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For MD-IQ on Family Practice News, but a regular topic for Rheumatology News
What Does Natural Healing of ACL Ruptures Mean for Long-Term Outcomes?
VIENNA — Nearly one third of anterior cruciate ligament (ACL) injuries appear to heal without surgery, according to an analysis of three-dimensional MRI data taken from the NACOX study, presented as a late-breaking poster at the OARSI 2024 World Congress.
At 2 years after injury, three-dimensional MRI showed that 13 of 43 (30%) knees had evidence of normal, continuous ACL fibers. Moreover, a further 14 (33%) knees had a continuous ACL fiber structure following rehabilitation alone. ACL fibers were partly (16%) or completely (21%) ruptured in the remainder of cases.
“If you think of the ACL like a rope, when there is continuity, it means those fibers have rejoined,” study coauthor Stephanie Filbay, PhD, an associate professor at the University of Melbourne in Australia, told this news organization.
“Within that, there’s a few variations of healing that we’re seeing. Some look like they’ve never been injured, while some have rejoined but appear thinner or longer than a normal ACL,” Dr. Filbay said.
She added: “What all this research is showing is that it’s happening at a much higher rate than we thought possible. And in some of the studies, it looks like ACL healing is associated with very favorable outcomes.”
At OARSI 2024, Dr. Filbay presented additional data from her and others’ research on the relationships between ACL healing and long-term functional outcomes and osteoarthritis (OA) incidence in comparisons between patients’ treatment pathways: Early ACL surgery, rehabilitation followed by delayed surgery, or rehabilitation only.
Healing Without Surgery
The idea that the ACL can heal without surgery is relatively recent and perhaps still not widely accepted as a concept, as Dr. Filbay explained during a plenary lecture at the congress.
Dr. Filbay explained that the ideal management of ACL injury depends on the severity of knee injury and whether someone’s knee is stable after trying nonsurgical management. Results of the ACL SNNAP trial, for example, have suggested that surgical reconstruction is superior to a rehabilitation strategy for managing non-acute ACL injuries where there are persistent symptoms of instability.
However, there have been two trials — COMPARE performed in the Netherlands and KANON performed in Sweden — that found that early surgery was no better than a strategy of initial rehabilitation with the option of having a delayed ACL surgery if needed.
What Happens Long Term?
Posttraumatic OA is a well-known long-term consequence of ACL injury. According to a recent meta-analysis, there is a sevenfold increased risk for OA comparing people who have and have not had an ACL injury.
ACL injury also results in OA occurring at an earlier age than in people with OA who have not had an ACL injury. This has been shown to progress at a faster rate and be associated with a longer period of disability, Dr. Filbay said at the congress, sponsored by the Osteoarthritis Research Society International.
But does the ACL really heal? Dr. Filbay thinks that it does and has been involved in several studies that have used MRI to look at how the ACL may do so.
In a recently published paper, Dr. Filbay and colleagues reported the findings from a secondary analysis of the KANON trial and found that nearly one in three (30%) of the participants who had been randomized to optional delayed surgery had MRI evidence of healing at 2 years. But when they excluded people who had delayed surgery, 53% of people managed by rehabilitation alone had evidence of healing.
The evaluation also found that those who had a healed vs non-healed ligament had better results using the Knee Injury and Osteoarthritis Outcome Score (KOOS), and that there were better outcomes at 2 years among those with ACL healing vs those who had early or delayed ACL surgery.
ACL Continuity and Long-Term Outcomes
At OARSI 2024, Dr. Filbay and colleagues reported an even longer-term secondary analysis of the KANON trial on the relationship between ACL healing at 5 years and outcomes at 11 years. The results were first reported in NEJM Evidence.
Dr. Filbay reported that participants with ACL continuity on MRI at 5 years actually had worse patient-reported outcomes 11 years later than those who were managed with early or delayed ACL reconstruction.
“This does not align with previous findings suggesting better 2-year outcomes compared to the surgically managed groups,” Dr. Filbay said.
However, people with ACL continuity following rehabilitation did seem to show numerically similar or fewer signs of radiographic OA at 11 years vs the surgical groups.
Radiographic OA of the tibiofemoral joint (TFJ) or patellofemoral joint (PFJ) at 11 years was observed in a respective 14% and 21% of people with ACL continuity at 5 years (n = 14) and in 22% and 11% of people with ACL discontinuity at 5 years in the rehabilitation alone group.
By comparison, radiographic OA of the TFJ or PFJ at 11 years was seen in a respective 23% and 35% of people who had rehabilitation with delayed surgery (n = 26) and in 18% and 41% of those who had early surgery (n = 49).
These are descriptive results, Dr. Filbay said, because the numbers were too small to do a statistical analysis. Further, larger, longitudinal studies will be needed.
Posttraumatic OA After ACL Surgery
Elsewhere at OARSI 2024, Matthew Harkey, PhD, and colleagues from Michigan State University, East Lansing, Michigan, reported data showing that nearly two thirds of people who undergo surgical reconstruction have symptoms at 6 months that could be indicative of early knee OA.
Knee symptoms indicative of OA declined to 53% at 12 months and 45% at 24 months.
“It’s a bit complex — we can’t outright say arthritis is developing, but there’s a large group of patients whose symptoms linger long after surgery,” Dr. Harkey said in a press release.
“Often, clinicians assume that these postoperative symptoms will naturally improve as patients reengage with their usual activities. However, what we’re seeing suggests these symptoms persist and likely require a targeted approach to manage or improve them,” Dr. Harkey said.
The analysis used data on 3752 individuals aged 14-40 years who were enrolled in the New Zealand ACL Registry and who completed the KOOS at 6, 12, and 24 months after having ACL reconstruction.
Dr. Harkey and team reported that one in three people had persistent early OA symptoms at 2 years, while 23% had no early OA symptoms at any timepoint.
The studies were independently supported. Dr. Filbay and Dr. Harkey had no relevant financial relationships to report.
Dr. Filbay and colleagues have developed a treatment decision aid for individuals who have sustained an ACL injury. This provides information on the different treatment options available and how they compare.
A version of this article appeared on Medscape.com.
VIENNA — Nearly one third of anterior cruciate ligament (ACL) injuries appear to heal without surgery, according to an analysis of three-dimensional MRI data taken from the NACOX study, presented as a late-breaking poster at the OARSI 2024 World Congress.
At 2 years after injury, three-dimensional MRI showed that 13 of 43 (30%) knees had evidence of normal, continuous ACL fibers. Moreover, a further 14 (33%) knees had a continuous ACL fiber structure following rehabilitation alone. ACL fibers were partly (16%) or completely (21%) ruptured in the remainder of cases.
“If you think of the ACL like a rope, when there is continuity, it means those fibers have rejoined,” study coauthor Stephanie Filbay, PhD, an associate professor at the University of Melbourne in Australia, told this news organization.
“Within that, there’s a few variations of healing that we’re seeing. Some look like they’ve never been injured, while some have rejoined but appear thinner or longer than a normal ACL,” Dr. Filbay said.
She added: “What all this research is showing is that it’s happening at a much higher rate than we thought possible. And in some of the studies, it looks like ACL healing is associated with very favorable outcomes.”
At OARSI 2024, Dr. Filbay presented additional data from her and others’ research on the relationships between ACL healing and long-term functional outcomes and osteoarthritis (OA) incidence in comparisons between patients’ treatment pathways: Early ACL surgery, rehabilitation followed by delayed surgery, or rehabilitation only.
Healing Without Surgery
The idea that the ACL can heal without surgery is relatively recent and perhaps still not widely accepted as a concept, as Dr. Filbay explained during a plenary lecture at the congress.
Dr. Filbay explained that the ideal management of ACL injury depends on the severity of knee injury and whether someone’s knee is stable after trying nonsurgical management. Results of the ACL SNNAP trial, for example, have suggested that surgical reconstruction is superior to a rehabilitation strategy for managing non-acute ACL injuries where there are persistent symptoms of instability.
However, there have been two trials — COMPARE performed in the Netherlands and KANON performed in Sweden — that found that early surgery was no better than a strategy of initial rehabilitation with the option of having a delayed ACL surgery if needed.
What Happens Long Term?
Posttraumatic OA is a well-known long-term consequence of ACL injury. According to a recent meta-analysis, there is a sevenfold increased risk for OA comparing people who have and have not had an ACL injury.
ACL injury also results in OA occurring at an earlier age than in people with OA who have not had an ACL injury. This has been shown to progress at a faster rate and be associated with a longer period of disability, Dr. Filbay said at the congress, sponsored by the Osteoarthritis Research Society International.
But does the ACL really heal? Dr. Filbay thinks that it does and has been involved in several studies that have used MRI to look at how the ACL may do so.
In a recently published paper, Dr. Filbay and colleagues reported the findings from a secondary analysis of the KANON trial and found that nearly one in three (30%) of the participants who had been randomized to optional delayed surgery had MRI evidence of healing at 2 years. But when they excluded people who had delayed surgery, 53% of people managed by rehabilitation alone had evidence of healing.
The evaluation also found that those who had a healed vs non-healed ligament had better results using the Knee Injury and Osteoarthritis Outcome Score (KOOS), and that there were better outcomes at 2 years among those with ACL healing vs those who had early or delayed ACL surgery.
ACL Continuity and Long-Term Outcomes
At OARSI 2024, Dr. Filbay and colleagues reported an even longer-term secondary analysis of the KANON trial on the relationship between ACL healing at 5 years and outcomes at 11 years. The results were first reported in NEJM Evidence.
Dr. Filbay reported that participants with ACL continuity on MRI at 5 years actually had worse patient-reported outcomes 11 years later than those who were managed with early or delayed ACL reconstruction.
“This does not align with previous findings suggesting better 2-year outcomes compared to the surgically managed groups,” Dr. Filbay said.
However, people with ACL continuity following rehabilitation did seem to show numerically similar or fewer signs of radiographic OA at 11 years vs the surgical groups.
Radiographic OA of the tibiofemoral joint (TFJ) or patellofemoral joint (PFJ) at 11 years was observed in a respective 14% and 21% of people with ACL continuity at 5 years (n = 14) and in 22% and 11% of people with ACL discontinuity at 5 years in the rehabilitation alone group.
By comparison, radiographic OA of the TFJ or PFJ at 11 years was seen in a respective 23% and 35% of people who had rehabilitation with delayed surgery (n = 26) and in 18% and 41% of those who had early surgery (n = 49).
These are descriptive results, Dr. Filbay said, because the numbers were too small to do a statistical analysis. Further, larger, longitudinal studies will be needed.
Posttraumatic OA After ACL Surgery
Elsewhere at OARSI 2024, Matthew Harkey, PhD, and colleagues from Michigan State University, East Lansing, Michigan, reported data showing that nearly two thirds of people who undergo surgical reconstruction have symptoms at 6 months that could be indicative of early knee OA.
Knee symptoms indicative of OA declined to 53% at 12 months and 45% at 24 months.
“It’s a bit complex — we can’t outright say arthritis is developing, but there’s a large group of patients whose symptoms linger long after surgery,” Dr. Harkey said in a press release.
“Often, clinicians assume that these postoperative symptoms will naturally improve as patients reengage with their usual activities. However, what we’re seeing suggests these symptoms persist and likely require a targeted approach to manage or improve them,” Dr. Harkey said.
The analysis used data on 3752 individuals aged 14-40 years who were enrolled in the New Zealand ACL Registry and who completed the KOOS at 6, 12, and 24 months after having ACL reconstruction.
Dr. Harkey and team reported that one in three people had persistent early OA symptoms at 2 years, while 23% had no early OA symptoms at any timepoint.
The studies were independently supported. Dr. Filbay and Dr. Harkey had no relevant financial relationships to report.
Dr. Filbay and colleagues have developed a treatment decision aid for individuals who have sustained an ACL injury. This provides information on the different treatment options available and how they compare.
A version of this article appeared on Medscape.com.
VIENNA — Nearly one third of anterior cruciate ligament (ACL) injuries appear to heal without surgery, according to an analysis of three-dimensional MRI data taken from the NACOX study, presented as a late-breaking poster at the OARSI 2024 World Congress.
At 2 years after injury, three-dimensional MRI showed that 13 of 43 (30%) knees had evidence of normal, continuous ACL fibers. Moreover, a further 14 (33%) knees had a continuous ACL fiber structure following rehabilitation alone. ACL fibers were partly (16%) or completely (21%) ruptured in the remainder of cases.
“If you think of the ACL like a rope, when there is continuity, it means those fibers have rejoined,” study coauthor Stephanie Filbay, PhD, an associate professor at the University of Melbourne in Australia, told this news organization.
“Within that, there’s a few variations of healing that we’re seeing. Some look like they’ve never been injured, while some have rejoined but appear thinner or longer than a normal ACL,” Dr. Filbay said.
She added: “What all this research is showing is that it’s happening at a much higher rate than we thought possible. And in some of the studies, it looks like ACL healing is associated with very favorable outcomes.”
At OARSI 2024, Dr. Filbay presented additional data from her and others’ research on the relationships between ACL healing and long-term functional outcomes and osteoarthritis (OA) incidence in comparisons between patients’ treatment pathways: Early ACL surgery, rehabilitation followed by delayed surgery, or rehabilitation only.
Healing Without Surgery
The idea that the ACL can heal without surgery is relatively recent and perhaps still not widely accepted as a concept, as Dr. Filbay explained during a plenary lecture at the congress.
Dr. Filbay explained that the ideal management of ACL injury depends on the severity of knee injury and whether someone’s knee is stable after trying nonsurgical management. Results of the ACL SNNAP trial, for example, have suggested that surgical reconstruction is superior to a rehabilitation strategy for managing non-acute ACL injuries where there are persistent symptoms of instability.
However, there have been two trials — COMPARE performed in the Netherlands and KANON performed in Sweden — that found that early surgery was no better than a strategy of initial rehabilitation with the option of having a delayed ACL surgery if needed.
What Happens Long Term?
Posttraumatic OA is a well-known long-term consequence of ACL injury. According to a recent meta-analysis, there is a sevenfold increased risk for OA comparing people who have and have not had an ACL injury.
ACL injury also results in OA occurring at an earlier age than in people with OA who have not had an ACL injury. This has been shown to progress at a faster rate and be associated with a longer period of disability, Dr. Filbay said at the congress, sponsored by the Osteoarthritis Research Society International.
But does the ACL really heal? Dr. Filbay thinks that it does and has been involved in several studies that have used MRI to look at how the ACL may do so.
In a recently published paper, Dr. Filbay and colleagues reported the findings from a secondary analysis of the KANON trial and found that nearly one in three (30%) of the participants who had been randomized to optional delayed surgery had MRI evidence of healing at 2 years. But when they excluded people who had delayed surgery, 53% of people managed by rehabilitation alone had evidence of healing.
The evaluation also found that those who had a healed vs non-healed ligament had better results using the Knee Injury and Osteoarthritis Outcome Score (KOOS), and that there were better outcomes at 2 years among those with ACL healing vs those who had early or delayed ACL surgery.
ACL Continuity and Long-Term Outcomes
At OARSI 2024, Dr. Filbay and colleagues reported an even longer-term secondary analysis of the KANON trial on the relationship between ACL healing at 5 years and outcomes at 11 years. The results were first reported in NEJM Evidence.
Dr. Filbay reported that participants with ACL continuity on MRI at 5 years actually had worse patient-reported outcomes 11 years later than those who were managed with early or delayed ACL reconstruction.
“This does not align with previous findings suggesting better 2-year outcomes compared to the surgically managed groups,” Dr. Filbay said.
However, people with ACL continuity following rehabilitation did seem to show numerically similar or fewer signs of radiographic OA at 11 years vs the surgical groups.
Radiographic OA of the tibiofemoral joint (TFJ) or patellofemoral joint (PFJ) at 11 years was observed in a respective 14% and 21% of people with ACL continuity at 5 years (n = 14) and in 22% and 11% of people with ACL discontinuity at 5 years in the rehabilitation alone group.
By comparison, radiographic OA of the TFJ or PFJ at 11 years was seen in a respective 23% and 35% of people who had rehabilitation with delayed surgery (n = 26) and in 18% and 41% of those who had early surgery (n = 49).
These are descriptive results, Dr. Filbay said, because the numbers were too small to do a statistical analysis. Further, larger, longitudinal studies will be needed.
Posttraumatic OA After ACL Surgery
Elsewhere at OARSI 2024, Matthew Harkey, PhD, and colleagues from Michigan State University, East Lansing, Michigan, reported data showing that nearly two thirds of people who undergo surgical reconstruction have symptoms at 6 months that could be indicative of early knee OA.
Knee symptoms indicative of OA declined to 53% at 12 months and 45% at 24 months.
“It’s a bit complex — we can’t outright say arthritis is developing, but there’s a large group of patients whose symptoms linger long after surgery,” Dr. Harkey said in a press release.
“Often, clinicians assume that these postoperative symptoms will naturally improve as patients reengage with their usual activities. However, what we’re seeing suggests these symptoms persist and likely require a targeted approach to manage or improve them,” Dr. Harkey said.
The analysis used data on 3752 individuals aged 14-40 years who were enrolled in the New Zealand ACL Registry and who completed the KOOS at 6, 12, and 24 months after having ACL reconstruction.
Dr. Harkey and team reported that one in three people had persistent early OA symptoms at 2 years, while 23% had no early OA symptoms at any timepoint.
The studies were independently supported. Dr. Filbay and Dr. Harkey had no relevant financial relationships to report.
Dr. Filbay and colleagues have developed a treatment decision aid for individuals who have sustained an ACL injury. This provides information on the different treatment options available and how they compare.
A version of this article appeared on Medscape.com.
FROM OARSI 2024
Will Diabetes Drugs Advance Osteoarthritis Management?
VIENNA — With the glucagon-like peptide (GLP) 1 receptor agonist semaglutide (Wegovy) recently shown to significantly induce weight loss in people with osteoarthritis (OA) and obesity in the STEP-9 trial, could drugs traditionally used to treat type 2 diabetes be the next big thing for OA management?
“Hormone-based weight loss drugs are a game changer” for obesity management, Sébastien Czernichow, MD, PhD, said during a plenary session at the OARSI 2024 World Congress.
Drugs such as semaglutide may also have a cardioprotective effect, reducing the risk for major adverse cardiovascular events by as much as 20% vs placebo, added Dr. Czernichow, professor of nutrition at Paris Cité University and head of the Department of Nutrition at the George Pompidou European Hospital in Paris, France.
“You have to keep in mind that the short-term side effects are mainly gastrointestinal and [are] manageable. The mid-term side effects are an increased gallbladder [disease] risk, and the long-term benefits and risks are not really well known yet,” Dr. Czernichow said. With regard to that, the effects of these drugs on lean body mass, bone health, and nutritional deficiencies need to be further evaluated and monitored.
Weight Loss Benefits
Weight loss is one of the cornerstones of OA management, and in addition to the weight loss seen with the GLP-1 receptor agonists, there have also been changes in body composition, Dr. Czernichow said.
In SURMOUNT-1, for example, the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide (Zepbound) was shown to significantly reduce total fat mass with a smaller decrease in total lean mass in a subanalysis.
It has been argued that effects on body composition need to be considered when evaluating new weight loss drugs, and that focusing only on the degree of weight reduction is “encouraging inaccurate measures of medication efficacy for both patients and clinicians,” Dr. Czernichow said, citing a viewpoint published in JAMA Internal Medicine.
“The real question is: Are we able to fund these drugs for everyone? Or will only the richest patients be allocated to these drugs?” Dr. Czernichow said.
