osteoprotegerin and Hypothyroidism

To investigate the alteration of plasma osteoprotegerin (OPG) concentration before and after levothyroxine (L-T4) replacement therapy and its association with endothelium-dependent arterial dilation in patients with overt hypothyroidism (oHT) and subclinical hypothyroidism (sHT).. L-T4 therapy was given to 20 oHT patients and 20 sHT patients, all female, till the free serum triiodothyronine (FT3), free thyroxin (FT4), and thyroid-stimulating hormone (TSH) were near or within the respective normal ranges. Twenty healthy women were used as controls. Sandwich ELISA was used to measure the plasma OPG concentration before and after treatment.. The plasma OPG levels before treatment of the oHT and sHT patients were 3.13 ng/L +/- 0.27 ng/L and 2.95 ng/L +/- 0.24 ng/L respectively, both significantly higher than that of the controls (2.42 ng/L +/- 0.26 ng/L, both P = 0.000). Multivariate analysis showed that OPG was significantly associated with TSH (r = 0.306, P < 0.05) and endothelium-dependent arterial dilation (r = -0.675, P < 0.01) at baseline. After the normalization of thyroid function the OPG levels of the oHT and sHT patients decreased markedly to 2.53 ng/L +/- 0.28 ng/L and 2.54 ng/L +/- 0.21 ng/L respectively (both P = 0.000), very close to that in the controls. The absolute changes of OPG was significantly positively correlated with the changes of TSH (P < 0.05), negatively correlated with the changes of endothelium-dependent arterial dilation (P < 0.01), and not significantly correlated with other parameters in the hypothyroid patients during the course of treatment.. OPG may act as an important regulatory molecule in the vasculature and, particularly, may be involved in the development of vascular dysfunction in hypothyroid patients.

Topics: Adult; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypothyroidism; Osteoprotegerin; Thyroxine; Treatment Outcome; Triiodothyronine

Recent study has shown that overt hypothyroidism (oHT) is associated with increased plasma osteoprotegerin (OPG) levels.. Our objective was to examine the plasma OPG level alteration before and after levothyroxine (L-T4) treatment in oHT and subclinical hypothyroidism (sHT).. The study subjects included oHT and sHT patients and healthy individuals (20 subjects in each group).. All patients were given L-T4 therapy to maintain a euthyroid state. Plasma OPG concentration was measured in duplicate by a sandwich ELISA.. Plasma OPG levels in oHT and sHT before treatment were significantly higher than levels in controls (P < 0.01). After normalization of thyroid function, OPG levels in both groups decreased markedly (P < 0.01). The absolute changes in OPG showed a significant positive correlation with the changes in TSH (P < 0.05) and negative correlation with the changes in endothelium-dependent arterial dilation (P < 0.01) in hypothyroid patients during the course of treatment.. OPG may be involved in the development of vascular dysfunction in hypothyroid patients.

Topics: Adult; Cholesterol; Endothelium, Vascular; Female; Glycoproteins; Hormone Replacement Therapy; Humans; Hypothyroidism; Lipoprotein(a); Lipoproteins, LDL; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Thyrotropin; Thyroxine; Vasodilation

In this study, we investigated the osteoprotegerin (OPG) and soluble receptor activator of nuclear factor-kappa Β ligand (sRANKL) serum levels in association with thyroid function in children with subclinical hypothyroidism.. In 143 children and adolescents with subclinical hypothyroidism and 343 with normal thyroid function, age, height, weight and pubertal status were recorded and TSH, free thyroxine (FT4), anti-thyroid antibodies, OPG and sRANKL were measured in serum. Multiple linear regression was used for the statistical analysis with P < .05.. Children with subclinical hypothyroidism had higher TSH and lower FT4 serum levels than the control group (P < .05). Both groups had similar BMI Z-score, OPG and sRANKL serum levels. After multiple regression analysis, in children with subclinical hypothyroidism, OPG was negatively associated with FT4 (P < .05) whilst no association was observed between OPG and sRANKL, as well as between FT4 serum levels and RANKL.. Osteoprotegerin levels in children with subclinical hypothyroidism do not differ from those of euthyroid children. However, there is a negative association between FT4 and OPG levels observed only in the SH group. Considering the link between vascular dysfunction and alterations in osteoprotegerin levels, further research is needed to establish the role of childhood subclinical hypothyroidism in the long-term cardiovascular risk.

