J Endocrinol Invest (2018) 41:99–109

https://doi.org/10.1007/s40618-017-0753-4

SHORT REVIEW

Thyroid diseases and bone health

G. R. Williams1 · J. H. D. Bassett2

Received: 10 August 2017 / Accepted: 21 August 2017 / Published online: 29 August 2017
© The Author(s) 2017. This article is an open access publication

Abstract Thyroid hormones are essential for skeletal fracture, but cases are rare because of prompt diagnosis and
development and are important regulators of bone mainte- treatment. Recent data, however, indicate that subclinical
nance in adults. Childhood hypothyroidism causes delayed hyperthyroidism is associated with low bone mineral density
skeletal development, retarded linear growth and impaired (BMD) and an increased risk of fracture. Population stud-
bone mineral accrual. Epiphyseal dysgenesis is evidenced ies have also shown that variation in thyroid status within
by classic features of stippled epiphyses on X-ray. In severe the reference range in post-menopausal women is associated
cases, post-natal growth arrest results in a complex skeletal with altered BMD and fracture risk. Thus, thyroid status at
dysplasia. Thyroid hormone replacement stimulates catch-up the upper end of the euthyroid reference range is associated
growth and bone maturation, but recovery may be incom- with low BMD and increased risk of osteoporotic fragility
plete dependent on the duration and severity of hypothyroid- fracture. Overall, extensive data demonstrate that euthyroid
ism prior to treatment. A severe phenotype characteristic of status is required for normal post-natal growth and bone
hypothyroidism occurs in children with resistance to thyroid mineral accrual, and is fundamental for maintenance of adult
hormone due to mutations affecting THRA encoding thyroid bone structure and strength.
hormone receptor α (TRα). Discovery of this rare condition
recapitulated animal studies demonstrating that TRα medi- Keywords Bone development · Osteoporosis ·
ates thyroid hormone action in the skeleton. In adults, thy- Hypothyroidism · Thyrotoxicosis · Thyroid hormone
rotoxicosis is well known to cause severe osteoporosis and receptor α

Bone cells

Chondrocytes, osteoblasts, osteocytes and osteoclasts com-

prise the four major cell types in the skeleton. Cartilage-
forming chondrocytes, bone-forming osteoblasts and termi-
* G. R. Williams
nally differentiated osteocytes are derived from mesenchyme
graham.williams@imperial.ac.uk
whereas bone-resorbing multinucleated osteoclasts differen-
J. H. D. Bassett
tiate from precursor cells of the monocyte/macrophage line-
d.bassett@imperial.ac.uk
age. Chondrocytes and osteoblasts are directly responsive
1
Molecular Endocrinology Laboratory, Department to thyroid hormone and, whilst osteoclast activity is also
of Medicine, Imperial College London, Hammersmith sensitive to changes in thyroid status, it remains uncertain
Campus, Du Cane Road, 10N5 Commonwealth Building,
whether osteoclasts are direct target cells or whether the
London W12 0NN, UK
2
effects of thyroid hormone on bone resorption are indirect
Molecular Endocrinology Laboratory, Department
and mediated via primary thyroid hormone actions in other
of Medicine, Imperial College London, Hammersmith
Campus, Du Cane Road, 10N6 Commonwealth Building, cell types. The effects of thyroid hormone on osteocyte func-
London W12 0NN, UK tion are unknown [1].

13
Vol.:(0123456789)
100 J Endocrinol Invest (2018) 41:99–109

Fig. 1  Intramembranous and

endochondral ossification. a
Skull vault stained with alizarin
red (bone) and alcian blue
(cartilage) from post-natal day 1
showing anterior and posterior
fontanelles and sutures. Sche-
matic representation of intram-
embranous bone formation at a
skull suture. b Proximal tibial
growth pate section at post-natal
day 21 stained with alcian blue
(cartilage) and van Gieson
(bone matrix, red). Schematic
representation of endochondral
ossification showing chondro-
cyte proliferation, differentia-
tion and apoptosis within the
growth plate

Bone formation and growth X. They ultimately undergo apoptosis and release growth
factors and cytokines that stimulate vascular invasion and
During skeletal development, bone formation occurs via the migration of osteoblasts and osteoclasts, which model
two distinct processes (Fig. 1). The flat bones of the skull and mineralize the developing bone during growth [4]. Lin-
vault and pelvis, together with the lateral third of the clavi- ear growth progresses until puberty when the growth plates
cle, form by intramembranous ossification in which mesen- fuse, but bone mineral accrual continues until peak bone
chyme progenitor cells condense and differentiate directly mass is achieved during the third decade [5].
into osteoblasts [2]. Long bones and vertebrae, by contrast,
form on an intermediary cartilage template by endochon-
dral ossification after mesenchyme precursors differentiate Adult bone maintenance
to chondrocytes [3]. Epiphyseal growth plates form at the
ends of developing long bones and contain chondrocytes that In adults, the structure and function of the skeleton are
organize into distinct reserve, proliferative, pre-hypertrophic maintained by a process of continuous repair, mediated
and hypertrophic zones (Fig. 1). Progression of reserve zone by the bone remodelling cycle (Fig. 2) [6]. Osteocytes are
progenitor cells through the proliferative and hypertrophic terminally differentiated cells of the osteoblast lineage that
zones is accompanied by a large increase in cell volume that become entombed within mature bone. They sense mechani-
is responsible for linear growth. Differentiating chondrocytes cal strain and bone micro-damage, and orchestrate the
secrete a cartilage matrix that is rich in collagen types II and activities of bone-resorbing osteoclasts and bone-forming

13
J Endocrinol Invest (2018) 41:99–109 101

Fig. 2  Bone remodelling cycle. The bone remodelling cycle is

orchestrated by osteocytes that are entombed within the bone struc-
ture. Bone remodelling is initiated by changes in mechanical load,
structural micro-damage or exposure to systemic or paracrine fac-
tors. Monocyte/macrophage precursors differentiate to mature osteo-
clasts and resorb bone. Differentiation is induced by macrophage
colony-stimulating factor (M-CSF) and receptor activator of NFkB
ligand (RANKL) and inhibited by osteoprotegerin (OPG). Following
resorption, osteoblastic progenitors are recruited, synthesize an oste-
oid matrix and regulate its mineralization to form new bone and thus
repair the defect

osteoblasts within a coordinated cycle of bone resorption

and formation [7]. Bone resorption and formation are cou-
pled in time and space, and so targeted bone modelling and
remodelling enables the adult skeleton to repair and replace
old and damaged tissue in response to injury and mechanical
loading, or react quickly to the demands of mineral homeo-
stasis [8]. Uncoupling of these processes leads to acceler-
ated bone loss in osteoporosis or accumulation of bone in
osteopetrosis.

