Methotrexate to treat hand osteoarthritis with synovitis (METHODS): an Australian, multisite, parallel-group, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hand osteoarthritis is a disabling condition with few effective therapies. Hand osteoarthritis with synovitis is a common inflammatory phenotype associated with pain. We aimed to examine the efficacy and safety of methotrexate at 6 months in participants with hand osteoarthritis and synovitis. METHODS: In this multisite, parallel-group, double-blind, randomised, placebo-controlled trial, participants (aged 40-75 years) with hand osteoarthritis (Kellgren and Lawrence grade ≥2 in at least one joint) and MRI-detected synovitis of grade 1 or more were recruited from the community in Melbourne, Hobart, Adelaide, and Perth, Australia. Participants were randomly assigned (1:1) using block randomisation, stratified by study site and self-reported sex, to receive methotrexate 20 mg or identical placebo orally once weekly for 6 months. The primary outcome was pain reduction (measured with a 100 mm visual analogue scale; VAS) in the study hand at 6 months assessed in the intention-to-treat population. Safety outcomes were assessed in all randomly assigned participants. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000877381). FINDINGS: Between Nov 22, 2017, and Nov 8, 2021, of 202 participants who were assessed for eligibility, 97 (48%) were randomly assigned to receive methotrexate (n=50) or placebo (n=47). 68 (70%) of 97 participants were female and 29 (30%) were male. 42 (84%) of 50 participants in the methotrexate group and 40 (85%) of 47 in the placebo group provided primary outcome data. The mean change in VAS pain at 6 months was -15·2 mm (SD 24·0) in the methotrexate group and -7·7 mm (25·3) in the placebo group, with a mean between-group difference of -9·9 (95% CI -19·3 to -0·6; p=0·037) and an effect size (standardised mean difference) of 0·45 (0·03 to 0·87). Adverse events occurred in 31 (62%) of 50 participants in the methotrexate group and 28 (60%) of 47 participants in the placebo group. INTERPRETATION: Treatment of hand osteoarthritis and synovitis with 20 mg methotrexate for 6 months had a moderate but potentially clinically meaningful effect on reducing pain, providing proof of concept that methotrexate might have a role in the management of hand osteoarthritis with an inflammatory phenotype. FUNDING: National Health and Medical Research Council of Australia.

Association between knee magnetic resonance imaging markers and knee symptoms over 6-9 years in young adults.

OBJECTIVES: To describe associations between MRI markers with knee symptoms in young adults. METHODS: Knee symptoms were assessed using the WOMAC scale during the Childhood Determinants of Adult Health Knee Cartilage study (CDAH-knee; 2008-2010) and at the 6- to 9-year follow-up (CDAH-3; 2014-2019). Knee MRI scans obtained at baseline were assessed for morphological markers (cartilage volume, cartilage thickness, subchondral bone area) and structural abnormalities [cartilage defects and bone marrow lesions (BMLs)]. Univariable and multivariable (age, sex, BMI adjusted) zero-inflated Poisson (ZIP) regression models were used for analysis. RESULTS: The participants' mean age in CDAH-knee and CDAH-3 were 34.95 (s.d. 2.72) and 43.27 (s.d. 3.28) years, with 49% and 48% females, respectively. Cross-sectionally, there was a weak but significant negative association between medial femorotibial compartment (MFTC) [ratio of the mean (RoM) 0.99971084 (95% CI 0.9995525, 0.99986921), P < 0.001], lateral femorotibial compartment (LFTC) [RoM 0.99982602 (95% CI 0.99969915, 0.9999529), P = 0.007] and patellar cartilage volume [RoM 0.99981722 (95% CI 0.99965326, 0.9999811), P = 0.029] with knee symptoms. Similarly, there was a negative association between patellar cartilage volume [RoM 0.99975523 (95% CI 0.99961427, 0.99989621), P = 0.014], MFTC cartilage thickness [RoM 0.72090775 (95% CI 0.59481806, 0.87372596), P = 0.001] and knee symptoms assessed after 6-9 years. The total bone area was negatively associated with knee symptoms at baseline [RoM 0.9210485 (95% CI 0.8939677, 0.9489496), P < 0.001] and 6-9 years [RoM 0.9588811 (95% CI 0.9313379, 0.9872388), P = 0.005]. The cartilage defects and BMLs were associated with greater knee symptoms at baseline and 6-9 years. CONCLUSION: BMLs and cartilage defects were positively associated with knee symptoms, whereas cartilage volume and thickness at MFTC and total bone area were weakly and negatively associated with knee symptoms. These results suggest that the quantitative and semiquantitative MRI markers can be explored as a marker of clinical progression of OA in young adults.

