Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

[FGG]

But are we regenerating the synapse or the spinal ganglion neuron or both? It sounds like the SGN has a finite lifespan.

"There is potentially a long therapeutic window because cell bodies of SGNs can survive for many months (in animal models) and years (in humans) after peripheral synaptic and neurite loss."

The SGN do degrade over time but it looks to be many, many decades to possibly never in most cases based on autopsy studies.

They degrade relatively quickly in cats (for instance, which a lot of the early studies were done on ) but it turns out humans have extremely different spiral ganglion nerves:

Impact of Morphometry, Myelinization and Synaptic Current Strength on Spike Conduction in Human and Cat Spiral Ganglion Neurons

The human spiral ganglion: new insights into ultrastructure, survival rate and implications for cochlear implants

I posted the autopsy study *somewhere* on this sight ages ago but I can't find it now. I believe one subject had been deaf since 20 and had normal SGN concentration at death at 80.

Tl;dr: this is probably not a worry most people should have.

 

[Tau]

I am thinking of trying IV Zoledronate as my synaptopathic hearing loss is recent and I have no hair cell dysfunction.

I will give an update in this thread if I do. My hearing loss is a bigger problem than tinnitus. I will consult with a few doctors and show them this paper. The problem is not getting the drug, it's weighing the pros and cons.

 

[Mentos]

I am thinking of trying IV Zoledronate as my synaptopathic hearing loss is recent and I have no hair cell dysfunction.

I will give an update in this thread if I do. My hearing loss is a bigger problem than tinnitus. I will consult with a few doctors and show them this paper. The problem is not getting the drug, it's weighing the pros and cons.

How did you confirm you have no hair cell dysfunction? I don't believe there is a 100% reliable diagnostic method to determine that.

 

[Tau]

How did you confirm you have no hair cell dysfunction? I don't believe there is a 100% reliable diagnostic method to determine that.

That's actually a good question. I guess it's more of a tentative conclusion based on the fact that I have perfect audiograms (and I confirmed that myself at home with all the in-between frequencies) and that my ABR and otoacoustic emissions tests are fine.

I guess some of my IHCs could be dysfunctional or even completely dead. But seeing as synaptopathy happens first, I think trying to regrow the synapses is worth a shot.

 

[Mentos]

That's actually a good question. I guess it's more of a tentative conclusion based on the fact that I have perfect audiograms (and I confirmed that myself at home with all the in-between frequencies) and that my ABR and otoacoustic emissions tests are fine.

I guess some of my IHCs could be dysfunctional or even completely dead. But seeing as synaptopathy happens first, I think trying to regrow the synapses is worth a shot.

Otoacoustic emission can confirm damage to hair cells, it cannot exclude it. In other words you may have ok otoacoustic emission results and still have damaged hair cells in the frequencies which are not measured (usually they sample 8 frequencies only).

 

[Ali.sy]

Can I buy Bisphosphonate medicine somewhere to try it?

 

[Ali.sy]

Effects of Bisphosphonates on OI-Related Hearing Loss

 

[Justin Mills]

"The repurposing of bisphosphonates shows promise in animal models for treating hidden hearing loss. At the present time, these drugs are not fit for hearing treatment because they have not yet been validated in human studies. For the purposes of treating metabolic bone disease—osteoporosis, etc.—they have demonstrated success. However, they are associated with some significant side effects and are absolutely contraindicated in pregnancy (they are known to cause birth defects). In time and with proper vetting, these techniques may ultimately be valuable treatments for a very common type of hearing loss."​

Source:
Why Can't I Understand Speech in a Noisy Environment?

According to the above quote from an ENT there's a question of whether it's worth the risk. There are probably people on this forum who know more about how effective something like this could be. Is it perhaps better to wait to see if there's an advancement with Pipeline Therapeutics' drug and Otonomy's OTO-413? Kind of biting the bullet. We wouldn't know how to use this drug, like what dose and how long and stuff like that. Although on the other hand, there's no doubt the study shows very promising results for something that can be applied systemically rather then locally injected:

Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

 

[paul mclean]

Can I buy Bisphosphonate medicine somewhere to try it?

Yes you can. I am going to try Zoledronic acid soon. Going to do 0.5 mg IV infusion. i believe it'll work for my cochlear synaptopathy. Worth a shot. There is no need to use the full dose in my opinion (4 mg or 5 mg) as those are intended for osteoporosis. The reason why systemic administration works of Zoledronic acid is because it is the most potent Bisphosphonate (5000 to 1) and it has a high affinity for bone. The region of the cochlear is obviously surrounded by a lot of bone. It is also long lasting, its effects can last anywhere from 12-24 months and sometimes even longer.

