The science of thyroid hormone and bone metabolism

The science of thyroid hormone and bone metabolism

This article is for people interested in getting an overview of the influence of thyroid hormones on bone health at the molecular level.

It outlines the way bone transports, metabolizes, and uses thyroid hormones T3 and T4.

It also raises theoretical implications for people with low T3 during TSH-suppressive T4 monotherapy.

Here I draw mainly on the molecular endocrinologists Bassett and Williams’ 2018 chapter, and I supplement it with additional cited sources.


Osteoblasts are cells responsible for bone formation. They are directly stimulated by T3 hormone. The osteoblasts express both thyroid hormone conversion enzymes found in bone, Deiodinase type 2 (D2) and Deiodinase type 3 (D3), so that they can locally both activate and inactivate T4 hormone to T3 or RT3, and can convert T3 into two types of T2.

Osteoclasts, on the other hand, are responsible for natural bone breakdown. They are also stimulated by T3 hormone, but it is unclear how exactly T3 functions in them. Interestingly, these cells express no D2 enzyme so they can’t locally convert T4 into T3, but they do express deiodinase type 3, which breaks down T3 into T2.

After osteoblasts (the bone-forming cells) mature, they become absorbed into the bone matrix as osteocytes, where they continue to perform functions of bone formation over many decades. It is important to build and maintain healthy osteocytes because as they die, they can cause osteoporosis. While the role of thyroid hormone in these important osteocyte cells is not yet understood, an implied principle is that osteoblasts would need appropriate T3 levels as they mature if they are to live longer as osteocytes.

Chondrocytes are cells that build and maintain cartilege in tissues such as tendons, joints, and growth plates. They form a matrix or scaffold that is used during bone development and remodeling. Importantly, they do not express DIO2, the gene for the D2 enzyme that converts T4 to T3, so like osteoclasts, they are very dependent on sufficient T3 levels in blood. They do express DIO3, however, which means they can handle mild excess in T3 levels by breaking it down to T2. There’s a good reason why they have D3 enzyme. Too much T3 (thyrotoxicosis) can slow down these cells’ proliferation and can speed up the process of cell enlargement (hypertrophy), which happens as chondrocytes reach the end of their life cycle and degenerate.

During childhood, when chondrocytes’ life cycle is too slow due to hypothyroidism, it results in short stature. When bone turnover speeds up after thyroid therapy is initiated, a child can experience “catch-up growth.” Too much thyroid hormone can result in a growth spurt, but ultimately short stature, as bone growth plates fuse too soon. (Williams, 2013). Later in life, degeneration of chondrocytes can lead to osteoarthritis, and severe OA can cause the need for hip replacements.

Therefore, overall, bone cells are well equipped at the local level to mildly enhance local T3 concentrations in osteoblasts in mild hypothyroidism, as long as the person does not have a genetic T4-T3 conversion defect in DIO2 that may inactivate this D2 enzyme. But because there is no D2 in osteoclasts, hypothyroidism will incapacitate osteoclasts, slowing down the overall rate of bone metabolism.

All bone cells appear to protect themselves from mild thyrotoxicosis in bloodstream by inactivating both T3 and T4 locally via D3. Yet bone cells do not handle well an extreme, constant delivery of excess T3 that exceeds their capacity to convert T3 into T2.

The bone cells’ affinity for T3 has led Williams to say, in his 2013 article “Thyroid Hormone Actions in Cartilage and Bone,” that “the skeleton is considered as a T3-target tissue.”

“Thus, all the factors required for locally regulated T3 action, including thyroid hormone transporters, metabolizing enzymes and receptors, are present in cartilage and
bone indicating the skeleton is a physiological target tissue for thyroid hormone [T3] throughout life.”

Compared to the role of T3, the role of TSH in these bone cells is not as clearly understood. As for the osteoblasts, Bassett and Williams say “Contradictory data suggest TSH may stimulate, inhibit, or have no effect on osteoblast differentiation and function.”

However, one thing is fairly clear — “The majority of studies indicate TSH inhibits osteoclast differentiation and function.”

This means that in a state of TSH excess (hypothyroidism), bone breakdown is further halted and the overall cycle of bone metabolism slows down, leading to osteoSCLERosis, which can lead to bone stiffness and increased risk of fracture, especially when combined with low vitamin D and low calcium, which contribute to poor bone quality.

As for osteoclasts, in the absence of TSH molecules, osteoclasts still have the “brake” on excess T3 from bloodstream of their expression of D3 enzyme.

TSH “may inhibit proliferation and matrix synthesis” in the chondrocytes that regulate collagen use in bone and connective tissue.


The ratio and levels of T3 and T4 in bloodstream are important factors because each tissue has a different expression of transport that prefer to transport T3, T4, or both, into cells.

One can think of it as an organ’s preference to “eat” (bring in and exchange) and “digest” (metabolize, use) relatively more T3 and/or T4.

The main thyroid hormone transporter used by bone is MCT10, which transports both T3 and T4 into and out of cells, but prefers to transport T3 up to 2x more than transporting T4. It also enhances the activity of D3, the enzyme that breaks down T3 into T2. Two minor transporters used in bone are LAT1 and LAT2. The former transports all thyroid hormones including T4, T3, RT3, and T2. The latter does not transport T4 or RT3. (Friesma et al, 2008; Zevenbergen, 2015; Krause & Hintz, 2017).

Overall, the transporters that bone relies on show that bone tissue is equipped to preferentially transport T3 and is also capable of enhancing the way bone cells protect themselves from mild T3 excess.

Theoretically, because bone transport of T4 and expression of D2 enzyme is more limited than T3 transport and D3 expression, bone metabolism may be more vulnerable to a state of hypothyroidism caused by a T3 deficiency in bloodstream, even when T4 is more dominant in bloodstream, especially if a patient has reduced expression of D2.

By extension, T4 treated patients with low or suppressed TSH who have high T4 levels but low T3 levels are at more risk of hypothyroid bones than thyrotoxicosis.


See resources listed in these two recent posts:

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