Weight Rebound
Tonia Vincent, MBBS, PhD, professor of musculoskeletal biology and an honorary rheumatologist at The Kennedy Institute of Rheumatology at University of Oxford in England, was concerned about rebound weight gain.
“We hear a lot about this, that people stopping drugs actually get worse weight gain than before they started, and that’s a concern about a drug that is going to have a huge pressure for supply,” Dr. Vincent said following Dr. Czernichow’s presentation.
Another delegate said that calling GLP-1 receptor agonists a “game changer” for weight loss in OA was premature because long-term results are needed.
“You mentioned that the double-digit weight loss is getting very close to the results from bariatric surgery, but bariatric surgery you do once, and for these drugs, to maintain the weight loss, you need to take them continuously,” she said.
Weight Loss Affects Bone
Yet another delegate cautioned on the potential effects of significant weight loss on bone and cartilage. There is evidence, he said, that weight loss of 5-10 kg can significantly affect bone turnover, increasing bone resorption and thus putting patients at a risk of becoming osteopenic. “Are we looking at a new population of osteoporosis patients who may then also be at risk for fractures?” he asked.
Separately at OARSI 2024, Anne C. Bay-Jensen, PhD, chief technology officer at Nordic Bioscience in Herlev, Denmark, and colleagues reported data showing that weight loss was associated with an increase in bone and cartilage degradation.
Although Dr. Bay-Jensen and colleagues found that losing weight was associated with improved patient outcomes, there was a 1.58-fold increase in the bone resorption marker CTX-I in people who had lost weight vs a 1.37-fold gain in those whose weight remained stable and 1.11-fold increase in those who gained weight.
Moreover, there was a 1.15-fold increase in the cartilage degradation marker C2M in the weight loss group and 0.84-fold decrease in the interstitial matrix degradation marker C3M.
GLP-1 and Bone Effects
Another question is whether GLP-1 receptor agonists might be having direct effects on the bone that may be beneficial in OA. They might, postdoctoral researcher Eda Çiftci, PhD, of AO Research Institute Davos in Switzerland, and collaborators, said during the poster sessions at OARSI 2024.
Dr. Çiftci and researchers reported the findings of an in vitro study that looked at whether liraglutide might have anti-inflammatory and anabolic effects on a human chondrocytes model that had been treated with interleukin (IL)-1-beta to “mimic an inflammatory OA condition.”
The release of the proinflammatory cytokines IL-6 and IL-8 was reduced by treatment with liraglutide when compared with control chondrocytes. Furthermore, the expression of the proteoglycan aggrecan — important for articular cartilage function — also was preserved.
These results suggest that liraglutide does indeed have anabolic and anti-inflammatory effects, Dr. Çiftci and fellow researchers concluded.
New Role for Dipeptidyl Transferase Inhibitors?
Researchers are also looking at the potential role for other diabetes medications in OA management, including the dipeptidyl peptidase (DPP) 4 inhibitors.
Although these drugs are considered “weight neutral,” in vitro studies have suggested that the DPP4 enzyme may have a role to play in chondrocyte survival and inflammation, Yu-Hsiu Chen, MD, of the Tri-Service General Hospital and the National Defense Medical Center in Taipei, Taiwan, told this news organization. The DPP4 enzyme inactivates GLP-1, so there is rationale there.
“Last year, we published a paper where we found the concentration of DPP4 in the synovial fluid was correlated with radiographic change in knee OA,” Dr. Chen said. This time, “we’re trying to see if a DPP4 inhibitor can be used as a treatment.”
For their analysis, they used data on people newly diagnosed with type 2 diabetes who were and were not using DPP4 inhibitors obtained from Taiwan’s National Health Insurance Research Database. This database contains information on 99% of the Taiwanese population, Dr. Chen said.
Matching 165,333 DPP4 inhibitor users with an equal number of nonusers showed that there was a significant 58% risk reduction for developing OA with DPP4 inhibitor use (hazard ratio, 0.42; 95% CI, 0.41-0.44).
DPP4 inhibitor use was also associated with a 58% risk lower risk for total knee replacement (TKR) and a 62% lower risk for total hip replacement.
Dr. Chen and colleagues concluded: “These results strongly indicate that DPP4 inhibitors could be considered as a viable treatment approach for individuals with type 2 [diabetes mellitus] who are at risk for developing OA or [who] already have OA.”
Could Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Be Beneficial?
So, what about SGLT2 inhibitors? Do they also have a potential role to play in managing people with OA, regardless of whether there is diabetes present? Perhaps, and their effect may be even greater than what’s been observed for GLP-1 receptor agonists, as data presented by epidemiologist S. Reza Jafarzadeh, DVM, PhD, suggested.
“While GLP-1 receptor agonist drugs have been reported to reduce OA risk, largely attributed to their weight loss effect, SGLT2 inhibitors may provide a greater protective effect on OA outcomes,” said Dr. Jafarzadeh, assistant professor at Boston University.
He presented data from a large analysis of new users of SGLT2 inhibitors and GLP-1 receptor agonists within two claims databases — Merative (n = 603,471) and TriNetX (n = 1,202,972) — showing that SGLT2 inhibitors were associated with significantly lower risks for OA and the need for TKR.
Comparing new users of SGLT2 inhibitors and GLP-1 receptor agonists in the Merative dataset, the relative risks and odds ratios for OA were a respective 0.96 and 0.80, and having a TKR, 0.88 and 0.76.
Similar results were seen using the TriNetX dataset, with respective relative risks and hazard ratios of 0.90 and 0.85 for OA, and 0.81 and 0.78 for TKR.
In an interview, Dr. Jafarzadeh said that the initial hypothesis was that because SGLT2 inhibitors have only a modest effect on weight loss, there would be no effect on OA outcomes.
“But we were surprised that it actually looked like they reduced the risk of OA outcomes even more than GLP-1 receptor agonists,” Dr. Jafarzadeh said.
Further work is needed to understand these data, but they could mean that SLGT2 inhibitors, like GLP-1 receptor agonists, may have a role to play outside their current use in type 2 diabetes.
The congress was sponsored by the Osteoarthritis Research Society International.
Dr. Czernichow disclosed ties with BariaTek Medical, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Janssen, Jellynov, Lilly, Novo Nordisk, Novartis, and ViiV Healthcare. Dr. Vincent had no relevant disclosures. Dr. Bay-Jensen is the chief technology officer and director of immunoscience at Nordic Bioscience, which funded the work in the poster she presented at OARSI 2024. The work presented by Dr. Çiftci and colleagues was funded by the Eurostars-2 joint program with co-funding from the European Horizon 2020 research and innovation program. Dr. Çiftci had no personal disclosures to report. Dr. Chen’s work was supported by the government of Taiwan, and she had no financial conflicts of interest to disclose. Dr. Jafarzadeh had no conflicts of interest to disclose.
A version of this article appeared on Medscape.com .
VIENNA — With the glucagon-like peptide (GLP) 1 receptor agonist semaglutide (Wegovy) recently shown to significantly induce weight loss in people with osteoarthritis (OA) and obesity in the STEP-9 trial, could drugs traditionally used to treat type 2 diabetes be the next big thing for OA management?
“Hormone-based weight loss drugs are a game changer” for obesity management, Sébastien Czernichow, MD, PhD, said during a plenary session at the OARSI 2024 World Congress.
Drugs such as semaglutide may also have a cardioprotective effect, reducing the risk for major adverse cardiovascular events by as much as 20% vs placebo, added Dr. Czernichow, professor of nutrition at Paris Cité University and head of the Department of Nutrition at the George Pompidou European Hospital in Paris, France.
“You have to keep in mind that the short-term side effects are mainly gastrointestinal and [are] manageable. The mid-term side effects are an increased gallbladder [disease] risk, and the long-term benefits and risks are not really well known yet,” Dr. Czernichow said. With regard to that, the effects of these drugs on lean body mass, bone health, and nutritional deficiencies need to be further evaluated and monitored.
Weight Loss Benefits
Weight loss is one of the cornerstones of OA management, and in addition to the weight loss seen with the GLP-1 receptor agonists, there have also been changes in body composition, Dr. Czernichow said.
In SURMOUNT-1, for example, the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide (Zepbound) was shown to significantly reduce total fat mass with a smaller decrease in total lean mass in a subanalysis.
It has been argued that effects on body composition need to be considered when evaluating new weight loss drugs, and that focusing only on the degree of weight reduction is “encouraging inaccurate measures of medication efficacy for both patients and clinicians,” Dr. Czernichow said, citing a viewpoint published in JAMA Internal Medicine.
“The real question is: Are we able to fund these drugs for everyone? Or will only the richest patients be allocated to these drugs?” Dr. Czernichow said.
Weight Rebound
Tonia Vincent, MBBS, PhD, professor of musculoskeletal biology and an honorary rheumatologist at The Kennedy Institute of Rheumatology at University of Oxford in England, was concerned about rebound weight gain.
“We hear a lot about this, that people stopping drugs actually get worse weight gain than before they started, and that’s a concern about a drug that is going to have a huge pressure for supply,” Dr. Vincent said following Dr. Czernichow’s presentation.
Another delegate said that calling GLP-1 receptor agonists a “game changer” for weight loss in OA was premature because long-term results are needed.
“You mentioned that the double-digit weight loss is getting very close to the results from bariatric surgery, but bariatric surgery you do once, and for these drugs, to maintain the weight loss, you need to take them continuously,” she said.
Weight Loss Affects Bone
Yet another delegate cautioned on the potential effects of significant weight loss on bone and cartilage. There is evidence, he said, that weight loss of 5-10 kg can significantly affect bone turnover, increasing bone resorption and thus putting patients at a risk of becoming osteopenic. “Are we looking at a new population of osteoporosis patients who may then also be at risk for fractures?” he asked.
Separately at OARSI 2024, Anne C. Bay-Jensen, PhD, chief technology officer at Nordic Bioscience in Herlev, Denmark, and colleagues reported data showing that weight loss was associated with an increase in bone and cartilage degradation.
Although Dr. Bay-Jensen and colleagues found that losing weight was associated with improved patient outcomes, there was a 1.58-fold increase in the bone resorption marker CTX-I in people who had lost weight vs a 1.37-fold gain in those whose weight remained stable and 1.11-fold increase in those who gained weight.
Moreover, there was a 1.15-fold increase in the cartilage degradation marker C2M in the weight loss group and 0.84-fold decrease in the interstitial matrix degradation marker C3M.
GLP-1 and Bone Effects
Another question is whether GLP-1 receptor agonists might be having direct effects on the bone that may be beneficial in OA. They might, postdoctoral researcher Eda Çiftci, PhD, of AO Research Institute Davos in Switzerland, and collaborators, said during the poster sessions at OARSI 2024.
Dr. Çiftci and researchers reported the findings of an in vitro study that looked at whether liraglutide might have anti-inflammatory and anabolic effects on a human chondrocytes model that had been treated with interleukin (IL)-1-beta to “mimic an inflammatory OA condition.”
The release of the proinflammatory cytokines IL-6 and IL-8 was reduced by treatment with liraglutide when compared with control chondrocytes. Furthermore, the expression of the proteoglycan aggrecan — important for articular cartilage function — also was preserved.
These results suggest that liraglutide does indeed have anabolic and anti-inflammatory effects, Dr. Çiftci and fellow researchers concluded.
New Role for Dipeptidyl Transferase Inhibitors?
Researchers are also looking at the potential role for other diabetes medications in OA management, including the dipeptidyl peptidase (DPP) 4 inhibitors.
Although these drugs are considered “weight neutral,” in vitro studies have suggested that the DPP4 enzyme may have a role to play in chondrocyte survival and inflammation, Yu-Hsiu Chen, MD, of the Tri-Service General Hospital and the National Defense Medical Center in Taipei, Taiwan, told this news organization. The DPP4 enzyme inactivates GLP-1, so there is rationale there.
“Last year, we published a paper where we found the concentration of DPP4 in the synovial fluid was correlated with radiographic change in knee OA,” Dr. Chen said. This time, “we’re trying to see if a DPP4 inhibitor can be used as a treatment.”
For their analysis, they used data on people newly diagnosed with type 2 diabetes who were and were not using DPP4 inhibitors obtained from Taiwan’s National Health Insurance Research Database. This database contains information on 99% of the Taiwanese population, Dr. Chen said.
Matching 165,333 DPP4 inhibitor users with an equal number of nonusers showed that there was a significant 58% risk reduction for developing OA with DPP4 inhibitor use (hazard ratio, 0.42; 95% CI, 0.41-0.44).
DPP4 inhibitor use was also associated with a 58% risk lower risk for total knee replacement (TKR) and a 62% lower risk for total hip replacement.
Dr. Chen and colleagues concluded: “These results strongly indicate that DPP4 inhibitors could be considered as a viable treatment approach for individuals with type 2 [diabetes mellitus] who are at risk for developing OA or [who] already have OA.”
Could Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Be Beneficial?
So, what about SGLT2 inhibitors? Do they also have a potential role to play in managing people with OA, regardless of whether there is diabetes present? Perhaps, and their effect may be even greater than what’s been observed for GLP-1 receptor agonists, as data presented by epidemiologist S. Reza Jafarzadeh, DVM, PhD, suggested.
“While GLP-1 receptor agonist drugs have been reported to reduce OA risk, largely attributed to their weight loss effect, SGLT2 inhibitors may provide a greater protective effect on OA outcomes,” said Dr. Jafarzadeh, assistant professor at Boston University.
He presented data from a large analysis of new users of SGLT2 inhibitors and GLP-1 receptor agonists within two claims databases — Merative (n = 603,471) and TriNetX (n = 1,202,972) — showing that SGLT2 inhibitors were associated with significantly lower risks for OA and the need for TKR.
Comparing new users of SGLT2 inhibitors and GLP-1 receptor agonists in the Merative dataset, the relative risks and odds ratios for OA were a respective 0.96 and 0.80, and having a TKR, 0.88 and 0.76.
Similar results were seen using the TriNetX dataset, with respective relative risks and hazard ratios of 0.90 and 0.85 for OA, and 0.81 and 0.78 for TKR.
In an interview, Dr. Jafarzadeh said that the initial hypothesis was that because SGLT2 inhibitors have only a modest effect on weight loss, there would be no effect on OA outcomes.
“But we were surprised that it actually looked like they reduced the risk of OA outcomes even more than GLP-1 receptor agonists,” Dr. Jafarzadeh said.
Further work is needed to understand these data, but they could mean that SLGT2 inhibitors, like GLP-1 receptor agonists, may have a role to play outside their current use in type 2 diabetes.
The congress was sponsored by the Osteoarthritis Research Society International.
Dr. Czernichow disclosed ties with BariaTek Medical, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Janssen, Jellynov, Lilly, Novo Nordisk, Novartis, and ViiV Healthcare. Dr. Vincent had no relevant disclosures. Dr. Bay-Jensen is the chief technology officer and director of immunoscience at Nordic Bioscience, which funded the work in the poster she presented at OARSI 2024. The work presented by Dr. Çiftci and colleagues was funded by the Eurostars-2 joint program with co-funding from the European Horizon 2020 research and innovation program. Dr. Çiftci had no personal disclosures to report. Dr. Chen’s work was supported by the government of Taiwan, and she had no financial conflicts of interest to disclose. Dr. Jafarzadeh had no conflicts of interest to disclose.
A version of this article appeared on Medscape.com .
VIENNA — With the glucagon-like peptide (GLP) 1 receptor agonist semaglutide (Wegovy) recently shown to significantly induce weight loss in people with osteoarthritis (OA) and obesity in the STEP-9 trial, could drugs traditionally used to treat type 2 diabetes be the next big thing for OA management?
“Hormone-based weight loss drugs are a game changer” for obesity management, Sébastien Czernichow, MD, PhD, said during a plenary session at the OARSI 2024 World Congress.
Drugs such as semaglutide may also have a cardioprotective effect, reducing the risk for major adverse cardiovascular events by as much as 20% vs placebo, added Dr. Czernichow, professor of nutrition at Paris Cité University and head of the Department of Nutrition at the George Pompidou European Hospital in Paris, France.
“You have to keep in mind that the short-term side effects are mainly gastrointestinal and [are] manageable. The mid-term side effects are an increased gallbladder [disease] risk, and the long-term benefits and risks are not really well known yet,” Dr. Czernichow said. With regard to that, the effects of these drugs on lean body mass, bone health, and nutritional deficiencies need to be further evaluated and monitored.
Weight Loss Benefits
Weight loss is one of the cornerstones of OA management, and in addition to the weight loss seen with the GLP-1 receptor agonists, there have also been changes in body composition, Dr. Czernichow said.
In SURMOUNT-1, for example, the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide (Zepbound) was shown to significantly reduce total fat mass with a smaller decrease in total lean mass in a subanalysis.
It has been argued that effects on body composition need to be considered when evaluating new weight loss drugs, and that focusing only on the degree of weight reduction is “encouraging inaccurate measures of medication efficacy for both patients and clinicians,” Dr. Czernichow said, citing a viewpoint published in JAMA Internal Medicine.
“The real question is: Are we able to fund these drugs for everyone? Or will only the richest patients be allocated to these drugs?” Dr. Czernichow said.
Weight Rebound
Tonia Vincent, MBBS, PhD, professor of musculoskeletal biology and an honorary rheumatologist at The Kennedy Institute of Rheumatology at University of Oxford in England, was concerned about rebound weight gain.
“We hear a lot about this, that people stopping drugs actually get worse weight gain than before they started, and that’s a concern about a drug that is going to have a huge pressure for supply,” Dr. Vincent said following Dr. Czernichow’s presentation.
Another delegate said that calling GLP-1 receptor agonists a “game changer” for weight loss in OA was premature because long-term results are needed.
“You mentioned that the double-digit weight loss is getting very close to the results from bariatric surgery, but bariatric surgery you do once, and for these drugs, to maintain the weight loss, you need to take them continuously,” she said.
Weight Loss Affects Bone
Yet another delegate cautioned on the potential effects of significant weight loss on bone and cartilage. There is evidence, he said, that weight loss of 5-10 kg can significantly affect bone turnover, increasing bone resorption and thus putting patients at a risk of becoming osteopenic. “Are we looking at a new population of osteoporosis patients who may then also be at risk for fractures?” he asked.
Separately at OARSI 2024, Anne C. Bay-Jensen, PhD, chief technology officer at Nordic Bioscience in Herlev, Denmark, and colleagues reported data showing that weight loss was associated with an increase in bone and cartilage degradation.
Although Dr. Bay-Jensen and colleagues found that losing weight was associated with improved patient outcomes, there was a 1.58-fold increase in the bone resorption marker CTX-I in people who had lost weight vs a 1.37-fold gain in those whose weight remained stable and 1.11-fold increase in those who gained weight.
Moreover, there was a 1.15-fold increase in the cartilage degradation marker C2M in the weight loss group and 0.84-fold decrease in the interstitial matrix degradation marker C3M.
GLP-1 and Bone Effects
Another question is whether GLP-1 receptor agonists might be having direct effects on the bone that may be beneficial in OA. They might, postdoctoral researcher Eda Çiftci, PhD, of AO Research Institute Davos in Switzerland, and collaborators, said during the poster sessions at OARSI 2024.
Dr. Çiftci and researchers reported the findings of an in vitro study that looked at whether liraglutide might have anti-inflammatory and anabolic effects on a human chondrocytes model that had been treated with interleukin (IL)-1-beta to “mimic an inflammatory OA condition.”
