‘Pain is normal’: The frustrating present and possible future of osteoarthritis treatment
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When it comes to patients with osteoarthritis adopting, much less maintaining, an exercise regimen to improve their condition, most rheumatologists have just one thought: “Easier said than done.”
However, because clinical trial programs for many potential OA drugs and surgical procedures have yielded mixed results, general wellness remains, at least for now, the optimal intervention for the condition.
Image: Ewa Roos, PT, PhD
Thus, the rheumatology community is tasked with a unique challenge: Encourage 32 million Americans, and 527 million individuals worldwide, to eat healthier and get moving.
“Behavioral changes, including diet and exercise, continue to be first-line treatment for knee OA,” Abigail Gilbert, MD, assistant professor of medicine in the division of rheumatology, allergy and immunology at the University of North Carolina Chapel Hill, told Healio Rheumatology.
It is not as though the pipeline for OA drugs has been lacking. Recent research has explored the Wnt pathway modulator lorecivivint (SM04690, Biosplice), as well as TPX-100 (OrthoTrophix), a 23-amino acid peptide that can be administered by intra-articular injection, among others.
“In addition, an anabolic agent that appears to stimulate cartilage regeneration — recombinant human fibroblast growth factor 18 (FGF18) — will soon be studied in phase 3 clinical trials,” Nancy E. Lane, MD, of the University of California, Davis Health System, told Healio Rheumatolgy, referring to the injectable drug sprifermin (TrialSpark).
However, while some OA trials have recently yielded successful or promising results, just as many, if not more, have historically produced frustrating dead ends.
“There have been many studies investigating some of these treatment for osteoarthritis,” Søren Thorgaard Skou, PT, PhD, MSc, head of research for PROgrez at Slagelse Hospital, and professor of exercise and human health, in the research unit for musculoskeletal function and physiotherapy at the University of Southern Denmark, said in an interview. “But there is no magic cure for OA, and it is quite important to remember that.”
As the various potential drugs and therapeutic mechanisms come and go, Ewa Roos, PT, PhD, professor in the faculty of health sciences, in the department of sports science and clinical biomechanics, and of the research unit of musculoskeletal function and physiotherapy, also at the University of Southern Denmark, suggested that it is just as important for providers to understand the whole of the OA patient experience.
“There is the disease of OA, which includes structural changes and damage to tissue that we can see on imaging,” Roos said. “But then there is the illness of OA, which includes the patient experience of pain and loss of function.”
It is the latter that drives patients to seek health care, according to Roos.
“As of today, there are no effective treatments for the disease of OA,” she said. “So, what we are doing in clinical practice is treating the illness, or the patient experience.”
The 2019 American College of Rheumatology recommendations for knee and hip OA, published by Kolasinski and colleagues in Arthritis & Rheumatology, are telling in this regard — and underscore the points made by the above experts. Various types of exercise, from yoga to tai chi, received strong recommendations in the document.
Conversely, there are strong recommendations against novel and experimental approaches like transcutaneous electric nerve stimulation (TENS), chondroitin, platelet-rich plasma injections and stem cell injections. In addition, while there was significant concern surrounding opioid use, as expected, the voting panel even had reservations about pain management with acetaminophen.
Clinical trial programs for novel compounds and off-label medications will continue. Patients will undergo joint replacement procedures and other surgeries. However, until one or more therapies show the capacity to dramatically improve both the disease and the illness of OA, rheumatologists must manage pain as best they can and do whatever possible to encourage patients to be more active.
‘Pain is Normal’
The benefits of physical exercise for a patient with OA are many, according to Tuhina Neogi, MD, PhD, chief of rheumatology and Alan S. Cohen professor of rheumatology at the Boston University School of Medicine and Boston Medical Center.
“Importantly, exercise and physical therapy approaches are important to help address obesity, one of the most important risk factors for OA,” she told Healio Rheumatology. “By reducing the prevalence of obesity, an important reduction in OA prevalence and burden would be achieved.”
For many experts, the issue of weight loss for OA is not one of “if,” but “how.”
“While we frequently talk about weight loss as benefiting many diseases, including knee OA, we recognize this is often easier said than done, and we need more ways to support patients in being successful with weight loss,” Gilbert said.
It is also important to remember that, in addition to obesity, patients with OA often have other chronic diseases like hypertension and diabetes that benefit from physical activity and weight loss, according to Gilbert.
“Knee pain can certainly limit physical activity, so approaches to decrease pain can help patients be more successful at efforts to increase physical activity,” she said.
Put simply, regardless of whether or not the patient demonstrates obesity or comorbid conditions, exercise is necessary. The question then becomes one of optimizing a regimen for each individual patient.
