**8. Conclusion**

264 Thyroid Hormone

**Tiratricol (Triac)** 

**Tiratricol (Triac)** 

**Tiratricol (Triac)** 

**Tiratricol (Triac)** 

**Tiratricol (Triac)** 

**Sobetirome (GC-1)** 

**Sobetirome (GC-1)** 

**Sobetirome (GC-1)** 

**Eprotirome (KB2115)** 

**Thyromimetic Study Design Skeletal effects Reference** 

T3

T3

Rats; Triac vs. T3 Greater increase in beta-CTX

links

to L-T4;

More potent stimulation of resorption and less potent stimulation of formation vs.

Equal or greater stimulation of bone resorption by Triac than

levels, no alteration of BMD

Increased serum osteocalcin and urinary excretion of calcium and pyridinium cross-

Significant increase in serum deoxypyridinoline and significant decrease in hip bone density, but ns compared

Increase in serum osteocalcin,

Induction of differentiation and activity of osteoblasts

No effects on BMD in L2-L5, femur, and tibia; no changes in

N-telopeptide and deoxypyridinoline

histomorphometric parameters of the femur

ns increase in PINP

**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

Induction of ossification, HC differentiation, expression of collagen II and X mRNA, increase in EGP thickness

No changes in b-ALP and type I collagen breakdown product; Kawaguchi 1994a

Kawaguchi 1994b

Alvarez 2004

Sherman 1997

Brenta 2003

Ladenson 2010b

Beber 2009

Freitas 2003

Freitas 2005

Ladenson 2010a

Cultured neonatal mouse calvariae: Triac

Cultured fetal rat long bones and neonatal mouse calvariae; Triac

Randomized clinical trial (2 months); athyreotic patients: Triac vs. L-T4

Randomized clinical trial (11 months); euthyroid goitrous

double-blind clinical trial (24 weeks): DITPA vs. placebo

Female adult Wistar rats; study groups (64

GC-1; T3 ; control

21-day old female hypothyroid rats, treatment for 5 weeks: GC-1 vs. placebo

Randomized, doubleblind, multicenter 12 week clinical trial: Eprotirome vs. placebo

significant; PINP - procollagen type I N-terminal propeptide

Rat and mouse osteoblast-like cells

vs. T3

vs. T3

women: Triac vs. L-T4

**DITPA** Prospective, controlled,

days):

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 hormone action remain still poorly defined.

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 health.

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.
