Evidence based information
Written by Medical editorial team head SIAHMSR
 Medically reviewed by Dr.Sanjana.V.B

Hyperthyroidism & its impact on bone health

   Thyroid gland is an endocrine gland situated on the base of neck and it produces hormones which are very important for physical and mental health of humans. The main thyroid hormones produced by the gland are thyroxine (T4) and 3,5,3′-triiodo-l-thyronine (T3). The synthesis and secretion of these hormones are regulated by the thyroid-stimulating hormone (TSH) secreted by pituitary gland in brain. TSH acts directly on the TSH receptor (TSH-R) expressed on the thyroid cells [i.e. follicular cell on the basolateral membrane].

    Euthyroid status [normal levels of thyroid hormones] is essential for normal skeletal development and the maintenance of adult bone structure and strength. It is a fact that hyperthyroidism has detrimental effects on bones in the long run.

   Hyperthyroidism is characterized by increased thyroid hormone synthesis and secretion from the thyroid gland. Thyrotoxicosis refers to the clinical syndrome of excess circulating thyroid hormones irrespective of the source. It could be non-thyroidal tissues which produce thyroid hormones in excess. The most common causes of hyperthyroidism are Graves’ disease and toxic nodular goiter. Other important causes of thyrotoxicosis include thyroiditis, iodine-induced and drug-induced thyroid dysfunction.

Hyperthyroidism may present as overt or subclinical. Overt hyperthyroidism is characterized by low serum thyroid-stimulating hormone (TSH) concentrations and raised serum concentrations of thyroid hormones  thyroxine (T4), or tri-iodothyronine (T3), or both. Subclinical hyperthyroidism is characterized by low serum TSH, but normal serum T4 and T3 concentrations.

Does hyperthyroidism cause osteoporotic fracture?

 Overt hyperthyroidism may cause high bone turnover and as a result osteoporosis and fracture of bones may occur.

  The first data related to hyperthyroid state and a bone disease was reported in 1891 when von Recklinghausen described the “worm eaten” appearance of long bones of a young woman who died due to hyperthyroidism. Later, Plummer also described about bone thinning and fragility of skull and ribs of patients died from hyperthyroid disease.

   Numerous studies have been conducted by many researchers to understand the link between hyperthyroidism and bone fragility. Hyperthyroidism was studied in relation to vitamin D, calcium & phosphorus metabolism, thyroid stimulating hormone etc.

The recent research data suggests that even subclinical hyperthyroidism and long-term suppressive doses of thyroxine (T4) hormone therapy for managing hypothyroidism may gradually lead to decreased bone mineral density (BMD) and enhance the risk of bone fracture.

 Osteoporotic bone fracture risk is enhanced particularly in postmenopausal women having subclinical or overt hypothyroidism. The cellular and molecular mechanisms of thyroid hormone action in bone are still not completely understood. Further extensive research is needed to find out the exact mechanism of thyroid related osteoporotic changes.

What is secondary osteoporosis?

 Osteoporosis is one of the most common metabolic bone diseases and is characterized by low bone mass with micro architectural alteration of bone structure, leading to reduced bone strength, which enhance the risk for fracture.

 Osteoporosis is defined based on bone density criteria. The World Health Organization defines osteoporosis as a bone mineral density (BMD) 2.5 or more standard deviations (SDs) below that of a young adult at any site (T score), whereas osteopenia is defined when BMD is >1 SD and <2.5 SD lower than the young- adult mean end.

  The osteoporosis in post-menopausal women is due to estrogen deficiency. Estrogen plays a key role in bone strength in women of reproductive age group. Estrogen decline post menopause may lead to low bone weakness and osteoporotic fracture.

It is estimated that about 75% of bone loss during the first 15 years after menopause is attributed to estrogen deficiency rather than to aging. Hyperthyroidism increases the risk for bone fracture in postmenopausal women.

     In premenopausal young women osteoporosis may occur from low bone density. Some hormonal diseases such hyperthyroidism can cause bone loss. Thyrotoxicosis including subclinical hyperthyroidism is being studied by researchers globally, regarding its impact on bone health leading to secondary osteoporosis in young women.

Recent studies [1] show that bone loss in thyrotoxicosis is independent of circulating thyroid stimulating hormone [TSH] levels and it is mediated predominantly by TRα [Thyroid hormone receptor alpha].

  However, the role of thyroid hormone receptor (TR) in impacting thyroid hormones mediated effects on bone formation and bone resorption are not clearly elucidated yet.

