**7. Bone effects of thyroid hormone analogues**

262 Thyroid Hormone

premenopausal women (Quan et al, 2002; Heemstra et al, 2006). However, both reviews found methodological differences between different studies, making a structured metaanalysis impossible. Lately, a randomized prospective controlled trial has shown significant adverse effects of TSH suppressive therapy on BMD in women ≥ 50 years of age (Sugitani et Fujimoto, 2011). However, the results have not been adjusted for confounding factors, such

Overall, literature data enhance the hypothesis that low TSH levels may have a deleterious effect on bone homeostasis. Nevertheless, the exact relationship between subclinical

We previously discussed (see paragraph 1.2) the role of TSH in the control of bone remodeling in animal models (Abe E, Marians RC et al, 2003). Systemic administration of TSH to ovariectomised rats has been shown to prevent bone loss and restore bone mass (Sampath et al, 2007; Sun et al, 2008) have demonstrated that intermittent administration of exogenous TSH in ovariectomised rats and mice have anti-resorptive effects. Recent findings indicate that TSH might play a crucial role in bone turnover in humans. Bone loss has been

There is a growing body of evidence that variations of TSH even in its reference range may influence BMD. A higher BMD has been reported in postmenopausal women with TSH within the physiological range comparing to these with the low level of TSH (Baqi et al, 2010). Clinical observations show that patients with subclinical hyperthyroidism and normal circulating thyroid hormone levels display osteoporotic changes (De Menis et al, 1992; Kisakol et al, 2003). Strong correlation between serum TSH and bone status has been demonstrated in postmenopausal women (Bauer et al, 2001; Morris et al, 2007). Based on these findings it has been suggested that it is the suppressed TSH rather than the elevated thyroid hormones that exert a deleterious effect on bone density. In a recent observational study, low-normal TSH values were shown to be associated with high prevalence of vertebral fractures in women with post-menopausal osteoporosis or osteopenia, even after correction for age, BMD, BMI and serum free-thyroxine values (Mazziotti et al, 2010). Svare et al, 2009, in a cross-sectional, population-based study, analyzed 5778 women without and 944 with self-reported thyroid disease aged >40 years. Women with the TSH level <0.50 mU/l had lower forearm BMD than the reference group and the prevalence of osteoporosis was higher in women who reported hyperthyroidism than in women without self-reported thyroid disease. Finally, Kim et al, 2010 investigated the association between serum thyrotropin (TSH) concentration and bone mineral density (BMD) in 1478 healthy euthyroid men in a cross-sectional community based survey. Lumbar spine BMD and femoral neck BMD were shown to increase with TSH level after adjustment for age, weight and height. The odds of lower BMD were significantly increased in subjects with low-normal TSH, when compared to high-normal TSH after adjustment for confounding factors. These results

shown in women with polymorphism in the TSHR gene (Onigata et al, 2005).

as menopause status, dietary calcium, vitamin D intake, and smoking.

hyperthyroidism and osteoporosis remains to be explained.

**6. TSH as a metabolic regulator** 

Synthetic analogues of thyroid hormones display tissue-specific actions (Baxter and Webb 2009). They have been developed for their lipid lowering activity by preferential activation of the TRβ1 isoform in the liver while sparing the TRα1 mediated cardiac effects (Angelin & Rudling, 2010; Pramfalk et al., 2010; Webb, 2010). Previous animal and human studies have demonstrated that thyromimetics can influence bone metabolism. Skeletal effects of thyroid hormone analogues recently reported in literature on cell lines, animal models and humans are summarized in Table 1.

