You have full access to this open access chapter, Download chapter PDF
Thyroid hormones play an important role in the development of the skeleton in children, and in maintaining bone mineral content in adults. Hyperthyroidism is associated with loss of bone mineral content, with increased risk of fractures. This has raised concerns that treatment (especially over treatment) with levothyroxine (LT4) might mimic these adverse effects on the skeleton. Clinical data on the effects of LT4 administration on bone are conflicting. In general, the use of LT4 to maintain euthyroid levels of thyroid hormones in patients with hypothyroidism, or even the use of thyrotropin-suppressive therapy following removal of thyroid tumours, does not appear to carry a substantial risk of osteoporosis or fractures. Nevertheless, a cautious approach to avoid over treatment is recommended, especially in patients with or at risk of developing osteoporosis.
1 Overview of the Effects of Thyroid Hormones on the Skeleton
Thyroid hormones (principally triiodothyronine, derived from naturally produced thyroxine or exogenously administered levothyroxine [LT4]) are essential for the normal development of the skeleton [1, 2]. Untreated congenital hypothyroidism, where there is a profound lack of thyroid function from birth, is associated with delayed development of the skeleton, impaired development of epiphyseal growth plates, short stature (dwarfism), reduced mineralisation of bones, scoliosis and congenital hip displacement, among other complications [1, 2]. Reduced bone turnover in adults with hypothyroidism may result in increased bone mineralisation and mass, but such changes are slow to develop and this phenomenon has not been well studied clinically [2]. Hypothyroidism is not strongly associated with fractures [3, 4] although one meta-analysis described such a relationship that was apparently independently of changes in bone mineral density (BMD).
Hyperthyroidism increases the rate of turnover of bone, with a net loss of bone mineralisation; accordingly, suboptimally managed hyperthyroidism can be a cause of osteoporosis and increased fracture risk [1, 2]. Restoration of euthyroid status reverses the loss of bone mineral content and also ameliorates the excess fracture risk in patients with hyperthyroidism [5]. Meta-analyses of cohort studies have revealed an excess risk of fractures in people with subclinical hyperthyroidism [3, 4, 6], and even in populations with high-normal free thyroxine (FT4) and low-normal thyrotropin (thyroid-stimulating hormone, TSH), according to current reference ranges [7].
The association of even mild severities of hyperthyroidism with bone loss and increased fracture risk raises a question over the possibility of an adverse effect on the skeleton of either over treatment with LT4, or during receipt of the TSH-suppressive doses of LT4 administered following the surgical removal of thyroid tumours. This chapter reviews clinical studies of bone health in people receiving treatment with LT4 in these settings.
2 Bone Health in Patients Receiving Treatment with Levothyroxine
2.1 Patients with Congenital Hypothyroidism
Early and continuous treatment with LT4 has been shown to promote normal growth [8, 9] and BMD or other indices of bone health [10,11,12] in children with congenital hypothyroidism, relative to their euthyroid peers (Fig. 1), and normal BMD in adults [13]. Maintenance of a healthy weight and calcium intake appears to be an important determinant of bone health in these children, as in other populations [11].
2.2 Adult Patients with Hypothyroidism
2.2.1 Subclinical Hypothyroidism
Administration of LT4 to women with subclinical hypothyroidism increased the rate of bone turnover although whether this effect of LT4 per se, or a reversal of a previous hypothyroid-induced reduction in bone turnover was unclear [14]. A meta-analysis of studies in populations with subclinical hypothyroidism found no clinically significant reduction in bone loss during LT4 treatment in pre-menopausal women (2.7% after 8.5 years of treatment), but there was more significant bone loss in post-menopausal women (9.0% after 9.9 years of treatment) [15]. In contrast, a randomised, controlled trial found no effect of 14 months of LT4 vs. no treatment on BMD in 17 women with subclinical hypothyroidism [16]. Observational data over 3 years showed that the bone-preserving effect of hormone replacement therapy for post-menopausal women was blunted during administration of LT4 for subclinical hypothyroidism [17]. Finally, BMD in adolescent girls treated with LT4 for subclinical hypothyroidism for 2–5 years had similar BMD to a control group [18].
