1. Top of page
  2. Introduction
  3. Approaches to efficacy
  4. Approaches to safety
  5. Disease modification
  6. Discussion

Approaches to the management of osteoarthritis (OA) have been the focus of many professional organizations, resulting in the development of numerous guidelines and recommendations. This article does not duplicate these efforts but rather turns to a discussion of potential new agents and, in some cases, new approaches with existing agents, for the treatment of OA.

The current management of OA provides symptomatic pain relief and, in many cases, increased functional ability to many people with OA. However, it is widely acknowledged that the pain relief achieved with all of the existing non-opioid interventions is often modest in magnitude, with effect sizes in most clinical trials being in the range of 0.3–0.5 (1, 2). Therefore, having an available agent that would yield better pain relief with similar or improved tolerability and safety to nonsteroidal antiinflammatory drugs (NSAIDs), the most widely used drugs, is clearly one goal in OA management.

The past 10–20 years have seen a rapid expansion in our knowledge of the neurobiology of pain. Although initial emphasis has been on elucidation of acute pain mechanisms with attention directed to the peripheral nervous system and spinal cord, more recently attention has turned to the role of supraspinal pathways and their role in chronic pain (3). One consequence of these investigations has been the identification of a myriad of neurotransmitters, their receptors, and downstream effectors, many of which could serve as possible targets for drug development (4). In many ways, this situation is not dissimilar to what rheumatology investigators were facing while attempting to target specific cytokines in the treatment of rheumatoid arthritis, with a plethora of targets but only very few amenable to intervention in a therapeutically useful fashion.

In addition to achieving greater pain relief, the development of NSAIDs with an improved gastrointestinal (GI) and cardiovascular (CV) profile has long been a goal for the pharmaceutical industry, patients, and doctors. Initial success was achieved by combining a synthetic prostanoid, misoprostol, with NSAIDs, either taken separately or combined in a single pill, with a resultant increase in GI safety but often at the expense of added GI symptoms (5). The subsequent identification of a second isoform of cyclooxygenase (COX) led to the development of COX-2–selective NSAIDs, drugs predicted and shown to result in greater upper GI safety (6). However, the study of these drugs ultimately also raised the question as to whether not only these drugs, but also possibly all NSAIDs, were associated with an increase in thrombotic CV events (7, 8). Therefore, currently there remains a need for agents providing better GI safety as well as those that may have an improved CV profile compared with existing NSAIDs.

A second therapeutic goal in OA is the development of disease-modifying agents, i.e., drugs that will have an effect on the structures of the joint that are altered by the OA process, with the goal of improving function and reducing the need for procedures such as joint arthroplasty. Much progress has been made in our understanding of the biology of cartilage, bone, and synovium, and the clinical course and expression of OA are being defined by programs such as the Osteoarthritis Initiative (9–11). A number of drugs have been evaluated in clinical trials (10, 12), and although positive results were not achieved, much was learned that serves as a basis for the ongoing work in this challenging field.

Approaches to efficacy

  1. Top of page
  2. Introduction
  3. Approaches to efficacy
  4. Approaches to safety
  5. Disease modification
  6. Discussion

Antibody to nerve growth factor (NGF).

NGF is a neurotrophin that, in adults, plays an important role in the structure and function of sensory neurons, with receptors for NGF (TrkA and p75) being found on a subset of small-diameter nociceptive afferents (13–15). NGF has been implicated in pain pathways based on a series of experimental observations over the past 15 years. In some of the earliest studies, inhibition of NGF elicited in the skin by an inflammatory stimulus resulted in reduced inflammatory hyperalgesia, suggesting that NGF was an important intermediary in the sensitization of nociceptors (16). NGF was also elevated in other animal models of inflammatory pain states, with inhibition of NGF activity leading to reduced signs of pain (14, 17). Exogenous NGF administered locally or systemically to animals and humans has been shown to elicit local hyperalgesia and pain (18, 19), and NGF expression is elevated in painful inflammatory states in humans, including in inflammatory arthritides, pancreatitis, prostatitis, and interstitial cystitis (20–24). At a cellular level, binding of NGF to its high-affinity TrkA receptor has been shown to result in downstream activation of kinases that potentiate the activity of TRPV1 pathway activation, implicated in heat- and capsaicin-mediated pain (14). Therefore, there is a strong rationale for developing means to inhibit NGF or NGF activity in order to modulate pain in clinical conditions.

