Safety of Suppressive Therapy With Levothyroxine: Effects on Bone Metabolism and Cardiac Function and Morphology and Potential Benefits of the Use of Alendronate and β-Blockers : The Endocrinologist

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00019616-200705000-00004ReportThe EndocrinologistThe Endocrinologist© 2007 Lippincott Williams & Wilkins, Inc.17May 2007 p 148-151Safety of Suppressive Therapy With LevothyroxineEffects on Bone Metabolism and Cardiac Function and Morphology and Potential Benefits of the Use of Alendronate and β-BlockersCase ReportSouza Rosário, Pedro Weslley do PhD*; Borges, Michelle Aparecida Ribeiro MD*; Vasconcelos, Flavio Jesus MD*; Alves, Maria Flávia Gatti MD*; Purisch, Saulo MD*; Padrao, Eduardo Lanza MD†; Rezende, Leonardo Lamego MD†; Barroso, Alvaro Luís MD†From the *Department of Thyroid, Endocrinology Service, and †Nuclear Medicine Service, Santa Casa de Belo Horizonte, Minas Gerais, Brazil.Reprints: Pedro Weslley Souza do Rosário, PhD, Centro de Estudos e Pesquisa da Clinica de Endocrinologia e Metabologia (CEPCEM), Av Francisco Sales, 1111, 5 andar Ala D, Santa Efigênia, CEP 30150-221, Belo Horizonte, MG, Brazil. E-mail: [email protected] study evaluated markers of bone remodeling and cardiac alterations in premenopausal women submitted to suppressive therapy with levothyroxine and the response to pharmacological intervention. Sixteen thyroidectomized patients undergoing suppressive therapy with levothyroxine were compared with 20 women taking replacement therapy only. After initial evaluation, the patients taking suppressive therapy were randomized into 2 subgroups (one received propranolol and the other alendronate) and reassessed after 3 months. Calcium, parathyroid hormone, and 1,25(OH)2 vitamin D3 did not differ between groups. Markers of bone remodeling (serum bone alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide) were significantly higher in patients treated with suppressive therapy. Urinary N-telopeptide levels were significantly reduced after 3 months of treatment with alendronate. Episodes of supraventricular tachycardia detected by electrocardiographic monitoring were more frequent in patients taking suppressive therapy. The mean heart rate, left ventricular mass index (LVMi), and ejection fraction were also higher in these patients. All of them were asymptomatic. LVMi showed a correlation with the daily levothyroxine dose. Propranolol treatment significantly reduced mean heart rate, LVMi, ejection fraction, and supraventricular tachycardia. We conclude that levothyroxine suppressive therapy is associated with an increase in bone turnover, cardiac changes, and a higher risk of arrhythmia in premenopausal women. Bisphosphonates and β-blockers are potentially beneficial.Serum thyroid-stimulating hormone (TSH) levels <0.1 mIU/mL are recommended for patients with differentiated thyroid carcinoma who are at risk for recurrence and/or mortality.1Hyperthyroidism, even when subclinical, can be related to a reduction in bone mineral density (BMD)2 and is associated with a higher risk of atrial fibrillation and functional and morphologic cardiac changes.2,3 The occurrence of these side effects is also of special interest in patients receiving levothyroxine-suppressive therapy. A reduction in bone mass does not seem to occur in men or premenopausal women receiving suppressive therapy.4,5 In contrast, effects on the cardiovascular system have been demonstrated in this situation.3Known therapeutic strategies, such as β-blockade to improve adverse cardiac effects3 and bisphosphonates6 and estrogen replacement7 to reduce the effects on bone metabolism, seem to be beneficial to patients treated with suppressive therapy.The objective of the present study was to evaluate markers of bone remodeling and cardiac function and morphology in premenopausal women receiving suppressive treatment with levothyroxine, and their response to pharmacological intervention.PATIENTS AND METHODSSixteen premenopausal patients [regular menstrual cycles, no use of anovulatory drugs and normal serum follicle-stimulating hormone (FSH) levels] with nonmetastatic differentiated thyroid carcinoma, treated with total thyroidectomy and maintained on suppressive therapy with levothyroxine, were studied. Serum TSH levels were maintained at ≤0.1 mIU/mL in all patients. A group of 20 premenopausal women submitted to thyroidectomy due to benign disease and were treated with replacement doses of levothyroxine. None of the patients had hypoparathyroidism, were pregnant, or were breast-feeding. Other causes of bone or cardiac disease were excluded in all women, and none were taking medications that would interfere with the proposed study. The characteristics of the patients of the 2 groups are shown in Table 1.JOURNAL/endst/04.03/00019616-200705000-00004/table1-4/v/2021-02-17T201830Z/r/image-tiff Characteristics of the Patients of the 2 GroupsThe following parameters were determined: serum calcium, phosphorus, 1,25(OH)2 vitamin D3, parathyroid hormone (PTH), bone-specific alkaline phosphatase (AP) and osteocalcin, urinary hydroxyproline, and N-telopeptide X (NTx). Total AP and γ-glutamyltransferase were measured to exclude cross-reactivity of the hepatic isoenzyme with bone-specific AP.8 The physical examinations were normal in all patients. Cardiologic assessment consisted of the investigation