Free Thyroxine Levels are Associated with Cold Induced Thermogenesis in Healthy Euthyroid Individuals.

Thyroid hormone (TH) is an important regulator of mammalian metabolism and facilitates cold induced thermogenesis (CIT) in brown adipose tissue (BAT). Profound hypothyroidism or hyperthyroidism lead to alterations in BAT function and CIT. In euthyroid humans the inter-individual variation of thyroid hormones is relatively large. Therefore, we investigated whether levels of free thyroxine (T4) or free triiodothyronine (T3) are positively associated with CIT in euthyroid individuals. We performed an observational study in 79 healthy, euthyroid volunteers (mean age 25.6 years, mean BMI 23.0 kg · m-2). Resting energy expenditure (REE) was measured by indirect calorimetry during warm conditions (EEwarm) and after a mild cold stimulus of two hours (EEcold). CIT was calculated as the difference between EEcold and EEwarm. BAT activity was assessed by 18F-FDG-PET after a mild cold stimulus in a subset of 26 participants. EEcold and CIT were significantly related to levels of free T4 (R2 = 0.11, p=0.0025 and R2 = 0.13, p=0.0011, respectively) but not to free T3 and TSH. Cold induced BAT activity was also associated with levels of free T4 (R2 = 0.21, p=0.018). CIT was approximately fourfold higher in participants in the highest tertile of free T4 as compared to the lowest tertile. Additionally, free T4 was weakly, albeit significantly associated with outdoor temperature seven days prior to the respective study visit (R2 = 0.06, p=0.037). These finding suggests that variations in thyroid hormone levels within the euthyroid range are related to the capability to adapt to cool temperatures and affect energy balance.

Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Health.

Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.

Intravenous bisphosphonates for postmenopausal osteoporosis: safety profiles of zoledronic acid and ibandronate in clinical practice.

BACKGROUND: Intravenous bisphosphonates are widely used for treatment of postmenopausal osteoporosis. They are associated with transient influenza-like symptoms, predominantly after the first zoledronic acid (up to 32 %) or ibandronate (up to 5 %) administration. The experience in clinical practice suggests that the incidence of post-dose symptoms is higher than has been reported in clinical trials. We assessed the safety of annual infusions of zoledronic acid and 3-monthly injections of ibandronate in women with postmenopausal osteoporosis. METHODS: In this retrospective study we analysed safety data from 272 postmenopausal women treated with zoledronic acid (n = 127; mean age 68.6 ± 9.4 years) or intravenous (IV) ibandronate (n = 145; mean age 69.1 ± 9.0 years). Safety data (including occurrence of acute-phase reactions and osteonecrosis of the jaw) were gathered in phone call interviews by using a standardized questionnaire. RESULTS: The number of patients with adverse events was significantly higher in zoledronic acid as compared to ibandronate-treated patients, primarily because of a larger number of post-dose symptoms after bisphosphonate administrations (54.3 % vs. 33.1 %, p < 0.001). Except for occurrence of fever (more common after zoledronic acid infusion), other influenza-like symptoms (myalgia, arthralgia, headache) appeared in a similar proportion of patients after IV treatment (within 24-36 h). Symptoms lasted for >3 days in approximately 50 % of patients. The incidence of symptoms decreased after subsequent infusions. The rate of influenza-like symptoms was more frequent after zoledronic acid than after IV ibandronate in bisphosphonate-naïve patients but comparable in patients pretreated with oral bisphosphonates. There were no spontaneous reports of osteonecrosis of the jaw, arrhythmia or delayed fracture healing. CONCLUSION: Although IV bisphosphonates are generally safe, the occurrence of transient influenza-like symptoms after IV bisphosphonates seems to be more frequent in clinical practice than has been reported in clinical trials.

[Osteoporosis: evaluation, diagnosis and monitoring]. / Diagnose und Verlaufskontrolle der Osteoporose.