Topics: Adolescent; Child; Humans; Hypothyroidism; Osteoprotegerin; RANK Ligand

Hypothyroidism is associated with changes in bone metabolism. The impact of hypothyroidism and the associated autoimmunity on the mediators of bone turnover in Hashimoto's thyroiditis (HT) is not known. In this study, we assessed the levels of OPG, RANKL, and IL-6 along with markers of bone formation as osteocalcin (OC) and markers of bone resorption as type 1 collagen C telopeptide (CTX) and tartrate-resistant acid phosphatase isoform 5b (TRAcP 5b) in 30 hypothyroid and 30 euthyroid premenopausal HT patients and 20 healthy premenopausal controls. We found that TRAcP 5b (p = 0.006), CTX (p = 0.01), OC (p = 0.017), and IL-6 (p < 0.001) levels were lower in the hypothyroid group compared to euthyroid HT patients and controls. OPG levels were higher (p < 0.001) and RANKL levels were lower (p = 0.021) in hypothyroid and euthyroid HT patients compared to controls. TSH was negatively correlated with IL-6 (rho = -0.434, p < 0.001), OC (rho = -0.313, p = 0.006), TRAcP 5b (rho = -0.335, p = 0.003), and positively correlated with OPG (rho = 0.248, p = 0.029). RANKL/OPG ratio was independently associated with the presence of HT. In conclusion, bone turnover is slowed down by hypothyroidism in premenopausal patients with HT. Thyroid autoimmunity might have a unique impact on OPG/RANKL levels apart from the resultant hypothyroidism.

Topics: Adult; Autoimmunity; Body Mass Index; Bone and Bones; Bone Remodeling; Collagen Type I; Cross-Sectional Studies; Female; Hashimoto Disease; Humans; Hypothyroidism; Interleukin-6; Middle Aged; Osteoprotegerin; Peptides; Premenopause; RANK Ligand; Risk Factors; Tartrate-Resistant Acid Phosphatase; Thyroid Gland; Ultrasonography

We measured the levels of osteoprotegerin, resistin, leptin, and adiponectin in patients with hypothyroidism differing in the thyroid status. The levels of osteoprotegerin, resistin, leptin were higher and those of adiponectin lower than normal. The patients suffered atherogenic dyslipidemia associated with enhanced insulin resistance and compensatory hyperinsulinemia. Leptin and adiponectin levels correlated with characteristics of lipid metabolism. It is concluded that leptin and adiponectin play a role in the development of dyslipidemia in hypothyroidism.

Topics: Adipokines; Anthropometry; Atherosclerosis; Dyslipidemias; Female; Humans; Hypothyroidism; Insulin Resistance; Lipid Metabolism; Middle Aged; Osteoprotegerin; Risk Factors

Postmenopausal women frequently develop hypothyroidism. Estrogen depletion is accompanied by an increase of IL-6, accelerating bone turnover. The influence of hypothyroidism on bone metabolism in postmenopausal women is poorly understood. The aim of the study was an attempt to clarify the role of interleukin-6 on RANKL-RANK/osteoprotegerin system in hypothyroid ovariectomized mice. The study was performed on 56, 12-13 weeks old, female mice: C57BL/6J (wild-type; WT) and C57BL/6JIL6-/-Kopf (IL-6 knock-out; IL6KO). The mice were randomly divided into 8 groups with 7 mice in each one: 1/ WT controls, 2/ IL6KO controls, 3/ WT hypothyroid mice, 4/ IL6KO hypothyroid mice, 5/ WT ovariectomized, 6/ IL6KO ovariectomized, 7/ WT ovariectomized hypothyroid mice and 8/ IL6KO ovariectomized hypothyroid mice. Experimental model of menopause was produced by bilateral ovariectomy carried out in 8-9 weeks old mice. Experimental model of hypothyroidism was induced by propylthiouracyl administration in driking water. The serum levels of TRACP 5b, osteocalcin, OPG and RANKL were determined by ELISA. Serum RANKL concentrations were elevated significantly in all groups of ovariectomized mice as compared to respective controls, but in a minor degree in IL6KO hypothyroid mice as compared to wild-type animals. Moreover sRANKL values were significantly lower in IL6KO as compared to WT controls and IL6KO PTU injected mice. Osteoprotegerin serum levels were decreased in all IL-6 deficient mice and in a highest degree in sham-operated hypothyroid mice. To sum up, the results of the present study suggest that estrogens deficit is a strong stimulus for RANKL-RANK/OPG pathway that breaks an inhibitory influence of hypothyroidism even in IL-6 deficient mice.

