"Osteophytes do not regress."
D.M. Yousem - American Journal of Neuroradiology December 2016.1
hile we all wait for some commercial milestones to one day get, well, launched (Apologies Pool_Dictorate)...I love dwelling into the science. Oh there is still so much to come in terms of Mozz Posts®, my list ain't getting smaller, it's getting longer and I'm having to close/throttle my eyes and ears a bit so I don't get too flooded with research!
We are getting a sense that this OA stuff is complex, there is a not only a lot going on both within and outside the joint, but there are a lot of knock on effects and other ramifications. Enter the realm of Osteophytes.
Tonight we cover what Osteophytes are, how they may play a much more active role than what was first thought and like a few of these posts, I like to make it personable; what role could Pentosan, in the SubQ version, play here?
I trust you will enjoy:
WHAT IS AN OSTEOPHYTE?
Think of it as a smooth bony protrusion or bump that grows off a bone. They can take ages to develop and oftentimes you will find them near the joints. Sometimes you may never know they are even there as they may cause no pain and no functional disruption. In other cases they may grow over the months and years and start to push against nerves, that's when you will sense pain and it can increase over time.
Ahh may not look like much (see arrows above) but these little 'smooth' bumps can play quite a role, read on to be enlightened!
While they are more common in older people, 60 and over, younger people can develop them too.
There is a link between OA and these bony spurs. In fact joint damage itself can cause these spurs. Once your cartilage starts to become hard and lose the flexibility, then you can be more susceptible to these osteophytes.
KNOCK ON EFFECTS
A number of problems can develop once these spurs occur:
- Reduce flexion
- Obstruct or press against nerves causing pain
- They can rub against other bones and tissues causing pain and further destruction
- Bumpy areas can protrude (specially the fingers and toes)
- Numbness and weakness can also occur
- Pain near the affected joint
- Reduced ROM
- Stiffness
- Tendinitis can result
- Tenon tears.
Certainly the observation of osteophtyes have links with OA. In a study conducted by a number of researchers including our own Dr D Felson (I like the sound of calling him our own)...they came to this conclusion:
"An MRI OA definition requiring cartilage damage and a small osteophyte with or without BMLs or synovitis had the best performance and was simplest for identifying radiographic OA and symptomatic OA".2
.
THE MEDIATOR
In 2022 an interesting paper came out titled "Osteophytes mediate the associations between cartilage morphology and changes in knee symptoms in patients with knee osteoarthritis". 2.5
One of several interesting points that came out of this study was that there is a causation link between osteophytes and symptomatic OA.
"To our knowledge, this is the first study to reveal that the associations between cartilage morphology and change in knee symptoms are partly mediated via osteophytes".
The paper goes on to say that there are plenty of studies that show links between knee pain and...
- Patellar cartilage volume had a strongly inverse relationship with WOMAC pain and WOMAC dysfunction
- A brief report from FNIH OA Biomarkers Consortium found that cartilage thickness loss was associated with pain progression
- In a study with 500 participants, the prevalence and severity of knee pain were significantly associated with medial tibial cartilage defects
- There was a dose-response relationship between knee pain and number of sites having grade 3 or 4 cartilage defects, with all participants having knee pain if all compartments of the knee had these defects.
- A population-based study with 2733 participants reported that joint space narrowing (a proxy for cartilage loss) had a significant association with knee pain.
All very good and known links but this paper indicated that there aren't so many studies out there showing and depicting HOW this pain comes about...the key, that this paper found, links back to our topic tonight:
"Our findings indicated that cartilage was not the direct source of knee pain and knee dysfunction but indirectly through osteophytes".
Thus osteophtyes at least in some circumstances may indeed play a mediator type role.
TREATMENTS
To be honest, once these osteophytes develop, there aint a lot we can do about them...we can possibly slow down the progressing through a balanced healthy diet and some appropriate exercise, however, to alleviate pain its the usual suspects such as NSAIDs but you and I both know that long term, generally that's going to result in a whole raft of other health problems. Certainly analgesics like NSAIDs and Corticosteroids aren't a long term solution and certainly don't do anything for the underlying problem in the first place.
Remember that very first quote I lead with in this post? Once a bone spur is grown, it will not disappear or reabsorb. There is no way to get rid of a bone spur besides cutting it off, but this is typically not recommended, unless the spur is critically compressing a nerve or the spinal cord, causing weakness. However, there are ways to reduce the risk of bone spur growth.3
In terms of pain? The usual suspects are offered:
"Take over-the-counter NSAIDs, like acetaminophen, ibuprofen, or naproxen, to help with the pain. Lose weight, which can ease the burden on your joints. Rest and ice the area, which can reduce pain and inflammation. Go to physical therapy, which can help keep your joints from getting any worse". 4
ENTER THE PARADIGM
So we know osteophytes aren't good, we know that they can result in a number of unwanted symptoms particularly if left unchecked. We also know there is a link between them and OA.
The very first opening quote, that was posted in the American Journal of Neuroradiology indicates that osteophytes do not generally regress. Once you have them, you have them and they are either going to (hopefully) stabilise OR they are going to get worse....
....until now...
The paper I mentioned above (Ref 2.5), then goes onto caution us from not getting too hung up ONLY on Cartilage Thickness:
"Many trials have used cartilage morphology as the main outcome of treatment and hope to delay the progression of symptoms by reducing cartilage loss. In two recent clinical trials, both sprifermin (fibroblast growth factor 18 agonist) and MIV-711 (selective cathepsin K inhibitor) can significantly improve cartilage thickness, but they had no effect on knee symptoms".
