Osteomalacia is caused by impaired vitamin D receptor (VDR) signaling, calcium deficiency, and altered bone mineralization. This can be due to insufficient sunlight exposure, malabsorption, reduced D hormone activation in chronic kidney disease, and rare alterations of VDR signaling and phosphate metabolism. Leading symptoms are bone pain, muscular cramps, and increased incidence of falls in the elderly. The adequate respective countermeasures are to optimize the daily intake of calcium and vitamin D3 and to replace active D hormone and phosphate if deficient. Osteoporosis is characterized by bone fragility fractures upon minor physical impact. Indications for diagnosis and treatment can be established by estimating the absolute fracture risk, taking into account bone mineral density, age, gender, and individual risk factors. Exercise, intervention programs to avoid falls, and specific drugs are capable of substantially reducing fracture risk even in the elderly. Secondary osteoporosis primarily requires both bone-altering medications and effective treatment of underlying diseases.
Abdelrazek, Saeid; Szumowski, Piotr; Rogowski, Franciszek; Kociura-Sawicka, Agnieszka; Mojsak, Małgorzata; Szorc, Małgorzata
Metabolic bone disease encompasses a number of disorders that tend to present a generalized involvement of the whole skeleton. The disorders are mostly related to increased bone turnover and increased uptake of radiolabelled diphosphonate. Skeletal uptake of 99mTc-labelled diphosphonate depends primarily upon osteoblastic activity, and to a lesser extent, skeletal vascularity. A bone scan image therefore presents a functional display of total skeletal metabolism and has valuable role to play in the assessment of patients with metabolic bone disorders. However, the bone scan appearances in metabolic bone disease are often non-specific, and their recognition depends on increased tracer uptake throughout the whole skeleton. It is the presence of local lesions, as in metastatic disease, that makes a bone scan appearance obviously abnormal. In the early stages, there will be difficulty in evaluating the bone scans from many patients with metabolic bone disease. However, in the more severe cases scan appearances can be quite striking and virtually diagnostic.
Grech, P.; Martin, T.J.; Barrington, N.A.; Ell, P.J.
This book presents a reference on the radiologic evaluation, features, and differential diagnosis of metabolic diseases involving the whole skeleton, calcium deficiencies resulting from pharmacologic agents, and bone changes related to endocrine disturbances. It also stresses how radiology, nuclear medicine, and biochemistry - either alone or in concert - contribute to clinical diagnosis. It covers renal bone disease, Paget's disease, hyperphosphatasia, extraskeletal mineralization, metabolic bone disorders related to malnutrition, tumors, plus radionuclide studies including materials and methods.
Metabolic bone and joint diseases in adults include osteomalacia, rheumatoid arthritis, gouty arthritis. Recently, the newest molecular biology procedures and the clinical observation studies can produce good results for understanding of these diseases. From this perspective, the author introduced updated information of the pathophysiology, the latest diagnostic criteria and the therapy of these diseases.
Zatoński, Tomasz; Temporale, Hanna; Krecicki, Tomasz
There are reports that hearing loss is one of the clinical manifestations of metabolic bone diseases. Demineralization can lead to a reduction in ossicular mass. Paget's disease can reveal loss of mineral density of the cochlear bone. Ear bone remodeling in osteoporosis is similar to the changes in otosclerosis. Moreover, osteoporosis, osteogenesis imperfecta and otosclerosis have a similar genetic mechanism. According to some researchers osteopenia and osteoporosis may well be associated with idiopathic benign positional vertigo (BPV). Dysfunction of the organ of hearing and balance in patients with renal insufficiency may be due to disturbances in calcium phosphate balance and renal osteodystrophy in the course of the disease. Proving the presence of hearing loss in patients with metabolic bone diseases may lead to determining the new indications for bone densitometry in some patients with hearing impairment. Furthermore, audiological examination in patients with osteoporosis may be important because of the impact of hearing loss on prognosis for patients with metabolic bone diseases.
Yamauchi, Mika; Sugimoto, Toshitsugu
Serum sclerostin levels are being investigated in various metabolic bone diseases. Since serum sclerostin levels are decreased in primary hyperparathyroidism and elevated in hypoparathyroidism, parathyroid hormone (PTH) is thought to be a regulatory factor for sclerostin. Serum sclerostin levels exhibit a significant positive correlation with bone mineral density. On the other hand, a couple of studies on postmenopausal women have shown that high serum sclerostin levels are a risk factor for fracture. Although glucocorticoid induced osteoporosis and diabetes are both diseases that reduce bone formation, serum sclerostin levels have been reported to be decreased in the former and elevated in the latter, suggesting differences in the effects of sclerostin in the two diseases. Serum sclerostin levels are correlated with renal function, and increase with reduction in renal function. Serum sclerostin level may be a new index of bone assessment that differs from bone mineral density and bone metabolic markers.
Undale, Anita H; Westendorf, Jennifer J; Yaszemski, Michael J; Khosla, Sundeep
Human mesenchymal stem cells offer a potential alternative to embryonic stem cells in clinical applications. The ability of these cells to self-renew and differentiate into multiple tissues, including bone, cartilage, fat, and other tissues of mesenchymal origin, makes them an attractive candidate for clinical applications. Patients who experience fracture nonunion and metabolic bone diseases, such as osteogenesis imperfecta and hypophosphatasia, have benefited from human mesenchymal stem cell therapy. Because of their ability to modulate immune responses, allogeneic transplant of these cells may be feasible without a substantial risk of immune rejection. The field of regenerative medicine is still facing considerable challenges; however, with the progress achieved thus far, the promise of stem cell therapy as a viable option for fracture nonunion and metabolic bone diseases is closer to reality. In this review, we update the biology and clinical applicability of human mesenchymal stem cells for bone repair and metabolic bone diseases.
Undale, Anita H.; Westendorf, Jennifer J.; Yaszemski, Michael J.; Khosla, Sundeep
Human mesenchymal stem cells offer a potential alternative to embryonic stem cells in clinical applications. The ability of these cells to self-renew and differentiate into multiple tissues, including bone, cartilage, fat, and other tissues of mesenchymal origin, makes them an attractive candidate for clinical applications. Patients who experience fracture nonunion and metabolic bone diseases, such as osteogenesis imperfecta and hypophosphatasia, have benefited from human mesenchymal stem cell therapy. Because of their ability to modulate immune responses, allogeneic transplant of these cells may be feasible without a substantial risk of immune rejection. The field of regenerative medicine is still facing considerable challenges; however, with the progress achieved thus far, the promise of stem cell therapy as a viable option for fracture nonunion and metabolic bone diseases is closer to reality. In this review, we update the biology and clinical applicability of human mesenchymal stem cells for bone repair and metabolic bone diseases. PMID:19797778
Recent advances of the measurement of bone turn over markers contribute to non-invasive assessment of bone-metabolic disorders. We can detect the cause of the metabolic disorders with bone turn over markers and hormonal profiles more easily than before. Today, we can diagnose and treat metabolic bone diseases without invasive procedure such as bone biopsy.
Chen, Xu Xu; Yang, Tianfu
Adipose tissue has been more accepted as an active contributor to whole body homeostasis, rather than just a fat depot, since leptin, a 16 kDa protein, was discovered as the product of the obese gene in 1994. With more and more studies conducted on this hormone, it has been shown that there is a close relationship between adipose tissue and bone, which have important effects on each other. Bone is the source of many hormones, such as osteocalcin, that can affect energy metabolism and then the anabolism or catabolism of fat tissue. In contrast, the adipose tissue synthesizes and releases a series of adipokines, which are involved in bone metabolism through direct or indirect effects on bone formation and resorption. Interestingly, leptin, one of the most important cytokines derived from fat tissue, seems to account for the largest part of effects on bone, through direct or indirect involvement in bone remodeling and by playing a significant role in many bone diseases, such as osteoporosis, osteoarthritis, rheumatic arthritis, bone tumors and even fractures. In this review, we will discuss the progress in leptin research, particularly focusing on the roles of leptin in bone diseases.
Raubenheimer, Erich J; Noffke, Claudia E; Hendrik, Hilde D
Metabolic bone diseases often are asymptomatic and progress sub clinically. Many patients present at a late stage with catastrophic skeletal and extra skeletal complications. In this article, we provide an overview of normal bone remodeling and a synopsis of recent developments in the following conditions: osteoporosis, rickets/osteomalacia, endocrine-induced bone disease, chronic kidney disease-mineral bone disorder and Paget's disease of bone. Our discussion will emphasize the clinical and microscopic manifestations of these diseases in the jaws.
Ito, Akemi; Yajima, Aiji
Histological analysis of undecalcified bone biopsy specimens is a valuable clinical and research tool for studying the etiology, pathogenesis and treatment of metabolic bone diseases. In case of osteoporosis, bone biopsy is not usually required for the diagnosis ; however, bone histomorphometry may be useful in rare cases with unusual skeletal fragility. Bone histomorphometry also provides valuable information on the mechanism of action, safety and efficacy of new anti-osteoporosis drugs. Bone histomorphometry is useful for the diagnosis and the assessment of treatment response in rickets/osteomalacia and in CKD-MBD (chronic kidney disease-mineral and bone disorders) . In Japan, bone biopsy is often performed to establish the diagnosis of Paget's disease of bone, especially to differentiate it from metastatic bone disease.
Ishii, Akira; Imanishi, Yasuo
Magnesium is abundantly distributed among the body. The half of the magnesium exists in the bone. In addition, magnesium is the second most abundant intracellular cation in vertebrates and essential for maintaining physiological function of the cells. Epidemiologic studies have demonstrated that magnesium deficiency is a risk factor for osteoporosis. The mechanism of bone fragility caused by magnesium deficiency has been intensely studied using animal models of magnesium deficiency. Magnesium deficiency causes decreased osteoblastic function and increased number of osteoclasts. Magnesium deficiency also accelerates mineralization in bone. These observations suggest that disturbed bone metabolic turnover and mineralization causes bone fragility.
Wu, Ying-Ying; Xiao, E; Graves, Dana T
Diabetes mellitus and periodontal disease are chronic diseases affecting a large number of populations worldwide. Changed bone metabolism is one of the important long-term complications associated with diabetes mellitus. Alveolar bone loss is one of the main outcomes of periodontitis, and diabetes is among the primary risk factors for periodontal disease. In this review, we summarise the adverse effects of diabetes on the periodontium in periodontitis subjects, focusing on alveolar bone loss. Bone remodelling begins with osteoclasts resorbing bone, followed by new bone formation by osteoblasts in the resorption lacunae. Therefore, we discuss the potential mechanism of diabetes-enhanced bone loss in relation to osteoblasts and osteoclasts. PMID:25857702
Wu, Ying-Ying; Xiao, E; Graves, Dana T
Diabetes mellitus and periodontal disease are chronic diseases affecting a large number of populations worldwide. Changed bone metabolism is one of the important long-term complications associated with diabetes mellitus. Alveolar bone loss is one of the main outcomes of periodontitis, and diabetes is among the primary risk factors for periodontal disease. In this review, we summarise the adverse effects of diabetes on the periodontium in periodontitis subjects, focusing on alveolar bone loss. Bone remodelling begins with osteoclasts resorbing bone, followed by new bone formation by osteoblasts in the resorption lacunae. Therefore, we discuss the potential mechanism of diabetes-enhanced bone loss in relation to osteoblasts and osteoclasts.
Metabolic bone diseases, especially osteoporosis, demand a multidisciplinary approach. The physical forces find a rationale in the treatment of local alterations in bone-cartilage metabolism. In integrated treatment of vertebral fractures caused by fragility, stimulation with electrical fields has been observed to be effective in reducing pain and improving patients' quality of life.
Volume 1 of ''Gamma images in benign and metabolic bone diseases'' comprises chapters devoted to: general remarks and considerations, radiopharmaceuticals, Paget disease, osteomyelitis, trauma, benign bone tumors, chronic renal dialysis, acute renal failure, osteomalacia and rickets, and osteoporosis. Although published in 1981, the most recent references in the book were 1978 and most are 1977 or earlier. One of the strongest aspects of the volume are tables which categorize diseases, pathophysiology of disease, and image abnormalities. (JMT)
Acca, M; Ragno, A; Francucci, C M; D'Erasmo, E
Long-term total parenteral nutrition (TPN) is a procedure commonly applied to patients with advanced forms of intestinal malabsorption. Among TPN complications, bone metabolic diseases, such as osteoporosis and osteomalacia, are a common finding. Initially considered to be a manifestation of aluminium toxicity which followed massive contamination with the element of the solutions used in TPN, metabolic osteopathy during TPN is currently considered a multiform syndrome, with a multifactorial pathogenesis, which may manifest itself with vague or clear clinical pictures. In this review, we analyse clinical, pathogenetic, and therapeutic aspects of the most common bone metabolic diseases in patients undergoing long-term TPN.
Kanazawa, Ippei; Sugimoto, Toshitsugu
The number of patients with lifestyle-related diseases is rapidly increasing in Japan. Metabolic syndrome caused by abdominal fat accumulation induces diabetes mellitus, dyslipidemia, and hypertension, resulting in an increase in cardiovascular diseases. On the other hand, recent studies have shown that the lifestyle-related diseases are risk factors of osteoporotic fractures. Although it remains still unclear how metabolic disorders affect bone tissue, oxidative stress and/or glycation stress might directly have negative impacts on bone tissue and increase the risk of fractures. In this review, we describe the association of diabetes mellitus and dyslipidemia with the fracture risk through oxidative stress and glycation stress.
Joyce, Nanette C; Hache, Lauren P; Clemens, Paula R
This article reviews the recent literature regarding bone health as it relates to the patient living with neuromuscular disease (NMD). Studies defining the scope of bone-related disease in NMD are scant. The available evidence is discussed, focusing on abnormal calcium metabolism, increased fracture risk, and the prevalence of both scoliosis and hypovitaminosis D in Duchenne muscular dystrophy, amyotrophic lateral sclerosis, and spinal muscular atrophy. Future directions are discussed, including the urgent need for studies both to determine the nature and extent of poor bone health, and to evaluate the therapeutic effect of available osteoporosis treatments in patients with NMD.
Osteopenia is defined as postnatal bone mineralization that is inadequate to fully mineralize bones. Osteopenia occurs commonly in very low birth weight (VLBW) infants. Prior to the use of high-mineral containing diets for premature infants, which is the current practice, significant radiographic ch...
Swanson, Christine M.; Shea, Steven A.; Stone, Katie L.; Cauley, Jane A.; Rosen, Clifford J.; Redline, Susan; Karsenty, Gerard; Orwoll, Eric S.
Obstructive sleep apnea (OSA) and low bone mass are two prevalent conditions, particularly among older adults, a section of the U.S. population that is expected to grow dramatically over the coming years. OSA, the most common form of sleep disordered breathing, has been linked to multiple cardiovascular, metabolic, hormonal and inflammatory derangements and may have adverse effects on bone. However, little is known about how OSA (including the associated hypoxia and sleep loss) affects bone metabolism. In order to gain insight into the relationship between sleep and bone, we review the growing information on OSA and metabolic bone disease and discuss the pathophysiological mechanisms by which OSA may affect bone metabolism/architecture. PMID:25639209
Goubraim, Rabia; Kabbaj, Nawal; Salihoun, Mouna; Chaoui, Zakia; Nya, M'Hamed; Amrani, Naima
Background/Aim. Metabolic Bone disorders are well-recognized extrahepatic complications of cirrhosis. The aim was to report their prevalence and the associated factors to their development in patients with viral cirrhosis. Patients and Methods. All consecutive patients with viral cirrhosis were prospectively enrolled. Parathyroid hormone, 25-hydroxyvitamin D, liver function, and phosphocalcic tests were measured in all patients. Bone mineral density was measured at the lumbar spine and total hip by dual-energy X-ray absorptiometry. Data were analyzed using SPSS software. Results. Forty-six cirrhotic patients were included with hepatitis C (87%) and hepatitis B (13%). The Child-Pugh score was grade A in 87% of cases and grade B in 13%. Thirty-seven patients had decreased bone mineral density with osteopenia in 24 patients and osteoporosis in 13 patients. Decreased 25-hydroxyvitamin D was found in 95.6% of cases. Bone disorders were significantly more frequent in old patients with low body mass index, long duration of liver disease, and low 25-hydroxyvitamin D level. None of these factors was an independent factor associated with bone disorders. Conclusion. Our study revealed a high prevalence of metabolic bone disorders among viral cirrhotic patients. Consequently, bone mineral density assessment should be performed systematically in all cirrhotic patients. PMID:27398385
Pathological and metabolic bone diseases are common and relevant occurrences in orthopedics and trauma surgery; however, fractures are often treated as being the illness itself and not seen as the symptom of an underlying bone disease. This is why further diagnostics and systemic treatment options are often insufficiently considered in the routine treatment of fractures. This review focuses on osteoporosis, osteopetrosis, hypophosphatasia and Paget's disease of bone.In patients with osteoporotic vertebral or proximal femur fractures, pharmaceutical treatment to prevent subsequent fractures is an integral part of fracture therapy together with surgical treatment. Osteopetrosis is caused by compromised osteoclastic bone resorption; therefore, even in the face of an elevated bone mass, vitamin D3 supplementation is crucial to avoid clinically relevant hypocalcemia. Unspecific symptoms of the musculoskeletal system, especially together with stress fractures, are typically found in patients suffering from hypophosphatasia. In these patients measurement of alkaline phosphatase shows reduced enzyme activity. Elevated levels of alkaline phosphatase are found in Paget's disease of bone where bisphosphonates are still the treatment of choice.
Cook, Gary J R; Gnanasegaran, Gopinath; Chua, Sue
The diphosphonate bone scan is ideally suited to assess many global, focal or multifocal metabolic bone disorders and there remains a role for conventional bone scintigraphy in metabolic bone disorders at diagnosis, investigation of complications, and treatment response assessment. In contrast, the role of bone scintigraphy in the evaluation of primary malignant bone tumors has reduced with the improvement of morphologic imaging, such as computed tomography and magnetic resonance imaging. However, an increasing role for (18)F-fluorodeoxyglucose positron emission tomography and positron emission tomography/computed tomography is emerging as a functional assessment at diagnosis, staging, and neoadjuvant treatment response assessment.
Skeletal abnormalities are a recognized component of Neurofibromatosis type I (NF1), but a generalized metabolic bone defect in NF1 has not been fully characterized thus far. The purpose of this study was to characterize at the densitometric, biochemical, and pathological level the bone involvement ...
Lewiecki, E Michael; Baron, Roland; Bilezikian, John P; Gagel, Robert E; Leonard, Mary B; Leslie, William D; McClung, Michael R; Miller, Paul D
The 2015 Santa Fe Bone Symposium was a venue for healthcare professionals and clinical researchers to present and discuss the clinical relevance of recent advances in the science of skeletal disorders, with a focus on osteoporosis and metabolic bone disease. Symposium topics included new developments in the translation of basic bone science to improved patient care, osteoporosis treatment duration, pediatric bone disease, update of fracture risk assessment, cancer treatment-related bone loss, fracture liaison services, a review of the most significant studies of the past year, and the use of telementoring with Bone Health Extension for Community Healthcare Outcomes, a force multiplier to improve the care of osteoporosis in underserved communities.
Okada, Yosuke; Tanaka, Yoshiya
A lifestyle-related disease and osteoporosis are diseases to increase with aging and a lifestyle-related disease has an influence on the bone metabolism. Because the number of patients with lifestyle-related disease is getting larger, it is necessary to prevent fracture in those. Unfortunately, substantial randomized control studies are yet to be done in patients with lifestyle-related disease to clarify if anti-osteoporotic drugs are effective to prevent fractures. It is suggested by the subanalysis in the existing clinical study with usefulness of bisphosphonates with evidence as an osteoporotic therapeutic drug in life-related disease. Here I will review about the effective and problem with bisphosphonate for the lifestyle-related disease with arteriosclerosis.
Tejwani, Vickram; Qian, Qi
The elderly chronic kidney disease (CKD) population is growing. Both aging and CKD can disrupt calcium (Ca2+) homeostasis and cause alterations of multiple Ca2+-regulatory mechanisms, including parathyroid hormone, vitamin D, fibroblast growth factor-23/Klotho, calcium-sensing receptor and Ca2+-phosphate product. These alterations can be deleterious to bone mineral metabolism and soft tissue health, leading to metabolic bone disease and vascular calcification and aging, termed CKD-mineral and bone disorder (MBD). CKD-MBD is associated with morbid clinical outcomes, including fracture, cardiovascular events and all-cause mortality. In this paper, we comprehensively review Ca2+ regulation and bone mineral metabolism, with a special emphasis on elderly CKD patients. We also present the current treatment-guidelines and management options for CKD-MBD. PMID:23760058
Sabrautzki, Sibylle; Rubio-Aliaga, Isabel; Hans, Wolfgang; Fuchs, Helmut; Rathkolb, Birgit; Calzada-Wack, Julia; Cohrs, Christian M; Klaften, Matthias; Seedorf, Hartwig; Eck, Sebastian; Benet-Pagès, Ana; Favor, Jack; Esposito, Irene; Strom, Tim M; Wolf, Eckhard; Lorenz-Depiereux, Bettina; Hrabě de Angelis, Martin
Metabolic bone disorders arise as primary diseases or may be secondary due to a multitude of organ malfunctions. Animal models are required to understand the molecular mechanisms responsible for the imbalances of bone metabolism in disturbed bone mineralization diseases. Here we present the isolation of mutant mouse models for metabolic bone diseases by phenotyping blood parameters that target bone turnover within the large-scale genome-wide Munich ENU Mutagenesis Project. A screening panel of three clinical parameters, also commonly used as biochemical markers in patients with metabolic bone diseases, was chosen. Total alkaline phosphatase activity and total calcium and inorganic phosphate levels in plasma samples of F1 offspring produced from ENU-mutagenized C3HeB/FeJ male mice were measured. Screening of 9,540 mice led to the identification of 257 phenodeviants of which 190 were tested by genetic confirmation crosses. Seventy-one new dominant mutant lines showing alterations of at least one of the biochemical parameters of interest were confirmed. Fifteen mutations among three genes (Phex, Casr, and Alpl) have been identified by positional-candidate gene approaches and one mutation of the Asgr1 gene, which was identified by next-generation sequencing. All new mutant mouse lines are offered as a resource for the scientific community.
Delmas, P D
There is not yet an ideal marker of bone formation, but circulating BGP is the most satisfactory at present. New developments include the use of sheep BGP64 and human BGP85 as an immunogen and monoclonal antibodies, which may recognize fragments of BGP released during resorption. The specific measurement of bone alkaline phosphatase and the assay of procollagen fragments and of other noncollagenous bone-related proteins will allow a more precise assessment of the complex osteoblastic functions in normal and pathologic conditions. Finding a sensitive and specific marker of resorption is a challenge because all constituents of bone matrix are likely to be degraded into minute peptides during osteoclastic bone resorption. The measurement of pyridinium crosslinks and possibly of tartrate-resistant acid phosphate by a bone-specific monoclonal antibody are the most tangible improvements in this area. These markers need to be validated by comparison with data obtained by direct measurement of bone turnover on iliac crest biopsy. It should be remembered, however, that circulating markers reflect the overall activity of the whole skeleton, including the cortical, subcortical, and trabecular envelopes, which have different remodeling rates in normal and abnormal states. A circulating marker will not detect a specific defect of the cellular activity of one compartment of bone if the summated turnover of the skeleton is unchanged. Conversely, bone histomorphometry is limited to a small area of the trabecular envelope but allows detection of a specific defect at the cellular level. These differences should be kept in mind, as there is growing evidence that, for example, bone mass and bone turnover of osteoporotic patients before and during treatment vary in different appendicular/axial and cortical/trabecular compartments. Finally, a single marker might be valuable in some diseases and not in others (such as serum BGP in Paget's disease of bone). Despite these difficulties
Wędrychowicz, Anna; Starzykk, Jerzy
Among long-term survivors after hematopoietic stem cell transplantation (HSCT) late endocrine complications are observed in 20-50%. Very often these complications influence significantly the patient´s life and have to be treated till the end of life. Their proper prevention and monitoring are extremely important in patients who underwent HSCT during childhood. Since the 90s of the last millennium/century, thyroid dysfunction, disorders of somatic and sexual development, and disturbances of fertility have been presented in several publications. In the paper, less known endocrine complications after HSCT published in the last years are discussed. Disorders of carbohydrate metabolism, post-transplant diabetes and insulin resistance are presented. Moreover, dyslipidemia, hypertension, and post-transplant bone metabolic disease are demonstrated/shown. The paper describes the etiopathogenesis, methods of prevention as well as treatment and the results of the treatment of these endocrine complications after HSCT. Moreover, actual recommendations for screening and prevention of endocrine complications in long-term HCT survivors are presented.
Carnovali, M; Ottria, R; Pasqualetti, S; Banfi, G; Ciuffreda, P; Mariotti, M
The endocannabinoid system (which includes fatty acid derivatives, receptors, and metabolizing enzymes) is involved in a variety of physiological processes, including bone metabolism in which it regulates the function of osteoblasts and osteoclasts, as well as differentiation of their precursors. The zebrafish (Danio rerio) provides a useful animal model for bone research since zebrafish bones develop rapidly and are anatomically similar to mammalian bones. Putative orthologues and paralogs of endocannabinoid genes have recently been identified in zebrafish, demonstrating the presence of cannabinoid type 1 (CB1) and type 2 (CB2) receptors with affinity to endocannabinoid ligands. To identify therapeutic molecules potentially useful in bone-related diseases, we evaluated the in vivo effects of exposure to long-chain fatty acid amides in adult zebrafish. Using a well-established zebrafish scale model, we found that anandamide and N-linoleoylethanolamine are able to stimulate bone formation by increasing alkaline phosphatase activity in physiological conditions. In addition, they prevent the alteration of bone markers in a prednisolone-induced osteoporosis model in adult zebrafish scales, whereas their esterified forms do not. These data suggest that long-chain fatty acid amides are involved in regulating bone metabolism in zebrafish scales and that the CB2 receptor is a key mediator in this process.
Richardson, M. L.; Genant, H. K.; Cann, C. E.; Ettinger, B.; Gordan, G. S.; Kolb, F. O.; Reiser, U. J.
Advances in the radiologic sciences have permitted the development of numerous noninvasive techniques for measuring the mineral content of bone, with varying degrees of precision, accuracy, and sensitivity. The techniques of standard radiography, radiogrammetry, photodensitometry, Compton scattering, neutron activation analysis, single and dual photon absorptiometry, and quantitative computed tomography (QCT) are described and reviewed in depth. Results from previous cross-sectional and longitudinal QCT investigations are given. They then describe a current investigation in which they studied 269 subjects, including 173 normal women, 34 patients with hyperparathyroidism, 24 patients with steroid-induced osteoporosis, and 38 men with idiopathic osteoporosis. Spinal quantitative computed tomography, radiogrammetry, and single photon absorptiometry were performed, and a spinal fracture index was calculated on all patients. The authors found a disproportionate loss of spinal trabecular mineral compared to appendicular mineral in the men with idiopathic osteoporosis and the patients with steroid-induced osteoporosis. They observed roughly equivalent mineral loss in both the appendicular and axial regions in the hyperparathyroid patients. The appendicular cortical measurements correlated moderately well with each other but less well with spinal trabecular QCT. The spinal fracture index correlated well with QCT and less well with the appendicular measurements. Knowledge of appendicular cortical mineral status is important in its own right but is not a valid predictor of axial trabecular mineral status, which may be disproportionately decreased in certain diseases. Quantitative CT provides a reliable means of assessing the latter region of the skeleton, correlates well with the spinal fracture index (a semiquantitative measurement of end-organ failure), and offers the clinician a sensitive means of following the effects of therapy.
Caraceni, M.P.; Molteni, N.; Bardella, M.T.; Ortolani, S.; Nogara, A.; Bianchi, P.A.
Bone mineral density (/sup 125/I photon absorptiometry) was lower in 20 untreated adult celiac patients than in sex- and age-matched controls (p less than 0.001), and plasma alkaline phosphatase, parathyroid hormone, urinary hydroxyproline/creatinine levels were higher than normal (p less than 0.05, less than 0.001, less than 0.05, respectively). Gluten-free diet was started, and the patients were divided randomly into two treatment groups, one which received oral 25-hydroxyvitamin D 50 micrograms/day and one which did not. After 12 months' treatment, bone turnover markers showed a decrease, which did not reach statistical significance, and bone mineral density did not show significant modifications compared with base line in either group. It was found that a gluten-free diet followed for 1 yr can prevent further bone loss, but no significant differences were detected between the two groups.
Lewiecki, E Michael; Bilezikian, John P; Bukata, Susan V; Camacho, Pauline; Clarke, Bart L; McClung, Michael R; Miller, Paul D; Shepherd, John
The Santa Fe Bone Symposium is an annual meeting of healthcare professionals and clinical researchers that details the clinical relevance of advances in knowledge of skeletal diseases. The 17th Santa Fe Bone Symposium was held in Santa Fe, New Mexico, USA, on August 5-6, 2016. The program included plenary lectures, oral presentations by endocrinology fellows, meet-the-professor sessions, and panel discussions, all aimed to provide ample opportunity for interactive discussions among all participants. Symposium topics included recent developments in the translation of basic bone science to patient care, new clinical practice guidelines for postmenopausal osteoporosis, management of patients with disorders of phosphate metabolism, new and emerging treatments for rare bone diseases, strategies to enhance fracture healing, and an update on Bone Health Extension for Community Healthcare Outcomes, using a teleconferencing platform to elevate the level of knowledge of healthcare professionals in underserved communities to deliver best practice care for skeletal diseases. The highlights and important clinical messages of the 2016 Santa Fe Bone Symposium are provided herein by each of the faculty presenters.
Bacchetta, Justine; Harambat, Jérôme; Cochat, Pierre; Salusky, Isidro B.; Wesseling-Perry, Katherine
Growth retardation, decreased final height and renal osteodystrophy (ROD) are common complications of childhood chronic kidney disease (CKD), resulting from a combination of abnormalities in the growth hormone (GH) axis, vitamin D deficiency, hyperparathyroidism, hypogonadism, inadequate nutrition, cachexia and drug toxicity. The impact of CKD-associated bone and mineral disorders (CKD–MBD) may be immediate (serum phosphate/calcium disequilibrium) or delayed (poor growth, ROD, fractures, vascular calcifications, increased morbidity and mortality). In 2012, the clinical management of CKD–MBD in children needs to focus on three main objectives: (i) to provide an optimal growth in order to maximize the final height with an early management with recombinant GH therapy when required, (ii) to equilibrate calcium/phosphate metabolism so as to obtain acceptable bone quality and cardiovascular status and (iii) to correct all metabolic and clinical abnormalities that can worsen bone disease, growth and cardiovascular disease, i.e. metabolic acidosis, anaemia, malnutrition and 25(OH)vitamin D deficiency. The aim of this review is to provide an overview of the mineral, bone and vascular abnormalities associated with CKD in children in terms of pathophysiology, diagnosis and clinical management. PMID:22851629
Ghishan, Fayez K.
Chronic inflammatory disorders such as inflammatory bowel diseases (IBDs) affect bone metabolism and are frequently associated with the presence of osteopenia, osteoporosis, and increased risk of fractures. Although several mechanisms may contribute to skeletal abnormalities in IBD patients, inflammation and inflammatory mediators such as TNF, IL-1β, and IL-6 may be the most critical. It is not clear whether the changes in bone metabolism leading to decreased mineral density are the result of decreased bone formation, increased bone resorption, or both, with varying results reported in experimental models of IBD and in pediatric and adult IBD patients. New data, including our own, challenge the conventional views, and contributes to the unraveling of an increasingly complex network of interactions leading to the inflammation-associated bone loss. Since nutritional interventions (dietary calcium and vitamin D supplementation) are of limited efficacy in IBD patients, understanding the pathophysiology of osteopenia and osteoporosis in Crohn's disease and ulcerative colitis is critical for the correct choice of available treatments or the development of new targeted therapies. In this review, we discuss current concepts explaining the effects of inflammation, inflammatory mediators and their signaling effectors on calcium and phosphate homeostasis, osteoblast and osteoclast function, and the potential limitations of vitamin D used as an immunomodulator and anabolic hormone in IBD. PMID:21088237
Masi, Laura; Brandi, Maria Luisa
According to European legislation, a disease can be considered rare or "orphan" when it affects less than 1 subject of 2000 (1). Often these diseases affecting the pediatric age, are complex diseases and chronically debilitating and for this motive need the intervention of multidisciplinary skills specific. Among the rare disease as affecting the skeleton more than 400 are characterized by dysplastic changes of the skeleton (2). Alongside the disorders affecting the skeleton primitively, many systemic diseases can have a bone involvement. Among these, the Gaucher disease (GD), an heterogeneous lysosomal storage determined by hereditary enzyme deficiency of β-glucosidase. Patients with this disease have skeletal disorders of varying severity (Erlenmeyer flask deformity, lytic lesions and osteonecrosis, pathological fractures) that affects both the bone marrow, both mineralized bone with progressive damage of the tissue. The bone disease is the most debilitating of GD and can have a significant impact on the quality of life of patients. Thorough evaluations by monitoring biochemical markers of bone turnover and instrumental, with a quantitative and qualitative evaluation of the bone, are of fundamental importance to intervene early so they can prevent complications irreversible.
Richardson, M.L.; Genant, H.K.; Cann, C.E.; Ettinger, B.; Gordan, G.S.; Kolb, F.O.; Reiser, U.J.
Advances in the radiologic sciences have permitted the development of numerous noninvasive techniques for measuring the mineral content of bone, with varying degrees of precision, accuracy, and sensitivity. The techniques of standard radiography, radiogrammetry, photodensitometry, Compton scattering, neutron activation analysis, single and dual photon absorptiometry, and quantitative computed tomography (QCT) are described and reviewed in depth. Results from previous cross-sectional and longitudinal QCT investigations are given. They then describe a current investigation in which they studied 269 subjects, including 173 normal women, 34 patients with hyperparathyroidism, 24 patients with steroid- induced osteoporosis, and 38 men with idiopathic osteoporosis. Spinal quantitative computed tomography, radiogrammetry, and single photon absorptiometry were performed, and a spinal fracture index was calculated on all patients. The authors found a disproportionate loss of spinal trabecular mineral compared to appendicular mineral in the men with idiopathic osteoporosis and the patients with steroid-induced osteoporosis. They observed roughly equivalent mineral loss in both the appendicular and axial regions in the hyperparathyroid patients. The appendicular cortical measurements correlated moderately well with each other but less well with spinal trabecular QCT. The spinal fracture index correlated well with QCT and less well with the appendicular measurements.
Zhang, Jingjing; Wang, Ningning
Anemia, dyslipidemia, malnutrition, together with mineral and bone disorders are common complications in patients with chronic kidney disease (CKD). All are associated with increased risk of mortality. Leptin is a small peptide hormone that is mainly but not exclusively produced in adipose tissue. It is also secreted by normal human osteoblasts, subchondral osteoblasts, placental syncytiotrophoblasts, and the gastric epithelium. Leptin binds to its receptors in the hypothalamus to regulate bone metabolism and food intake. Leptin also has several other important metabolic effects on peripheral tissues, including the liver, skeletal muscle, and bone marrow. Leptin is cleared principally by the kidney. Not surprisingly, serum leptin appears to increase concurrently with declines in the glomerular filtration rate in patients with CKD. A growing body of evidence suggests that leptin might be closely related to hematopoiesis, nutrition, and bone metabolism in CKD patients. Results are conflicting regarding leptin in patients with CKD, in whom both beneficial and detrimental effects on uremia outcome are found. This review elucidates the discovery of leptin and its receptors, changes in serum or plasma leptin levels, the functions of leptin, relationships between leptin and the complications mentioned above, and pharmaceutical interventions in serum leptin levels in patients with CKD.
Metabolic bone diseases (MBDs) are a common presenting complaint in reptiles and amphibians to veterinarians; however, understanding of the causes and diagnostic and treatment options is often extrapolated from human or other mammalian medicine models. Although the roles of UV-B, calcium, phosphorus, and cholecalciferol are better understood in some MBDs, there remain many X factors that are not. Likewise, quantitative diagnosis of MBDs has been difficult not only in terms of staging a disease but also regarding whether or not a condition is present. Treatment options also present challenges in corrective husbandry and diet modifications, medication/modality selection, and dosing/regimen parameters.
Garnero, P.; Delmas, P.D.
The authors measured serum bone alkaline phosphatase (B-ALP) with a new immunoradiometric assay (IRMA) in a large sample of healthy controls comprising 173 women and 180 men, 20-88 yr of age, and in patients with metabolic bone disease. Using serum samples from patients with liver disease and patients with Paget's disease with elevated total alkaline phosphatase (T-ALP) as a source of, respectively, liver and bone isoenyzmes, they determined a liver cross-reactivity of the IRMA of 16% that was confirmed by electrophoresis of the circulating alkaline phosphatase isoenzymes. The IRMA was linear for serial sample dilutions, the recovery ranged from 89-110%, and the intra- and interassay variations were below 7% and 9%, respectively. B-ALP increased linearly with age in both sexes, and the mean B-ALP serum levels were not significantly different for women and men (11.3 [+-] 4.8 ng/mL for women; 11.0 [+-] 4.0 ng/mL for men). The increase in B-ALP after the menopause was significantly higher than that in T-ALP (+77% vs. +24%; P<0.001). When the values of postmenopausal women were expressed as the SD from the mean of premenopausal women, the mean Z scores were 2.2[+-] 1.8 for B-ALP and 0.9 [+-] 1.3 for T-ALP (P<0.001 between the two).
Uebelhart, Brigitte; Rizzoli, René
Calcium intake shows a small impact on bone mineral density and fracture risk. Denosumab is a more potent inhibitor of bone resorption than zoledronate. Abaloparatide, PTHrP analog, increases bone mineral density and decreases fracture incidence. Teriparatide could be delivered via a transdermic device. Romosozumab and odanacatib improve calculated bone strength. Sequential or combined treatments with denosumab and teriparatide could be of interest, but not denosumab followed by teriparatide. Fibrous dysplasia, Paget disease and hypophosphatasia are updated, as well as atypical femoral fracture and osteonecrosis of the jaw.
Sclerostin, a glycoprotein encoded by SOST gene and secreted from osteocyte, is known as an antagonist for bone formation induced in canonical Wnt/β-catenin signaling pathway by inhibiting receptor complex formation through binding to LDL receptor-related protein 5/6 (LRP 5/6) . From clinical symptoms observed in the patients with a loss-of-function mutation in LRP 6, disorder of that signal transduction pathway is considered as one of candidate molecular mechanism for the simultaneous occurrence of diabetes mellitus and osteoporosis. The serum sclerostin levels of diabetic patients as well as non-diabetic subjects are significantly and positively correlated with bone mineral density, which is the strongest determinant factor especially for diabetic patients. In addition, sclerostin concentrations are associated with prevalent vertebral fractures independent of bone mineral density as well as bone turnover, suggesting that elevated sclerostin levels reflect poor bone quality.
In 1984, an initial report was published on the use of BMT for inborn errors of metabolism. Our first BMT patient had a diagnosis of Maroteaux-Lamy syndrome. She had end-stage cardiopulmonary disease at the time of the transplant and was considered likely to die within months. (69) She is still alive 2 decades later, albeit with limited pulmonary function. In 1992, experimental data demonstrated the prevention of CNS deterioration in fucosidase-deficient dogs after BMT.70 These findings have been noted in many other similar studies. (46) Ample data indicate that BMT can reconstitute the CNS in several of these diseases. Progress is continuing in reducing the morbidity and mortality. In the near future, additional advances may allow for no loss of life and no illness during the bone marrow transplantation process. There is hope that by using neonatal screening techniques, infants at risk can have metabolic storage diseases diagnosed before the diseases progress so that effective treatment can be provided. The combination of all of these advances should result in a logarithmic improvement within the next 2 decades. The plan will be to avoid any mortality or morbidity and to always provide complete engraftment that is permanent and enters all tissues completely.
Fernández, María C; Parisi, Muriel S; Díaz, Sergio P; Mastaglia, Silvina R; Deferrari, Juan M; Seijo, Mariana; Bagur, Alicia; Micheli, Federico; Oliveri, Beatriz
The impact of body composition on bone and mineral metabolism in Parkinson's disease (PD) was evaluated. Body fat mass, lean mass, bone mineral content, and bone mineral density (BMD) were measured by DXA in 22 PD patients and 104 controls. Female patients exhibited reduced body mass index, fat mass, and BMD compared to controls (p<0.05). Significant positive correlation was found between 25 OHD levels and BMC. Diminished bone mass in women with PD was found to be associated with alterations in body composition and low 25 OHD levels.
Xiaomei, Wang; Hang, Xiao; Lingling, Liu; Xuejun, Li
The prevalence of osteoporosis in older patients with chronic obstructive pulmonary disease (COPD) is higher than in the age-matched elderly patients, but the exact cause in relation to COPD is not clear. We hypothesized that the underlying causes for this difference are related to bone metabolism with the possible risk factors that include the duration of COPD, GOLD grade, cor pulmonale, the frequencies of acute exacerbations within the past year, smoking and inhaled corticosteroid therapy. We conducted a matched-pair study of 100 patients aged older than 65 years at the Southwest Hospital from May to November 2012. The enrolled patients with COPD were matched to controls for age and gender. Clinical characteristics of cohorts were recorded. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry and osteoporosis was diagnosed according to the definition of WHO. All cohorts accepted bone metabolism marker measurement, including Procollagen type 1 aminoterminal propeptide (P1NP), β-C-telopeptides of type I collagen (βCTX), and N-terminal midmolecule fragment osteocalcin (N-MID OC). Statistical analysis was calculated using the student's t test, ANOVA and multiple regression analysis at a significance level set at a p < 0.05. Circulating biochemical markers of bone formation (P1NP), resorption (βCTX) and turnover (N-MID OC) were significantly lower in the COPD group than control group, while mean 25-OH Vitamin D was similar in two groups. The P1NP, βCTX, and N-MID OC were still lower in men with COPD, but only P1NP was lower in women with COPD compared to that of controls. Multiple regression analysis in COPD group suggests that age, the frequency of acute exacerbation, and BMD are independent risk factors for P1NP. The frequency of acute exacerbation within the past one year and 25-OH D level are independent risk factors for βCTX; the frequency of acute exacerbation is the only independent risk factor for N-MID OC. These were significant
Ohshima, Toshio; Schiffmann, Raphael; Murray, Gary J.; Kopp, Jeffrey; Quirk, Jane M.; Stahl, Stefanie; Chan, Chi-Chao; Zerfas, Patricia; Tao-Cheng, Jung-Hwa; Ward, J. M.; Brady, Roscoe O.; Kulkarni, Ashok B.
Fabry disease is an X-linked metabolic disorder caused by a deficiency of α-galactosidase A (α-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with α-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated α-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of α-Gal A −/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of α-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease. PMID:10339603
Your bones help you move, give you shape and support your body. They are living tissues that rebuild constantly ... childhood and your teens, your body adds new bone faster than it removes old bone. After about ...
Chesney, Russell W; Hedberg, Gail E; Rogers, Quinton R; Dierenfeld, Ellen S; Hollis, Bruce E; Derocher, Andrew; Andersen, Magnus
Rickets and fractures have been reported in captive polar bears. Taurine (TAU) is key for the conjugation of ursodeoxycholic acid (UDCA), a bile acid unique to bears. Since TAU-conjugated UDCA optimizes fat and fat-soluble vitamin absorption, we asked if TAU deficiency could cause vitamin D malabsorption and lead to metabolic bone disease in captive polar bears. We measured TAU levels in plasma (P) and whole blood (WB) from captive and free-ranging cubs and adults, and vitamin D3 and TAU concentrations in milk samples from lactating sows. Plasma and WB TAU levels were significantly higher in cubs vs captive and free-ranging adult bears. Vitamin D in polar bear milk was 649.2 +/- 569.2 IU/L, similar to that found in formula. The amount of TAU in polar bear milk is 3166.4 +/- 771 nmol/ml, 26-fold higher than in formula. Levels of vitamin D in bear milk and formula as well as in plasma do not indicate classical nutritional vitamin D deficiency. Higher dietary intake of TAU by free-ranging cubs may influence bile acid conjugation and improve vitamin D absorption.
Favus, Murray J.
Hypercalciuria plays an important causal role in many patients with calcium oxalate (CaOx) stones. The source of the hypercalciuria includes increased intestinal Ca absorption and decreased renal tubule Ca reabsorption. In CaOx stone formers with idiopathic hypercalciuria (IH), Ca metabolic balance studies have revealed negative Ca balance and persistent hypercalciuria in the fasting state and during low dietary Ca intake. Bone resorption may also contribute to the high urine Ca excretion and increase the risk of bone loss. Indeed, low bone mass by DEXA scanning has been discovered in many IH patients. Thiazide diuretic agents reduce urine Ca excretion and may increase bone mineral density (BMD), thereby reducing fracture risk. Dietary Ca restriction that has been used unsuccessfully in the treatment of CaOx nephrolithiasis in the past may enhance negative Ca balance and accelerate bone loss. DEXA scans may demonstrate low BMD at the spine, hip, or forearm, with no predictable pattern. The unique pattern of bone histologic changes in IH differs from other causes of low DEXA bone density including postmenopausal osteoporosis, male hypogonadal osteoporosis, and glucocorticoid-induced osteoporosis. Hypercalciuria appears to play an important pathologic role in the development of low bone mass, and therefore correction of urine Ca losses should be a primary target for treatment of the bone disease accompanying IH.
Fitch, Kathleen; Grinspoon, Steven
The treatment of HIV infection has dramatically reduced the incidence of AIDS-related illnesses. At the same time, non-AIDS-related illnesses such as cardiovascular and bone disease are becoming more prevalent in this population. The mechanisms of these illnesses are complex and are related in part to the HIV virus, antiretroviral medications prescribed for HIV infection, traditional risk factors exacerbated by HIV, and lifestyle and nutritional factors. Further prospective research is needed to clarify the mechanisms by which HIV, antiretroviral medications, and nutritional abnormalities contribute to bone and cardiovascular disease in the HIV population. Increasingly, it is being recognized that optimizing the treatment of HIV infection to improve immune function and reduce viral load may also benefit the development of non-AIDS-related illnesses such as cardiovascular and bone disease.
