PTH and Bone?

[ulikedaggers]

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FA14 says "PTH at low, intermittent levels, exerts anabolic effects on osteoblasts and osteoclasts."

I thought PTH at low, intermittent levels, stimulated bone resorption?

 

[acciddropping]

PTH stimulates RANK-L and inhibits OPG in osteoblasts (OPG otherwise inhibits RANK-L) and RANK receptors on osteoclast. So, increased PTH will cause bone resorption since you're stimulating RANK-L expression, that then signals to Osteoclast to carry out bone resorption.

 

[oingoboingo]

But at low intermittent doses the opposite happens and PTH stimulates osteoblasts more than osteoclasts. This is the MOA of teriparatide.

 

[ulikedaggers]

PTH stimulates RANK-L and inhibits OPG in osteoblasts (OPG otherwise inhibits RANK-L) and RANK receptors on osteoclast. So, increased PTH will cause bone resorption since you're stimulating RANK-L expression, that then signals to Osteoclast to carry out bone resorption.

Right, but this makes FA wrong, which it isn't.. which is why I'm confused.

But at low intermittent doses the opposite happens and PTH stimulates osteoblasts more than osteoclasts. This is the MOA of teriparatide.

This is what I thought as well.. FA isn't wrong (this same sentence is in FA13 and FA11), so what am I missing?

 

[oingoboingo]

I don't think that aciddropping's statement makes FA wrong.
Low dose intermittent PTH - anabolic - bone formation
Crazy high PTH all the time - catabolic - bone resorption
Maybe I'm missing something?

 

[ulikedaggers]

I don't think that aciddropping's statement makes FA wrong.
Low dose intermittent PTH - anabolic - bone formation
Crazy high PTH all the time - catabolic - bone resorption
Maybe I'm missing something?

Normally one of PTH's functions is to maintain plasma [Ca++]. It accomplishes this by stimulating osteoblasts to release factors (like M-CSF), which ends up stimulating bone resorption by osteoclasts. That alone seems to contradict that PTH at low dose results in bone formation. That's where my confusion lies.

 

[ChessMaster3000]

Normally one of PTH's functions is to maintain plasma [Ca++]. It accomplishes this by stimulating osteoblasts to release factors (like M-CSF), which ends up stimulating bone resorption by osteoclasts. That alone seems to contradict that PTH at low dose results in bone formation. That's where my confusion lies.

It's all about pulstaile vs constant. Pulsatile (presumably at low dose) does have an anabolic effect. Not sure how it works, but it does.

 

[ulikedaggers]

It's all about pulstaile vs constant. Pulsatile (presumably at low dose) does have an anabolic effect. Not sure how it works, but it does.

So constant is when it has a bone resorbing effect?

 

[ChessMaster3000]

So constant is when it has a bone resorbing effect?

Yeah--on the test, with respect to bone promotion, it will either specify pulsatile OR, perhaps, simply say teriparatide (which I believe is dosed as "pulsatile" once a day). anything else would be resorbing.

 

[targ489]

With pulsatile secretion the osteoblasts can keep up with the catabolic turnover of bone, whereas at constant secretion they can't.

You're still getting turnover in both instances it's just with pulsatile you're blasts are able to compensate their loss, in essence osteoclasts take one step and the blasts take five more

 

[ulikedaggers]

Yeah--on the test, with respect to bone promotion, it will either specify pulsatile OR, perhaps, simply say teriparatide (which I believe is dosed as "pulsatile" once a day). anything else would be resorbing.

With pulsatile secretion the osteoblasts can keep up with the catabolic turnover of bone, whereas at constant secretion they can't.

You're still getting turnover in both instances it's just with pulsatile you're blasts are able to compensate their loss, in essence osteoclasts take one step and the blasts take five more

Ok thanks guys. I'm still not understanding the physiologic effect of PTH in terms of increasing serum calcium via increasing bone resorbtion. Is the physiologic effect of PTH due to constant secretion?

 

[targ489]

I think (not 100% sure, maybe someone else can verify) but at physiologic levels it's secreted pulsatile to account for minor changes in calcium, which is where vitamin d activation also comes into play. Pth also activates vitamin d, which plays in increasing more calcium.

It becomes pathological when secretion is occurring too often. Teriparatide therapy (pulsatile pth) is only used as a temporary therapy. I think the reason why it works is the time period between dosing. Essentially making it seem as though it's normal physiologic PTH secretion.

 

[ulikedaggers]

I think (not 100% sure, maybe someone else can verify) but at physiologic levels it's secreted pulsatile to account for minor changes in calcium, which is where vitamin d activation also comes into play. Pth also activates vitamin d, which plays in increasing more calcium.

It becomes pathological when secretion is occurring too often. Teriparatide therapy (pulsatile pth) is only used as a temporary therapy. I think the reason why it works is the time period between dosing. Essentially making it seem as though it's normal physiologic PTH secretion.

That makes sense. I hope you're right!

 

[targ489]

Me too, shame the human body isn't as easy as we would like it to be haha

 

[ulikedaggers]

Does PTH directly increase Ca2+ absorption in the DCT or is it only indirectly via 1a-hydroxylase -> Vit D?

 

[Transposony]

Does PTH directly increase Ca2+ absorption in the DCT or is it only indirectly via 1a-hydroxylase -> Vit D?

It does both - directly (by activating adenylate cyclase in DCT) and indirectly (by stimulating 1a-hydroxylase in PCT).