There was a human study, watch the video again. Small 20 person pilot study with very significant difference in cartilage thickness. I was trying to find it but I don’t have access to the full paper.
Again, just like you I used to think all the benefits were due to the weight loss, I still think that most are but there is definitely mounting evidence of glp-1 having direct effect on cells/tissue independent of weight loss.
I agree. The benefits of calorie restriction are so wast that I’m going to assume that any benefits of GLP-1 drugs are caused entirely or almost entirely by the weight loss rather than by independent effects. To prove otherwise someone would have to do a study where the people take low doses of GLP-1 drugs and make sure to not eat any less or lose any weight. If that still shows benefits then we can assume it has significant independent health benefits.
Uhhh did you read the digest? They HAD controlled for caloric intake and weight loss.
I’m genuinely surprised by how many people seem to not even read the content they comment on.
Can you provide a link to that?
That is, controlling for calorie intake in humans. I just clicked on one link that was a study that literally showed that people on GLP1s lost more weight and had a reduction in knee pain score compared to placebo. Like that isn’t helpful.
Understand some skepticism here. These are some of the most profitable drugs ever produced. Denmark’s GDP is smaller than the market value of Novo Nordisk. Novo is the primary driver of GDP growth in Denmark.
Controlling for calorie intake in humans is almost impossible outside of prison. So the skeptics know that you can’t really prove a benefit outside of calorie restriction.
I spent my career hearing from people who had less pain (and various other markers of inflammation) from calorie restriction before significant weight loss. Like magic they thought.
I tried clicking on the Cell article about cartilage in humans. All I got was a summary and I did note that it was a Chinese article. But the summary didn’t have much and the full article was behind a paywall.
GLP-1RAs are fantastic, and their benefits are probably largely independent of weight loss. Just a warning for people with a personal or family history of depression/suicidal ideation, these drugs might not be the best ones for you (or at least, to keep in mind if you try them): Retatrutide - Possibly better than semaglutide b/c lower nausea/side effect profile, but higher heart rate - #326 by adssx
What do you think is going on with the mental health signal — reward dampening too much?
And yes the benefits seem to extend well beyond weight loss. No one losing weight by any other means had previously been shown to regrow cartilage. I first got excited over them from reading a paper from maybe 2-3 years ago over how tirzapetide had caused multi organ rejuvenation in mice completely independent of weight loss.
There are also plenty of people taking a GLP1-RA for glucose control and who don’t loose any weight nor appetite at a 5mg dose.
In my case I’ve not lost any weight at all and I’m still at the same 65kg (BMI 21.5) after 1.5 year of TZ.
My diet has not changed, and I’m doing the same marathon training/running.
Besides a small reduction in glucose, I’ve noticed a slight increase in ketones and my DEXA body fat went from 18% to 14% which is nice.
Obviously it’s only an N=1 data point.
The study is mainly Chinese, but has also authors from Aberdeen and Washington university
The Cell article is only about metabolic OA, not OA in general.
In both trials, mice and human, all particpipants were obese.
So what might have worked in obese mice/human in this study might not work for non-metabolic OA meaning people with OA which are not obese or having a metabolic disease.
Weight loss was controlled only in the mice study, but not in the human clinic trial. So in humans it might still be a weight loss effect. Although unlikely as cartilage has partially recovered. But maybe nobody checked this before and it happens frequently after significant weight loss?
Nevertheless, the mechansim study with mice looks very sound to me and together with the human trial I inclined to think that it is a GLP1 effect.
For the ones who want to try this: They have used 0.5 Semaglutide per week for 24 weeks.
And no, I would not recommend to use another GLP1 RA if the target is OA as GLP1 is the key driver here. Semglutide has the strongest affinity to GLP1 receptor. The other ones have signfiicant lower GLP-1 activity.
A bit more info on the idea that GLP1’s may have a benefit, not related to weight loss, with respect to cartilage health
GLP1 find the recent study on the effect of increa.pdf (619.1 KB)
Thank you for that. More info than the article.
It is seeming a well written summary and reminds us this is a pilot study with short FU and small number of patients.
This summary and available on line summary has no confidence interval or p value. 17% in 20 patients (20 in each group or total?) isn’t a slam dunk.
Just playing the skeptic although I am open minded.
