**3. Thyroid hormones and skeletal growth in infancy and adolescence**

In prepubertal children, the linear growth is controlled mainly by GH-IGF-I axis, with influence from glucocorticoids and thyroid hormones. Thyroid hormones were shown to play an essential role for normal onset of the childhood component of growth (Heyerdahl, 1997). Role of the GH/IGF-I axis in the regulation of thyroid gland growth has recently been demonstrated (Boas et al, 2009). During pubertal period, sex steroids are important coregulators of skeletal growth. Age related consequences of thyroid dysfunction on bone development have largely been described. Nevertheless, the exact role of thyroid hormone in the peak bone mass acquisition during childhood and early adulthood is not well understood. The same is for the gender specific action of T3 in the developing skeleton (Gauthier et al, 1999).

Euthyroid status is essential for normal skeletal development and linear growth. Generalized retardation in endochondral and intramembranous ossification associated with alterations in the EGPs, such as reduced thickness, disorganized columns of chondrocytes, and impaired differentiation of hypertrophic chondrocytes, have been reported in hypothyroid status during development (Lewinson et al, 1989; Stevens et al, 2000). The clinical consequences are reduced growth and skeletal abnormalities (Allain & McGregor, 1993). Theodore Kocher was awarded the Nobel Prize in Medicine in 1909 for his description of consequences of thyroidectomy. He showed the impact of hypothyroidism on the child growth (Kocher, 1883). Hypothyroid children present with the growth retardation and disproportionately short limbs in relation to the trunk. Radiographic skeletal examination may reveal, depending on the age and onset of hypothyroidism, a delayed closure of the fontanelles, enlargement of pituitary fossa and epiphyseal dysgenesis. Reilly & Smyth have described in 1937 stippled appearance of epiphyses on X-ray films in hypothyroid children. The pathognomonic nature of these changes was later confirmed by Wilkis (Wilkis, 1941). Epiphyseal dysgenesis has been demonstrated in the ossification centers that normally ossify after the onset of the hypothyroid status. Delayed appearance of ossification centers and delayed bone age are also noted in hypothyroid children. BMD

seems to be also affected by a hypothyroid status during childhood. In one cross-sectional study, BMD was reported to be lower in prepubertal children with congenital hypothyroidism than in controls (Demartini et al, 2007).

Thyroid Disorders and Bone Mineral Homeostasis 257

also been reported, but has not been confirmed by others (Lee et al, 2006, 2010; Bertoli et al, 2002). Overall, the literature data have so far presented conflicting results. We will review the current literature and discuss changes in the bone metabolism, BMD and fracture risk in

Slight perturbations in some parameters of bone and mineral metabolism have been reported in hypothyroid patients. Minor abnormalities of calcium metabolism may exist with slightly elevated serum calcium, PTH and 1,25(OH)2 vitamin D, decreased level of alkaline phosphatase, decreased urinary calcium excretion and glomerular filtration rate. The exchangeable pool of calcium and its rate of turnover may be reduced, reflecting decreased bone formation and resorption. However, these changes seem not to be different, even during the treatment, in hypothyroid patients compared to euthyroid controls

Large population based studies identified an increased fracture risk in individuals with hypothyroidism (Vestegaard et al 2000; 2002). The first of these studies (Vestegaard et al, 2000) analyzed 408 patients with primary hypothyroidism and found a temporary increase in fracture risk within the first 2 years after diagnosis, mainly in the age group >50 years, and was limited to the forearms. In the following study (Vestegaard, 2002), 4473 patients with autoimmune hypothyroidism (mean age, 66.1 +/- 17.3) were shown to present a significantly increased fracture risk up to 8 years prior to diagnosis with a peak around the time of diagnosis. The fracture risk was found to return to normal more than 5 years after its

An increased fracture risk in hypothyroid patients is not probably due to modifications of bone density. There are no convincing literature data as to changes in bone architecture during hypothyroidism. Neuromuscular symptoms and impaired muscle energy metabolism could be responsible for bone changes in this population. Hypothyroid patients have been shown to display impaired neuromuscular response to exercise persisting even

Subclinical hypothyroidism is a relatively frequent clinical condition, particularly among aged population, characterized by a low-normal free T4 level and a slightly elevated TSH level. The prevalence of subclinical hypothyroidism has been reported between 3.9 and 6.5%

In Trosmo study, Grimnes et al. (2008) have demonstrated that, after multivariate adjustment, 25 out of 950 postmenopausal women with serum TSH above the 97.5 percentile had significantly higher BMD at the femoral neck than women with serum TSH in the

adult men and women with overt and subclinical hypothyroidism.

*4.1.1. Mineral metabolism in hypothyroidism* 

*4.1.2. Overt hypothyroidism and skeletal changes* 

after restoration of euthyroid status (Caraccio et al, 2005).

*4.1.3. Subclinical hypothyroidism and skeletal changes* 

(Hollowell et al, 2002; Huber et al, 2002)

(Sabuncu et al, 2001).

diagnosis.

Treatment with thyroxine results in a period of rapid catch-up growth, although predicted final height based on midparental height calculations may not be achieved, particularly when hypothyroidism is prolonged (Rivkees et al, 1988). The LT4 replacement for 8 years in children with congenital hypothyroidism did not have a negative effect on BMD for the lumbar spine and the femoral site and on biochemical markers of bone turnover (Leger et al, 1997). The results showed normal serum levels of calcium, phosphate, alkaline phosphatase, parathyroid hormone and 25-hydroxyvitamin D and did not demonstrate any relationship between BMD and L-T4 dosage or biochemical markers of bone formation. These findings were confirmed by other studies reporting no alterations of bone mass in adolescents and young adults with congenital hypothyroidism, treated from the neonatal period (Salerno et al, 2004, Demeester-Mirkine et al, 1990).

On the other hand, thyroid hormone excess results in accelerated skeletal maturation, premature closure of the EGPs and subsequent decrease in longitudinal bone growth with a compromised final adult height (Allain & McGregor, 1993; O'Shea et al, 1993; Harvey et al, 2002). In severe cases, hyperthyroidism during early childhood may also cause craniosynostosis due to premature fusion of the sutures of the skull (Segni et al 1999). Low bone density values and high bone resorption rates were demonstrated at diagnosis of hyperthyroidism in children and adolescents (Mora et al, 1999). Successful treatment of hyperthyroidism was shown to increase BMD in children and improve the conditions for the best obtainable peak bone mass (Mora et al, 1999).

Consequences of syndrome of resistance to thyroid hormone (RTH) on the skeletal development have been described in literature. RTH results from dominant negative mutations in the carboxyl terminus of the thyroid hormone receptor β gene. The mutant receptors are transcriptionally impaired and inhibit thyroid hormone receptor action. RTH is characterized by phenotypic variability including skeletal manifestations (Weiss et Refetoff, 2000). Our current understanding is based mainly on the published case reports. Involvement of the skeleton can cause a short stature, advanced or delayed bone age, increased bone turnover, osteoporosis, fractures, craniofacial abnormalities and craniosynostosis. The clinical variability might be secondary to functional properties of mutant proteins and heterogeneity of cofactors mediating action of TR (Kvistad et al, 2004).