Di Stefano, Michele; Mengoli, Caterina; Bergonzi, Manuela; Corazza, Gino Roberto
Osteoporosis affects many patients with celiac disease (CD), representing the consequence of calcium malabsorption and persistent activation of mucosal inflammation. A slight increase of fracture risk is evident in this condition, particularly in those with overt malabsorption and in postmenopausal state. The adoption of a correct gluten-free diet (GFD) improves bone derangement, but is not able to normalize bone mass in all the patients. Biomarkers effective in the prediction of bone response to gluten-free diet are not yet available and the indications of guidelines are still imperfect and debated. In this review, the pathophysiology of bone loss is correlated to clinical aspects, defining an alternative proposal of management for this condition. PMID:24284619
Barbato, Luigi; Francioni, Edoardo; Bianchi, Massimiliano; Mascitelli, Eleonora; Marco, Leila Brancato; Tonelli, Duvina Paolo
Summary Periodontitis is a plaque induced disease characterized by tissue destruction. The extent of the alveolar bone loss depends on the host response stimulated by bacterial infection. Recently researchers have focused on the role of the immune system, of RANK/RANKL/OPG pathway and of cytokines network. Another recent field of interest is osteoimmunology that try to explain the relationship between immune and bone cells in activating bone resorption. Advances in the understanding of the pathogenic mechanisms allowed a better understanding of the relationship with other diseases like osteoporosis and also to hypothesize new therapies based on modulation of host response (host modulatory therapy - HMT). The purpose of this mini-review is to briefly discuss these topics. PMID:26604945
Wang, Xiao-Qin; Zou, Xin-Rong; Zhang, Yuan Clare
Although traditional Chinese medicine (TCM) and Western medicine have evolved on distinct philosophical foundations and reasoning methods, an increasing body of scientific data has begun to reveal commonalities. Emerging scientific evidence has confirmed the validity and identified the molecular mechanisms of many ancient TCM theories. One example is the concept of "Kidneys Govern Bones." Here we discuss the molecular mechanisms supporting this theory and its potential significance in treating complications of chronic kidney disease (CKD) and diabetes mellitus. Two signaling pathways essential for calcium-phosphate metabolism can mediate the effect of kidneys in bone homeostasis, one requiring renal production of bioactive vitamin D and the other involving an endocrine axis based on kidney-expressed Klotho and bone-secreted fibroblast growth factor 23. Disruption of either pathway can lead to calcium-phosphate imbalance and vascular calcification, accelerating metabolic bone disorder. Chinese herbal medicine is an adjunct therapy widely used for treating CKD and diabetes. Our results demonstrate the therapeutic effects and underlying mechanisms of a Chinese herbal formulation, Shen-An extracts, in diabetic nephropathy and renal osteodystrophy. We believe that the smart combination of Eastern and Western concepts holds great promise for inspiring new ideas and therapies for preventing and treating complications of CKD and diabetes.
Yamada, Shinsuke; Inaba, Masaaki
Chronic kidney disease (CKD) has a high mortality rate of cardiovascular disease (CVD) . As CKD-mineral and bone disorder (CKD-MBD) is the one of the major risk factors in CVD, it is necessary that CKD patients are controlled CKD-MBD appropriately as early as possible. However, it is difficulty that CKD-MBD condition is exactly diagnosed and controlled, because it presents various conditions according to the difference of patient's background such as having diabetes or stage of CKD. We will give an outline of the mechanism in CKD-MBD according to patient's condition and the association between CKD-MBD and vascular calcification.
Mekahli, Djalila; Bacchetta, Justine
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of kidney failure. It is a systemic disorder, not only affecting the kidneys, but also associated with cyst formation in other organs such as the liver, spleen, pancreas, and seminal vesicles. Other extra-renal symptoms may consist of intracranial arterial aneurysms, cardiac valvular defects, abdominal and inguinal hernias and colonic diverticulosis. Very little is known regarding bone involvement in ADPKD; however, recent evidence has revealed the potential role of fibroblast growth factor 23 (FGF23). FGF23 is an endocrine fibroblast growth factor acting in the kidney as a phosphaturic hormone and a suppressor of active vitamin D with key effects on the bone/kidney/parathyroid axis, and has been shown to increase in patients with ADPKD, even with normal renal function. The aim of this review is to provide an overview of bone and mineral abnormalities found in experimental models and in patients with ADPKD, and to discuss the possible role of FGF23 in this disease.
Recently, fibroblast growth factor 23 (FGF23) has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism. In this review, we summarized the FGF superfamily, the mechanism of FGF23 on phosphate and vitamin D metabolism, and the FGF23 related bone disease.
Sharan, Kunal; Yadav, Vijay K
Bones are structures in vertebrates that provide support to organs, protect soft organs, and give them shape and defined features, functions that are essential for their survival. To perform these functions, bones are constantly renewed throughout life. The process through which bones are renewed is known as bone remodeling, an energy demanding process sensitive to changes in energy homeostasis of the organism. A close interplay takes place between the diversity of nutritional cues and metabolic signals with different elements of the hypothalamic circuits to co-ordinate energy metabolism with the regulation of bone mass. In this review, we focus on how mouse and human genetics have elucidated the roles of hormonal signals and neural circuits that originate in, or impinge on, the hypothalamus in the regulation of bone mass. This will help to understand the mechanisms whereby regulation of bone is gated and dynamically regulated by the hypothalamus.
Levinger, I; Brennan-Speranza, T C; Zulli, A; Parker, L; Lin, X; Lewis, J R; Yeap, B B
Undercarboxylated osteocalcin (ucOC) may play a role in glucose homeostasis and cardiometabolic health. This review examines the epidemiological and interventional evidence associating osteocalcin (OC) and ucOC with metabolic risk and cardiovascular disease. The complexity in assessing such correlations, due to the observational nature of human studies, is discussed. Several studies have reported that higher levels of ucOC and OC are correlated with lower fat mass and HbA1c. In addition, improved measures of glycaemic control via pharmacological and non-pharmacological (e.g. exercise or diet) interventions are often associated with increased circulating levels of OC and/or ucOC. There is also a relationship between lower circulating OC and ucOC and increased measures of vascular calcification and cardiovascular disease. However, not all studies have reported such relationship, some with contradictory findings. Equivocal findings may arise because of the observational nature of the studies and the inability to directly assess the relationship between OC and ucOC on glycaemic control and cardiovascular health in humans. Studying OC and ucOC in humans is further complicated due to numerous confounding factors such as sex differences, menopausal status, vitamin K status, physical activity level, body mass index, insulin sensitivity (normal/insulin resistance/T2DM), tissue-specific effects and renal function among others. Current observational and indirect interventional evidence appears to support a relationship between ucOC with metabolic and cardiovascular disease. There is also emerging evidence to suggest a direct role of ucOC in human metabolism. Further mechanistic studies are required to (a) clarify causality, (b) explore mechanisms involved and
Shahi, Maryam; Peymani, Amir; Sahmani, Mehdi
Bone is formed through the processes of endochondral and intramembranous ossification. In endochondral ossification primary mesenchymal cells differentiate to chondrocytes and then are progressively substituted by bone, while in intramembranous ossification mesenchymal stem cells (MSCs) differentiate directly into osteoblasts to form bone. The steps of osteogenic proliferation, differentiation, and bone homeostasis are controlled by various markers and signaling pathways. Bone needs to be remodeled to maintain integrity with osteoblasts, which are bone-forming cells, and osteoclasts, which are bone-degrading cells.In this review we considered the major factors and signaling pathways in bone formation; these include fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs), wingless-type (Wnt) genes, runt-related transcription factor 2 (RUNX2) and osteoblast-specific transcription factor (osterix or OSX). PMID:28367467
Shahi, Maryam; Peymani, Amir; Sahmani, Mehdi
Bone is formed through the processes of endochondral and intramembranous ossification. In endochondral ossification primary mesenchymal cells differentiate to chondrocytes and then are progressively substituted by bone, while in intramembranous ossification mesenchymal stem cells (MSCs) differentiate directly into osteoblasts to form bone. The steps of osteogenic proliferation, differentiation, and bone homeostasis are controlled by various markers and signaling pathways. Bone needs to be remodeled to maintain integrity with osteoblasts, which are bone-forming cells, and osteoclasts, which are bone-degrading cells.In this review we considered the major factors and signaling pathways in bone formation; these include fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs), wingless-type (Wnt) genes, runt-related transcription factor 2 (RUNX2) and osteoblast-specific transcription factor (osterix or OSX).
López-Gómez, Juan J; Pérez Castrillón, José L; de Luis Román, Daniel A
High weight is a protective factor against osteoporosis and risk of fracture. In obesity, however, where overweight is associated to excess fat, this relationship does not appear to be so clear, excess weight has sometimes been associated to decreased bone mass. Obesity interferes with bone metabolism through mechanical, hormonal, and inflammatory factors. These factors are closely related to weight, body composition, and dietary patterns of these patients. The net beneficial or harmful effect on bone mass or risk of fracture of the different components of this condition is not well known. We need to recognize patients at a greater risk of bone disease related to obesity to start an adequate intervention.
Bone marrow is the spongy tissue inside some of your bones, such as your hip and thigh bones. It contains stem cells. The stem cells can ... the platelets that help with blood clotting. With bone marrow disease, there are problems with the stem ...
... secrete factors that interact with the naturally occurring cells in the bone and cause bone destruction, new bone formation, or both. Eﬀects Because MBD weakens the aﬀected bones, people with the disease are prone to fractures. Broken ...
Lotfi, Asghar; Shiasi, Kobra; Amini, Razieh; Jahangiri, Mohammad; Sharif, Mohammad Reza; Akbari, Hossein; Talari, Hamidreza; Hajmobini, Zahra; Hami, Kamran; Kashani, Hamed Haddad
Introduction: Bone metabolic disease is an important issue in newborns with very low birth weight. The 80 percent of the transport of calcium (Ca) and phosphor (P) from mother to fetus takes place in the third trimester of pregnancy. This transport process is impaired with the preterm delivery of the newborn. On the other side, breast milk and formula are not competent resources to supply sufficient amounts of Ca and P to meet the requirements of the preterm newborn, thereby a greater reduction in the storage of these minerals. The current study has been done with the purpose of comparing the effects of two feeding methods on the indices of metabolic bone disease in newborns with very low birth weights (VLBW). Materials and Methods: The study design was cohort and the study was done on a total of 58 newborns with very low birth weights in Kashan Shahid Beheshti Hospital. The newborns were divided into two groups with 29 placed in the group of alternate feeding on preterm formula (preNan) and the other 29 placed in the group of breast milk and preterm formula (preNan). Eventually, the indices of bone metabolic disease were measured in both groups and were statistically analyzed. Results: The difference between the mean serum levels of Ca in different weeks and also between the two groups were significant (p=0.001). However, the changes in mean serum level of P in the two groups were not significant (P=0.151). The comparison of serum levels of alkaline phosphatase between the two groups indicated that their difference was significant and that they had been influenced by the feeding method (P=0.001). The serum level of bicarbonate, when compared between the two groups, was found to make a significant difference (P=0.001). The difference between the two feeding methods in precipitating rickets and osteopenia was not significant. Conclusion: According to the findings of current study, feeding on preterm formula (preNan) is associated with better and more desirable
Fisher, A; Srikusalanukul, W; Davis, M; Smith, P
Background Considerable controversy exists regarding the contribution of mineral/bone metabolism abnormalities to the association between cardiovascular diseases (CVDs) and osteoporotic fractures. Aims and methods To determine the relationships between mineral/bone metabolism biomarkers and CVD in 746 older patients with hip fracture, clinical data were recorded and serum concentrations of parathyroid hormone (PTH), 25-hydroxyvitamin D, calcium, phosphate, magnesium, troponin I, parameters of bone turnover, and renal, liver, and thyroid functions were measured. Results CVDs were diagnosed in 472 (63.3%) patients. Vitamin D deficiency was similarly prevalent in patients with (78.0%) and without (82.1%) CVD. The CVD group had significantly higher mean PTH concentrations (7.6 vs 6.0 pmol/L, P < 0.001), a higher prevalence of secondary hyperparathyroidism (SPTH) (PTH > 6.8 pmol/L, 43.0% vs 23.3%, P < 0.001), and excess bone resorption (urinary deoxypyridinoline corrected by creatinine [DPD/Cr] > 7.5 nmol/μmol, 87.9% vs 74.8%, P < 0.001). In multivariate regression analysis, SHPT (odds ratio [OR] 2.6, P = 0.007) and high DPD/Cr (OR 2.8, P = 0.016) were independent indictors of CVD. Compared to those with both PTH and DPD/Cr in the normal range, multivariate-adjusted ORs for the presence of CVD were 17.3 (P = 0.004) in subjects with SHPT and 9.7 (P < 0.001) in patients with high DPD/Cr. CVD was an independent predicator of SHPT (OR 2.8, P = 0.007) and excess DPD/Cr (OR 2.5, P = 0.031). CVD was predictive of postoperative myocardial injury, while SHPT was also an independent predictor of prolonged hospital stay and in-hospital death. Conclusion SHPT and excess bone resorption are independent pathophysiological mediators underlying the bidirectional associations between CVD and hip fracture, and therefore are important diagnostic and therapeutic targets. PMID:23460043
Microdensitometry of the metacarpal bone on radiograph was first set up as the endpoint of the treatment in clinical trials in Japan in 1980s. Then, radial bone mineral content obtained by single photon absorptiometry was used. In 1990s, lumbar spine BMD measured by DXA became the major endpoint of the study which was designed as prospective, randomized, double-blind, controlled trial. In 2000s, assessments on the incidences of the vertebral fractures have become mandatory as the primary endpoint of the placebo-controlled trial. The numbers of the subjects required in the study are getting larger and the subtleties in the study including adverse events more important along the progress of evidence-based medicine.
Cao, Jay J
obesity rates have doubled since 1980 and as of 2007, 33% of men and 35% of women in the US are obese. Obesity is positively associated to many chronic disorders such as hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, and certain cancers. It is estimated that the direct medical cost associated with obesity in the United States is ~$100 billion per year.Bone mass and strength decrease during adulthood, especially in women after menopause. These changes can culminate in osteoporosis, a disease characterized by low bone mass and microarchitectural deterioration resulting in increased bone fracture risk. It is estimated that there are about 10 million Americans over the age of 50 who have osteoporosis while another 34 million people are at risk of developing the disease. In 2001, osteoporosis alone accounted for some $17 billion in direct annual healthcare expenditure. Several lines of evidence suggest that obesity and bone metabolism are interrelated. First, both osteoblasts (bone forming cells) and adipocytes (energy storing cells) are derived from a common mesenchymal stem cell and agents inhibiting adipogenesis stimulated osteoblast differentiation and vice versa, those inhibiting osteoblastogenesis increased adipogenesis. Second, decreased bone marrow osteoblastogenesis with aging is usually accompanied with increased marrow adipogenesis. Third, chronic use of steroid hormone, such as glucocorticoid, results in obesity accompanied by rapid bone loss. Fourth, both obesity and osteoporosis are associated with elevated oxidative stress and increased production of proinflammatory cytokines. At present, the mechanisms for the effects of obesity on bone metabolism are not well defined and will be the focus of this review.
Stern, Sara M; Ferguson, Polly J
Autoinflammatory bone disease is a new branch of autoinflammatory diseases caused by seemingly unprovoked activation of the innate immune system leading to an osseous inflammatory process. The inflammatory bone lesions in these disorders are characterized by chronic inflammation that is typically culture negative with no demonstrable organism on histopathology. The most common autoinflammatory bone diseases in childhood include chronic nonbacterial osteomyelitis (CNO), synovitis, acne, pustulosis, hyperostosis, osteitis syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist, and cherubism. In this article, the authors focus on CNO and summarize the distinct genetic autoinflammatory bone syndromes.
Derlin, Thorsten; Weiberg, Desiree; Sohns, Jan M
Paget disease is a chronic disorder resulting in enlarged and misshapen bones, and is caused by disorganized bone remodeling. We present the case of an 85-year-old man with prostatic adenocarcinoma and known Paget disease of the right iliac bone who underwent Ga-prostate-specific membrane antigen ligand, C-acetate, and F-fluoride PET/CT for restaging of cancer. On all PET scans, increased tracer accumulation was observed in Paget disease of bone. Besides that Paget disease may mimic metastases on PET/CT using various radiotracers, including Ga-prostate-specific membrane antigen ligands and C-acetate, this case highlights the potential of multiparametric disease characterization on PET.
Hautmann, Anke Heidewig; Elad, Sharon; Lawitschka, Anita; Greinix, Hildegard; Bertz, Hartmut; Halter, Joerg; Faraci, Maura; Hofbauer, Lorenz Christian; Lee, Stephanie; Wolff, Daniel; Holler, Ernst
With improved outcome of allogeneic stem cell transplantation (allo-SCT) for hematologic malignancies, long-term complications gain greater importance. Skeletal complications such as osteoporosis or avascular necrosis (AVN) occur frequently in allogeneic recipients with a cumulative incidence of diminished bone mineral density of 24-50% between 2 and 12 months after allo-SCT and a cumulative incidence of AVN in as many as 19% of patients 3 years after allo-SCT. Here, we present a review as part of the German, Austrian, and Swiss Consensus Conference on clinical practice in chronic graft-versus-host disease, held 2009 in Regensburg. The Consensus Conference aimed to achieve a consensus on the current evidence of diagnosis, prevention, and therapeutic options of late complications after allo-SCT summarizing and discussing the literature on these topics. In this report, we provide recommendations for metabolic bone diseases agreed upon by the working party. This includes guidelines for diagnosis, prevention, and therapeutic options in patients with low bone mass or AVN.
Rehman, Moghis Ur; Narchi, Hassib
Neonatal osteopenia is an important area of interest for neonatologists due to continuing increased survival of preterm infants. It can occur in high-risk infants such as preterm infants, infants on long-term diuretics or corticosteroids, and those with neuromuscular disorders. Complications such as rickets, pathological fractures, impaired respiratory function and poor growth in childhood can develop and may be the first clinical evidence of the condition. It is important for neonatologists managing such high-risk patients to regularly monitor biochemical markers for evidence of abnormal bone turnover and inadequate mineral intake in order to detect the early phases of impaired bone mineralization. Dual-energy X-ray absorptiometry has become an increasingly used research tool for assessing bone mineral density in children and neonates, but more studies are still needed before it can be used as a useful clinical tool. Prevention and early detection of osteopenia are key to the successful management of this condition and oral phosphate supplements should be started as soon as is feasible. PMID:26413483
Wnt signal has been known to play various roles in many organ from the beginning of embryogensis. Its role in bone metabolism has also been investigated and established. Lipoprotein receptor-related protein 5 (LRP5) is one of the important molecules in wnt signal pathway whose point mutations are related to both bone loss and excessive bone formation. Wnt signal is involved in the action of sclerostin which was found as a gene for osteosclerosis, one of the diseases of excessive bone formation. Wnt signal is keeping the position as an important research target for normal and pathological bone formation.
Roca Espiau, Mercedes
The exposition aims, is to review the pathophysiological mechanisms of bone marrow involvement and the patterns of marrow infiltration by Gaucher cells. We have reviewed the different methods of assessment of bone marrow infiltration and its temporal development. Qualitative methods include simple radiography, magnetic resonance imaging (MRI), computed tomography (CT) and radioisotope. The simple radiography is the basic element, but its sensitivity is limited and only allows for assessing changes and trabecular bone remodeling MRI allows us to appreciate the bone marrow infiltration, detection of complications and response to therapy. Radioisotopes can contribute to the differential diagnosis of osteomyelitis and bone crises. Among the quantitative methods are the QCSI (quantitative chemical shift imaging) and the dual-energy X-ray absorptiometry (DEXA), as well as new quantitative techniques of CT, MRI and ultrasound densitometry. The QCSI performed an assessment of fat content of bone marrow in the spine. DEXA quantifies bone density by measuring the attenuation coefficient. The semiquantitative methods have various "scores" to establish criteria for generalized bone disease endpoints of disease progression and response to therapy.
Braga, V; Dorizzi, R; Brocco, G; Rossini, M; Zamberlan, N; Gatti, D; Adami, S
Bone alkaline phosphatase was evaluated by wheat-germ lectin precipitation in several clinical conditions. The study included 33 premenopausal healthy women, 46 postmenopausal apparently healthy women, 19 growing children, 24 patients with Paget's disease, 31 patients with primary hyperparathyroidism and 66 patients with hepatobiliary diseases. In postmenopausal women the mean T score (i.e.: the number of SD below or above the mean for premenopausal women) was 2.6 +/- 1.3 (SD) for bone alkaline phosphatase and 1.61 +/- 1.21 for total alkaline phosphatase (p < 0.001). The T score for bone alkaline phosphatase provided a better discrimination from normals for both Paget's disease (22.1 +/- 27.8 versus 12.8 +/- 16 p < 0.001) and primary hyperparathyroidism (8.2 +/- 4.3 versus 4.6 +/- 3.7 p < 0.005 for bone alkaline phosphatase and total alkaline phosphatase respectively). After treatment with intravenous bisphosphonate the percent decrease of bone alkaline phosphatase was larger than that of total alkaline phosphatase both in patients with Paget's disease (-46% versus -72% p < 0.01) and in patients with primary hyperparathyroidism (-21% versus -47% p < 0.02) and an estimate of the precision (delta mean/SD of the delta mean) for bone alkaline phosphatase was 1.9-3.7 times higher than that of total alkaline phosphatase. In twelve osteoporotic patients treated for six months with oral alendronate the decrease in bone turnover was detected with significantly higher precision with bone alkaline phosphatase than with total alkaline phosphatase (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Zanchetta, María Belén; Longobardi, Vanesa; Bai, Julio César
More than 50% of untreated patients with celiac disease (CD) have bone loss detected by bone densitometry (dual-energy X-ray absorptiometry:DXA). Moreover, patients with CD are more likely to have osteoporosis and fragility fractures, especially of the distal radius. Although still controversial, we recommend DXA screening in all celiac disease patients, particularly in those with symptomatic CD at diagnosis and in those who present risk factors for fracture such as older age, menopausal status, previous fracture history, and familial hip fracture history. Bone microarchitecture, especially the trabecular network, may be deteriorated, explaining the higher fracture risk in these patients. Adequate calcium and vitamin D supplementation are also recommended to optimize bone recovery, especially during the first years of gluten free diet (GFD). If higher fracture risk persists after 1 or 2 years of GFD, specific osteoactive treatment may be necessary to improve bone health.
Tsourdi, Elena; Rachner, Tilman D; Rauner, Martina; Hamann, Christine; Hofbauer, Lorenz C
Signalling of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) through RANK is a critical pathway to regulate the differentiation and activity of osteoclasts and, hence, a master regulator of bone resorption. Increased RANKL activity has been demonstrated in diseases characterised by excessive bone loss such as osteoporosis, rheumatoid arthritis and osteolytic bone metastases. The development and approval of denosumab, a fully MAB against RANKL, has heralded a new era in the treatment of bone diseases by providing a potent, targeted and reversible inhibitor of bone resorption. This article summarises the molecular and cellular biology of the RANKL/RANK system and critically reviews preclinical and clinical studies that have established denosumab as a promising novel therapy for metabolic and malignant bone diseases. We will discuss the potential indications for denosumab along with a critical review of safety and analyse its potential within the concert of established therapies.
... that may indicate Paget disease include: Bone scan Bone x-ray Elevated markers of bone breakdown (for example, N-telopeptide) This disease may ... of Paget disease. Alternative Names Osteitis deformans Images ... X-ray References Ralston SH. Paget disease of bone. In: Goldman L, Schafer AI, eds. Goldman's Cecil ...
Al-Rashid, Mamun; Ramkumar, Dipak B; Raskin, Kevin; Schwab, Joseph; Hornicek, Francis J; Lozano-Calderón, Santiago A
The current understanding of Paget disease of bone (PDB) has vastly changed since Paget described the first case in 1877. Medical management of this condition remains the mainstay of treatment. Surgical intervention is usually only used in fractures through pagetic bone, need for realignment to correct deformity in major long bones, prophylactic treatment of impending fractures, joint arthroplasty in severe arthritis, or spinal decompression in cases of bony compression of neural elements. Advances in surgical technique have allowed early return to function and mobilization. Despite medical and surgical intervention, a small subset of patients with PDB develops Paget sarcoma.
Balsa, José A; Lafuente, Christian; Gómez-Martín, Jesús M; Galindo, Julio; Peromingo, Roberto; García-Moreno, Francisca; Rodriguez-Velasco, Gloria; Martínez-Botas, Javier; Gómez-Coronado, Diego; Escobar-Morreale, Héctor F; Botella-Carretero, José I
Metabolic bone disease may appear as a complication of obesity surgery. Because an imbalance in the osteoprotegerin and receptor-activator of nuclear factor-κB ligand system may underlie osteoporosis, we aimed to study this system in humans in the metabolic bone disease occurring after obesity surgery. In this study we included sixty women with a mean age of 47 ± 10 years studied 7 ± 2 years after bariatric surgery. The variables studied were bone mineral density, β-isomer of C-terminal telopeptide of type I collagen cross-links (a bone resorption marker), the bone formation markers osteocalcin and N-terminal propeptide of procollagen 1, serum osteoprotegerin and receptor-activator of nuclear factor-κB ligand. Serum osteoprotegerin inversely correlated with the bone remodeling markers osteocalcin, β-isomer of C-terminal telopeptide of type I collagen cross-links and N-terminal propeptide of procollagen 1. The osteoprotegerin and receptor-activator of nuclear factor-κB ligand ratio also correlated inversely with serum parathormone and osteocalcin. Bone mineral density at the lumbar spine was associated with age (β = -0.235, P = 0.046), percentage of weight loss (β = 0.421, P = 0.001) and osteoprotegerin and receptor-activator of nuclear factor-κB ligand ratio (β = 0.259, P = 0.029) in stepwise multivariate analysis (R (2) = 0.29, F = 7.49, P < 0.001). Bone mineral density at the hip site was associated only with percentage of weight loss (β = 0.464, P < 0.001) in stepwise multivariate regression (R (2) = 0.21, F = 15.1, P < 0.001). These data show that the osteoprotegerin and receptor-activator of nuclear factor-κB ligand system is associated with bone markers and bone mineral density at the lumbar spine after obesity surgery.
Mori, Giorgio; D'Amelio, Patrizia; Faccio, Roberta; Brunetti, Giacomina
Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma.
Although traditional Chinese medicine (TCM) and Western medicine have evolved on distinct philosophical foundations and reasoning methods, an increasing body of scientific data has begun to reveal commonalities. Emerging scientific evidence has confirmed the validity and identified the molecular mechanisms of many ancient TCM theories. One example is the concept of “Kidneys Govern Bones.” Here we discuss the molecular mechanisms supporting this theory and its potential significance in treating complications of chronic kidney disease (CKD) and diabetes mellitus. Two signaling pathways essential for calcium-phosphate metabolism can mediate the effect of kidneys in bone homeostasis, one requiring renal production of bioactive vitamin D and the other involving an endocrine axis based on kidney-expressed Klotho and bone-secreted fibroblast growth factor 23. Disruption of either pathway can lead to calcium-phosphate imbalance and vascular calcification, accelerating metabolic bone disorder. Chinese herbal medicine is an adjunct therapy widely used for treating CKD and diabetes. Our results demonstrate the therapeutic effects and underlying mechanisms of a Chinese herbal formulation, Shen-An extracts, in diabetic nephropathy and renal osteodystrophy. We believe that the smart combination of Eastern and Western concepts holds great promise for inspiring new ideas and therapies for preventing and treating complications of CKD and diabetes. PMID:27668003
Tiemann, A H; Krenn, V; Krukemeyer, M G; Seyfert, C; Jakobs, M; Baumhoer, D; Hofmann, G O
Bacterial infection of the bone is a severe disease with complications, potentially including long-term physical disability. The diagnosis and therapy of osteomyelitis include several elements: histopathology, microbiology, radiologic imagining, as well as antibiotic and surgical therapy. Histopathologists differentiate between acute osteomyelitis (infiltration of cancellous bone with neutrophil granulocytes); specific osteomyelitis (epithelioid-like granulomatous inflammation, tuberculosis, mycotic infections); primary/secondary chronic osteomyelitis (lymphocytic infiltration); and special forms of chronic osteomyelitis (varying histomorphology, Brodie abscess, SAPHO syndrome). Another important task in the histopathological diagnosis of inflammatory bone diseases is to differentiate osteomyelitis from malignant entities (sarcoma, lymphoma). Therefore, biopsy samples should be of sufficient size for safe diagnosis. Clinical information and imaging as well as interdisciplinary teamwork between radiologists, microbiologists, orthopedic surgeons and pathologists is mandatory to verify these diagnoses.
Nakagami, Hironori; Morishita, Ryuichi
The patients with "Hypertension" and "Chronic Kidney Disease (CKD) " are accompanied with an osteoporosis. In hypertension patients, excess urinary calcium secretion induces secondary parathyroidsim to increase serum calcium (Ca) level, which may lead to Ca release from bone. In this aspect, there are several reports that anti-hypertensive drugs, especially thiazides, increase bone mineral density and decrease the incidence of bone fracture. In addition, we demonstrated that renin-angiotensin system can be involved in the process of osteoporosis. Angiotensin II significantly induced the expression of RANKL (receptor activator of NF-κB ligand) in osteoblasts, leading to the activation of osteoclasts, while these effects were completely blocked by an Ang II type 1 receptor blockade. As for CKD, excess phosphorus (P) due to renal dysfunction induces secondary parathyroidism to decrease serum P level, which similarly leads to osteoporosis. Moreover, excess P can increase FGF23 expression and decrease activated vitamin D, which also resulted in progression of osteoporosis. Both "Hypertension" and "Chronic Kidney Disease (CKD) " are inducible factor to osteoporosis.
Dermience, Michael; Lognay, Georges; Mathieu, Françoise; Goyens, Philippe
The human skeleton, made of 206 bones, plays vital roles including supporting the body, protecting organs, enabling movement, and storing minerals. Bones are made of organic structures, intimately connected with an inorganic matrix produced by bone cells. Many elements are ubiquitous in our environment, and many impact bone metabolism. Most elements have antagonistic actions depending on concentration. Indeed, some elements are essential, others are deleterious, and many can be both. Several pathways mediate effects of element deficiencies or excesses on bone metabolism. This paper aims to identify all elements that impact bone health and explore the mechanisms by which they act. To date, this is the first time that the effects of thirty minerals on bone metabolism have been summarized.
The Association between Elevated Levels of Peripheral Serotonin and Its Metabolite – 5-Hydroxyindoleacetic Acid and Bone Strength and Metabolism in Growing Rats with Mild Experimental Chronic Kidney Disease
Oksztulska-Kolanek, Ewa; Znorko, Beata; Domaniewski, Tomasz; Rogalska, Joanna; Roszczenko, Alicja; Brzóska, Małgorzata Michalina; Pryczynicz, Anna; Kemona, Andrzej
Chronic kidney disease (CKD) is associated with disturbances in bone strength and metabolism. The alterations of the serotonergic system are also observed in CKD. We used the 5/6 nephrectomy model of CKD to assess the impact of peripheral serotonin and its metabolite– 5-hydroxyindoleacetic acid on bone biomechanical properties and metabolism in growing rats. The animals were sacrificed one and three months after nephrectomy. Biomechanical properties were determined on two different bone types: the cortical bone of the femoral diaphysis using three-point bending test and the mixed cortico-trabecular bone by the bending test of the femoral neck. Biomechanical tests revealed preserved cortical bone strength, whereas work to fracture (W) and yield load (Fy) of mixed cortico-trabecular bone were significantly lower in CKD compared to controls. Serum activity of alkaline phosphatase (ALP), a bone formation marker, and tartrate-resistant acid phosphatase (TRACP 5b) reflecting bone resorption, were similar in CKD and controls. ALP was associated with lower femoral stiffness and strength, and higher displacements and W. TRACP 5b was inversely associated with cortical Fu and W. The elevated peripheral serotonergic system in CKD was: inversely associated with stiffness but positively related to the displacements and W; inversely associated with cortical Fy but positively correlated with this parameter in cortico-trabecular bone; inversely associated with ALP in controls but positively correlated with this biomarker in CKD animals. In conclusion, this study demonstrates the distinct effect of mild degree of CKD on bone strength in rapidly growing rats. The impaired renal function affects the peripheral serotonin metabolism, which in turn may influence the strength and metabolism of bones in these rats. This relationship seems to be beneficial on the biomechanical properties of the cortico-trabecular bone, whereas the cortical bone strength can be potentially reduced. PMID
Tatsumi, Sawako; Nagamoto, Kenta; Ogata, Mao; Miyamoto, Ken-ichi
Osteocytes orchestrate bone resorption and bone formation by controlling osteoclast and osteoblast activity. On the other hand, osteocytes secret FGF23 (fibroblast growth factor 23), FGF23 acts on the kidney to control phosphate homeostasis. Sclerostin is also released from osteocytes and it regulated osteoblast activity through Wnt/β-catenin pathway. Therefore, an antibody that targets sclerostin is currently in phase- III clinical trials for the treatment of osteoporosis and it is expected as new therapeutics.
Harinathbabu, Maheswari; Thillaigovindan, Ranjani; Prabhu, Geetha
Osteopetrosis, or marble bone disease, is a rare skeletal disorder due to a defective function of the osteoclasts. This defect renders bones more susceptible to osteomyelitis due to decreased vascularity. This disorder is inherited as autosomal dominant and autosomal recessive. Healthcare professionals should urge these patients to maintain their oral health as well as general health, as this condition makes these patients more susceptible to frequent infections and fractures. This case report emphasizes the signs and symptoms of marble bone disease and presents clinical and radiographic findings. PMID:26594603
Spinks, T.J.; Bewley, D.K.; Paolillo, M.; Vlotides, J.; Joplin, G.F.; Ranicar, A.S.O.
Turnover of sodium in the human hand was studied by neutron activation. Patients suffering from various metabolic abnormalities affecting the skeleton, who were undergoing routine neutron activation for the measurement of calcium, were investigated along with a group of healthy volunteers. Neutron activation labels the sodium atoms simultaneously and with equal probability regardless of the turnover time of individual body compartments. The loss of sodium can be described either by a sum of two exponentials or by a single power function. Distinctions between patients and normal subjects were not apparent from the exponential model but were brought out by the power function. The exponent of time in the latter is a measure of clearance rate. The mean values of this parameter in (a) a group of patients suffering from acromegaly; (b) a group including Paget's disease, osteoporosis, Cushing's disease, and hyperparathyroidism; and (c) a group of healthy subjects, were found to be significantly different from each other.
Smith, Scott M.; Heer, Martina
Weightlessness induces bone loss. Understanding the nature of this loss and developing means to counteract it are significant challenges to potential human exploration missions. This article reviews the existing information from studies of bone and calcium metabolism conducted during space flight. It also highlights areas where nutrition may play a specific role in this bone loss, and where countermeasures may be developed to mitigate that loss.
Smith, S. M.; Heer, M. A.; Shackelford, L. C.; Zwart, S. R.
Spaceflight-induced bone loss is associated with increased bone resorption (1, 2), and either unchanged or decreased rates of bone formation. Resistive exercise had been proposed as a countermeasure, and data from bed rest supported this concept (3). An interim resistive exercise device (iRED) was flown for early ISS crews. Unfortunately, the iRED provided no greater bone protection than on missions where only aerobic and muscular endurance exercises were available (4, 5). In 2008, the Advanced Resistive Exercise Device (ARED), a more robust device with much greater resistance capability, (6, 7) was launched to the ISS. Astronauts who had access to ARED, coupled with adequate energy intake and vitamin D status, returned from ISS missions with bone mineral densities virtually unchanged from preflight (7). Bone biochemical markers showed that while the resistive exercise and adequate energy consumption did not mitigate the increased bone resorption, bone formation was increased (7, 8). The typical drop in circulating parathyroid hormone did not occur in ARED crewmembers. In 2014, an updated look at the densitometry data was published. This study confirmed the initial findings with a much larger set of data. In 42 astronauts (33 male, 9 female), the bone mineral density response to flight was the same for men and women (9), and those with access to the ARED did not have the typical decrease in bone mineral density that was observed in early ISS crewmembers with access to the iRED (Figure 1) (7). Biochemical markers of bone formation and resorption responded similarly in men and women. These data are encouraging, and represent the first in-flight evidence in the history of human space flight that diet and exercise can maintain bone mineral density on long-duration missions. However, the maintenance of bone mineral density through bone remodeling, that is, increases in both resorption and formation, may yield a bone with strength characteristics different from those
Krela-Kaźmierczak, Iwona; Kaczmarek-Ryś, Marta; Szymczak, Aleksandra; Michalak, Michał; Skrzypczak-Zielińska, Marzena; Drwęska-Matelska, Natalia; Marcinkowska, Michalina; Eder, Piotr; Łykowska-Szuber, Lilianna; Wysocka, Ewa; Linke, Krzysztof; Słomski, Ryszard
Osteoporosis is more frequent in inflammatory bowel disease (IBD) patients. A reduction in bone mineral mass in these individuals is caused not only by inflammatory processes in the bowel, because osteoporosis occurs already in very young IBD patients and in newly diagnosed individuals who have not yet undergone any pharmacological treatment. One of individual determinants of the bone turnover parameters is osteoprotegerin (OPG) encoded by the TNFRSF11B gene. The c.-223C > T polymorphism in this gene has been extensively studied in post-menopausal osteoporosis patients. However, no such studies exist for osteoporosis related to IBD. The aim of our study was to determine whether the c.-223C > T (rs2073617) polymorphism in the 5'UTR region of the gene encoding osteoprotegerin is a functional polymorphism which may change the gene expression and resulting OPG levels, and so be associated with osteopenia and osteoporosis, and impaired bone metabolism in Crohn's disease and ulcerative colitis patients. Our study included 198 IBD patients and 41 healthy controls. Lumbar spine and femoral neck bone mineral density, T-score, Z-score as well as OPG, RANKL, vitamin D, calcium and interleukin 4 and 10 concentrations were determined for all study subjects. Genotyping of the TNFRSF11B polymorphic site was performed by restriction fragment length polymorphism technique. Statistical analyses were conducted using Statistica software. Odds ratios, 95 % confidence intervals, and P values were calculated using the HWE calculator. Our results did not allow determining an unequivocal association between the polymorphic variants of the TNFRSF11B 5'UTR region and a susceptibility to osteoporosis in IBD patients. We have shown, however, that the c.-223T allele was twice as more frequent in Crohn's disease (CD) patients than among controls (OR = 1.99, P value = 0.009). Interestingly, average osteoprotegerin levels in CD patients did not significantly differ from those in
Manolagas, Stavros C.; Parfitt, A. Michael
Osteocytes are long-lived and far more numerous than the short-lived osteoblasts and osteoclasts. Immured within the lacunar-canalicular system and mineralized matrix, osteocytes are ideally located throughout bone to detect the need for, and accordingly choreograph, the bone regeneration process by independently controlling rate limiting steps of bone resorption and formation. Consistent with this role, emerging evidence indicates that signals arising from apoptotic and old/or dysfunctional osteocytes are seminal culprits in the pathogenesis of involutional, post-menopausal, steroid-, and immobilization-induced osteoporosis. Osteocyte-originated signals may also contribute to the increased bone fragility associated with bone matrix disorders like osteogenesis imperfecta, and perhaps the rapid reversal of bone turnover above baseline following discontinuation of anti-resorptive treatments, like denosumab. PMID:23010104
Manolagas, Stavros C; Parfitt, A Michael
Osteocytes are long-lived and far more numerous than the short-lived osteoblasts and osteoclasts. Immured within the lacunar-canalicular system and mineralized matrix, osteocytes are ideally located throughout the bone to detect the need for, and accordingly choreograph, the bone regeneration process by independently controlling rate limiting steps of bone resorption and formation. Consistent with this role, emerging evidence indicates that signals arising from apoptotic and old/or dysfunctional osteocytes are seminal culprits in the pathogenesis of involutional, post-menopausal, steroid-, and immobilization-induced osteoporosis. Osteocyte-originated signals may also contribute to the increased bone fragility associated with bone matrix disorders like osteogenesis imperfecta, and perhaps the rapid reversal of bone turnover above baseline following discontinuation of anti-resorptive treatments, like denosumab.
de Paula, Francisco J. A.; Rosen, Clifford J.
Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. Adipose tissue store lipids and cholecalciferol, which, in turn, can influence calcium balance and energy expenditure. Hormones long-thought to solely modulate energy and mineral homeostasis may influence adipocytic function. Osteoblasts are a target of insulin action in bone. Moreover, endocrine mediators, such as osteocalcin, are synthesized in the skeleton but regulate carbohydrate disposal and insulin secretion. Finally, osteoblasts and adipocytes originate from the same mesenchymal progenitor. The mutual crosstalk between osteoblasts and adipocytes within the bone marrow microenvironment plays a crucial role in bone remodeling. In the present review we provide an overview of the reciprocal control between bone and energy metabolism and its clinical implications. PMID:26273493
Smith, Scott M.
The ability to understand and counteract weightlessness-induced bone loss will be critical for crew health and safety during and after space station or exploration missions lasting months or years, respectively. Until its deorbit in 2001 , the Mir Space Station provided a valuable platform for long-duration space missions and life sciences research. Long-duration flights are critical for studying bone loss, as the 2- to 3-week Space Shuttle flights are not long enough to detect changes in bone mass. This review will describe human spaceflight data, focusing on biochemical surrogates of bone and calcium metabolism. This subject has been reviewed previously. 1-
Misra, D P
The crosslink in bone collagen was analysed in specimens of bone obtained at necropsy from cases of Paget's disease and compared with normal bone collagen of the same age. The specimens were stored at -20 degrees C before analysis. The predominant crosslink in a normal bone collagen was hydroxylysinohydroxynorleucine (di OH-LNL) (F1), which was designated syndesine in the past; another fraction, hydroxylysinorleucine (HLNL) (F2), musch less prominent than di OH-LNL, was also noted in a normal bone collagen. Both fractions were reduced in bone tissue of advancing age. The peak corresponding to HLNL was considerably increased in Paget's disease. This abnormality was constantly seen in specimens of bone from cases of Paget's disease, but the significance of the finging could not be assessed from the present investigation. Calcitonin has been shown to produce complete remission in Paget's disease and the crosslink pattern was found to be normal in specimens examined froma calcitonin-treated patient. This shows that calcitonin has some effect on the metabolism of collagen and a normal crosslink in such a situation lends support to this idea. PMID:1127123
Osteoporosis is a major health problem in elderly men and women. Epidemiological evidence has shown association between tea consumption and age-related bone loss in elderly men and women. The aim of this review is to provide a systemic review of green tea and bone health to cover the following topi...
Lim, Y; Jo, K; Ha, H-S; Yim, H-W; Yoon, K-H; Lee, W-C; Son, H-Y; Baek, K H; Kang, M-I
Because the rate of bone loss is an important risk factor for fracture, we studied longitudinal changes in bone mineral density (BMD). Although the BMD of the hip decreased over time, spine BMD remained largely stable or increased. Therefore, spine BMD may not be appropriate for assessing BMD change.
Blair, Harry C.; Robinson, Lisa J.; Huang, Christopher L.-H.; Sun, Li; Friedman, Peter A.; Schlesinger, Paul H.; Zaidi, Mone
Calcium transport and calcium signaling are of basic importance in bone cells. Bone is the major store of calcium and a key regulatory organ for calcium homeostasis. Bone, in major part, responds to calcium-dependent signals from the parathyroids and via vitamin D metabolites, although bone retains direct response to extracellular calcium if parathyroid regulation is lost. Improved understanding of calcium transporters and calcium-regulated cellular processes has resulted from analysis of genetic defects, including several defects with low or high bone mass. Osteoblasts deposit calcium by mechanisms including phosphate and calcium transport with alkalinization to absorb acid created by mineral deposition; cartilage calcium mineralization occurs by passive diffusion and phosphate production. Calcium mobilization by osteoclasts is mediated by acid secretion. Both bone forming and bone resorbing cells use calcium signals as regulators of differentiation and activity. This has been studied in more detail in osteoclasts, where both osteoclast differentiation and motility are regulated by calcium. PMID:21674636
Cao, Haihui; Nazarian, Ara; Ackerman, Jerome L; Snyder, Brian D; Rosenberg, Andrew E; Nazarian, Rosalynn M; Hrovat, Mirko I; Dai, Guangping; Mintzopoulos, Dionyssios; Wu, Yaotang
In this study, bone mineral density (BMD) of normal (CON), ovariectomized (OVX), and partially nephrectomized (NFR) rats was measured by (31)P NMR spectroscopy; bone matrix density was measured by (1)H water- and fat-suppressed projection imaging (WASPI); and the extent of bone mineralization (EBM) was obtained by the ratio of BMD/bone matrix density. The capability of these MR methods to distinguish the bone composition of the CON, OVX, and NFR groups was evaluated against chemical analysis (gravimetry). For cortical bone specimens, BMD of the CON and OVX groups was not significantly different; BMD of the NFR group was 22.1% (by (31)P NMR) and 17.5% (by gravimetry) lower than CON. For trabecular bone specimens, BMD of the OVX group was 40.5% (by (31)P NMR) and 24.6% (by gravimetry) lower than CON; BMD of the NFR group was 26.8% (by (31)P NMR) and 21.5% (by gravimetry) lower than CON. No significant change of cortical bone matrix density between CON and OVX was observed by WASPI or gravimetry; NFR cortical bone matrix density was 10.3% (by WASPI) and 13.9% (by gravimetry) lower than CON. OVX trabecular bone matrix density was 38.0% (by WASPI) and 30.8% (by gravimetry) lower than CON, while no significant change in NFR trabecular bone matrix density was observed by either method. The EBMs of OVX cortical and trabecular specimens were slightly higher than CON but not significantly different from CON. Importantly, EBMs of NFR cortical and trabecular specimens were 12.4% and 26.3% lower than CON by (31)P NMR/WASPI, respectively, and 4.0% and 11.9% lower by gravimetry. Histopathology showed evidence of osteoporosis in the OVX group and severe secondary hyperparathyroidism (renal osteodystrophy) in the NFR group. These results demonstrate that the combined (31)P NMR/WASPI method is capable of discerning the difference in EBM between animals with osteoporosis and those with impaired bone mineralization.
