The skeletal consequences of thyrotoxicosis

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   Figure 1

   Systemic thyroid hormone concentrations are controlled by the negative feedback regulation of the hypothalamic–pituitary–thyroid (HPT) axis. TRH stimulates the release of TSH from the anterior pituitary, which then stimulates the synthesis and secretion of T₄ and T₃ by the thyroid gland. DIO2 converts the pro-hormone T₄ to the active hormone T₃, which binds and activates TRβ2 in the hypothalamus and pituitary, resulting in the feedback inhibition of TRH production and TSH secretion. DIO1 also converts T₄ to T₃ in the liver, contributing to the pool of circulating T₃. Thyroid hormones enter target cells via specific cell membrane transporters and intracellular supplies of T₃ to the nucleus of T₃-target cells are regulated by the relative activities of DIO2 and DIO3. Expression of DIO2 results in the activation of T₄ to T₃, increased intracellular T₃ concentrations and stimulation of T₃-target gene transcription. Expression of DIO3 prevents the activation of T₄ and inactivates T₃, resulting in the repression of T₃-target gene transcription. PVN, paraventricular nucleus; TRH, thyrotrophin-releasing hormone; TSH, thyroid-stimulating hormone; DIO1, DIO2 and DIO3, type 1, 2 and 3 deiodinases; MCT8 and MCT10, monocarboxylate transporters 8 and 10; OATP1C1, organic acid transporter protein-1C1; TR, thyroid hormone receptor; TRβ2, thyroid hormone receptor β2; RXR, retinoid X receptor; T₄, thyroxine; T₃, 3,5,3′-l-triiodothyronine; rT₃, 3,3′,5′-triiodothyronine; T₂, 3,3′-diiodothyronine.
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   Figure 2

   Schematic representation of the basic multicellular unit of the bone remodelling cycle. The bone remodelling cycle is initiated and orchestrated by osteocytes, which are embedded within mineralised bone and communicate via ramifications of dendritic processes. Bone remodelling may result from changes in mechanical load, structural damage or exposure to systemic or paracrine factors. Haemopoietic cells of the monocyte/macrophage lineage differentiate to mature osteoclasts and resorb bone. During the reversal phase, osteoblastic progenitors are recruited to the site of resorption, differentiate and synthesise osteoid, and mineralise the new bone matrix to repair the defect. Crosstalk between bone-forming osteoblasts and bone-resorbing osteoclasts regulates bone remodelling and maintains skeletal homeostasis. M-CSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANK, receptor activator of NFκB; RANKL, RANK ligand.
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   Figure 3

   Effect of variation in fT₄ concentration within the normal reference range on bone mineral density (BMD) in healthy euthyroid postmenopausal women from the Osteoporosis and Ultrasound Study (OPUS; Murphy et al. 2010). Graphs showing mean hip BMD±95% confidence intervals at the time of entry into the study (white bars) and after 6 years prospective follow-up (grey bars) in relation to quintiles of fT₄ concentration. The fT₄ reference range was determined in 1754 healthy postmenopausal women ≥55 years old (fT₄: 9.15–16.99 pmol/l). Individuals with fT₄ levels in the highest quintile had lower hip BMD than women with fT₄ in the lowest quintile at the time of entry into the study (P=0.02) and after 6 years of follow-up (P=0.04).

• © 2012 Society for Endocrinology