The main nonsurgical treatments for osteoarthritis are nonpharmacologic, including land- and water-based exercise,24b low-intensity strength training,A1b,A1c weight management, assistive devices to help patients perform activities of daily living, thermal modalities, and joint splints and braces.25,25b Based on the 2018 scientific report on physical activity and health to the U.S. Secretary of Health and Human Services (updated each decade), for individuals with lower extremity osteoarthritis, physical activity provides pain relief, improves physical function, and improves quality of life without concern of worsening the condition for exposures less than 10,000 steps per day. Measurable benefits of physical activity seem to persist for periods of up to 6 months following cessation of a defined program. Exercise raises high-density lipoprotein that helps clear lipopolysaccharide and, by dynamic fluid pressurization, provides nutrition to cartilage, which is avascular. Biomechanical aids, such as footwear, can also be beneficial.A1d
Consensus recommendations conditionally endorse additional treatments on the basis of the risk-to-benefit ratio and comorbidities of the patient; this group of treatments includes analgesics such as acetaminophen, oral and topical nonsteroidal anti-inflammatory drugs (NSAIDs),26,26b opioids (such as tramadol), and intra-articular agents such as steroids and hyaluronates, although the benefit of these various treatments is limited.A1 For example, a randomized clinical trial of the effectiveness of opioid versus nonopioid drugs (acetaminophen, NSAIDs) for chronic back, hip, or knee pain in patients with osteoarthritis found that treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function over 12 months.A2 Older age is also a contraindication to opioid use. Glucosamine and chondroitin appear to be safe but without evidence that they can modify the progression of joint degeneration.
Because the presence of comorbidities, such as renal cardiovascular, and/or gastrointestinal ulcer history limit the use of existing osteoarthritis therapies such as oral NSAIDs, selective cyclooxygenase 2 (COX2) inhibitors are an option. In a randomized trial, celecoxib (a COX2 inhibitor at 200 mg daily) conferred a similar or lower risk for cardiovascular, gastrointestinal, and renal adverse events compared with treatment with the nonspecific COX1/COX2 NSAIDs ibuprofen or naproxen.A3
Low-dose (10 mg daily) oral prednisolone is safe and efficacious for short-term (6 weeks) treatment, but symptoms return rapidly when it is discontinued.A3b In one trial of standard intra-articular steroids in osteoarthritis, 2 years of intra-articular triamcinolone, compared with intra-articular saline for knee osteoarthritis, resulted in significantly greater cartilage volume loss and no significant difference in knee pain.A4 However, a microsphere-based, extended release preparation of triamcinolone can provide clinically meaningful pain reduction in knee osteoarthritis patients at 12 weeks compared with placebo injection.A5 Nevertheless, physical therapy appears to be better than standard glucocorticoid injections for relieving pain and preserving function in patients with osteoarthritis of the knee.A5b Intra-articular injection of anakinra, a modified human IL-1 receptor antagonist, has not improved osteoarthritis symptoms compared with placebo.