Krill Oil for Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Knee osteoarthritis is disabling, with few effective treatments. Preliminary evidence suggested that krill oil supplementation improved knee pain, but effects on knee osteoarthritis remain unclear. Objective: To evaluate efficacy of krill oil supplementation, compared with placebo, on knee pain in people with knee osteoarthritis who have significant knee pain and effusion-synovitis. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled clinical trial in 5 Australian cities. Participants with clinical knee osteoarthritis, significant knee pain, and effusion-synovitis on magnetic resonance imaging were enrolled from December 2016 to June 2019; final follow-up occurred on February 7, 2020. Interventions: Participants were randomized to 2 g/d of krill oil (n = 130) or matching placebo (n = 132) for 24 weeks. Main Outcomes and Measures: The primary outcome was change in knee pain as assessed by visual analog scale (range, 0-100; 0 indicating least pain; minimum clinically important improvement = 15) over 24 weeks. Results: Of 262 participants randomized (mean age, 61.6 [SD, 9.6] years; 53% women), 222 (85%) completed the trial. Krill oil did not improve knee pain compared with placebo (mean change in VAS score, -19.9 [krill oil] vs -20.2 [placebo]; between-group mean difference, -0.3; 95% CI, -6.9 to 6.4) over 24 weeks. One or more adverse events was reported by 51% in the krill oil group (67/130) and by 54% in the placebo group (71/132). The most common adverse events were musculoskeletal and connective tissue disorders, which occurred 32 times in the krill oil group and 42 times in the placebo group, including knee pain (n = 10 with krill oil; n = 9 with placebo), lower extremity pain (n = 1 with krill oil; n = 5 with placebo), and hip pain (n = 3 with krill oil; n = 2 with placebo). Conclusions and Relevance: Among people with knee osteoarthritis who have significant knee pain and effusion-synovitis on magnetic resonance imaging, 2 g/d of daily krill oil supplementation did not improve knee pain over 24 weeks compared with placebo. These findings do not support krill oil for treating knee pain in this population. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12616000726459; Universal Trial Number: U1111-1181-7087.

Association between diet quality in adolescence and adulthood and knee symptoms in adulthood: a 25-year cohort study.

We aimed to describe associations between diet quality in adolescence and adulthood and knee symptoms in adulthood. Two hundred seventy-five participants had adolescent diet measurements, 399 had adult diet measurements and 240 had diet measurements in both time points. Diet quality was assessed by Dietary Guidelines Index (DGI), reflecting adherence to Australian Dietary Guidelines. Knee symptoms were collected using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Data were analysed using zero-inflated negative binomial regressions. The overall adolescent DGI was not associated with adult knee symptoms, although lower intake of discretionary foods (e.g. cream, alcohol, bacon and cake) in adolescence was associated with lower pain (mean ratio (MR) 0·96) and dysfunction (MR 0·94). The overall adult DGI was not associated with knee symptoms; however, limiting saturated fat was associated with lower WOMAC (Pain: MR 0·93; stiffness: MR 0·93; dysfunction: MR 0·91), drinking water was associated with lower stiffness (MR 0·90) and fruit intake was associated with lower dysfunction (MR 0·90). Higher DGI for dairy products in adulthood was associated with higher WOMAC (Pain: MR 1·07; stiffness: MR 1·13; dysfunction: MR 1·11). Additionally, the score increases from adolescence to adulthood were not associated with adult knee symptoms, except for associations between score increase in limiting saturated fat and lower stiffness (MR 0·89) and between score increase in fruit intake and lower dysfunction (MR 0·92). In conclusion, the overall diet quality in adolescence and adulthood was not associated with knee symptoms in adulthood. However, some diet components may affect later knee symptoms.

Acute and sub chronic toxicity studies with herbal pain relieving formula (Rhuleave-K™) in rats.

