**6. TSH as a metabolic regulator**

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

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 suggested that a serum TSH concentration at the lower end of the reference range may be associated with low BMD in men.

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 differentiation of osteoblasts precursors.

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

Overall, these data constitute the evidence for relationship between TSH and a change in bone mass in humans.