A paradigm change is taking place in the diagnosis of osteoporosis - away from the overemphasis on bone mineral density (BMD) as the sole gauge of need for diagnosis and treatment towards a comprehensive risk assessment of all the components of increased bone fragility. The main risk factors, and thereby reasons for further diagnostics, are previous non-traumatic vertebral and non-vertebral fractures, long-term glucocorticoid therapy, low body weight, increased risk of fall, and disorders associated with an increased fracture risk. The indication for osteoporosis therapy is based on the individual fracture risk and should not be based purely on a single BMD value. Monitoring the effectiveness of osteoporosis treatment presents a challenge in everyday clinical practice. As an alternative to fracture incidence, surrogate markers (BMD, biochemical markers of bone turnover) can be used to assess effectiveness of treatment in the individual patient. Correct employment and interpretation of surrogate markers in osteoporosis therapy requires knowledge of pre-analytical and analytical factors which co-determine the measurement methods. The purpose of this overview is to examine the possibilities of clinical investigation, BMD measurement and determination of bone turnover markers for the evaluation of therapeutic response.

Parathyroid hormone analogues in the treatment of osteoporosis.

Osteoporosis is characterized by the occurrence of fragility fractures. Over the past years, various treatment options have become available, mostly antiresorptive agents such as bisphosphonates. However, antiresorptive therapy cannot restore bone mass and structure that has been lost due to increased remodeling. In this case, recombinant human parathyroid hormone (PTH) analogues-the full-length PTH(1-84) or the shortened molecule PTH(1-34), which is also known as teriparatide-present the possibility of increasing the formation of new bone substance by virtue of their anabolic effects. The bone formation induced by PTH analogues not only increases BMD or bone mass but also improves the microarchitecture of the skeleton, thereby leading to improved strength of bone and increased mechanical resistance. Controlled trials have shown that both analogues significantly reduce the incidence of vertebral fractures, and PTH(1-34) also reduces the risk of nonvertebral fractures. The need for daily self-injection and the higher cost compared with other forms of treatment limit the widespread use of PTH analogues. Nevertheless, treatment with PTH analogues should be considered in postmenopausal women and men with severe osteoporosis, as well as in patients on established glucocorticoid treatment with a high fracture risk. Concurrent therapy with antiresorptive agents should be avoided, but sequential therapy with these agents might consolidate the beneficial effects on the skeleton.

[Primary hyperparathyroidism]. / Primärer Hyperparathyreoidismus.

Primary hyperparathyroidism is frequently an incidental finding in asymptomatic patients. Often the diagnosis of primary hyperparathyroidism is made in evaluation for osteoporosis, rarely in the context of hypercalcemic crisis, myopathy, kidney stones, nephrocalcinosis, and osteitis fibrosa. The most frequent cause for primary hyperparathyroidism is benign parathyroid adenoma, reminders have hyperplasia. Primary hyperparathyroidism is defined as hypercalcemia with inappropriately high parathyroid hormone levels. Surgery is the definitive treatment for patients with symptomatic primary hyperparathyroidism and asymptomatic patients, who meet one of the following criteria: serum calcium>0.25 mmol/L (1.0 mg/dl) above the accepted normal reference range, renal failure (GFR<60 ml/min) and presence of osteoporosis (T-score<-2.5 or fracture). Parathyroidectomy should be performed by an experienced surgeon. As an alternative in inoperable patients or preoperatively in severe hypercalcemia cinacalcet successfully reduces calcium levels. In asymptomatic patients not meeting the above mentioned criteria serum calcium and creatinin levels should be measured once a year and DXA every two years, since 30% of the patients with asymptomatic primary hyperparathyroidism are progressive.

Patients on injectable diacetylmorphine maintenance have low bone mass.

