Bone Metabolism in Patients With Differentiated Thyroid Carcinoma Receiving Suppressive Levothyroxine Treatment

P. Mikosch, B. Obermayer-Pietsch, R. Jost, B. Jauk, H.J. Gallowitsch, E. Kresnik, G. Leb, P. Lind


Thyroid. 2003;13(4) 

In This Article

Abstract and Introduction

Aim: Patients with differentiated thyroid carcinoma (DTC) must receive suppressive levothyroxine (LT4) therapy for the rest of their lives. The literature, however, presents conflicting results on how this affects bone metabolism. The aim of this study was to assess the influence of the estrogen status and LT4 therapy, in particular LT4 dosage in micrograms per kilograms (µg/kg), on bone metabolism in female patients with DTC.
Material and Methods: Three markers of bone metabolism (C-terminal telopeptide of type I collagen in serum [SCTx]; N-terminal telopeptide of type I collagen in urine [U-NTx]; and osteocalcin [OC]) were investigated in four groups: group REF (healthy premenopausal female controls), group DTC-ES (premenopausal women with DTC and normal estrogen levels), group DTC-ED (postmenopausal women with DTC and estrogen deficiency), and group DTC-HRT (postmenopausal women with DTC undergoing hormone replacement therapy [HRT]). All patients with DTC were on a well-adjusted suppressive LT4 therapy with TSH levels 0.1 mU/L or less.
Results: In group DTC-ES bone turnover was comparable to group REF, whereas in group DTC-ED, all three markers were significantly increased as compared to groups REF and DTC-ES. In group DTC-HRT, the HRT normalized U-NTx and OC. However, in this group S-CTx was not completely normalized by HRT in all patients, although also significantly lowered compared to group DTC-ED. The analysis of LT4 dosage per kilogram showed that premenopausal DTC-patients had increased markers of bone metabolism if LT4 dosage exceeded 2.6 µg/kg. Estrogen-deficient patients with DTC, however, had a much lower critical LT4 dosage, above which increased markers of bone metabolism were seen.
Conclusion: A well-adjusted suppressive LT4 therapy of less than 2.6 µg/kg and normal estrogen levels do not seem to increase bone metabolism in estrogen-sufficient patients with DTC. The normalization of an estrogen deficiency by HRT or other antiresorptive therapies and minimal suppressive dosages of LT4 are attempts to optimize the care of patients with DTC. In postmenopausal patients with DTC and patients with DTC who require LT4 dosages in excess of 2.6 µg/kg, the information provided by markers of bone metabolism may help to prevent bone damage.

The treatment of patients with differentiated thyroid carcinoma (DTC) is based primarily on surgery and radioiodine remnant ablation therapy and, in cases with local metastases or incomplete surgical resection (R1 resection), on external beam radiation.[1,2,3] After these initial therapies, patients with DTC receive suppressive levothyroxine (LT4) to prevent thyroid hormone deficiency and to suppress thyrotropin (TSH) stimulation of growth of potential residual disease.[1] Most specialists agree that patients with DTC should receive suppressive LT4 therapy for the rest of their lives although this life-long therapy has potentially deleterious effects on bone metabolism.

Thyroid hormones may act on bone metabolism either indirectly by increasing the secretion of growth hormone or insulin-like growth factor,[4,5] or directly via thyroid hormone receptors.[6] Recently, the presence of thyroid hormone receptors could be demonstrated in human osteoblasts and osteoclasts.[6,7] Moreover, thyroid hormones seem to accelerate osteoblastic differentiation.[8] Although the exact mechanisms of thyroid hormone action on bone remodeling are still poorly understood,[6,8] chronic thyrotoxicosis is well recognized as a risk factor for osteoporosis in clinical practice.[9,10] Thyroid hormone excess increases the activity of both the osteoblasts and the osteoclasts, resulting in increased bone remodeling.[7,8,9,10] The increased osteoclast activity predominates over osteoblast activity, resulting in a net loss of cortical and trabecular bone.[8,10]

The deleterious effects of thyrotoxicosis on bone can be regularly observed in Graves' disease or autonomous thyroid adenoma; however, the significance of possible bone loss and fracture risk in patients with DTC on suppressive doses of LT4 has been discussed controversially in the literature.[10,11] Schneider et al.[12] showed that long-term daily treatment with LT4 equivalent doses of 1.6 µg/kg or more are associated with osteopenia, and women taking 200 µg LT4 per day or more had significantly less bone mineral density (BMD) at the midshaft radius and hip compared to those taking less that 200 µg of LT4. Other studies[13,14,15,16] also demonstrated a loss of BMD because of suppressive LT4 therapy and Solomon et al.[17] concluded that fractures may occur earlier in life in patients on suppressive LT4 therapy. In contrast to these results, Müller et al.[18] detected a significant reduction in BMD only within the extremities, but an insignificant BMD reduction in the lumbar spine, femoral neck, and trunk. Other studies did not show any significant effects on BMD.[17,19,20,21,22,23,24]

Although BMD measurements are currently used as the main diagnostic tool in osteoporosis, it has to be stressed that BMD summarizes various influences on bone during life. However, markers of bone metabolism are valuable to reflect the actual degree of bone degradation and bone formation that may not necessarily correspond to BMD.

With regard to negative influences on bone metabolism in prescribing drugs, a quick laboratory test to assure clinicians would be useful. This is evident in case of a suppressive LT4 therapy in patients with DTC, because chronic thyrotoxicosis is a known risk factor for osteoporosis.[9,10]

Biochemical indices of bone metabolism and their relation to suppressive LT4 therapy have also been discussed controversially in the literature. High bone turnover has been associated with low bone mass[25,26,27] and bone markers have been suggested to contribute to the evaluation of osteoporosis risk[16,26] Recent results of the EPIDOS[28] and the OFELY studies[29] concluded that elevated bone resorption markers in both younger[29] and older[28] post-menopausal women seem to be associated with an increased risk for hip fractures. Thus, if care and life-long suppressive LT4 treatment for patients with DTC are to be optimized, the effect of increased bone turnover should be known.

The present study analyzed the impact of both suppressive LT4 therapy and estrogen status on bone metabolism in women with DTC and a critical daily suppressive LT4 dosage was evaluated.