In recent years I’ve had to come to terms with the fact that my knees aren’t what they used to be. They’re creaky and they’re achy. They crackle when I sit down, and they hurt when I stand up.
The pain’s not awful, so I get on with my daily life – but it puts me off running, which keeps me active as I get older. And every stiff stride is accompanied by the same worry: could I be developing osteoarthritis?
I’m not alone in this concern. Knee pain is remarkably common.
A study in the journal Rheumatology found that half of those aged over 50 (my age bracket) had experienced knee pain in the previous year, and that a third had visited their doctor because of it.
The culprit? Osteoarthritis is the most common cause. Osteoarthritis is a disease of the joints, with large, weight-bearing bones, such as the knees and the hips, most likely to be affected.
Worldwide, it impacts more than 500 million people, causing pain and disability. But, despite being a common affliction, there are no drugs to slow its progression… yet.
Currently, in the early stages, you can only guess whether your niggly joints are arthritic or not.
That’s because diagnosis, which involves symptom assessment, examination and sometimes imaging, tends to happen in the late stages of the disease, when much of the damage is already done.
In fact, osteoarthritis is thought to begin years, or perhaps even decades, before symptoms escalate and the joint degenerates.
This means there’s a huge window of opportunity when the disease could be curtailed, if only there was a way to detect it earlier and stop it in its tracks.
With a billion people projected to have osteoarthritis by 2050, better diagnostics and new therapies have never been more needed. But as our understanding of the disease improves, researchers are now tantalisingly close to reaching that goal.
“There’s a lot of progress being made,” says Peter Gowler, research liaison manager at the charity Versus Arthritis, “yet osteoarthritis is very often dismissed.”
With new detection tests on the horizon, all that could be set to change.
Common risk factors of arthritis
Often, when people visit their doctor with symptoms, like mine, that are painful but manageable, they get told that they probably have a ‘touch’ of arthritis.
“But they wouldn’t say that for any other disease,” he says. People don’t talk about a ‘touch’ of heart disease or a ‘touch’ of multiple sclerosis.
At that point, the doctor’s diagnosis is a well-meaning guess. Although clinicians know what osteoarthritis ‘looks’ like in its final stages when the cartilage is well worn, there’s currently no test that predicts the progression of early knee pain.
We know there are things we can do to help prevent the disease. These include maintaining a healthy weight relative to your height and body type (ask your doctor if you are unsure what this means for you) and keeping active.
Contrary to popular belief, regular running has been shown to strengthen the knee joint and make osteoarthritis less likely.
But we also know there are risk factors that make the disease more likely. These include being older, being female, being overweight and having had a previous joint injury.
I score three out of four here, but while this checklist tells me I’d be wise to adopt preventative measures, it still doesn’t tell me if I’m in the early stages of the disease or not.
The mystery of early arthritis
“One of the big problems we have is we don’t have a way of defining what early osteoarthritis is,” says Gowler.
Early on, the changes that occur inside the joint are subtle, but standard imaging methods, such as X-rays and magnetic resonance imaging (MRI), aren’t sensitive enough to detect them.
At Aberdeen University, physicist Dr James Ross and colleagues have been developing a new type of MRI, called Field-Cycling Imaging (FCI).
Where traditional MRI uses a constant magnetic field to create images of the body, FCI can dial the strength of the magnetic field up and down.
“This allows us to see how different tissues respond to different magnetic fields, and see how their properties vary,” he says.
The team took cartilage samples from the knee joints of people with advanced osteoarthritis, and from healthy controls, and then imaged them with their benchtop FCI scanner. The machine is a prototype, so it doesn’t produce images, but it does generate graphs.
“Clinicians get excited about pictures,” says Ross. “Physicists, like me, get excited about graphs.”
Huge differences were seen in the signals from the two tissues, showing that FCI can distinguish osteoarthritic cartilage from its healthy counterpart. But Ross thinks the method is so sensitive that it could also pick up earlier changes.
The next step, which is currently underway, is to see if it can. As part of the PIOKNEER study, researchers will give annual FCI scans to 300 individuals who have sore knees but no diagnosed osteoarthritis.
The participants will be followed for five years, during which time some, but not all, are expected to develop osteoarthritis. The hope is that FCI will be able to detect early signs of the disease.
