J-Shaped Association Between Postoperative Levothyroxine Dosage and Fracture Risk in Thyroid Cancer Patients: A Retrospective Cohort Study
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Long-term administration of supraphysiologic dosages of levothyroxine can have detrimental effect on the bone. We aimed to investigate fracture incidence among post-thyroidectomy thyroid cancer patients compared with a matched comparison group, and explore the association between levothyroxine dosage and fracture risk. From the Korean National Health Insurance database, virtually all thyroid cancer patients who received thyroidectomy in Korea from January 1, 2004 to December 31, 2012 were included. Matched subjects were selected by 1:1 propensity score matching. Cox proportional hazards regression analysis was used to determine relative risk of osteoporotic fracture. Of 185,956 thyroid cancer patients identified, fracture events were observed in 1096 subjects (0.56%) over a mean 4.35 years of follow-up. Compared to the matched comparison group, thyroid cancer patients had no elevated risk of osteoporotic fracture (hazard ratio [HR] 1.03; 95% confidence interval [CI], 0.94 to 1.12); however, the highest dosage group (≥170 μg/day) showed significantly higher risk (HR 1.25; 95% CI, 1.07 to 1.45), while the second quartile dosage group (115-144 μg/day) showed lower risk (HR 0.71; 95% CI, 0.59 to 0.84) compared to a matched comparison group. When the second quartile dosage group was considered as reference, increased fracture risk was observed in those who took either lower (first quartile: adjusted HR 1.31; 95% CI, 1.08 to 1.59) or higher dosage of levothyroxine (third quartile: adjusted HR 1.50; 95% CI, 1.26 to 1.79; fourth quartile: adjusted HR 1.79; 95% CI, 1.51 to 2.13). Thyroid cancer patients were more likely to be treated with osteoporosis medication (HR 1.22; 95% CI, 1.18 to 1.26) than the matched comparison group. Both high and low dosage of levothyroxine treatment was associated with a higher risk for fractures in a J-shaped dose-dependent manner in post-thyroidectomy patients. Future studies are needed to determine how to optimize thyroid-stimulating hormone (TSH) suppression and how to screen and manage fracture risk. © 2018 American Society for Bone and Mineral Research.
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Several large cohorts or prospective studies reporting the prevalence of osteoporosis or fractures in patients with TSH suppression therapy were not included because they did not provide accurate data.
“In addition, several large cohorts or prospective studies reporting the prevalence of osteoporosis or fractures in patients with TSH suppression therapy were not included because they did not provide the accurate data (52)(53)(54)(55).”
From Effect of TSH Suppression Therapy on Bone Mineral Density in Differentiated Thyroid Cancer: A Systematic Review and Meta-analysis (2021) · cites this paper as [53]
The Introduction identifies this as a large nationwide study of fracture outcomes in thyroid cancer patients, and the Results report fracture incidence. It does not report fracture prevalence or directly measure TSH suppression; the Exposure section says levothyroxine dose was used as a surrogate. The decision to exclude the study is the citing authors’ own, not a finding attributed to this paper. (LLM, conf=0.82)
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Cites
Haugen, B. R., Alexander, E. K., Bible, K. C., Doherty, G. M., Mandel, S. J., Nikiforov, Y. E., Pacini, F., Randolph, G. W., Sawka, A. M., Schlumberger, M., et al. (2016) · Thyroid® · doi:10.1089/thy.2015.0020 · Cited by 16,535 · see citing works
Cooper, D. S., Doherty, G. M., Haugen, B. R., Kloos, R. T., Lee, S. L., Mandel, S. J., Mazzaferri, E. L., McIver, B., Pacini, F., Schlumberger, M., et al. (2009) · Thyroid · doi:10.1089/thy.2009.0110 · Cited by 6,707 · see citing works
