The effect of teriparatide on serum Dickkopf-1 levels in postmenopausal women with established osteoporosis.

OBJECTIVE: Parathyroid hormone increases the differentiation of osteoblast precursors through canonical wingless (Wnt) signalling, resulting in an osteoanabolic effect. We aimed to evaluate serum levels of the Wnt-inhibitor Dickkopf-1 (Dkk-1) in postmenopausal women with established osteoporosis and their changes with teriparatide (TPTD - human recombinant PTH 1-34). DESIGN AND PATIENTS: A total of 31 postmenopausal Caucasian women with established osteoporosis (mean age 66.3 +/- 1.4 years) received daily injections of 20 microg TPTD for 18 months. Follow-up was continued for another 6 months after treatment discontinuation (total duration of treatment 24 months). MEASUREMENTS: Serum samples for total calcium (Ca), intact PTH (iPTH), bone-specific alkaline phosphatase, C-terminal cross-linking telopeptide of type 1 collagen (CTx) and Dkk-1 were obtained at baseline, and at 6, 18 and 24 months after TPTD initiation. Lumbar spine bone mineral density (BMD) was measured before and after 18 months of TPTD treatment. A total of 16 age- and gender-matched healthy controls were also analysed at baseline. RESULTS: Serum Dkk-1 levels at baseline were significantly higher in osteoporotic women compared with that in controls (P < 0.002). Dkk-1 increased significantly during TPTD administration (P < 0.044) and decreased to baseline 6 months after TPTD discontinuation. Dkk-1 change was positively correlated to Ca (r = 0.530, P = 0.004) and negatively correlated to iPTH change (r = -0.398, P = 0.040). There was no correlation between Dkk-1 and BMD changes. CONCLUSIONS: Our data suggest that Dkk-1 levels are increased in women with postmenopausal osteoporosis. TPTD therapy results in further increase of Dkk-1 that may be compensative to TPTD-induced enhanced Wnt signalling.

No difference between strontium ranelate (SR) and calcium/vitamin D on bone turnover markers in women with established osteoporosis previously treated with teriparatide: a randomized controlled trial.

UNLABELLED: Objective To evaluate the effect of strontium ranelate (SR) on bone turnover markers in women with established osteoporosis previously treated with teriparatide (TPTD--recombinant human PTH 1-34). DESIGN PATIENTS: Twenty-two postmenopausal Caucasian women (aged 65.7 +/- 1.7 years) with established osteoporosis previously treated with TPTD 20 microg daily for 18 months were randomly assigned to receive either SR (SR group, n = 11) or calcium and vitamin D (control group, n = 11). MEASUREMENTS: Blood samples for serum N-terminal propeptide of type 1 collagen (P1NP), C-terminal telopeptide of type 1 collagen (CTx) and total alkaline phosphatase (ALP) were obtained from all women before (pre-TPTD) and after (post-TPTD) TPTD administration, as well as 6 months after SR or calcium/vitamin D administration (post-SR/Ca). RESULTS: Serum P1NP, CTx and total ALP increased significantly after TPTD treatment and decreased at the end of the study in both SR and control groups, with no difference between them. CONCLUSIONS: SR following TPTD administration acts predominantly as an antiresorptive agent with no evidence of additional osteoanabolic action. In this setting, SR is not more effective than Ca/vitamin D as far as bone turnover markers are concerned.

Serum thyrotropin concentration as a biochemical predictor of thyroid malignancy in patients presenting with thyroid nodules.