An arthritis blood test
In the US, meanwhile, researchers are developing a blood test. At Duke University, scientists analysed the blood serum (what’s left in the blood after the solids like blood cells have been removed) of 200 women.
Half of the women had been diagnosed with osteoarthritis, and the other half were healthy controls.
Although osteoarthritis is a disease of the joints, they found differences in the composition of the women’s blood. Specifically, levels of just six different proteins distinguished the two groups.
The discovery provides the basis for a diagnostic test, which the researchers found was 85-per-cent accurate in identifying the disease and 74-per-cent accurate in predicting its progression.
For some of the women, the test detected signs of the disease eight years before joint damage was visible on X-rays.
Here then is a test with the potential to spot those individuals with achy joints who, very likely, will go on to develop osteoarthritis.
This opens up a window of opportunity in which drugs, designed to tackle the core biology of osteoarthritis, can get to work.
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On the road to recovery
At present, the only treatments that exist for osteoarthritis focus on relieving symptoms, rather than countering the underlying disease.
People are often offered pain relief and anti-inflammatory medications, such as ibuprofen.
Steroid injections into the affected joint can sometimes bring temporary relief, while studies show that taking glucosamine, which is found naturally in joints, can improve pain and mobility in some of those with knee osteoarthritis.
Not everyone benefits, however – and when the disease progresses, the only option is surgery. Every year, around 1.5 million people have a total knee replacement.
This can improve mobility, but the procedure isn’t risk free. And while 80 per cent are happy with their new knees, many of the remainder struggle with ongoing pain.
That’s why scientists have been devising new, disease-modifying therapies. In the last 20 years, the treatments have been tested in hundreds of clinical trials, yet none have made it through to the clinic.
There are lots of reasons for this. Some just didn’t work, and others caused unpleasant side effects. But another key issue is the growing realisation that osteoarthritis isn’t a single disease.
“Osteoarthritis is complex,” says Prof Nidhi Sofat from St George’s, University of London. “There are lots of different subtypes.”
The sort of osteoarthritis that a menopausal woman develops, for example, will be different to the sort of osteoarthritis that develops in the wake of a knee injury.
Some people will have a strong genetic component to their disease. Others will have an internal biology that’s inherently more inflammatory, or worse at healing.
Each of these subtypes will have its own intricacies and its own bespoke biology. As a result, they’re likely to respond differently to different drugs.
The problem comes when all of the subtypes are lumped under the same label of osteoarthritis and chucked into the same clinical trial.
Drugs that could work for one of the subgroups might be being overlooked because they don’t work so well for the rest. The baby is being thrown out with the bathwater.
Even positive results can sometimes be misleading. In one clinical trial for a medication called tanezumab, pain improved, but inside the joint the disease accelerated.
Some of those taking the medicine needed knee replacement surgery sooner than was expected, prompting the FDA to pull the plug on the trial.
It’s important then, for new drugs not just to focus the pain caused by osteoarthritis, but on the physical changes that happen to the joint too.
Towards a cure for arthritis
For a long time, the focus was on cartilage. Cartilage is the smooth, slippery tissue that covers the surface of bones and helps them to move freely against each other.
In osteoarthritis, the cartilage deteriorates – but changes also occur to the bone, the lining of the joint capsule (called the synovium) and the tissues surrounding the joint.
Sofat’s research focuses on bone – specifically, tiny abnormalities inside the bone, called bone marrow lesions. In osteoarthritis, these lesions can form early, and co-localise with the pain that people feel.
By dissecting out the lesions and studying them, Sofat has shown they display a whole slew of molecular traits, including signals related to inflammation, pain, nerve and blood vessel formation, cartilage formation and bone cell activity.
It’s as if the bone is trying to make new joint tissue, Sofat explains, but then falling short.
There’s a mechanical component to the process, too. We already know that people whose joints are ‘a bit wonky’ – with ligament problems, for example, or spinal misalignment – are more likely to develop osteoarthritis. This is thought to be because the anomaly puts extra pressure on the joint.
Prof Deborah Mason from Cardiff University has demonstrated the molecular repercussions of this.
She grows osteocytes, which are the most common type of bone cell, in a squishy collagen gel, and then puts pressure on them – literally – using a 3D-printed mechanical loading device.