2.2.2 Overt Hypothyroidism
LT4 dosage >150 mg/day, vs. lower doses, was associated with increased risk of fractures in women aged ≥65 years with hypothyroidism and a prior history of osteoporosis (Fig. 2) [19]. There was no significant effect in women without prior osteoporosis in this study. Another cross-sectional, observational study in post-menopausal women found reduced BMD associated with a longer duration of LT4 treatment, with no significant relationship between LT4 dosage and BMD in these women [20]. Another observational study in post-menopausal women found no association between LT4 treatment and bone loss, irrespective of the degree of suppression of TSH [21].
Large database studies have also evaluated the effect of LT4 treatment on bone in general populations of patients with hypothyroidism. In one study, patients receiving LT4 therapy were at increased risk of fractures if they had either a high TSH level (>4 mIU/L) or a suppressed TSH level (≤0.03 mIU/L), compared with patients with TSH within the reference range (Fig. 3) [22]. Patients with TSH 0.4–4.0 mIU/L were not at increased risk of fractures in this study. Another large database study of 162,369 people with hypothyroidism, of whom 97% received LT4 during follow-up, found increased fracture risk among those with TSH >10 mIU/L, compared with those well controlled to within the euthyroid range (HR 1.15 (95%CI 1.01–1.31, p = 0.03) [23]. These studies demonstrated the importance of optimisation of LT4 treatment, rather than LT4 treatment per se, for maintaining bone health.
A case-control study from Denmark, where all 124,655 patients with a fracture served as cases and 373,962 randomly selected age- and gender-matched people without fractures served as controls, found no association between LT4 treatment and risk of fracture [24]. An analysis of 23,183 LT4 users from the UK General Practice Research Database (i.e. managed in the primary care setting) also found no significant association between LT4 use and fracture risk overall although there was an apparent increased risk in males [25]. Other observational data also did not identify a significant effect of LT4 treatment on bone health [26].
The recent SORTED 1 trial found no difference in effects on bone health measured using circulating levels of C-terminal telopeptide (CTx) levels in very elderly patients (≥80 years) with hypothyroidism randomised to control of TSH in the standard reference range (0.4–4.0 mIU/L), or to a higher target range (4.1–8.0 mIU/L) [27]; see chapter, “Levothyroxine in the Older Patient” for a fuller account of this trial. CTx correlates inversely with TSH, including during treatment with LT4, and may provide a useful marker for following effects of LT4 on bone metabolism [28].
2.3 Effects of Thyrotropin-Suppressive Doses of Levothyroxine
Long-term treatment with high doses of LT4 may be administered to suppress the activity of residual thyroid tumour cells after total thyroidectomy for well-differentiated thyroid carcinoma (see chapter, “Levothyroxine and Cancer”). This setting has been likened to a state of “subclinical hyperthyroidism” by some authors [29].
The application of TSH-suppressive doses of LT4 has raised concern over its effects on bone health, given the known association between hyperthyroidism, osteoporosis and increased risk of fractures, as described above. Indeed, many clinical studies have applied various measures of bone mineral density or other markers of skeletal function to post-surgical, athyroid patients receiving TSH-suppressive therapy. Conflicting results of the effects of TSH suppression were reported in pre-menopausal women (adverse effect [30,31,32,33,34,35,36,37,38,39,40,41], or no clear adverse effect [42,43,44,45,46,47]), or post-menopausal women (adverse effect [40, 48, 49] or no clear adverse effect [31, 45, 47, 50,51,52,53]). Clear adverse safety signals for osteoporosis during TSH suppression did not emerge from several studies in populations that included female populations of mixed pre-/post-menopausal status [54,55,56,57,58,59,60], men [31, 45, 61,62,63] or a mixture of either gender [37, 64,65,66,67] (one small study in a mixed population demonstrated increased bone loss with TSH suppression in patients with thyroid cancer [68]). Trabecular bone score may be a more sensitive measure than bone mineral density of the effects of treatment with LT4 on bone structure this parameter has been used in patients who have [31, 32], or have not [69], received thyroidectomy and TSH suppression for thyroid cancer, although changes in this measure did not correlate with changes in BMD in LT4-treated patients in another study [70]. An absence of marked effects on bone health was also observed in studies in which pre-menopausal women [71,72,73,74], post-menopausal women [71, 74, 75] or mixed populations [76, 77] received less intensive TSH-suppressive therapy for benign thyroid nodules, or for goitre.
