Osteoarthritis: Updates On Etiology And Treatment

      Osteoarthritis: Updates On Etiology And Treatment

                                            Dr. KS Dhillon

Introduction

Osteoarthritis (OA) is a degenerative joint disease that usually affects the weight-bearing joints of the body and the hand[1]. 

According to the National Health Interview Survey (NHIS) in the USA between 2010 and 2012, 52.5 million adults have been diagnosed with osteoarthritis [2]. OA produces functional disability, pain, stiffness, and reduces mobility. In the USA the health care expenditure for OA is about $185.5 billion a year [3]. The productivity loss due to OA in the USA is between 0.25 and 0.50% of the Gross Domestic Product (GDP)[4].

Etiology of OA

Osteoarthritis (OA) has always been considered as a “wear and tear” disease where cartilage loss occurs. It was believed to be due to overload on weight-bearing joints, anatomical joint incongruency, and genetic fragility of the cartilage matrix. This was based on the observation that chondrocytes have low metabolic activity and no ability to repair cartilage. Furthermore, articular cartilage cannot respond by inflammatory activity once damaged, because it is avascular and not innervated.

The paradigm has made a major shift following progress in molecular biology in the 1990s.

Osteoarthritis is an inflammatory disease. Although initially OA was considered cartilage driven, now it is certain that OA is a much more complex disease with inflammatory mediators released by cartilage, bone, and synovium [5,6,7]. The source and type of mediators vary with OA phenotypes [8].

Many soluble mediators such as cytokines and prostaglandins can increase the production of matrix metalloproteinases (MMPs) by chondrocytes leading to an inflammatory process. It is now established that synovitis is a critical feature and driver of OA. Experimental data is now available which shows that subchondral bone may have a substantial role in the OA process. It acts as a mechanical damper, as well as a source of inflammatory mediators implicated in the OA pain process. It is also implicated in the degradation of the deep layer of cartilage[9]. 

How the synovium becomes inflamed remains controversial. 

One of the more widely accepted hypotheses is that cartilage flakes or fragments fall into the joint and they come in contact with the synovium. The synovial cell considers these fragments as foreign bodies and the synovial cells react by producing inflammatory mediators which are found in synovial fluid. These mediators activate superficial chondrocytes to synthesize metalloproteinases which then degrade cartilage.

Synovial angiogenesis is induced by the mediators and the mediators also increase the synthesis of inflammatory cytokines and matrix metalloproteinases by synovial cells. Hence, the synovitis perpetuates the cartilage degradation leading to OA [9].

Macrophages in the synovium are key players in OA pathology. They generate several MMPs in the synovium and also generate neoepitopes in the cartilage during an early phase of the disease. Macrophages therefore can contribute to cartilage damage[10].

Innate immunity can also trigger local inflammation in patients with OA. The innate(non-specific) immune system comprises of cells and mechanisms that defend the host against infection in a nonspecific manner. This immune system is triggered after the binding of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) on pattern-recognition receptors (PRRs) [11,12]. 

The PRRs include membrane-associated PRRs (TLRs), cytoplasmic PRRs (nucleotide-binding oligomerization domains (NODs), and secreted PRRs PAMPs are recognized by TLRs as well as by other PRRs. 

The level of TLRs are increased in OA cartilage lesions[13]. TLR-2 and TLR-4 ligands such as low molecular-weight hyaluronic acid, alarmins, fibronectin, and tenascin-C have been found in OA synovial fluid[14,15,16]. These factors are known to induce catabolic responses in chondrocytes as well as inflammatory responses in synovial cells. 

Proteins such as S100A8 and S100A9 are known to produce synovial activation and cartilage destruction. High levels of these proteins may cause joint destruction in OA[17]. Proteins from OA synovial fluid can induce macrophage production of inflammatory cytokines via TLR-4 signaling[18]. 

There is some degree of low-grade systemic inflammation in OA. Inflammatory mediators produced locally are known to contribute to cartilage degradation and synovial cell activation. Inflammatory events occurring within the joint can be reflected outside the joint in plasma as well as in peripheral blood leukocytes (PBLs) in patients with OA. It is well known that the levels of several inflammatory mediators are higher in the serum of patients with OA than in healthy patients[17,19,20].

