Osteoarthritis (OA) is the most common form of arthritis and is a whole joint disease (not just cartilage) eventually leading to joint failure. The ageing of the Australian population has meant the number of joint replacements for osteoarthritis in Australia is increasing rapidly and is now approaching 120,000 per annum in Australia. Our understanding of […]
Osteoarthritis (OA) is the most common form of arthritis and is a whole joint disease (not just cartilage) eventually leading to joint failure. The ageing of the Australian population has meant the number of joint replacements for osteoarthritis in Australia is increasing rapidly and is now approaching 120,000 per annum in Australia.
Our understanding of OA has improved dramatically in the last decade primarily due to better ways of imaging the disease but also due to better understanding of metabolic and genetic pathways involved in this disease.
Currently, the definition of OA utilises a combination of symptoms plus or minus radiographic criteria. These criteria are non-specific, meaning many people over 50 can be diagnosed as having OA on the basis mainly of pain.
X-ray grading scales mainly assess osteophytes and joint space narrowing in a two- dimensional plane, which can miss much pathology. For example, in our TASOAC cohort 10% have osteophytes on radiographs but 85% have them on MRI and these ‘hidden’ osteophytes are associated with symptoms and structural change.
MRI provides a much more in-depth view of structures within the knee. It can directly visualise knee structures, including cartilage volume, cartilage defects, cartilage biochemistry, meniscal pathology, bone marrow lesions, subchondral bone size and fat pads.
Many of these abnormalities are very common in asymptomatic elderly subjects, but the literature is maturing in terms of their association with pain and structure, with mainly consistent evidence for bone marrow lesions, synovitis/effusion, meniscal tears and cartilage defects. These changes are associated with pain and cartilage loss and some have the capacity to change over time making them ideal targets for therapy.
STATE OF THE ART THERAPY
This is actually disappointing for OA.
There have been major developments in most areas of rheumatology, but OA has been relatively neglected.
The mainstay of therapy is weight loss, exercise, paracetamol, NSAIDs and some nutraceuticals such as glucosamine and chondroitin. Many of these therapies are controversial and their benefit is much less than patients desire. There is an ongoing opioid epidemic but, there is only marginal evidence of efficacy and substantial evidence of toxicity with a much higher death rate in subjects taking narcotics for chronic non-cancer related pain.
Surgery is effective (hip more than knee) but very costly and often the decision on who should have surgery is not fully informed, for example, patients with fibromyalgia do much worse from surgery but this is not screened for in orthopaedic practice.
Given the limitations of current therapy, there is substantial scope for improvement.
The rest of this opinion piece will speculate on what the future might hold. Given that history is littered with educated people making predictions that subsequently turned out to be totally wrong, the reader should feel free to exercise a degree of scepticism.
PERSONALISED PAIN THERAPY
One of the oft-cited hypotheses for why OA therapy is so modest in terms of benefit is that current therapy takes a one-size-fits-all approach despite there being a multitude of different pathologies at joint level or even at whole person level.
The literature is now replete with an ever-expanding repertoire of OA phenotypes which is generating much scope for testing these ideas.
BONE THERAPY
This is the most exciting area of OA treatment but the path of development has not been smooth. Bone marrow lesions in the knee have almost ideal characteristics for intervention with the exception being that the MRI appearance is non-specific and can be seen with other conditions such as osteonecrosis or trauma.
Initial targeted trials look very promising with much greater improvements in pain seen with zoledronic acid or neridronate. The phase 3 trials presented in 2018 however have dampened this enthusiasm, with the exception being treatment for early disease.
Denosumab and zoledronate have both shown promise for spinal Modic type 1 change which could be considered the spine equivalent of a knee bone marrow lesion. There are many trials under way and this area will be much further developed in five years’ time.
INFLAMMATION
It is clear that inflammation is present in many patients with OA, with as many as 50% having effusion/synovitis on MRI. This inflammation is of a lower grade than that seen with rheumatoid arthritis but expresses many similar cytokines suggesting therapies aimed at these cytokines should be effective.
However, trials of fish oil, hydroxychloroquine and TNF inhibitors have not met their primary endpoints (despite some tantalising post-hoc analyses) and can’t be recommended. Corticosteroid injections provide short-term benefit and triamcinolone may actually be harmful for structure. Diacerein (and perhaps other IL-1 inhibitors) seem to be modestly effective but need to be tested in a model where all subjects have effusion/synovitis. Such trials are underway.
Methotrexate remains of uncertain benefit, but I suspect many of us use it. NHMRC recently funded a trial to test its effectiveness in erosive hand OA. One might have expected these trials to be more positive. The fact they weren’t brings into question the causal role of inflammation in OA, or perhaps just reflects that much higher doses are needed to get benefit.
METABOLIC
It is clear that obesity affects OA through multiple pathways. Thus, there are many potential targets in the overweight patient (which is most of our patients).
Weight loss leads to some benefit but maybe not as much as you would predict and prevention of weight gain seems much more effective. However, lap banding is as effective as knee replacement in overweight individuals and is much cheaper.
There is epidemiologic evidence that both statins and metformin may be effective through multiple mechanisms and these should be tested in trials. Recent studies have implicated arginine and phospholipids in late-stage OA which may be amenable to intervention.
CENTRAL PAIN
Duloxetine is effective for knee OA pain but is quite toxic. It has also been unclear if this benefit is global or it is mainly seen in those with associated fibromyalgia.
It should be possible to test this in trials and a trial of venlafaxine in knee OA is currently underway testing this hypothesis and trying to identify a fibromyalgia score which will lead to the greatest benefit.
PERIPHERAL NERVE PAIN
This is an area of acute interest, with some initial trials showing great improvement in pain for anti NGF and TRPV1 antagonists. But this appears to come at the cost of faster disease progression for the former, and probably for the latter as well due to a Charcot-like effect on joints. My view is that they need to trial homeopathic doses which will lead to less pain relief and thus less risk of damage.
GENE-BASED OR GUIDED THERAPY
Here my prediction is negative. The gene studies in OA have largely been a waste of money, shown very little and will be unlikely to ever be able to be used at a patient level.
They may help in identifying new targets for therapy if they can take the structure-based approach discussed above and move away from X-ray or joint replacement (a composite measure of all the structural changes and pain and income).
STRUCTURE MODIFICATION
Structure modification remains the holy grail of OA therapy. It isoften sought but rarely found.
Longitudinal radiographs have major problems with measurement error and positioning. Based on our studies, most measure change in meniscal pathology more than cartilage so should be jettisoned from trials.
There are many other ways of measuring joint health such as cartilage volume/thickness and bone marrow lesions which have excellent metrics. Even so, there are some issues.
An agent that reduces both pain and structural change is ideal but how do you treat something that slows damage but has no effect on symptoms or an agent that helps symptoms but speeds up damage.
My view is that joint replacement (or meeting the criteria for virtual joint replacement) is a better outcome to study in large trials which are supported by preliminary data in MRI trials.
However, this is my opinion and I have only minor influence on decisions of the FDA (the FDA have accepted bone marrow lesions as both an indication and an outcome measure based on one of my trials).
My hope for this area is that the many OA research organisations worldwide put aside their financial ambitions and present a consensus approach to move this area forward. This is my least optimistic prediction.
Despite roadblocks, detours and negative trials, I remain optimistic about there being substantial progress on OA into the future.
Graeme Jones, MD, FRACP, works for the Menzies Institute for Medical Research, Hobart. The author’s salary is provided by NHMRC. He has no other conflicts of interest with regard to this work.
