Search tips
Search criteria

Results 1-10 (10)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
1.  New Insights into Osteoporosis: The Bone-Fat Connection 
Journal of internal medicine  2012;272(4):317-329.
Osteoporosis and obesity are chronic disorders that are increasing in prevalence. The pathophysiology of these diseases is multifactorial and includes genetic, environmental and hormonal determinants. Long considered as distinct disorders that rarely are found in the same individual, emerging evidence from basic and clinical studies support an important interaction between adipose tissue and the skeleton. Adiposity can influence bone remodeling through three possible mechanisms including secretion of cytokines that directly target bone, adipokines that influence the central nervous system thereby changing sympathetic impulses to bone, and paracrine influences on adjacent skeletal cells. This review will focus on our current understanding of bone-fat interactions and the clinical implications of recent studies linking obesity to osteoporosis.
PMCID: PMC3634716  PMID: 22702419
2.  The Consequences of GHRH-R Haplo-Insufficiency for Bone Quality and Insulin resistance 
Clinical endocrinology  2012;77(3):379-384.
Growth hormone (GH)/insulin like growth factor (IGF) axis and insulin are key determinants of bone remodeling. Homozygous mutations in the GH releasing hormone receptor (GHRHR) gene (GHRHR) are a frequent cause of genetic isolated GHD (IGHD). Heterozygosity for GHRHR mutation causes changes in body composition and possibly an increase in insulin sensitivity, but its effects on bone quality are still unknown. The objective of this study was to assess the bone quality and metabolism and its correlation with insulin sensitivity in subjects heterozygous for a null mutation in the GHRHR.
A cross-sectional study was performed on 76 normal subjects (68.4% females) (N/N) and 64 individuals (64.1% females) heterozygous for a mutation in the GHRHR (MUT/N). Anthropometric features, quantitative ultrasound (QUS) of the heel, bone markers (osteocalcin and CrossLaps), IGF-I, glucose, and insulin were measured and homeostasis model assessment of insulin resistance (HOMAIR) was calculated.
There were no differences in age or height between the two groups, but weight (p = 0.007) and BMI (p = 0.001) were lower in MUT/N. There were no differences in serum levels of IGF-I, glucose, T score, or absolute values of stiffness and osteocalcin, but insulin (p = 0.01), HOMAIR (p = 0.01) and CrossLaps (p = 0.01) were lower in MUT/N. There was no correlation between osteocalcin and glucose, osteocalcin and HOMAIR in the140 individuals as a whole or in the separate MUT/N or N/N groups.
The present study suggests that one allele mutation in the GHRHR gene has a greater impact on energy metabolism than on bone quality.
PMCID: PMC3272308  PMID: 21995288
Growth Hormone; Growth Hormone Deficiency; Osteoporosis; Bone Ultrasound; Bone Remodeling
3.  Vitamin D Safety and Requirements 
Vitamin D an ancient secosteroid is essential for mineral homeostasis, bone remodeling, immune modulation, and energy metabolism. Recently, debates have emerged about the daily vitamin D requirements for healthy and elderly adults, the safety and efficacy of long term supplementation and the role of vitamin D deficiency in several chronic disease states. Since this molecule acts as both a vitamin and a hormone, it should not be surprising that the effects of supplementation are multi-faceted and complex. Yet despite significant progress in the last decade, our understanding of vitamin D physiology and the clinical relevance of low circulating levels of this vitamin remains incomplete. The present review provides the reader with a comprehensive and up-to-date understanding of vitamin D requirements and safety. It also raises some provocative research questions.
PMCID: PMC3311750  PMID: 22179017
Vitamin D; diagnosis; treatment
4.  α1-Acid Glycoprotein Decreases Neutrophil Migration and Increases Susceptibility to Sepsis in Diabetic Mice 
Diabetes  2012;61(6):1584-1591.
The mechanisms underlying immune deficiency in diabetes are largely unknown. In the present study, we demonstrate that diabetic mice are highly susceptible to polymicrobial sepsis due to reduction in rolling, adhesion, and migration of leukocytes to the focus of infection. In addition, after sepsis induction, CXCR2 was strongly downregulated in neutrophils from diabetic mice compared with nondiabetic mice. Furthermore, CXCR2 downregulation was associated with increased G-protein–coupled receptor kinase 2 (GRK2) expression in these cells. Different from nondiabetic mice, diabetic animals submitted to mild sepsis displayed a significant augment in α1-acid glycoprotein (AGP) hepatic mRNA expression and serum protein levels. Administration of AGP in nondiabetic mice subjected to mild sepsis inhibited the neutrophil migration to the focus of infection, as well as induced l-selectin shedding and rise in CD11b of blood neutrophils. Insulin treatment of diabetic mice reduced mortality rate, prevented the failure of neutrophil migration, impaired GRK2-mediated CXCR2 downregulation, and decreased the generation of AGP. Finally, administration of AGP abolished the effect of insulin treatment in diabetic mice. Together, these data suggest that AGP may be involved in reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice.