A study by Attur et al[21] assessed gene expression profiles in PBLs from

patients with OA and they found a subset of individuals with activated PBLs. Cluster analysis showed 2 distinct subgroups among the patients with OA. In one group there was an increased level of IL-1b and in the other group, there was normal expression. They found that in patients

with the inflammatory “IL-1b signature” the pain scores were higher and

there was decreased function and these individuals were at higher risk of radiographic progression of OA.

There is a two-fold increase in the risk of hand OA in obese patients[22].

Mechanical effect of overload cannot be the cause of this increased risk. What then is the cause of this increased risk? 

The increased risk is due to adipokines, which provides a metabolic link between obesity and osteoarthritis. Adipose tissue is now considered to be a real endocrine organ which releases several factors, including cytokines, such as interleukin 1 and tumour necrosis factor α. Adipose tissue also releases adipokines, such as leptin, resistin, visfatin, adiponectin, and so on. 

These adipokines exhibit pleiotropic functions that are mediated through both central and peripheral systems, including lipid and glucose metabolism, reproductive functions, haemostasis, blood pressure regulation, angiogenesis, insulin sensitivity, and bone formation[23]. Recent studies show that osteoarthritis is a systemic disorder in which dysregulation of lipid homeostasis is one of the pathophysiological mechanisms leading to osteoarthritis[24].

There is a link between atherosclerosis and OA. There is an independent association between carotid intima media thickness with the prevalence of knee OA  and carotid plaque with distal interphalangeal OA[25]. One hypothesis for this link relies on the inflammatory theory of atherosclerosis.  Oxidized lipids are the most likely triggering factors for cytokine production.  Concentration of plasma adipokines is known to be associated with metabolic syndrome. There is an association between concentrations of serum adipokine  and severity of OA[26,27]. Systemic adipokines have been found to be associated with local synovial tissue inflammation[28]. 

The infrapatellar fat pad in the knee has been found to be a potential source of adipokines such as IL-653[29].

In patients with knee OA, massive weight loss by gastric surgery improves pain and function and decreases low-grade inflammation. There are changes in levels of joint biomarkers with weight loss and this suggests a structural effect on cartilage[30]. OA, hence, can be initiated and/or aggravated by the presence of a systemic low-grade inflammation. 

OA is a prototypic age-related disease. External mediators such as cytokines and proteases trigger inflammation. The inflammation leads to increased production of inflammatory mediators and also to a lack of elimination of oxidated proteins. These oxidated proteins increase the concentration of reactive oxygen species (ROS) in the cells, adding to the oxidative damage which triggers inflammation[31]. Oxidative stress can cause cell senescence including chondrocyte senescence[32].

Advanced glycation end products (AGEs) are produced by a non-enzymatic process in aging tissues. These end products weaken cartilage by modifying its mechanical properties. 

Treatment of Osteoarthritis

There are limited therapeutic approaches for OA because of its complex pathophysiology. A core set of evidence based-modalities of therapy has been established for management of OA. These modalities included non-pharmacological and pharmacological modalities. 

Non-pharmacological modalities include patient education and awareness, physical exercises and rehabilitation aids. 

Physical therapy in the form of mind–body exercises, strength training exercises and aerobic exercises has shown good outcome provided patients are consistently compliant with their therapy [33]. Nutritional supplements such as dimethyl sulphoxide and methylsulfonylmethane have been tried with some success [33].

The pharmacological modalities include prescription of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors agents and some even give opioid prescription. 

NSAIDs are the most commonly prescribed agents for treatment of pain and stiffness in patients with OA. NSAIDS have both anti-inflammatory and analgesic effects. They inhibit biosynthesis of prostaglandins at the level of the cyclooxygenase enzyme. 

Different NSAIDs belong to different chemical class. They, however, all block production of prostaglandins (PGs). Prostaglandin blockage is accomplished by inhibition of the activity of the enzyme PGG/H synthase, which is also known as cyclooxygenase (COX). There are two COX  isoforms namely COX-1 and COX-2. These two COX differ in their tissue distribution and regulation.

