leptin and Osteoporosis

Adipose tissue is the source of a broad array of signalling molecules (adipokines), which mediate interorgan communication and regulate metabolic homeostasis. Alterations in adipokine levels have been causally implicated in various metabolic disorders, including changes in bone mass. Osteoporosis is the commonest progressive metabolic bone disease, characterized by elevated risk of fragility fractures as a result of a reduced bone mass and microarchitectural deterioration. The effects of different adipokines on bone mass have been studied in an attempt to identify novel modulators of bone mass or diagnostic biomarkers of osteoporosis.. In this review, we sought to aggregate and assess evidence from independent studies that quantify specific adipokines and their effect on bone mineral density (BMD).. A literature search identified 57 articles that explored associations between different adipokines and BMD. Adiponectin and leptin were the most frequently studied adipokines, with most studies demonstrating that adiponectin levels are associated with decreased BMD at the lumbar spine and femoral neck. Conversely, leptin levels are associated with increased BMD at these sites. However, extensive heterogeneity with regards to sample size, characteristics of study subjects, ethnicity, as well as direction and magnitude of effect at specific skeletal anatomical sites was identified. The broad degree of conflicting findings reported in this study can be attributed several factors. These include differences in study design and ascertainment criteria, the analytic challenges of quantifying specific adipokines and their isoforms, pre-analytical variables (in particular patient preparation) and confounding effects of co-existing disease.. This review highlights the biological relevance of adipokines in bone metabolism and reinforces the need for longitudinal research to elucidate the causal relationship of adipokines on bone mass.

Topics: Adipokines; Adiponectin; Bone Density; Humans; Leptin; Osteoporosis

The clinical correlation between adipokines levels in the blood and the incidence of senile osteoporosis (SOP) has not been clearly studied. We conducted this meta-analysis to elucidate the relationship between three common adipokines levels (leptin, adiponectin, and chemerin) and the incidence of SOP.. We searched databases such as CNKI, CBM, VIP, Wanfang, PubMed, Web of Science, Embase, and the Cochrane Library to collect articles published since the establishment of the database until July 30, 2022.. In total, 11 studies met the selection criteria. Our meta-analysis showed that serum leptin levels were significantly lower (mean difference [MD], -2.53, 95% CI: -3.96 to -1.10,. The likelihood of having SOP was higher in older individuals with low levels of leptin and higher levels of chemerin. In addition, BMI was somewhat lower with low levels of leptin and adiponectin.. https://www.crd.york.ac.uk/prospero/, identifier CRD42022356469.

Topics: Adipokines; Adiponectin; Aged; Bone Density; Humans; Leptin; Osteoporosis

Genetics in model organisms has progressively broken down walls that previously separated different disciplines of biology. One example of this holistic evolution is the recognition of the complex relationship that exists between the control of bone mass (bone remodeling) and energy metabolism in mammals. Numerous hormones orchestrate this crosstalk. In particular, the study of the leptin-mediated regulation of bone mass has not only revealed the existence of a central control of bone mass but has also led to the realization that sympathetic innervation is a major regulator of bone remodeling. This happened at a time when the use of drugs aiming at treating osteoporosis, the most frequent bone disease, has dwindled. This review will highlight the main aspects of the leptin-mediated regulation of bone mass and how this led to the realization that β-blockers, which block the effects of the sympathetic nervous system, may be a viable option to prevent osteoporosis.

Topics: Animals; Bone Density; Bone Remodeling; Energy Metabolism; Leptin; Mammals; Osteoporosis; Sympathetic Nervous System

Chronic psychological stress affects many body systems, including the skeleton, through various mechanisms. This review aims to provide an overview of the factors mediating the relationship between psychological stress and bone health. These factors can be divided into physiological and behavioural changes induced by psychological stress. The physiological factors involve endocrinological changes, such as increased glucocorticoids, prolactin, leptin and parathyroid hormone levels and reduced gonadal hormones. Low-grade inflammation and hyperactivation of the sympathetic nervous system during psychological stress are also physiological changes detrimental to bone health. The behavioural changes during mental stress, such as altered dietary pattern, cigarette smoking, alcoholism and physical inactivity, also threaten the skeletal system. Psychological stress may be partly responsible for epigenetic regulation of skeletal development. It may also mediate the relationship between socioeconomic status and bone health. However, more direct evidence is required to prove these hypotheses. In conclusion, chronic psychological stress should be recognised as a risk factor of osteoporosis and stress-coping methods should be incorporated as part of the comprehensive osteoporosis-preventing strategy.

Topics: Adaptation, Psychological; Alcoholism; Animals; Bone and Bones; Bone Density; Bone Development; Cigarette Smoking; Epigenesis, Genetic; Feeding Behavior; Glucocorticoids; Humans; Leptin; Models, Animal; Osteoporosis; Parathyroid Hormone; Prolactin; Risk Factors; Stress, Psychological

The age-related accumulation of bone marrow adipose tissue (BMAT) negatively impacts bone metabolism and hematopoiesis. This review provides an overview about BMAT-secreted factors as biomarkers for BMAT accumulation and osteoporosis risk.. The adipokines leptin and adiponectin are regulators of BMAT. It remains to be clarified if locally produced adipokines substantially contribute to their peripheral serum levels and if they influence bone metabolism beyond that of extraosseous adipokine production. Existing data also suggests that BMAT disturbs bone metabolism primarily through palmitate-mediated toxic effects on osteoblasts and osteocytes, including dysregulated autophagy and apoptosis. BMAT-secreted factors are important modulators of bone metabolism. However, the majority of our understanding about MAT-secreted factors and their paracrine and endocrine effects is derived from in vitro studies and animal experiments. Therefore, more research is needed before BMAT-secreted biomarkers can be applied in medical practice.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Apoptosis; Autophagy; Bone and Bones; Bone Marrow; Extracellular Vesicles; Fatty Acids; Humans; Leptin; Osteoblasts; Osteocytes; Osteoporosis; Palmitates

Decreased mineral density is one of the major complications of anorexia nervosa. The phenomenon is even more pronounced when the disease occurs during adolescence and when the duration of amenorrhoea is long. The mechanisms underlying bone loss in anorexia are complex. Oestrogen deficiency has long been considered as the main factor, but cannot explain the phenomenon on its own. The essential role of nutrition-related factors-especially leptin and adiponectin-has been reported in recent studies. Therapeutic strategies to mitigate bone involvement in anorexia are still a matter for debate. Although resumption of menses and weight recovery appear to be essential, they are not always accompanied by a total reversal of bone loss. There are no studies in the literature demonstrating that oestrogen treatment is effective, and the best results seem to have been obtained with agents that induce bone formation-such as IGF-1-especially when associated with oestrogen. As such, bone management in anorexia remains difficult, hence, the importance of early detection and multidisciplinary follow-up.

Topics: Absorptiometry, Photon; Adiponectin; Amenorrhea; Anorexia Nervosa; Bone Density; Bone Density Conservation Agents; Drug Therapy, Combination; Estrogens; Exercise; Female; Humans; Insulin-Like Growth Factor I; Leptin; Lipolysis; Osteoporosis; Recombinant Proteins; Treatment Outcome; Weight Gain

Multiple sclerosis (MS) is a multifactorial, inflammatory, and neurodegenerative disease of the central nervous system, where environmental factors interact with genetic susceptibility. The role of diet on MS has not been comprehensively elucidated; therefore, through an extensive search of relevant literature, this review reports the most significant evidence regarding nutrition as a possible co-factor influencing the inflammatory cascade by acting on both its molecular pathways and gut microbiota. Since nutritional status and dietary habits in MS patients have not been extensively reported, the lack of a scientific-based consensus on dietary recommendation in MS could encourage many patients to experiment alternative dietetic regimens, increasing the risk of malnutrition. This work investigates the health implications of an unbalanced diet in MS, and collects recent findings on nutrients of great interest among MS patients and physicians. The aim of this review is to elucidate the role of an accurate nutritional counseling in MS to move toward a multidisciplinary management of the disease and to encourage future studies demonstrating the role of a healthy diet on the onset and course of MS.

Topics: Animals; Antioxidants; Body Composition; Complementary Therapies; Diet; Disease Models, Animal; Dysbiosis; Fatty Acids; Fatty Acids, Unsaturated; Humans; Inflammation; Leptin; Lipopolysaccharides; Malnutrition; Micronutrients; Multiple Sclerosis; Nutritional Status; Obesity; Osteoporosis; Randomized Controlled Trials as Topic; Recommended Dietary Allowances; Risk Factors; Vitamin D

The high prevalence of osteoporosis, observed in multiple sclerosis (MS) patients, has been attributed to reduced mobility and or the use of disease-modifying drugs. However, MS-impaired cardiovascular autonomic nervous system (ANS) function has the potential of reducing bone mass density (BMD) by altering the expression and/or function of the neuronal, systemic, and local mediators of bone remodeling. This review describes the complex regulation of bone homeostasis with a focus on MS, providing evidence that ANS dysfunction and low BMD are intertwined with MS inflammatory and neurodegenerative processes, and with other MS-related morbidities, including depression, fatigue, and migraine. Strategies for improving ANS function could reduce the prevalence of MS osteoporosis and slow the rate of MS progression, with a significant positive impact on patients' quality of life.

Topics: Adiponectin; Autonomic Nervous System; Bone Density; Bone Remodeling; Brain; Cardiovascular System; Depression; Endocannabinoids; Fatigue; Humans; Inflammation; Leptin; Migraine Disorders; Multiple Sclerosis; Nerve Degeneration; Neuropeptide Y; Osteocalcin; Osteopontin; Osteoporosis; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Serotonin; Vitamin D

To demonstrate the underlying pathogenesis of osteoporosis occurring in patients with lipodystrophy.. MEDLINE was searched using the following key terms: lipodystrophy, osteoporosis, and reduced bone mineral density. Manual searching identified additional studies from the bibliographies of reports and reviews obtained in the MEDLINE search.. Lipodystrophy is a very rare disease characterized by pathologic alterations in the distribution of adipose tissues in association with a diverse range of metabolic derangements such as hypertriglyceridemia, insulin resistance, diabetes, and abnormal bone formation. Reduced bone mineral density has been assessed extensively in human immunodeficiency virus-infected patients with lipodystrophy, but far less is known in other lipodystrophy types. This is the first review to discuss the mechanisms of osteoporosis occurrence in various types of lipodystrophy. We herein focus on the cross-regulation of fat and bone and propose that marrow fat accumulation and reduced serum leptin and adiponectin levels may play important roles in the pathophysiologic process of osteoporosis in patients with lipodystrophy.. Osteoporosis is an emerging threat to patients with lipodystrophy. When evaluating the clinical course of a patient with lipodystrophy, osteoporosis should also be considered.. BMD = bone mineral density; CGL = congenital generalized lipodystrophy; HIV = human immunodeficiency virus; MAT = marrow adipose tissue; OB-R = leptin receptor.

Topics: Adiponectin; Adipose Tissue; Bone Marrow; Humans; Leptin; Lipodystrophy; Osteoporosis

Osteoporosis is a high-prevalence disease, particularly in developed countries, and results in high costs both to the individual and to society through associated fragility fractures. There is an urgent need for identification of novel drug targets and development of new anti-osteoporotic agents. Between 30 and 80% of osteoporotic fractures cannot be prevented despite current treatments achieving relative fracture risk reduction of up to 20%, 50%, and 70% for non-vertebral, hip and spine fractures, respectively. Traditionally, the decline in gonadal hormones has been studied as the sole hormonal determinant for the loss of bone mineral density in osteoporosis. However, recent studies have identified receptors for numerous non-gonadal hormones such as PTH, angiotensin II, leptin, adiponectin, insulin and insulin-like growth factor-1 on the osteoblast lineage cells that directly regulate bone turnover. These hormones are also involved in the pathogenesis of metabolic syndrome risk factors, particularly hypertension, type-II diabetes and obesity. By activating their respective receptors on osteoblastic lineage cells, these hormones appear to act through a common mechanism by down-regulating receptors for activation of nuclear factor kappa B ligand (RANKL) and up-regulating osteoprotegerin (OPG) with inverse responses for adiponectin. Receptors for amylin, gastric inhibitory polypeptide and ghrelin and have also been identified on the osteoblast lineage cells although the roles of these receptors in bone turnover are controversial or poorly studied. Moreover, bone turnover may be independently regulated by modulation of osteoclast-osteoblast function and bone marrow adiposity. Leptin appears to be the only hormone that is a known regulator of both bone mineralisation and bone adiposity.

Topics: Adiposity; Animals; Bone Remodeling; Hormones; Humans; Hyperglycemia; Hypertension; Leptin; Osteoclasts; Osteoporosis; Parathyroid Hormone; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cell Surface; Signal Transduction

Osteoporosis is less common in individuals with high fat mass. This putative osteoprotection is likely an adaptive mechanism that allows obese individuals to better carry their increased body mass. Recent studies have focused on hormones that link fat to bone. Adipokines, such as leptin, modulate bone cells through both direct and indirect actions, whereas molecules activating peroxisome proliferator-activated receptor γ drive mesenchymal stem cell differentiation towards adipocytes away from the osteoblastic lineage. There is emerging evidence that bone-derived osteocalcin regulates insulin release and insulin sensitivity and, hence, might indirectly affect fat mass. Despite these molecular connections between fat and bone, animal and human studies call into question a primary role for body fat in determining bone mass. Mice devoid of fat do not have a skeletal phenotype, and in humans, the observed correlations between bone and body mass are not just due to adipose tissue. An improved understanding of the integrative physiology at the fat-bone interface should allow us develop therapies for both osteoporosis and obesity.

Topics: Adipose Tissue; Animals; Bone and Bones; Bone Density; Humans; Leptin; Organ Size; Osteoporosis

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

Adipose tissue is an endocrine organ able to produce a wide series of pleiotropic molecules, defined "adipokines". In addition to the regulation of food intake and energy metabolism, adipokines are also implicated in the complex control of bone biology and specifically of bone remodeling. Leptin, the most studied adipokine, promotes satiety and energy expenditure and its circulating levels are proportional to fat mass. Some paradoxical findings originally suggested the involvement of leptin in controlling bone mass. For example, obese postmenopausal women, with elevated circulating leptin and leptin resistance, appear protected against the development of osteoporosis. Moreover, genetically leptin-deficient mice, which are hypogonadal and obese, display a decreased trabecular volume in long bones, but an increased vertebral bone mass, which is reduced by leptin administration. The complex mechanisms of leptin regulation of bone mass appear to involve selected hypothalamic neuronal populations and the sympathetic outflow, with an important role of osteoblastic beta2-adrenergic receptors. Adiponectin is another adipokine, which promotes insulin sensitivity and is reduced in obese and diabetic subjects. Adiponectin appears to exert a negative effect on bone mass and seems to be an independent predictor of lower bone mass. Although the adipokines resistin and visfatin do not seem to significantly affect bone metabolism, the potential impact of them and other adipokines is still to be determined. Moreover, the molecular adipokine-bone interactions should also be considered in the context of the adipokine changes observed in diseases such as obesity and the metabolic syndrome.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Humans; Leptin; Nicotinamide Phosphoribosyltransferase; Osteoporosis; Resistin

In recent decades the population of both elderly men and women has grown substantially worldwide. Aging is associated with a number of pathologies involving various organs including the skeleton. Age-related bone loss and resultant osteoporosis put the elderly population at an increased risk for fractures and morbidity. Fortunately, in parallel our understanding of this malady has also grown substantially in recent years. A number of clinical as well as translational studies have been pivotal in providing us with an understanding of the pathophysiology of this condition. This article discusses the current concepts of age-related modulation of the skeleton involving intrinsic factors such as genetics, hormonal changes, levels of oxidative stress, and changes in telomere length, as well as extrinsic factors such as nutritional and lifestyle choices. It also briefly outlines recent studies on the relationship between bone and fat in the marrow as well as the periphery.

Topics: Aged; Aging; Bone and Bones; Bone Remodeling; Elder Nutritional Physiological Phenomena; Exercise; Female; Humans; Leptin; Life Style; Male; Osteoporosis; Osteoporosis, Postmenopausal; Oxidative Stress; Serotonin; Telomere

Convincing evidence has accumulated of regulation of bone by the central nervous system. The neural connection between brain and bone is mediated centrally by classic neurotransmitters and several neuropeptides, and peripherally by many of the same neurotransmitters and neuropeptides, albeit with actions opposite to their central effects. Pharmacologic blockade of ß2-adrenergic receptors or disruption of the gene encoding them increases bone mass, whereas increased activity of the sympathetic nervous system (SNS) contributes to bone loss. Brainstem serotonergic neurons regulate SNS activity and its modulation by leptin. Physiologic stimulation of osteoblastic nicotinic receptors results in proliferation and deposition of bone, whereas higher levels inhibit osteoblast function. Activation of sensory nerves has a centrally mediated action on bone, albeit poorly understood. The relative importance of, and interactions between autonomic, sensory, and peripheral nervous system actions on bone mass are also not clear in healthy individuals, and less so in pathologic states.

Topics: Acetylcholine; Animals; Bone Remodeling; Calcitonin Gene-Related Peptide; Humans; Hypothalamus; Leptin; Neuropeptides; Norepinephrine; Osteoporosis; Parasympathetic Nervous System; Primary Dysautonomias; Stroke; Sympathetic Nervous System

Osteoporosis is caused by a failure of bone homeostasis, but the precise molecular mechanisms controlling bone homeostasis are largely unknown. Increasing evidence that neurons and neurotransmitters are intimately involved in bone remodelling has shed light on a novel regulatory mechanism for bone homeostasis. Namely, like all other homeostatic functions, bone remodelling is under the control of the hypothalamus, and osteoporosis is considered to be a neuroskeletal disease.

Topics: Animals; Bone Remodeling; Cell Differentiation; Circadian Rhythm; Homeostasis; Humans; Leptin; Nerve Regeneration; Neuropeptides; Osteoblasts; Osteoclasts; Osteoporosis; Signal Transduction; Sympathetic Nervous System

There are data to suggest low bone mineral density is disproportionately prevalent among those with psychiatric disorders. This paper aims to review the current evidence on the relationship between depression and bone mineral density, and identify potential mechanisms.. Relevant sources were identified from the Pubmed and Web of Science (ISI) databases from the first relevant publication in 1994 to the present, 2007, using a combination of key words and terms including depression, major depressive disorder, osteoporosis, bone mineral density, hypothalamic-pituitary-adrenal axis, cortisol, cytokines, leptin, antidepressants, selective serotonin reuptake inhibitors, smoking, alcohol, physical activity and diet. Reference lists of chosen articles were further reviewed for associated publications.. The possible association between psychiatric illness, in particular depression, and osteoporosis has been the subject of a growing body of research yielding various findings, although most identify some effect on bone. In addition to medication-related processes and/or modifiable lifestyle factors associated with mood disturbances, endocrine and immune alteration secondary to depression may play a pathogenetic role in bone metabolism.. Additional longitudinal studies, with the advantage of temporal sequencing, remain to be conducted, as well as research into potential mechanisms surrounding the association. Nevertheless, the current findings are of clinical relevance, given the health burden of both depression and osteoporosis.