Rhuleave-K™ is a proprietary combination of Curcuma longa extract, Boswellia serrata extract and black sesame seed oil. Acute toxicity was evaluated as per OECD guidelines 423. Rhuleave-K™ was fed at 2000 mg/kg to overnight fasted female rats. Clinical signs of abnormality and mortality was observed daily for 14 days. Sub-chronic toxicity was studied by feeding Rhuleave-K™ at 100, 500 and 1000 mg/kg/day to rats as per OECD guidelines 408. After 90 days feeding, hematological and biochemical parameters were analyzed. Histopathology of all the major organs was also studied. In the acute toxicity study, there was no clinical sign of toxicity in any of the rats at maximum dose of 2000 mg/kg. The LD50 was computed as >2000 mg/kg in rats. The repeated dosing of Rhuleave-K™ at the maximum dose level of 1000 mg/kg for 90 days did not induce any observable toxic effects in rats, when compared to its corresponding control. The hematology and biochemistry profiles of treated rats were similar to control animals and difference was non-significant (p > 0.05). The histopathology of major organs of all the control and treated animals was normal. In this study the NOAEL for Rhuleave-K™ was calculated as 1000 mg/kg daily in rats.

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.

Prediction of the production of crops with respect to rainfall.

Agriculture is one of the most important sectors in the Indian context. It is one of the highest employing sectors in the Indian scenario. Unlike other sectors agriculture is highly dependent on the quality and the quantity of both the external factors like rainfall, climate, pH of the soil, fertilizers and insecticides used, and internal factors like the quality of seeds. This paper predicts the production of crops as a function of rainfall for four Indian States. This knowledge can be implemented in generating a rough overview of how the production is based on rainfall and how much can a specific crop production for the amount of rainfall it receives. Two crops each belonging to four different states are chosen and the best regression model for the crop of the state is chosen. There is no research done solely on how rainfall affects crops of particular states. The proposed method of evaluation is better than other existing methods of evaluation as it evaluates all the regression techniques (Linear Regression, Polynomial Regression, Support Vector Regression, Decision Tree Regression, Random Forest, and XGBRegression) for two crops of four individual states. For balanced evaluation, two states of North India and two states of South India are selected. The regression techniques are evaluated based on their Mean Squared Error.

Association between knee symptoms, change in knee symptoms over 6-9 years, and SF-6D health state utility among middle-aged Australians.

OBJECTIVES: Health state utilities (HSUs) are an input metric for estimating quality-adjusted life-years (QALY) in cost-utility analyses. Currently, there is a paucity of data on association of knee symptoms with HSUs for middle-aged populations. We aimed to describe the association of knee symptoms and change in knee symptoms with SF-6D HSUs and described the distribution of HSUs against knee symptoms' severity. METHODS: Participants (36-49-years) were selected from the third follow-up (completed 2019) of Australian Childhood Determinants of Adult Health study. SF-6D HSUs were generated from the participant-reported SF-12. Association between participant-reported WOMAC knee symptoms' severity, change in knee symptoms over 6-9 years, and HSUs were evaluated using linear regression models. RESULTS: For the cross-sectional analysis, 1,567 participants were included; mean age 43.5 years, female 54%, BMI ± SD 27.18 ± 5.31 kg/m2. Mean ± SD HSUs for normal, moderate, and severe WOMAC scores were 0.820 ± 0.120, 0.800 ± 0.120, and 0.740 ± 0.130, respectively. A significant association was observed between worsening knee symptoms and HSUs in univariable and multivariable analyses after adjustment (age and sex). HSU decrement for normal-to-severe total-WOMAC and WOMAC-pain was - 0.080 (95% CI - 0.100 to - 0.060, p < 0.01) and - 0.067 (- 0.085 to - 0.048, p < 0.01), exceeding the mean minimal clinically important difference (0.04). Increase in knee pain over 6-9 years was associated with a significant reduction in HSU. CONCLUSION: In a middle-aged population-based sample, there was an independent negative association between worse knee symptoms and SF-6D HSUs. Our findings may be used by decision-makers to define more realistic and conservative baseline and ongoing HSU values when assessing QALY changes associated with osteoarthritis interventions.

Depression in patients with knee osteoarthritis: risk factors and associations with joint symptoms.