The COVID-19 pandemic, among its myriad impacts, brought a host of new technologies to the forefront in rheumatology, including a closer look at how wearable devices and other tech interventions can be wielded in patient care. At a time when many patients were confined indoors for months at a time, some of these interventions were used to remind patients to stand up, walk around or, if possible, run.
In a paper published in JMIR mHealth and uHealth by Bricca and colleagues, on which Skou was an investigator, 60 smartphone apps from the Apple App Store and Google Play underwent an analysis of their quality and potential for promoting behavior change, including exercise.
“Apps for patients with a chronic condition or multimorbidity appear to be of acceptable quality but have low to moderate potential for promoting behavior change,” the researchers wrote.
According to Skou, the use of technology in OA care is promising but needs further development. The main problem, he said, is in the maintenance phase.
“It is easier to get patients to start exercising, but much more difficult to get them to maintain it,” Skou said.
Until technology improves, Roos continues to rely on education as a cornerstone of managing weight and exercise habits in her patients.
“The primary aim of education is to address common beliefs that exist,” she said. “For example, it is a common myth that exercise will be bad for your joints and cartilage. We have shown repeatedly in animals and humans that exercise therapy is not bad for the cartilage.”
Another myth is that patients should not exercise if they are in pain.
“It is OK to exercise if you are in pain,” Roos said.
In fact, a certain amount of muscle fatigue and pain is expected, particularly for patients who have not exercised much previously, she added.
“You are using your body in a way that maybe you have not used it before,” Roos said. “It will hurt. Pain is normal.”
It is important in these situations to communicate to patients that muscle pain will decrease after the initial flare and, ideally, disappear with regular exercise.
The final myth described by Roos was that patients with radiographic changes, or who have undergone joint replacement, should not exercise.
“I encourage all of my patients to exercise,” she said. “You can expect similar pain relief regardless of severity of radiographic changes.”
Because it can be so difficult to get patients to lose weight and be more active — even with consistent education or regular reminders from a phone or watch — it is unavoidable that many patients progress to a point where further intervention is necessary. For those individuals, surgical options remain viable.
A ‘Complicated and Personal Choice’
“Joint replacement continues to be life-changing for some patients with advanced arthritis,” Gilbert said. “Some patients have been able to return to prior activities that they had set aside due to pain and have significantly improved quality of life.”
Of course, as with any major surgery, there is potential for complications and adverse outcomes. The risks and benefits need to be carefully discussed and considered, Gilbert added.
“It is definitely not for everyone, and not the first option to try,” Roos said.
Findings from a randomized, controlled trial published by Skou and colleagues in The New England Journal of Medicine underscore this point. They randomly assigned 100 patients with moderate-to-severe knee OA to total knee replacement (TKR) followed by 12 weeks of non-surgical treatment, or only 12 weeks of non-surgical treatment. Change from baseline to 12 months in four Knee Injury and Osteoarthritis Outcome Score (KOOS4) subscales assessing pain, function and quality of life served as the primary outcome measure.
According to the researchers, the surgery group experienced a 32.5-point improvement on the KOOS4 scale compared with a 16-point improvement for the non-surgery group (95% CI, 10-21.5). However, surgery also yielded significantly more serious adverse events (P = .005).
For these reasons, TKR is often a “complicated and personal choice,” according to Gilbert.
“Many patients want to exhaust conservative management before undergoing the knife,” she said.
The good news is that the technology involved in joint surgery continues to improve, according to Lane.
“The materials used for the implants and the ability to 3D print implants, to customize them to patients, is impressive,” she said. “In addition, the lifespan of joint replacements has increased to the point that a 60-year-old patient may only need one joint replacement in their lifetime.”
Shoulder joint replacements have also improved, Lane added.
“Patients report significant improvements in pain and function after the surgery,” she said.
Additionally, although Skou agrees that it is possible to “come a long way without surgery,” he still sees joint replacement as “a desirable and effective option” for patients who do not improve from non-surgical care, albeit with one caveat.
“If you have an unsuccessful surgery, the chances of success for a second or third surgery are lower,” he said.
With exercise and weight loss presenting adherence challenges and joint replacement subject to pitfalls regarding patient choice and selection, a robust armamentarium of therapeutic options would be hugely beneficial for OA populations. Unfortunately, that is not what rheumatologists have to work with.
‘Identify the Right Target Population’
Lorecivivint and sprifermin were top of mind for Neogi when discussing potential new therapeutic agents.