INTRODUCTION AND AIMS: Risk factors for osteoporosis are prevalent in chronic heroin users who often start using opiates in their late teens. This study was the first to evaluate bone mineral density (BMD) in relatively young heroin-dependent patients on injectable heroin maintenance. DESIGN AND METHODS: Using cross-sectional design, BMD was assessed in a convenience sample of 19 patients (mean age ± SD = 33.9 ± 5.4; 13 men) prescribed injectable diacetylmorphine for heroin dependence. BMD of the lumbar spine and proximal femur was measured by dual-energy X-ray absorptiometry. Substance use and menstrual history, psychopathology and risk factors for low BMD were assessed by questionnaire-based interviews. RESULTS: According to World Health Organisation criteria almost three-quarters (74%) of the sample had osteopenia (n = 11) or osteoporosis (n = 3) at one or more sites of measurement. All patients showed multiple risk factors for bone loss, with pack-years of tobacco use and years of heroin use reaching marginally significant associations with spine Z-scores. Moreover, BMD Z-scores correlated significantly negatively with increasing age at all sites, indicating that the older the patient, the greater the BMD deviation from an age-controlled population. DISCUSSION AND CONCLUSIONS: Prolonged heroin dependence appears to be associated with lower-than-normal bone mass already at early age and these individuals might be at greater risk for fracture with advancing age. The negative correlation of age-adjusted Z-scores with increasing age suggests factors other than age for low BMD in this population (e.g. smoking, heroin use). Prospective studies are warranted to determine the necessity for diagnostic and preventive measures.

Antiepileptics and bone health.

In recent years there has been increasing evidence suggesting that epilepsy and its treatment can have adverse effects on bone mineralization and calcium metabolism. Many studies have shown a significant reduction in bone mineral density (BMD) and an increased fracture risk in patients treated with enzyme-inducing antiepileptics (phenobarbital, carbamazepine, phenytoin). It is assumed that CYP450-inducing antiepileptic drugs (AEDs) upregulate the enzymes which are responsible for vitamin D metabolism, with the effect of converting 25(OH) vitamin D into inactive metabolites, resulting in reduced calcium absorption with consecutive secondary hyperparathyroidism. Data on bone-specific effects of newer AEDs are limited; nevertheless, alterations of bone metabolism have been reported for oxcarbazepine, gabapentin and, in preclinical studies, for levetiracetam. Prophylactic administration of adequate amounts of calcium and vitamin D is recommended for all patients. For patients with long-term AED exposure, BMD measurement is recommended as part of osteoporosis investigation (especially for patients treated with enzyme-inducing AEDs and where there are major risk factors for fractures). Drug therapy (bisphosphonates) is reserved for the treatment of patients who have a high fracture risk; there are no specific intervention studies available in patients with epilepsy.

Proton pump inhibitors and fracture risk: true effect or residual confounding?

Fracture is a major contributor to human morbidity and mortality, especially in the elderly. It has been discussed in the literature that conditions associated with decreased stomach acidity may lead to a decrease in intestinal calcium absorption and, consequently, to an increased fracture risk. In recent years, several observational studies reported a slightly increased fracture risk in association with the use of proton pump inhibitors (PPIs) and/or histamine H(2) receptor antagonists. It was the objective of this review to critically assess the available evidence linking PPI use to an increased fracture risk. A MEDLINE and EMBASE search from 1960 to June 2010 was performed to identify the relevant articles using predefined search terms. Because (i) there is no proven mechanism, (ii) the reported magnitude of the risk elevation associated with the use of PPIs was only weak, and (iii) the likelihood of residual confounding despite adjustment for known co-morbidities and drug use cannot be ruled out, we conclude that the currently available literature does not support the notion that the use of PPIs is causally related to a materially increased fracture risk in humans.

Use of depot medroxyprogesterone acetate and fracture risk.

