Re: Gleevec may be useful as an antiosteolytic agent -

[Guest guest]

Hi Tracey,

Osteoclasts (osteo=bone, clast=break, as in iconoclasts) are bone dissolving

cells, while osteoblasts (blast=grow) build new bone. What they're saying

is that at a concentration of 0.3µM (3 micromoles per cc of serum) or

higher, IM blocks the action of the osteoclasts and so may protect against

bone loss. At still higher concentrations, IM blocks the formation of

osteoclasts themselves, but it's not clear to me from the abstract what

clinical relevance this might have.

What I don't know - and couldn't find in the prescribing info for the drug -

is whether 400-800mg/day achieves a concentration of 0.3µM. Do any of you

on the list know? If not, I imagine I can look it up somewhere - but it's

annoying that Novartis doesn't publish this.

I've copied the abstract below Tracey's post.

Cheers,

R

PS - glossary:

antiosteolytic: anti + osteo (bone) + lytic (lysis means something like

" clastic " - it has to do with breakdown. So antiosteolytic means it stops

bone breakdown.

antiresorptive: a shortened version of anti-reabsorptive - meaning, it stops

reabsorption of bone.

> Quite some time ago I posted an abstract that showed how Gleevec

> inhibited c-fms but at the time, this implication wasn't well

> understood.

>

> In the past we've seen concerns that Gleevec may negatively impact

> bone development especially in those who tend to be low on phosphorus

> but this article seems to indicate that Gleevec can be useful to

> treat various bone diseases such as osteoporosis, metastatic bone

> disease, and multiple myeloma because of the fact that it inhibits

> this enzyme called c-fms.

>

> I hope will be able to " translate " this article for us so

> that we can understand it better.

Imatinib as a potential antiresorptive therapy for bone disease

L. Dewar, N. Farrugia, Mark R. Condina, L. Bik To, P.

, Barrie Vernon-, and C. W. Zannettino

From the Myeloma and Mesenchymal Research Laboratory, the Division of

Haematology, Level 2 Hanson Institute, and the Adelaide Centre for Spinal

Research, Institute of Medical and Veterinary Science (IMVS), Adelaide,

South Australia, Australia.

Osteoclasts (OCs) are large multinucleated cells derived from progenitor

cells of the monocyte-macrophage lineage. Signal transduction via the

macrophage­colony-stimulating factor (M-CSF) receptor, c-fms, is essential

for OC formation. Since we have previously demonstrated inhibition of c-fms

by imatinib, we examined the effect of imatinib on OC formation and

activity. OC formation was not affected by concentrations of 1.0 µM imatinib

and lower, but was reduced by 75% at 3.0 µM imatinib. In contrast, both the

area of resorption and the number of resorption lacunae were reduced by 80%

at 0.3 µM imatinib, and no resorption was observed at concentrations above

3.0 µM. A dose-dependent decrease in receptor activator of nuclear factor B

(RANK) expression was observed in OCs when cultured in the presence of

imatinib, providing a mechanism for the decrease in OC function. In vivo

analysis of the effect of imatinib on OC activity in adult mice following 8

weeks of imatinib treatment also demonstrated a decrease in OC activity.

These results suggest that imatinib may have therapeutic value as an

antiosteolytic agent in diseases such as osteoporosis, metastatic bone

disease, and multiple myeloma.

[Guest guest]

Thanks for that explanation . I'm trying to understand how

this fits in with the finding that Gleevec can decrease levels of

osteocalcin

(http://professional.cancerconsultants.com/oncology_leukemia_news.aspx

?id=36932).

So if Gleevec can interfere with osteoclast formation and it can also

decrease levels of osteocalcin, how does this play out when put

together? Is this not contradictory?

For me personally, I had a bone density test done when the news first

came out that Gleevec can interfere with bone metabolism and it

showed that I am at the early stages of osteopenia. At my age (36)

some would think that it's a bit early to have osteopenia but then

when I think of the fact that I've never drank milk or eaten a large

variety of calcium rich foods, it really isn't all the surprising to

me. I'm now wondering how (or if), Gleevec will have any effect on

my bones as this research seems contradictory but then again maybe

I'm just not understanding it properly.

