Osteopenia in mice related to suppressed TSH even after replacement therapy

[katyabat1]

The study below is very detailed and scholarly- it talks about the mechanism by which TSH helps to model bone. It's uncomfortable reading for me, as I have osteopenia after years (at least 20) of being TSH almost undetectable (around 0.01or 0.02).

You could say these are mice, we are people, but we share probably 97% DNA and we are mammals like them.

Here's an extract below:

Hyperthyroid-associated osteoporosis is exacerbated by the loss of TSH signaling

Ramkumarie Baliram,1 Li Sun,2 Jay Cao,3 Jianhua Li,2 Rauf Latif,1 Amanda K. Huber,1 Tony Yuen,2 Harry C. Blair,4 Mone Zaidi,2 and Terry F. Davies1

First published September 17, 2012 -

jci.org/articles/view/63948#sd

Brief Report Bone biology

Abstract

The osteoporosis associated with human hyperthyroidism has traditionally been attributed to elevated thyroid hormone levels. There is evidence, however, that thyroid-stimulating hormone (TSH), which is low in most hyperthyroid states, directly affects the skeleton. Importantly, Tshr-knockout mice are osteopenic. In order to determine whether low TSH levels contribute to bone loss in hyperthyroidism, we compared the skeletal phenotypes of wild-type and Tshr-knockout mice that were rendered hyperthyroid. We found that hyperthyroid mice lacking TSHR had greater bone loss and resorption than hyperthyroid wild-type mice, thereby demonstrating that the absence of TSH signaling contributes to bone loss. Further, we identified a TSH-like factor that may confer osteoprotection. These studies suggest that therapeutic suppression of TSH to very low levels may contribute to bone loss in people.

Introduction

Hyperthyroidism, a common health risk affecting approximately 1 in 100 individuals, is often accompanied by worsening osteoporosis, especially in postmenopausal women (1). There is compelling evidence from early in vitro and more recent mouse genetic studies that both thyroxine (T4) and triiodothyronine (T3) stimulate the resorption of bone by osteoclasts (2). This leaves no doubt that thyroid hormone excess is a major contributor to the profound bone loss and high risk of fracture in hyperthyroidism. Physiology tells us that high serum thyroid hormone suppresses the production of thyroid-stimulating hormone (TSH) from the anterior pituitary, although in subclinical hyperthyroidism, thyroid hormone levels can be normal, while TSH is low or undetectable. The osteoporosis associated with subclinical hyperthyroidism is therefore unlikely to arise from thyroid hormone excess alone (3).

We and others have shown that, in addition to its known function in stimulating thyroid follicular cells, TSH can act directly on the skeleton (4–8). Activation of the TSH receptor (TSHR) on the osteoclast prevents the resorption of bone (4). When administered intermittently, TSH stimulates osteoblastic bone formation and, in rodent models, rescues ovariectomy-induced bone loss (5–8). In contrast, absence of the TSHR in the global Tshr–/– mouse causes high-turnover osteoporosis (4). That this osteoporosis is not reversed upon thyroid hormone replacement suggests that absent TSH signaling may have a permissive role in causing this bone loss. Epidemiologic evidence favors strong correlations between low TSH and high bone turnover; low TSH and low bone mineral density (BMD); and low TSH and high fracture risk in hyperthyroid patients (9–23). This raises the question of whether low TSH levels might contribute to the bone loss in hyperthyroidism that has been attributed solely to high thyroid hormone levels.

... Likewise, euthyroid women with serum TSH levels in the lowest tertile of the normal range have a higher incidence of vertebral fractures, independent of thyroid hormone levels (19).

[...pictures as well of the bones and descriptions of how the cells are remodelled badly, even if the mice are given thyroid supplements...]

*****************************************************************************************

I am actively trying to assess the risk of Low TSH- like many of you, I want quality of life now, and for me that means suppressing my TSH, which never rises, however little T4 I take. I get very depressed when I lower my dose, stop being able to think, no energy, body can't cope with exercise, bloated, constipated, etc etc

I would like to know your reactions to the above study, and would appreciate if any of you can wade through it!

[humanbean]

I actually found the paper was beyond me. If anyone can understand it thoroughly I would be interested in a few things :

1) When the authors refer to hyperthyroidism are they talking only about test subjects (in this case mice) who are or were truly hyperthyroid (TSH below reference range and Free T4 and Free T3 above range before treatment began), or are they including test subjects with hypothyroidism who, in the opinion of the authors, are over-medicated because their TSH is below range?

2) Are they taking account of Free T3 and Free T4 when declaring a test subject to be hyperthyroid or are they only interested in TSH?

3) Reverting to discussing people, when anyone is hypothyroid or hyperthyroid there is a good chance that they have low levels of nutrients (in range but lower than optimal, low in range, or below range). I'm assuming the same conditions can occur in mice.

I wonder if the researchers have ever tried checking nutrient levels in the mice they test. It may be loss of nutrients that is driving the problem rather than TSH, or perhaps a combination of the two.