BACKGROUND: To describe demographic and clinical factors associated with the presence and incidence of depression and explore the temporal relationship between depression and joint symptoms in patients with symptomatic knee osteoarthritis (OA). METHODS: Three hundred ninety-seven participants were selected from a randomized controlled trial in people with symptomatic knee OA and vitamin D deficiency (age 63.3 ± 7.1 year, 48.6% female). Depression severity and knee joint symptoms were assessed using the patient health questionnaire (PHQ-9) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), respectively, at baseline and 24 months. RESULTS: The presence and incidence of depression was 25.4 and 11.2%, respectively. At baseline, having younger age, a higher body mass index (BMI), greater scores of WOMAC pain (PR: 1.05, 95%CI:1.03, 1.07), dysfunction (PR: 1.02, 95%CI:1.01, 1.02) and stiffness (PR: 1.05, 95%CI: 1.02, 1.09), lower education level, having more than one comorbidity and having two or more painful body sites were significantly associated with a higher presence of depression. Over 24 months, being female, having a higher WOMAC pain (RR: 1.05, 95%CI: 1.02, 1.09) and dysfunction score (RR: 1.02, 95%CI: 1.01, 1.03) at baseline and having two or more painful sites were significantly associated with a higher incidence of depression. In contrast, baseline depression was not associated with changes in knee joint symptoms over 24 months. CONCLUSION: Knee OA risk factors and joint symptoms, along with co-existing multi-site pain are associated with the presence and development of depression. This suggests that managing common OA risk factors and joint symptoms may be important for prevention and treatment depression in patients with knee OA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01176344 . Anzctr.org.au identifier: ACTRN12610000495022 .

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.

Efficacy and safety of tocilizumab in treatment of Takayasu arteritis: A systematic review of randomized controlled trials.

BACKGROUND: Takayasu arteritis (TAK) is a chronic immune vasculitis in which Interleukin-6 (IL-6) receptors play a key role in pathogenesis. Tocilizumab (TCZ), an IL-6 receptor antagonist with a favorable safety and efficacy profile, has been tried as an option for patients with TAK. This systematic review analyzed the evidence from randomized control trials (RCT) assessing the safety and efficacy of TCZ in patients with TAK. METHODS: MEDLINE, Embase, the Cochrane Library, and clinical trial registries were searched from inception to July 2018. We included RCT assessing the efficacy and safety of TCZ versus placebo/other comparators for the treatment of patients with TAK. The risk of bias (RoB) was assessed using Cochrane RoB tool. RESULTS: 2799 identified articles were screened as per abstract and title; 42 selected full-texts articles were assessed for the potential inclusion. One trial, reported in two publications, comparing subcutaneous TCZ (162 mg/week) versus matching placebo in 36 patients with TAK was included. The relapse-free rate at 24 weeks was 50.6% and 22.9% in TCZ and placebo arm, respectively. The hazard ratio (HR) for time to first relapse was statistically significant in the per-protocol population (HR 0.34 [95.41% CI, 0.11-1.00]; p = .0345), while non-significant in the intention-to-treat population (HR 0.41 [95.41% CI, 0.15-1.10]; p = .0596). The serious adverse events were higher in the placebo arm. CONCLUSIONS: This systematic review finds the existing evidence from RCT on efficacy and safety profile of TCZ in TAK to be promising but limited. Additional evidence is required to draw a stronger conclusion.

Association of body composition, physical activity and physical performance with knee cartilage thickness and bone area in young adults.

OBJECTIVE: To describe associations of body composition, physical activity and physical performance with knee cartilage thickness and subchondral bone area in young adults. METHODS: Body composition, physical activity and physical performance were measured 4-5 years prior to knee MRI. Cartilage thickness and bone area were measured quantitatively from MRI. Associations were assessed using linear regression analysis, with mediators being identified using mediation analysis. RESULTS: Participants (n = 186) were 31-41 years of age when the MRI was acquired and 48% were female. Greater lean mass was positively associated with cartilage thickness [ß = 6.52 µm/kg (95% CI 0.86, 12.18)] and bone area [ß = 13.37 mm2/kg (95% CI 5.43, 21.31)]. Physical performance measures were positively associated with cartilage thickness [long jump: ß = 2.44 µm/cm (95% CI 0.70, 4.18); hand grip strength: 7.74 µm/kg (95% CI 1.50, 13.98); physical work capacity: 1.07 µm/W (95% CI 0.29, 1.85)] and bone area [long jump: ß = 3.99 mm2/cm (95% CI 0.64, 7.34); hand grip strength: 19.06 mm2/kg (95% CI 7.21, 30.92); leg strength: 3.18 mm2/kg (95% CI 1.09, 5.28); physical work capacity: 3.15 mm2/W (95% CI 1.70, 4.60)]. Mediation analysis suggested these associations were mediated by lean mass (effect mediated: 27-95%). CONCLUSION: Greater lean mass and better physical performance measured 4-5 years prior were associated with greater knee cartilage thickness and subchondral bone area in young adults, and the associations of physical performance were largely mediated by lean mass. These findings suggest lean mass may play an important role in maintaining knee joint health in young adults.

Thiazolidinedione use is associated with reduced risk of Parkinson's disease in patients with diabetes: a meta-analysis of real-world evidence.