of symptoms (exertional and nocturnal dyspnea, orthopnea, palpitations), 12-lead electrocardiogram (ECG), 24-hour Holter monitor, and an echocardiogram.After initial evaluation, the patients taking suppressive therapy were randomized into 2 groups of 8 individuals each, one group receiving 80 mg/d propranolol and the other receiving 10 mg/d alendronate. Urinary NTx, 24-hour Holter, and echocardiogram were reassessed after 3 months. The study was approved by the research ethics committee of our institution.Laboratory DeterminationsNTx was measured by enzyme immunoassay in a 2-hour urine collected in the morning (reference range for premenopausal women: 5 to 65 nM bone collagen equivalents (BCE)/mM creatinine). Hydroxyproline was measured by a colorimetric method in 24-hour urine collection after an appropriate diet for 48 hours (reference: 5 to 25 mg/24 hours). Serum osteocalcin was determined by radioimmunoassay (reference range for women younger than 50 years: 8 to 35 ng/mL). Bone AP was assayed by capture immunoassay (reference: 10 to 22 U/L), TSH and PTH were measured by immunoradiometric assay (reference: 0.3 to 4 mIU/mL and 10 to 53 pg/mL, respectively), free T4 was measured by radioimmunoassay (reference: 0.8 to 1.8 μg/dL), and 1,25(OH)2 vitamin D3 was determined by high-performance liquid chromatography (reference: 20 to 76 pg/mL).All samples, except for the 24-hour urine samples, were collected in the morning. All measurements were performed during the follicular phase of the menstrual cycle, and the patients were instructed to avoid any exhaustive physical activity or to modify their diet in the week of the tests. The study was conducted between September 2003 and February 2004 to minimize seasonal variability in the markers analyzed.All measurements were repeated after an interval of 6 weeks, and the interassay coefficient of variation showed a 97.5% confidence limit of 25% for NTx, 30% for hydroxyproline, and 15% for bone AP and osteocalcin. Smaller differences (inter- and intraindividual) were not considered to be significant. The mean of the 2 determinations was used in the comparison of the 2 groups and the last NTx measurement in the comparison with values obtained after pharmacologic intervention.ECG, Holter Monitoring, and EchocardiogramA standard 12-lead ECG was performed in all subjects. Evidence of left ventricular (LV) hypertrophy and conduction and repolarization abnormalities was assessed. All patients underwent 24-hour ECG monitoring to detect rhythm disturbance. The tapes were read by an electrophysiologist in a blinded fashion. All tapes were considered acceptable for analysis because they had at least 18 hours of interpretable data.Complete M-mode and 2-dimensional Doppler echocardiographic analysis was performed with an ultrasound mechanical system equipped with a 3.5-MHz transducer. All measurements were made with the patient in left lateral decubitus positions. The investigator reading the echo studies was blinded as to source. LV dimensions were measured by M-mode at end-systole and end-diastole.9 LV mass was calculated using the following equation10: LV mass = 0.8 [1.04 (DIVS + DLVPW)3 − DLVD3] + 0.3, where DIVS, DLVPW and DLVD correspond to measurements of diastolic left interventricular septum, LV posterior wall, and LV diameter, respectively. LV mass was indexed for body surface area derived from subjects' height and weight.LV volumes and ejection fraction were calculated from 2-dimensional echocardiographic apical view images at end-systole and end-diastole using the modified Simpson's rule biplane method.11Statistical AnalysisThe significance of differences in continuous variables between the 2 groups was computed using ANOVA and multiple comparison testing if the data were normally distributed or the Kruskal-Wallis test if the data were not normally distributed. The significance of changes in bone turnover and cardiac function over time were computed by paired t testing of baseline and subsequent values. Correlation between parameters was determined by Pearson correlation analysis. A P value <0.05 was considered significant.RESULTSCalcium, phosphorus, PTH, and 1,25(OH)2 vitamin D3 did not differ significantly between the 2 groups. All markers of bone remodeling were significantly higher in patients taking suppressive therapy (Table 2), and none of them were significantly correlated with levothyroxine dose, serum-free T4, duration of treatment, age, or body mass index.JOURNAL/endst/04.03/00019616-200705000-00004/table2-4/v/2021-02-17T201830Z/r/image-tiff Markers of Bone Remodeling in the 2 GroupsThe patients taking suppressive therapy and randomized to receive either propranolol or alendronate did not differ significantly in terms of initial urinary NTx values. In the group that received propranolol, no significant alterations in NTx levels were observed after 3 months, and the variations were below the 97.5% confidence limit of the interassay coefficient of variation (25%). In contrast, in patients receiving alendronate, the levels of this marker showed a 38% to 75% reduction compared with basal levels (mean of 52% ± 6%, P < 0.01).None of the patients showed symptoms of LV dysfunction or palpitations. Twelve-lead ECG monitoring showed alterations suggestive of LV hypertrophy in 5 of 16 patients taking suppressive treatment but in none of the patients taking