Topics: Bone and Bones; Bone Density; Cytokines; Depressive Disorder, Major; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Leptin; Osteoporosis; Pituitary-Adrenal System; Posture; Prevalence; Smoking

Hypoleptinemia is a key endocrinological feature of anorexia nervosa (AN). Several symptoms in acute AN are related to the low circulating leptin levels including amenorrhea and semi-starvation-induced hyperactivity. The drop in leptin levels results from the loss of fat mass; once leptin levels fall below specific thresholds the hypothalamic-pituitary-gonadal and -thyroid axes are down-regulated; in contrast, the hypothalamic-pituitary-adrenal axis is up-regulated. Hypoleptinemia is the major signal underlying both somatic and behavioral adaptations to starvation. Because the mechanisms involved in this adaptation are similar in rodents and humans, rodent models can be used to investigate the relevant central pathways which underly the respective starvation-induced symptoms. During therapeutically induced weight gain, leptin levels can intermittently increase above normal concentrations. This hyperleptinemia could predispose to renewed weight loss.

Topics: Adolescent; Amenorrhea; Anorexia Nervosa; Body Weight; Female; Humans; Leptin; Motor Activity; Neurosecretory Systems; Osteoporosis; Starvation; Weight Loss

Emerging evidence points to a critical role for the skeleton in several homeostatic processes, including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Mature bone cells secrete factors that influence insulin sensitivity, and fat cells synthesize cytokines that regulate osteoblast differentiation; thus, these two pathways are closely linked. The emerging importance of the bone-fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures. In this article, we discuss three pathways that could be pharmacologically targeted for the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk: the leptin, peroxisome proliferator-activated receptor gamma and osteocalcin pathways. Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will probably be activated by this targeting, which could prove to be beneficial or detrimental for the organism. Hence, a more complete picture of energy utilization and skeletal remodeling will be required to bring any potential agents into the future clinical armamentarium.

Topics: Adipose Tissue; Animals; Bone and Bones; Bone Density; Bone Remodeling; Disease Models, Animal; Energy Metabolism; Female; Homeostasis; Humans; Leptin; Male; Mice; Mice, Knockout; Osteocalcin; Osteoporosis; PPAR gamma

It was previously believed that obesity and osteoporosis were two unrelated diseases, but recent studies have shown that both diseases share several common genetic and environmental factors. Body fat mass, a component of body weight, is one of the most important indices of obesity, and a substantial body of evidence indicates that fat mass may have beneficial effects on bone. Contrasting studies, however, suggest that excessive fat mass may not protect against osteoporosis or osteoporotic fracture. Differences in experimental design, sample structure, and even the selection of covariates may account for some of these inconsistent or contradictory results. Despite the lack of a clear consensus regarding the impact of effects of fat on bone, a number of mechanistic explanations have been proposed to support the observed epidemiologic and physiologic associations between fat and bone. The common precursor stem cell that leads to the differentiation of both adipocytes and osteoblasts, as well the secretion of adipocyte-derived hormones that affect bone development, may partially explain these associations. Based on our current state of knowledge, it is unclear whether fat has beneficial effects on bone. We anticipate that this will be an active and fruitful focus of research in the coming years.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Adipocytes; Adiponectin; Adipose Tissue; Amyloid; Aromatase; Bone Density; Cell Differentiation; Female; Humans; Insulin; Insulin-Like Growth Factor II; Interleukin-6; Islet Amyloid Polypeptide; Leptin; Male; Obesity; Osteoblasts; Osteoporosis; Peptide Fragments; PPAR gamma; Resistin; Transforming Growth Factor beta; Wnt Proteins

Body weight impacts both bone turnover and bone density, making it, therefore, an important risk factor for vertebral and hip fractures and ranking it alongside age in importance. The effect of body weight is probably contributed to by both fat mass and lean mass, though in postmenopausal women, fat mass has been more consistently demonstrated to be important. A number of mechanisms for the fat-bone relationship exist and include the effect of soft tissue mass on skeletal loading, the association of fat mass with the secretion of bone active hormones from the pancreatic beta cell (including insulin, amylin, and preptin), and the secretion of bone active hormones (e.g., estrogens and leptin) from the adipocyte. These factors alone probably do not fully explain the observed clinical associations, and study of the actions on bone of novel hormones related to nutrition is an important area of further research. An understanding of this aspect of bone biology may open the way for new treatments of osteoporosis. More immediately, the role of weight maintenance in the prevention of osteoporosis is an important public health message that needs to be more widely appreciated.

Topics: Body Mass Index; Bone and Bones; Bone Density; Calcium; Female; Fractures, Bone; Humans; Insulin; Leptin; Male; Obesity; Osteoporosis; Risk Factors

Leptin, a cytokine-like hormone secreted by adipocytes, is known to regulate food intake but has also emerged as a significant factor in the regulation of bone mass. In humans, states of energy deprivation with low serum leptin have been associated with low bone mass. In mice, leptin deficiency led to increased trabecular bone mass with overall decrease in cortical bone. Leptin regulates bone metabolism indirectly in the hypothalamus thereby activating the sympathetic nervous system (SNS). In addition to the SNS, leptin also interacts with various hypothalamic neuropeptides, such as cocaine- and amphetamine-regulated transcript, neuropeptide Y and/or neuromedin U, which might modulate the effects of leptin on bone. In osteoblasts sympathetic signaling is further gated by the transcriptional factors called molecular clock. As a result, bone loss is accelerated showing that the central effect of leptin seems to be antiosteogenic. Additionally, leptin has a direct anabolic effect within the bone driving the differentiation of bone marrow stem cells into the osteoblastic cell lineage. Besides the interaction between the central and peripheral pathways, the overall effect of leptin on bone might be bimodal depending on leptin serum concentrations. Regulatory pathways triggering osteoblast activity might open new possibilities for anabolic treatment of osteoporosis.

Topics: Adipocytes; Animals; Bone and Bones; Humans; Leptin; Osteoblasts; Osteoporosis; Sympathetic Nervous System

Obesity regulates bone metabolism not only by increasing weight loading but by modulating cytokines or hormones which are known to affect bone remodeling. As a result, it has been generally believed that obesity leads to an increase in bone mass. However, recent observations revealed that excessive fat mass may not protect against osteoporotic fractures.

Topics: Adipocytes; Body Weight; Bone and Bones; Bone Remodeling; Cell Differentiation; Diet, Reducing; Fractures, Bone; Humans; Leptin; Obesity; Osteoblasts; Osteoporosis; Risk

Osteoporosis and obesity, two disorders of body composition, are growing in prevalence. Interestingly, these diseases share several features including a genetic predisposition and a common progenitor cell. With aging, the composition of bone marrow shifts to favor the presence of adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis. Secondary causes of osteoporosis, including diabetes mellitus, glucocorticoids and immobility, are associated with bone-marrow adiposity. In this review, we ask a provocative question: does fat infiltration in the bone marrow cause low bone mass or is it a result of bone loss? Unraveling the interface between bone and fat at a molecular and cellular level is likely to lead to a better understanding of several diseases, and to the development of drugs for both osteoporosis and obesity.

Topics: Adipocytes; Adipose Tissue; Aging; Animals; Body Composition; Bone and Bones; Bone Density; Bone Marrow; Cell Differentiation; Humans; Leptin; Magnetic Resonance Imaging; Obesity; Osteoporosis; PPAR gamma

Anorexia nervosa (AN), a condition of severe undernutrition, is associated with low bone mineral density (BMD) in adults and adolescents. Whereas adult women with AN have an uncoupling of bone turnover markers with increased bone resorption and decreased bone formation markers, adolescents with AN have decreased bone turnover overall. Possible contributors to low BMD in AN include hypoestrogenism and hypoandrogenism, undernutrition with decreased lean body mass, and hypercortisolemia. IGF-I, a known bone trophic factor, is reduced despite elevated growth hormone (GH) levels, leading to an acquired GH resistant state. Elevated ghrelin and peptide YY levels may also contribute to impaired bone metabolism. Weight recovery is associated with recovery of BMD but this is often partial, and long-term and sustained weight recovery may be necessary before significant improvements are observed. Anti-resorptive therapies have been studied in AN with conflicting results. Oral estrogen does not increase BMD or prevent bone loss in AN. The combination of bone anabolic and anti-resorptive therapy (rhIGF-I with oral estrogen), however, did result in a significant increase in BMD in a study of adult women with AN. A better understanding of the pathophysiology of low BMD in AN, and development of effective therapeutic strategies is critical. This is particularly so for adolescents, who are in the process of accruing peak bone mass, and in whom a failure to attain peak bone mass may occur in AN in addition to loss of established bone.

Topics: Androgens; Anorexia Nervosa; Bone Density Conservation Agents; Calcium; Diphosphonates; Eating; Estrogen Replacement Therapy; Ghrelin; Humans; Hypogonadism; Insulin-Like Growth Factor I; Leptin; Malnutrition; Motor Activity; Osteoporosis; Peptide Hormones; Peptide YY; Recombinant Proteins; Vitamin D

Bone remodeling is the concerted interplay of two cellular activities: osteoclastic bone resorption and osteoblastic bone formation. Bone remodeling is the physiologic process that maintains bone mass, skeletal integrity and skeletal function. A molecular understanding of this process is therefore of paramount importance for almost all aspects of skeletal physiology and many facets of bone diseases. Based on the morphological observation of the BMU-"bone multicellular unit" or "bone metabolic unit"-and a wide body of in vitro data, bone remodeling was thought to be controlled locally through functional coupling of resorption and formation and vice versa. However, recent genetic studies have shown that there is no obligatory tight cross-control of bone formation and bone resorption in vivo and that there is also a central axis controlling bone formation, one aspect of bone remodeling. The molecule that inhibits bone formation through a hypothalamic relay is leptin. Following binding to its receptor located on the ventromedial nuclei of the hypothalamus, leptin's action on bone formation is mediated via a neuronal signaling cascade that involves the ss-adrenergic system. The overall goal of this review is to show how the dialogue between clinical medicine and mouse genetics helped to uncover a new concept in skeletal physiology.

Topics: Bone and Bones; Bone Remodeling; Bone Resorption; Dopamine beta-Hydroxylase; Humans; Hypothalamus; Leptin; Osteogenesis; Osteoporosis; Sympathetic Nervous System

Young women have become increasingly active in athletics during the 20th century. Those involved in sports that emphasize lean body type are at high risk for the development of menstrual dysfunction, including amenorrhea. This is mediated by an alteration in function of the hypothalamic-pituitary-ovarian (HPO) axis, with loss of normal secretion of luteinizing hormone, and subsequent lack of estrogen production. Disruption of the HPO axis appears to be dependent on the body's recognition of an energy imbalance, which may be due to a lack of compensatory caloric intake in the face of significant energy expenditure. Other pituitary hormones, such as triiodothyronine, growth hormone, and insulin-like growth factor-1 may also be affected. These metabolic changes have an impact on bone mineralization during a critical period in the development of bone mass. Recognition by physicians of the so-called 'female athlete triad', consisting of disordered eating, amenorrhea, and osteoporosis, may allow therapeutic intervention. Diagnosis of eating disorders and decreased bone mineral density can have significant impact on the health of the young athlete. Treatment is aimed at restoring normal menstrual function by increasing caloric intake to balance the increased energy demands of athletic participation. Concurrent treatment of the hypoestrogenemic state using estrogen replacement is controversial, but may aid in alleviating further loss of bone mass.

Topics: Adolescent; Amenorrhea; Bone Density; Diet; Energy Metabolism; Exercise; Female; Ghrelin; Hormone Replacement Therapy; Humans; Hypothalamus; Leptin; Menstruation Disturbances; Osteoporosis; Ovary; Peptide Hormones; Pituitary Gland; Sports

Osteoporosis and atherosclerosis are both widely prevalent in an ageing population, and induce serious morbidities and death. There is growing evidence that in addition to their relationship to ageing, osteoporosis and atherosclerosis are also linked by biological associations. This article reviews their clinical interrelations, discusses the basic biology of bone and the arterial wall, and presents five examples that illustrate their biological linkages. Current therapeutic approaches emerging from these linkages, including statins, bisphosphonates, and the thiazolidinediones, have dual effects on bone and the vasculature. Additional therapies derived from experimental studies that enhance bone density and reduce atherogenesis hold further promise to diminish the morbidity and mortality of osteoporosis and atherosclerosis, with attendant benefits to society.

Topics: Adiponectin; Arteries; Arteriosclerosis; Bone and Bones; Calcinosis; Diphosphonates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Signaling Peptides and Proteins; LDL-Receptor Related Proteins; Leptin; Lipoxygenase; NF-kappa B; Osteoblasts; Osteoclasts; Osteoporosis; PPAR gamma; Thiazolidinediones

Obesity and osteoporosis have grave consequences for human health, quality of life, and even the efficiency of the labor force and economy. However, these pathologies share a common cell progenitor, revealing a surprising target for drug research and development. Recent findings show that high adipocyte count in bone marrow is directly related to bone loss, as fat cells replace osteoblasts (or bone-forming cells). The objective of this review is to examine the importance of adipocyte apoptosis in the treatment of obesity and/or osteoporosis, with special emphasis on natural products as promising leads for drug development. We have induced in vivo adipocyte apoptosis, using leptin, ciliary neurotrophic factor (CNTF), beta adrenergic agonists and conjugated linoleic acid (CLA) in rodents. The results of leptin treatments on rats are suppressed food intake, reduced body weight, reduced body fat, adipocyte apoptosis, and elevated energy expenditure. Further, leptin treatment of leptin-deficient (ob/ob) mice increases endosteal bone formation and bone mineral density. Adipocyte apoptosis has also been induced in vitro using tumor necrosis factor-alpha (TNF-alpha), (-)-epigallocatechin gallate (EGCG) from Camellia sinensis and ajoene, from Allium sativum. Natural products have potential for inducing apoptosis of adipose tissue, inhibiting bone marrow adipogenesis and increasing the expression of osteogenic factors in bone, thereby yielding effective treatments for obesity and osteoporosis.

Topics: Adipocytes; Adrenergic beta-Agonists; Animals; Anti-Obesity Agents; Apoptosis; Bone Marrow; Catechin; Cell Differentiation; Ciliary Neurotrophic Factor; Disulfides; Flavonoids; Humans; Leptin; Linoleic Acid; Mesenchymal Stem Cells; Obesity; Osteoporosis; Plant Extracts; Sulfoxides; Tumor Necrosis Factor-alpha

Osteoporosis is a disorder in which loss of bone strength leads to fragility fractures. This review examines the fundamental pathogenetic mechanisms underlying this disorder, which include: (a) failure to achieve a skeleton of optimal strength during growth and development; (b) excessive bone resorption resulting in loss of bone mass and disruption of architecture; and (c) failure to replace lost bone due to defects in bone formation. Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute. There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors. Polymorphisms of a large number of genes have been associated with differences in bone mass and fragility. It is now possible to diagnose osteoporosis, assess fracture risk, and reduce that risk with antiresorptive or other available therapies. However, new and more effective approaches are likely to emerge from a better understanding of the regulators of bone cell function.

Topics: Animals; Bone and Bones; Bone Density; Bone Remodeling; Calcium; Cell Differentiation; Collagen; Estrogens; Fractures, Bone; Glycoproteins; Hematopoietic Stem Cells; Hormones; Humans; Leptin; Ligands; Mice; Models, Biological; Neurons; NF-kappa B; Nitric Oxide; Osteoblasts; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; Parathyroid Hormone; Prostaglandins; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vitamin D; Vitamin D Deficiency

In this work, I stand out the rich endocrine role of adipocytes, that together with its function of lipidic deposit and regulating of metabolism, this confers them a central place in physiology and pathology.

Topics: Adipocytes; Adiponectin; Adolescent; Adult; Aged; Animals; Child; Diabetes Mellitus, Type 2; Female; Humans; Hypothalamus; Infant, Newborn; Insulin Resistance; Interleukins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Middle Aged; Obesity; Osteoporosis; Osteoporosis, Postmenopausal; Puberty; Rats; Tumor Necrosis Factor-alpha

Topics: Amyloid; Animals; Biomarkers; Bone and Bones; Bone Density; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Humans; Insulin; Insulin-Like Growth Factor I; Islet Amyloid Polypeptide; Leptin; Osteoblasts; Osteoporosis; Rats

It has been shown that leptin, initially discovered as an anorexigenic hormone, exerts various biological effects. We demonstrated that leptin negatively regulates bone formation via the neuronal network composed of central nervous system and sympathetic nervous system. Administration of beta-blockers in mice led to an increase in bone mass. Moreover, recent report showing that beta-blockers reduce the risk of fracture suggests their therapeutic application for osteoporosis.

Topics: Adrenergic beta-Antagonists; Animals; Fractures, Spontaneous; Humans; Leptin; Mice; Osteogenesis; Osteoporosis

There is a need for "anabolic" drugs that can directly stimulate bone growth, improve bone microarchitecture, accelerate fracture healing, and, thus, restore bone strength to osteoporosis patients and, hopefully, regenerate eroded bone in arthritis patients. The anabolic agents currently leading the way to the clinic are the parathyroid hormone (PTH) and some of its adenylyl cyclase-stimulating fragments. This article is a summary of what is known about how PTHs stimulate bone growth. The controversial bone anabolic activities of the cholesterol-lowering lipophilic statins are also described, and mechanisms by which they may stimulate bone growth are presented. Finally, evidence is presented for the body's "fat-o-stat" cytokine--leptin--indirectly restraining bone growth via a hypothalamic factor, while at the same time serving as a local PTH-like autocrine/paracrine stimulator of osteoblast activity, as well as an inhibitor of osteoclast generation.

Topics: Animals; Bone and Bones; Bone Regeneration; Cell Transformation, Neoplastic; Fractures, Bone; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Models, Animal; Osteogenesis; Osteoporosis; Parathyroid Hormone

In health, growth hormone (GH) is secreted in a circadian rhythm with superimposed pulsatility. Temporal fluctuations of hormone concentrations are essential for physiological action, and loss of diurnal rhythm is important in the development of disease. GH feedback occurs through the hypothalamus and involves neuropeptides such as somatostatin, GH-releasing hormone, GH-releasing peptides and neuropeptide Y. In addition, the same neuropeptides are involved in the regulation of other hormone axes and biological systems, thus, establishing a link through which regulation by GH may occur. Clinical features of adult growth hormone deficiency (AGHD) include abnormal body composition, reduction in quality of life, osteoporosis and increased risk of cardiovascular mortality. In health, many of the factors which regulate these features demonstrate circadian rhythmicity and pulsatility. Furthermore, AGHD is associated with abnormalities in the periodic variation of such controlling factors. GH replacement therapy, administered in the form of timed, intermittent subcutaneous injections, results in improvement of many of the clinical effects of AGHD, and is associated with normalization of the temporal fluctuations. Currently, there remains scope for further investigation of the effects of AGHD and subsequent GHR on the circadian rhythmicity of many hormones and systems; and additional studies are required to understand the physiological significance of the changes observed to date.

