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PurposeMost insulinomas are small solitary, benign neoplasms. Imaging and surgical techniques improved over the last 20 years. Thus, the aim of the present study was to analyze changes in diagnosis and surgery of insulinoma patients in a referral center over two decades.MethodsOperated patients with a histologically proven insulinoma were retrieved from a prospective database. Clinico-pathological characteristics and outcomes were retrospectively analyzed with regard to the time periods 2000–2010 (group 1) and 2011–2020 (group 2).ResultsSixty-one of 202 operated patients with pNEN had an insulinoma, 37 (61%) in group 1 and 24 (39%) in group 2. Of those 61 insulinomas, 49 (80%) were sporadic benign, 8 (13%) benign MEN1-associated insulinomas, and 4 (7%) sporadic malignant insulinomas. In 35 of 37 (95%) patients of group 1 and all patients of group 2, the insulinoma was preoperatively identified by imaging. The most sensitive imaging modality was endoscopic ultrasound (EUS) with correctly diagnosed and localized insulinomas in 89% of patients in group 1 and 100% in group 2. In group 1, significantly less patients were operated via minimally invasive approach compared to group 2 (19% (7/37) vs. 50% (12/24), p = 0.022). Enucleation was the most frequently performed operation (31 of 61, 51%), followed by distal resection (15 of 61, 25%) without significant differences between groups 1 and 2. The rate of relevant postoperative complications was not different between groups 1 and 2 (24% vs. 21%, p = 0.99). Two patients with benign insulinoma (1 out of each group) experienced disease recurrence and underwent a second resection. After a median follow-up of 134 (1–249) months, however, all 57 (100%) patients with benign insulinoma and 3 out of 4 patients with malignant insulinoma had no evidence of disease.ConclusionInsulinoma can be preoperatively localized in almost all patients, allowing for a minimally invasive, parenchyma-sparing resection in selected patients. The long-term cure rate is excellent.

Objective:Familial pancreatic cancer (FPC) accounts for approximately 3% of all pancreatic cancer (PC) cases. It has been suggested that high-risk individuals (HRIs) should be offered a screening programme.Aim:To evaluate the diagnostic yield of a prospective screening programme in HRIs from families with FPC over a period of 5 years.Methods:HRIs of families with FPC of the National German Familial Pancreatic Cancer Registry (FaPaCa) were counselled and enrolled in a prospective, board-approved PC screening programme. Screening included clinical examination, laboratory tests, endoscopic ultrasound (EUS) and MRI with magnetic resonance cholangiopancreaticography (MRCP) and MR angiography.Results:Between June 2002 and December 2007, 76 HRIs of families with FPC took part in the screening programme with a total of 182 examination visits. Twenty-eight patients revealed abnormalities in EUS (n = 25) and/or MR/MRCP (n = 12). In 7 patients fine needle aspiration cytology was performed. Operative pancreatic explorations were performed in 7 individuals, resulting in limited resections in 6 cases. Histopathological examination of the resected specimens showed serous oligocystic adenomas (n = 3), pancreatic intraepithelial neoplasia 1 (PanIN1) lesions with lobular fibrosis (n = 1), PanIN2 lesions (n = 1) and PanIN1 lesion plus a gastric type intraductal papillary mucinous neoplasm (IPMN) (n = 1).Conclusions:In FPC an EUS/MR/MRCP-based screening programme leads to the detection of potential precursor lesions of PC. However, the yield of an extensive screening programme is low, especially since the tumourigenic value of low grade PanIN lesions is not yet defined. Taking into account the enormous psychological stress for the tested individual and the high costs, a general PC screening in HRIs is not justified.