PMCID: PMC3357278  PMID: 22415874
5.  Trabecular bone loss after administration of the second-generation antipsychotic risperidone is independent of weight gain 
Bone  2011;50(2):490-498.
Second generation antipsychotics (SGAs) have been linked to metabolic and bone disorders in clinical studies, but the mechanisms of these side effects remain unclear. Additionally, no studies have examined whether SGAs cause bone loss in mice. Using in vivo and in vitro modeling we examined the effects of risperidone, the most commonly prescribed SGA, on bone in C57BL6/J (B6) mice. Mice were treated with risperidone orally by food supplementation at a dose of 1.25 mg/kg daily for 5 and 8 weeks, starting at 3.5 weeks of age. Risperidone reduced trabecular BV/TV, trabecular number and percent cortical area. Trabecular histomorphometry demonstrated increased resorption parameters, with no change in osteoblast number or function. Risperidone also altered adipose tissue distribution such that white adipose tissue mass was reduced and liver had significantly higher lipid infiltration. Next, in order to tightly control risperidone exposure, we administered risperidone by chronic subcutaneous infusion with osmotic minipumps (0.5 mg/kg daily for 4 weeks) in 7 week old female B6 mice. Similar trabecular and cortical bone differences were observed compared to the orally treated groups (reduced trabecular BV/TV, and connectivity density, and reduced percent cortical area) with no change in body mass, percent body fat, glucose tolerance or insulin sensitivity. Unlike in orally treated mice, risperidone infusion reduced bone formation parameters (serum P1NP, MAR and BFR/BV). Resorption parameters were elevated, but this increase did not reach statistical significance. To determine if risperidone could directly affect bone cells, primary bone marrow cells were cultured with osteoclast or osteoblast differentiation media. Risperidone was added to culture medium in clinically relevant doses of 0, 2.5 or 25 ng/ml. The number of osteoclasts was significantly increased by addition in vitro of risperidone while osteoblast differentiation was not altered. These studies indicate that risperidone treatment can have negative skeletal consequences by direct activation of osteoclast activity and by indirect non-cell autonomous mechanisms. Our findings further support the tenet that the negative side effects of SGAs on bone mass should be considered when weighing potential risks and benefits, especially in children and adolescents who have not yet reached peak bone mass.
PMCID: PMC3261344  PMID: 21854880
6.  VDR Haploinsufficiency Impacts Body Composition and Skeletal Acquisition in a Gender-Specific Manner 
Calcified tissue international  2011;89(3):179-191.
The vitamin D receptor (VDR) is crucial for virtually all of vitamin D’s actions and is thought to be ubiquitously expressed. We hypothesized that disruption of one allele of the VDR gene would impact bone development and would have metabolic consequences. Body composition and bone mass (BMD) in VDR heterozygous (VDR HET) mice were compared to those obtained in male and female VDR KO and WT mice at 8 weeks of age. Male mice were also evaluated at 16 weeks, and bone marrow mesenchymal stem cell (MSC) differentiation was evaluated in VDR female mice. Additionally, female VDR HET and WT mice received intermittent PTH treatment or vehicle (VH) for 4 weeks. BMD was determined at baseline and after treatment. MRI was done in vivo at the end of treatment; μCT and bone histomorphometry were performed after killing the animals. VDR HET male mice had normal skeletal development until 16 weeks of age but showed significantly less gain in fat mass than WT mice. In contrast, female VDR HET mice showed decreased total-body BMD at age 8 weeks but ad a normal skeletal response to PTH. MSC differentiation was also impaired in VDR HET female mice. Thus, female VDR HET mice show early impairment in bone acquisition, while male VDR HET mice exhibit a lean phenotype. Our results indicate that the VDR HET mouse is a useful model for studying the metabolic and skeletal impact of decreased vitamin D sensitivity.
PMCID: PMC3157554  PMID: 21637996
Vitamin D; Parathyroid hormone; Body composition
7.  DXA, bioelectrical impedance, ultrasonography and biometry for the estimation of fat and lean mass in cats during weight loss 
Few equations have been developed in veterinary medicine compared to human medicine to predict body composition. The present study was done to evaluate the influence of weight loss on biometry (BIO), bioimpedance analysis (BIA) and ultrasonography (US) in cats, proposing equations to estimate fat (FM) and lean (LM) body mass, as compared to dual energy x-ray absorptiometry (DXA) as the referenced method. For this were used 16 gonadectomized obese cats (8 males and 8 females) in a weight loss program. DXA, BIO, BIA and US were performed in the obese state (T0; obese animals), after 10% of weight loss (T1) and after 20% of weight loss (T2). Stepwise regression was used to analyze the relationship between the dependent variables (FM, LM) determined by DXA and the independent variables obtained by BIO, BIA and US. The better models chosen were evaluated by a simple regression analysis and means predicted vs. determined by DXA were compared to verify the accuracy of the equations.
