**Author details**

Eva Feigerlova, Marc Klein, Anna Angelousi, Lelia Groza and Georges Weryha\* *Department of Endocrinology, CHU Nancy, Vandoeuvre, France* 

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

<sup>\*</sup> Corresponding Author

## **9. References**

[1] Abe E, Marians RC, Yu W, Wu XB, Ando T, Li Y, Iqbal J, Eldeiry L, Rajendren G, Blair HC, Davies TF, Zaidi M. (2003) TSH is a negative regulator of skeletal remodeling. Cell 115: 151–162.

Thyroid Disorders and Bone Mineral Homeostasis 267

[18] Baxter, J. D., & Webb, P. (2009). Thyroid hormone mimetics: Potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov 8(4), 308–320. [19] Beber EH, Capelo LP, Fonseca TL, Costa CC, Lotfi CF, Scanlan TS, et al (2009) The thyroid hormone receptor (TR) beta-selective agonist GC-1 inhibits proliferation but induces differentiation and TR beta mRNA expression in mouse and rat osteoblast-like

[20] Begic-Karup S, Wagner B, Raber W, Schneider B, Hamwi A, Waldhäusl W, Vierhapper H (2001) Serum calcium in thyroid disease. Wien Klin Wochenschr. 113(1-2):65-8. [21] Berkenstam, A., Kristensen, J., Mellstrom, K., Carlsson, B., Malm, J., Rehnmark, S., et al. (2008). The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans. Proc

[22] Bertoli A, Fusco A, Andreoli A, Magnani A et al (2002) Effect of subclinical hypothyroidism and obesity on whole-body and regional bone mineral content. Horm

[23] Beus KS, Stack BC Jr (2004) Synchronous thyroid pathology in patients presenting with

[24] Biondi B, Palmieri EA, Klain M, Schlumberger M, Filetti S, Lombardi G (2005) Subclinical hyperthyroidism: clinical features and treatment options. Eur J Endocrinol

[25] Boas M et al (2009) Association of Thyroid Gland Volume, Serum Insulin-Like Growth Factor-I, and Anthropometric Variables in Euthyroid Prepubertal Children. J Clin

[26] Bookout, A.L. et al. (2006) Anatomical profiling of nuclear receptor expression reveals a

[27] Bradley DJ, Towle HC, & Young WS 3rd (1992) Spatial and temporal expression of alpha- and beta-thyroid hormone receptor mRNAs, including the beta 2-subtype, in the

[28] Brenta G, Schnitman M, Fretes O, Facco E, Gurfinkel M, Damilano S, et al (2003) Comparative efficacy and side effects of the treatment of euthyroid goiter with levo-

[29] Britto JM, Fenton AJ, Holloway WR, Nicholson GC (1994) Osteoblasts mediate thyroid hormone stimulation of osteoclastic bone resorption. Endocrinology 134:169–176. [30] Campos-Pastor MM, Munoz-Torres M, Escobar-Jimenez F, et al (1993) Bone mass in females with different thyroid disorders: influence of menopausal status. Bone and

[31] Caraccio N, Natali A, Sironi A, et al (2005) Muscle metabolism and exercise tolerance in subclinical hypothyroidism: a controlled trial of levothyroxine. J Clin Endocrinol Metab

[32] Chassande O, Fraichard A, Gauthier K, Flamant F, Legrand C, Savatier P, Laudet V, Samarut J (1997) Identification of transcripts initiated from an internal promoter in the c-erbA alpha locus that encode inhibitors of retinoic acid receptor-alpha and

thyroxine or triiodothyroacetic acid. J. Clin. Endocrinol. Metab. 88:5287–92.

primary hyperparathyroidism. Am J Otolaryngol. 25:308-12.

hierarchical transcriptional network. Cell 126: 789–799

developing mammalian nervous system. J Neurosci 12: 2288–2302

triiodothyronine receptor activities. Mol Endocrinol 11:1278–1290.

cells. Calcif. Tissue Int. 84:324–33

Natl Acad Sci U S A 105(2), 663–667.

Endocrinol Metab 94: 4031–4035.

Res. 57:79-84.

152:1-9.

Mineral 21:1-8.

90:4057–62


[18] Baxter, J. D., & Webb, P. (2009). Thyroid hormone mimetics: Potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov 8(4), 308–320.

266 Thyroid Hormone

**9. References** 

331.

Metab. Res. 36:291–7.

1550–1556, 1999.

Regul. 44: 9-15.

115: 151–162.