Although early diagnosis and intervention in osteoarthritis would improve the likelihood of disease modification and thereby reduce medical costs, morbidity, and disability, there are presently no drugs approved that can prevent, stop, or restrain progression of osteoarthritis. In a randomized clinical trial, hydroxychloroquine was found to be no more effective than placebo for pain relief in patientswith moderate to severe hand pain and radiographic osteoarthritis.A6 The ultimate treatment option currently available is surgical, including joint distraction (emerging therapy), osteotomy, and joint replacement (Chapter 260).27,28 Unfortunately, undergoing a joint replacement does not equate with remission or reversal of disability, but rather is associated with a lessening of disease severity in the replaced joint; up to 30% of individuals continue to experience pain and disability after total joint replacement, and one in five require joint replacement in another joint within 2 years. In a randomized clinical trial, patients with knee osteoarthritis who were eligible for unilateral knee replacement, treatment with knee replacement was associated with a higher number of serious adverse events than was nonsurgical treatment, and most patients who were assigned to receive nonsurgical treatment alone did not undergo total knee replacement during the 12-month follow-up period.A7 The operation has also reflected racial disparities, with African American patients being less likely to undergo total knee replacement than white patients, despite worse baseline knee pain and function in the former. The efficacy of arthroscopic surgery is limited, with some improvement commonly seen at 3 months but little improvement at 2 years.A8
Given that established osteoarthritis is a chronic disease, intermittent administration of long-acting agents or chronic administration of short-acting agents is likely required. A potentially promising finding was a 40% reduction in hip or knee replacement surgery in a large randomized trial to determine whether interleukin (IL)-1β inhibition with canakinumab could reduce adverse cardiovascular outcomes in patients with elevated levels of C-reactive protein and a history of myocardial infarction (Chapter 64).A8b In further support of this concept, intra-articular IL-1 receptor antagonist for knee osteoarthritis provided brief (up to 4 days) pain relief but not beyond in keeping with its known brief (4 hours) intra-articular half-life. Drug and molecule entry into the joint cavity from the systemic circulation is size dependent (through arterioles and venules in synovium) and increased with synovial inflammation due to increased vascular permeability. However, drug and molecule exit from the joint cavity is size independent and rapid through lymphatics in synovium as well as through capillaries (in the case of small molecules); increased rates of exit occur with synovial inflammation due to increased lymphatic flow. Intra-articular half-lives of substances within joints range from 1 to 4 hours for NSAIDs and soluble steroids to 26.3 hours for non–cross-linked hyaluronic acid (molecular weight 3 × 106 D). This problem of rapid clearance of drugs from the joint has been the motivation for developing strategies to improve intra-articular drug efficacy based on increasing residence time of drugs in joints; current strategies for prolonging treatment effects include, to name a few examples, using nanoparticles (steroids), molecular cross-linking (hyaluronans), cell-based delivery (TGF-β1), and targeting gene expression and chondrogenic differentiation (Wnt signaling inhibition) (E-Table 246-1).29 For example, intraarticular injection of sprifermin, which is a recombinant human fibroblast growth factor, can increase the thickness of femorotibial cartilage but without obvious clinical benefits.A8c
E-TABLE 246-1. INTRA-ARTICULAR AGENTS ALREADY APPROVED OR IN HUMAN TRIALS CURRENTLY
DRUG CLASSEXAMPLESteroidTriamcinolone acetonide in a poly(lactic-co-glycolic acid) (PLGA) extended-release, microsphere-based formulation (FX006; U.S. Food and Drug Administration [FDA]-approved Zilretta) has a prolonged intra-articular residence time (mean, 18.9 days, with variable but quantifiable concentrations measurable through 16 wk postinjection) vs. the standard crystalline suspension (mean, 2.5 days, with quantifiable concentrations measurable through 6 wk)ViscosupplementsMultiple FDA-approved agents with half-lives from 13 hr to 9 days; cross-linked hyaluronan formulations have higher residence times but are twice as likely to cause local adverse reactions and postinjection flares compared with intermediate- or low-molecular-weight hyaluronanGrowth factorsTransforming growth factor-β1 (TGF-β1) cell-mediated gene therapy currently in human trials consists of genetically engineered chondrocytes virally transduced with TGF-β1 (GECTGF-b1, currently in trials) delivered as a 3 : 1 mixture of normal allogeneic human chondrocytes and human chondrocytes transduced with the human TGF-β1 gene that are irradiated before dosing to render them replication incompetent; injection is associated with joint inflammation, arthralgia, and effusion in up to 28% of patientsWnt signaling inhibitorWnt inhibitor SM04690 (currently in human trials) causes human mesenchymal stem cells to differentiate into chondrocytes and reduces metalloproteinase gene expression in vitro; shows promising results in a rodent injury model of osteoarthritisFGF18Anabolic growth factor injected into the knee joint shows increased cartilage thickness and reduced cartilage loss by MRI in a phase III trial