PURPOSE: Serum thyrotropin (TSH) is a well-established growth factor for thyroid nodules and suppression of TSH concentrations by administering exogenous thyroxine may interfere with the growth of established nodules as well as the formation of new thyroid nodules. The aim of this study was to investigate whether serum TSH at presentation is a predictor of thyroid malignancy in patients with thyroid nodules. METHODS: A total of 565 patients without overt thyroid dysfunction, who presented with palpable thyroid nodule(s) between 1988 and 2004 and underwent at least one fine-needle aspiration biopsy, were retrospectively evaluated. RESULTS: The final diagnostic outcome was established after surgery (n = 122) or after a minimum of 1-year clinical follow-up period. Higher rates of malignancy were observed in patients with serum TSH in the upper tertile of the normal range (P = 0.026). Binary logistic regression analysis revealed significantly increased adjusted odds ratios for the diagnosis of malignancy in patients with serum TSH 1.5-4.0 mIU/l when compared to those with either TSH 0.4-0.8 mIU/l (P = 0.005) or TSH 0.9-1.4 mIU/l (P = 0.007). CONCLUSIONS: The risk of malignancy in thyroid nodules increases in parallel with TSH concentrations within the normal range. TSH concentration at presentation is an independent predictor of thyroid malignancy.

Sustained clinical inactivity and stabilization of GH/IGF-1 levels in an acromegalic patient after discontinuation of somatostatin analogue treatment.

BACKGROUND: A 38-year-old woman first presented complaining of foot enlargement, finger numbness, arthralgia, fatigue, galactorrhoea and oligomenorrhea. Her symptoms in conjunction with her coarsened facial features and prognathism led to the suspicion of acromegaly. BASIC PROCEDURES: Oral glucose tolerance tests (OGTT) were performed at initial presentation and almost yearly thereafter for a period of 14 years. Pituitary computerized tomographies (CT) were performed annually for the first six years and magnetic resonance imaging every two years thereafter. MAIN FINDINGS: The diagnosis of acromegaly was confirmed by OGTT at presentation. A pituitary CT revealed a large invasive pituitary macroadenoma. She remained acromegalic after adenomectomy (evidently partial tumor resection), but was controlled with subsequent long-term somatostatin analogue (SRL) administration. After eight years of SRL administration, she had acceptable stabilization of acromegaly and at that point SRL administration was discontinued. The patient maintained the same control for the following six years up to the present time without further SRL administration. PRINCIPAL CONCLUSION: This is the first case with stabilization of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) to nearly normal levels and clinical inactivity of acromegaly after withdrawal of long-term treatment with SRLs.

Endogenous intact PTH is suppressed during Teriparatide (rhPTH 1-34) administration in postmenopausal women with established osteoporosis.

INTRODUCTION: Teriparatide (recombinant human PTH 1-34/TPTD) is an osteoanabolic agent available for osteoporosis treatment. The aim of this prospective trial was to evaluate the acute and chronic effects of TPTD in endogenous intact PTH (iPTH) levels in postmenopausal women with established osteoporosis. MATERIALS AND METHODS: Thirty-six postmenopausal Caucasian women (age 66.6 1.4 years) with established osteoporosis received TPTD 20 mug once daily for eighteen months. Follow-up was continued for another six months after treatment discontinuation for a total of 24 months. Serum calcium, phosphate, total alkaline phosphatase (ALP) and iPTH were obtained from all women before and one hour, one day, as well as one, six, twelve, 18 and 24 months after treatment initiation. Lumbar spine bone mineral density was measured before, as well as twelve and eighteen months after treatment initiation. RESULTS: iPTH levels decreased from the first hour of treatment, remained suppressed as long as TPTD was administered and increased after treatment discontinuation (p<0.001). Total ALP followed an opposite pattern. Serum calcium remained within normal range. CONCLUSIONS: iPTH levels are suppressed rapidly and persistently during TPTD administration whereas they return to baseline after treatment discontinuation; therefore, they can serve as an index of patient's compliance to treatment.

Thyroid nodules - stepwise diagnosis and management.

Thyroid nodules are common in clinical practice. They may be solitary within a "normal" thyroid gland or dominant within a multinodular goiter. The incidence of thyroid nodules has been on the rise in recent decades, mainly due to the wider use of neck imaging. Therefore, the incidental finding of a thyroid nodule in an asymptomatic patient is not rare. The differential diagnosis of a thyroid nodule is crucial, as malignancy necessitates surgery, while strict patient follow-up is necessary in the case of benignity. Fine-Needle Aspiration biopsy is considered to be the "gold standard" in the selection of patients for surgery. Ultrasonography (US) can be used to determine changes in the size of nodules during follow-up or to detect recurrent lesions in patients suspected for thyroid malignancy, although there are no specific US findings that suggest malignancy. Surgery is mandatory in cytologically malignant nodules or in cases suspicious for malignancy. The definite diagnosis and consequent therapy is based on the histological findings after surgery. In this review we present an approach to thyroid nodules in five distinct steps, from the clinical or incidental finding of a nodule to the suggested treatment baselines.

