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

Pregnancy and lactation, a challenge for the skeleton

In this review we discuss skeletal adaptations to the demanding situation of pregnancy and lactation. Calcium demands are increased during pregnancy and lactation, and this is effectuated by a complex series of hormonal changes. The changes in bone structure at the tissue and whole bone level observed during pregnancy and lactation appear to largely recover over time. The magnitude of the changes observed during lactation may relate to the volume and duration of breastfeeding and return to regular menses. Studies examining long-term consequences of pregnancy and lactation suggest that there are small, site-specific benefits to bone density, and that bone geometry may also be affected. Pregnancy- and lactation-induced osteoporosis (PLO) is a rare disease for which the pathophysiological mechanism is as yet incompletely known; here we discuss and speculate on the possible roles of genetics, oxytocin, sympathetic tone and bone marrow fat. Finally, we discuss fracture healing during pregnancy and lactation and the effects of estrogen on this process

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

Mechanisms of marrow adiposity and its implications for skeletal health

The bone marrow niche is composed of cells from hematopoietic and mesenchymal origin. Both require energy to power differentiation and these processes are intimately connected to systemic metabolic homeostasis. Glycolysis is the preferred substrate for mesenchymal stromal cells in the niche, although fatty acid oxidation and glutaminolysis are important during stage specific differentiation. Autophagy and lipophagy, in part triggered by adenosine monophosphate-activated protein kinase (AMPK), may also play an important but temporal specific role in osteoblast differentiation. Enhanced marrow adiposity is caused by clinical factors that are genetically, environmentally, and hormonally mediated. These determinants mediate a switch from the osteogenic to the adipogenic lineage. Preliminary evidence supports an important role for fuel utilization in those cell fate decisions. Although both the origin and function of the marrow adipocyte remain to be determined, and in some genetic mouse models high marrow adiposity may co-exist with greater bone mass, in humans changes in marrow adiposity are closely linked to adverse changes in skeletal metabolism. This supports an intimate relationship between bone and fat in the marrow. Future studies will likely shed more light on the relationship of cellular as well as whole body metabolism on the ultimate fate of bone marrow stromal cell

Bone as a regulator of glucose metabolism

For a long time the only functions attributed to the skeleton were locomotion and calcium storage. Over the last decade, this view has changed. Genetic studies in mice have shown that bone metabolism is regulated by the autonomic nervous system and interacts with energy metabolism and reproduction. Osteocalcin, one of the main organic ingredients of the bone matrix, was discovered to stimulate insulin production by the pancreas, as well as energy expenditure and insulin sensitivity. Administration of recombinant osteocalcin to mice on a high fat diet decreased weight gain and insulin resistance. These unanticipated results stimulated studies on osteocalcin and glucose metabolism in humans. This review will discuss these clinical studies and their perspective for the futur

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