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To evaluate the preferences of patients with osteoarthritis for treatment. A discrete-choice experiment was conducted among adult OA patients who were presented with 12 choice sets of two treatment options and asked in each to select the treatment they would prefer. Based on literature reviews, expert consultation, patient survey and expert meeting, treatment options were characterized by seven attributes: improvement in pain, improvement in walking, ability to manage domestic activities, ability to manage social activities, improvement in overall energy and well-being, risk of moderate/severe side effects and impact on disease progression. Random parameters logit model was used to estimate patients' preferences and a latent class model was conducted to explore preferences classes. 253 OA patients from seven European countries were included (74% women; mean age 71.3 years). For all seven treatment attributes, significant differences were observed between levels. Given the range of levels of each attribute, the most important treatment attribute in this group was impact on disease progression (29.5%) followed by walking improvement (17.1%) and pain improvement (16.3%). The latent class model identified two preference classes. In the first class (probability of 56%), patients valued impact of disease progression the most (39%). In the second class, walking improvement and improvement in overall energy and well-being were the most important (23%). This study suggests that all seven treatment attributes were important for OA patients. Overall, given the range of levels, the most important outcomes were impact on disease progression and improvement in pain and walking. [ABSTRACT FROM AUTHOR]

The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) sought to revisit the 2014 algorithm recommendations for knee osteoarthritis (OA), in light of recent efficacy and safety evidence, in order to develop an updated stepwise algorithm that provides practical guidance for the prescribing physician that is applicable in Europe and internationally. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process, a summary of evidence document for each intervention in OA was provided to all members of an ESCEO working group, who were required to evaluate and vote on the strength of recommendation for each intervention. Based on the evidence collected, and on the strength of recommendations afforded by consensus of the working group, the final algorithm was constructed. An algorithm for management of knee OA comprising a stepwise approach and incorporating consensus on 15 treatment recommendations was prepared by the ESCEO working group. Both "strong" and "weak" recommendations were afforded to different interventions. The algorithm highlights the continued importance of non-pharmacological interventions throughout the management of OA. Benefits and limitations of different pharmacological treatments are explored in this article, with particular emphasis on safety issues highlighted by recent literature analyses. The updated ESCEO stepwise algorithm, developed by consensus from clinical experts in OA and informed by available evidence for the benefits and harms of various treatments, provides practical, current guidance that will enable clinicians to deliver patient-centric care in OA practice. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) and osteoarthritis (OA) are common diseases that frequently co-exist, along with overweight/obesity. While the mechanical impact of excess body weight on joints may explain lower limb OA, we sought to explore whether T2DM is linked to OA outside of excess weight and whether T2DM may play a role in OA pathophysiology. The consequence of T2DM on OA outcomes is a question of research interest. We conducted a critical review of the literature to explore the association between T2DM and OA, whether any association is site-specific for OA, and whether the presence of T2DM impacts on OA outcomes. We also reviewed the literature to assess the safety of anti-OA treatments in patients with T2DM. T2DM has a pathogenic effect on OA through 2 major pathways involving oxidative stress and low-grade chronic inflammation resulting from chronic hyperglycemia and insulin resistance. T2DM is a risk factor for OA progression and has a negative impact on arthroplasty outcomes. Evidence is mounting for safety concerns with some of the most frequently prescribed anti-OA medications, including paracetamol, non-steroidal anti-inflammatory drugs, and corticosteroid injections, while other anti-OA medications may be safely prescribed in OA patients with T2DM, such as glucosamine and intra-articular hyaluronic acid. Future research is needed to better understand whether diabetes control and prevention can modulate OA occurrence and progression. The selection of therapy to treat OA symptoms in patients with T2DM may require careful consideration of the evidence based to avoid untoward safety issues. [ABSTRACT FROM AUTHOR]

Objectives To gather expert opinion on the conduct of clinical trials that will facilitate regulatory review and approval of appropriate efficacious pharmacological treatments for hand osteoarthritis (OA), an area of high unmet clinical need. Methods The European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO) organized a working group under the auspices of the International Osteoporosis Foundation (IOF) and the World Health Organization (WHO). Results This consensus guideline is intended to provide a reference tool for practice, and should allow for better standardization of the conduct of clinical trials in hand OA. Hand OA is a heterogeneous disease affecting different, and often multiple, joints of the thumb and fingers. It was recognized that the various phenotypes and limitations of diagnostic criteria may make the results of hand OA trials difficult to interpret. Nonetheless, practical recommendations for the conduct of clinical trials of both symptom and structure modifying drugs are outlined in this consensus statement, including guidance on study design, execution, and analysis. Conclusions While the working group acknowledges that the methodology for performing clinical trials in hand OA will evolve as knowledge of the disease increases, it is hoped that this guidance will support the development of new pharmacological treatments targeting hand OA. [ABSTRACT FROM AUTHOR]