Oral bisphosphonate adverse effects in 849 patients with metabolic bone diseases.

OBJECTIVE: Bisphosphonates are potent antiresorptive agents used for a spectrum of metabolic bone diseases. The aim of this study was to compare the adverse effects (AEs) of alendronate, etidronate and risedronate prescribed in a non-selected population, attending a single institution on an outpatient basis. DESIGN: 849 patients receiving either alendronate (n=710), etidronate (n=181) or risedronate (n=130) were studied for a period of 1916 person-years. RESULTS: AEs were reported by 25.2% [21% gastrointestinal (GI) system-related], 11.1% (9.9%) and 20.8% (15.4%) of patients on alendronate/etidronate/risedronate, respectively, resulting in permanent discontinuation in 21.0%, 7.7% and 13.8%, respectively. The odds ratio (95% Ci) for AEs in the case of a history of gi disease was 2.4 (1.4-3.8), 2.1 (0.8-5.1) and 2.5 (0.9-6.6), respectively. The majority of AEs were of a mild nature and usually occurred within six months of therapy initiation. The odds ratio for AEs given the concurrent use of NSAIDS was 2.0 (1.4-3.0), 0.8 (0.3-2.4) and 2.2 (0.8-5.9), respectively. CONCLUSIONS: Etidronate appears to have a better Ae profile. Bisphosphonate AEs are fairly mild, affect the gi system, occur most frequently in the presence of gi disease or concurrent use of NSAIDS and tend to be of the same type in the event of administration of a different bisphosphonate.

Cushing's syndrome in pregnancy: report of a case and review of the literature.

Cushing's syndrome (CS) during pregnancy is a rare nosology with only a few cases reported in the literature. Misdiagnosis is common, as the syndrome may be easily confused with preeclampsia or gestational diabetes. CS during pregnancy is usually associated with severe maternal and fetal complications. A high degree of clinical awareness is therefore required to avoid miscarriage or premature delivery. We report an 18-year old female referred to our institution with amenorrhea and truncal obesity. Physical examination revealed cushingoid characteristics, including mild hypertension (130/100 mmHg). She was also found to be 8 weeks pregnant. A provisional diagnosis of CS was made based on plasma cortisol and adrenocorticotropin hormone (ACTH) measurements but the patient did not receive any relevant therapy. She eventually gave birth to a healthy full-term infant via vaginal delivery. A right adrenal adenoma was diagnosed post-labor and was subsequently treated with surgical resection. The patient's condition remained stable and 19 months after the adrenalectomy she gave birth to a second healthy full-term infant. Hydrocortisone (30 mg/day) was administered throughout the second gestation. Six months post-labor the treatment was discontinued after a normal hypothalamic-pituitary-adrenal (HPA) axis was ascertained.

Sequential treatment of severe postmenopausal osteoporosis after teriparatide: final results of the randomized, controlled European Study of Forsteo (EUROFORS).