She has found that one burst of pressure changes the activity of more than 7,500 genes, many of which are related to inflammation, bone activity and pain pathways.
Studies like those by Mason and Sofat are important because they highlight some of the key biological changes that underpin the disease. This is helping to inform drug development.
Mason, for example, found that the activity of genes related to the neurotransmitter glutamate become altered. So, she has treated rodents with artificially-induced osteoarthritis, with an injection of a drug that lowers levels of the chemical.
The result? She discovered that it reduces pain, swelling and joint degeneration.
“If we give it very early on (at onset, before they get osteoarthritis) as a single intervention, we can reduce their disease at the end stage by about a third,” she says. “We find that quite promising.”
Now, the team are planning to test the drug in human clinical trials.
Meanwhile, Sofat is encouraged by a different drug, called pentosan polysulphate. The drug, which was previously used to treat bladder issues, is known to have both anti-inflammatory and cartilage-protecting properties.
After promising animal studies, a handful of small-scale, early-phase clinical trials have shown that the drug can reduce pain and stiffness, shrink bone marrow lesions, slow the loss of cartilage and improve joint function.
“We’re seeing change at the level of the whole joint,” says Sofat, who was involved in one of the trials.
The hope is that, by targeting early molecular changes with medications that affect the whole joint, osteoarthritis could be prevented. Drugs could modify the disease process and patients need never develop full-blown osteoarthritis at all.
Cellular solutions for arthritis
Another approach involves cell therapy. In the UK and elsewhere, cell therapy is available for early osteoarthritis in the guise of Autologous Chondrocyte Implantation (ACI).
The technique involves taking a small sample of cartilage from an undamaged spot in the problem knee, then growing those cells (known as chondrocytes) in culture for a few weeks, before returning them to the joint immobilised in a scaffold-like membrane.
(‘Autologous’ means the transplant cells come from the patient’s own tissue.)
At the RJAH Orthopaedic Hospital in the UK, experienced clinicians have treated more than 600 patients.
“In the first 12 months, most patients experience a good level of symptomatic relief,” says bioengineer Prof Karina Wright, who works at the hospital and Keele University. “This can be retained for many, many years.”
The technique is available in a dozen or so specialist hospitals in the UK, but its use is currently restricted on the NHS to a subgroup of patients who have minimal osteoarthritis, no previous knee surgery, and a hole in their cartilage that is bigger than a 1p coin (which, at 20mm or 0.8 inches in diameter, is a little bigger than a dime).
So, researchers are looking at other, cell-based options. Stem cells are attractive because they can make other cell types, and potentially be used to repair the damaged joint.
The focus is on a particular type called mesenchymal stem cells, which can be isolated from tissues (such as bone marrow and fat) and coaxed to make bone, cartilage and other tissue types. They also secrete useful molecules that stimulate tissue regeneration.
When they’re injected into the joint in animal models of osteoarthritis, they reduce inflammation, lessen pain, promote cartilage regeneration and improve joint function.
“There’s lots of preclinical evidence for mesenchymal stem cells,” says Wright. Indeed, the treatment is already available for some animals.
Some vets offer stem cell therapy for osteoarthritis in dogs and horses, and in 2023 an elderly gorilla called Liesel, who lives at Budapest Zoo in Hungary, had mesenchymal stem cell injections for her osteoarthritic knees and hip.
Meanwhile, human clinical trials are promising. At RJAH, for example, the ASCOT trial is just winding up.
Wright and colleagues have been comparing their tried-and-tested ACI treatment against mesenchymal stem cells and a combination of both cell types in 114 patients with osteoarthritis of the knee.
While the full results are yet to be published, Wright is optimistic. “We typically see an 80 per cent success rate with ACI,” she says, “and are seeing similar results across the whole trial.”
Slowly but surely, new drug treatments and cell therapies are emerging, as are early tests to identify those most at risk.
As researchers unravel the biology of the disease and what makes one person’s osteoarthritis so different from another’s, we move towards an era not of ‘one treatment fits all’ but of ‘which treatment fits best.’
At this point in time, I don’t know if my knee pain will develop into osteoarthritis, but I do know that if I can just hang on, in the not too distant future, there will be tests and treatments that help me.
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