Objective: Evaluation of the efficacy and safety of a single oral dose of a 1200 mg sachet of chondroitin 4&6 sulfate (CS 1200) vs three daily capsules of chondroitin 4&6 sulfate 400 mg (CS 3*400) (equivalence study) and vs placebo (superiority study) during 3 months, in patients with knee osteoarthritis (OA).Design: Comparative, double-blind, randomized, multicenter study, including 353 patients of both genders over 45 years with knee OA. Minimum inclusion criteria were a Lequesne index (LI) ≥ 7 and pain ≥ 40 mm on a visual analogue scale (VAS). LI and VAS were assessed at baseline and after 1-3 months. Equivalence between CS was tested using the per-protocol procedure and superiority of CS vs placebo was tested using an intent-to-treat procedure.Results: After 3 months of follow-up, no significant difference was demonstrated between the oral daily single dose of CS 1200 formulation and the three daily capsules of CS 400. Patients treated with CS 1200 or CS 3*400 were significantly improved compared to placebo after 3 months of follow-up in terms of LI (<0.001) and VAS (P < 0.01). No significant difference in terms of security and tolerability was observed between the three groups.Conclusion: This study suggests that a daily administration of an oral sachet of 1200 mg of chondroitin 4&6 sulfate allows a significant clinical improvement compared to a placebo, and a similar improvement when compared to a regimen of three daily capsules of 400 mg of the same active ingredient. [ABSTRACT FROM AUTHOR]

Objective: Knee osteoarthritis is a major cause of disability and pain. This phase III, double-blind (patient and observer blinded,) multicenter, randomized, non-inferiority study was conducted to demonstrate the non-inferiority of the highly purified intra-articular injection of hyaluronic acid (Sinovial(®)) in comparison to Hylan G-F20 (Synvisc(®)) in the treatment of knee osteoarthritis.Methods: A total of 381 patients were randomly assigned to receive either the test drug, 16 mg/2 ml (0.8%) highly purified ia hyaluronic acid of biofermentative origin (Sinovial(®)), or the comparative drug, 16 mg/2 ml of 0.8% hylan G-F20 (Synvisc(®)). The duration of the treatment was 2 weeks (three injections at 1-week interval), followed by an observation period of 6 months. The primary efficacy variable was the improvement in mean Western Ontario and McMaster Universities (WOMAC) pain subscore from baseline to the final visit (week 26), compared between the two treatment groups. The acceptable margin for non-inferiority was chosen to be 8 mm.Results: At week 26, WOMAC pain subscores decreased by a mean of 32.5 for both Sinovial(®) and Synvisc(®). These results met prespecified criteria for non-inferiority for both the Intent-to-Treat and Per-Protocol populations. There were no statistically significant differences between groups at 26 weeks, although Sinovial(®)-treated patients tended to have a slightly better outcome for select variables, as they did at earlier time-points, some of which reached statistical significance. Both hyaluronic acid preparations were well-tolerated, with no statistically significant differences in tolerability profile between groups.Conclusion: Sinovial(®) and Synvisc(®) treatments were found to be equivalent, both in terms of efficacy and safety.Clinical Trial Number: NCT00556608 (ClinicalTrials.gov Identifier). [ABSTRACT FROM AUTHOR]

Summary: Objective: Knee osteoarthritis is a major cause of disability and pain. This phase III, double-blind (patient and observer blinded,) multicenter, randomized, non-inferiority study was conducted to demonstrate the non-inferiority of the highly purified intra-articular injection of hyaluronic acid (Sinovial®) in comparison to Hylan G-F20 (Synvisc®) in the treatment of knee osteoarthritis. Methods: A total of 381 patients were randomly assigned to receive either the test drug, 16mg/2ml (0.8%) highly purified ia hyaluronic acid of biofermentative origin (Sinovial®), or the comparative drug, 16mg/2ml of 0.8% hylan G-F20 (Synvisc®). The duration of the treatment was 2weeks (three injections at 1-week interval), followed by an observation period of 6months. The primary efficacy variable was the improvement in mean Western Ontario and McMaster Universities (WOMAC) pain subscore from baseline to the final visit (week 26), compared between the two treatment groups. The acceptable margin for non-inferiority was chosen to be 8mm. Results: At week 26, WOMAC pain subscores decreased by a mean of 32.5 for both Sinovial® and Synvisc®. These results met prespecified criteria for non-inferiority for both the Intent-to-Treat and Per-Protocol populations. There were no statistically significant differences between groups at 26weeks, although Sinovial®-treated patients tended to have a slightly better outcome for select variables, as they did at earlier time-points, some of which reached statistical significance. Both hyaluronic acid preparations were well-tolerated, with no statistically significant differences in tolerability profile between groups. Conclusion: Sinovial® and Synvisc® treatments were found to be equivalent, both in terms of efficacy and safety. Clinical Trial Number: NCT00556608 (ClinicalTrials.gov Identifier). [ABSTRACT FROM AUTHOR]

