Overlooked: Hypothyroidism causes osteosclerosis

T3 levels and boneWe should all know that thyrotoxicosis in bone, caused by too much T3 binding to receptors in cells, leads to osteoporosis. (Bassett et al, 2007; Gogakos et al, 2010)

Hypothyroidism in bone, characterized by low T3 in bone, is not good for bone, either. (Bassett et al, 2008)

Hypothyroidism results in a different bone disorder you rarely hear of: osteoSCLERosis. (Williams, 2013; Bhatnagar et al, 2017).

After the prefix “osteo” meaning bone, the word “sclerosis” means abnormal hardening.

How many studies and clinical cautions focus on this problem of local T3 deficiency in bone leading to sclerosis? Few.

It’s such a rare word that even my spell-checker is highlighting “osteosclerosis” as a spelling error.


In hypothyroidism, T3 deficiency exists in bone cells.

Due to lack of T3 binding to receptors in cells, bone turnover slows down, and bone mineral density is increased. It may increase so much that it leads to osteosclerosis.

Osteosclerosis contributes to bone stiffness.

Bone quality is also more likely to be poor due to low calcium and vitamin D status, which is common in hypothyroidism.

These factors together increase risk of fracture in stiff, dense bones. (Bhatnagar et al, 2017).

In fact, “hypothyroidism is associated with a two- to three-fold increased risk of fracture, whilst thyrotoxicosis is an established cause of osteoporosis and fragility fracture.” (Williams, 2013).


This similar health outcome (fracture) in both high and low thyroid hormone can be confusing to people who want to see the two thyroid hormone disorders as complete opposites in every way.

Scientists often presume that hormone relationships to health outcomes are linear — as the hormone increases (or decreases), the risk of an adverse health outcome increases (or decreases).

So often in thyroid disorders, both high and low levels are harmful to a particular organ, tissue, or symptom — such as bones. If increasing “risk to bone health” is plotted on the Y axis and hormone levels are on the X axis, the relationship is often U-shaped — like the letter “U,” the line on the graph shows risk is high at both ends of the spectrum.

In an effort to explain away the higher fracture rates in people with hypothyroidism who don’t have osteoPORosis, some researchers have suggested that fracture rates are higher in some hypothyroid patients because they have problems with balance while walking and are more likely to fall (which may also be true).

Some scientists have a hard time grappling with the paradox that poor bone health exists at both ends of the spectrum of hypothyroidism and hyperthyroidism / thyrotoxicosis, and therefore they try to find an explanation outside of bone quality.

Fracture is not the only sign, symptom, or health outcome that occurs at both ends of the hypo-hyper spectrum. Heart failure is seen in hypothyroidism as well as hyperthyroidism, but low-output heart failure is a subtype of heart failure more common to hypothyroidism.

The list of symptoms found in both hyper- and hypothyroidism includes hair loss, fatigue, and anxiety. Having similar symptoms and health risks appear in both hypo and hyper often confuses scientists, doctors and patients, but it is a fact of thyroid disease that risk is often U-shaped.


In hypothyroid patients, which hormone has the most direct and profound effect on osteosclerosis, poor bone quality, and fracture? High TSH, low T4, or low T3?

A high TSH is likely to correlate with hypothyroidism in bone. However, the hormone that sticks farthest out of reference range is not necessarily the one that causes the biggest problem.

The experts believe the cause is low T3 within bone cells.

In studies of mice who are bred with a defect in the dominant nuclear thyroid hormone receptor found in bone, THR-alpha (THRA gene), they can look perfectly normal in their thyroid hormones and TSH levels in blood, but they can develop hypothyroid, osteosclerotic bones. This is because no signal is coming from the missing T3 thyroid hormone receptors, and a normal level of T3 signaling is necessary for healthy bones. (Williams, 2013)

In addition a flaw in Deiodinase type 2 (D2, gene DIO2), the enzyme responsible for converting T4 to T3 within bone, is a culprit. A dysfunction in D2 reduces intracellular T4-T3 conversion and therefore reduces T3 signaling levels in osteoblast bone cells:

“Studies of mice with deletion of the Dio2 gene further demonstrate a critical requirement for T3 in osteoblasts [17]. Dio2 knockout mice have increased bone mineralization density and brittle bones due to impaired osteoblast activity.”