The role of thyroid hormones in the pathogenesis of osteoporotic fracture is still not completely understood. One study [1] suggests that TRα as a new drug target in the prevention and treatment of osteoporosis.

 Another study in 2011 reveals that TRβ receptors mediate the acute effects produced by transient changes of Thyroid hormone [TH] concentrations on bone remodeling, whereas TRα receptors mediate long-term effects of chronic alterations of TH metabolism [2].

   Untreated severe hyperthyroidism also leads to lowered bone mass and accelerates the risk for high bone turnover osteoporosis. Thyrotoxicosis causes increased   bone mineral resorption and calcium loss through kidneys.

Subclinical hyperthyroid state also may eventually lead to osteoporosis. Subclinical hyperthyroidism may not produce much symptoms but it may affect bone metabolism resulting in decreased bone mineral density (BMD) and increased risk of fracture, particularly in postmenopausal women

   Bone remodeling is a dynamic process and characterized by coupling between resorption and formation. The osteoclasts cause bone resorption. The osteoblasts promote bone formation. The sequence of events in remodelling, i.e. activation – resorption – formation is known as ARF sequence.

 The space corresponding to the amount of bone resorbed by osteoclasts but not formed by osteoblasts is the remodeling space. Activation frequency indicates how often a given site of the bone surface undergoes resorption and subsequent bone formation. The activation frequency is regulated by a variety of hormones; parathormone, 1, 25(OH) 2D, growth hormone and thyroid hormones increase the activation frequency, while calcitonin, corticosteroid and estrogen reduce the activation frequency.

    Renal calcium excretion is usually increased in hyperthyroidism and correlates positively with excess thyroid hormone levels and cortical osteoclastic activity. Calcium is one of the most essential minerals for bone mineralization process which imparts strength to bones. Hyperthyroidism result in loss of calcium through kidneys and calcium deficiency ensues.

Hyperthyroidism is also associated with hyper phosphatemic [ increased phosphorus in blood] state. However, a few studies show normal or low levels of serum phosphorous.

 Another study shows that there can be elevated levels of serum alkaline phosphatase in as many as 50% of cases [4].

  In subjects with hyperthyroidism, high serum calcium, low PTH[parathyroid hormone] and high phosphorous levels suppress renal 25(OH)D1-α hydroxylase activity leading to decrease in 1,25(OH)2D levels. Therefore concomitant vitamin D deficiency has been found in some Indian hyperthyroid patients with osteoporosis [5].

 Further research is needed to study the impact of vitamin D supplementation in these subjects with hyperthyroidism on bone density and fracture risk reduction.

Extra notes

What is thyroid hormone receptor TR?

The biological effect of thyroid hormone in a given tissue depends on a number of factors:

·       The  amount of available hormone

·        the levels of different TR subtypes and their post-translational modifications

·        the type of heterodimerization partner and their interaction with corepressors and coactivators .

·        In addition, accurate translocation of TRs from their synthesis in the cytosol to their ultimate destination is essential for maintaining proper cellular functions and activities

The nuclear genomic effect of thyroid hormones is mediated by the intracellular binding of T3 to nuclear receptor where it activates either thyroid hormone receptor α (TRα) or β (TRβ).

TRα is expressed in higher concentration than TRβ in the skeleton, where it mediates T3 action on bone and cartilage.

Thyroid hormone receptor alpha (TR-alpha) is a nuclear receptor protein that in humans is encoded by the THRA gene.

 TRs act as a hormone-dependent transcription factor that mediates transcriptional repression in the unliganded state. T3  binding results in the dissociation of co-repressors and the recruitment of co-activators resulting in stimulation of gene transcription.

Reference

1.    https://pubmed.ncbi.nlm.nih.gov/17327419/

2.    https://pubmed.ncbi.nlm.nih.gov/21594896/

3.    https://pubmed.ncbi.nlm.nih.gov/576531/

4.    https://pubmed.ncbi.nlm.nih.gov/580520/

5.    https://pubmed.ncbi.nlm.nih.gov/20663698/

6.    https://pubmed.ncbi.nlm.nih.gov/32059423/

7.    https://pubmed.ncbi.nlm.nih.gov/19179434/

8.    https://pubmed.ncbi.nlm.nih.gov/20051527/

9.    https://pubmed.ncbi.nlm.nih.gov/22454529/

10.                       https://joe.bioscientifica.com/view/journals/joe/237/1/JOE-17-0708.xml