Abstract: Knols RH, de Bruin ED, Aufdemkampe G, Uebelhart D, Aaronson NK. Reliability of ambulatory walking activity in patients with hematologic malignancies. Objectives: To determine the relative and absolute reliability of the assessment of ambulatory walking activity during 2 consecutive weeks in patients with hematologic malignancies recovering at home from their medical treatment and to compare the physical activity level of hematologic cancer patients after high-dose chemotherapy with healthy subjects. Design: Test-retest study of 2 consecutive 7-day recordings using the microprocessor-based step accelerometer 3 (SAM3). Setting: Home and community. Participants: Patients (n=23) with hematologic malignancies recovering from high-dose chemotherapy and healthy controls (n=30). Interventions: Not applicable. Main Outcome Measures: The intraclass correlation coefficient (ICC3,1) and its 95% confidence interval (CI), SE of measurement procedure and its 95% CI, the smallest detectable difference (SDD), the coefficient of variation (CV), and t tests for the variables total steps and peak activity. Results: The day-to-day and week-to-week CVs for walking activity and peak activity were 35.17% and 13.17% and 18.61% and 6.90%, respectively. For relative reliability, the ICCs for 2 consecutive 7-day recordings including the 95% CI for total steps and peak activity were 0.90 (95% CI, 0.75–0.98) and 0.85 (95% CI, 0.66–0.94), respectively. The absolute reliability for total steps and peak activity including the SE of measurement procedure and the 95% CI were 564 (95% CI, ±1106) and 2.42 steps (95% CI, ±4.74), respectively, for 2 consecutive 7-day recordings. The week-to-week SDD was 1564 for total steps and 6.70 for peak activity. The 7-day mean for total step activity was 5355 for the patients with hematologic malignancies and 6364 for healthy subjects (P<0.05). Conclusions: The results of this study indicate that there is good relative reliability for the assessment of 2 consecutive 7-day recordings of ambulatory walking activity, and it showed that the SDD derived from this sample may be useful in detecting changes in daily walking activity in hematologic cancer patients who are recovering from intensive medical treatment. The study also documented compromised levels of ambulatory walking activity among hematologic cancer patients recovering from high-dose chemotherapy as compared with healthy controls. [Copyright &y& Elsevier]

BackgroundDietary calcium and proteins are important determinants of bone health. Among the various methods to evaluate dietary intakes, food frequency questionnaires provide a self-administered, quick and simple estimation of dietary intakes.ObjectivesTo validate a simple, rapid, self-administered food frequency questionnaire for the estimation of dietary protein intake.Design and methodsA self-administrable food frequency questionnaire comprising 20 items was developed. The accuracy of dietary protein evaluation by this questionnaire was verified by comparing it to the results of a diary performed over a 4-day-period in 29 normal healthy subjects (mean age+/-SD, 40.1+/-12.3), and to the mean of three last 24-h recalls, administered at 6-week intervals in 43 healthy men (mean age+/-SD, 51.2+/-5.1).ResultsAs compared with the values from both reference methods, the slope coefficient of linear regression analysis was statistically different from zero, but the percent of variance explained by the frequency questionnaire results amounted to 35% (diary) and 18% (24-h recall), respectively. Bland and Altman graphs as well as the Pitman's test did not show any difference in variability between the reference methods and the new food frequency questionnaire. This indicates a reliable estimate of group average dietary protein intakes.ConclusionThis rapid, self-administered food frequency questionnaire could be a useful tool for the evaluation of dietary protein intakes in groups of subjects. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) of the knee is common in the aging population. In patients with OA, bone mineral density (BMD) is usually increased, but the fracture rate does not appear to be systematically lower than in age-matched healthy controls. The aim of our study was to describe hip BMD in patients presenting with unilateral symptomatic knee OA. Patients with painful knee OA were prospectively included in a single-center, randomized, double-blind, placebocontrolled clinical trial to evaluate the structure-modifying efficacy of an oral chondroitin sulfate treatment on the knee joint. The majority of these patients underwent additional measurements of BMD of their lumbar spine and both hips using dual-energy X-ray absorptiometry (DXA). The hip BMD values of the leg with symptomatic knee OA were compared with the contralateral hip. One-hundred and sixty-one patients (81 men and 80 women; aged 62.6 ± 9.2 yr, range 40-82 yr) underwent DXA. The median total hip BMD was higher than in age-matched controls, but patients had a relatively lower hip BMD in the knee OA-affected leg (p = 0.001). Our knee OA patients rarely presented with concomitant osteoporosis, but usually had a relatively lower hip BMD on the affected leg. Therefore, we suggest that the hip of the leg with symptomatic knee OA should be measured if DXA is acquired only at one hip. Future studies have to assess whether the relative decrease of BMD at the hip of the leg with knee OA might influence fracture incidence. [ABSTRACT FROM AUTHOR]