Previously studied selective thyromimetic, tiratricol (3,5,3'-triiodothyroacetic acid; Triac) was shown to enhance skeletal metabolic activity (Sherman, et al 1997) and to produce adverse effects on bone metabolism (Alvarez et al 2004; Brenta et al 2003; Kawaguchi et al 1994a, 1994b). DITPA, 3,5-diiodothyropropionic acid, has a higher affinity for the TRβ compared to the TRα. Administration of DITPA to humans for 24 weeks was associated with a significant rise in serum osteocalcin, N-telopeptide, and deoxypyridinoline levels, indicating an increased bone turnover (Ladenson el al 2010b). GC-1, [3,5-dimethyl-4-(4′ hydroxy-3′isopropylbenzyl)-phenoxy acetic acid], binds TRβ1 with the same affinity as T3, but TRα1 with a 10-fold lower affinity (Scanlan, 2010). Bone sparing effects in adult female rats have been observed after treatment by GC-1 for 64 days (Freitas et al, 2003). In another


Thyroid Disorders and Bone Mineral Homeostasis 265

study, partial reversion of the skeletal development and maturation defects has been shown in hypothyroid rats after 5 week therapy by GC-1 (Freitas et al 2005). Eprotirome, (KB2115), 3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid, displays a higher affinity for TRβ1 isoform with hepatic uptake (Berkenstam 2008). Administration of eprotirome to humans for 12 weeks has not been associated with

Altogether the data are consistent with potentially adverse skeletal effects of thyroid hormone analogues. However, no conclusive evidence can be drawn and further investigations would be justified to establish an accurate benefice/risk ratio before their

The last decades have seen an increasing interest in the action of thyroid hormones in bone mineral homeostasis. *In vivo* and *in vitro* studies in cell lines as well as animal models have demonstrated a critical role of thyroid hormones, TSH and their receptors in the skeletal growth and its maintenance. However, many of the molecular mechanisms of thyroid

Clinical studies, consistently with animal data, indicate a close association between thyroid status and bone metabolism. Thyrotoxicosis results in an increased bone turnover, osteoporosis and a risk of fragility fracture. Thyroid hormone deficiency decreases bone turnover with a subsequent risk of bone fragility. Exogenous administration of suppressive doses of thyroxine was shown to negatively influences BMD and bone turnover. In future, prospective studies a prolonged time of observation will be necessary, as well as to increase the number of studied patients, in order to better assess the relative risk of osteoporosis in patients undergoing TSH-suppressive treatment. Another question that remains to be answered is if there is a benefit from treatment of subclinical thyroid disease on skeletal

Finally, thyroid hormone analogues represent a promising therapeutic option for their lipid lowering activity. Nevertheless, literature data suggest their potentially adverse skeletal effects. No conclusive evidence can be drawn and further investigations would be justified

to establish an accurate benefice/risk ratio before their clinical use.

*Department of Pediatric Endocrinology, CHU Nancy, Vandoeuvre, France* 

*Department of Endocrinology, CHU Nancy, Vandoeuvre, France* 

Eva Feigerlova, Marc Klein, Anna Angelousi, Lelia Groza and Georges Weryha\*

unfavorable bone effects (Ladenson et al 2010a).

hormone action remain still poorly defined.

clinical use.

health.

**Author details** 

Bruno Leheup

Corresponding Author

 \*

**8. Conclusion** 

**Table 1. Skeletal effects of thyroid hormone analogues:** b-ALP – bone alcalic phosphatase; BMD bone mineral density; EGP - epiphyseal growth plate; HC – hypertrophic chondrocytes; ns – non significant; PINP - procollagen type I N-terminal propeptide

study, partial reversion of the skeletal development and maturation defects has been shown in hypothyroid rats after 5 week therapy by GC-1 (Freitas et al 2005). Eprotirome, (KB2115), 3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid, displays a higher affinity for TRβ1 isoform with hepatic uptake (Berkenstam 2008). Administration of eprotirome to humans for 12 weeks has not been associated with unfavorable bone effects (Ladenson et al 2010a).

Altogether the data are consistent with potentially adverse skeletal effects of thyroid hormone analogues. However, no conclusive evidence can be drawn and further investigations would be justified to establish an accurate benefice/risk ratio before their clinical use.