Summary This retrospective database study assessed 2-year persistence with bisphosphonates or denosumab in a large German cohort of women with a first-time prescription for osteoporosis treatment. Compared with intravenous or oral bisphosphonates, 2-year persistence was 1.5–2 times higher and risk of discontinuation was significantly lower ( P  < 0.0001) with denosumab. Introduction Persistence with osteoporosis therapies is critical for fracture risk reduction. Detailed data on long-term persistence (≥2 years) with bisphosphonates and denosumab are sparse. Methods From the German IMS® database, we included women aged 40 years or older with a first-time prescription for bisphosphonates or denosumab between July 2010 and August 2014; patients were followed up until December 2014. The main outcome was treatment discontinuation, with a 60-day permissible gap between filled prescriptions. Two-year persistence was estimated using Kaplan–Meier survival curves, with treatment discontinuation as the failure event. Denosumab was compared with intravenous (i.v.) and oral bisphosphonates separately. Cox proportional hazard ratios (HRs) for the 2-year risk of discontinuation were calculated, with adjustment for age, physician specialty, health insurance status, and previous medication use. Results Two-year persistence with denosumab was significantly higher than with i.v. or oral bisphosphonates (39.8 % [ n  = 21,154] vs 20.9 % [i.v. ibandronate; n  = 20,472] and 24.8 % [i.v. zoledronic acid; n  = 3966] and 16.7–17.5 % [oral bisphosphonates; n  = 114,401]; all P  < 0.001). Patients receiving i.v. ibandronate, i.v. zoledronic acid, or oral bisphosphonates had a significantly increased risk of treatment discontinuation than did those receiving denosumab (HR = 1.65, 1.28, and 1.96–2.02, respectively; all P  < 0.0001). Conclusions Two-year persistence with denosumab was 1.5–2 times higher than with i.v. or oral bisphosphonates, and risk of discontinuation was significantly lower with denosumab than with bisphosphonates. A more detailed understanding of factors affecting medication-taking behavior may improve persistence and thereby reduce rates of fracture.

Introduction The open-label Rapid Onset and Sustained Efficacy (ROSE) study was designed to compare a once-yearly intravenous (iv) dose of zoledronic acid with a once-weekly oral dose of alendronate with respect to markers of bone turnover in approximately 600 postmenopausal women in Germany. Methods Levels of N-telopeptide of collagen type I (NTx) and procollagen 1 C terminal extension peptide (P1NP) were assessed during the study. The primary objective was to assess if zoledronic acid was superior to alendronate in reducing serum NTx levels after 12 months’ treatment. Results A significantly greater reduction in NTx levels from baseline to month 12 (as determined by the area under the curve) was observed in patients treated with zoledronic acid ( n  = 408) versus those receiving alendronate ( n  = 196; 0.282 ng/mL vs. 0.270 ng/mL; P  = 0.012). The reduction in levels of P1NP after 1 year was also significantly greater in patients treated with zoledronic acid compared with those receiving alendronate (28.21 vs. 25.53 ng/mL; P  = 0.0024). The overall incidence of adverse events was similar between groups; both treatments were generally well tolerated. Although post-dose symptoms, including the incidence of influenza-like symptoms, were higher with zoledronic acid than alendronate initially, the incidence was similar between groups from days 4–360. Gastrointestinal symptoms were more frequent with alendronate than zoledronic acid throughout the study. Conclusion In this study, once-yearly iv zoledronic acid provided a greater and faster reduction in the levels of NTx and P1NP versus once-weekly oral alendronate.

