue scale (VAS). The secondary outcomes include change in knee pain, patient global assessment, physical function, quality of life, gait speed, biomarkers, and others over 12 and 24 weeks. We will also assess whether the presence of neuropathic pain moderates the effects of yoga compared to strengthening exercise. Additional data, such as cost and resource utilization, will be collected for the cost-effectiveness analysis. The primary analysis will be conducted using an intention-to-treat approach. Adverse events will be monitored throughout the study. Once completed, this trial will contribute to the knowledge of whether yoga can be used as a simple, effective, low-cost option for the management of knee OA, thus saving economic costs in the healthcare system.

Assessing the causal associations of obstructive sleep apnea with serum uric acid levels and gout: a bidirectional two-sample Mendelian randomization study.

OBJECTIVE: Multiple observational studies have reported the close associations of obstructive sleep apnea (OSA) with serum uric acid (SUA) levels and gout. However, the causal nature and direction remains unclear. METHODS: A bidirectional two-sample Mendelian randomization (MR) study was performed, based on publicly available genome-wide association studies (GWAS) summary statistics, to investigate whether OSA is causally related to SUA levels, gout and vice versa. The inverse-variance weighted (IVW) was used as the primary analysis approach, supplemented with four sensitive analysis methods applied to assess the robustness of the results. Moreover, multivariable MR (MVMR) was utilized to evaluate the independent causal effect of OSA on SUA and gout after adjusting for body mass index (BMI), hypertension, type 2 diabetes (T2D), coronary artery disease (CAD), and chronic kidney disease (CKD). RESULTS: Genetically predicted OSA liability was significantly associated with increased levels of SUA (IVW method: ß = 0.19, 95% CI = 0.11 - 0.26, P = 7.24 × 10-7) and risk of gout [IVW method: odds ratio (OR) = 1.75 95% CI = 1.13 - 2.69, P = 0.01] in univariable MR. The MVMR results suggested that OSA retained its significant association with increased SUA levels, whereas the significant association between OSA and gout was attenuated to null after adjusting for BMI and T2D. No causal effect of OSA on SUA levels and gout was found in the reverse direction. CONCLUSIONS: Our findings suggest that OSA was causally associated with increased levels of SUA, but was not independently associated with gout risk.

Highly effective rheumatoid arthritis therapy by peptide-promoted nanomodification of mesenchymal stem cells.

Traditional medication is not satisfied in rheumatoid arthritis (RA) therapy due to its long-term side effects and failure in cartilage repair. Nanomodification of mesenchymal stem cells (MSCs) holds promise for lifting such hurdles but delivering therapeutic nanomaterials (NPs) into MSCs remains challenging in this new strategy. Here, we show that CuS@MnO2 NPs functionalized with a short phage-selected MSC-targeting peptide enabled the NPs to be uptaken by MSCs. The resultant NP-modified MSCs, further loaded with metformin, significantly improved stem cell therapy of RA. Specifically, the NP-modified MSCs survived the RA-associated oxidized stress through regulating the stress by the superoxide dismutase (SOD)- and catalase (CAT)-like activity of the NPs. They also exhibited an increased capability of cell migration, anti-inflammation, and chondrogenesis due to the nanomodification, thereby effectively inhibiting synovial inflammation and reducing cartilage erosion to relieve RA symptoms in two rat models 28 days post intravenous injection. Our peptide-promoted NP-modified MSCs may be used to enhance therapeutic effects in treating not only RA but also other degenerative and inflammatory diseases.

Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases.