Daneault, Audrey; Prawitt, Janne; Fabien Soulé, Véronique; Coxam, Véronique; Wittrant, Yohann
Osteoporosis is a chronic and asymptomatic disease characterized by low bone mass and skeletal microarchitectural deterioration, increased risk of fracture, and associated comorbidities most prevalent in the elderly. Due to an increasingly aging population, osteoporosis has become a major health issue requiring innovative disease management. Proteins are important for bone by providing building blocks and by exerting specific regulatory function. This is why adequate protein intake plays a considerable role in both bone development and bone maintenance. More specifically, since an increase in the overall metabolism of collagen can lead to severe dysfunctions and a more fragile bone matrix and because orally administered collagen can be digested in the gut, cross the intestinal barrier, enter the circulation, and become available for metabolic processes in the target tissues, one may speculate that a collagen-enriched diet provides benefits for the skeleton. Collagen-derived products such as gelatin or hydrolyzed collagen (HC) are well acknowledged for their safety from a nutritional point of view; however, what is their impact on bone biology? In this manuscript, we critically review the evidence from literature for an effect of HC on bone tissues in order to determine whether HC may represent a relevant alternative in the design of future nutritional approaches to manage osteoporosis prevention.
The nature of the relationship between affective disorders, bone mineral density (BMD), and bone metabolism is unresolved, although there is growing evidence that many medications used to treat affective disorders are associated with low BMD or alterations in neuroendocrine systems that influence bone turnover. The objective of this review is to describe the current evidence regarding the association of unipolar and bipolar depression with BMD and indicators of bone metabolism, and to explore potential mediating and confounding influences of those relationships. The majority of studies of unipolar depression and BMD indicate that depressive symptoms are associated with low BMD. In contrast, evidence regarding the relationship between bipolar depression and BMD is inconsistent. There is limited but suggestive evidence to support an association between affective disorders and some markers of bone turnover. Many medications used to treat affective disorders have effects on physiologic systems that influence bone metabolism, and these conditions are also associated with a range of health behaviors that can influence osteoporosis risk. Future research should focus on disentangling the pathways linking psychotropic medications and their clinical indications with BMD and fracture risk. PMID:23874147
Parker, Charles E.
Continuing investigation of the system that hydroxylates phenylalanine to tyrosine has led to new insights into diseases associated with the malfunction of this system. Good evidence has confirmed that phenylketonuria (PKU) is not caused by a simple lack of phenylalanine hydroxylase. Dihydropteridine reductase deficiency as well as defects in biopterin metabolism may also cause the clinical features of phenylketonuria. Furthermore, these diseases do not respond to the standard treatment for phenylketonuria. PMID:388868
Zerwekh, Joseph E.
Observational and epidemiological studies alike have demonstrated that idiopathic hypercalciuric (IH) stone-forming patients typically demonstrate bone mineral density scores significantly less than those observed for age- and gender-matched normal subjects or those for non-hypercalciuric stone-forming patients. Most of these studies have relied on changes in bone mineral density (BMD) and have not explored the mechanism(s) involved. There have been a small number of studies that have relied on dynamic bone histomorphometry to ascertain the nature of the bone defect in IH patients. When performed, these studies have clearly demonstrated increased bone resorption and high bone turnover in patients with fasting hypercalciuria while suppressed bone formation indices are the most consistent finding in patients with the absorptive variant of IH. The causes of this apparent difference in bone remodeling between the two variants of IH is still uncertain. Available evidence suggests that potential mechanisms may be dependent in large part to genetic, metabolic, and nutritional causes of hypercalciuria and bone loss in patients with IH. PMID:18359394
Bover, J; Górriz, J L; Martín de Francisco, A L; Caravaca, F; Barril, G; Molinero, L M
Since its publication in 2003, the K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease (CKD) have become a worldwide reference. The aim of this study was to analyze the observance to these guidelines in patients with a glomerular filtration rate < 60 ml/min/1,73m2 not yet included in dialysis in a Spanish multicenter cohort. A questionnaire by investigator/centre was completed by 32 different nephrologists participating in the OSERCE study and representing the overall Spanish public health net. We observed that biochemical parameters were measured less frequently than recommended, except in CKD stage 3. The therapeutic goals for intact PTH were not properly reported by 59 % of the consulted nephrologists for stages 3 and 4, whereas only 22% did not report them properly for stage 5. The goals for phosphorus were not adequately reported in 50 % of cases (stages 3 y 4) and 60 % (stage 5). For calcium, these values were 70 %, 73.3 % and 65.5 % for stages 3, 4 and 5, respectively. A corrected plasma calcium between 9.5 and 10.2 mg/dl is still considered adequate for 31%. As much as 87% nephrologists stated that they did not sistematically measure calcidiol plasma levels. In general, these results demonstrate that there is a great degree of unawareness of K/DOQITM predialysis guidelines. Thus, their poor implementation is probably not only due to the lower availability of approved therapeutic agents, the difficult achievement of goals or the disbelief on current recommendations. It would be desirable that forthcoming guidelines such as the KDIGO could also consider the need of educational efforts for CKD-Mineral and Bone Disorder.
Smith, Scott M.
Understanding bone loss during space flight is one of the most critical challenges for maintaining astronaut health on space exploration missions. Flight and ground-based studies have been conducted to better understand the nature and mechanisms of weightlessness-induced bone loss, and to identify a means to counteract the loss. Maintenance of bone health requires a balance between bone formation and bone resorption. Early space research identified bone loss as a critical health issue, but could not provide a distinction between the bone formation and breakdown processes. The recent identification of collagen crosslinks as markers of bone resorption has made possible a clear understanding that a decrease in bone resorption is an important effect of space flight, with bone formation being unchanged or only slightly decreased. Calcium regulatory factors have also been studied, in an attempt to understand their role in bone loss. The lack of ultraviolet light exposure and insufficient dietary sources of vitamin D often lead to reduced vitamin D stores on long-duration flights. Serum parathyroid hormone (PTH) concentrations are decreased during flight compared to before flight, although small subject numbers often make this hard to document statistically. As expected, reduced PTH concentrations are accompanied by reduced 1,25-dihydroxyvitamin D concentrations. Calcium kinetic studies during space flight confirm and extend the information gained from biochemical markers of bone metabolism. Calcium kinetic studies demonstrate that bone resorption is increased, bone formation is unchanged or decreased, and dietary calcium absorption is reduced during space flight. Evaluations have also been conducted of countermeasures, including dietary, exercise, and pharmacological treatments. In recent studies, many potential countermeasures show promise at mitigating bone loss in ground-based analogs of weightlessness (e.g., bed rest), but require further ground and flight testing to
Ke, Hua Zhu; Richards, William G; Li, Xiaodong; Ominsky, Michael S
The processes of bone growth, modeling, and remodeling determine the structure, mass, and biomechanical properties of the skeleton. Dysregulated bone resorption or bone formation may lead to metabolic bone diseases. The Wnt pathway plays an important role in bone formation and regeneration, and expression of two Wnt pathway inhibitors, sclerostin and Dickkopf-1 (DKK1), appears to be associated with changes in bone mass. Inactivation of sclerostin leads to substantially increased bone mass in humans and in genetically manipulated animals. Studies in various animal models of bone disease have shown that inhibition of sclerostin using a monoclonal antibody (Scl-Ab) increases bone formation, density, and strength. Additional studies show that Scl-Ab improves bone healing in models of bone repair. Inhibition of DKK1 by monoclonal antibody (DKK1-Ab) stimulates bone formation in younger animals and to a lesser extent in adult animals and enhances fracture healing. Thus, sclerostin and DKK1 are emerging as the leading new targets for anabolic therapies to treat bone diseases such as osteoporosis and for bone repair. Clinical trials are ongoing to evaluate the effects of Scl-Ab and DKK1-Ab in humans for the treatment of bone loss and for bone repair.
... and ill-fitting or loose dentures. Effects of Osteoporosis Treatments on Oral Health It is not known ... Resources For more information on osteoporosis, visit: NIH Osteoporosis and Related Bone Diseases ~ National Resource Center Website: ...
Amorosa, Valerianna; Tebas, Pablo
The high prevalence of bone demineralization among human immunodeficiency virus (HIV)-infected patients in the current therapeutic era has been described in multiple studies, sounding the alarm that we may expect an epidemic of fragility fractures in the future. However, despite noting high overall prevalences of osteopenia and osteoporosis, recent longitudinal studies that we review here have generally not observed accelerated bone loss during antiretroviral therapy beyond the initial period after treatment initiation. We discuss the continued progress toward understanding the mechanisms of HIV-associated bone loss, particularly the effects of HIV infection, antiretroviral therapy, and host immune factors on bone turnover. We summarize results of clinical trials published in the past year that studied the safety and efficacy of treatment of bone loss in HIV-infected patients and provide provisional opinions about who should be considered for bone disease screening and treatment.
Metabolic Bone Disease in the Context of Metastatic Neuroendocrine Tumor: Differentiation from Skeletal Metastasis, the Molecular PET–CT Imaging Features, and Exploring the Possible Etiopathologies Including Parathyroid Adenoma (MEN1) and Paraneoplastic Humoral Hypercalcemia of Malignancy Due to PTHrP Hypersecretion
Ranade, Rohit; Basu, Sandip
Three cases of metabolic bone disease in the setting of metastatic neuroendocrine tumor (NET) are illustrated with associated etiopathologies. One of these cases harbored mixed lesions in the form of vertebral metastasis (biopsy proven) while the other skeletal lesions were caused due to metabolic bone disease related to multiple parathyroid adenomas. While the metastatic lesion was positive on 68Ga-DOTATATE positron emission tomography-computed tomography (PET-CT), the lesions of metabolic bone disease were negative and the 18F-fluoride PET-CT demonstrated the features of metabolic bone scan. Similar picture of metabolic bone disease [18-sodium fluoride (18NaF)/68Ga-DOTATATE mismatch] was documented in the other two patients, while fluorodeoxyglucose (FDG)-PET-CT was variably positive, primarily showing tracer uptake in the metabolic skeletal lesions of the patient with hypersecretion of parathyroid hormone-related protein (PTHrP) by the underlying tumor. Discordance between 18NaF PET-CT and 68Ga-DOTATATE PET-CT serves as a good marker for identification of metabolic bone disease and diagnosing such a clinical entity. In a patient of NET with metabolic bone disease and hypercalcemia, thus, two causes need to be considered: (i) Coexisting parathyroid adenoma in multiple endocrine neoplasia type I (MEN-I) syndrome and (ii) humoral hypercalcemia of malignancy (HHM) related to hypersecretion of PTHrP by the tumor. The correct diagnosis of metabolic bone disease in metastatic NET can alter the management substantially. Interestingly, peptide receptor radionuclide therapy (PRRT) can emerge as a very promising treatment modality in patients of metabolic bone disease caused by HHM in the setting of NET. PMID:28217023
Bell, N H
Important differences exist in the metabolism of bone and mineral and the vitamin D endocrine system between whites and African Americans and include rate o f skeletal remodeling, bone mass, and vitamin D metabolism. A higher bone mineral density (BMD) in African Americans is associated with a diminished incidence o f osteoporosis and fractures. Serum 17beta-estradiol and the rate of GH secretion are higher in black than in white men, but there is no racial difference in women in this regard. The mechanisms for reduced rate o f skeletal remodeling and for greater BMD in blacks are not known, but diminished rate of skeletal remodeling could be a contributing factor for greater bone mass. Reduction in serum 25-hydroxyvitamin D in blacks is attributed to increased skin pigment and to diminished dermal production of vitamin D(3) and consequent decreased hepatic synthesis o f the metabolite. There is no evidence that alteration of the vitamin D endocrine system contributes to or is responsible for racial differences in skeletal remodeling and bone mass. Black infants, however, are at risk for developing vitamin D-deficient rickets, particularly when breast-fed.
Martino, S; Cavalieri, C; Emiliani, C; Dolcetta, D; Cusella De Angelis, M G; Chigorno, V; Severini, G M; Sandhoff, K; Bordignon, C; Sonnino, S; Orlacchio, A
The therapeutic potential of bone marrow-derived stromal cells for the therapy of Tay-Sachs disease is primarily related to the restoration of their own GM2 ganglioside storage. With this aim, we produced bone marrow-derived stromal cells from the adult Tay-Sachs animal model and transduced them with a retroviral vector encoding for the alpha-subunit of the lysosomal enzyme beta-hexosaminidase A (E.C. 184.108.40.206). Our results demonstrate that transduced Tay-Sachs bone marrow-derived stromal cells have beta-hexosaminidase A comparable to that of bone marrow-derived stromal cells from wild-type mice. Moreover, beta-hexosaminidase A in transduced Tay-Sachs bone marrow-derived stromal cells was able to hydrolyze the GM2 ganglioside in a feeding experiment, thus demonstrating the correction of the altered phenotype.
Negri, Armando Luis; Ayus, Juan Carlos
Hip fractures represent a serious health risk in the elderly, causing substantial morbidity and mortality. There is now a considerable volume of literature suggesting that chronic hyponatremia increases the adjusted odds ratio (OR) for both falls and fractures in the elderly. Hyponatremia appears to contribute to falls and fractures by two mechanisms. First, it produces mild cognitive impairment, resulting in unsteady gait and falls; this is probably due to the loss of glutamate (a neurotransmitter involved in gait function) as an osmolyte during brain adaptation to chronic hyponatremia. Second, hyponatremia directly contributes to osteoporosis and increased bone fragility by inducing increased bone resorption to mobilize sodium stores in bone. Low extracellular sodium directly stimulates osteoclastogenesis and bone resorptive activity through decreased cellular uptake of ascorbic acid and the induction of oxidative stress; these effects occur in a sodium level-dependent manner. Hyponatremic patients have elevated circulating arginine-vasopressin (AVP) levels, and AVP acting on two receptors expressed in osteoblasts and osteoclasts, Avpr1α and Avpr2, can increase bone resorption and decrease osteoblastogenesis. Should we be screening for low serum sodium in patients with osteoporosis or assessing bone mineral density (BMD) in patients with hyponatremia? The answers to these questions have not been established. Definitive answers will require randomized controlled studies that allocate elderly individuals with mild hyponatremia to receive either active treatment or no treatment for hyponatremia, to determine whether correction of hyponatremia prevents gait disturbances and changes in BMD, thereby reducing the risk of fractures. Until such studies are conducted, physicians caring for elderly patients must be aware of the association between hyponatremia and bone disorders. As serum sodium is a readily available, simple, and affordable biochemical measurement
Eda, Homare; Santo, Loredana; David Roodman, G; Raje, Noopur
Bone involvement represented by osteolytic bone disease (OBD) or osteopenia is one of the pathognomonic and defining characteristics of multiple myeloma (MM). Nearly 90 % of patients with MM develop osteolytic bone lesions, frequently complicated by skeletal-related events (SRE) such as severe bone pain, pathological fractures, vertebral collapse, hypercalcemia, and spinal cord compression. All of these not only result in a negative impact on quality of life but also adversely impact overall survival. OBD is a consequence of increased osteoclast (OC) activation along with osteoblast (OB) inhibition, resulting in altered bone remodeling. OC number and activity are increased in MM via cytokine deregulation within the bone marrow (BM) milieu, whereas negative regulators of OB differentiation suppress bone formation. Inhibition of osteolysis and stimulation of OB differentiation leads to reduced tumor growth in vivo. Therefore, novel agents targeting OBD are promising therapeutic strategies not only for the treatment of MM OBD but also for the treatment of MM. Several novel agents in addition to bisphosphonates are currently under investigation for their positive effect on bone remodeling via OC inhibition or OB stimulation. Future studies will look to combine or sequence all of these agents with the goal of not only alleviating morbidity from MM OBD but also capitalizing on the resultant antitumor activity.
... About Paget’s Disease and Other Related Conditions: NIH Osteoporosis and Related Bone Diseases ~ National Resource Center 2 ... org) in the preparation of this publication. NIH Osteoporosis and Related Bone Diseases ~ National Resource Center 2 ...
Palmer, H. E.
Sodium-22 was studied as a tracer for bone mineral metabolism in rats and dogs. When incorporated into bone during growth from birth to adulthood, the bone becomes uniformly tagged with (22)Na which is released through the metabolic turnover of the bone. The (22)Na which is not incorporated in the bone matrix is rapidly excreted within a few days when animals are fed high but nontoxic levels of NaCl. The (22)Na tracer can be used to measure bone mineral loss in animals during space flight and in research on bone disease.
Since it is well known that insulin actions have direct and indirect effects on bone metabolism, bone metabolism and bone fragility in patients with diabetes mellitus is a clinically important issue to be addressed. As in glucose metabolism, an involvement of insulin deficiency and insulin resistance should be discussed independently in bone metabolism. Impaired bone formation is primarily involved in bone loss in patients with type 1 diabetes who are lack in insulin secretion. In contrast, bone fragility due to poor bone quality is a major problem in patients with type 2 diabetes who are resistant to insulin actions. Through clinical investigations, it has been established that elderly women with diabetes are at high risk in fracture. Taken together, one should be aware of bone integrity in patients with diabetes, especially in elderly women.
Fukuda, Toru; Takeda, Shu
The traditional view of bone metabolism as a primarily endocrine activity has been expanded in recent years following the identification of nervous system controlling bone metabolism by leptin studies. Especially, hypothalamic appetite regulating-peptides, such as NPY, CART and NMU have been demonstrated to be bone-regulating neuropeptides. Recently, other neuropeptides, such as serotonin and oxytocin, are reported to be associated with bone metabolism.
Smith, Scott M.; Zwart, S. R.; Hargens, A. R.
Several classic twin studies show genetic effects on markers of bone health, including bone mineral density and parathyroid hormone (PTH). This study was performed to assess the relative contribution of genetics to biochemical markers of bone metabolism. Fifteen sets of identical twins (8 male, 7 female) were housed in a clinical research center where diet was controlled (15% protein, 55% carbohydrate, 30% fat) for 3 consecutive days. Each day, 24-h urine pools were collected and N-telopeptide (NTX), deoxypyridinoline (DPD), calcium, and serum PTH were measured. The broad-sense heritability factor (H2) is an estimation of the portion of the total variance of a given phenotype that is attributable to genetic variance. H2 was estimated from the correlation coefficient of the phenotype data. H2 for NTX was 94% for males and 80% for females, DPD was 88% for males and 97% for females, urinary calcium excretion was 97% for males and 90% for females, and PTH was 92% for males and 79% for females. Since environmental variability was minimized for the 3 days of data collection, these heritability factors are likely overestimated. Nonetheless, the data support the concept that PTH is a predominantly heritable trait, and suggest that NTX, DPD, and calcium excretion are as well. These biochemical data support the previously documented heritability of bone health.
Górriz, José L; Molina, Pablo; Bover, Jordi; Barril, Guillermina; Martín-de Francisco, Angel L; Caravaca, Francisco; Hervás, José; Piñera, Celestino; Escudero, Verónica; Molinero, Luis M
OSERCE is a multi-centre and cross-sectional study with the aim of analysing the biochemical, clinical, and management characteristics of bone mineral metabolism alterations and the level of compliance with K/DOQI guideline recommendations in patients with chronic kidney disease (CKD) not on dialysis. The study included a total of 634 patients from 32 different Spanish nephrology units, all with CKD, estimated glomerular filtration rates <60 ml/min/1.73 m(2), and not on dialysis (K/DOQI stage: 33% stage 3, 46% stage 4, and 21% stage 5). In 409 of these patients, laboratory parameters were also measured in a centralised laboratory, including creatinine, calcium, phosphorous, intact parathyroid hormone (PTH), 25-OH-vitamin D, and 1,25-OH2-Vitamin D levels. The rates of non-compliance with the K/DOQI objectives for calcium, phosphorous, intact PTH, and calcium x phosphate product among these patients were 45%, 22%, 70%, and 4%, respectively. Of the 70% of patients with intact PTH levels outside of the target range established by the K/DOQI guidelines, 55.5% had values above the upper limit and 14.5% had values below the lower limit. Of the 45% of patients with calcium levels outside of the target range, 40% had values above the upper limit and 5% had values below the lower limit. Of the 22% of patients with phosphorous levels outside of the target range, 19% had values above the upper limit, and 3% had values below the lower limit. Finally, 4% of patients also had values for the calcium x phosphate product that were outside of the recommended range. Only 1.8% of patients complied with all four K/DOQI objectives. The values detected in centralised laboratory analyses were not significantly different from those measured in the laboratories at each institution. In addition, 81.5% of patients had a deficiency of calcidiol (25-OH-D3) (<30 ng/ml); of these, 35% had moderate-severe deficiency (<15 ng/ml) and 47% had mild deficiency (15-30 ng/ml). Calcitriol (1,25-OH2-D3
Dehydroepiandrosterone(DHEA), an adrenal androgen, has attracted much attention as an anti-aging hormone as well as a marker for senescence because of its unique change along with aging. DHEA is reported to have beneficial effects such as anti-diabetes, anti-obesity, and anti-atherosclerosis. It is also shown that DHEA has anti-osteoporosis effects to increase bone mineral density in randomized controlled trials(RCTs). As osteoblasts express aromatase which will convert androgen to estrogen, DHEA may act protectively against osteoporosis through its metabolites. Because there is no report on fracture risk by DHEA administration, further studies are required to clarify DHEA effects on human bone metabolism.
Scotece, M; Conde, J; Lopez, V; Lago, F; Pino, J; Gomez-Reino, J J; Gualillo, O
Leptin is an adipokine with pleiotropic actions that regulates food intake, energy metabolism, inflammation and immunity, and also participates in the complex mechanism that regulates skeleton biology, both at bone and cartilage level. Leptin is increased in obesity and contributes to the "low-grade inflammatory state" of obese subjects causing a cluster of metabolic aberrations that affects joints and bone. In this review, we report the most recent research advances about the role of leptin in bone and cartilage function and its implication in inflammatory and degenerative joint diseases, such as osteoarthritis, rheumatoid arthritis and osteoporosis.
D’Marco, Luis; Bellasi, Antonio; Mazzaferro, Sandro; Raggi, Paolo
The development of end stage renal failure can be seen as a catastrophic health event and patients with this condition are considered at the highest risk of cardiovascular disease among any other patient groups and risk categories. Although kidney transplantation was hailed as an optimal solution to such devastating disease, many issues related to immune-suppressive drugs soon emerged and it became evident that cardiovascular disease would remain a vexing problem. Progression of chronic kidney disease is accompanied by profound alterations of mineral and bone metabolism that are believed to have an impact on the cardiovascular health of patients with advanced degrees of renal failure. Cardiovascular risk factors remain highly prevalent after kidney transplantation, some immune-suppression drugs worsen the risk profile of graft recipients and the alterations of mineral and bone metabolism seen in end stage renal failure are not completely resolved. Whether this complex situation promotes progression of vascular calcification, a hall-mark of advanced chronic kidney disease, and whether vascular calcifications contribute to the poor cardiovascular outcome of post-transplant patients is reviewed in this article. PMID:26722649
Egido, Jesús; Martínez-Castelao, Alberto; Bover, Jordi; Praga, Manuel; Torregrosa, José Vicente; Fernández-Giráldez, Elvira; Solozábal, Carlos
Secondary hyperparathyroidism (SHPT) is a common complication in patients with chronic kidney disease (CKD) that is characterised by elevated parathyroid hormone (PTH) levels and a series of bone-mineral metabolism anomalies. In patients with SHPT, treatment with paricalcitol, a selective vitamin D receptor activator, has been shown to reduce PTH levels with minimal serum calcium and phosphorus variations. The classic effect of paricalcitol is that of a mediator in mineral and bone homeostasis. However, recent studies have suggested that the benefits of treatment with paricalcitol go beyond PTH reduction and, for instance, it has a positive effect on cardiovascular disease and survival. The objective of this study is to review the most significant studies on the so-called pleiotropic effects of paricalcitol treatment in patients with CKD.
Hamed, Sherifa A
Data from cross-sectional and prospective studies revealed that patients with epilepsy and on long-term treatment with antiepileptic drugs (AEDs) are at increased risk for metabolic bone diseases. Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone turnover markers and fractures were reported with phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs-induced bone diseases are heterogeneous and include hypovitaminosis D, hypocalcemia and direct acceleration of bone loss and/or reduction of bone formation. This article reviews the evidence, predictors and mechanisms of AEDs-induced bone abnormalities and its clinical implications. For patients on AEDs, regular monitoring of bone health is recommended. Prophylactic administration of calcium and vitamin D is recommended for all patients. Treatment doses of calcium and vitamin D and even anti-resorptive drug therapy are reserved for patients at high risk of pathological fracture.
Poh, Stanley; Mohamed Abdul, Riswana Banu Binte; Lamoureux, Ecosse L; Wong, Tien Y; Sabanayagam, Charumathi
Metabolic syndrome is becoming a worldwide medical and public health challenge as it has been seen increasing in prevalence over the years. Age-related eye diseases, the leading cause of blindness globally and visual impairment in developed countries, are also on the rise due to aging of the population. Many of the individual components of the metabolic syndrome have been shown to be associated with these eye diseases. However, the association of metabolic syndrome with eye diseases is not clear. In this review, we reviewed the evidence for associations between metabolic syndrome and certain ocular diseases in populations. We also reviewed the association of individual metabolic syndrome components with ocular diseases due to a paucity of research in this area. Besides, we also summarised the current understanding of etiological mechanisms of how metabolic syndrome or the individual components lead to these ocular diseases. With increasing evidence of such associations, it may be important to identify patients who are at risk of developing metabolic syndrome as prompt treatment and intervention may potentially decrease the risk of developing certain ocular diseases.
Gennari, L; Bianciardi, S; Merlotti, D
MicroRNAs are small, noncoding single-stranded RNAs that have emerged as important posttranscriptional regulators of gene expression, with an essential role in vertebrate development and different biological processes. This review highlights the recent advances in the function of miRNAs and their roles in bone remodeling and bone diseases. MicroRNAs (miRNAs) are a class of small (∼22 nt), noncoding single-stranded RNAs that have emerged as important posttranscriptional regulators of gene expression. They are essential for vertebrate development and play critical roles in different biological processes related to cell differentiation, activity, metabolism, and apoptosis. A rising number of experimental reports now indicate that miRNAs contribute to every step of osteogenesis and bone homeostasis, from embryonic skeletal development to maintenance of adult bone tissue, by regulating the growth, differentiation, and activity of different cell systems inside and outside the skeleton. Importantly, emerging information from animal studies suggests that targeting miRNAs might become an attractive and new therapeutic approach for osteoporosis or other skeletal diseases, even though there are still major concerns related to potential off target effects and the need of efficient delivery methods in vivo. Moreover, besides their recognized effects at the cellular level, evidence is also gathering that miRNAs are excreted and can circulate in the blood or other body fluids with potential paracrine or endocrine functions. Thus, they could represent suitable candidates for becoming sensitive disease biomarkers in different pathologic conditions, including skeletal disorders. Despite these promising perspectives more work remains to be done until miRNAs can serve as robust therapeutic targets or established diagnostic tools for precision medicine in skeletal disorders.
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Bisland, Stuart K.; Yee, Albert; Siewerdsen, Jeffery; Wilson, Brian C.; Burch, Shane
Objective: Photodynamic therapy (PDT) defines the oxygen-dependent reaction that occurs upon light-mediated activation of a photosensitizing compound, culminating in the generation of cytotoxic, reactive oxygen species, predominantly, singlet oxygen. We are investigating PDT treatment of diseased bone. Methods: Using a rat model of human breast cancer (MT-1)-derived bone metastasis we confirmed the efficacy of benzoporphyrin-derivative monoacid (BPD-MA)-PDT for treating metastatic lesions within vertebrae or long bones. Results: Light administration (150 J) 15 mins after BPDMA (2.5 mg/Kg, i.v.) into the lumbar (L3) vertebra of rats resulted in complete ablation of the tumour and surrounding bone marrow 48 hrs post-PDT without paralysis. Porcine vertebrae provided a model comparable to that of human for light propagation (at 150 J/cm) and PDT response (BPD-MA; 6 mg/m2, i.v.) in non-tumour vertebrae. Precise fibre placement was afforded by 3-D cone beam computed tomography. Average penetration depth of light was 0.16 +/- 0.04 cm, however, the necrotic/non-necrotic interface extended 0.6 cm out from the treatment fiber with an average incident fluence rate of 4.3 mW/cm2. Non-necrotic tissue damage was evident 2 cm out from the treatment fiber. Current studies involving BPD-MA-PDT treatment of primary osteosarcomas in the forelimbs of dogs are very promising. Magnetic resonance imaging 24 hr post treatment reveal well circumscribed margins of treatment that encompass the entire 3-4 cm lesion. Finally, we are also interested in using 5-aminolevulinic acid (ALA) mediated PDT to treat osteomyelitis. Response to therapy was monitored as changes in bioluminescence signal of staphylococcus aureus (SA)-derived biofilms grown onto 0.5 cm lengths of wire and subjected to ALA-PDT either in vitro or in vivo upon implant into the intramedullary space of rat tibia. Transcutaneous delivery of PDT (75 J/cm2) effectively eradicated SAbiofilms within bone. Conclusions: Results support
Arifin, Syamsul A.; Falasca, Marco
Metabolism is a chemical process used by cells to transform food-derived nutrients, such as proteins, carbohydrates and fats, into chemical and thermal energy. Whenever an alteration of this process occurs, the chemical balance within the cells is impaired and this can affect their growth and response to the environment, leading to the development of a metabolic disease. Metabolic syndrome, a cluster of several metabolic risk factors such as abdominal obesity, insulin resistance, high cholesterol and high blood pressure, and atherogenic dyslipidaemia, is increasingly common in modern society. Metabolic syndrome, as well as other diseases, such as diabetes, obesity, hyperlipidaemia and hypertension, are associated with abnormal lipid metabolism. Cellular lipids are the major component of cell membranes; they represent also a valuable source of energy and therefore play a crucial role for both cellular and physiological energy homeostasis. In this review, we will focus on the physiological and pathophysiological roles of the lysophospholipid mediator lysophosphatidylinositol (LPI) and its receptor G-protein coupled receptor 55 (GPR55) in metabolic diseases. LPI is a bioactive lipid generated by phospholipase A (PLA) family of lipases which is believed to play an important role in several diseases. Indeed LPI can affect various functions such as cell growth, differentiation and motility in a number of cell-types. Recently published data suggest that LPI plays an important role in different physiological and pathological contexts, including a role in metabolism and glucose homeostasis. PMID:26784247
Bezsmertnyĭ, Iu O
In article described research of the metabolic status and bone mineral density in 153 patients with with pseudarthrosis of long bones, in individuals with consolidated fractures and healthy people. The violations of reparative osteogenesis at hyperhomocysteinemia are accompanied by disturbances of the functional state of bone tissue, inhibition of biosynthetic and increased destruction processes, reduced bone mineral density in the formation of osteopenia and osteoporosis. The degree and direction of change of bone depends on the type of violation of reparative osteogenesis.
Moore, Benjamin T; Xiao, Peng
MicroRNAs (miRNAs), which mainly inhibit protein expression by targeting the 3'UTR (untranslated region) of mRNAs, are known to play various roles in the pathogenesis of many different types of diseases. Specifically, in bone diseases, recent emphasis has been placed on the involvement of miRNAs in the differentiation and proliferation of bone and cartilage cells, particularly with regards to how these mechanisms contribute to bone homeostasis. In this review, we summarize miRNAs that are important in the differentiation and proliferation of bone cells, and specific miRNAs associated with bone diseases, such as osteoporosis, osteoarthritis and rheumatoid arthritis. This review also provides the perspective that miRNA studies will identify not only new mechanisms in basic bone research, but also potential novel diagnostic biomarkers and drug targets for bone diseases.
Curran, David R; McArdle, John R; Talwalkar, Jaideep S
Patients with cystic fibrosis are frequently affected with pancreatic insufficiency and are predisposed to the development of diabetes mellitus (DM) and bone demineralization. Cystic fibrosis-related diabetes mellitus is a clinical entity distinct from type 1 and type 2 diabetes, with important implications for the nutritional and pulmonary health of cystic fibrosis patients. This form of diabetes owes largely to insulin deficiency, but alterations in insulin sensitivity and hepatic glucose production have also been described. Therapy for cystic fibrosis-related diabetes differs substantially from type 2 DM, with careful attention to prandial glycemic excursions crucial to controlling its metabolic effects. Bone disease, including osteopenia and osteoporosis, also occurs with increased frequency in cystic fibrosis, owing to defects in intestinal absorption, chronic inflammation, lung disease, low body weight, and gonadal dysfunction. The pathogenesis, implications, diagnosis, and therapy of cystic fibrosis-related bone demineralization are discussed, with attention to recommended approaches to prevention of and treatment of established bone disease.
Cortis, K; Micallef, K; Mizzi, A
Paget's disease of the bone is a common, non-inflammatory, metabolic, skeletal disorder of unknown aetiology characterized by an increase in osteoclast-mediated bone resorption and compensatory excessive osteoblast activation. Prevalence increases with age, and a pronounced geographical variation is well documented. The disease is often an incidental finding on a radiological examination requested for an unrelated indication. The osteolytic, mixed osteolytic/osteoblastic, and osteosclerotic phases may occur in the same patient and same bone in a synchronous or metachronous fashion. Radiological features in each phase mirror the histopathological appearances, and are distinctive enough to establish a diagnosis with confidence. Using multi-technique imaging, this review illustrates the most common and the not so common radiological patterns of involvement in Paget's disease of bone observed at our centre during the past 20 years.
Pereira, Rosa Maria Rodrigues; de Carvalho, Jozélio Freire; Bonfá, Eloísa
Metabolic syndrome is characterized by a combination of various cardiovascular risk factors (age, gender, smoking, hypertension and dyslipidemia) that imply additional cardiovascular morbidity that is greater than the sum of the risks associated with each individual component. Herein, the authors review the rheumatological diseases in which metabolic syndrome has been studied: gout, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and ankylosing spondylitis. The prevalence of metabolic syndrome in these disorders varies from 14% to 62.8%. The great majority of these studies demonstrated that this frequency was higher in rheumatological diseases than in the control populations, suggesting that either the presence or the treatment of those diseases seems to influence the risk of developing metabolic syndrome.
Anandarajah, Allen P
Bone remodeling is a tightly regulated process of osteoclast-mediated bone resorption, balanced by osteoblast-mediated bone formation. Disruption of this balance can lead to increased bone turnover, resulting in excessive bone loss or extra bone formation and consequent skeletal disease. The receptor activator of nuclear factor kappaB ligand (RANKL) (along with its receptor), the receptor activator of nuclear factor kappaB and its natural decoy receptor, osteoprotegerin, are the final effector proteins of osteoclastic bone resorption. Here, I provide an overview of recent studies that highlight the key role of RANKL in the pathophysiology of several bone diseases and discuss the novel therapeutic approaches afforded by the modulation of RANKL.
Cavnar, Stephen P.; Xiao, Annie; Gibbons, Anne E.; Rickelmann, Andrew D.; Neely, Taylor; Luker, Kathryn E.; Takayama, Shuichi; Luker, Gary D.
Malignant cells from breast cancer and other common cancers such as prostate and melanoma may persist in bone marrow as quiescent, non-dividing cells that remain viable for years or even decades before resuming proliferation to cause recurrent disease. This phenomenon, referred to clinically as tumor dormancy, poses tremendous challenges to curing patients with breast cancer. Quiescent tumor cells resist chemotherapy drugs that predominantly target proliferating cells, limiting success of neo-adjuvant and adjuvant therapies. We recently developed a 3D spheroid model of quiescent breast cancer cells in bone marrow for mechanistic and drug testing studies. We combined this model with optical imaging methods for label-free detection of cells preferentially utilizing glycolysis versus oxidative metabolism to investigate the metabolic state of co-culture spheroids with different bone marrow stromal and breast cancer cells. Through imaging and biochemical assays, we identified different metabolic states of bone marrow stromal cells that control metabolic status and flexibilities of co-cultured breast cancer cells. We tested metabolic stresses and targeted inhibition of specific metabolic pathways to identify approaches to preferentially eliminate quiescent breast cancer cells from bone marrow environments. These studies establish an integrated imaging approach to analyze metabolism in complex tissue environments to identify new metabolically-targeted cancer therapies. PMID:27478871
Stegemann, Rachel; Buchner, David A.
Metabolic disease encompasses several disorders including obesity, type 2 diabetes, and dyslipidemia. Recently, the incidence of metabolic disease has drastically increased, driven primarily by a worldwide obesity epidemic. Transgenerational inheritance remains controversial, but has been proposed to contribute to human metabolic disease risk based on a growing number of proof-of-principle studies in model organisms ranging from C. elegans to M. musculus to S. scrofa. Collectively, these studies demonstrate that heritable risk is epigenetically transmitted from parent to offspring over multiple generations in the absence of a continued exposure to the triggering stimuli. A diverse assortment of initial triggers can induce transgenerational inheritance including high-fat or high-sugar diets, low-protein diets, various toxins, and ancestral genetic variants. Although the mechanistic basis underlying the transgenerational inheritance of disease risk remains largely unknown, putative molecules mediating transmission include small RNAs, histone modifications, and DNA methylation. Due to the considerable impact of metabolic disease on human health, it is critical to better understand the role of transgenerational inheritance of metabolic disease risk to open new avenues for therapeutic intervention and improve upon the current methods for clinical diagnoses and treatment. PMID:25937492
Stegemann, Rachel; Buchner, David A
Metabolic disease encompasses several disorders including obesity, type 2 diabetes, and dyslipidemia. Recently, the incidence of metabolic disease has drastically increased, driven primarily by a worldwide obesity epidemic. Transgenerational inheritance remains controversial, but has been proposed to contribute to human metabolic disease risk based on a growing number of proof-of-principle studies in model organisms ranging from Caenorhabditis elegans to Mus musculus to Sus scrofa. Collectively, these studies demonstrate that heritable risk is epigenetically transmitted from parent to offspring over multiple generations in the absence of a continued exposure to the triggering stimuli. A diverse assortment of initial triggers can induce transgenerational inheritance including high-fat or high-sugar diets, low-protein diets, various toxins, and ancestral genetic variants. Although the mechanistic basis underlying the transgenerational inheritance of disease risk remains largely unknown, putative molecules mediating transmission include small RNAs, histone modifications, and DNA methylation. Due to the considerable impact of metabolic disease on human health, it is critical to better understand the role of transgenerational inheritance of metabolic disease risk to open new avenues for therapeutic intervention and improve upon the current methods for clinical diagnoses and treatment.
Hallanger Johnson, Julie E; Kearns, Ann E; Doran, Patric M; Khoo, Teck Kim; Wermers, Robert A
Acquired osteosclerosis is a rare disorder of bone formation but an important consideration in adults with sclerotic bones or elevated bone density results. In such patients, malignancy, hepatitis C, and fluorosis should all be considered when making a diagnosis. We describe 4 patients evaluated at our Metabolic Bone Disease Clinic from May 1, 1997, to July 1, 2006, whose bone disorders resulted from chronic fluoride exposure due to excessive tea intake. Three of these patients had toxic serum fluoride levels (> 15 micromol/L). Although the clinical presentation of the patients varied, all 4 had an unexpectedly elevated spine bone mineral density that was proportionately higher than the bone mineral density at the hip. Other clinical features included gastrointestinal symptoms such as nausea, vomiting, and weight loss; lower extremity pain sometimes associated with stress fractures of the lower extremities; renal insufficiency; and elevated alkaline phosphatase levels. Readily available, tea often contains high levels of fluoride. Obsessive-compulsive drinking behaviors and renal insufficiency may predispose to excessive fluoride consumption and accumulation. The current cases show that fluoride-related bone disease is an important clinical consideration in patients with dense bones or gastrointestinal symptoms and a history of excessive tea consumption. Furthermore, fluoride excess should be considered in all patients with a history of excessive tea consumption, especially due to its insidious nature and nonspecific clinical presentation.
Lipton, Allan; Cook, Richard J; Coleman, Robert E; Smith, Matthew R; Major, Pierre; Terpos, Evangelos; Berenson, James R
Osteolytic bone lesions from advanced multiple myeloma (MM) result in significant skeletal morbidity. Therefore, biochemical markers of bone metabolism, such as the N-terminal and C-terminal telopeptides of type I collagen, bone-specific alkaline phosphatase, and osteocalcin, have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity, and response to antiresorptive treatment. Several studies have shown that the majority of biochemical markers of bone metabolism are increased in patients with MM with osteolytic bone lesions, thus reflecting changes in bone metabolism associated with tumor growth. There is also a growing body of evidence that markers of bone metabolism correlate with the risk of skeletal complications, disease progression, and death. In addition, bone markers could potentially be used as a tool for early diagnosis of bone lesions. The aim of this review is to improve our understanding of bone markers as a clinical tool for the management of malignant bone disease in patients with MM.
Hirota, Takako; Hirota, Kenji
Dieting methods for preventing age-related diseases such as cardiovascular disease, hypertension and diabetes, as well as osteoporosis are proposed here. Losing weight to prevent and ameliorate metabolic syndrome can lead to loss of bone and muscle mass. However, when subjects had milk before dinner while dieting, their fat mass was efficiently decreased and their muscle mass increased without any change of bone mass. Increased intake of vitamin D enhanced these effects. Therefore we suggest that people with high risk of metabolic disorders should take more low fat dairy products and fish, together with fruits, vegetables, and soy in order to increase their intake of calcium, vitamin D, n-3 polyunsaturated fatty acids, protein, antioxidants, various vitamins and minerals, and fiber to protect them from the deterioration of arteries and bones.
DeBerardinis, Ralph J.; Thompson, Craig B.
An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states – often genetically programmed – that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This review discusses the broad impact of metabolism in cellular function, how modern concepts of metabolism can inform our understanding of common diseases like cancer, and considers the prospects of developing new metabolic approaches to disease treatment. PMID:22424225
Daci, E; van Cromphaut, S; Bouillon, R
Bone is permanently renewed by the coordinated actions of bone-resorbing osteoclasts and bone-forming osteoblasts, which model and remodel bone structure during growth and adult life. The origin of osteoblastic cells (osteoblasts, osteocytes and bone-lining cells) differs from that of osteoclasts, but both cell groups communicate with each other using cytokines and cell-cell contact as to optimally maintain bone homeostasis. This communication in many ways uses the same players as the communication between cells in the immune system. During acute life-threatening illness massive bone resorption is the rule, while bone formation is suppressed. During chronic illness, the balance between bone formation and bone resorption also shifts, frequently resulting in decreased bone mass and density. Several factors may contribute to the osteopenia that accompanies chronic illness, the most important being undernutrition and low body weight, inflammatory cytokines, disorders of the neuroendocrine axis (growth hormone/IGF-1 disturbances, thyroid and gonadal deficiency), immobilization, and the long-term use of glucocorticoids. Their combined effects not only influence the generation and activity of all bone cells involved, but probably also regulate their life span by apoptotic mechanisms. Osteopenia or even osteoporosis and bone fragility, and before puberty also decreased linear growth and lower peak bone mass are therefore frequent consequences of chronic illnesses.
Demetrius, Lloyd A; Driver, Jane
Empirical evidence indicates that impaired mitochondrial energy metabolism is the defining characteristic of almost all cases of Alzheimer's disease (AD). Evidence is reviewed supporting the general hypothesis that the up-regulation of OxPhos activity, a metabolic response to mitochondrial dysregulation, drives the cascade of events leading to AD. This mode of metabolic alteration, called the Inverse Warburg effect, is postulated as an essential compensatory mechanism of energy production to maintain the viability of impaired neuronal cells. This article appeals to the inverse comorbidity of cancer and AD to show that the amyloid hypothesis, a genetic and neuron-centric model of the origin of sporadic forms of AD, is not consistent with epidemiological data concerning the age-incidence rates of AD. A view of Alzheimer's as a metabolic disease-a condition consistent with mitochondrial dysregulation and the Inverse Warburg effect, will entail a radically new approach to diagnostic and therapeutic strategies.
Numan, Mohamed S; Amiable, Nathalie; Brown, Jacques P; Michou, Laëtitia
Osteoimmunology represents a large area of research resulting from the cross talk between bone and immune systems. Many cytokines and signaling cascades are involved in the field of osteoimmunology, originating from various cell types. The RANK/receptor activator of nuclear factor Kappa-B ligand (RANKL)/osteoprotegerin (OPG) signaling has a pivotal role in osteoimmunology, in addition to proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17. Clinically, osteoimmunological disorders, such as rheumatoid arthritis, osteoporosis, and periodontitis, should be classified according to their pattern of osteoimmunological serum biomarkers. Paget’s disease of bone is a common metabolic bone disorder, resulting from an excessively increased bone resorption coupled with aberrant bone formation. With the exception of the cellular responses to measles virus nucleocapsid protein and the interferon-gamma signature, the exact role of the immune system in Paget’s disease of bone is not well understood. The cytokine profiles, such as the increased levels of IL-6 and the interferon-gamma signature observed in this disease, are also very similar to those observed in other osteoimmunological disorders. As a potential osteoimmunological disorder, the treatment of Paget’s disease of bone may also benefit from progress made in targeted therapies, in particular for receptor activator of nuclear factor Kappa-B ligand and IL-6 signaling inhibition. PMID:26316708
Asada, Noboru; Sato, Mari; Katayama, Yoshio
The bone contains the bone marrow. The functional communication between bone cells and hematopoiesis has been extensively studied in the past decade or so. Osteolineage cells and their modulators, such as the sympathetic nervous system, macrophages and osteoclasts, form a complex unit to maintain the homeostasis of hematopoiesis, called the ‘microenvironment'. Recently, bone-embedded osteocytes, the sensors of gravity and mechanical stress, have joined the microenvironment, and they are demonstrated to contribute to whole body homeostasis through the control of immunity and energy metabolism. The inter-organ communication orchestrated by the bone is summarized in this article. PMID:26512322
Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease will impact approaches to cancer management and prevention. PMID:20181022
Salanova Villanueva, Laura; Sánchez González, Carmen; Sánchez Tomero, José Antonio; Aguilera, Abelardo; Ortega Junco, Esther
Cardiovascular factors are one of the main causes of morbidity and mortality in patients with chronic kidney disease. Bone mineral metabolism disorders and inflammation are pathological conditions that involve increased cardiovascular risk in chronic kidney disease. The cardiovascular risk involvement of bone mineral metabolism classical biochemical parameters such as phosphorus, calcium, vitamin D and PTH is well known. The newest markers, FGF23 and klotho, could also be implicated in cardiovascular disease.
