Increased levels of serum osteoprotegerin in hypothyroid patients and its normalization with restoration of normal thyroid function

Abstract

Hypothyroidism is associated with increased morbidity from cardiovascular disease, and an increase in serum osteoprotegerin (OPG) has recently been reported to be associated with the severity of coronary heart disease and cardiovascular mortality. The present study was designed to examine whether hypothyroidism causes an increase in serum OPG, and to determine whether levothyroxine (L-T4) replacement therapy might suppress serum OPG levels in hypothyroid patients. Fifty-three hypothyroid patients with chronic thyroiditis and age-and sex-matched normal control subjects were examined for the levels of serum OPG and plasma von Willebrand factor (vWF), a vascular injury marker. Thirty-seven of the hypothyroid patients were further monitored for changes in these markers during 1 year in a euthyroid state induced by L-T4 replacement therapy. Baseline OPG was significantly higher in hypothyroid patients than in normal controls (4.51^0.50 vs 3.72^0.23 pmol/l (mean^S.E.); P ¼ 0.0182). In multivariate analysis, baseline OPG was significantly associated with baseline levels of TSH (r ¼ 0.280, P ¼ 0.0162) and vWF (r ¼ 0.626, P , 0.0001). During one year of L-T4 replacement therapy, hypothyroid patients showed a significant decrease in OPG levels from 4.35^0.51 to 3.48^0.26 pmol/l (P ¼ 0.0166), a level comparable to normal controls. The change in serum OPG levels during L-T4 replacement therapy was significantly and independently associated in a negative fashion with baseline vWF (r ¼ 2 0.503, P ¼ 0.0014). This study suggested that the severity of hypothyroidism and vascular injury might have important independent roles in increasing the serum OPG level in hypothyroid patients. Furthermore, it was demonstrated that a sustained euthyroid state might have the potential to decrease the serum OPG level in hypothyroid patients and that the degree of vascular injury in the hypothyroid state is independently associated with a decrease in serum OPG during a 1-year normalization of thyroid function.

Thyroid hormone deficiency and postmenopausal status independently increase serum osteoprotegerin concentrations in women

“…However, those studies included patients with autoimmune thyroid disease with unknown duration of hypothyroidism, and therefore the possibility that thyroid autoimmunity may modulate osteoprotegerin production could have been a confounding factor (19). Two of these studies included only premenopausal women (11,12) and the other one included both men and women, with no information about the postmenopausal status of these women (10). As postmenopausal status is an important regulator of serum osteoprotegerin concentrations (5, 6), those studies did not provide information about the possible interaction of the former with thyroid function.…”

“…The precise mechanisms by which thyroid hormone deficiency increases serum osteoprotegerin have not yet been elucidated. It has been proposed that the increased cardiovascular risk associated with hypothyroidism or a reduced renal clearance of osteoprotegerin could be possible explanations (10). Furthermore, we cannot completely exclude the possibility that the elevation in serum osteoprotegerin concentrations during hypothyroidism might represent a response to the inhibition of bone metabolism that results from thyroid hormone deficiency (17,20), although this mechanism seems unlikely as osteoprotegerin usually increases in response to increased bone resorption (4), and is positively associated with osteocalcin levels (5).…”

“…Secondly, the administration of thyrotropin (TSH)-suppressive doses of thyroxine (T4) may also increase serum osteoprotegerin levels in men (9). Finally, chronic autoimmune hypothyroidism also increases serum osteoprotegerin concentrations and hormone replacement therapy with T4 normalizes its level (10)(11)(12).…”

Correlation between Serum Osteoprotegerin and Biomarkers of Bone Metabolism during Anti-Thyroid Treatment in Patients with Graves’ Disease

“…Increased OPG levels in overt and subclinical hypothyroid patients and decreased OPG levels with levothyroxine therapy have been reported [16, 17]. It is clear that hypothyroidism is associated with cardiovascular disease [18].…”

RANKL/Osteoprotegerin System and Bone Turnover in Hashimoto Thyroiditis

“…The clinical implications of this slow turnover in hypothyroidism have been conflicting and the influence of hypothyroidism on bone metabolism still remains poorly understood [8][9][10]. Recent studies suggested that thyroid disorders might influence serum OPG and RANKL levels [11][12][13][14]. Hypothyroid patients were reported to have higher concentrations of OPG compared to euthyroid controls [12][13][14] and that increase returned to normal once thyroid function had been normalized with levothyroxine (LT4) replacement [13,14].…”