INTRODUCTION: Autoimmune diseases (ADs) are disorders induced by multiple inflammatory mediators, in which immune system attacks healthy tissues and triggers tissue injury. Targeted regulation of the activity of kinases that influence inflammation is one of the major therapies for ADs. Recently, investigational spleen tyrosine kinase (SYK) inhibitors have shown encouraging results in the AD therapy. AREAS COVERED: This article provides a background on autoimmune diseases and provides an update on investigational SYK inhibitors. This literature review was conducted by searching publications about investigational SYK inhibitors in the treatment of ADs from experimental to clinical studies. The search terms used were SYK inhibitors, R406, fostamatinib (R788), P505-15 (PRT062607), entospletinib (GS-9973), R112, lanraplenib (GS-9876), cerdulatinib, R343, BAY-61-3606, GSK compound 143 (GSK143), R211, SKI-G-618, SKI-O-85, ER-27319, YM193306, RO9021 in conjunction with autoimmune disease using electronic databases including PubMed, EMBASE, MEDLINE and Google Scholar. EXPERT OPINION: SYK inhibitors are promising drugs with unique advantages and acceptable tolerability and safety for the treatment of ADs. However, the difficulties in developing highly selective SYK inhibitors and the unknown effects are challenges. Long-term and real-world data are essential to determine the risk-benefit ratio and true role of SYK inhibitors in the therapy of ADs.

Associations of blood pressure and arterial stiffness with knee cartilage volume in patients with knee osteoarthritis.

OBJECTIVE: To describe the associations of blood pressure and arterial stiffness with knee cartilage volume in patients with knee OA. METHODS: A secondary analysis was performed on the data from participants in a randomized controlled trial that identified the effects of vitamin D supplementation on knee structures and symptoms among patients with symptomatic knee OA. Brachial and central blood pressure, arterial stiffness indicators and knee cartilage volume were measured at baseline and the 2 year follow-up. Associations were assessed using generalized estimating equations. RESULTS: Among 231 participants (average age 63.2 years), 48.9% were females. Higher supine systolic and diastolic pressures were significantly associated with lower tibial cartilage volume (systolic: lateral ß -6.23, medial ß -5.14, total ß -11.35 mm3/mmHg; diastolic: lateral ß -10.25, medial ß -11.29, total ß -21.50 mm3/mmHg). Higher supine systolic pressure was associated with lower femoral cartilage volume (lateral ß -17.35, total ß -28.31 mm3/mmHg). Central systolic pressure and arterial stiffness indicators (including pulse wave velocity, central pulse pressure and peripheral pulse pressure) were largely not associated with knee cartilage volume; however, higher augmentation index was associated with lower tibial and femoral cartilage volume (tibial: medial ß -8.24, total ß -19.13 mm3/%; femoral: lateral ß -23.70, medial ß -26.42, total ß -50.12 mm3/%). CONCLUSIONS: Blood pressure and arterial stiffness are associated with knee cartilage volume at several sites in knee OA patients. This supports that blood pressure and arterial stiffness may involve in the progression of knee OA.

Efficacy and Safety of Turmeric Extracts for the Treatment of Knee Osteoarthritis: a Systematic Review and Meta-analysis of Randomised Controlled Trials.

PURPOSE OF THE REVIEW: Finding appropriate pharmacological options to treat osteoarthritis (OA) remain challenging. We aimed to determine the efficacy and safety of all types of turmeric extracts for the management of knee OA. RECENT FINDINGS: Sixteen RCTs of up to 16 weeks duration including 1810 adults with knee OA were included. Eleven RCTs compared the efficacy of turmeric extracts with placebo and five with active comparators (NSAIDs). The overall risk bias of included RCTs was moderate. Turmeric extracts significantly reduced knee pain (SMD - 0.82, 95% CI - 1.17 to - 0.47, I2 = 86.23%) and improved physical function (SMD - 0.75, 95% CI - 1.18 to - 0.33, I2 = 90.05%) compared to placebo but had similar effects compared to NSAIDs. BMI was the major contributor to heterogeneity in the placebo-controlled studies (explained 37.68% and 67.24%, respectively, in the models) and modified the effects of the turmeric on pain and physical function with less improvement with higher BMI (SMD 0.26 95% CI 0.04 to 0.48; SMD 0.48 95% CI 0.21 to 0.74). No significant between-group differences were reported for either biochemical markers or imaging outcomes. Turmeric extracts had 12% fewer adverse events than NSAIDs and similar rates to placebo. Turmeric extract is a safe and effective option for the symptomatic management of knee OA, compared to placebo or NSAIDs. However, current evidence from short-term studies is heterogeneous and has moderate risk of bias leading to some uncertainty about the true effect.

