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Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system. ATC code: M09AX01.
Pharmacology: Pharmacodynamics: Mechanism of action: Hyaluronic acid is an important component of the synovial fluid and of the articular cartilage. It provides lubricant and shock absorbing properties to the synovial fluid owing to its viscoelasticity. Moreover, it coats and protects the surface of the articular cartilage forming the backbone of the proteoglycan aggregates essential for structural and functional integrity.
In osteoarthritic joints, the concentration and the quality of hyaluronic acid is markedly reduced. As a consequence, the affected joint is exposed to mechanical damage, which may lead to synovial inflammation and cartilage destruction, and may result in pain and restricted mobility. Intraarticular administration of exogenous hyaluronic acid into osteoarthritic joints enhances the mechanical properties of the synovial fluid and has been shown to display viscoinduction, chondroprotectant, anti-inflammatory, and analgesic effects. Through these effects, its action in the joint may persist over longer periods, beyond its residency time in the synovial fluid.
Clinical efficacy and safety: A total of 1059 patients with degenerative and traumatic changes of the knee and other synovial joints were recruited into 9 clinical studies. Of these, 506 patients were treated with OSTENIL PLUS.
Three randomised controlled studies including a total of 191 patients treated with OSTENIL PLUS demonstrated that OSTENIL PLUS was efficacious in relieving pain and improving joint function in patients with knee osteoarthritis. A double-blind, randomised controlled trial conducted in France showed that a single injection of OSTENIL PLUS administered to 142 patients significantly relieved pain (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A score) and improved function (Lequesne index) for up to 6 months after treatment, with a responder rate of 83.0% according to the Outcome Measures in Rheumatology-Osteoathritis Research Society International (OMERACT-OARSI) response criteria. Similar findings were obtained in two other randomised clinical trials. The open randomised study by Lertwanich and Lamsam (2016) showed that 10 patients who received a single intraarticular injection of OSTENIL PLUS experienced a significant improvement in pain, stiffness and physical function (WOMAC scores) over the 6-month follow-up period and required lower amounts of diclofenac. The 12-month open randomised trial by Duymus et al. (2017) demonstrated that 1 injection of OSTENIL PLUS (39 treated patients) significantly improved pain, stiffness and physical function (visual analogue scale and WOMAC scores) for up to 6 months after treatment in patients with mild-moderate and moderate knee osteoarthritis.
Two open uncontrolled studies performed on a total of 105 patients also supported the efficacy of OSTENIL PLUS in the treatment of osteoarthritis. In the 3-month study by Frobenius (2009), 25 patients with hip or knee osteoarthritis received 1 or 3 (2-week interval) intraarticular injections of OSTENIL PLUS, respectively. At 3 months, pain, stiffness and function (WOMAC scores) significantly improved compared with baseline. Similarly, Borras-Verdera et al. (2012) demonstrated that a single OSTENIL PLUS injection (80 patients) relieved pain and improved joint function (visual analogue scale and WOMAC scores) over a period of 6 months in patients with knee osteoarthritis. Moreover, the patients significantly reduced their consumption of rescue medication at 3 months compared with baseline. Additionally, in the comparative study by Stoilov et al. (2011), a single injection of OSTENIL PLUS (95 treated patients) significantly relieved pain and improved function (WOMAC A score and Lequesne index, respectively) over 18 months in patients with knee osteoarthritis.
Three retrospective studies (115 injected patients) demonstrated the effectiveness of OSTENIL PLUS in the management of degenerative and traumatic changes of the knee joint. Dernek et al. (2016) reported that a single injection of OSTENIL PLUS significantly improved pain, stiffness and function (visual analogue scale and WOMAC scores) at 1 month post-injection in 28 patients with early-stage knee osteoarthritis, and that these benefits still persisted after 3 and 6 months. Guler et al. (2015) also observed a significant pain and function improvement (Knee Society's Knee Scoring System and visual analogue scales) in early-stage knee osteoarthritis patients (63 patients treated with 3 injections of OSTENIL PLUS at weekly interval) at 2 and 6 months after treatment. Finally, Dernek et al. (2017) showed the effectiveness of OSTENIL PLUS on pain and function (visual analogue scale and WOMAC scores) in 24 patients with early-stage meniscal injuries at 1, 3 and 6 months.
No significant safety concerns were identified.
In summary, all the previously-mentioned studies demonstrated the efficacy, effectiveness and safety of OSTENIL PLUS in the treatment of pain and restricted mobility in degenerative and traumatic changes of the knee joint and other synovial joints.
Pharmacokinetics: Hyaluronic acid has a local mode of action (see Pharmacodynamics as previously mentioned), which involves both the synovial fluid and the joint tissues. While the majority of exogenous hyaluronic acid remains in the joint for a few days, its half-life in the synovial fluid may vary from 1.5 hours to 4 weeks, depending on its molecular weight and structure.
The formulation of OSTENIL PLUS contains 2% high molecular weight sodium hyaluronate and 0.5% mannitol as antioxidant agent. These properties may prolong the presence of hyaluronic acid in the affected joint and allow the treatment of patients with fewer injections.
Toxicology: Preclinical safety data: No special hazard for humans is expected based on biocompatibility studies, namely implantation, cytotoxicity, intracutaneous reactivity, sensitisation, acute systemic toxicity, subacute/subchronic toxicity, and genotoxicity testing.
