Risk Factors for OA Development

Genetics certainly play a role in the development of OA. The overall genetic contribution to OA can be estimated through the use of twin studies, where a comparison is made between the “shared” genetic risk of identical, monozygotic twins and compared to the “half-shared” genetic risk of fraternal, dizygotic twins. Older twin studies of hip OA studies, including the UK Adult Twin Registry, have estimated genetic contributions to hand OA at around 50% and hip OA at around 60% [31]. A newer study published in 2018 used more advanced data modeling techniques to adjust for modifiable risk factors and included a large number (n = 18,058) of twins from Norway [32]. Their model suggested that 73% of hip and 45% of knee variance was genetically determined.

Investigations into individual genetic risk alleles (single nucleotide polymorphisms, SNPs) in OA have been somewhat less fruitful, and are quite specific to joint site (hand vs. hip vs. knee). The largest genome-wide association studies (GWAS) have been performed in knee and hip OA. The only risk alleles that have been independently confirmed for knee OA include mutations in the collagen gene COL11A1 and vascular endothelial growth factor VEGF [33]. Another gene, growth differentiation factor 5 (GDF5), deserves special mention. This gene and the rs143383 SNP located within it have been strongly associated with both hip and knee OA in both humans and mice; furthermore, the risk allele causes reduced gene expression in joint tissues [34–37]. GDF5 is also under epigenetic control via changes in DNA methylation, and this conspires with underlying genetic changes to modulate gene expression further [38]. Relatively fewer genetic studies have been performed in hand OA; in fact, only two large GWAS studies have been completed to date. The first study, in 2014, found an association with the retinaldehyde dehydrogenase gene ALDH1A2, involved in vitamin A metabolism [39]. The second study, published in 2018, identified changes within the matrix GLA protein (MGP) gene, involved in cartilage calcification [40].

Epigenetics also play a role in OA development, as mentioned previously. A number of epigenome-wide association studies have been performed in both hip and knee OA, and have both identified and confirmed a number of genes and genetic pathways as strongly dysregulated in OA cartilage and subchondral bone [6, 12, 41–44], including a number of inflammatory pathways and inflammation-related transcription factors. As in genetics, epigenetic patterns are distinctly geographic (different in knee OA samples compared to hips).

The strongest environmental risk factor for OA is advanced age, although how exactly age contributes to OA is still somewhat unclear. Aging increases levels of c-reactive protein (C-RP), interleukin 6 (IL6), and tumor necrosis factor alpha (TNFα), a phenomenon known as “inflammaging” [34]. Levels of systemic inflammatory mediators correlate with knee pain and decreased functional capacity in older adults with knee OA [35, 36]; furthermore, elevated levels of C-RP and IL6 are found in patients with knee OA and the level of these markers are related to the risk of OA progression [37, 38]. A dysregulated epigenome appears at least partly responsible for this phenomenon [39]. For example, using a DNA methylation-based age estimator, OA cartilage has been shown to be epigenetically “older” than control cartilage [45]. Autophagy, the process by which normal cells “clean up” old proteins, is defective in both aging and in OA articular cartilage and has been proposed as another possible explanation for the increased risk of OA associated with aging [46]. Supporting this theory, aged mice also demonstrate a reduced autophagy phenotype in cartilage, and this defect precedes the development of OA-like cartilage damage [47].

Another quite important risk factor for OA development is obesity. Notably, like epigenetic and genetic risk, the risk conferred by obesity varies by joint. In knees, those with the highest body mass index (BMI) have an approximate 8.5-fold increased risk for OA compared to individuals with a “normal” BMI [48]. Even more striking, each 2-unit increase in BMI equates to an increase in OA risk by 1.36-fold. A recent meta-analysis of 14 studies confirmed this finding that being overweight increased the risk of knee OA by 2.45-fold and obesity carried an increased risk of 4.55-fold [49]. In hips, the risk is somewhat lower, with increased risk of around 1.1-fold [50]. Hand OA is also associated with obesity, with increased risk in the 1.1-fold range [51]. How obesity contributes to OA pathogenesis is complex and is not simply related to increased stress on the joint itself; rather, it likely also involves the increased basal systemic inflammation related to obesity, as well as an increased production of “adipokines,” inflammatory signaling molecules originating in adipose tissue [52, 53].

Trauma and “traumatic” occupations also increase the risk of OA. Dock workers, agricultural workers, carpenters, and cleaners have an increased risk of OA [54, 55]. Perhaps counterintuitively, running does not carry an increased risk for OA [56], nor does running worsen OA when it already is present [57]. However, “elite” athletes, mainly those with a history of high impact activities, do have a higher chance of developing OA as they age [58]. A history of previous injury is strongly associated with OA; this is perhaps best seen in the military population, where soldiers are more than five times more likely to develop PTOA compared to the general population. Soldiers with a history of knee joint trauma during active duty have a 5.7-fold increased risk of knee OA compared to those without a history of trauma [59].