Thanks for your help ,

Tracey

PS-- in spite of my " weak " bones, I have never broken any, so I guess

they can't be too weak after all

>

> Hi Tracey,

>

> Osteoclasts (osteo=bone, clast=break, as in iconoclasts) are bone

dissolving

> cells, while osteoblasts (blast=grow) build new bone. What they're

saying

> is that at a concentration of 0.3µM (3 micromoles per cc of serum)

or

> higher, IM blocks the action of the osteoclasts and so may protect

against

> bone loss. At still higher concentrations, IM blocks the formation

of

> osteoclasts themselves, but it's not clear to me from the abstract

what

> clinical relevance this might have.

>

> What I don't know - and couldn't find in the prescribing info for

the drug -

> is whether 400-800mg/day achieves a concentration of 0.3µM. Do any

of you

> on the list know? If not, I imagine I can look it up somewhere -

but it's

> annoying that Novartis doesn't publish this.

>

> I've copied the abstract below Tracey's post.

>

> Cheers,

>

> R

>

> PS - glossary:

> antiosteolytic: anti + osteo (bone) + lytic (lysis means something

like

> " clastic " - it has to do with breakdown. So antiosteolytic means it

stops

> bone breakdown.

> antiresorptive: a shortened version of anti-reabsorptive - meaning,

it stops

> reabsorption of bone.

>

> > Quite some time ago I posted an abstract that showed how Gleevec

> > inhibited c-fms but at the time, this implication wasn't well

> > understood.

> >

> > In the past we've seen concerns that Gleevec may negatively impact

> > bone development especially in those who tend to be low on

phosphorus

> > but this article seems to indicate that Gleevec can be useful to

> > treat various bone diseases such as osteoporosis, metastatic bone

> > disease, and multiple myeloma because of the fact that it inhibits

> > this enzyme called c-fms.

> >

> > I hope will be able to " translate " this article for us so

> > that we can understand it better.

>

> Imatinib as a potential antiresorptive therapy for bone disease

>

> L. Dewar, N. Farrugia, Mark R. Condina, L. Bik To,

P.

> , Barrie Vernon-, and C. W. Zannettino

> From the Myeloma and Mesenchymal Research Laboratory, the Division

of

> Haematology, Level 2 Hanson Institute, and the Adelaide Centre for

Spinal

> Research, Institute of Medical and Veterinary Science (IMVS),

Adelaide,

> South Australia, Australia.

>

> Osteoclasts (OCs) are large multinucleated cells derived from

progenitor

> cells of the monocyte-macrophage lineage. Signal transduction via

the

> macrophage­colony-stimulating factor (M-CSF) receptor, c-fms, is

essential

> for OC formation. Since we have previously demonstrated inhibition

of c-fms

> by imatinib, we examined the effect of imatinib on OC formation and

> activity. OC formation was not affected by concentrations of 1.0 µM

imatinib

> and lower, but was reduced by 75% at 3.0 µM imatinib. In contrast,

both the

> area of resorption and the number of resorption lacunae were

reduced by 80%

> at 0.3 µM imatinib, and no resorption was observed at

concentrations above

> 3.0 µM. A dose-dependent decrease in receptor activator of nuclear

factor B

> (RANK) expression was observed in OCs when cultured in the presence

of

> imatinib, providing a mechanism for the decrease in OC function. In

vivo

> analysis of the effect of imatinib on OC activity in adult mice

following 8

> weeks of imatinib treatment also demonstrated a decrease in OC

activity.

> These results suggest that imatinib may have therapeutic value as an

> antiosteolytic agent in diseases such as osteoporosis, metastatic

bone

> disease, and multiple myeloma.

>

[Guest guest]

The average blood concentration that can be achieved when taking 400 mg

of Gleevec is about 1.5 uM.

This article seems to have only studied osteoclast activity. Yes that

could be a great way to lessen osteoporosis but keep in mind that bone

remodeling involves both resorption (osteolclast function) and

deposition (osteoblast function).

