leptin and Bone-Diseases--Metabolic

Premature infants have an increased risk of osteopenia due to limited bone mass accretion in utero and a greater need for bone nutrients. Until recently, most efforts to prevent osteopenia of prematurity focused on nutritional changes. Recent studies indicate that passive range-of-motion exercise of the extremities may lead to beneficial effects on body weight, increased bone mineralization, increased bone formation markers and leptin levels, and attenuation of the natural postnatal decline in bone speed of sound. These results suggest that exercise may play an important role in the prevention and treatment of osteopenia of prematurity. This review summarizes our current knowledge on the role of exercise in the prevention and treatment of osteopenia of prematurity.

Topics: Bone Density; Bone Diseases, Metabolic; Exercise Therapy; Humans; Infant, Newborn; Infant, Premature; Leptin; Osteogenesis

Leptin was initially best known for its role in energy homeostasis and regulation of energy expenditure. In the past few years we have realized that leptin also plays a major role in neuroendocrine regulation and bone metabolism. Here, we review the literature the indirect and direct pathways through which leptin acts to influence bone metabolism and discuss bone abnormalities related to leptin deficiency in both animal and human studies. The clinical utility of leptin in leptin deficient individuals and its potential to improve metabolic bone disease are also discussed. We are beginning to understand the critical role leptin plays in bone metabolism; future randomized studies are needed to fully assess the potential and risk-benefit of leptin's use in metabolic bone disease particularly in leptin deficient individuals.

Topics: Animals; Bone and Bones; Bone Diseases, Metabolic; Humans; Leptin; Neurosecretory Systems

Anemia, dyslipidemia, malnutrition, together with mineral and bone disorders are common complications in patients with chronic kidney disease (CKD). All are associated with increased risk of mortality. Leptin is a small peptide hormone that is mainly but not exclusively produced in adipose tissue. It is also secreted by normal human osteoblasts, subchondral osteoblasts, placental syncytiotrophoblasts, and the gastric epithelium. Leptin binds to its receptors in the hypothalamus to regulate bone metabolism and food intake. Leptin also has several other important metabolic effects on peripheral tissues, including the liver, skeletal muscle, and bone marrow. Leptin is cleared principally by the kidney. Not surprisingly, serum leptin appears to increase concurrently with declines in the glomerular filtration rate in patients with CKD. A growing body of evidence suggests that leptin might be closely related to hematopoiesis, nutrition, and bone metabolism in CKD patients. Results are conflicting regarding leptin in patients with CKD, in whom both beneficial and detrimental effects on uremia outcome are found. This review elucidates the discovery of leptin and its receptors, changes in serum or plasma leptin levels, the functions of leptin, relationships between leptin and the complications mentioned above, and pharmaceutical interventions in serum leptin levels in patients with CKD.

Topics: Anemia; Bone and Bones; Bone Diseases, Metabolic; Dyslipidemias; Hematopoiesis; Humans; Leptin; Malnutrition; Nutritional Status; Receptors, Leptin; Renal Insufficiency, Chronic

The prevalence of anorexia nervosa has increased in recent years and a large proportion of patients with this disorder have low bone density at diagnosis and, therefore, an increased risk of early and late fractures. The mechanism of bone loss in anorexia nervosa is not well understood, yet it likely includes hypogonadism, alterations of the GH-IGF-1 axis and hypercortisolism. DEXA is the most effective tool for assessing and monitoring bone density in these patients, and it is important to improve or at least stabilize bone metabolism in those with low bone mass. No agent has yet been proven to be effective in improving bone density. However, sustained weight recovery and menses besides an adequate intake of calcium and vitamin D are recommended to optimize the conditions in which bone mass accrual may occur.

Topics: Adipose Tissue; Adolescent; Adult; Anorexia Nervosa; Bone and Bones; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcium; Cushing Syndrome; Fractures, Bone; Gonadal Steroid Hormones; Humans; Hypogonadism; Intercellular Signaling Peptides and Proteins; Leptin; Male; Minerals; Osteoporosis; Vitamin D; Young Adult

Anorexia nervosa (AN), a disorder characterized by the refusal to sustain a healthy weight, has the highest mortality of any psychiatric disorder. This review presents a model of AN that ties together advances in our understanding of how leptin, serotonin, and hypogonadism are brought about in AN and how they influence bone mass. Serotonin (5-hydroxytryptamine) is a key regulator of satiety and mood. The primary disturbance in AN results from alterations in serotonin signaling. AN patients suffer from serotonergic hyperactivity of Htr1a-dependent pathways that causes dysphoric mood and promotes restrictive behavior. By limiting carbohydrate ingestion, anorexics decrease their serotonin levels. Reduced serotonergic signaling in turn suppresses appetite through Htr1a/2b, decreases dysphoric mood through Htr1a/2a, and activates the sympathetic nervous system (SNS) through Htr2c receptors in the ventromedial hypothalamus. Activation of the SNS decreases bone mass through β2-adrenergic signaling in osteoblasts. Additional topics reviewed here include osteoblastic feedback of metabolism in anorexia, mechanisms whereby dietary changes exacerbate bone loss, the role of caloric restriction and Sirt1 in bone metabolism, hypothalamic hypogonadism's effects on bone mass, and potential treatments.