[1] Abe E, Marians RC, Yu W, Wu XB, Ando T, Li Y, Iqbal J, Eldeiry L, Rajendren G, Blair HC, Davies TF, Zaidi M. (2003) TSH is a negative regulator of skeletal remodeling. Cell

[2] Abu EO, Bord S, Horner A, Chatterjee VKK, and Compston JE (1997) The expression of

[3] Ahmed LA, Schirmer H, Berntsen GK et al (2006) Self-reported diseases and the risk of

[4] Akalin A, Colak O, Alatas O, Efe B (2002) Bone remodeling markers and serum

[5] Allain TJ, Chambers TJ, Flanagan AM, McGregor AM (1992) Tri-iodothyronine stimulates rat osteoclastic bone resorption by an indirect effect. J Endocrinol 133:327–

[8] Angelin, B., & Rudling, M. (2010). Lipid lowering with thyroid hormone and

[9] Ballock R, Mita BC, Zhou X, Chen DH, and Mink LM (1999) Expression of thyroid hormone receptor isoforms in rat growth plate cartilage in vivo. J Bone Miner Res 14:

[10] Ballock RT, Reddi AH (1994) Thyroxine is the serum factor that regulates morphogenesis of columnar cartilage from isolated chondrocytes in chemically defined

[11] Ballock RT, Zhou X, Mink LM, Chen DH, Mita BC, Stewart MC (2000) Expression of cyclin-dependent kinase inhibitors in epiphyseal chondrocytes induced to terminally

[12] Baqi L, Payer J, Killinger Z, Susienkova K et al (2010) The level of TSH appeared favourable in maintaining bone mineral density in postmenopausal women. Endocr

[13] Barnard, J.C. et al. (2005) Thyroid hormones regulate fibroblast growth factor receptor

[14] Bassett JH, Williams GR (2003) The molecular actions of thyroid hormone in bone.

[15] Bassett, J.H. et al. (2007a) Thyroid hormone excess rather than thyrotropin deficiency

[16] Bassett, J.H. et al. (2007b) Thyroid status during skeletal development determines adult

[17] Bauer DC, Ettinger B, Nevitt MC et al (2001) Risk for fracture in women with low serum

induces osteoporosis in hyperthyroidism. Mol. Endocrinol. 21: 1095–1107

bone structure and mineralization. Mol. Endocrinol. 21: 1893–1904

levels of thyroid-stimulating hormone. Ann Intern Med134: 561–568.

differentiate with thyroid hormone. Endocrinology. 141:4552-7.

signaling during chondrogenesis. Endocrinology 146: 5568–5580

[6] Allain TJ, McGregor AM (1993) Thyroid hormones and bone. J Endocrinol 139:9–18. [7] Alvarez L, Burgueño A, Zeni S, Randi AS, Hernández S, Hockl P, et al (2004) Comparison of the effects of 3,5,3'-triiodothyroacetic Acid and triiodothyronine on goiter prevention and involution and on hepatic and skeletal parameters in rats. Horm.

thyroid hormone receptors in human bone. Bone 21: 137–142.

thyromimetics. Curr Opin Lipidol 21(6), 499–506.

medium. J Cell Biol 126:1311–1318.

Trends Endocrinol Metab 14: 356–364.

non-vertebral fractures: the Tromso study. Osteoporos Int 17: 46–53.

cytokines in patients with hyperthyroidism. Clin Endocrinol 57:125-129


[33] Cheng SY, Leonard JL, & Davis PJ (2010) Molecular aspects of thyroid hormone actions. Endocr Rev 31: 139–170

Thyroid Disorders and Bone Mineral Homeostasis 269

reveals different functions for the products of the thyroid hormone receptor alpha

[49] Gothe S, Wang Z, Ng L, Kindblom JM, Barros AC, Ohlsson C, Vennstrom B, Forrest D (1999) Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev

[50] Gouveia CH, Schultz JJ, Bianco AC, Brent GA (2001) Thyroid hormone stimulation of osteocalcin gene expression in ROS17/2.8 cells is mediated by transcriptional and post-

[51] Greenspan SL & Greenspan FS (1999) The effect of thyroid hormone on skeletal

[52] Grimnes G, Emaus N, Joakimsen RM, Figenschau Y, Jorde R (2008) The relationship between serum TSH and bone mineral density in men and postmenopausal women:

[53] Harvey CB, O'Shea PJ, Scott AJ, Robson H, Siebler T, Shalet SM, Samarut J, Chassande O, Williams GR (2002) Molecular mechanisms of thyroid hormone effects on bone

[54] Hase H, Ando T, Eldeiry L, Brebene A, Peng Y, Liu L, Amano H, Davies TF, Sun L, Zaidi M, Abe E (2006) TNF mediates the skeletal effects of thyroid-stimulating

[55] Heemstra KA, Hamdy NA, Romijn JA & Smit JW (2006) The effects of thyrotropinsuppressive therapy on bone metabolism in patients with well-differentiated thyroid

[56] Heyerdahl S (1997) Linear growth in early treated children with congenital

[57] Himeno, M. et al. (2002) Impaired vascular invasion of Cbfa1-deficient cartilage

[58] Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE (2002) Serum TSH, T(4), and thyroid antibodies in the United Statuss population (1988 to 1994): National Health and Nutrition Examination Survey

[59] Huber G, Staub JJ, Meier C, Mitrache C, Guglielmetti M, Huber P, Braverman LE (2002) Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab

[60] Iakovou I, Chrisoulidou A, Balaris V, Balaris C, Doumas A, Karatzas N (2010) Acute effects of recombinant human TSH on bone markers in differentiated thyroid cancer.