Drenjančević, Ines; Davidović Cvetko, Erna
Bone remodeling is a lifetime process. Peak bone mass is achieved in the twenties, and that value is very important for skeleton health in older years of life. Modern life style with its diet poor in nutrients, and very low intensity of physical activity negatively influences health in general, and bone health as well. Bones are adapting to changes in load, so applying mechanical strain to bones results in greater bone mass and hardness. That makes physical activity important in maintaining skeleton health. Numerous studies confirm good influence of regular exercising to bone health, and connection of physical activity in youth to better bone density in older age. To activate bone remodeling mechanisms, it is necessary to apply mechanical strain to bones by exercise. Considering global problem of bone loss and osteoporosis new ways of activating young people to practice sports and active stile of life are necessary to maintain skeleton health and health in general. This paper aims to review physiological mechanisms of bone remodeling that are influenced by physical exercise.
Chandler, Randy J.; Venditti, Charles P.
SUMMARY Gene therapy has recently shown great promise as an effective treatment for a number of metabolic diseases caused by genetic defects in both animal models and human clinical trials. Most of the current success has been achieved using a viral mediated gene addition approach, but gene-editing technology has progressed rapidly and gene modification is being actively pursued in clinical trials. This review focuses on viral mediated gene addition approaches, because most of the current clinical trials utilize this approach to treat metabolic diseases. PMID:27853673
Thiam, Desmond; Teo, Tse Yean; Malhotra, Rishi; Tan, Kong Bing; Chee, Yu Han
Black bone disease refers to the hyperpigmentation of bone secondary to prolonged usage of minocycline. We present a report of a 34-year-old man who underwent femoral shaft fracture fixation complicated by deep infection requiring debridement. The implants were removed 10 months later after long-term treatment with minocycline and fracture union. A refracture of the femoral shaft occurred 2 days after implant removal and repeat fixation was required. Intraoperatively, abundant heavily pigmented and dark brown bone callus was noted over the old fracture site. There was no evidence of other bony pathology and the appearance was consistent with minocycline-associated pigmentation. As far as we are aware, this is the first case of black bone disease affecting callus within the interval period of bone healing. We also discuss the relevant literature on black bone disease to bring light on this rare entity that is an unwelcomed surprise to operating orthopaedic surgeons.
Carulli, Christian; Innocenti, Massimo; Brandi, Maria Luisa
Bone vasculature is essential for many processes, such as skeletal development and growth, bone modeling and remodeling, and healing processes. Endothelium is an integral part of bone tissue, expressing a physiological paracrine function via growth factors and chemokines release, and interacting with several cellular lines. Alterations of the complex biochemical interactions between vasculature and bone cells may lead to various clinical manifestations. Two different types of pathologies result: a defect or an excess of bone vasculature or endothelium metabolism. Starting from the molecular basis of the interactions between endothelial and bone cells, the Authors present an overview of the recent acquisitions in the physiopathology of the most important clinical patterns, and the modern therapeutic strategies for their treatments. PMID:23986744
Miura, Kohji; Oznono, Keiichi
Skeletal dysplasia is the term which represents disorders including growth and differentiation of bone, cartilage and ligament. A lot of diseases are included, and new disorders have been added. However, the therapy of most bone diseases is less well-established. Achondroplasia, hypochondroplasia, and osteogenesis imperfecta are most frequent bone diseases. There is no curative treatment for these diseases, however, supportive therapies are available ; for example, growth-hormone therapy for achondroplasia and hypochondroplasia, and bisphosphonate therapy for osteogenesis imperfecta. In addition, enzyme replacement therapy for hypophosphatasia is now on clinical trial.
During aging process in men, decline of androgen level is involved in symptoms of hypogonadism, and recent findings suggest that sex hormones are crucial for skeletal development and maintenance of bone mineral properties. In practice, androgen replacement therapy has not been established for bone-related symptoms in late onset hypogonadisim or male osteoporosis. Whereas recent evidences suggest that bone mineral properties are improved by androgen replacement therapy in aging male, further studies including large clinical trials are necessary to assess long-term benefits and risks by the therapy.
Scotece, Morena; Conde, Javier; Vuolteenaho, Katriina; Koskinen, Anna; López, Veronica; Gómez-Reino, Juan; Lago, Francisca; Moilanen, Eeva; Gualillo, Oreste
White adipose tissue is now recognized to be a multifactorial organ secreting several adipose-derived factors that have been collectively termed 'adipokines'. Adipokines are pleiotropic molecules that contribute to the so-called 'low-grade inflammatory state' of obese subjects creating a cluster of metabolic aberrations including autoimmune and inflammatory diseases that affect joints and bone. The aim of this review is to present knowledge about the role of adipokines in bone and cartilage function, as well as in inflammatory and degenerative joint disease. We discuss clinical implications and then survey attempts to exploit this role for therapeutic gain, which holds potential as a novel approach for drug development in bone and joint disease.
Rieu, I; Boirie, Y; Morio, B; Derost, P; Ulla, M; Marques, A; Debilly, B; Bannier, S; Durif, F
Parkinson's disease is a neurodegenerative disorder clinically characterized by motor impairments (tremor, bradykinesia, rigidity and postural instability) associated or not with non-motor complications (cognitive disorders, dysautonomia). Most of patients loose weight during evolution of their disease. Dysregulations of hypothalamus, which is considered as the regulatory center of satiety and energy metabolism, could play a major role in this phenomenon. Deep brain stimulation of the subthalamic nucleus (NST) is an effective method to treat patients with advanced Parkinson's disease providing marked improvement of motor impairments. This chirurgical procedure also induces a rapid and strong body weight gain and sometimes obesity. This post-operative weight gain, which exceeds largely weight lost recorded in non-operated patient, could be responsible of metabolic disorders (such as diabetes) and cardiovascular diseases. This review describes body weight variations generated by Parkinson' disease and deep brain stimulation of the NST, and focuses on metabolic disorders capable to explain them. Finally, this review emphasizes on the importance of an adequate nutritional follow up care for parkinsonian patient.
Session TA4 includes short reports concerning: (1) Human Bone Tissue Changes after Long-Term Space Flight: Phenomenology and Possible Mechanics; (2) Prediction of Femoral Neck Bone Mineral Density Change in Space; (3) Dietary Calcium in Space; (4) Calcium Metabolism During Extended-Duration Space Flight; (5) External Impact Loads on the Lower Extremity During Jumping in Simulated Microgravity and the Relationship to Internal Bone Strain; and (6) Bone Loss During Long Term Space Flight is Prevented by the Application of a Short Term Impulsive Mechanical Stimulus.
Saito, D; Mikami, T; Oda, Y; Hasebe, D; Nishiyama, H; Saito, I; Kobayashi, T
The aim of this study was to determine the relationships among bone properties, bone metabolic markers, and types of jaw deformity. The subjects were 55 female patients with jaw deformities. Skeletal morphology was examined using lateral cephalograms, and the patients were divided into three groups according to the type of anteroposterior skeletal pattern. Serum osteocalcin, bone alkaline phosphatase, and tartrate-resistant acid phosphatase isoform 5b, as well as deoxypyridinoline in urine, were measured as bone metabolic markers. Quantitative ultrasound (QUS) measurements were used to assess bone properties at the calcaneal bone. The bone volume and bone density of the condylar process were measured in 43 patients by computed tomography. There were no significant differences in bone metabolic markers and QUS parameters between the groups, although bone formation and resorption markers tended to be higher in patients with a protrusive mandible. On the other hand, patients with mandibular retrusion had a higher tendency to have small and dense condylar processes. In conclusion, the results suggest that growth depression or a degenerative change in the mandibular condyle is involved in the pathogenesis of mandibular retrusion, although risk factors for progressive condylar resorption were not determined.
Despite being a risk factor for many chronic health disorders, obesity is thought to promote bone formation and protect against osteoporosis in humans. Although body mass has a positive effect on bone health, whether mass derived from an obesity condition or excessive fat accumulation is beneficial ...
López-Martínez, Fanny; Olivares Ponce, Patricia N; Guerra Rodríguez, Miriam; Martínez Pedraza, Ricardo
Throughout life, bone tissue undergoes a continuous process of resorption and formation. Melatonin, with its antioxidant properties and its ability to detoxify free radicals, as suggested by Conconi et al. (2000) may interfere in the osteoclast function and thereby inhibit bone resorption, as suggested by Schroeder et al. (1981). Inhibition of bone resorption may be enhanced by a reaction of indoleamine in osteoclastogenesis. That it has been observed melatonin, at pharmacological doses, decrease bone mass resorption by suppressing through down regulation of the RANK-L, as suggested by Penarrocha Diago et al. (2005) and Steflik et al. (1994). These data point an osteogenic effect towards that may be of melatonin of clinical importance, as it could be used as a therapeutic agent in situations in which would be advantageous bone formation, such as in the treatment of fractures or osteoporosis or their use as, a bioactive surface on implant as suggested by Lissoni et al. (1991).
López-Martínez, Fanny; Olivares Ponce, Patricia N.; Guerra Rodríguez, Miriam; Martínez Pedraza, Ricardo
Throughout life, bone tissue undergoes a continuous process of resorption and formation. Melatonin, with its antioxidant properties and its ability to detoxify free radicals, as suggested by Conconi et al. (2000) may interfere in the osteoclast function and thereby inhibit bone resorption, as suggested by Schroeder et al. (1981). Inhibition of bone resorption may be enhanced by a reaction of indoleamine in osteoclastogenesis. That it has been observed melatonin, at pharmacological doses, decrease bone mass resorption by suppressing through down regulation of the RANK-L, as suggested by Penarrocha Diago et al. (2005) and Steflik et al. (1994). These data point an osteogenic effect towards that may be of melatonin of clinical importance, as it could be used as a therapeutic agent in situations in which would be advantageous bone formation, such as in the treatment of fractures or osteoporosis or their use as, a bioactive surface on implant as suggested by Lissoni et al. (1991). PMID:22927853
Epstein, Joshua; Walker, Ronald
Osteolytic bone disease is the most debilitating manifestation of myeloma. However, myeloma-induced effects on the bone-active cells in the bone marrow are more than just a manifestation of disease--the myeloma derives essential support from the changed balance between bone-forming and -resorbing cells. This observation has lead to the notion that effective control of myeloma bone disease by reducing osteoclast activity and restoring osteoblast activity will contribute to long-term control of myeloma progression. Unlike osteolysis associated with other tumors that metastasize to bone, myeloma-associated lytic lesions are unique in that they do not repair even after many years in complete remission, reflecting a total loss of osteoblastic activity in areas of myeloma foci, apparently induced by the myeloma. Advances in imaging technology including positron emission tomography-computed tomography scanning allows accurate detection of lytic lesions and the monitoring of treatment effects. Effective antimyeloma therapy combined with anti-osteoclast drugs can halt the progression of osteolysis; in severe cases with vertebral compression fractures, effective physical support in the form of vertebroplasty or kyphoplasty is required for control of function, pain, and stature. Fractures of the long bones are usually treated by intramedullary rod placement. New approaches to enhance osteoblast activity while controlling osteoclast activity currently under investigation may prove effective in controlling lytic bone disease and myeloma progression.
Blake, Glen M; Siddique, Musib; Frost, Michelle L; Moore, Amelia E B; Fogelman, Ignac
Quantitative radionuclide imaging using (18)F-fluoride positron emission tomography (18F-PET) or (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scans provides a novel tool for studying regional and whole skeleton bone turnover that complements the information provided by biochemical markers. Radionuclide bone scans can be quantified by measuring either tracer uptake or, if blood sampling is performed, bone plasma clearance. This study examines whether these two methods provide equivalent information about bone turnover. We examined data from two clinical trials of the bone anabolic agent teriparatide. In Study 1 twenty osteoporotic women had 18F-PET scans of the lumbar spine at baseline and after 6 months treatment with teriparatide. Bone uptake in the lumbar spine was expressed as standardised uptake values (SUV) and blood samples taken to evaluate plasma clearance. In Study 2 ten women had (99m)Tc-MDP scans at baseline, 3 and 18 months after starting teriparatide. Blood samples were taken and whole skeleton plasma clearance and bone uptake calculated. In Study 1 spine plasma clearance increased by 23.8% after 6-months treatment (P=0.0003), whilst SUV increased by only 3.0% (P=0.84). In Study 2 whole skeleton plasma clearance increased by 37.1% after 18-months treatment (P=0.0002), whilst the 4-hour whole skeleton uptake increased by only 25.5% (P=0.0001). During treatment the 18F- plasma concentration decrease by 20% and (99m)Tc-MDP concentration by 13%, and these latter changes were sufficient to explain the differences between the uptake and plasma clearance results. Measurements of response to treatment using bone uptake and plasma clearance gave different results because the effects of teriparatide on bone resulted in a sufficiently increased demand for radionuclide tracer from the skeleton that the concentration in the circulation decreased. Similar effects may occur with other therapies that have a large enough effect on bone metabolism. In these
Hinton, Pamela S
Worldwide, 387 million adults live with type 2 diabetes (T2D) and an additional 205 million cases are projected by 2035. Because T2D has numerous complications, there is significant morbidity and mortality associated with the disease. Identification of early events in the pathogenesis of insulin resistance and T2D might lead to more effective treatments that would mitigate health and monetary costs. Here, we present our hypothesis that impaired bone blood flow is an early event in the pathogenesis of whole-body metabolic insulin resistance that ultimately leads to T2D. Two recent developments in different fields form the basis for this hypothesis. First, reduced vascular function has been identified as an early event in the development of T2D. In particular, before the onset of tissue or whole body metabolic insulin resistance, insulin-stimulated, endothelium-mediated skeletal muscle blood flow is impaired. Insulin resistance of the vascular endothelium reduces delivery of insulin and glucose to skeletal muscle, which leads to tissue and whole-body metabolic insulin resistance. Second is the paradigm-shifting discovery that the skeleton has an endocrine function that is essential for maintenance of whole-body glucose homeostasis. Specifically, in response to insulin signaling, osteoblasts secret osteocalcin, which stimulates pancreatic insulin production and enhances insulin sensitivity in skeletal muscle, adipose, and liver. Furthermore, the skeleton is not metabolically inert, but contributes to whole-body glucose utilization, consuming 20% that of skeletal muscle and 50% that of white adipose tissue. Without insulin signaling or without osteocalcin activity, experimental animals become hyperglycemic and insulin resistant. Currently, it is not known if insulin-stimulated, endothelium-mediated blood flow to bone plays a role in the development of whole body metabolic insulin resistance. We hypothesize that it is a key, early event. Microvascular dysfunction is a
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Eimar, Hazem; Alebrahim, Sharifa; Manickam, Garthiga; Al-Subaie, Ahmed; Abu-Nada, Lina; Murshed, Monzur; Tamimi, Faleh
The autonomous nervous system regulates bone mass through the sympathetic and parasympathetic arms. The sympathetic nervous system (SNS) favors bone loss whereas the parasympathetic nervous system (PNS) promotes bone mass accrual. Donepezil, a central-acting cholinergic agonist, has been shown to down-regulate SNS and up-regulate PNS signaling tones. Accordingly, we hypothesize that the use of donepezil could have beneficial effects in regulating bone mass. To test our hypothesis, two groups of healthy female mice were treated either with donepezil or saline. Differences in body metabolism and bone mass of the treated groups were compared. Body and visceral fat weights as well as serum leptin level were increased in donepezil-treated mice compared to control, suggesting that donepezil effects on SNS influenced metabolic activity. Donepezil-treated mice had better bone quality than controls due to a decrease in osteoclasts number. These results indicate that donepezil is able to affect whole body energy metabolism and favors bone mass in young female WT mice.
Nagano, Satoshi; Nakamura, Shunsuke; Shimada, Hirofumi; Yokouchi, Masahiro; Setoguchi, Takao; Ishidou, Yasuhiro; Sasaki, Hiromi; Komiya, Setsuro
The purpose of the present study was to analyze the effect of treatment of Paget's disease of bone (PDB) with bone scintigraphy using a computer-assisted diagnosis system (BONENAVI) that quantitatively evaluates bone metabolism. Seven patients with PDB (three male, four female; average age, 60 years; age range, 33–80 years) underwent bone scintigraphy and measurement of serum alkaline phosphatase (ALP), bone-specific ALP (BAP), serum cross-linked N-telopeptide (NTx) of type I collagen, urinary NTx, and deoxypyridinoline (DPD) before and after bisphosphonate treatment. Bone scan index (BSI), artificial neural network (ANN) value, and hotspot number (HSn) were calculated using BONENAVI software. Mean follow-up period was 22 months (range, 11–35 months). Among three BONENAVI parameters (ANN, BSI, and HSn), only BSI was significantly lower after bisphosphonate treatment as compared with before. All bone metabolic markers excluding DPD were significantly lower following bisphosphonate treatment than before. Bone formation markers (ALP and BAP) were significantly lower than bone resorption markers (U-NTx and S-NTx). The correlation of BONENAVI parameters with four bone metabolic markers was analyzed before and after bisphosphonate treatment. Before treatment, the majority of the four markers did not correlate with the BONENAVI parameters. In contrast, post-treatment ALP, BAP, and U-NTx were significantly correlated with BSI and HSn. To the best of our knowledge, this is the first study to evaluate the treatment of PDB by bone scintigraphy using a computer-assisted diagnosis system that quantitatively evaluates bone metabolism. The findings demonstrated that, using BONENAVI software, bone scintigraphy is able to quantitatively and spatially evaluate the bisphosphonate treatment effect, particularly in patients with polyostotic PDB. PMID:28105116
Nebot Valenzuela, Elena; Pietschmann, Peter
Paget's disease of bone (PDB) is a noninflammatory, metabolic, skeletal disorder characterized by localized excessive osteoclastic bone resorption that is followed by compensatory increased osteoblastic activity leading to unstructured, fibroblastic, and biomechanically unstable bone. As a result, there is deformity and enlargement of the bone with a defective and disorganized pattern. Here, we review the epidemiology, etiology, pathology, macrostructure, histology, and quantitative histomorphometry findings of PDB. Hyperosteoclastosis and poor definition of the boundary between cortical and medullary bone are the main histological findings in PDB. Additionally, Pagetic bone is also characterized by hypertrophy and alteration of trabecular parameters.
Wakino, Shu; Hasegawa, Kazuhiro; Itoh, Hiroshi
Sirtuin is a nicotinamide adenine dinucleotide-dependent deacetylase. One of its isoforms, Sirt1, is a key molecule in glucose, lipid, and energy metabolism. The renal protective effects of Sirt1 are found in various models of renal disorders with metabolic impairment, such as diabetic nephropathy. Protective effects include the maintenance of glomerular barrier function, anti-fibrosis effects, anti-oxidative stress effects, and regulation of mitochondria function and energy metabolism. Various target molecules subject to direct deacetylation or epigenetic gene regulation have been identified as effectors of the renal protective function of sirtuin. Recently, it was demonstrated that Sirt1 expression decreases in proximal tubules before albuminuria in a mouse model of diabetic nephropathy, and that albuminuria is suppressed in proximal tubule-specific mice overexpressing Sirt1. These findings suggest that decreased Sirt1 expression in proximal tubular cells causes abnormal nicotine metabolism and reduces the supply of nicotinamide mononucleotide from renal tubules to glomeruli. This further decreases expression of Sirt1 in glomerular podocytes and increases expression of a tight junction protein, claudin-1, which results in albuminuria. Activators of the sirtuin family of proteins, including resveratrol, may be important in the development of new therapeutic strategies for treating metabolic kidney diseases, including diabetic nephropathy.
Karasinska, Joanna M; Hayden, Michael R
The CNS is rich in cholesterol, which is essential for neuronal development and survival, synapse maturation, and optimal synaptic activity. Alterations in brain cholesterol homeostasis are linked to neurodegeneration. Studies have demonstrated that Huntington disease (HD), a progressive and fatal neurodegenerative disorder resulting from polyglutamine expansion in the huntingtin protein, is associated with changes in cellular cholesterol metabolism. Emerging evidence from human and animal studies indicates that attenuated brain sterol synthesis and accumulation of cholesterol in neuronal membranes represent two distinct mechanisms occurring in the presence of mutant huntingtin that influence neuronal survival. Increased knowledge of how changes in intraneuronal cholesterol metabolism influence the pathogenesis of HD will provide insights into the potential application of brain cholesterol regulation as a therapeutic strategy for this devastating disease.
Palmer, H. E.
Two techniques were studied for measuring changes in bone mass in rats. One technique measures the Ar-37 produced from calcium during neutron irradiation and the other measures the changes in the Na-22 content which has been incorporated within the rat bone. Both methods are performed in VIVO and cause no significant physiological damage. The Ar-37 leaves the body of a rat within an hour after being produced, and it can be quantitatively collected and measured with a precision of - or + 2% on the same rat. With appropriate irradiation conditions it appears that the absolute quantity of calcuim in any rat can be determined within - or + 3% regardless of animal size. The Na-22 when uniformly distributed in bone, can be used to monitor bone mineral turnover and this has been demonstrated in conditions of calcium deficiency during growth and also pregnancy coupled with calcium deficiency.
Smeyne, Michelle; Smeyne, Richard Jay
It has been established that oxidative stress, defined as the condition in which the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson disease. Glutathione is a ubiquitous thiol tripeptide that acts alone or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals, and peroxynitrites. In this review, we examine the synthesis, metabolism, and functional interactions of glutathione and discuss how these relate to the protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson disease.
Nuti, Niccolò; Ferrari, Marco
Summary A 59-year-old man suffering from Paget’s disease of bone and periodontal disease was examined in anticipation of bisphosphonate treatment. The previous therapy with clodronate resulted ineffective and markers of bone turnover were markedly elevated. Periodontal disease was correctly approached and treated with an excellent outcome. 5 mg zoledronate iv infusion induced a remarkable reduction of bone markers which persisted on time within the normal range. After zoledronate treatment no signs of osteonecrosis of the jaw (ONJ) were observed. A correct management of periodontal disease is mandatory in pagetic patients on bisphosphonate treatment. PMID:26604949
Haffner-Luntzer, M; Liedert, A; Ignatius, A
Mechanical stimuli are known to significantly influence bone metabolism and fracture healing. Various studies have demonstrated the involvement of complex molecular mechanotransduction pathways, such as the Wnt/beta-catenin, bone morphogenetic protein (BMP) and estrogen receptor signaling pathways in mechanotransduction. Mechanotransduction is influenced by aging and the comorbidities of the patient. Pharmacological modulation of signal transduction influences bone formation and the mechanosensitivity of skeletal tissue. The combination of pharmacological and biomechanical therapies may be useful for the treatment of fractures with impaired healing.
Kitamura, Kei-Ichiro; Andoh, Tadashi; Okesaku, Wakana; Tazaki, Yuya; Ogai, Kazuhiro; Sugitani, Kayo; Kobayashi, Isao; Suzuki, Nobuo; Chen, Wenxi; Ikegame, Mika; Hattori, Atsuhiko
Increased risk of fracture associated with type 2 diabetes has been a topic of recent concern. Fracture risk is related to a decrease in bone strength, which can be affected by bone metabolism and the quality of the bone. To investigate the cause of the increased fracture rate in patients with diabetes through analyses of bone metabolism and bone matrix protein properties, we used goldfish scales as a bone model for hyperglycemia. Using the scales of seven alloxan-treated and seven vehicle-treated control goldfish, we assessed bone metabolism by analyzing the activity of marker enzymes and mRNA expression of marker genes, and we measured the change in molecular weight of scale matrix proteins with SDS-PAGE. After only a 2-week exposure to hyperglycemia, the molecular weight of α- and β-fractions of bone matrix collagen proteins changed incrementally in the regenerating scales of hyperglycemic goldfish compared with those of euglycemic goldfish. In addition, the relative ratio of the γ-fraction significantly increased, and a δ-fraction appeared after adding glyceraldehyde-a candidate for the formation of advanced glycation end products in diabetes-to isolated type 1 collagen in vitro. The enzymatic activity and mRNA expression of osteoblast and osteoclast markers were not significantly different between hyperglycemic and euglycemic goldfish scales. These results indicate that hyperglycemia is likely to affect bone quality through glycation of matrix collagen from an early stage of hyperglycemia. Therefore, non-enzymatic glycation of collagen fibers in bone matrix may lead to the deterioration of bone quality from the onset of diabetes.
Derman, Orhan; Cinemre, Alphan; Kanbur, Nuray; Doğan, Muhsin; Kiliç, Mustafa; Karaduman, Erdem
Physical activity has been shown to have a positive effect on bone metabolism among adolescents. The objective of this study was to determine the effect of swimming on bone metabolism during adolescence. Swimming, as a non-weight-bearing sport, has been considered to be insignificant in the maintenance of bone mass. We studied whether swimming is associated with a higher peak bone mass. Forty swimmers (males aged 10-17 years and females aged 9-16 years) were studied. The control group consisted of the same number of adolescents aged between 10-16 years who did not swim; distribution of male and female gender was similar in the non-swimming control group compared to the swimming group. Adolescents were matched for age, gender and pubertal stages based on Tanner staging. All subjects underwent combined measurement of bone mineral metabolism by dual-energy X-ray absorptiometry of total body calcium content, and specific biochemical markers of turnover including osteocalcin, calcium, phosphorus and alkaline phosphatase. Bone age (determined by Greulich and Pyle's Radiographic Atlas of Skeletal Development of the Hand and Wrist), weight, height, ideal body weight, ideal body weight ratio, body mass index, Tanner classification (rated by examiner), diet, history of tobacco and alcohol exposure, exercise, socioeconomic status and history of chronic illness and medications were recorded to evaluate potential mediators that would affect bone metabolism. Tanner staging was used to assess puberty, and diet was evaluated based on reported consumption of milk, yogurt and cheese and cola/caffeine beverage consumption daily. There was significant difference in bone mineral content between adolescent male swimmers and the control group males. Consumption of cola beverages were significantly higher among the control group compared with the swimmer group. Ideal body weight ratio was significantly high among the female control group compared with female swimmers. Milk consumption was
Burnham, Jon M; Leonard, Mary B
Children with rheumatic disorders have multiple risk factors for impaired bone health, including delayed growth and development, malnutrition, decreased weight-bearing activity, inflammation, and glucocorticoid therapy. The impact of rheumatic disease during childhood may be immediate, resulting in fragility fractures, or delayed, because of suboptimal peak bone mass accrual. Recent years have seen increased interest in the effects of pediatric rheumatic disorders on bone mineralization, such as juvenile rheumatoid arthritis, systemic lupus erythematosus, and juvenile dermatomyositis. This review outlines the expected gains in bone size and mass during childhood and adolescence, and summarizes the advantages and disadvantages of available technologies for the assessment of skeletal growth and fragility in children. The varied threats to bone health in pediatric rheumatic disorders are reviewed, with emphasis on recent insights into the molecular mechanisms of inflammation-induced bone resorption. The literature assessing bone deficits and risk factors for impaired bone health in pediatric rheumatic disorders is reviewed, with consideration of the strengths and limitations of prior studies. Finally, future research directions are proposed.
El-Sayed, Eman; Ibrahim, Khadiga
Nutrients beyond calcium and vitamin D have a role on bone health, and in treatment and prevention of osteoporosis. Quality and quantity of dietary fat may have consequences on skeletal health. Diets with highly saturated fat content produce deleterious effects on bone mineralization in growing animals. Conversely, dietary n-3-long chain polyunsaturated fatty acids play an important role in bone metabolism and may help in prevention and treatment of bone disease. Some reports suggest a correlation between the dietary ratio of n-6 and n-3 polyunsaturated fatty acids and bone formation. Specific dietary fatty acids were found to modulate prostanoid synthesis in bone tissue and improve bone formation in both animal and clinical trials. The skeletal benefits of dietary isoprenoids are extremely documented. Higher isoprenoids intake may relate to higher bone mineral density. Dietary supplements containing fish oil, individual polyunsaturated fatty acids, and isoprenoids could be used as adjuvant with bone medications in osteoportic conditions but their doses must be considered to avoid detrimental effect of over dosages.
Pater, Agnieszka; Odrowąż-Sypniewska, Grażyna
Diabetes mellitus type 1 is one of the most common chronic diseases in children and adolescents. The incidence of diabetes mellitus type 1 is increasing rapidly worldwide. Recently, the largest rate of increase is observed in children aged 0-4 years. Chronic hyperglycemia leads to microvascular and macrovascular complications including retinopathy, nephropathy, neuropathy and cardiomyopathy. Pathological changes occur in the bone structure. The lack of diagnosis and treatment of alterations of the bone tIssue metabolism may lead to osteoporosis, which is characterized by much reduced bone mineral density and changes in the microarchitecture of the bone tIssue, which in consequence results in increased susceptibility to fractures. Diabetes mellitus type 1 most often starts before achieving peak bone mass, which constitutes a point of reference for predicting risk of fractures in a later period of life. Mechanisms responsible for loss of the bone tIssue in diabetes of type 1 still remain unexplained. Many research findings indicate the anabolic role of insulin and insulin-like growth factors, mainly IGF-1. The aim of this manuscript is to review recent papers about alterations of bone metabolism in children and adolescents with diabetes mellitus type 1.
Protein is the major structural constituent of bone (50% by volume). But it is also a major source of metabolic acid, especially protein from animal sources because it contains sulfur amino acids that generate sulfuric acid. Increased potential renal acid load has been closely associated with increa...
Raska, O; Bernásková, K; Raska, I
This minireview briefly surveys the complexity of regulations governing the bone metabolism. The impact of clinical studies devoted to osteoporosis is briefly summarized and the emphasis is put on the significance of experimental mouse models based on an extensive use of genetically modified animals. Despite possible arising drawbacks, the studies in mice are of prime importance for expanding our knowledge on bone metabolism. With respect to human physiology and medicine, one should be always aware of possible limitations as the experimental results may not be, or may be only to some extent, transposed to humans. If applicable to humans, results obtained in mice provide new clues for assessing unforeseen treatment strategies for patients. A recent publication representing in our opinion the important breakthrough in the field of bone metabolism in mice is commented in detail. It provides an evidence that skeleton is endocrine organ that affects energy metabolism and osteocalcin, a protein specifically synthesized and secreted by osteoblasts, is a hormone involved. If confirmed by other groups and applicable to humans, this study provides the awaited connection of long duration between bone disorders on one hand and obesity and diabetes on the other.
Donahue, S.W.; Vaughan, M.R.; Demers, L.M.; Donahue, H.J.
Disuse osteopenia was studied in hibernating black bears (Ursus americanus) using serum markers of bone metabolism. Blood samples were collected from male and female, wild black bears during winter denning and active summer periods. Radioimmunoassays were done to determine serum concentrations of cortisol, the carboxy-terminal cross-linked telopeptide, and the carboxy-terminal propeptide of Type I procollagen, which are markers of hone resorption and formation, respectively. The bone resorption marker was significantly higher during winter hibernation than it was in the active summer months, but the bone formation marker was unchanged, suggesting an imbalance in bone remodeling and a net bone loss during disuse. Serum cortisol was significantly correlated with the bone resorption marker, but not with the bone formation marker. The bone formation marker was four- to fivefold higher in an adolescent and a 17-year-old bear early in the remobilization period compared with the later summer months. These findings raise the possibility that hibernating black bears may minimize bone loss during disuse by maintaining osteoblastic function and have a more efficient compensatory mechanism for recovering immobilization-induced bone loss than that of humans or other animals.
... For more information about Paget’s disease , contact: NIH Osteoporosis and Related Bone Diseases ~ National Resource Center Website: ... drug products. NIH Pub. No. 15-7919 NIH Osteoporosis and Related Bone Diseases ~ National Resource Center 2 ...
Ryu, Seong-Jun; Ryu, Dal-Sung; Kim, Jong-Yeol; Park, Jeong-Yoon; Kim, Kyung-Hyun; Chin, Dong-Kyu; Kim, Keun-Su; Cho, Yong-Eun
Purpose To determine the window of time during which osteoporosis affects the management of spinal surgery and the mechanism of bone metabolism changes in males with osteoporosis by examining changes in bone metabolism in young castrated male rats. Materials and Methods A total of 30 Sprague-Dawley rats were randomly allocated into two study groups. Group 1 (control) received a sham surgery and Group 2 received bilateral orchiectomy to change bone mineral density (BMD). Serum osteocalcin, alkaline phosphatase (ALP), and collagen type 1 cross-linked C-telopeptide (CTX) were analyzed at postoperative date (POD) 8, 10, and 12 weeks. BMDs were measured using micro computed tomography scans. Results Femoral and lumbar BMDs were decreased in the orchiectomy groups. BMDs in the sham and orchiectomy groups showed statistically differences at POD 8, 10, and 12 weeks for the femur (p=0.032, 0.008, 0.008) and lumbar spine (p=0.151, 0.008, 0.008, respectively). Serum osteocalcin, ALP, and CTX decreased gradually; however, N-terminal type 1 procollagen (P1NP) showed a slight increase yet no significant change. Conclusion In young castrated male rats, a significant decrease in BMD was observed after orchiectomy due to the mixture of two detrimental factors. Young castrated male rats did not reach peak BMD. Increased bone turnover causes bone resorption to exceed bone formation. This study may contribute to the creation of a valuable model for studies of male osteoporosis and the spinal surgery field. PMID:27593866
Metz, Lionel N; Wustrack, Rosanna; Lovell, Alberto F; Sawyer, Aenor J
Sports and weight-bearing activities can have a positive effect on bone health in the growing, mature, or aging athlete. However, certain athletic activities and training regimens may place the athlete at increased risk for stress fractures in the spine. In addition, some athletes have an underlying susceptibility to fracture due to either systemic or focal abnormalities. It is important to identify and treat these athletes in order to prevent stress fractures and reduce the risk of osteoporosis in late adulthood. Therefore, the pre-participation physical examination offers a unique opportunity to screen athletes for metabolic bone disease through the history and physical examination. Positive findings warrant a thorough workup including a metabolic bone laboratory panel, and possibly a DEXA scan, which includes a lateral spine view.
Menéndez-Bueyes, Luis R; Soler Fernández, María Del Carmen
Paget's disease of bone is the second most common bone disease after osteoporosis. It is characterized by focal regions of highly exaggerated bone remodeling, with abnormalities in all phases of the remodeling process. This study aims to investigate the hypothesis of a possible British origin of Paget's disease of bone by studying the worldwide geographic distribution of cases identified in ancient skeletons excavated from archaeological sites. The methodology consists in reviewing cases of Paget's disease of bone described in the literature.
Yang, Lei; Webster, Thomas J
Rapid developments at the intersection of nanotechnology and controlled drug delivery have triggered exceptional growth in treating various bone diseases. As a result, over the past decade, nanotechnology has contributed tremendously to controlling drug delivery for treating various bone diseases, and in many cases, has led to increased bone regeneration. In this review paper, the recent experimental progress towards using nanotechnology to treat bone-specific diseases is reviewed. Novel applications of different types of nanomaterials (from nanoparticles to 3D nanostructured scaffolds) for treating bone diseases are summarized. In addition, fundamental principles for utilizing nanomaterials to create better drug delivery systems, especially for treating bone diseases and regenerating bone, are emphasized.
Hough, F S
A critical review of the literature leads to the conclusion that alterations of bone and mineral metabolism occur both in diabetic patients and in animals with experimentally induced insulin deficiency syndromes. The coexistence of juvenile insulin-dependent diabetes mellitus (type 1) and radiological evidence of decreased bone mass (osteopenia) appears to be firmly established. Available data support the view that these patients have an increased propensity to skeletal fracture. Adult-onset, non-insulin-dependent diabetic populations, more heterogeneous as regards the type of diabetes, the therapy and the presence of complications or coexistent disease, are characterised by subpopulations with either a decreased, a normal or an increased bone mass. The pathogenesis of diabetic osteopenia is multifactorial. Data obtained from studies employing appropriate animal models of chronic insulin deficiency indicate that various metabolic and hormonal abnormalities may be involved.
Diabetes is associated with increased risk of osteoporosis. Gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide(GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones released upon meal ingestion, and GIP and/or GLP-1 signaling is decreased in diabetic state. We have demonstrated that both GIP receptor knockout mice and GLP-1 receptor knockout mice have osteoporosis. GIP has anabolic effects on bone mainly by stimulating osteoblastic bone formation through intermittent elevation of intracellular cAMP levels. On the other hand, GLP-1 is suggested to regulate bone resorption indirectly through the thyroid C cell. Our studies show that incretins play important roles in bone metabolism by distinct mechanisms.
Ismaili-Alaoui, Nadia; Vuong, Valerie; Marcu-Marin, M; Sergent-Alaoui, Aline; Chevallier, Bertrand; de Labriolle-Vaylet, Claire
Cat-scratch disease is a bacterial infection caused by Bartonella henselae. Bone involvement is rare. We describe the case of a 7-year-old boy with a systemic form of the disease. He presented with a 15-day history of fever, altered general condition, weight loss and cough, associated with back pain, and right-sided coxalgia. Bone scintigraphy with Tc-99m hydroxymethylene diphosphonate showed spinal involvement, the iliac crest, the right ankle, and the right first metatarsal. Magnetic resonance imaging confirmed these locations. He was positive for anti-Bartonella henselae. The fever regressed before treatment with rifampicin began, and he made a full recovery.
Zhang, Qian; Chen, Bin; Yan, Fuhua; Guo, Jianbin; Zhu, Xiaofeng; Ma, Shouzhi; Yang, Wenrong
Periodontitis and other bone loss diseases, decreasing bone volume and strength, have a significant impact on millions of people with the risk of tooth loss and bone fracture. The integrity and strength of bone are maintained through the balance between bone resorption and bone formation by osteoclasts and osteoblasts, respectively, so the loss of bone results from the disruption of such balance due to increased resorption or/and decreased formation of bone. The goal of therapies for diseases of bone loss is to reduce bone loss, improve bone formation, and then keep healthy bone density. Current therapies have mostly relied on long-term medication, exercise, anti-inflammatory therapies, and changing of the life style. However there are some limitations for some patients in the effective treatments for bone loss diseases because of the complexity of bone loss. Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine, and recent studies have indicated that IL-10 can contribute to the maintenance of bone mass through inhibition of osteoclastic bone resorption and regulation of osteoblastic bone formation. This paper will provide a brief overview of the role of IL-10 in bone loss diseases and discuss the possibility of IL-10 adoption in therapy of bone loss diseases therapy.
Ankrom, M A; Shapiro, J R
Paget's disease of bone is important in geriatric populations because it is the second most common bone disorder after osteoporosis. In older people, it may be responsible for chronic back pain and joint pain, skeletal deformities, hearing loss, and cranial nerve compression. Paget's disease can reduce both function and mobility in the older people. In addition to newer tests for assessing the activity of Paget's disease, effective therapy is available in the form of salmon calcitonin for nasal administration and new third generation bisphosphonates. Frequently, treatment can reverse the course of the disease. For these reasons, it is feasible for the physician to adopt an aggressive approach to diagnosis and treatment. The objective should be to relieve pain, improve mobility, and forestall debilitating complications. This review will focus on the manifestations and clinical management of Paget's disease. Two cases are presented that illustrate common management problems in older patients.
Rendina, Elizabeth; Hembree, Kelsey D; Davis, McKale R; Marlow, Denver; Clarke, Stephen L; Halloran, Bernard P; Lucas, Edralin A; Smith, Brenda J
Interest in dried plum has increased over the past decade due to its promise in restoring bone and preventing bone loss in animal models of osteoporosis. This study compared the effects of dried plum on bone to other dried fruits and further explored the potential mechanisms of action through which dried plum may exert its osteoprotective effects. Adult osteopenic ovariectomized (OVX) C57BL/6 mice were fed either a control diet or a diet supplemented with 25% (w/w) dried plum, apple, apricot, grape or mango for 8 weeks. Whole body and spine bone mineral density improved in mice consuming the dried plum, apricot and grape diets compared to the OVX control mice, but dried plum was the only fruit to have an anabolic effect on trabecular bone in the vertebra and prevent bone loss in the tibia. Restoration of biomechanical properties occurred in conjunction with the changes in trabecular bone in the spine. Compared to other dried fruits in this study, dried plum was unique in its ability to down-regulate osteoclast differentiation coincident with up-regulating osteoblast and glutathione (GPx) activity. These alterations in bone metabolism and antioxidant status compared to other dried fruits provide insight into dried plum's unique effects on bone.
Holick, M F
As humans venture into space to colonize the moon and travel to distant planets in the 21st century, they will be confronted with a bone disease that could potentially limit their space exploration activities or put them at risk for fracture when they return to earth. It is now recognized that an unloading of the skeleton, either due to strict bed rest or in zero gravity, leads on average to a 1%-2% reduction in bone mineral density at selected skeletal sites each month. The mechanism by which unloading of the skeleton results in rapid mobilization of calcium stores from the skeleton is not fully understood, but it is thought to be related to down regulation in PTH and 1,25-dihydroxyvitamin D3 production. Bone modeling and mineralization in chick embryos is not affected by microgravity, suggesting that bone cells adapt and ultimately become addicted to gravity in order to maintain a structurally sound skeleton. Strategies need to be developed to decrease microgravity-induced bone resorption by either mimicking gravity's effect on bone metabolism, or enhancing physically or pharmacologically bone formation in order to preserve astronauts' bone health.
Holick, M. F.
As humans venture into space to colonize the moon and travel to distant planets in the 21st century, they will be confronted with a bone disease that could potentially limit their space exploration activities or put them at risk for fracture when they return to earth. It is now recognized that an unloading of the skeleton, either due to strict bed rest or in zero gravity, leads on average to a 1%-2% reduction in bone mineral density at selected skeletal sites each month. The mechanism by which unloading of the skeleton results in rapid mobilization of calcium stores from the skeleton is not fully understood, but it is thought to be related to down regulation in PTH and 1,25-dihydroxyvitamin D3 production. Bone modeling and mineralization in chick embryos is not affected by microgravity, suggesting that bone cells adapt and ultimately become addicted to gravity in order to maintain a structurally sound skeleton. Strategies need to be developed to decrease microgravity-induced bone resorption by either mimicking gravity's effect on bone metabolism, or enhancing physically or pharmacologically bone formation in order to preserve astronauts' bone health.
The efficacy of biologics targeting inflammatory cytokines such as TNF and IL-6 for bone and joint diseases has been emerging. Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis and bone damage. By the use of TNF-inhibitors, clinical remission, structural remission and functional remission have become possible during the treatment of RA. Especially, the progress of joint and bone destruction is completely suppressed by TNF-inhibitors in the vast majority of RA patients. On the other hand, anti-RANKL antibody inhibits joint destruction as well as systemic osteoporosis, though no effects on synovitis of RA. Thus, differential efficacy of different therapies in bone destruction and osteoporosis would warrant further study to clarify the mechanisms of bone and joints diseases.
Resende, Aline Lázara; dos Reis, Luciene Machado; Dias, Cristiane Bitencourt; Custódio, Melani Ribeiro; Jorgetti, Vanda; Woronik, Viktoria
Introduction Bone loss in Lupus Nephritis (LN) patients is common and multifactorial. The aim of this study was to evaluate the bone status of newly diagnosed LN patients and their correlation with inflammatory factors involved in LN physiopathology. Methods We studied 15 pre-menopausal patients with ≤2 months of diagnosed SLE and LN. Patients with prior kidney or bone disease were excluded. In addition to biochemical evaluation (including 25-hydroxyvitamin D3 [25(OH)D] and Monocyte Chemotactic Protein (MCP1) dosage), we performed bone biopsies followed by osteoblast culture, histomorphometric and immunohistochemistry analysis. Results LN patients presented a mean age of 29.5±10 years, a proteinuria of 4.7±2.9 g/day and an estimated glomerular filtration rate (GFR) of 37(31–87) ml/min/1,73 m2. They were on glucocorticoid therapy for 34±12 days. All patients presented vitamin D insufficiency (9.9±4.4 ng/ml, range 4–20). Urinary MCP1 correlated negatively with 25(OH)D (r = −0.53, p = 0.003) and positively with serum deoxypyridinoline (r = 0.53, p = 0.004). Osteoblasts isolated from LN bone biopsies presented a significantly higher expression of MCP-1 when compared to controls (32.0.±9.1 vs. 22.9±5.3 mean fluorescence intensities, p = 0.01). LN patients presented a significantly reduced osteoid volume, osteoid thickness, osteoid surface, mineralization surface and bone formation rate, associated with an increased eroded surface and osteoclast surface. Patient’s bone specimens demonstrated a reduced immunostaining for osteoprotegerin (0.61±0.82 vs. 1.08±0.50%, p = 0.003), and an increased expression of Receptor Activator of NF-κB ligand (RANKL) (1.76±0.92 vs. 0.41±0.28%, p<0.001) when compared to controls. Discussion Newly diagnosed LN patients presented a significant disturbance in bone metabolism, characterized by an impaired bone formation and mineralization, associated with an increase in resorption parameters
Alnot, J-Y; Rossarie, R; Welby, F
Syringomyelia can occur in patients presenting bone and joint diseases of various origins. When joint destruction of the shoulder or elbow produces little pain, a neurological cause might be involved. In this case, the disease history can be of utmost importance because an initial diagnosis of rheumatoid polyarthritis, polyosteoarthritis, or destructive joint disease can be misleading before the syringomyelic origin of the bone and joint disease becomes patent. We report two cases illustrating this association and the diagnostic pitfalls which can delay recognition of the syringomyelia. Better awareness of the prevalence of this condition should be helpful in establishing the diagnosis and in selecting patients who can benefit from neurosurgical treatment. The two cases presented here suggest that syringomyelia could be underdiagnosed in certain patients with an initially atypical presentation. A review of the current knowledge of syringomyelia suggests that arthroplasty is generally not advisable for destroyed dislocated syringomyelic joints.