Topics: Animals; Anorexia Nervosa; Bone Density; Bone Diseases, Metabolic; Bone Resorption; Humans; Leptin; Serotonin; Signal Transduction; Sympathetic Nervous System

Clinically, fatty marrow, accumulation of adipocytes in bone marrow, is often observed in the patients who manifest bone diseases such as osteoporosis. Since adipocytes and osteoblasts are differentiated from mesenchymal stem cells, it would be clinically and biologically important to understand regulatory mechanisms of the balance between adipogenesis and osteoblastogenesis. Recently, experimental findings indicated the involvement of adipokines including leptin and adiponectin in bone metabolisms. Thus, adipocytes appear to play a role in regulation of bone metabolisms.

Topics: Adipocytes; Adipogenesis; Adiponectin; Animals; Bone and Bones; Bone Diseases, Metabolic; Bone Morphogenetic Proteins; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; High Mobility Group Proteins; Humans; Leptin; Mesenchymal Stem Cells; Osteoblasts; PPAR gamma; SOX9 Transcription Factor; Transcription Factors

Amenorrhea is a hallmark sign of anorexia nervosa. Its cause is multifactorial and its resolution necessitates treatment of the underlying eating disorder. The neuroendocrine changes associated with menstrual abnormalities in underweight and weight recovered anorexia nervosa, recent research on osteopenia, and treatment recommendations are addressed.

Topics: Adolescent; Adult; Anorexia Nervosa; Bone Density; Bone Diseases, Metabolic; Exercise; Female; Humans; Hypothalamic Diseases; Leptin; Menstruation Disturbances; Risk Factors

Osteopenia and excess adiposity occur following treatment of childhood acute lymphoblastic leukaemia (ALL) and the use of cranial irradiation is thought to be a significant contributory factor. Hyperleptinaemia has also been demonstrated following cessation of treatment for childhood ALL. Therefore a prospective study was undertaken to evaluate serial changes in percentage bone mineral content (BMC), adiposity and serum leptin concentrations during 2 years of treatment of children with ALL with chemotherapy but without cranial irradiation.. Only patients treated using the MRC ALL 97/ALL 97 (modified 99) protocols for childhood ALL were eligible for entry into the study. A total of 14 patients (seven male, with a median age of 7.5 years (range 3.4-16.7 years) were recruited. Serial dual energy X-ray absorptiometry (DEXA) scanning was undertaken at diagnosis and during two years of treatment. Serum leptin concentrations were determined at the same time as the scans.. Reductions in %BMC were observed at the hip and lumbar spine by 12 months (P < 0.01) and remained low after 24 months of treatment. Subanalysis of %BMC measurements at the hip demonstrated a greater reduction in %BMC at the trochanteric region compared to the femoral neck. The percentage corrected fat mass increased from 6 months whereas the body mass index (BMI) standard deviation score (SDS) was increased after 24 months of treatment (P < 0.05). Serum leptin concentrations increased following 24 months of therapy (P < 0.05).. Children treated for ALL with contemporary regimens have a predisposition to osteopenia, excess adiposity and hyperleptinaemia during treatment without cranial irradiation administration. We speculate that in addition to glucocorticoid administration, leptin resistance may account in part for these observations.

Topics: Adolescent; Bone Diseases, Metabolic; Child; Child, Preschool; Female; Humans; Leptin; Male; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies

Animal studies provide strong evidence that the CNS directly regulates bone remodeling through the actions of the hypothalamus via two distinct pathways, the neural (mediated by leptin) arm and neurohumoral (mediated by neurohormones and growth factors) arm. The impact of AD on central regulatory mechanisms of bone mass is not known.. To test a model that assesses the relationship between hypothalamic atrophy and bone loss in Alzheimer's disease (AD) and potential mediation through neural (leptin) and neurohumoral (insulin-like growth factor -1, IGF-1) mechanisms.. AD-related hypothalamic structural change alters neural and neurohumoral regulatory systems of bone remodeling and contributes to bone loss in early AD.. A secondary data analysis of data obtained in a two-year longitudinal study with path analysis and longitudinal mediation modeling.. The data were collected as a part of the University of Kansas Brain Aging Project, a two-year observational study of 71 older adults with early stage AD and 69 non-demented controls.. Demographic characteristics and measures of bone density, body composition, and hypothalamic volume, serum levels of leptin, growth hormone, and IGF-1 were collected.. Hypothalamic atrophy and bone loss were observed in AD group and were associated. Data modeling suggests that bone loss may precede measurable changes in the brain. Leptin increased over two years in AD and the increase in leptin was associated with hypothalamic atrophy. However, changes in leptin or IGF-1 levels did not mediate the relationship between hypothalamic atrophy and bone loss.. This study extends previous findings by suggesting that bone loss in AD may be related to neurodegenerative changes (atrophy) in the hypothalamus. Further studies are needed to explore the role of brain atrophy and mediating mechanisms in bone loss. Further exploring temporal relationship between bone loss and AD may have an important diagnostic value.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Animals; Atrophy; Body Composition; Bone Density; Bone Diseases, Metabolic; Brain; Case-Control Studies; Central Nervous System; Female; Human Growth Hormone; Humans; Hypothalamus; Insulin-Like Growth Factor I; Leptin; Life Style; Longitudinal Studies; Male; Models, Statistical