The release of the proinflammatory cytokines IL-6 and IL-8 was reduced by treatment with liraglutide when compared with control chondrocytes. Furthermore, the expression of the proteoglycan aggrecan — important for articular cartilage function — also was preserved.
These results suggest that liraglutide does indeed have anabolic and anti-inflammatory effects, Dr. Çiftci and fellow researchers concluded.
New Role for Dipeptidyl Transferase Inhibitors?
Researchers are also looking at the potential role for other diabetes medications in OA management, including the dipeptidyl peptidase (DPP) 4 inhibitors.
Although these drugs are considered “weight neutral,” in vitro studies have suggested that the DPP4 enzyme may have a role to play in chondrocyte survival and inflammation, Yu-Hsiu Chen, MD, of the Tri-Service General Hospital and the National Defense Medical Center in Taipei, Taiwan, told this news organization. The DPP4 enzyme inactivates GLP-1, so there is rationale there.
“Last year, we published a paper where we found the concentration of DPP4 in the synovial fluid was correlated with radiographic change in knee OA,” Dr. Chen said. This time, “we’re trying to see if a DPP4 inhibitor can be used as a treatment.”
For their analysis, they used data on people newly diagnosed with type 2 diabetes who were and were not using DPP4 inhibitors obtained from Taiwan’s National Health Insurance Research Database. This database contains information on 99% of the Taiwanese population, Dr. Chen said.
Matching 165,333 DPP4 inhibitor users with an equal number of nonusers showed that there was a significant 58% risk reduction for developing OA with DPP4 inhibitor use (hazard ratio, 0.42; 95% CI, 0.41-0.44).
DPP4 inhibitor use was also associated with a 58% risk lower risk for total knee replacement (TKR) and a 62% lower risk for total hip replacement.
Dr. Chen and colleagues concluded: “These results strongly indicate that DPP4 inhibitors could be considered as a viable treatment approach for individuals with type 2 [diabetes mellitus] who are at risk for developing OA or [who] already have OA.”
Could Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Be Beneficial?
So, what about SGLT2 inhibitors? Do they also have a potential role to play in managing people with OA, regardless of whether there is diabetes present? Perhaps, and their effect may be even greater than what’s been observed for GLP-1 receptor agonists, as data presented by epidemiologist S. Reza Jafarzadeh, DVM, PhD, suggested.
“While GLP-1 receptor agonist drugs have been reported to reduce OA risk, largely attributed to their weight loss effect, SGLT2 inhibitors may provide a greater protective effect on OA outcomes,” said Dr. Jafarzadeh, assistant professor at Boston University.
He presented data from a large analysis of new users of SGLT2 inhibitors and GLP-1 receptor agonists within two claims databases — Merative (n = 603,471) and TriNetX (n = 1,202,972) — showing that SGLT2 inhibitors were associated with significantly lower risks for OA and the need for TKR.
Comparing new users of SGLT2 inhibitors and GLP-1 receptor agonists in the Merative dataset, the relative risks and odds ratios for OA were a respective 0.96 and 0.80, and having a TKR, 0.88 and 0.76.
Similar results were seen using the TriNetX dataset, with respective relative risks and hazard ratios of 0.90 and 0.85 for OA, and 0.81 and 0.78 for TKR.
In an interview, Dr. Jafarzadeh said that the initial hypothesis was that because SGLT2 inhibitors have only a modest effect on weight loss, there would be no effect on OA outcomes.
“But we were surprised that it actually looked like they reduced the risk of OA outcomes even more than GLP-1 receptor agonists,” Dr. Jafarzadeh said.
Further work is needed to understand these data, but they could mean that SLGT2 inhibitors, like GLP-1 receptor agonists, may have a role to play outside their current use in type 2 diabetes.
The congress was sponsored by the Osteoarthritis Research Society International.
Dr. Czernichow disclosed ties with BariaTek Medical, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Janssen, Jellynov, Lilly, Novo Nordisk, Novartis, and ViiV Healthcare. Dr. Vincent had no relevant disclosures. Dr. Bay-Jensen is the chief technology officer and director of immunoscience at Nordic Bioscience, which funded the work in the poster she presented at OARSI 2024. The work presented by Dr. Çiftci and colleagues was funded by the Eurostars-2 joint program with co-funding from the European Horizon 2020 research and innovation program. Dr. Çiftci had no personal disclosures to report. Dr. Chen’s work was supported by the government of Taiwan, and she had no financial conflicts of interest to disclose. Dr. Jafarzadeh had no conflicts of interest to disclose.
A version of this article appeared on Medscape.com .
FROM OARSI 2024
Diacerein, Resveratrol, Botulinum Toxin Disappoint in Knee Osteoarthritis
VIENNA — Data do not back the use of diacerein or resveratrol for managing the pain of knee osteoarthritis (OA), according to the results of two well-performed, multicenter, double-blind, randomized controlled clinical trials.
During the News in Therapies session at the OARSI 2024 World Congress, the null findings of the DICKENS study and ARTHROL trial were presented alongside a reappraisal of the possible role of botulinum toxin.
DICKENS Study of Diacerein
“The role of diacerein in the treatment of OA is controversial,” acknowledged Dawn Aitken, PhD, associate professor at the University of Tasmania in Hobart, Tasmania, Australia. “There are only a few acceptable quality trials to date, and the results are inconsistent,” Dr. Aitken added.
Indeed, a Cochrane review performed in 2014 had concluded that there was “low-quality evidence that diacerein had a small beneficial effect on pain,” she said. The reported overall effect size on a 100-mm visual analog scale, based on a meta-analysis of 10 trials, has been just −8.65 mm, equating to just a 9% pain reduction.
At the time the DICKENS study was conceived, diacerein was recommended by a number of international guidelines for the management of hip and knee OA, although further, higher-quality studies were needed.
Diacerein blocks interleukin-1 beta, which is one of the key inflammatory markers of OA, so Dr. Aitken and collaborators postulated that perhaps it would work better if used in patients with an inflammatory phenotype.
They set about to test their hypothesis by recruiting 260 individuals with knee OA and MRI-detected effusion synovitis. The participants were then randomly allocated to treatment with either diacerein or a matching placebo for 24 weeks.
Individuals in the diacerein group were treated with an oral dose of 50 mg once daily for the first 2 weeks. If tolerated, the dose was increased to 50 mg twice daily.
No significant improvement in the primary endpoint of knee pain was seen comparing diacerein with placebo, with mean values of 53.2 mm and 56.4 mm, respectively, at 24 weeks using a 0-100 mm visual analog scale where 0 represented no pain and 100 represented the worst pain. It followed that there was no significant difference in the change from baseline to week 24 (−19.9 mm vs −18.6 mm; P = .77).
There was also no difference in the secondary endpoints, which included Western Ontario and McMaster Universities Arthritis Index pain, function, and stiffness. In fact, placebo-treated patients appeared to do better in terms of resolution of effusion synovitis as measured by a repeat MRI and quality of life, Dr. Aitken reported.
“These findings do not support the use of diacerein in treating patients with knee OA and effusion synovitis,” Dr. Aitken concluded.
ARTHROL Trial of Resveratrol
Similarly, negative results were reported for resveratrol from the ARTHROL trial, with 55% of the resveratrol- and 55% of placebo-treated individuals achieving a 20% reduction in knee pain intensity at 3 months. The actual change in knee pain from baseline to 3 months was −15.7 for resveratrol and −15.2 for placebo on a numerical rating scale that went from 0 (no pain) up to 100 (worst pain).
Resveratrol is found naturally in grapes, peanuts, pine cones, and Chinese knotweed, and there is a growing body of evidence that it may have pleiotropic effects, said investigator Christelle Nguyen, PhD, MD, a professor of physical and rehabilitation medicine at Université Paris Cité, Paris, France.
It’s available in a powder form over the counter as a treatment for multiple ailments, but more recently, became available as an oral formulation. Dr. Nguyen and colleagues wanted to know if this would make a difference to OA knee pain when added to usual care.
A double-blind, multicenter, placebo-controlled randomized trial was therefore conducted that involved 142 people with knee OA who had been experiencing knee pain for at least 1 month. The participants were equally randomly allocated to receive either oral resveratrol given as two caplets of 20 mg twice daily for the first week, then once daily for a total of 6 months, or a matched placebo.
There was also no effect of resveratrol vs placebo on a host of secondary outcomes measured at 3 and 6 months.
The interpretation is that oral resveratrol may not be effective in this indication or have a biologic effect on the pain pathway, Dr. Nguyen said.
“Our findings do not support the use of [trans-resveratrol] supplementation in this patented formulation for reducing knee pain in adults with painful knee OA,” she concluded.
Botulinum Toxin: Over But Not Out?
Dr. Nguyen separately reported data from a new systematic review and meta-analysis on the use of intra-articular (IA) botulinum toxin type A (BoNT-A) for knee OA pain.
Seven of the 14 randomized controlled trials included in the meta-analysis had looked specifically at knee OA outcomes in the short, intermediate, and long term.
Results showed a nonsignificant trend favoring BoNT-A use, with the standard mean difference in pain of 0.35 (−0.82; 0.12), −0.27 (−0.61; 0.08), and −0.43 (−1.12; 0.26) for short-, intermediate-, and long-term use, respectively.
In contrast, pain reductions were seen with BoNT-A in three trials that included people with OA of the shoulder or base of the thumb. This begs the question as to whether botulinum toxin may still have a role to play, Dr. Nguyen said in an interview.
“It seems like there may be a positive effect for the shoulder joint and base of the thumb,” she told this news organization.
“So, basically, we found differences between large and small to intermediate joints,” Dr. Nguyen added. “It questions the dilution of botulinum toxin into the joint. If it’s a big joint, maybe the dilution is too high,” she suggested.
This hypothesis will be tested in the upcoming RHIBOT II trial that will begin recruitment later this year. This is a follow-on from the RHIBOT trial that was published in The Lancet Rheumatology 2 years ago.
Meanwhile, the use of botulinum toxin is off-label, Dr. Nguyen said. “We use it in our clinics only when first-line treatment had failed for base of thumb OA.” It’s not offered as a stand-alone intervention, and the IA injections need to be given by someone with experience, she said.
Methodologically Sound Studies
Commenting on the studies, Nancy E. Lane, MD, said: “There have been small botulinum studies before but not powered enough so that you could confirm or refute hypotheses.”
Dr. Lane, endowed professor of medicine, rheumatology, and aging research and director for the Center for Musculoskeletal Health at the University of California Davis School of Medicine, Sacramento, California, added: “Similarly for resveratrol, there have been lots of studies.”
Moreover, Dr. Lane observed that the studies were “really well-designed. They were well-powered. The subjects were selected in such a way that was good rigor in the methodologic design, and there were enough people in the studies so that you could really believe the results.”
The take-home is probably that these approaches do not work, Dr. Lane said, “at least when you apply them to moderate-severe knee OA patients, they don’t seem to make a difference.”
The congress was sponsored by the Osteoarthritis Research Society International.
The DICKENS study of diacerein was an investigator-initiated trial that was funded by the National Health and Medical Research Council of Australia. TRB Chemedica International S.A. provided diacerein free of charge for the trial but was not involved in the implementation or data analysis. Dr. Aitken had no conflicts of interest to disclose.
The ARTHROL trial of oral resveratrol was funded by the French Ministry of Health and Solidarity (Ministré des Solidarités et de la Santé). Yvery Laboratory provided the resveratrol caplet and matching placebo free of charge. Dr. Nguyen has financial relationships with Actelion, Grünenthal, Ipsen, Lilly, Meda, Merz, Novartis, Preciphar, Sandoz, Takeda, Thuasne, and UCB.
Dr. Lane had no relevant conflicts of interest to declare.
A version of this article appeared on Medscape.com.
VIENNA — Data do not back the use of diacerein or resveratrol for managing the pain of knee osteoarthritis (OA), according to the results of two well-performed, multicenter, double-blind, randomized controlled clinical trials.
During the News in Therapies session at the OARSI 2024 World Congress, the null findings of the DICKENS study and ARTHROL trial were presented alongside a reappraisal of the possible role of botulinum toxin.
DICKENS Study of Diacerein
“The role of diacerein in the treatment of OA is controversial,” acknowledged Dawn Aitken, PhD, associate professor at the University of Tasmania in Hobart, Tasmania, Australia. “There are only a few acceptable quality trials to date, and the results are inconsistent,” Dr. Aitken added.
Indeed, a Cochrane review performed in 2014 had concluded that there was “low-quality evidence that diacerein had a small beneficial effect on pain,” she said. The reported overall effect size on a 100-mm visual analog scale, based on a meta-analysis of 10 trials, has been just −8.65 mm, equating to just a 9% pain reduction.
At the time the DICKENS study was conceived, diacerein was recommended by a number of international guidelines for the management of hip and knee OA, although further, higher-quality studies were needed.
Diacerein blocks interleukin-1 beta, which is one of the key inflammatory markers of OA, so Dr. Aitken and collaborators postulated that perhaps it would work better if used in patients with an inflammatory phenotype.
They set about to test their hypothesis by recruiting 260 individuals with knee OA and MRI-detected effusion synovitis. The participants were then randomly allocated to treatment with either diacerein or a matching placebo for 24 weeks.
Individuals in the diacerein group were treated with an oral dose of 50 mg once daily for the first 2 weeks. If tolerated, the dose was increased to 50 mg twice daily.
No significant improvement in the primary endpoint of knee pain was seen comparing diacerein with placebo, with mean values of 53.2 mm and 56.4 mm, respectively, at 24 weeks using a 0-100 mm visual analog scale where 0 represented no pain and 100 represented the worst pain. It followed that there was no significant difference in the change from baseline to week 24 (−19.9 mm vs −18.6 mm; P = .77).
There was also no difference in the secondary endpoints, which included Western Ontario and McMaster Universities Arthritis Index pain, function, and stiffness. In fact, placebo-treated patients appeared to do better in terms of resolution of effusion synovitis as measured by a repeat MRI and quality of life, Dr. Aitken reported.
“These findings do not support the use of diacerein in treating patients with knee OA and effusion synovitis,” Dr. Aitken concluded.
ARTHROL Trial of Resveratrol
Similarly, negative results were reported for resveratrol from the ARTHROL trial, with 55% of the resveratrol- and 55% of placebo-treated individuals achieving a 20% reduction in knee pain intensity at 3 months. The actual change in knee pain from baseline to 3 months was −15.7 for resveratrol and −15.2 for placebo on a numerical rating scale that went from 0 (no pain) up to 100 (worst pain).
Resveratrol is found naturally in grapes, peanuts, pine cones, and Chinese knotweed, and there is a growing body of evidence that it may have pleiotropic effects, said investigator Christelle Nguyen, PhD, MD, a professor of physical and rehabilitation medicine at Université Paris Cité, Paris, France.
It’s available in a powder form over the counter as a treatment for multiple ailments, but more recently, became available as an oral formulation. Dr. Nguyen and colleagues wanted to know if this would make a difference to OA knee pain when added to usual care.
A double-blind, multicenter, placebo-controlled randomized trial was therefore conducted that involved 142 people with knee OA who had been experiencing knee pain for at least 1 month. The participants were equally randomly allocated to receive either oral resveratrol given as two caplets of 20 mg twice daily for the first week, then once daily for a total of 6 months, or a matched placebo.
There was also no effect of resveratrol vs placebo on a host of secondary outcomes measured at 3 and 6 months.
The interpretation is that oral resveratrol may not be effective in this indication or have a biologic effect on the pain pathway, Dr. Nguyen said.
“Our findings do not support the use of [trans-resveratrol] supplementation in this patented formulation for reducing knee pain in adults with painful knee OA,” she concluded.
Botulinum Toxin: Over But Not Out?
Dr. Nguyen separately reported data from a new systematic review and meta-analysis on the use of intra-articular (IA) botulinum toxin type A (BoNT-A) for knee OA pain.
Seven of the 14 randomized controlled trials included in the meta-analysis had looked specifically at knee OA outcomes in the short, intermediate, and long term.
Results showed a nonsignificant trend favoring BoNT-A use, with the standard mean difference in pain of 0.35 (−0.82; 0.12), −0.27 (−0.61; 0.08), and −0.43 (−1.12; 0.26) for short-, intermediate-, and long-term use, respectively.
In contrast, pain reductions were seen with BoNT-A in three trials that included people with OA of the shoulder or base of the thumb. This begs the question as to whether botulinum toxin may still have a role to play, Dr. Nguyen said in an interview.
“It seems like there may be a positive effect for the shoulder joint and base of the thumb,” she told this news organization.
“So, basically, we found differences between large and small to intermediate joints,” Dr. Nguyen added. “It questions the dilution of botulinum toxin into the joint. If it’s a big joint, maybe the dilution is too high,” she suggested.
This hypothesis will be tested in the upcoming RHIBOT II trial that will begin recruitment later this year. This is a follow-on from the RHIBOT trial that was published in The Lancet Rheumatology 2 years ago.
Meanwhile, the use of botulinum toxin is off-label, Dr. Nguyen said. “We use it in our clinics only when first-line treatment had failed for base of thumb OA.” It’s not offered as a stand-alone intervention, and the IA injections need to be given by someone with experience, she said.
Methodologically Sound Studies
Commenting on the studies, Nancy E. Lane, MD, said: “There have been small botulinum studies before but not powered enough so that you could confirm or refute hypotheses.”
Dr. Lane, endowed professor of medicine, rheumatology, and aging research and director for the Center for Musculoskeletal Health at the University of California Davis School of Medicine, Sacramento, California, added: “Similarly for resveratrol, there have been lots of studies.”
Moreover, Dr. Lane observed that the studies were “really well-designed. They were well-powered. The subjects were selected in such a way that was good rigor in the methodologic design, and there were enough people in the studies so that you could really believe the results.”
The take-home is probably that these approaches do not work, Dr. Lane said, “at least when you apply them to moderate-severe knee OA patients, they don’t seem to make a difference.”
The congress was sponsored by the Osteoarthritis Research Society International.
The DICKENS study of diacerein was an investigator-initiated trial that was funded by the National Health and Medical Research Council of Australia. TRB Chemedica International S.A. provided diacerein free of charge for the trial but was not involved in the implementation or data analysis. Dr. Aitken had no conflicts of interest to disclose.
The ARTHROL trial of oral resveratrol was funded by the French Ministry of Health and Solidarity (Ministré des Solidarités et de la Santé). Yvery Laboratory provided the resveratrol caplet and matching placebo free of charge. Dr. Nguyen has financial relationships with Actelion, Grünenthal, Ipsen, Lilly, Meda, Merz, Novartis, Preciphar, Sandoz, Takeda, Thuasne, and UCB.
Dr. Lane had no relevant conflicts of interest to declare.
A version of this article appeared on Medscape.com.
VIENNA — Data do not back the use of diacerein or resveratrol for managing the pain of knee osteoarthritis (OA), according to the results of two well-performed, multicenter, double-blind, randomized controlled clinical trials.
During the News in Therapies session at the OARSI 2024 World Congress, the null findings of the DICKENS study and ARTHROL trial were presented alongside a reappraisal of the possible role of botulinum toxin.
DICKENS Study of Diacerein
“The role of diacerein in the treatment of OA is controversial,” acknowledged Dawn Aitken, PhD, associate professor at the University of Tasmania in Hobart, Tasmania, Australia. “There are only a few acceptable quality trials to date, and the results are inconsistent,” Dr. Aitken added.
Indeed, a Cochrane review performed in 2014 had concluded that there was “low-quality evidence that diacerein had a small beneficial effect on pain,” she said. The reported overall effect size on a 100-mm visual analog scale, based on a meta-analysis of 10 trials, has been just −8.65 mm, equating to just a 9% pain reduction.