Clinical development of antibodies to NGF as a treatment for the signs and symptoms of OA is actively being pursued by several pharmaceutical companies. Results of a phase II dose-ranging study in OA with one of these compounds, tanezumab, has been presented in abstract form (25), as has a longer-term extension study (26), and the compound itself is currently being further evaluated in a number of phase III trials (27). Tanezumab is a humanized anti-NGF monoclonal antibody that, when administered as an intravenous infusion every 8 weeks, results in effective, sustained pain relief that was shown to be superior to placebo (Table 1). The effect size of the treatment was moderate to large, but because there was no NSAID control group in the study, a comparison is not possible. At the highest doses tested, the side effect profile was notable for reports of abnormalities of peripheral sensation, including hypoesthesia, dysesthesia, and paresthesia, which occurred in up to 14% of subjects. In general, these side effects were of limited duration and of mild or moderate severity. No other significant neurologic adverse events were reported, including any involving the sympathetic nervous system or cognition, and no other organ toxicity of note was identified.

Table 1. Walking pain and SGA at baseline and averaged over weeks 1–16*
 PlaceboTanezumab, 10 μg/kgTanezumab, 25 μg/kgTanezumab, 50 μg/kgTanezumab, 100 μg/kgTanezumab, 200 μg/kg
  • *

    SGA = subject global assessment (25).

  • P <0.001 vs. placebo.

  • P ≤0.005 vs. placebo.

Baseline walking pain71.670.671.768.171.172.4
 Change from baseline (SEM)−16.0 (2.4)−33.0 (2.3)−36.9 (2.3)−31.8 (2.4)−44.0 (2.3)−43.8 (2.3)
 Difference vs. placebo (SEM) −17.0 (3.3)−20.9 (3.3)−15.8 (3.3)−28.0 (3.3)−27.8 (3.3)
Baseline SGA score48.855.751.051.649.954.4
 Change from baseline (SEM)8.9 (1.6)15.1 (1.5)21.6 (1.5)15.8 (1.5)22.9 (1.5)18.4 (1.5)
 Difference vs. placebo (SEM) 6.2 (2.2)12.8 (2.2)6.9 (2.2)14.1 (2.2)9.5 (2.2)

In addition to testing in patients with OA, tanezumab is being evaluated in other chronic painful conditions, including low back pain, pelvic pain, and neuropathic pain (27). Other antibodies to NGF are also being investigated, and formulations of these antibodies for subcutaneous administration are also being assessed (27). Studies assessing the long-term safety of these compounds will need to specifically evaluate the extent and duration of potential mechanism-based adverse effects such as neurologic dysfunction, as well as possible adverse consequences of pain reduction such as rapid progression of OA changes due to greater loading and overuse. If such studies continue to support the marked efficacy of this approach to pain modulation while providing evidence of adequate long-term safety, this could provide patients with chronic pain with a useful alternative to the currently existing compounds.

Serotonin–norepinephrine reuptake inhibitors (SNRIs).

Over the past 10 years, there has been a growing appreciation of both peripheral and central sensitization in patients with longstanding OA, with a number of investigators reporting areas of hyperalgesia surrounding the affected joint (28, 29). Bradley et al extended these studies and demonstrated not only localized sensory changes in patients with OA, but also a generalized change in pain thresholds at other peripheral sites away from the affected joint, as well as a general disinhibition of painful stimuli compared with control subjects (30). Further studies with these same OA patients suggested alterations in affective response to painful stimuli compared with controls, and single-photon–emission computed tomography scanning showed differential brain activity in the subjects with OA. Since this report, 3 additional studies (31–33) have evaluated brain activity in patients with OA pain, and all have demonstrated distinct cortical responses localized to specific regions of the brain (cingulate cortex, thalamus, amygdala, medial prefrontal cortex) and brainstem (periaqueductal grey), involving areas important for affective responses (fear, emotions, aversive conditioning) and for descending inhibitory activity. These changes are not unique for OA pain and are also seen in other chronic, but not acute, painful conditions (3). Modulation of these cortical areas that play a role in chronic pain may be expected to result in altered perception of pain, particularly alteration in the affective dimension of the pain, but also potentially in the magnitude of the pain sensation itself.