Thyroid hormone action

Thyroid hormones have important effects on skeletal devel-

opment, linear growth and the maintenance of adult bone Fig. 3  Hypothalamic–pituitary–thyroid axis. The thyroid gland
mass and strength. The thyroid gland mainly secretes thyrox- secretes the pro-hormone T4 and the active hormone T3 and circu-
ine (3,5,3′,5′-l-tetraiodothyronine, T4), and the circulating lating concentrations are regulated by a classical endocrine negative
level of T4 is approximately fourfold higher than the con- feedback loop that maintains an inverse physiological relationship
between TSH, and T4 and T3
centration of the biologically active hormone 3,5,3′-l-triio-
dothyronine (T3) [9]. A classic endocrine negative feedback
loop (Fig. 3) maintains an inverse relationship between the amino acid transporters 1 and 2 (LAT1, LAT2) [12]. Once
circulating concentrations of thyroid hormones and thyroid inside the target cell, T4 and T3 are metabolized by either
stimulating hormone (thyrotropin, TSH), thus establishing the activating type 2 iodothyronine deiodinase (DIO2) or
the hypothalamic–pituitary–thyroid (HPT) axis set-point the inactivating type 3 enzyme (DIO3). DIO2 catalyses
[10, 11]. 5′-deiodination of T4 to generate the active hormone T3,
T4 and T3 enter target cells via active transport involv- whereas DIO3 catalyses removal of the 5-iodine atom from
ing several specific transporter proteins, including mono- T4 or T3 to generate the inactive metabolites, reverse T3
carboxylate transporters 8 and 10 (MCT8, MCT10), organic (3,3′,5′-l-triiodothyronine, rT3) or 3,3′-diiodotyrosine (T2),
anion transporter protein 1c1 (OATP1c1), and the l-type respectively. Thus, the balance of DIO2 and DIO3 activities

13
102 J Endocrinol Invest (2018) 41:99–109

Skeletal consequences of thyroid disease

in children

Hypothyroidism

Hypothyroidism in childhood is relatively common and

causes delayed skeletal development, growth retardation and
short stature with impaired bone maturation due to defec-
tive endochondral ossification. Impaired intramembranous
ossification results in delayed closure of the fontanelles,
persistently patent skull sutures and a typically flat nasal
bridge and broad face. In severe undiagnosed cases, there is
complete post-natal growth arrest and skeletal dysplasia with
characteristic X-ray features that include stippled epiphyses
reflecting epiphyseal dysgenesis, congenital hip disloca-
tion, vertebral immaturity, scoliosis, patent fontanelles and
sutures with delayed tooth eruption [1, 15].
Prompt treatment of children with thyroid hormone
replacement induces a period of rapid “catch-up” growth
in which skeletal maturation and bone age are also accel-
erated. Ultimately, normal adult height and bone mineral
density (BMD) can be expected [16]. However, predicted
adult height may not always be achieved and in such cases
the deficit correlates with the severity of hypothyroidism
and its duration prior to commencement of thyroid hormone
replacement [17].

Hyperthyroidism

Thyrotoxicosis in children is relatively rare and causes

accelerated intramembranous and endochondral ossifica-
tion and an increase in linear growth rate [1]. Paradoxically,
the accompanying advancement in bone age may result in
premature fusion of the growth plates and early cessation of
growth leading to persistent short stature [18, 19]. In severe
Fig. 4  Thyroid hormone action in bone cells. Thyroid hormones thyrotoxicosis in young children, early closure of the cra-
enter T3 target cells via specific membrane transporters. The relative nial sutures can result in craniosynostosis with neurological
activities of the type 2 and type 3 deiodinases (D2 and D3) are regu- sequelae. Untreated hyperthyroidism during pregnancy is
lated to ensure optimal intracellular T3 availability resulting in the
displacement of the co-repressor and the binding of the co-activator
also associated with craniosynostosis and may be a causative
and thus the physiological transcriptional activity of TRα1 risk factor [20].

Summary of skeletal consequences of thyroid disease

regulates the intracellular supply of the active hormone, T3 in children
[9, 13]. T3 then enters the nucleus where it binds and acti-
vates either thyroid hormone receptor α or β (TRα, TRβ) Overall, T3 acts via TRα in chondrocytes and osteoblasts to
(Fig. 4). TRs function as hormone-dependent transcription regulate intramembranous and endochondral ossification and
factors that repress target gene expression in the absence control the rate of linear growth and bone maturation and
of hormone and stimulate gene transcription in response mineralization. Hypothyroidism in childhood causes delayed
to T3 binding [14]. TRβ is the main receptor expressed in skeletal development and mineralization but prompt treat-
the hypothalamus and pituitary where it mediates negative ment with thyroid hormone initiates “catch-up” growth and
feedback control of the HPT axis, whereas TRα is the main stimulates bone maturation. Thyrotoxicosis, by contrast,
receptor expressed in the skeleton and mediates T3 action accelerates skeletal development and bone mineral deposi-
in bone and cartilage [1]. tion, but may also result in short stature. Thus, the opposing

13
J Endocrinol Invest (2018) 41:99–109 103

skeletal consequences of childhood hypothyroidism and thy- Subclinical thyroid disease