replacement therapy. During 24-hour ECG monitoring, episodes of supraventricular tachycardia were observed in 15 of 16 patients taking suppressive therapy and 8 of 20 subjects taking replacement therapy (P < 0.05). All patients were asymptomatic. Three of 16 patients taking suppressive therapy showed LV hypertrophy, as opposed to none taking replacement therapy. Mean heart rate determined by 24-hour Holter monitoring, LV mass index12 and LV ejection fraction was significantly higher in patients taking suppressive therapy (Table 3). The LV mass index only showed a correlation with the levothyroxine dose (r = 0.56, P < 0.01).JOURNAL/endst/04.03/00019616-200705000-00004/table3-4/v/2021-02-17T201830Z/r/image-tiff Parameters of Cardiologic Assessment in the 2 GroupsThe patients randomized to receive either the β-blocker or alendronate did not differ significantly in terms of mean heart rate, LV mass index and ejection fraction. Mean heart rate determined by 24-hour Holter monitor did not differ significantly in the 8 patients taking suppressive therapy who received alendronate, and 6 of 7 continued to have episodes of supraventricular tachycardia after 3 months. There was also no significant change in LV mass index and ejection fraction. In contrast, heart rate was significantly reduced in the 8 patients receiving a β-blocker (from 88 ± 10 to 69 ± 8 beats/min; P < 0.01), and atrial tachycardia persisted in only 1 of 8 patients after 3 months of treatment. A significant reduction in LV mass index (91 ± 12 versus 82 ± 9 g/m2; P < 0.01) and ejection fraction (51% ± 5% versus 47% ± 4%; P < 0.05) was detected on the echocardiogram after propranolol treatment.DISCUSSIONThe effects of levothyroxine suppressive therapy on bone metabolism and BMD are more consistent in postmenopausal women, especially effects on cortical bone, with no convincing evidence indicating that the same effects also occur in premenopausal women.4,5 However, some studies have demonstrated a reduction in BMD and/or an increase in bone remodeling markers even during this period of life.13–16 In the present series, a significant increase in markers of bone formation and resorption was observed in premenopausal women taking suppressive therapy with levothyroxine, but the study was incomplete since it did not evaluate BMD in these patients.Estrogen replacement apparently has a protective effect on bone metabolism in postmenopausal patients taking suppressive therapy.7,17 The effect of bisphosphonates on bone and bone mass in patients taking levothyroxine suppressive therapy has been demonstrated clinically with the cyclic use of pamidronate, although the BMD of these patients did not differ from that of the control group.6 In the present study, the use of alendronate led to a significant short-term (3 months) decrease in urinary NTx values in patients taking suppressive treatment. A correlation has been observed between the short-term reduction in resorption and subsequent gain in bone mass in postmenopausal women treated with alendronate.18 Long-term studies are necessary, however, to confirm the therapeutic and/or preventive benefit of this treatment on BMD in premenopausal women taking suppressive therapy with levothyroxine.In the present study, significant differences between patients taking suppressive and replacement therapy were observed for all cardiac parameters analyzed (heart rate, arrhythmias, LV mass, and systolic function). However, these findings did not have any clinical repercussions. Alterations in cardiac morphology and/or function have been demonstrated in patients receiving TSH-suppressive therapy,3 including an increase in LV mass,19–23 a higher mean heart rate, an increased risk for arrhythmias,21,22 increased systolic function,20–22 impaired diastolic function,19,21 and a lower exercise tolerance.20,21The use of β-blockers causes improvement of symptoms,24 exercise capacity,20 and might reverse LV hypertrophy19,20,24 and improves diastolic19,20 and systolic20,24 functions in these patients. In the present series, we confirmed the normalization of heart rate, the disappearance of episodes of tachyarrhythmias, the reduction in LV mass index, and improvement of systolic function upon application of this medication.We conclude that TSH-suppressive therapy is associated with an increase in bone turnover even in premenopausal women. In addition, morphologic and functional cardiac alterations and a higher risk of arrhythmias, although asymptomatic, are demonstrated with this therapy. Follow-up of these patients is necessary, and therapeutic strategies such as bisphosphonates and β-blockers are potentially beneficial.REFERENCES1. Ringel MD, Ladenson PW. Controversies in the follow-up and management of well-differentiated thyroid cancer. Endocr Relat Cancer. 2004;11:97–116.[Context Link][CrossRef][Medline Link]2. Toft AD. Subclinical hyperthyroidism. N Engl J Med. 2001;345:512–516.[Context Link][Full Text][CrossRef][Medline Link]3. Fazio S, Palmieri EA, Lombardi G, et al. Effects of thyroid hormone on the cardiovascular system. Recent Prog Horm Res. 2004;59:31–50.[Context Link][CrossRef][Medline Link]4. Quan ML, Pasieka JL, Rorstad O. Bone mineral density in well-differentiated thyroid cancer patients treated with suppressive thyroxine: a systematic overview of the literature. 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