Duloxetine is an SNRI initially approved by the Food and Drug Administration (FDA) for the treatment of depression that has subsequently been shown to be effective in the treatment of two chronic pain conditions: fibromyalgia (34, 35) and diabetic peripheral neuropathy (35). Its analgesic effects have been ascribed to modulation of central pain inhibitory activity (36), although the exact mechanism by which this occurs, and clear demonstration of these effects by brain imaging, have not been reported. Nevertheless, further studies of duloxetine in patients with chronic painful knee OA have been undertaken. Results of one study have been published (37) and the other results are presented as an abstract (38). In both studies, duloxetine was compared with placebo for OA patients requiring additional pain relief, whether already receiving an analgesic or not. Subjects in these studies continued on their baseline medications and then underwent a 1-week titration of duloxetine 30 mg or placebo, followed by treatment with duloxetine 60 mg or placebo for 6 weeks and then, in one study, a rerandomization of the active group to either 60 mg or 120 mg for a final 6 weeks, and in the other study, an increase to 120 mg in those who had not achieved >30% pain relief. In both studies, the prespecified primary end point was met (improvement in mean change of weekly 24-hour average pain score and improvement in the Brief Pain Inventory) (Figure 1). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and function subscales were statistically different between the duloxetine and placebo groups in one study, whereas in the other study, only the difference in the WOMAC function subscale reached statistical significance. The magnitudes of the effects were modest but in the range seen with other studies of adjunctive treatment in OA (39). Side effects were more frequent in the duloxetine-treated subjects compared with those receiving placebo, with fatigue, somnolence, dizziness, hypertension, constipation, and decreased libido occurring in >3% of people exposed and at a rate of more than twice that of the placebo group.

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Figure 1. Mean change in the weekly 24-hour average pain score from baseline to each week. P values are from mixed-models repeated-measures analysis (37). LS = least squares.

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Therefore, initial studies have demonstrated the potential for this centrally acting compound to provide modest clinical benefit to patients with chronic painful OA, albeit with a tolerability profile that merits further attention. Additional clinical trials in OA are ongoing with duloxetine to provide a robust database on which to more fully evaluate both efficacy and safety, and other studies are also being undertaken in chronic low back pain (40). The availability of a drug with a different mechanism of action to NSAIDs and opioids in OA highlights both the opportunities and challenges of dealing with chronic pain states in humans.

Approaches to safety

  1. Top of page
  2. Introduction
  3. Approaches to efficacy
  4. Approaches to safety
  5. Disease modification
  6. Discussion

COX-inhibiting nitric oxide (NO) donors (CINODs).

NO is an important intercellular signaling molecule whose activity was first identified based on its causing vascular dilatation (endothelial relaxing factor [41]) and now is recognized to play an important role in a wide range of both physiologic and pharmacologic processes (42, 43). In the GI tract, NO helps maintain gastric integrity through effects on mucosal blood flow, leukocyte adherence, and mucous and bicarbonate secretion, all of which are negatively impacted by NSAID-induced prostaglandin inhibition (44, 45). In the CV system, NO has been shown to have beneficial effects, playing a central homeostatic role in maintaining blood pressure by its vasodilatory action and prevention of vascular smooth muscle proliferation while also acting to inhibit platelet aggregation and leukocyte adherence to vessel walls (42, 46). Therefore, the NO activity on both the CV and GI systems counters many of the known, deleterious effects of NSAIDs, providing a rationale for the development of compounds such as CINODs that contain both of these activities (47). Structurally, CINODs are a class of drugs that contain NSAIDs to which an NO-donating group has been covalently linked to form a novel molecule. Once CINODs are absorbed from the gut, the NO-donating group is chemically cleaved, releasing the NSAID and the NO-containing moiety (48). Animal studies have shown that, unlike simple organic nitrates, the NO-containing moiety can circulate for longer periods of time before being metabolized, leading to more persistent NO-mediated bioactivity (48).

Naproxcinod, consisting of naproxen to which an NO-donating group has been linked by means of an ester bond, is the first of the CINOD class. Naproxcinod has been studied in 3 phase III, randomized, placebo- and naproxen-controlled trials, two in patients with knee OA (13 weeks and 26 weeks) (49, 50) with naproxcinod 750 mg twice a day and 375 mg twice a day, and one in patients with hip OA (13 weeks) (51) with naproxcinod 750 mg twice a day. The trials in knee OA demonstrated the efficacy of naproxcinod at both doses to be superior to placebo, with statistically significant differences in WOMAC pain, stiffness, and patient global assessment; noninferiority of naproxcinod 750 mg to an equimolar dose of naproxen has also been reported at both 13 weeks and 26 weeks (50). Data from the trial in hip OA have not yet been reported. During the course of the development program, particular attention was paid to effects of naproxcinod on GI safety and blood pressure. Early endoscopy studies demonstrated fewer GI erosions and ulcers with naproxcinod compared with equimolar doses of naproxen (52, 53); a larger phase II trial confirmed these findings, showing a lower rate of gastroduodenal ulcers over 12 weeks in patients taking naproxcinod (9.7%) compared with naproxen (13.7%), but this reduction did not reach statistical significance (P = 0.07) (54). Blood pressure response to naproxcinod was also closely assessed in the phase III studies: patients receiving naproxcinod compared with naproxen had lower mean systolic blood pressure after 13 weeks of treatment (least square mean difference in change from baseline −2.1 mm Hg; P < 0.01), and naproxcinod was shown to be associated with a lower likelihood of destabilization of blood pressure in individuals who had preexisting hypertension compared with naproxen (55). Specific studies utilizing ambulatory blood pressure monitoring have confirmed a differential blood pressure effect of naproxcinod compared with naproxen (56) (Figure 2).