rotoxicosis, together with the rapid response of the hypothy-
roid skeleton to thyroid hormone replacement, demonstrate Subclinical hypothyroidism is defined biochemically as the
that normal euthyroid status during growth and adolescence occurrence of circulating concentrations of T4 and T3 within
is essential to establish peak bone mass and strength in early their normal reference ranges in the presence of a TSH level
adulthood [1]. elevated above its reference range. Conversely, subclinical
hyperthyroidism occurs when T4 and T3 levels are within
their reference ranges, but the TSH concentration is sup-
Skeletal consequences of thyroid disease in adults pressed below its reference range. The effect of subclinical
hypothyroidism on bone mineralization and fracture suscep-
A large number of studies investigating the influence of tibility has not been studied extensively [1], but a recent
thyroid disease on the adult skeleton have been published individual participant meta-analysis of data from 70,298
and reviewed. However, overall interpretation of findings subjects from 13 prospective cohort studies consisting of
from these studies is limited by heterogeneous study design, 762,401 person-years follow-up demonstrated no association
confounding factors, lack of power and differing end-point with fracture [28].
analyses [1]. Nevertheless, large studies including extensive More studies have investigated the relationship between
individual participant meta-analyses have been performed subclinical hyperthyroidism and BMD or fracture risk [1]
and this review will concentrate on the larger and more and large population studies have suggested an increase in
recent studies that have strengthened our understanding. bone turnover, decrease in BMD and an increased risk of
fracture, especially in post-menopausal women, although
Hypothyroidism heterogeneity between studies prevented firm conclusions
in several meta-analyses and reviews [32–38]. Nevertheless,
Early histomorphometry analysis demonstrated that hypo- the recent large individual participant meta-analysis of data
thyroidism results in low bone turnover with decreased from 70,298 subjects demonstrated that a TSH value below
osteoblastic bone formation and reduced osteoclastic bone 0.01 mU/L was associated with a 2- and 3.5-fold increased
resorption. The prolonged bone remodelling cycle includes risk of hip and spine fractures, respectively. Overall, sub-
a longer period of secondary mineralization resulting in a net clinical hyperthyroidism was associated with bone loss and
increase in bone mineralization and mass without a change fracture, particularly in individuals with endogenous disease
in bone volume [21, 22]. These changes are very slow, and [28]. Furthermore, a register-based cohort of 222,138 sub-
long-term prospective follow-up of untreated hypothyroid jects with a normal TSH level plus 9217 individuals with a
patients would be required to demonstrate clinically signifi- low TSH were followed up for 7.5 years. This study dem-
cant changes in BMD by non-invasive imaging techniques. onstrated an exponential association between the duration
Thus, there are no good clinical data that demonstrate the of thyrotoxicosis and fracture. In euthyroid individuals, the
skeletal consequences of hypothyroidism in adults. risk of fracture increased with each standard deviation unit
decrease in TSH (hazard ratio 1.45, p < 0.001 for hip frac-
Hyperthyroidism ture; HR 1.32, p < 0.001 for major osteoporotic fracture)
[39].
Hyperthyroidism, in contrast, causes high bone turnover
with an increased frequency of initiation of bone remodel- Variation within the euthyroid reference range
ling sites together with increased bone resorption and forma-
tion rates. The remodelling time is shortened with imbalance These findings suggest the possibility that thyroid status
between resorption and formation that results in a net loss of even across the normal reference range is a continuous
approximately 10% of bone per remodelling cycle [23, 24]. variable related to BMD and strength. A number of studies
Thus, hyperthyroidism is an established cause of high bone have been published to address this issue, but data have been
turnover with accelerated bone loss leading to osteoporosis conflicting, largely because of heterogeneity especially with
and increased fracture susceptibility. Severe osteoporosis regard to the age and gender of cohorts and differences in
resulting from untreated thyrotoxicosis is now rare because study size [40–51]. Recently, an individual participant meta-
of early diagnosis and treatment, although undiagnosed analysis was undertaken that included data from 56,835 sub-
hyperthyroidism is an important risk factor for secondary jects (n = 2565 with hip fracture) from 12 prospective cohort
bone loss and osteoporosis in patients presenting to hospital studies consisting of 659,059 person-years follow-up. This
with fracture [25, 26]. Accordingly, population studies have study demonstrated that lower TSH and higher fT4 within
demonstrated an increased risk of fracture in thyrotoxicosis the reference range were associated with 22–25% increased
especially in post-menopausal women [27–31]. risk of hip fractures [52]. Taken together, these studies

13
104 J Endocrinol Invest (2018) 41:99–109

indicate that thyroid status at within the upper end of the TSH suppression therapy in thyroid cancer may be associ-
euthyroid reference range is associated with low BMD and ated with bone loss and fracture in post-menopausal women.
an increased risk of fracture [1]. There is potential for the use of bisphosphonates to prevent
bone loss in post-menopausal women at risk of fracture
TSH suppression therapy for thyroid cancer who are receiving long-term TSH suppression therapy [56].
There are no prospective studies in this area but, although
Thyroid cancer cells express TSH receptor, and TSH stimu- the adverse side-effect of atrial fibrillation in patients taking
lates cell proliferation, iodine uptake and thyroglobulin bisphosphonates is controversial, it could be important as
secretion from tumour cells. This is also true in metastatic exposure to excess thyroid hormones in the elderly is also
cells in about 65% of cases. There is, therefore, a good associated with AF and cardiovascular mortality [57, 58].
rationale for TSH suppression therapy using thyroxine. Thus, despite preclinical studies supporting the potential
Treatment has been shown to reduce recurrence and disease- use of bisphosphonates for prevention of bone loss in post-
specific mortality in retrospective studies [53, 54], whilst menopausal women at risk of fracture who are exposed to
a prospective non-randomized study demonstrated that a thyroid hormone excess [56], other anti-resorptive drugs
lesser degree of TSH suppression is an independent predic- may theoretically be used according to the latest treatment
tor of disease progression in patients at high-risk of recur- guidelines [59]. Nevertheless, targeted prospective clinical
rent disease [55]. trials are still needed to provide a clear evidence base for
In pre-menopausal women, three systematic literature therapeutic intervention.
reviews showed that suppressive treatment with T4 had no Overall, and in contrast to the effects on the juvenile skel-
effect on BMD [32, 35, 36] and two meta-analyses demon- eton in which thyroid hormones are anabolic and stimulate
strated no effect on BMD at the hip, lumbar spine or radius bone growth and mineralization, T3 exerts catabolic actions
[34, 37]. No fracture data are available. in the adult skeleton and stimulates bone loss [1].
In post-menopausal women, three systematic literature
reviews demonstrated conflicting effects of suppressive treat-
ment with T4 on BMD [32, 35, 36], while two meta-analyses
showed BMD was reduced by 7% at the lumbar spine (CI Skeletal consequences of genetic disorders
4–10%) and 5% at the femur (CI 2–8%) [34, 37]. No prospec- of thyroid function
tive fracture data are available, but hospital admission data
for patients with fracture demonstrated that the incidence Mutations affecting TSH (TSHB) and TSH receptor
of admissions for fracture was 2.5× higher in patients with (TSHR)
TSH <0.05 mU/l [29]. In patients with hyperthyroidism,
there was a 3× increase in hip and 4× increase in vertebral Loss-of-function mutations in TSHB, encoding the TSHβ
fracture if TSH was suppressed <0.01 mU/l [27]. subunit, result in biologically inactive TSH and congenital
Overall, post-menopausal women on suppressive doses of hypothyroidism (OMIM 275100). Loss- and gain-of-func-
T4 may be at risk of bone loss and osteoporosis [1]. tion mutations in TSHR, encoding the TSH receptor, result
in TSH resistance with congenital hypothyroidism (OMIM
Summary of skeletal consequences of thyroid disease 275200) or autosomal dominant hyperthyroidism (OMIM
in adults 609152), respectively. Few reports have documented the
skeletal consequences of these genetic disorders because
Thyroid hormones act via TRα in osteoblasts, but their children are treated early and the long-term outcomes reflect
actions in osteocytes and osteoclasts have not been defined the response to thyroid hormone supplementation or thyroid-
[1]. Thyroid hormones stimulate adult bone turnover via ectomy/ablation [1]. Nevertheless, normal growth occurs in
increased osteoclastic bone resorption. In euthyroid subjects, individuals with congenital hypothyroidism following proper
variation across the reference ranges for thyroid hormones thyroid hormone replacement [60–62], and improvement of
and TSH is associated with bone loss. Thus, thyroid status skeletal developmental manifestations is seen in patients
at the upper end of the normal reference range is associated with autosomal dominant hyperthyroidism following thy-
with lower BMD and an increased risk of fragility fracture. roidectomy and normalization of thyroid status [63, 64].
Thyrotoxicosis is a well-established cause of high bone turn- Overall, the limited available studies demonstrate that per-
over osteoporosis, resulting in an increased susceptibility to sistent absence of TSH signalling during normal skeletal
fracture. This complication is now rare because of prompt development following adequate thyroid hormone replace-
diagnosis and treatment. Subclinical hyperthyroidism is also ment does not affect bone mineralization in children, whilst
associated with an increased risk of fracture in both men constitutive activation of the TSHR is not detrimental for
and women, but especially those with endogenous disease. skeletal development and maturation in patients who have