The two isoforms serve different biological functions. COX-1 is expressed under basal conditions and it is involved in biosynthesis of PG serving homeostatic functions. COX-2 expression on the other hand is increased during inflammation and other pathologic situations [34]. The clinical effects of NSAIDs are evaluated in terms of effects on the different COX isoforms.  COX-2 inhibition by NSAIDs blocks PG production at sites of inflammation or other forms of tissue damage. Inhibition of COX-1 in certain other tissues such as platelets and the gastroduodenal mucosa can lead to common adverse effects of NSAIDs such as bleeding and gastrointestinal ulceration [35].

There are 3 common classes and 9 subclasses of NSAIDs [36]. 

Classification of common NSAIDs

Class                            Subclass                Drugs

Carboxylic acids     Salicylic acids      Acetylsalicylic acid (aspirin)

                                                                     Diflunisal (dolobid)

                                                                     Trisalicyliate (trilisate)

                                                                     Salsalate (disalcid, amigesic, salflex)

                                     Acetic acids       Diclofenac (voltaren, cataflam)

                                                                     Etodolac (lodine)

                                                                    Indomethacin (indocin)

                                                                   Sulindac (clinoril)

                                                                   Tolmetin (tolectin)

                                                                  Ketorolac (toradol)

                                 Propionic acids       Flurbiprofen (ansaid)

                                                                Ketoprofen (orudis, oruvail)

                                                                Oxaprozin (daypro)

                                                                Ibuprofen (motrin, advil, duexisc)

                                                                Naproxen (naprosyn, aleve)

                                                                Fenoprofen (nalfon)

                               Fenamic acids        Meclofenamate (meclomen)

Enolic acids       Pyrazolones        Phenylbutazone

                               Oxicams              Piroxicam (feldene)

                                                              Meloxicam (mobic)

                                                              Nabumetone (relafen)

Nonacidic                                   Nabumetone (relafen)

COX-2 selective   Sulfonamide       Celecoxib (celebrex)

                                  Sulfonylurea       Etoricoxib (arcoxia)

                                  Nonacid       Lumiracoxib (prexige)

Most traditional NSAIDs such as diclofenac inhibit both COX isoforms. There are, however, some differences in the relative potency for COX-1 and COX-2 inhibition. COX-2 selective NSAIDs such as celebrex lack inhibition of platelet function.

Traditional NSAIDs, such as diclofenac and meloxicam show some selectivity for inhibiting COX-2 over COX-1. NSAIDs such as celebrex, valdecoxib, rofecoxib, tend to enhance COX-2 selectivity. 

There is a common spectrum of clinical toxicities among the various NSAIDs. The frequency of particular side effects varies with the compound [36]. 

Toxicities of NSAIDs

Organ system         Toxicity

Gastrointestinal Dyspepsia

                               Esophagitis

                              Gastroduodenal ulcers

                              Ulcer complications (bleeding, perforation obstruction)

                              Small bowel erosions and strictures

                             Colitis

Renal            Sodium retention

                           Weight gain and edema

                           Hypertension

                           Type IV renal tubular acidosis and hyperkalemia

                           Acute renal failure

                           Papillary necrosis

                           Acute interstitial nephritis

                           Accelerated chronic kidney disease

Cardiovascular   Heart failure

                           Myocardial infarction

                           Stroke

                           Cardiovascular death

Hepatic          Elevated transaminases

Asthma/allergic  Aspirin-exacerbated respiratory diseases

                            Rash

Hematologic       Cytopenias

Nervous             Dizziness, confusion, drowsiness

                            Seizures

                           Aseptic meningitis

Bone                   Delayed healing

Renal effects of NSAIDs

A vital role is played by prostaglandins in solute and renal vascular homeostasis. Sodium retention occurs in about 25% of patients who are treated with NSAID. This is particularly apparent in patients who have mild heart failure or liver disease [37]. Sodium retention can lead to weight gain and peripheral edema. It may also cause clinically important exacerbations of congestive heart failure.

NSAIDs can affect the blood pressure. Average increases in mean arterial pressure of between 5 and 10 mmHg has been seen in patients on NSAIDs. NSAIDs use increases the risk of initiating antihypertensive therapy in older patients. NSAIDs use increases the risk of incident hypertension in both males and females [38,39]. NSAIDs are also known to attenuate the effects of antihypertensive agents such as β-blockers, diuretics and angiotensin-converting enzyme inhibitors, thereby interfering with control of blood pressure.