Michou, Laëtitia; Brown, Jacques P
Paget’s disease of bone (PDB) is a progressive monostotic or polyostotic metabolic bone disease characterized by focal abnormal bone remodeling, with increased bone resorption and excessive, disorganized, new bone formation. PDB rarely occurs before middle age, and it is the second most frequent metabolic bone disorder after osteoporosis, affecting up to 3% of adults over 55 years of age. One of the most striking and intriguing clinical features is the focal nature of the disorder, in that once the disease is established within a bone, there is only local spread within that bone and no systemic dissemination. Despite many years of intense research, the etiology of PDB has still to be conclusively determined. Based on a detailed review of genetic and viral factors incriminated in PDB, we propose a unifying hypothesis from which we can suggest emerging strategies and therapies. PDB results in weakened bone strength and abnormal bone architecture, leading to pain, deformity or, depending on the bone involved, fracture in the affected bone. The diagnostic assessment includes serum total alkaline phosphatase, total body bone scintigraphy, skull and enlarged view pelvis x-rays, and if needed, additional x-rays. The ideal therapeutic option would eliminate bone pain, normalize serum total alkaline phosphatase with prolonged remission, heal radiographic osteolytic lesions, restore normal lamellar bone, and prevent recurrence and complications. With the development of increasingly potent bisphosphonates, culminating in the introduction of a single intravenous infusion of zoledronic acid 5 mg, these goals of treatment are close to being achieved, together with long-term remission in almost all patients. Based on the recent pathophysiological findings, emerging strategies and therapies are reviewed: ie, pulse treatment with zoledronic acid; denosumab, a fully human monoclonal antibody directed against RANK ligand; tocilizumab, an interleukin-6 receptor inhibitor; odanacatib
Youn, Min-Young; Inoue, Kazuki; Takada, Ichiro; Kouzmenko, Alexander; Kato, Shigeaki
During the last decade, our view on the skeleton as a mere solid physical support structure has been transformed, as bone emerged as a dynamic, constantly remodeling tissue with systemic regulatory functions including those of an endocrine organ. Reflecting this remarkable functional complexity, distinct classes of humoral and intracellular regulatory factors have been shown to control vital processes in the bone. Among these regulators, nuclear receptors (NRs) play fundamental roles in bone development, growth, and maintenance. NRs are DNA-binding transcription factors that act as intracellular transducers of the respective ligand signaling pathways through modulation of expression of specific sets of cognate target genes. Aberrant NR signaling caused by receptor or ligand deficiency may profoundly affect bone health and compromise skeletal functions. Ligand dependency of NR action underlies a major strategy of therapeutic intervention to correct aberrant NR signaling, and significant efforts have been made to design novel synthetic NR ligands with enhanced beneficial properties and reduced potential negative side effects. As an example, estrogen deficiency causes bone loss and leads to development of osteoporosis, the most prevalent skeletal disorder in postmenopausal women. Since administration of natural estrogens for the treatment of osteoporosis often associates with undesirable side effects, several synthetic estrogen receptor ligands have been developed with higher therapeutic efficacy and specificity. This review presents current progress in our understanding of the roles of various nuclear receptor-mediated signaling pathways in bone physiology and disease, and in development of advanced NR ligands for treatment of common skeletal disorders. PMID:23589826
Oz, S. Gul; Guven, Gulay Sain; Kilicarslan, Alpaslan; Calik, Nursel; Beyazit, Yavuz; Sozen, Tumay
The objectives of this study were to determine whether type-2 diabetes was associated with a higher bone mineral density (BMD) in men and women and to evaluate the differences in mineral metabolism between diabetic and normal subjects by using biochemical bone turnover markers. In this study, 52 patients (37 females/15 males) aged 41-64 with type-2 diabetes mellitus and 48 nondiabetic control subjects (34 females/14 males) were evaluated. In men, BMD was significantly higher in diabetics at the forearm (p <0.05), whereas in women tended to be higher at the hip (p=0.002). Serum osteocalcin (p<0.0001), bone alkaline phosphatase (BAP) (p<0.05) and carboxyterminal telopeptide (CTx) (p<0.05) were higher in the control group than in diabetics. In men, serum osteocalcin (p<0.05) and CTx (p<0.005) and, in women, serum osteocalcin (p<0.0001) and BAP (p<0.05) were lower in diabetic subjects. In conclusion, our findings suggest that although bone formation is decreased in type-2 diabetes, diabetic patients are not susceptible to bone resorption. This low bone turnover can slow the rate of bone loss and cause a higher bone density than expected for their age. PMID:17052049
Significant bone loss is one of the most serious medical concerns during long-duration space flight. This article provides the results of bone loss and bone metabolism obtained from American and Russian long-duration human space flight. Bone loss in astronauts before and after long-duration space flight was evaluated by dual energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). DXA revealed bone loss at rates of 0.9%/month in the lumbar spine and 1.5%/month in the femoral neck. QCT revealed cortical, trabecular and integral BMD in the femoral neck at rates of 0.5%/month, 2.5%/month, and 1.5%/month, respectively. Biochemical markers of bone resorption increased during space flight and several months after landing. Bone formation marker was unchanged during space flight, but since 3 weeks after landing it was significantly higher than before flight. A calcium kinetics study confirmed that bone resorption increased, and intestinal calcium absorption decreased during space flight.
Metabolic disorders are disturbances to one or more of the metabolic processes in dairy cattle. Dysfunction of any of these processes is associated with the manifestation of metabolic diseases or disorders. In this review, data recording, incidences, genetic parameters, predictors and status of gene...
Metabolic bone disease is a frequent co-morbidity in newly diagnosed adults with celiac disease (CD), an autoimmune disorder triggered by the ingestion of dietary gluten. This systematic review of studies looked at the efficacy of the gluten-free diet, physical activity, nutrient supplementation, and bisphosphonates for low bone density treatment. Case control and cohort designs were identified from PubMed and other academic databases (from 1996 to 2015) that observed newly diagnosed adults with CD for at least one year after diet treatment using the dual-energy x-ray absorptiometry (DXA) scan. Only 20 out of 207 studies met the inclusion criteria. Methodological quality was assessed using the Strengthening of the Reporting of Observational Studies in Epidemiology (STROBE) statement checklist. Gluten-free diet adherence resulted in partial recovery of bone density by one year in all studies, and full recovery by the fifth year. No treatment differences were observed between the gluten-free diet alone and diet plus bisphosphonates in one study. For malnourished patients, supplementation with vitamin D and calcium resulted in significant improvement. Evidence for the impact of physical activity on bone density was limited. Therapeutic strategies aimed at modifying lifestyle factors throughout the lifespan should be studied.
Over the last 15 years several biological markers of bone turnover have been developed with increased specificity and sensitivity. In osteoporosis clinical studies, the IOF and IFCC organizations have recently recommended the measurements of serum type I collagen N-propeptide (PINP) and the crosslinked C-terminal telopeptide (serum CTX) as markers of bone formation and bone resorption, respectively. However these markers have some limitations including a lack of specificity for bone tissue, their inability to reflect osteocyte activity or periosteal apposition. In addition they do not allow the investigation of bone tissue quality an important determinant of skeletal fragility. To address these limitations, new developments in markers of bone metabolism have been recently achieved. These include assays for periostin, a matricellular protein preferentially localized in the periosteal tissue, sphingosine 1-phosphate, a lipid mediator which acts mainly on osteoclastogenesis and the osteocyte factors such as sclerostin and FGF-23. Recent studies have shown an association between the circulating levels of these biological markers and fracture risk in postmenopausal women or elderly men, although data require confirmation in additional prospective studies. Finally, recent studies suggest that the measurements of circulating microRNAs may represent a novel class of early biological markers in osteoporosis. It is foreseen that with the use of genomics and proteomics, new markers will be developed to ultimately improve the management of patients with osteoporosis.
Cotter, David G.; Schugar, Rebecca C.
Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states. PMID:23396451
Eddington, Helen; Kalra, Philip A
Chronic kidney disease-mineral bone disorder (CKD-MBD) is a multifaceted definition used to help describe the systemic derangement of mineral bone metabolism in renal disease. This was previously referred to, rather simplistically, as 'renal osteodystrophy' or 'renal bone disease'. In this review, we will try to show the evidence relating these factors to cardiovascular morbidity and mortality and give some evidence as to the mechanisms for this. The treatments used for this condition are also integral to the increased cardiovascular mortality seen in renal patients and a summary of these effects will also be covered.
The K vitamins, a group of napthoquinones, are required for the carboxylation of a limited number of proteins including the bone matrix protein osteocalcin. Vitamin K1 (phylloquinone) and vitamin K2 (menaquinones), differ regarding food source (green vegetables and fermented products, respectively), bioavailability and intermediate metabolism. Epidemiological studies provide evidence for an association between a low vitamin K intake and an enhanced osteoporotic fracture risk. Doses of vitamin K1 up to 15 times the current recommended dietary allowance have successfully been used to reduce the percentage of undercarboxylated osteocalcin in the circulation. Studies demonstrating clear beneficial effects on bone health, however, are still lacking. In contrast, therapy with very high pharmacological doses of the vitamin K2 menatetrenone has impressively been used to prevent further bone mineral loss and fracture risk in osteoporotic patients.
Larmonier, C. B.; McFadden, R.-M. T.; Hill, F. M.; Schreiner, R.; Ramalingam, R.; Besselsen, D. G.; Ghishan, F. K.
Decreased bone mineral density (BMD) represents an extraintestinal complication of inflammatory bowel disease (IBD). Vitamin D3 has been considered a viable adjunctive therapy in IBD. However, vitamin D3 plays a pleiotropic role in bone modeling and regulates the bone formation-resorption balance, depending on the physiological environment, and supplementation during active IBD may have unintended consequences. We evaluated the effects of vitamin D3 supplementation during the active phase of disease on colonic inflammation, BMD, and bone metabolism in an adoptive IL-10−/− CD4+ T cell transfer model of chronic colitis. High-dose vitamin D3 supplementation for 12 days during established disease had negligible effects on mucosal inflammation. Plasma vitamin D3 metabolites correlated with diet, but not disease, status. Colitis significantly reduced BMD. High-dose vitamin D3 supplementation did not affect cortical bone but led to a further deterioration of trabecular bone morphology. In mice fed a high vitamin D3 diet, colitis more severely impacted bone formation markers (osteocalcin and bone alkaline phosphatase) and increased bone resorption markers, ratio of receptor activator of NF-κB ligand to osteoprotegrin transcript, plasma osteoprotegrin level, and the osteoclast activation marker tartrate-resistant acid phosphatase (ACp5). Bone vitamin D receptor expression was increased in mice with chronic colitis, especially in the high vitamin D3 group. Our data suggest that vitamin D3, at a dose that does not improve inflammation, has no beneficial effects on bone metabolism and density during active colitis or may adversely affect BMD and bone turnover. These observations should be taken into consideration in the planning of further clinical studies with high-dose vitamin D3 supplementation in patients with active IBD. PMID:23639807
Geng, Wei; Wu, Gaoyi; Huang, Fei; Zhu, Yong; Nie, Jia; He, Yuhong; Chen, Lei
Background: The purpose of this study was to explore the effect of experimental sleep deprivation (SD) on the temporomandibular joint (TMJ) of rats and the possible mechanism related to abnormal bone metabolism. Material and methods: SD was induced by a modified multiple platform method and assessed by serum adrenocorticotropic hormone (ACTH) level. TMJs were detached and stained with hematoxylin and eosin (H&E). Expression of interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) was evaluated by quantitative reverse transcription polymerase chain reaction, H&E staining, immunohistochemical staining and enzyme linked immunosorbent assay. Results: Compared with controls, SD significantly increased serum ACTH, indicating that the SD model was successful. In the SD group, H&E staining revealed greater vessel hyperplasia in the synovial membrane and thicker hypertrophic layers in condylar cartilages. Compared with controls, RNA and protein expression of the inflammatory factors IL-1β and TNF-α and the bone metabolism-related factor RANKL increased in condylar cartilage in the SD group, whereas OPG and the OPG/RANKL ratio decreased. Immunohistochemical staining revealed that OPG/RANKL immunopositive cells were mainly located in hypertrophic layers. Conclusions: These results suggest that sleep deprivation might play an important role in the occurrence and development of temporomandibular disorders, which may occur through abnormal secretion of inflammatory and bone metabolism-related factors. PMID:25785010
Tigas, Stelios; Tsatsoulis, Agathocles
Extraintestinal manifestations from nearly every organ system are common in inflammatory bowel disease (IBD). This review article describes the epidemiology, pathogenesis, diagnosis and management of the main endocrine and metabolic manifestations in IBD, including metabolic bone disease, growth retardation, hypogonadism, pubertal delay, lipid abnormalities and insulin resistance. These clinical problems are commonly interrelated and they share a common basis, influenced by disease-related inflammation and nutritional status. In addition to nutritional support, every effort should be made to achieve and maintain disease remission, thus correcting the underlying chronic inflammation. The criteria for screening and diagnosing osteoporosis are described and treatment options are discussed (lifestyle advice, vitamin D and calcium supplementation, use of bisphosphonates or other specific antiosteoporotic agents, correction of hypogonadism). Chronic glucocorticoid therapy may affect growth as well as predispose to osteoporosis. The diagnosis and management of growth failure, pubertal delay and hypogonadism in IBD are discussed.
A new organ culture system for the study of bone formation has been developed using medullary bone, a non-structural, metabolically active form of bone which is found in the marrow cavities of egg-laying birds. In the presence of fetal calf serum, bone explants were viable in culture by morphological criteria, and retained large numbers of osteoblasts and osteoclasts. Incorporation of /sup 3/H-proline into collagenase-digestible protein (CDP) and non-collagen protein (NCP) was determined using purified bacterial collagenase. Collagen accounted for over 10% of the total protein labeled. The calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), caused a dose-dependent inhibition of /sup 3/H-proline incorporation into CDP. The effective dose range of 1,25(OH)2D3 was 0.1 nM to 100 nM, while that of PTH was 1.0 nM to 100 nM. The effect of both hormones was specific for collagen, since /sup 3/H-proline incorporation into NCP was unaffected. Hydroxyproline analysis of bone explants and culture medium revealed that both hormones decreased the total hydroxyroline content of the cultures, suggesting that the inhibition of /sup 3/H-proline incorporation into DCP is due to inhibition of collagen synthesis.
Krishnan, Abhaya; Muthusami, Sridhar
According to the World Health Organization (WHO) polycystic ovary syndrome (PCOS) occurs in 4-8% of women worldwide. The prevalence of PCOS in Indian adolescents is 12.2% according to the Indian Council of Medical Research (ICMR). The National Institute of Health has documented that it affects approximately 5 million women of reproductive age in the United States. Hormonal imbalance is the characteristic of many women with polycystic ovarian syndrome (PCOS). The influence of various endocrine changes in PCOS women and their relevance to bone remains to be documented. Hormones, which include gonadotrophin-releasing hormone (GnRH), insulin, the leutinizing/follicle-stimulating hormone (LH/FSH) ratio, androgens, estrogens, growth hormones (GH), cortisol, parathyroid hormone (PTH) and calcitonin are disturbed in PCOS women. These hormones influence bone metabolism in human subjects directly as well as indirectly. The imbalance in these hormones results in increased prevalence of osteoporosis in PCOS women. Limited evidence suggests that the drugs taken during the treatment of PCOS increase the risk of bone fracture in PCOS patients through endocrine disruption. This review is aimed at the identification of the relationship between bone mineral density and hormonal changes in PCOS subjects and identifies potential areas to study bone-related disorders in PCOS women.
Zwart, S. R.; Davis-Street, J. E.; Paddon-Jones, D.; Ferrando, A. A.; Wolfe, R. R.; Smith, S. M.
High-protein and acidogenic diets induce hypercalciuria. Foods or supplements with excess sulfur-containing amino acids increase endogenous sulfuric acid production and therefore have the potential to increase calcium excretion and alter bone metabolism. In this study, effects of an amino acid/carbohydrate supplement on bone resorption were examined during bed rest. Thirteen subjects were divided at random into two groups: a control group (Con, n = 6) and an amino acid-supplemented group (AA, n = 7) who consumed an extra 49.5 g essential amino acids and 90 g carbohydrate per day for 28 days. Urine was collected for n-telopeptide (NTX), deoxypyridinoline (DPD), calcium, and pH determinations. Bone mineral content was determined and potential renal acid load was calculated. Bone-specific alkaline phosphatase was measured in serum samples collected on day 1 (immediately before bed rest) and on day 28. Potential renal acid load was higher in the AA group than in the Con group during bed rest (P < 0.05). For all subjects, during bed rest urinary NTX and DPD concentrations were greater than pre-bed rest levels (P < 0.05). Urinary NTX and DPD tended to be higher in the AA group (P = 0.073 and P = 0.056, respectively). During bed rest, urinary calcium was greater than baseline levels (P < 0.05) in the AA group but not the Con group. Total bone mineral content was lower after bed rest than before bed rest in the AA group but not the Con group (P < 0.05). During bed rest, urinary pH decreased (P < 0.05), and it was lower in the AA group than the Con group. These data suggest that bone resorption increased, without changes in bone formation, in the AA group.
González-Rodríguez, Juan David; Luis-Yanes, María Isabel; Inglés-Torres, Esther; Arango-Sancho, Pedro; Cabrera-Sevilla, José Eugenio; Duque-Fernández, María Rosario; Gil-Sánchez, Salvador; García-Nieto, Víctor Manuel
Summary Sclerosing bone dysplasias are a series of clinically and genetically heterogeneous diseases characterized by functional failure of the osteoclasts in bone resorption, leading to an excessive amount of bone mineral density (BMD) which could have serious clinical consequences. We treated three children affected with seriously high levels of BMD with acetazolamide, with the intention of inducing metabolic acidosis, thus increasing bone resorption and reducing BMD. All our patients tolerated and followed the treatment well and the clinical response was satisfactory in all cases. PMID:27904825
Ruscitti, Piero; Cipriani, Paola; Carubbi, Francesco; Liakouli, Vasiliki; Di Benedetto, Paola; Berardicurti, Onorina; Alesse, Edoardo; Giacomelli, Roberto
Several inflammatory diseases have been associated with increased bone resorption and fracture rates and different studies supported the relation between inflammatory cytokines and osteoclast activity. The main factor required for osteoclast activation is the stimulation by receptor activator of nuclear factor kappa-B ligand (RANKL) expressed on osteoblasts. In this context, interleukin- (IL-) 1β, one of the most powerful proinflammatory cytokines, is a strong stimulator of in vitro and in vivo bone resorption via upregulation of RANKL that stimulates the osteoclastogenesis. The resulting effects lead to an imbalance in bone metabolism favouring bone resorption and osteoporosis. In this paper, we review the available literature on the role of IL-1β in the pathogenesis of bone loss. Furthermore, we analysed the role of IL-1β in bone resorption during rheumatic diseases and, when available, we reported the efficacy of anti-IL-1β therapy in this field. PMID:25954061
Several dietary phytochemicals exhibit anti-oxidative, anti-inflammatory and anti-osteoporotic activities relevant to prevention of chronic diseases, including lifestyle-related diseases. Soybean isoflavones are similar in structure to estrogen and have received considerable attention as potential alternatives to hormone replacement therapy. Daidzein, a major isoflavone found in soybean, is metabolized to equol by intestinal microflora; this metabolite exhibits stronger estrogenic activity than daidzein. Recent studies suggest that the clinical effectiveness of isoflavones might be due to their ability to produce equol in the gut. This review focused on the metabolic pathway of equol and possible bioactivities of equol and O-desmethylangolensin, another metabolite of daidzein, with regard to bone metabolism and the status of intestinal microflora. Furthermore, we considered risk-benefit analyses of isoflavones and their metabolites. PMID:23704808
Sabharwal, Robin; Gupta, Shivangi; Sepolia, Shipra; Panigrahi, Rajat; Mohanty, Saumyakanta; Subudhi, Santosh Kumar; Kumar, Manish
Paget's disease of bone (PDB) is a common disorder which may affect one or many bones. Although many patients are asymptomatic, a variety of symptoms and complications may occur. PDB is a focal disorder of bone turnover characterized by excessive bone resorption coupled with bone formation. PDB begins with a period of increased osteoclastic activity and bone resorption, followed by increased osteoblast production of woven bone that is poorly mineralized. In the final phase of the disease process, dense cortical and trabecular bone deposition predominates, but the bone is sclerotic and poorly organized and lacks the structural integrity and strength of normal bone. This article briefly reviews the etiopathogenesis, clinical radiographic and histological features of Paget's disease. PMID:24665195
Ager, J.W.; Balooch, G.; Ritchie, R.O.
fracture resistance, whereas regulating the level of the cytokine TGF-beta can offer significant improvements in the stiffness, strength and toughness of bone, and as such may be considered as a therapeutic target to treat increased bone fragility induced by aging, drugs, and disease.
Aqeilan, Rami I; Hassan, Mohammad Q; de Bruin, Alain; Hagan, John P; Volinia, Stefano; Palumbo, Titziana; Hussain, Sadiq; Lee, Suk-Hee; Gaur, Tripti; Stein, Gary S; Lian, Jane B; Croce, Carlo M
The WW domain-containing oxidoreductase (WWOX) gene encodes a tumor suppressor. We have previously shown that targeted ablation of the Wwox gene in mouse increases the incidence of spontaneous and chemically induced tumors. To investigate WWOX function in vivo, we examined Wwox-deficient (Wwox(-/-)) mice for phenotypical abnormalities. Wwox(-/-) mice are significantly reduced in size, die at the age of 2-3 weeks, and suffer a metabolic disorder that affects the skeleton. Wwox(-/-) mice exhibit a delay in bone formation from a cell autonomous defect in differentiation beginning at the mineralization stage shown in calvarial osteoblasts ex vivo and supported by significantly decreased bone formation parameters in Wwox(-/-) mice by microcomputed tomography analyses. Wwox(-/-) mice develop metabolic bone disease, as a consequence of reduced serum calcium, hypoproteinuria, and hypoglycemia leading to increased osteoclast activity and bone resorption. Interestingly, we find WWOX physically associates with RUNX2, the principal transcriptional regulator of osteoblast differentiation, and on osteocalcin chromatin. We show WWOX functionally suppresses RUNX2 transactivation ability in osteoblasts. In breast cancer MDA-MB-242 cells that lack endogenous WWOX protein, restoration of WWOX expression inhibited Runx2 and RUNX2 target genes related to metastasis. Affymetrix mRNA profiling revealed common gene targets in multiple tissues. In Wwox(-/-) mice, genes related to nucleosome assembly and cell growth genes were down-regulated, and negative regulators of skeletal metabolism exhibited increased expression. Our results demonstrate an essential requirement for the WWOX tumor suppressor in postnatal survival, growth, and metabolism and suggest a central role for WWOX in regulation of bone tissue formation.
El-Kouba, Gabriel; de Araújo Santos, Romilton; Pilluski, Paulo César; Severo, Antonio; Lech, Osvandré
Gorham-Stout syndrome is a disease that presents idiopathic osteolysis of a bone or closely contiguous area. The etiology is unknown. It is a rare condition that is difficult to diagnose, and its treatment is controversial. It affects individuals irrespective of age or sex. In this study, we conducted a bibliographic review of the disease, specifically focusing on the differential diagnosis, and we demonstrated the follow-up on a patient with this syndrome from the time of its diagnosis, through treatment, to its current state of evolution. PMID:27026974
Redmond, J; Jarjou, L M A; Zhou, B; Prentice, A; Schoenmakers, I
The prevalence of osteoporosis and the incidence of age-related fragility fracture vary by ethnicity. There is greater than 10-fold variation in fracture probabilities between countries across the world. Mineral and bone metabolism are intimately interlinked, and both are known to exhibit patterns of daily variation, known as the diurnal rhythm (DR). Ethnic differences are described for Ca and P metabolism. The importance of these differences is described in detail between select ethnic groups, within the USA between African-Americans and White-Americans, between the Gambia and the UK and between China and the UK. Dietary Ca intake is higher in White-Americans compared with African-Americans, and is higher in White-British compared with Gambian and Chinese adults. Differences are observed also for plasma 25-hydroxy vitamin D, related to lifestyle differences, skin pigmentation and skin exposure to UVB-containing sunshine. Higher plasma 1,25-dihydroxy vitamin D and parathyroid hormone are observed in African-American compared with White-American adults. Plasma parathyroid hormone is also higher in Gambian adults and, in winter, in Chinese compared with White-British adults. There may be ethnic differences in the bone resorptive effects of parathyroid hormone, with a relative skeletal resistance to parathyroid hormone observed in some, but not all ethnic groups. Renal mineral excretion is also influenced by ethnicity; urinary Ca (uCa) and urinary P (uP) excretions are lower in African-Americans compared with White-Americans, and in Gambians compared with their White-British counterparts. Little is known about ethnic differences in the DR of Ca and P metabolism, but differences may be expected due to known differences in lifestyle factors, such as dietary intake and sleep/wake pattern. The ethnic-specific DR of Ca and P metabolism may influence the net balance of Ca and P conservation and bone remodelling. These ethnic differences in Ca, P and the bone metabolism may
Kanazawa, Ippei; Sugimoto, Toshitsugu
Osteoporosis and sarcopenia directly affect healthy life expectancy in elderly people ; therefore, both diseases become social problem around the world. Sarcopenia increases the risk of osteoporotic fracture. Thus, not only agents affecting bone tissue directly but also treatments for sarcopenia are important for management of osteoporosis. Recently, it has been shown that there is an interaction between bone and muscle. Several hormones affect muscle and bone simultaneously. Moreover, myokines secreted from muscle are reported to regulate bone metabolism. On the other hand, several systemic and local factors derived from bone also affect muscle tissue. Therefore, further studies are necessary to develop the integrated treatments for osteoporosis toward harmony of bone and muscle.
Miller, Lisa M.; Hamerman, David; Chance, Mark R.; Carlson, Cathy S.
Infrared (IR) microspectroscopy is an analytical technique that is highly sensitive to the chemical components in bone. The brightness of a synchrotron source permits the examination of individual regions of bone in situ at a spatial resolution superior to that of a conventional infrared source. At Beamlines U10B and U2B at the National Synchrotron Light Source, we are examining the role of bone chemical composition in bone disease. In osteoarthritis (OA), it has been demonstrated that the bone underlying the joint cartilage (subchondral bone) becomes thickened prior to cartilage breakdown. Using synchrotron infrared microspectroscopy, we have examined the chemical composition of the subchondral bone in histologically normal and OA monkeys. Results demonstrate that the subchondral bone of OA monkeys is significantly more mineralized than the normal bone, primarily due to an increase in carbonate concentration in the OA bone. High resolution analysis indicates that differences in carbonate content are uniform throughout the subchondral bone region, suggesting that high subchondral bone carbonate may be a marker for OA. Conversely, increases in phosphate content are more pronounced in the region near the marrow space, suggesting that, as the subchondral bone thickens, the bone also becomes more mineralized. Osteoporosis is a disease characterized by a reduction in bone mass and a skeleton that is more susceptible to fracture. To date, it is unclear whether bone remodeled after the onset of osteoporosis differs in chemical composition from older bone. Using fluorescence-assisted infrared microspectroscopy, we are comparing the composition of monkey bone remodeled at various time points after the onset of osteoporosis (induced by ovariectomy). We find that the chemical composition of bone remodeled one year after ovariectomy and one year prior to necropsy is similar to normal bone. On the other hand, bone remodeled two years after ovariectomy is less mature, indicated
Ballhausen, Diana; Dépraz, Nuria Garcia; Kern, Ilse; Unger, Sheila; Bonafé, Luisa
Considerable progress has been achieved in recent years in treating children affected by bone diseases. Advances in the understanding of the molecular pathophysiology of genetic bone diseases have led to the development of enzyme replacement therapies for various lysosomal storage diseases, following the breakthrough initiated in treating Gaucher disease. Clinical studies are underway with tailored molecules correcting bone fragility and alleviating chronic bone pain and other manifestations of hypophosphatasia, or promoting growth of long bones in achondroplasia patients. We further report our very encouraging experience with intravenous bisphosphonate treatment in children suffering from secondary osteopenia and the high prevalence of calcium and vitamin D deficits in these severely disabled children.
Loddenkemper, Konstanze; Bohl, Nicole; Perka, Carsten; Burmester, Gerd-Rüdiger; Buttgereit, Frank
Osteoporosis is a common concomitant disease in patients with rheumatic diseases on glucocorticoid (GC) therapy. Bone status is usually evaluated by determination of bone density in combination with clinical examinations and laboratory tests. However, the strength of individual biochemical bone makers in GC-induced osteoporosis has yet to be fully clarified. For this reason, different bone markers were investigated in correlation with bone density in patients with rheumatic diseases. Approximately 238 patients (212 women, 26 men) with a rheumatic disease and under GC therapy were examined consecutively for the first time with regard to bone density (BMD) and bone markers [osteocalcin, bone-specific alkaline phosphatase (precipitation method/tandem-MP ostase), crosslinks [pyridinoline (PYD), deoxypyridinoline (DPX), N-terminal telopeptide (NTX)
Ferrell, Jessica M; Chiang, John Y L
Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease.
Ferrell, Jessica M.; Chiang, John Y.L.
Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease. PMID:26579436
Khouzam, Nadine M; Wesseling-Perry, Katherine; Salusky, Isidro B
Cardiovascular disease is the leading cause of death in pediatric patients with chronic kidney disease (CKD), and vascular calcifications start early in the course of CKD. Based on the growing body of evidence that alterations of bone and mineral metabolism and the therapies designed to treat the skeletal consequences of CKD are linked to cardiovascular calcifications, the Kidney Disease, Improving Global Outcomes (KDIGO) working group redefined renal osteodystrophy as a systemic disorder of mineral and bone metabolism due to CKD, and this newly defined disorder is now known as "chronic kidney disease-mineral bone disorder (CKD-MBD)". Elevated fibroblast growth factor 23 (FGF23), a bone-derived protein, is the first biochemical abnormality to be associated with CKD-MBD, and high FGF23 levels correlate with increased cardiovascular morbidity and mortality, suggesting that bone is central to both initiating and perpetuating the abnormal mineral metabolism and vascular disease in CKD. The current standard therapies for CKD-MBD affect FGF23 levels differently; non-calcium-based binders with or without concurrent use of dietary phosphate restriction reduce FGF23 levels, while calcium-based binders seem to either increase or have no effect on FGF23 levels. Active vitamin D sterols increase FGF23 levels, whereas therapy with calcimimetics decreases FGF23 levels. Thus, the appropriate therapy that will minimize the rise in FGF23 and prevent cardiovascular morbidity remains to be defined.
Maïmoun, L; Galy, O; Manetta, J; Coste, O; Peruchon, E; Micallef, J P; Mariano-Goulart, D; Couret, I; Sultan, C; Rossi, M
This longitudinal study evaluated the effects of a triathlon season on bone metabolism and hormonal status. Seven male competitive triathletes (mean age 19.3 years, range 18 - 20) with 5.0 +/- 0.3 years of competition experience were tested twice during the season: at the beginning of training and 32 weeks later. Total and regional bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry, while bone turnover was evaluated by specific biochemical markers: bone-specific alkaline phosphatase (B-ALP), osteocalcin, and urinary type I collagen C-telopeptide. In addition, sexual, calciotropic and somatotropic hormones were also analyzed. After 32 weeks, a BMD increase was found at the lumbar spine (1.9 %; p = 0.031) and skull (3.1 %; p = 0.048), while no variation was observed for total body or at the proximal femur. The B-ALP level decreased (-23.2 %; p = 0.031), but no variation was found for the other bone markers. 1.25 (OH) (2)D3, IGF-1 and the bioavailability IGF-1 index (IGF-1/IGFBP-3) increased by 18.3 % (p = 0.047), 29 % (p = 0.048), 33 % (p = 0.011), respectively, while PTH, testosterone, IGFBP-3 and cortisol concentrations were unchanged. In conclusion, the triathlon season had a moderately favourable effect on BMD, although a slowing down of bone formation activity was observed. No variation in hormonal levels was observed that could have limited the effects of exercise on bone tissue.
Kaelin, William G.; McKnight, Steven L.
Chemical modifications of histones and DNA, such as histone methylation, histone acetylation, and DNA methylation, play critical roles in epigenetic gene regulation. Many of the enzymes that add or remove such chemical modifications are known, or might be suspected, to be sensitive to changes in intracellular metabolism. This knowledge provides a conceptual foundation for understanding how mutations in the metabolic enzymes SDH, FH, and IDH can result in cancer and, more broadly, for how alterations in metabolism and nutrition might contribute to disease. Here, we review literature pertinent to hypothetical connections between metabolic and epigenetic states in eukaryotic cells. PMID:23540690
Marie, Pierre J
Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the commitment, differentiation or survival of cells of the osteoblast lineage. During the recent years, significant advances have been made in our understanding of the cellular and molecular mechanisms underlying the osteoblast dysfunctions in osteoporosis, skeletal dysplasias and primary bone tumors. This led to suggest novel therapeutic approaches to correct these abnormalities such as the modulation of WNT signaling, the pharmacological modulation of proteasome-mediated protein degradation, the induction of osteoprogenitor cell differentiation, the repression of cancer cell proliferation and the manipulation of epigenetic mechanisms. This article reviews our current understanding of the major cellular and molecular mechanisms inducing osteoblastic cell abnormalities in age-related bone loss, genetic skeletal dysplasias and primary bone tumors, and discusses emerging therapeutic strategies to counteract the osteoblast abnormalities in these disorders of bone formation.
Agrawal, Archi; Purandare, Nilendu; Shah, Sneha; Rangarajan, Venkatesh
An 18-month-old boy with history of fever of 4 months duration and with swelling of the limbs was referred for a bone scan. There were multiple swellings over his upper and lower limbs, with bowing of the lower limbs. His radiological skeletal survey revealed marked periosteal new bone formation surrounding the diaphysis of long bones. A bone scan done with 99m Tc-MDP showed diffusely increased tracer uptake in all the long bones. A fluorodeoxyglucose positron emission tomography (FDG PET) scan done to assess the metabolic activity showed patchy FDG uptake in the long bones, ankle joint and anterior ends of few ribs. His clinical and imaging findings led to the diagnosis of Caffey's disease.
Duarte, João M. N.; Schuck, Patrícia F.; Wenk, Gary L.; Ferreira, Gustavo C.
Degeneration of specific neuronal populations and progressive nervous system dysfunction characterize neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. These findings are also reported in inherited diseases such as phenylketonuria and glutaric aciduria type I. The involvement of mitochondrial dysfunction in these diseases was reported, elicited by genetic alterations, exogenous toxins or buildup of toxic metabolites. In this review we shall discuss some metabolic alterations related to the pathophysiology of diseases with neurological involvement and aging process. These findings may help identifying early disease biomarkers and lead to more effective therapies to improve the quality of life of the patients affected by these devastating illnesses. PMID:25110608
Gray, Lawrence R; Tompkins, Sean C; Taylor, Eric B
Pyruvate is a keystone molecule critical for numerous aspects of eukaryotic and human metabolism. Pyruvate is the end-product of glycolysis, is derived from additional sources in the cellular cytoplasm, and is ultimately destined for transport into mitochondria as a master fuel input undergirding citric acid cycle carbon flux. In mitochondria, pyruvate drives ATP production by oxidative phosphorylation and multiple biosynthetic pathways intersecting the citric acid cycle. Mitochondrial pyruvate metabolism is regulated by many enzymes, including the recently discovered mitochondria pyruvate carrier, pyruvate dehydrogenase, and pyruvate carboxylase, to modulate overall pyruvate carbon flux. Mutations in any of the genes encoding for proteins regulating pyruvate metabolism may lead to disease. Numerous cases have been described. Aberrant pyruvate metabolism plays an especially prominent role in cancer, heart failure, and neurodegeneration. Because most major diseases involve aberrant metabolism, understanding and exploiting pyruvate carbon flux may yield novel treatments that enhance human health.
Maayan, C; Bar-On, E; Foldes, A J; Gesundheit, B; Pollak, R Dresner
Familial dysautonomia (FD) patients suffer from multiple fractures and have reduced bone pain, which defers the diagnosis. The pathogenesis of bone fragility in FD is unknown. This study aimed to characterize bone mineral metabolism and density in FD. Seventy-nine FD patients aged 8 months to 48 years (mean age 13.9 +/- 10.4 years, median 12.3) were studied. Clinical data included weight, height, bone age, weekly physical activity and history of fractures. Bone mineral density (BMD) of the lumbar spine (n = 43), femoral neck (n = 26), total hip (n = 22) and whole body (n = 15) were determined by dual-energy X-ray absorptiometry. Serum 25-hydroxyvitamin D3, osteocalcin, bone alkaline phosphatase (B-ALP), parathyroid hormone and urinary N-telopeptide cross-linked type 1 collagen (NTx) were determined in 68 patients and age- and sex-matched controls. Forty-two of 79 patients (53%) sustained 75 fractures. Twenty-four of 43 patients had a spine Z-score < -2.0, and 13 of 26 had a femoral neck Z-score < -2.0. Mean femoral neck BMD Z-score was lower in patients with fractures compared with those without (-2.5 +/- 0.9 vs -1.5 +/- 1.0, p = 0.01). Mean body mass index (BMI) was 16 kg/m2 in prepubertal patients and 18.4 kg/m2 in postpubertal patients. Bone age was significantly lower than chronological age (75.5 vs 99.3 months in prepubertal patients, p < 0.001; 151 vs 174 in postpubertal patients, p < 0.05). NTx and osteocalcin levels were higher in FD patients compared with controls (400 +/- 338 vs 303 +/- 308, BCE/mM creatinine p < 0.02; 90 +/- 59.5 vs 61.8 +/- 36.9 ng/ml, p < 0.001, respectively). B-ALP was lower in FD patients compared with controls (44.66 +/- 21.8 vs 55.36 +/- 36.6 ng/ml, p < 0.04). Mean spine Z-score was significantly lower in physically inactive compared with active patients (-3.00 +/- 1.70 vs -1.77 +/- 1.3, respectively, p = 0.05). We conclude that fractures in FD patients are associated with reduced BMD. FD patients have increased NTx and osteocalcin
Litten-Brown, J C; Corson, A M; Clarke, L
The aim of this review article is to provide an overview of the role of pigs as a biomedical model for humans. The usefulness and limitations of porcine models have been discussed in terms of metabolic, cardiovascular, digestive and bone diseases in humans. Domestic pigs and minipigs are the main categories of pigs used as biomedical models. One drawback of minipigs is that they are in short supply and expensive compared with domestic pigs, which in contrast cost more to house, feed and medicate. Different porcine breeds show different responses to the induction of specific diseases. For example, ossabaw minipigs provide a better model than Yucatan for the metabolic syndrome as they exhibit obesity, insulin resistance and hypertension, all of which are absent in the Yucatan. Similar metabolic/physiological differences exist between domestic breeds (e.g. Meishan v. Pietrain). The modern commercial (e.g. Large White) domestic pig has been the preferred model for developmental programming due to the 2- to 3-fold variation in body weight among littermates providing a natural form of foetal growth retardation not observed in ancient (e.g. Meishan) domestic breeds. Pigs have been increasingly used to study chronic ischaemia, therapeutic angiogenesis, hypertrophic cardiomyopathy and abdominal aortic aneurysm as their coronary anatomy and physiology are similar to humans. Type 1 and II diabetes can be induced in swine using dietary regimes and/or administration of streptozotocin. Pigs are a good and extensively used model for specific nutritional studies as their protein and lipid metabolism is comparable with humans, although pigs are not as sensitive to protein restriction as rodents. Neonatal and weanling pigs have been used to examine the pathophysiology and prevention/treatment of microbial-associated diseases and immune system disorders. A porcine model mimicking various degrees of prematurity in infants receiving total parenteral nutrition has been established to
Laurent, M R; Cook, M J; Gielen, E; Ward, K A; Antonio, L; Adams, J E; Decallonne, B; Bartfai, G; Casanueva, F F; Forti, G; Giwercman, A; Huhtaniemi, I T; Kula, K; Lean, M E J; Lee, D M; Pendleton, N; Punab, M; Claessens, F; Wu, F C W; Vanderschueren, D; Pye, S R; O'Neill, T W
We examined cross-sectional associations of metabolic syndrome and its components with male bone turnover, density and structure. Greater bone mass in men with metabolic syndrome was related to their greater body mass, whereas hyperglycaemia, hypertriglyceridaemia or impaired insulin sensitivity were associated with lower bone turnover and relative bone mass deficits.
Shaw, Anita T.; Gravallese, Ellen M.
Remodeling of bone is a continuous process that occurs throughout life. Under normal physiologic conditions, bone-resorbing osteoclasts and bone-forming osteoblasts are tightly coupled and regulated to ensure the proper balance, such that there is no net change in bone mass. However, inflammation perturbs normal bone homeostasis. The impact of inflammation on bone is dependent upon the anatomic site affected, cell types, factors and cytokines present in the local microenvironment, and local mechanical forces. Cytokines are central to the pathogenesis of inflammation-induced bone loss and contribute to the uncoupling of osteoclast-mediated bone resorption and osteoblast-mediated bone formation, thereby disrupting normal remodeling. In this review, we will discuss the effects of cytokines on bone in two settings, rheumatoid arthritis (RA) and spondyloarthritis (SpA), a disease category that includes ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, inflammatory bowel disease, and juvenile onset spondyloarthropathy. The outcome for bone in these disease settings is quite different, and an understanding of the pathogenic mechanisms leading to the net impact on bone has been essential in developing new therapeutic approaches to bone health in these diseases. PMID:26481971
Baris, Hagit N; Weisz Hubshman, Monika; Bar-Sever, Zvi; Kornreich, Liora; Shkalim Zemer, Vered; Cohen, Ian J
Bone crises in type 1 Gaucher disease are reported in long bones and occasionally in weight bearing bones and other bones, but rarely in small bones of the hands and feet. We retrospectively examined the incidence of bone pain in patients followed at the Rabin Medical Center, Israel, before and following the initiation of enzyme replacement therapy (ERT) and evaluated them for bone crises. Of 100 type I Gaucher disease patients, 30 (30%) experienced one or more bone crises. Small bone crises represented 31.5% of all bone crises and were always preceded by crises in other bones. While the incidence of long bone crises reduced after the initiation of ERT, small bone crises increased. Almost 60% of patients with bone crises were of the N370S/84GG genotype suggesting a greater susceptibility of N370S/84GG patients to severe bone complications. These patients also underwent the greatest number of splenectomies (70.6% of splenectomised patients). Splenectomised patients showed a trend towards increased long and small bone crises after surgery. Active investigation of acute pain in the hands and feet in patients in our cohort has revealed a high incidence of small bone crises. Physicians should consider imaging studies to investigate unexplained pain in these areas.
Gu, Wenyi; Wu, Chengtie; Chen, Jiezhong; Xiao, Yin
Nanotechnology is a vigorous research area and one of its important applications is in biomedical sciences. Among biomedical applications, targeted drug delivery is one of the most extensively studied subjects. Nanostructured particles and scaffolds have been widely studied for increasing treatment efficacy and specificity of present treatment approaches. Similarly, this technique has been used for treating bone diseases including bone regeneration. In this review, we have summarized and highlighted the recent advancement of nanostructured particles and scaffolds for the treatment of cancer bone metastasis, osteosarcoma, bone infections and inflammatory diseases, osteoarthritis, as well as for bone regeneration. Nanoparticles used to deliver deoxyribonucleic acid and ribonucleic acid molecules to specific bone sites for gene therapies are also included. The investigation of the implications of nanoparticles in bone diseases have just begun, and has already shown some promising potential. Further studies have to be conducted, aimed specifically at assessing targeted delivery and bioactive scaffolds to further improve their efficacy before they can be used clinically.
Hotamisligil, Gökhan S; Erbay, Ebru
The proper functioning of the pathways that are involved in the sensing and management of nutrients is central to metabolic homeostasis and is therefore among the most fundamental requirements for survival. Metabolic systems are integrated with pathogen-sensing and immune responses, and these pathways are evolutionarily conserved. This close functional and molecular integration of the immune and metabolic systems is emerging as a crucial homeostatic mechanism, the dysfunction of which underlies many chronic metabolic diseases, including type 2 diabetes and atherosclerosis. In this Review we provide an overview of several important networks that sense and manage nutrients and discuss how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.
Williams, Kristen M
Children and adolescents with chronic disease are predisposed to impaired bone health. Pediatric illness, including type 1 diabetes mellitus, celiac disease, and cystic fibrosis, have significant risk of low bone mineralization and fracture due to underlying inflammation, malabsorption, lack of physical activity, and delayed puberty. Dual-energy x-ray absorptiometry is the primary imaging method to assess bone health in this population. The purpose of this review is to update readers about the assessment and management of bone health in children with common pediatric chronic illnesses and review recent advances in the prevention and treatment of impaired bone health.
