Teresa Porcelli

Serum TSH values and risk of vertebral fractures in euthyroid post-menopausal women with low bone mineral density

INTRODUCTION There is evidence that variations of thyrotropin (TSH) even in its reference range may influence bone mineral density (BMD). In fact, low-normal TSH values have been associated with high prevalence of osteoporosis in post-menopausal women. However, data associating TSH and risk of fractures are scanty and limited to subjects with subclinical thyrotoxicosis. MATERIALS AND METHODS In this observational study, we investigated the correlation between serum TSH and prevalence of radiological vertebral fractures in a cohort of 130 post-menopausal women with normal thyroid function. RESULTS Osteoporosis was observed in 80 women (61.5%), whereas 49 women (37.7%) had osteopenia. Vertebral fractures were found in 49 women (37.7%), who were significantly older, with higher prevalence of osteoporosis and with lower serum TSH values as compared with women who did not fracture. Stratifying the patients according to serum TSH values, vertebral fractures were found to be significantly (p=0.004) more prevalent in first tertile (56.8%) of TSH values as compared with the second (23.3%) and third tertiles (32.6%). Multivariate logistic regression analysis demonstrated that low serum TSH maintained a significant correlation with vertebral fractures (odds ratio 2.8, C.I. 95% 1.20-6.79) even after correction for age, BMD, BMI and serum free-thyroxine values. DISCUSSION Low-normal TSH values are associated with high prevalence of vertebral fractures in women with post-menopausal osteoporosis or osteopenia, independently of thyroid hormones, age and BMD.

Vertebral Fractures in Patients With Acromegaly: A 3-Year Prospective Study

CONTEXT Cross-sectional studies showed an elevated prevalence of vertebral fractures in acromegaly. However, no data are available on incident vertebral fractures in this clinical setting. OBJECTIVE The objective of the study was to investigate the incidence and risk factors of vertebral fractures in patients with acromegaly. DESIGN This was a 3-year prospective study. SETTING The study was conducted at referral centers. SUBJECTS Eighty-eight patients with acromegaly (33 females, 55 males; mean age 50 years, range 21-85 years) and 106 control subjects, matched for sex and age (43 females and 63 males, mean age 55 years, range 33-79 years), attending outpatient bone clinics participated in the study. MAIN MEASURES Patients and control subjects were evaluated for the incidence of vertebral fractures using a quantitative morphometric approach on spine x-ray, which was performed at baseline and after 3 years of follow-up. At the same time points, patients with acromegaly were also evaluated for bone mineral density with dual-energy X-ray absorptiometry at lumbar spine and femoral neck. RESULTS After a 3-year follow-up, 37 patients with acromegaly (42.0%) and 4 control subjects (3.8%) experienced incident vertebral fractures (P < .001). The incidence of vertebral fractures was significantly higher in patients with active disease as compared with those who had controlled/cured acromegaly at the study entry (62.5% vs 25.0%; P < .001). The risk of incident vertebral fractures was significantly associated with hypogonadism, a change in the femoral neck bone mineral density, and prevalent vertebral fractures at the study entry only in patients with controlled/cured acromegaly, whereas in patients with active disease, the fracture risk was not influenced by the above-mentioned clinical factors, but it was significantly associated with the duration of active acromegaly. CONCLUSIONS This prospective study demonstrates a high rate of incident vertebral fractures both in patients with active and controlled acromegaly.

Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency

OBJECTIVE GH deficiency (GHD) and glucocorticoid excess are associated with increased risk of fragility fractures. We aimed to evaluate whether the prevalence of vertebral fractures may be influenced by glucocorticoid over-replacement in hypopituitary males with GHD. DESIGN Cross-sectional study. METHODS Fifty-one adult hypopituitary patients (all males; mean age 55 years, range: 23-81) with severe adult-onset GHD (replaced in 21 patients and untreated in 30 patients) and glucocorticoid deficiency on replacement treatment were studied for vertebral fractures using a radiological and morphometric approach. RESULTS Vertebral fractures were observed in 31 patients (60.8%) in correlation with untreated GHD, urinary cortisol values, and cortisone doses. Patients were stratified according to treatment of GHD, and current and cumulative cortisone doses. In untreated GHD, vertebral fractures occurred more frequently in patients who had received higher (greater than median) cumulative and current doses of cortisone compared with patients who had received lower (less than median) drug doses (95.2 vs 50.0%, P=0.009 and 90.5 vs 55.6%, P=0.04 respectively). In untreated GHD, fractured patients had significantly higher urinary cortisol values compared with patients without vertebral fractures (84 microg/24 h, range: 24-135 vs 49 microg/24 h, range: 30-96; P=0.04). In treated GHD patients, by contrast, the prevalence of vertebral fractures was not influenced by cumulative and current cortisone doses and urinary cortisol values. CONCLUSIONS Glucocorticoid over-replacement may increase the prevalence of vertebral fractures in patients with untreated GHD. However, treatment of GHD seems to protect the skeleton from the deleterious effects of glucocorticoid overtreatment in hypopituitary patients.