Topics: Adult; Blood Pressure; Cardiovascular Diseases; Circadian Rhythm; Drug Administration Schedule; Feedback, Physiological; Female; Growth Hormone; Human Growth Hormone; Humans; Hypopituitarism; Hypothalamo-Hypophyseal System; Injections, Subcutaneous; Insulin-Like Growth Factor I; Leptin; Male; Osteoporosis; Parathyroid Hormone; Pulsatile Flow; Quality of Life; Receptors, Somatotropin; Syndrome

Reduced bone mass and the increased risk of fracture in gastrointestinal diseases have a multifactorial pathogenesis. Undoubtedly, genetics play an important role, but other factors such as systemic inflammation, malnutrition, hypogonadism, glucocorticoid therapy in inflammatory bowel disease (IBD) and other lifestyle factors, such as smoking or being sedentary, may contribute to reduced bone mass. At a molecular level the proinflammatory cytokines that contribute to the intestinal immune response in IBD and probably also in coeliac disease are also known to enhance bone resorption. The discovery of the role of the receptor to activated NFkappaB (RANK) interaction with its ligand RANKL in orchestrating the balance between bone resorption and formation may link mucosal and systemic inflammation with bone remodelling, since RANK-RANKL are also involved in lymphopoiesis and T-cell apoptosis. Low circulating leptin in response to weight loss in any gastrointestinal disease may be an important factor in reducing bone mass. This report will summarize current concepts regarding gastrointestinal diseases (primarily IBD, coeliac disease and postgastrectomy states) and low bone mass and fracture.

Topics: Bone and Bones; Bone Density; Celiac Disease; Diagnosis, Differential; Gastrectomy; Gastrointestinal Diseases; Humans; Inflammatory Bowel Diseases; Leptin; Nutritional Status; Osteomalacia; Osteoporosis; Risk Factors; Vitamin D

Leptin was initially proposed to be the antiobesity hormone. Now it is realised that leptin is more a signal molecule that communicates nutritional status to the brain, and that it is involved in bone formation by having an antiosteogenic action.. Recently, Florent Elefteriou and colleagues (Endocrinology 2003; 144: 3842-47) found that hypothalamic neurons control bone mass. These researchers used monosodium glutamate to obliterate neurons in the arcuate nucleus. Previously, this group (Cell 2002; 101: 305-17) had shown that leptin inhibits bone formation by modulating the sympathetic nervous system. Although leptin influences both energy balance and bone mass by acting on the hypothalamus, the two processes involve different proteins and neurons. WHERE NEXT? Leptin has antiosteogenic activity in mice, mediated by hypothalamic nervous pathways and the sympathetic nervous system. Yet some human studies dispute leptin's antiosteogenic role. Large clinical studies are necessary to consolidate leptin's role in the physiology of human bone. In mice the beta blocker propranolol, a widely used drug with no major deleterious effects, significantly increases bone formation and bone mass without affecting bodyweight, a finding that may provide novel opportunities to design efficient bone-forming drugs for human beings.

Topics: Adrenergic beta-Antagonists; Animals; Bone Density; Energy Metabolism; Humans; Hypothalamus; Leptin; Mice; Mice, Obese; Neural Pathways; Neurons; Osteogenesis; Osteoporosis; Propranolol; Sympathetic Nervous System

The growing number of patients with osteoporosis in our aging population need "anabolic" drugs to stimulate bone growth, improve bone microarchitecture, and accelerate fracture healing. Potent anabolic agents such as parathyroid hormone (PTH) and some of its adenylyl cyclase-stimulating fragments are either on their way, or have just now reached the clinic. This article discusses how PTHs might stimulate bone growth. The controversial bone anabolic activities of the widely used cholesterol-lowering lipophilic statins and how they might stimulate bone growth are also probed. Also, evidence is presented for leptin, a controller of body fat stores and the ovarian cycle. It has the remarkable property of being an anabolic and antianabolic that uses a hypothalamic factor to restrain osteoblast activity but by itself stimulates osteoblasts and inhibits osteoclasts.

Topics: Animals; Bone and Bones; Bone Development; Bone Remodeling; Disease Models, Animal; Drug Therapy, Combination; Fractures, Spontaneous; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Osteogenesis; Osteoporosis; Parathyroid Hormone; Prognosis; Risk Assessment

Protein tyrosine phosphatases (PTPs) control signal transduction pathways and have recently emerged as potential drug targets. Inhibition of individual PTPs can result in the activation of therapeutically relevant kinase cascades. This is particularly useful in cases where disease is associated with hormonal resistance, such as insensitivity to insulin or leptin. Currently, PTP1B is being investigated by a number of companies as a promising target for leptin/insulin mimetics and in the treatment of diabetes and obesity. Since all 90-100 PTPs have been identified in the human genome, the challenge now is to identify the function of these enzymes and the therapeutic indications that may exist for specific PTP inhibitors.

Topics: Capillary Permeability; Cyclin-Dependent Kinases; Diabetes Mellitus; Drug Design; Drug Evaluation, Preclinical; Genes, Tumor Suppressor; Humans; Immune System; Infections; Insulin; Leptin; Multigene Family; Neoplasm Proteins; Neoplasms; Obesity; Osteoporosis; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Receptors, Antigen; Signal Transduction; src-Family Kinases

Osteoporosis is a condition of increasing importance and prevalence in all parts of the world and particularly in Asia. Recent advances have led to the introduction of effective drugs that decrease bone resorption and stabilize bone mass. However, these drugs have been identified by serendipity rather than rational drug design and are not ideal because of limited bioavailability, mode of administration, or other unwanted effects. There is still a place for even more suitable and effective resorption inhibitors than those currently available. The more compelling need in this field is an acceptable drug that is anabolic for bone, that safely and acceptably increases bone mass and improves the disturbances in bone microarchitecture that characterize established and advanced osteoporosis. Possible approaches to identifying more effective resorption inhibitors and new anabolic agents are discussed.

Topics: Animals; Bone Resorption; Cross-Cultural Comparison; Cysteine Endopeptidases; Diphosphonates; Humans; Hydroxymethylglutaryl CoA Reductases; Leptin; Multienzyme Complexes; Osteoblasts; Osteoporosis; Proteasome Endopeptidase Complex

Eating disorders are an important health concern among adolescents. Young women frequently present with signs and symptoms of anorexia nervosa and bulimia nervosa. These disorders represent clinically significant illnesses with serious and sometimes permanent medical complications, including a number of endocrine conditions, that, in general, result from the body s adaptive response to malnutrition. Examples include disorders of metabolism, cortisol and leptin regulation, fluid and electrolyte homeostasis, thyroid function, glucose regulation, growth and development, and reproductive function with the development of amenorrhea as well as the risk of osteoporosis.

Topics: Adolescent; Adult; Amenorrhea; Anorexia Nervosa; Bulimia; Diabetes Mellitus, Type 1; Diagnosis, Differential; Endocrine System Diseases; Feeding and Eating Disorders; Female; Humans; Hydrocortisone; Leptin; Osteoporosis; Thyroid Hormones; Water-Electrolyte Balance

Vertebrates constantly remodel bone to maintain a constant bone mass. Bone remodeling comprises two phases: bone resorption by the osteoclasts followed by bone formation by the osteoblasts. Although the prevailing view about the control of bone remodeling is that it is an autocrine/paracrine phenomenon, the bone resorption arm of bone remodeling is under a tight endocrine control. To date little is known about the regulation of bone formation. We took the observations that gonadal failure favors bone loss and obesity protects from it as an indication that bone mass, body weight, and reproduction could be regulated by the same hormone(s). Leptin is one of these hormones. Leptin inhibits bone formation by the osteoblasts. This function is dominant, and leptin deficiency results in a high bone mass phenotype despite the hypogonadism characterizing these animals. Genetic biochemical and physiological studies demonstrate that leptin inhibits bone formation following its binding to its receptor in the hypothalamus. These results are the first evience that bone remodeling is a hypothalamic process; they imply necessarily that osteoporosis, the most frequent bone remodeling disease, is partly at least a hypothalamic disease. This finding also has therapeutic implications.

Topics: Animals; Autocrine Communication; Bone Development; Bone Remodeling; Humans; Leptin; Obesity; Osteoporosis

Topics: Animals; Bone Remodeling; Gene Expression Regulation; Humans; Hypothalamus; Leptin; Mice; Osteoporosis

Topics: Animals; Bone and Bones; Bone Remodeling; Endocrine Glands; Humans; Hypothalamus; Leptin; Mice; Mice, Obese; Osteogenesis; Osteoporosis

The means by which obesity leads to high bone density and protects individuals from osteoporosis is not known. The study of bone biology in two mouse models of obesity, leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice, points to a role for leptin in the control of bone density. When leptin action is missing in these mice, bone density is high. This is true despite concurrent hypogonadism and hypercortisolism, two strong proresorptive signals that would normally lead to low bone density. Curiously, leptin does not have a direct effect on osteoblasts, which suggests the existence of a central, neuroendocrine pathway that controls bone mass.

Topics: Animals; Bone Density; Leptin; Mice; Mice, Obese; Obesity; Osteoporosis

This study was to investigate the effect of proprioceptive neuromuscular facilitation techniques (NFT) on osteoporosis and serum leptin level in cerebral infarction patients or rats.. Forty cerebral infarction rats were randomly grouped into control, sham operation, conventional treatment (CT) group and CT+NFT group. Fifty-two stroke patients with hemiplegia were included in this study.. The bone mineral densities (BMD) of proximal hemiplegia limbs and serum ALP, BALP, BGP, IL-6 and leptin levels were detected using commercial kits.. In cerebral infarction rats, the BMD, BGP, BALP, ALP and leptin concentrations in the CT+NFT group was higher compared with the control and CT group, while serum IL-6 level was more reduced by CT+NFT than control and CT. In cerebral infarction patients, both CT and CT+NFT increased the BMD, ALP, BGP and leptin levels. In addition, compared with CT, the BMD, ALP, BGP and leptin levels were markedly increased by CT+NFT. C Conclusion: NFC elevated the BMD of hemiplegia limbs, serum ALP, BGP, IL-6 and leptin levels and, thus, alleviated osteoporosis in rats and patients with cerebral infarction.

Topics: Aged; Analysis of Variance; Animals; Bone Density; Cerebral Infarction; Disease Models, Animal; Female; Follow-Up Studies; Hemiplegia; Humans; Leptin; Magnetic Resonance Imaging; Male; Middle Aged; Muscle Stretching Exercises; Osteoporosis; Rats; Tomography Scanners, X-Ray Computed

Low-dose radon hyperthermia balneo treatment (LDRnHBT) is applied as a traditional measure in the non-pharmacological treatment of rheumatic diseases in Europe. During the last decades, the main approach of LDRnHBT was focused on the treatment of musculoskeletal disorders, but scientific evidence for the biological background of LDRnHBT is weak. Recently, evidence emerged that LDRnHBT influences bone metabolism. We investigated, whether combined LDRnHBT and exercise treatment has an impact on bone metabolism and quality of life in a study population in an age group at risk for developing osteoporosis. This randomized, double-blind, placebo-controlled trial comprised guided hiking tours and hyperthermia treatment in either radon thermal water (LDRnHBT) or radon-free thermal water (PlaceboHBT). Markers of bone metabolism, quality of life and somatic complaints were evaluated. Statistics was performed by linear regression and a linear mixed model analysis. Significant changes over time were observed for most analytes investigated as well as an improvement in self-assessed health in both groups. No significant impact from the LDRnHBT could be observed. After 6 months, the LDRnHBT group showed a slightly stronger reduction of the osteoclast stimulating protein receptor activator of nuclear kB-ligand compared to the PlaceboHBT group, indicating a possible trend. A combined hyperthermia balneo and exercise treatment has significant immediate and long-term effects on regulators of bone metabolism as well as somatic complaints. LDRnHBT and placeboHBT yielded statistically equal outcomes.

Topics: Adrenocorticotropic Hormone; Balneology; Bone and Bones; Bone Resorption; Double-Blind Method; Exercise Therapy; Female; Humans; Leptin; Male; Middle Aged; Osteocalcin; Osteogenesis; Osteoporosis; Osteoprotegerin; Parathyroid Hormone; Quality of Life; Radon; RANK Ligand

Major depressive disorder (MDD) has been associated with adverse medical consequences, including cardiovascular disease and osteoporosis. Patients with MDD may be classified as having melancholic, atypical, or undifferentiated features. The goal of the present study was to assess whether these clinical subtypes of depression have different endocrine and metabolic features and consequently, varying medical outcomes.. Premenopausal women, ages 21 to 45 years, with MDD (N = 89) and healthy controls (N = 44) were recruited for a prospective study of bone turnover. Women with MDD were classified as having melancholic (N = 51), atypical (N = 16), or undifferentiated (N = 22) features. Outcome measures included: metabolic parameters, body composition, bone mineral density (BMD), and 24 hourly sampling of plasma adrenocorticotropin (ACTH), cortisol, and leptin.. Compared with control subjects, women with undifferentiated and atypical features of MDD exhibited greater BMI, waist/hip ratio, and whole body and abdominal fat mass. Women with undifferentiated MDD characteristics also had higher lipid and fasting glucose levels in addition to a greater prevalence of low BMD at the femoral neck compared to controls. Elevated ACTH levels were demonstrated in women with atypical features of depression, whereas higher mean 24-hour leptin levels were observed in the melancholic subgroup.. Pre-menopausal women with various features of MDD exhibit metabolic, endocrine, and BMD features that may be associated with different health consequences.. ClinicalTrials.gov NCT00006180.

Topics: Adrenocorticotropic Hormone; Adult; Alendronate; Biomarkers; Body Composition; Bone Density; Circadian Rhythm; Depressive Disorder, Major; Endocrine System; Female; Humans; Hydrocortisone; Laboratories; Leptin; Middle Aged; Osteoporosis; Premenopause; Reproducibility of Results; Young Adult

The thiazolidinedione (TZD) class of antidiabetic drugs has been shown to inhibit the formation of bone-resorbing osteoclasts in vitro and to decrease bone resorption markers in vivo. These drugs also inhibit the expression of leptin in adipocytes. Less leptin can be associated with higher bone mass, based on analyses of mice deficient in leptin action. Effects of 1-year treatment with troglitazone, a member of the TZDs, on bone mineral density (BMD) and bone metabolism were examined in 25 Japanese type 2 diabetic patients. Glucose metabolism was improved, whereas body mass index and percent body fat did not change throughout the study. The percent change of BMD was negatively correlated with that of serum leptin, whereas it was not associated with changes of bone metabolic markers, type I collagen N-telopeptide (NTx), bone alkaline phosphatase (ALP), body mass index, or HbA1c. Serum leptin decreased in 68% of subjects (responders) after 1-month treatment and was consistently lower than the basal level throughout the treatment. Percent changes of BMD were significantly higher in the responders than in the nonresponders and in nondiabetic subjects at 6 and 12 months. NTx and bone ALP decreased at 1 month but increased thereafter in either group of patients. Thus, it is suggested that the decrease in serum leptin with no reduction in body fat mass by troglitazone is associated with preventing bone loss in type 2 diabetic patients. Hence, TZDs may have an advantage for diabetic patients who have risk factors for osteoporosis.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Bone Density; Chromans; Collagen; Collagen Type I; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Leptin; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis; Peptides; Prospective Studies; Thiazolidinediones; Troglitazone

The goal was to investigate the correlations of peripheral blood Omentin-1 and leptin (LEP) levels with bone metabolism and plasma glucose in patients with type 2 diabetes mellitus (T2DM) complicated with oste-oporosis (OP).. One hundred patients with T2DM admitted from September 2019 to September 2021 were divided into group A (n = 36, OP with T-score ≤ -2.5), group B (n = 50, osteopenia with T-score between -1 and -2.5), and group C (n = 14, non-OP with T-score > -1) according to the values of bone mineral density (BMD). Thirty healthy adults physically examined in the same period were selected as group D. The levels of peripheral blood Omentin-1 and LEP, bone metabolism, and plasma glucose were compared among the four groups. The correlations of peripheral blood Omentin-1 and LEP levels with bone metabolism and plasma glucose were explored by Pearson's analysis.. In group A, the levels of Omentin-1 and LEP in peripheral blood were lowest, the serum levels of beta C-terminal cross-linked telopeptides of type I collagen (β-CTX) and osteocalcin (OCN) were highest, the serum level of total N-terminal propeptide of type I procollagen (tPINP) was lowest, and the levels of fasting plasma glucose (FPG), 2-hours postprandial plasma glucose (2hPG) and glycosylated hemoglobin A1c (HbA1c) were highest, se-quentially followed by those of group B, group C, and group D (p < 0.05). Omentin-1 and LEP in peripheral blood were negatively correlated with β-CTX, OCN, 2hPG, and HbA1c and positively correlated with tPINP and FPG (p < 0.05).. The expressions of Omentin-1 and LEP in peripheral blood have correlations with bone metabolism and plasma glucose in patients with T2DM complicated with OP.

Topics: Adult; Blood Glucose; Bone Density; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Leptin; Osteoporosis

The current study aims to investigate the regulatory impact of leptin or melatonin on bone metabolism as well as the underlying mechanism in conjunction with Sema4D (monoclonal antibody to semaphorin 4D).. Rats were used to create the osteoporosis model utilizing the OVX (OVariectomize) technique. Rat tibial specimens from each side were collected for three-dimensional reconstruction and Micro-CT scanning examination. The Hematoxylin-osinstaining (HE) staining technique was used to determine the pathological condition of bone tissues. The ELISA (Enzyme-Linked Immunosorbent Assay) assay was used to measure the amount of estradiol present in the serum. In the current study, there were six groups: control, OVX, OVX + NL (no load group), OVX + Sema4D, OVX + Sema4D + leptin, and OVX + Sema4D + MT (melatonin). Rats were given injections of the Sema4D or leptin overexpressing vectors via the tail vein in accordance with the aforementioned classification. By using a high-resolution micro-CT technology, 3D bone structure was discovered. The activity of tartrate-resistant acid phosphatase-5b (TRAP-5b) and bone-derived alkaline phosphatase (BALP) in serum was assessed using an ELISA. The number of osteoclasts in the metaphysis of the upper tibia was determined using TRAP (tartrate-resistant acid phosphatase) staining. Immunohistochemistry was used to find leptin and bone morphogenetic protein-2 (BMP-2) expressions in bone tissue.. The BV/TV (Bone volume/Tissue volume), Tb.N (Trabecular number), BMD (Bone Mineral Density), and BMC (Bone Mineral Content) levels were significantly higher in the OVX + Sema4D + leptin and OVX + Sema4D + MT groups compared to OVX + NL, while Tb.Sp (Trabecular separation) levels were significantly lower. In contrast to the OVX group, the bone trabeculae in the OVX + Sema4D + leptin and OVX + Sema4D + MT groups had a relatively complete structure and tended to be organized closely. The amount of bone trabeculae grew drastically, whereas the proportion of TRAP-positive osteoclasts declined dramatically. BMP-2 and leptin were also elevated, while BALP and TRAP-5b activity was reduced.. Leptin or melatonin improved Sema4d's role in trabecular bone microstructure, bone production, and repairment of trabecular bone loss in osteoporosis rats.