BACKGROUND: The thiazolidinedione (TZD) class of oral antidiabetic agents are used to treat type 2 diabetes mellitus (DM). This meta-analysis aimed to understand the protective effect of TZD on Parkinson's disease (PD) in people with diabetes. METHOD: A literature search was performed in PubMed, Embase, and Cochrane central from inception to until 30 September 2019. We included all real-world evidence studies assessing the use of TZD class of drugs and the risk of PD in people with diabetes. Quality of the studies was evaluated using the Newcastle-Ottawa scale. The primary outcome was the pooled hazard ratio (HR) of PD among type 2 DM TZD users as compared with TZD non-users in people with diabetes. The secondary outcome was the HR of PD among type 2 DM TZD users as compared with non-users (include both diabetic and nondiabetic population). Meta-analysis was performed using RevMan software. RESULTS: Out of five studies selected for inclusion, four studies fulfilled the criteria for primary outcomes. The participants' mean age and follow-up duration were 66.23 ± 9.59 years and 5.25 years (2.97-7.9 years), respectively. There was a significant reduction in the risk of PD (pooled adjusted HR of 0.81 [95% CI 0.70-0.93, p = 0.004]) in TZD users compared with non-TZD users in people with diabetes. A significant protective effect of TZD was observed in Caucasian population (3 studies) (HR 0.78 (95% CI 0.66-0.92), p = 0.003). CONCLUSION: This meta-analysis demonstrates a potential neuroprotective effect of TZD for PD risk in the population with DM.

Effect of Intravenous Zoledronic Acid on Tibiofemoral Cartilage Volume Among Patients With Knee Osteoarthritis With Bone Marrow Lesions: A Randomized Clinical Trial.

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 Participants: A 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 Measures: The 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). Results: Of 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 mm3 vs -919 mm3; between-group difference, 41 mm3 [95% CI, -79 to 161 mm3]; 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 mm2 vs -6 mm2; between-group difference, -27 mm2 [95% CI, -127 to 73 mm2]; 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 findings do not support the use of zoledronic acid in the treatment of knee osteoarthritis. Trial Registration: anzctr.org.au Identifier: ACTRN12613000039785.

Association of adiposity measures in childhood and adulthood with knee cartilage thickness, volume and bone area in young adults.

OBJECTIVE: To describe the associations of childhood and adulthood adiposity measures with knee cartilage thickness, volume and bone area in young adults. METHODS: Childhood and adulthood adiposity measures (weight, height, waist circumference and hip circumference) of 186 participants were collected in 1985 (aged 7-15 years) and during 2004-2006 (aged 26-36 years). Knee magnetic resonance imaging was conducted during 2008-2010 (aged 31-41 years) and cartilage thickness, volume and bone area were measured using a quantitative approach (Chondrometrics, Germany). Linear regressions were used to examine the above associations. RESULTS: The prevalence of overweight was 7.6% in childhood and 42.1% in adulthood. Childhood weight (ß = - 5.57 mm2/kg) and body mass index (BMI) (ß = - 11.55 mm2/kg/m2) were negatively associated with adult patellar bone area, whereas adult weight was positively associated with bone area in medial femorotibial compartment (MFTC) (ß = 3.37 mm2/kg) and lateral femorotibial compartment (LFTC) (ß = 2.08 mm2/kg). Adult waist-hip ratio (WHR) was negatively associated with cartilage thickness (MFTC: ß = - 0.011; LFTC: ß = - 0.012 mm/0.01 unit), volume (Patella: ß = - 20.97; LFTC: ß = - 21.71 mm3/0.01 unit) and bone area (Patella: ß = - 4.39 mm2/0.01 unit). The change in WHR z-scores from childhood to adulthood was negatively associated with cartilage thickness (MFTC: ß = - 0.056 mm), volume (patella: - 89.95; LFTC: - 93.98 mm3), and bone area (patella: - 20.74 mm2). All p-values < 0.05. CONCLUSIONS: Childhood weight and BMI were negatively but adult weight was positively associated with adult bone area. Adult WHR and the change in WHR from childhood to adulthood were negatively associated with cartilage thickness, volume, and bone area. These suggest early-life adiposity measures may affect knee structures in young adults.

The Association between First Fractures Sustained during Childhood and Adulthood and Bone Measures in Young Adulthood.