Several studies evaluated fracture risk. One study found that the 10-year fracture risk (assessed using FRAX, an online risk assessment tool) in women (mean age 52 years) did not correlate significantly with LT4 dose, the duration of LT4 therapy or FT4 [42]. Others found no marked increase in the risk of fractures associated with TSH-suppressive therapy [65, 78, 79]. One study found associations between the intensity of TSH suppression and fracture risk: the incidence of vertebral fractures was 45% for patients with TSH <0.5 mIU/L, compared with 24% for TSH 0.5–1.0 mIU/L and 4% for TSH >1.0 mIU/L [80]. Similarly, the risk of osteoporosis was increased in patients receiving a cumulative LT4 dose over time of >395 mg, but not in patients receiving a lower dose, among 9398 patients with new-onset thyroid cancer followed for an average of 6.6 years [81].
Determinants of bone health in patients receiving TSH-suppressive therapy appear to be complex and multifactorial. A family history of osteoporosis and oestrogen deficiency have been identified as risk factors for adverse effects on bone in this population [57, 58, 82]. TSH-suppressive therapy itself was shown not to affect levels of sex hormone-binding globulin [83]. More data on the relationship of TSH-suppressive therapy and bone health are required, relating to older subjects, and men, in particular, however [84].
3 Clinical Perspectives
Clinical data on the effects of LT4 administration on bone are conflicting. The many studies reviewed above differed importantly in design, their populations, their durations and the indices of bone health measured, especially with regard to important clinical outcomes, such as fractures. In general, the use of LT4 to maintain euthyroid levels of thyroid hormones in patients with hypothyroidism, or even the use of TSH-suppressive therapy following removal of thyroid tumours, does not appear to carry a substantial risk of osteoporosis or fractures. Nevertheless, the associations between LT4 administration and loss of bone mineralisation of increased fracture risk in some studies suggests the use of a cautious approach to avoid over treatment, especially in patients with or at risk of developing osteoporosis, such as post-menopausal women, or the elderly.
References
Bassett JH, Williams GR. Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev. 2016;37:135–87.
Williams GR, Bassett JHD. Thyroid diseases and bone health. J Endocrinol Investig. 2018;41:99–109.
Yang R, Du C, Xu J, Yao L, Zhang S, Wu Y. The relationship between subclinical thyroid dysfunction and the risk of fracture or low bone mineral density: a systematic review and meta-analysis of cohort studies. J Bone Miner Metab. 2018;36:209–20.
Yan Z, Huang H, Li J, Wang J. Relationship between subclinical thyroid dysfunction and the risk of fracture: a meta-analysis of prospective cohort studies. Osteoporos Int. 2016;27:115–25.
Vestergaard P, Mosekilde L. Hyperthyroidism, bone mineral, and fracture risk—a meta-analysis. Thyroid. 2003;13:585–93.
Blum MR, Bauer DC, Collet TH, et al. Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA. 2015;313:2055–65.
Aubert CE, Floriani C, Bauer DC, et al. Thyroid function tests in the reference range and fracture: individual participant analysis of prospective cohorts. J Clin Endocrinol Metab. 2017;102:2719–28.
Uyttendaele M, Lambert S, Tenoutasse S, et al. Congenital hypothyroidism: long-term experience with early and high levothyroxine dosage. Horm Res Paediatr. 2016;85:188–97.
Salerno M, Lettiero T, Esposito-del Puente A, et al. Effect of long-term L-thyroxine treatment on bone mineral density in young adults with congenital hypothyroidism. Eur J Endocrinol. 2004;151:689–94.
Pitukcheewanont P, Safani D, Gilsanz V, Klein M, Chongpison Y, Costin G. Quantitative computed tomography measurements of bone mineral density in prepubertal children with congenital hypothyroidism treated with L-thyroxine. J Pediatr Endocrinol Metab. 2004;17:889–93.
Leger J, Ruiz JC, Guibourdenche J, Kindermans C, Garabedian M, Czernichow P. Bone mineral density and metabolism in children with congenital hypothyroidism after prolonged L-thyroxine therapy. Acta Paediatr. 1997;86:704–10.