Look, you can give your cartilage a break by losing weight which can stave off further damage. But we don’t have any reports to date that anything can grow it back. Once you lose it that’s it. So this report is groundbreaking. I don’t understand what there is to fuss about. Yes we’re awaiting confirmation and more info but if it pans out it’s astounding. The only skepticism I can relate to is, let’s wait till there’s more data. But if the claims pan out, they’d have zilch to do with weight loss.
Jesus Joseph and Mary!
If they can report even a single case of cartilage regeneration that’s earth shattering in itself. Cartilage is supposed to only deteriorate with time, a one way street. So if found an intervention that only resulted in pulling off time friggin travel in 17% of a 20 subject group, would you ask, “but what’s the p value” or holler, “holy shit time travel is possible!?”
Thankfully no. Cartilage, like tendon, is a living tissue that adapts to the load. For instance long term runners have thicker cartilage areas. As usual it’s a U-shaped curve and extreme volume of running might be detrimental to cartilage though.
Science is skeptical.
This is an MRI finding not a tissue biopsy. X-rays lie is surgical dogma. Yes, MRI is not x-ray but same idea. As a general surgeon, we always meant CTs lie. I can tell you that MRIs are significantly worse but cartilage is not my field. But MRIs are not nearly as good as the radiologists think.
What we don’t know -
There is no way a MRI finding proves to me there is cartilage regrowth on 20 people without strict controls and blinding and placebo comparison statistics.
I have a blind spot for MRI technology and with cartilage, even more of a blind spot. And I am skeptical. And I have a career of disagreement at times with radiologists - even a paper published that says CTs lie - on a specific diagnosis with pathologic confirmation.
None of this means that GLP1s aren’t great for joints. Does that mean every BMI 20 person who eats a good clean diet should start GLP1s? Probably not yet. It is well documented that people lose muscle with GLP1s so let’s not pretend they don’t have any downside. Does that mean a weight lifter who doesn’t change calories will lose muscle? Probably not but could be if the same thing grows cartilage, right?
Everything has a down side.
I think I’ve found the paper that this video is referring to. Should make the discussion more concrete and shed more relevant details.
cell-oa-paper.pdf (4.3 MB)
The provided document detailing a 2026 study in Cell Metabolism describes how semaglutide (SG), a GLP-1 receptor agonist, effectively treats osteoarthritis (OA) through a mechanism that is independent of its well-known weight-loss effects.
The study identifies the “GLP-1R-AMPK-PFKFB3” axis as the primary pathway for SG’s therapeutic effect:
The pilot clinical trial described in the study evaluated the efficacy of semaglutide (SG) in treating obesity-related knee osteoarthritis (OA) by comparing its effects against a standard treatment.
The pre-clinical study utilized an obesity-related mouse model to investigate the effects of semaglutide (SG) on osteoarthritis (OA). This phase of the research was critical in demonstrating that SG’s benefits for joint health are independent of its well-known weight-loss effects.
The researchers assessed the health of the joint cartilage using histology (Safranin-O-fast green staining) and micro-CT imaging after 12 weeks of treatment.
| Group | Cartilage Condition & Change Analysis |
|---|---|
| Obesity + DMM (Control) | Showed severe OA-like changes, including significant cartilage degradation and a notable reduction in cartilage area. |
| Obesity + DMM + SG (Treatment) | Demonstrated a significant increase in cartilage area and reduced degradation compared to the DMM group. The OARSI scores (which measure OA severity) were markedly lower. |
| Obesity + DMM + PF (Weight Control) | Despite achieving a comparable weight loss to the SG group, these mice showed no significant cartilage protection. Their cartilage area remained reduced, and OA progression was similar to the DMM control. |
Because both groups lost the same amount of weight, but only the SG group showed preserved cartilage area and thickness, the authors concluded that semaglutide mitigates OA progression through mechanisms independent of its weight-lowering effect. Instead, the drug works by reprogramming chondrocyte metabolism from harmful glycolysis to beneficial oxidative phosphorylation.
The study utilized Magnetic Resonance Imaging (MRI) to assess changes in cartilage degradation. The findings revealed a stark contrast between the two groups:
While the animal models proved the cartilage protection was weight-loss independent, the human trial recorded the following at week 24:
The researchers concluded that semaglutide acts as a disease-modifying drug by shifting chondrocyte metabolism from harmful glycolysis to beneficial oxidative phosphorylation, thereby directly restoring cartilage integrity.