To evaluate the potential bone defect in neuromuscular diseases, we conducted a longitudinal study including three groups of patients: 14 Duchenne muscular dystrophies (DMD) and 2 limb-girdle muscular dystrophies (LGMD); 3 Becker muscular dystrophies (BeMD) and 7 spinal muscular atrophies (SMA). Yearly osteodensitometries assessed body composition and bone mineral density (BMD) associated with bone markers and leptin. Along the 7-year study, 107 osteodensitometries showed that bone status evolved to osteopenia in most patients except BeMD. When analyzing the crude values, BMD improved with age in BeMD and SMA but not in DMD/LGMD. The correlation using the Z-scores displayed a decrease in BMD with age in DMD/LGMD for all regions, in SMA at total body less head, whereas BMD increased in BeMD at lumbar spine. As observed in healthy persons, muscular mass and bone tissue were significantly correlated. Glucocorticoids were deleterious on trabecular and cortical bone. Leptin was high in most patients and correlated to fat mass and bone parameters. This study confirms a secondary bone defect in neuromuscular diseases, further confirming the functional relationship between bone and muscle and arguing for regular bone follow-up in patients to prevent fracture risk. Adipose tissue seems to interfere with bone remodeling in neuromuscular diseases.

Topics: Absorptiometry, Photon; Adolescent; Adult; Bone Density; Bone Diseases, Metabolic; Child; Child, Preschool; Female; Humans; Leptin; Longitudinal Studies; Male; Muscular Atrophy, Spinal; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Duchenne; Young Adult

Roux-en-Y gastric bypass (RYGB) has proved successful in attaining sustained weight loss but may lead to metabolic bone disease. To assess impact on bone mass and structure, we measured a real bone mineral density at the hip and spine by dual-energy X-ray absorptiometry, and volumetric BMD (vBMD) and bone microarchitecture at the distal radius and tibia by high-resolution peripheral quantitative CT in 25 morbidly obese subjects (15 females, 10 males) at 0, 12 and 24 months after RYGB. Bone turnover markers (BTMs), calciotropic and gut hormones and adipokines were measured at the same time points.. After a 24.1% mean weight loss from baseline to month 12 (. Despite weight stabilization and maintenance of metabolic parameters, bone loss and deterioration in bone strength continued and were substantial in the second year. The clinical importance of these changes in terms of increased risk of developing osteoporosis and fragility fractures remain an important concern.

Topics: Absorptiometry, Photon; Adiponectin; Adult; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Collagen Type I; Female; Follicle Stimulating Hormone; Gastric Bypass; Hip Joint; Humans; Insulin; Leptin; Longitudinal Studies; Lumbar Vertebrae; Luteinizing Hormone; Male; Middle Aged; Obesity, Morbid; Osteoporosis; Parathyroid Hormone; Peptide Fragments; Peptides; Postoperative Complications; Procollagen; Radius; Tibia; Tomography, X-Ray Computed; Vitamin D; Weight Loss

The prospective study assessed the influence of serum leptin levels on markers of bone metabolism and bone mineral density in 2-year-old infants born preterm. A total of 57 randomized preterm Caucasian newborns (32nd-37th week of gestation) were included in the study. Bone metabolism markers were measured every 6 months. The infants were monitored prospectively up to the age of 2 years. When the infants turned 2 years of age, they were investigated by dual energy X-ray absorptiometry (lumbar spine). The median cord blood leptin levels was 3.07 μg/L. The median leptin level during check-ups before 2 years of age was 9.96 μg/L. The other laboratory markers were within the normal ranges for that age. The bone mineral density reached, on average, 0.410 g/cm2. Lower leptin levels in the cord blood and in the serum of preterm infants do not influence bone mineral density during the first 2 years of life.

Topics: Absorptiometry, Photon; Biomarkers; Body Mass Index; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Child, Preschool; Female; Fetal Blood; Humans; Infant; Infant, Newborn; Infant, Premature; Leptin; Male; Prospective Studies

Adipokines and ghrelin exert well-documented effects on energy expenditure and glucose metabolism. Experimental data also support a role in bone metabolism, although data from clinical studies are conflicting. The purpose of this cross-sectional study was to investigate the association of serum concentrations of leptin, adiponectin and ghrelin with bone mineral density (BMD) in post-menopausal women.. BMD in lumbar spine and femoral neck, and circulating leptin, adiponectin and ghrelin concentrations were measured in 110 healthy post-menopausal women. Patients with secondary causes of osteoporosis were excluded.. Osteoporosis was diagnosed in 30 (27%) women and osteopenia in 54 (49%). Serum leptin concentrations were positively correlated with both lumbar spine (r=0.343, p<0.01) and femoral neck BMD (r=0.370, p<0.01). Adiponectin concentrations were negatively associated with BMD at both sites (r=-0.321, p<0.01 and r=-0.448, p<0.01 respectively). No significant correlation between ghrelin concentrations and BMD was found. Osteoporotic women had lower body weight, body mass index (BMI) and leptin concentrations, but higher adiponectin concentrations compared with non-osteoporotic women. In multivariate stepwise regression analysis, the association of adiponectin concentrations with BMD remained significant only for femoral neck, after adjustment for body weight or BMI.. An inverse association between adiponectin and femoral neck BMD was found in post-menopausal women, independently of body weight. The positive association between leptin and BMD was dependent on body weight, whereas no effect of ghrelin on BMD was evident.