Kooh SW, Brnjac L, Ehrlich RM, Qureshi R, Krishnan S. Bone mass in children with congenital hypothyroidism treated with thyroxine since birth. J Pediatr Endocrinol Metab. 1996;9:59–62.
Kempers MJ, Vulsma T, Wiedijk BM, de Vijlder JJ, van Eck-Smit BL, Verberne HJ. The effect of life-long thyroxine treatment and physical activity on bone mineral density in young adult women with congenital hypothyroidism. Pediatr Endocrinol Metab. 2006;19:1405–12.
Meier C, Beat M, Guglielmetti M, Christ-Crain M, Staub JJ, Kraenzlin M. Restoration of euthyroidism accelerates bone turnover in patients with subclinical hypothyroidism: a randomized controlled trial. Osteoporos Int. 2004;15:209–16.
Faber J, Galløe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: a meta-analysis. Eur J Endocrinol. 1994;130:350–6.
Ross DS. Bone density is not reduced during the short-term administration of levothyroxine to postmenopausal women with subclinical hypothyroidism: a randomized, prospective study. Am J Med. 1993;95:385–8.
Pines A, Dotan I, Tabori U, et al. L-thyroxine prevents the bone-conserving effect of HRT in postmenopausal women with subclinical hypothyroidism. Gynecol Endocrinol. 1999;13:196–201.
Saggese G, Bertelloni S, Baroncelli GI, Costa S, Ceccarelli C. Bone mineral density in adolescent females treated with L-thyroxine: a longitudinal study. Eur J Pediatr. 1996;155:452–7.
Ko YJ, Kim JY, Lee J, et al. Levothyroxine dose and fracture risk according to the osteoporosis status in elderly women. J Prev Med Public Health. 2014;47:36–46.
Affinito P, Sorrentino C, Farace MJ, et al. Effects of thyroxine therapy on bone metabolism in postmenopausal women with hypothyroidism. Acta Obstet Gynecol Scand. 1996;75:843–8.
Grant DJ, McMurdo ME, Mole PA, Paterson CR, Davies RR. Suppressed TSH levels secondary to thyroxine replacement therapy are not associated with osteoporosis. Clin Endocrinol (Oxf). 1993;39:529–33.
Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab. 2010;95:186–93.
Thayakaran R, Adderley NJ, Sainsbury C, et al. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ. 2019;366:l4892.
Vestergaard P, Rejnmark L, Mosekilde L. Influence of hyper- and hypothyroidism, and the effects of treatment with antithyroid drugs and levothyroxine on fracture risk. Calcif Tissue Int. 2005;77:139–44.
Sheppard MC, Holder R, Franklyn JA. Levothyroxine treatment and occurrence of fracture of the hip. Arch Intern Med. 2002;162:338–43.
Fowler PB, McIvor J, Sykes L, Macrae KD. The effect of long-term thyroxine on bone mineral density and serum cholesterol. J R Coll Physicians Lond. 1996;30:527–32.
Razvi S, Ryan V, Ingoe L, Pearce SH, Wilkes S. Age-related serum thyroid-stimulating hormone reference range in older patients treated with levothyroxine: a randomized controlled feasibility trial (SORTED 1). Eur Thyroid J. 2020;9:40–8.
Christy AL, D’Souza V, Babu RP, et al. Utility of C-terminal telopeptide in evaluating levothyroxine replacement therapy-induced bone loss. Biomark Insights. 2014;9:1–6.
Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid. 2010;20:135–46.
Bin-Hong D, Fu-Man D, Yu L, Xu-Ping W, Bing-Feng B. Effects of levothyroxine therapy on bone mineral density and bone turnover markers in premenopausal women with thyroid cancer after thyroidectomy. Endokrynol Pol. 2020;71:15–20.
Moon JH, Kim KM, Oh TJ, et al. The effect of TSH suppression on vertebral trabecular bone scores in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2017;102:78–85.
De Mingo Dominguez ML, Guadalix Iglesias S, Martin-Arriscado Arroba C, et al. Low trabecular bone score in postmenopausal women with differentiated thyroid carcinoma after long-term TSH suppressive therapy. Endocrine. 2018;62:166–73.
Kim MK, Yun KJ, Kim MH, et al. The effects of thyrotropin-suppressing therapy on bone metabolism in patients with well-differentiated thyroid carcinoma. Bone. 2015;71:101–5.