Clinical Presentation

Other frequently-occurring signs and symptoms include bony hypertrophy, reflecting osteophyte formation (see section “Pathophysiology”), which tends to occur on marginal surfaces of OA-affected joints. Osteophyte formation and/or cartilage degradation can lead to frank joint deformities, which subsequently lead to joint instability. In fact, joint “buckling” or “giving out” is a very common symptom, particularly of knee OA. Over a quarter of patients with physician-diagnosed knee osteoarthritis will report knee instability symptoms, and a substantial number of these also report falls. Frequent falls in elderly OA patients can lead not only to fractures and other sequelae, but perhaps even more damaging, to fear of falling and poor balance confidence which can reduce physical activity further and worsen pre-existing deconditioning [64].

Hand OA generally affects the distal interphalangeal joints (DIP), first carpometacarpal joint (CMC, base of the thumb), proximal interphalangeal (PIP) joints, and occasionally the index and long finger metacarpophalangeal (MCP) joint, especially in cases associated with calcium pyrophosphate deposition disease. Like large-joint OA, hand OA is generally characterized by pain with activity. Some patients may complain mainly of stiffness, although this is generally less prolonged than autoimmune causes of hand arthritis. A frequent finding in hand OA are Heberden’s (DIP) and Bouchard’s (PIP) nodes. The appearance of these nodules is the result of early inflammation at the insertion of ligaments on the phalanges [65], further reinforcing the role of inflammation in OA. A less common but more aggressive variant of hand OA, known as erosive OA , is characterized by synovitis of the DIP joints with more extensive pain, erythema, and tenderness than one would expect of typical hand OA [66]. Erosive OA tends to progress more rapidly than traditional hand OA. Cartilage and joint capsule erosion lead to lateral DIP instability and sclerosis, causing characteristic “twisting” and lateral deviation of the distal phalanges, with eventual and spontaneous DIP fusion a common finding. As one might expect, this erosive form of OA carries with it worse functional outcomes [67].

Diagnosis

When the suspicion for OA is high based on clinical symptoms, there is not generally an indication for additional testing, and empiric treatment can commence. The presence of atypical symptoms may, however, indicate the need for additional workup; these include rapid progression of pain (imaging may be necessary here), a clear-cut periodicity of symptoms (periodic symptoms self-resolving after just a few days to weeks is suggestive of a crystal arthritis), or other constitutional symptoms such as weight loss, fevers, recent or current infections, etc. Testing for autoantibodies associated with rheumatoid arthritis (rheumatoid factor and anti-cyclic citrullinated peptide), along with systemic inflammatory markers (erythrocyte sedimentation rate or c-reactive peptide) can be useful in ruling out an autoimmune cause of arthritis symptoms in patients with a more inflammatory presentation.

Radiography is not generally indicated for the diagnosis of OA but can be useful in ruling out alternative causes for arthritis, making a diagnosis of erosive OA, and in monitoring the degree of cartilage loss if one is considering joint replacement. Moderately to severely affected OA joints are characterized radiographically by joint space narrowing (generally asymmetrical), subchondral sclerosis, marginal osteophyte formation, and the presence of subchondral cysts. Hand and knee radiographs are frequently obtained in patients with OA-like symptoms to rule out cartilage calcification, which is suggestive of concomitant calcium pyrophosphate deposition disease. Erosive OA of the hands is associated with a particular appearance of DIP joints, including cartilage erosion leading to a “gullwing” pattern in DIP joints and/or “sawtooth”-type pattern in PIP joints [70]. Magnetic resonance imaging (MRI) can allow for direct quantitation both of synovitis, cartilage thickness, and screen for the presence of chondral lesions. Although MRI screening and monitoring of OA is not routinely done, it can predict patients who will have subsequent clinical OA progression [71]. Finally, synovial fluid analysis is not generally indicated to diagnose OA; however, it can be quite useful in ruling out alternative diagnoses, particularly the crystalline arthropathies .

Treatment

First, modifiable risk factors should always be addressed. Weight loss should be discussed with every OA patient, and dietary changes made (including referral to a dietician if necessary) to achieve sustained weight loss. Several studies have indicated that even as little as 10% weight loss has substantial benefits in reducing OA-related pain and decreasing functional disability in OA patients. For example, a recent large study combined dietary and exercise interventions in knee OA patients and resulted in a mean weight loss of 11%. In the intervention group, significant reductions in pain and improvements in function were noted, along with better physical health-related quality of life scores and even reductions in serum levels of the inflammatory cytokine interleukin 6 (IL6) [72]. Bariatric surgery, both for the treatment of OA and as an adjunct to total joint replacement, has been the focus of recent interest. Although studies have shown that massive weight loss induced by bariatric surgery does improve both pain and serum inflammatory markers in knee OA [73], several studies have also shown that bariatric surgery before joint replacement does not improve postarthroplasty functional or pain outcomes [74]. There have not been definitive studies to indicate that one particular diet is any better than another for the treatment of OA symptoms, and no dietary supplements have been shown effective for OA.