Effects of Vitamin D Supplementation on Disabling Foot Pain in Patients With Symptomatic Knee Osteoarthritis.

OBJECTIVE: The present study was undertaken to determine whether vitamin D supplementation or maintaining sufficient vitamin D level reduces foot pain over 2 years in patients with symptomatic knee osteoarthritis (OA). METHODS: A post hoc study was conducted from a randomized, double-blind, placebo-controlled trial named the Vitamin D Effect on Osteoarthritis (VIDEO) study. Symptomatic knee OA patients with serum 25-hydroxyvitamin D levels between 12.5 nmoles/liter and 60 nmoles/liter were included and randomly allocated to either monthly vitamin D3 or placebo treatment (1:1) for 2 years. Manchester Foot Pain and Disability Index (MFPDI) was used to evaluate foot pain and disabling foot pain was defined as at least 1 of the 10 functional limitation items (items 1-9 and 11) being documented as on "most/every day(s)" in the last month. A repeated-measures, mixed-effects model was used to analyze the change of MFPDI scores between groups adjusting for potential confounders. RESULTS: A total of 413 patients with a mean age of 63.2 years (49.7% males) were enrolled and 340 completed the study. The mean MFPDI score was 22.8 ± 7.3, with 23.7% of participants having disabling foot pain at baseline. There were significant differences in MFPDI scores change between groups over 2 years, with more improvements in the vitamin D group than in the placebo group (-0.03 versus 1.30; P = 0.013) and more improvement in those maintaining sufficient vitamin D levels (n = 226) than those who did not (n = 114) (-0.09 versus 2.19; P = 0.001). CONCLUSION: Vitamin D supplementation and maintenance of sufficient vitamin D levels may improve foot pain in those with knee OA.

Effectiveness of Curcuma longa Extract for the Treatment of Symptoms and Effusion-Synovitis of Knee Osteoarthritis : A Randomized Trial.

BACKGROUND: Current pharmacologic therapies for patients with osteoarthritis are suboptimal. OBJECTIVE: To determine the efficacy of Curcuma longa extract (CL) for reducing knee symptoms and effusion-synovitis in patients with symptomatic knee osteoarthritis and knee effusion-synovitis. DESIGN: Randomized, double-blind, placebo-controlled trial. (Australian New Zealand Clinical Trials Registry: ACTRN12618000080224). SETTING: Single-center study with patients from southern Tasmania, Australia. PARTICIPANTS: 70 participants with symptomatic knee osteoarthritis and ultrasonography-defined effusion-synovitis. INTERVENTION: 2 capsules of CL (n = 36) or matched placebo (n = 34) per day for 12 weeks. MEASUREMENTS: The 2 primary outcomes were changes in knee pain on a visual analogue scale (VAS) and effusion-synovitis volume on magnetic resonance imaging (MRI). The key secondary outcomes were change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and cartilage composition values. Outcomes were assessed over 12 weeks. RESULTS: CL improved VAS pain compared with placebo by -9.1 mm (95% CI, -17.8 to -0.4 mm [P = 0.039]) but did not change effusion-synovitis volume (3.2 mL [CI, -0.3 to 6.8 mL]). CL also improved WOMAC knee pain (-47.2 mm [CI, -81.2 to -13.2 mm]; P = 0.006) but not lateral femoral cartilage T2 relaxation time (-0.4 ms [CI, -1.1 to 0.3 ms]). The incidence of adverse events was similar in the CL (n = 14 [39%]) and placebo (n = 18 [53%]) groups (P = 0.16); 2 events in the CL group and 5 in the placebo group may have been treatment related. LIMITATION: Modest sample size and short duration. CONCLUSION: CL was more effective than placebo for knee pain but did not affect knee effusion-synovitis or cartilage composition. Multicenter trials with larger sample sizes are needed to assess the clinical significance of these findings. PRIMARY FUNDING SOURCE: University of Tasmania and Natural Remedies Private Limited.