Tang, Tian Tian; Zhang, Lucia; Bansal, Anil; Grynpas, Marc
ABSTRACT Lyme disease is caused by members of the Borrelia burgdorferi sensu lato species complex. Arthritis is a well-known late-stage pathology of Lyme disease, but the effects of B. burgdorferi infection on bone at sites other than articular surfaces are largely unknown. In this study, we investigated whether B. burgdorferi infection affects bone health in mice. In mice inoculated with B. burgdorferi or vehicle (mock infection), we measured the presence of B. burgdorferi DNA in bones, bone mineral density (BMD), bone formation rates, biomechanical properties, cellular composition, and two- and three-dimensional features of bone microarchitecture. B. burgdorferi DNA was detected in bone. In the long bones, increasing B. burgdorferi DNA copy number correlated with reductions in areal and trabecular volumetric BMDs. Trabecular regions of femora exhibited significant, copy number-correlated microarchitectural disruption, but BMD, microarchitectural, and biomechanical properties of cortical bone were not affected. Bone loss in tibiae was not due to increased osteoclast numbers or bone-resorbing surface area, but it was associated with reduced osteoblast numbers, implying that bone loss in long bones was due to impaired bone building. Osteoid-producing and mineralization activities of existing osteoblasts were unaffected by infection. Therefore, deterioration of trabecular bone was not dependent on inhibition of osteoblast function but was more likely caused by blockade of osteoblastogenesis, reduced osteoblast survival, and/or induction of osteoblast death. Together, these data represent the first evidence that B. burgdorferi infection induces bone loss in mice and suggest that this phenotype results from inhibition of bone building rather than increased bone resorption. PMID:27956598
Johnsson, Martin; Jonsson, Kenneth B.; Andersson, Leif; Jensen, Per; Wright, Dominic
Birds have a unique bone physiology, due to the demands placed on them through egg production. In particular their medullary bone serves as a source of calcium for eggshell production during lay and undergoes continuous and rapid remodelling. We take advantage of the fact that bone traits have diverged massively during chicken domestication to map the genetic basis of bone metabolism in the chicken. We performed a quantitative trait locus (QTL) and expression QTL (eQTL) mapping study in an advanced intercross based on Red Junglefowl (the wild progenitor of the modern domestic chicken) and White Leghorn chickens. We measured femoral bone traits in 456 chickens by peripheral computerised tomography and femoral gene expression in a subset of 125 females from the cross with microarrays. This resulted in 25 loci for female bone traits, 26 loci for male bone traits and 6318 local eQTL loci. We then overlapped bone and gene expression loci, before checking for an association between gene expression and trait values to identify candidate quantitative trait genes for bone traits. A handful of our candidates have been previously associated with bone traits in mice, but our results also implicate unexpected and largely unknown genes in bone metabolism. In summary, by utilising the unique bone metabolism of an avian species, we have identified a number of candidate genes affecting bone allocation and metabolism. These findings can have ramifications not only for the understanding of bone metabolism genetics in general, but could also be used as a potential model for osteoporosis as well as revealing new aspects of vertebrate bone regulation or features that distinguish avian and mammalian bone. PMID:26023928
Xue-shan, Zhao; Juan, Peng; Qi, Wu; Zhong, Ren; Li-hong, Pan; Zhi-han, Tang; Zhi-sheng, Jiang; Gui-xue, Wang; Lu-shan, Liu
Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease that is mainly caused by β-amyloid accumulation. A large number of studies have shown that elevated cholesterol levels may perform a function in AD pathology, and several cholesterol-related gene polymorphisms are associated with this disease. Although numerous studies have shown the important function of cholesterol in AD pathogenesis and development, the underlying mechanism remains unclear. To further elucidate cholesterol metabolism disorder and AD, we first, review metabolism and regulation of the cholesterol in the brain. Second, we summarize the literature stating that hypercholesterolemia is one of the risk factors of AD. Third, we discuss the main mechanisms of abnormal cholesterol metabolism that increase the risk of AD. Finally, the relationships between AD and apolipoprotein E, PCSK9, and LRP1 are discussed in this article.
Hur, Suzy S J; Cropley, Jennifer E; Suter, Catherine M
Parental health or exposures can affect the lifetime health outcomes of offspring, independently of inherited genotypes. Such 'epigenetic' effects occur over a broad range of environmental stressors, including defects in parental metabolism. Although maternal metabolic effects are well documented, it has only recently been established that that there is also an independent paternal contribution to long-term metabolic health. Both paternal undernutrition and overnutrition can induce metabolic phenotypes in immediate offspring, and in some cases, the induced phenotype can affect multiple generations, implying inheritance of an acquired trait. The male lineage transmission of metabolic disease risk in these cases implicates a heritable factor carried by sperm. Sperm-based transmission provides a tractable system to interrogate heritable epigenetic factors influencing metabolism, and as detailed here, animal models of paternal programming have already provided some significant insights. Here, we review the evidence for paternal programming of metabolism in humans and animal models, and the available evidence on potential underlying mechanisms. Programming by paternal metabolism can be observed in multiple species across animal phyla, suggesting that this phenomenon may have a unique evolutionary significance.
Güler, A H; Sapan, N; Ediz, B; Genç, Z; Ozkan, K
This study was planned to investigate the effects of copper (Cu) deficiency on liver and bone metabolism in malnourished children. Serum total calcium (Ca), inorganic phosphorus (P), Ca/P, Cu/Ca, Cu/P ratios and alkaline phosphatase (ALP) activity values were analyzed. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (GGT) enzyme activities and the ALT/AST (De Ritis) ratio as well as their correlations with Cu were tested to determine liver function. The results of the study showed that Cu deficiency directly affects the organic matrix formation, and by the suppression of ALP activity, indirectly causes decalcification. In the liver, however, no direct effect of Cu deficiency was seen. Deterioration in liver function and Cu deficiency increased parallel with the severity of malnutrition. Thus we concluded that a correlation exists between Cu and the parameters that indicate liver function.
Gallagher, James A; Ranganath, Lakshminarayan R; Boyde, Alan
Studying severe phenotypes of rare syndromes can elucidate disease mechanisms of more common disorders and identify potential therapeutic targets. Lessons from rare bone diseases contributed to the development of the most successful class of bone active agents, the bisphosphonates. More recent research on rare bone diseases has helped elucidate key pathways and identify new targets in bone resorption and bone formation including cathepsin K and sclerostin, for which drugs are now in clinical trials. By contrast, there has been much less focus on rare cartilage diseases and osteoarthritis (OA) remains a common disease with no effective therapy. Investigation of rare cartilage syndromes is identifying new potential targets in OA including GDF5 and lubricin. Research on the arthropathy of the ultra-rare disease alkaptonuria has identified several new features of the OA phenotype, including high density mineralized protrusions (HDMPs) which constitute a newly identified mechanism of joint destruction.
Fujii, Hideki; Joki, Nobuhiko
The mineral bone disorder of CKD, called Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), has a major role in the etiology and progression of cardiovascular disease in CKD patients. Since the main emphasis in CKD-MBD is on three categories (bone abnormalities, laboratory abnormalities, and vascular calcifications), we have routinely accepted ectopic cardiovascular calcifications as a central risk factor in the pathophysiology of CKD-MBD for cardiac events. However, recent compelling evidence suggests that some CKD-MBD-specific factors other than vascular calcification might contribute to the onset of cardiovascular disease. Most notable is fibroblast growth factor-23 (FGF23), which is thought to be independently associated with cardiac remodeling. Slow progression of cardiac disorders, such as vascular calcification and cardiac remodeling, characterizes cardiac disease due to CKD-MBD. In contrast, fatal arrhythmia may be induced when QT prolongation occurs with CKD-MBD treatment, such as with lower Ca dialysate or the use of calcimimetics. Sudden onset of fatal cardiac events, such as heart failure and sudden cardiac death, due to fatal arrhythmia would be another distinctive phenomenon of CKD-MBD. This may be defined as CKD-MBD-specific cardiac complex syndrome.
Yajima, Aiji; Inaba, Masaaki; Tominaga, Yoshihiro; Tanaka, Motoko; Otsubo, Shigeru; Nitta, Kosaku; Ito, Akemi; Satoh, Shigeru
Among the most serious problems in patients with chronic kidney disease (CKD) is fragility of cortical bone caused by cortical thinning and increased cortical porosity; the cortical fragility is sometimes irreversible, with fractures generally initiating from cortical bone. Therefore, development of treatments for problems of cortical bone is urgently desired. Cortical bone has the three surfaces, including the periosteal surface, intracortical spaces and endocortical surface. Bone turnover at the endocortical surface and intracortical resorption spaces are increased as compared with that at cancellous surface. Bone growth sometimes depends on apposition at the periosteal surface. We treated hyperphosphatemia in two hemodialysis patients with adynamic bone disease with 750-1500 mg/day of lanthanum carbonate, which is a non-calcium containing phosphate binder; the treatment resulted in a decrease of the serum phosphorus levels (P levels), without significant change of the serum intact parathyroid hormone levels. We now report that treatment of these patients with lanthanum carbonate increased mineralization of the periosteal surface, increased bone mass within the intracortical resorption spaces and increased mineralization of the minimodeling surface at the endocortical surface. In addition, woven bone volume in cortical bone was decreased and mineralization of bone units, namely, osteons, was increased. Although these findings were not observed across all surfaces of the cortical bone in the patients, it is expected that lanthanum carbonate would increase the cortical stability in CKD patients, with consequent reduction in the fracture rate in these patients.
Most genetic causes of neurodegenerative disorders in childhood are due to neurometabolic disease. There are over 200 disorders, including aminoacidopathies, creatine disorders, mitochondrial cytopathies, peroxisomal disorders and lysosomal storage disorders. However, diagnosis can pose a challenge to the clinician when patients present with non-specific problems like epilepsy, developmental delay, autism, dystonia and ataxia. The variety of specialist tests involved can also be daunting. This review aims to give a practical approach to the investigation and diagnosis of neurometabolic disease from the neonatal period to late childhood while prioritising disorders where there are therapeutic options. In particular, patients who have a complex clinical picture of several neurological and non-neurological features should be investigated.
Yuan, P; Yu, Y; Luo, J; Tian, F; Zhang, H; Chang, S; Ramachandran, R; Zhang, L; Song, J
Marek's disease (MD) is a lymphoproliferative disease of chickens caused by MD virus and has an important impact on the poultry industry worldwide. There have been reports showing different physiological characteristics between MD susceptible and resistant chickens. However, little is known about whether there are differences in lipid metabolism between MD susceptible and resistant lines of chickens. In this study, we examined the BW and the weight of tissues (abdominal fat, breast muscle with bone, leg muscle with bone, liver, and heart), the lipoprotein-cholesterol concentrations and distributions, and the plasma and tissue levels of adiponectin and its receptors in the highly resistant and susceptible lines during chicken growth. Our data showed that the increase in total cholesterol during growth was mainly due to the elevation of cholesterol in the low-density/very low-density lipoprotein fraction in MD susceptible chickens, whereas the increase of total cholesterol was mainly attributable to the increase in high-density lipoprotein-cholesterol in MD resistant chickens. Meanwhile, the MD resistant line appeared to have increased plasma adiponectin levels compared with MD susceptible chickens during growth. Taken together, our data suggested that lipoprotein-cholesterol and adiponectin metabolism are different between MD susceptible and resistant chickens.
Wat, Winnie Zee Man
Paget’s disease of bone is a chronic metabolic bone disease with focal increase in bone turnover. The exact etiology of the disease is uncertain, although genetic and environmental factors are believed to be important. Bisphosphonate is the main class of medication being used to control disease activity via its antiresorptive effect. This review discusses the controversies concerning the use of bisphosphonates in the treatment of Paget’s disease of bone, the efficacy of different bisphosphonates in controlling disease activity, and the possible rare side effects of bisphosphonates. Symptoms are the main indication for treatment in Paget’s disease of bone. As treatment benefits in asymptomatic individuals remain controversial and nonevidence based, the decision to treat these patients should be individualized to their risk and benefit profiles. There are several trials conducted to evaluate and compare the efficacy of different regimes of bisphosphonates for treating Paget’s disease of bone. Most trials used biochemical markers rather than clinical symptoms or outcomes as parameters for comparison. Zoledronate is an attractive option as it can achieve high rates of biochemical remission and sustain long duration of suppression by a single dose. Atypical femoral fracture and osteonecrosis of the jaw are two rare and severe side effects reported, possibly related to the use of bisphosphonates in patients with osteoporosis and malignancy-induced hypercalcemia. As the regimes of bisphosphonates used for treating Paget’s disease of bone are different from those two diseases, the risks of developing these two possible side effects are expected to be very low, although this remains unknown. Vitamin D and calcium supplement should be given to patients at risk of vitamin D insufficiency when given zoledronate, as symptomatic hypocalcemia may develop. For those intolerant of bisphosphonates, subcutaneous calcitonin can be used for a limited period due to its
Jansson, J.K.; Willing, B.; Lucio, M.; Fekete, A.; Dicksved, J.; Halfvarson, J.; Tysk, C.; Schmitt-Kopplin, P.
The causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention.
Saparin, Peter I.; Gowin, Wolfgang; Kurths, Jürgen; Felsenberg, Dieter
We introduce a generalization of symbolic dynamics to analyze two-dimensional objects and propose measures of complexity to quantify the structure of symbol encoded images. This technique is applied to evaluate the architecture of human cancellous bone by analyzing computed tomography images of vertebrae acquired from specimens and in vivo. The pixels of the preprocessed images are encoded using a mixture of static and dynamic encoding. The architecture of encoded cancellous bone is evaluated as a whole using measures of complexity. A set of new parameters are introduced to quantify the different aspects of structure: complexity and degree of disorder of the architecture as a whole, or spatial arrangements of hard or soft elements of the bone separately. It is found that the complexity of the bone structure relates to its density exponentially. Normal bone has a complex ordered structure, while the architecture during the initial stage of bone loss is characterized by lower complexity and a maximal level of disorder. Increased bone loss leads again to ordered structure, however, its complexity is minimal. This phenomenon was observed in a series of osteoporotic specimens as well as in vivo in patients treated with fluor, and hormone replacement therapy. We found that different bone diseases demonstrate distinctive features captured by the measurements of complexity of the bone's structural composition. It is shown that the application of the proposed technique leads to new insights for understanding of the bone's response on medical treatment and provide important additional information for the diagnostics of bone diseases.
Rubin, Mishaela R; Patsch, Janina M
Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due to altered bone properties in diabetes. Circulating biochemical markers of bone turnover have been found to be decreased in type 2 diabetes (T2D) and may be predictive of fractures independently of bone mineral density (BMD). Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Bone imaging technologies, including trabecular bone score (TBS) and quantitative CT testing have revealed differences in diabetic bone as compared to non-diabetic individuals. Specifically, high resolution peripheral quantitative CT (HRpQCT) imaging has demonstrated increased cortical porosity in diabetic postmenopausal women. Other factors such as bone marrow fat saturation and advanced glycation endproduct (AGE) accumulation might also relate to bone cell function and fracture risk in diabetes. These data have increased our understanding of how T2D adversely impacts both bone metabolism and fracture risk. PMID:27019762
Qualls, Clifford; Appenzeller, Otto
We examine two important measures that can be made in bioarcheology on the remains of human and vertebrate animals. These remains consist of bone, teeth, or hair; each shows growth increments and each can be assayed for isotope ratios and other chemicals in equal intervals along the direction of growth. In each case, the central data is a time series of measurements. The first important measures are spectral estimates in spectral analyses and linear system analyses; we emphasize calculation of periodicities and growth rates as well as the comparison of power in bands. A low frequency band relates to the autonomic nervous system (ANS) control of metabolism and thus provides information about the life history of the individual of archeological interest. Turning to nonlinear system analysis, we discuss the calculation of SM Pinus' approximate entropy (ApEn) for short or moderate length time series. Like the concept that regular heart R-R interval data may indicate lack of health, low values of ApEn may indicate disrupted metabolism in individuals of archeological interest and even that a tipping point in deteriorating metabolism may have been reached just before death. This adds to the list of causes of death that can be determined from minimal data. PMID:26347356
Qualls, Clifford; Appenzeller, Otto
We examine two important measures that can be made in bioarcheology on the remains of human and vertebrate animals. These remains consist of bone, teeth, or hair; each shows growth increments and each can be assayed for isotope ratios and other chemicals in equal intervals along the direction of growth. In each case, the central data is a time series of measurements. The first important measures are spectral estimates in spectral analyses and linear system analyses; we emphasize calculation of periodicities and growth rates as well as the comparison of power in bands. A low frequency band relates to the autonomic nervous system (ANS) control of metabolism and thus provides information about the life history of the individual of archeological interest. Turning to nonlinear system analysis, we discuss the calculation of SM Pinus' approximate entropy (ApEn) for short or moderate length time series. Like the concept that regular heart R-R interval data may indicate lack of health, low values of ApEn may indicate disrupted metabolism in individuals of archeological interest and even that a tipping point in deteriorating metabolism may have been reached just before death. This adds to the list of causes of death that can be determined from minimal data.
Vilanova, J C; Luna, A
Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases.
Kim, Do Rim; Lee, Ji Eun; Shim, Kyung Jun; Cho, Jin Hyoung; Lee, Ho Chul; Park, Seong Kyu; Chang, Mun Seog
Herbal Epimedium (HE) has been commonly used as a tonic, antirheumatic agent and in the treatment of bone-associated diseases including osteoporosis. Treatment for osteoporosis is important to increase bone mass density and maintain to balance of bone remodeling. The present study was performed to investigate the effects of HE on mouse bone marrow mesenchymal stem cell (mBMMSC) proliferation and osteogenic differentiation, using MTT assays, proliferating cell nuclear antigen (PCNA) detection and apoptosis and differentiation assays. HE was demonstrated to inhibit the proliferation of mBMMSCs up to 45.43±3.33% and to decrease the level of PCNA expression compared with untreated cells. HE also induced late apoptosis at 24 and 48 h after treatment up to 71.93 and 67.03%, respectively, while only 14.93% of untreated cells exhibited apoptosis. By contrast, HE induced differentiation of mBMMSCs into an osteogenic lineage at the beginning of three weeks after commencement of treatment. This suggested that HE is a candidate as an inducer of osteogenesis from bone marrow mesenchymal stem cells, and additionally has potential for use in the treatment of bone metabolic disorders such as osteoporosis. PMID:27959402
Delitala, Alessandro P; Fanciulli, Giuseppe; Maioli, Margherita; Delitala, Giuseppe
Subclinical hypothyroidism is defined by elevated serum thyrotropin in presence of normal free thyroid hormones. Lipid metabolism is influenced by thyroid hormone and many reports showed that lipids status worsen along with TSH level. Subclinical hypothyroidism has been also linked to other cardiovascular risk factors such as alteration in blood pressure and increased atherosclerosis. Further evidences suggested that mild dysfunction of thyroid gland is associated with metabolic syndrome and heart failure. Thyrotropin level seems the best predictor of cardiovascular disease, in particular when its levels are above 10mU/L. However, despite these observations, there is no clear evidence that levothyroxine therapy in subjects with milder form of subclinical hypothyroidism could improve lipid status and the other cardiovascular risk factors. In this review, we address the effect of thyroid hormone and cardiovascular risk, with a focus on lipid metabolism.
Nicholls, Thomas J; Rorbach, Joanna; Minczuk, Michal
Post-transcriptional control of RNA stability, processing, modification, and degradation is key to the regulation of gene expression in all living cells. In mitochondria, these post-transcriptional processes are also vital for proper expression of the thirteen proteins encoded by the mitochondrial genome, as well as mitochondrial tRNAs and rRNAs. Our knowledge on mitochondrial RNA (mt-RNA) metabolic pathways, however, is far from complete. All the proteins involved in mt-RNA metabolism are encoded by the nucleus, and must be imported into the organelle. Mutations in these nuclear genes can lead to perturbations in mitochondrial RNA processing, modification, stability and decay and thus are a cause of human mitochondrial disease. This review summarises the current knowledge on mt-RNA metabolism and its links with human mitochondrial pathologies.
Privalov, V. A.; Krochek, I. V.; Abushkin, I. A.; Shumilin, I. I.; Lappa, A. V.
The method of laser osteoperforation was developed in experiment and then applied for treatment of 508 patients with osteomyelitis, 51 patients with nonunion and pseudo-joint and 34 patients with different forms of osteochondropathy. The clinical trial proved the efficiency of laser osteoperforation for treatment of both inflammatory and destructive bone diseases. This method is minimally invasive, promotes rapid reduction of bone and soft tissue inflammation, and apparently stimulates bone reparation.
Yamamoto, Kengo; Ohshiro, Toshio; Ohshiro, Takafumi
In recent years, through the availability of examination by bone metabolism markers, diagnosis and treatment for osteoporosis in elderly people has been greatly advanced. However, bone metabolism in cases of cerebral palsy has not been fully examined. Though children with cerebral palsy tend to be susceptible to insufficiency fractures, a method of treatment for insufficiency fractures has not been established. In the longitudinal progress of bone metabolism, although there was a difference depending on the severity, reduced bone resorption tended to be mild but osteo-genesis tended to decrease in the severe cases. Osteogenesis and bone resorption markers decreased at around ages 8 and 15. The bone resorption marker maintained mild advancement after age 15. With LED irradiation, all of IGF-1, ucOC, osteogenic marker; BAP, and urinary bone resorption marker; NTx/Cr showed a tendency to normalize. In particular, IGF-1, BAP, and NTx/Cr increased significantly one month after irradiation, compared to the non-irradiation group. Bone density assessed by the DIP method showed no apparent change in the short term either. Irradiation by a commercial LED light bulb indicated a possible positive effect on bone metabolism for children with severe cerebral palsy. PMID:24610978
Smith, Scott M; Heer, Martina; Shackelford, Linda C; Sibonga, Jean D; Spatz, Jordan; Pietrzyk, Robert A; Hudson, Edgar K; Zwart, Sara R
Bone loss and renal stone risk are longstanding concerns for astronauts. Bone resorption brought on by spaceflight elevates urinary calcium and the risk of renal stone formation. Loss of bone calcium leads to concerns about fracture risk and increased long-term risk of osteoporosis. Bone metabolism involves many factors and is interconnected with muscle metabolism and diet. We report here bone biochemistry and renal stone risk data from astronauts on 4- to 6-month International Space Station missions. All had access to a type of resistive exercise countermeasure hardware, either the Advanced Resistance Exercise Device (ARED) or the Interim Resistance Exercise Device (iRED). A subset of the ARED group also tested the bisphosphonate alendronate as a potential anti-resorptive countermeasure (Bis+ARED). While some of the basic bone marker data have been published, we provide here a more comprehensive evaluation of bone biochemistry with a larger group of astronauts. Regardless of exercise, the risk of renal stone formation increased during spaceflight. A key factor in this increase was urine volume, which was lower during flight in all groups at all time points. Thus, the easiest way to mitigate renal stone risk is to increase fluid consumption. ARED use increased bone formation without changing bone resorption, and mitigated a drop in parathyroid hormone in iRED astronauts. Sclerostin, an osteocyte-derived negative regulator of bone formation, increased 10-15% in both groups of astronauts who used the ARED (p<0.06). IGF-1, which regulates bone growth and formation, increased during flight in all 3 groups (p<0.001). Our results are consistent with the growing body of literature showing that the hyper-resorptive state of bone that is brought on by spaceflight can be countered pharmacologically or mitigated through an exercise-induced increase in bone formation, with nutritional support. Key questions remain about the effect of exercise-induced alterations in bone
This book contains 13 selections. Some of the titles are: Radionuclides and the Normal Bone Scan; The Radionuclide Bone Scan in Malignant Disease; Pediatric Applications of Radionuclide Bone Imaging; The Radionuclide Bone Scan in Arthritis and Metabolic and Miscellaneous Disorders; and Soft Tissue Activity on the Radionuclide Bone Scan.
Zhang, Sufeng; Gangal, Geeti; Uludağ, Hasan
An ideal therapeutic agent for bone diseases should act solely on bone tissue with no pharmacological activity at other anatomical sites. Current therapeutic agents, however, do not usually display a preferential affinity to bones and non-specifically distribute throughout the body after administration. Attempts to design bone-specific agents have relied on engineering a desired therapeutic agent with bone-seeking molecules so that the latter delivers the therapeutic agents specifically to bones. In this critical review, we summarize the latest attempts to engineer bone-seeking therapeutic agents based on formulating therapeutic agents with bisphosphonates, a class of compounds with high affinity to biological apatite. We first provide a relevant summary of the structure of bone mineral and bisphosphonates, highlighting the mode of interaction between these two entities. The use of bisphosphonates in the diagnosis of bone diseases is then presented, since this application helps us to understand the bone-carrier properties of bisphosphonates under physiological conditions. A summary of recent attempts to formulate bisphosphonates with traditional therapeutic agents to restrict their activities to bone tissues is then provided, with special emphasis on the structure-function relationships of the engineered compounds. Finally, attempts to use bisphosphonates to deliver macromolecular therapeutics (i.e., proteins) are summarized, based on recent data from the authors' lab. The collective research into bone-seeking medicinal agents is progressively laying the foundation for next-generation 'magic bullets' that display desirable activities at the disease sites with no undesirable activity on other organ systems. (164 references.).
Braidy, Nady; Grant, Ross
Immune-mediated activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP) is a consistent finding in all inflammatory disorders. Several studies by our group and others have examined the neurotoxic potential of neuroreactive TRYP metabolites, including quinolinic acid (QUIN) in neuroinflammatory neurological disorders, including Alzheimer's disease (AD), multiple sclerosis, amylotropic lateral sclerosis (ALS), and AIDS related dementia complex (ADC). Our current work aims to determine whether there is any benefit to the affected individuals in enhancing the catabolism of TRYP via the KP during an immune response. Under physiological conditions, QUIN is metabolized to the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+), which represents an important metabolic cofactor and electron transporter. NAD+ also serves as a substrate for the DNA ‘nick sensor’ and putative nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP). Free radical initiated DNA damage, PARP activation and NAD+ depletion may contribute to brain dysfunction and cell death in neuroinflammatory disease. PMID:28250737
Abdallah, K A; Jorgetti, V; Pereira, R C; Reis, L M dos; Pereira, L M; Corrêa, P H S; Borelli, A; Ianhez, L E; Moysés, R M A; David-Neto, E
Low bone remodeling and relatively low serum parathyroid hormone (PTH) levels characterize adynamic bone disease (ABD). The impact of renal transplantation (RT) on the course of ABD is unknown. We studied prospectively 13 patients with biopsy-proven ABD after RT. Bone histomorphometry and bone mineral density (BMD) measurements were performed in the 1st and 12th months after RT. Serum PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and osteocalcin were measured regularly throughout the study. Serum PTH levels were slightly elevated at transplantation, normalized at the end of the third month and remained stable thereafter. Bone biopsies performed in the first month after RT revealed low bone turnover in all patients, with positive bone aluminum staining in 5. In the 12th month, second biopsies were performed on 12 patients. Bone histomorphometric dynamic parameters improved in 9 and were completely normalized in 6, whereas no bone mineralization was detected in 3 of these 12 patients. At 12 months post-RT, no bone aluminum was detected in any patient. We also found a decrease in lumbar BMD and an increase in femoral BMD. Patients suffering from ABD, even those with a reduction in PTH levels, may present partial or complete recovery of bone turnover after successful renal transplantation. However, it is not possible to positively identify the mechanisms responsible for the improvement. Identifying these mechanisms should lead to a better understanding of the physiopathology of ABD and to the development of more effective treatments.
Rendina, Elizabeth; Hembree, Kelsey D.; Davis, McKale R.; Marlow, Denver; Clarke, Stephen L.; Halloran, Bernard P.; Lucas, Edralin A.; Smith, Brenda J.
Interest in dried plum has increased over the past decade due to its promise in restoring bone and preventing bone loss in animal models of osteoporosis. This study compared the effects of dried plum on bone to other dried fruits and further explored the potential mechanisms of action through which dried plum may exert its osteoprotective effects. Adult osteopenic ovariectomized (OVX) C57BL/6 mice were fed either a control diet or a diet supplemented with 25% (w/w) dried plum, apple, apricot, grape or mango for 8 weeks. Whole body and spine bone mineral density improved in mice consuming the dried plum, apricot and grape diets compared to the OVX control mice, but dried plum was the only fruit to have an anabolic effect on trabecular bone in the vertebra and prevent bone loss in the tibia. Restoration of biomechanical properties occurred in conjunction with the changes in trabecular bone in the spine. Compared to other dried fruits in this study, dried plum was unique in its ability to down-regulate osteoclast differentiation coincident with up-regulating osteoblast and glutathione (GPx) activity. These alterations in bone metabolism and antioxidant status compared to other dried fruits provide insight into dried plum’s unique effects on bone. PMID:23555991
Woting, Anni; Blaut, Michael
Gut bacteria exert beneficial and harmful effects in metabolic diseases as deduced from the comparison of germfree and conventional mice and from fecal transplantation studies. Compositional microbial changes in diseased subjects have been linked to adiposity, type 2 diabetes and dyslipidemia. Promotion of an increased expression of intestinal nutrient transporters or a modified lipid and bile acid metabolism by the intestinal microbiota could result in an increased nutrient absorption by the host. The degradation of dietary fiber and the subsequent fermentation of monosaccharides to short-chain fatty acids (SCFA) is one of the most controversially discussed mechanisms of how gut bacteria impact host physiology. Fibers reduce the energy density of the diet, and the resulting SCFA promote intestinal gluconeogenesis, incretin formation and subsequently satiety. However, SCFA also deliver energy to the host and support liponeogenesis. Thus far, there is little knowledge on bacterial species that promote or prevent metabolic disease. Clostridium ramosum and Enterococcus cloacae were demonstrated to promote obesity in gnotobiotic mouse models, whereas bifidobacteria and Akkermansia muciniphila were associated with favorable phenotypes in conventional mice, especially when oligofructose was fed. How diet modulates the gut microbiota towards a beneficial or harmful composition needs further research. Gnotobiotic animals are a valuable tool to elucidate mechanisms underlying diet–host–microbe interactions. PMID:27058556
Bhowmik, D; Tiwari, S C
Obesity is fast becoming a bane for the present civilization, as a result of sedentary lifestyle, atherogenic diet, and a susceptible thrifty genotype. The concept of metabolic syndrome, which is a constellation of metabolic disturbances, has crystallized over the last 80 years with the aim of identifying those at greater risk of developing type 2 diabetes and cardiovascular disease. These patients have visceral obesity and insulin resistance characterized by hypertyriglyceridemia. Recently, it has been realized that they are also at an increased risk of chronic renal disease. Release of adipocytokines leads to endothelial dysfunction. There is also activation of systemic and local renin-angiotensin-aldosterone system, oxidative stress, and impaired fibrinolysis. This leads to glomerular hyperfiltration, proteinuria, focal segmental glomerulosclerosis (FSGS), and ultimately end-stage renal disease (ESRD). Treatment consists of lifestyle modifications along with optimal control of blood pressure, blood sugar and lipids. Metformin and thiazolidenidiones reduce insulin resistance; while angiotensin converting enzyme inhibitors and angiotensin receptor blockers reduce proteinuria and have a renoprotective effect. Exciting new medical therapies on the horizon include rimonabant a cannabinoid receptor type 1 antagonist, soy proteins, and peroxisome proliferator-activated receptor (PPAR) agonist. Bariatric surgery for morbid obesity has also been shown to be effective in treating metabolic syndrome.
It has been established that oxidative stress, defined as the condition when the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson’s disease. Glutathione is a ubiquitous thiol tripeptide that acts alone, or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals and peroxynitrites. In this review, we examine the synthesis, metabolism and functional interactions of glutathione, and discuss how this relates to protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson’s disease. PMID:23665395
Li, Xiaozhong; Shi, Lenian; Liu, Taiyun; Wang, Lin
Sesamoid bones and accessory ossicles are research focuses of foot and ankle surgery. Pains of the foot and ankle are related to sesamoid bones and accessory ossicles. The specific anatomical and functional relationship of sesamoid bones and accessory ossicles can cause such bone diseases as the dislocation of sesamoid bones and accessory bones, infection, inflammation and necrosis of sesamoid bones, cartilage softening, tenosynovitis of sesamoid bones and the sesamoid bone syndrome. However, these bone diseases are often misdiagnosed or mistreated. In patients with trauma history, relevant diseases of sesamoid bones and accessory ossicles as above mentioned are highly probable to be misdiagnosed as avulsion fractures. In such cases, radiographic findings may provide a basis for clinical diagnosis.
Behera, Jyotirmaya; Bala, Jyoti; Nuru, Mohammed; Tyagi, Suresh C; Tyagi, Neetu
In the last few decades, perturbation in methyl-group and homocysteine (Hcy) balance have emerged as independent risk factors in a number of pathological conditions including neurodegenerative disease, cardiovascular dysfunction, cancer development, autoimmune disease and kidney disease. Recent studies report Hcy to be a newly recognized risk factor for osteoporosis. Elevated Hcy levels are known to modulate osteoclastgenesis by causing detrimental effects on bone via oxidative stress induced metalloproteinase-mediated extracellular matrix degradation and decrease in bone blood flow. Evidence from previous studies also suggests that the decreased chondrocytes mediated bone mineralization in chick limb-bud mesenchymal cells and during the gestational period of ossification in rat model. However, Hcy imbalance and its role in bone loss, regression in vascular invasion, and osteoporosis, are not clearly understood. More investigations are required to explore the complex interplay between Hcy imbalance and onset of bone disease progression. This article reviews the current body of knowledge on regulation of Hcy mediated oxidative stress and its role in bone remodeling, vascular blood flow and progression of bone disease. This article is protected by copyright. All rights reserved.
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Mori, Hiroko; Okada, Yosuke; Kishikawa, Hirofumi; Inokuchi, Nobuo; Sugimoto, Hidekatsu; Tanaka, Yoshiya
Evidence suggests that bone quality is poorer and fracture risk is higher in patients with diabetes, even those with normal bone mineral density. The aim of this study was to determine the effects of raloxifene on lipid, bone, and glucose metabolism in postmenopausal women with type 2 diabetes. The study subjects (144 postmenopausal women aged less than 80 years with type 2 diabetes) were randomly assigned into three groups: no medication, alfacalcidol 1 μg/day, or raloxifene hydrochloride 60 mg/day. The primary endpoint was the change in LDL-C at 6 months. Raloxifene significantly decreased the levels of bone metabolism markers NTX and BAP at 6 months in patients with diabetes. The primary endpoint, LDL-C at 6 months, was significantly lower in the raloxifene group than in the other two groups. However, percent changes in HDL-C were not significantly different among the three groups. Although glucose metabolism was unaffected, homocysteine, a bone quality marker, was significantly decreased at 6 months in the raloxifene group. The percent improvement in LDL-C did not correlate with percent improvement in any bone metabolism or bone quality markers. Raloxifene, unlike estrogen, improved LDL-C and decreased homocysteine, indicating that raloxifene can potentially improve LDL-C as well as bone quality in postmenopausal women with type 2 diabetes.
Rachner, Tilman D; Hadji, Peyman; Hofbauer, Lorenz C
With an ageing population and improving cancer therapies, the two most common benign and malignant bone diseases, osteoporosis and bone metastases, will continue to affect an increasing number of patients. Our expanding knowledge of the molecular processes underlying these conditions has resulted in novel bone targets that are currently being explored in clinical trials. Clearly, the approval of denosumab, a monoclonal antibody directed against RANKL, has just marked the beginning of a new era for bone therapy with several additional new therapies lining up for clinical approval in the coming years. Potential agents targeting the osteoclast include cathepsin K, currently in phase 3 trials, and src inhibitors. Amongst anabolic agents, inhibitors of the Wnt-inhibitor sclerostin and dickkopf-1 are promising in clinical trials. Here, we will provide a comprehensive overview of the most promising agents currently explored for the treatment of bone diseases.
Figard, Hélène; Mougin, Fabienne; Gaume, Vincent; Berthelot, Alain
Soybean proteins, a rich source of isoflavones, taken immediately after an ovariectomy prevent bone loss in rats. Exercise-induced stimuli are essential for bone growth. Few studies exist about the combined effects of swim training and soybean protein supplementation on bone metabolism. So, the purpose of this study was to investigate, in 48 female Sprague-Dawley rats (12 weeks old) the effects of an 8-week swim-training regimen (1 h/day, 5 days/week) and dietary soybean proteins (200 g/kg diet) on bone metabolism. Rats were randomly assigned to four groups: (1) ovariectomized fed with a semisynthetic control diet; (2) ovariectomized fed with a soybean protein-enriched semisynthetic diet; (3) ovariectomized trained to exercise and fed with control diet; (4) ovariectomized trained to exercise and fed with a soybean protein diet. Following the treatment period, body weight gain was identical in the four groups. Soybean protein supplementation increased bone calcium content, and reduced plasma osteocalcin values, without significant modification of calcium balance and net calcium absorption. Swim training enhanced plasma and bone calcium content and calcium balance and net calcium absorption. It did not modify either plasma osteocalcin values or urinary deoxypyridinoline excretion. Both exercise and soybean protein intake increased plasma on bone calcium without modifying net calcium absorption or bone markers. In conclusion, we demonstrated, in ovariectomized rats, that swimming exercise and dietary supplementation with soy proteins do not have synergistic effects on calcium metabolism and bone markers.
Kara, Semra; Güzoğlu, Nilüfer; Göçer, Emine; Arıkan, Fatma Inci; Dilmen, Uğur; Dallar Bilge, Yıldız
Metabolic bone disease (MBD) is one of the important complications of prematurity. Early and adequate nutritional interventions may reduce the incidence and potential complications of MBD. The present study aimed to evaluate bone metabolism in twins via biochemical parameters and quantitative ultrasound (QUS) and to compare the results between twin pairs. Moreover, twin infants were evaluated in terms of potential risk factors likely to have impact on MBD. Forty-three pairs of twins were included in the study. Serum calcium, phosphorus, magnesium, and alkaline phosphatase concentrations were assessed and bone mineral density was measured using QUS (speed of sound, SOS) at postnatal 30 d. Co-twin with the higher birth weight was assigned to Group 1 (n = 36) and the other twin was assigned to Group 2 (n = 36). Birth weight and head circumference were significantly higher in the infants of Group 1 compared with Group 2. No significant difference was found among the groups in terms of gender, history of resuscitation, length of stay in intensive care unit (ICU) or in the incubator, duration of total parenteral nutrition (TPN), type of nutrition, vitamin D use, biochemical parameters, and the SOS value. The factors likely to affect SOS, including type of pregnancy, maternal drug use, gender of infant, birth weight, head circumference at birth, gestational week, length of stay at the ICU, duration of TPN, type of nutrition, resuscitation, vitamin D use, and levels of calcium, phosphorus, magnesium, and alkaline phosphatase were entered into the model. The phosphorus level and the maternal drug use were found to be the factors that significantly reduced SOS, whereas pregnancy after assisted reproductive techniques was found to be a significant enhancing factor.
Brzóska, Małgorzata M; Moniuszko-Jakoniuk, Janina
The effect of cadmium (Cd) on bone metabolism during skeletal development and maturity was investigated on a rat model of human exposure. Young female Wistar rats were exposed to 1, 5, or 50 mg Cd/l in drinking water for 3, 6, 9, and 12 months. Total bone mineral density (T-BMD), bone mineral content (BMC), density (BMD), and bone area at the femur and lumbar spine (L1-L5) were measured densitometrically. Alkaline phosphatase (ALP) and osteocalcin (OC) as bone formation markers, and carboxy-terminal cross-linking telopeptides of type I collagen (CTX) in bone (trabecular and cortical) or serum as bone resorption markers were measured. Renal calcium (Ca) handling and Cd body burden were evaluated as well. At the stage of intensive skeletal development (the first 6 months of the experiment), at all exposure levels, Cd inhibited the processes of bone formation and as a result disturbed the accumulation of bone mass leading to osteopenia (- 1 > Z score/T score BMD > -2.5) and at 5 and 50 mg Cd/l even to more advanced disorders in the BMD. Continuation of the exposure up to skeletal maturity led to high bone turnover with increased resorption enhancing the prevalence of osteopenia or the BMD values having the Z score/T score < -2.5. The results allow for the conclusion that chronic, even low-level exposure to Cd disturbs bone metabolism during skeletal development and maturity by affecting bone turnover most probably through a direct influence on bone formation and resorption, and indirectly via disorders in Ca metabolism. Our findings confirm the hypothesis that environmental exposure to Cd may be a risk factor for low BMD.
Kazama, Junichiro James; Yamamoto, Suguru; Narita, Ichiei; Kurihara, Satoshi
The morphological appearance of an osteoblast largely alters with its differentiation and maturation, along with the change of cell function. We quantitatively observed the osteoblast morphology and compared it with bone metabolism. Biopsied iliac bone samples obtained from 77 dialysis patients (14 mild change, 37 osteitis fibrosa, 2 osteomalacia, 8 mixed, and 16 adynamic bone) were included in the study. Osteoblast appearances were classified into three groups: (i) type II and III osteoblasts, namely, active osteoblasts characterized by cuboidal or columnar shapes with or without a nuclear clear zone; (ii) type IV osteoblasts, lining osteoblasts characterized by extremely thin cytoplasm; and (iii) type V osteoblasts, apoptotic osteoblasts characterized by nuclear chromatin concentration. The results were quantitatively expressed as the length of bone surface covered by each type of osteoblasts. The type II and III osteoblasts were predominant in osteitis fibrosa, mixed, and mild change. The type IV osteoblasts were overwhelmingly predominant in adynamic bone. The type V osteoblasts appeared most frequently in osteitis fibrosa, followed by mixed and mild change. Both absolute and relative lengths of bone surface covered by the type V osteoblasts were significantly higher in the high-turnover bone group (osteitis fibrosa and mixed) than the low-turnover bone group (adynamic bone and osteomalacia). The type V osteoblasts were slightly correlated with serum intact parathyroid hormone levels. In conclusion, a high bone-turnover condition seems to be associated with the promotion of osteoblastic apoptosis in dialysis patients. This finding may explain the fact that osteopenia develops faster in CKD patients with high turnover of bone.
Coleman, Robert; Aksnes, Anne-Kirsti; Naume, Bjørn; Garcia, Camilo; Jerusalem, Guy; Piccart, Martine; Vobecky, Nancy; Thuresson, Marcus; Flamen, Patrick
Radium-223 dichloride (radium-223) mimics calcium and emits high-energy, short-range alpha-particles resulting in an antitumor effect on bone metastases. This open-label, phase IIa nonrandomized study investigated safety and short-term efficacy of radium-223 in breast cancer patients with bone-dominant disease. Twenty-three advanced breast cancer patients with progressive bone-dominant disease, and no longer candidates for further endocrine therapy, were to receive radium-223 (50 kBq/kg IV) every 4 weeks for 4 cycles. The coprimary end points were change in urinary N-telopeptide of type 1 (uNTX-1) and serum bone alkaline phosphatase (bALP) after 16 weeks of treatment. Exploratory end points included sequential (18)F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) to assess metabolic changes in osteoblastic bone metastases. Safety data were collected for all patients. Radium-223 significantly reduced uNTX-1 and bALP from baseline to end of treatment. Median uNTX-1 change was -10.1 nmol bone collagen equivalents/mmol creatinine (-32.8 %; P = 0.0124); median bALP change was -16.7 ng/mL (-42.0 %; P = 0.0045). Twenty of twenty-three patients had FDG PET/CT identifying 155 hypermetabolic osteoblastic bone lesions at baseline: 50 lesions showed metabolic decrease (≥25 % reduction of maximum standardized uptake value from baseline) after 2 radium-223 injections [32.3 % metabolic response rate (mRR) at week 9], persisting after the treatment period (41.5 % mRR at week 17). Radium-223 was safe and well tolerated. Radium-223 targets areas of increased bone metabolism and shows biological activity in advanced breast cancer patients with bone-dominant disease.
Calzada, Elizabeth; Onguka, Ouma; Claypool, Steven M.
Phosphatidylethanolamine (PE) is the second most abundant glycerophospholipid in eukaryotic cells. The existence of four only partially redundant biochemical pathways that produce PE, highlights the importance of this essential phospholipid. The CDP-ethanolamine and phosphatidylserine decarboxylase pathways occur in different subcellular compartments and are the main sources of PE in cells. Mammalian development fails upon ablation of either pathway. Once made, PE has diverse cellular functions that include serving as a precursor for phosphatidylcholine and a substrate for important posttranslational modifications, influencing membrane topology, and promoting cell and organelle membrane fusion, oxidative phosphorylation, mitochondrial biogenesis, and autophagy. The importance of PE metabolism in mammalian health has recently emerged following its association with Alzheimer's disease, Parkinson's disease, nonalcoholic liver disease, and the virulence of certain pathogenic organisms. PMID:26811286
Rennert, O M; Chan, W Y; Hidalgo, H; Cushing, W; Griesmann, G
Clinical investigations of the urinary excretion of putrescine and the polyamines spermidine and spermine in a patient with Menkes kinky hair disease are reported. This disorder, characterized by intra- and extracellular copper deficiency, is associated with significant depression of diamine oxidase and monoamine oxidase activity. Urinary excretion of diamine and polyamines, monitored over a 2-month interval in a 4-month old patient with Menkes kinky hair disease, documented a 3- to 10-fold increase in the excretion of free putrescine, spermidine and spermine as well as the conjugated derivatives of putrescine and spermidine. These observations suggest that abnormalities in diamine and polyamine concentration occur in disease states in which the metabolic transformation of these compounds is impaired.
Jiang, Zhenghui Gordon; Robson, Simon C.; Yao, Zemin
Nonalcoholic fatty liver disease (NAFLD), an escalating health problem worldwide, covers a spectrum of pathologies characterized by fatty accumulation in hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellular role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metabolism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD. PMID:23554788
Santini, Daniele; Fratto, Maria Elisabetta; Vincenzi, Bruno; Galluzzo, Sara; Tonini, Giuseppe
Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. Moreover, in vivo preclinical and preliminary clinical data suggest that bisphosphonates may prevent cancer treatment-induced bone loss and the onset of malignant bone disease in patients with early-stage cancer. This comprehensive review critically reports the several preclinical evidences of action of bisphosphonates on osteoclasts, lymphocytes and tumour cells. In addition, all the clinical trials evaluating the effects of principal bisphosphonates on skeletal disease progression in patients with breast cancer, prostate cancer, non-small cell lung cancer and other cancers have been reported. Of the available bisphosphonates, intravenous zoledronic acid has demonstrated the broadest clinical activity and is actually approved for the treatment of bone metastases from any solid tumour in many countries. Renal safety is an important consideration for oncologists who are treating patients with bisphosphonates. This issue and the other topics relating to the safety of bisphosphonates are discussed in this review.