[61] Iqbal AA, Burgess EH, Gallina DL, Nanes MS, Cook CB (2003) Hypercalcemia in hyperthyroidism: patterns of serum calcium, parathyroid hormone, and 1,25 dihydroxyvitamin D3 levels during management of thyrotoxicosis. Endocr Pract 9:517-

locus. Mol Cell Biol 21:4748–4760.

transcriptional mechanisms. J Endocrinol 170:667–675

integrity. Annals of Internal Medicine 130:750–758.

growth and function. Mol Genet Metab 75:17–30.

hormone. Proc Natl Acad Sci USA 103:12849–12854.

engrafted in the spleen. J. Bone Miner. Res. 17, 1297–1305

(NHANES III). J Clin Endocrinol Metab.87:489-99.

The Tromsø study. Thyroid. 18:1147–55.

carcinoma. Thyroid 16:583–591.

87:3221-6.

21.

Hell J Nucl Med 13:208-12.

hypothyroidism. Acta Paediatr. 86:479-83.

13:1329–1341.


reveals different functions for the products of the thyroid hormone receptor alpha locus. Mol Cell Biol 21:4748–4760.

[49] Gothe S, Wang Z, Ng L, Kindblom JM, Barros AC, Ohlsson C, Vennstrom B, Forrest D (1999) Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev 13:1329–1341.

268 Thyroid Hormone

73.

Endocr Rev 31: 139–170

Bone 7: 101–108.

1998 48:285-90.

Bras Endocrinol Metabol. 51:1084–92.

[33] Cheng SY, Leonard JL, & Davis PJ (2010) Molecular aspects of thyroid hormone actions.

[34] Cummings SR, Nevitt MC, Browner WS, et al (1995) Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332:767–

[35] Demartini Ade A, Kulak CA, Borba VC, Cat MN, Dondoni RS, Sandrini R, et al (2007) Bone mineral density of children and adolescents with congenital hypothyroidism. Arq

[36] De Menis E, Da Rin G, Roiter I, et al. (1992) Bone turnover in overt and subclinical hyperthyroidism due to autonomous thyroid adenoma. Horm Res 37:217–220. [37] Demeester-Mirkine N, Bergmann P, Body JJ, et al (1990) Calcitonin and bone mass

[38] Eriksen EF, Mosekilde L, Melsen F (1986) Kinetics of trabecular bone resorption and formation in hypothyroidism: evidence for a positive balance per remodeling cycle.

[39] Faber J, Jensen IW, Petersen L, Nygaard B, Hegedüs L, Siersbaek-Nielsen K (1998) Normalization of serum thyrotrophin by means of radioiodine treatment in subclinical hyperthyroidism: effect on bone loss in postmenopausal women. Clin Endocrinol (Oxf).

[40] Flamant F, Poguet AL, Plateroti M, Chassande O, Gauthier K, Streichenberger N, Mansouri A, Samarut J (2002) Congenital hypothyroid Pax8(−/−) mutant mice can be

[41] Foldes J, Tarjan G, Szathmari M, et al (1993) Bone mineral density in patients with endogenous subclinical hyperthyroidism: is this thyroid status a risk factor for

[42] Forrest D, Erway LC, Ng L, Altschuler R, Curran T (1996) Thyroid hormone receptor beta is essential for development of auditory function. Nat Genet 13:354–357. [43] Freitas FRS, Capelo LP, O'Shea PJ, Jorgetti V, Moriscot AS, Scanlan TS, et al. (2005) The thyroid hormone receptor beta-specific agonist GC-1 selectively affects the bone

[44] Freitas FRS, Moriscot AS, Jorgetti V, Soares AG, Passarelli M, Scanlan TS, et al (2003) Spared bone mass in rats treated with thyroid hormone receptor TR beta-selective

[45] Glass CK, Franco R, Weinberger C, Albert VR, Evans RM, Rosenfeld MG (1987) A c-erb-A binding site in rat growth hormone gene mediates trans-activation by thyroid

[46] Garnero P, Vassy V, Bertholin A, Riou JP, Delmas PD (1994) Markers of bone turnover in hyperthyroidism an the effects of treatment. J Clin Endocrinol Metab. 78:955–959. [47] Gauthier, K. et al. (1999) Different functions for the thyroid hormone receptors TRalpha and TRbeta in the control of thyroid hormone production and post-natal development.

[48] Gauthier K, Plateroti M, Harvey CB, Williams GR, Weiss RE, Refetoff S, Willott JF, Sundin V, Roux JP, Malaval L, Hara M, Samarut J, Chassande O (2001) Genetic analysis

status in congenital hypothyroidism. Calcif Tissue Int 46:222–6

rescued by inactivating the TRalpha gene. Mol Endocrinol 16:24–32.

development of hypothyroid rats. J. Bone Miner. Res. 20:294–304.

compound GC-1. Am. J. Physiol. Endocrinol. Metab.285:E1135–1141.

osteoporosis? Clin Endocrinol (Oxf) 39:521–7.

hormone. Nature 329:738–741.

EMBO J. 18, 623–631


[62] Jamal SA, Leiter RE, Bayoumi AM et al (2005) Clinical utility of laboratory testing in women with osteoporosis. Osteoporos Int 16: 534–540.