At the time the DICKENS study was conceived, diacerein was recommended by a number of international guidelines for the management of hip and knee OA, although further, higher-quality studies were needed.
Diacerein blocks interleukin-1 beta, which is one of the key inflammatory markers of OA, so Dr. Aitken and collaborators postulated that perhaps it would work better if used in patients with an inflammatory phenotype.
They set about to test their hypothesis by recruiting 260 individuals with knee OA and MRI-detected effusion synovitis. The participants were then randomly allocated to treatment with either diacerein or a matching placebo for 24 weeks.
Individuals in the diacerein group were treated with an oral dose of 50 mg once daily for the first 2 weeks. If tolerated, the dose was increased to 50 mg twice daily.
No significant improvement in the primary endpoint of knee pain was seen comparing diacerein with placebo, with mean values of 53.2 mm and 56.4 mm, respectively, at 24 weeks using a 0-100 mm visual analog scale where 0 represented no pain and 100 represented the worst pain. It followed that there was no significant difference in the change from baseline to week 24 (−19.9 mm vs −18.6 mm; P = .77).
There was also no difference in the secondary endpoints, which included Western Ontario and McMaster Universities Arthritis Index pain, function, and stiffness. In fact, placebo-treated patients appeared to do better in terms of resolution of effusion synovitis as measured by a repeat MRI and quality of life, Dr. Aitken reported.
“These findings do not support the use of diacerein in treating patients with knee OA and effusion synovitis,” Dr. Aitken concluded.
ARTHROL Trial of Resveratrol
Similarly, negative results were reported for resveratrol from the ARTHROL trial, with 55% of the resveratrol- and 55% of placebo-treated individuals achieving a 20% reduction in knee pain intensity at 3 months. The actual change in knee pain from baseline to 3 months was −15.7 for resveratrol and −15.2 for placebo on a numerical rating scale that went from 0 (no pain) up to 100 (worst pain).
Resveratrol is found naturally in grapes, peanuts, pine cones, and Chinese knotweed, and there is a growing body of evidence that it may have pleiotropic effects, said investigator Christelle Nguyen, PhD, MD, a professor of physical and rehabilitation medicine at Université Paris Cité, Paris, France.
It’s available in a powder form over the counter as a treatment for multiple ailments, but more recently, became available as an oral formulation. Dr. Nguyen and colleagues wanted to know if this would make a difference to OA knee pain when added to usual care.
A double-blind, multicenter, placebo-controlled randomized trial was therefore conducted that involved 142 people with knee OA who had been experiencing knee pain for at least 1 month. The participants were equally randomly allocated to receive either oral resveratrol given as two caplets of 20 mg twice daily for the first week, then once daily for a total of 6 months, or a matched placebo.
There was also no effect of resveratrol vs placebo on a host of secondary outcomes measured at 3 and 6 months.
The interpretation is that oral resveratrol may not be effective in this indication or have a biologic effect on the pain pathway, Dr. Nguyen said.
“Our findings do not support the use of [trans-resveratrol] supplementation in this patented formulation for reducing knee pain in adults with painful knee OA,” she concluded.
Botulinum Toxin: Over But Not Out?
Dr. Nguyen separately reported data from a new systematic review and meta-analysis on the use of intra-articular (IA) botulinum toxin type A (BoNT-A) for knee OA pain.
Seven of the 14 randomized controlled trials included in the meta-analysis had looked specifically at knee OA outcomes in the short, intermediate, and long term.
Results showed a nonsignificant trend favoring BoNT-A use, with the standard mean difference in pain of 0.35 (−0.82; 0.12), −0.27 (−0.61; 0.08), and −0.43 (−1.12; 0.26) for short-, intermediate-, and long-term use, respectively.
In contrast, pain reductions were seen with BoNT-A in three trials that included people with OA of the shoulder or base of the thumb. This begs the question as to whether botulinum toxin may still have a role to play, Dr. Nguyen said in an interview.
“It seems like there may be a positive effect for the shoulder joint and base of the thumb,” she told this news organization.
“So, basically, we found differences between large and small to intermediate joints,” Dr. Nguyen added. “It questions the dilution of botulinum toxin into the joint. If it’s a big joint, maybe the dilution is too high,” she suggested.
This hypothesis will be tested in the upcoming RHIBOT II trial that will begin recruitment later this year. This is a follow-on from the RHIBOT trial that was published in The Lancet Rheumatology 2 years ago.
Meanwhile, the use of botulinum toxin is off-label, Dr. Nguyen said. “We use it in our clinics only when first-line treatment had failed for base of thumb OA.” It’s not offered as a stand-alone intervention, and the IA injections need to be given by someone with experience, she said.
Methodologically Sound Studies
Commenting on the studies, Nancy E. Lane, MD, said: “There have been small botulinum studies before but not powered enough so that you could confirm or refute hypotheses.”
Dr. Lane, endowed professor of medicine, rheumatology, and aging research and director for the Center for Musculoskeletal Health at the University of California Davis School of Medicine, Sacramento, California, added: “Similarly for resveratrol, there have been lots of studies.”
Moreover, Dr. Lane observed that the studies were “really well-designed. They were well-powered. The subjects were selected in such a way that was good rigor in the methodologic design, and there were enough people in the studies so that you could really believe the results.”
The take-home is probably that these approaches do not work, Dr. Lane said, “at least when you apply them to moderate-severe knee OA patients, they don’t seem to make a difference.”
The congress was sponsored by the Osteoarthritis Research Society International.
The DICKENS study of diacerein was an investigator-initiated trial that was funded by the National Health and Medical Research Council of Australia. TRB Chemedica International S.A. provided diacerein free of charge for the trial but was not involved in the implementation or data analysis. Dr. Aitken had no conflicts of interest to disclose.
The ARTHROL trial of oral resveratrol was funded by the French Ministry of Health and Solidarity (Ministré des Solidarités et de la Santé). Yvery Laboratory provided the resveratrol caplet and matching placebo free of charge. Dr. Nguyen has financial relationships with Actelion, Grünenthal, Ipsen, Lilly, Meda, Merz, Novartis, Preciphar, Sandoz, Takeda, Thuasne, and UCB.
Dr. Lane had no relevant conflicts of interest to declare.
A version of this article appeared on Medscape.com.
FROM OARSI 2024
Knee Osteoarthritis Trials Show Promising Results for Several Novel Injectables
VIENNA — Encouraging primary or secondary analyses of trial data for the use of several novel injectables and gene therapy for knee osteoarthritis (OA) were reported at the OARSI 2024 World Congress.
Of all the approaches discussed during the News in Therapies session at OARSI 2024, the most intriguing was the use of the placental extract PTP-001 (MOTYS, Bioventus), session chair Nancy E. Lane, MD, of the University of California Davis School of Medicine, Sacramento, California, told this news organization.
Other notable presentations of data from trials of investigational agents for knee OA included an update from the SPRINGBOARD phase 2B trial of EP-104IAR, a novel long-acting formulation of the corticosteroid fluticasone propionate; a phase 2 trial of pentosan polysulfate sodium (PPS), a non-opioid, semi-synthetic xylose-based polysaccharide; and an update on phase 2 study results for XT-150, a non-viral, plasmid-based gene therapy designed to express a proprietary variant of interleukin 10 (IL-10).
PTP-001 (MOTYS)
Indeed, promising results were seen in a phase 2 trial testing a single intra-articular (IA) injection of PTP-001 vs an IA saline placebo in just over 200 individuals with symptomatic knee OA. Results of this dose-finding study were presented by Alessandra Pavesio, senior vice president and the chief science officer of Bioventus/Doron Therapeutics, Durham, North Carolina.
Ms. Pavesio reported there were decreases in knee pain and improvements in knee function, as measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). These changes were seen after 26 weeks of treatment with PTP-001 given at either a low (100 mg, n = 74) or high (200 mg, n = 40) dose.
Although the changes were only numerically and not statistically different from placebo (n = 71) when looking at the total study population, Ms. Pavesio noted that a key objective of the trial had been to identify populations of patients that may benefit.
When they looked at the effects of PTP-001 solely in those with unilateral knee OA, WOMAC pain scores were decreased to a significantly greater extent with both the high and low doses of PTP-001 vs placebo. Decreases in the least squares mean (LSM) change in WOMAC pain from baseline to week 26 were 26.8 with 100-mg PTP-001, 36.1 with 200-mg PTP-001, and 24.0 with placebo (P = .072). A similarly greater effect for PTP-001 was also seen for LSM change in WOMAC function (26.4, 36.0, and 20.0, respectively; P = .023).
Ms. Pavesio noted that the only real side effect seen during the trial was an initial inflammatory reaction within the first 2 days of IA injection, which resolved within a few days without further problems.
The results are promising enough for Ms. Pavesio and her team to consider a phase 3 trial.
Dr. Lane asked Ms. Pavesio: “So, what’s in the secret sauce? You said it was ground-up placentas?” To which Ms. Pavesio replied that it contained about 300 different molecules which came from amnion, chorion, and umbilical cord tissue obtained from consented placental donation.
Dr. Lane subsequently told this news organization: “It’s probably a bunch of growth factors and cytokines, but if it’s not toxic, and they can standardize it, then it might be good. We remain open minded because we haven’t figured it out.”
Novel Fluticasone Delivery
In the same session, James A. Helliwell, MD, cofounder, director, and chief executive officer of Eupraxia Pharmaceuticals in Victoria, British Columbia, Canada, presented updated data from the SPRINGBOARD phase 2B trial of EP-104IAR, a novel long-acting formulation of the corticosteroid fluticasone propionate.
Dr. Helliwell, a cardiothoracic anesthesiologist, explained that EP-104IAR uses proprietary technology to form fluticasone into a crystal that can then be injected directly into the joint. This then slowly diffuses out to provide a highly localized treatment.
The SPRINGBOARD trial recruited just over 300 individuals with moderate knee OA and moderate to severe WOMAC pain and randomly allocated 164 to a single IA injection of EP-104IAR and 164 to a matching vehicle injection as a placebo. The latter was a slightly viscous substance that behaved like hyaluronic acid, Dr. Helliwell said.
The LSM change in total WOMAC score from baseline to week 12 showed a greater improvement with EP-104IAR than with placebo in a per protocol analysis (−2.79 vs −2.07; P = .002). Similar results were seen for the WOMAC subscales of pain (−2.97 vs −2.24; P = .003), function (−2.64 vs −1.99; P = .005), and stiffness (−2.85 vs −2.05; P = .001).
These differences persisted, Dr. Helliwell reported, out to a 20-week assessment for total WOMAC score, function, and stiffness and out to a 15-week assessment for WOMAC pain.
It’s probably no surprise that a steroid works, Dr. Helliwell said, noting that the safety profile of EP-104IAR may be better than that of regular IA steroid injection because it has “few off-target” effects. He reported that there were “minimal, clinically insignificant, and transient effects” of EP-104IAR on serum cortisol. There was no effect on glucose metabolism, even in patients with diabetes, he said.
“There is a group of our patients that we give long-acting steroids to in the joint, so it looked like [the EP-104IAR] safety profile was really good,” Dr. Lane told this news organization. However, she added: “I’m worried about the price tag associated with it.”
PPS
Although it perhaps can’t be described as a novel injectable per se, Mukesh Ahuja, MBBS, global clinical head of osteoarthritis at Paradigm Biopharmaceuticals, presented results of the novel use of PPS.
“PPS is a non-opioid, semi-synthetic xylose-based polysaccharide that is derived from beechwood trees,” Dr. Ahuja said. “It has a long-track record for treating pain, inflammation, and thrombosis in humans.”
There are currently two approved formulations: Oral capsules used for the treatment of interstitial cystitis in the European Union, United States, and Australia and an injectable form used in Italy for thromboprophylaxis.
Dr. Ahuja presented data from a phase 2 trial that looked at the effect of once- or twice-weekly subcutaneous injections of PPS vs placebo in 61 people with knee OA pain. Assessments were made after 56, 168, and 365 days of treatment.
Results showed PPS injections resulted in significant improvements in total WOMAC score, WOMAC pain, and WOMAC function, with more PPS- than placebo-treated individuals achieving and then maintaining at least a 30% or greater improvement in pain and a 56% improvement in function.
Rescue medication use was lower in the PPS-treated patients, and Patient Global Impression of Change were significantly higher, Dr. Ahuja said.
Exploratory analyses of synovial fluid biomarkers showed PPS could be having a direct inflammatory effect, with reductions in several proinflammatory cytokines, such as IL-6 and tumor necrosis factor alpha.
An assessment of OA disease progression using MRI analysis suggested that there may be an effect on cartilage thickness and volume, as well as bone marrow lesions and overall joint inflammation.
Gene Therapy
Elsewhere at OARSI 2024, updated data were reported on XT-150, a non-viral, plasmid-based gene therapy designed to express a proprietary variant (v) of IL-10.
Howard Rutman, MD, MBA, chief medical officer of Xalud Therapeutics, reported data from a patient subgroup analysis of a phase 2 trial, which evaluated the effects of single and repeat IA injections of XT-150.
Previously, it was found that a single dose of XT-150 (0.15 mg/mL or 0.45 mg/mL) given as a 1-mL IA injection did not meet its primary endpoint of a greater proportion of patients achieving a 30% or more improvement in WOMAC pain at 180 days vs a matching placebo.
However, it was noted that 17% of the patients in the trial had a baseline WOMAC pain score of less than 8, so the new analysis focused on a modified intention-to-treat population of 210 patients who had baseline WOMAC pain scores of 9 or higher.
Two injections of XT-150 at a dose of 0.45 mg were found to produce the best effect on WOMAC pain, with a LSM change from baseline of −4.09 vs −2.74 for a single 0.45-mg injection (P = .044).
Dr. Rutman reported that the 0.45-mg dose would be the one moving forward into future studies as this had the best effect when they looked at various patient demographics, including baseline age, gender, body mass index, Kellgren-Lawrence grade, and use of concomitant medications.
XT-150 acts locally, does not integrate into the host genome, and “has a very favorable safety profile,” Dr. Rutman said. As it is not a protein, there is no antibody response, and this gives it the possibility for repeat dosing, with no drug-drug serious adverse events so far reported.
The Best Is Yet to Come?
“There’s a lot of things cooking that haven’t been presented here [at OARSI],” Dr. Lane observed.
“We are figuring out how to regenerate cartilage, and it’s a little different than throwing some stem cells in there. There’s some ground-breaking stuff [coming], it just takes us a while.”
Dr. Lane also noted that researchers were “really figuring out” how joints become painful, which will be a major step in figuring out how to make them less painful for patients.
“We’re making a lot of progress in ways that I don’t think we previously thought of, for example, the weight loss drugs. They probably have a central pain reduction effect, I think there’s a little overlap with the opioid receptors, so that’s pretty exciting. So, we’re getting there,” Dr. Lane said.
The congress was sponsored by the Osteoarthritis Research Society International.
Dr. Lane had no relevant conflicts to declare. The trial of PTP-001 (MOTYS) was funded by Bioventus. Ms. Pavesio is an employee of Doron Therapeutics, a subsidiary of Bioventus. The SPRINGBOARD trial with EP-104IAR was funded by Eupraxia Pharmaceuticals. Dr. Helliwell is an employee and stockholder of Eupraxia Pharmaceuticals. The trial of PPS was funded by Paradigm Biopharmaceuticals. Dr. Ahuja is an employee and stockholder of Paradigm Biopharmaceuticals and holds stock in ChitogenX. The trial of XT-150 was funded by Xalud Therapeutics. Dr. Rutman is an employee and equity holder of the company.
A version of this article appeared on Medscape.com.
VIENNA — Encouraging primary or secondary analyses of trial data for the use of several novel injectables and gene therapy for knee osteoarthritis (OA) were reported at the OARSI 2024 World Congress.
Of all the approaches discussed during the News in Therapies session at OARSI 2024, the most intriguing was the use of the placental extract PTP-001 (MOTYS, Bioventus), session chair Nancy E. Lane, MD, of the University of California Davis School of Medicine, Sacramento, California, told this news organization.
Other notable presentations of data from trials of investigational agents for knee OA included an update from the SPRINGBOARD phase 2B trial of EP-104IAR, a novel long-acting formulation of the corticosteroid fluticasone propionate; a phase 2 trial of pentosan polysulfate sodium (PPS), a non-opioid, semi-synthetic xylose-based polysaccharide; and an update on phase 2 study results for XT-150, a non-viral, plasmid-based gene therapy designed to express a proprietary variant of interleukin 10 (IL-10).
PTP-001 (MOTYS)
Indeed, promising results were seen in a phase 2 trial testing a single intra-articular (IA) injection of PTP-001 vs an IA saline placebo in just over 200 individuals with symptomatic knee OA. Results of this dose-finding study were presented by Alessandra Pavesio, senior vice president and the chief science officer of Bioventus/Doron Therapeutics, Durham, North Carolina.
Ms. Pavesio reported there were decreases in knee pain and improvements in knee function, as measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). These changes were seen after 26 weeks of treatment with PTP-001 given at either a low (100 mg, n = 74) or high (200 mg, n = 40) dose.
Although the changes were only numerically and not statistically different from placebo (n = 71) when looking at the total study population, Ms. Pavesio noted that a key objective of the trial had been to identify populations of patients that may benefit.
When they looked at the effects of PTP-001 solely in those with unilateral knee OA, WOMAC pain scores were decreased to a significantly greater extent with both the high and low doses of PTP-001 vs placebo. Decreases in the least squares mean (LSM) change in WOMAC pain from baseline to week 26 were 26.8 with 100-mg PTP-001, 36.1 with 200-mg PTP-001, and 24.0 with placebo (P = .072). A similarly greater effect for PTP-001 was also seen for LSM change in WOMAC function (26.4, 36.0, and 20.0, respectively; P = .023).
Ms. Pavesio noted that the only real side effect seen during the trial was an initial inflammatory reaction within the first 2 days of IA injection, which resolved within a few days without further problems.
The results are promising enough for Ms. Pavesio and her team to consider a phase 3 trial.
Dr. Lane asked Ms. Pavesio: “So, what’s in the secret sauce? You said it was ground-up placentas?” To which Ms. Pavesio replied that it contained about 300 different molecules which came from amnion, chorion, and umbilical cord tissue obtained from consented placental donation.
Dr. Lane subsequently told this news organization: “It’s probably a bunch of growth factors and cytokines, but if it’s not toxic, and they can standardize it, then it might be good. We remain open minded because we haven’t figured it out.”
Novel Fluticasone Delivery
In the same session, James A. Helliwell, MD, cofounder, director, and chief executive officer of Eupraxia Pharmaceuticals in Victoria, British Columbia, Canada, presented updated data from the SPRINGBOARD phase 2B trial of EP-104IAR, a novel long-acting formulation of the corticosteroid fluticasone propionate.
Dr. Helliwell, a cardiothoracic anesthesiologist, explained that EP-104IAR uses proprietary technology to form fluticasone into a crystal that can then be injected directly into the joint. This then slowly diffuses out to provide a highly localized treatment.
The SPRINGBOARD trial recruited just over 300 individuals with moderate knee OA and moderate to severe WOMAC pain and randomly allocated 164 to a single IA injection of EP-104IAR and 164 to a matching vehicle injection as a placebo. The latter was a slightly viscous substance that behaved like hyaluronic acid, Dr. Helliwell said.