Luria, Tal; Matsliah, Yinnon; Adir, Yochai; Josephy, Noam; Moran, Daniel S; Evans, Rachel K; Abramovich, Amir; Eliakim, Alon; Nemet, Dan
Submariners taking part in prolonged missions are exposed to environmental factors that may adversely affect bone health. Among these, relatively high levels of CO(2), lack of sunlight exposure affecting vitamin D metabolism, limited physical activity, and altered dietary habits. The aims of this study were to examine the effect of a prolonged submersion (30 days) on changes in bone strength using quantitative bone speed of sound and in markers of bone metabolism that include bone turnover (BAP, PINP, TRAP5b, and CTx) and endocrine regulators (serum calcium, PTH, and 25[OH]D) in a group of 32 young healthy male submariners. The prolonged submersion led to increases in body weight and BMI and to a decrease in fitness level. There was a significant decrease in bone strength following the submersion. Speed of sound exhibited continued decline at 4 weeks after return to shore and returned to baseline levels at the 6-month follow-up. There was a significant increase in circulating calcium level. PTH and 25(OH)D levels decreased significantly. Significant decreases were observed in both TRAP5b and CTx levels, markers of bone resorption, as well as in N-terminal propeptide of type I collagen (PINP), a bone formation marker. Prolonged submersion led to a significant decrease in bone strength, accompanied by an overall decrease in bone metabolism. Bone strength was regained only 6 months after return to shore. Prevention and/or rehabilitation programs should be developed following periods of relative disuse even for young submariners. The effects of repeated prolonged submersions on bone health are yet to be determined.
Lirani, Ana Paula R; Lazaretti-Castro, Marise
The action of physical agents such as low level laser therapy, low-intensity pulsed ultrasound and electrical and electromagnetic fields on bone have been often studied, showing that they are able to promote osteogenesis, accelerate fracture consolidation and augment bone mass. The use of these therapeutic modalities was first based on the finding that bone is a piezoelectric material, that means it can generate polarization when deformed, transforming mechanical energy into electric energy, and this has widen therapeutic possibilities to bony tissue. The present work aims to present evidences of physiologic effects and mechanisms of action of these physical agents on bone metabolism, based on articles published in international scientific literature.
Li, Hui; Li, Xiaoyi; Ramanathan, Murali; Zhang, Aidong
With the booming of healthcare industry and the overwhelming amount of electronic health records (EHRs) shared by healthcare institutions and practitioners, we take advantage of EHR data to develop an effective disease risk management model that not only models the progression of the disease, but also predicts the risk of the disease for early disease control or prevention. Existing models for answering these questions usually fall into two categories: the expert knowledge based model or the handcrafted feature set based model. To fully utilize the whole EHR data, we will build a framework to construct an integrated representation of features from all available risk factors in the EHR data and use these integrated features to effectively predict osteoporosis and bone fractures. We will also develop a framework for informative risk factor selection of bone diseases. A pair of models for two contrast cohorts (e.g., diseased patients versus non-diseased patients) will be established to discriminate their characteristics and find the most informative risk factors. Several empirical results on a real bone disease data set show that the proposed framework can successfully predict bone diseases and select informative risk factors that are beneficial and useful to guide clinical decisions.
Martineau, Corine; Martin-Falstrault, Louise; Brissette, Louise; Moreau, Robert
A positive correlation between plasma levels of HDL and bone mass has been reported by epidemiological studies. As scavenger receptor class B, type I (SR-BI), the gene product of Scarb1, is known to regulate HDL metabolism, we recently characterized bone metabolism in Scarb1-null mice. These mice display high femoral bone mass associated with enhanced bone formation. As gender differences have been reported in HDL metabolism and SR-BI function, we investigated gender-specific bone alterations in Scarb1-null mice by microtomography and histology. We found 16% greater relative bone volume and 39% higher bone formation rate in the vertebrae from 2-month-old Scarb1-null females. No such alteration was seen in males, indicating gender- and region-specific differences in skeletal phenotype. Total and HDL-associated cholesterol levels, as well as ACTH plasma levels, were increased in both Scarb1-null genders, the latter being concurrent to impaired corticosterone response to fasting. Plasma levels of estradiol did not differ between null and WT females, suggesting that the estrogen metabolism alteration is not relevant to the higher vertebral bone mass in female Scarb1-null mice. Constitutively, high plasma levels of leptin along with 2.5-fold increase in its expression in white adipose tissue were measured in female Scarb1-null mice only. In vitro exposure of bone marrow stromal cells to ACTH and leptin promoted osteoblast differentiation as evidenced by increased gene expression of osterix and collagen type I alpha. Our results suggest that hyperleptinemia may account for the gender-specific high bone mass seen in the vertebrae of female Scarb1-null mice.
Nagata, K; Kondoh, Y; Atchison, R; Sato, M; Satoh, Y; Watahiki, Y; Hirata, Y; Yokoyama, E
Vascular and metabolic reserve were analyzed in probable Alzheimer's disease (AD) and vascular dementia (VaD). Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO(2)), and oxygen extraction fraction (OEF) were measured quantitatively with positron emission tomography (PET). Vascular reactivity (VR) was also calculated by comparing the CBF during 5% CO(2) inhalation with the CBF during normal breathing. Vascular transit time (VTT) that was calculated as a ratio of CBV/CBF and VR reflect vasodilating capacity of the small resistance vessels, whereas OEF designates metabolic (oxygen-extraction) reserve in threatening brain ischemia. Significant increase in OEF was seen in the parieto-temporal cortex and both VTT and VR were preserved in AD patients. By constrast, there was no significant increase in OEF whereas VTT was prolonged and VR was markedly depressed in VaD patients. The increase of OEF and preserved VTT and VR seen in AD patients indicate the possible participation of vascular factors in the pathogenesis of AD perhaps at the capillary level.
Alonso, N; Calero-Paniagua, I; Del Pino-Montes, J
Paget's disease of bone (PDB) is the second most common metabolic bone disorder, after osteoporosis. It is characterised by focal areas of increased and disorganised bone turnover, coupled with increased bone formation. This disease usually appears in the late stages of life, being slightly more frequent in men than in women. It has been reported worldwide, but primarily affects individuals of British descent. Majority of PDB patients are asymptomatic, but clinical manifestations include pain, bone deformity and complications, like pathological fractures and deafness. The causes of the disease are poorly understood and it is considered as a complex trait, combining genetic predisposition with environmental factors. Linkage analysis identified SQSTM1, at chromosome 5q35, as directly related to the disease. A number of mutations in this gene have been reported, pP392L being the most common variant among different populations. Most of these variants affect the ubiquitin-associated (UBA) domain of the protein, which is involved in autophagy processes. Genome-wide association studies enlarged the number of loci associated with PDB, and further fine-mapping studies, combined with functional analysis, identified OPTN and RIN3 as causal genes for Paget's disease. A combination of risk alleles identified by genome-wide association studies led to the development of a score to predict disease severity, which could improve the management of the disease. Further studies need to be conducted to elucidate other important aspects of the trait, such as its focal nature and the epidemiological changes found in some populations. In this review, we summarize the clinical characteristics of the disease and the latest genetic advances to identify susceptibility genes. We also list current available treatments and prospective options.
Planas Vilà, Mercè
The central nervous system regulates food intake, homoeostasis of glucose and electrolytes, and starts the sensations of hunger and satiety. Different nutritional factors are involved in the pathogenesis of several neurological diseases. Patients with acute neurological diseases (traumatic brain injury, cerebral vascular accident hemorrhagic or ischemic, spinal cord injuries, and cancer) and chronic neurological diseases (Alzheimer's Disease and other dementias, amyotrophic lateral sclerosis, Parkinson's Disease) increase the risk of malnutrition by multiple factors related to nutrient ingestion, abnormalities in the energy expenditure, changes in eating behavior, gastrointestinal changes, and by side effects of drugs administered. Patients with acute neurological diseases have in common the presence of hyper metabolism and hyper catabolism both associated to a period of prolonged fasting mainly for the frequent gastrointestinal complications, many times as a side effect of drugs administered. During the acute phase, spinal cord injuries presented a reduction in the energy expenditure but an increase in the nitrogen elimination. In order to correct the negative nitrogen balance increase intakes is performed with the result of a hyper alimentation that should be avoided due to the complications resulting. In patients with chronic neurological diseases and in the acute phase of cerebrovascular accident, dysphagia could be present which also affects intakes. Several chronic neurological diseases have also dementia, which lead to alterations in the eating behavior. The presence of malnutrition complicates the clinical evolution, increases muscular atrophy with higher incidence of respiratory failure and less capacity to disphagia recuperation, alters the immune response with higher rate of infections, increases the likelihood of fractures and of pressure ulcers, increases the incapacity degree and is an independent factor to increase mortality. The periodic nutritional
Oksztulska-Kolanek, Ewa; Znorko, Beata; Michałowska, Małgorzata; Pawlak, Krystyna
Mineral metabolism disturbances are common in chronic kidney disease (CKD) and have been classified as a new clinical entity, also known as CKD-mineral and bone disorders (CKD-MBD). A decrease in the bone strength, whose clinical manifestation is a tendency for fracture, has been recognized as an important component of CKD-MBD. Because of ethical issues, measurements of the bone strength in the human body are usually limited to noninvasive techniques, such as radiography, dual-energy X-ray absorptiometry and the assays of bone turnover biomarkers. However, it has been postulated recently that the evidence concerning bone strength based solely on the determination of the bone quantity may be insufficient and that bone quality should also be examined. In this regard, an animal model of CKD can represent an experimental tool to test the effectiveness of new therapeutic strategies. Despite the many available methods that are used to diagnose metabolic bone disorders and predict fracture risk especially in small rodents with CKD, it turns out that the most appropriate are biomechanical tests, which can provide information about the structural and material properties of bone. The present review summarizes and discusses the principles for carrying out selected biomechanical tests (3-point bending test and compression test) and their application in clinical practice.
Recently, attention has been focused on the disorders of bone and calcium metabolism during space flight. The skeletal system has evolved on the Earth under 1-g. Space flights under low gravity appear to cause substantial changes in bone and calcium homeostasis of the animals adapted to 1-g. A space experiment for the First Materials Processing Test (FMPT) was proposed to examine the effects of low gravity on calcium metabolism and bone formation using chick embryos loaded in a space shuttle. This space experiment was proposed based on the following two experimental findings. First, it has been reported that bone density decreases significantly during prolonged space flight. The data obtained from the US Skylab and the U.S.S.R. Salyut-6 cosmonauts have also documented that the degree of bone loss is related to the duration of space flight. Second, the US-Soviet joints space experiment demonstrated that the decrease in bone density under low gravity appears to be due to the decrease in bone formation rather than the increase in bone resorption. The purpose of our space experiment is, therefore, to investigate further the mechanisms of bone growth under low gravity using fertilized chick embryos.
da Silva, Valéria Nóbrega; Fiorelli, Luciana Nunes Mosca; da Silva, Carla Cristiane; Kurokawa, Cilmery Suemi; Goldberg, Tamara Beres Lederer
In recent years, there has been growing concern about the occurrence of metabolic syndrome (MetS) at an early age and its effects on bone mass in adolescents. Adolescence is considered a critical period for bone mass gain. Impaired bone acquisition during this phase can lead to "suboptimal" peak bone mass and increase the risk of osteopenia/osteoporosis and fractures in old age. The objective of this review was to perform a critical analysis of articles that specifically focus on this age group, evaluating the influence of MetS and its components on bone mineral density in adolescents. A possible relationship between this syndrome and bone mass has been demonstrated, but the number of studies addressing this topic in adolescents is small. Despite the scarcity of evidence, the results of those studies show that Metabolic Syndrome is negatively correlated with bone mass and also that some components of MetS are negatively correlated with bone mineral density in adolescents. However, the associations between MetS and bone mass development need to be further explored in the age group corresponding to adolescence. Further good-quality studies are necessary to complement the understanding of this relationship.
Vogel, J. M.; Rambaut, P. C.; Smith, M. C., Jr.
Loss of mineral from bone during periods of immobilization, recumbency, or weightlessness is examined. This report describes the instrumentation, technique, and bone mineral changes observed preflight and postflight for the Apollo 14, 15, and 16 missions. The bone mineral changes documented during the Apollo Program are reviewed, and their relevance to future missions is discussed.
Inoue, Koichi; Tsutsui, Haruhito; Akatsu, Hiroyasu; Hashizume, Yoshio; Matsukawa, Noriyuki; Yamamoto, Takayuki; Toyo'Oka, Toshimasa
Alzheimer's disease (AD) is an irreversible, progressive brain disease and can be definitively diagnosed after death through an examination of senile plaques and neurofibrillary tangles in several brain regions. It is to be expected that changes in the concentration and/or localization of low-molecular-weight molecules are linked to the pathological changes that occur in AD, and determining their identity would provide valuable information regarding AD processes. Here, we propose definitive brain metabolic profiling using ultra-performance liquid chromatography coupled with electrospray time-of-flight mass spectrometry analysis. The acquired data were subjected to principal components analysis to differentiate the frontal and parietal lobes of the AD/Control groups. Significant differences in the levels of spermine and spermidine were identified using S-plot, mass spectra, databases and standards. Based on the investigation of the polyamine metabolite pathway, these data establish that the downstream metabolites of ornithine are increased, potentially implicating ornithine decarboxylase activity in AD pathology.
Hummel, M; Standl, E; Schnell, O
Chromium is an essential mineral that appears to have a beneficial role in the regulation of insulin action, metabolic syndrome, and cardiovascular disease. There is growing evidence that chromium may facilitate insulin signaling and chromium supplementation therefore may improve systemic insulin sensitivity. Tissue chromium levels of subjects with diabetes are lower than those of normal control subjects, and a correlation exists between low circulating levels of chromium and the incidence of type 2 diabetes. Controversy still exists as to the need for chromium supplementation. However, supplementation with chromium picolinate, a stable and highly bioavailable form of chromium, has been shown to reduce insulin resistance and to help reduce the risk of cardiovascular disease and type 2 diabetes. Since chromium supplementation is a safe treatment, further research is necessary to resolve the confounding data. The existing data suggest to concentrate future studies on certain forms as chromium picolinate and doses as at least 200 mcg per day.
Chakravorty, N. K.; Das, S. K.; Kataria, M. S.
Paget's disease of bone has been known for about 100 years and the usual deformities of bone, e.g. bowed tibia, large head, are well described in medical text books. However, there does not appear to have been a description of corrugation of the skull as a recognized deformity in Paget's disease. Three cases are now described to illustrate this deformity as an unusual but valuable sign in this disease. Images Fig. 5 Fig. 6 Fig. 1 Fig. 2 Fig. 3 Fig. 4 Figs. 7 and 8 PMID:876912
Marmotti, Antonio; de Girolamo, Laura; Bonasia, Davide Edoardo; Bruzzone, Matteo; Mattia, Silvia; Rossi, Roberto; Montaruli, Angela; Dettoni, Federico; Castoldi, Filippo; Peretti, Giuseppe
Stem cells have huge applications in the field of tissue engineering and regenerative medicine. Their use is currently not restricted to the life-threatening diseases but also extended to disorders involving the structural tissues, which may not jeopardize the patients' life, but certainly influence their quality of life. In fact, a particularly popular line of research is represented by the regeneration of bone and cartilage tissues to treat various orthopaedic disorders. Most of these pioneering research lines that aim to create new treatments for diseases that currently have limited therapies are still in the bench of the researchers. However, in recent years, several clinical trials have been started with satisfactory and encouraging results. This article aims to review the concept of stem cells and their characterization in terms of site of residence, differentiation potential and therapeutic prospective. In fact, while only the bone marrow was initially considered as a "reservoir" of this cell population, later, adipose tissue and muscle tissue have provided a considerable amount of cells available for multiple differentiation. In reality, recently, the so-called "stem cell niche" was identified as the perivascular space, recognizing these cells as almost ubiquitous. In the field of bone and joint diseases, their potential to differentiate into multiple cell lines makes their application ideally immediate through three main modalities: (1) cells selected by withdrawal from bone marrow, subsequent culture in the laboratory, and ultimately transplant at the site of injury; (2) bone marrow aspirate, concentrated and directly implanted into the injury site; (3) systemic mobilization of stem cells and other bone marrow precursors by the use of growth factors. The use of this cell population in joint and bone disease will be addressed and discussed, analysing both the clinical outcomes but also the basic research background, which has justified their use for the
Rodríguez C, Magdalena; Giachetto L, Gustavo; Cuneo E, Alejandro; Gutiérrez B, María del C; Shimchack R, Mario; Pírez G, M Catalina
Fever, headache, myalgias and lymphadenopathy are characteristic manifestations of cat-scratch disease but other less common findings are described in 2 to 10% of cases. We report two children that presented with hepatosplenic abscesses and bone involvement. One child, had multiple areas of increased uptake in the bone scintigram with a positive serology (IgG > 1/256, IgM slightly positive). The second child had destruction of the L2 vertebral body that compromised the channel and right foramen as visualized by MRI. In both cases, bacilli were observed in the bone biopsy by Warthing-Starry stain.
Abella, Vanessa; Scotece, Morena; Conde, Javier; López, Verónica; Lazzaro, Verónica; Pino, Jesús; Gómez-Reino, Juan J; Gualillo, Oreste
The metabolic syndrome (MetS) is a cluster of cardiometabolic disorders that result from the increasing prevalence of obesity. The major components of MetS include insulin resistance, central obesity, dyslipidemia, and hypertension. MetS identifies the central obesity with increased risk for cardiovascular diseases (CVDs) and type-2 diabetes mellitus (T2DM). Patients with rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis, have increased prevalence of CVDs. Moreover, CVD risk is increased when obesity is present in these patients. However, traditional cardiovascular risk factors do not completely explain the enhanced cardiovascular risk in this population. Thus, MetS and the altered secretion patterns of proinflammatory adipokines present in obesity could be the link between CVDs and rheumatic diseases. Furthermore, adipokines have been linked to the pathogenesis of MetS and its comorbidities through their effects on vascular function and inflammation. In the present paper, we review recent evidence of the role played by adipokines in the modulation of MetS in the general population, and in patients with rheumatic diseases.
Abella, Vanessa; Scotece, Morena; López, Verónica; Lazzaro, Verónica; Pino, Jesús; Gómez-Reino, Juan J.; Gualillo, Oreste
The metabolic syndrome (MetS) is a cluster of cardiometabolic disorders that result from the increasing prevalence of obesity. The major components of MetS include insulin resistance, central obesity, dyslipidemia, and hypertension. MetS identifies the central obesity with increased risk for cardiovascular diseases (CVDs) and type-2 diabetes mellitus (T2DM). Patients with rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis, have increased prevalence of CVDs. Moreover, CVD risk is increased when obesity is present in these patients. However, traditional cardiovascular risk factors do not completely explain the enhanced cardiovascular risk in this population. Thus, MetS and the altered secretion patterns of proinflammatory adipokines present in obesity could be the link between CVDs and rheumatic diseases. Furthermore, adipokines have been linked to the pathogenesis of MetS and its comorbidities through their effects on vascular function and inflammation. In the present paper, we review recent evidence of the role played by adipokines in the modulation of MetS in the general population, and in patients with rheumatic diseases. PMID:24741591
Over twenty five years ago epidemiological studies revealed that there was a relationship between patterns of early growth and subsequent risk of diseases such as type 2 diabetes, cardiovascular disease and the metabolic syndrome. Studies of identical twins, individuals who were in utero during periods of famine, discordant siblings and animal models have provided strong evidence that the early environment plays an important role in mediating these relationships. Early nutrition is one such important environmental factor. The concept of early life programming is therefore widely accepted and the underlying mechanisms starting to emerge. These include: (1) Permanent structural changes in an organ due to exposure to suboptimal levels of essential hormones or nutrients during a critical period of development leading to permanent changes in tissue function (2) Persistent epigenetic changes such as DNA methylation and histone modifications and miRNAs leading to changes in gene expression. (3) Permanent effects on regulation of cellular ageing through increases in oxidative stress and mitochondrial dysfunction leading to DNA damage and telomere shortening. Further understanding of these processes will enable the development of preventative and intervention strategies to combat the burden of common diseases such as type 2 diabetes and cardiovascular disease.
Clarke, M; Ward, M; Strain, J J; Hoey, L; Dickey, W; McNulty, H
Osteoporosis, a metabolic skeletal disease characterised by decreased bone mass and increased fracture risk, is a growing public health problem. Among the various risk factors for osteoporosis, calcium and vitamin D have well-established protective roles, but it is likely that other nutritional factors are also implicated. This review will explore the emerging evidence supporting a role for certain B-vitamins, homocysteine and the 677 C → T polymorphism in the gene encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase, in bone health and disease. The evidence, however, is not entirely consistent and as yet no clear mechanism has been defined to explain the potential link between B-vitamins and bone health. Coeliac disease, a common condition of malabsorption, induced by gluten ingestion in genetically susceptible individuals, is associated with an increased risk both of osteoporosis and inadequate B-vitamin status. Given the growing body of evidence linking low bone mineral density and/or increased fracture risk with low B-vitamin status and elevated homocysteine, optimal B-vitamin status may play an important protective role against osteoporosis in coeliac disease; to date, no trial has addressed this possible link.
Baecker, Natalie; Frings-Meuthen, Petra; Heer, Martina; Mester, Jochen; Liphardt, Anna-Maria
The absence of mechanical loading leads to a prompt increase in bone resorption measured by bone resorption markers. There is high potential that vibration training can positively influence bone metabolism in immobilized subjects, reduce the increase in osteoclastic activity and increase bone formation processes. We investigated whether vibration training at 20 Hz with an amplitude of 2-4 mm influences bone metabolism during immobilization. Eight male subjects (26.4 ± 4.9 years; 78.1 ± 9.5 kg) performed a 14 day bed rest in 6°-head down tilt (HDT). Subjects received vibration training for 2 × 5 min/day or a control intervention without vibration (crossover design). Calcium excretion and bone resorption markers C-telopeptide (CTX) and N-telopeptide (NTX) were analyzed from 24 h urine samples. Bone formation markers, bone alkaline phosphatase (bAP) and procollagen-N propeptide (PINP) were analyzed from fasting blood samples. Our results show an increase in bone resorption very early during HDT bed rest in both interventions (CTX: p < 0.01; NTX: p < 0.001). Vibration training did not have any different effect on bone resorption markers (CTX: p = 0.10; NTX: p = 0.58), bone formation markers (PINP: p = 0.21; bAP: p = 0.12) and calcium excretion (p < 0.64) compared to the control condition. Mere vibration training with 20 Hz for 2 × 5 min/day does not prevent increase in bone resorption as measured with the described methods in our short-term HDT bed rest.
Cahoon, S.; Boden, S. D.; Gould, K. G.; Vailas, A. C.
Measurement of bone turnover in conditions such as osteoporosis has been limited by the need for invasive iliac bone biopsy to reliably determine parameters of bone metabolism. Recent advances in the area of serum and urinary markers of bone metabolism have raised the possibility for noninvasive measurements; however, little nonhuman primate data exist for these parameters. The purpose of this experiment was to define the normal range and variability of several of the newer noninvasive bone markers which are currently under investigation in humans. The primary intent was to determine age and gender variability, as well as provide some normative data for future experiments in nonhuman primates. Twenty-four rhesus macaques were divided into equal groups of male and female according to the following age groupings: 3 years, 5-10 years, 15-20 years, and > 25 years. Urine was collected three times daily for a four-day period and measured for several markers of bone turnoverm including pyridinoline (PYD), deoxypyrodinoline (DPD), hydroxyproline, and creatinine. Bone mineral density measurements of the lumbar spine were performed at the beginning and end of the study period. Serum was also obtained at the time of bone densitometry for measurement of osteocalcin levels by radioimmunoassay. There were no significant differences in bone mineral density, urine PYD, or urine DPD based on gender. Bone density was lowest in the youngest animals, peaked in the 15-20-year group, but again decreased in the oldest animals. The osteocalcin, PYD, and DPD levels followed an inversely related pattern to bone density. The most important result was the relative age insensitivity of the ratio of PYD:DPD in monkeys up to age 20 years. Since bone density changes take months or years to become measurable and iliac biopsies are invasive, the PYD/DPD marker ratio may have important implications for rapid noninvasive measurement of the effects of potential treatments for osteoporosis in the non
Suzuki, Nobuo; Somei, Masanori; Seki, Azusa; Reiter, Russel J; Hattori, Atsuhiko
Several reports indicate that melatonin is involved in the regulation of bone metabolism. To examine the direct effect of melatonin on osteoclasts and osteoblasts, we developed an in vitro assay using fish scales that contain osteoclasts, osteoblasts, and bone matrix, all of which are similar to those found in mammalian membrane bone. Using the assay, we demonstrated that melatonin suppressed osteoclastic and osteoblastic activities. These findings are in agreement with the reports from in vivo studies in mice and rats. In an attempt to develop molecules that increase bone mass, novel bromomelatonin derivatives were synthesized, and the effects of these chemicals on osteoclasts and osteoblasts using the scale assay were examined. As a result, novel bromomelatonin derivatives with the ability to possibly increase bone formation were identified. In scale osteoclasts, particularly, 1-benzyl-2,4,6-tribromomelatonin had a more potent activity than melatonin. In reference to osteoblasts, this agent (10(-9)-10(-6)M) significantly activated osteoblasts. The effect of 1-benzyl-2,4,6-tribromomelatonin on bone formation was confirmed in ovariectomized rats. Thus, the oral administration of 1-benzyl-2,4,6-tribromomelatonin augmented the total bone mineral density of the femoral metaphysis of ovariectomized rats. The stress-strain index of the diaphysis in 1-benzyl-2,4,6-tribromomelatonin-treated rats significantly increased in comparison with that in ovariectomized rats. In rats fed a low-calcium diet, the total bone mineral density of the femoral metaphysis significantly increased following the oral administration of 1-benzyl-2,4,6-tribromomelatonin. These studies identified a melatonin derivative that may have potential use in the treatment of bone diseases, such as osteoporosis.
Bain, M D; Jones, M; Borriello, S P; Reed, P J; Tracey, B M; Chalmers, R A; Stacey, T E
Metronidazole, an antibiotic with specific activity against anaerobic bacteria, was of clinical and biochemical benefit in two patients with methylmalonic aciduria. The virtual elimination of propionic acid from the stool suggested that propionic acid derived from faecal bacterial metabolism contributes substantially to methylmalonate production. These findings point to a novel avenue of treatment for these disorders of intermediary metabolism, and indicate the importance of microbial gut flora in normal human metabolism.
Kanaya, K.; Iba, K.; Dohke, T.; Okazaki, S.; Yamashita, T.
Objectives: Nociceptors are expressed at peripheral terminals of neurons. Recent studies have shown that TRPV1, a nociceptor, is expressed in bone tissue and regulates bone metabolism. We have demonstrated that a TRPV1 antagonist improved pain-like behavior in ovariectomized (OVX) mice. The aim of this study was to determine whether nociceptors, including TRPV1, acid-sensing ion channel (ASIC) and P2X2/3 are expressed in bone cells, and to examine the effects of nociceptor antagonists on bone metabolism. Methods: The expression of nociceptors in femoral bone tissue and cultured bone marrow cells in OVX and sham-operated mice were examined. The effects of nociceptor antagonists on the up-regulated expression of bone metabolic markers, Runx2, Osterix, osteocalcin and RANKL, were also examined. Results: TRPV1, ASIC 2 and 3, and P2X2 and 3, were expressed in bone tissue and bone marrow cells, and the expression levels of ASIC1 and 2, and P2X2 were significantly increased in OVX mice in comparison with those in sham mice. Treatment with nociceptor antagonists significantly inhibited the expression of bone metabolic markers in OVX mice. Conclusion: An array of nociceptors, TRPV1, ASICs and P2X2/3, could simultaneously regulate not only increases in skeletal pain but also bone turnover in OVX mice. PMID:27282458
van Dijk, S C; de Herder, W W; Kwekkeboom, D J; Zillikens, M C; Feelders, R A; van Schaik, R H N; van Driel, M; van Leeuwen, J P T M
In patients with a carcinoid syndrome and neuroendocrine tumors of the digestive tract (carcinoids), elevated circulating serotonin (5-hydroxytryptamine, 5-HT) levels can be demonstrated. It can be hypothesized that bone metabolism will be affected in these patients, since serotonin receptors are expressed on bone cells and serotonin effects on bone have been demonstrated. However, to date, no data are available on bone metabolism parameters in patients with neuroendocrine tumors of the digestive tract (carcinoids). In the current retrospective study we have measured serum bone formation markers P1CP (pro-collagen type I C-terminal), and osteocalcin, and the bone resorption marker NTx (collagen breakdown product N-terminal), in a group of 61 carcinoid patients with increased circulating serotonin levels as demonstrated by increased excretion of the serotonin breakdown product, 5-hydroxy indole acetic acid (5-HIAA), in the urine (>50 μmol/24 h, so-called "hyper-secretors") and a control group of 23 carcinoid patients, without increased 5-HIAA excretion (so-called non-secretors). The 24-h urinary excretion of 5-HIAA reflects the 24-h production of serotonin. Measurements of markers of bone metabolism were performed in serum samples obtained before the start of medical treatment. The hypersecretor group had on average a 10-fold higher urinary 5-HIAA excretion than the control (non-secretor) group. No significant differences in bone metabolism parameters could be demonstrated between hyper-secretors and controls (non-secretors). Correlation and regression analyses could not demonstrate significant age- and sex-adjusted correlations between urinary 5-HIAA excretion and any of the markers for bone turnover. A limitation is that the exposure time to elevated levels of serotonin is unknown, which might have been too short to induce effects on bone metabolism. Treatment of human pre-osteoblasts SV-HFO with serotonin didn't change alkaline phosphatase activity throughout
Shigematsu, Takashi; Akizawa, Tadao; Uchida, Eiji; Tsukamoto, Yusuke; Iwasaki, Manabu; Koshikawa, Shouzo
Background/Aims Few clinical trials conducted with cinacalcet have thoroughly addressed its effects of on bone metabolism. We assessed the effects of cinacalcet on bone markers in Japanese hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). Methods 200 Japanese HD patients with intact PTH (iPTH) levels ≥300 pg/ml were enrolled. The dose of cinacalcet was titrated from 25 up to 100 mg/day to achieve iPTH levels ≤250 pg/ml for 52 weeks. Results At the end of the study visit, 57.8% of patients (115/199) had achieved iPTH levels ≤250 pg/ml. Serum Ca, phosphorus (P) and Ca × P levels decreased rapidly and were maintained throughout the study. At week 52, all bone metabolic markers levels had decreased significantly from baseline. Although bone resorption markers gradually decreased throughout the study period, bone alkaline phosphatase significantly increased during the first 4 weeks and then gradually decreased. Conclusions The time courses of changes in bone markers after cinacalcet treatment resembled those observed after surgical parathyroidectomy (PTx), sometimes described as the hungry bone syndrome, indicating that cinacalcet treatment induces a rapid recovery in bone response to calcium. In addition, long-term efficacy and safety of cinacalcet were also observed in Japanese patients undertaking long-term hemodialysis (167.0 ± 81.4 months). PMID:18797166
Ceccarelli, Elena; Guarino, Elisa G; Merlotti, Daniela; Patti, Aurora; Gennari, Luigi; Nuti, Ranuccio; Dotta, Francesco
Diabetes mellitus (DM) and osteoporosis (OP) are common disorders with a significant health burden, and an increase in fracture risk has been described both in type 1 (T1DM) and in type 2 (T2DM) diabetes. The pathogenic mechanisms of impaired skeletal strength in diabetes remain to be clarified in details and they are only in part reflected by a variation in bone mineral density. In T2DM, the occurrence of low bone turnover together with a decreased osteoblast activity and compromised bone quality has been shown. Of note, some antidiabetic drugs (e.g., thiazolidinediones, insulin) may deeply affect bone metabolism. In addition, the recently introduced class of incretin-based drugs (i.e., GLP-1 receptor agonists and DPP-4 inhibitors) is expected to exert potentially beneficial effects on bone health, possibly due to a bone anabolic activity of GLP-1, that can be either direct or indirect through the involvement of thyroid C cells. Here we will review the established as well as the putative effects of incretin hormones and of incretin-based drugs on bone metabolism, both in preclinical models and in man, taking into account that such therapeutic strategy may be effective not only to achieve a good glycemic control, but also to improve bone health in diabetic patients.
Reeves, J; Arnaud, S; Gordon, S; Subryan, B; Block, M; Huffer, W; Arnaud, C; Mundy, G; Haussler, M
Bone mineral metabolism was studied in five infants aged 8 to 22 months with severe osteopetrosis. There were findings consistent with biochemical osteomalacia. These included hypocalcemia, hypophosphatemia, high serum acid phosphatase and alkaline phosphatase activity, high levels of serum parathyroid hormone, and high urinary cyclic AMP. Serum 1,25(OH)2 vitamin D3 level was high in the one patient tested. Radiographs in all infants revealed rachitic changes in the metaphyses. However, dense bones on radiographs, calcium balance studies, and radio-calcium absorption studies demonstrated markedly positive calcium balance. Iliac crest bone biopsies showed increased quantity of woven bone with abundant numbers of osteoclasts, excessive amounts of osteoid, myelofibrosis, and a decreased number of Howship's lacunae. The wide bands of unmineralized osteoid did not take up tetracycline. In vitro bone resorbing activity due to osteoclast activating factor from cultured stimulated leukocytes was normal. Bone turnover however, was now as evidenced by low urinary hydroxyproline levels. We interpret these findings as indicating there is decreased bone remodeling and resorption in spite of increased humoral stimuli and osteoclasts. Since calcitonin levels were normal for age, the most likely cause of the impaired bone remodeling sequence was defective osteoclast function. We postulate that there may be a common genetic defect in phagocyte cells, including monocytes, neutrophils and osteoclasts, which accounts for the abnormalities of mineral metabolism and previously reported hematologic, neurologic, and infectious complications.
Bikle, D. D.
As the mean age of our population increases, increasing attention has been paid to the diseases associated with aging, including diseases of the skeleton such as osteoporosis. Effective means of treating and possibly preventing such skeletal disorders are emerging, making their early recognition an important goal for the primary care physician. Although bone density measurements and skeletal imaging studies remain of primary diagnostic importance in this regard, a large number of assays for biochemical markers of bone formation and resorption are being developed that promise to complement the densitometry measurements and imaging studies, providing an assessment of the rates of bone turnover and an earlier evaluation of the effects of therapy. In this review, emphasizing the recent literature, the major biochemical markers currently in use or under active investigation are described, and their application in a number of diseases of the skeleton including osteoporosis is evaluated.
Khan, Shoukat H; Rather, Tanveer A; Koul, Parvaiz A; Makhdoomi, Rumana; Bhat, Abdul Rashid; Malik, Dharmender; Manohar, Ram
Ollier's disease is characterized by multiple skeletal enchondroma. There are published data regarding Ollier's disease being associated with vascular malformations and non-skeletal neoplasms. We report a case of Ollier's disease in a young male associated with osteochondroma, low grade glioma in the insular cortex of brain and Gilbert's syndrome. Technetium-99m methylene diphosphonate whole body bone scan is a sensitive investigation to ascertain the complete extent of skeletal involvement particularly the asymptomatic sites. PMID:24379533
Foster, B.L.; Ramnitz, M.S.; Gafni, R.I.; Burke, A.B.; Boyce, A.M.; Lee, J.S.; Wright, J.T.; Akintoye, S.O.; Somerman, M.J.; Collins, M.T.
Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease. PMID:24700690
Foster, B L; Ramnitz, M S; Gafni, R I; Burke, A B; Boyce, A M; Lee, J S; Wright, J T; Akintoye, S O; Somerman, M J; Collins, M T
Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease.
Brestoff, Jonathan R.; Artis, David
Obesity is an increasingly prevalent disease worldwide. While genetic and environmental factors are known to regulate the development of obesity and associated metabolic diseases, emerging studies indicate that innate and adaptive immune cell responses in adipose tissue have critical roles in the regulation of metabolic homeostasis. In the lean state, type 2 cytokine-associated immune cell responses predominate in white adipose tissue and protect against weight gain and insulin resistance through direct effects on adipocytes and elicitation of beige adipose. In obesity, these metabolically beneficial immunologic pathways become dysregulated, and adipocytes and other factors initiate metabolically deleterious type 1 inflammation that impairs glucose metabolism. This review discusses our current understanding of the functions of different types of adipose tissue, how immune cells regulate adipocyte function and metabolic homeostasis in the context of health and disease, and highlights the potential of targeting immuno-metabolic pathways as a therapeutic strategy to treat obesity and associated diseases. PMID:25815992
VanderJagt, Dorothy J.; Okeke, Edith; Calvin, Christine; Troncoso, Carmen; Crossey, Michael; Glew, Robert H.
Bone loss has been shown to be associated with chronic liver disease (CLD) caused by ethanol consumption or viral infection, and trabecular bone is affected more than cortical bone. We therefore used calcaneal ultrasound to compare the bone status of 54 males and 20 females with CLD in northern Nigeria with 88 age- and gender-matched healthy controls. Serum levels of bone-specific alkaline phosphatase (BSAP) and the N-terminal telopeptide of type-1 collagen (NTx) were also measured to estimate relative rates of bone synthesis and turnover, respectively. The mean stiffness index (SI) of the males with CLD and the male controls were not different; however, the mean SI of the female subjects with CLD was lower than for the female controls (101 vs. 86, p=0.003). The levels of NTx and BSAP were markedly elevated in the males, but not in the females, with CLD. Liver function tests did not correlate with ultrasound parameters or biochemical markers of bone metabolism. These results show that Nigerian women, but not males, with CLD have decreased bone density as assessed by calcaneal ultrasound; however, the high rate of bone turnover in Nigerian males with CLD indicates that they are at risk for bone loss. PMID:17913112
Liu, R S; Chou, C S; Yeh, S H
In a patient with Pellegrini-Stieda disease, radiographs of the knees were unremarkable at the time the three-phase bone scintigraphy was abnormal. The results of follow-up radiographs three months later remained normal in the left knee, where local steroid injection was given, but revealed typical positive results in the right knee with no treatment. The three-phase bone scintigraphic pattern is rather typical and antedates the radiographic changes. Thus, the radionuclide technique would provide a useful procedure for the early diagnosis and treatment of Pellegrini-Stieda disease.
Vaishya, Raju; Agarwal, Amit Kumar; Singh, Harsh; Vijay, Vipul
'Brown tumors' are known as 'osteitis fibrosa cystica' or 'Von Recklinghausen's disease' of the bone. A high index of suspicion is required by the treating doctor for diagnosing a 'brown tumor' in its early stage. Clinical suspicion, along with laboratory and radiological investigations, is required to diagnose this condition. We present a case of a 65-year-old woman who had multiple bony lesions and a thyroid nodule, which was initially considered as a metastatic bone disease, but later turned out to be 'brown tumors.' In all cases with multiple osteolytic lesions, a possibility of 'brown tumor' must be kept in mind.
Yamaguchi, Toru; Sugimoto, Toshitsugu
Osteoporosis and type 2 diabetes mellitus (T2DM), both prevalent in aging and westernized societies, adversely affect the health of elderly people by causing fractures and vascular complications, respectively. Recent experimental and clinical studies show that the disorders are etiologically related through the actions of osteocalcin and adiponectin. Meta-analyses of multiple clinical studies show that the hip fracture risk of T2DM patients is increased 1.4-1.7-fold compared with non-DM controls, even though the patients' bone mineral density (BMD) is not diminished. Vertebral fracture risk of the T2DM patients is also increased, and BMD measurement is not sensitive enough to assess this risk. These findings suggest that bone fragility in T2DM patients depends on bone quality deterioration rather than bone mass reduction. Surrogate markers are therefore needed to supplement the partial effectiveness of BMD testing in assessing the fracture risk of the T2DM patients. Markers related to advanced glycation end products may be candidates. These substances modulate bone quality in DM. Until research establishes the usefulness of surrogate markers, physicians should assess fracture risk in T2DM patients not only by measuring the BMD, but also by taking a fracture history and evaluating prior vertebral fractures using spinal X-rays.
The distal radius is one of the most commonly fractured long bone. Colles' fracture results from a fall on the dorsiflexed and pronated hand. The dinner-fork deformity is the typical deformity of the Colles' fracture. For patients with no or a little displacement, conservative treatment is applied. The non-bridge type external fixator is applied for patients without an intra articular fracture. For patients with a comminuted fracture, the locking plate (volar approach) is recommended. During the healing period, shoulder, elbow and finger exercise should be insisted.
Suh, Sunghwan; Lee, Moon-Kyu
There has been a rapid increase in the prevalence of obesity, type 2 diabetes and metabolic syndrome(MetS) over the past two to three decades in most Asian countries. According to the Korean National Health and Nutrition Examination Survey(KNHANES), the prevalence of MetS significantly increased from 24.9% to 31.3% between 1998 and 2007. The clinical significance of MetS is based on the increased risk for the development of cardiovascular disease(CVD). We analyzed the 8-year follow-up data of 2,435 healthy subjects and found that MetS was associated with an increased risk of CVD in both men and women(OR: 1.98, 95% CI: 1.30-3.03 in men; OR: 4.04, 95% CI: 1.78-9.14 in women). MetS was significantly associated with the risk for future coronary heart disease(CHD) in men(OR: 3.68; 95% CI: 1.93-7.01) and stroke in women(OR: 3.96; 95% CI: 1.58- 9.94). We also analyzed the echocardiographic findings of 1,600 healthy subjects to evaluate the relationship between metabolic syndrome and left ventricular diastolic dysfunction(LVDD). The patients with MetS exhibited significant differences in parameters of cardiac structure and the LV diastolic function compared to that observed in the patients without MetS. MetS was associated with an increased risk of LVDD(OR: 1.67; 95% CI: 1.18-2.37). These results suggest that the presence of MetS is associated with an increased risk for the development of serious CVD and abnormal changes in the LV structure and diastolic function, even before the development of overt CVD.
Yamamoto, Masahiro; Sugimoto, Toshitsugu
Growth hormone (GH) as well as insulin like growth factor-1 (IGF-1) are essential hormones to maintain homeostasis of bone turnover by activating osteoblastogenesis and osteoclastogenesis. Results from GH replacement therapy for primary osteoporosis and adult-onset GH deficiency (AGHD) suggest that one year or more treatment period by this agent is required to gain bone mineral density (BMD) over the basal level after compensating BMD loss caused by dominant increase in bone resorption which was observed at early phase of GH treatment. A recent meta-analysis demonstrates the efficacy of GH replacement therapy on increases in BMD in male patients with AGHD. Additional analyses are needed to draw firm conclusions in female patients with AGHD, because insufficient amounts of GH might be administrated to them without considerations of influence of estrogen replacement therapy on IGF-1 production. Further observational studies are needed to clarify whether GH replacement therapy prevent fracture risk in these patients.
Dao, Tien Tuan
Multi-scale modeling of the musculoskeletal system plays an essential role in the deep understanding of complex mechanisms underlying the biological phenomena and processes such as bone metabolic processes. Current multi-scale models suffer from the isolation of sub-models at each anatomical scale. The objective of this present work was to develop a new fully integrated computational workflow for simulating bone metabolic processes at multi-scale levels. Organ-level model employs multi-body dynamics to estimate body boundary and loading conditions from body kinematics. Tissue-level model uses finite element method to estimate the tissue deformation and mechanical loading under body loading conditions. Finally, cell-level model includes bone remodeling mechanism through an agent-based simulation under tissue loading. A case study on the bone remodeling process located on the human jaw was performed and presented. The developed multi-scale model of the human jaw was validated using the literature-based data at each anatomical level. Simulation outcomes fall within the literature-based ranges of values for estimated muscle force, tissue loading and cell dynamics during bone remodeling process. This study opens perspectives for accurately simulating bone metabolic processes using a fully integrated computational workflow leading to a better understanding of the musculoskeletal system function from multiple length scales as well as to provide new informative data for clinical decision support and industrial applications.
Locatelli, Vittorio; Bianchi, Vittorio E.
Background. Growth hormone (GH) and insulin-like growth factor (IGF-1) are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered. PMID:25147565
Fan, Hueng-Chuen; Lee, Herng-Shen; Chang, Kai-Ping; Lee, Yi-Yen; Lai, Hsin-Chuan; Hung, Pi-Lien; Lee, Hsiu-Fen; Chi, Ching-Shiang
Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities. PMID:27490534
... than-usual level of a chemical substance called serum alkaline phosphatase (SAP), it is a sign that the disease may be present. SAP is a type of ... than twice the usual level strongly suggests Paget’s disease, especially if the person’s serum calcium level, phosphorus level, and kidney function are ...
Rubinacci, A; Covini, M; Bisogni, C; Villa, I; Galli, M; Palumbo, C; Ferretti, M; Muglia, M A; Marotti, G
To detect whether the mutual interaction occurring between the osteocytes-bone lining cells system (OBLCS) and the bone extracellular fluid (BECF) is affected by load through a modification of the BECF-extracellular fluid (ECF; systemic extracellular fluid) gradient, mice metatarsal bones immersed in ECF were subjected ex vivo to a 2-min cyclic axial load of different amplitudes and frequencies. The electric (ionic) currents at the bone surface were measured by a vibrating probe after having exposed BECF to ECF through a transcortical hole. The application of different loads and different frequencies increased the ionic current in a dose-dependent manner. The postload current density subsequently decayed following an exponential pattern. Postload increment's amplitude and decay were dependent on bone viability. Dummy and static loads did not induce current density modifications. Because BECF is perturbed by loading, it is conceivable that OBLCS tends to restore BECF preload conditions by controlling ion fluxes at the bone-plasma interface to fulfill metabolic needs. Because the electric current reflects the integrated activity of OBLCS, its evaluation in transgenic mice engineered to possess genetic lesions in channels or matrix constituents could be helpful in the characterization of the mechanical and metabolic functions of bone.