It is unclear which treatment should be given after stopping teriparatide therapy for severe osteoporosis. In a prospective, randomized, controlled, 2-yr study, we compared BMD effects and clinical safety of three follow-up treatments (anabolic with teriparatide, antiresorptive with raloxifene, or no active treatment) after 1 yr of teriparatide. Postmenopausal women with osteoporosis and a recent fragility fracture received open-label teriparatide (20 microg/d) for 12 mo before they were randomized (3:1:1) to continue teriparatide (n = 305), switch to raloxifene 60 mg/d (n = 100), or receive no active treatment for the second year (n = 102). All patients received calcium and vitamin D supplementation. Changes in areal BMD from baseline to 24 mo were analyzed using mixed-model repeated measures. Daily teriparatide treatment for 2 yr significantly increased spine BMD by 10.7%. Patients receiving raloxifene in year 2 had no further change in spine BMD from year 1 (change from baseline, 7.9%), whereas patients receiving no active treatment had a BMD decrease of 2.5% in year 2 (change from baseline, +3.8%). At the total hip, BMD increases from baseline at 2 yr were 2.5% with teriparatide, 2.3% with raloxifene, and 0.5% with no active treatment; the respective changes at the femoral neck were 3.5%, 3.1%, and 1.3%. The study had insufficient power to assess antifracture efficacy. In conclusion, BMD increases progressively over 2 yr of teriparatide therapy in women with severe osteoporosis. After discontinuation of teriparatide, raloxifene maintains spine BMD and increases hip BMD.

Scintigraphic, biochemical, and clinical response to zoledronic acid treatment in patients with Paget's disease of bone.

Bisphosphonates have long been used with success in the treatment of Paget's disease of bone (PDB). The aim of this study was to evaluate the early (up to 3 months) and late (at 12 months) scintigraphic, biochemical, and clinical response to a single intravenous infusion of zoledronic acid (ZOL) in patients with PDB serially assessed for 1 year. Nine patients with 30 bone lesions caused by PDB were prospectively evaluated. Total serum alkaline phosphatase (SAP) was serially measured. Scintigraphy was performed before and at 3 and 12 months after ZOL administration, and bone lesions were assessed quantitatively. After treatment, pain was alleviated in five of six patients starting from the first month. At 3 months, a significant decrease of SAP levels compared to baseline values was found (322 +/- 211 IU/l before vs. 101 +/- 36 IU/l 3 months after; P < 0.05), with normal values attained in all except one patient. The scintigraphic index of involvement (SII), a marker for the per-patient activity of the disease, was reduced from 14.4 +/- 7.6 to 7.2 +/- 1.8 (P = 0.01). The scintigraphic ratio (SR), a marker for the per-lesion activity of the disease, was reduced from 12.8 +/- 7.7 to 7.0 +/- 2.9 (P < 0.001). The values of markers of disease activity remained unchanged up to 12 months. A single intravenous administration of ZOL leads to a favorable clinical, biochemical, and scintigraphic response in patients with PDB starting as early as 3 months after treatment and lasting no less than 12 months (i.e., considerably longer than the other existing therapies).

Acute changes in serum osteoprotegerin and receptor activator for nuclear factor-kappaB ligand levels in women with established osteoporosis treated with teriparatide.

OBJECTIVE: The mechanisms regulating the anabolic response of the skeleton to intermittent exogenous parathyroid hormone (PTH) administration are not fully elucidated. The aim of this prospective study was to evaluate the acute effect (up to 1 month) of teriparatide (TPTD; human recombinant PTH 1-34) on serum levels of osteoprotegerin (OPG) and receptor activator for nuclear factor-kappaB ligand (RANKL) in women with established osteoporosis. DESIGN: Twenty-three postmenopausal Caucasian women with established osteoporosis (mean age 66.7+/-1.6 years) received daily injections of 20 microg TPTD for 12 months. METHODS: Serum samples for total calcium (Ca), phosphate, alkaline phosphatase, N-terminal propeptide of type I collagen, intact PTH (iPTH), OPG, and RANKL were obtained at baseline, 1 h, 1 day, and 1 month after initiation of therapy. Lumbar spine bone mineral density (BMD) was measured before and 12 months after TPTD treatment. RESULTS: Serum total Ca increased and iPTH gradually decreased with TPTD treatment. Serum OPG levels remained unchanged, while RANKL increased gradually during the study (P<0.001). There was no correlation between OPG or RANKL and BMD changes or iPTH levels. CONCLUSIONS: TPTD therapy in women with postmenopausal osteoporosis results in acute increase in serum RANKL levels but does not affect serum OPG. These changes may reflect an increase in the number of active osteoblasts with therapy and might be responsible for the acceleration of bone turnover rate that characterizes TPTD.