13
J Endocrinol Invest (2018) 41:99–109 105

been treated and had their normal euthyroid status restored mutant TRα1 proteins was also consistent with the pheno-
[1]. type–genotype correlation described above, while all stud-
ies showed that wild-type and mutant TRα2 proteins were
Mutations affecting thyroid hormone receptors transcriptionally inactive and had no dominant-negative
activity [67, 69, 72, 76]. Nevertheless, a severe and atypical
Resistance to thyroid hormone α (RTHα) (OMIM 614450) phenotype was described in a 27-year-old woman with an
N359Y substitution affecting both TRα1 and TRα2 [68].
The key role of TRα in the human skeleton has been exem- Her unique combination of skeletal abnormalities includes
plified by discovery of a new syndrome of resistance to thy- intrauterine growth retardation and failure to thrive, macro-
roid hormone due to dominant-negative mutations in THRA cephaly, hypertelorism, micrognathia, short and broad nose,
(RTHα) [65]. The skeletal manifestations of this condition agenesis of the clavicles and 12th ribs, elongated thorax,
(OMIM 614450) are consistent with the characteristic con- ovoid vertebrae, scoliosis, congenital hip dislocation, short
sequences of congenital and juvenile hypothyroidism, and limbs and dwarfism, unilateral humero-radial synostosis,
reflect impaired T3 action in cartilage and bone. To date, 15 elbow dislocation and syndactyly. The TRα1N359Y mutant
THRA mutations in 11 separate codons affecting 29 indi- protein had impaired T3 binding and transactivation function
viduals from 16 families have been described. Nine result with moderate dominant-negative activity, while no clear
in the expression of a mutant TRα1 protein alone, and six functional abnormality of the TRα2N359Y mutant was identi-
affect both TRα1 and TRα2 [66–76]. Affected individuals fied [68, 79].
have normal serum TSH with low/normal T4, high/normal Together, these reports define a new genetic disorder,
T3 concentrations and characteristically elevated fT3:fT4 RTHα, characterized by profound and consistent devel-
and T3:rT3 ratios [77, 78]. opmental abnormalities of the skeleton that recapitulate
Children with RTHα due to expression of mutant TRα1 findings in mice with dominant-negative Thra mutations
alone have skeletal dysplasia manifest by variable features [80–85]. Overall, similar phenotypes in patients with muta-
that include delayed bone age and tooth eruption, patent tions affecting either TRα1 alone, or both TRα1 and TRα2,
skull sutures with wormian bones and delayed closure of suggest TRα2 has little or no physiological role in the skel-
the fontanelles, macrocephaly, flattened nasal bridge, hyper- eton. However, the unique phenotype in the patient with
telorism, disproportionate (sub-ischial) short stature mainly the N359Y substitution affecting both TRα1 and TRα2, in
affecting the lower limbs, epiphyseal dysgenesis, acetabular whom no other de novo mutations could be identified by
hypoplasia, congenital hip dislocation, vertebral ossification whole exome sequencing [68], raises the intriguing possi-
defects and defective bone mineralization [66, 67, 71, 73]. bility that TRα2 may fulfil an unrecognized function during
Adults have been studied less comprehensively, but variable skeletal development.
skeletal abnormalities include increased cortical bone mass,
disproportionate short stature, macrocephaly with skull vault Resistance to thyroid hormone β (RTHβ) (OMIM 188570)
thickening and hearing loss due to otosclerosis [67, 70, 73,
74]. As the number of reported cases has increased, a pheno- RTHβ results from dominant-negative mutations of THRB
type–genotype correlation has emerged. Missense mutations that cause disruption of the HPT axis leading to a character-
that impair T3 binding and result in only mild or moderate istic increase in TSH along with inappropriately normal or
dominant-negative activity of mutant TRα1 are associated increased circulating T4 and T3 levels [86–88]. The clinical
with fewer and less severe abnormalities. By contrast, non- syndrome is complex with a mixed phenotype comprising
sense mutations resulting in the expression of a truncated hyperthyroid-like responses in some tissues and hypothyroid
TRα1 protein with absent T3 binding and potent dominant- effects in others. These variable tissue responses depend on
negative activity result in marked skeletal dysplasia and several factors including genetic background, the severity
developmental delay. Accordingly, T4 treatment of children of the THRB mutation, the relative amounts of expressed
harbouring severe mutations has had little effect on growth mutant and wild-type TRβ proteins and tissue-specific dif-
and skeletal development, whereas treatment of individuals ferences in the ratio of TRα and TRβ protein expression.
with milder missense mutations has been more promising In addition to these confounding issues, patients may have
[66, 67, 70, 71, 73, 74, 76]. received varying prior management including treatment with
More recently, THRA mutations affecting both TRα1 and anti-thyroid drugs, thyroid hormone analogues or surgery. In
TRα2 have been described [67, 69, 72, 76]. Affected children this context, it is not surprising that descriptions of skeletal
and adults had a similar spectrum of abnormalities charac- abnormalities in RTHβ are variable and largely restricted to
teristic of the skeletal dysplasia and variable response to T4 case reports or case series. Long-term prospective studies in
treatment reported in individuals with mutations affecting large families will be necessary to advance understanding
TRα1 alone. In vitro analysis of the functional defects of [1]. Nevertheless, analysis of the skeletal consequences of