The LSM change in total WOMAC score from baseline to week 12 showed a greater improvement with EP-104IAR than with placebo in a per protocol analysis (−2.79 vs −2.07; P = .002). Similar results were seen for the WOMAC subscales of pain (−2.97 vs −2.24; P = .003), function (−2.64 vs −1.99; P = .005), and stiffness (−2.85 vs −2.05; P = .001).
These differences persisted, Dr. Helliwell reported, out to a 20-week assessment for total WOMAC score, function, and stiffness and out to a 15-week assessment for WOMAC pain.
It’s probably no surprise that a steroid works, Dr. Helliwell said, noting that the safety profile of EP-104IAR may be better than that of regular IA steroid injection because it has “few off-target” effects. He reported that there were “minimal, clinically insignificant, and transient effects” of EP-104IAR on serum cortisol. There was no effect on glucose metabolism, even in patients with diabetes, he said.
“There is a group of our patients that we give long-acting steroids to in the joint, so it looked like [the EP-104IAR] safety profile was really good,” Dr. Lane told this news organization. However, she added: “I’m worried about the price tag associated with it.”
PPS
Although it perhaps can’t be described as a novel injectable per se, Mukesh Ahuja, MBBS, global clinical head of osteoarthritis at Paradigm Biopharmaceuticals, presented results of the novel use of PPS.
“PPS is a non-opioid, semi-synthetic xylose-based polysaccharide that is derived from beechwood trees,” Dr. Ahuja said. “It has a long-track record for treating pain, inflammation, and thrombosis in humans.”
There are currently two approved formulations: Oral capsules used for the treatment of interstitial cystitis in the European Union, United States, and Australia and an injectable form used in Italy for thromboprophylaxis.
Dr. Ahuja presented data from a phase 2 trial that looked at the effect of once- or twice-weekly subcutaneous injections of PPS vs placebo in 61 people with knee OA pain. Assessments were made after 56, 168, and 365 days of treatment.
Results showed PPS injections resulted in significant improvements in total WOMAC score, WOMAC pain, and WOMAC function, with more PPS- than placebo-treated individuals achieving and then maintaining at least a 30% or greater improvement in pain and a 56% improvement in function.
Rescue medication use was lower in the PPS-treated patients, and Patient Global Impression of Change were significantly higher, Dr. Ahuja said.
Exploratory analyses of synovial fluid biomarkers showed PPS could be having a direct inflammatory effect, with reductions in several proinflammatory cytokines, such as IL-6 and tumor necrosis factor alpha.
An assessment of OA disease progression using MRI analysis suggested that there may be an effect on cartilage thickness and volume, as well as bone marrow lesions and overall joint inflammation.
Gene Therapy
Elsewhere at OARSI 2024, updated data were reported on XT-150, a non-viral, plasmid-based gene therapy designed to express a proprietary variant (v) of IL-10.
Howard Rutman, MD, MBA, chief medical officer of Xalud Therapeutics, reported data from a patient subgroup analysis of a phase 2 trial, which evaluated the effects of single and repeat IA injections of XT-150.
Previously, it was found that a single dose of XT-150 (0.15 mg/mL or 0.45 mg/mL) given as a 1-mL IA injection did not meet its primary endpoint of a greater proportion of patients achieving a 30% or more improvement in WOMAC pain at 180 days vs a matching placebo.
However, it was noted that 17% of the patients in the trial had a baseline WOMAC pain score of less than 8, so the new analysis focused on a modified intention-to-treat population of 210 patients who had baseline WOMAC pain scores of 9 or higher.
Two injections of XT-150 at a dose of 0.45 mg were found to produce the best effect on WOMAC pain, with a LSM change from baseline of −4.09 vs −2.74 for a single 0.45-mg injection (P = .044).
Dr. Rutman reported that the 0.45-mg dose would be the one moving forward into future studies as this had the best effect when they looked at various patient demographics, including baseline age, gender, body mass index, Kellgren-Lawrence grade, and use of concomitant medications.
XT-150 acts locally, does not integrate into the host genome, and “has a very favorable safety profile,” Dr. Rutman said. As it is not a protein, there is no antibody response, and this gives it the possibility for repeat dosing, with no drug-drug serious adverse events so far reported.
The Best Is Yet to Come?
“There’s a lot of things cooking that haven’t been presented here [at OARSI],” Dr. Lane observed.
“We are figuring out how to regenerate cartilage, and it’s a little different than throwing some stem cells in there. There’s some ground-breaking stuff [coming], it just takes us a while.”
Dr. Lane also noted that researchers were “really figuring out” how joints become painful, which will be a major step in figuring out how to make them less painful for patients.
“We’re making a lot of progress in ways that I don’t think we previously thought of, for example, the weight loss drugs. They probably have a central pain reduction effect, I think there’s a little overlap with the opioid receptors, so that’s pretty exciting. So, we’re getting there,” Dr. Lane said.
The congress was sponsored by the Osteoarthritis Research Society International.
Dr. Lane had no relevant conflicts to declare. The trial of PTP-001 (MOTYS) was funded by Bioventus. Ms. Pavesio is an employee of Doron Therapeutics, a subsidiary of Bioventus. The SPRINGBOARD trial with EP-104IAR was funded by Eupraxia Pharmaceuticals. Dr. Helliwell is an employee and stockholder of Eupraxia Pharmaceuticals. The trial of PPS was funded by Paradigm Biopharmaceuticals. Dr. Ahuja is an employee and stockholder of Paradigm Biopharmaceuticals and holds stock in ChitogenX. The trial of XT-150 was funded by Xalud Therapeutics. Dr. Rutman is an employee and equity holder of the company.
A version of this article appeared on Medscape.com.
VIENNA — Encouraging primary or secondary analyses of trial data for the use of several novel injectables and gene therapy for knee osteoarthritis (OA) were reported at the OARSI 2024 World Congress.
Of all the approaches discussed during the News in Therapies session at OARSI 2024, the most intriguing was the use of the placental extract PTP-001 (MOTYS, Bioventus), session chair Nancy E. Lane, MD, of the University of California Davis School of Medicine, Sacramento, California, told this news organization.
Other notable presentations of data from trials of investigational agents for knee OA included an update from the SPRINGBOARD phase 2B trial of EP-104IAR, a novel long-acting formulation of the corticosteroid fluticasone propionate; a phase 2 trial of pentosan polysulfate sodium (PPS), a non-opioid, semi-synthetic xylose-based polysaccharide; and an update on phase 2 study results for XT-150, a non-viral, plasmid-based gene therapy designed to express a proprietary variant of interleukin 10 (IL-10).
PTP-001 (MOTYS)
Indeed, promising results were seen in a phase 2 trial testing a single intra-articular (IA) injection of PTP-001 vs an IA saline placebo in just over 200 individuals with symptomatic knee OA. Results of this dose-finding study were presented by Alessandra Pavesio, senior vice president and the chief science officer of Bioventus/Doron Therapeutics, Durham, North Carolina.
Ms. Pavesio reported there were decreases in knee pain and improvements in knee function, as measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). These changes were seen after 26 weeks of treatment with PTP-001 given at either a low (100 mg, n = 74) or high (200 mg, n = 40) dose.
Although the changes were only numerically and not statistically different from placebo (n = 71) when looking at the total study population, Ms. Pavesio noted that a key objective of the trial had been to identify populations of patients that may benefit.
When they looked at the effects of PTP-001 solely in those with unilateral knee OA, WOMAC pain scores were decreased to a significantly greater extent with both the high and low doses of PTP-001 vs placebo. Decreases in the least squares mean (LSM) change in WOMAC pain from baseline to week 26 were 26.8 with 100-mg PTP-001, 36.1 with 200-mg PTP-001, and 24.0 with placebo (P = .072). A similarly greater effect for PTP-001 was also seen for LSM change in WOMAC function (26.4, 36.0, and 20.0, respectively; P = .023).
Ms. Pavesio noted that the only real side effect seen during the trial was an initial inflammatory reaction within the first 2 days of IA injection, which resolved within a few days without further problems.
The results are promising enough for Ms. Pavesio and her team to consider a phase 3 trial.
Dr. Lane asked Ms. Pavesio: “So, what’s in the secret sauce? You said it was ground-up placentas?” To which Ms. Pavesio replied that it contained about 300 different molecules which came from amnion, chorion, and umbilical cord tissue obtained from consented placental donation.
Dr. Lane subsequently told this news organization: “It’s probably a bunch of growth factors and cytokines, but if it’s not toxic, and they can standardize it, then it might be good. We remain open minded because we haven’t figured it out.”
Novel Fluticasone Delivery
In the same session, James A. Helliwell, MD, cofounder, director, and chief executive officer of Eupraxia Pharmaceuticals in Victoria, British Columbia, Canada, presented updated data from the SPRINGBOARD phase 2B trial of EP-104IAR, a novel long-acting formulation of the corticosteroid fluticasone propionate.
Dr. Helliwell, a cardiothoracic anesthesiologist, explained that EP-104IAR uses proprietary technology to form fluticasone into a crystal that can then be injected directly into the joint. This then slowly diffuses out to provide a highly localized treatment.
The SPRINGBOARD trial recruited just over 300 individuals with moderate knee OA and moderate to severe WOMAC pain and randomly allocated 164 to a single IA injection of EP-104IAR and 164 to a matching vehicle injection as a placebo. The latter was a slightly viscous substance that behaved like hyaluronic acid, Dr. Helliwell said.
The LSM change in total WOMAC score from baseline to week 12 showed a greater improvement with EP-104IAR than with placebo in a per protocol analysis (−2.79 vs −2.07; P = .002). Similar results were seen for the WOMAC subscales of pain (−2.97 vs −2.24; P = .003), function (−2.64 vs −1.99; P = .005), and stiffness (−2.85 vs −2.05; P = .001).
These differences persisted, Dr. Helliwell reported, out to a 20-week assessment for total WOMAC score, function, and stiffness and out to a 15-week assessment for WOMAC pain.
It’s probably no surprise that a steroid works, Dr. Helliwell said, noting that the safety profile of EP-104IAR may be better than that of regular IA steroid injection because it has “few off-target” effects. He reported that there were “minimal, clinically insignificant, and transient effects” of EP-104IAR on serum cortisol. There was no effect on glucose metabolism, even in patients with diabetes, he said.
“There is a group of our patients that we give long-acting steroids to in the joint, so it looked like [the EP-104IAR] safety profile was really good,” Dr. Lane told this news organization. However, she added: “I’m worried about the price tag associated with it.”
PPS
Although it perhaps can’t be described as a novel injectable per se, Mukesh Ahuja, MBBS, global clinical head of osteoarthritis at Paradigm Biopharmaceuticals, presented results of the novel use of PPS.
“PPS is a non-opioid, semi-synthetic xylose-based polysaccharide that is derived from beechwood trees,” Dr. Ahuja said. “It has a long-track record for treating pain, inflammation, and thrombosis in humans.”
There are currently two approved formulations: Oral capsules used for the treatment of interstitial cystitis in the European Union, United States, and Australia and an injectable form used in Italy for thromboprophylaxis.
Dr. Ahuja presented data from a phase 2 trial that looked at the effect of once- or twice-weekly subcutaneous injections of PPS vs placebo in 61 people with knee OA pain. Assessments were made after 56, 168, and 365 days of treatment.
Results showed PPS injections resulted in significant improvements in total WOMAC score, WOMAC pain, and WOMAC function, with more PPS- than placebo-treated individuals achieving and then maintaining at least a 30% or greater improvement in pain and a 56% improvement in function.
Rescue medication use was lower in the PPS-treated patients, and Patient Global Impression of Change were significantly higher, Dr. Ahuja said.
Exploratory analyses of synovial fluid biomarkers showed PPS could be having a direct inflammatory effect, with reductions in several proinflammatory cytokines, such as IL-6 and tumor necrosis factor alpha.
An assessment of OA disease progression using MRI analysis suggested that there may be an effect on cartilage thickness and volume, as well as bone marrow lesions and overall joint inflammation.
Gene Therapy
Elsewhere at OARSI 2024, updated data were reported on XT-150, a non-viral, plasmid-based gene therapy designed to express a proprietary variant (v) of IL-10.
Howard Rutman, MD, MBA, chief medical officer of Xalud Therapeutics, reported data from a patient subgroup analysis of a phase 2 trial, which evaluated the effects of single and repeat IA injections of XT-150.
Previously, it was found that a single dose of XT-150 (0.15 mg/mL or 0.45 mg/mL) given as a 1-mL IA injection did not meet its primary endpoint of a greater proportion of patients achieving a 30% or more improvement in WOMAC pain at 180 days vs a matching placebo.
However, it was noted that 17% of the patients in the trial had a baseline WOMAC pain score of less than 8, so the new analysis focused on a modified intention-to-treat population of 210 patients who had baseline WOMAC pain scores of 9 or higher.
Two injections of XT-150 at a dose of 0.45 mg were found to produce the best effect on WOMAC pain, with a LSM change from baseline of −4.09 vs −2.74 for a single 0.45-mg injection (P = .044).
Dr. Rutman reported that the 0.45-mg dose would be the one moving forward into future studies as this had the best effect when they looked at various patient demographics, including baseline age, gender, body mass index, Kellgren-Lawrence grade, and use of concomitant medications.
XT-150 acts locally, does not integrate into the host genome, and “has a very favorable safety profile,” Dr. Rutman said. As it is not a protein, there is no antibody response, and this gives it the possibility for repeat dosing, with no drug-drug serious adverse events so far reported.
The Best Is Yet to Come?
“There’s a lot of things cooking that haven’t been presented here [at OARSI],” Dr. Lane observed.
“We are figuring out how to regenerate cartilage, and it’s a little different than throwing some stem cells in there. There’s some ground-breaking stuff [coming], it just takes us a while.”
Dr. Lane also noted that researchers were “really figuring out” how joints become painful, which will be a major step in figuring out how to make them less painful for patients.
“We’re making a lot of progress in ways that I don’t think we previously thought of, for example, the weight loss drugs. They probably have a central pain reduction effect, I think there’s a little overlap with the opioid receptors, so that’s pretty exciting. So, we’re getting there,” Dr. Lane said.
The congress was sponsored by the Osteoarthritis Research Society International.
Dr. Lane had no relevant conflicts to declare. The trial of PTP-001 (MOTYS) was funded by Bioventus. Ms. Pavesio is an employee of Doron Therapeutics, a subsidiary of Bioventus. The SPRINGBOARD trial with EP-104IAR was funded by Eupraxia Pharmaceuticals. Dr. Helliwell is an employee and stockholder of Eupraxia Pharmaceuticals. The trial of PPS was funded by Paradigm Biopharmaceuticals. Dr. Ahuja is an employee and stockholder of Paradigm Biopharmaceuticals and holds stock in ChitogenX. The trial of XT-150 was funded by Xalud Therapeutics. Dr. Rutman is an employee and equity holder of the company.
A version of this article appeared on Medscape.com.
FROM OARSI 2024
Risk of Knee OA From Weight-Bearing Exercise Seen Only With Low Muscle Mass
Weight-bearing recreational activity was associated with a 22% increased odds of developing knee osteoarthritis (OA) in a large prospective cohort study in the Netherlands, but notably, the increased risk was seen only in those with low levels of lower-limb muscle mass.
The findings point toward the value of “tailored advice” for physical activity, and suggest that “caution is needed when engaging in weight-bearing activity, especially for individuals with low levels of lower-limb muscle mass,” Yahong Wu, MD, and coinvestigators, of the Erasmus Medical Center in Rotterdam, the Netherlands, wrote in JAMA Network Open.
Investigators used data from sequential cohorts of the longitudinal Rotterdam Study, which enrolled people aged 45 and older starting in 1990. The 5003 participants in this new analysis of physical activity and knee OA had complete records of baseline recreational physical activity, baseline knee pain, and knee radiographs from both baseline and at least one follow-up exam. Those with radiographically defined knee OA at baseline were excluded.
The incident rate of radiographically defined (x-ray) knee OA among all participants was 8.4%, with a mean follow-up time of 6.33 years. Among 3492 individuals without baseline knee pain, the researchers found no increased odds of incident radiographic OA with non–weight-bearing activity (odds ratio [OR], 1.04; 95% CI, 0.95-1.15; P = .37) but a significant association of weight-bearing activity with OA incidence (OR, 1.22; 95% CI, 1.10-1.35; P < .001).
A stratification analysis of a subset of participants whose lower-limb mass had been measured by dual-energy x-ray absorptiometry (DXA) showed, however, that the association of weight-bearing activity with incident OA was limited to patients in the lowest third of lower-limb muscle mass index (LMI), who had a 53% increased likelihood of developing knee OA (OR, 1.53; 95% CI, 1.15-2.04; P = .003).
For patients in the middle and upper tertiles, there was no significant association between weight-bearing activity and the odds of incident OA (OR, 0.93; P = .73, and OR, 1.15; P = .40, respectively).
The findings are reassuring overall, said Kelli D. Allen, PhD, research professor of medicine and exercise physiologist at the University of North Carolina at Chapel Hill, who was asked to comment on the study. “The study corroborates prior research showing that for most people, weight-bearing recreational activity does not increase the risk of knee osteoarthritis. This should be encouraging for people who want to increase their physical activity,” she said.
The study also suggests that “for people with low lower-limb muscle mass, there may be some considerations to make regarding the best type of physical activity to prevent future knee osteoarthritis,” she said in an e-mail. “The best approach may include non–weight-bearing activities, which could include biking, swimming, or other water exercises, along with strengthening exercises that help to increase muscle mass.”
Other studies, Dr. Allen said, have shown that low muscle mass itself is a risk factor for knee OA.
Physical Activity Types, Other Analyses
The researchers assessed total, weight-bearing, and non–weight-bearing physical activity using two validated questionnaires (an adapted version of the Zutphen Physical Activity Questionnaire and the Longitudinal Aging Study Amsterdam physical activity questionnaire) that asked participants about the frequency and duration of various types of physical activity. Activity was quantified as metabolic equivalent of task (MET) hours per week, and weight-bearing activities were defined as those in which the knee joint bears the body’s weight.
Walking, gardening, golf, dancing, and ball sports were among the activities qualifying as weight-bearing activities. Non–weight-bearing activities included cycling, rowing, and swimming.
Sex, body mass index, and follow-up time were among the covariates adjusted for in the primary analysis. Similar results were found when adjustments were also made for educational level, alcohol intake, lipid levels, and diabetes.
While incident radiographic knee OA (measured using the Kellgren & Lawrence grading system) was the primary outcome, the researchers also looked at symptomatic knee OA, as defined by x-ray and a knee pain questionnaire, and found no significant association of its incidence with any of the exercise categories (total, weight-bearing, or non-weight-bearing).
Coauthor Joyce B. J. van Meurs, PhD, of the departments of internal medicine and orthopedics & sports medicine at Erasmus Medical Center, told this news organization that “pain as a subjective, recurrent symptom is more difficult to study … [and] a larger sample size or more precise measurements [of pain] in future studies would help to better understand the true association” of symptomatic knee OA and physical activity.
Similarly, analyses of the 1511 patients (out of 5003) who had knee pain at baseline found no significant association of weight-bearing or non–weight-bearing physical activity with incident radiographic knee OA. The trends were similar to those found in the population without knee pain, however, which suggests the analysis was underpowered, the researchers wrote, noting too that patients with baseline pain had lower activity levels than those without pain. (Low case numbers precluded a stratification analysis on LMI for incident symptomatic OA.)
