Hyaluronan derivative HYMOVIS® increases cartilage volume and type ii collagen turnover in osteoarhritic knee: data from MOKHA study.

BACKGROUND: The objective of this pilot study was to identify biological, clinical or structural biomarkers of an intra-articular hyaluronic acid injection efficacy (HYMOVIS®) for the design of a larger placebo-controlled clinical trial studying the disease-modifying activity of this treatment. METHODS: Forty six patients with symptomatic knee Osteoarthritis (OA) were enrolled in this open-label, prospective, multicenter, pilot study. Patients received two treatment cycles of intra-articular injections (3 mL) of HYMOVIS® (8 mg/mL of hyaluronic acid hexadecylamide) at 6 months interval. Each treatment cycle involved two intra-articular injections 1 week apart. All patients had Magnetic Resonance Imaging (MRI) of the target knee at baseline and 1 year, and blood samples to assess joint biomarkers. The primary outcome was the change in type II collagen-specific biomarkers (Coll2-1, Coll2-1NO2 and CTX-II) after HYMOVIS® treatment versus baseline. Secondary endpoints included levels changes in aggrecan chondroitin sulfate 846 epitope (CS-846), Cartilage Oligomeric Matrix Protein (COMP), procollagen type II N-terminal propeptide (PIIANP), Matrix Metalloprotease (MMP)-3, Myeloperoxidase (MPO) and Interleukin (IL)-6 serum biomarkers, the ratio Coll2-1/PIIANP, CTX-II/PIIANP, variation of MRI cartilage volume, and Knee injury and Osteoarthritis Outcome Score (KOOS) index. RESULTS: Coll2-1 serum levels significantly increased overtime while Coll2-1NO2 levels were only increased at D360. Serum PIIANP levels also progressively and significantly enhanced with time. In contrast, other serum biomarker levels including CTX-II, CS-846, COMP, MMP-3, MPO or IL-6 did not change significantly overtime. Interestingly, the ratios Coll2-1/PIIANP and CTX-II/PIIANP decreased, indicating a decrease of cartilage catabolism. Compared to baseline value, MRI cartilage volume and thickness increased in lateral femoral and lateral trochlea compartments and not in medial compartment. These results, in addition to an improvement of T2 mapping score suggest a positive structural effect of the product. Interestingly, WORMS effusion score, an indicator of synovitis, significantly decreased. Finally, global KOOS score and subscales significantly increased overtime while pain at rest, walking pain and patients or investigators global assessment of disease activity decreased. The safety profile was favorable with a low incidence of injection-site pain. CONCLUSION: HYMOVIS®, a well-tolerated intra-articular treatment, significantly enhanced type II collagen turnover as suggested by the increase in Coll2-1 and PIIANP levels and cartilage volume observed by MRI in lateral knee compartment. Importantly, this study provides critical information for the design of a larger phase III clinical trial investigating Disease Modifying effect of HYMOVIS®. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN12227846 11/02/2015.

Role of alendronate in therapy for posttraumatic complex regional pain syndrome type I of the lower extremity.

OBJECTIVE: To evaluate the effects of the antiresorptive agent alendronate at a daily oral dose of 40 mg in patients with posttraumatic complex regional pain syndrome type I (CRPS I) of the lower extremity. METHODS: Forty patients were enrolled in this 8-week randomized, double-blind, placebo-controlled study of alendronate therapy for CRPS I, a condition associated with regional osteoclastic overactivity. An optional 8-week open extension of alendronate therapy (weeks 12-20) was available after a 4-week period without therapy. Clinical assessments included joint mobility, edema of the lower extremity, tolerance to pressure in the lower extremity, and levels of spontaneous pain. Urinary levels of type I collagen N-telopeptide (NTX) were assessed by enzyme-linked immunosorbent assay. Patients were examined at weeks 4, 8, 12, 16, 20, and 24. Statistical analysis included two-way factorial analysis of variance. RESULTS: In contrast to placebo-treated patients (n = 20), all of the alendronate-treated patients (n = 19) exhibited a marked and sustained improvement in levels of spontaneous pain, pressure tolerance, and joint mobility, as well as a significant reduction in urinary levels of NTX at weeks 4 and 8. The improvement was maintained at week 12. Twelve patients from each treatment group volunteered for the 8-week open trial, and all of them had a positive response to alendronate. CONCLUSION: Our findings support the use of oral alendronate in posttraumatic CRPS I. By reducing local acceleration of bone remodeling, alendronate might relieve pain by effects on nociceptive primary afferents in bone, pain-associated changes in the spinal cord, and possibly also through a central mechanism.