13
106 J Endocrinol Invest (2018) 41:99–109

mutations of Thrb in mouse models of RTHβ is consistent 11. Bassett JH, Williams GR (2008) Critical role of the hypothalamic–
with a skeletal phenotype of accelerated bone development pituitary–thyroid axis in bone. Bone 43(3):418–426
12. Visser WE, Friesema EC, Visser TJ (2011) Minireview: thyroid
in juveniles and increased bone turnover with osteoporosis hormone transporters: the knowns and the unknowns. Mol Endo-
in adults that is due to increased T3 action in cartilage and crinol 25(1):1–14
bone [1, 83, 89–91]. 13. Williams AJ, Robson H, Kester MH, van Leeuwen JP, Shalet SM,
Visser TJ, Williams GR (2008) Iodothyronine deiodinase enzyme
Acknowledgements G.R.W. and J.H.D.B. are funded by a Wellcome activities in bone. Bone 43(1):126–134
Trust Strategic Award (101123), Wellcome Trust Joint Investigator 14. Brent GA (2012) Mechanisms of thyroid hormone action. J Clin
Award (110140 and 110141) and a European Commission Horizon Invest 122(9):3035–3043. doi:10.1172/JCI60047
2020 Grant (666869, THYRAGE). 15. Huffmeier U, Tietze HU, Rauch A (2007) Severe skeletal dys-
plasia caused by undiagnosed hypothyroidism. Eur J Med Genet
Compliance with ethical standards 50(3):209–215. doi:10.1016/j.ejmg.2007.02.002
16. Salerno M, Micillo M, Di Maio S, Capalbo D, Ferri P, Lettiero
T, Tenore A (2001) Longitudinal growth, sexual maturation and
Conflict of interest On behalf of all authors, the corresponding au- final height in patients with congenital hypothyroidism detected
thor states that there is no conflict of interest. by neonatal screening. Eur J Endocrinol 145(4):377–383
17. Rivkees SA, Bode HH, Crawford JD (1988) Long-term growth
Ethical approval This article does not contain any studies with in juvenile acquired hypothyroidism: the failure to achieve nor-
human participants or animals performed by any of the authors. mal adult stature. N Engl J Med 318(10):599–602. doi:10.1056/
NEJM198803103181003
Informed consent No informed consent. 18. Segni M, Gorman CA (2001) The aftermath of childhood hyper-
thyroidism. J Pediatr Endocrinol Metab 14(Suppl 5):1277–1282
19. Segni M, Leonardi E, Mazzoncini B, Pucarelli I, Pasquino AM
Open Access This article is distributed under the terms of the (1999) Special features of Graves’ disease in early childhood. Thy-
Creative Commons Attribution 4.0 International License (http://crea- roid 9(9):871–877
tivecommons.org/licenses/by/4.0/), which permits unrestricted use, 20. Rasmussen SA, Yazdy MM, Carmichael SL, Jamieson DJ, Can-
distribution, and reproduction in any medium, provided you give appro- field MA, Honein MA (2007) Maternal thyroid disease as a risk
priate credit to the original author(s) and the source, provide a link to factor for craniosynostosis. Obstet Gynecol 110(2 Pt 1):369–377.
the Creative Commons license, and indicate if changes were made. doi:10.1097/01.AOG.0000270157.88896.76
21. Eriksen EF, Mosekilde L, Melsen F (1986) Kinetics of trabecular
bone resorption and formation in hypothyroidism: evidence for a
positive balance per remodeling cycle. Bone 7(2):101–108
22. Mosekilde L, Melsen F (1978) Morphometric and dynamic studies
References of bone changes in hypothyroidism. Acta Pathol Microbiol Scand
86(1):56–62
1. Bassett JH, Williams GR (2016) Role of thyroid hormones in skel- 23. Mosekilde L, Eriksen EF, Charles P (1990) Effects of thyroid
etal development and bone maintenance. Endocr Rev 37(2):135– hormones on bone and mineral metabolism. Endocrinol Metab
187. doi:10.1210/er.2015-1106 Clin N Am 19(1):35–63
2. Rice DP, Rice R (2008) Locate, condense, differentiate, grow and 24. Mosekilde L, Melsen F (1978) Effect of antithyroid treatment
confront: developmental mechanisms controlling intramembra- on calcium-phosphorus metabolism in hyperthyroidism. II: Bone
nous bone and suture formation and function. Front Oral Biol histomorphometry. Acta Endocrinol (Cph) 87(4):751–758
12:22–40. doi:10.1159/0000115030 25. Bours SP, van Geel TA, Geusens PP, Janssen MJ, Janzing HM,
3. Karsenty G, Kronenberg HM, Settembre C (2009) Genetic con- Hoffland GA, Willems PC, van den Bergh JP (2011) Contribu-
trol of bone formation. Ann Rev Cell Dev Biol 25:629–648. tors to secondary osteoporosis and metabolic bone diseases in
doi:10.1146/annurev.cellbio.042308.113308 patients presenting with a clinical fracture. J Clin Endocrinol
4. Kronenberg HM (2003) Developmental regulation of the growth Metab 96(5):1360–1367. doi:10.1210/jc.2010-2135
plate. Nature 423(6937):332–336 26. Patel KV, Brennan KL, Brennan ML, Jupiter DC, Shar A, Davis
5. Bonjour JP, Chevalley T (2014) Pubertal timing, bone acquisition, ML (2014) Association of a modified frailty index with mor-
and risk of fracture throughout life. Endocr Rev 35(5):820–847. tality after femoral neck fracture in patients aged 60 years and
doi:10.1210/er.2014-1007 older. Clin Orthop Relat Res 472(3):1010–1017. doi:10.1007/
6. Raggatt LJ, Partridge NC (2010) Cellular and molecular mecha- s11999-013-3334-7
nisms of bone remodeling. J Biol Chem 285(33):25103–25108. 27. Bauer DC, Ettinger B, Nevitt MC, Stone KL (2001) Risk for
doi:10.1074/jbc.R109.041087 fracture in women with low serum levels of thyroid-stimulating
7. Bonewald LF (2011) The amazing osteocyte. J Bone Miner Res hormone. Ann Intern Med 134(7):561–568
26(2):229–238. doi:10.1002/jbmr.320 28. Blum MR, Bauer DC, Collet TH, Fink HA, Cappola AR, da Costa
8. Khosla S, Westendorf JJ, Oursler MJ (2008) Building bone BR, Wirth CD, Peeters RP, Asvold BO, den Elzen WP, Luben RN,
to reverse osteoporosis and repair fractures. J Clin Invest Imaizumi M, Bremner AP, Gogakos A, Eastell R, Kearney PM,
118(2):421–428. doi:10.1172/JCI33612 Strotmeyer ES, Wallace ER, Hoff M, Ceresini G, Rivadeneira F,
9. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR Uitterlinden AG, Stott DJ, Westendorp RG, Khaw KT, Langham-
(2002) Biochemistry, cellular and molecular biology, and physi- mer A, Ferrucci L, Gussekloo J, Williams GR, Walsh JP, Juni
ological roles of the iodothyronine selenodeiodinases. Endocr Rev P, Aujesky D, Rodondi N, Thyroid Studies Collaboration (2015)
23(1):38–89 Subclinical thyroid dysfunction and fracture risk: a meta-analysis.
10. Andersen S, Bruun NH, Pedersen KM, Laurberg P (2003) Bio- JAMA 313(20):2055–2065. doi:10.1001/jama.2015.5161
logic variation is important for interpretation of thyroid function 29. Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris
tests. Thyroid 13(11):1069–1078 AD, Leese GP (2010) Serum thyroid-stimulating hormone