Effect of vitamin D supplementation on pain and physical function in patients with knee osteoarthritis (OA): an OA Trial Bank protocol for a systematic review and individual patient data (IPD) meta-analysis.

INTRODUCTION: Observational data suggest that vitamin D deficiency is associated with the onset and progression of knee osteoarthritis (OA). However, randomised controlled trials (RCTs) to date investigating the efficacy of vitamin D supplementation in knee OA have reported conflicting results. Further research is needed to clarify the effects of vitamin D on patient-reported outcomes and determine whether there are patient subgroups who may benefit from the supplementation. The aim of this individual patient data (IPD) meta-analysis is to identify patient-level predictors of treatment response to vitamin D supplementation on pain and physical function. METHODS AND ANALYSIS: A systematic literature search will be conducted for RCTs of vitamin D supplementation on knee OA. Authors of original RCTs will be contacted to obtain the IPD. The primary outcomes will include long-term (≥12 months) pain and physical function. Secondary outcomes will include medium-term (≥6 months and <12 months) and short-term (<6 months) pain and physical function, as well as patient global assessment, quality of life and adverse events. Potential treatment effect modifiers to be examined in the subgroup analyses include age, gender, body mass index, baseline knee pain severity and physical function, baseline vitamin D level, radiographic stage, presence of bone marrow lesions on MRI, presence of clinical signs of local inflammation and concomitant depressive symptoms. Both one-step and two-step modelling methods will be used to determine the possible modifiable effect of each subgroup of interest. ETHICS AND DISSEMINATION: Research ethical or governance approval is exempt for this study as no new data are being collected. This study will be the first IPD meta-analysis to clarify the effect of vitamin D supplementation on clinical symptoms in different subgroups of patients with knee OA. The findings will be disseminated through peer-review publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42018107740.

Effect of Vitamin D Supplementation on Depressive Symptoms in Patients With Knee Osteoarthritis.

OBJECTIVES: To determine the effect of vitamin D supplementation and maintaining sufficient serum vitamin D on depressive symptoms in patients with knee osteoarthritis (OA) and vitamin D deficiency. DESIGN: A prespecified secondary analysis of a multicentre, randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to receive oral vitamin D3 (50,000 IU, n = 209) or placebo (n = 204) monthly for 24 months. In addition, participants who completed the trial were classified into 2 groups according to their serum 25(OH)D levels at month 3 and 24 as follows: not consistently sufficient (serum 25(OH)D ≤ 50 nmol/L at month 3 and/or 24), and consistently sufficient (serum 25(OH)D > 50 nmol/L at both month 3 and 24). Multilevel mixed-effect models were used to compare differences of change in PHQ-9 scores between groups. SETTING AND PARTICIPANTS: This clinical trial was conducted in participants with symptomatic knee OA and vitamin D deficiency from June 2010 to December 2013 in Tasmania and Victoria, Australia. MEASURES: The primary outcome was the depressive symptoms change over 24 months, which was measured using the Patient Health Questionnaire (PHQ-9, 0-27). RESULTS: Of 599 participants who were screened for eligibility, 413 participants were enrolled (mean age: 63.2 years; 50.3% female) and 340 participants (intervention n = 181, placebo n = 159, 82.3% retention rate) completed the study. The baseline prevalence of depression (PHQ-9 score ≥5) was 25.4%. Depressive symptoms improved more in the vitamin D supplementation group compared to the placebo group [ß: -0.66, 95% confidence interval (CI): -1.22 to -0.11, P for difference = .02] and in the participants who maintained vitamin D sufficiency compared to those who did not (ß: -0.73, 95% CI: -1.41 to -0.05, P for difference = .04) over 24 months. CONCLUSIONS/IMPLICATIONS: These findings suggest that vitamin D supplementation and maintaining adequate vitamin D levels over 24 months may be beneficial for depressive symptoms in patients with knee OA.

Vitamin D supplements for trunk muscle morphology in older adults: secondary analysis of a randomized controlled trial.