Phase 2b data published by Yazici and colleagues in Osteoarthritis and Cartilage showed that lorecivivint yielded improvements over placebo, in terms of patient-reported outcomes like WOMAC pain and function, in a cohort of nearly 700 patients. A dosage of 0.07 mg yielded the best responses and may be optimal for future studies, according to the researchers.
However, in a review paper published in Deutsche Medizinische Wochenschrift, Krasselt and Baerwald described phase 2 results for lorecivivint as “barely encouraging.”
Regarding sprifermin, Zeng and colleagues published a meta-analysis of studies focusing on the drug in Arthritis Research & Therapy. They suggested that sprifermin had no adverse effects but “did not likely have any positive effect on symptom alleviation.”
“Lorecivivint and sprifermin are the two agents that have had the most data available recently regarding potential disease-modifying effects,” Neogi said. “Both programs have highlighted the need for phenotyping to identify the right target population, particularly to demonstrate symptom modification.”
Matching the right patient to the right intervention is no easy task for any rheumatologist. Often, the clinical community must look in unlikely places for answers of how to accomplish that goal.
Meanwhile, in a post-hoc analysis of a large cardiovascular trial of the interleukin (IL)-1 inhibitor canakinumab (Ilaris, Novartis) published in the Annals of Internal Medicine, Scheiker and colleagues reported a lower risk for joint replacement in the treatment arms compared with placebo.
“This raises the possibility that IL-1 inhibition may have a symptom- and/or perhaps structure-modifying effect,” Neogi said. “This analysis also illustrated that promising signals may be missed in smaller phase 1/2 trials that are likely to have enrolled participants that are too heterogeneous to pick up an efficacy signal, whereas the much larger canakinumab trial was able to pick up a signal despite the noise due to sheer sample size.”
Turning to more experimental interventions like platelet-rich plasma and stem cell therapies, Neogi called on the research community for “well-designed and powered RCTs” before recommendations can be made.
Despite the current lack of high-powered trials, Lane expressed optimism regarding these potential therapies.
“Please note that while small clinical studies have shown that platelet-rich plasma, hyaluronic acid and mesenchymal stem cell injections are effective in some phase 2 and 3 clinical trials,” Lane said.
However, she ultimately agreed with Neogi’s assessment that more data are necessary.
“Additional study is needed to determine what patients would benefit from these therapies,” Lane added.
What is (and isn’t) Around the Corner?
According to Neogi, the “biggest story of the past year,” in terms of pain management, was that the anti-NGF tanezumab (Pfizer and Eli Lilly & Co.) program was discontinued. Meanwhile, another major anti-NGF program, fasinumab (Regeneron), was also recently discontinued, she added.
“We will have to wait and see whether any future programs emerge for this target,” Neogi said.
For Lane, the list of “exciting new therapeutics” in the OA space includes the use of adenovirus technology to introduce inhibitors of inflammatory cytokines like IL-1R and anti-inflammatory molecules like IL-10, which are entering, or have entered, phase 2 studies.
Another approach highlighted by Lane, and currently heading into phase 2 trials, involves targeting senolytic cells.
“It will be important to know if reducing the burden of senolytic cells within the knee joint will reduce both symptoms and reduce structural deterioration in our OA patients,” she said.
Looking deeper into the pipeline, research into cartilage transplants and bioengineered cartilage is also underway, according to Lane.
“However, for the most part, the studies currently are preclinical,” she said.
Despite the excitement surrounding these interventions, and the potential they hold, it remains unlikely that any of them will emerge as a cure-all for OA any time soon, according to Neogi. Instead, rheumatologists should focus their energies on using a “multimodal” approach to managing OA, she said. This involves treating patients based on their individual symptoms, needs and goals.
“There is no longer a pyramid approach or hierarchy of therapies to consider in order,” Neogi said. “A multimodal approach should be considered, individualizing management plans by matching therapies to the patient’s symptoms, impairments, goals of care, acceptability, safety and feasibility. In addition, therapies may be revisited at multiple times over the course of someone’s OA journey.”
To that point, patients may also look beyond traditional pharmacotherapies to relieve pain and reduce inflammation, among other outcomes.
‘We Need More Evidence’
Neogi suggested that turmeric and krill oil may have benefits in improving knee OA symptoms.
“These provide additional modalities people may wish to try that are likely to have minimal side effects,” she said.
Other non-pharmacotherapeutic interventions, according to Neogi, include radiofrequency ablation and genicular artery embolization. However, they come with some important caveats.
“These procedures have shown some short-term symptom relief, but longer-term safety data are needed before they can be recommended given the theoretical concerns regarding long-term sequelae of disruption to sensation in joints,” she said.
There may be some evidence that muscle mass and quality may be associated with knee OA, according to Lane.
