Osteoarthritis treatment: Is it finally time to consider glucosamine seriously?

The prevalence of primary osteoarthritis (OA) has substantially increased in the general population during the last decades. The aging of the population and increment in life expectancy are contributing factors; however, there is also a high incidence of OA in younger aged individuals. An optimal treatment for OA would ideally provide relief of symptoms and preservation of function, be safe, and delay joint structure damage. No such intervention clearly addressing all these important treatment dimensions has yet been discovered. Appropriate glucosamine compounds may be good candidates for such a therapeutic challenge, but the lack of enthusiasm on the part of physicians, especially in North America, was further fueled by the latest (2012) guidelines of the American College of Rheumatology (ACR)1 and the (2013) American Academy of Orthopedic Surgeons (AAOS)2 that moderately to strongly recommended against their usage to treat OA. Still, patients continue to demand these therapies as the global market for glucosamine usage3 will be more than USD757 million by 2022. Despite more than 5 decades of use and many controlled and uncontrolled trials, the overall effects of glucosamine on OA outcomes are not clearly proven. One possible explanation is the lack of a standard preparation of glucosamine in North America as the US Food and Drug Administration classifies glucosamine compounds as dietary supplements, hence not requiring standardization of their content and purity. Conversely, a patented formulation of glucosamine sulfate (GS) is approved as a prescription drug in Europe, Asia, and elsewhere. This very specific issue is addressed very convincingly by Saengnipanthkul et al4 in this issue of the International Journal of Rheumatic Diseases. The differences among glucosamine preparations presented by the authors, especially the better pharmacokinetics data of serum concentrations of glucosamine of the prescription patented crystalline glucosamine sulfate (pCGS) over other preparations, such as glucosamine hydrochloride, along with supportive clinical trial results of pCGS on symptoms and structure, may indeed explain the heterogeneous results on the overall impact of glucosamine on OA provided by the medical literature. This is further supported by a recent comprehensive network meta-analysis by Gregori et al5 stating that long-term knee OA pain control was significantly achieved only with the prescription-grade crystalline glucosamine sulfate and not with other glucosamine formulations or combinations. However, other explanations should also be put forward to explore the lack of consistent data on the efficacy of glucosamine in OA. OA is a heterogeneous disease; its origin is multi-factorial and the speed of structural damage progression varies. Symptoms also have a wide spectrum, with which imaging findings do not correlate well. OA clinical trial patient selection and design are therefore challenging. The American Board of Internal Medicine states6 as part of their “Choosing Wisely” campaign that glucosamine and chondroitin sulfate (CS) supplements do not work and are no better than placebo. However, similar to the ACR and AAOS recommendations,1, 2 they mainly consider trials performed with non-prescription glucosamines. In addition, and perhaps despite our best efforts, patients with knee OA who enroll in randomized controlled trials (RCTs) are simply not representative of real-world patients. Does comparing interventions for OA pain to placebo fail to fully incorporate other effects on centrally mediated pain, which may be similar between study arms? Could a better design choice be to enroll patients with more severe OA, as their disease may progress more rapidly, making it easier to observe the effects of different glucosamine preparations? In retrospect, larger and longer-term studies with a different patient population may be needed to definitively conclude whether different glucosamine preparations do or do not affect OA. Although Saengnipanthkul et al4 show that patients taking pCGS do benefit from glucosamine, this still does not provide a definitive answer with regard to the possible effects of pCGS and other glucosamine preparations in patients with more severe disease. The issue of OA structural damage progression over time is important. We and others7, 8 have demonstrated the feasibility of long-term longitudinal follow-up using quantitative magnetic resonance imaging (qMRI) to assess cartilage volume loss over time in patients with knee OA. Such knee cartilage volume loss was demonstrated as early as 6 months in a typical OA cohort and was more sensitive to change than standardized radiographs. Interestingly, half of OA studies and >80% of those funded by industry are of <6 months duration9 and none of the glucosamine clinical trials have ever used qMRI to assess OA structural damage progression as cartilage volume loss (CVL) over time. Saengnipanthkul et al4 point out, rightfully so, the Bruyère et al10 paper stating that standardized radiographic joint space narrowing (JSN) protection by pCGS over 3 years may predict fewer occurrences of total knee replacement (TKR) up to 8 years. Indeed, TKR is considered a “hard” outcome that investigators should look at to assess the long-term benefit of any OA treatment.11 However, it would be interesting to duplicate these studies with MRI endpoints, rather than plain radiography. Interestingly, these same methodological issues were implicated in the development of CS, another symptomatic slow-acting drug for OA (SYSADOA). CS, also a natural product, is extracted from animal cartilage (eg bovine trachea). A recent Cochrane review also concluded that CS has a beneficial effect on pain and JSN in patients with knee OA.12 Of note, different sources of CS with variable composition and purity have been used in these studies, explaining some heterogeneity in results,13 commensurate with the explanation put forward by the Saengnipanthkul et al4 report. However, a RCT14 using pharmaceutical grade preparations of CS showed that at 800 mg/d it significantly reduced CVL as assessed by qMRI at 12 and 24 months in the medial tibiofemoral compartment (P = 0.017, P = 0.013) and in the global knee (P = 0.034, P = 0.054) compared to the cyclooxygenase-2 (COX-2) inhibitor celecoxib. Both treatment groups experienced marked reduction in incidence of joint swelling plus effusion and disease symptoms over time. This is very interesting as CS has also previously been reported to have a beneficial effect on the need for TKR in a 4-year follow-up study in knee OA.15 The reports of Saengnipanthkul et al4 and Gregori et al5 exemplify the differences between SYSADOA preparations and glucosamine in particular; the pharmacokinetics data for the pCGS for OA could well explain the heterogeneous results on OA symptom and structure response to therapy. However, clinical trials are still difficult to conduct in OA due to disease heterogeneity and chronicity and inadequate tools for measuring outcomes. We need better biomarkers and more guidance from in vivo experimental studies, as qMRI should be the gold standard to assess structural damage progression. Despite the many clinical trials performed and patients’ wide use of glucosamine and chondroitin, their place in the treatment of OA is still under debate. Perhaps it's time to take glucosamine and other SYSADOAs seriously while at the same time realizing that many may “piggy back” on the well-studied and proper preparations which may not be beneficial for patients.

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