Summary The ROSE study compared annual infusion with zoledronic acid and weekly generic alendronate. No significant differences in quality of life or health status between treatment groups were observed. Adherence to alendronate during the study was high, with 80.9% of patients achieving adequate adherence. Introduction A secondary analysis to evaluate quality of life, health status, adherence to alendronate and therapy preference in postmenopausal women with low bone mass who received treatment with zoledronic acid or alendronate was conducted. Methods Postmenopausal women with low bone mass were randomised 2:1 to receive an annual infusion of zoledronic acid or weekly oral generic alendronate in this open-label, multicentre study. Changes in quality of life and health status were assessed using questionnaires at baseline and month 12. Adherence to alendronate was assessed by the investigator and/or study personnel, and subjective therapy preference was assessed using a questionnaire at month 12. Results Patients were randomised to zoledronic acid ( n  = 408) and alendronate ( n  = 191). Overall, there were no significant differences in quality of life between zoledronic acid and alendronate. However, improvements in quality of life with zoledronic acid versus alendronate could be detected by posthoc analysis in patients with previous fractures. There were no significant differences in health status between patients receiving zoledronic acid or alendronate. Adherence to alendronate during the study was high, with 80.9% of patients achieving adequate adherence. A total of 81% of patients who had received zoledronic acid indicated that they would prefer to continue with that treatment, and 43% of the patients who received oral alendronate would like to switch to zoledronic acid. Conclusions There were no significant differences in quality of life between patients receiving zoledronic acid or alendronate.

BackgroundAdrenal tumors are a common manifestation of the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Prevalence in recent studies varies between 9 and 45%. A genotype–phenotype correlation has been described as well as the development of adrenocortical carcinomas. Long-term prospective data are still lacking.Materials and methodsThirty-eight MEN-1 patients with proven germline mutations have been prospectively observed in a regular screening program in our hospital. Adrenal glands have been screened by biochemical analysis and either by endoscopic ultrasound (EUS) or computed tomography (CT) or both. Median follow-up was 48 months (12–108 months). Age at diagnosis of MEN-1, type of adrenal tumor, genotype, therapy, and clinical characteristics have been analyzed.ResultsIn 21 (55%) patients, adrenal involvement of the disease was detected. Adrenal lesions were detected in average 6.9 years after the initial diagnosis of MEN-1. Median tumor size was 12 mm (5–40 mm). Tumor size smaller than 10 mm was observed in 11 patients. Twelve patients had unilateral while nine had bilateral adrenal lesions. EUS detected all adrenal tumors, whereas CT failed in seven cases. In three patients, functioning tumors (one pheochromocytoma, one bilateral Cushing adenoma, and one adrenocortical carcinoma) and one nonfunctioning adenoma were diagnosed by histology and biochemical assessment. Two laparoscopic adrenalectomies and one laparoscopic subtotal resection were performed. Nonfunctioning adrenal lesions, not characterized by histology yet, were found in 18 patients. There was no statistical difference with regard to adrenal involvement between patients with germline mutations in exons 2 and 10 (12/21) and those with mutations in exons 3–9 (6/11).ConclusionMEN-1-associated adrenal tumors are mostly small, benign, and nonfunctioning and much more common than previously reported. EUS was the most sensitive imaging procedure. The genotype–pheotype correlation previously suggested by our group could not be confirmed.

Background Radiological tumor size of non-functioning pancreatic neuroendocrine neoplasms (Nf-pNENs) associated with multiple endocrine neoplasia type 1 (MEN1) is a crucial parameter to indicate surgery. The aim of this study was to compare radiological size (RS) and pathologic size (PS) of MEN1 associated with pNENs. Methods Prospectively collected data of MEN1 patients who underwent pancreatic resections for pNENs were retrospectively analyzed. RS was defined as the largest tumor diameter measured on endoscopic ultrasound (EUS), magnetic resonance imaging (MRI) or computed tomography (CT). PS was defined as the largest tumor diameter on pathological analysis. Student’s t test and linear regression analysis were used to compare the median RS and PS. p  < 0.05 was considered significant. Results Forty-four patients with a median age of 37 (range 10–68) years underwent primary pancreatic resections for pNENs. Overall, the median RS (20 mm, range 3–100 mm) was significantly larger than the PS (13 mm, range 4–110 mm) ( p  = 0.001). In patients with pNENs < 20 mm ( n  = 27), the size difference (median RS 15 mm vs PS 12 mm) was also significant ( p  = 0.003). However, the only modality that significantly overestimated the PS was EUS (median RS 14 mm vs 11 mm; p  = 0.0002). RS overestimated the PS in 21 patients (21 of 27 patients, 78%). Five of 11 patients (12%) with a Nf-pNEN and a RS > 20 mm had in reality a PS < 20 mm. MRI was the imaging technique that best correlated with PS in the total cohort ( r  = 0.8; p  < 0.0001), whereas EUS was the best correlating imaging tool in pNENs < 20 mm ( r  = 0.5; p  = 0.0001). Conclusion Preoperative imaging, especially EUS, frequently overestimates the size of MEN1-pNENs, especially those with a PS < 20 mm. This should be considered when indicating surgery in MEN1 patients with small Nf-pNENs.