CONTEXT: Depot medroxyprogesterone acetate (DMPA), which has a high rate of use among teenagers in Europe and the United States, has been associated with impaired bone mineral acquisition during adolescence and accelerated bone loss in later life. Studies on the association between DMPA use and fracture risk are limited. OBJECTIVE: We aimed at evaluating the relationship between use of hormonal contraceptives, specifically DMPA, and fracture risk. DESIGN: We conducted a case-control analysis using the United Kingdom-based General Practice Research Database. SETTING AND PARTICIPANTS: Participants were females aged 20-44 yr with an incident fracture diagnosis between 1995 and 2008. MAIN OUTCOME MEASURES: Odds ratios (OR) with 95% confidence intervals (CI) of incident fracture in relation to exposure to DMPA or combined oral contraceptives were assessed. Adjustments were made for smoking, body mass index, and additional potential confounders. RESULTS: We identified 17,527 incident fracture cases and 70,130 control patients (DMPA exposure: 11 and 8%, respectively). Compared with nonuse, current use of one to two, three to nine, or 10 or more DMPA prescriptions yielded adjusted OR for fractures of 1.18 (95% CI = 0.93-1.49), 1.36 (95% CI = 1.15-1.60), and 1.54 (95% CI = 1.33-1.78), respectively. Fracture risk was highest after longer treatment duration (>2-3 yr), and there was no difference in patients below and above the age of 30 yr. For users of combined estrogen-containing oral contraceptives, the OR were around 1. CONCLUSIONS: This population-based study suggests that use of DMPA is associated with a slightly increased risk of fractures.

Possible beneficial effect of bisphosphonates in osteonecrosis of the knee.

UNLABELLED: Osteonecrosis (ON) in the knee occurs as a localized inflammatory disease in relation to spontaneous or non-traumatic ON. Conservative treatment possibilities are limited, and prognosis appears to be poor; in most cases, ON results in knee arthroplasty. Bisphosphonates are suggested to prevent bone resorption and collapse of necrotic bone. In this observational, prospective study we investigated the effect of bisphosphonate treatment in patients with spontaneous or arthroscopy-induced ON of the knee. Twenty-eight patients with osteonecrotic lesions and bone marrow oedema in the knee were included. In 22 patients (80%), ON was identified after arthroscopic surgery of the knee; six patients were diagnosed with spontaneous ON. Patients were initially given pamidronate 120 mg i.v. divided in 3-4 perfusions over 2 weeks, followed by oral bisphosphonate treatment with alendronate 70 mg weekly for 4-6 months. Bisphosphonate treatment resulted in a rapid pain relief, VAS decreasing from 8.2 ± 1.2 at baseline to 5.02 ± 0.6 after 4-6 weeks (p < 0.001). After 6 months, the VAS decreased by 80% (p < 0.001). At the 6-month follow-up, symptoms had resolved completely in 15 patients out of 28; in 6 patients, minimal symptoms (VAS 1-2) remained. In two patients, treatment effect was unsatisfactory, and surgical intervention was needed (arthroplasty). Bone marrow oedema on MRI resolved completely in 18 patients out of 28 with substantial reduction in the remaining. Furthermore, osteonecrotic area resolved completely or demarcation with sclerotic changes of the necrotic area could be observed. Bisphosphonate treatment in patients with osteonecrosis of the knee was associated with a rapid improvement in pain score and radiological consolidation of the area of osteonecrosis. Further randomized, controlled trials are warranted to confirm the potential beneficial role of bisphosphonates in the treatment of osteonecrosis of the knee. LEVEL OF EVIDENCE: observational study, level IV.

Impact of bisphosphonate wash-out prior to teriparatide therapy in clinical practice.

