Bone Resorption Is Increased in Pheochromocytoma Patients and Normalizes following Adrenalectomy

Context: The sympathetic nervous system (SNS) controls bone turnover in rodents, but it is uncertain whether a similar role for the SNS exists in humans. Pheochromocytomas are catecholamine-producing neuroendocrine tumors. Because catecholamines are the neurotransmitters of the SNS, we hypothesized that pheochromocytoma patients have increased bone turnover. Objective: Our objective was to compare bone turnover in pheochromocytoma patients and controls. Design and Setting: This retrospective case-control study was performed at the Endocrine Department of the Academic Medical Center of the University of Amsterdam in The Netherlands from 2007 until 2011. Patients: All patients were screened for pheochromocytoma. Cases (n = 21) were identified by 24-h urinary excretion of fractionated metanephrines above the institutional reference value and confirmed by histology after adrenalectomy. All patients screened and diagnosed as not having pheochromocytoma served as controls (n = 126). Main Outcome Measure: The difference in bone turnover markers C-terminal cross-linking telopeptides of collagen type I (CTx) and procollagen type 1 N propeptide (P1NP) between cases and controls was the main outcome measure. Results: CTx concentrations were higher in cases [343 ng/liter; interquartile range (IQR), 295 ng/liter] than in controls (232 ng/liter; IQR, 168 ng/liter; P <0.001) and decreased after adrenalectomy [before, 365 ng/liter (IQR, 450 ng/liter); after, 290 ng/liter (IQR, 241 ng/liter); P = 0.044]. The effect remained after adjustment for possible confounders. P1NP concentrations did not differ. Conclusions: This study shows that pheochromocytoma patients have increased bone resorption, which normalizes after adrenalectomy. This finding supports the concept of regulation of bone remodeling by the SNS in humans. (J Clin Endocrinol Metab 97: E2093-E2097, 2012

Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density

Summary: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts. Introduction: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism. Methods: We performed nested case–control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800–829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961). Results: Meta-analysis of the two nested case–control studies showed pooled odds ratios of 0.98 (0.91–1.05, p = 0.52), 1.04 (0.97–1.12, p = 0.28), and 1.16 (0.83–1.62, p = 0.38) for the associations betwee

SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Neuroendocrine regulation of human bone metabolism

The skeleton is perhaps the most multifunctional part of our body. It not only provides outer strength, a protective shell and enables locomotion, but it also hosts the bone marrow and serves many metabolic and endocrine functions. This thesis investigates two aspects of human bone metabolism, firstly the role of the sympathetic nervous system (SNS) in human bone metabolism and hematopoiesis and secondly the hormonal control and activity of bone and bone marrow. In the first part of this thesis we used a clinical approach, a genetic approach, and a pharmacological approach to study the SNS and bone metabolism. We showed that bone resorption is increased in pheochromocytoma patients as a model of sympathetic overstimulation and decreases following adrenalectomy. But we did not find an association between polymorphisms in the beta-2 adrenergic receptor and fracture risk or bone mineral density in two large, Dutch cohorts and a large international consortium. Furthermore, there was no effect of a beta-adrenergic agonist and an antagonist on bone turnover or circulating CD34+ hematopoietic stem cells in healthy, postmenopausal women in a randomized controlled trial. In the second part of this thesis we described the variation in bone marrow fat during the menstrual cycle and we showed a large decrease in bone marrow fat during two weeks of estradiol treatment in postmenopausal women. Finally, we put into clinical perspective the evidence concerning the interaction between human bone metabolism and glucose metabolism

The Effect of Roux-en-Y Gastric Bypass on Bone Marrow Adipose Tissue and Bone Mineral Density in Postmenopausal, Nondiabetic Women

Objectives This study aimed to determine the effect of bariatric surgery-induced weight loss on bone marrow adipose tissue (BMAT) and bone mineral density (BMD) in postmenopausal, nondiabetic women.Methods A total of 14 postmenopausal, nondiabetic women with obesity who were scheduled for laparoscopic Roux-en-Y gastric bypass surgery (RYGB) were included in this study. Vertebral bone marrow fat signal fraction was determined by quantitative chemical shift magnetic resonance imaging, and vertebral volumetric BMD (vBMD) was determined by quantitative computed tomography before surgery and 3 and 12 months after surgery. Data were analyzed by linear mixed model.Results Body weight [mean (SD)] decreased after surgery from 108 (13) kg at baseline to 89 (12) kg at 3 months and 74 (11) kg at 12 months (P < 0.001). BMAT decreased after surgery from 51% (8%) at baseline to 50% (8%) at 3 months and 46% (7%) at 12 months (P = 0.004). vBMD decreased after surgery from 101 (26) mg/cm(3) at baseline to 94 (28) mg/cm(3) at 3 months (P = 0.003) and 94 (28) mg/cm(3) at 12 months (P = 0.035). Changes in BMAT and vBMD were not correlated (rho = -0.10 and P = 0.75). Calcium and vitamin D concentrations did not change after surgery.Conclusions RYGB decreases both BMAT (after 12 months) and vBMD (both after 3 months and 12 months) in postmenopausal, nondiabetic women. Changes in BMAT and vBMD were not correlated. These findings suggest that BMAT does not contribute to bone loss following RYGB.Diabetes mellitus: pathophysiological changes and therap

Voluntary technological disclosure as an efficient knowledge management device: An empirical study

This paper investigates three questions related to endogenous information and knowledge disclosure by firms: Which industry sectors are more apt to disclose information and knowledge? Why is such knowledge released? Is knowledge disclosure an efficient strategy? An empirical analysis on four French data sets that focus on appropriation, the practices of innovation, and the related payoffs suggests answers to these questions. A firm with high R&D intensity, from a high-tech sector, participating in R&D partnerships is found to be more likely to engage in disclosure. Firms in the sample were found to 'leak' their knowledge to public laboratories to a greater degree than to other private sector firms. Leakage also was found to be associated with improved innovation performance. This research helps broaden the literature on knowledge management practices to include not only the pursuit of formal intellectual property rights such as patents but also less formal inter-organizational knowledge transmission mechanisms.Innovation, Endogenous spillovers, Cooperation, Appropriation,

The effect of raloxifene on bone marrow adipose tissue and bone turnover in postmenopausal women with osteoporosis

Bone and mineral researc