Thyroid Disorders and Bone Mineral Homeostasis 271

[78] Kvistad PH, Lovas K, Boman H et al (2004) Retarded bone growth in thyroid hormone resistance. A clinical study of a large family with a novel thyroid hormone receptor

[79] Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I, et al (2010a) Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N.

[80] Ladenson PW, McCarren M, Morkin E, Edson RG, Shih M-C, Warren SR, et al (2010b) Effects of the thyromimetic agent diiodothyropropionic acid on body weight, body mass index, and serum lipoproteins: a pilot prospective, randomized, controlled study.

[81] Lassova, L. et al. (2009) Thyroid hormone treatment of cultured chondrocytes mimics in vivo stimulation of collagen X mRNA by increasing BMP 4 expression. J. Cell. Physiol.

[82] Lazar MA (1993) Thyroid hormone receptors: Multiple forms, multiple possibilities.

[83] Lazar MA, & Chin WW (1990) Nuclear thyroid hormone receptors. J Clin Invest 86:

[84] Lee JS, Buzková P, Fink HA, Vu J, Carbone L, Chen Z et al (2010) Subclinical thyroid dysfunction and incident hip fracture in older adults. Arch Intern Med. 170:1876-83. [85] Lee WY, Oh KW, Rhee EJ, Jung CH, Kim SW et al (2006) Relationship between subclinical thyroid dysfunction and femoral neck bone mineral density in women.

[86] Leger J, Ruiz JC, Guibourdenche J, Kindermans C, Garabedian M, Czernichow P (1997) Bone mineral density and metabolism in children with congenital hypothyroidism after

[87] Lewinson D, Harel Z, Shenzer P, Silbermann M, Hochberg Z (1989) Effect of thyroid hormone and growth hormone on recovery from hypothyroidism of epiphyseal growth

[88] Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF

[89] Ma R, Latif R, Zaidi M, Davies T (2009) Thyroid and bone: TSH inhibits osteoclastogenesis from embryonic stem cells. Presented at the 91st Annual Meeting of

[90] Ma R, Morshed S, Latif R, Zaidi M, Davies TF (2011) The influence of thyroidstimulating hormone and thyroid-stimulating hormone receptor antibodies on

[91] Makihira, S. et al. (2003) Thyroid hormone enhances aggrecanase-2/ADAM-TS5 expression and proteoglycan degradation in growth plate cartilage. Endocrinology 144,

[92] Martini G, Gennari L, De Paola V, Pilli T, Salvadori S, Merlotti D, Valleggi F, Campagna S, Franci B, Avanzati A, Nuti R, Pacini F (2008) The effects of recombinant TSH on bone turnover markers and serum osteoprotegerin and RANKL levels. Thyroid. 18:455-60.

mutation. Eur J Endocrinol 150: 425-430.

J Clin Endocrinol Metab. 95:1349–54.

Archives of Medical Research 37:511–516.

receptor (Igf1r). Cell 75:59–72.

osteoclastogenesis. Thyroid 21:897-906.

prolonged L-thyroxine therapy. Acta Paediatr. 86:704-10.

the Endocrine Society. Washington DC; June 10–13, 2009.

plate cartilage and its adjacent bone. Endocrinology 124:937–945.

Engl. J. Med 362: 906–16.

Endocr Rev 14: 184–193.

219, 595–605

1777–1782.

2480–2488


[78] Kvistad PH, Lovas K, Boman H et al (2004) Retarded bone growth in thyroid hormone resistance. A clinical study of a large family with a novel thyroid hormone receptor mutation. Eur J Endocrinol 150: 425-430.

270 Thyroid Hormone

135: 971–6.

Endocrinol (Oxf) 64:86–90

[62] Jamal SA, Leiter RE, Bayoumi AM et al (2005) Clinical utility of laboratory testing in

[63] Jodar E, Munoz-Torres M, Escobar-Jimenez F, et al (1997) Bone loss in hyperthyroid patients and in former hyperthyroid patients controlled on medical therapy: influence

[64] Karga H, Papaioannou G, Polymeris A, Papamichael K, Karpouza A, Samouilidou E, Papaioannou P (2010) The effects of recombinant human TSH on bone turnover in

[65] Karner I, Hrgović Z, Sijanović S, Buković D, Klobucar A, Usadel KH, Fassbender WJ (2005) Bone mineral density changes and bone turnover in thyroid carcinoma patients

[66] Kawaguchi H, Pilbeam CC, Raisz LG (1994a) Anabolic effects of 3,3',5-triiodothyronine and triiodothyroacetic acid in cultured neonatal mouse parietal bones. Endocrinology

[67] Kawaguchi H, Pilbeam CC, Woodiel FN, Raisz LG (1994b) Comparison of the effects of 3,5,3'-triiodothyroacetic acid and triiodothyronine on bone resorption in cultured fetal

[68] Kim DJ, Khang YH, Koh JM, Shong YK, Kim GS (2006) Low normal TSH levels are associated with low bone mineral density in healthy postmenopausal women. Clin