A previous study from Berman et al (NEJM) suggested that people taking

Gleevec had significant drop off in both osteoclast as well as

osteoblast function. Therefore, someone with osteoporosis taking

Gleevec would not necessarily see an improvement in bone density. It

could perhaps halt further progression.

It is certainly worth studying.

[Guest guest]

Hello All,

It's been a while since I posted because I have absolutely so much drama

going on in my life, for which I could be grateful for, but am not. since

many of us know it is so important to remember that life is short and we

shouldn't waste it on such things!

But somehow I can't seem to escape it.

And. that's not really what I want to post about. That's just my valid

excuse for being able to read but not post like I use to.

After reviewing this topic a thought came to my mind. Could it be relevant?

Maybe not. but maybe.

Each time I have my BMB done (scheduled to have another the end of this

month) My Oncologist, who is really good at performing the procedure keeps

saying with a very confused tone " your bones are just getting stronger

and stronger " Its getting more difficult to do each time.

That wasn't the case when I was on interferon- It was more difficult to do

because the marrow was softer I believe.

Some of you who were on Interferon prior to Gleevec may remember that some

of us had that problem and I don't recall seeing anyone mention that problem

recently.

Osteoporosis is something my mother has and so did my grandmother. I admit I

have put a lot of emphasis on physical exercise and hopefully that has

helped my bones to be stronger. I also love hearing that at 41 my bones feel

like that of an 18 year old.

But it was only several years ago that all the symptoms of arthritis that my

mother had were affecting me too.

Is it possible that Gleevec is responsible for slowing this down and or

making our bones stronger?

I also know that I am the only one without cholesterol problems in my

family. I would like to contribute this to Gleevec as well.

I just couldn't help but share that thought with all of you. It sounds very

positive!

Take care everyone!

ez

Dx 5-2000

[Guest guest]

Hi ,

It's good to hear from you. I can't answer your question about

Gleevec's effect on our bones (hopefully or will

chime in on that one) but I can say that Gleevec has shown to reduce

cholesterol in some patients

(http://www.ohsu.edu/news/2003/041003druker.html).

I saw a dramatic improvement in my cholesterol after I started taking

it. It went from " above average risk for heart disease " to " below

average risk for heart disease " and my eating habits actually got

worse after I started taking it so I certainly can't credit my diet

for the improvement.

Take care,

Tracey

-- In , " ez " <lmartinez@...> wrote:

>

> Hello All,

>

> It's been a while since I posted because I have absolutely so much

drama

> going on in my life, for which I could be grateful for, but am not.

since

> many of us know it is so important to remember that life is short

and we

> shouldn't waste it on such things!

>

> But somehow I can't seem to escape it.

>

> And. that's not really what I want to post about. That's just my

valid

> excuse for being able to read but not post like I use to.

>

> After reviewing this topic a thought came to my mind. Could it be

relevant?

> Maybe not. but maybe.

>

> Each time I have my BMB done (scheduled to have another the end of

this

> month) My Oncologist, who is really good at performing the

procedure keeps

> saying with a very confused tone " your bones are just getting

stronger

> and stronger " Its getting more difficult to do each time.

>

> That wasn't the case when I was on interferon- It was more

difficult to do

> because the marrow was softer I believe.

>

> Some of you who were on Interferon prior to Gleevec may remember

that some

> of us had that problem and I don't recall seeing anyone mention

that problem

> recently.

>

> Osteoporosis is something my mother has and so did my grandmother.

I admit I

> have put a lot of emphasis on physical exercise and hopefully that

has

> helped my bones to be stronger. I also love hearing that at 41 my

bones feel

> like that of an 18 year old.

>

> But it was only several years ago that all the symptoms of

arthritis that my

> mother had were affecting me too.

>

> Is it possible that Gleevec is responsible for slowing this down

and or

> making our bones stronger?

>

> I also know that I am the only one without cholesterol problems in

my

> family. I would like to contribute this to Gleevec as well.

>

> I just couldn't help but share that thought with all of you. It

sounds very

> positive!

>

> Take care everyone!