NSAIDs can cause deleterious effects on kidney function. They affect solute homeostasis, maintenance of renal perfusion and glomerular filtration. NSAIDs produce qualitative changes in urinary prostaglandin excretion, glomerular filtration rate, sodium retention. Patients treated with NSAIDs can develop hyporeninemic hypoaldosteronism syndrome which is characterized by type IV renal tubular acidosis and hyperkalemia [37]. The degree of hyperkalemia is usually mild. Patients with renal insufficiency,  diabetes mellitus and those on angiotensin-converting enzyme inhibitors or potassium-sparing diuretics may be at greater risk.

NSAIDS are known to produce acute renal failure though it is uncommon. This failure is caused by vasoconstrictive effects of NSAIDs and is fortunately reversible. Renal failure is usually seen in patients who have a depleted intravascular volume such as in patients with congestive heart failure, cirrhosis, or renal insufficiency [37]. Excessive reduction in medullary blood flow can lead to papillary necrosis that can result from apoptosis of medullary interstitial cells . Inhibition of COX-2 may be a predisposing factor for renal failure [40].

Idiosyncratic reaction accompanied by massive proteinuria and acute interstitial nephritis is also known to occur with the use of NSAIDs. Fever, rash, and eosinophilia due to hypersensitivity can also occur. 

Aspirin and acetaminophen use has been associated with nephropathy leading to chronic renal failure [41]. 

Hepatic effects of NSAIDS

In about 15% of the patients taking NSAIDs small elevations of one or more liver tests can occur. Upto 3 times or more elevations of ALT or AST may be seen in about 1% of the patients. This elevation of levels usually produces no symptoms. Discontinuation or reduction in the dosage of NSAIDs usually results in normalization of the trans-aminase values. Rarely fatal outcome can be seen with all NSAIDs. Hepatic adverse events are more likely to be seen with diclofenac and sulindac [36].

Cardiovascular effects of NSAIDs

Risk of adverse cardiovascular events associated with NSAID use came into the limelight with the introduction of COX-2-selective NSAIDs into clinical practice. Rofecoxib (Viox), a potent COX-2 inhibitor was shown to have a substantially increased risk of stroke and myocardial infarction and because of that it was removed from the market [42,43].

The cardiovascular risk for all NSAIDs is related to the degree of COX-2 inhibition and an absence of complete inhibition of COX-1 [44]. The risk of myocardial infarction increases with treatment duration and the daily dose of NSAID [44]. 

COX-2 inhibition is not the only mechanism that contributes to cardiovascular complications. Other actions of NSAIDs which produces cardiovascular complications include their effects on blood pressure, nitric acid production, endothelial function, and other renal effects [42,45,46]. The risk of cardiovascular complications is significantly higher in patients with pre-existing coronary artery disease.

Ibuprofen and some other NSAIDs can interfere with the irreversible inhibition of platelet COX-1 by aspirin. This can increase the risk of  cardiovascular hazard in patients who are taking aspirin [44]. 

The incidence of myocardial infarction, stroke and cardiovascular death is low with use of NSAIDs.  All NSAIDS including COX-2-selective NSAIDs except naproxen carry an increased risk of myocardial infarction. Naproxen has the lowest risk for cardiovascular complication as compared to other NSAIDs [47]. Lower doses and once-daily regimens are associated with lower relative risks of cardiovascular complications.

The use of NSAIDs is associated with reduced sodium excretion, volume expansion, increased preload, as well as hypertension. Therefore, as a result of these properties, patients with pre-existing heart failure are at risk of decompensation. Older patients are at a higher risk for heart failure exacerbation.

Gastrointestinal effects of NSAIDs

Castellsague et al [48] carried out at systematic review and meta-analysis to examine the relative risk (RR) of upper GI complications including upper GI bleeding, perforation and peptic ulcers in patients on NSAIDs. They found an increased risk of upper GI complications across all 16 NSAIDs they studied. Their data showed that the risk was lowest for celecoxib and aceclofenac and highest for azapropazone and ketorolac. They also found that risk was dose dependent. Higher the dose higher the risk of GI complications.

