**5.1. Thyroid hormone replacement therapy**

The objective of thyroid hormone replacement therapy is to normalize TSH levels. Some authors have suggested that treatment with levothyroxine may cause long-term osteoporosis, but there is no evidence to support this theory, and studies have shown no difference in bone density or fracture risk in patients undergoing treatment.

Previously, the effects of thyroid hormone treatment upon lumbar spine BMD were studied in a consecutive series of patients with myxedema. Patients with myxoedema did not differ from normal individuals as regards initial lumbar BMD, but levothyroxine-treatment caused a significant reduction in this variable. The median decrease in lumbar BMC after 1 year was 8.9% (95% confidence limits 1.5-15.4%, P less than 0.05). This loss of bone might be attributed to an inappropriate increase in bone turnover in the euthyroid status (Krolner et al, 1983). Accelerated bone turnover was shown to occur in women with subclinical hypothyroidism during replacement L-T4 treatment and normal TSH levels (Meier et al, 2004; Tarraga Lopez et al, 2011). In these women, bone loss was attributed to an adaptive mechanism on decreased bone turnover in pre-existent hypothyroidism. Finally, a long-term L-T4 treatment in children and adolescents with congenital hypothyroidism, diffuse goiter or with chronic lymphocytic thyroiditis did not affect BMD nor had a negative effect on the attainment of peak bone mass (Kooh et al, 1996; Saggese et al, 1996; Tumer et al, 1999). These results suggest that careful regulation of thyroid replacement is critical. Significant effects of prolonged L-T4-replacement therapy on bone tissue in patients with congenital hypothyroidism can be avoided by careful monitoring of serum TSH and adjustment of doses of L-T4 (Salerno et al, 2004).

### **5.2. Thyroid hormone suppressive therapy**

260 Thyroid Hormone

discussed.

(Vestergaard et al, 2005).

*4.2.3. Subclinical hyperthyroidism and skeletal changes* 

associated with low BMD in men (Kim et al, 2010).

**5.1. Thyroid hormone replacement therapy** 

Decreased bone density in hyperthyroid patients tended to normalize under treatment (Wejda et al, 1995, Jodar et al, 1997). The improvement of BMD was noted even though no other specific anti-osteoporotic measures were introduced. The type of treatment of hyperthyroidism, iodine 131 or anti-thyroid drugs was not shown to alter the fracture risk

Subclinical hyperthyroidism is defined as subnormal serum TSH with normal serum free thyroid hormones without signs or symptoms of thyrotoxicosis. Its prevalence in the U.S. population has been reported 0.7% (Hollowell et al, 2002). By definition, such patients should not have any clinical abnormalities associated with thyrotoxicosis (Biondi et al, 2005). However, a reduced bone mass was reported among postmenopausal patients (Bauer et al 2001). These observations could thus have a broader impact on the healthcare systems, as the subclinical hyperthyroidism is more frequent than overt thyrotoxicosis (Hollowell et al, 2002). Improvement of bone mineral density was shown in postmenopausal women with subclinical hyperthyroidism after normalization of their thyroid function (Faber et al, 1998). These data would justify indications of treatment in the older population. However, the

On the other hand, the bone mineral density of the lumbar spine, femoral neck and the midshaft of the radius were not significantly decreased in premenopausal women (Foldes et al, 1993). The impact of subclinical hyperthyroidism in men is less known. A recent work suggests that a serum TSH concentration at the lower end of the reference range may be

Effects of thyroid replacement therapy or thyroid suppressive therapy on bone mineral density (BMD) are controversial. Results of previous studies are confounded by differences in study design, insufficient prospective data and small numbers of subjects. In the population study by Vestergaard et al (2005), the use of anti-thyroid drugs was associated with a significantly reduced fracture risk, no effect of levothyroxine on fracture risk was observed. No influence of L-thyroxine therapy on BMD was reported in young adults with congenital hypothyroidism (Salerno et al, 2004). Recently published population based casecontrol study has demonstrated a significantly increased fracture risk in adults over 70 years treated by levothyroxine (Turner et al, 2011). Publications on the association between the thyroid replacement and suppressive treatments and the bone mineral metabolism will be

The objective of thyroid hormone replacement therapy is to normalize TSH levels. Some authors have suggested that treatment with levothyroxine may cause long-term

risk/benefit ratio needs to be demonstrated by long-term, randomized studies.

**5. Impact of thyroid hormone treatment on bone metabolism** 

Treatment with thyroid hormones with the objective to suppress TSH levels is used for example after surgery and radioiodine in differentiated thyroid carcinomas. The patients are maintained in subclinical hyperthyroidism, a condition associated with increased bone turnover.

Previous studies indicated that adults receiving high doses of L-T4-replacement therapy may be at risk of excessive bone loss. Reduction in BMD was observed after exogenous administration of high L-T4 doses used to fully suppress TSH in cases of thyroid cancer, goiters or nodules. Further, a review of cross-sectional and prospective studies examining the effect of thyroid hormone suppression on skeletal integrity in adults showed neither significant negative effect nor a decrease in BMD (Greenspan et al, 1990). Conflicting results were reported also in children. A significant reduction in peripheral BMD was found in children and adolescents receiving suppressive doses of L-T4 treatment for endemic goiter, Hashimoto's thyroiditis or thyroid cancer (Radetti et al, 1993).

More recently, suppression of TSH in hyperthyroidism or after thyroid hormone treatment has been shown to result in decrease in BMD and increase in fracture risk in postmenopausal women (Vestergaard et al, 2000; Bauer et al, 2001; Jamal et al, 2005; Kim et al, 2006). Similar results have been demonstrated in premenopausal women and men by Karner et al (2005). Recently realized systematic reviews analyzing effects of subclinical hyperthyroidism showed that postmenopausal women with subclinical hyperthyroidism may present an increased risk, whereas no increased risk has been demonstrated in men and

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

Thyroid Disorders and Bone Mineral Homeostasis 263

suggested that a serum TSH concentration at the lower end of the reference range may be

The role of TSH on bone metabolism has also been analyzed through markers of bone metabolism after administration of recombinant TSH (rhTSH). TSH has been demonstrated to activate directly osteoblasts according to the increased levels of N-terminal propeptide of type I procollagen (PINP) (Martini et al, 2008). Others showed that TSH promotes the production and activity of alkaline phosphatase and of osteocalcin (Sampath et al, 2007; Abe et al, 2003), while some studies found inhibition of osteoblast differentiation induced by the administration of TSH (Abe et al, 2003). These finding suggested that TSH may enhance the

Clinically, it has been found that the administration of exogenous TSH may have antiresorptive effects of TSH on bone turnover. In women monitored for thyroid carcinoma, a short-term stimulation with rhTSH had inhibitory effect on bone resorption. Acute administration of rhTSH in thyroidectomised postmenopausal women with suppressed endogenous serum TSH resulted in diminution in serum C-telopeptides of type-1 collagen and increase in bone alkaline phosphatase (Mazziotti et al., 2005). A transient inhibition of bone resorption and increase in osteoblastic activity, measured by markers of bone metabolism, after acute TSH administration was demonstrated also by other studies (Karga

Overall, these data constitute the evidence for relationship between TSH and a change in

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

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

associated with low BMD in men.

differentiation of osteoblasts precursors.

et al, 2010; Iakovou et al, 2010; Martini et al, 2008).

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

bone mass in humans.

are summarized in Table 1.

Overall, literature data enhance the hypothesis that low TSH levels may have a deleterious effect on bone homeostasis. Nevertheless, the exact relationship between subclinical hyperthyroidism and osteoporosis remains to be explained.