BACKGROUND: The effect of vitamin D supplementation on postural muscles of the trunk is of particular interest because low 25-hydroxyvitamin D [25(OH) D] levels are associated with decreased postural balance and increased risk of falls. Understanding the role of vitamin D supplementation plays in trunk muscle function of older adults is necessary, as this is a potentially modifiable factor to improve postural muscle function and decrease the risk of falling of older adults. The objective of this randomized controlled trial was to evaluate the effect of 12 months of vitamin D supplementation compared with placebo, on morphology and function of the trunk muscles of adults aged 50 to 79 years with low serum 25(OH) D levels. METHODS: This was a secondary analysis of a randomized, placebo-controlled, and double-blind clinical trial conducted between June 2010 and December 2013 in Tasmania, Australia. The clinical trial was registered with the Australian New Zealand clinical trial registration agency, ClinicalTrials.gov identifier: NCT01176344; Australian New Zealand Clinical Trials Registry: ACTRN 12610000495022. Participants were aged 50-79 years with ongoing symptoms of knee osteoarthritis and with low serum [25(OH) D] (12.5 to 60 nmol/L, 5.2 to 24 ng/mL). Participants were randomly assigned to either monthly 50 000 IU oral vitamin D3 (n = 104) or an identical placebo (n = 113) for 24 months as per clinical trial protocol. The primary outcomes in this pre-specified secondary analysis were between-group differences in change in size of rectus abdominis, transversus abdominis, internal oblique, external oblique, and lumbar multifidus muscles and function (assessed by change in thickness on contraction) of these muscles (excepting rectus abdominis) from baseline to 12 months. Muscle size was assessed using ultrasound imaging. RESULTS: Of 217 participants (mean age 63 years, 48% women), 186 (85.7%) completed the study. There were no significant between-group differences in change in size or function of the abdominal or multifidus muscles after 12 months of vitamin D supplementation. CONCLUSIONS: A monthly dose of 50 000 IU of vitamin D3 alone for 12 months does not affect the size or ability to contract trunk muscles of independent community-dwelling older adults with symptomatic knee osteoarthritis and low serum 25(OH) D levels regardless of body mass index status or degree of vitamin D deficiency. An effect of vitamin D supplementation on other aspects of trunk muscle function such as strength, power, or physical function cannot be ruled out.

Vitamin D supplementation and inflammatory and metabolic biomarkers in patients with knee osteoarthritis: post hoc analysis of a randomised controlled trial.

The aim of this study was to determine whether vitamin D supplementation and maintaining vitamin D sufficiency are associated with changes in inflammatory and metabolic biomarkers in patients with knee osteoarthritis (OA) and vitamin D deficiency. A total of 413 participants with symptomatic knee OA and vitamin D deficiency were enrolled in a randomised, placebo-controlled trial and received 1·25 mg vitamin D3 or placebo monthly for 24 months across two sites. In this post hoc analysis, 200 participants from one site (ninety-four from the placebo group and 106 from the vitamin D group; mean age 63·1 (sd 7·3) years, 53·3 % women) were randomly selected for measurement of serum levels of inflammatory and metabolic biomarkers at baseline and 24 months using immunoassays. In addition, participants were classified into two groups according to serum 25-hydroxyvitamin D (25(OH)D) levels at months 3 and 24: (1) not consistently sufficient (25(OH)D≤50 nmol/l at either month 3 or 24, n 61), and (2) consistently sufficient (25(OH)D>50 nmol/l at both months 3 and 24, n 139). Compared with placebo, vitamin D supplementation had no significant effect on change in serum high-sensitive C-reactive protein, IL-6, IL-8, IL-10, leptin, adiponectin, resistin, adipsin and apelin. Being consistently vitamin D sufficient over 2 years was also not associated with changes in these biomarkers compared with not being consistently sufficient. Vitamin D supplementation and maintaining vitamin D sufficiency did not alter serum levels of inflammatory and metabolic biomarkers over 2 years in knee OA patients who were vitamin D insufficient, suggesting that they may not affect systemic inflammation in knee OA patients.