(Williams, 2013)

Appropriate intracellular T3 signaling is a “critical requirement” for healthy osteoblast activity.

Williams explains that research proves “impaired T3 action in skeletal cells” is the key factor that leads to osteosclerosis, not the elevated TSH found in untreated hypothyroidism.

The same principle is often found by researchers who study thyroid hormones in other organs and tissues. TSH excess or deficiency is often less important than intracellular T3 excess or deficiency.


T3-toxicosis is an official word in endocrinology. I’m not sure why hypo-T3-ism should not be a word for the opposite condition of isolated low(er) T3 in blood or in tissues such as bone.

From the perspective of any given organ, including bone, the state of “hypothyroidism” is neither caused nor defined by a high TSH above a statistical reference range, but primarily by T3 insufficiency that fails to meet cellular demands.

Too many people are looking for a high TSH to co-present with hypothyroidism because that’s how our medical culture has defined it, as a pituitary hormone sticking out of its reference range. It’s not how our body defines hypothyroidism.

As mentioned above, hypothyroidism often presents with low vitamin D.  In a research study of hypothyroid patients, Low Vitamin D was strongly correlated with lower T3 levels in blood, even while T3 was within reference range. It was more strongly associated with T3 than with TSH, and not at all with T4 levels. (Mackawy et al, 2013)

It’s also not our body’s fault that the Free T3 reference range cutoff is so low, due to poor screening of blood samples. Laboratories cannot be trusted to exclude blood samples from patients who have “low T3 syndrome” caused by chronic or acute illness, nor do they always exclude blood drawn from patients on LT4 monotherapy, even though both conditions are known to induce abnormally low FT3:FT4 ratios despite normal TSH. Laboratories may decide to include samples from patients whose TSH is normal, but they should also exclude samples from patients whose FT3:FT4 ratios are below a certain cutoff. This TSH-centric bias in the creation of reference ranges hides genuine hypoT3ism within the reference range so that it looks normal when it in fact may be a signal of pathology.

This is why I resort to saying “low(er) T3,” or “low or low-normal T3.” Given the flawed methods of establishing the FT3 reference range, a FT3 in the lower third of reference is likely to be abnormally rare in most healthy people under the age of 70, and yet many treated thyroid patients are forced to live with these levels for years or decades.


The blindness to osteosclerosis has practical implications for treated thyroid patients who suffer chronic symptoms of hypothyroidism while their TSH is normalized.

Who has studied treated thyroid patients’ chronic low T3 levels in relation to their bone mineral density to look for osteoSCLERosis?

No one, that I can find.

Everyone is assuming that because their TSH is normalized, their tissues are no longer hypothyroid.

Given the wide diversity in patients’ response to T4 monotherapy, a significant percentage of patients remain chronically hypothyroid in Free T3 levels in their blood. (Midgley et al, 2015; Gullo et al, 2011)

Many of these patients are being maintained at a Free T3 level below the mean (average, not reference range) found in healthy people at the same TSH. They live in a T3 deficit, from the perspective of population statistics.

If they are relatively T3-impoverished in blood, what about their tissues?

In a state of thyrotoxicosis, hypermetabolism in tissues often correlates with elevated T3, but not always. All that is needed is for tissue T3 to be far enough above the individual’s setpoint to cause a health problem, even if FT3 is not yet above range.

Conversely, in a state of hypothyroidism, symptoms in tissues often correlate with a Free T3 level below the average found in the healthy population, even if it’s not (yet) below reference range.