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Figure 2. Probability curves illustrating the chances that a patient entering the trial with normal systolic blood pressure (BP; <140 mm Hg) would become hypertensive (systolic BP ≥140 mm Hg) according to treatment group.

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CINODs offer the potential to ameliorate a number of the common side effects of NSAIDs so as to increase safety. The distinction in blood pressure response between naproxcinod and naproxen is the consequence of the addition of the NO-donating group and reflects well-known activity of NO. For chronic NSAID users, lower blood pressure over prolonged periods of time is desirable and may be expected to result in better CV outcomes (57). Whether naproxcinod is able to offer such advantages, however, can only be answered by the results of future large well-designed and -implemented outcome trials.

Gastroprotective agents (GPAs) plus NSAIDs.

Because of the well-documented association of NSAIDs with GI symptoms, as well as an increased incidence of serious GI adverse events (ulcers, perforations, bleeds), GPAs have been recommended to be used in people at high risk of serious GI outcomes (58). Significant evidence exists that proton-pump inhibitors are effective at reducing NSAID-associated ulcers (59), and some proton-pump inhibitors have such an indication as part of their approved prescribing information. In addition, high doses of H2 receptor antagonists have also been shown to reduce NSAID-associated ulcers, although at lower doses these drugs appear to be less effective for this end point (59, 60). Despite the availability of these drugs and the evidence of their effectiveness, they are used as often as would be desirable, particularly in individuals at high risk of serious GI events. One barrier to their use is lack of adherence, i.e., the fact that taking a second pill is often neglected by the patient or even the doctor (61). An approach to assuring that such GPAs will be used with NSAIDs is to combine the two agents in one pill.

Two combination GPA-NSAID products are in the final stages of evaluation: enteric-coated naproxen plus immediate-release esomeprazole and ibuprofen plus famotidine. Initial pharmacokinetic and pharmacodynamic dose-ranging studies of the naproxen and esomeprazole combination resulted in the selection of the fixed-dose combination of 500 mg naproxen plus 20 mg esomeprazole combined in a single enteric-coated pill based on its providing similar acid suppression and naproxen exposure as the individual components (62). Two identical phase III endoscopy trials comparing the combination product with enteric-coated naproxen 500 mg twice a day have been performed and reported in abstract form (63, 64). In both trials, the combination enteric-coated naproxen plus immediate-release esomeprazole taken twice daily resulted in a lower incidence of cumulative gastric ulcers over 6 months (primary end point) compared with the enteric-coated naproxen group (4.1% versus 23.1% and 7.1% versus 24.3%, respectively; P < 0.001 for both). Similar differences were reported regardless of low-dose aspirin use. The incidence of duodenal ulcers was also decreased by the combination, as were GI symptoms; overall safety was similar between both treatment groups.

The single-pill combination of ibuprofen 800 mg plus famotidine 26.6 mg in comparison with ibuprofen 800 mg, each taken 3 times per day, was also investigated in two 6-month endoscopy trials. The results from the individual studies, which have been reported in abstract form, indicated a reduction over 6 months in upper GI ulcers in the combination group versus the ibuprofen group in both studies (11.5% versus 23.3% in one study, 10.5% versus 20.0% in the other; P < 0.05 for each) (65).

The studies reported to date with the combination products have all focused on reduction in endoscopic ulcer rates. No evidence has been presented that these combinations lead to a reduction in clinically important GI outcomes, as had been done with many of the COX-2 selective drugs (6, 66). Such studies would be helpful to understand better the clinical benefit of these combination products. The availability of a single pill that combines an effective GPA with an NSAID would be expected to lead to enhanced adherence compared with taking the two medications separately. Limitations to the combination medications will be the fixed dose available; the likelihood that non–acid-related GI side effects, particularly effects on the lower GI track, will not be altered; the potential for new adverse effects due to prolonged periods of acid suppression, e.g., nutritional deficiencies; infectious complications (67); and the fact that the non-GI side effects of NSAIDs will continue to require careful attention.

Disease modification

  1. Top of page
  2. Introduction
  3. Approaches to efficacy
  4. Approaches to safety
  5. Disease modification
  6. Discussion

Cartilage-targeting agents.