13
J Endocrinol Invest (2018) 41:99–109 107

concentration and morbidity from cardiovascular disease and 45. Mazziotti G, Porcelli T, Patelli I, Vescovi PP, Giustina A (2010)
fractures in patients on long-term thyroxine therapy. J Clin Serum TSH values and risk of vertebral fractures in euthyroid
Endocrinol Metab 95(1):186–193 post-menopausal women with low bone mineral density. Bone
30. Vestergaard P, Mosekilde L (2002) Fractures in patients 46(3):747–751. doi:10.1016/j.bone.2009.10.031
with hyperthyroidism and hypothyroidism: a nationwide 46. Morris MS (2007) The association between serum thyroid-stimu-
follow-up study in 16,249 patients. Thyroid 12(5):411–419. lating hormone in its reference range and bone status in postmeno-
doi:10.1089/105072502760043503 pausal American women. Bone 40(4):1128–1134
31. Vestergaard P, Rejnmark L, Mosekilde L (2005) Influence of 47. Noh HM, Park YS, Lee J, Lee W (2015) A cross-sectional study
hyper- and hypothyroidism, and the effects of treatment with to examine the correlation between serum TSH levels and the
antithyroid drugs and levothyroxine on fracture risk. Calcif Tis- osteoporosis of the lumbar spine in healthy women with normal
sue Int 77(3):139–144. doi:10.1007/s00223-005-0068-x thyroid function. Osteoporos Int 26(3):997–1003. doi:10.1007/
32. Murphy E, Williams GR (2004) The thyroid and the skeleton. s00198-014-2906-z
Clin Endocrinol (Oxf) 61(3):285–298 48. Roef G, Lapauw B, Goemaere S, Zmierczak H, Fiers T, Kaufman
33. Wirth CD, Blum MR, da Costa BR, Baumgartner C, Collet JM, Taes Y (2011) Thyroid hormone status within the physiologi-
TH, Medici M, Peeters RP, Aujesky D, Bauer DC, Rodondi N cal range affects bone mass and density in healthy men at the age
(2014) Subclinical thyroid dysfunction and the risk for frac- of peak bone mass. Eur J Endocrinol 164(6):1027–1034
tures: a systematic review and meta-analysis. Ann Intern Med 49. Svare A, Nilsen TI, Asvold BO, Forsmo S, Schei B, Bjoro T,
161(3):189–199. doi:10.7326/M14-0125 Langhammer A (2013) Does thyroid function influence fracture
34. Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret risk? Prospective data from the HUNT2 study, Norway. Eur J
GY (1996) Effects on bone mass of long term treatment with Endocrinol 169(6):845–852. doi:10.1530/EJE-13-0546
thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 50. van der Deure WM, Uitterlinden AG, Hofman A, Rivadeneira F,
81(12):4278–4289 Pols HA, Peeters RP, Visser TJ (2008) Effects of serum TSH and
35. Quan ML, Pasieka JL, Rorstad O (2002) Bone mineral density FT4 levels and the TSHR-Asp727Glu polymorphism on bone: the
in well-differentiated thyroid cancer patients treated with sup- Rotterdam Study. Clin Endocrinol (Oxf) 68(2):175–181
pressive thyroxine: a systematic overview of the literature. J 51. van Rijn LE, Pop VJ, Williams GR (2014) Low bone mineral
Surg Oncol 79(1):62–69 density is related to high physiological levels of free thyroxine
36. Heemstra KA, Hamdy NA, Romijn JA, Smit JW (2006) The in peri-menopausal women. Eur J Endocrinol 170(3):461–468.
effects of thyrotropin-suppressive therapy on bone metabolism doi:10.1530/EJE-13-0769
in patients with well-differentiated thyroid carcinoma. Thyroid 52. Aubert CE, Floriani C, Bauer DC, da Costa BR, Segna D, Blum
16(6):583–591 MR, Collet TH, Fink HA, Cappola AR, Syrogiannouli L, Peeters
37. Faber J, Galloe AM (1994) Changes in bone mass dur- RP, Asvold BO, den Elzen WP, Luben RN, Bremner AP, Goga-
ing prolonged subclinical hyperthyroidism due to l -thy- kos A, Eastell R, Kearney PM, Hoff M, Le Blanc E, Ceresini
roxine treatment: a meta-analysis. Eur J Endocr inol G, Rivadeneira F, Uitterlinden AG, Khaw KT, Langhammer A,
130(4):350–356 Stott DJ, Westendorp RG, Ferrucci L, Williams GR, Gussekloo
38. Yang R, Yao L, Fang Y, Sun J, Guo T, Yang K, Tian L (2017) J, Walsh JP, Aujesky D, Rodondi N, Thyroid Studies Collabo-
The relationship between subclinical thyroid dysfunction and ration (2017) Thyroid function tests in the reference range and
the risk of fracture or low bone mineral density: a systematic fracture: individual participant analysis of prospective cohorts. J
review and meta-analysis of cohort studies. J Bone Miner Clin Endocrinol Metab. doi:10.1210/jc.2017-00294
Metab. doi:10.1007/s00774-017-0828-5 53. Mazzaferri EL, Jhiang SM (1994) Long-term impact of initial
39. Abrahamsen B, Jorgensen HL, Laulund AS, Nybo M, Brix TH, surgical and medical therapy on papillary and follicular thyroid
Hegedus L (2014) Low serum thyrotropin level and duration of cancer. Am J Med 97(5):418–428
suppression as a predictor of major osteoporotic fractures-the 54. Pujol P, Daures JP, Nsakala N, Baldet L, Bringer J, Jaffiol C
OPENTHYRO register cohort. J Bone Miner Res 29(9):2040– (1996) Degree of thyrotropin suppression as a prognostic deter-
2050. doi:10.1002/jbmr.2244 minant in differentiated thyroid cancer. J Clin Endocrinol Metab
40. Murphy E, Gluer CC, Reid DM, Felsenberg D, Roux C, Eastell 81(12):4318–4323. doi:10.1210/jcem.81.12.8954034
R, Williams GR (2010) Thyroid function within the upper nor- 55. Cooper DS, Specker B, Ho M, Sperling M, Ladenson PW, Ross
mal range is associated with reduced bone mineral density and DS, Ain KB, Bigos ST, Brierley JD, Haugen BR, Klein I, Rob-
an increased risk of nonvertebral fractures in healthy euthyroid bins J, Sherman SI, Taylor T, Maxon HR 3rd (1998) Thyrotropin
postmenopausal women. J Clin Endocrinol Metab 95(7):3173– suppression and disease progression in patients with differentiated
3181. doi:10.1210/jc.2009-2630 thyroid cancer: results from the National Thyroid Cancer Treat-
41. Grimnes G, Emaus N, Joakimsen RM, Figenschau Y, Jorde R ment Cooperative Registry. Thyroid 8(9):737–744
(2008) The relationship between serum TSH and bone mineral 56. Williams GR (2014) Is prophylactic anti-resorptive therapy
density in men and postmenopausal women: the Tromso study. required in thyroid cancer patients receiving TSH-suppressive
Thyroid 18(11):1147–1155 treatment with thyroxine? J Endocrinol Invest 37(8):775–779.
42. Hwangbo Y, Kim JH, Kim SW, Park YJ, Park DJ, Kim SY, Shin doi:10.1007/s40618-014-0110-9
CS, Cho NH (2015) High-normal free thyroxine levels are asso- 57. Biondi B, Wartofsky L (2014) Treatment with thyroid hormone.
ciated with low trabecular bone scores in euthyroid postmeno- Endocr Rev 35(3):433–512. doi:10.1210/er.2013-1083
pausal women. Osteoporos Int. doi:10.1007/s00198-015-3270-3 58. Sharma A, Einstein AJ, Vallakati A, Arbab-Zadeh A, Walker MD,
43. Kim DJ, Khang YH, Koh JM, Shong YK, Kim GS (2006) Low Mukherjee D, Homel P, Borer JS, Lichstein E (2014) Risk of atrial
normal TSH levels are associated with low bone mineral den- fibrillation with use of oral and intravenous bisphosphonates. Am
sity in healthy postmenopausal women. Clin Endocrinol (Oxf) J Cardiol 113(11):1815–1821. doi:10.1016/j.amjcard.2014.03.008
64(1):86–90 59. Vescini F, Attanasio R, Balestrieri A, Bandeira F, Bonadonna
44. Lin JD, Pei D, Hsia TL, Wu CZ, Wang K, Chang YL, Hsu CH, S, Camozzi V, Cassibba S, Cesareo R, Chiodini I, Francucci
Chen YL, Chen KW, Tang SH (2011) The relationship between CM, Gianotti L, Grimaldi F, Guglielmi R, Madeo B, Marcocci
thyroid function and bone mineral density in euthyroid healthy C, Palermo A, Scillitani A, Vignali E, Rochira V, Zini M (2016)
subjects in Taiwan. Endocr Res 36(1):1–8 Italian association of clinical endocrinologists (AME) position