Schneider R, Schneider M, Reiners C, Schneider P. Effects of levothyroxine on bone mineral density, muscle force, and bone turnover markers: a cohort study. J Clin Endocrinol Metab. 2012;97:3926–34.
Sugitani I, Fujimoto Y. Effect of postoperative thyrotropin suppressive therapy on bone mineral density in patients with papillary thyroid carcinoma: a prospective controlled study. Surgery. 2011;150:1250–7.
Mazokopakis EE, Starakis IK, Papadomanolaki MG, Batistakis AG, Papadakis JA. Changes of bone mineral density in pre-menopausal women with differentiated thyroid cancer receiving L-thyroxine suppressive therapy. Curr Med Res Opin. 2006;22:1369–73.
Karner I, Hrgović Z, Sijanović S, et al. Bone mineral density changes and bone turnover in thyroid carcinoma patients treated with supraphysiologic doses of thyroxine. Eur J Med Res. 2005;10:480–8.
Guang-Da X, Hui-Ling S, Zhi-Song C, Lin-Shuang Z. Alteration of plasma concentrations of OPG before and after levothyroxine replacement therapy in hypothyroid patients. J Endocrinol Investig. 2005;28:965–72.
Marcocci C, Golia F, Bruno-Bossio G, Vignali E, Pinchera A. Carefully monitored levothyroxine suppressive therapy is not associated with bone loss in premenopausal women. J Clin Endocrinol Metab. 1994;78:818–23.
Jódar E, Begoña López M, García L, Rigopoulou D, Martínez G, Hawkins F. Bone changes in pre- and postmenopausal women with thyroid cancer on levothyroxine therapy: evolution of axial and appendicular bone mass. Osteoporos Int. 1998;8:311–6.
Pioli G, Pedrazzoni M, Palummeri E, et al. Longitudinal study of bone loss after thyroidectomy and suppressive thyroxine therapy in premenopausal women. Acta Endocrinol (Copenh). 1992;126:238–42.
Vera L, Gay S, Campomenosi C, et al. Ten-year estimated risk of bone fracture in women with differentiated thyroid cancer under TSH-suppressive levothyroxine therapy. Endokrynol Pol. 2016;67:350–8.
Kim CW, Hong S, Oh SH, et al. Change of bone mineral density and biochemical markers of bone turnover in patients on suppressive levothyroxine therapy for differentiated thyroid carcinoma. J Bone Metab. 2015;22:135–41.
Mendonça Monteiro de Barros G, Madeira M, Vieira Neto L, et al. Bone mineral density and bone microarchitecture after long-term suppressive levothyroxine treatment of differentiated thyroid carcinoma in young adult patients. J Bone Miner Metab. 2016;34:417–21.
Eftekhari M, Asadollahi A, Beiki D, et al. The long term effect of levothyroxine on bone mineral density in patients with well differentiated thyroid carcinoma after treatment. Hell J Nucl Med. 2008;11:160–3.
Sajjinanont T, Rajchadara S, Sriassawaamorn N, Panichkul S. The comparative study of bone mineral density between premenopausal women receiving long term suppressive doses of levothyroxine for well-differentiated thyroid cancer with healthy premenopausal women. J Med Assoc Thail. 2005;88(Suppl 3):S71–6.
Görres G, Kaim A, Otte A, Götze M, Müller-Brand J. Bone mineral density in patients receiving suppressive doses of thyroxine for differentiated thyroid carcinoma. Eur J Nucl Med. 1996;23:690–2.
Giannini S, Nobile M, Sartori L, et al. Bone density and mineral metabolism in thyroidectomized patients treated with long-term L-thyroxine. Clin Sci (Lond). 1994;87:593–7.
Kung AW, Lorentz T, Tam SC. Thyroxine suppressive therapy decreases bone mineral density in post-menopausal women. Clin Endocrinol (Oxf). 1993;39:535–40.
Zhang P, Xi H, Yan R. Effects of thyrotropin suppression on lumbar bone mineral density in postmenopausal women with differentiated thyroid carcinoma. Onco Targets Ther. 2018;11:6687–92.
de Melo TG, da Assumpção LV, Santos Ade O, Zantut-Wittmann DE. Low BMI and low TSH value as risk factors related to lower bone mineral density in postmenospausal women under levothyroxine therapy for differentiated thyroid carcinoma. Thyroid Res. 2015;8:7.