4) I also noted this sentence

"Likewise, euthyroid women with serum TSH levels in the lowest tertile of the normal range have a higher incidence of vertebral fractures, independent of thyroid hormone levels "

A tertile - divide the reference range into three equal parts and a tertile is one third of the range. (Side note - what a funny word!)

My first thought was to wonder who the euthyroid women are being compared to? They have to have a higher incidence than some group but it isn't spelled out who. I'm guessing (but I shouldn't have to) that they are being compared to the 2 higher tertiles.

I then went and checked out one of my favourite papers :

eje-online.org/content/143/...

If you look at the right hand half of Table 3 in that link it shows values for TSH in a healthy population with no thyroid antibodies. Just checking females under 40, more than 50% of women have a TSH in the lowest tertile of the normal range (i.e. the lowest third of the normal range). So perhaps vertebral fractures are normal in women as they get older? I'm not really sure what point I'm trying to make here...

Enough waffle... Time for dinner.

[Justiina in reply to humanbean]

I would also ask where and who was tested. Over here in Finland regardless of the amount of milk we drink we have a lot of osteoporosis. So why is it happening then? The highest rate of osteoporosis is in the countries consuming the most calcium and the lowest where calcium consumption is ridiculously low. Eskimos eat a lot of meat and fish, providing a lot of calcium, so they might consume 3000 mg /day. In Africa it can be as low as 100 mg and they have the strongest bones.

Naturally there is a correlation between vitamin D, but also consuming a lot of animal protein either prevents absorbing calcium or causes high cortisol which dissolves calcium from bones. So if you have a glass of milk, what is it? Calcium and surprise surprise animal protein. Add that to high protein consumption during the day and voila. Like eskimos, they get enough calcium but something is causing osteoporosis. 1+1, you can say calcium does not prevent osteoporosis

So, I think it is fair to question what was tested. Age group? Menopause? Other values? Are these people who don't exercise as that helps to have strong bones? Was anything else considered.

So I am asking the same question than you ,who they were compared to?

[Hidden in reply to Justiina]

I would put that down to Vit D. You're too Northern and don't get anywhere near as much sunshine as Africa!

I think in the next year or two, Vit D research and importance will just explode and be the next "big thing".

[Justiina in reply to Hidden]

I think so too. I know so many people who eat normally and have low vitamin D when tested. Add antibiotics and you get lack of vitamin K2 too. And the soil in many countries is so poor that magnesium is low too.

So the bigger picture is very different when you add all these variables. Let alone the fact that ssri's causes osteoporosis. So people in tests like this should not be in any medication and have optimal level of vitamins. Then we can start to think if low TSH could increase the risk of osteoporosis.

[SAMBS]

Hi katyabat1 - I also read humanbean's reply to this - I to an extent understand where his answer is coming from. Your post though had me wondering initially

A) aresearch using mice than can't talk and say if they feel better or worse always leave me cold - not because they are animals - purely because the final 3% of their physiology is NOT human! In my book it's always the living, speaking, breathing human being that contains the most, even if last, relevant piece of the 'proof positive'.

B) the article constantly refer to hyperthyroid - not hypo! I was Dx 2000, so almost 16 years now in the UK but never saw or was told after each annual only blood test what the blood test results were. Just told initially I had Hypothyroidism . Given both types are treated with Levo and its the TSH results doctors go on. do any of know if our initial result and diagnosis was in fact correct. For last 8 years I've been tested and treated in France and have 99% of my qtrly tests here in writing.

i have however had various bone problems from a young age, toes deformed 1st on one foot later on another. I spent 6 weeks in plaster aged 14 when r foot ties had pins put in to straighten them. My leg muscles wasted while I was in plaster from toe ends to just below kneecap. My leg never recovered, my ankle bone was weak. Over years I had to have 2 follow up surgeries on same foot because toes were dislocating.

I also aged 7/8 had to have deportment physio because I was quite round shouldered (in hindsight I had put that down to being hunched over the old small individual school desks that had lids with inkwells. and sitting on long wooden benches at long dining tables for all meals (I was at boarding school). After my brain haemorrhage 3 yrs ago, I also had walking problems - because of my other foot.

At present, due to dietary deficiency I know, but yes I do look very skeletal now - just pressing on a bone anywhere and it hurts. I have always drunk a lot of milk, thinking the calcium would strengthen my bones. I have difficulty both in walking and standing for any length of time. I can't say I've ever associated hypothyroidism with my longstanding bone structure differences. I did lose by operation an infected gland in my neck when I was a baby. That will have impacted health wise on the HPTA axis.

But where does all that fit in again with the published article - it probably doesn't, though my own research has suggested underlying and recurrent infections affects so many of our additional health conditions in weird ways.

[Framboise]

Thank you for this katyabat1. I'm going to send it to my endocrinologist for the sentence which humanbean has quoted below:

"Likewise, euthyroid women with serum TSH levels in the lowest tertile of the normal range have a higher incidence of vertebral fractures, independent of thyroid hormone levels ".