[69] Kim BJ, Lee SH, Bae SJ, Kim HK, Choe JW, Kim HY, Koh JM, Kim GS (2010) The association between serum thyrotropin (TSH) levels and bone mineral density in

[70] Kindblom JM, Gothe S, Forrest D, Tornell J, Vennstrom B, Ohlsson C (2001) GH substitution reverses the growth phenotype but not the defective ossification in thyroid

[71] Kisakol G, Kaya A, Gonen S, Tunc R (2003) Bone and calcium metabolism in subclinical

[73] Koenig RJ, Brent GA, Warne RL, Larsen PR, Moore DD (1987) Thyroid hormone receptor binds to a site in the rat growth hormone promoter required for induction by

[74] Kooh SW, Brnjac L, Ehlrich RM, Qureshi R & Krishnan S (1996) Bone mass in children with congenital hypothyroidism treated with thyroxine since birth. Journal of Pediatric

[75] Kraenzlin ME, Kraenzlin CA, Meier C, Giunta C, Steinmann B (2008) Automated HPLC assay for urinary collagen cross-links: effect of age, menopause, and metabolic bone

[76] Krolner B, Jorgensen JV, Nielsen SP (1983) Spinal bone mineral content in myxedema and thyrotoxicosis. Effects of thyroid hormone(s) and anti-thyroid treatment. Clin

[77] Kumeda Y, Inaba M, Tahara H et al (2000) Persistent increase in bone turnover in Graves' patients with subclinical hyperthyroidism. J Clin Endocrinol Metab 85:4157-61.

autoimmune hyperthyroidism and hypothyroidism. Endocr J 50:657–661. [72] Kocher T (1883) Ueber Kropfexstirpation und ihre Folgen. Arch Klin Chir 29:254.

treated with supraphysiologic doses of thyroxine. Eur J Med Res. 10:480-8.

rat long bones and neonatal mouse calvariae. J. Bone Miner. Res. 9:247–53.

women with osteoporosis. Osteoporos Int 16: 534–540.

of aetiology and menopause. Clin Endocrinol (Oxf) 47: 279–85.

patients after thyroidectomy. J Bone Miner Metab 28:35-41.

healthy euthyroid men. Clin Endocrinol (Oxf). 73:396-403.

thyroid hormone. Proc Natl Acad Sci USA 84:5670–5674

Endocrinology and Metabolism 9:59–62.

diseases. Clin Chem 54:1546-1553.

Endocrinol (Oxf) 18:439–46.

hormone receptor alpha 1−/−beta−/<sup>−</sup> mice. J Endocrinol 171:15–22.


[93] Mazziotti G, Sorvillo F, Piscopo M, Cioffi M, Pilla P, Biondi B, Iorio S, Giustina A, Amato G, Carella C (2005) Recombinant human TSH modulates in vivo C-telopeptides of type-1 collagen and bone alkaline phosphatase, but not osteoprotegerin production in postmenopausal women monitored for differentiated thyroid carcinoma. J Bone and Min Res 20:480-486.

Thyroid Disorders and Bone Mineral Homeostasis 273

[107] O'Shea PJ, Harvey CB, Suzuki H, Kaneshige M, Kaneshige K, Cheng SY, Williams GR (2003) A thyrotoxic skeletal phenotype of advanced bone formation in mice with

[108] O'Shea PJ, Williams GR (2002) Insight into the physiological actions of thyroid hormone receptors from genetically modified mice. J Endocrinol 175:553–570. [109] O'Shea, P.J. et al. (2005) Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta. Mol. Endocrinol. 19,

[110] O'Shea, P.J. et al. (2006) Characterization of skeletal phenotypes of TRalpha1 and TRbeta mutant mice: implications for tissue thyroid status and T3 target gene

[111] Pantazi H, Papapetrou PD (2000) Changes in parameters of bone and mineral metabolism during therapy for hyperthyroidism. J Clin Endocrinol Metab. 85:1099-106. [112] Pereira RC, Jorgetti V, Canalis E (1999) Triiodothyronine induces collagenase-3 and

[113] Pramfalk C, Pedrelli M, & Parini P (2011) Role of thyroid receptor beta in lipid

[114] Radetti G, Castellan C, Tato` L, Platter K, Gentili L & Adami S (1993) Bone mineral density in children and adolescent females treated with high doses of L-thyroxine.