Fujiyama K, Maki H, Kinoshita S, Yoshida T. Suppressive doses of thyroxine do not accelerate age-related bone loss in late postmenopausal women. Thyroid. 1995;5:13–7.
Hawkins F, Rigopoulou D, Papapietro K, Lopez MB. Spinal bone mass after long-term treatment with L-thyroxine in postmenopausal women with thyroid cancer and chronic lymphocytic thyroiditis. Calcif Tissue Int. 1994;54:16–9.
Lee MY, Park JH, Bae KS, et al. Bone mineral density and bone turnover markers in patients on long-term suppressive levothyroxine therapy for differentiated thyroid cancer. Ann Surg Treat Res. 2014;86:55–60.
Reverter JL, Holgado S, Alonso N, Salinas I, Granada ML, Sanmartí A. Lack of deleterious effect on bone mineral density of long-term thyroxine suppressive therapy for differentiated thyroid carcinoma. Endocr Relat Cancer. 2005;12:973–81.
Chen CH, Wang PH, Chiu LH, Chang WH. Bone mineral density in women receiving thyroxine suppressive therapy for differentiated thyroid carcinoma. Formos Med Assoc. 2004;103:442–7.
Mikosch P, Jauk B, Gallowitsch HJ, Pipam W, Kresnik E, Lind P. Suppressive levothyroxine therapy has no significant influence on bone degradation in women with thyroid carcinoma: a comparison with other disorders affecting bone metabolism. Thyroid. 2001;11:257–63.
Mikosch P, Obermayer-Pietsch B, Jost R, et al. Bone metabolism in patients with differentiated thyroid carcinoma receiving suppressive levothyroxine treatment. Thyroid. 2003;13:347–56.
Müller CG, Bayley TA, Harrison JE, Tsang R. Possible limited bone loss with suppressive thyroxine therapy is unlikely to have clinical relevance. Thyroid. 1995;5:81–7.
Florkowski CM, Brownlie BE, Elliot JR, Ayling EM, Turner JG. Bone mineral density in patients receiving suppressive doses of thyroxine for thyroid carcinoma. N Z Med J. 1993;106:443–4.
Reverter JL, Colomé E, Holgado S, et al. Bone mineral density and bone fracture in male patients receiving long-term suppressive levothyroxine treatment for differentiated thyroid carcinoma. Endocrine. 2010;37:467–72.
Jódar E, Martínez-Díaz-Guerra G, Azriel S, Hawkins F. Bone mineral density in male patients with L-thyroxine suppressive therapy and Graves disease. Calcif Tissue Int. 2001;69:84–7.
Marcocci C, Golia F, Vignali E, Pinchera A. Skeletal integrity in men chronically treated with suppressive doses of L-thyroxine. J Bone Miner Res. 1997;12:72–7.
Kachui A, Tabatabaizadeh SM, Iraj B, Rezvanian H, Feizi A. Evaluation of bone density, serum total and ionized calcium, alkaline phosphatase and 25-hydroxy vitamin D in papillary thyroid carcinoma, and their relationship with TSH suppression by levothyroxine. Adv Biomed Res. 2017;6:94.
Heijckmann AC, Huijberts MS, Geusens P, de Vries J, Menheere PP, Wolffenbuttel BH. Hip bone mineral density, bone turnover and risk of fracture in patients on long-term suppressive L-thyroxine therapy for differentiated thyroid carcinoma. Eur J Endocrinol. 2005;153:23–9.
Rosen HN, Moses AC, Garber J, et al. Randomized trial of pamidronate in patients with thyroid cancer: bone density is not reduced by suppressive doses of thyroxine, but is increased by cyclic intravenous pamidronate. J Clin Endocrinol Metab. 1998;83:2324–30.
Franklyn JA, Betteridge J, Daykin J, et al. Long-term thyroxine treatment and bone mineral density. Lancet. 1992;340:9–13.
MT MD, Perloff JJ, Kidd GS. A longitudinal assessment of bone loss in women with levothyroxine-suppressed benign thyroid disease and thyroid cancer. Calcif Tissue Int. 1995;56:521–5.