Topics: Adiponectin; Aged; Aged, 80 and over; Body Mass Index; Body Weight; Bone Density; Bone Diseases, Metabolic; Cross-Sectional Studies; Female; Femur Neck; Ghrelin; Humans; Leptin; Lumbar Vertebrae; Middle Aged; Osteoporosis; Postmenopause

Energy restriction causes bone loss, increasing stress fracture risk. The impact of exercise during energy restriction on bone and endocrine factors is examined. Exercise with energy restriction did not influence endocrine factors, but did mitigate some bone loss seen with energy restriction in sedentary rats.. Chronic dietary energy restriction (ER) leads to bone loss and increased fracture risk. Strictly controlled trials of long-term ER with and without vigorous exercise are required to determine whether exercise loading can counterbalance ER-induced bone loss. The aim of this current project is to elucidate the impact of exercise and ER on bone mass, estrogen status, and metabolic hormones.. Twenty-four virgin female Sprague-Dawley rats (n = 8/group) were divided into three groups-ad libitum fed + exercise (Adlib + EX), 40 % energy restricted + exercise (ER + EX), and 40 % energy restricted + sedentary (ER + SED). Energy availability between ER groups was equal. Treadmill running was performed 4 days/week at 70 % VO2max for 12 weeks.. Fat and lean mass and areal bone mineral density (aBMD) were lower after 12 weeks (p < 0.05) for ER + EX vs Adlib + EX, but ER + EX aBMD was higher than ER + SED (p < 0.0001). Serum leptin and a urinary estrogen metabolite, estrone-1-glucuronide (E1G), were lower at week 12 (p = 0.0002) with ER, with no impact of exercise. Serum insulin-like growth factor I (IGF-I) declined (p = 0.02) from baseline to week 12 in both ER groups. ER + EX exhibited higher cortical volumetric bone mineral density (vBMD) at the midshaft tibia (p = 0.006) vs ER + SED.. Exercise during ER mitigated some, but not all, of the bone loss observed in sedentary ER rats, but had little impact on changes in urinary E1G and serum IGF-I and leptin. These data highlight the importance of both adequate energy intake and the mechanical loading of exercise in maintaining bone mass.

Topics: Animals; Bone Density; Bone Diseases, Metabolic; Caloric Restriction; Estrogens; Female; Insulin-Like Growth Factor I; Leptin; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley

The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity. We found that mice with Ucp2 gene deletion, in which AgRP neuronal function was impaired, were osteopenic. This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of Sirt1 (AgRP-Sirt1(-/-)), mice also developed reduced bone mass. No impact of leptin receptor deletion in AgRP neurons was found on bone homeostasis. Suppression of sympathetic tone in AgRP-Sirt1(-/-) mice reversed osteopenia in transgenic animals. Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin action.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Bone Density; Bone Diseases, Metabolic; Femur; Gene Expression Regulation; Homeostasis; Hypothalamus; Ion Channels; Leptin; Male; Mice; Mice, Knockout; Mitochondrial Proteins; Neurons; Norepinephrine; Phenotype; Propranolol; Receptors, Adrenergic, beta; Receptors, Leptin; Signal Transduction; Sirtuin 1; Tibia; Uncoupling Protein 2

Osteoporosis and overweight/obesity constitute major worldwide public health burdens that are associated with aging. A high proportion of women develop osteoporosis and increased intraabdominal adiposity after menopause. which leads to bone fractures and metabolic disorders. There is no efficient treatment without major side effects for these 2 diseases. We previously showed that the administration of oxytocin (OT) normalizes ovariectomy-induced osteopenia and bone marrow adiposity in mice. Ovariectomized mice, used as an animal model mimicking menopause, were treated with OT or vehicle. Trabecular bone parameters and fat mass were analyzed using micro-computed tomography. Herein, we show that this effect on trabecular bone parameters was mediated through the restoration of osteoblast/osteoclast cross talk via the receptor activator of nuclear factor-κB ligand /osteoprotegerin axis. Moreover, the daily administration of OT normalized body weight and intraabdominal fat depots in ovariectomized mice. Intraabdominal fat mass is more sensitive to OT that sc fat depots, and this inhibitory effect is mediated through inhibition of adipocyte precursor's differentiation with a tendency to lower adipocyte size. OT treatment did not affect food intake, locomotors activity, or energy expenditure, but it did promote a shift in fuel utilization favoring lipid oxidation. In addition, the decrease in fat mass resulted from the inhibition of the adipose precursor's differentiation. Thus, OT constitutes an effective strategy for targeting osteopenia, overweight, and fat mass redistribution without any detrimental effects in a mouse model mimicking the menopause.

Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Bone Diseases, Metabolic; Cell Culture Techniques; Coculture Techniques; Disease Models, Animal; Female; Leptin; Lipids; Menopause; Mice; Mice, Inbred C57BL; Osteoblasts; Osteoclasts; Osteoporosis; Ovariectomy; Oxygen; Oxytocin; Weight Gain; X-Ray Microtomography

To understand, in greater detail, the molecular mechanisms regulating the complex relationship between mechanical strain and alveolar bone metabolism during orthodontic treatment, passive cross-arch palatal springs were bonded to the maxillary molars of 6-wk-old rats, which were killed after 4 and 8 d. Outcome measures included serum assays for markers of bone formation and resorption and for the multifunctional hormone leptin, and histomorphometry of the inter-radicular bone. The concentration of the bone-formation marker alkaline phosphatase (ALP) was significantly reduced at both time points in the appliance group, accompanied by a 50% reduction in inter-radicular bone volume; however, osteocalcin (bone Gla protein) levels remained unaffected. Bone collagen deoxypyridinoline (DPD) crosslinks increased 2.3-fold at 4 d only, indicating a transient increase in bone resorption; in contrast, the level of the osteoclast-specific marker, tartrate-resistant acid phosphatase 5b (TRACP 5b), was unchanged. Leptin levels closely paralleled ALP reductions at both time points, suggesting an important role in the mechanostat negative-feedback loop required to normalize bone mass. These data suggest that an orthodontic appliance, in addition to remodeling the periodontal ligament (PDL)-bone interface, may exert unexpected side-effects on the tooth-supporting alveolar bone, and highlights the importance of recognizing that bone strains can have negative, as well as positive, effects on bone mass.