Treatment of Cushing disease: overview and recent findings

Endogenous Cushing syndrome is an endocrine disease caused by excessive secretion of adrenocorticotropin hormone in approximately 80% of cases, usually by a pituitary corticotroph adenoma (Cushing disease [CD]). It is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. The goals of treatment of CD include the reversal of clinical features, the normalization of biochemical changes with minimal morbidity, and long-term control without recurrence. Generally, the treatment of choice is the surgical removal of the pituitary tumor by transsphenoidal approach, performed by an experienced surgeon. Considering the high recurrence rate, other treatments should be considered. Second-line treatments include more radical surgery, radiation therapy, medical therapy, and bilateral adrenalectomy. Drug treatment has been targeted at the hypothalamic or pituitary level, at the adrenal gland, and also at the glucocorticoid receptor level. Frequently, medical therapy is performed before surgery to reduce the complications of the procedure, reducing the effects of severe hypercortisolism. Commonly, in patients in whom surgery has failed, medical management is often essential to reduce or normalize the hypercortisolemia, and should be attempted before bilateral adrenalectomy is considered. Medical therapy can be also useful in patients with CD while waiting for pituitary radiotherapy to take effect, which can take up to 10 years or more. So far, results of medical treatment of CD have not been particularly relevant; however, newer tools promise to change this scenario. The aim of this review is to analyze the results and experiences with old and new medical treatments of CD and to reevaluate medical therapies for complications of CD and hypopituitarism in patients with cured CD.

Effects of high-dose octreotide LAR on glucose metabolism in patients with acromegaly inadequately controlled by conventional somatostatin analog therapy

OBJECTIVE In this study, the effect of high-dose octreotide LAR on glucose metabolism in patients with acromegaly was investigated. DESIGN A post-hoc analysis of a clinical trial enrolling 26 patients with acromegaly not controlled by standard maximal somatostatin analog (SSAs) dose and randomized to receive high-dose (60  mg/28 days) or high-frequency (30  mg/21 days) octreotide i.m. injection (octreotide LAR) for 6 months. METHODS Glucose metabolic status was defined as worsened when a progression from normoglycemia to impaired fasting glucose (IFG) or from IFG to diabetes occurred or when an increase of HbAlc by at least 0.5% was demonstrated. An improvement of glucose metabolism was defined in the presence of a regression from IFG to normoglycemia and/or when HbAlc decreased by at least 0.5%. RESULTS Glucose metabolic status remained unchanged in a majority of patients (16/26 patients, 65.3%), worsened in six patients, and improved in four patients. Pre-existing metabolic status did not predict worsening of glucose metabolism, which, conversely, was significantly related to persistent biochemical activity of the disease. In fact, patients with worsened glucose metabolism exhibited a less frequent decrease in serum GH and IGF1 levels, compared with patients with improved or unchanged glucose metabolism (2/6 vs 18/20; P=0.01). CONCLUSION An increase in octreotide LAR dose or frequency did not impact on glucose metabolism in most patients. Worsening of glucose metabolic status occurred in close relation with persistently uncontrolled acromegaly.

PREVALENCE OF THORACIC VERTEBRAL FRACTURES IN HOSPITALIZED ELDERLY PATIENTS WITH HEART FAILURE.

OBJECTIVE Heart failure (HF) has been associated with increased risk of fragility fractures. Indeed, most literature data on fractures were based on an historical and clinical approach focused on the identification of peripheral fractures, whereas the risk of vertebral fractures in this clinical setting is still unclear. DESIGN Cross-sectional study. AIM To evaluate the prevalence and determinants of radiological thoracic vertebral fractures in patients with HF. METHODS The study includes 1031 elderly hospitalized patients (491 females and 540 males; median age, 75 years; range, 65-90; 430 patients with HF) who were evaluated for the presence of thoracic vertebral fractures by quantitative morphometric analysis, using chest X-ray routinely performed in the diagnostic work-up of HF. RESULTS Vertebral fractures were found in 166 patients (16.1%), the prevalence being significantly higher in patients with HF as compared with those without HF, both in females (30.9 vs 15.8%; P<0.001) and in males (16.4 vs 7.4%; P=0.001). The association between HF and vertebral fractures remained statistically significant (odds ratio, 2.14; 95% CI, 1.25-3.66; P=0.01) even after adjustment for age, sex, loop diuretic therapy, anticoagulant therapy, proton pump therapy, coexistent chronic obstructive pulmonary disease, diabetes mellitus, renal insufficiency, and chronic liver diseases. In patients with HF, vertebral fractures were positively correlated with female sex, duration of HF, ischemic heart disease, cigarette smoking, and treatment with anti-osteoporotic drugs, and inversely correlated with left ventricular ejection fraction. CONCLUSIONS Hospitalized patients suffering from HF are at higher risk of vertebral fractures than patients without HF in the same clinical context.

Effects of recombinant follicle-stimulating hormone on bone turnover markers in infertile women undergoing in vitro fertilization procedure.