Clinician’s Guide to Prevention and Treatment of Osteoporosis
Cosman, F., de Beur, S. J., LeBoff, M. S., Lewiecki, E. M., Tanner, B., Randall, S., & Lindsay, R. (2014) · Osteoporosis International · doi:10.1007/s00198-014-2794-2 · Cited by 4,149 · see citing works
Pacini, F., Schlumberger, M. J., Dralle, H., Elisei, R., Smit, J. W. A., Wiersinga, W. M., & _, _. (2006) · European Journal of Endocrinology · doi:10.1530/eje.1.02158 · Cited by 1,970 · see citing works
Current Thyroid Cancer Trends in the United States
Davies, L., & Welch, H. G. (2014) · JAMA Otolaryngology–Head & Neck Surgery · doi:10.1001/jamaoto.2014.1 · Cited by 1,619 · see citing works
Guidelines for the management of thyroid cancer
Perros, P., Boelaert, K., Colley, S., Evans, C., Evans, R. M., Gerrard, G. E., Gilbert, J., Harrison, B. J., Johnson, S. J., Giles, T. E., et al. (2014) · Clinical Endocrinology · doi:10.1111/cen.12515 · Cited by 1,390 · see citing works
Korea's Thyroid-Cancer “Epidemic” — Screening and Overdiagnosis
Ahn, H. S., Kim, H. J., & Welch, H. G. (2014) · New England Journal of Medicine · doi:10.1056/nejmp1409841 · Cited by 1,238 · see citing works
Song, S. O., Jung, C. H., Song, Y. D., Park, C., Kwon, H., Soo, B., Park, J., Lee, K., Ko, K. S., & Lee, B. (2014) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2014.38.5.395 · Cited by 677 · see citing works
Self-citationAddressing overdiagnosis and overtreatment in cancer: a prescription for change
Esserman, L. J., Thompson, I. M., Reid, B. J., Nelson, P. S., Ransohoff, D. F., Welch, H. G., Hwang, S. E., Berry, D. A., Kinzler, K. W., Black, W. C., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70598-9 · Cited by 506 · see citing works
Flynn, R. W., Bonellie, S. R., Jung, R. T., MacDonald, T. M., Morris, A. D., & Leese, G. P. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1625 · Cited by 415 · see citing works
Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis
Blum, M. R., Bauer, D. C., Collet, T.-H., Fink, H. A., Cappola, A. R., da Costa, B. R., Wirth, C. D., Peeters, R. P., Åsvold, B. O., den Elzen, W. P. J., et al. (2015) · JAMA · doi:10.1001/jama.2015.5161 · Cited by 343 · see citing works
Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer
Pujol, P., Daurès, J., Nsakala, N., Baldet, L., Bringer, J., & Jaffiol, C. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.12.8954034 · Cited by 319 · see citing works
Which fractures are most attributable to osteoporosis?
Warriner, A. H., Patkar, N. M., Curtis, J. R., Delzell, E., Gary, L. C., Kilgore, M. L., & Saag, K. G. (2010) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2010.07.007 · Cited by 308 · see citing works
Hyperthyroidism, Bone Mineral, and Fracture Risk—A Meta-Analysis
Vestergaard, P., & Mosekilde, L. (2003) · Thyroid · doi:10.1089/105072503322238854 · Cited by 306 · see citing works
On principles for modeling propensity scores in medical research
Rubin, D. B. (2004) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.968 · Cited by 288 · see citing works
Biondi, B., & Cooper, D. S. (2010) · Thyroid · doi:10.1089/thy.2009.0311 · Cited by 286 · see citing works
Korean National Health Insurance Database
Shin, D. W., Cho, B., & Güallar, E. (2016) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2015.7110 · Cited by 285 · see citing works
Self-citationCho, B. Y., Choi, H. S., Park, Y. J., Lim, J., Ahn, H. Y., Lee, E. K., Kim, K. W., Yi, K. H., Chung, J.-K., Youn, Y., et al. (2013) · Thyroid · doi:10.1089/thy.2012.0329 · Cited by 188 · see citing works
Self-citationThyroid Hormone Actions in Cartilage and Bone
Williams, G. R. (2012) · European Thyroid Journal · doi:10.1159/000345548 · Cited by 167 · see citing works