Topics: Acid Phosphatase; Alkaline Phosphatase; Alveolar Process; Amino Acids; Animals; Biomarkers; Bone Diseases, Metabolic; Bone Resorption; Enzyme-Linked Immunosorbent Assay; Isoenzymes; Leptin; Male; Orthodontic Appliances; Osteocalcin; Rats; Rats, Wistar; Tartrate-Resistant Acid Phosphatase

Leptin is the protein product of the obesity gene, which is produced in fat tissue. It was originally thought to be involved only in the regulation of food intake and energy balance. We aimed to investigate the relationship of serum leptin levels with bone mineral density (BMD) and biochemical markers of bone turnover in patients on hemodialysis (HD). This study included 72 patients (43 males and 29 females), whose mean age was 55.1 ± 11.4 years, mean body mass index was 23.13 ± 2.75 kg/m 2 and mean duration on HD was 5 ± 3.4 years. The BMD values were calculated using dual-energy X-ray absorptiometry (DEXA) at the femoral neck and lumbar spine. Blood samples were taken for leptin, intact parathyroid hormone (I-PTH), bone alkaline phosphatase (BAP), calcium (Ca), phosphate (P) and albumin. The leptin levels were higher in females than in males (22.3 ± 19.6 vs 20.8 ± 23), but this difference was not significant. The serum leptin level had a strong positive correlation with Ca levels in the female patients (r = 0.659 and P = 0.01) and a negative correlation with albumin levels (r = -0.461 and P = 0.01). No correlation was found with age, BMI, duration on dialysis, BMD and serum levels of PTH, BAP and P for the entire patient group or either gender separately. The serum leptin level was significantly lower in females with PTH >300 pg/mL when compared with patients with PTH = 100-300 pg/mL (86 ± 85 vs 47 ± 48) (P = 0.011).Women with BAP <300 IU/L had significantly higher serum leptin than those with BAP 300-600 IU/L (P = 0.024). Women with Ca <8.5 mg/dL had significantly lower serum leptin levels compared with those with Ca levels of 8.5-10.5 mg/dL (P = 0.011). There was no significant difference between the two genders among variables such as age, BMI, duration on dialysis, serum leptin, I-PTH, Ca, P, BAP, albumin and BMD of the femoral neck and lumbar spine.

Topics: Absorptiometry, Photon; Adult; Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Bone Density; Bone Diseases, Metabolic; Cross-Sectional Studies; Female; Femur Neck; Follow-Up Studies; Humans; Incidence; Iran; Kidney Failure, Chronic; Leptin; Lumbar Vertebrae; Male; Middle Aged; Obesity; Parathyroid Hormone; Prognosis; Renal Dialysis; Retrospective Studies

A high prevalence of bone loss is observed in patients with inflammatory bowel disease (IBD). Leptin, ghrelin, insulin-like growth factor (IGF)-1, and IGF binding protein (IGFBP)-3 have been suggested to interfere in the bone metabolism. The aim of this study was to investigate the role of these peptides in the development of osteoporosis in IBD.. One hundred and eighteen consecutive IBD patients were included. All patients underwent bone densitometry by dual energy x-ray absorptiometry at the femoral neck and lumbar spine levels. Serum samples were collected from all patients and analyzed for concentrations of the aforementioned peptides by radioimmunoassay.. Forty (33.9%) patients were normal, 55 (46.6%) were osteopenic, and 23 (19.5%) were osteoporotic. Positive statistically significant correlations were found between body mass index (BMI), leptin, IGFBP-3 levels, and the bone mineral density (BMD) of the femoral neck and lumbar spine. Moreover, an inverse statistically significant correlation was found between BMD of the femoral neck and the lumbar spine, and age, duration of the disease, and ghrelin levels. Multivariate analysis revealed that the most significant factors associated with the BMD were age and BMI. A weak but statistically significant correlation was found between IGFBP-3 and femoral neck BMD (P=0.045) and between ghrelin and spine BMD (P=0.039). No correlation was observed between leptin and BMD.. Low BMI is the most important independent risk factor for osteoporosis in IBD patients. There is no independent influence of leptin but ghrelin and IGFBP-3 may play a role in the bone metabolism in the IBD.