“Studies are underway to perform deep phenotyping of the muscle in knee OA subjects,” she said, noting that her group is looking into this issue.
Meanwhile, although there is consensus among experts that biomarkers like type II collagen, PRO-C2, PRO-C2, C2M, CTX-II and T2CM could hold many clues as to OA disease pathogenesis and progression, there is just as much agreement that the data produced by research into these biomarkers are lacking.
When asked about “new or promising” biomarkers that are going to fundamentally alter the nature of OA management, Lane stated that none so far are ready for actual use in practice.
“While there are some novel biomarkers from large longitudinal studies that have shown associations with development and progression of knee OA, these markers are not yet ready to be incorporated into OA management,” she said. “However, studies are closely evaluating serum for both proteomics and metabolics, and in the next few years we may know more.”
Regarding injectable approaches, TPX-100 is a novel, 23-amino-acid peptide derived from matrix extracellular phosphoglycoprotein (MEPE), a 525-amino-acid protein that occurs naturally in humans and is known to be involved in the regulation of hard tissue and phosphate metabolism, according to Lane.
“MEPE is a sibling protein made by osteocytes and osteoblasts, and its actions are often related to mineralization of musculoskeletal tissues,” she said. “Its mechanism related to reducing pain in knee OA is not clear. However, the phase 2 study does have some interesting results.”
The findings for TPX-100 were presented by McGuire at the 2022 OARSI World Congress on Osteoarthritis. According to the presenter, the intervention yielded strong improvements in bone shape change and function that may ultimately minimize the need for knee replacement.
However, whether these results will lead to clinical use remains to be seen, according to Lane.
“It is too soon to know if the results of this study — a reduction in femoral bone shape change over 5 years — translates to overall reduction in disease activity and change in joint degeneration,” she said.
Further findings presented by McGuire showed that the symptoms of knee pain and knee function were different from placebo at the 2-year endpoint.
“The results of this long-term extension study are intriguing, and hopefully will be followed by a phase 3 study that will incorporate both joint structure and symptoms as endpoints,” Lane said.
Skou was more pointed in his assessment.
“The results for TPX-100 look interesting, but we need more evidence before we can recommend it to patients,” he said.
As the rheumatology community awaits results for this and other interventions, it may be useful to get back to basics, according to Roos.
“We know that patients who have OA tend to die prematurely, but OA is usually not on the death certificate,” she said.
More commonly, patients die of cardiovascular disease, malignancy or one of the many outcomes associated with obesity.
“My goal, then, is to have patients live as long a life span as someone without OA, and with a good quality of life,” Roos said. “To make that happen, and to improve their general health, you have to keep them active. It’s as simple as that.”
- References:
- Bricca A, et al. JMIR Mhealth Uhealth. 2022;doi:10.2196/33168.
- Kolasinski SL, et al. Arth & Rheum. 2020;doi:10.1002/art.41142.
- Krasselt M, Baerwald C. Dtsch Med Wochenschr. 2022;doi:10.1055/a-1612-6927.
- McGuire D. “Improved WOMAC Physical Function is Associated with Slowed Pathological Bone Shape Change after TPX-100: Towards a Surrogate Marker for Virtual Knee Replacement?” Presented at: OARSI 2022 World Congress on Osteoarthritis; April 7-10; Berlin, Germany (virtual meeting).
- Schieker M, et al. Ann Intern Med. 2020;doi: 10.7326/M20-0527.
- Skou SJ, et al. Engl J Med. 2015;doi:10.1056/NEJMoa1505467.
- Yazici Y, et al. Osteoarthritis Cartilage. 2021;doi:10.1016/j.joca.2021.02.004.
- Zeng N, et al. Arthritis Res Ther. 2021;doi: 10.1186/s13075-021-02488-w.
- For more information:
- Abigail Gilbert, MD, can be reached at 3300 Thurston Building, Campus Box 7280, Chapel Hill, NC 27519; email: abigail.gilbert@unc.edu; bradd_pavur@med.unc.edu.
- Nancy E. Lane, MD, can be reached at 4625 2nd Ave., Suite 2000 | Sacramento, CA 95817; email: nelane@ucdavis.edu.
- Tuhina Neogi, MD, PhD, can be reached at 725 Albany St. 6th Floor, Suite 6B, Boston, MA 02118; email: tneogi@bu.edu.
- Ewa Roos, PT, PhD, can be reached at Campusvej 55, DK-5230 Odense M, Denmark; email: eroos@health.sdu.dk.
- Søren Thorgaard Skou, PT, PhD, MSc, can be reached at Fælledvej 2C, 1., 4200 Slagelse, Denmark; email: stskou@health.sdu.dk.
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