Stefano Frara

Current and Emerging Aspects of Diabetes Mellitus in Acromegaly

Diabetes mellitus is a frequent complication of acromegaly, a disease characterized by chronic hypersecretion of growth hormone (GH) by a pituitary adenoma. Diabetes occurs commonly but not only as a consequence of an insulin-resistant state induced by GH excess. The development of diabetes in patients with acromegaly is clinically relevant, since such a complication is thought to increase the already elevated cardiovascular morbidity and mortality risk of the disease. Emerging data suggest that a specific cardiomyopathy can be identified in acromegaly patients with diabetes. Moreover, the presence of diabetes may also influence therapeutic decision making in acromegaly, since traditional and newly developed drugs used in this clinical setting may impact glucose metabolism regardless of control of GH hypersecretion.

The Modern Criteria for Medical Management of Acromegaly

Acromegaly is an insidious disorder characterized by excess secretion of growth hormone (GH) and elevated circulating levels of insulin-like growth factor-I (IGF-I), generally caused by a pituitary adenoma. It is a rare disease associated with an average 10-year reduction in life expectancy due to metabolic, cardiovascular, and cerebrovascular comorbidities and reduced quality of life caused by paresthesias, fatigue, osteoarthralgia, or bone fractures. In 2000, Cortina Consensus Conference established general criteria for diagnosis and biochemical control of acromegaly, which have been revised in recent years, adapting them to emerging clinical evidences as well as the evolving assay techniques. Authors have proposed a binary definition of cure for acromegaly, where both GH and IGF-I are important determinants: the former is more linked to the presence of residual adenomatous tissue, while the latter to the peripheral activity of the disease. Control of tumor growth and complications is also an essential goal of treatment. Surgical, medical, and radiotherapy approaches are all valid alternatives. The surgical option is, however, unsuccessful in about 50% of patients. Somatostatin analogs (SRLs), octreotide LAR, and lanreotide ATG can inhibit cell growth, besides their beneficial effects on GH hypersecretion and on most comorbidities. Pasireotide is a new multireceptor-targeted SRL with reported superior biochemical efficacy to octreotide, due to higher affinity for SSTR-5, but potentially causing detrimental effects on glucose homeostasis. Pegvisomant could be a valid choice in all patients resistant to SRLs. It is a competitive GH antagonist, which efficaciously blocks IGF-I production, inhibiting the dimerization of GH receptor. Normal IGF-I levels represent, therefore, its only relevant efficacy endpoint, while only few cases of tumor growth on pegvisomant have been reported, so far.

MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects

The effects of long-term replacement therapy of adrenal insufficiency (AI) are still a matter of controversy. In fact, the established glucocorticoid replacement regimens do not completely reproduce the endogenous hormonal production and the monitoring of AI treatment may be a challenge for the lack of reliable clinical and biochemical markers. Consequently, several AI patients are frequently exposed to relative glucocorticoid excess potentially leading to develop chronic complications, such as diabetes mellitus, dyslipidemia, hypertension and fragility fractures with consequent impaired QoL and increased mortality risk. This review deals with the pathophysiological and clinical aspects concerning the over-replacement therapy of primary and secondary AI.

Morphometric vertebral fractures in breast cancer patients treated with adjuvant aromatase inhibitor therapy: A cross-sectional study

BACKGROUND The impact of long-term adjuvant therapy with aromatase inhibitors (AIs) on vertebral fracture (VF) risk is still unclear. OBJECTIVE In this cross-sectional study, we explored the prevalence and determinants of VFs in breast cancer (BC) patients before and during AI therapy. Each woman underwent a dual-energy X-ray absorptiometry (DXA) to evaluate bone mineral density (BMD) and identify VFs by a quantitative morphometric approach. Blood samples were collected to measure serum hormone and calcium levels. RESULTS We consecutively included 263 postmenopausal women with hormone receptor-positive early BC. One-hundred-sixty-nine women were AI-naïve, and 94 were AI-treated. AI-treated patients had lower BMD at total hip (p=0.01) and lumbar spine (p=0.03), higher serum vitamin D (p<0.001) and parathyroid hormone (p=0.006) values as compared to AI-naïve patients. The prevalence of VFs was 18.9% in AI-naïve patients, and 31.2% in those assessed during AI therapy (odds ratio 1.90, 95% CI 1.1-3.5, p=0.03). In AI-naïve patients, VFs were associated with older age (p=0.002) and lower BMD values at femoral neck (p=0.04) and total hip (p=0.007), whereas VFs occurred without association with any parameter analyzed in AI-treated patients. In AI-treated group, the prevalence of VFs was not significantly different between patients with osteoporosis and those with normal BMD (36.7% vs. 20.0%; p=0.31). CONCLUSIONS In women with early BC, AI therapy is associated with high prevalence of radiological VFs, which were shown to be independent of BMD values during the adjuvant treatment. These findings may be clinically relevant since they may lead to a change in management of AI-induced skeletal fragility. Specifically, the results of this study provide a rationale for performing a morphometric evaluation of VFs in all women undergoing treatment with AIs.