Topics: Absorptiometry, Photon; Adult; Body Mass Index; Bone Density; Bone Diseases, Metabolic; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Female; Femur Neck; Ghrelin; Humans; Inflammatory Bowel Diseases; Insulin-Like Growth Factor Binding Protein 3; Leptin; Lumbar Vertebrae; Male; Osteoporosis; Risk Factors

Skeletal growth is tightly coupled to energy balance via complex and incompletely understood mechanisms. Leptin-deficient ob/ob mice are obese and develop multiple pathologies associated with the metabolic syndrome. Additionally, ob/ob mice have skeletal abnormalities. The objective of this study was to evaluate the effects of leptin deficiency and long duration selective central leptin repletion via recombinant adeno-associated virus-leptin (rAAV-lep) gene therapy on bone in growing ob/ob mice. The ob/ob mice were injected in the hypothalamus with either rAAV-lep or rAAV-GFP (control vector). Treated ob/ob and untreated wild-type (WT) mice were then maintained on a normal diet for 15 weeks. In a second experiment, similarly treated mice along with a group of pair-fed mice were maintained for 30 weeks. Leptin was not detected in blood of either rAAV-lep- or rAAV-GFP-treated mice although rAAV-lep-treated mice displayed leptin transgene expression in the hypothalamus. As expected, rAAV-lep normalized body weight and food intake. Compared to WT mice, rAAV-GFP-treated ob/ob mice had decreased femoral length (by 1.6 mm or 10%, P<0.001), decreased total femur bone volume (by 3.3 mm(3) or 19%, P<0.001), but increased cancellous bone volume in the distal femur (by 0.04 mm(3) or 60%, P<0.09) and lumbar vertebrae (by 0.26 mm(3) or 118%, P<0.001). Treatment with rAAV-lep rescued the ob/ob skeletal phenotype by increasing femoral length and total bone volume, and decreasing femoral and vertebral cancellous bone volume, so that at 15 weeks post-rAAV-lep injection the ob/ob mice no longer differed from WT mice. No further skeletal changes in either the femur or lumbar vertebra were observed at 30 weeks post-rAAV-lep administration. The results suggest that hypothalamic leptin functions as an essential permissive factor for normal bone growth.

Topics: Animals; Body Weight; Bone and Bones; Bone Diseases, Metabolic; Dependovirus; Femur; Genetic Therapy; Genetic Vectors; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Treatment Outcome

Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) are key factors in bone remodeling in patients with anorexia nervosa (AN) and osteopenia. The purpose of this study was to investigate basal serum levels of OPG, RANKL and leptin, as well as bone mineral density (BMD) measured by DEXA at lumbar vertebrae L1-L4, and their evolution during one year in two groups of patients with AN.. Group I included 10 adolescent girls suffering from malnutrition and secondary amenorrhea with an evolution of more than one year at the beginning of the study who received oral estrogen treatment throughout the follow-up period. Group II comprised 10 girls with malnutrition and secondary amenorrhea with an evolution of less than one year who received nutritional treatment only. All parameters were compared with those of a control group of 19 healthy, age-matched girls with normal BMI and regular menstrual cycles.. The OPG/RANKL ratio was significantly decreased (p<0.05) after 1 year in group I, a fact that was due to an increase (p<0.05) in serum RANKL values. A correlation between OPG/RANKL and BMD was found in group I at the beginning of the study (r = 0.95; p<0.001). Patients in this group showed lower BMD values (p<0.01), both at diagnosis and at the end of the study, than those of group II patients, who showed normal BMD values.. The decrease in the OPG/RANKL ratio in girls with AN could partly explain the increase in bone loss that occurs in these patients.

Topics: Absorptiometry, Photon; Adolescent; Amenorrhea; Anorexia Nervosa; Biomarkers; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Bone Resorption; Enzyme-Linked Immunosorbent Assay; Estradiol; Female; Follow-Up Studies; Humans; Leptin; Lumbar Vertebrae; Malnutrition; Osteoprotegerin; Radioimmunoassay; RANK Ligand; Receptors, Leptin; Reference Values; Treatment Outcome

Sparc null mutants have been generated independently via targeted mutations in exons 4 and 6. Previous studies have identified low-turnover osteopenia in the 129Sv/C57BL/6 exon 4 knockout. Since both Sparc null mutations result in complete absence of Sparc protein, similar phenotypic outcomes are likely. However, genetic background (strain) and/or linkage disequilibrium effects can influence phenotype. Different inactivating mutations should be tested in various mouse strains; similar phenotypic outcomes can then confidently be assigned to the mutated gene. We have evaluated the bone phenotype in the 129Sv/EvSparc(tm1cam) exon 6 knockout at 4 and 9 mo, using physical measurement, mechanical strength tests, and DXA scanning. We have also quantified bone marrow adiposity and circulating leptin levels to assess adipose tissue metabolism. 129Sv/EvSparc(tm1cam) null mice show decreased bone mineral density and bone mineral content and increased mechanical fragility of bone, in line with previous studies. Differences were also noted. Increased body weight and levels of bone marrow adiposity but decreased circulating leptin concentrations were identified at 4, but not 9 mo, and 129Sv/EvSparc(tm1cam) null mice also had shorter femurs. Molecular phenotyping was carried out using mouse HGMP NIA microarrays with cortical femur samples at various ages, using semiquantitative RT-PCR validation. We identified 429 genes highly expressed in normal bone. Six genes (Sparc, Zfp162, Bysl, E2F4, two ESTs) are differentially regulated in 129Sv/EvSparc(tm1cam) cortical femur vs. 129Sv/Ev controls. We confirm low-turnover osteopenia as a feature of the Sparc null phenotype, identifying the usefulness of this mouse as a model for human osteoporosis.