Topics: Animals; Bone Density; Female; Humans; Leptin; Melatonin; Osteoporosis; Ovariectomy; Rats; Rats, Sprague-Dawley; Tartrate-Resistant Acid Phosphatase; X-Ray Microtomography

This study aims to examine the effects of leptin and melatonin intervention on bone metabolism in ovariectomize (OVX) rodents, as well as their potential mechanisms of action.. Prepare an OVX model of osteoporosis in rodents and validate the model by collecting bilateral tibia samples for Micro-CT scanning and histological analysis. A control group of normal size, the OVX group, the OVX+Sema4D (Semaphorin 4D) group, the OVX+Sema4D+Leptin group, the OVX+Sema4D+ Melatonin(MT) group and the OVX+Sema4D+Leptin+ MT group were the experimental groups. Adenovirus vector construction and tibial medullary injection validation were conducted in accordance with the aforementioned experimental groups. Four groups of rats were injected with the Sema4D overexpression adenovirus vector into the tibial medullary cavity, and two groups were injected with the Leptin overexpression adenovirus vector. The repair of osteoporosis was observed using micro-CT and histological analysis. Immunohistochemical detection of bone morphogenetic protein-2 (BMP-2) expression in bone tissue was employed to ascertain the amount of osteoclasts in the upper tibial metaphysis, utilizing TRAP(tartrate-resistant acid phosphatase) staining.. Increased levels of BV/TV, Tb.N, BMD, and BMC were seen in the OVX+ Sema4D+Leptin, OVX+ Sema4D+MT, and OVX+ Sema4D+Leptin+ MT groups compared to the OVX group, whereas Tb. Sp levels were lowered. When compared to the Sema4D overexpression group, the trabecular bone structure of the OVX + Sema4D + Leptin, OVX + Sema4D + MT, and OVX + Sema4D + Leptin + MT groups is largely intact, tends to be closer, and the amount of trabecular bone increases. The OVX + Sema4D + Leptin + MT group in particular.The expression of BMP-2 was dramatically upregulated (p<0.05), the number of TRAP-stained osteoclasts was significantly reduced (p<0.05), and BALP(bone-derived alkaline phosphatase) and TRAP-5b(tartrate-resistant acid phosphatase-5b) activities were significantly downregulated (p<0.05).. In rats with osteoporosis, leptin and melatonin can be seen to augment the trabecular microstructure of the bone, augment bone growth, diminish trabecular harm, and mend the bone. The combined effect is more powerful.

Topics: Animals; Bone Density; Leptin; Melatonin; Osteoporosis; Rats; Rats, Sprague-Dawley; Rodentia; Tartrate-Resistant Acid Phosphatase; X-Ray Microtomography

Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease in adults that is associated with significant joint issues and systemic inflammation. One of the signs of bone damage in RA is osteoporosis (OP). Leptin is an inflammatory protein that has been reported to be related to RA. The potential relationships among leptin, disease activity, and OP in Chinese patients with RA are not well known.. In total, 245 patients with RA and 120 healthy controls were included in this study. Detailed data on the clinical characteristics and laboratory features were collected. Information about physical activity and functional status was recorded using specific questionnaires. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). The MECALL castor-50-hf model X-ray scanner was used for the two-hand (including wrist) photographs.. Serum leptin levels differed significantly between the RA group and healthy control subjects (1.27/3.29 vs. 0.17/0.24, Z=13.29, P<0.001). The positive rate of leptin protein in RA patients was 86.35%, which was higher than that in controls (19.55%) (χ. These results suggest that the level of serum leptin is associated with disease activity and secondary OP among Chinese patients with RA. Key Points • Serum leptin levels in RA patients are higher than those in normal control group. • Leptin was associated with disease activity. • Leptin was associated with the occurrence of systemic osteoporosis and affects bone erosion in RA patients.

Topics: Absorptiometry, Photon; Adult; Arthritis, Rheumatoid; Bone Density; East Asian People; Humans; Leptin; Osteoporosis

Diabetic osteoporosis is a poorly managed serious skeletal complication, characterized by high fracture risk, increased bone resorption, reduced bone formation, and disrupted bone architecture. There is a need to investigate drugs that can improve bone health along with managing glycemic control. DPP-4 inhibitors and metformin have proven benefits in improving bone health. Here, we investigated the effects of linagliptin, a DPP inhibitor, and metformin alone and in combination to treat diabetic osteoporosis in high-fat-fed mice.. C57BL/6 mice were kept on the high-fat diet (HFD) for 22 weeks to induce diabetic osteoporosis. Linagliptin (10mg/Kg), metformin (150mg/Kg), and their combination were orally administered to the diabetic mice from the 18. HFD feeding resulted in impaired bone microarchitecture, reduced BMD, distorted bone histology, and altered bone turnover biomarkers as indicated by the significant reduction in bone ALP, BMP-2, osteocalcin, and an increase in sclerostin, TRAP, and serum calcium. Interestingly, treatment with linagliptin and its combination with metformin significantly reverted the impaired bone architecture, BMD, and positively modulated bone turnover biomarkers, while metformin alone did not exhibit any significant improvement. Further, HFD induced diabetes and metabolic abnormalities (including an increase in body weight, FBG, impaired glucose and insulin tolerance, leptin, triglycerides, cholesterol), and pro-inflammatory cytokines (TNF-alpha and IL-1β) were successfully reversed by treatment with linagliptin, metformin, and their combination.. Linagliptin and its combination with metformin successfully ameliorated diabetic osteoporosis in HFD-fed mice possibly through modulation of BMP-2 and sclerostin. The study provides the first evidence for the possible use of linagliptin and metformin combination for managing diabetic osteoporosis.

Topics: Animals; Biomarkers; Body Weight; Calcium; Cytokines; Diabetes Mellitus, Experimental; Diet, High-Fat; Glucose; Insulin; Leptin; Linagliptin; Metformin; Mice; Mice, Inbred C57BL; Osteocalcin; Osteoporosis

Topics: Adipocytes; Amino Acid Transport Systems, Neutral; Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Line; Diet, High-Fat; Homeodomain Proteins; Intra-Abdominal Fat; Leptin; Mice; Mice, Inbred C57BL; MicroRNAs; Osteoblasts; Osteoporosis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Peroxisomes; Receptors, Purinergic P2X5; Symporters; Thermogenesis; Uncoupling Protein 1

MicroRNAs (miRNAs) regulate osteogenic differentiation and influence osteoporosis (OP). The aim of this study was to determine the potential role of miR-874-3p in OP. The expression levels of miR-874-3p and leptin (LEP) in the femoral neck trabeculae of 35 patients with or without OP were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The effects of miR-874-3p or LEP on the cell proliferation and alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osterix (OSX) levels were observed by upregulating miR-874-3p in human bone marrow mesenchymal stem cells (hBMSCs). Additionally, calcium deposition levels were evaluated using alizarin red staining (ARS). Molecular mechanisms of miR-874-3p and LEP underlying the osteogenic differentiation of hBMSCs were also evaluated using bioinformatics analysis, luciferase reporter assays, and RNA pull-down assays. The miR-874-3p levels were significantly lower in the femoral neck trabeculae of patients with OP than those of the control group, while the opposite was observed regarding the levels of LEP. Expression levels of miR-874-3p in hBMSCs were upregulated during osteogenic differentiation, while those of LEP were downregulated. Moreover, miR-874-3p upregulation promoted ALP, RUNX2, OCN, and OSX mRNA expression, cell proliferation, and calcium deposition in hBMSCs. LEP was found to be a target gene of miR-874-3p. Overexpression of LEP inhibited the expression of osteoblast markers and reversed the effect of osteogenic differentiation induced by the upregulation of miR-874-3p. In conclusion, miR-874-3p promoted the proliferation and differentiation of hBMSCs by downregulating the expression of LEP, thus inhibiting OP.

Topics: Cell Differentiation; Gene Expression Regulation, Neoplastic; Gene Ontology; Humans; Leptin; Mesenchymal Stem Cells; MicroRNAs; Osteoblasts; Osteogenesis; Osteoporosis

Although alterations in the plasma levels of leptin, glucagon-like peptide-1, and gastrin were linked with bariatric surgery outcomes, gastric production of these peptides was not elucidated before.. The aim was to evaluate the impact of estrogen depletion and estrogen receptors (ERs) on sleeve gastrectomy (SG)-induced alterations in gastric hormone production, gastric mucosal integrity, and bone mass.. Physiology Research Lab at the University.. Female Sprague-Dawley rats underwent ovariectomy or sham operation (control), and 2 months later SG or sham SG was performed. Rats received either nonselective agonist 17 β, ER-α agonist, ER-β agonist, or vehicle for 3 weeks. Trunk blood and gastric tissues were collected for biochemical measurements, while histopathologic examination was performed in gastric and femur samples.. In the presence of intact ovaries, SG-induced weight loss was accompanied by reductions in the gastric synthesis of leptin and gastrin, while gastric glucagon-like peptide-1 was additionally decreased when SG was performed at the postmenopausal state. SG elevated the depleted serum estradiol levels of menopause, implicating a beneficial effect, but the occurrence of severe gastric mucosal injury was triggered. On the other hand, using ER agonists upregulated gastrin-expressing cells, ameliorated gastric injury, and improved bone loss.. SG, either at premenopausal or postmenopausal state, resulted in considerable loss in bone mass, along with reductions in the gastric levels of gastrin and leptin. Functional status of the ovaries needs to be taken into consideration when monitoring the outcomes of SG, and ER agonists could be of value in controlling SG-induced complications.

Topics: Animals; Estrogens; Female; Gastrectomy; Gastric Stump; Gastrins; Leptin; Osteoporosis; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptors, Estrogen

Long-term caloric restriction (CR) has been shown to be beneficial to various tissues and organs. In contrast, CR exerts differential effects on bone, which could be due in part to the nature of the protein regime utilized. Male Sprague Dawley rats (8-month-old) were subjected for 12 months to 40% CR in macronutrients and compared with rats fed ad libitum for the same period. Casein- and soy-fed groups were compared. There was a significant decrease in bone quality in both CR groups, which was independent of the source of protein in the diet. In contrast, the group fed soy protein ad libitum showed better bone quality and higher levels of bone formation compared with casein-fed animals. Notably, bone marrow adipocytes were not mobilized upon CR as demonstrated by an absence of change in adipocyte number and tissue expression of leptin. This study demonstrates that the negative effect of CR on bone quality could not be prevented by the most common protein regimes.

Topics: Adipocytes; Adipose Tissue; Aging; Animals; Bone Marrow; Caloric Restriction; Caseins; Dietary Proteins; Disease Models, Animal; Leptin; Male; Osteogenesis; Osteoporosis; Rats; Rats, Sprague-Dawley; Soybean Proteins

The alternation of resorption of preexisting bone by the osteoclasts followed by de novo bone formation by osteoblasts is called bone modeling during childhood and bone remodeling during adulthood. A central question raised by this physiological process that is fundamental to longitudinal growth during childhood and adolescence and that is attacked at the other end of life in the context of osteoporosis is to know how it is regulated. This question was rejuvenated in the late 1990s and early 2000s years when the application of mouse genetics made it feasible to test whether there were new endocrine determinants of bone (re)modeling. Addressing this question, taking into account fundamental cell biology features of bone led to the hypothesis that there should be a coordinated control of bone growth/mass, energy metabolism, and reproduction. Testing genetically and molecularly, this hypothesis revealed that, in vivo, the adipocyte-derived hormone leptin is a powerful inhibitor of bone mass accrual following its signaling in the brain. This chapter details the molecular bases and biological relevance of this regulation of bone mass accrual by leptin.

Topics: Animals; Bone Remodeling; Leptin; Mice; Osteoblasts; Osteoporosis

Glucocorticoid therapy, especially at higher doses, is associated with significant adverse side effects including osteoporosis. Leptin, secreted from adipose tissue, has diverse effects on bone tissue regulation. As glucocorticoids stimulate leptin synthesis and secretion directly in adipose tissue we hypothesised that dexamethasone (DEX) induced osteoporosis may, in part, be mediated by an osteoblast dependent leptin-leptin receptor pathway. Human bone cells expressed leptin and leptin receptors (Ob-Ra and Ob-Rb). DEX increased leptin, Ob-Ra and Ob-Rb expression in a dose-dependent manner while decreasing expression of osteocalcin. In the presence of leptin, Cbfa1 and osteonectin expression showed no significant change, whereas osteocalcin expression was decreased. Recombinant human quadruple antagonist leptin suppressed DEX-induced osteocalcin downregulation. The signaling pathway involved up-regulation of JAK2. In conclusion, upregulation of leptin and Ob-Rb in human bone cells by DEX is associated with down-regulation of osteocalcin expression. The down regulation of osteocalcin by DEX was partially through a leptin autocrine/paracrine loop. Adverse effects of DEX on the skeleton may be modified by targeting leptin signaling pathways.

Topics: Bone and Bones; Cell Culture Techniques; Core Binding Factor Alpha 1 Subunit; Dexamethasone; Gene Expression Regulation; Humans; Janus Kinase 2; Leptin; Osteoblasts; Osteocalcin; Osteocytes; Osteoporosis; Receptors, Leptin; Signal Transduction

Osteoporosis is associated with widespread periodontitis and impaired periodontal healing. However, there is a lack of information about the outcomes of regenerative approaches under the influence of osteoporosis. This study investigates the effect of leptin (LEP) overexpression on the regenerative potential of bone marrow stromal cells (BMSCs) in an osteoporotic rat periodontal fenestration defect model.. Rat BMSCs were transfected with adenoviruses harboring the human (h)LEP gene. Cell proliferation and osteogenic differentiation were evaluated. A β-tricalcium phosphate scaffold seeded with transfected cells was implanted into nude mice to investigate ectopic osteogenesis and into an osteoporotic rat defect to study periodontal regeneration. Regenerated periodontal and bone-like tissues were analyzed by histologic methods.. hLEP overexpression induced osteogenic differentiation of BMSCs as evidenced by the upregulation of osteogenesis-related genes such as Runt-related transcription factor 2, alkaline phosphatase (ALP), and collagen Type I, as well as increased ALP activity and enhanced mineralization. Mice implanted with hLEP-BMSC-containing scaffolds showed more extensive formation of bone-like tissue than those in other groups. Periodontal defects were also filled to a greater degree when treated with hLEP-BMSCs and contained cementum and a well-organized periodontal ligament after 10 and 28 days.. hLEP overexpression in BMSCs can stimulate periodontal regeneration in osteoporotic conditions and might be a promising strategy for periodontal regeneration in patients with osteoporosis.

Topics: Animals; Bone Marrow Cells; Bone Regeneration; Calcium Phosphates; Cell Differentiation; Cell Proliferation; Coculture Techniques; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Leptin; Mesenchymal Stem Cells; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron, Scanning; Osteoporosis; Periodontal Diseases; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Tissue Scaffolds; Transfection

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

Notwithstanding compelling contribution of NF-κB to the progression of osteoporosis has been reported, little is known regarding direct inhibition of NF-κB benefiting osteoporosis. In this study, therefore, we evaluated the role of celastrol, an NF-κB inhibitor, in a mouse model of secondary osteoporosis. Animals were divided into three groups as Sham (control), SO (secondary osteoporosis) and SO + CA (secondary osteoporosis treated with celastrol). Significant decreases in body weight and body fat were observed following celastrol treatment in SO group, but leptin levels were much higher. Celastrol also exhibited a significant decrease in urinary calcium excretion. Moreover, other important events were observed after celastrol treatment, covering substantial decrements in serum concentrations of PTH, TRAP-5b, CTX and DPD, improved structure of articular cartilage and cancellous bone (revealed by H&E and safranin-O staining), and significant decline in levels of NF-κB (P65), MMP-1, and MMP-9. These findings demonstrated that celastrol treatment not only improved abnormal lipid metabolism and hypercalciuria in mice subjected to secondary osteoporosis, but also ameliorated articular cartilage lesions. Our results provided evidence of targeted therapy for NF-κB in the clinical treatment of secondary osteoporosis.

Topics: Adipose Tissue; Animals; Body Weight; Cartilage, Articular; Disease Models, Animal; Disease Progression; Hypercalciuria; Leptin; Lipid Metabolism; Male; Mice, Inbred C57BL; Molecular Targeted Therapy; NF-kappa B; Osteoporosis; Parathyroid Hormone; Pentacyclic Triterpenes; Triterpenes

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

Epidemiological studies suggest an increased fracture risk in patients taking proton pump inhibitors (PPIs) for long term. The underlying mechanism, however, has been disputed. By binding to the gastric proton pump, PPIs inhibit gastric acid secretion. We have previously shown that proton pump (H(+)/K(+)ATPase beta subunit) KO mice exhibit reduced bone mineral density (BMD) and inferior bone strength compared with WT mice. Patients using PPIs as well as these KO mice exhibit gastric hypoacidity, and subsequently increased serum concentrations of the hormone gastrin. In this study, we wanted to examine whether inhibition of the gastrin/CCK2 receptor influences bone quality in these mice. KO and WT mice were given either the gastrin/CCK2 receptor antagonist netazepide dissolved in polyethylene glycol (PEG) or only PEG for 1year. We found significantly lower bone mineral content and BMD, as well as inferior bone microarchitecture in KO mice compared with WT. Biomechanical properties by three-point bending test also proved inferior in KO mice. KO mice receiving netazepide exhibited significantly higher cortical thickness, cortical area fraction, trabecular thickness and trabecular BMD by micro-CT compared with the control group. Three-point bending test also showed higher Young's modulus of elasticity in the netazepide KO group compared with control mice. In conclusion, we observed that the gastrin receptor antagonist netazepide slightly improved bone quality in this mouse model, suggesting that hypergastrinemia may contribute to deteriorated bone quality during acid inhibition.

Topics: Absorptiometry, Photon; Adaptor Proteins, Signal Transducing; Animals; Benzodiazepinones; Bone and Bones; Bone Density; Drug Evaluation, Preclinical; Female; Gastrins; Glycoproteins; H(+)-K(+)-Exchanging ATPase; Intercellular Signaling Peptides and Proteins; Leptin; Mice, Inbred BALB C; Mice, Knockout; Osteocalcin; Osteoporosis; Phenylurea Compounds; Proton Pump Inhibitors; RANK Ligand; Receptor, Cholecystokinin B; Stomach; X-Ray Microtomography

Thuja occidentalis L. (Cupressaceae) has been used in folk medicine for the treatment of rheumatism, amenorrhea, cystitis, and uterine carcinomas, and as an abortifacient and contraceptive.. The present study aimed to determine whether T. occidentalis oil and α-thujone could be beneficial in the treatment of polycystic ovary syndrome (PCOS).. T. occidentalis oil and α-thujone were administered to rats with letrozole-induced PCOS for 21 days. At the end of 21 days, the rats were sacrificed and blood samples were taken by cardiac puncture. The levels of serum gonadotropins, steroids, blood lipid, leptin, and glucose and the values of antioxidant parameters were measured.. The results demonstrated that estradiol and progesterone levels significantly increased, while luteinizing hormone (LH) and testosterone levels decreased in the T. occidentalis- and α-thujone-administered groups. The plasma low-density lipoprotein-cholesterol (LDL-C), leptin, and glucose concentrations were also significantly decreased in the T. occidentalis and α-thujone groups when compared to the control group. Histopathological findings demonstrated that the T. occidentalis and α-thujone groups displayed good healing. According to the phytochemical analyses, 25 compounds were identified in the T. occidentalis oil. The main constituents of the oil were the monoterpene ketones α- and β-thujone, fenchone, and sabinene, as well as the diterpenes beyerene and rimuene.. T. occidentalis essential oil and its active component, α-thujone, can be used for the treatment of PCOS without inducing osteoporosis.