Thigh Circumference as an Indicator of Muscle Mass
The findings build upon an international meta-analysis published in 2021 that found no association between total physical activity and knee OA and align with other studies suggesting a link between greater mechanical stress/strain and greater OA risk, the researchers wrote. (The meta-analysis couldn’t investigate different types of activity.)
“Although we cannot establish a causal relationship … we hypothesize that the mechanical loading on joints and cartilage could explain the association of weight-bearing activity with osteoarthritis in the low LMI tertile group,” they said.
It is possible that thigh muscle-specific strength or mass may temper the risk of knee OA, they wrote, but the lack of thigh strength data in the Rotterdam Study precluded such evaluation. Still, in everyday practice, the researchers noted, lower limb muscle function could be assessed using thigh circumference.
Dr. Allen agreed. “ ‘Gold standard’ assessment of muscle mass is not common in routine practice, but clinicians can evaluate muscle mass in other ways, such as thigh circumference,” she told this news organization, noting that measurement should align with procedures described by the National Health and Nutrition Examination Survey in its anthropometry procedures manual.
“If low lower-limb muscle mass is suspected, a referral to a physical therapist can be helpful for more formally assessing muscle mass and muscle strength,” she added, “and for instructions for a safe and appropriate exercise program for building muscle and protecting joints.”
Among other limitations of the study, according to the researchers, are an ethnically nondiverse population, the unavailability of knee injury data, and the assessment of physical activity only at baseline.
Moving forward, Dr. van Meurs told this news organization, “the main question regarding physical activity and OA is still, if people already have pain or early OA complaints, what kinds of sports they can do without hurting their joints?” This “should be tested,” she said, “in a real-life, ideally trial-like intervention study.”
The study was funded by the Erasmus Medical Center and Erasmus University as well as through various government grants. Dr. Wu also had study support from the China Scholarship Council. Two of the authors reported relationships with arthritis-related organizations. Dr. Allen reported having no disclosures relevant to her comments.
Weight-bearing recreational activity was associated with a 22% increased odds of developing knee osteoarthritis (OA) in a large prospective cohort study in the Netherlands, but notably, the increased risk was seen only in those with low levels of lower-limb muscle mass.
The findings point toward the value of “tailored advice” for physical activity, and suggest that “caution is needed when engaging in weight-bearing activity, especially for individuals with low levels of lower-limb muscle mass,” Yahong Wu, MD, and coinvestigators, of the Erasmus Medical Center in Rotterdam, the Netherlands, wrote in JAMA Network Open.
Investigators used data from sequential cohorts of the longitudinal Rotterdam Study, which enrolled people aged 45 and older starting in 1990. The 5003 participants in this new analysis of physical activity and knee OA had complete records of baseline recreational physical activity, baseline knee pain, and knee radiographs from both baseline and at least one follow-up exam. Those with radiographically defined knee OA at baseline were excluded.
The incident rate of radiographically defined (x-ray) knee OA among all participants was 8.4%, with a mean follow-up time of 6.33 years. Among 3492 individuals without baseline knee pain, the researchers found no increased odds of incident radiographic OA with non–weight-bearing activity (odds ratio [OR], 1.04; 95% CI, 0.95-1.15; P = .37) but a significant association of weight-bearing activity with OA incidence (OR, 1.22; 95% CI, 1.10-1.35; P < .001).
A stratification analysis of a subset of participants whose lower-limb mass had been measured by dual-energy x-ray absorptiometry (DXA) showed, however, that the association of weight-bearing activity with incident OA was limited to patients in the lowest third of lower-limb muscle mass index (LMI), who had a 53% increased likelihood of developing knee OA (OR, 1.53; 95% CI, 1.15-2.04; P = .003).
For patients in the middle and upper tertiles, there was no significant association between weight-bearing activity and the odds of incident OA (OR, 0.93; P = .73, and OR, 1.15; P = .40, respectively).
The findings are reassuring overall, said Kelli D. Allen, PhD, research professor of medicine and exercise physiologist at the University of North Carolina at Chapel Hill, who was asked to comment on the study. “The study corroborates prior research showing that for most people, weight-bearing recreational activity does not increase the risk of knee osteoarthritis. This should be encouraging for people who want to increase their physical activity,” she said.
The study also suggests that “for people with low lower-limb muscle mass, there may be some considerations to make regarding the best type of physical activity to prevent future knee osteoarthritis,” she said in an e-mail. “The best approach may include non–weight-bearing activities, which could include biking, swimming, or other water exercises, along with strengthening exercises that help to increase muscle mass.”
Other studies, Dr. Allen said, have shown that low muscle mass itself is a risk factor for knee OA.
Physical Activity Types, Other Analyses
The researchers assessed total, weight-bearing, and non–weight-bearing physical activity using two validated questionnaires (an adapted version of the Zutphen Physical Activity Questionnaire and the Longitudinal Aging Study Amsterdam physical activity questionnaire) that asked participants about the frequency and duration of various types of physical activity. Activity was quantified as metabolic equivalent of task (MET) hours per week, and weight-bearing activities were defined as those in which the knee joint bears the body’s weight.
Walking, gardening, golf, dancing, and ball sports were among the activities qualifying as weight-bearing activities. Non–weight-bearing activities included cycling, rowing, and swimming.
Sex, body mass index, and follow-up time were among the covariates adjusted for in the primary analysis. Similar results were found when adjustments were also made for educational level, alcohol intake, lipid levels, and diabetes.
While incident radiographic knee OA (measured using the Kellgren & Lawrence grading system) was the primary outcome, the researchers also looked at symptomatic knee OA, as defined by x-ray and a knee pain questionnaire, and found no significant association of its incidence with any of the exercise categories (total, weight-bearing, or non-weight-bearing).
Coauthor Joyce B. J. van Meurs, PhD, of the departments of internal medicine and orthopedics & sports medicine at Erasmus Medical Center, told this news organization that “pain as a subjective, recurrent symptom is more difficult to study … [and] a larger sample size or more precise measurements [of pain] in future studies would help to better understand the true association” of symptomatic knee OA and physical activity.
Similarly, analyses of the 1511 patients (out of 5003) who had knee pain at baseline found no significant association of weight-bearing or non–weight-bearing physical activity with incident radiographic knee OA. The trends were similar to those found in the population without knee pain, however, which suggests the analysis was underpowered, the researchers wrote, noting too that patients with baseline pain had lower activity levels than those without pain. (Low case numbers precluded a stratification analysis on LMI for incident symptomatic OA.)
Thigh Circumference as an Indicator of Muscle Mass
The findings build upon an international meta-analysis published in 2021 that found no association between total physical activity and knee OA and align with other studies suggesting a link between greater mechanical stress/strain and greater OA risk, the researchers wrote. (The meta-analysis couldn’t investigate different types of activity.)
“Although we cannot establish a causal relationship … we hypothesize that the mechanical loading on joints and cartilage could explain the association of weight-bearing activity with osteoarthritis in the low LMI tertile group,” they said.
It is possible that thigh muscle-specific strength or mass may temper the risk of knee OA, they wrote, but the lack of thigh strength data in the Rotterdam Study precluded such evaluation. Still, in everyday practice, the researchers noted, lower limb muscle function could be assessed using thigh circumference.
Dr. Allen agreed. “ ‘Gold standard’ assessment of muscle mass is not common in routine practice, but clinicians can evaluate muscle mass in other ways, such as thigh circumference,” she told this news organization, noting that measurement should align with procedures described by the National Health and Nutrition Examination Survey in its anthropometry procedures manual.
“If low lower-limb muscle mass is suspected, a referral to a physical therapist can be helpful for more formally assessing muscle mass and muscle strength,” she added, “and for instructions for a safe and appropriate exercise program for building muscle and protecting joints.”
Among other limitations of the study, according to the researchers, are an ethnically nondiverse population, the unavailability of knee injury data, and the assessment of physical activity only at baseline.
Moving forward, Dr. van Meurs told this news organization, “the main question regarding physical activity and OA is still, if people already have pain or early OA complaints, what kinds of sports they can do without hurting their joints?” This “should be tested,” she said, “in a real-life, ideally trial-like intervention study.”
The study was funded by the Erasmus Medical Center and Erasmus University as well as through various government grants. Dr. Wu also had study support from the China Scholarship Council. Two of the authors reported relationships with arthritis-related organizations. Dr. Allen reported having no disclosures relevant to her comments.
Weight-bearing recreational activity was associated with a 22% increased odds of developing knee osteoarthritis (OA) in a large prospective cohort study in the Netherlands, but notably, the increased risk was seen only in those with low levels of lower-limb muscle mass.
The findings point toward the value of “tailored advice” for physical activity, and suggest that “caution is needed when engaging in weight-bearing activity, especially for individuals with low levels of lower-limb muscle mass,” Yahong Wu, MD, and coinvestigators, of the Erasmus Medical Center in Rotterdam, the Netherlands, wrote in JAMA Network Open.
Investigators used data from sequential cohorts of the longitudinal Rotterdam Study, which enrolled people aged 45 and older starting in 1990. The 5003 participants in this new analysis of physical activity and knee OA had complete records of baseline recreational physical activity, baseline knee pain, and knee radiographs from both baseline and at least one follow-up exam. Those with radiographically defined knee OA at baseline were excluded.
The incident rate of radiographically defined (x-ray) knee OA among all participants was 8.4%, with a mean follow-up time of 6.33 years. Among 3492 individuals without baseline knee pain, the researchers found no increased odds of incident radiographic OA with non–weight-bearing activity (odds ratio [OR], 1.04; 95% CI, 0.95-1.15; P = .37) but a significant association of weight-bearing activity with OA incidence (OR, 1.22; 95% CI, 1.10-1.35; P < .001).
A stratification analysis of a subset of participants whose lower-limb mass had been measured by dual-energy x-ray absorptiometry (DXA) showed, however, that the association of weight-bearing activity with incident OA was limited to patients in the lowest third of lower-limb muscle mass index (LMI), who had a 53% increased likelihood of developing knee OA (OR, 1.53; 95% CI, 1.15-2.04; P = .003).
For patients in the middle and upper tertiles, there was no significant association between weight-bearing activity and the odds of incident OA (OR, 0.93; P = .73, and OR, 1.15; P = .40, respectively).
The findings are reassuring overall, said Kelli D. Allen, PhD, research professor of medicine and exercise physiologist at the University of North Carolina at Chapel Hill, who was asked to comment on the study. “The study corroborates prior research showing that for most people, weight-bearing recreational activity does not increase the risk of knee osteoarthritis. This should be encouraging for people who want to increase their physical activity,” she said.
The study also suggests that “for people with low lower-limb muscle mass, there may be some considerations to make regarding the best type of physical activity to prevent future knee osteoarthritis,” she said in an e-mail. “The best approach may include non–weight-bearing activities, which could include biking, swimming, or other water exercises, along with strengthening exercises that help to increase muscle mass.”
Other studies, Dr. Allen said, have shown that low muscle mass itself is a risk factor for knee OA.
Physical Activity Types, Other Analyses
The researchers assessed total, weight-bearing, and non–weight-bearing physical activity using two validated questionnaires (an adapted version of the Zutphen Physical Activity Questionnaire and the Longitudinal Aging Study Amsterdam physical activity questionnaire) that asked participants about the frequency and duration of various types of physical activity. Activity was quantified as metabolic equivalent of task (MET) hours per week, and weight-bearing activities were defined as those in which the knee joint bears the body’s weight.
Walking, gardening, golf, dancing, and ball sports were among the activities qualifying as weight-bearing activities. Non–weight-bearing activities included cycling, rowing, and swimming.
Sex, body mass index, and follow-up time were among the covariates adjusted for in the primary analysis. Similar results were found when adjustments were also made for educational level, alcohol intake, lipid levels, and diabetes.
While incident radiographic knee OA (measured using the Kellgren & Lawrence grading system) was the primary outcome, the researchers also looked at symptomatic knee OA, as defined by x-ray and a knee pain questionnaire, and found no significant association of its incidence with any of the exercise categories (total, weight-bearing, or non-weight-bearing).
Coauthor Joyce B. J. van Meurs, PhD, of the departments of internal medicine and orthopedics & sports medicine at Erasmus Medical Center, told this news organization that “pain as a subjective, recurrent symptom is more difficult to study … [and] a larger sample size or more precise measurements [of pain] in future studies would help to better understand the true association” of symptomatic knee OA and physical activity.
Similarly, analyses of the 1511 patients (out of 5003) who had knee pain at baseline found no significant association of weight-bearing or non–weight-bearing physical activity with incident radiographic knee OA. The trends were similar to those found in the population without knee pain, however, which suggests the analysis was underpowered, the researchers wrote, noting too that patients with baseline pain had lower activity levels than those without pain. (Low case numbers precluded a stratification analysis on LMI for incident symptomatic OA.)
Thigh Circumference as an Indicator of Muscle Mass
The findings build upon an international meta-analysis published in 2021 that found no association between total physical activity and knee OA and align with other studies suggesting a link between greater mechanical stress/strain and greater OA risk, the researchers wrote. (The meta-analysis couldn’t investigate different types of activity.)
“Although we cannot establish a causal relationship … we hypothesize that the mechanical loading on joints and cartilage could explain the association of weight-bearing activity with osteoarthritis in the low LMI tertile group,” they said.
It is possible that thigh muscle-specific strength or mass may temper the risk of knee OA, they wrote, but the lack of thigh strength data in the Rotterdam Study precluded such evaluation. Still, in everyday practice, the researchers noted, lower limb muscle function could be assessed using thigh circumference.
Dr. Allen agreed. “ ‘Gold standard’ assessment of muscle mass is not common in routine practice, but clinicians can evaluate muscle mass in other ways, such as thigh circumference,” she told this news organization, noting that measurement should align with procedures described by the National Health and Nutrition Examination Survey in its anthropometry procedures manual.
“If low lower-limb muscle mass is suspected, a referral to a physical therapist can be helpful for more formally assessing muscle mass and muscle strength,” she added, “and for instructions for a safe and appropriate exercise program for building muscle and protecting joints.”
Among other limitations of the study, according to the researchers, are an ethnically nondiverse population, the unavailability of knee injury data, and the assessment of physical activity only at baseline.
Moving forward, Dr. van Meurs told this news organization, “the main question regarding physical activity and OA is still, if people already have pain or early OA complaints, what kinds of sports they can do without hurting their joints?” This “should be tested,” she said, “in a real-life, ideally trial-like intervention study.”
The study was funded by the Erasmus Medical Center and Erasmus University as well as through various government grants. Dr. Wu also had study support from the China Scholarship Council. Two of the authors reported relationships with arthritis-related organizations. Dr. Allen reported having no disclosures relevant to her comments.
FROM JAMA NETWORK OPEN
Blood Biomarkers Predict Knee Osteoarthritis Years in Advance
A small number of blood biomarkers can identify patients who will develop knee osteoarthritis (OA) up to 8 years before signs of the disease are detectable via X-ray, according to new research.
The study “provides more evidence for a pre-radiographic phase of disease,” wrote Virginia Byers Dr. Kraus, MD, PhD, a professor of medicine, pathology, and orthopedic surgery at Duke University School of Medicine in Durham, North Carolina, and colleagues. The results also “provide valuable information for understanding the molecular events of early disease that could inform strategies to develop disease-modifying drugs for preclinical OA,” they continued.
In the study, published in Science Advances, researchers analyzed blood samples from a population-based, longitudinal study of women in London that assessed participants annually for osteoporosis and OA. They selected individuals at low risk for radiographic knee OA, who did not have traditional risk factors for knee OA such as a history of major knee injury, knee surgery, or OA of the hand or opposite knee.
The researchers analyzed serum of 100 women who went on to develop radiographic knee OA and 100 controls who were matched by age and body mass index (BMI). Participants were, on average, aged 54 years with a BMI of 26 and all were White. They analyzed serum peptides via mass spectrometry and used machine learning to select which out of the 115 identified peptides were most predictive of OA.
Ultimately, the team zeroed in on six peptides, corresponding to six proteins, that could most accurately distinguish women who went on to develop radiographic signs of OA from controls (area under the receiver operating characteristic curve, 0.77) up to 8 years before x-rays detected these changes.
“The value of our study is a panel that, in the absence of clinical factors indicative of high-risk knee OA, has the potential to discriminate individuals at risk for incident radiographic knee OA from those not at risk,” the authors wrote.
In earlier work, a similar group of biomarkers could accurately diagnose knee OA as well as predict the progression of the disease. More than half (58%) of biomarkers that predicted incident OA also predicted OA progression.
“Even for the ones that didn’t overlap with OA progression, they all pointed to the same sort of disease process, which is an unresolved acute phase response type of biological process,” Dr. Kraus told this news organization.
Commenting on the study, Andrew Grose, MD, an orthopedic trauma surgeon at the Hospital for Special Surgery in New York City, noted that the methods and conclusions seemed sound but cautioned that the study only looked for radiographic evidence of OA, and not symptomatic OA.
“Clinically relevant OA is correlated with what you see on an x-ray, but the x-ray is definitely not the whole story,” he said in an interview with this news organization.
To be clinically relevant, patients must also have symptoms, such as pain and stiffness, and interfere with daily life. But what shows up on an x-ray is not necessarily indicative of what patients are experiencing, he said. Solely focusing on radiographic findings could lead to overdiagnosis and overtreatment of OA, he said.
The study population was also small, and only included White women, he added, so further validation is necessary. Dr. Kraus and colleagues also acknowledged these limitations.
“Further validation will be needed in independent and larger cohorts, preferability prospectively collected and including male participants and the combination of incident radiographic and symptomatic OA,” they wrote. They noted that while this current study included only women, the biomarkers were not associated with sex in previous studies that used larger and mixed-sex cohorts.
“If they did more studies showing that this [test] was able to predict clinically relevant OA, then I think you could have a meaningful conversation with a patient in a primary care doctor’s office,” Dr. Grose added. “Until that time, just the fact that it predicts an x-ray finding is a little bit of a red herring.”
This work was supported by grants from the National Institutes of Health. Dr. Kraus is an inventor on a patent related to OA progression biomarkers. Dr. Grose had no relevant disclosures.
A version of this article appeared on Medscape.com.
A small number of blood biomarkers can identify patients who will develop knee osteoarthritis (OA) up to 8 years before signs of the disease are detectable via X-ray, according to new research.
The study “provides more evidence for a pre-radiographic phase of disease,” wrote Virginia Byers Dr. Kraus, MD, PhD, a professor of medicine, pathology, and orthopedic surgery at Duke University School of Medicine in Durham, North Carolina, and colleagues. The results also “provide valuable information for understanding the molecular events of early disease that could inform strategies to develop disease-modifying drugs for preclinical OA,” they continued.
In the study, published in Science Advances, researchers analyzed blood samples from a population-based, longitudinal study of women in London that assessed participants annually for osteoporosis and OA. They selected individuals at low risk for radiographic knee OA, who did not have traditional risk factors for knee OA such as a history of major knee injury, knee surgery, or OA of the hand or opposite knee.
The researchers analyzed serum of 100 women who went on to develop radiographic knee OA and 100 controls who were matched by age and body mass index (BMI). Participants were, on average, aged 54 years with a BMI of 26 and all were White. They analyzed serum peptides via mass spectrometry and used machine learning to select which out of the 115 identified peptides were most predictive of OA.
Ultimately, the team zeroed in on six peptides, corresponding to six proteins, that could most accurately distinguish women who went on to develop radiographic signs of OA from controls (area under the receiver operating characteristic curve, 0.77) up to 8 years before x-rays detected these changes.
“The value of our study is a panel that, in the absence of clinical factors indicative of high-risk knee OA, has the potential to discriminate individuals at risk for incident radiographic knee OA from those not at risk,” the authors wrote.