Hwangbo Y, Kim JH, Kim SW, et al. High-normal free thyroxine levels are associated with low trabecular bone scores in euthyroid postmenopausal women. Osteoporos Int. 2016;27:457–62.
Kim K, Kim IJ, Pak K, et al. Evaluation of bone mineral density using dxa and cqct in postmenopausal patients under thyrotropin suppressive therapy. J Clin Endocrinol Metab. 2018;103:4232–40.
Appetecchia M. Effects on bone mineral density by treatment of benign nodular goiter with mildly suppressive doses of L-thyroxine in a cohort women study. Horm Res. 2005;64:293–8.
Larijani B, Gharibdoost F, Pajouhi M, et al. Effects of levothyroxine suppressive therapy on bone mineral density in premenopausal women. J Clin Pharm Ther. 2004;29:1–5.
Nuzzo V, Lupoli G, Esposito Del Puente A, et al. Bone mineral density in premenopausal women receiving levothyroxine suppressive therapy. Gynecol Endocrinol. 1998;12:333–7.
De Rosa G, Testa A, Maussier ML, Callà C, Astazi P, Albanese C. A slightly suppressive dose of L-thyroxine does not affect bone turnover and bone mineral density in pre- and postmenopausal women with nontoxic goitre. Horm Metab Res. 1995;27:503–7.
Chen CY, Chen ST, Huang BY, Hwang JS, Lin JD, Liu FH. The effect of suppressive thyroxine therapy in nodular goiter in postmenopausal women and 2 year’s bone mineral density change. Endocr J. 2018;65:1101–9.
Baldini M, Serafino S, Zanaboni L, Cappellini MD. Treatment of benign nodular goitre with mildly suppressive doses of L-thyroxine: effects on bone mineral density and on nodule size. J Intern Med. 2002;251:407–14.
Zelmanovitz F, Genro S, Gross JL. Suppressive therapy with levothyroxine for solitary thyroid nodules: a double-blind controlled clinical study and cumulative meta-analyses. J Clin Endocrinol Metab. 1998;83:3881–5.
Nguyen TT, Heath H 3rd, Bryant SC, O’Fallon WM, Melton LJ 3rd. Fractures after thyroidectomy in men: a population-based cohort study. J Bone Miner Res. 1997;12:1092–9.
Melton LJ 3rd, Ardila E, Crowson CS, O’Fallon WM, Khosla S. Fractures following thyroidectomy in women: a population-based cohort study. Bone. 2000;27:695–700.
Mazziotti G, Formenti AM, Frara S, et al. High prevalence of radiological vertebral fractures in women on thyroid-stimulating hormone-suppressive therapy for thyroid carcinoma. J Clin Endocrinol Metab. 2018;103:956–64.
Lin SY, Lin CL, Chen HT, Kao CH. Risk of osteoporosis in thyroid cancer patients using levothyroxine: a population-based study. Curr Med Res Opin. 2018;34:805–12.
Soydal Ç, Özkan E, Nak D, Elhan AH, Küçük NÖ, Kır MK. Risk factors for predicting osteoporosis in patients who receive thyrotropin suppressive levothyroxine treatment for differentiated thyroid carcinoma. Mol Imaging Radionucl Ther. 2019;28:69–75.
Lecomte P, Lecureuil N, Osorio-Salazar C, Lecureuil M, Valat C. Effects of suppressive doses of levothyroxine treatment on sex-hormone-binding globulin and bone metabolism. Thyroid. 1995;5:19–23.
Papaleontiou M, Hawley ST, Haymart MR. Effect of thyrotropin suppression therapy on bone in thyroid cancer patients. Oncologist. 2016;21:165–71.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.
The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Copyright information
© 2021 The Author(s)
About this chapter
Cite this chapter
Teng, W. (2021). Levothyroxine and Bone. In: Kahaly, G.J. (eds) 70 Years of Levothyroxine. Springer, Cham. https://doi.org/10.1007/978-3-030-63277-9_8
Download citation
DOI: https://doi.org/10.1007/978-3-030-63277-9_8
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-63276-2
Online ISBN: 978-3-030-63277-9
eBook Packages: MedicineMedicine (R0)