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

Plasma Concentration of Estradiol Following Transdermal Administration of Systen 50 or Menorest 50

Circulating levels of 17 beta estradiol (E2) following the administration of fixed doses of E2, show a great variability in kinetics depending upon the product administrated, the routes of administration, and the interindividual variations in absorption and metabolism. This might have important implications both in terms of tolerance and effectiveness. Two new forms of transdermal E2 (SYSTEN Cilag and MENOREST Rhone-Poulenc Rorer) have been recently accepted in Europe for the treatment of climacteric symptoms. The present study was undertaken to compare the pharmacokinetic characteristics of plasma E2 profile under these two drugs. It was carried out in 30 healthy postmenopausal volunteers according to good clinical practice after informed consent, as a single blind, randomised, cross-over study during the classical wearing period of 4 days. Plasma E2 concentration was determined 24 hours before, 1/2 hour before and then 2, 4, 8, 12, 24, 48, 72, 84, 96 hours after the first patch administration. E2 measurement was performed using a specific direct radioimmunoassay developed in the FRH laboratories. The main criteria for this method were an intraassay coefficient of variation (CV) less than 6%, an interassay CV less than 8% in a concentration range of 15-140 pg/ml and a quantitative detection limit (LOQ) of 2.7 pg/ml with a 20% CV. The following kinetic parameters were analysed: C(max), C(mean), C96 and MRT. The bioequivalence was assessed by analysis of variance of C(max), C(mean), C96 and AuC after logarithmic transformation, complemented by Westlake test (95%). Data show that these two products are identical in terms of C(max) but C(mean), C96 and AuC are statistically greater when MENOREST 50(R) is administered; furthermore, E2 levels decrease more rapidly and more deeply with SYSTEN 50 than MENOREST 50. The differences of pharmacokinetic profiles after administration of two different forms of the same dose of 50 micrograms transdermal 17 beta estradiol might have important medical consequences

Plasma Estradiol Concentrations and Pharmacokinetics Following Transdermal Application of Menorest 50 or Systen (Evorel) 50

OBJECTIVES: In order to compare the pharmacokinetics of two transdermal estrogen replacement therapy (ERT) systems designed to release 50 micrograms 17 beta-estradiol/day, two studies were performed in healthy postmenopausal volunteers. METHODS: Both studies had a cross-over design and incorporated a 1-week wash-out period between treatments. In the first study, Menorest 50 and Systen 50 (Evorel 50) were compared over four days of application in 30 women. In the second, 13 women wore each of the two systems for a total of 12 days each (three patches each for 4 days), and comparison was made during the third patch period (steady state, between days 8 and 12). Plasma 17 beta-estradiol levels were assayed using specific direct radioimmunoassays, and pharmacokinetic parameters were calculated by standard methods. All the samples of the first study were re-analysed using a different radioimmunoassay and the results of both assays were compared. RESULTS: In both studies, plasma 17 beta-estradiol levels rose at a comparable rate and reached similar peak levels with each of the two formulations. Levels then remained relatively constant throughout both evaluation periods with Menorest 50, but began to decline after 12 hours in the first study and after 30 h under steady state conditions in the second study with Systen 50. The difference between the two products was statistically significant in both studies. Analysis of pharmacokinetic parameters confirmed the greater bioavailability of Menorest 50. In addition, 17 beta-estradiol levels remained within the suggested therapeutic ranges for relief of acute symptoms and protection against osteoporosis for longer periods of time with Menorest 50 than with Systen 50. CONCLUSION: Since the acute efficacy, long-term protective effects, side effects and risks associated with ERT may depend on critical threshold plasma levels, much attention should be paid to the pharmacokinetic profiles of different formulations. The comparison of these two different radioimmunoassays demonstrates the comparability of their results