OA is a disease of the entire joint, and changes in bone, cartilage, synovium, and supporting tissues may ultimately be expressed clinically as OA. Regardless of the etiology, however, alterations in cartilage are central to the development of OA. Changes in proteoglycan and collagen content and integrity arise as a consequence of adaptive chondrocytic responses to changes in the biomechanical environment (68). New knowledge of mechanisms involved in OA-related cartilage degradation has permitted the definition of novel targets for possible therapeutic intervention. Two such agents are currently in phase III trials at this time.

Calcitonin is a hormone that has a normal physiologic role in calcium homeostasis and, when administered subcutaneously or intranasally, has been shown to have effects on osteoclasts, maintains and/or increases bone density (69), and has been approved by the FDA for treatment of postmenopausal osteoporosis. More recent studies have also demonstrated an effect of calcitonin on cartilage. Ex vivo studies with cartilage explants demonstrated inhibition of matrix metalloproteinase activity and cartilage degradation, and in animal models of OA, calcitonin has been shown to have beneficial activity on bone and cartilage (70, 71). In a 14-day study in people with OA, an oral formulation of salmon calcitonin (SCT) was shown to have pharmacologic activity on cartilage, reducing serum levels of type II collagen compared with placebo (72) (Figure 3). As a peptide hormone, calcitonin would not be expected to be able to be administered orally. However, absorption of SCT after oral intake has been made possible by a novel formulation, combining the peptide hormone with 5-CNAC (8–[N-2-hydroxy-5-chlorobenzoyl]–aminocaprylic acid), an enhancer of GI peptide absorption (73). Based on its demonstrated activity on cartilage, oral SCT is currently under investigation in a 2-year, phase III, randomized, placebo-controlled trial in OA, with the primary end point being joint space width in the medial tibiofemoral knee joint in the signal knee measured by radiographs (74).

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Figure 3. Time course and area under the curve of urine C-terminal crosslinking telopeptide of type II collagen (CTXII) assay following dosing with 0.6 mg of salmon calcitonin (SCT; open circles), 0.8 mg of SCT (solid circles), and placebo (dotted line). Dosing is for treatment day 14, with doses given at 8:00 AM and 5:00 PM. Values shown are the levels relative to the predose concentration measured in blood samples taken immediately prior to dosing at 8:00 AM. Crea = creatinine.

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Cartilage degradation in OA is believed to be closely associated with an increased inflammatory state within the tissue, and along with a number of other inflammatory mediators, NO has been posited to play an important role in these processes. In human OA, one isoform of NO synthase, inducible NO synthase (iNOS), has been shown to be present and highly expressed; similarly, in animal models of OA, iNOS is up-regulated as well in various pain states (75, 76). These findings, coupled with the report of elevated levels of peroxynitrite in OA, have led to the suggestion that inhibitors of iNOS may be beneficial in preventing cartilage destruction and relieving pain in OA. To test this hypothesis, a specific iNOS inhibitor, SD-6010, is being investigated in a 2-year, phase II/phase III, randomized, placebo-controlled trial in OA, with the primary end point being the progression rate of joint space narrowing in the study knee (77). Data from earlier human trials and from animal studies that have been completed are not available in published form at this time.


  1. Top of page
  2. Introduction
  3. Approaches to efficacy
  4. Approaches to safety
  5. Disease modification
  6. Discussion

New pharmacologic agents with unique mechanisms of action are being actively explored to treat the signs and symptoms of OA as well as the cartilage destruction that is at the basis of the disease process and its progression. As we develop further understandings of pain and the pain pathways, the development of agents targeting specific steps is to be expected and should result in drugs with potentially greater efficacy while demonstrating different, and preferably fewer, side effects than currently available agents. Similarly, our understanding of the role of altered biomechanics, changes in bone, and subsequent chondrocytic-mediated processes in driving inflammation and the degradation of cartilage, the hallmark of OA, continues to lead to the development of new agents to test. Future progress in identifying OA disease-modifying agents will also depend heavily on currently ongoing work, exemplified by the Osteoarthritis Initiative (9), that will help define optimal approaches to measurement, definition of end points, and potential use of biomarkers to reflect disease and drug activity as well as to act as surrogate end points.


  1. Top of page
  2. Introduction
  3. Approaches to efficacy
  4. Approaches to safety
  5. Disease modification
  6. Discussion

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Schnitzer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Schnitzer.

Acquisition of data. Schnitzer.

Analysis and interpretation of data. Schnitzer.


  1. Top of page
  2. Introduction
  3. Approaches to efficacy
  4. Approaches to safety
  5. Disease modification
  6. Discussion
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