Concurrent use of bisphosphonate therapy reduces the anabolic effect of teriparatide. Consequently, in clinical practice bisphosphonates are discontinued and teriparatide therapy held for a few months to allow bone turnover to increase. We aimed to evaluate the effect of prior bisphosphonate exposure and the effect of bisphosphonate wash-out on the treatment response to teriparatide. Thirty-nine patients with primary osteoporosis (mean age 63.6 +/- 14.0 years), including 26 patients previously treated with oral bisphosphonates (median duration 53 months) and 13 bisphosphonate-naïve patients were started on teriparatide (20 mug daily) and followed prospectively over 12 months. The primary study outcome was change in bone formation markers (PINP, bone ALP, osteocalcin). Secondary outcomes included changes in bone resorption (betaCTX) and 12-month changes in BMD. Markers of bone formation increased early during teriparatide therapy and were followed by an increase in betaCTX (p < 0.001). The magnitude of the increase in bone markers was comparable in both patient groups irrespective of prior bisphosphonate exposure; similarly, increases in BMD after 12 months were not significantly different between bisphosphonate-pretreated and bisphosphonate-naïve patients (lumbar spine 7.1 vs. 8.9%, p = 0.58; total hip 4.1 vs. 1.1%, p = 0.48). The response of teriparatide was not related to the duration of bisphosphonate wash-out (median duration 4.2 months). This study confirms that beneficial effects of teriparatide on intermediate bone endpoints can be translated into clinical practice with less constringent methodological circumstances than in RCTs. Furthermore, as bisphosphonate wash-out does not appear to influence the treatment effect, teriparatide therapy can be started immediately after ceasing bisphosphonate therapy and wash-out.

Risk of fractures with glitazones: a critical review of the evidence to date.

The insulin-sensitizing thiazolidinediones (commonly known as glitazones) are an important and widely prescribed class of antidiabetic agents. Glitazones exert their action through activation of proliferator-activated receptor gamma (PPAR-gamma) nuclear transcription factor and are effective drugs to achieve glycaemic control in patients with type 2 diabetes mellitus. Recent rapidly growing evidence suggests that glitazone use is associated with accelerated bone loss and an increased risk of fracture. This review aims to evaluate the current knowledge of adverse effects of glitazone therapy on the skeleton. Articles in English, Spanish, German and French published up until April 2009 are included. Results from preclinical studies have demonstrated that activation of PPAR-gamma inhibits bone formation by primarily diverting mesenchymal stem cells to the adipocytic rather than to the osteogenic lineage, and that glitazones may increase bone resorption by stimulating osteoclasts. Numerous studies in humans have demonstrated decreased bone turnover, accelerated bone loss and impaired bone mineral density both in healthy volunteers and in patients with type 2 diabetes. Furthermore, results from recent large, randomized controlled trials and from observational studies provided evidence for an increased fracture risk for glitazone users, mostly for women, but possibly also for men. As a consequence of these observations, clinicians should carefully assess the fracture risk in patients with type 2 diabetes before starting therapy with glitazones.

The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways.

BACKGROUND: Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. CONCLUSIONS/SIGNIFICANCE: Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-beta signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-beta signaling and connective tissue dysfunction.

[Laboratory assessment of osteoporosis]. / Die Rolle des Labors in der Diagnostik und Verlaufskontrolle der Osteoporose.

Osteoporosis is characterized by a generalized and progredient bone loss, leading to low bone mass and microarchitectural deterioration with subsequent bone fragility. For some percent of the patients at risk, laboratory findings may reveal unsuspected secondary osteoporosis or may influence some aspects of diagnostics and therapy. The aim of the laboratory tests is, therefore, to exclude to a large extent the most important forms of secondary osteoporosis and other potential bone diseases. Among other determinants, increased bone resorption evaluated by specific biochemical markers has been shown to be associated with increased risk of fractures independently of BMD. The combination of bone mass measurement and assessment of bone turnover by biochemical markers are thus helpful in the assessment of osteoporotic fracture risk. Repeated measurements of biochemical markers during treatment appear to improve the management of osteoporotic patients.

Automated HPLC assay for urinary collagen cross-links: effect of age, menopause, and metabolic bone diseases.