OBJECTIVE: To describe the association between fractures sustained at different stages of growth and bone measures in early adulthood. STUDY DESIGN: Participants (n = 201) in southern Tasmania were at birth at a higher risk of sudden infant death syndrome; they were followed to age 25. Outcomes were areal bone mineral density at the spine, hip, and total body (by dual-energy x-ray absorptiometry) and trabecular and cortical bone measures at the radius and tibia (by high-resolution peripheral quantitative computed tomography). Fractures were self-reported and confirmed by radiographs at 8, 16, and 25 years of age. Multivariable linear regression was used to analyze the association of the occurrence of prepubertal (<9 years of age), pubertal (9-16 years of age), and postpubertal (17-25 years of age) fractures with all bone measures. RESULTS: Over 25 years, 99 participants had at least 1 fracture. For high-resolution peripheral quantitative computed tomography measures at age 25, prepubertal fractures were negatively associated with cortical and trabecular volumetric bone mineral density and most microarchitecture measures at both the tibia and radius. Prepubertal fractures had a significant association with smaller increase of areal bone mineral density from age 8 to 16 years and at 25 years of age compared with participants with no fractures. Pubertal fractures had no association with any bone measures and postpubertal fractures were only associated with a lower trabecular number at the tibia. CONCLUSIONS: Prepubertal fractures are negatively associated with areal bone mineral density increases during growth and high-resolution peripheral quantitative computed tomography bone measures in young adulthood. There is little evidence that fractures occurring from age 8 years onward with bone measures in young adulthood, implying that prepubertal fractures may be associated with bone deficits later in life.

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.

Curcumin and metformin-mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells.

Effective chemoprevention is critical for improving outcomes of oral cancer. As single agents, curcumin and metformin are reported to exhibit chemopreventive properties, in vitro as well as in patients with oral cancer. In this study, the chemopreventive efficacy of this drug combination was tested in a 4-nitro quinoline-1-oxide (4NQO) induced mice oral carcinogenesis model. Molecular analysis revealed a cancer stem cell (CSC)-driven oral carcinogenic progression in this model, wherein a progressive increase in the expression of CSC-specific markers (CD44 and CD133) was observed from 8th to 25th week, at transcript (40-100-fold) and protein levels (P ≤ 0.0001). Chemopreventive treatment of the animals at 17th week with curcumin and metformin indicated that the combination regimen decreased tumor volume when compared to the control arm (0.69+0.03 vs 6.66+2.4 mm3 ; P = 0.04) and improved overall survival of the animals (P = 0.03). Assessment of the molecular status showed an overall downregulation of CSC markers in the treatment arms as compared to the untreated control. Further, in vitro assessment of the treatment on the primary cells generated from progressive stages of 4NQO-induced mice tissue showed a concordant and consistent downregulation of the CSC markers following combination treatment (P < 0.05). The treatment also inhibited the migratory and self-renewal properties of these cells; the effect of which was prominent in the cultures of early dysplastic tissue (P < 0.002). Collectively, our observations suggest that the combination of curcumin and metformin may improve chemopreventive efficacy against oral squamous cell carcinoma through a CSC-associated mechanism.

Signal intensity alteration in the infrapatellar fat pad at baseline for the prediction of knee symptoms and structure in older adults: a cohort study.

OBJECTIVE: To describe the associations between infrapatellar fat pad (IPFP) signal intensity alteration at baseline and knee symptoms and structural changes in older adults. METHODS: A total of 874 subjects (mean 62.1 years, 50.1% female) selected randomly from local community were studied at baseline and 770 were followed up (only 357 had MRI at follow-up) over 2.6 years. T1-weighted or T2-weighted fat suppressed MRI was used to assess IPFP signal intensity alteration (0-3), cartilage volume, cartilage defects and bone marrow lesions (BMLs) at baseline and 2.6 years later. Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index questionnaire. Radiographic osteoarthritis (OA) was assessed. RESULTS: In cross-sectional analyses, IPFP signal intensity alteration was significantly and positively associated with total knee pain as well as knee cartilage defects, BMLs and knee radiographic OA and negatively associated with patellar cartilage volume after adjustment for age, sex, body mass index and/or radiographic OA. Longitudinally, baseline signal intensity alteration within IPFP was significantly and positively associated with increases in knee pain when going upstairs/downstairs as well as increases in tibiofemoral cartilage defects and BMLs, and negatively associated with change in lateral tibial cartilage volume in multivariable analyses. CONCLUSIONS: IPFP signal intensity alteration at baseline was associated with knee structural abnormalities and clinical symptoms cross-sectionally and longitudinally in older adults, suggesting that it may serve as an important imaging biomarker in knee OA.