I've had my synaptopathy since October 2018 after falling asleep with headphones on for 13 hours on loud. So it's been a little bit of time but there is evidence suggesting SGNs stay intact for multiple years. I'll report back with my results. If I can regenerate at least some synapses I'll be happy. I'm doing the lowest dose possible just to try decrease any adverse reactions.

 

[GregCA]

Yes you can. I am going to try Zoledronic acid soon. Going to do 0.5 mg IV infusion. i believe it'll work for my cochlear synaptopathy. Worth a shot. There is no need to use the full dose in my opinion (4 mg or 5 mg) as those are intended for osteoporosis. The reason why systemic administration works of Zoledronic acid is because it is the most potent Bisphosphonate (5000 to 1) and it has a high affinity for bone. The region of the cochlear is obviously surrounded by a lot of bone. It is also long lasting, its effects can last anywhere from 12-24 months and sometimes even longer.

I've had my synaptopathy since October 2018 after falling asleep with headphones on for 13 hours on loud. So it's been a little bit of time but there is evidence suggesting SGNs stay intact for multiple years. I'll report back with my results. If I can regenerate at least some synapses I'll be happy. I'm doing the lowest dose possible just to try decrease any adverse reactions.

Let us know how it goes. Bisphosphonates have been looked into as a treatment for otosclerosis. There are a few studies available for your perusal on PubMed. They discuss potential risks too.

 

[paul mclean]

Let us know how it goes. Bisphosphonates have been looked into as a treatment for otosclerosis. There are a few studies available for your perusal on PubMed. They discuss potential risks too.

Will report back here soon, it has almost arrived at my place.

I've read the study you're referring to
.
Here is another study using Bisphosphonates (Risedronate) and a TRKB agonist (7,8,DHF).

They use Risedronate as a delivery method to get the TRKB agonist to the cochlear which increases NT3 and BDNF to repair the synapses. Pretty cool stuff.

I went with Zoledronic acid though due to its 100% bioavailability due to the IV and not oral. Risedronate's bioavailability is poor and can cause real bad stomach and esophagus issues. I already have bad acid reflux so this was a no go for me.

Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss

The main things I've taken from the research I've done is that they do reach the cochlear and repair synapses (in mice) but they are pretty serious drugs with potential for awful side effects.

I actually have some 7,8-DHF too as I am into my nootropics so I'll be taking a large dose of that along with my Zoledronic acid IV.

I'd say I'll be doing this within 2-4 weeks. Just waiting for a little break from work. Zoledronic acid has an acute phrase reaction period which lasts around 3 days (APR) where people get flu like symptoms and bad body pain, bone aches and diarrhoea.
Now this is at the full doses (4 or 5 mg) and I'll be doing 0.5 mg . So pretty much 1/10 of the dose for osteoporosis. So I think it'll minimize the chances for the unwanted adverse reactions but safe to just take a couple days off and rest anyway.

I'm getting excited but a little nervous too.

 

[Hottopic29]

I read before that osteoporosis affects the little bones in the ear. Will Bisphosphonate only help people who got tinnitus from osteoporosis?

 

[paul mclean]

It depends. If your tinnitus is from cochlear synaptopathy and the Bisphosphonates regenerate the IHC afferent synapses then it'll affect your tinnitus whether you have osteoporosis or not.

Also my Zoledronic acid arrived today. The preparation begins, I'll need a period of 3-4 days off work so I'll figure that out in the next 4 weeks and report back.

 

[Ela Stefan]

my Zoledronic acid arrived today. The preparation begins, I'll need a period of 3-4 days off work so I'll figure that out in the next 4 weeks and report back.

How can you get that drug? How could you convince a doctor to prescribe the treatment to you since it is not a conventional one?

 

[paul mclean]

How can you get that drug? How could you convince a doctor to prescribe the treatment to you since it is not a conventional one?

It's actually very easy.

AllDayChemist or IndiaMART. No prescription required.

 

[Ela Stefan]

Any news about your treatment please, @paul mclean?

 

[AnonymousPie]

It's actually very easy.

AllDayChemist or IndiaMART. No prescription required.

Keep us updated, I hope it works! Would it also be effective for IHC and OHC damage?

 

[paul mclean]

Any news about your treatment please, @paul mclean?

I've been real busy recently but I've pivoted slightly in my approach.

I have the Zoledronate ready to go but I've actually found a biotech company that can custom synthesise Risedronate-7,8,DHF conjugate for me which I can take in a pill/capsule form.