Many patients remain symptomatically hypothyroid even during TSH-normalized thyroid therapy while Free T3 is low within reference range, and this reduces their quality of life for the rest of their lives.


Sadly, this process of osteosclerosis and its cause, low(er) T3 in bones, which co-presents with low(er) T3 in blood in overt hypothyroidism, seems to be unknown to many researchers and physicians.

A 2016 case study of a middle aged woman with lupus found that she had osteosclerosis. Although lupus is an autoimmune disorder and may co-present with autoimmune hypothyroidism, nobody thought to measure her thyroid hormone levels or look into history of hypothyroid symptoms. Every other biomarker under the sun was mentioned. Over many tests throughout the years, her ferritin and serum iron were rather low, a finding often occurring in hypothyroidism. Her vitamin D levels were rather low. Serum calcium varied within reference. There was no mention of T3 or even of the word “thyroid.” (Guañabens et al, 2016)


Thyroid patients should rise up against their unethical exclusion from research. It is unjust and it harms vulnerable people.

Too often, scientists study thyroid hormone levels in relation to health outcomes, but they exclude anyone who is dosing thyroid hormones because they know that dosing will manipulate hormone levels.

Why is nobody studying the long term health effects in people who are forced to live with chronically below-average Free T3 while on thyroid therapy? Because it is inconvenient to create a separate category in a research study just for treated thyroid patients, essentially doing two studies in one.

The problem is that this conventional exclusion means some of the most vulnerable people are not being studied. Of course treating hypothyroidism is better than leaving it untreated, but an average improvement cannot tell you how many patients fail to improve sufficiently with treatment. Doctors are unaware of how often thyroid hormone treatments fail to achieve health outcomes despite statistically normalizing hormone levels.

There are millions of us being treated for hypothyroidism with T4 medication, which is well known to raise our FT4 and lower our FT3 per unit of TSH. Some patients have much lower Free T3 levels than others.

Those who wish to defend LT4 monotherapy at all costs will claim that our significantly reduced FT3:FT4 ratio is unimportant because it’s not sticking out of reference range and because not enough research has shown there’s anything wrong with it.

  • The current medical reaction to health risk caused by thyrotoxic tissues, which correlates with low TSH and high FT3 and/or FT4, is panic and fear.
  • The current medical reaction to health risk caused by hypothyroid tissues, which is correlated with normal or high TSH and normal or low FT3 and/or FT4, is apathy and disbelief.

This is not right.

People who minimize the pathology of undertreated hypothyroidism that hides under a normal TSH clearly aren’t reading studies on low Free T3 levels during acute and chronic illness, which correlate with death and morbidity despite a normal TSH. They are obviously not in a hurry to do the missing research to show anything is wrong with our low or low-normal FT3 levels, because they’re already presuming nothing must be wrong with us whenever our TSH is normal during thyroid therapy. They are also presuming that a hormone pill providing one hormone can perfectly replace flexible, TSH-adjustable gland function providing two hormones at variable T3/T4 secretion ratios.

We treated thyroid patients ought to be front and center in studies that focus on isolated low(er) T3 and health outcomes, since so many of us suffer from abnormally low or low-in-range T3 despite normalized TSH and high-normal FT4.

We are perfect test subjects for such studies.

Certain cause-effect relationships can be learned by “recruiting” genetically altered mice with Dediodinase type 2 knockout or THR-alpha knockout. However, the more pressing question is to learn how millions of humans with intact DIO2 and THRA genes respond to thyroid hormone therapy with little to no thyroid function. Hello! Here we are! Recruit low-normal FT3 treated thyroid patients for a longitudinal study.

Our invisibility to research exists partly because policies often forbid measuring Free T3 during hypothyroid therapy due to the high probability that when TSH is normal, FT3 is likely to be normal. The belief that it’s not worth measuring a hormone that is likely to be “normal” is based on a deeply ingrained biochemical prejudice. It is a prejudice to believe that all statistically “normal” levels of FT3 will be acceptable to all human bodies and that normal levels can’t cause pathologies when an individual’s healthy setpoint could be high-normal. This mistaken prohibition against collecting vital hormone data means that scientists doing retrospective analyses have little to no FT3 data to analyze.