Summary: Symptomatic slow-acting drugs for the treatment of osteoarthritis (SYSADOA; OA) are compounds which are prescribed as drugs in European countries since many years, whereas they are sold as nutraceuticals in USA. In Europe, the publication of the EULAR Recommendations for the Treatment of Knee OA in 2003 has listed oral chondroitin sulfate (CS) as evidence 1A and strength of recommendation A which represents the highest level for a therapeutic strategy. Symptomatic slow-acting drugs are intended to be used as ground therapy for OA; these compounds are not rapidly acting agents such as Non Steroidal Anti-Inflammatory Drugs (NSAIDs), and their clinical efficacy on algo-functional symptoms can only be demonstrated after a couple of weeks of regular intake. Interestingly, once the administration is stopped, they do show carry-over effects of various durations, from about 3 months with the oral formulations to 6–9 months with intra-articular formulations. The main rationale behind the use of the SYSADOA therapeutic class is the reduction of NSAIDs in the overall drug management of OA disease and therefore consequently to limit the very significant risks of upper Gastro-intestinal (GI) tract erosions, ulcers with bleeding and/or deleterious renal effects in elderly patients. The evidence for clinical efficacy of oral CS as a drug able to significantly improve the algo-functional symptoms of OA disease does come from a set of randomized clinical studies published a couple of years ago. Indeed, it was demonstrated that the drug was effective in knee and finger OA, whereas previous data suggested that hip OA patients could also benefit from it. In addition, oral CS supported the comparison with NSAIDs such as diclofenac sodium in a medium/long-term clinical study in patients with knee OA. A dose-finding study in patients with knee OA did provide strong data supporting the administration of 800mg of CS orally which had nearly the same effects as 1200mg/day, whereas the use of a sequential 3 months administration mode, twice a year was also shown to provide the same results as a continuous treatment. The good tolerability and safety aspects of oral CS were largely documented in these CTs. Taking these important points into account, we definitively have enough clinical data available supporting the view that oral CS is a valuable and safe symptomatic treatment for OA disease. More recent data based on a couple of previous trials and two pivotal studies do provide further evidence that oral CS does also have structure-modifying effects in knee OA patients. A couple of other compounds such as hyaluronan, diacerein, avocado and soya unsaponifiables, doxycycline have also been tested with respect to their potential disease-modifying effects. Additional compounds including receptor activator of NF-κB (RANK) ligand inhibitors, cathepsin K inhibitors, bisphosphonates are further assessed regarding their potential structure-modifying effect. [Copyright &y& Elsevier]

Bicontinuous lipidic cubic phases (LCPs) exhibit a combination of material properties that make them highly interesting for various biomaterial applications: they are nontoxic, biodegradable, optically transparent, thermodynamically stable in excess water, and can incorporate active molecules of virtually any polarity. Here we present a molecular system comprising host lipid, water, and designed lipidic additive, which form a structured, pH-sensitive lipidic matrix for hydrophilic as well as hydrophobic drug incorporation and release. The model drug doxorubicin (Dox) was loaded into the LCP. Tunable interactions with the lipidic matrix led to the observed pH-dependent drug release from the phase. The rate of Dox release from the cubic phase at pH 7.4 was low but increased significantly at more acidic pH. A small amount of a tailored diacidic lipid (lipid 1) added to the monoolein LCP modified the release rate of the drug. Phase identity and structural parameters of pure and doped mesophases were characterized by small-angle X-ray scattering (SAXS), and release profiles from the matrix were monitored electrochemically. Analysis of the release kinetics revealed that the total amount of drug released from the LCP matrix is linearly dependent on the square root of time, implying that the release mechanism proceeds according to the Higuchi model.

A series of novel lipids with designed functionalities were synthesized. These lipids are based on conjugation of α-amino acids and their esters, cationic, anionic, neutral, and photochromic moieties to the lipophilic 9-cis octadecenyl chains by amide, ester, thioester, or amine bonds. Because of the plasticity of lipidic cubic phases, it is envisaged that when mixed with monooleoyl-rac-glycerol (monoolein, MO) and water at appropriate proportions, they would assemble to form bicontinuous lipidic cubic phases (LCPs) that exhibit the well-known material properties of LCPs such as phase stability, optical transparency, and chemical permeability. Moreover, due to the nature and position of the functionality at the headgroup region, we envision them to perform as functional materials by design.