[115] Ray RD, Asling CW, Walker DG, Simpson ME, Li CH, Evans HM (1954) Growth and differentiation of the skeleton in thyroidectomized-hypophysectomized rats treated with thyroxin, growth hormone, and combination. J Bone Joint Surg Am 36:94–103 [116] Rivkees SA, Bode HH, Crawford JD (1988) Long-term growth in juvenile acquired hypothyroidism: the failure to achieve normal adult stature. N Engl J med 3:599-602. [117] Robson H, Siebler T, Stevens DA et al (2000) Thyroid hormone acts directly on growth plate chondrocytes to promote hypertrophic differentiation and inhibit clonal

[118] Sabuncu T, Aksoy N, Arikan E, Ugur B, Tasan E, Hatemi H (2001) Early changes in parameters of bone and mineral metabolism during therapy for hyper- and

[119] Saggese G, Bertelloni S, Baroncelli GI, Costa S & Ceccarelli C (1996) Bone mineral denisty in adolescent females treated with L-thyroxine: a longitudinal study. European

[120] Salerno M, Lettiero T, Esposito-del Puente A et al. ( 2004) Effect of long-term Lthyroxine treatment on bone mineral density in young adults with congenital

[121] Sampath TK, Simic P, Sendak R, Draca N, Bowe AE, O'Brien S, Schiavi SC, McPherson JM, Vukicevic S (2007) Thyroid-stimulating hormone restores bone volume, microarchitecture, and strength in aged ovariectomized rats. J Bone Miner Res. 22:849-

[122] Sap J, Munoz A, Damm K, Goldberg Y, Ghysdael J, Leutz A, et al. (1986) The c-erb-A

protein is a high-affinity receptor for thyroid hormone. Nature 324: 635–640.

gelatinase B expression in murine osteoblasts. Am J Physiol 277:E496–E504

expansion and cell proliferation. Endocrinology 141:3887–3897.

hypothyroidism. European Journal of Endocrinology 151:689–694.

resistance to thyroid hormone. Mol Endocrinol 17:1410–1424.

expression. Nucl. Receptor Signal. 4, e011

metabolism. Biochim Biophys Acta 1812:929-37

Hormon Research 39:127–131.

hypothyroidism. Endocr Res. 27:203-13.

Journal of Pediatrics 155: 452–457.

59.

3045–3059


[107] O'Shea PJ, Harvey CB, Suzuki H, Kaneshige M, Kaneshige K, Cheng SY, Williams GR (2003) A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone. Mol Endocrinol 17:1410–1424.

272 Thyroid Hormone

Min Res 20:480-486.

density. Bone. 46:747-51.

D deficiency. Thyroid 14:789-91.

1134.

285–298.

Endocr J 54:625–30.

[93] Mazziotti G, Sorvillo F, Piscopo M, Cioffi M, Pilla P, Biondi B, Iorio S, Giustina A, Amato G, Carella C (2005) Recombinant human TSH modulates in vivo C-telopeptides of type-1 collagen and bone alkaline phosphatase, but not osteoprotegerin production in postmenopausal women monitored for differentiated thyroid carcinoma. J Bone and

[94] Mazziotti G, Porcelli T, Patelli I, Vescovi PP, Giustina A (2010) Serum TSH values and risk of vertebral fractures in euthyroid post-menopausal women with low bone mineral

[95] Meier C, Beat M, Guglielmetti M, Christ-Crain M, Staub JJ, Kraenzlin M. (2004) Restoration of euthyroidism accelerates bone turnover in patients with subclinical hypothyroidism: a randomized controlled trial. Osteoporosis International 15:209–216. [96] Melsen F, Mosekilde L (1977) Morphometric and dynamic studies of bone changes in

[97] Miell JP, Taylor AM, Zini M, Maheshwari G, Ross RJM, Valcani R (1993) Effects of hypothyroidism and hyperthyroidism on insulin-like growth factors (IGFs) and growth

[98] Milne M, Kang MI, Quail JM, Baran DT (1998) Thyroid hormone excess increases insulin-like growth factor I transcripts in bone marrow cell cultures: divergent effects

[99] Milne M, Quail JM, Rosen CJ, Baran DT (2001) Insulin-like growth factor binding proteins in femoral and vertebral bone marrow stromal cells: expression and regulation

[100] Mohan HK, Groves AM, Fogelman I, Clarke SE (2004) Thyroid hormone and parathyroid hormone competing to maintain calcium levels in the presence of vitamin

[101] Mora S, Weber G, Marenzi K, Signorini E, Rovelli R, Proverbio MC & Chiumello G (1999) Longitudinal changes of bone density and bone resorption in hyperthyroid girls

[102] Morris MS (2007) The association between serum thyroid stimulating hormone in its reference range and bone status in postmenopausal American women. Bone 40:1128-

[103] Mosekilde L, Eriksen EF, Charles P. Effects of thyroid hormones on bone and mineral

[104] Murphy E, Williams GR. The thyroid and the skeleton. Clin Endocrinol (Oxf) 2004; 61:

[105] Nagata M, Suzuki A, Sekiguchi S, Ono Y, Nishiwaki-Yasuda K, Itoi T, et al (2007) Subclinical hypothyroidism is related to lower heel QUS in postmenopausal women.

[106] Onigata K, Kowasi T, Nishiyama S, Micuno H, Morikawa A. Bone mineral density in human cases with TSH receptor gene mutations. Proceedings of the New York Academy of Sciences 1rst Conference on Skeletal Development and Remodeling in

hormone- and IGF-binding proteins. J Clin Endocrinol Metab. 76:950 –955.

on vertebral and femoral cell cultures. Endocrinology 139:2527–2534

by thyroid hormone and dexamethasone. J Cell Biochem. 81:229-40.

during treatment. Journal of Bone and Mineral Research 14: 1971–1977.

metabolism. Endocrinol Metab Clin North Am 1990; 19: 35–63.