BACKGROUND: The pyridinium cross-links pyridinoline (PYD) and deoxypyridinoline (DPD) are established markers of bone resorption. We evaluated the analytical and clinical performance of a commercially available PYD HPLC assay and established reference intervals in children and adults. METHODS: We used a commercially available reagent set (Chromsystems Instruments & Chemicals) to measure PYD and DPD in 319 healthy controls (156 premenopausal women, 80 healthy men, and 83 healthy children age 1 month to 14 years) and 397 patients with metabolic bone diseases (postmenopausal osteoporosis, n = 175; male osteoporosis, n = 176; hyperparathyroidism, n = 17; hyperthyroidism, n = 19; Paget disease, n = 10). RESULTS: The mean intraassay and interassay CVs were <6% and <8% for both PYD and DPD, respectively. The reference interval was constant for premenopausal women in the age group 20-49 years. In men, cross-link values peaked at 20-29 years and decreased thereafter. Women with postmenopausal osteoporosis had significantly higher PYD (51%) and DPD (58%) values compared to premenopausal women. Similar results were found in osteoporotic men. In children the highest values were found in the first weeks and months after birth, followed by a decrease of 50%-60% at age 11-14 years. In metabolic bone diseases cross-link concentrations were significantly increased. The DPD:PYD ratio (mean value approximately 0.2) was remarkably constant in all populations evaluated. CONCLUSIONS: The automated HPLC assay is a precise and convenient method for PYD and DPD measurement. We established reference intervals for adult women and men and for children up to 14 years old. The cross-link concentrations we determined by use of this HPLC method confirm its clinical value in enabling identification of increased bone resorption in patients with metabolic bone diseases.

Use of thiazolidinediones and fracture risk.

BACKGROUND: Thiazolidinediones may adversely affect the skeleton owing to decreased bone formation and accelerated bone loss. METHODS: This study examines the association between the use of thiazolidinediones or other oral antidiabetic drugs and the risk of fracture. This nested case-control analysis uses the UK General Practice Research Database, including case patients with fracture aged 30 to 89 years with an incident fracture diagnosis between January 1994 and December 2005 and control subjects who were matched to case patients on age, sex, calendar time, and general practice attended. We assessed the odds ratios (ORs) of having a fracture associated with the use of rosiglitazone maleate, pioglitazone hydrochloride, other oral antidiabetic agents, or insulin. RESULTS: There were 1020 case patients with an incident low-trauma fracture and 3728 matched controls. After adjustment for age, body mass index, other antidiabetic drugs, comedication, and comorbidities, the ORs for users of 8 or more thiazolidinedione prescriptions (corresponding to approximately 12-18 months of therapy) compared with nonuse was 2.43 (95% confidence interval [CI], 1.49-3.95). Rosiglitazone (OR, 2.38; 95% CI, 1.39-4.09) and pioglitazone (OR, 2.59; 95% CI, 0.96-7.01) were used more frequently by case patients with fracture (predominantly hip and wrist fractures) than by controls. The association was independent of patient age and sex and tended to increase with thiazolidinedione dose. No materially altered relative fracture risk was found in association with the use of other oral antidiabetic drugs. CONCLUSION: This analysis provides further evidence of a possible association between long-term use of thiazolidinediones and fractures, particularly of the hip and wrist, in patients with diabetes mellitus.

Use of recombinant human thyroid-stimulating hormone in the management of well-differentiated thyroid cancer.

Recombinant human (rh) thyroid-stimulating hormone (TSH) has changed the care of patients with well-differentiated thyroid cancer (DTC). Traditionally, thyroid hormone withdrawal has been used to increase TSH concentrations for optimising trapping and retention of radioiodine for thyroid remnant ablation and for diagnostic procedures (measurement of thyroglobulin and whole body scan) used in the follow-up of patients with DTC. The resulting hypothyroidism is, however, accompanied by substantial morbidity. rhTSH is an effective and safe alternative to thyroid hormone withdrawal for follow-up of DTC. Its ability to detect persistent or recurrent disease is similar to that of thyroid hormone withdrawal. At the present time, rhTSH is approved for diagnostic monitoring of patients with DTC as well as for pretherapeutic stimulation in low-risk patients for remnant ablation with 100 mCi (131)I (in the EU). In addition, rhTSH has potential for use in facilitating the treatment of metastasis in patients with DTC and in patients with non-toxic nodular goiter; however, more clinical trials are needed to confirm its use in these situations.