>

>

>

>

>

>

>

>

>

> ez

>

> Dx 5-2000

>

>

>

>

[Guest guest]

Hi ,

Thanks so much for your input on this issue. I hope you'll be able

to elaborate a bit more, if you can, on what your thoughts are

regarding Gleevec's inpact on bone health.

Tracey

>

> The average blood concentration that can be achieved when taking

400 mg

> of Gleevec is about 1.5 uM.

>

> This article seems to have only studied osteoclast activity. Yes

that

> could be a great way to lessen osteoporosis but keep in mind that

bone

> remodeling involves both resorption (osteolclast function) and

> deposition (osteoblast function).

>

> A previous study from Berman et al (NEJM) suggested that people

taking

> Gleevec had significant drop off in both osteoclast as well as

> osteoblast function. Therefore, someone with osteoporosis taking

> Gleevec would not necessarily see an improvement in bone density.

It

> could perhaps halt further progression.

>

> It is certainly worth studying.

>

[Guest guest]

Hi Tracey,

IM does appear to have contradictory effects on bone metabolism, but this is

not unusual. For example aspirin inhibits two enzyme systems with opposite

effects on blood clotting. In practice aspirin acts as a blood thinner

because its clot inhibiting effect is stronger than its clot promoting

effect, but its opposing actions explain the paradoxical finding that

aspirin thins blood better at low than at high doses: its inhibition of

clotting maxes out at low doses, whereas its inhibition of the clot reducing

enzyme continues to increase as you increase the dose. That's why low dose

aspirin is recommended to prevent strokes and heart attack. A baby aspirin

every other day works best! I bet this is more than you wanted to know, but

thought you'd find it interesting.

Anyway, the net effect of IM is likely to vary patient to patient, depending

on the degree to which opposing bone metabolism pathways are affected (it's

even more complicated because phosphate metabolism is involved, but I won't

go into that. I couldn't, anyway, because I don't remember that part of

bone physiology too well!). It's also quite possible that IM's contradictory

effects cancel one another out such that it doesn't affect most patients'

bone densities much at all. I doubt whether this is known, but it would be

easy to research and probably fundable by Novartis, so I bet we'll be

hearing more.

I have mild osteopenia too, but it began before I had CML so I don't

attribute it to taking IM. I take calcium and Vitamin D to prevent the

osteopenia from getting worse, and it hasn't in the 5 years since I started.

Now it turns out that vitamin D may also prevent the common cold (see

http://www.sciencedaily.com/releases/2005/06/050628064753.htm), and as I

really hate colds I'm even more motivated to stay on it!

Best,

R

> Thu Feb 1, 2007 10:51 am (PST)

>

> Thanks for that explanation . I'm trying to understand how this fits

> in with the finding that Gleevec can decrease levels of osteocalcin

> (http://professional.cancerconsultants.com/oncology_leukemia_news.aspx

> ?id=36932).

>

> So if Gleevec can interfere with osteoclast formation and it can also decrease

> levels of osteocalcin, how does this play out when put together? Is this not

> contradictory?

>

> For me personally, I had a bone density test done when the news first came out

> that Gleevec can interfere with bone metabolism and it showed that I am at the

> early stages of osteopenia. At my age (36) some would think that it's a bit

> early to have osteopenia but then when I think of the fact that I've never

> drank milk or eaten a large variety of calcium rich foods, it really isn't all

> the surprising to me. I'm now wondering how (or if), Gleevec will have any

> effect on my bones as this research seems contradictory but then again maybe

> I'm just not understanding it properly.

>

> Thanks for your help ,

> Tracey

[Guest guest]

At 02:24 PM 2/2/07 -0500, you wrote:

>Each time I have my BMB done (scheduled to have another the end of this

>month) My Oncologist, who is really good at performing the procedure keeps

>saying with a very confused tone " your bones are just getting stronger

>and stronger " Its getting more difficult to do each time.

Hi ,

Nice to see you on the list again. Here is my take on the hard bones issue.

For the BMB, they are really aiming at a small place on the pelvic, called

the anterior superior iliac spine. You only have 2 of these, right and

left. When they bore a hole for the BMB, the body then heals the area like

it would a fracture....which means it lays down more bone in that

area......and that can make it harder. When a fracture heals, you think of

that area as being 'even stronger' than normal bone. So, I don't think this

is unusual at all for this area to get harder after many BMBs.