Health, Disease, and Aging, May 18–21, 2005, New York, NY, USA.

hyperthyroidism. Acta Pathol Microbiol Scand A. 85A:141-50.


[123] Scanlan TS (2010). Sobetirome: A case history of bench-to-clinic drug discovery and development. Heart Fail Rev 15(2), 177–182.

Thyroid Disorders and Bone Mineral Homeostasis 275

[139] Thorngren KG, Hansson LI 1974 Bioassay of growth hormone II. Determination of longitudinal bone growth with tetracycline in thyroxine-treated hypophysectomized

[140] Thompson CC, Weinberger C, Lebo R, & Evans RM (1987) Identification of a novel thyroid hormone receptor expressed in the mammalian central nervous system. Science

[141] Tumer L, Hasanoglu A, Cinaz P & Bideci A (1999) Bone mineral density and metabolism in children treated with L-thyroxine. Journal of Pediatric Endocrinology

[142] Turner MR et al. (2011) Levothyroxine dose and risk of fractures in older adults:

[143] Udayakumar N, Chandrasekaran M, Rasheed MH, Suresh RV, Sivaprakash S (2006) Evaluation of bone mineral density in thyrotoxicosis. Singapore Med J 47:947-950. [144] Varga F, Rumpler M, Luegmayr E, Fratzl-Zelman N, Glantschnig H, Klaushofer K (1997) Triiodothyronine, a regulator of osteoblastic differentiation: depression of histone H4, attenuation of c-fos/c-jun, and induction of osteocalcin expression. Calcif

[145] Vadiveloo T, Donnan PT, Cochrane L, Leese GP (2011) The Thyroid Epidemiology, Audit, and Research Study (TEARS): morbidity in patients with endogenous subclinical

[146] Vestergaard P, Mosekilde L (2002) Fractures in patients with hyperthyroidism and hypothyroidism: a nationwide follow-up study in 16,249 patients. Thyroid 12: 411–419. [147] Vestergaard P, Rejnmark L, Mosekilde L (2005) Influence of hyper- and hypothyroidism, and the effects of treatment with anti-thyroid drugs and levothyroxine

[148] Vestergaard P, Rejnmark L, Weeke J, Mosekilde L (2000) Fracture risk in patients

[149] Wagner B, Begic-Karup S, Raber W, Schneider B, Waldhäusl W, Vierhapper H (1999) Prevalence of primary hyperparathyroidism in 13387 patients with thyroid diseases, newly diagnosed by screening of serum calcium. Exp Clin Endocrinol Diabetes.

[150] Wang, L. et al. (2007) Thyroid hormone interacts with the Wnt/betacatenin signaling pathway in the terminal differentiation of growth plate chondrocytes. J. Bone Miner.

[151] Webb P (2010). Thyroid hormone receptor and lipid regulation. Curr Opin Investig

[152] Weinberger C, Thompson CC, Ong, ES, Lebo R, Gruol DJ, & Evans RM (1986) The c-

[153] Weiss RE, Refetoff S (2000) Resistance to thyroid hormone. Rev Endocr Metab Disord

[154] Wejda B, Hintze G, Katschinski B, Olbricht T, Benker G (1995) Hip fractures and the

erb-A gene encodes a thyroid hormone receptor. Nature 324: 641–646.

rats. Acta Endocrinol (Copenh) 75:669–682.

nested case-control study. BMJ. 342:d2238

hyperthyroidism. J Clin Endocrinol Metab 96:1344-51.

on fracture risk. Calcif Tissue Int 77: 139–144.

treated for hyperthyroidism. Thyroid 10:341–348.

thyroid: A case study. J Intern Med 237:241–247

237:1610–1614.

and Metabolism 12:519–523.

Tissue Int 61:404–411

107:457-61.

1:97–108.

Res. 22, 1988–1995

Drugs 11(10), 1135–1142.


[139] Thorngren KG, Hansson LI 1974 Bioassay of growth hormone II. Determination of longitudinal bone growth with tetracycline in thyroxine-treated hypophysectomized rats. Acta Endocrinol (Copenh) 75:669–682.

274 Thyroid Hormone

871–877

[123] Scanlan TS (2010). Sobetirome: A case history of bench-to-clinic drug discovery and

[124] Segni M et al. (1999) Special features of Graves' disease in early childhood. Thyroid 9:

[125] Sherman SI, Ringel MD, Smith MJ, Kopelen HA, Zoghbi WA, Ladenson PW (1997) Augmented hepatic and skeletal thyromimetic effects of tiratricol in comparison with

[126] Siddiqi A, Burrin JM, Noonan K, James I, Wood DF, Price CP, Monson JP (1997) A longitudinal study of markers of bone turnover in Graves' disease and their value in

[127] Siddiqi A, Burrin JM, Wood DF, Monson JP (1998) Tri-iodothyronine regulates the production of interleukin-6 and interleukin-8 in human bone marrow stromal and

[128] Siddiqi A, Parsons MP, Lewis JL et al. (2002) TR expression and function in human bone marrow stromal and osteoblast- like cells. J Clin Endocrinol Metab 87: 906–914. [129] Sjogren K, Bohlooly YM, Olsson B, Coschigano K, Tornell J, Mohan S, Isaksson OG, Baumann G, Kopchick J, Ohlsson C (2000) Disproportional skeletal growth and markedly decreased bone mineral content in growth hormone receptor−/− mice.