13
108 J Endocrinol Invest (2018) 41:99–109

statement: drug therapy of osteoporosis. J Endocrinol Invest mutations in the thyroid hormone receptor alpha gene (THRA). J
39(7):807–834. doi:10.1007/s40618-016-0434-8 Med Genet 52(5):312–316. doi:10.1136/jmedgenet-2014-102936
60. Papadimitriou A, Papadimitriou DT, Papadopoulou A, Nico- 72. van Gucht AL, Meima ME, Zwaveling-Soonawala N, Visser WE,
laidou P, Fretzayas A (2007) Low TSH levels are not asso- Fliers E, Wennink JM, Henny C, Visser TJ, Peeters RP, van Trot-
ciated with osteoporosis in childhood. Eur J Endocrinol senburg AS (2016) Resistance to thyroid hormone alpha in an
157(2):221–223 18-month-old girl: clinical, therapeutic, and molecular character-
61. Bretones P, Duprez L, Parma J, David M, Vassart G, Rodien P istics. Thyroid 26(3):338–346. doi:10.1089/thy.2015.0463
(2001) A familial case of congenital hypothyroidism caused by a 73. van Mullem A, van Heerebeek R, Chrysis D, Visser E, Medici M,
homozygous mutation of the thyrotropin receptor gene. Thyroid Andrikoula M, Tsatsoulis A, Peeters R, Visser TJ (2012) Clinical
11(10):977–980. doi:10.1089/105072501753211064 phenotype and mutant TRalpha1. N Engl J Med 366(15):1451–
62. Sunthornthepvarakui T, Gottschalk ME, Hayashi Y, Refetoff S 1453. doi:10.1056/NEJMc1113940
(1995) Brief report: resistance to thyrotropin caused by mutations 74. van Mullem AA, Chrysis D, Eythimiadou A, Chroni E, Tsatsoulis
in the thyrotropin-receptor gene. N Engl J Med 332(3):155–160. A, de Rijke YB, Visser WE, Visser TJ, Peeters RP (2013) Clinical
doi:10.1056/NEJM199501193320305 phenotype of a new type of thyroid hormone resistance caused by
63. Chawla R, Alden TD, Bizhanova A, Kadakia R, Brickman W, a mutation of the TRalpha1 receptor: consequences of LT4 treat-
Kopp PA (2015) Squamosal suture craniosynostosis due to hyper- ment. J Clin Endocrinol Metab 98(7):3029–3038. doi:10.1210/
thyroidism caused by an activating thyrotropin receptor mutation jc.2013-1050
(T632I). Thyroid. doi:10.1089/thy.2014.0503 75. Yuen RK, Thiruvahindrapuram B, Merico D, Walker S, Tam-
64. Fuhrer D, Wonerow P, Willgerodt H, Paschke R (1997) Identifica- mimies K, Hoang N, Chrysler C, Nalpathamkalam T, Pellecchia
tion of a new thyrotropin receptor germline mutation (Leu629Phe) G, Liu Y, Gazzellone MJ, D’Abate L, Deneault E, Howe JL, Liu
in a family with neonatal onset of autosomal dominant nonautoim- RS, Thompson A, Zarrei M, Uddin M, Marshall CR, Ring RH,
mune hyperthyroidism. J Clin Endocrinol Metab 82(12):4234– Zwaigenbaum L, Ray PN, Weksberg R, Carter MT, Fernandez
4238. doi:10.1210/jcem.82.12.4405 BA, Roberts W, Szatmari P, Scherer SW (2015) Whole-genome
65. Refetoff S, Bassett JH, Beck-Peccoz P, Bernal J, Brent G, Chat- sequencing of quartet families with autism spectrum disorder. Nat
terjee K, De Groot LJ, Dumitrescu AM, Jameson JL, Kopp PA, Med 21(2):185–191. doi:10.1038/nm.3792
Murata Y, Persani L, Samarut J, Weiss RE, Williams GR, Yen 76. Moran C, Agostini M, McGowan A, Schoenmakers E, Fairall L,
PM (2014) Classification and proposed nomenclature for inherited Lyons G, Rajanayagam O, Watson L, Offiah A, Barton J, Price S,
defects of thyroid hormone action, cell transport, and metabo- Schwabe J, Chatterjee K (2017) Contrasting phenotypes in resist-
lism. J Clin Endocrinol Metab 99(3):768–770. doi:10.1210/ ance to thyroid hormone alpha correlate with divergent proper-
jc.2013-3393 ties of thyroid hormone receptor alpha1 mutant proteins. Thyroid
66. Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, 27(7):973–982. doi:10.1089/thy.2017.0157
Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, 77. Schoenmakers N, Moran C, Peeters RP, Visser T, Gurnell M,
Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe Chatterjee K (2013) Resistance to thyroid hormone mediated by
JW, Bain M, Lindley K, Muntoni F, Khadem FV, Dattani M, defective thyroid hormone receptor alpha. Biochim Biophys Acta
Farooqi IS, Gurnell M, Chatterjee K (2012) A mutation in the thy- 1830(7):4004–4008. doi:10.1016/j.bbagen.2013.03.018
roid hormone receptor alpha gene. N Engl J Med 366(3):243–249. 78. van Mullem AA, Visser TJ, Peeters RP (2014) Clinical conse-
doi:10.1056/NEJMoa1110296 quences of mutations in thyroid hormone receptor-α1. Eur Thy-
67. Demir K, van Gucht AL, Buyukinan M, Catli G, Ayhan Y, Nijat roid J 3:17–24
Bas V, Dundar B, Ozkan B, Meima ME, Edward Visser W, Peeters 79. Vlaeminck-Guillem V, Espiard S, Flamant F, Wemeau JL (2015)
RP, Visser TJ (2016) Diverse genotypes and phenotypes of three TRalpha receptor mutations extend the spectrum of syndromes of
novel thyroid hormone receptor alpha mutations. J Clin Endo- reduced sensitivity to thyroid hormone. Presse Med 44(11):1103–
crinol Metab. doi:10.1210/jc.2016-1404 1112. doi:10.1016/j.lpm.2015.07.022
68. Espiard S, Savagner F, Flamant F, Vlaeminck-Guillem V, Guyot 80. Bassett JH, Boyde A, Zikmund T, Evans H, Croucher PI, Zhu X,
R, Munier M, d’Herbomez M, Bourguet W, Pinto G, Rose C, Park JW, Cheng SY, Williams GR (2014) Thyroid hormone recep-
Rodien P, Wemeau JL (2015) A novel mutation in THRA gene tor alpha mutation causes a severe and thyroxine-resistant skel-
associated with an atypical phenotype of resistance to thyroid hor- etal dysplasia in female mice. Endocrinology 155(9):3699–3712.
mone. J Clin Endocrinol Metab 100(8):2841–2848. doi:10.1210/ doi:10.1210/en.2013-2156
jc.2015-1120 81. Bassett JH, Nordstrom K, Boyde A, Howell PG, Kelly S,
69. Moran C, Agostini M, Visser WE, Schoenmakers E, Schoenmak- Vennstrom B, Williams GR (2007) Thyroid status during skeletal
ers N, Offiah AC, Poole K, Rajanayagam O, Lyons G, Halsall D, development determines adult bone structure and mineralization.
Gurnell M, Chrysis D, Efthymiadou A, Buchanan C, Aylwin S, Mol Endocrinol 21(8):1893–1904. doi:10.1210/me.2007-0157
Chatterjee KK (2014) Resistance to thyroid hormone caused by 82. Desjardin C, Charles C, Benoist-Lasselin C, Riviere J, Gilles M,
a mutation in thyroid hormone receptor (TR)alpha1 and TRal- Chassande O, Morgenthaler C, Laloe D, Lecardonnel J, Flamant
pha2: clinical, biochemical, and genetic analyses of three related F, Legeai-Mallet L, Schibler L (2014) Chondrocytes play a major
patients. Lancet Diabetes Endocrinol 2(8):619–626. doi:10.1016/ role in the stimulation of bone growth by thyroid hormone. Endo-
S2213-8587(14)70111-1 crinology. doi:10.1210/en.2014-1109
70. Moran C, Schoenmakers N, Agostini M, Schoenmakers E, Offiah 83. O’Shea PJ, Bassett JH, Sriskantharajah S, Ying H, Cheng SY,
A, Kydd A, Kahaly G, Mohr-Kahaly S, Rajanayagam O, Lyons Williams GR (2005) Contrasting skeletal phenotypes in mice
G, Wareham N, Halsall D, Dattani M, Hughes S, Gurnell M, Park with an identical mutation targeted to thyroid hormone receptor
SM, Chatterjee K (2013) An adult female with resistance to thy- alpha1 or beta. Mol Endocrinol 19(12):3045–3059. doi:10.1210/
roid hormone mediated by defective thyroid hormone receptor me.2005-0224
alpha. J Clin Endocrinol Metab. doi:10.1210/jc.2013-2215 84. Quignodon L, Vincent S, Winter H, Samarut J, Flamant F (2007)
71. Tylki-Szymanska A, Acuna-Hidalgo R, Krajewska-Walasek M, A point mutation in the activation function 2 domain of thyroid
Lecka-Ambroziak A, Steehouwer M, Gilissen C, Brunner HG, hormone receptor alpha1 expressed after CRE-mediated recom-
Jurecka A, Rozdzynska-Swiatkowska A, Hoischen A, Chrzanow- bination partially recapitulates hypothyroidism. Mol Endocrinol
ska KH (2015) Thyroid hormone resistance syndrome due to 21(10):2350–2360. doi:10.1210/me.2007-0176