Topics: Animals; Bicyclic Monoterpenes; Blood Glucose; Catalase; Estradiol; Female; Glutathione Peroxidase; Leptin; Letrozole; Lipids; Luteinizing Hormone; Malondialdehyde; Monoterpenes; Nitriles; Oils, Volatile; Osteoporosis; Phytotherapy; Polycystic Ovary Syndrome; Progesterone; Rats, Sprague-Dawley; Superoxide Dismutase; Testosterone; Thuja; Triazoles

Osteoporosis leads to increased bone fractures and net bone loss, in part because of the dysfunction of bone marrow stromal cells (BMSCs). Leptin is an adipokine that plays important roles in many biological processes, including the regulation of the actions of mesenchymal stem cells. Our aim is to investigate the osteogenic effects of leptin in osteoporotic BMSCs in vitro and in vivo. The leptin gene was transferred into BMSCs isolated from osteoporotic rats by using recombinant adenoviruses. Once the gene and protein expression of leptin had been confirmed, MTT assays were performed; leptin overexpression was confirmed not to affect the viability of osteoporotic BMSCs. However, alkaline phosphatase (ALP) activity measurements, Alizarin red staining and analyses by quantitative real-time reverse transcription with the polymerase chain reaction revealed that leptin upregulated ALP activity, mineral deposition and the mRNA levels of runt-related transcription factor 2, ALP and collagen type І. Lastly, the effects of leptin on osteogenic differentiation were assessed in vivo. Cells transfected with leptin exhibited increased osteogenic differentiation and enhanced formation of bone-like structures. This study thus reveals, for the first time, that the overexpression of leptin in osteoporotic BMSCs (1) enhances their capacity to differentiate into osteoblasts and to form bone-like tissue and (2) might be a useful skeletal regenerative therapy in osteoporotic patients.

Topics: Animals; Bone and Bones; Bone Marrow Cells; Cell Differentiation; Cell Proliferation; Cells, Cultured; Female; Leptin; Mesenchymal Stem Cells; Osteoblasts; Osteogenesis; Osteoporosis; Rats, Sprague-Dawley

This study investigated the effects of green tea polyphenols (GTP) supplementation on body composition, bone properties, and serum markers in obese rats fed a high-fat diet (HFD) or a caloric restricted diet (CRD). Forty-eight female rats were fed an HFD ad libitum for 4 months, and then either continued on the HFD or the CRD with or without 0.5% GTP in water. Body composition, bone efficacy, and serum markers were measured. We hypothesized that GTP supplementation would improve body composition, mitigate bone loss, and restore bone microstructure in obese animals fed either HFD or CRD. CRD lowered percent fat mass; bone mass and trabecular number of tibia, femur and lumbar vertebrae; femoral strength; trabecular and cortical thickness of tibia; insulin-like growth factor-I and leptin. CRD also increased percent fat-free mass; trabecular separation of tibia and femur; eroded surface of tibia; bone formation rate and erosion rate at tibia shaft; and adiponectin. GTP supplementation increased femoral mass and strength (P = .026), trabecular thickness (P = .012) and number (P = .019), and cortical thickness of tibia (P < .001), and decreased trabecular separation (P = .021), formation rate (P < .001), and eroded surface (P < .001) at proximal tibia, and insulin-like growth factor-I and leptin. There were significant interactions (diet type × GTP) on osteoblast surface/bone surface, mineral apposition rate at periosteal and endocortical bones, periosteal bone formation rate, and trabecular thickness at femur and lumbar vertebrate (P < .05). This study demonstrates that GTP supplementation for 4 months benefited body composition and improved bone microstructure and strength in obese rats fed with HFD or HFD followed by CRD diet.

Topics: Adiponectin; Adipose Tissue; Animals; Body Composition; Body Fluid Compartments; Bone and Bones; Bone Density; Caloric Restriction; Camellia sinensis; Diet, High-Fat; Dietary Supplements; Energy Intake; Female; Insulin-Like Growth Factor I; Leptin; Obesity; Osteogenesis; Osteoporosis; Phytotherapy; Plant Extracts; Polyphenols; Rats, Sprague-Dawley

Fat-bone relationship involves the interaction among endocrine, inflammatory, immune processes and bone turnover. We tried to assess the association between Leptin and bone turnover markers (OCN, β-CTx, ALP), calciotropic hormones PTH and 25(OH)D in obese Saudi children.. A cross-sectional study performed with 60 obese children and 36 lean children. For all subjects, OCN, ALP, β-CTx, PTH, 25(OH)D, leptin, Ca and Pi were investigated. Levels of leptin were measured by [ELISA] method, and OCN, β-CTx, PTH and 25-(OH)D by an electrochemiluminescence immunoassay.. Sixty obese Saudi children had means weight (38.3 vs. 13.8 kg), height (121.0 vs. 91.8 cm) leptin (23.04 vs.16.88 ng/ml), PTH (31.5 vs. 14.7 pg/ml), Pi (1.67 vs. 1.54 mmol/l) were significantly higher and 25(OH)D (21.02 vs. 29.45 ng/ml) was significantly lower than controls. There was no difference in serum OCN, β-CTx, ALP and calcium between groups (p > 0.05). In the correlation study, OCN were significantly positively correlated with height, ALP, age, PTH, and β-CTx (r = 0.347, 0.32, p < 0.05), (r = 0.35, 0.51, 0.66, p < 0.01 respectively), while serum 25(OH)D was negatively correlated with PTH, weight, height and BMI (r = -0.45, -0.55, -0.55, -0.47, p < 0.01 respectively). PTH was positively correlated with leptin and β-CTx (r = 0.41, 0.44, p < 0.01), but not to ALP and BMI percentile. β-CTx correlated significantly positive with Pi (r = 0.34 p < 0.05) and ALP with BMI percentile (r = 0.42, p < 0.05). Multiple regression analysis demonstrated that PTH was predicted by leptin and β-CTx (R2 = 0.55); β-CTx by leptin and OCN (R2 = 0.498); OCN by PTH and β-CTx (R2 = 0.47); and 25(OH)D by PTH (R2 = 0.21).. The obese children had increased levels of leptin and PTH with strong associated with bone turn over markers OCN, β-CTx and deficiency of 25(OH)D which may be playing an important role in the pathogenesis of obesity and related bone metabolic risk diseases as osteoporosis and fractures.

Topics: Adolescent; Biomarkers; Bone Remodeling; Calcium; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Leptin; Male; Obesity; Osteocalcin; Osteoporosis; Parathyroid Hormone; Saudi Arabia; Vitamin D

Adipose tissue is a major regulator of bone metabolism and in the general population obesity is associated with greater bone mineral density (BMD). However, bone-fat interactions are multifactorial, and may involve pathways that influence both bone formation and resorption with competing effects on the skeleton. One such pathway involves adipocyte production of adipokines that regulate bone metabolism. In this study we determined the association between BMD, walking status, and circulating adipokines (adiponectin and leptin) in 149 men with chronic spinal cord injury (SCI). Although adipokine levels did not vary significantly based on walking status, there was a significant inverse association between adiponectin and BMD in wheelchair users independent of body composition. We found no association between adiponectin and BMD in the walkers and no association between leptin and BMD in either group. These findings suggest that for subjects with chronic SCI, walking may mitigate the effect of adiponectin mediated bone loss. For wheelchair users, adipose-derived adiponectin may contribute to SCI-induced osteoporosis because the osteoprotective benefits of obesity appear to require mechanical loading during ambulation.

Topics: Absorptiometry, Photon; Adiponectin; Adult; Biomarkers; Bone Density; Bones of Lower Extremity; Humans; Leptin; Male; Middle Aged; Osteoporosis; Osteoporotic Fractures; Spinal Cord Injuries; Walking; Wheelchairs

The purpose of this study was to investigate the relationship between fasting serum leptin, adiponectin and resistin levels and bone mineral density (BMD) in osteoporosis patients and a non-osteoporosis control group. We studied 81 non-diabetic osteoporosis patients (92 % female, 8 % male; mean age 54.5 ± 15.5 years and body mass index [BMI] 28.2 ± 4.6) and 120 non-diabetic individuals with normal BMD as controls (86 % female, 14 % male; mean age 39.7 ± 10.4 years and BMI 28.8 ± 4.4). BMD was studied by dual-energy X-ray absorptiometry from the lumbar spine (L1-L4) and femoral neck and fasting blood samples were taken for biochemical measurement of fasting blood glucose, leptin, adiponectin and resistin. Fasting levels of plasma adiponectin had a significant negative correlation with BMD of the femoral neck and lumbar spine in the osteoporosis group (r = -0.478, P = 0.003, r = -0.513, P = 0.023) but not in the non-osteoporosis group (r = -0.158, P = 0.057, r = -0.23, P = 0.465). Fasting plasma levels of resistin were significantly correlated only with femur BMD in the osteoporosis group, and not significantly correlated with lumbar spine BMD (r = -0.244, P = 0.048 vs r = 0.276, P = 0.56). Leptin did not have a significant correlation with BMD in either the osteoporosis or non-osteoporosis groups (P > 0.05). Adiponectin had a significant negative correlation with BMD of the lumbar spine and femoral neck. The correlation between leptin and resistin are not inconclusive.

Topics: Adiponectin; Adult; Bone Density; Fasting; Female; Femur Neck; Humans; Leptin; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis; Radiography; Resistin

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

Bone mass and inflammation are implicated in the pathogenesis of osteoporosis. We hypothesized that leptin and leptin receptor gene might be associated with osteoporosis by activating the inflammatory pathway. Therefore, we analyzed polymorphisms of the leptin (gene symbol, LEP) and leptin receptor (gene symbol, LEPR) genes and determined their associations with proinflammatory cytokine levels in patients with osteoporosis. We assessed polymorphisms in LEP (-2548G > A) and LEPR (Lys109Arg, Gln223Arg, and Lys656Asn) and calculated odds ratios for the genotype and allele distributions between patients and controls. Serum leptin, soluble leptin receptor, interleukin (IL)-1, IL-6, IL-7, and tumor necrosis factor (TNF) levels were measured by enzyme-linked immunosorbent assays (ELISA) and were verified by in vitro lymphocyte proliferation assays and ELISAs. We found a higher frequency of the A allele for LEP at -2548 in patients with osteoporosis compared with the control group. The A allele was associated with differences in serum leptin, soluble leptin receptor, IL-1, IL-6, and TNF levels compared with the wild-type G allele (p < 0.05). The G allele in Lys109Arg and Gln223Arg was associated with increased risk of osteoporosis and with differences in serum leptin, soluble leptin receptor, IL-1, IL-6, and TNF levels compared with the wild-type A allele (p < 0.05). The Lys656Asn genotype was not associated with the risk of osteoporosis. In vitro lymphocyte proliferation assays and ELISAs confirmed these results. Polymorphisms in LEP and LEPR are associated with increased risk of osteoporosis, possibly by increasing the expression of proinflammatory cytokines.

Topics: Bone Density; Case-Control Studies; Cells, Cultured; Female; Gene Frequency; Genetic Association Studies; Genotype; Humans; Inflammation Mediators; Leptin; Male; Middle Aged; Osteoporosis; Polymorphism, Single Nucleotide; Receptors, Leptin

Obesity is a chronic inflammatory condition with numerous metabolic consequences to the organism, highlighting its influence on bone mass. Therefore, the aim of this study was to verify the role of visceral fat, leptin, adiponectin and ghrelin on bone mineral density in obese post-puberty adolescents girls, submitted to an interdisciplinary therapy. The study involved 20 post-puberty obese adolescent girls: 16±1.5 years of age, 98.9±15.8 kg (weight), 1.60±0.72 m (height) and 37.2±4.8 kg/m2 [body mass index (BMI)]. Anthropometric measurements, body composition, visceral fat, subcutaneous fat, bone mineral density and content were determined. Ghrelin, leptin and adiponectin were analyzed and the leptin/adiponectin ratio was calculated. Our findings showed a significant increase in adiponectin concentration and a reduction in body weight, BMI, total fat mass, visceral and subcutaneous fat. In addition, ghrelin (r2=-0.53; p=0.02) visceral fat (r2=-0.46, p=0.04) (r2 -0.66, p=0.001) and leptin/adiponectin ratio (r2 -0.56, p=0.01) were negative predictors for bone mineral density and content in obese adolescent girls, respectively. It provides a novel physiologically concept that may shed light on the etiology of osteoporosis and help to identify new therapeutic targets. However this should be confirmed in a large cohort study.

Topics: Adiponectin; Adolescent; Bone Density; Female; Ghrelin; Humans; Intra-Abdominal Fat; Leptin; Obesity; Osteoporosis; Regression Analysis

Mesenchymal stem cells (MSCs) are multipotent adult stem cells capable of differentiating along the osteoblast, adipocyte, and chondrocyte lineages. Regulation of MSCs differentiation may be a useful tool for regenerative medicine and cell-based therapy. The discovery of small molecule that activates the osteogenic differentiation of MSCs could aid in the development of a new anabolic drug for osteoporosis treatment. We identified CW008, a derivative of pyrazole-pyridine, that stimulates osteoblast differentiation of human MSCs and increases bone formation in ovariectomized mice. CW008 promotes osteogenesis by activating cAMP/PKA/CREB signaling pathway and inhibiting leptin secretion. These results suggest that CW008 is an agonist of cAMP/PKA/CREB pathway in osteogenic differentiation and that application of CW008 may be useful for the treatment of bone-related diseases and for the study of bone biology.

Topics: Adult Stem Cells; Animals; Cell Differentiation; Cells, Cultured; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Female; Humans; Leptin; Mesenchymal Stem Cells; Mice; Osteogenesis; Osteoporosis; Pyrazoles; Pyridines; Signal Transduction

Osteoporosis is a chronic disease characterized by bone loss and increased skeletal fragility. Large animal models are required for preclinical testing of new therapeutic approaches. We have recently demonstrated that continuous intracerebroventricular (ICV) application of leptin into the lateral ventricle (LV) induces bone loss in ewe. On the basis of these findings, we reasoned that the third ventricle (TV) is an even better target because of its closer location to the hypothalamus that mediates leptin effects on bone.. Corriedale sheep were randomly mixed to four groups of four ewe each: control entire (control), ovarectomy plus ICV application of cerebrospinal fluid (OVX), OVX plus ICV application of leptin into the LV (leptin-LV); and ICV application of leptin into the TV (leptin-TV). After 3 months, histomorphometric characterization and bone turnover parameters were analyzed.. Highly significant loss of trabecular bone was observed only in leptin-LV group. Increased osteoclast indices and urinary cross-lap excretion were observed in OVX and leptin-TV group. In contrast, serum parameters of osteoblast activity were only significantly decreased in leptin-LV group. Autopsy of ewe brain showed fibrosis around the stainless steel cannula in leptin-TV group.. ICV application of leptin into the LV strongly reduces bone formation and leads to a highly significant trabecular bone loss in ewe. In contrast, ICV application of leptin into the TV is technically more demanding and results are unpredictable, because the required use of stainless steel cannula induces peri-implant fibrosis that might prevent leptin to enter the cerebrospinal fluid.

Topics: Animals; Brain Diseases; Disease Models, Animal; Female; Injections, Intraventricular; Lateral Ventricles; Leptin; Osteoblasts; Osteoporosis; Prognosis; Sheep; Third Ventricle

This study evaluated the influence of diet-induced obesity on bone tissue quantity and quality in the proximal tibiae of growing mice and also examined the relationships between the serum total cholesterol, leptin, and adiponectin levels and trabecular and cortical bone mineral parameters.. Six-week-old male C57BL/6J mice were divided into two groups; one received a control diet, and the other received a high-fat-diet. After treatment for 4, 8, or 12 weeks, the bone quantity and quality were analyzed using peripheral quantitative computed tomography (pQCT), micro-computed tomography and histomorphometry.. In the early stages, trabecular bone density decreased with an increase in the number of adipocytes and the deterioration of trabeculae. In contrast, although cortical bone formation was slower in obese mice compared with control mice, bone formation on the periosteal surface increased with age. Serum leptin levels were correlated with trabecular, but not cortical bone density, whereas neither the adiponectin nor total cholesterol level was correlated with bone mass in mice with diet-induced obesity.. We conclude that bone loss at these two sites is differentially regulated in mice. Furthermore, we demonstrate that serum leptin may be a useful indicator of risk for osteoporosis associated with diet-induced obesity.

Topics: Adiponectin; Animals; Bone and Bones; Bone Density; Cholesterol; Diet, High-Fat; Disease Models, Animal; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Osteoporosis; Radiography

Cardiovascular disease (CVD) and osteoporosis share some common risk factors such as old age, smoking, alcoholic drinking, hypertension, diabetes mellitus, and hyperlipidemia. Although previous studies have investigated the association of bone mineral density (BMD) with CVD, the results were conflicting. There are limited studies on the association of BMD loss rate with CVD. We therefore conducted a 5-year prospective study to examine the relation among BMD, bone loss, and risk of CVD in a Chinese cohort. Of 9,657 community residents 30 to 75 years old, 6,092 were enrolled in the study and followed annually for 5 years. At baseline demographic data, BMD, smoking and drinking statuses, medical history, and blood samples were collected. Cox proportional hazards analysis was used to evaluate the association of BMD and incidence of CVD. Over the 5-year follow-up period, CVD developed in 118 subjects. Baseline BMD, bone loss rate, current smoking, daily alcoholic ingestion, and higher osteoprotegerin and leptin levels were independently associated with increased risk of CVD, whereas higher baseline adiponectin level was associated with decreased risk of CVD in women and men. In conclusion, uncovering the relation linking osteoporosis and CVD is important for understanding the pathogenesis of these 2 common disorders.

Topics: Absorptiometry, Photon; Adiponectin; Adult; Aged; Alcohol Drinking; Biomarkers; Bone Density; Cardiovascular Diseases; China; Female; Humans; Incidence; Leptin; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Proportional Hazards Models; Prospective Studies; Risk; Risk Factors; Smoking; Statistics, Nonparametric

The present study assessed the potential role of leptin administration in the protection and intervention against glucocorticoid-induced secondary osteoporosis in female rats.. For this purpose five groups of female Sprague Dawley rats were classified into: (1) negative control group in which the healthy rats received saline as vehicle, (2) a group orally administered with prednisolone (5 mg kg b.wt.-1) daily for six months (osteoporotic group), (3) a group subcutaneously administered with leptin (400 microg kg b.wt.-1) three times weekly for six months (positive control), (4) a group orally administered with prednisolone daily with simultaneous subcutaneous administration of leptin three times weekly for six months (protective group), and (5) a group orally administered with prednisolone daily for six months then subcutaneously administered with leptin three times weekly for other six months (therapeutic group).. The obtained data revealed that prednisolone administration resulted in significant decrease in serum osteoprotegerin (OPG) level accompanied with significant increase in serum receptor activator of nuclear factor-κB ligand (RANKL) and beta2-microglobulin levels in comparison with the negative control group. Moreover, prednisolone significantly decreased bone mineral density and content of different areas of the right femur bones as compared to the negative control group. Furthermore, administration of leptin with/after stopping prednisolone administration resulted in a marked modulation in the majority of bone biomarkers as well as improvement in bone mineral density and content.. Leptin provided promising effect on bone through its direct action on bone and matrix mineralization.