Bone biopsy is a diagnostic procedure restricted to untypical, unclear and complicated cases in evidence-based guidelines on diagnosis and treatment of osteoporosis. Its relevance has been a topic of recent controversial discussion. This study was performed to evaluate its role and relevance in routine use. A total of 99 horizontal transiliac bone biopsies performed over a time period of 14 years because of an osteological indication in one single centre were analysed, which reflects that bone biopsy followed about 0.003% of patients' consultations. Bone biopsies were indicated for osteoporotic males (n = 63) and premenopausal osteoporotic females (n = 18) without endocrine abnormality and normal immunofixation (serum and urine), suspected systemic/malignant disease such as mastocytosis, osteogenesis imperfecta, non-secreting plasmocytoma, metastatic infiltration (n = 16) and decreasing bone mineral density under anti-osteoporotic treatment (n = 2). The most frequent diagnoses besides osteoporosis were normal histology, borderline finding towards mild osteoporosis, and osteoporomalacia with relevant osteoidosis. In some cases, pathological findings in bone marrow were detected. In most cases (82/99), bone biopsy led to consequences in medical treatment. Following histopathological diagnosis, 16 patients did not receive any anti-osteoporotic treatment. In six patients, further diagnostic procedures were initiated because of bone histology. Bone biopsy was well tolerated and complications were rare and mild. In conclusion, despite all progress in non-invasive diagnostic procedures for metabolic bone diseases such as osteoporosis, there remains a small but significant subset of patients who may benefit from inclusion of bone biopsy into the diagnostic procedure.

[corrected] There are many drugs which can cause osteoporosis or at least favor its initiation. The effect of hormones and drugs with antihormonal activity, such as glucocorticoids and aromatase inhibitors, on initiation of osteoporosis is well known. In addition, proton pump inhibitors, glitazones and diuretics also influence the formation of osteoporosis. The results of currently available studies on the correlation between proton pump inhibitors, glitazones and diuretics on formation of osteoporosis were evaluated and summarized. Proton pump inhibitors and glitazones increase the risk for osteoporotic fractures. Loop diuretics may slightly increase fracture risk, whereas thiazides were shown to be osteoprotective by reducing fracture probability on a relevant scale. Proton pump inhibitors should not be prescribed without serious consideration and then only as long as necessary. Alternatively, the administration of the less effective H2 antagonists should be considered when possible due to the reduction of acid secretion. Because the long-term intake of thiazides is associated with a clinically relevant reduction in the risk of fractures and they are economic and well-tolerated, prescription can be thoroughly recommended within the framework of differential diagnostic considerations in an appropriate clinical context. The briefly increased risk of falling immediately after starting diuretic therapy is the only point which needs to be considered.

Growth hormone (GH) stimulates bone turnover. Deficiency of GH due to hypopituitarism is related to low bone mineral density and increased fracture risk. GH substitution increases and thus normalizes bone mineral density in these patients, which is one of a number of arguments for GH substitution in hypopituitarism. In contrast, a possible therapeutic use of GH in idiopathic osteoporosis and glucocorticoid-induced osteoporosis is speculative and not established. Reduction of osteoporosis risk is an argument brought up for a use of GH in healthy elderly persons (anti-aging medicine). However, since only very limited data are available yet, this cannot be based on scientific evidence, and there are important concerns about the safety of use of GH in healthy elderly persons.