I'd much rather take a pill that works than the intravenous injection. Risedronate also has significantly less side effects than Zoledronate. Zoledronate stays in your bones for up to 10 years. Risedronate for 6-12 months.

Here is the study of the Risedronate-7,8,DHF conjugate. The Risedronate is pretty much a delivery system for the DHF to get to the cochlear and repair the synapses:

Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss

So the plan is to order the Risedronate-7,8,DHF conjugate and try that first. If that fails/doesn't work, then I will resort to the Zoledronate. The whole process may take me another month or two but I'll definitely post updates.

Keep us updated, I hope it works! Would it also be effective for IHC and OHC damage?

Someone can correct me if I'm wrong but I'm fairly certain cochlear synaptopathy is only damage to the synapses of the inner hair cells.

So I'm uncertain what effects the bisphosphonates would have on outer hair cells.

Read through this study if you have the time, you may find some more information:

Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

 

[NikoD]

@paul mclean, do you have any update on your progress with Zolendronate?

 

[NikoD]

I recently started taking Risedronate 35 mg weekly. It's been around 8 weeks since I began.

I believe it has helped calm my tinnitus somewhat. It has not gone entirely but I no longer get periods where the tinnitus is extremely loud, it's much more stable. I go over and explain some of my reasoning below. It has done nothing to improve my hearing.

I have otosclerosis and recently noticed a massive drop in hearing, and subsequently was diagnosed with cochlear otosclerosis. This means I have a degree of sensorineural hearing loss caused by otosclerosis. It's not completely understood why this happen but the short of some of the theories is the bone remodelling releases toxic compounds into the cochlear fluid and bone damaging various neural components. This drug works by inhibiting the remodelling processes namely osteoclasts, which is why it's popular for patients with osteoporsis.

The idea to take Risedronate was not to improve my hearing or tinnitus, but only to try and preserve the gradual hearing loss. I don't believe that has worked, but I did notice a side effect and that was the stabilization of tinnitus which has happened in the past 3-4 weeks and was not immediate.

Additionally I used to get very strange types of tinnitus after exercising followed with muffled hearing loss 7-8 days after, only to return to normal after a few weeks if I stopped exercising entirely. If there's one thing I refuse otosclerosis to take from me is my overall fitness. I have accepted I will one day be deaf. Since starting Risedronate, I have done high intensity workouts and have noticed little effect to my tinnitus. However, I will continue to monitor as it is early days.

How long will I continue? The side effects for this drug are pretty worrisome, risk increases the longer I take it. I am also self-prescribing it with no oversight with a doctor. I would like to continue, however, I need to have a follow up at some point with my GP.

It's very important to note when taking this drug to follow instructions to maximize bioavailability, pharmacology of this drug is clearly outlined. The last thing you want is to take the drug and for it not to be properly absorbed.

 

[Nick47]

I recently started taking Risedronate 35 mg weekly. It's been around 8 weeks since I began.

I believe it has helped calm my tinnitus somewhat. It has not gone entirely but I no longer get periods where the tinnitus is extremely loud, it's much more stable. I go over and explain some of my reasoning below. It has done nothing to improve my hearing.

I have otosclerosis and recently noticed a massive drop in hearing, and subsequently was diagnosed with cochlear otosclerosis. This means I have a degree of sensorineural hearing loss caused by otosclerosis. It's not completely understood why this happen but the short of some of the theories is the bone remodelling releases toxic compounds into the cochlear fluid and bone damaging various neural components. This drug works by inhibiting the remodelling processes namely osteoclasts, which is why it's popular for patients with osteoporsis.

The idea to take Risedronate was not to improve my hearing or tinnitus, but only to try and preserve the gradual hearing loss. I don't believe that has worked, but I did notice a side effect and that was the stabilization of tinnitus which has happened in the past 3-4 weeks and was not immediate.

Additionally I used to get very strange types of tinnitus after exercising followed with muffled hearing loss 7-8 days after, only to return to normal after a few weeks if I stopped exercising entirely. If there's one thing I refuse otosclerosis to take from me is my overall fitness. I have accepted I will one day be deaf. Since starting Risedronate, I have done high intensity workouts and have noticed little effect to my tinnitus. However, I will continue to monitor as it is early days.

How long will I continue? The side effects for this drug are pretty worrisome, risk increases the longer I take it. I am also self-prescribing it with no oversight with a doctor. I would like to continue, however, I need to have a follow up at some point with my GP.