CONTEXT There is experimental but limited clinical evidence that FSH may have direct effects on bone. OBJECTIVE The aim of the study was to evaluate the effects of acute FSH stimulation on bone turnover in premenopausal women. DESIGN AND SETTING We conducted a prospective study at a referral center. PATIENTS Twenty-nine infertile women (age range, 30-40 yr) undergoing an in vitro fertilization procedure were included in the study. INTERVENTIONS Pharmacological suppression of endogenous gonadotropin and estradiol (E2) production by GnRH analog (leuprolide 1 mg/d s.c.) was followed by stimulation with recombinant FSH (rFSH; starting dose, 375 IU/d s.c.). MAIN OUTCOME MEASURES We measured serum osteocalcin, C-telopeptides of type-1 collagen (β-CTX), FSH, and E2 at the beginning of leuprolide administration (T0), at the beginning of rFSH administration (T1), and 3 d (T2) and 10 d (T3) after the first dose of rFSH. RESULTS At T1, the suppression of FSH and E2 secretion, as an effect of leuprolide administration, led to a significant increase in serum β-CTX values vs. T0 (P < 0.001). After the administration of rFSH, a rapid increase in serum FSH was observed, whereas serum E2 values increased more slowly. At T2, the increase in serum FSH values above our reference range for early follicular phase (with E2 in the reference range) did not induce any significant change in median serum β-CTX values as compared to T1. At T3 (when both FSH and E2 were high), serum β-CTX values decreased significantly vs. T1 (P < 0.001). Osteocalcin did not change significantly throughout the study period. CONCLUSIONS Our model suggests that FSH does not acutely exert relevant direct effects on bone metabolism in premenopausal women.

Bone safety of dual-release hydrocortisone in patients with hypopituitarism

Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis in both sexes [1, 2]. The glucocorticoid-induced decline in bone formation is associated with an increased fracture risk related both to the dose and duration of glucocorticoid treatment [3, 4]. Glucocorticoid replacement therapy is mandatory in all patients affected by adrenal insufficiency, defined as a primary or secondary impairment of adrenal gland function. Over the last few years it has become evident that patients with adrenal insufficiency, even if treated, show reduced life expectancy, poor quality of life (QoL), and increased comorbidities [5]. In fact, the absence of reliable biochemical and/or clinical markers of adequate substitution may lead clinicians to overtreat these patients in order to avoid complications such as life-threatening adrenal crises. Moreover, it is well known that the conventional glucocorticoid replacement regimens do not completely mirror the normal hormonal secretion, inducing serum cortisol peaks far beyond physiological levels. This consequent mild to moderate glucocorticoid excess may have detrimental effects at several target organ levels [6]. Negative effects on bone metabolism, including high risk of vertebral fractures, during conventional glucocorticoid replacement therapies in both primary and secondary adrenal insufficiency have been reported [7, 8], and even though data regarding central corticotropin (ACTH) deficiency are scanty so far, we have observed that a high comulative glucocorticoid replacement dose is associated with higher prevalence of vertebral morphometric fractures [9]. In this clinical setting, new drug formulations has become recently available in many countries and dual-release hydrocortisone tablets (Plenadren, Shire), reproducing the endogenous cortisol rhythm [10], have a more favorable clinical profile [11] as far as dyslipidemia, hyperglycemia and body composition are concerned [12]. However, most of the published studies on Plenadren were focused on primary adrenal insufficiency, whereas data concerning secondary adrenal insufficiency are scanty [1, 13]. This is the first study specifically evaluating the effects of dual-release hydrocortisone on bone in patients with secondary adrenal insufficiency. In total 14 patients (10 females, 4 males: median age 55 years, range 31–77) were enrolled retrospectively in this longitudinal study. The inclusion criteria were: (1) age older than 18 years; (2) central hypoadrenalism treated by conventional glucocorticoid regimens for at least 12 months before the shift to Plenadren; (3) at least 24 months of Plenadren treatment; (4) availability of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) data before and during Plenadren. The exclusion criteria were: (1) treatment with anti-osteoporotic drugs except for calcium and vitamin D (Table 1); (2) treatment with drugs causing osteoporosis except for those used to replace hypopituitarism. In total 12 patients had post-surgical hypopituitarism with (n. 2) or without radiotherapy. Two patients had primary empty sella syndrome and one patient had pre-existing Cushing disease. Glucocorticoid deficiency was defined by basal serum cortisol values lower than 3 μg/dL or by lowdose (1 μg ev) ACTH-stimulated cortisol below 18 μg/dL. The main features of patients with central hypoadrenalism at baseline are reported in Table 1. All patients had growth hormone deficiency (GHD), as defined by GH peak lower than 9 μg/L for patients with a body mass index (BMI) less * Andrea Giustina giustina.andrea@hsr.it

Pituitary gland: Medical therapy for acromegaly: can we predict response?

Response to medical therapy for acromegaly is highly variable, with few predictive factors available to help clinicians make informed treatment choices. Researchers in the UK now suggest that prior radiotherapy might influence an individuals response to secondary therapy with dopamine agonists or somatostatin analogs.