Another meta-analysis [49] which examined the relationship between the use of NSAIDs and upper GI complications, such as bleeding, peptic ulcer perforations and obstructions found that there was an elevated risk of GI complications with use of all NSAIDs studied. Data was available for naproxen, ibuprofen, and diclofenac, as well as for the COX-2 inhibitors etoricoxib, rofecoxib, lumiracoxib and valdecoxib. The risk was higher for ibuprofen and naproxen as compared to diclofenac and COX-2 inhibitors.

Another study by Rahme et al [50] showed that patients on NSAIDs had a risk of developing GI adverse events that was 2.5 times higher than that in patients not taking NSAIDs.

Drug-drug interactions

Most NSAIDs are extensively bound to plasma proteins. They can displace other drugs from the binding sites or they may be displaced by other agents. Due to these interactions NSAIDs can increase the activity or toxicity of sulfonylurea, phenytoin, hypoglycemic agents, sulfonamides, oral anticoagulants and methotrexate [51]. 

The use of NSAIDs with methotrexate appears to be safe provided there is appropriate monitoring [52].

NSAIDs can blunt the antihypertensive effects of β-blockers, angiotensin-converting enzyme inhibitors, as well as thiazides, and lead to de-stabilization of blood pressure control [53].

Concurrent use of selective serotonin reuptake inhibitors (SSRI) and NSAID increases the risk of gastrointestinal complications such as bleeding. Care must be taken to avoid these negative outcomes by altering NSAID or SSRI therapy, or by using ulcer-protective drugs [54].

Drug reactions in older people

Physiology changes occur with age and these changes result in altered pharmacodynamics and pharmacokinetics. Drug clearance can be reduced due reductions in hepatic mass, blood flow, enzymatic activity, glomerular filtration rate, renal plasma flow and tubular function associated with aging. 

Adverse gastrointestinal and renal effects related to NSAIDs are more common in the older population. The cardiovascular risks are also more common in the elderly and there concerns of accelerated myocardial infarction and stroke. 

Concomitant use of NSAIDs and Aspirin lead to problems. Aspirin can increase the toxicity of NSAIDs. NSAIDs can also increase aspirin resistance. 

The use of proton pump inhibitors for gastric protection can interfere with the efficacy of antiplatelet agents such as clopidogrel [55].

Older individuals have more illnesses and therefore take more medications, increasing the possibility of drug-drug interactions. Hence the use of NSAIDs in older people must be closely monitored.

In patients with risk factors for NSAID toxicity, the lowest dose of a drug with a short half-life, only when it is needed, is probably the safest treatment option.

Other potential non-operative treatment methods for OA.

There are several other non-operative treatment methods used for the treatment of OA. These include the intra-articular injections of visco-supplements, corticosteroids, or blood-derived products and the use of glucosamines and chondroitin sulfate.

Controversy, however, exists about their efficacy and long-term safety in improving the patients' symptoms. 

Nutritional supplements such as dimethyl sulphoxide and methylsulfonylmethane have been tried with limited success. 

The American Academy Orthopaedic Surgeons (AAOS's) 2013 guidelines provided “Inconclusive” recommendations for both acetaminophen and intra-articular corticosteroids. For intra-articular steroids (IACS) there is a “lack of compelling evidence that has resulted in an unclear balance between benefits and potential harm” [56].

The OA Research Society International (OARSI) and American College of Rheumatology (ACR) 2012, guidelines, on the other hand, recommend both Acetaminophen (for those without relevant comorbidities) and IACS as appropriate for treatment of OA. They found that the potential benefits outweigh associated risks in certain clinical scenarios. 

The AAOS strongly recommends against the use of glucosamine and chondroitin. ACR conditionally recommended against the use of chondroitin and glucosamine [57]. The OARSI guidelines list chondroitin and glucosamine under the category of uncertain recommendation for symptom relief and non-appropriate recommendation for disease modification.

The AAOS recommends against the use of hyaluronic acid treatment, citing a lack of efficacy. The OARSI and ACR guidelines provide an “Uncertain” recommendation for intra-articular hyaluronic acid injections.

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