Topics: Animals; Bone Density; Female; Leptin; Osteoporosis; Osteoprotegerin; Prednisolone; RANK Ligand; Rats; Rats, Sprague-Dawley

In our previous study to evaluate the effects of soluble silicon (Si) on bone metabolism, Si and coral sand (CS) as a natural Si-containing material suppressed peroxisome proliferator-activated receptor γ (PPARγ), which regulates both glucose and bone metabolism and increases adipogenesis at the expense of osteogenesis, leading to bone loss. In this study, we investigated the anti-diabetic effects of bone-seeking elements, Si and stable strontium (Sr), and CS as a natural material containing these elements using obese diabetic KKAy mice.. Weanling male mice were fed diets containing 1% Ca supplemented with CaCO(3) as the control and CS, and diets supplemented with 50 ppm Si or 750 ppm Sr to control diet for 56 d. The mRNA expressions related to energy expenditure in the pancreas and kidney were quantified by real-time polymerase chain reaction.. At the end of feeding, plasma glucose, insulin, leptin, and adiponectin levels decreased significantly in three test groups, while pancreatic PPARγ and adiponectin mRNA expression levels increased significantly toward the normal level, improving the glucose sensitivity of β-cells and inducing a significant decrease in insulin expression. The renal PPARγ, PPARα, and adiponectin expression levels, histologic indices of diabetic glomerulopathy, and plasma indices of renal function were also improved significantly in the test groups.. Taken together, anti-osteoporotic trace minerals, Si and Sr, and CS containing them showed novel anti-diabetic effects of lowering blood glucose level, improving the tolerance to insulin, leptin, and adiponectin, and reducing the risk of glomerulopathy through modulation of related gene expression in the pancreas and kidney.

Topics: Adiponectin; Animals; Biomarkers; Blood Glucose; Bone Density Conservation Agents; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dietary Supplements; Hypoglycemic Agents; Insulin; Kidney; Kidney Diseases; Kidney Glomerulus; Leptin; Male; Mice; Mice, Inbred Strains; Osteoporosis; Pancrelipase; PPAR gamma; Silicon; Silicon Compounds; Soil; Trace Elements

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

Alzheimer's disease (AD) and osteoporosis are common chronic degenerative disorders which are strongly associated with advanced age. Some studies suggest that low bone mineral density (BMD) is related to the increased risk of AD. We conducted a 5-year prospective study to exam the association between BMD and the risk of AD in a cohort of Chinese elderly people. Of 3263 community residents aged 65 years and over, 2019 were enrolled into the study and followed up annually for 5 years. At baseline demographic data, smoking and drinking status, medical history, cognitive status, and blood samples were collected. BMD was measured by dual energy X-ray absorptiometry (DEXA) scanning at baseline and during follow-up. Cox proportional hazards analysis was used to evaluate the association with BMD and incidence of AD. Over the follow-up of 5 years, AD developed in 132 subjects. Baseline BMD, bone loss rate, current smoking, and daily drinking were associated with increased risk of AD, while higher baseline plasma leptin level was associated with decreased risk of AD, in both women and men. Low BMD and increased loss rate of BMD were associated with higher risk of AD. Cigarette smoking, alcohol drinking, and lower leptin level are risk factors for AD. Uncovering the relation linking osteoporosis and AD is important for understanding the pathogenesis and developing therapeutic strategies for these two common disorders afflicting elderly people.

Topics: Aged; Alzheimer Disease; Asian People; Bone Density; Cohort Studies; Female; Follow-Up Studies; Humans; Leptin; Male; Osteoporosis; Prospective Studies; Risk Factors

The role of fat-bone interactions in the pathogenesis of osteoporosis in chronic obstructive pulmonary disease (COPD) is poorly understood. Our aim was to investigate expressions of leptin and osteoprotegerin (OPG) in the adipose tissue, and their relationships to osteoporosis in patients with COPD.. In 39 patients with stable COPD, bone mineral density (BMD) and body composition was assessed by Dual Energy X-Ray Absorptiometry. Serum leptin was determined by the enzyme-linked immunosorbent assay, and bone turnover markers osteocalcin and β-crosslaps by the electrochemiluminiscence immunoassays. Subcutaneous adipose tissue samples were analyzed using real-time PCR.. Twenty-one patients without, and 18 with osteoporosis were enrolled (35 men; age 62.2 ± 7.3years). Compared to patients without osteoporosis, those with the disease had significantly lower serum levels and adipose tissue expressions of leptin, in association with increased serum β-crosslaps (p=0.028, p=0.034, p=0.022, respectively). Log adipose tissue leptin was inversely related to serum β-crosslaps (p=0.015), and directly to serum leptin (p<0.001) and to the total, femoral, and lumbar BMD and T-score (p<0.02 for all relationships). Adipose tissue OPG expression was related to all variables of bone density except for lumbar BMD and T-score (p<0.05 for all relationships). Log adipose tissue leptin and OPG expressions predicted femoral T-score independently of age, gender and pulmonary function (p<0.001, adjusted R(2)=0.383; p=0.008, adjusted R(2)=0.301, respectively). Introducing body mass (or fat mass) index into these models eliminated independent predictive value of leptin and OPG expressions.. Our results suggest that adipose tissue leptin and OPG expressions are related to osteoporosis in patients with COPD, and appear to act as mediators between fat mass and BMD.

Topics: Adipose Tissue; Biomarkers; Bone Density; Bone Remodeling; Female; Humans; Inflammation; Leptin; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests

The present paper is aimed to investigate the correlation between the fat mass and the bone mass, and to investigate the effect of leptin on bone metabolism in female ovariectomic rats. Forty Wistar female rats, 6-month-old, were randomly divided into the sham surgical (Sham) group and ovariectomic (OVX) group. The body weight, the fat mass inside the abdominal cavity, the bone mineral density (BMD) were determined by DEXA method, and the concentration of leptin was measured by ELISA after operation. The Rats' body mass in ovariectomized group increased significantly (P < 0.05), while the fat mass in abdominal cavity was not increased obviously in ovariectomized group (P = 0.499). The concentration of leptin was no difference between the two groups (P = 0.166). Bone mineral content (BMC)/weight in ovariectomized group was decreased significantly than the sham group (P = 0. 003). The weight at 8th week post-operation was negative correlation with BMC/weight in Sham group and was positive with BMD in OVX group. The fat mass and the leptin concentration were negative correlation with BMC/ weight in Sham group. It was concluded that the fat mass and the leptin were raleted to the BMC/weight.

Topics: Adipose Tissue; Animals; Bone Density; Female; Leptin; Osteoporosis; Ovariectomy; Random Allocation; Rats; Rats, Wistar

Methods: Leptin levels were measured in 103 consecutive women with anorexia nervosa. Results: Spine BMD and Z-score values were found to be significantly lower in the low tertile compared with the highest tertile. Duration of amenorrhea and leptin level accounted for 27% of the variance in lumbar spine BMD.. The purpose of this study was to assess leptin levels and other biological variables in a population of anorexia nervosa patients.. Leptin levels were measured consecutively in 103 women with anorexia nervosa (AN) with a mean age of 24.9 +/- 7.4 years. Osteodensitometry was also performed by dual energy X-ray absorptiometry (DXA).. Spine bone mineral density (BMD) and Z-score values were found to be significantly lower in the low tertile compared with the highest tertile. Duration of amenorrhea and leptin level accounted for 27% of the variance in lumbar spine BMD. The mean leptin level was 3.9 +/- 4.6 ng/mL (normal values, 3.5-11 ng/mL). The distribution of leptin values was not a Gaussian distribution, and a log-transformed was therefore performed. A significant correlation was found between leptin level and spinal BMD (r = 0.3; p = 0.002); significant correlations were observed for both femoral neck and total hip BMDs. When leptin level values were divided into tertiles, spine BMD and Z-score values were found to be significantly lower in the lower tertile (p = 0.04 and p = 0.02) compared with the highest tertile. For femoral neck BMDs, the T-score was slightly lower between low and high tertile, but the difference was not statistically significant (p = 0.07). When multivariate analyses were performed, two independent factors which could possibly account for the variance in spinal BMDs were found. Duration of amenorrhea and leptin level accounted for 27% of the variance (p < 0.0001).. The mechanisms underlying bone loss in AN patients remain unclear and complex, involving hypoestrogenia as well as nutritional factors such as insulin-like growth factor and leptin.

Topics: Absorptiometry, Photon; Adolescent; Adult; Amenorrhea; Anorexia Nervosa; Bone Density; Female; Femur Neck; Hip Joint; Humans; Leptin; Lumbar Vertebrae; Osteoporosis; Young Adult

Clinical data have suggested that obesity protects against osteoporosis. Leptin, mainly secreted by white adipose tissue, might be involved by mediating an effect on bone metabolism. This study was conducted to investigate a possible relationship of leptin and bone turn-over in postmenopausal women with osteoporosis.. We measured bone mineral density (BMD), serum leptin levels and markers of bone metabolism, including osteocalcin and cross-laps in 44 patients with osteoporosis. The main group consisted of 32 postmenopausal women.. Mean serum leptin was 13.1 microg/L and showed no statistically significant difference to the levels measured in a collective of normal persons adjusted for age and BMI. When related to serum cross-laps as markers of bone resorption, a positive correlation (p<0.05) was observed, whereas no correlation with osteocalcin could be seen.. A dual control of bone formation by leptin is assumed: This involves local mechanisms acting on osteoblasts and a central inhibitory effect on bone metabolism via a hypothalamic relay. Our data indicate that the net effect of circulating leptin may cause bone loss and is significantly related to high-turnover serum bone markers, at least in postmenopausal women with osteoporosis.

Topics: Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Bone and Bones; Bone Density; Bone Remodeling; Calcium; Female; Humans; Leptin; Male; Middle Aged; Osteoporosis

Major depressive disorder (MDD) is associated with immune system dysfunction and disruption of multiple circadian systems. Adiponectin is an adipocytokine with anti-inflammatory and antiatherogenic effects. Circulating concentrations are inversely related to adiposity and risks of metabolic syndrome and diabetes mellitus. Our goals were (1) to establish whether premenopausal women with MDD exhibit decreased plasma adiponectin concentrations and/or disruption of circadian adiponectin rhythmicity; (2) to assess whether there is a relationship between adiponectin and MDD; and (3) to explore the temporal relationships among adiponectin, leptin, corticotropin, and cortisol secretion.. We conducted a case-control study of community-dwelling premenopausal women with DSM-IV MDD (n = 23) and age- and body mass index (BMI)-matched control subjects (n = 23). Main outcome measures were circulating concentrations of adiponectin, leptin, corticotropin, and cortisol measured hourly for 24 hours. Subjects were recruited from July 1, 2001, to February 28, 2003.. Women with MDD had approximately 30% lower mean 24-hour concentration of adiponectin than did control subjects. Adiponectin concentration was inversely related to depression severity and total duration of disease, suggesting a causal link. In contrast, mean nocturnal leptin concentration was higher in the MDD versus control groups. Mean leptin concentration was inversely related to cortisol and adiponectin concentrations, both in subjects with depression and in control subjects. In cross-correlation analyses, the relationship between corticotropin and cortisol concentrations was stronger in women with MDD than in control subjects, a finding consistent with hypothalamic-pituitary-adrenal (HPA) axis activation in MDD.. In premenopausal women with MDD, reduced daily adiponectin production may increase the risk of diabetes mellitus, and elevated leptin may contribute to osteoporosis.

Topics: Adiponectin; Adrenocorticotropic Hormone; Adult; Alendronate; Body Mass Index; Case-Control Studies; Circadian Rhythm; Depressive Disorder, Major; Diabetes Mellitus, Type 2; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Hydrocortisone; Leptin; Middle Aged; Osteoporosis; Premenopause; Psychiatric Status Rating Scales; Risk Factors; Women's Health

Bone metastasis is a serious complication of patients with tumor, and most primary tumors can metastasize to bone. And the main threat and the reason for most cancer deaths are not the primary neoplasias, but secondary tumors, the metastases. To minimize the morbidity and economic expenditure associated with bone metastases, it is important to decrease the etiological factors of bone metastasis. Although current evidence suggested that the therapies to the underlying malignancy bone metastasis might result in bone loss leading to osteoporosis, no studies have shown direct evidence the successful seeding of bone metastases of cancer cells is the part played by osteoporosis. In the state of osteoporosis, for the enhancement of the osteolysis, the increased inflammatory factors could make blood vessels leakier, resulting in the easier hematogenous metastasis to bone and bone marrow. Moreover, leptin, which was positive correlation with osteoporosis, has been showed to exert angiogenic effects and could regulate VEGF expression, promoting the proliferation of the cancer blood vessel. In addition, the increased growth factors in osteoporosis could enrich the local microenvironment, promoting the growth of the metastasis mass. Given the above background, we hypothesize that osteoporosis may be a potential contributor to the bone metastases.

Topics: Bone Neoplasms; Humans; Leptin; Neoplasm Metastasis; Neovascularization, Pathologic; Osteoporosis; Vascular Endothelial Growth Factor A

Topics: Animals; Bone and Bones; Bone Remodeling; Diabetes Mellitus; Energy Metabolism; Female; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Obesity; Osteocalcin; Osteoporosis; Receptor, Insulin

To evaluate the association between circulating leptin and bone mineral density (BMD) in patients with rheumatoid arthritis (RA).. One-hundred thirty postmenopausal women with RA were assessed for body mass index (BMI), disease characteristics, history of drug use, rheumatoid factor, and erythrocyte sedimentation rate (ESR). BMD (g/cm(2)) was determined in the hip and spine by DEXA. Serum leptin concentrations were measured by ELISA. Spearman's correlation coefficients (rho) were determined between BMD and leptin and other variables. A multiple regression analysis was used to adjust for confounders.. Patients' serum leptin levels varied widely (range 2-128 ng/ml). Thirty-three patients (25%) had osteoporosis. Higher levels of leptin correlated significantly with BMD in the lumbar spine (rho = 0.17, p = 0.04) and total hip (rho = 0.21, p = 0.01). The variables that were negatively correlated with BMD were age, duration of menopause, and ESR. After adjustment for confounders, leptin was no longer associated with BMD. In the multivariate model, factors that remained associated with BMD in the total hip were age (p = 0.021) and BMI (p = 0.003); and the factors that remained associated with BMD in the lumbar spine were BMI (p = 0.03) and ESR (p = 0.01).. No relevant association was found between circulating leptin levels and BMD in patients with RA in this cross-sectional study. Followup studies are needed to evaluate whether abnormal leptin levels confer a risk for fractures due to osteoporosis.

Topics: Adult; Aged; Arthritis, Rheumatoid; Bone Density; Cross-Sectional Studies; Humans; Leptin; Middle Aged; Osteoporosis; Statistics, Nonparametric

The aim of this study was to compare the osteogenic potential and responsiveness to leptin of mesenchymal stem cells (MSCs) from bone marrow between postmenopausal women with osteoarthritis (OA) and osteoporosis (OP). MSCs of the proximal femur from OA and OP donors were cultured under control and different experimental mediums. After verifying the availability of primary cells, their osteogenic potential and responsiveness to leptin were compared between two groups. Similar patterns of cell growth were shown in both OA and OP groups. However, after the sixth passage, the viability of undifferentiated cells decreased more in OP than in OA donors. Under the same osteogenic supplements condition, the mRNA expression of osteogenesis-specific genes, osteocalcin (OC) and alkaline phosphatase (ALP) were higher in OA group. Comparison of bone matrix mineralization was parallel to that of mRNA expression. The level of bone-specific ALP (BAP) was higher in cells from donors with OA, whereas osteoprotegerin (OPG) was higher in OP group. This difference in BAP expression proved to be insignificant after the administration of leptin. Although leptin upregulated the expression of OPG, a significant difference still existed between OA and OP. In conclusion, differential osteogenic potential and responsiveness to leptin of MSCs were noted between postmenopausal women with OA and OP. Differential biological behavior of MSCs seems to be partly related to the different distribution of bone mass between OA and OP populations.

Topics: Adipogenesis; Aged; Aged, 80 and over; Alkaline Phosphatase; Calcification, Physiologic; Cell Differentiation; Cells, Cultured; Collagen Type I; Female; Hip Fractures; Humans; Leptin; Lipoprotein Lipase; Mesenchymal Stem Cells; Osteoarthritis; Osteogenesis; Osteoporosis; Postmenopause; PPAR gamma

Topics: Adult; Feeding and Eating Disorders; Humans; Hypogonadism; Leptin; Male; Osteoporosis

Topics: Bone Density; Bone Diseases; Collagen; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fractures, Bone; Homeostasis; Humans; Hypoglycemic Agents; Leptin; Metformin; Osteoporosis; Pregnancy; Thiazolidinediones

Osteoporosis is common in patients with chronic obstructive pulmonary disease (COPD). Data regarding the relationship between adipokines and bone mineral density (BMD) in this population is lacking. The purpose of this pilot study was to determine associations between the adipokines tumor necrosis factor-alpha (TNF-alpha), leptin, adiponectin and resistin, body composition, and BMD in men with severe COPD. This was a cross-sectional study of men with severe COPD who visited the University of Colorado Hospital COPD Center. Bone density and parameters of body composition were measured by dual-energy X-ray absorptiometry. Twenty-three men were included (mean age = 66 years, mean percent predicted forced expiratory volume in one second = 32%). On bivariate analysis, there was no association between TNF-alpha and BMD. Parameters of body composition and serum concentrations of leptin and adiponectin were significantly associated with total hip and spine bone density. However, with partial correlation analysis, total body mass was the only independent predictor of total hip BMD, explaining approximately 50% of the variability. Overall, 18 out of 23 men enrolled (78%) had low bone density by T-score, and nine (39%) were classified as having osteoporosis. The men with osteoporosis had lower parameters of body composition, lower mean serum leptin concentrations, and a greater impairment in measures of lung function compared to the men without osteoporosis. We conclude that the effect of adipokines on BMD does not appear to be independent of body mass. However, larger studies are needed to further evaluate the relationship between adipokines, body weight, and BMD in patients with COPD.