Its these such clues that play into our story so well...we actually have a multi factorial observation set...we see improved the early signs of cartilage volume improvement against placebo, we see BML regression, we see the potential of at least some osteophyte growth rates being arrested but while all that's happening, unlike other drugs that may have some degree of structural ramifications, we are giving the authorities their number one flagged Primary Endpoint.... Pain relief.
But lets make this personal...what about our findings, let's just take a look:
This is what Paradigm found in our 6 month 008 program:
"Marginal osteophytes—also known as bone spurs—form between the cartilage and bone and are an early finding in OA. They are associated with bone remodelling, as osteophytes typically increase in number and size as the disease progresses. In this study, osteophytes decreased slightly or remained stable in all three compartments of the knee among patients treated with iPPS, compared to an increase (numerically, though not statistically significantly) in the placebo arm". 5
Paradigmers, this was observed not over 3 years, not 2 years...but 6 months!?
The above PAR quote is compelling for two distinct reasons:
1) The osteophytes decreased slightly or remained stable due to the safe action of our drug
2) The observation of stabilisation or decrease of the osteophytes occurred in ALL THREE COMPARTMENTS of the knee as stated in the above quote..
The three compartments of the knee joint
Why is 2) above such a stand out for me? Because one of these compartments, namely the Medial Compartment is load bearing. I have a pal who is an expert in Musculoskeletal pathologies and he mentioned that this Medial compartment is one to watch.There already is good evidence of BMEL regression in the medial compartment.
Now in case you are wondering about the connection between these osteophytes and Bone Marrow Lesions...here it is:
Two quotes to be shared with you from the above paper: 4.5:
"Statistically significant interactions were found between MRI-detected osteophytes and BMLs or effusion-synovitis on increased knee symptoms".
...and...
"In participants with BMLs, higher baseline scores of MRI-detected osteophytes in most compartments were significantly associated with increased total knee pain, weight-bearing pain, stiffness, and physical dysfunction, after adjustment for age, sex, body mass index, intervention and effusion-synovitis".
I offer you two such examples to back up what I'm inferring:
"Bone marrow edema lesions in the entire lateral tibiofemoral compartment decreased by an average 17% in the once-weekly iPPS arm, but increased by 56% in the placebo arm (p=0.028)". 5
Not only did iPPS result in a good decrease/reversal of BMELs but the placebo group continued to deteriorate worsening by a huge 56% in such a short time!
"We report the case of a 70-year-old female with knee osteoarthritis presenting with a high level of knee pain, scoring 8 on the Numerical Rating Scale (NRS), and functional limitation demonstrating a poor Lysholm Knee Score of 37. MRI scans of the knee revealed subchondral BML in the medial femoral condyle and medial tibial plateau.
The patient was administered a course of Pentosan Polysulphate Sodium (PPS) intramuscularly twice weekly, for 3 weeks. MRI scans 2 weeks post-treatment showed complete resolution of the bone marrow edema at the medial femoral condyle and medial tibial plateau with concomitant recovery from pain (NRS pain score of 0), and a 43% improvement of the Lysholm Knee Score. In addition, marked reduction in joint effusion was also demonstrated in the MRI scan post PPS therapy".6
The MES (Mozz Executive Summary) for the above is this one line:
MRI scans 2 weeks post-treatment showed complete resolution of the bone marrow edema at the medial femoral condyle and medial tibial plateau with concomitant recovery from pain (NRS pain score of 0), and a 43% improvement of the Lysholm Knee Score.Now look, our drug is wonderful, it reduces pain materially, it improves function, do these two things with a large degree of safety and we are set to be a blockbuster at some future point in time...we see the example of the case above, pain was 8...now zero.
Yes it is n =1...but yes, we have many other examples, we have one that's close to us here at HC...Mr S. In terms of pain, he achieved the very same result...Pre iPPS 8 out of 10 pain, post iPPS...now zero.
BUT....And it's a big but....we don't
just do that....
"Complete resolution of BME".This is happening and it's happening fast...within 6 months, Mozz?
I give you one even better....
The above case was within
2 weeks of last treatment with iPPS.Paradigmers, that's not only profound...thats a MULTI blockbuster, one fine day. (Spec. comment)
Such is the drug effect size. We observed structural morphology with
n so low AND within literally weeks/months of last dosing.
Yeah so when could we see the top Pharma's vying for us? Well it may not necessarily be a 'wait till 2026 and beyond'...we just don't know how and when this story will play out...there will be some point when all this data becomes just too compelling for the big guys...something or someone may strike outta the blue.
Who will be our future dance partner? Tango to the tunes of Billions? Anyone?We have heard it a number of times from many sources, OA is complex, there is a lot involved. Osteophytes indeed play a role in amongst a number of complex pathologies.... We are literally seeing the red carpet unrolling, the spot lights all being set up...the lectern being adjusted. It may seem early still in our story..but this is a show that's just starting to really take shape...
My views of course.
REFERENCES1]
https://www.ajnr.org/content/37/12/21802]
https://pubmed.ncbi.nlm.nih.gov/36693143/2.5]
https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-022-02905-8#Fig23]
https://orthoarizona.org/blog/bone-spurs-in-the-back-a-brief-guide4] https://www.upmc.com/services/orthopaedics/conditions-treatments/bone-spurs#:~:text=Take%20over%2Dthe%2Dcounter%20NSAIDs,joints%20from%20getting%20any%20worse.
4.5]
https://pubmed.ncbi.nlm.nih.gov/34216729/5]
https://app.sharelinktechnologies.com/announcement/asx/63a249bdb0b4e5e1dc93c8ee2644f3a26]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596862/7]
https://www.proclinical.com/blogs/2023-7/the-top-10-pharmaceutical-companies-in-the-world-20238]
https://en.wikipedia.org/wiki/Osteophyte
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