The authors determined that the 17% increase in cartilage thickness in the semaglutide-treated group was statistically significant.
The key statistical findings regarding this increase include:
Significant Improvement vs. Control: The semaglutide (SG) group (specifically the HA + SG group) showed a significant reduction in cartilage degradation compared to the control group.
Statistical Threshold: The study consistently utilized a threshold of p<0.05 to define statistical significance for its primary and secondary endpoints, including MRI-based cartilage parameters.
Comparative Result: While the HA + SG group experienced this ~17% increase in thickness, the control group receiving only sodium hyaluronate (HA) showed no significant change in cartilage thickness over the same period.
The authors noted that these clinical results were “encouraging” as they mirrored the strong chondroprotective effects observed in their weight-loss-independent mouse models. However, they also cautioned that because of the small sample size (n=20), these results should be validated in larger clinical trials
My bad. My comment was more of a general comment on interventions that reduce calorie intake. It is indeed interesting that the GLP-1 drugs seem to be able to amplify some of the benefits of weight loss due to independent effects. I wonder if such effects are significant in people that don’t need to lose weight.
Also I am most curious to know if GLP-1 drugs cause benefits in people that do not need to lose weigh at all, and make sure to not eat less at all when on these drugs. For such people, if they have any benefits at all, they would likely be much smaller, since they don’t have the problems the GLP-1 drugs are mainly used to solve. I would only call them longevity drugs if they improve lifespan in animals that are already lean and calorie restricted by adding benefits beyond what you could achieve by merely reducing calorie intake.
I’m not trying to nitpick, but this study does have some issues.
There were no statistically significant differences between the HA monotherapy group and the HA+SG combination group in terms of WOMAC pain scores or joint stiffness scores. The only area where the combination group showed a clear advantage was in physical function scores. So why did semaglutide win on this measure? At 24 weeks, the SG combination group saw a roughly 7.96% drop in BMI, compared to just 0.49% in the control group. If you look at the 17 assessed items in the paper—such as “going up and down stairs,” “rising from sitting,” “getting in and out of a car,” and “doing heavy housework”—these are all anti-gravity movements that heavily rely on lower limb loading. An 8% reduction in body weight means the mechanical load on the knee joint during these activities is greatly reduced.
Then the MRI data showed that cartilage thickness increased by about 17% in the HA+SG group, compared to less than 1% in the HA group. But here’s the catch: MRI resolution is sub-millimeter. With such a small sample size (only 14 participants completed the trial), manually segmented cartilage thickness measurements using 3D Slicer are highly susceptible to measurement error and individual variation.
Some might think I’m being biased, but the mouse study was flawless. In mice, the PF group had body weight and food intake curves identical to those of the SG treatment group, and SG treatment significantly raised pain thresholds in pain sensitivity tests. In humans, however, weight loss didn’t translate into a statistically significant difference in WOMAC pain scores. Moreover, the average cartilage thickness in the human knee is only about 2 to 3 mm. At sub-millimeter resolution, a cartilage layer may occupy just a handful of pixels in the image. Frankly, there are countless ways the authors could have made the results look significant. If cartilage truly had been repaired, the clinical outcomes in human patients would not look like this.
The mouse study used micro-CT (10 µm resolution), and that research does support the conclusion that cartilage repair in mice is achievable.
A large body of research supports that GLP-1 drugs should absolutely not be used casually in people with normal weight. However, in the current climate of biohackers widely misusing these drugs, such research is highly unwelcome. So I’m curious to hear doctors’ perspectives. @KarlT @DrFraser
I don’t know if they’re longevity drugs in the sense you mean. Personally I take 2.5 mg of tirzapetide as I can use a bit of weight loss and because of all the positive signals I am seeing. In this particular case I am pretty amazed at the reported results. A couple years back I was binge watching orthopedists’ & podiatrists’ videos on YT due to a sprained ankle and I kept hearing how there’s all sorts of things you can do to prevent cartilage degeneration but that once under way, you can’t reverse damage … as of today … or two years ago. These were the words from the experts in the field. So the result is super impressive to me. But yeah if I were very lean I would think more than twice before dabbling with GLP1s. That’s neither here nor there for the purposes of cartilage regeneration.