Topics: Animals; Female; Hypothyroidism; Interleukin-6; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoprotegerin; Ovariectomy; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

Autoantibodies against osteoprotegerin, which block the inhibitory effect of osteoprotegerin on signaling by the receptor activator of nuclear factor (NF)-kappaB (RANK), were identified in a man with celiac disease who presented with severe osteoporosis and high bone turnover. The osteoporosis did not respond to the treatment of his celiac disease but was completely reversed by bisphosphonate therapy. Autoantibodies against osteoprotegerin were detected in three additional patients with celiac disease. Such autoantibodies may be associated with the development of high-turnover osteoporosis, but whether autoantibodies against osteoprotegerin commonly contribute to the pathogenesis of osteoporosis in patients with celiac disease remains to be determined.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Biomarkers; Bone Density; Bone Remodeling; Celiac Disease; Diet, Gluten-Free; Humans; Hypothyroidism; Immunoglobulin A; Male; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Transglutaminases

Hypothyroidism is associated with an increased risk for cardiovascular disease. Exercise-induced silent myocardial ischaemia (SI) is an early stage of coronary artery disease. Recently, many studies have shown that endothelial dysfunction is an early physiological event in atherosclerosis, and osteoprotegerin (OPG) acts as an important regulatory molecule in the vasculature. The aim of this study was to investigate the alteration of endothelial function and its association with plasma OPG in hypothyroidism with SI.. Forty-eight female postmenopausal hypothyroid patients with normal rest electrocardiography (ECG) were selected. Of these, 19 cases had SI. Twenty healthy females without SI were selected as controls. High-resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperaemia and after sublingual glyceryltrinitrate (GTN). Plasma OPG concentration was measured in duplicate by a sandwich enzyme-linked immunosorbent assay (ELISA).. Flow-mediated arterial dilation (FMD) in the total hypothyroid group, the hypothyroidism with SI group and the hypothyroidism without SI group was 3.51 +/- 0.62%, 3.20 +/- 0.54% and 3.72 +/- 0.60%, respectively, significantly lower than that in the controls (5.08 +/- 0.61%) (P < 0.01). Compared with the hypothyroidism without SI group, FMD in the hypothyroidism with SI group was significantly lower (P < 0.05). Plasma OPG levels in the total hypothyroid group, patients with SI and patients without SI were significantly higher than in the control group (P < 0.05). Compared with patients without SI, OPG levels were significantly higher in patients with SI (P < 0.05). On multiple regression analysis, low density lipoprotein cholesterol (LDL-C), lipoprotein (a) [Lp(a)], C-reactive protein (CRP), OPG, TSH, free T3 (FT3) and thyroid peroxidase antibody (TPO-Ab) were found to be significant factors that were associated with FMD. Logistic analysis also showed that LDL-C, TSH, OPG, CRP and FMD were independently and significantly associated with SI in hypothyroidism.. Impaired endothelial function and increased levels of OPG exist in hypothyroid patients, especially those with SI. These findings support the growing concept that endothelial dysfunction may be associated with vascular disease, and subsequently elevated plasma OPG may have a role in the development of vascular dysfunction in hypothyroid patients.