Topics: Absorptiometry, Photon; Adipokines; Adiponectin; Aged; Biological Factors; Body Composition; Bone Density; Cross-Sectional Studies; Hip Joint; Humans; Leptin; Lumbar Vertebrae; Lung; Male; Middle Aged; Osteoporosis; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Resistin; Severity of Illness Index; Tumor Necrosis Factor-alpha

Post-menopausal osteoporosis is considered to be an inflammatory process, in which numerous pro-inflammatory and T-cell-derived cytokines play a bone-destructive role. IL-17A is the signature cytokine of the pro-inflammatory Th17 population and plays dichotomous roles in diseases that affect bone turnover. Although IL-17A promotes bone loss in rheumatoid arthritis, it is protective against pathogen-induced bone destruction in a periodontal disease model. We used a model of ovariectomy-induced osteoporosis (OVX) in IL-17 receptor (IL-17RA)(-/-) mice to evaluate the role of the IL-17A in bone loss caused by estrogen deficiency. Unexpectedly, IL-17RA(-/-) mice were consistently and markedly more susceptible to OVX-induced bone loss than controls. There were no changes in prototypical Th1, Th2 or Th17 cytokines in serum that could account for increased bone loss. However, IL-17RA(-/-) mice exhibited constitutively elevated leptin, which further increased following OVX. Consistently, IL-17A and IL-17F treatment of 3T3-L1 pre-adipocytes inhibited adipogenesis, leading to reduced production of leptin. In addition to its role in regulating metabolism and satiety, leptin can regulate bone turnover. Accordingly, these data show that IL-17A negatively regulates adipogenesis and subsequent leptin expression, which correlates with increased bone destruction during OVX.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Bone Density; Cytokines; Down-Regulation; Estrogens; Female; Interleukin-17; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Osteoporosis; Ovariectomy; Receptors, Interleukin-17; Signal Transduction; Spine; Tumor Necrosis Factor-alpha; Weight Gain

In the elderly, nutritional deficiencies, such as low energy and protein intake, are suggested to increase the risk of osteoporotic fractures. Modulation of the amount and quality of protein intake under energy deficient conditions represents an interesting strategy to prevent aged-related bone loss. We investigated the effect of a 5-month dietary restriction on bone status in 16-month-old male rats. Rats were randomised into six groups (n 10 per group). Control animals were fed a normal diet containing either casein (N-C) or whey protein (N-WP). The other groups received a 40 % protein and energy-restricted diet with casein or whey protein (PER-C and PER-WP) or a normal protein and energy-restricted diet (ER-C and ER-WP). Both restrictions (PER and ER) induced a decrease in femoral bone mineral density (BMD), consistent with impaired biomechanical properties and a reduced cortical area at the diaphysis. Plasma osteocalcin and urinary deoxypyridinoline levels suggested a decrease in bone turnover in the PER and ER groups. Interestingly, circulating insulin-like growth factor 1 (IGF-1) levels were also lowered. Overall, normal protein intake did not elicit any bone sparing effect in energy-deficient rats. Regarding protein quality, neither casein nor WP appeared to significantly prevent the BMD decrease. This study confirms that nutritional deficiencies may contribute to osteopenia through decreased IGF-1 levels. Moreover, it seems that impaired bone status could not be significantly prevented by modulating the amount and quality of dietary proteins.

Topics: Amino Acids; Animals; Biomarkers; Bone and Bones; Bone Density; Bone Resorption; Calcium; Caloric Restriction; Caseins; Dietary Supplements; Femur; Insulin-Like Growth Factor I; Leptin; Male; Milk Proteins; Models, Animal; Osteocalcin; Osteoporosis; Random Allocation; Rats; Rats, Wistar; Whey Proteins

A comparative study of bone metabolism between postmenopausal women with osteoarthritis and osteoporosis showed that differential levels of bone remodeling markers, leptin, free leptin index, and osteoprotegerin might partly contribute to the proposed inverse relationship in bone mass between postmenopausal women with osteoarthritis and osteoporosis.. Osteoarthritis (OA) and osteoporosis (OP) are two common disorders affecting the quality of life in the elderly. The association between OA and OP has always been debated. The objective of this study was to compare bone metabolism between postmenopausal women with OA and OP.. A total of 120 postmenopausal women with OA and OP (n = 60, respectively) were included in this comparative study. Anthropometric parameters and BMD at the spine and the proximal femur were measured. Serum leptin, soluble leptin receptor (sLR), osteoprotegerin (OPG), and bone remodeling markers, including bone-specific alkaline phosphatase (BALP), osteocalcin (OC), deoxypyridinoline cross-links (DPD), and cross-linked N-telopeptides of type I collagen (NTX), were quantified with commercial ELISA or EIA kits. Free leptin index (FLI) was also calculated by the ratio between serum leptin and sLR levels.. Postmenopausal women with OA had higher body weight, body mass index, fat mass, and percentage of fat than those suffered from OP. Compared with the patients in OP group, the patients in OA group had significantly higher BMD values at all sites measured. Higher serum leptin and FLI and lower OPG levels were shown in the OA group (leptin: 31.22 +/- 6.4 versus 26.50 +/- 9.27 ng/ml, p < 0.001; FLI: 3.20 +/- 1.02 versus 2.50 +/- 0.95, p < 0.05; OPG: 4.75 +/- 1.97 versus 6.96 +/- 2.75 pM, p < 0.001), whereas lower serum OC and higher urine DPD were noted in the OP group (OC: 16.45 +/- 8.45 versus 13.06 +/- 6.25 ng/ml, p < 0.05; DPD: 10.83 +/- 7.12 versus 15.29 +/- 6.65 nM BCE/mM Cr, p < 0.001). Serum OPG levels negatively correlated with BMD at all sites assessed. However, no correlation was found between leptin and BMD. Only in the OA group di positive correlations exist between FLI and Z-score at the femoral neck and Ward's triangle region. After stepwise regression analysis, it was found that differential factors were able to predict the variance of BMD at different sites to a certain extent.. Our study suggests that there are significant differences in bone metabolism between postmenopausal women with OA and OP and provides evidence for the inverse relationship between OA and OP. Differential levels of bone remodeling markers, leptin, FLI, and OPG may partly contribute to the proposed inverse relationship. Roles of leptin and its soluble receptor in bone metabolism regulation should be explored further.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Bone and Bones; Bone Density; Female; Humans; Leptin; Middle Aged; Osteoarthritis; Osteocalcin; Osteoporosis; Postmenopause; Reproducibility of Results

To find out which of the following parameters-serum levels of insulin-like growth factor 1 (IGF-1), osteoprotegerin (OPG), leptin, osteocalcin (OC), and urinary excretion of N-terminal telopeptide of type I collagen (NTx), can be used as an early marker for osteopenia/osteoporosis in women diagnosed by dual-energy X-ray absorptiometry (DXA), 282 premenopausal and 222 postmenopausal women aged 20-75 years were investigated by the measurement of bone mineral densities (BMDs) at lumbar spine (LS) and femoral neck (FN) by DXA, together with serum concentrations of IGF-1, OPG, leptin, OC, and urinary NTx. The characteristics of the earliest marker(s) were tested with the receiver operating characteristic (ROC) analysis. The area under the curve (AUC), sensitivity, and specificity parameters were determined. It was revealed that serum levels of IGF-1 and leptin changed the earliest, with both markers significantly decreasing (P < 0.0001) or increasing (P = 0.020), respectively, at age 30. However, in ROC analysis, IGF-1 was the only early parameter that had the capacity to differentiate the low bone mass/osteoporosis women from the normal ones (P < 0.0001). If the serum level of IGF-1 at 1.5 SD below its peak was adopted as a cutoff point, it could identify women with low bone mass/osteoporosis with a sensitivity of 73% and specificity of 67%. In the premenopausal women subgroup analysis, the low bone mass women (30/282, 10.6%) were older (38.2 +/- 1.7 vs. 34.5 +/- 0.5 years; P = 0.026), with lower serum levels of IGF-1 (215.1 +/- 22.4 vs. 278.8 +/- 9.4 ng/ml; P = 0.02) and less lean mass (33.1 +/- 0.6 vs. 34.8 +/- 0.2 kg; P = 0.010) than the normal ones. After controlling for age, the serum level of IGF-1 had a weak, but still significant, positive correlation with lean mass (r = 0.17, P < 0.001). In conclusion, measurement of serum IGF-1 in young women may help in the early identification of those at risk for developing low bone mass and osteoporosis.

Topics: Adult; Age Distribution; Aged; Aging; Area Under Curve; Biomarkers; Bone and Bones; Bone Density; Cytokines; Diagnosis, Differential; Female; Femur Neck; Humans; Insulin-Like Growth Factor I; Leptin; Middle Aged; Organ Size; Osteoporosis; Osteoprotegerin; Postmenopause; Premenopause; ROC Curve

A paradox is hidden in the increasing number of patients with insulin resistance, Type 2 diabetes and osteoporosis, as the world wide diabetes epidemic is driven by the same obesity which protects the bones in the obese females. Our aim was to investigate the connection between the early glucose intolerance, insulin resistance and bone density and metabolism. After metabolic status of matched 20 healthy and 51 glucose intolerant women (age: 49 +/- 9 y.) was determined, hyperinsulinemic-euglycemic clamps were done, while adipo- and cytokine levels were measured. Bone mineral density over lumbar spine and the femur neck were measured by DEXA. No differences in bone density were observed between groups at any sites measured. Tight correlations were found between total body glucose utilization and bone density in healthy group (lumbar spine r = -0.4921, p < 0.05, femur neck: r = -0.4972, p < 0.05), while with deterioration of glucose metabolism this correlation disappeared (lumbar spine: r = -0.022, ns; femur neck: r = -0.3136, ns). The adiponectin was the only adipokine which correlated with lumbar spine density in both groups ( r = -0.5081, p < 0.05; -0.2804, p < 0.05), but not with femur density, where this connection disappeared with glucose intolerance ( r = -0.6742, p < 0.01; -0.1723, ns). Relations of bone metabolic markers indicated that bone resorption decreases with worsening of insulin resistance. In conclusion inverse correlations were found between bone density and glucose metabolism, or insulin sensitivity in healthy women in perimenopause, but this connection disappeared with the deterioration of glucose metabolism and progression of insulin resistance measured by the "gold standard" insulin-glucose clamps. Decreasing insulin sensitivity of bones and escape from "metabolic control" may result in frequently observed hyperdensity in Type 2 diabetics.

Topics: Absorptiometry, Photon; Adiponectin; Adult; Biomarkers; Blood Glucose; Body Mass Index; Bone and Bones; Bone Density; Diabetes Mellitus, Type 2; Disease Progression; Female; Glucose; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Leptin; Lumbar Vertebrae; Middle Aged; Obesity; Osteoporosis; Perimenopause; Resistin

This cross-sectional study examined bone mineral density, bone turnover, body composition and calciotropic hormones in 24 boys with Duchenne muscular dystrophy (DMD) (2.3-19.7 years), most of whom were being treated with prednisolone, and 24 age-matched healthy boys. Our study demonstrated lower bone mineral density in the DMD group for total body, spine, hip, heel and forearm measurements. These differences between DMD patients and controls increased with increasing age. Biochemical markers of both bone formation and resorption revealed reduced bone turnover in DMD patients. The fracture rate was not higher in DMD patients. The DMD group had low vitamin D levels but high leptin levels in comparison with the control group. Muscle strength correlated with bone mineral density assessed at the hip and heel in the DMD group. Interventions that increase bone formation should be considered, as DMD patients have reduced bone turnover in addition to their low bone mineral density.

Topics: Adolescent; Adult; Biomarkers; Bone and Bones; Bone Density; Bone Resorption; Calcium; Child; Child, Preschool; Cross-Sectional Studies; Diet; Glucocorticoids; Humans; Leptin; Male; Muscle Strength; Muscular Dystrophy, Duchenne; Nutrition Assessment; Nutritional Physiological Phenomena; Osteogenesis; Osteoporosis; Prednisolone; Vitamin D Deficiency

To evaluate the effects of body adiposity on bone mineral density in the presence and absence of ovarian hormones in female mice and postmenopausal women.. We assessed percentage body fat, serum leptin levels, and bone mineral density in ovariectomized and non-ovariectomized C57BL/6 female mice that had been fed various calorically dense diets to induce body weight profiles ranging from lean to very obese. Additionally, we assessed percentage body fat and whole body bone mineral density in 37 overweight and extremely obese postmenopausal women from the Women's Contraceptive and Reproductive Experiences study.. In mice, higher levels of body adiposity (>40% body fat) were associated with lower bone mineral density in ovariectomized C57BL/6 female mice. A similar trend was observed in a small sample of postmenopausal women.. The complementary studies in mice and women suggest that extreme obesity in postmenopausal women may be associated with reduced bone mineral density. Thus, extreme obesity (BMI > 40 kg/m2) may increase the risk for osteopenia and osteoporosis. Given the obesity epidemic in the U.S. and in many other countries, and, in particular, the rising number of extremely obese adult women, increased attention should be drawn to the significant and interrelated public health issues of obesity and osteoporosis.

Topics: Adult; Animals; Body Composition; Body Weight; Bone Density; Female; Humans; Leptin; Linear Models; Mice; Mice, Inbred C57BL; Middle Aged; Obesity; Osteoporosis; Ovariectomy; Random Allocation

Osteoporosis is a common and severe condition in elderly men, which is poorly characterized. In order to identify the hallmarks of age-related bone loss in the male mammalian skeleton, we studied several aspects of bone structure and metabolism in 23-month-old male Sprague-Dawley rats and compared them to 5-month-old animals. Cancellous bone mineral density, bone volume and trabecular number were markedly reduced in the proximal tibia of aged rats when compared to the young rats. An increase in bone matrix material density indicating a reduced deposition of new bone matrix was seen. Also, serum levels of osteocalcin, a marker of bone formation, were reduced in old males. The decreased bone formation could in part be linked to the decreased serum insulin-like growth factor 1 (IGF-1) levels which were observed in these animals. Serum levels of RatLaps (c-terminal telopeptide of type I collagen) were increased. Interestingly, an ex vivo osteoclast generation assay revealed that bone marrow from aged rats formed fewer osteoclasts than that from young rats. Consistent with this observation, serum levels of soluble RANKL, a critical osteoblast derived factor for osteoclastogenesis, were decreased in aged rats and RANKL mRNA expression was slightly reduced in bone marrow cells. Elevated leptin and adiponectin levels present in these animals could have contributed further to impaired osteoclastogenesis. We conclude that aged male rodents are characterized by a severely diminished cancellous bone network and a bone turnover situation in which bone formation is decreased to such an extent that it is outweighed by bone resorption, despite a blunted osteoclast generation potential of the bone marrow.

Topics: Adiponectin; Aging; Animals; Biomarkers; Bone Resorption; Cytokines; Immunophenotyping; Insulin-Like Growth Factor I; Leptin; Male; Models, Animal; Osteoblasts; Osteoclasts; Osteoporosis; RANK Ligand; Rats; Rats, Sprague-Dawley; Tibia; Tomography, X-Ray Computed

Mechanical unloading of bone causes an imbalance in bone formation and resorption leading to bone loss and increased fracture risk. Black bears (Ursus americanus) are inactive for up to six months during hibernation, yet bone mineral content and strength do not decrease with disuse or aging. To test whether hibernating bears have biological mechanisms to prevent disuse osteoporosis, we measured the serum concentrations of hormones and growth factors involved in bone metabolism and correlated them with the serum concentration of a bone formation marker (osteocalcin). Serum was obtained from black bears over a 7-month duration that included periods of activity and inactivity. Both resorption and formation markers increased during hibernation, suggesting high bone turnover occurred during inactivity. However, bone formation appeared to be balanced with bone resorption. The serum concentration of parathyroid hormone (PTH) was higher in the hibernation (P=0.35) and post-hibernation (P=0.006) seasons relative to pre-hibernation levels. Serum leptin was lower (P<0.004) post-hibernation relative to pre-hibernation and hibernation periods. Insulin-like growth factor I (IGF-I) decreased (P<0.0001) during hibernation relative to pre-hibernation and reached its highest value during remobilization. There was no difference (P=0.64) in 25-OH vitamin D between the three seasons. Serum osteocalcin (bone formation marker) was significantly correlated with PTH, but not with leptin, IGF-I or 25-OH vitamin D. Osteocalcin and PTH were positively correlated when samples from all seasons were pooled and when only hibernation samples were considered, raising the possibility that the anabolic actions of PTH help maintain bone formation to prevent disuse osteoporosis. Prostaglandin E(2) (PGE(2)) release from MC3T3 osteoblastic cells was significantly affected by treatment with bear serum from different seasons (i.e. hibernation versus active periods). The seasonal changes in PGE(2) release showed trends similar to the seasonal changes in serum IGF-I. Since both PGE(2) and IGF-I are associated with collagenous bone formation, it is possible that seasonal changes in a circulating factor influence IGF-I levels in vivo in bears and PGE(2) release in osteoblastic cells in vitro. The significant decrease in serum leptin following arousal from hibernation may promote bone formation during remobilization, assuming there is a similar decrease in intracerebroventricular leptin. These finding

Topics: 3T3 Cells; Animals; Bone Resorption; Calcium; Dinoprostone; Female; Hibernation; Insulin-Like Growth Factor I; Leptin; Mice; Osteocalcin; Osteogenesis; Osteoporosis; Parathyroid Hormone; Seasons; Ursidae

Topics: Adrenergic beta-Antagonists; Animals; Bone Density; Female; Fractures, Bone; Humans; Hypothalamus; Leptin; Osteoporosis; Osteoporosis, Postmenopausal; Receptors, Adrenergic, beta-2

Topics: Adiponectin; Adipose Tissue; Animals; Body Composition; Body Weight; Bone Density; Female; Fractures, Bone; Humans; Insulin; Leptin; Male; Menopause; Nutritional Physiological Phenomena; Obesity; Osteoporosis; Resistin

To evaluate the influence of Body Mass Index, body composition and hormonal factors on bone mass in young women with amenorrhea related to restrictive eating disorders.. Descriptive study of 55 patients with secondary amenorrhea due to restrictive eating disorders and 14 healthy girls used for comparison. Assessment of Bone Mineral Density, Fat Mass and Lean Mass by DEXA and of the serum hormonal profile.. Patients had lower BMI, lower Fat Mass and lower Bone Mass compared to controls; their serum levels of LH, FT(3), DHEAS, Insulin and Leptin were significantly reduced. Low Bone Density, especially in the lumbar region, correlated with concentrations of FT(3), Cortisol, Insulin and Leptin, hormones expressive of metabolic adjustment to malnutrition. Lean Mass was a strong predictor of osteopenia and osteoporosis.. Hormonal nutritional markers, together with soft tissue composition measurements, are viable options for ongoing monitoring of subjects with eating disorders.

Topics: Adolescent; Adult; Amenorrhea; Body Composition; Body Mass Index; Bone Density; Dehydroepiandrosterone Sulfate; Estradiol; Feeding and Eating Disorders; Female; Follicle Stimulating Hormone; Humans; Hydrocortisone; Insulin; Leptin; Luteinizing Hormone; Osteoporosis; Testosterone; Triiodothyronine

Topics: Adolescent; Androgens; Bone Density; Bone Development; Child; Estrogens; Female; Genetic Predisposition to Disease; Hormones; Humans; Leptin; Male; Osteoporosis; Phenotype; Puberty; Sex Factors; Syndrome

The pathogenesis of bone loss in major depressive disorder is a matter of debate. Studies of bone loss in nonpsychiatric medical disorders have found an association between the activation of osteoclastic cells and an imbalance of pro- and antiinflammatory cytokines. Since major depressive disorder is also associated with alterations in serum cytokine concentrations, the authors hypothesized that bone loss in patients with major depressive disorder and comorbid borderline personality disorder may be associated with cytokines capable of activating osteoclastic cells.. Twenty-two patients with borderline personality disorder and comorbid current or lifetime major depressive disorder were compared with 16 patients with borderline personality disorder who did not have major depressive disorder and 20 healthy volunteers. Bone mineral density was assessed by means of dual-energy x-ray absorptiometry. Markers of bone turnover as well as endocrine and immune measures were determined.. The bone mineral density of 10 patients with borderline disorder plus current major depressive episode was significantly lower than that of the healthy subjects and the patients with borderline personality disorder without depression. Values of crosslaps, osteocalcin, serum cortisol, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 were significantly higher in the patients with borderline disorder plus current major depressive episode than in the healthy subjects. Crosslaps correlated positively with TNF-alpha but negatively with bone mineral density at the lumbar spine. Patients with borderline personality disorder who did not have current or lifetime depression displayed no alterations of either bone mineral density or the immunological and hormonal measures examined.. Young women with comorbid borderline personality disorder and major depressive disorder have an elevated risk for osteoporosis. Borderline personality disorder per se is not associated with low bone mineral density. These data suggest that the immune and endocrine disturbances associated with depressive disorders in the context of borderline personality disorder may play a role in the pathophysiological process underlying bone loss in the patients studied.