Hovens, G. C., Stokkel, M. P. M., Kievit, J., Corssmit, E. P. M., Pereira, A. M., Romijn, J. A., & Smit, J. W. A. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2566 · Cited by 163 · see citing works
Wang, L. Y., Smith, A. W., Palmer, F. L., Tuttle, R. M., Mahrous, A., Nixon, I. J., Patel, S. G., Ganly, I., Fagin, J. A., & Boucai, L. (2015) · Thyroid · doi:10.1089/thy.2014.0287 · Cited by 161 · see citing works
The Impact of Overt and Subclinical Hyperthyroidism on Skeletal Muscle
Brennan, M. D., Powell, C., Kaufman, K. R., Sun, P. C., Bahn, R. S., & Nair, K. S. (2006) · Thyroid · doi:10.1089/thy.2006.16.375 · Cited by 155 · see citing works
Levothyroxine dose and risk of fractures in older adults: nested case-control study
Turner, M. R., Camacho, X., Fischer, H. D., Austin, P. C., Anderson, G. M., Rochon, P. A., & Lipscombe, L. L. (2011) · BMJ · doi:10.1136/bmj.d2238 · Cited by 152 · see citing works
The skeletal consequences of thyrotoxicosis
Nicholls, J. J., Brassill, M. J., Williams, G. R., & Bassett, J. H. D. (2012) · Journal of Endocrinology · doi:10.1530/joe-12-0059 · Cited by 138 · see citing works
Heemstra, K. A., Hamdy, N. A. T., Romijn, J. A., & Smit, J. W. A. (2006) · Thyroid · doi:10.1089/thy.2006.16.583 · Cited by 134 · see citing works
Barrett-Connor, E. L., Weiss, T. W., McHorney, C. A., Miller, P. D., & Siris, E. S. (2008) · Osteoporosis International · doi:10.1007/s00198-008-0748-2 · Cited by 129 · see citing works
Sugitani, I., & Fujimoto, Y. (2011) · Surgery · doi:10.1016/j.surg.2011.09.013 · Cited by 124 · see citing works
Lee, H., Cho, J., Shin, D. W., Lee, S., Hwang, S.-S., Oh, J., Yang, H. K., Hwang, S.-H., Son, K. Y., Chun, S., et al. (2014) · Preventive Medicine · doi:10.1016/j.ypmed.2014.11.007 · Cited by 117 · see citing works
Self-citationThe influence of thyroid dysfunction on bone metabolism
Tuchendler, D., & Bolanowski, M. (2014) · Thyroid Research · doi:10.1186/s13044-014-0012-0 · Cited by 117 · see citing works
Dießl, S., Holzberger, B., Mäder, U., Grelle, I., Smit, J. W. A., Buck, A. K., Reiners, C., & Verburg, F. A. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04272.x · Cited by 86 · see citing works
Quan, M. L., Pasieka, J. L., & Rorstad, O. P. (2001) · Journal of Surgical Oncology · doi:10.1002/jso.10043 · Cited by 75 · see citing works
Baliram, R., Latif, R., Berkowitz, J., Frid, S., Colaianni, G., Sun, L., Zaidi, M., & Davies, T. F. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1110286108 · Cited by 71 · see citing works
Jódar, E., Begoña López, M., García, L., Rigopoulou, D., Martínez, G., & Hawkins, F. (1998) · Osteoporosis International · doi:10.1007/s001980050069 · Cited by 59 · see citing works
Levothyroxine Suppression of Thyroglobulin in Patients with Differentiated Thyroid Carcinoma1
Wang, P., Wang, S., Liu, R., Chien, W.-Y., Tung, S., Lu, Y.-C., Chen, H.-Y., & Lee, C.-H. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.12.6190 · Cited by 41 · see citing works
Levothyroxine Suppression of Thyroglobulin in Patients with Differentiated Thyroid Carcinoma
Wang, P.-W. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.84.12.4549 · Cited by 30 · see citing works
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Shin, D. W., Cho, J., Park, J., & Cho, B. (2022) · Precision and Future Medicine · doi:10.23838/pfm.2021.00135 · Cited by 354 · see citing works
Self-citationCho, S. W., Kim, J. H., Choi, H. S., Ahn, H. Y., Kim, M. K., & Rhee, E. (2023) · Endocrinology and Metabolism · doi:10.3803/enm.2023.102 · Cited by 69 · see citing works
Suh, B., Shin, D. W., Park, Y., Lim, H., Yun, J. M., Song, S. O., Park, J., Cho, B., & Güallar, E. (2018) · European Journal of Endocrinology · doi:10.1530/eje-18-0551 · Cited by 61 · see citing works
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Lee, E. A., Shin, D. W., Yoo, J., Ko, H., & Jeong, S. M. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3675 · Cited by 45 · see citing works