In earlier work, a similar group of biomarkers could accurately diagnose knee OA as well as predict the progression of the disease. More than half (58%) of biomarkers that predicted incident OA also predicted OA progression.
“Even for the ones that didn’t overlap with OA progression, they all pointed to the same sort of disease process, which is an unresolved acute phase response type of biological process,” Dr. Kraus told this news organization.
Commenting on the study, Andrew Grose, MD, an orthopedic trauma surgeon at the Hospital for Special Surgery in New York City, noted that the methods and conclusions seemed sound but cautioned that the study only looked for radiographic evidence of OA, and not symptomatic OA.
“Clinically relevant OA is correlated with what you see on an x-ray, but the x-ray is definitely not the whole story,” he said in an interview with this news organization.
To be clinically relevant, patients must also have symptoms, such as pain and stiffness, and interfere with daily life. But what shows up on an x-ray is not necessarily indicative of what patients are experiencing, he said. Solely focusing on radiographic findings could lead to overdiagnosis and overtreatment of OA, he said.
The study population was also small, and only included White women, he added, so further validation is necessary. Dr. Kraus and colleagues also acknowledged these limitations.
“Further validation will be needed in independent and larger cohorts, preferability prospectively collected and including male participants and the combination of incident radiographic and symptomatic OA,” they wrote. They noted that while this current study included only women, the biomarkers were not associated with sex in previous studies that used larger and mixed-sex cohorts.
“If they did more studies showing that this [test] was able to predict clinically relevant OA, then I think you could have a meaningful conversation with a patient in a primary care doctor’s office,” Dr. Grose added. “Until that time, just the fact that it predicts an x-ray finding is a little bit of a red herring.”
This work was supported by grants from the National Institutes of Health. Dr. Kraus is an inventor on a patent related to OA progression biomarkers. Dr. Grose had no relevant disclosures.
A version of this article appeared on Medscape.com.
A small number of blood biomarkers can identify patients who will develop knee osteoarthritis (OA) up to 8 years before signs of the disease are detectable via X-ray, according to new research.
The study “provides more evidence for a pre-radiographic phase of disease,” wrote Virginia Byers Dr. Kraus, MD, PhD, a professor of medicine, pathology, and orthopedic surgery at Duke University School of Medicine in Durham, North Carolina, and colleagues. The results also “provide valuable information for understanding the molecular events of early disease that could inform strategies to develop disease-modifying drugs for preclinical OA,” they continued.
In the study, published in Science Advances, researchers analyzed blood samples from a population-based, longitudinal study of women in London that assessed participants annually for osteoporosis and OA. They selected individuals at low risk for radiographic knee OA, who did not have traditional risk factors for knee OA such as a history of major knee injury, knee surgery, or OA of the hand or opposite knee.
The researchers analyzed serum of 100 women who went on to develop radiographic knee OA and 100 controls who were matched by age and body mass index (BMI). Participants were, on average, aged 54 years with a BMI of 26 and all were White. They analyzed serum peptides via mass spectrometry and used machine learning to select which out of the 115 identified peptides were most predictive of OA.
Ultimately, the team zeroed in on six peptides, corresponding to six proteins, that could most accurately distinguish women who went on to develop radiographic signs of OA from controls (area under the receiver operating characteristic curve, 0.77) up to 8 years before x-rays detected these changes.
“The value of our study is a panel that, in the absence of clinical factors indicative of high-risk knee OA, has the potential to discriminate individuals at risk for incident radiographic knee OA from those not at risk,” the authors wrote.
In earlier work, a similar group of biomarkers could accurately diagnose knee OA as well as predict the progression of the disease. More than half (58%) of biomarkers that predicted incident OA also predicted OA progression.
“Even for the ones that didn’t overlap with OA progression, they all pointed to the same sort of disease process, which is an unresolved acute phase response type of biological process,” Dr. Kraus told this news organization.
Commenting on the study, Andrew Grose, MD, an orthopedic trauma surgeon at the Hospital for Special Surgery in New York City, noted that the methods and conclusions seemed sound but cautioned that the study only looked for radiographic evidence of OA, and not symptomatic OA.
“Clinically relevant OA is correlated with what you see on an x-ray, but the x-ray is definitely not the whole story,” he said in an interview with this news organization.
To be clinically relevant, patients must also have symptoms, such as pain and stiffness, and interfere with daily life. But what shows up on an x-ray is not necessarily indicative of what patients are experiencing, he said. Solely focusing on radiographic findings could lead to overdiagnosis and overtreatment of OA, he said.
The study population was also small, and only included White women, he added, so further validation is necessary. Dr. Kraus and colleagues also acknowledged these limitations.
“Further validation will be needed in independent and larger cohorts, preferability prospectively collected and including male participants and the combination of incident radiographic and symptomatic OA,” they wrote. They noted that while this current study included only women, the biomarkers were not associated with sex in previous studies that used larger and mixed-sex cohorts.
“If they did more studies showing that this [test] was able to predict clinically relevant OA, then I think you could have a meaningful conversation with a patient in a primary care doctor’s office,” Dr. Grose added. “Until that time, just the fact that it predicts an x-ray finding is a little bit of a red herring.”
This work was supported by grants from the National Institutes of Health. Dr. Kraus is an inventor on a patent related to OA progression biomarkers. Dr. Grose had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM SCIENCE ADVANCES
Semaglutide Trial for Knee Osteoarthritis Shows Improvements in Pain, Physical Function
VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024 World Congress.
From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).
As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.
“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.
Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
Not Approved in OA
Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.
“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.
“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.
“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
Previous Work
The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.
Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.
“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.
“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
STEP 9 Study Design
No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.
STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.
In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.
A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.
Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.
Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
Other Findings
In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.
“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.
Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.
“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.
Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.
The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.
A version of this article appeared on Medscape.com.
VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024 World Congress.
From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).
As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.
“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.
Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
Not Approved in OA
Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.
“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.
“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.
“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
Previous Work
The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.
Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.
“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.
“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
STEP 9 Study Design
No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.
STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.
In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.
A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.
Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.
Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
Other Findings
In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.
“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.
Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.
“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.
Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.
The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.
A version of this article appeared on Medscape.com.
VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024 World Congress.
From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).
As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.
“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.
Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
Not Approved in OA
Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.
“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.
“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.
“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
Previous Work
The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.
Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.
“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.
“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
STEP 9 Study Design
No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.
STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.
In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.
A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.
Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.
Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
Other Findings
In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.
“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.
Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.
“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.
Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.
The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.
A version of this article appeared on Medscape.com.
FROM OARSI 2024
No Major Differences in Improvement Seen with Progressive Resistance Training Versus Neuromuscular Exercise for Hip Osteoarthritis
Progressive resistance training (PRT) and neuromuscular exercise (NEMEX) programs result in similar improvements in hip function, pain, and hip-related quality of life (QOL) in people with osteoarthritis (OA), according to the results of a randomized controlled trial.
At the end of the 12-week exercise period, both interventions yielded changes from baseline on the 30-second chair stand test (30s-CST) that were below the threshold for a major clinical effect.
Mean changes in the Hip Disability and Osteoarthritis Outcome Score (HOOS) pain subscale and HOOS QOL score were also similar among the participants, regardless of which exercise program they had been assigned to.
“The lack of superiority of PRT for increasing muscle strength and power is surprising given the principle of specificity (higher-intensity resistance training yields greater improvements in maximal muscle strength),” according to the Danish researchers who reported the results online today in Annals of Internal Medicine.
“However, the point estimates only showed modest and uncertain superiority of PRT for increasing muscle strength and power and no differences for any functional performance tests or self-reported physical function,” they added.
The Power of Exercise
Worldwide, most clinical guidelines recommend exercise as a first-line conservative treatment option in both hip and knee OA. However, there is not much evidence to help guide healthcare practitioners in deciding which type of exercises to use with their patients, Troels Kjeldsen, MSc, the principal investigator for the study, told this news organization.
“Neuromuscular exercise is a very commonly used exercise program in clinical practice, but, to our knowledge, it has never been compared to another type of exercise in hip OA,” observed Mr. Kjeldsen, who is a PhD student in the department of orthopedic surgery at Aarhus University Hospital, Aarhus, Denmark.
“Each year, many thousands of patients are referred to having neuromuscular exercise therapy with a physiotherapist,” Mr. Kjeldsen said. “So, we thought it would be worthwhile to compare it to PRT, another promising exercise type, to see if it really did perform as well as I think most people thought it did,” he added.
Comparing the Two Exercise Programs
PRT and NEMEX are two different types of exercise programs. PRT involves using resistance-training machines, and the focus is to maximize the exercise intensity by using as high an exercise load or weight as possible. By contrast, NEMEX consists of exercises that are low to moderate in intensity and emphasizes alignment, control, and stability of the movements.
To compare the two exercise strategies, Mr. Kjeldsen and fellow investigators recruited 160 participants at five hospitals and 10 physiotherapy clinics across three of five healthcare regions in Denmark.
For inclusion in the trial, the participants had to have a clinical diagnosis of hip OA, be older than 45 years, and experience pain during activity in one or both hips that was rated as 3 or higher on a 10-point numerical rating scale. Participants also had to have no or less than 30 minutes of hip joint stiffness in the morning as well as no surgery involving the lower extremities in the previous 6 months.
Participants were then randomized to undertake the PRT (n = 82) or NEMEX (n = 78) program, delivered as two physiotherapist-led group sessions every week for 12 weeks. Exercise sessions were held at least 72 hours apart and consisted of a 10-minute warm-up on an exercise bike and then 50 minutes of PRT or NEMEX. PRT consisted of five generic resistance-based exercises targeting hip and knee joint muscles and NEMEX consisted of 10 exercises that increased in difficulty by varying the number, direction, speed, and surface of the movements performed.
Dead Heat Between PRT and NEMEX
The primary endpoint was the 30s-CST, which counted the number of times participants could stand from a seated position in 30 seconds. Participants in the PRT and NEMEX groups were able to do this maneuver a respective 11.3 and 11.6 times at baseline and 12.8 and 13.1 times after completion of the exercise programs.
Other functional performance tests included a 40-m fast-paced walk, a nine-step timed stair climb, leg extensor power in the affected and unaffected limb, and a unilateral single repetition leg press. None of these showed a statistically significant benefit of PRT over NEMEX, or vice versa.
HOOS pain scores at baseline and 12 weeks for PRT were a respective 57.5 and 66.1, representing an overall 8.6-point increase, and for NEMEX they were 58.9 and 68.2, giving a 9.3-point increase, meaning there was only a -0.7 mean change when comparing the two groups.
Corresponding baseline and 12-week HOOS QOL scores for PRT were 43.7 and 51.7; for NEMEX, they were 47.1 and 52.8 thus giving 8.0- and 5.7-point increases and a 2.3 difference in change between the groups. Again, this wasn’t quite enough to show a clinically meaningful effect.
Future Steps
“The effect of exercise seems to be at its highest at 3-4 months when you implement exercise, so we compared the effects of the exercises at the time when they are probably going to be at their highest,” Mr. Kjeldsen explained. He said the research team also plans to look at what happens after 1 year of follow-up.
“The key take home message is that patients can be encouraged to pick the type of exercise that they find the most enjoyable, or the type that is available to them,” Mr. Kjeldsen suggested.
Stephanie Chang, MD, MPH, who is the Deputy Editor of Annals of Internal Medicine and practices in Rockville, Maryland, commented on the paper to this news organization. “In this small study, we learned that exercises to strengthen lower extremity muscles did not improve pain or function any more than exercises for core stability and balance,” she said.
Dr. Chang pointed out that there was variance in the levels of activity that people already undertook at baseline: 40% of the PRT group and 41% of the NEMEX group already did 150 minutes or more of moderate intensity physical activity.
“It’s possible that benefit or differences between interventions would be greater in people with different levels of baseline activity or even in those with different osteoarthritis severity,” she said.
“In the meantime,” Dr. Chang added, “with the findings from this study, I would feel comfortable advising my patients with hip osteoarthritis to engage in whichever type of exercise they prefer — whether that exercise focuses on core strengthening and balance or on specific lower extremity muscle strengthening.”
The trial was funded by the Independent Research Fund Denmark, the Physiotherapy Practice Foundation, the Health Foundation, Aarhus University, Region Zealand, the Association of Danish Physiotherapists, Andelsfonden, and Hede Nielsens Family Foundation. Mr. Kjeldsen and Dr. Chang report no relevant financial relationships.
A version of this article appeared on Medscape.com.
Progressive resistance training (PRT) and neuromuscular exercise (NEMEX) programs result in similar improvements in hip function, pain, and hip-related quality of life (QOL) in people with osteoarthritis (OA), according to the results of a randomized controlled trial.
At the end of the 12-week exercise period, both interventions yielded changes from baseline on the 30-second chair stand test (30s-CST) that were below the threshold for a major clinical effect.
Mean changes in the Hip Disability and Osteoarthritis Outcome Score (HOOS) pain subscale and HOOS QOL score were also similar among the participants, regardless of which exercise program they had been assigned to.
“The lack of superiority of PRT for increasing muscle strength and power is surprising given the principle of specificity (higher-intensity resistance training yields greater improvements in maximal muscle strength),” according to the Danish researchers who reported the results online today in Annals of Internal Medicine.
“However, the point estimates only showed modest and uncertain superiority of PRT for increasing muscle strength and power and no differences for any functional performance tests or self-reported physical function,” they added.
The Power of Exercise
Worldwide, most clinical guidelines recommend exercise as a first-line conservative treatment option in both hip and knee OA. However, there is not much evidence to help guide healthcare practitioners in deciding which type of exercises to use with their patients, Troels Kjeldsen, MSc, the principal investigator for the study, told this news organization.
“Neuromuscular exercise is a very commonly used exercise program in clinical practice, but, to our knowledge, it has never been compared to another type of exercise in hip OA,” observed Mr. Kjeldsen, who is a PhD student in the department of orthopedic surgery at Aarhus University Hospital, Aarhus, Denmark.
“Each year, many thousands of patients are referred to having neuromuscular exercise therapy with a physiotherapist,” Mr. Kjeldsen said. “So, we thought it would be worthwhile to compare it to PRT, another promising exercise type, to see if it really did perform as well as I think most people thought it did,” he added.
Comparing the Two Exercise Programs
PRT and NEMEX are two different types of exercise programs. PRT involves using resistance-training machines, and the focus is to maximize the exercise intensity by using as high an exercise load or weight as possible. By contrast, NEMEX consists of exercises that are low to moderate in intensity and emphasizes alignment, control, and stability of the movements.
To compare the two exercise strategies, Mr. Kjeldsen and fellow investigators recruited 160 participants at five hospitals and 10 physiotherapy clinics across three of five healthcare regions in Denmark.
For inclusion in the trial, the participants had to have a clinical diagnosis of hip OA, be older than 45 years, and experience pain during activity in one or both hips that was rated as 3 or higher on a 10-point numerical rating scale. Participants also had to have no or less than 30 minutes of hip joint stiffness in the morning as well as no surgery involving the lower extremities in the previous 6 months.
Participants were then randomized to undertake the PRT (n = 82) or NEMEX (n = 78) program, delivered as two physiotherapist-led group sessions every week for 12 weeks. Exercise sessions were held at least 72 hours apart and consisted of a 10-minute warm-up on an exercise bike and then 50 minutes of PRT or NEMEX. PRT consisted of five generic resistance-based exercises targeting hip and knee joint muscles and NEMEX consisted of 10 exercises that increased in difficulty by varying the number, direction, speed, and surface of the movements performed.
Dead Heat Between PRT and NEMEX
The primary endpoint was the 30s-CST, which counted the number of times participants could stand from a seated position in 30 seconds. Participants in the PRT and NEMEX groups were able to do this maneuver a respective 11.3 and 11.6 times at baseline and 12.8 and 13.1 times after completion of the exercise programs.
Other functional performance tests included a 40-m fast-paced walk, a nine-step timed stair climb, leg extensor power in the affected and unaffected limb, and a unilateral single repetition leg press. None of these showed a statistically significant benefit of PRT over NEMEX, or vice versa.
HOOS pain scores at baseline and 12 weeks for PRT were a respective 57.5 and 66.1, representing an overall 8.6-point increase, and for NEMEX they were 58.9 and 68.2, giving a 9.3-point increase, meaning there was only a -0.7 mean change when comparing the two groups.
Corresponding baseline and 12-week HOOS QOL scores for PRT were 43.7 and 51.7; for NEMEX, they were 47.1 and 52.8 thus giving 8.0- and 5.7-point increases and a 2.3 difference in change between the groups. Again, this wasn’t quite enough to show a clinically meaningful effect.
Future Steps
“The effect of exercise seems to be at its highest at 3-4 months when you implement exercise, so we compared the effects of the exercises at the time when they are probably going to be at their highest,” Mr. Kjeldsen explained. He said the research team also plans to look at what happens after 1 year of follow-up.
“The key take home message is that patients can be encouraged to pick the type of exercise that they find the most enjoyable, or the type that is available to them,” Mr. Kjeldsen suggested.
Stephanie Chang, MD, MPH, who is the Deputy Editor of Annals of Internal Medicine and practices in Rockville, Maryland, commented on the paper to this news organization. “In this small study, we learned that exercises to strengthen lower extremity muscles did not improve pain or function any more than exercises for core stability and balance,” she said.
Dr. Chang pointed out that there was variance in the levels of activity that people already undertook at baseline: 40% of the PRT group and 41% of the NEMEX group already did 150 minutes or more of moderate intensity physical activity.
“It’s possible that benefit or differences between interventions would be greater in people with different levels of baseline activity or even in those with different osteoarthritis severity,” she said.
“In the meantime,” Dr. Chang added, “with the findings from this study, I would feel comfortable advising my patients with hip osteoarthritis to engage in whichever type of exercise they prefer — whether that exercise focuses on core strengthening and balance or on specific lower extremity muscle strengthening.”
The trial was funded by the Independent Research Fund Denmark, the Physiotherapy Practice Foundation, the Health Foundation, Aarhus University, Region Zealand, the Association of Danish Physiotherapists, Andelsfonden, and Hede Nielsens Family Foundation. Mr. Kjeldsen and Dr. Chang report no relevant financial relationships.
A version of this article appeared on Medscape.com.
Progressive resistance training (PRT) and neuromuscular exercise (NEMEX) programs result in similar improvements in hip function, pain, and hip-related quality of life (QOL) in people with osteoarthritis (OA), according to the results of a randomized controlled trial.
At the end of the 12-week exercise period, both interventions yielded changes from baseline on the 30-second chair stand test (30s-CST) that were below the threshold for a major clinical effect.
Mean changes in the Hip Disability and Osteoarthritis Outcome Score (HOOS) pain subscale and HOOS QOL score were also similar among the participants, regardless of which exercise program they had been assigned to.
“The lack of superiority of PRT for increasing muscle strength and power is surprising given the principle of specificity (higher-intensity resistance training yields greater improvements in maximal muscle strength),” according to the Danish researchers who reported the results online today in Annals of Internal Medicine.
“However, the point estimates only showed modest and uncertain superiority of PRT for increasing muscle strength and power and no differences for any functional performance tests or self-reported physical function,” they added.
The Power of Exercise
Worldwide, most clinical guidelines recommend exercise as a first-line conservative treatment option in both hip and knee OA. However, there is not much evidence to help guide healthcare practitioners in deciding which type of exercises to use with their patients, Troels Kjeldsen, MSc, the principal investigator for the study, told this news organization.