My endocrinologist wants me to keep lowering my NDT due to my suppressed TSH which he blames for causing my osteoporosis and he does not believe I have ever been hypothyroid. But - I know that my TSH hovered between 0.54 and 0.19 for at least 7 years prior to my diagnosis because, thankfully, my GP kept testing me and always gave me the results, so according to that sentence I would have had osteoporosis anyway! I don't like having it and am treating it with the help of a nutritionist not drugs, but in a way it's good to know that it probably was not a consequence of taking thyroid hormones, although I have always doubted that. On the other hand I also think that, for many women, osteoporosis is a natural condition which has become medicalised since pharmaceutical companies realised the potential for treatment.

[greygoose]

I find this study very odd. They never once defined what they meant by 'hyper' or 'subclinical hyper' by giving lab values. And, on a side note, I find the idea of 'subclinical hyper' very odd. Low TSH and normal Frees - firstly, what do they call 'normal', and secondly, how do they know that's not a pituitary problem rather than a thyroid problem. Their ideas of a 'low TSH' might be very different from ours.

And, then again, nothing was actually proved. it was just a load of perhaps's and maybe's. And, it was done on mice. Have they found any kind of proof that we react the same as mice to these things?

It was very difficult to understand. I felt they kept going round in circles in their 'explanations' and even contradicting themselves. But, if I understood this correctly, what they actually did was remove the TSH receptors from the bones - is this correct? Surely, that's a whole different kettle of fish from just having a low TSH, no? Even if your TSH is suppressed - 0.01, say - there is still 0.01 TSH in the blood. How do they know that this isn't enough for the bones if the receptors are still there?

But, maybe I didn't understand correctly. I wish someone would come along and explain it in words of one syllable...

[katyabat1]

Humanbean: your questions are thoughtful! You say:

1)When the authors refer to hyperthyroidism are they talking only about test subjects (in this case mice) who are or were truly hyperthyroid (TSH below reference range and Free T4 and Free T3 above range before treatment began), or are they including test subjects with hypothyroidism who, in the opinion of the authors, are over-medicated because their TSH is below range?

In my reading, these mice were rendered hyper thyroid: both the wild ones and the ones whose TSH was removed. Both were given too much T4 but the effect was worse in the ones without TSH.

I think the supplement thing is interesting, but it would mean in this case that normal lab mice would be hypothyroid as a matter of course through the probably standard poor nutrition they are given.

"Likewise, euthyroid women with serum TSH levels in the lowest tertile of the normal range have a higher incidence of vertebral fractures, independent of thyroid hormone levels "

2)Who are the women being compared to? Probably to the other two thirds as you suggest. but it's mainly about mice. I think this is an aside: what they are really looking at is when TSH is removed from the mice, the bone problem is exacerbated. They are trying to extrapolate the mechanism by which the bone is remodelled and they actually talk about how it's kind of weedy in the absence of TSH.

[katyabat1]

Sambs: Interesting post! Sorry to hear about all your bone problems. I believe that in my case there may be some osteopenic effect from putting on too much suncream (lack of Vit D): I don’t have any side effects from my osteopenia, and I feel great. But now I’m worried.

I have trawled the internet for scholarly articles on whether my low TSH is a problem and there is considerable evidence that I have found that connects low TSH with poor bone remodelling. This particular study may be about mice, but what they were able to do was look at the bone structure in some detail under the microscope, and suppose that TSH is actually preventing bone break down. On the other hand they also say this:

"Nonetheless, we and others have shown that TSH administered intermittently acts upon the osteoblast to promote bone formation in rodents and humans (5–7)."

[katyabat1]

Greygoose: They removed the TSH I believe.

[greygoose in reply to katyabat1]

TSHr, the receptors. I can't see how you can 'remove' the the TSH. But my point was, that's a whole different thing from being hyper. You can't compare the two.

[katyabat1]

If the TSHr was interfered with, the feedback system with TSH was interrupted, so TSH no longer was working on the thyroid gland itself. But that's not the same as removing all trace of TSH from the body, thus affecting the bone.

[greygoose in reply to katyabat1]

No, I Don't think that's right. If the TSH receptors were removed on the bones, that would have no effect on the thyroid, I Don't think. In any case, I Don't see what difference that would make because they were talking about the effects of thyroid hormones, just the TSH. I think this whole thing is a muddle.

[katyabat1]

so it doesn't seem to prove what it claims to prove, but I'm not sure I understand the science or mechanisms

[greygoose in reply to katyabat1]

Well, as I understand it, it doesn't seem to prove anything at all. Especially as there are so many other studies saying that TSH does not affect bone. I Don't know. I'd like someone to explain it to me, but nobody on here seems inclined to do so.

But what I do think is, before blood tests were invented, people just took as much thyroid hormone replacement as they needed. Nobody worried about TSH. But there are no records of people dropping like flies with osteoporosis. Same goes with cancer patients today. They have to have their TSH suppressed so that the cancer doesn't come back. If they were all badly affected by osteoporosis, I think we would have heard about it by now, Don't you? Even without any research.