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Brancatella, A., & Marcocci, C. (2020) · Endocrine Connections · doi:10.1530/ec-20-0167 · Cited by 40 · see citing works
Papaleontiou, M., Banerjee, M., Reyes-Gastelum, D., Hawley, S. T., & Haymart, M. R. (2019) · The Oncologist · doi:10.1634/theoncologist.2019-0234 · Cited by 38 · see citing works
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Ye, C., & Leslie, W. D. (2022) · Osteoporosis International · doi:10.1007/s00198-022-06631-4 · Cited by 37 · see citing works
Kwak, D., Ha, J., Won, Y., Kwon, Y., & Park, S. (2021) · BMJ Open · doi:10.1136/bmjopen-2020-043007 · Cited by 34 · see citing works
Yeo, Y., Shin, D. W., Han, K., Kim, D., Kim, T. H., Chun, S., Jeong, S., & Song, Y. (2022) · Thyroid · doi:10.1089/thy.2021.0675 · Cited by 32 · see citing works
Self-citationShin, D. W., Suh, B., Lim, H., Suh, Y., Choi, Y. J., Jeong, S., Yun, J. M., Song, S. O., & Park, Y. (2019) · The American Journal of Gastroenterology · doi:10.14309/ajg.0000000000000436 · Cited by 29 · see citing works
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Roh, E., Noh, E., Hwang, S. Y., Kim, J. A., Song, E., Park, M., Choi, K. M., Baik, S. H., Cho, G. J., & Yoo, H. J. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab776 · Cited by 26 · see citing works
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Zhu, N., Ni, H., Guo, S., Shen, Y., & Chen, Q. (2024) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2024.102828 · Cited by 24 · see citing works
Yeo, Y., Han, K., Shin, D.-W., Kim, D., Jeong, S., Chun, S., Choi, I.-Y., Jeon, K. H., & Kim, T. H. (2021) · Cancers · doi:10.3390/cancers13102343 · Cited by 24 · see citing works
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Wang, S., Wang, Y., Li, Z., He, L., Lv, M., Zhang, H., Wang, H., Zhang, F., Lai, Y., Li, Y., et al. (2022) · Endocrine · doi:10.1007/s12020-022-03186-6 · Cited by 14 · see citing works
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Kim, G. L., Yi, Y. H., Hwang, H. R., Kim, J., Park, Y., Kim, Y. J., Lee, J. G., Tak, Y. J., Lee, S. H., Lee, S. Y., et al. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10092044 · Cited by 9 · see citing works
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Jin, Y.-J., Song, C. M., Park, B.-J., & Choi, H. G. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18094732 · Cited by 6 · see citing works
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Self-citation
- Authors
- Shin, D. W., Suh, B., Lim, H., Yun, J. M., Song, S. O., & Park, Y.
- Affiliations
- Samsung Medical Center (KR)
- Lunit (South Korea) (KR)
- National Health Insurance Service Ilsan Hospital (KR)
- Seoul National University (KR)
- Corresponding author
- Park, Youngmin
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-02-15
- Volume
- 33
- Issue
- 6
- Pages
- 1037-1043
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2790425734
- Cited by
- 32
- References
- 35
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 8 · 2020: 2 · 2019: 4 · 2018: 1
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NHIS Ilsan Hospital (2015-20-006)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- levothyroxine, thyroid cancer, thyroidectomy, osteoporotic fractures, fracture risk, levothyroxine dosage, bone health, osteoporosis drugs, J-shaped association, propensity score matching, Korean patients, dose-response relationship, bone mineral density, osteoporosis risk factors
- MeSH terms
- Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Postoperative Care, Retrospective Studies, Risk Factors, Thyroid Neoplasms, Thyroxine, Incidence, Fractures, Bone, Republic of Korea, Osteoporotic Fractures
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