Consensus statement from 2nd International Conference on Controversies in Vitamin D.

The 2nd International Conference on Controversies in Vitamin D was held in Monteriggioni (Siena), Italy, September 11-14, 2018. The aim of this meeting was to address ongoing controversies and timely topics in vitamin D research, to review available data related to these topics and controversies, to promote discussion to help resolve lingering issues and ultimately to suggest a research agenda to clarify areas of uncertainty. Several issues from the first conference, held in 2017, were revisited, such as assays used to determine serum 25-hydroxyvitamin D [25(OH)D] concentration, which remains a critical and controversial issue for defining vitamin D status. Definitions of vitamin D nutritional status (i.e. sufficiency, insufficiency and deficiency) were also revisited. New areas were reviewed, including vitamin D threshold values and how they should be defined in the context of specific diseases, sources of vitamin D and risk factors associated with vitamin D deficiency. Non-skeletal aspects related to vitamin D were also discussed, including the reproductive system, neurology, chronic kidney disease and falls. The therapeutic role of vitamin D and findings from recent clinical trials were also addressed. The topics were considered by 3 focus groups and divided into three main areas: 1) "Laboratory": assays and threshold values to define vitamin D status; 2) "Clinical": sources of vitamin D and risk factors and role of vitamin D in non-skeletal disease and 3) "Therapeutics": controversial issues on observational studies and recent randomized controlled trials. In this report, we present a summary of our findings.

Prevalence of morphometric vertebral fractures in "difficult" patients with acromegaly with different biochemical outcomes after multimodal treatment.

INTRODUCTION: Skeletal fragility with high risk of vertebral fractures is an emerging complication of acromegaly in close relationship with duration of active disease. The aim of this cross-sectional study was to evaluate the prevalence and determinants of vertebral fractures in males and females with a history of long-standing active acromegaly undergoing treatment with Pegvisomant. SUBJECTS AND METHODS: Thirty-eight patients (25 females, 13 males) with acromegaly under Pegvisomant therapy were evaluated for vertebral fractures and bone mineral density at lumbar spine and femoral neck. Gonadal status, serum IGF1 levels and growth hormone receptor genotype were also assessed. RESULTS: Vertebral fractures were detected in 12 patients (31.6%). Fractured patients had longer duration of active disease (p = 0.01) with higher frequency of active acromegaly (p = 0.04), received higher dose of Pegvisomant (p = 0.008), and were more frequently hypogonadic (p = 0.02) as compared to patients who did not fracture. Stratifying the patients for gender, vertebral fractures were significantly associated with Pegvisomant dose (p = 0.02) and untreated hypogonadism (p = 0.02) in males and with activity of disease (p = 0.03), serum insulin-like growth factor-I values (p = 0.01) and d3GHR polymorphism (p = 0.005) in females. No significant association was found between vertebral fractures and bone mineral density at either skeletal site. CONCLUSION: Vertebral fractures are a frequent complication of long-standing active acromegaly. When patients are treated with Pegvisomant, vertebral fractures may occur in close relationship with active acromegaly and coexistent untreated hypogonadism.

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

PURPOSE AND PATIENTS: The 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). RESULTS: Radio-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. CONCLUSIONS: SREs 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.

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.

Diabetes in Cushing Disease.

PURPOSE OF REVIEW: This review focuses on the pathophysiological and clinical aspects of diabetes mellitus occurring in patients with Cushing disease (CD). RECENT FINDINGS: Insulin resistance and impairment in insulin secretion are both involved in the pathogenesis of glucocorticoid-induced diabetes. Correction of glucocorticoid excess does not always resolve abnormalities of glucose homeostasis, and correction of hyperglycaemia is specifically required. In fact, insulin resistance may persist even after correction of glucocorticoid excess and diabetes needs to be treated for long term. On the other hand, emerging drugs used in the treatment of CD, such as the novel somatostatin analog pasireotide, may have direct effects on glucose homeostasis regardless of control of cortisol excess. Diabetes mellitus is a frequent and early complication of CD with important diagnostic, prognostic and therapeutic implications. Specifically, diagnosis of CD in patients with diabetes may be difficult due to potential misinterpretation of markers of cortisol hypersecretion. Moreover, diabetes mellitus is often difficult to be controlled in CD requiring a careful and dedicated therapeutic approach. Finally, the coexistence of diabetes may influence the therapeutic decision making in CD, since drugs used in this setting may variably influence glucose homeostasis regardless of control of hypercortisolism.

Growth hormone receptor isoforms and fracture risk in adult-onset growth hormone-deficient patients.

INTRODUCTION: Growth hormone deficiency is considered the most important factor determining skeletal fragility in hypopituitary patients. Osteoblasts and chondrocytes express growth hormone (GH) receptor. Two GH receptor isoforms (GHRi) have been identified: they differ for the presence/absence of a protein fragment encoded by exon 3 of GHR gene. Consequently, three genotypes were identified: carriers of both the full-length proteins (flfl-GHR), carriers of one full-length protein and one deleted protein (fld3-GHR) and carriers of both deleted proteins (d3d3-GHR). This polymorphism confers a higher sensitivity to endogenous GH and to recombinant human GH (rhGH); its effect on bone metabolism and skeletal fragility is unknown. The aim of this article was to investigate the role of GHRi in predicting skeletal fragility in adult-onset GHD (AO-GHD) patients. SUBJECTS AND METHODS: A cross-sectional study was conducted to investigate the association between the d3-GHR isoform and the prevalence of morphometric vertebral fractures (VFs) in AO-GHD. Ninety-three AO-GHD were enrolled. Forty-nine patients carried flfl-GHRi (52·7%), and 44 patients (47·3%) carried at least one allele of the d3-GHR isoform. Thirty-two VFs were documented. Fifty-seven patients underwent rhGH replacement therapy. RESULTS: Median age was significantly higher in fractured patients as compared to nonfractured ones; d3-carrier patients showed a lower VF risk as compared to flfl-GHRi (OR: 0·37, 95% IC: 0·24-0·55, P < 0·0001). This finding was also confirmed in AO-GHD undergoing rhGH replacement therapy. CONCLUSION: This study suggests that d3-GHR may protect AO-GHD particularly when treated with rhGH from the risk of VFs.

Ultrasound findings of subacute thyroiditis: a single institution retrospective review.

BACKGROUND: High resolution ultrasonography features have also been described as having a useful supporting role in the diagnosis of subacute granulomatous thyroiditis (ST), and images are generally characterized by heterogeneous hypoechoic areas of the affected tissue with lack of flow on color Doppler US. PURPOSE: To determine the sonographic features of subacute granulomatous thyroiditis. MATERIAL AND METHODS: We reviewed the medical records of patients referred at the Endocrine and Metabolic Unit of our Institution between January 2010 and December 2011. RESULTS: A total of 7520 patients were evaluated in our department between January 2010 and December 2011. Among them, 22 (0.3%) patients had a diagnosis of ST (19 women and 3 men, 45.4 ± 9.7 year; range, 33-62 years). Ultrasound examination showed bilateral ST in 64% of patients. Thyroid volume was 13.2 ± 7.7 mL, without difference if ST was unilateral (13.2 ± 7.1 mL) or bilateral (13.9 ± 8.3 mL). On grayscale US, heterogeneous diffusely or focally marked hypoechoic areas, like "lava flow", were found in all the lesions. CONCLUSION: Our data confirm the high sensitivity of US in the diagnosis of ST: diffuse hypoechoic and confluent areas with the characteristic features like "lava flow".