Physical therapy should be a part of every OA prescription. Exercise in essentially any form is beneficial in OA and should be part of every OA treatment plan. There do not appear to be differences between land-based and water-based exercise from an efficacy standpoint, and the beneficial effects of exercise last for up to 6 months after cessation (although patients should be encouraged to continue an exercise regimen indefinitely) [75]. Tai Chi, a Chinese martial art practiced with slow, methodical movements and an emphasis on balance, has a similar benefit in improving OA pain, physical function, and quality of life when compared to physical therapy regimens, with the added benefit of improving depression in OA patients [76].

Pharmacologic treatment in OA consists of a stepwise approach to analgesia. The best practice guidelines for the treatment of knee and hip OA come from several national and international societies, including the Osteoarthritis Research Society International (OARSI), the American College of Rheumatology (ACR), and the American Academy of Orthopedic Research (AAOS). The most recently updated of these are the OARSI guidelines for the management of knee osteoarthritis [77], and will be the basis for the following recommendations. Contrary to popular practice, acetaminophen has little place in the modern treatment of OA, as it has been demonstrated in multiple meta-analyses to be no better than placebo at pain relief in OA [78]. The first question when treating a patient with OA regards their comorbidities. These include comorbidities which place the patient at moderate risk, including diabetes, advanced age, hypertension, cardiovascular disease (CVD), acute renal failure, history of gastrointestinal (GI) complications, depression, or physical impairment resulting in severe limitation of activity or exercise, including obesity. High-risk comorbidities include a history of a GI bleed, history of myocardial infarction, and chronic renal failure. Patients are then subdivided into knee-only OA or multijoint OA.

For knee-only OA without comorbidities, pharmacologic treatment may include nonsteroidal anti-inflammatory medications (NSAIDs), either “traditional” nonselective NSAIDs (i.e., naproxen), or COX-2-selective NSAIDs (i.e., celecoxib), or via topical application (i.e., diclofenac gel), or intra-articular (IA) therapies. Knee-only OA with comorbidities should avoid systemic nonselective NSAIDs and use instead IA treatments and topical NSAIDs. Multijoint OA benefits from systemic NSAIDs and IA treatments; generally, topical NSAIDs are not recommended, as the maximum dose may be inadequate to treat all involved joints. Multijoint OA in patients with comorbidities represents a challenge, with IA therapy and COX-2-selective NSAIDs being the preferred pharmacologic agents.

There have been surprisingly few head-to-head studies comparing the efficacy of various individual NSAIDs. One recent large meta-analysis including 76 individual trials suggested that the most effective oral NSAID for pain relief in OA was diclofenac at a dose of 150 mg total daily dose, followed by ibuprofen at 2400 mg total daily dose and naproxen at 1000 mg total daily dose [79]. This should be interpreted with caution, however, given the lack of direct comparison in published data. There was some concern recently over the cardiovascular safety of COX-2-selective NSAIDs (the one in the US market being celecoxib) when compared to nonselective NSAIDs; however, the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial, published in 2016, did not find evidence for an increased risk of celecoxib compared to either ibuprofen or naproxen [80]. One area where there is a clear difference based on COX selectivity is in the risk of GI bleed, where COX-2-selective NSAIDs are strongly superior to nonselective NSAIDs; in patients with a past history of GI bleed, topical NSAIDs should be used if at all possible, with COX-2-selective oral NSAIDs used cautiously, and consideration given to concomitant proton pump inhibitor therapy. Nonselective NSAID use should be avoided in these patients. Duloxetine, an oral serotonin-norepinephrine reuptake inhibitor (SNRI), is a nonopiate, non-NSAID alternative appropriate for OA treatment and has good evidence for its efficacy; it may be an appropriate choice in patients with contraindications for NSAID or IA therapy or to be used in combination with NSAIDs [81]. Other oral pharmacologic therapies with dubious evidence for efficacy (and not recommended) include glucosamine/chondroitin, diacerein, both oral and transdermal opiates, and risedronate.

IA corticosteroid injections should also be considered. IA steroids have strong evidence for pain improvement in the short term, although longer-term data are lacking. A trial published in 2017 also demonstrated a statistically significant increase in the rate of cartilage loss after 2 years of every-three-month short-acting steroid injection, although the incremental cartilage loss was not likely to be clinically significant [82]. An extended-release steroid preparation of triamcinolone for IA injection has been recently approved which may offer both extended symptom improvement and a reduction in systemic side effects owing to a reduction in acute diffusion of steroid out of the joint [83]. The other intra-articular therapy frequently used for knee OA, hyaluronic acid, does not have robust support in the literature and has received either an “inappropriate” or “not certain” recommendation from OARSI [77, 84].

Surgical treatment is the only definitive therapy available to physicians for knee and hip OA at the present time and demonstrates substantial pain relief and improvement of physical function that are better than the best pharmacologic management. The benefits of joint replacement for OA should not be overstated, however, as a measurable percentage (up to one-third in some studies) of patients have persistent symptoms following arthroplasty [85]. The morbidity and mortality associated with joint replacement is low but should always be carefully considered before a decision is made to go to the operating room, with patient age and the presence of medical comorbidities (diabetes, obesity, and cardiovascular risks) being the strongest predictors of poor outcomes [86].

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