13
J Endocrinol Invest (2018) 41:99–109 109

85. Williams GR (2014) Role of thyroid hormone receptor-alpha1 89. Bassett JH, O’Shea PJ, Sriskantharajah S, Rabier B, Boyde A,
in endochondral ossification. Endocrinology 155(8):2747–2750. Howell PG, Weiss RE, Roux JP, Malaval L, Clement-Lacroix P,
doi:10.1210/en.2014-1527 Samarut J, Chassande O, Williams GR (2007) Thyroid hormone
86. Dumitrescu AM, Refetoff S (2013) The syndromes of reduced sen- excess rather than thyrotropin deficiency induces osteoporosis in
sitivity to thyroid hormone. Biochim Biophys Acta 1830(7):3987– hyperthyroidism. Mol Endocrinol 21(5):1095–1107
4003. doi:10.1016/j.bbagen.2012.08.005 90. O’Shea PJ, Bassett JH, Cheng SY, Williams GR (2006) Charac-
87. Refetoff S, DeWind LT, DeGroot LJ (1967) Familial syndrome terization of skeletal phenotypes of TRalpha1 and TRbeta mutant
combining deaf-mutism, stippled epiphyses, goiter and abnor- mice: implications for tissue thyroid status and T3 target gene
mally high PBI: possible target organ refractoriness to thyroid expression. Nucl Recept Signal 4:e011. doi:10.1621/nrs.04011
hormone. J Clin Endocrinol Metab 27(2):279–294 91. O’Shea PJ, Harvey CB, Suzuki H, Kaneshige M, Kaneshige K,
88. Sakurai A, Takeda K, Ain K, Ceccarelli P, Nakai A, Seino S, Cheng SY, Williams GR (2003) A thyrotoxic skeletal phenotype
Bell GI, Refetoff S, DeGroot LJ (1989) Generalized resistance to of advanced bone formation in mice with resistance to thyroid
thyroid hormone associated with a mutation in the ligand-binding hormone. Mol Endocrinol 17(7):1410–1424
domain of the human thyroid hormone receptor beta. Proc Natl
Acad Sci USA 86(22):8977–8981

13