Topics: Adipocytes; Animals; Bone Diseases, Metabolic; Bone Marrow Cells; Compressive Strength; Disease Models, Animal; Exons; Femur; Gene Expression Regulation; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Osteonectin; Phenotype

A prospective study was designed to investigate the circulating leptin level in girls with adolescent idiopathic scoliosis (AIS).. To determine the circulating leptin levels in AIS girls, and to investigate its associations with body mass and bone mass.. Abnormal growth pattern and osteopenia have been well documented in AIS patients throughout the peripubertal growth period. Leptin has been shown to regulate the growth of the whole body and bone particularly during childhood and adolescence. However, the circulating level of leptin, the relationships between leptin and lower body mass, and the relationships between leptin and lower bone mass in AIS patients remain unclear.. One hundred twenty AIS girls and 80 healthy controls were recruited in this study. Measurements of anthropometry and circulating leptin were performed both in AIS and non-AIS girls. Evaluations of curve severity and measurements of bone mineral content/density (BMC/BMD) were performed only in AIS girls. The anthropometric data and circulating leptin levels were compared between older AIS girls and controls. The relationships between leptin and age, menstrual status, body weight, height, body mass index (BMI), Risser sign, curve magnitude, and BMC/BMD were analyzed in AIS girls.. Compared with healthy controls, an abnormal growth pattern (higher corrected height, lower weight, and lower BMI), and a marked decrease of circulating leptin were found in AIS girls, even after the adjustment for age and menstrual status. Positive correlations were found between leptin and age, menstrual status, body weight, height, BMI, and Risser sign. No significant correlation was found between leptin and curve magnitude. There was no significant difference in age at menarche between menstruating AIS and non-AIS girls, though an inverse correlation was observed between leptin and the age at menarche. The relationship between leptin and BMC/BMD remained significantly positive after controlling for age and menstrual status, although it was not independent of body weight or BMI.. A marked decrease of circulating leptin was observed in the current study. There was an association between leptin and body weight, BMI, other growth parameters, and BMC/BMD. This correlation suggests that leptin might play an important role in the lower body and bone mass in AIS girls.

Topics: Adolescent; Body Mass Index; Bone Density; Bone Diseases, Metabolic; Child; Female; Femur Neck; Humans; Leptin; Lumbar Vertebrae; Menarche; Menstruation; Prospective Studies; Scoliosis

Leptin has important effects on bone metabolism. Possible relationships between leptin and bone mineral density were evaluated in the survivors of the childhood leukemia and lymphoma. Twenty patients were included the study. Anthropometric parameters, growth hormone response to provocative test, serum calcium, phosphorus, alkaline phosphates, osteocalcin, leptin levels, urinary calcium and deoxyypyridinoline levels, and bone mineral density were obtained. Anthropometric parameters of patients were not significantly different from those of a control group. Growth hormone provocative test was abnormal in 3 patients who received cranial radiotherapy. The osteocalcin levels and bone mineral density of patients were significantly lower than in the control group (p=.001, p=.02). Nine patients were in the osteopenic and 7 were in the osteoporotic range. The leptin levels of patients were significantly lower (p=.01) than in the control group. Bone mineral density (BMD) was significantly correlated with leptin level, age, body mass index, and Tanner stage in simple correlation analysis. However, in multivariate analysis only age was significant (p<.000, r: .752). Markers of bone metabolism, BMD, and leptin levels were not related with the growth hormone status of patients and did not present a correlation with the cumulative doses of drugs. There are a few studies evaluating the relationship between BMD and leptin levels in childhood cancer. Although this study did not find any correlation between the leptin level and BMD, detailed studies of larger numbers of patients are necessary to evaluate causes of decreased leptin level and the possible role of leptin on osteopenia observed in survivors of childhood cancer.

Topics: Adolescent; Body Mass Index; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Child; Disease-Free Survival; Female; Humans; Leptin; Leukemia; Lymphoma; Male; Minerals; Osteocalcin

Advances in diagnosis and improved methods of treatment have resulted in increasing number of long-term survivors in children with Wilms tumor. Growth and puberty are important for accumulation of bone mass; chemotherapy nad radiotherapy used in treatment for Wilms tumor can influence bone structure and physical development. Leptin plays an important role in metabolism of adipose tissue and bone mineralization. Considering that neoplasm and its treatment can affect normal development in childhood, we analysed the influence of antineoplastic treatment on bone mineralization and the correlations between serum leptin levels, body composition and bone mineral density in survivors of Wilms tumor. Twenty subjects (12 boys) treated for Wilms tumor at the mean age of 10.9 (range 3-20 years) participated in this study. Mean follow up period after discontinuation of therapy was 5.6 years (range 2 months - 13.5 years). Mean age of diagnosis was 3.9 years (range 1 month - 12.6 years). 18 patients received chemotherapy, 7 - additionally radiotherapy and 2 infants had only surgery treatment. We measured fat mass - FM, fat free mass - FFM, bone mineral density - BMD total and BMD spine using dual energy x-ray absorptiometry (DXA) and compared to the results obtained for healthy references (SD score). Leptin levels were measured with RIA method.. 1. No difference was found in leptin levels, body mass index, FM, FFM, BMD total and spine in relation to sex. 2. Means of SDS BMI, FM, FFM, BMD and leptin were in the normal range for the age and sex matched controls. 3. We found the correlation between leptin level and BMI, FM, FFM and BMD total and spine, no correlation was found between SDS values. 4. We observed a positive correlation between SDS BMD and SDS BMI, FM, FFM, BMD spine. 5. BMI, FM and leptin levels were higher in children treated with radiotherapy and chemotherapy than in children treated with only chemotherapy. However, the SDS values were comparable with the healthy controls. 6. SDS BMD total was decreased in 5/20 subjects (25% of all studied patients) compared with healthy controls.. The results demonstrated the risk of osteopenia in the group of children treated for Wilms tumor and the necessity for long-term monitoring of bone mineralization.