Topics: Absorptiometry, Photon; Adult; Biomarkers; Bone and Bones; Bone Density; Borderline Personality Disorder; Collagen; Comorbidity; Cytokines; Depressive Disorder, Major; Female; Humans; Insulin-Like Growth Factor I; Leptin; Osteoclasts; Osteoporosis; Peptide Fragments; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

The disruption between the brain and the spinal cord leads to a decentralized sympathetic nervous system in people with chronic, cervical spinal cord lesions. These tetraplegic subjects are prone to disorders of energy metabolism and osteoporosis, and they experience alterations in their body composition with a relative accumulation of fat. The adipocyte-derived cytokine leptin is a key signal in caloric intake and energy expenditure, and it might modify bone remodelling, possibly regulated by sympathetic neuronal signalling. In able-bodied subjects leptin exhibits circadian variations, possibly mediated via sympathetic neurones. We have examined the plasma concentration of leptin among tetraplegics, to determine whether plasma leptin in these subjects exhibits circadian variations.. Blood samples were collected during a 24-h study period from tetraplegic subjects (n = 6) and from able-bodied controls (n = 8). Fasting, tetraplegic subjects had mean plasma concentrations of leptin about four times those of able-bodied controls (P < 0.05). In tetraplegia, plasma leptin was negatively correlated with total lean mass (r =-0.88, P < 0.05) but correlated positively with total fat mass (r = 0.89, P < 0.05). A marked circadian variation in plasma leptin concentrations was more evident in tetraplegia than in able-bodied controls.. Plasma leptin is markedly elevated and it shows more prominent circadian variations in tetraplegia compared with able-bodied subjects. Possibly the regulation of leptin metabolism is impaired among these patients. This might distort thermogenesis and energy expenditure, thus explaining the enhanced risk of the metabolic syndrome and of osteoporosis among tetraplegic subjects.

Topics: Adult; Body Composition; Case-Control Studies; Circadian Rhythm; Humans; Leptin; Male; Metabolic Syndrome; Osteoporosis; Quadriplegia; Risk

Little is known regarding the health effects of a raw food (RF) vegetarian diet.. We performed a cross-sectional study on 18 volunteers (mean +/- SD age, 54.2 +/- 11.5 years; male/female ratio, 11:7) on a RF vegetarian diet for a mean of 3.6 years and a comparison age- and sex-matched group eating typical American diets. We measured body composition, bone mineral content and density, bone turnover markers (C-telopeptide of type I collagen and bone-specific alkaline phosphatase), C-reactive protein, 25-hydroxyvitamin D, insulin-like growth factor 1, and leptin in serum.. The RF vegetarians had a mean +/- SD body mass index (calculated as weight in kilograms divided by the square of height in meters) of 20.5 +/- 2.3, compared with 25.4 +/- 3.3 in the control subjects. The mean bone mineral content and density of the lumbar spine (P= .003 and P<.001, respectively) and hip (P = .01 and P<.001, respectively) were lower in the RF group than in the control group. Serum C-telopeptide of type I collagen and bone-specific alkaline phosphatase levels were similar between the groups, while the mean 25-hydroxyvitamin D concentration was higher in the RF group than in the control group (P<.001). The mean serum C-reactive protein (P = .03), insulin-like growth factor 1 (P = .002), and leptin (P = .005) were lower in the RF group.. A RF vegetarian diet is associated with low bone mass at clinically important skeletal regions but is without evidence of increased bone turnover or impaired vitamin D status.

Topics: Absorptiometry, Photon; Alkaline Phosphatase; Biomarkers; Body Composition; Bone Density; C-Reactive Protein; Collagen; Collagen Type I; Cross-Sectional Studies; Diet, Vegetarian; Female; Humans; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Proteins; Leptin; Male; Middle Aged; Osteoporosis; Peptides; Pregnancy Proteins; Statistics, Nonparametric; Vitamin D

Evidence is accumulating that the risk of osteoporosis in later life may be determined in part by environmental influences on bone development during intrauterine and early postnatal life. A potential role for fetal leptin in mediating these effects is suggested by animal studies showing that leptin influences prenatal osteoblast growth and development, and that fetal leptin concentrations are altered by changes in maternal nutrition. In a group of term human infants we reported previously that maternal birthweight, smoking, fat mass, and exercise during late pregnancy independently predict neonatal bone mass. To investigate the potential role of leptin in mediating these effects, we now relate leptin concentrations in umbilical venous serum to neonatal bone mass and body composition in 117 infants. There were strong positive associations between umbilical venous leptin concentration and each of whole body bone mineral contents (BMC) (r = 0.42, P < or = 0.001) and estimated volumetric bone density (r = 0.21, P = 0.02); whole body lean mass (r = 0.21, P < or = 0.024); and whole body fat mass (r = 0.60, P < 0.001). The associations with neonatal BMC and fat mass, but not with lean mass, were independent of associations that we have reported previously between cord serum insulin-like growth factor 1 (IGF-1) concentrations and neonatal body composition. Among the maternal determinants of neonatal bone mass, cord leptin explained the relationship with maternal fat stores, but not those with the mother's own birthweight, smoking, or physical activity. We conclude that umbilical venous leptin predicts both the size of the neonatal skeleton and its estimated volumetric mineral density. In addition, among previously documented maternal determinants of neonatal bone mass in healthy pregnancies, maternal fat stores may mediate their effect on fetal bone accrual through variation in fetal leptin concentrations.

Topics: Absorptiometry, Photon; Adipose Tissue; Anthropometry; Birth Weight; Body Composition; Bone and Bones; Bone Density; Female; Fetal Blood; Humans; Infant, Newborn; Leptin; Male; Osteoporosis

Topics: Animals; Bone Density; Bone Resorption; Brain; Humans; Leptin; Mice; Osteoblasts; Osteoclasts; Osteoporosis; Receptor, Cannabinoid, CB1

Topics: Animals; Black People; Female; Humans; Leptin; Obesity; Osteoporosis; White People

The pathophysiology of osteoporosis in chronic liver diseases is unknown. Recent data suggest that serum leptin is associated with bone mineral density (BMD). In animal studies leptin was found to be a potent inhibitor of bone formation. We investigated the relationship between serum leptin levels, soluble leptin receptor (sOB-R), free leptin index (FLI) and BMD in patients with primary biliary cirrhosis (PBC).. Ninety-four female patients with PBC were included in this study; 122 healthy women served as controls. Serum leptin levels were measured by radioimmunoassay, sOB-R by enzyme-linked immunosorbent assay. BMD was measured by dual energy X-ray absorptiometry in the lumbar spine and femoral neck.. Serum leptin was significantly lower in patients with PBC compared with healthy controls. No difference was found between the body mass index (BMI) of patients and controls. There was a strong positive correlation between leptin and BMI. In PBC no association was found between leptin, sOB-R and liver function tests, histological stages or the presence of osteoporosis. Osteoporosis was present in 38 patients. A positive correlation was found between serum leptin and femoral neck z-score even after adjustment for BMI, whereas serum sOB-R correlated inversely with the serum leptin level. There was no difference in FLI between the subgroups of PBC patients according to the stages of the disease.. We found a lower serum leptin level and a higher sOB-R in patients with PBC, which could not be explained by the difference in BMI. As leptin was associated with BMD, it may be hypothesized that leptin is involved in the complex regulation of bone metabolism in PBC.

Topics: Absorptiometry, Photon; Aged; Bone Density; Collagen Type I; Female; Femur Neck; Humans; Leptin; Liver Cirrhosis, Biliary; Lumbar Vertebrae; Middle Aged; Osteocalcin; Osteoporosis; Receptors, Cell Surface; Receptors, Leptin

The role of leptin during the progression of osteoporosis was investigated in ovariectomized rats by correlation of serum leptin levels with N-telopeptide of collagen type I (NTx) and osteocalcin levels before ovariectomy and 20, 40 and 60 days after the operation. Furthermore, peripheral quantitative computed tomography was used to confirm the development of severe osteoporosis in rats on day 60. The levels of NTx and osteocalcin were significantly increased on day 20 [61.9+/-5.4 nM BCE (bone collagen equivalents) and 215.6+/-53.3 ng/mL, respectively] in comparison to those before ovariectomy (41.3+/-1.7 nM BCE and 60.4+/-10.9 ng/mL). Accordingly, leptin was significantly elevated on day 20 (3033+/-661 vs. 606+/-346 pg/mL before ovariectomy). Bone markers and leptin levels remained constant up to day 40, while a slight, but not statistically significant, decrease was noted for osteocalcin and leptin on day 60. Although leptin and bone markers did not correlate before ovariectomy (r=0.09 for NTx and r=-0.05 for osteocalcin), strong correlation was observed at all time points after ovariectomy. The data obtained suggest that the alterations in serum leptin levels during the progression of osteoporosis in ovariectomized rats follow the alterations in bone markers.

Topics: Animals; Biomarkers; Bone and Bones; Collagen; Collagen Type I; Female; Leptin; Osteocalcin; Osteoporosis; Ovariectomy; Peptides; Rats; Time Factors; Tomography, X-Ray Computed

Topics: Adrenergic beta-Antagonists; Bone and Bones; Bone Density; Humans; Leptin; Osteoporosis; Propranolol; Recombinant Proteins

Topics: Antioxidants; Bone Resorption; Carrier Proteins; Contraindications; Female; Hormone Replacement Therapy; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Isoflavones; Leptin; Membrane Glycoproteins; Osteoporosis; Phytoestrogens; Plant Preparations; Raloxifene Hydrochloride; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Selective Estrogen Receptor Modulators; Teriparatide

Topics: Adaptation, Physiological; Animals; Biomarkers; Bone and Bones; Bone Remodeling; Bone Resorption; Hibernation; Leptin; Models, Animal; Osteoporosis; Sensitivity and Specificity; Ursidae

Over the past 20 years, there have been a growing number of reports of low bone mineral density (BMD) or premature bone loss in individuals with a high physical activity level. These skeletal problems have been documented mainly in underweight women with amenorrhea and have often been linked to a sex hormone deficiency. However, sex hormone treatment has been shown to have limited efficacy for the prevention or treatment of low BMD in such women. Studies of bone turnover in women with sustained exercise-associated amenorrhea using metabolic markers of osteoblast activities and collagen synthesis have demonstrated an apparent reduction of bone formation that is associated with a low body mass index (BMI) and with endocrine disturbances that are characteristic of energy deficit. Comparable metabolic and endocrine disturbances have been observed in anorexic women that reverse with weight gain. Furthermore, increases of BMD accompany weight gain in both groups of women, even without a return of menses. Collectively, these observations suggest an important link between energy balance and the balance of bone turnover in women with exercise and/or diet-associated amenorrhea. Although there have been few studies that have explored relations between bone turnover, BMD, and energy balance in physically active men, there is evidence for a link between reduced bone formation and an abrupt, short-term energy deficit. Interestingly, the presence of low BMD in physically active men has not been associated with a sex hormone deficiency. This review evaluates the evidence that underlies the hypothesis that an energy deficit is instrumental in the disturbance of bone turnover that has been observed in physically active individuals.

Topics: Adult; Bone and Bones; Bone Density; Bone Remodeling; Energy Metabolism; Exercise; Female; Humans; Insulin-Like Growth Factor I; Leptin; Male; Nutritional Physiological Phenomena; Osteoporosis

Growing evidence suggests that positive associations between fat mass (FM) and bone mineral density (BMD) are mediated by not only biomechanical but also biochemical factors. Adiponectin is a novel adipocyte-derived hormone that regulates energy homeostasis and has anti-inflammatory and anti-atherogenic effects. Unlike other adipokines such as leptin, adiponectin levels decrease in obesity and type 2 diabetes. The purpose of our study was to investigate associations of serum adiponectin with BMD (DXA and QCT), FM (DXA and QCT), and serum leptin and soluble leptin receptor levels in 38 women and 42 men (age 39-81, BMI 17-55, 86% with type 2 diabetes). After adjusting for age, gender, race, smoking, and diabetes status, serum adiponectin was inversely associated with areal BMD (r = -0.20 to -0.3, all P < 0.01), volumetric BMD (r = -0.35 to -0.44, all P < 0.01), and visceral fat volume (r = -0.30, P < 0.01). These associations remained significant after adjusting for whole body fat mass. The associations of adiponectin with subcutaneous fat volume, whole body FM, and serum leptin level were not significant (all P > 0.1). These data suggest that adiponectin may play a role in the protective effects of visceral fat on BMD.

Topics: Adiponectin; Adipose Tissue; Adult; Aged; Aged, 80 and over; Bone Density; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Osteoporosis; Proteins; Receptors, Cell Surface; Receptors, Leptin

Overweight is associated with both higher bone mineral density (BMD) and higher serum leptin concentrations. In humans, little is known about the relationship of leptin concentration and bone density. We studied this relationship in a large, national population-based sample. Participants included 5815 adults in the Third U.S. National Health and Nutrition Examination Survey (NHANES III; 1988-1994) who underwent DXA of the proximal femur and measurement of fasting serum leptin. Mean +/- SE BMD (gm/cm2) of the total hip was 1.01 +/- 0.005 in men, 0.94 +/- 0.004 in premenopausal women, and 0.78 +/- 0.007 in postmenopausal women. Bone density increased with increasing leptin concentration in men (p = 0.003), premenopausal women (p < 0.001), and postmenopausal women (p < 0.001). However, after adjusting for body mass index (BMI) and other bone density-related factors, an inverse association emerged in men (p < 0.001), being most evident among men < 60 years old. There was no association of leptin and BMD in premenopausal women (p = 0.66) or postmenopausal women (p = 0.69) in multivariate analysis. Controlling for leptin had no effect on the strong positive association of BMI and BMD in either men or women. Serum leptin concentration did not appear to affect directly BMD. If present, the association appeared to be limited to younger men who are at lower risk of osteoporosis.

Topics: Absorptiometry, Photon; Adult; Aged; Body Mass Index; Bone Density; Feeding Behavior; Female; Femur; Health Surveys; Hormones; Humans; Leptin; Life Style; Male; Middle Aged; Obesity; Osteoporosis; Postmenopause; Premenopause; Reproductive History; Smoking; United States; Vitamin D

Topics: Animals; Bone Resorption; Calcitonin; Humans; Leptin; Osteoclasts; Osteogenesis; Osteoporosis; Parathyroid Hormone; Radiography; Spine

Bone mineral density increases with fat body mass, and obesity has a protective effect against osteoporosis. However, the relationship between fat body mass and bone mineral density is only partially explained by a combination of hormonal and mechanical factors. Serum leptin levels are strongly and directly related to fat body mass. We report here the effects of leptin administration compared with estrogen therapy on ovariectomy-induced bone loss in rats. Leptin was effective at reducing trabecular bone loss, trabecular architectural changes, and periosteal bone formation. Interestingly, the combination of estrogen and leptin further decreased bone turnover compared with that in estrogen-treated ovariectomized rats. Leptin also significantly increased osteoprotegerin mRNA steady state levels and protein secretion and decreased RANK ligand mRNA levels in human marrow stromal cells in vitro. Our findings suggest that leptin could modulate bone remodeling in favor of a better bone balance in rats. This study is the first evidence that leptin therapy has a significant effect in preventing ovariectomy-induced bone loss, and this effect may at least in part be mediated by the osteoprotegerin/RANK ligand pathway.

Topics: Animals; Bone and Bones; Bone Development; Bone Marrow Cells; Gene Expression; Glycoproteins; Leptin; Osteoporosis; Osteoprotegerin; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Stromal Cells; Weight Gain

Bone remodeling is the physiologic process used by vertebrates to maintain a constant bone mass between the end of puberty and gonadal failure. Besides the well-characterized and critical local regulation of bone remodeling, recent genetic studies have shown that there is a central control of bone formation, one aspect of bone remodeling. This central regulation involves leptin, an adipocyte-secreted hormone that controls body weight, reproduction, and bone remodeling following binding to its receptor located on the hypothalamic nuclei. This genetic result in rodents is in line with clinical observations in humans and offers a whole new direction for research in bone physiology.

Topics: Adolescent; Adult; Age Factors; Animals; Body Weight; Bone and Bones; Bone Density; Bone Development; Bone Remodeling; Carrier Proteins; Female; Fractures, Bone; Humans; Hypothalamus; Leptin; Mice; Middle Aged; Osteoporosis; Rats; Receptors, Cell Surface; Receptors, Leptin; Research; Risk Factors

The pathophysiology of osteoporosis complicating chronic liver disease is unknown. Recent animal studies have found leptin to be a potent inhibitor of bone formation. The aim of this study was to investigate the relationship between serum leptin levels and bone mineral density in patients with chronic liver disease.. Fifty-eight patients, 39 females and 19 males, and age- and gender-matched controls were included. Bone mineral density was measured by using dual energy X-ray absorptiometry. Serum leptin was measured by using a radioimmunoassay.. The mean serum leptin concentration was 10.4 +/- 11.3 and 15.2 +/- 17.9 ng/mL; P=0.11, in the patients and controls, respectively. Leptin correlated positively with body mass index in patients (r=0.40; P=0.003) and in controls (r=0.55; P < 0.0001). In patients classified as Child-Pugh grade B and C, serum leptin correlated negatively with bone mineral density in females at both the lumbar spine and the femoral neck (r=-0.78; P=0.04 and r=-0.86; P=0.03, respectively). In male patients, the correlation was only significant at the lumbar spine (r=-0.99; P=0.002 and r=-0.86; P=0.06, at the lumbar spine and femoral neck, respectively). No correlation was found between serum leptin and bone mineral density in the controls.. An inverse relationship between serum leptin and bone mineral density was found in patients with advanced chronic liver disease. The reasons for these findings are uncertain, but a pathophysiological role of circulating leptin in osteoporosis in chronic liver disease is possible.

Topics: Absorptiometry, Photon; Adult; Aged; Body Mass Index; Bone Density; Case-Control Studies; Chronic Disease; Cohort Studies; Female; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Osteoporosis

Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.

Topics: Animals; Bone Density; Bone Remodeling; Carrier Proteins; Cells, Cultured; Hypothalamus; Injections, Intraventricular; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Neuropeptide Y; Obesity; Osteoblasts; Osteoclasts; Osteoporosis; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction

Topics: Animals; Bone Density; Bone Regeneration; Humans; Leptin; Mice; Osteoporosis

Topics: Body Weight; Female; Humans; Leptin; Male; Osteoporosis

Topics: Adolescent; Adult; Amenorrhea; Animals; Anorexia Nervosa; Estradiol; Female; Humans; Leptin; Menstruation; Osteoporosis; Proteins