Effects of glucosamine and chondroitin supplementation on knee osteoarthritis: an analysis with marginal structural models.

Osteoarthritis (OA) is the most common type of arthritis and a leading cause of pain and physical disability in older adults (1). Although currently no effective remedies for OA exist, clinical guidelines recommend both pharmacological and non-pharmacological therapies to relieve symptoms (2). In the United States, glucosamine and chondroitin are two dietary supplements that are commonly used among patients with OA (3). Both glucosamine and chondroitin are essential components of the proteoglycans in normal cartilage and were purported to provide substrate for the biosynthesis of proteoglycans (4). In vitro and animal studies suggest that glucosamine and chondroitin simulate the synthesis of proteoglycans and inhibit the synthesis of proteolytic enzymes that lead to the premature breakdown of cartilage (5,6). Despite the biologic plausibility, evidence regarding the efficacy of glucosamine and chondroitin in relieving OA symptoms and modifying structural progression is not established. Several meta-analyses which pooled results from existent randomized clinical trials that assessed symptomatic benefits reported substantial heterogeneity in findings across studies (7-10). Differences in study quality, preparation of the interventions, industry involvement and study size may have explained the observed heterogeneity (7-10). Large-scale trials with high quality and little connection to industry often reported a much smaller effect size of symptoms relief than earlier small industry-funded studies (8,9). Regarding the efficacy of glucosamine and chondroitin in modifying disease progression, several meta-analyses (11,12) reported small to moderate effect sizes and found that studies with longer intervention periods demonstrated a stronger effect of glucosamine on slowing joint space narrowing than studies with a shorter treatment period, whereas another meta-analysis concluded no benefits from glucosamine or chondroitin treatment (13). The purpose of this study was to quantify the effectiveness of glucosamine and chondroitin in relieving OA symptoms and modifying structural progression. This study is warranted for several reasons. First, in the United States, glucosamine and chondroitin are almost always sold in a combination pill (14). Despite the extensive research on single treatment with glucosamine or chondroitin, studies of the combined treatment are sparse (13). Second, to our knowledge, the longest studies were three-year trials conducted more than a decade ago in Europe and supported by one pharmaceutical company (15,16). The Osteoarthritis Initiative (OAI) provides a unique opportunity to examine the long-term effectiveness of glucosamine and chondroitin on treating OA, because it administered comprehensive measurements on treatment use and changes in knee symptoms and joint structure for up to four years (17). Third, efficacy evidence of a treatment derived from clinical trials is often limited in generalizability because they often use strict study protocols and highly selected patients and are typically conducted at large medical centers (18). Non-experimental studies, on the other hand, can provide clinicians and patients with a more realistic expectation for treatment benefits in real-world environments (18). We are aware of one non-experimental study which assessed the impact of glucosamine and chondroitin on slowing structural progression (19). Our study used different designs and analytic methods and extended their work by assessing both symptoms relief and reduction in structural progression.