The independent variables determined by BIO, BIA and US that best correlated (p < 0.005) with the dependent variables (FM and LM) were BW (body weight), TC (thoracic circumference), PC (pelvic circumference), R (resistance) and SFLT (subcutaneous fat layer thickness). Using Mallows’Cp statistics, p value and r2, 19 equations were selected (12 for FM, 7 for LM); however, only 7 equations accurately predicted FM and one LM of cats.
The equations with two variables are better to use because they are effective and will be an alternative method to estimate body composition in the clinical routine. For estimated lean mass the equations using body weight associated with biometrics measures can be proposed. For estimated fat mass the equations using body weight associated with bioimpedance analysis can be proposed.
PMCID: PMC3413556  PMID: 22781317
8.  Bone mineral density and body composition in girls with idiopathic central precocious puberty before and after treatment with a gonadotropin-releasing hormone agonist 
Clinics  2012;67(6):591-596.
Idiopathic central precocious puberty and its postponement with a (gonadotropin-releasing hormone) GnRH agonist are complex conditions, the final effects of which on bone mass are difficult to define. We evaluated bone mass, body composition, and bone remodeling in two groups of girls with idiopathic central precocious puberty, namely one group that was assessed at diagnosis and a second group that was assessed three years after GnRH agonist treatment.
The precocious puberty diagnosis and precocious puberty treatment groups consisted of 12 girls matched for age and weight to corresponding control groups of 12 (CD) and 14 (CT) girls, respectively. Bone mineral density and body composition were assessed by dual X-ray absorptiometry. Lumbar spine bone mineral density was estimated after correction for bone age and the mathematical calculation of volumetric bone mineral density. CONEP: CAAE-0311.0.004.000-06.
Lumbar spine bone mineral density was slightly increased in individuals diagnosed with precocious puberty compared with controls; however, after correction for bone age, this tendency disappeared (CD = -0.74±0.9 vs. precocious puberty diagnosis = -1.73±1.2). The bone mineral density values of girls in the precocious puberty treatment group did not differ from those observed in the CT group.
There is an increase in bone mineral density in girls diagnosed with idiopathic central precocious puberty. Our data indicate that the increase in bone mineral density in girls with idiopathic central precocious puberty is insufficient to compensate for the marked advancement in bone age observed at diagnosis. GnRH agonist treatment seems to have no detrimental effect on bone mineral density.
PMCID: PMC3370310  PMID: 22760897
Precocious puberty; Osteoporosis in children; Bone density; Gonadotropin-Releasing Hormone
9.  Novel Insights into the Relationship between Diabetes and Osteoporosis 
Only three decades ago adipose tissue was considered inert with little relationship to insulin resistance. Similarly bone has long been thought purely in its structural context. In the last decade, emerging evidence has revealed important endocrine roles for both bone and adipose tissue. The interaction between these two tissues is remarkable. Bone marrow mesenchymal stem cells give rise to both osteoblasts and adipocytes. Leptin and adiponectin, two adipokines secreted by fat tissue, control energy homeostasis, but also have complex actions on the skeleton. In turn, the activities of bone cells are not limited to their bone remodeling activities, but also to modulation of adipose sensitivity and insulin secretion. This review will discuss these new insights linking bone remodeling to the control of fat metabolism and the association between diabetes mellitus and osteoporosis.
PMCID: PMC3259009  PMID: 20938995
Osteoporosis; diabetes mellitus; obesity; leptin; osteocalcin
10.  Consequences of lifetime isolated growth hormone (GH) deficiency and effects of short-term GH treatment on bone in adults with a mutation in the GHRH-receptor gene 
Clinical endocrinology  2008;70(1):35-40.
Growth hormone (GH) influences bone mass maintenance. However, the consequences of lifetime isolated GH deficiency on bone are not well established. We assessed the bone status and the effect of 6 months of GH replacement in GH-naïve adults with IGHD due to a homozygous mutation of the GHRH-R gene.
Patients and methods
We studied 20 individuals (10 men) with IGHD at baseline, after six months of depot GH treatment, and six and 12 months after GH discontinuation. Quantitative heel ultrasound (QUS) was performed and serum osteocalcin (OC) and cross-linking telopeptide of type I collagen (ICTP) were measured. QUS was also performed at baseline and one year later in a group of 20 normal control individuals (CO), who did not receive GH treatment.
At baseline, the IGHD group had lower QUS than CO (T-score: IGHD = -1.15 ± 0.9 vs. C = -0.07 ± 0.9 p< 0.001). GH treatment improved this parameter, with improvement persisting for one year post-treatment (12 months: IGHD = -0.59 ± 0.9 p< 0.05). GH also caused an increase in serum OC (baseline vs. pGH, p< 0.001) and ICTP (baseline vs. pGH p< 0.01). The increase in OC was more marked during treatment and its reduction was slower after GH discontinuation than in ICTP.
These data suggest that lifetime severe IGHD is associated with significant reduction in QUS parameters, which are partially reverse by short-term depot GH treatment which induces a biochemical pattern of bone anabolism that persists for at least 6 months after treatment discontinuation.
PMCID: PMC2615796  PMID: 18494866
growth hormone deficiency; bone density; bone ultrasound; IGF-I

Results 1-10 (10)