“Neuromuscular exercise is a very commonly used exercise program in clinical practice, but, to our knowledge, it has never been compared to another type of exercise in hip OA,” observed Mr. Kjeldsen, who is a PhD student in the department of orthopedic surgery at Aarhus University Hospital, Aarhus, Denmark.
“Each year, many thousands of patients are referred to having neuromuscular exercise therapy with a physiotherapist,” Mr. Kjeldsen said. “So, we thought it would be worthwhile to compare it to PRT, another promising exercise type, to see if it really did perform as well as I think most people thought it did,” he added.
Comparing the Two Exercise Programs
PRT and NEMEX are two different types of exercise programs. PRT involves using resistance-training machines, and the focus is to maximize the exercise intensity by using as high an exercise load or weight as possible. By contrast, NEMEX consists of exercises that are low to moderate in intensity and emphasizes alignment, control, and stability of the movements.
To compare the two exercise strategies, Mr. Kjeldsen and fellow investigators recruited 160 participants at five hospitals and 10 physiotherapy clinics across three of five healthcare regions in Denmark.
For inclusion in the trial, the participants had to have a clinical diagnosis of hip OA, be older than 45 years, and experience pain during activity in one or both hips that was rated as 3 or higher on a 10-point numerical rating scale. Participants also had to have no or less than 30 minutes of hip joint stiffness in the morning as well as no surgery involving the lower extremities in the previous 6 months.
Participants were then randomized to undertake the PRT (n = 82) or NEMEX (n = 78) program, delivered as two physiotherapist-led group sessions every week for 12 weeks. Exercise sessions were held at least 72 hours apart and consisted of a 10-minute warm-up on an exercise bike and then 50 minutes of PRT or NEMEX. PRT consisted of five generic resistance-based exercises targeting hip and knee joint muscles and NEMEX consisted of 10 exercises that increased in difficulty by varying the number, direction, speed, and surface of the movements performed.
Dead Heat Between PRT and NEMEX
The primary endpoint was the 30s-CST, which counted the number of times participants could stand from a seated position in 30 seconds. Participants in the PRT and NEMEX groups were able to do this maneuver a respective 11.3 and 11.6 times at baseline and 12.8 and 13.1 times after completion of the exercise programs.
Other functional performance tests included a 40-m fast-paced walk, a nine-step timed stair climb, leg extensor power in the affected and unaffected limb, and a unilateral single repetition leg press. None of these showed a statistically significant benefit of PRT over NEMEX, or vice versa.
HOOS pain scores at baseline and 12 weeks for PRT were a respective 57.5 and 66.1, representing an overall 8.6-point increase, and for NEMEX they were 58.9 and 68.2, giving a 9.3-point increase, meaning there was only a -0.7 mean change when comparing the two groups.
Corresponding baseline and 12-week HOOS QOL scores for PRT were 43.7 and 51.7; for NEMEX, they were 47.1 and 52.8 thus giving 8.0- and 5.7-point increases and a 2.3 difference in change between the groups. Again, this wasn’t quite enough to show a clinically meaningful effect.
Future Steps
“The effect of exercise seems to be at its highest at 3-4 months when you implement exercise, so we compared the effects of the exercises at the time when they are probably going to be at their highest,” Mr. Kjeldsen explained. He said the research team also plans to look at what happens after 1 year of follow-up.
“The key take home message is that patients can be encouraged to pick the type of exercise that they find the most enjoyable, or the type that is available to them,” Mr. Kjeldsen suggested.
Stephanie Chang, MD, MPH, who is the Deputy Editor of Annals of Internal Medicine and practices in Rockville, Maryland, commented on the paper to this news organization. “In this small study, we learned that exercises to strengthen lower extremity muscles did not improve pain or function any more than exercises for core stability and balance,” she said.
Dr. Chang pointed out that there was variance in the levels of activity that people already undertook at baseline: 40% of the PRT group and 41% of the NEMEX group already did 150 minutes or more of moderate intensity physical activity.
“It’s possible that benefit or differences between interventions would be greater in people with different levels of baseline activity or even in those with different osteoarthritis severity,” she said.
“In the meantime,” Dr. Chang added, “with the findings from this study, I would feel comfortable advising my patients with hip osteoarthritis to engage in whichever type of exercise they prefer — whether that exercise focuses on core strengthening and balance or on specific lower extremity muscle strengthening.”
The trial was funded by the Independent Research Fund Denmark, the Physiotherapy Practice Foundation, the Health Foundation, Aarhus University, Region Zealand, the Association of Danish Physiotherapists, Andelsfonden, and Hede Nielsens Family Foundation. Mr. Kjeldsen and Dr. Chang report no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
Chronic Pain Linked to Accelerated Brain Aging
, new research showed.
Using structural MRI data from more than 9000 adults with knee osteoarthritis (KOA) from the UK Biobank, investigators developed a brain age model to compare an individual’s brain age with their chronological age. Those with KOA showed a much faster rate of brain aging than healthy individuals.
The acceleration in brain aging was largely driven by the hippocampus and predicted memory decline and incident dementia during follow-up. Researchers identified a gene highly expressed in glial cells as a possible genetic factor for accelerated brain aging.
“We demonstrate the accelerated brain aging and cognitive decline in chronic musculoskeletal pain, in particular knee osteoarthritis, and provide a neural marker for early detection and intervention,” said co-first author Jiao Liu, PhD candidate, Chinese Academy of Sciences, Beijing.
“We are interested to know how to slow down the aging brain in chronic musculoskeletal pain patients. Proper exercise and lifestyle may reduce the risk,” Dr. Liu said.
The study was published online in Nature Mental Health.
Common Condition
CMP affects more than 40% of the world’s population and has been shown to have a harmful impact on cognitive function, although the exact mechanisms remain unclear. Prior research suggests that inflammatory markers associated with brain aging are higher in patients with CMP, suggesting a link between brain aging and CMP.
To investigate further, researchers explored patterns of brain aging in healthy cohorts and cohorts with four common types of CMP — chronic knee pain, chronic back pain, chronic neck pain, and chronic hip pain.
Using their brain age model, investigators observed significantly increased brain aging, or “predicted age difference,” only in individuals with KOA (P < .001). The observation was validated in an independent dataset (P = .020), suggesting a pattern of brain aging acceleration specific to KOA.
This acceleration was primarily driven by key brain regions involved in cognitive processing, including hippocampus and orbitofrontal cortex, and was correlated with longitudinal memory decline and dementia risk.
These data also suggest that the SLC39A8 gene, which is highly expressed in glial cells, might be a key genetic factor underpinning this acceleration.
“We not only revealed the specificity of accelerated brain aging in knee osteoarthritis patients, but importantly, we also provided longitudinal evidence suggesting the ability of our brain aging marker to predict future memory decline and increased dementia risk,” corresponding author Yiheng Tu, PhD, also with Chinese Academy of Sciences, Beijing, said in a news release.
A Future Treatment Target?
Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, noted that in this study, people with KOA showed signs of “faster brain aging on scans. Think of it as your brain wearing a disguise, appearing older than its actual years,” Dr. Lakhan said.
“Inflammation, a key player in osteoarthritis, might be playing a double agent, wreaking havoc not just on your joints but potentially on your memory too. Researchers even identified a specific gene linked to both knee pain and faster brain aging, hinting at a potential target for future treatments,” he added.
“Importantly, the increased risk of cognitive decline and dementia associated with chronic pain is likely one of many factors, and probably not a very high one on its own,” Dr. Lakhan noted.
The “good news,” he said, is that there are many “well-established ways to keep your brain sharp. Regular exercise, a healthy diet, and staying mentally stimulated are all proven strategies to reduce dementia risk. Think of chronic pain management as another tool you can add to your brain health toolbox.”
Support for the study was provided by the STI-2030 Major Project, the National Natural Science Foundation of China, the Scientific Foundation of the Institute of Psychology, Chinese Academy of Sciences, and the Young Elite Scientist Sponsorship Program by the China Association for Science and Technology. Dr. Liu and Dr. Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
, new research showed.
Using structural MRI data from more than 9000 adults with knee osteoarthritis (KOA) from the UK Biobank, investigators developed a brain age model to compare an individual’s brain age with their chronological age. Those with KOA showed a much faster rate of brain aging than healthy individuals.
The acceleration in brain aging was largely driven by the hippocampus and predicted memory decline and incident dementia during follow-up. Researchers identified a gene highly expressed in glial cells as a possible genetic factor for accelerated brain aging.
“We demonstrate the accelerated brain aging and cognitive decline in chronic musculoskeletal pain, in particular knee osteoarthritis, and provide a neural marker for early detection and intervention,” said co-first author Jiao Liu, PhD candidate, Chinese Academy of Sciences, Beijing.
“We are interested to know how to slow down the aging brain in chronic musculoskeletal pain patients. Proper exercise and lifestyle may reduce the risk,” Dr. Liu said.
The study was published online in Nature Mental Health.
Common Condition
CMP affects more than 40% of the world’s population and has been shown to have a harmful impact on cognitive function, although the exact mechanisms remain unclear. Prior research suggests that inflammatory markers associated with brain aging are higher in patients with CMP, suggesting a link between brain aging and CMP.
To investigate further, researchers explored patterns of brain aging in healthy cohorts and cohorts with four common types of CMP — chronic knee pain, chronic back pain, chronic neck pain, and chronic hip pain.
Using their brain age model, investigators observed significantly increased brain aging, or “predicted age difference,” only in individuals with KOA (P < .001). The observation was validated in an independent dataset (P = .020), suggesting a pattern of brain aging acceleration specific to KOA.
This acceleration was primarily driven by key brain regions involved in cognitive processing, including hippocampus and orbitofrontal cortex, and was correlated with longitudinal memory decline and dementia risk.
These data also suggest that the SLC39A8 gene, which is highly expressed in glial cells, might be a key genetic factor underpinning this acceleration.
“We not only revealed the specificity of accelerated brain aging in knee osteoarthritis patients, but importantly, we also provided longitudinal evidence suggesting the ability of our brain aging marker to predict future memory decline and increased dementia risk,” corresponding author Yiheng Tu, PhD, also with Chinese Academy of Sciences, Beijing, said in a news release.
A Future Treatment Target?
Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, noted that in this study, people with KOA showed signs of “faster brain aging on scans. Think of it as your brain wearing a disguise, appearing older than its actual years,” Dr. Lakhan said.
“Inflammation, a key player in osteoarthritis, might be playing a double agent, wreaking havoc not just on your joints but potentially on your memory too. Researchers even identified a specific gene linked to both knee pain and faster brain aging, hinting at a potential target for future treatments,” he added.
“Importantly, the increased risk of cognitive decline and dementia associated with chronic pain is likely one of many factors, and probably not a very high one on its own,” Dr. Lakhan noted.
The “good news,” he said, is that there are many “well-established ways to keep your brain sharp. Regular exercise, a healthy diet, and staying mentally stimulated are all proven strategies to reduce dementia risk. Think of chronic pain management as another tool you can add to your brain health toolbox.”
Support for the study was provided by the STI-2030 Major Project, the National Natural Science Foundation of China, the Scientific Foundation of the Institute of Psychology, Chinese Academy of Sciences, and the Young Elite Scientist Sponsorship Program by the China Association for Science and Technology. Dr. Liu and Dr. Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
, new research showed.
Using structural MRI data from more than 9000 adults with knee osteoarthritis (KOA) from the UK Biobank, investigators developed a brain age model to compare an individual’s brain age with their chronological age. Those with KOA showed a much faster rate of brain aging than healthy individuals.
The acceleration in brain aging was largely driven by the hippocampus and predicted memory decline and incident dementia during follow-up. Researchers identified a gene highly expressed in glial cells as a possible genetic factor for accelerated brain aging.
“We demonstrate the accelerated brain aging and cognitive decline in chronic musculoskeletal pain, in particular knee osteoarthritis, and provide a neural marker for early detection and intervention,” said co-first author Jiao Liu, PhD candidate, Chinese Academy of Sciences, Beijing.
“We are interested to know how to slow down the aging brain in chronic musculoskeletal pain patients. Proper exercise and lifestyle may reduce the risk,” Dr. Liu said.
The study was published online in Nature Mental Health.
Common Condition
CMP affects more than 40% of the world’s population and has been shown to have a harmful impact on cognitive function, although the exact mechanisms remain unclear. Prior research suggests that inflammatory markers associated with brain aging are higher in patients with CMP, suggesting a link between brain aging and CMP.
To investigate further, researchers explored patterns of brain aging in healthy cohorts and cohorts with four common types of CMP — chronic knee pain, chronic back pain, chronic neck pain, and chronic hip pain.
Using their brain age model, investigators observed significantly increased brain aging, or “predicted age difference,” only in individuals with KOA (P < .001). The observation was validated in an independent dataset (P = .020), suggesting a pattern of brain aging acceleration specific to KOA.
This acceleration was primarily driven by key brain regions involved in cognitive processing, including hippocampus and orbitofrontal cortex, and was correlated with longitudinal memory decline and dementia risk.
These data also suggest that the SLC39A8 gene, which is highly expressed in glial cells, might be a key genetic factor underpinning this acceleration.
“We not only revealed the specificity of accelerated brain aging in knee osteoarthritis patients, but importantly, we also provided longitudinal evidence suggesting the ability of our brain aging marker to predict future memory decline and increased dementia risk,” corresponding author Yiheng Tu, PhD, also with Chinese Academy of Sciences, Beijing, said in a news release.
A Future Treatment Target?
Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, noted that in this study, people with KOA showed signs of “faster brain aging on scans. Think of it as your brain wearing a disguise, appearing older than its actual years,” Dr. Lakhan said.
“Inflammation, a key player in osteoarthritis, might be playing a double agent, wreaking havoc not just on your joints but potentially on your memory too. Researchers even identified a specific gene linked to both knee pain and faster brain aging, hinting at a potential target for future treatments,” he added.
“Importantly, the increased risk of cognitive decline and dementia associated with chronic pain is likely one of many factors, and probably not a very high one on its own,” Dr. Lakhan noted.
The “good news,” he said, is that there are many “well-established ways to keep your brain sharp. Regular exercise, a healthy diet, and staying mentally stimulated are all proven strategies to reduce dementia risk. Think of chronic pain management as another tool you can add to your brain health toolbox.”
Support for the study was provided by the STI-2030 Major Project, the National Natural Science Foundation of China, the Scientific Foundation of the Institute of Psychology, Chinese Academy of Sciences, and the Young Elite Scientist Sponsorship Program by the China Association for Science and Technology. Dr. Liu and Dr. Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM NATURE MENTAL HEALTH
Congress Directly Provides $10 Million for Arthritis Research for First Time
Congress provided $10 million to fund arthritis research in the recently passed federal fiscal year 2024 budget.
The new arthritis program is part of the Department of Defense’s (DOD’s) Congressionally Directed Medical Research Programs (CDMRP), which provides dedicated funding to study certain diseases and health conditions.
This is the first stand-alone research program for arthritis of the CDMRP, though the organization had previously funded arthritis-related research through their other programs, including chronic pain management, joint warfighter medical, peer-reviewed orthopedic, peer-reviewed medical, and tick-borne disease programs.
It is not yet known what specific aspects of arthritis this funding will go toward. The standard process for new programs involves speaking with researchers, clinicians, and individuals with these targeted health conditions to better understand research gaps and narrow focus, Akua Roach, PhD, the program manager for this new CDMRP arthritis research program, told this news organization.
“We’re not going to be able to solve every question,” she said, though the allocated $10 million is “a great number to do a lot of great work.”
While the CDMRP is under the DOD, research funding can go to studying patient populations outside of military personnel or veterans, she added.
“I think that is perhaps a common misconception that if you are getting funding from the DOD, that you have to have a DOD population, and that is not true,” she said.
Another misconception is that CDMRP funding only goes to military treatment facilities. In fact, on average, 92% of CDMRP funding goes to academia, industry, and other nonmilitary recipients, noted CDMRP Director Colonel Sarah Goldman.
“Anyone around the world can apply for funding,” she told this news organization. “We want to fund the best research.”
Because the funding is provided under the defense bill, there will be discussions around the military relevance of research, she added, which not only includes service members but also their families.
CDMRP anticipates that funding opportunities through this new arthritis research program will be available by July or August 2024.
A version of this article appeared on Medscape.com.
Congress provided $10 million to fund arthritis research in the recently passed federal fiscal year 2024 budget.
The new arthritis program is part of the Department of Defense’s (DOD’s) Congressionally Directed Medical Research Programs (CDMRP), which provides dedicated funding to study certain diseases and health conditions.
This is the first stand-alone research program for arthritis of the CDMRP, though the organization had previously funded arthritis-related research through their other programs, including chronic pain management, joint warfighter medical, peer-reviewed orthopedic, peer-reviewed medical, and tick-borne disease programs.
It is not yet known what specific aspects of arthritis this funding will go toward. The standard process for new programs involves speaking with researchers, clinicians, and individuals with these targeted health conditions to better understand research gaps and narrow focus, Akua Roach, PhD, the program manager for this new CDMRP arthritis research program, told this news organization.
“We’re not going to be able to solve every question,” she said, though the allocated $10 million is “a great number to do a lot of great work.”
While the CDMRP is under the DOD, research funding can go to studying patient populations outside of military personnel or veterans, she added.
“I think that is perhaps a common misconception that if you are getting funding from the DOD, that you have to have a DOD population, and that is not true,” she said.
Another misconception is that CDMRP funding only goes to military treatment facilities. In fact, on average, 92% of CDMRP funding goes to academia, industry, and other nonmilitary recipients, noted CDMRP Director Colonel Sarah Goldman.
“Anyone around the world can apply for funding,” she told this news organization. “We want to fund the best research.”
Because the funding is provided under the defense bill, there will be discussions around the military relevance of research, she added, which not only includes service members but also their families.
CDMRP anticipates that funding opportunities through this new arthritis research program will be available by July or August 2024.
A version of this article appeared on Medscape.com.
Congress provided $10 million to fund arthritis research in the recently passed federal fiscal year 2024 budget.
The new arthritis program is part of the Department of Defense’s (DOD’s) Congressionally Directed Medical Research Programs (CDMRP), which provides dedicated funding to study certain diseases and health conditions.
This is the first stand-alone research program for arthritis of the CDMRP, though the organization had previously funded arthritis-related research through their other programs, including chronic pain management, joint warfighter medical, peer-reviewed orthopedic, peer-reviewed medical, and tick-borne disease programs.
It is not yet known what specific aspects of arthritis this funding will go toward. The standard process for new programs involves speaking with researchers, clinicians, and individuals with these targeted health conditions to better understand research gaps and narrow focus, Akua Roach, PhD, the program manager for this new CDMRP arthritis research program, told this news organization.
“We’re not going to be able to solve every question,” she said, though the allocated $10 million is “a great number to do a lot of great work.”
While the CDMRP is under the DOD, research funding can go to studying patient populations outside of military personnel or veterans, she added.
“I think that is perhaps a common misconception that if you are getting funding from the DOD, that you have to have a DOD population, and that is not true,” she said.
Another misconception is that CDMRP funding only goes to military treatment facilities. In fact, on average, 92% of CDMRP funding goes to academia, industry, and other nonmilitary recipients, noted CDMRP Director Colonel Sarah Goldman.
“Anyone around the world can apply for funding,” she told this news organization. “We want to fund the best research.”
Because the funding is provided under the defense bill, there will be discussions around the military relevance of research, she added, which not only includes service members but also their families.
CDMRP anticipates that funding opportunities through this new arthritis research program will be available by July or August 2024.
A version of this article appeared on Medscape.com.