Correlation between mean and minimum joint space measurements in a long-term trial with glucosamine sulfate, an osteoarthritis modifying agent

peer reviewe

Experimental Pharmacology of Glucosamine Sulfate

Several clinical studies demonstrated that glucosamine sulfate (GS) is effective in controlling osteoarthritis (OA), showing a structure-modifying action. However, little is known about the molecular mechanism(s) by which GS exerts such action and about the effects of GS at a tissue level on osteoarthritic cartilage and other joint structures. Here we provide mechanistic evidence suggesting that in vitro GS attenuates NF-κB activation at concentrations in the range of those observed after GS administration to volunteers and patients, thus strengthening previous findings. Furthermore, we describe the effects of GS at a tissue level on the progression of the disease in a relevant model of spontaneous OA, the STR/ort mouse. In this model, the administration of GS at human corresponding doses was associated with a significant decrease of OA scores. Histomorphometry showed that the lesion surface was also significantly decreased, while the number of viable chondrocytes within the matrix was significantly increased. GS improved the course of OA in the STR/Ort mouse, by delaying cartilage breakdown as assessed histologically and histomorphometrically

Long-term low-dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency.

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) age-related withdrawal is very likely to be involved in the aging process and the onset of age-related diseases, giving rise to the question of whether preventing or compensating the decline of these steroids may have endocrine and clinical benefits. The aim of the present trial was to evaluate the endocrine, neuroendocrine and clinical consequences of a long-term (1 year), low-dose (25 mg/day) replacement therapy in a group of aging men who presented the clinical characteristics of partial androgen deficiency (PADAM). Circulating DHEA, DHEAS, androstenedione, total testosterone and free testosterone, dihydrotestosterone (DHT), progesterone, 17-hydroxyprogesterone, allopregnanolone, estrone, estradiol, sex hormone binding globulin (SHBG), cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were evaluated monthly to assess the endocrine effects of the therapy, while beta-endorphin values were used as a marker of the neuroendocrine effects. A Kupperman questionnaire was performed to evaluate the subjective symptoms before and after treatment. The results showed a great modification of the endocrine profile; with the exception of cortisol levels, which remained unchanged, DHEA, DHEAS, androstenedione, total and free testosterone, DHT, progesterone, 17-hydroxyprogesterone, estrone, estradiol, GH, IGF-1 and beta-endorphin levels increased significantly with respect to baseline values, while FSH, LH and SHBG levels showed a significant decrease. The Kupperman score indicated a progressive improvement in mood, fatigue and joint pain. In conclusion, the present study demonstrates that 25 mg/day of DHEA is able to cause significant changes in the hormonal profile and clinical symptoms and can counteract the age-related decline of endocrine and neuroendocrine functions. Restoring DHEA levels to young adult values seems to benefit the age-related decline in physiological functions but, however promising, placebo-controlled trials are required to confirm these preliminary results

The role of diet and exercise and of glucosamine sulfate in the prevention of knee osteoarthritis: Further results from the PRevention of knee Osteoarthritis in Overweight Females (PROOF) study

Background and objectives: The PRevention of knee Osteoarthritis in Overweight Females (PROOF) study (ISRCTN 42823086) described a trend for a decrease in the incidence of knee osteoarthritis (OA) by a tailored diet and exercise program (DEP) or by oral glucosamine sulfate in women at risk for the disease, using a composite clinical and/or radiological outcome. The aim of this updated post-hoc analysis was to re-assess the results according to more precise techniques and take advantage of the 2×2 factorial design. Methods: A total of 407 overweight (BMI ≥ 27 kg/m2) women of 50-60 years of age with no diagnosis of knee OA were randomized to: (1) no DEP + placebo (Control, N = 102), (2) DEP + placebo (DEP, N = 101), (3) glucosamine sulfate + no DEP (GS, N = 102), and (4) DEP + glucosamine sulfate (DEP + GS, N =102) and followed for 2.5 years, with standardized postero-anterior, semiflexed (MTP) view knee radiographs at baseline and end of the study. DEP consisted of a tailored low fat and/or low caloric diet and easy to implement physical activities. Glucosamine was given as oral crystalline glucosamine sulfate 1500 mg once daily, double-blinded vs. placebo. Incident knee OA was defined as radiographic progression of ≥1 mm minimum joint space narrowing (mJSN) in the medial tibiofemoral compartment, as previously assessed by the visual (manual) technique and by a new semi-automated method. Logistic regression analysis was used to calculate the odds ratio for the effect of the interventions. Results: After 2.5 years, 11.8% of control subjects developed knee OA. This incidence was decreased with glucosamine sulfate, either alone or in combination with the DEP, but not by the DEP alone. Since there was no statistical interaction between treatments, the 2×2 factorial design allowed analysis of patients receiving glucosamine sulfate (= 204) vs. those not receiving it (= 203), similarly for those on the DEP (= 203) or not (= 204). Glucosamine sulfate significantly decreased the risk of developing knee OA: odds ratio (OR) = 0.41 (95% CI: 0.20-0.85, P = 0.02) by the manual JSN assessment method and OR = 0.42 (95% CI: 0.20-0.92, P = 0.03) by the semi-automated technique. Conversely, there was no decrease in risk with the DEP. Conclusions: Glucosamine sulfate decreased the risk of developing radiographic knee OA over 2.5 years in overweight, middle-aged women at risk, as determined by medial mJSN progression. Conversely a tailored diet and exercise program exerted no preventive effect, possibly because of the lower than expected effect on weight loss

Type 2 diabetes mellitus and osteoarthritis

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.The meeting was funded by the ESCEO, a Belgian not-for-profit organization. The authors thank the Chair for Biomarkers of Chronic Diseases and the International Scientific Partnership Program (ISPP#0111) at King Saud University, Riyadh, Saudi Arabia for their suppor

A reference case for economic evaluations in osteoarthritis: An expert consensus article from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)

Background: General recommendations for a reference case for economic studies in rheumatic diseases were published in 2002 in an initiative to improve the comparability of cost-effectiveness studies in the field. Since then, economic evaluations in osteoarthritis (OA) continue to show considerable heterogeneity in methodological approach. Objectives: To develop a reference case specific for economic studies in OA, including the standard optimal care, with which to judge new pharmacologic and non-pharmacologic interventions. Methods: Four subgroups of an ESCEO expert working group on economic assessments (13 experts representing diverse aspects of clinical research and/or economic evaluations) were charged with producing lists of recommendations that would potentially improve the comparability of economic analyses in OA: outcome measures, comparators, costs and methodology. These proposals were discussed and refined during a face-to-face meeting in 2013. They are presented here in the format of the recommendations of the recently published Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, so that an initiative on economic analysis methodology might be consolidated with an initiative on reporting standards. Results: Overall, three distinct reference cases are proposed, one for each hand, knee and hip OA; with diagnostic variations in the first two, giving rise to different treatment options: interphalangeal or thumb-based disease for hand OA and the presence or absence of joint malalignment for knee OA. A set of management strategies is proposed, which should be further evaluated to help establish a consensus on the "standard optimal care" in each proposed reference case. The recommendations on outcome measures, cost itemisation and methodological approaches are also provided. Conclusions: The ESCEO group proposes a set of disease-specific recommendations on the conduct and reporting of economic evaluations in OA that could help the standardisation and comparability of studies that evaluate therapeutic strategies of OA in terms of costs and effectiveness