And also, just because the bmb site is hard.....that does not mean that

your bones are hard all over. I would watch for other signs or do other

tests to determine bone density.

I did not read yet all the other posts on bone health and Gleevec, and

maybe something will contradict this 'thought'. It was Dr. Mauro at OHSU

who told me that the BMB site healed just like a fx heals.

C.

[Guest guest]

Hi ,

Thanks for sharing your insights. I had no idea that was the reason

they recommended low dose Aspirin as opposed to the regular dose. I

just assumed that the lower dose did the job so there was no need for

an increase in dose (like why take 800mg of Gleevec if 400mg will do

the same job). I found your explanation for the Aspirin dose

fascinating.

I look forward to learning more about Gleevec's effect on bone

metabolism but for the mean time, I'm inclined to think that it will

have little to no effect. After 5 years of taking it, I haven't

broken anything and somehow, I just don't think there's been any

difference in my bones in those 5 years. I guess time will tell for

sure.

The link you provided about vit D possibly being able to prevent the

common cold, brought me to an article about vit C and how it's effect

on the common cold was negligible. Was I supposed to click somewhere

else?

Take care,

Tracey

>

> Hi Tracey,

>

> IM does appear to have contradictory effects on bone metabolism,

but this is

> not unusual. For example aspirin inhibits two enzyme systems with

opposite

> effects on blood clotting. In practice aspirin acts as a blood

thinner

> because its clot inhibiting effect is stronger than its clot

promoting

> effect, but its opposing actions explain the paradoxical finding

that

> aspirin thins blood better at low than at high doses: its

inhibition of

> clotting maxes out at low doses, whereas its inhibition of the clot

reducing

> enzyme continues to increase as you increase the dose. That's why

low dose

> aspirin is recommended to prevent strokes and heart attack. A baby

aspirin

> every other day works best! I bet this is more than you wanted to

know, but

> thought you'd find it interesting.

>

> Anyway, the net effect of IM is likely to vary patient to patient,

depending

> on the degree to which opposing bone metabolism pathways are

affected (it's

> even more complicated because phosphate metabolism is involved, but

I won't

> go into that. I couldn't, anyway, because I don't remember that

part of

> bone physiology too well!). It's also quite possible that IM's

contradictory

> effects cancel one another out such that it doesn't affect most

patients'

> bone densities much at all. I doubt whether this is known, but it

would be

> easy to research and probably fundable by Novartis, so I bet we'll

be

> hearing more.

>

> I have mild osteopenia too, but it began before I had CML so I don't

> attribute it to taking IM. I take calcium and Vitamin D to prevent

the

> osteopenia from getting worse, and it hasn't in the 5 years since I

started.

> Now it turns out that vitamin D may also prevent the common cold

(see

> http://www.sciencedaily.com/releases/2005/06/050628064753.htm), and

as I

> really hate colds I'm even more motivated to stay on it!

>

> Best,

> R

>

> > Thu Feb 1, 2007 10:51 am (PST)

> >

> > Thanks for that explanation . I'm trying to understand

how this fits

> > in with the finding that Gleevec can decrease levels of

osteocalcin

> >

(http://professional.cancerconsultants.com/oncology_leukemia_news.aspx

> > ?id=36932).

> >

> > So if Gleevec can interfere with osteoclast formation and it can

also decrease

> > levels of osteocalcin, how does this play out when put together?

Is this not

> > contradictory?

> >

> > For me personally, I had a bone density test done when the news

first came out

> > that Gleevec can interfere with bone metabolism and it showed

that I am at the

> > early stages of osteopenia. At my age (36) some would think that

it's a bit

> > early to have osteopenia but then when I think of the fact that

I've never

> > drank milk or eaten a large variety of calcium rich foods, it

really isn't all

> > the surprising to me. I'm now wondering how (or if), Gleevec

will have any

> > effect on my bones as this research seems contradictory but then

again maybe

> > I'm just not understanding it properly.

> >

> > Thanks for your help ,

> > Tracey

>