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Byline: Christian Meier (1,2), Muller Beat (1), Merih Guglielmetti (1), Mirjam Christ-Crain (1), Jean-Jacques Staub (1), Marius Kraenzlin (1) Keywords: Bone density; Bone remodeling; Replacement; Subclinical hypothyroidism; Thyroxine Abstract: This study evaluated the effect of physiological l-thyroxine (L-T4) treatment on bone metabolism in patients with subclinical hypothyroidism. Sixty-six women with subclinical hypothyroidism (TSH 11.7 +- 0.8 mIU/l) were randomly assigned to receive L-T4 or placebo for 48 weeks. Sixty-one of 66 patients completed the study. Individual L-T4 replacement (mean dosage 85.5 +- 4.3 ug/day) was performed targeting euthyroid thyroid-stimulating hormone (TSH) levels. The primary outcome measure was 24- and 48-week change in markers of bone formation (total and bone alkaline phosphatase [ALP, bone ALP], osteocalcin [OC]) and resorption (pyridinoline [PYD] and deoxypyridinoline [DPD], C-terminal cross-linking telopeptide type I [CTX]). Secondary outcomes were 48-week changes in bone mineral density (BMD) of the lumbar spine and hip, measured by dual-energy X-ray absorptiometry. Compared with placebo, l-thyroxine (n=31) resulted in significant activation of bone turnover. Overall, a significant treatment effect was observed for DPD (between-group difference 16.0% 95%CI, 10.9 to 21.1), CTX (29.9% 95%CI, 23.3 to 36.5), and bone ALP (13.2% 95%CI, 6.6 to 19.7) after 24 weeks. At the end of the study, lumbar BMD in the both treatment groups differed by 1.3% (95%CI, -2.9 to 0.5) with lower levels in l-thyroxine treated women. Significant difference in BMD between groups was also observed at the trochanter. We conclude that physiological l-thyroxine treatment accelerates bone turnover reflecting early activation of bone remodeling units in the initial replacement of subclinical hypothyroidism. The observed bone loss could be interpreted as an adaptive mechanism on decreased bone turnover in preexistent hypothyroidism, and not as l-thyroxine-induced clinically important bone loss. However, long-term studies are needed to confirm this assumption. Author Affiliation: (1) Division of Endocrinology, Department of Medicine, University Hospitals, CH-4031, Basel, Switzerland (2) Bone Research Laboratory, ANZAC Research Institute, University of Sydney, NSW 2139, Concord, Australia Article History: Registration Date: 23/09/2003 Received Date: 24/03/2003 Accepted Date: 12/09/2003 Online Date: 16/01/2004 Article note: This work was supported by grants from the Swiss National Science Foundation (32.27866.89, 32.37792.93, and 32.37792.98) and unconditional research grants from Henning Berlin, Sandoz Research, and Roche Research foundations. Presented in part at the 24th annual meeting of the American Society for Bone and Mineral Research, San Antonio, 2002, and at the 84th annual meeting of The Endocrine Society, San Francisco, 2002.