[130] Solomon BL, Wartofsky L, Burman KD (1993) Prevalence of fractures in

[131] Stevens DA, Hasserjian RP, Robson H, Siebler T, Shalet SM, Williams GR (2000) Thyroid hormones regulate hypertrophic chondrocyte differentiation and expression of parathyroid hormone-related peptide and its receptor during endochondral bone

[132] Stevens, D.A. et al. (2003) Thyroid hormone activates fibroblast growth factor receptor-

[133] St Germain, D.L. et al. (2009) Defining the roles of the iodothyronine deiodinases:

[134] Sugitani I, Fujimoto Y (2008) Effect of postoperative thyrotropin suppressive therapy on bone mineral density in patients with papillary thyroid carcinoma: a prospective

[135] Sun L et al. (2008) Intermittent recombinant TSH injections prevent ovariectomy-

[136] Svare A, Nilsen TI, Bjøro T, Forsmo S, Schei B, Langhammer A (2009) Hyperthyroid levels of TSH correlate with low bone mineral density: the HUNT 2 study. Eur J

[137] Tárraga López PJ, López CF, de Mora FN, Montes JA, Albero JS, Mañez AN, Casas AG (2011) Osteoporosis in patients with subclinical hypothyroidism treated with thyroid

[138] Thorngren KG, Hansson LI 1973 Effect of thyroxine and growth hormone on longitudinal bone growth in the hypophysectomized rat. Acta Endocrinol (Copenh)

predicting bone mineral density. J Clin Endocrinol Metab. 82:753–759.

postmenopausal women with thyroid disease. Thyroid. 3:17-23.

current concepts and challenges. Endocrinology 150: 1097–1107

development. Heart Fail Rev 15(2), 177–182.

levothyroxine. J. Clin. Endocrinol. Metab. 82:2153–8.

osteoblast-like cells. J Endocrinol. 157:453-61.

Biochem Biophys Res Commun 267:603–608.

formation. J Bone Miner Res 15:2431–2442.

1 in bone. Mol. Endocrinol. 17, 1751–1766

controlled study. Surgery. 150:1250-7.

Endocrinol. 161:779-86.

74:24–40.

induced bone loss. PNAS. 105:4289-4294.

hormone. Clin Cases Miner Bone Metab. 8:44-8.


[155] Williams GR, Bland R, and Sheppard MC (1994) Characterization of thyroid hormone (T3) receptors in three osteosarcoma cell lines of distinct osteoblast phenotype: interactions among T3, vitamin D3, and retinoid signaling. Endocrinology 135: 2375– 2385, 1994.

**Chapter 10** 

© 2012 Bar-Tana et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Thyroid Hormone and Energy Expenditure** 

One of the most pronounced effects of Thyroid Hormone (TH, Triiodothyronine (T3), Tetraiodothyronine (T4)) is modulation of metabolic efficiency, energy expenditure and calorigenesis. Thus, hypothyroidism results in decreased energy expenditure and basal metabolic rate accompanied by weight gain and cold intolerance, while hyperthyroidism results in hypermetabolism, weight loss despite increased energy intake, intolerance to heat, loss of lean mass, bone resorption and tachycardia. TH role in modulating metabolic efficiency has been realized for over a century but its cellular mode-of-action remained to be

The first description of TH-induced calorigenesis dates to 1895 (1). That initial report has been followed by exhaustive data focusing on the phenomenology of TH action as reflected by hyper- and hypothyroidsm. Thus, high levels of TH in mammals increase oxygen consumption and heat production, resulting in pronounced body weight loss, while low levels of TH are associated with a decrease in metabolic rate and the oxidation of energy substrates (glucose, fatty acids and amino acids), resulting in pronounced increase in body weight (2-6). Although it was widely accepted that TH stimulates calorigenesis by affecting respiration, its cellular mode-of-action remained to be resolved. Hence, exhaustive attempts were made by the scientific community throughout the twentieth century to verify the mechanism(s) involved in modulating metabolic efficiency by TH. Studies by Lardy and Feldott (7) and Hess and Martius (8) have pointed out during the 1950s, that the respiratory control ratio of isolated mitochondria was robustly decreased in the presence of added T4. TH was thus claimed to have direct action at the mitochondrial level by inducing 'mitochondrial uncoupling', namely, dissociating mitochondrial phosphorylation from its substrate oxidation driver. However, the high T4 doses used in those studies implied possible non-physiological activity rather than authentic TH-induced calorigenesis. Later

Einav Yehuda-Shnaidman, Bella Kalderon and Jacob Bar-Tana

**2. Mode-of-action of TH in modulating metabolic efficiency** 

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/48309

**1. Introduction** 

resolved.