Topics: Absorptiometry, Photon; Adolescent; Antineoplastic Agents; Body Composition; Body Mass Index; Bone Diseases, Metabolic; Calcification, Physiologic; Case-Control Studies; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Kidney Neoplasms; Leptin; Male; Radiotherapy, Adjuvant; Wilms Tumor

In males, aging, health and disease are processes that occur over physiologic time and involve a cascade of hormonal, biochemical and physiological changes that accompany the down-regulation of the hypothalamic-anterior pituitary-testicular axis. As aging progresses there are relative increases of body fat and decreases in muscle mass. The increased adipose tissue mass is associated with the production of a number of newly generated factors. These include aromatase, leptin, PAI-1, insulin resistance, and the dyslipidemias, all of which can lead to tissue damage. Fatty tissue becomes the focal point for study as it represents the intersection between energy storage and mobilization. The increase in adipose tissue is associated with an increase in the enzyme aromatase that converts testosterone to estradiol and leads to diminished testosterone levels that favor the preferential deposition of visceral fat. As the total body fat mass increases, hormone resistance develops for leptin and insulin. Increasing leptin fails to prevent weight gain and the hypogonadal-obesity cycle ensues causing further visceral obesity and insulin resistance. The progressive insulin resistance leads to a high triglyceride-low HDL pattern of dyslipidemia and increased cardiovascular risk. All of these factors eventually contribute to the CHAOS Complex: coronary disease, hypertension, adult-onset diabetes mellitus, obesity and/or stroke as permanent changes unfold. Other consequences of the chronic hypogonadal state include osteopenia, extreme fatigue, depression, insomnia, loss of aggressiveness and erectile dysfunction all of which develop over variable periods of time.

Topics: Adipose Tissue; Aging; Aromatase; Body Composition; Bone Diseases, Metabolic; Estradiol; Humans; Hyperlipidemias; Insulin; Leptin; Male; Muscles; Obesity; Testosterone

Osteopenia is a frequent, often persistent, complication of anorexia nervosa (AN) in adolescent girls and occurs during a critical time in bone development. Little is known about bone metabolism in this patient population. Therefore, we measured bone density (BMD) and body composition by dual energy x-ray absorptiometry, nutritional status, bone turnover, calcium, and hormonal status in 19 adolescent girls with AN (mean +/- SEM, 16.0+/-0.4 yr) and 19 bone age-matched controls. The mean duration of AN was 19+/-5 months. Spinal (L1-L4) osteopenia was common in AN. Lumbar anterioposterior BMD was more than 1 SD below the mean in 42% of patients, and lateral spine BMD was more than 1 SD below in 63% of patients compared with controls. Lean body mass significantly predicted lumbar bone mineral content (r = 0.75; P < 0.0001) in controls only. In AN, duration of illness was the most significant predictor of spinal BMD (lumbar: r = -0.44; P = 0.06; lateral: r = -0.59; P = 0.008). AN adolescents with mature BA (15 yr and greater) were hypogonadal [estradiol, 16.2+/-1.9 vs. 23.3+/-1.6 pg/mL (P = 0.01); free testosterone, 0.70+/-0.17 vs. 1.36+/-0.14 pg/mL (P = 0.01)] although dehydroepiandrosterone sulfate and urinary free cortisol levels did not differ. Leptin levels were reduced in AN (2.9+/-2.1 vs. 16.5+/-1.8 ng/mL; P < 0.0001). Insulin-like growth factor I (IGF-I) was reduced in AN to 50% of control levels (219+/-41 vs. 511+/-35 ng/mL; P < 0.0001) and correlated with all measures of nutritional status, particularly leptin (r = 0.80; P < 0.0001). Surrogate markers of bone formation, serum osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP), were significantly (P = 0.02) reduced in AN vs. controls (OC, 39.1+/-6.4 vs. 59.2+/-5.2 ng/mL; BSAP, 27.9+/-4.0 vs. 40.6+/-3.4 U/L). The majority of the variation in bone formation in AN was due to IGF-I levels (OC: r2 = 0.72; P = 0.002; BSAP: r2 = 0.53; P = 0.01) in stepwise regression analyses. Bone resorption was comparable in patients and controls. These data demonstrate that bone formation is reduced and uncoupled to bone resorption in mature adolescents with AN in association with low bone density. Lean body mass was a significant predictor of BMD in controls, but not AN patients. The major correlate of bone formation in AN was the nutritionally dependent bone trophic factor, IGF-I. Reduced IGF-I during the critical period of bone mineral accumulation may be an important factor in the development of osteopenia

Topics: Absorptiometry, Photon; Adolescent; Alkaline Phosphatase; Anorexia Nervosa; Body Composition; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Calcium; Estradiol; Female; Humans; Leptin; Lumbar Vertebrae; Nutritional Status; Osteocalcin; Spine; Testosterone