Topics: Blood Pressure; Case-Control Studies; Endothelium, Vascular; Exercise; Female; Humans; Hypothyroidism; Lipids; Middle Aged; Myocardial Ischemia; Osteoprotegerin; Risk Factors

To study the impact of thyroxine (T4) withdrawal on serum osteoprotegerin concentrations in women, using a healthy euthyroid control group matched for age and postmenopausal status as reference.. Nineteen women with differentiated thyroid carcinoma were studied the last day on T4 suppressive treatment, 4-7 days after withdrawal and the day before whole body scanning. Eighteen women matched for age and postmenopausal status served as controls. Serum thyroid hormones, urinary bone markers and serum osteoprotegerin concentrations were measured. Statistical methods included repeated measures analysis of variance and one-way analysis of variance.. Patients progressed from subclinical or mild hyperthyroidism at baseline to normal free T4 and triiodothyronine levels 4-7 days later, ending in overt hypothyroidism before scanning. Serum osteoprotegerin increased, and urinary deoxypyridolines/creatinine and pyridolines/creatinine ratios decreased, with acute hypothyroidism (P = 0.026, P = 0.003, and P < 0.001 respectively). Urinary deoxypyridolines/creatinine ratio, pyridolines/creatinine ratio, and serum osteocalcin during hypothyroidism were lower compared with those of healthy controls (P = 0.023, P = 0.019, and P = 0.011 respectively). Serum osteoprotegerin concentrations were higher in postmenopausal patients when compared with premenopausal ones, irrespective of the changes in thyroid function (P = 0.001).. Serum osteoprotegerin concentrations increase following acute hypothyroidism after T4 withdrawal in women with differentiated thyroid carcinoma, and also with postmenopausal status.

Topics: Adult; Amino Acids; Cohort Studies; Creatinine; Female; Humans; Hypothyroidism; Osteocalcin; Osteoprotegerin; Postmenopause; Prospective Studies; Thyroid Neoplasms; Thyrotropin; Thyroxine; Triiodothyronine

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 = 0.0182). In multivariate analysis, baseline OPG was significantly associated with baseline levels of TSH (r = 0.280, P = 0.0162) and vWF (r = 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 = 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 = -0.503, P = 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.

Topics: Female; Glycoproteins; Hormone Replacement Therapy; Humans; Hypothyroidism; Male; Middle Aged; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Thyrotropin; Thyroxine; von Willebrand Factor

Osteoprotegerin (OPG) is a newly identified inhibitor of bone resorption. Recent studies indicate that OPG also acts as an important regulatory molecule in the vasculature. Hypothyroidism is associated with increased morbidity from cardiovascular disease. More recently, one study showed that plasma OPG increases significantly, and decreases markedly with levothyroxine (L-T4) replacement therapy in patients with overt hypothyroidism (oHT). The purpose of this study was to investigate the alteration of plasma OPG concentrations before and after L-T4 replacement therapy, and its association with endothelium-dependent arterial dilation in patients with oHT and subclinical hypothyroidism (sHT).. The study subjects included 20 women with oHT, 20 women with sHT, and 20 healthy women. All patients were then given L-T4 therapy individually to maintain all serum free T3 (FT3), free T4 (FT4), and TSH near or within the respective normal ranges. Plasma OPG concentration was measured in duplicate by a sandwich ELISA method.. Plasma OPG levels in oHT and sHT patients before treatment were 3.13 +/- 0.27 and 2.95 +/- 0.24 ng/l, respectively, which were significantly higher than that in controls (2.42 +/- 0.26 ng/l) (p = 0.000). In multivariate analysis, OPG was significantly associated with TSH (r = 0.306, p < 0.05) and endothelium-dependent arterial dilation (r = -0.675, p < 0.01) at baseline. After normalization of thyroid function, OPG levels in both groups decreased markedly (2.53 +/- 0.28, 2.54 +/- 0.21 ng/l) (p = 0.000), and were very close to that in controls. The absolute changes in OPG showed significant positive correlation with the changes in TSH (p < 0.05) and negative correlation with the changes in endothelium-dependent arterial dilation (p < 0.01), and no significant correlation with other parameters in hypothyroid patients during the course of treatment.. The plasma OPG levels were significantly increased from hypothyroid patients, and were close to those of control subjects after normalization of thyroid function, indicating that OPG acts as an important regulatory molecule in the vasculature and, particularly, that it may be involved in the development of vascular dysfunction in hypothyroid patients.

Topics: Adult; Brachial Artery; Case-Control Studies; Endothelium, Vascular; Female; Glycoproteins; Hormone Replacement Therapy; Humans; Hypothyroidism; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Thyroid Function Tests; Thyroxine; Vasodilation