Most doctors and patients are left in the dark about Free T3 levels in thyroid patients who suffer as they age and their FT3 drops further. Only a few researchers know how often it happens and what it means to patients’ lives. Well-informed thyroid patient communities know what “suboptimal T3” means to our lives.


  • How long does it take for even mild hypothyroidism during therapy to add up its effects over the years?
  • In some patients, does chronic Low(er) T3 in blood and/or chronic hypothyroid symptoms result in syndromes like osteosclerosis and fragile bones?
  • Do bones symptomatically “ache” when they are low in T3?
  • Does mild hypothyroidism lead to risk of fracture in one’s 80s and 90s?
  • Can supplementing Vitamin D and calcium compensate for the bone stiffness of osteosclerosis?
  • Can increasing the patients’ Free T3 supply strengthen brittle, fragile bones?

Under the normalized TSH potentially hides a multitude of Low(er) T3 maladies.

It’s time to look in the right place for these maladies, understand them, and stop them.

  • Tania S. Smith, PhD.
    Thyroid patient and thyroid science analyst
    President, Thyroid Patients Canada


Click to reveal reference list

Bassett, J. H. D., O’Shea, P. J., Sriskantharajah, S., Rabier, B., Boyde, A., Howell, P. G. T., … Williams, G. R. (2007). Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism. Molecular Endocrinology (Baltimore, Md.), 21(5), 1095–1107. https://doi.org/10.1210/me.2007-0033

Bassett, J. H. D., Williams, A. J., Murphy, E., Boyde, A., Howell, P. G. T., Rowan Swinhoe, … Graham R. Williams. (2008). A Lack of Thyroid Hormones Rather than Excess Thyrotropin Causes Abnormal Skeletal Development in Hypothyroidism. Molecular Endocrinology, 22(2), 501–512. https://doi.org/10.1210/me.2007-0221

Bhatnagar, S., Srivastva, R. K., Jahan, S., & Ranjan, R. (2017). Multiple Effects of Hypothyroidism on Bone Mineral Density and Its Association with Vitamin D, Serum Calcium: A Cross-sectional Study. International Journal of Scientific Study, 5(6), 120–124.

Gogakos, A. I., Duncan Bassett, J. H., & Williams, G. R. (2010). Thyroid and bone. Archives of Biochemistry and Biophysics, 503(1), 129–136. https://doi.org/10.1016/j.abb.2010.06.021

Guañabens, N., Mumm, S., Gifre, L., Gaspà, S. R., Demertzis, J. L., Stolina, M., … Whyte, M. P. (2016). Idiopathic Acquired Osteosclerosis In A Middle-aged Woman With Systemic Lupus Erythematosus. Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research, 31(9), 1774–1782. https://doi.org/10.1002/jbmr.2842

Gullo, D., Latina, A., Frasca, F., Squatrito, S., Belfiore, A., & Vigneri, R. (2017). Seasonal variations in TSH serum levels in athyreotic patients under L-thyroxine replacement monotherapy. Clinical Endocrinology, 87(2), 207–215. https://doi.org/10.1111/cen.13351

Mackawy, A. M. H., Al-ayed, B. M., & Al-rashidi, B. M. (2013). Vitamin D Deficiency and Its Association with Thyroid Disease. International Journal of Health Sciences, 7(3), 267–275.

Midgley, J. E. M., Larisch, R., Dietrich, J. W., & Hoermann, R. (2015). Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency. Endocrine Connections, 4(4), 196–205. https://doi.org/10.1530/EC-15-0056

Williams, G. R. (2013). Thyroid Hormone Actions in Cartilage and Bone. European Thyroid Journal, 2(1), 3–13. https://doi.org/10.1159/000345548

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