It's very important to note when taking this drug to follow instructions to maximize bioavailability, pharmacology of this drug is clearly outlined. The last thing you want is to take the drug and for it not to be properly absorbed.

How were you diagnosed with otosclerosis?

Also, this:

Meanwhile, in addition to acetylcholine, existing pharmacologic treatments used to address decreased ST (sound tolerance) include bisphosphonate risedronate, fluvoxamine, fluoxetine, gabapentin, clonazepam, and carbamazepine.

Exploring the origins of decreased sound tolerance in tinnitus patients

 

[GregCA]

I recently started taking Risedronate 35 mg weekly. It's been around 8 weeks since I began.

I believe it has helped calm my tinnitus somewhat. It has not gone entirely but I no longer get periods where the tinnitus is extremely loud, it's much more stable. I go over and explain some of my reasoning below. It has done nothing to improve my hearing.

I have otosclerosis and recently noticed a massive drop in hearing, and subsequently was diagnosed with cochlear otosclerosis. This means I have a degree of sensorineural hearing loss caused by otosclerosis. It's not completely understood why this happen but the short of some of the theories is the bone remodelling releases toxic compounds into the cochlear fluid and bone damaging various neural components. This drug works by inhibiting the remodelling processes namely osteoclasts, which is why it's popular for patients with osteoporsis.

The idea to take Risedronate was not to improve my hearing or tinnitus, but only to try and preserve the gradual hearing loss. I don't believe that has worked, but I did notice a side effect and that was the stabilization of tinnitus which has happened in the past 3-4 weeks and was not immediate.

Additionally I used to get very strange types of tinnitus after exercising followed with muffled hearing loss 7-8 days after, only to return to normal after a few weeks if I stopped exercising entirely. If there's one thing I refuse otosclerosis to take from me is my overall fitness. I have accepted I will one day be deaf. Since starting Risedronate, I have done high intensity workouts and have noticed little effect to my tinnitus. However, I will continue to monitor as it is early days.

How long will I continue? The side effects for this drug are pretty worrisome, risk increases the longer I take it. I am also self-prescribing it with no oversight with a doctor. I would like to continue, however, I need to have a follow up at some point with my GP.

It's very important to note when taking this drug to follow instructions to maximize bioavailability, pharmacology of this drug is clearly outlined. The last thing you want is to take the drug and for it not to be properly absorbed.

I'm in a similar predicament (cochlear otosclerosis) and have both conductive and sensorineural losses. My hearing was degrading very fast (from no symptoms to a 55 dB air-bone gap in 8 weeks) until I went through surgery (stapedotomy). After that, my hearing (and tinnitus) stabilized. I can't tell if it's the surgery or the Fluoride (which I've been taking since the surgery) or something else (vitamin D - which I was deficient in) that's keeping things as stable as they are, but it's something to think about that may be relevant to you.

Good luck, and take care!

 

[NikoD]

How were you diagnosed with otosclerosis?

Also, this:

Exploring the origins of decreased sound tolerance in tinnitus patients

Thanks for the article. It seems interesting.

I was diagnosed in early 2010 and had a Stapedectomy in 2014. I've had frequent follow-ups since I noticed a big change in hearing. In hindsight I didn't have enough follow-ups before, which may have helped spot the issue earlier.

It was really tough accepting that one day I will be deaf. The hardest thing is noticing my hearing diminish in areas I was once able to pick up slowly as the days go. Sometimes in a span of a few weeks. It's very distracting and I built a very successful & well paid career which I am considering I may have to leave and start something which does not fully rely on hearing. Demotivating is an understatement and I have my dark days.

I'm in a similar predicament (cochlear otosclerosis) and have both conductive and sensorineural losses. My hearing was degrading very fast (from no symptoms to a 55 dB air-bone gap in 8 weeks) until I went through surgery (stapedotomy). After that, my hearing (and tinnitus) stabilized. I can't tell if it's the surgery or the Fluoride (which I've been taking since the surgery) or something else (vitamin D - which I was deficient in) that's keeping things as stable as they are, but it's something to think about that may be relevant to you.

Thanks. Just out of curiosity, have you had any issues with tinnitus after high intensity exercise? And was your drop in hearing associated with any lifestyle changes that happened beforehand?

 

[GregCA]

Thanks. Just out of curiosity, have you had any issues with tinnitus after high intensity exercise?

No. My tinnitus is extremely consistent: always very loud, without any fluctuations, no matter what I do.

And was your drop in hearing associated with any lifestyle changes that happened beforehand?

Not that I can pinpoint, no.

 

[dd314]

@Tau, did this work for you?