HIGH PREVALENCE OF RADIOLOGICAL VERTEBRAL FRACTURES IN WOMEN ON TSH-SUPPRESSIVE THERAPY FOR THYROID CARCINOMA

Context Bone loss and nonvertebral fractures have been reported in patients with differentiated thyroid carcinoma (DTC) undergoing thyroid-stimulating hormone (TSH) suppressive therapy. Radiological vertebral fractures (VFs) are an early and clinically crucial marker of bone fragility. Objective and Design A cross-sectional study to evaluate the prevalence and determinants of radiological VFs in women receiving l-thyroxine (L-T4) therapy for DTC. Patients and Interventions A total of 179 consecutive women (median age, 59 years; n = 178 postmenopausal) who had undergone thyroidectomy for DTC and were currently receiving L-T4 were evaluated for radiological VFs and bone mineral density (BMD). There were three TSH target levels [<0.5 mU/L, group 1 (n = 83); 0.5 to 1.0 mU/L, group 2 (n = 50); >1.0 mU/L, group 3 (n = 46)]. Results VFs were found in 51 patients (28.5%), with significantly (P < 0.001) higher prevalence in group 1 (44.6%) as compared with group 2 (24.0%) and group 3 (4.3%). VF prevalence was not significantly different among patients in group 1 with normal BMD, osteopenia, or osteoporosis, whereas in groups 2 and 3, VFs were more frequent in patients with osteoporosis than in those with either osteopenia or normal BMD. In the whole population, VFs were significantly and independently associated with TSH level <1.0 mU/L; densitometric diagnosis of osteoporosis at lumbar spine, femoral neck, or total hip; age of patients; and duration of L-T4 therapy. Conclusion The prevalence of VFs was high in women with DTC who were undergoing long-term, suppressive L-T4 therapy.

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

Real-life management and outcome of thyroid carcinoma-related bone metastases: results from a nationwide multicenter experience

Purpose and PatientsThe M.O.S.CA.TI. (Metastases of the Skeleton from CArcinoma of the ThyroId) is a multicenter, retrospective study investigating the real-life outcome and management of bone metastases (BM) in 143 patients (63 M, 80 F; median age 64 years, range 11–87) with differentiated thyroid carcinoma (DTC).ResultsRadio-active iodine (RAI) treatment was performed in 131 patients (91.6%), surgical approach and/or external radiotherapy in 68 patients (47.6%), and anti-resorptive bone-active drugs in 32 patients (22.4%; in 31 zoledronate and in one denosumab). At the start of treatment, 24 patients (75.0%) receiving anti-resorptive bone-active drugs had at least one clinical skeletal-related event (SRE) (p < 0.001). One or more clinical SREs (pathological fractures and/or malignant hypercalcemia and/or spinal cord compression) developed in 53 patients (37.1%). Development of SREs was significantly associated with metachronous BM (hazard ratio (HR) 2.04; p = 0.04), localization of BM to cervical spine (HR 3.89; p = 0.01), and lack of avid RAI uptake (HR 2.66; p = 0.02). Thirty-nine patients (27.3%) died in correlation with development of SREs (HR 6.97; p = 0.006) and localization of BM to the hip (HR 3.86; p = 0.02). Moreover, overall mortality was significantly decreased by RAI therapy (HR 0.10; p = 0.02), whereas no significant effects were induced by bone-active drugs (p = 0.36), external radiotherapy (p = 0.54), and surgery (p = 0.43) of BM.ConclusionsSREs are very frequent in BM from DTC and they impact patient survival. In the real life, the use of bone-active drugs is currently limited to zoledronate in patients with pre-existing SREs. In this clinical setting, RAI therapy, but not zoledronate, decreased mortality.

Pituitary Diseases and Bone

Neuroendocrinology of bone is a new area of research based on the evidence that pituitary hormones may directly modulate bone remodeling and metabolism. Skeletal fragility associated with high risk of fractures is a common complication of several pituitary diseases such as hypopituitarism, Cushing disease, acromegaly, and hyperprolactinemia. As in other forms of secondary osteoporosis, pituitary diseases generally affect bone quality more than bone quantity, and fractures may occur even in the presence of normal or low-normal bone mineral density as measured by dual-energy X-ray absorptiometry, making difficult the prediction of fractures in these clinical settings. Treatment of pituitary hormone excess and deficiency generally improves skeletal health, although some patients remain at high risk of fractures, and treatment with bone-active drugs may become mandatory. The aim of this review is to discuss the physiological, pathophysiological, and clinical insights of bone involvement in pituitary diseases.

Somatostatin analogs in the treatment of neuroendocrine tumors: Current and emerging aspects

ABSTRACT Introduction: Neuroendocrine tumors (NETs) harbor somatostatin receptors and there is a strong rationale for using somatostatin analogs (SSAs) for treatment of NETs. Areas covered: This article discusses i) pharmacology of somatostatin and its analogs; ii) antisecretory and anti-proliferative effects of SSAs in NETs; iii) efficacy and safety of emerging therapeutic regimens with first generation SSAs administered at either high doses or in combination with antineoplastic drugs; iv) efficacy and safety of pasireotide and chimeric molecules; v) efficacy of radionuclide therapy of NETs using SSAs. Expert opinion: SSAs are the first-line medical therapy for functioning and non-functioning well-differentiated NETs. In patients not responder to first generation SSAs, the increase of drug dose over the conventional regimens, the combination of SSAs with other biotherapies or molecular targeted therapies, the switch to pasireotide or the use of SSAs in radionuclide therapy may improve the therapeutic success.

Correction to: Effects of pegvisomant and somatostatin receptor ligands on incidence of vertebral fractures in patients with acromegaly

The original version of the article contained an error in the results section of the Abstract. The vertebral fractures (VFs) odds ratio is incorrectly published as 61.0 and the correct value is 6.10.