Zhou, Ji-Yin; Chan, Lawrence; Zhou, Shi-Wen
Omentin is an adipokine preferentially produced by visceral adipose tissue with insulin-sensitizing effects. Its expression is reduced in obesity, insulin resistance and type 2 diabetes. Omentin is also positively related with adiponectin, high-density lipoprotein levels and negatively related with body mass index, waist circumference, insulin resistance, triglyceride and leptin levels. Lower plasma omentin levels contribute to the pathogenesis of insulin resistance, type 2 diabetes and cardiovascular diseases in obese or overweight patients. Omentin has anti-inflammatory, antiatherogenic, anti-cardiovascular disease and antidiabetic properties. With respect to vascular biology, omentin causes vasodilatation of blood vessels and attenuates C-reactive protein-induced angiogenesis. The ability of omentin to reduce insulin resistance in conjunction with its anti-inflammatory and anti-atherogenic properties makes it a promising therapeutic target. Thus, omentin may have beneficial effects on the metabolic syndrome and could potentially be used as a biologic marker and/or pharmacologic agent/target in this respect.
Levine, Robert J.; Conn, Harold O.
Plasma levels of tyrosine were assayed in the fasting state and after oral administration of either tyrosine (tyrosine tolerance test) or phenylalanine (phenlyalanine conversion test) in normal subjects and in patients with hepatitis, biliary obstruction, or cirrhosis. Fasting tyrosine levels tended to be slightly increased in patients with hepatitis and biliary obstruction and markedly increased in patients with cirrhosis. Tyrosine tolerance tests in patients with cirrhosis were characterized by larger than normal increments in tyrosine levels and by delayed returns toward fasting levels. The results of phenylalanine conversion tests were abnormal in approximately one-half of patients with either hepatitis or biliary obstruction and four-fifths of patients with cirrhosis. Abnormalities were characterized by elevated fasting plasma tyrosine levels, or small and delayed increments in tyrosine levels, or both. Abnormal phenylalanine conversion test results in patients with cirrhosis did not correlate closely with any clinical feature of cirrhosis or with the results of any standard liver function test; there was positive correlation only with abnormal ammonia tolerance, a test of portalsystemic shunting. Tests of tyrosine metabolism do not appear to be useful for routine clinical assessment of liver function. Tyrosine tolerance tests and phenylalanine conversion tests done for purposes of diagnosis of other diseases may yield misleading results in patients with liver disease. PMID:6074004
Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn
Demirtas, Abdullah; Sahin, Nurettin; Caniklioglu, Mehmet; Kula, Mustafa; Ekmekcioglu, Oguz; Tatlisen, Atila
Purpose. Assessment of effects of zoledronic acid therapy on bone metabolic indicators in hormone-resistant prostate cancer patients with bone metastasis. Material and Methods. Hormone-resistant prostate cancer patients who were identified to have metastases in their bone scintigraphy were taken to trial group. Before administration of zoledronic acid, routine tests for serum calcium, total alkalen phosphates were studied. Sample sera for bone metabolic indicators BALP, PINP, and ICTP were collected. Bone pain was assessed via visual analogue scale and performance via Karnofsky performance scale. Four mg zoledronic acid was administered intravenously once a month. Results. When serum levels of bone forming indicators PINP; BALP were compared before and after therapy, there were insignificant decreases (P = .33, P = .21, resp.). Serum levels of bone destruction indicator ICTP was compared, and there was a significant decrease after zoledronic acid therapy (P = .04). When performances of the patients were compared during therapy period, performances decreased significantly due to progress of illness (P = .01). All patients had ostalgia caused by bone metastases at various degrees. Significant decrease in pain scores was observed (P < .01). Conclusion. Zoledronic acid therapy decreased bone destruction and was effective in palliation of pain in patient with bone metastasis. Using bone metabolic indicators during followup of zoledronic acid therapy might be useful. PMID:22084798
Saito, Yusuke; Chapple, Richard H.; Lin, Angelique; Kitano, Ayumi; Nakada, Daisuke
SUMMARY How cancer cells adapt to metabolically adverse conditions in patients and strive to proliferate is a fundamental question in cancer biology. Here we show that AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase, confers metabolic stress resistance to leukemia-initiating cells (LICs) and promotes leukemogenesis. Upon dietary restriction, MLL-AF9-induced murine AML activated AMPK and maintained leukemogenic potential. AMPK deletion significantly delayed leukemogenesis and depleted LICs by reducing the expression of glucose transporter 1 (Glut1), compromising glucose flux, and increasing oxidative stress and DNA damage. LICs were particularly dependent on AMPK to suppress oxidative stress in the hypoglycemic bone marrow environment. Strikingly, AMPK inhibition synergized with physiological metabolic stress caused by dietary restriction and profoundly suppressed leukemogenesis. Our results indicate that AMPK protects LICs from metabolic stress, and that combining AMPK inhibition with physiological metabolic stress potently suppresses AML by inducing oxidative stress and DNA damage. PMID:26440282
Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that include obesity, impaired glucose tolerance or diabetes, hyperinsulinemia, hypertension, and dyslipidemia. Recently, more attention has been reserved to the correlation between periodontitis and systemic health. MetS is characterized by oxidative stress, a condition in which the equilibrium between the production and the inactivation of reactive oxygen species (ROS) becomes disrupted. ROS have an essential role in a variety of physiological systems, but under a condition of oxidative stress, they contribute to cellular dysfunction and damage. Oxidative stress may act as a common link to explain the relationship between each component of MetS and periodontitis. All those conditions show increased serum levels of products derived from oxidative damage, promoting a proinflammatory state. Moreover, adipocytokines, produced by the fat cells of fat tissue, might modulate the balance between oxidant and antioxidant activities. An increased caloric intake involves a higher metabolic activity, which results in an increased production of ROS, inducing insulin resistance. At the same time, obese patients require more insulin to maintain blood glucose homeostasis – a state known as hyperinsulinemia, a condition that can evolve into type 2 diabetes. Oxidation products can increase neutrophil adhesion and chemotaxis, thus favoring oxidative damage. Hyperglycemia and an oxidizing state promote the genesis of advanced glycation end-products, which could also be implicated in the degeneration and damage of periodontal tissue. Thus, MetS, the whole of interconnected factors, presents systemic and local manifestations, such as cardiovascular disease and periodontitis, related by a common factor known as oxidative stress. PMID:23009606
De Nardo, Dominic; Latz, Eicke
A strong link between inflammation and metabolism is becoming increasingly evident. A number of recent landmark studies have implicated the activation of the NLRP3 inflammasome, an interleukin-1β family cytokine-activating protein complex, in a variety of metabolic diseases including obesity, atherosclerosis and type 2 diabetes. Here, we review these new developments and discuss their implications for a better understanding of inflammation in metabolic disease, and the prospects of targeting the NLRP3 inflammasome for therapeutic intervention.
Riminucci, Mara; Remoli, Cristina; Robey, Pamela G; Bianco, Paolo
Postnatal skeletal stem cells are a unique class of progenitors with biological properties that extend well beyond the limits of stemness as commonly defined. Skeletal stem cells sustain skeletal tissue homeostasis, organize and maintain the complex architectural structure of the bone marrow microenvironment and provide a niche for hematopoietic progenitor cells. The identification of stem cells in the human post-natal skeleton has profoundly changed our approach to the physiology and pathology of this system. Skeletal diseases have been long interpreted essentially in terms of defective function of differentiated cells and/or abnormal turnover of the matrix that they produce. The notion of a skeletal stem cell has brought forth multiple, novel concepts in skeletal biology that provide potential alternative concepts. At the same time, the recognition of the complex functions played by skeletal progenitors, such as the structural and functional organization of the bone marrow, has provided an innovative, unifying perspective for understanding bone and bone marrow changes simultaneously occurring in many disorders. Finally, the possibility to isolate and highly enrich for skeletal progenitors, enables us to reproduce perfectly normal or pathological organ miniatures. These, in turn, provide suitable models to investigate and manipulate the pathogenetic mechanisms of many genetic and non-genetic skeletal diseases. This article is part of a Special Issue entitled Stem cells and Bone.
Ellis, K.J.; Kelleher, S.P.
Contamination of the dialysis solution with trace amounts of aluminum and long-term use of aluminum-based phosphate binders have led to increased body burden of aluminum in patients with end-stage renal disease. A significant clinical problem associated with aluminum-overload is the early diagnosis of aluminum-induced dialysis dementia and osteomalacic osteodystrophy. There are few, if any, blood or urine indices that provide an early monitor of this bone disease, especially in the asymptomatic patient. Although a bone biopsy is usually the basis for the final clinical diagnosis, this procedure is not recommended for routine monitoring of patients. The present technique demonstrates the direct in vivo measurement of bone aluminum levels in patients with renal failure. The interference normally present from activation of bone phosphorus is eliminated by using a thermal/epithermal neutron beam. For the clinical management of the patients, the Al/Ca ratio for the hand may be more useful than an absolute measurement of the total body or skeletal aluminum burden. The relationship between the increased serum Al levels following disferrioxamine infusion and the direct in vivo measurement of bone aluminum using the Al/Ca ratio are currently under investigation. The neutron activation procedure presented in this pilot study is a promising new technique with an immediate clinical application. 5 refs., 3 figs., 1 tab.
Vis, M; Havaardsholm, E A; Haugeberg, G; Uhlig, T; Voskuyl, A E; van de Stadt, R J; Dijkmans, B A C; Woolf, A D; Kvien, T K; Lems, W F
Objectives To examine whether treatment with anti‐tumour necrosis factor (TNF) α prevents loss of bone mineral density (BMD) at the spine and hip (generalised) and in the hands (local) of patients with rheumatoid arthritis, and to study the changes in markers of bone metabolism, including receptor activator of the NFκB ligand (RANKL) and osteoprotegerin (OPG), during anti‐TNF treatment. Patients and methods 102 patients with active rheumatoid arthritis, who were treated with infliximab during 1 year, were included in this open cohort study. The BMD of the spine and hip (dual x ray absorptiometry ) and hands dual x ray radiogrammetry was measured before the start of treatment and after 1 year. Changes in osteocalcin formation, β‐isomerised carboxy terminal telopeptide of type 1 collagen (β‐CTx, resorption), RANKL and OPG were determined at 0, 14, 30 and 46 weeks. Results The BMD of the spine and hip was unchanged during treatment with infliximab, whereas BMD of the hand decreased significantly by 0.8% (p<0.01). The BMD of the hip in patients with a good European League Against Rheumatism response showed a favourable change compared with patients not achieving such a response. Serum β‐CTx and RANKL were both considerably decreased compared with baseline at all time points. The decrease in β‐CTx was associated with the decrease in Disease Activity Score of 28 joints and C reactive protein during the 0–14 weeks interval. Conclusion In patients with rheumatoid arthritis treated with infliximab, spine and hip bone loss is arrested, whereas metacarpal cortical hand bone loss is not stopped. The outcome of the study also supports a relationship between clinical response, in terms of reduced inflammatory activity, and changes in bone loss of the spine, hip and hands. PMID:16606653
Lin-Su, Karen; New, Maria I
The primary treatment for patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is glucocorticoid replacement therapy, which at supraphysiologic levels can result in diminished bone accrual and lead to osteopenia and osteoporosis. Unlike other diseases treated with chronic glucocorticoid therapy, previous studies of patients with 21OHD have not demonstrated a detrimental effect of glucocorticoid treatment on bone mineral density (BMD). It has been postulated that the elevated androgens typically found in these patients have a protective effect on bone integrity, but the precise mechanism remains unknown. We propose that the inhibitory effect of corticosteroid therapy on bone formation is counteracted by estrogen's effect on bone resorption through the RANK-L/osteoprotegerin (OPG) system. A better understanding of the mechanism by which patients with 21OHD are protected against bone loss may lead to novel therapeutic measures to prevent or treat osteopenia and osteoporosis in other conditions, including postmenopausal women.
Smith, Scott M.; Arnaud, Sara B.; Abrams, Steven A.; Paloski, W. H. (Technical Monitor)
The acceleration of age-related bone loss is one of the most detrimental effects of space flight. The ability to understand and counteract this loss will be critical for crew health and safety during and after long-duration missions. Studies in healthy ambulatory individuals have linked high salt (sodium) diets, hypercalciuria, and increased renal stone risk. Dietary salt may modulate bone loss through changes in calcium metabolism and the calcium endocrine system. The research proposed here will determine the role of dietary salt in the loss of bone during simulated space flight. Calcium metabolism will be determined through calcium kinetics studies, endocrine and biochemical measurements; and estimates of the mass, distribution and mechanical properties of bone, in subjects fed low (100 mmol sodium/day) or high (250 mmol sodium/day) levels of dietary salt during 28 days of headdown tilt bedrest. This research addresses the role of dietary salt in the loss of bone and calcium in space flight, and integrates the changes in calcium metabolism with those occurring in other physiologic systems. These data will be critical for both countermeasure development, and in determination of nutritional requirements for extended-duration space flight. The potential countermeasures resulting from this research will reduce health risks due to acceleration of age-related osteoporosis and increased risk of renal stone formation..
Seymour, Roger S.; Smith, Sarah L.; White, Craig R.; Henderson, Donald M.; Schwarz-Wings, Daniela
The cross-sectional area of a nutrient foramen of a long bone is related to blood flow requirements of the internal bone cells that are essential for dynamic bone remodelling. Foramen area increases with body size in parallel among living mammals and non-varanid reptiles, but is significantly larger in mammals. An index of blood flow rate through the foramina is about 10 times higher in mammals than in reptiles, and even higher if differences in blood pressure are considered. The scaling of foramen size correlates well with maximum whole-body metabolic rate during exercise in mammals and reptiles, but less well with resting metabolic rate. This relates to the role of blood flow associated with bone remodelling during and following activity. Mammals and varanid lizards have much higher aerobic metabolic rates and exercise-induced bone remodelling than non-varanid reptiles. Foramen areas of 10 species of dinosaur from five taxonomic groups are generally larger than from mammals, indicating a routinely highly active and aerobic lifestyle. The simple measurement holds possibilities offers the possibility of assessing other groups of extinct and living vertebrates in relation to body size, behaviour and habitat. PMID:21733896
Seymour, Roger S; Smith, Sarah L; White, Craig R; Henderson, Donald M; Schwarz-Wings, Daniela
The cross-sectional area of a nutrient foramen of a long bone is related to blood flow requirements of the internal bone cells that are essential for dynamic bone remodelling. Foramen area increases with body size in parallel among living mammals and non-varanid reptiles, but is significantly larger in mammals. An index of blood flow rate through the foramina is about 10 times higher in mammals than in reptiles, and even higher if differences in blood pressure are considered. The scaling of foramen size correlates well with maximum whole-body metabolic rate during exercise in mammals and reptiles, but less well with resting metabolic rate. This relates to the role of blood flow associated with bone remodelling during and following activity. Mammals and varanid lizards have much higher aerobic metabolic rates and exercise-induced bone remodelling than non-varanid reptiles. Foramen areas of 10 species of dinosaur from five taxonomic groups are generally larger than from mammals, indicating a routinely highly active and aerobic lifestyle. The simple measurement holds possibilities offers the possibility of assessing other groups of extinct and living vertebrates in relation to body size, behaviour and habitat.
Wysolmerski, John J
Calcium is required for skeletal growth in all vertebrate offspring. In eutherian mammals, calcium is provided by the mother via the placenta during fetal growth and via milk until weaning. Transferring calcium to offspring during pregnancy and lactation significantly stresses maternal calcium homeostasis. During human pregnancy, the extra calcium requirements are met primarily by an increase in absorption of calcium from the diet and by a modest increase in rates of bone resorption. In nursing mothers, the calcium required for milk production is generated by a dramatic increase in rates of bone resorption and a decrease in the rate of renal calcium excretion. To consider the evolution of these maternal adaptations in bone and calcium metabolism, comparisons are made across different species of mammals, and the fundamental problem of maternal transfer of calcium to young is explored in lower vertebrates. These comparisons suggest that maternal adaptations in calcium and bone metabolism during pregnancy and lactation in mammals originate from adaptations in bone and mineral metabolism that supply calcium for egg production in lower vertebrates.
Smink, Jeske J; Leutz, Achim
Lytic bone diseases and in particular osteoporosis are common age-related diseases characterized by enhanced bone fragility due to loss of bone density. Increasingly, osteoporosis poses a major global health-care problem due to the growth of the elderly population. Recently, it was found that the gene regulatory transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) is involved in bone metabolism. C/EBPbeta occurs as different protein isoforms of variable amino terminal length, and regulation of the C/EBPbeta isoform ratio balance was found to represent an important factor in osteoclast differentiation and bone homeostasis. Interestingly, adjustment of the C/EBPbeta isoform ratio by the process of translational control is downstream of the mammalian target of rapamycin kinase (mTOR), a sensor of the nutritional status and a target of immunosuppressive and anticancer drugs. The findings imply that modulating the process of translational control of C/EBPbeta isoform expression could represent a novel therapeutic approach in osteolytic bone diseases, including cancer and infection-induced bone loss.
Vellenga, C.J.L.R.; Pauwels, E.K.J.; Bijvoet, O.L.M.; Frijlink, W.B.; Mulder, J.D.; Hermans, J.
The authors determined that the concentration of radioactivity in a lesion of Paget disease correlates with the grade of radiological deformation and the frequency of pain; the total skeletal uptake correlates with the severity of the biochemical abnormalities. They suggest that the major determinant of uptake in untreated lesions is abnormal metabolic activity, and in lesions in remission it is structural deformation of mineralized tissue. It is likely that the metabolic activity, and possibly also the rate of progression of the individual lesions, will differ in the individual patient, and that metabolic activity determines the amount of deformation and the chance of pain. Lesions not visible on the radiograph usually show only low uptake of Tc-99m-Sn-EHDP; the majority of these lesions are asymptomatic and reflect low activity of the disease. Radiological differentiation between sclerotic and osteolytic lesions does not reflect differences in either scintigraphic uptake, metabolic acitivity, or pain.
Kita, S.; Iwasaki, K.; Onishi, R.; Fujisawa, M.; Kim, H.; Shibata, S.; Ito, M.
The purpose of this study is to reveal the effect of chronic hypergravity exposure on the bone formation and the bone metabolism when mammals produce offspring in a 2G environment. We measured the length and width of the thighbone, the length of the pelvis, the width of the pelvic cavity and the width of the fourth cervical vertebra on the second (F2) and the third (F3) generation mice bred in a 2G environment every ten days from 20 days old to 60 days old in an experiment on bone formation. In an experiment on bone metabolism, we measured calcium and phosphorus in the bones of the F3 in the 2G group.Ratios of the thighbone length, pelvis length, pelvic cavity width, and fourth cervical vertebra width versus the body length were calculated.These ratios were higher in the 2G group than the control group during all measuring periods.Calcium and phosphorus concentrations in the thighbone and the lumbar vertebra were lower in the 2G group than in the control group. However, the calcium and phosphorus concentrations in the cervical vertebrae of the 2G group were higher. These results suggest that the influence of gravity load may vary in the bones.
Halloran, B. P.; Bikle, D. D.; Globus, R. K.; Levens, M. J.; Wronski, T. J.; Morey-Holton, E.
Weightlessness, as experienced during space flight, and simulated weightlessness induce osteopenia. Using the suspended rat model to simulate weightlessness, a reduction in total tibia Ca and bone formation rate at the tibiofibular junction as well as an inhibition of Ca-45 and H-3-proline uptake by bone within 5-7 days of skeletal unloading was observed. Between days 7 and 15 of unloading, uptake of Ca-45 and H-3-proline, and bone formation rate return to normal, although total bone Ca remains abnormally low. To examine the relationship between these characteristic changes in bone metabolism induced by skeletal unloading and vitamin D metabolism, the serum concentrations of 25-hydroxyvitamin D (25-OH-D), 24, 25-dihydroxyvitamin D (24,25(OH)2D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) at various times after skeletal unloading were measured. The effect of chronic infusion of 1,25(OH)2D3 on the bone changes associated with unloading was also determined.
Robbins, Gregory R.; Wen, Haitao; Ting, Jenny P.-Y.
Summary Modern medical and hygienic practices have greatly improved human health and longevity; however, increased human lifespan occurs concomitantly with the emergence of metabolic and age-related diseases. Studies over the past decade have strongly linked host inflammatory responses to the etiology of several metabolic diseases including atherosclerosis, type 2 diabetes (T2D), obesity and gout. A common immunological factor to these diseases is the activation of the inflammasome and release of pro-inflammatory cytokines that promote disease progression. Here we review the molecular mechanism(s) of inflammasome activation in response to metabolic damage associated molecular patterns (DAMPs) and discuss potential targets for therapeutic intervention. PMID:24766894
Massé, Priscilla G; Boskey, Adele L; Ziv, Israel; Hauschka, Peter; Donovan, Sharon M; Howell, David S; Cole, David EC
Background Classical homocystinuria is an autosomal recessive disorder caused by cystathionine β-synthase (CBS) deficiency and characterized by distinctive alterations of bone growth and skeletal development. Skeletal changes include a reduction in bone density, making it a potentially attractive model for the study of idiopathic osteoporosis. Methods To investigate this aspect of hyperhomocysteinemia, we supplemented developing chicks (n = 8) with 0.6% dl-homocysteine (hCySH) for the first 8 weeks of life in comparison to controls (n = 10), and studied biochemical, biomechanical and morphologic effects of this nutritional intervention. Results hCySH-fed animals grew faster and had longer tibiae at the end of the study. Plasma levels of hCySH, methionine, cystathionine, and inorganic sulfate were higher, but calcium, phosphate, and other indices of osteoblast metabolism were not different. Radiographs of the lower limbs showed generalized osteopenia and accelerated epiphyseal ossification with distinct metaphyseal and suprametaphyseal lucencies similar to those found in human homocystinurics. Although biomechanical testing of the tibiae, including maximal load to failure and bone stiffness, indicated stronger bone, strength was proportional to the increased length and cortical thickness in the hCySH-supplemented group. Bone ash weights and IR-spectroscopy of cortical bone showed no difference in mineral content, but there were higher Ca2+/PO43- and lower Ca2+/CO32- molar ratios than in controls. Mineral crystallization was unchanged. Conclusion In this chick model, hyperhomocysteinemia causes greater radial and longitudinal bone growth, despite normal indices of bone formation. Although there is also evidence for an abnormal matrix and altered bone composition, our finding of normal biomechanical bone strength, once corrected for altered morphometry, suggests that any increase in the risk of long bone fracture in human hyperhomocysteinemic disease is small. We
Malesci, D; Valentini, G; La Montagna, G
Toward the end of the last century a better knowledge of cardiovascular (CV) risk factors and their associations led investigators to propose the existence of a unique pathophysiological condition called "metabolic" or "insulin resistance syndrome". Among all, insulin-resistance and compensatory hyperinsulinemia are considered its most important treatment targets. Different definitions have been provided by World Health Organization (WHO) and by The Third Report of The National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP III). In particular, abdominal obesity, hypertension, low HDL cholesterol and hyperglicemia are the most common items used for its definition. The presence of MetS is effective in predicting the future risk of diabetes and coronaropathies. The evidence of a higher CV risk rate among different rheumatic inflammatory diseases has recently been associated with high prevalence of MetS in some cases. Rheumatoid or psoriatic arthritis have the large series among arthritis, whereas systemic lupus erythematosus among connective tissue disorders. This review analyses all most important studies about the evidence of MetS in rheumatic patients and the main clinical and prognostic significance of this relation.
Siira, Stefan J; Shearwood, Anne-Marie J; Bracken, Cameron P; Rackham, Oliver; Filipovska, Aleksandra
The expression of mitochondrially-encoded genes requires the efficient processing of long precursor RNAs at the 5' and 3' ends of tRNAs, a process which, when disrupted, results in disease. Two such mutations reside within mt-tRNA(Leu(UUR)); a m.3243A>G transition, which is the most common cause of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), and m.3302A>G which often causes mitochondrial myopathy (MM). We used parallel analysis of RNA ends (PARE) that captures the 5' terminal end of 5'-monophosphorylated mitochondrial RNAs to compare the effects of the m.3243A>G and m.3302A>G mutations on mitochondrial tRNA processing and downstream RNA metabolism. We confirmed previously identified RNA processing defects, identified common internal cleavage sites and new sites unique to the m.3243A>G mutants that do not correspond to transcript ends. These sites occur in regions of predicted RNA secondary structure, or are in close proximity to such regions, and may identify regions of importance to the processing of mtRNAs.
van der Eerden, B C J; Oei, L; Roschger, P; Fratzl-Zelman, N; Hoenderop, J G J; van Schoor, N M; Pettersson-Kymmer, U; Schreuders-Koedam, M; Uitterlinden, A G; Hofman, A; Suzuki, M; Klaushofer, K; Ohlsson, C; Lips, P J A; Rivadeneira, F; Bindels, R J M; van Leeuwen, J P T M
We explored the role of transient receptor potential vanilloid 4 (TRPV4) in murine bone metabolism and association of TRPV4 gene variants with fractures in humans. Urinary and histomorphometrical analyses demonstrated reduced osteoclast activity and numbers in male Trpv4(-/-) mice, which was confirmed in bone marrow-derived osteoclast cultures. Osteoblasts and bone formation as shown by serum procollagen type 1 amino-terminal propeptide and histomorphometry, including osteoid surface, osteoblast and osteocyte numbers were not affected in vivo. Nevertheless, osteoblast differentiation was enhanced in Trpv4(-/-) bone marrow cultures. Cortical and trabecular bone mass was 20% increased in male Trpv4(-/-) mice, compared to sex-matched wild type (Trpv4(+/+)) mice. However, at the same time intracortical porosity was increased and bone matrix mineralization was reduced. Together, these lead to a maximum load, stiffness and work to failure of the femoral bone, which were not different compared to Trpv4(+/+) mice, while the bone material was less resistant to stress and less elastic. The differential impacts on these determinants of bone strength were likely responsible for the lack of any changes in whole bone strength in the Trpv4(-/-) mice. None of these skeletal parameters were affected in female Trpv4(-/-) mice. The T-allele of rs1861809 SNP in the TRPV4 locus was associated with a 30% increased risk (95% CI: 1.1-1.6; p=0.013) for non-vertebral fracture risk in men, but not in women, in the Rotterdam Study. Meta-analyses with the population-based LASA study confirmed the association with non-vertebral fractures in men. This was lost when the non-population-based studies Mr. OS and UFO were included. In conclusion, TRPV4 is a male-specific regulator of bone metabolism, a determinant of bone strength, and a potential risk predictor for fractures through regulation of bone matrix mineralization and intra-cortical porosity. This identifies TRPV4 as a unique sexually
Olson, E J; Shaw, G C; Hutchinson, E K; Schultz-Darken, N; Bolton, I D; Parker, J B; Morrison, J M; Baxter, V K; Pate, K A Metcalf; Mankowski, J L; Carlson, C S
The common marmoset (Callithrix jacchus) is a New World primate that is used in biomedical research due to its small size and relative ease of handling compared with larger primates. Although bone disease in common marmosets is well recognized, there are very few detailed descriptions in the literature that cover the range of lesions seen in these animals. For all animals used to model human disease, it is important to be aware of background lesions that may affect the interpretation of study findings. This retrospective study details bone diseases encountered in marmoset breeding colonies at 2 different institutions. Affected marmosets at Johns Hopkins University had lesions compatible with diagnoses of rickets, fibrous osteodystrophy and osteopenia. Affected marmosets at the Wisconsin National Primate Research Center exhibited severe lesions of osteoclastic bone resorption and remodeling that had an unusual distribution and were not easily categorized into a known disease entity. The purpose of this report is to document these naturally occurring skeletal lesions of common marmosets and suggest an approach to evaluating skeletal disease in prospective studies of these animals that will allow the most accurate diagnoses.
Gal-Moscovici, Anca; Sprague, Stuart M.
Secondary hyperparathyroidism develops relatively early in chronic kidney disease as a consequence of impaired phosphate, calcium, and vitamin D homeostasis. The disease state in chronic kidney disease, which includes the histologic features of bone disease, defined as renal osteodystrophy, and the hormonal and biochemical disturbances, have recently been redefined as a disease syndrome and is referred to as “chronic kidney disease–mineral and bone disorder.” As chronic kidney disease progresses, specific histologic disturbances in the bone develop, which may or may not be predictable from the biochemical and hormonal changes that are associated with chronic kidney disease. In addition, patients may have had underlying bone disease before developing kidney failure or may have been treated with agents that will alter the classical pathologic findings of the bones in chronic kidney disease and their relation to parathyroid hormone. Thus, in stage 5 chronic kidney disease, bone biopsy with quantitative histomorphometric analysis is considered the gold standard in the diagnosis of renal osteodystrophy. In contrast to stage 5 chronic kidney disease, there are very few data on the histologic changes in bone in earlier stages of chronic kidney disease. There also is no adequate information on the etiopathogenesis of bone disease in stages 3 and 4 chronic kidney disease. Thus, because biochemical data cannot predict bone pathology in stages 3 and 4 chronic kidney disease, bone biopsy should be used to define these bone changes and to allow appropriate therapeutic approaches. PMID:18988703
Scott, Jonathan P R; Sale, Craig; Greeves, Julie P; Casey, Anna; Dutton, John; Fraser, William D
Individuals often perform exercise in the fasted state, but the effects on bone metabolism are not currently known. We compared the effect of an overnight fast with feeding a mixed meal on the bone metabolic response to treadmill running. Ten, physically-active males aged 28 ± 4y (mean ±SD) completed two, counterbalanced, 8d trials. After 3d on a standardised diet, participants performed 60 min of treadmill running at 65% VO(2max) on Day 4 following an overnight fast (FAST) or a standardised breakfast (FED). Blood samples were collected at baseline, before and during exercise, for 3h after exercise, and on four consecutive follow-up days (FU1-FU4). Plasma/serum were analysed for the c-terminal telopeptide region of collagen type 1 (β-CTX), n-terminal propeptides of procollagen type 1 (P1NP), osteocalcin (OC), bone alkaline phosphatase (bone ALP), parathyroid hormone (PTH), albumin-adjusted calcium, phosphate, osteoprotegerin (OPG), cortisol, leptin and ghrelin. Only the β-CTX response was significantly affected by feeding. Pre-exercise concentrations decreased more in FED compared with FAST (47% vs 26%, P<0.001) but increased during exercise in both groups and were not significantly different from baseline at 1h post-exercise. At 3h post-exercise, concentrations were decreased (33%, P<0.001) from baseline in FAST and significantly lower (P<0.001) than in FED. P1NP and PTH increased, and OC decreased during exercise. Bone markers were not significantly different from baseline on FU1-FU4. Fasting had only a minor effect on the bone metabolic response to subsequent acute, endurance exercise, reducing the duration of the increase in β-CTX during early recovery, but having no effect on changes in bone formation markers. The reduced duration of the β-CTX response with fasting was not fully explained by changes in PTH, OPG, leptin or ghrelin.
Hameed, Abdul; Brady, Jennifer J; Dowling, Paul; Clynes, Martin; O’Gorman, Peter
Myeloma bone disease (MBD) is a devastating complication of multiple myeloma (MM). More than 80% of MM patients suffer from destructive bony lesions, leading to pain, fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also increases the cost of management. Bone destruction and lack of bone formation are main factors in the development of MBD. Some novel factors are found to be involved in the pathogenesis of MBD, eg, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) system (RANKL/OPG), Wingless (Wnt), dickkopf-1 (Wnt/DKK1) pathway. The addition of novel agents in the treatment of MM, use of bisphosphonates and other supportive modalities such as radiotherapy, vertebroplasty/kyphoplasty, and surgical interventions, all have significant roles in the treatment of MBD. This review provides an overview on the pathophysiology and management of MBD. PMID:25187738
Cohen, M.D.; Klatte, E.C.; Baehner, R.; Smith, J.A.; Martin-Simmerman, P.; Carr, B.E.; Provisor, A.J.; Weetman, R.M.; Coates, T.; Siddiqui, A.
Seven children underwent magnetic resonance imaging (MRI) of the bone marrow: results showed that it is technically feasible to obtain good MR images of marrow in children. MR has detected abnormality in the bone marrow of a child who had metastatic neuroblastoma. The extent of abnormality in the femur correlated well with findings of a bone marrow isotope scan. In one child who had idiopathic aplastic anemia, diseased marrow could not be distinguished from normal marrow on MR images. MRI identified abnormality of the marrow in osteogenic sarcoma, and demonstrated change in response to chemotherapy. It displayed marrow spread of tumors as well as CT. MRI showed marrow abnormality in four children who had leukemia.
Guo, Qinyue; Fan, Ping; Luo, Jing; Wu, Shufang; Sun, Hongzhi; He, Lan; Zhou, Bo
Objective Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease. However, the exact mechanism underlying SLE-related osteopenia and osteoporosis in patients newly diagnosed with SLE remains unknown. Methods 60 male subjects with SLE aged 20-30 years were enrolled. Serum osteocalcin was examined as a marker of bone formation and type I collagen degradation products (β-crosslaps) as markers of bone resorption. Lumbar spine (L1-L4) and total hip bone mineral density (BMD) were determined by dual energy X-ray absorption (DXA). Results Among the 60 subjects with SLE at the time of diagnosis, the cohort showed a significant reduction of osteocalcin (12.62 ± 2.16 ng/mL), and serum β-crosslaps level (992.6 ± 162.6 pg/mL) was markedly elevated. Univariate correlation analyses revealed negative correlations between osteocalcin and SLEDAI, dsDNA antibody and β-crosslaps. A positive correlation was also observed between osteocalcin and C3, C4, 25-OH vitamin D, BMD L1-L4 and BMD total hip (see Table 3). Osteocalcin and β-crosslaps were strongly associated with SLE disease activity by multiple stepwise logistic regression analysis. Conclusion Osteocalcin was negatively associated with SLE disease activity, and β-crosslaps was positively associated with SLE disease activity, suggesting SLE disease activity itself directly contributed to the development of SLE-associated osteopenia and osteoporosis.
Tu, S-M; Som, A; Tu, B; Logothetis, C J; Lee, M-H; Yeung, S-CJ
Background: Patients with prostate cancer tend to die from bone metastases. Until now, no evidence has shown that Paget's disease of bone (PDB) affects the progression of bone metastasis or overall survival of patients with prostate cancer. Methods: We searched our patient database for men who had presented with prostate cancer and PDB between June 1993 and March 2009, and identified best-matched control patients according to stage, grade, age, date of diagnosis, treatment, and race. Results: Among 1346 consecutive patients with prostate cancer diagnosed before 2008, 15 were confirmed to have comorbid PDB. Twenty-six more were identified from the institutional billing search. Including the 41 best-matched controls, our total study population was 82 patients. In the Kaplan–Meier analysis, we estimated median times from diagnosis of prostate cancer to bone metastasis to be 21.5 years for those with PDB and 9.4 years for those without PDB (P=0.044). Median overall survival times were 11.8 and 9.2 years for the two groups, respectively (P=0.008). Conclusion: For the first time, we have obtained evidence that patients with prostate cancer and PDB have delayed time to bone metastases and improved overall survival than do patients with prostate cancer alone. PMID:22805323
Sidiropoulos, Prodromos I; Karvounaris, Stylianos A; Boumpas, Dimitrios T
Subjects with metabolic syndrome--a constellation of cardiovascular risk factors of which central obesity and insulin resistance are the most characteristic--are at increased risk for developing diabetes mellitus and cardiovascular disease. In these subjects, abdominal adipose tissue is a source of inflammatory cytokines such as tumor necrosis factor-alpha, known to promote insulin resistance. The presence of inflammatory cytokines together with the well-documented increased risk for cardiovascular diseases in patients with inflammatory arthritides and systemic lupus erythematosus has prompted studies to examine the prevalence of the metabolic syndrome in an effort to identify subjects at risk in addition to that conferred by traditional cardiovascular risk factors. These studies have documented a high prevalence of metabolic syndrome which correlates with disease activity and markers of atherosclerosis. The correlation of inflammatory disease activity with metabolic syndrome provides additional evidence for a link between inflammation and metabolic disturbances/vascular morbidity.
Chung, Soo Im; Ryu, Su Noh; Kang, Mi Young
The effect of germinated Superhongmi, a reddish brown pigmented rice cultivar, on the glucose profile and bone turnover in the postmenopausal-like model of ovariectomized rats was determined. The ovariectomized Sprague-Dawley rats were randomly divided into three dietary groups (n = 10): normal control diet (NC) and normal diet supplemented with non-germinated Superhongmi (SH) or germinated Superhongmi (GSH) rice powder. After eight weeks, the SH and GSH groups showed significantly lower body weight, glucose and insulin concentrations, levels of bone resorption markers and higher glycogen and 17-β-estradiol contents than the NC group. The glucose metabolism improved through modulation of adipokine production and glucose-regulating enzyme activities. The GSH rats exhibited a greater hypoglycemic effect and lower bone resorption than SH rats. These results demonstrate that germinated Superhongmi rice may potentially be useful in the prevention and management of postmenopausal hyperglycemia and bone turnover imbalance. PMID:27775654
Amarasekara, Dulshara Sachini; Yu, Jiyeon; Rho, Jaerang
Bone remodeling is a lifelong process in vertebrates that relies on the correct balance between bone resorption by osteoclasts and bone formation by osteoblasts. Bone loss and fracture risk are implicated in inflammatory autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and systemic lupus erythematosus. The network of inflammatory cytokines produced during chronic inflammation induces an uncoupling of bone formation and resorption, resulting in significant bone loss in patients with inflammatory autoimmune diseases. Here, we review and discuss the involvement of the inflammatory cytokine network in the pathophysiological aspects and the therapeutic advances in inflammatory autoimmune diseases. PMID:26065006
Rowe, Peter S N
More than 300 million years ago, vertebrates emerged from the vast oceans to conquer gravity and the dry land. With this transition, new adaptations occurred that included ingenious changes in reproduction, waste secretion, and bone physiology. One new innovation, the egg shell, contained an ancestral protein (ovocleidin-116) that likely first appeared with the dinosaurs and was preserved through the theropod lineage in modern birds and reptiles. Ovocleidin-116 is an avian homolog of matrix extracellular phosphoglycoprotein (MEPE) and belongs to a group of proteins called short integrin-binding ligand-interacting glycoproteins (SIBLINGs). These proteins are all localized to a defined region on chromosome 5q in mice and chromosome 4q in humans. A unifying feature of SIBLING proteins is an acidic serine aspartate-rich MEPE-associated motif (ASARM). Recent research has shown that the ASARM motif and the released ASARM peptide have regulatory roles in mineralization (bone and teeth), phosphate regulation, vascularization, soft-tissue calcification, osteoclastogenesis, mechanotransduction, and fat energy metabolism. The MEPE ASARM motif and peptide are physiological substrates for PHEX, a zinc metalloendopeptidase. Defects in PHEX are responsible for X-linked hypophosphatemic rickets (HYP). There is evidence that PHEX interacts with another ASARM motif containing SIBLING protein, dentin matrix protein-1 (DMP1). DMP1 mutations cause bone and renal defects that are identical with the defects caused by a loss of PHEX function. This results in autosomal recessive hypophosphatemic rickets (ARHR). In both HYP and ARHR, increased FGF23 expression plays a major role in the disease and in autosomal dominant hypophosphatemic rickets (ADHR), FGF23 half-life is increased by activating mutations. ASARM peptide administration in vitro and in vivo also induces increased FGF23 expression. FGF23 is a member of the fibroblast growth factor (FGF) family of cytokines, which surfaced 500
Mucopolysaccharidosis; Hurler Syndrome; Hunter Syndrome; Maroteaux-Lamy Syndrome; Sly Syndrome; Alpha Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Adrenoleukodystrophy (ALD); Krabbe Disease; Metachromatic Leukodystrophy (MLD); Sphingolipidoses; Peroxisomal Disorders
Liesegang, A; Hüttenmoser, D; Risteli, J; Leiber, F; Kreuzer, M; Wanner, M
The objective of this study was to identify the effect of high alpine grazing, associated with varying pasture grass qualities and more pronounced exercise on typically steep slopes, on bone metabolism by improving bone density and enhancing bone turnover in growing sheep. Twenty-four 5-month-old sheep were randomly assigned to two groups. One group was kept at high altitude (HA; 2000-2200 m a.s.l.) for 3 months, and the other group (C; control) remained in the lowlands (400 m a.s.l.). Both groups were kept in grazing pastures with access to good-quality swards. Before the start of the experiment, blood samples were taken, the sheep were weighed, and the left metatarsus of each animal was analysed by quantitative computer tomography. After 1 month, blood samples were taken and body weight was measured, followed by biweekly sampling. Finally, the animals were slaughtered, and the bones were collected for analysis of various bone parameters. Body weight development did not differ between the groups. Concentrations of 25-OH-Vitamin D, carboxy-terminal telopeptide of type I collagen and activities of bone-specific alkaline phosphatase were always higher in the HA group than in the C group, except on the last two sampling dates. Bone mineral content and density increased in both groups during the experiment, but more intensively in the HA group. In addition, the cortical thickness of the HA group increased. The present study demonstrates an increase in bone turnover and mineral content of the bones of the growing sheep grazing in high alpine pastures. The factors associated with HA grazing, therefore, clearly seem to improve bone composition.
Lu, Bingwei; Gehrke, Stephan; Wu, Zhihao
Neurodegenerative diseases such as Parkinson׳s disease are progressive disorders of the nervous system that affect the function and maintenance of specific neuronal populations. While most disease cases are sporadic with no known cause, a small percentage of disease cases are caused by inherited genetic mutations. The identification of genes associated with the familial forms of the diseases and subsequent studies of proteins encoded by the disease genes in cellular or animal models have offered much-needed insights into the molecular and cellular mechanisms underlying disease pathogenesis. Recent studies of the familial Parkinson׳s disease genes have emphasized the importance of RNA metabolism, particularly mRNA translation, in the disease process. It is anticipated that continued studies on the role of RNA metabolism in Parkinson׳s disease will offer unifying mechanisms for understanding the cause of neuronal dysfunction and degeneration and facilitate the development of novel and rational strategies for treating this debilitating disease.
Lonardo, Amedeo; Ballestri, Stefano; Marchesini, Giulio; Angulo, Paul; Loria, Paola
The conventional paradigm of nonalcoholic fatty liver disease representing the "hepatic manifestation of the metabolic syndrome" is outdated. We identified and summarized longitudinal studies that, supporting the association of nonalcoholic fatty liver disease with either type 2 diabetes mellitus or metabolic syndrome, suggest that nonalcoholic fatty liver disease precedes the development of both conditions. Online Medical databases were searched, relevant articles were identified, their references were further assessed and tabulated data were checked. Although several cross-sectional studies linked nonalcoholic fatty liver disease to either diabetes and other components of the metabolic syndrome, we focused on 28 longitudinal studies which provided evidence for nonalcoholic fatty liver disease as a risk factor for the future development of diabetes. Moreover, additional 19 longitudinal reported that nonalcoholic fatty liver disease precedes and is a risk factor for the future development of the metabolic syndrome. Finally, molecular and genetic studies are discussed supporting the view that aetiology of steatosis and lipid intra-hepatocytic compartmentation are a major determinant of whether fatty liver is/is not associated with insulin resistance and metabolic syndrome. Data support the novel paradigm of nonalcoholic fatty liver disease as a strong determinant for the development of the metabolic syndrome, which has potentially relevant clinical implications for diagnosing, preventing and treating metabolic syndrome.
Regan, Jenna N; Lim, Joohyun; Shi, Yu; Joeng, Kyu Sang; Arbeit, Jeffrey M; Shohet, Ralph V; Long, Fanxin
The bone marrow environment is among the most hypoxic in the body, but how hypoxia affects bone formation is not known. Because low oxygen tension stabilizes hypoxia-inducible factor alpha (HIFα) proteins, we have investigated the effect of expressing a stabilized form of HIF1α in osteoblast precursors. Brief stabilization of HIF1α in SP7-positive cells in postnatal mice dramatically stimulated cancellous bone formation via marked expansion of the osteoblast population. Remarkably, concomitant deletion of vascular endothelial growth factor A (VEGFA) in the mouse did not diminish bone accrual caused by HIF1α stabilization. Thus, HIF1α-driven bone formation is independent of VEGFA up-regulation and increased angiogenesis. On the other hand, HIF1α stabilization stimulated glycolysis in bone through up-regulation of key glycolytic enzymes including pyruvate dehydrogenase kinase 1 (PDK1). Pharmacological inhibition of PDK1 completely reversed HIF1α-driven bone formation in vivo. Thus, HIF1α stimulates osteoblast formation through direct activation of glycolysis, and alterations in cellular metabolism may be a broadly applicable mechanism for regulating cell differentiation.
Kristinsson, Sigurdur Y; Minter, Alex R; Korde, Neha; Tan, Esther; Landgren, Ola
The manifestations of bone involvement in patients with multiple myeloma (MM) can have devastating clinical effects and increase mortality. Recent studies demonstrate that patients with the precursor conditions smoldering MM (SMM) and monoclonal gammopathy of undetermined significance (MGUS) show evidence of bone disease and increased risk of fractures. The understanding of the pathogenesis of bone disease in MM has expanded in recent years. The traditional skeletal survey will probably be replaced by newer and more sensitive imaging techniques, which may have a prognostic impact and change our definition of MGUS and SMM. Bisphosphonates are recommended to prevent skeletal events in patients with MM, and have also been studied in SMM and MGUS. This article summarizes the current knowledge of bone disease in plasma cell disorders, and discusses the current standard and future role of novel imaging techniques, as well as the evidence and current guidelines for bisphosphonates in MM, SMM and MGUS.
Nakamura, Yukiko K; Omaye, Stanley T
Metabolic diseases, such as obesity and type 2 diabetes, are world-wide health problems. The prevalence of metabolic diseases is associated with dynamic changes in dietary macronutrient intake during the past decades. Based on national statistics and from a public health viewpoint, traditional approaches, such as diet and physical activity, have been unsuccessful in decreasing the prevalence of metabolic diseases. Since the approaches strongly rely on individual's behavior and motivation, novel science-based strategies should be considered for prevention and therapy for the diseases. Metabolism and immune system are linked. Both overnutrition and infection result in inflammation through nutrient and pathogen sensing systems which recognize compounds with structural similarities. Dietary macronutrients (fats and sugars) can induce inflammation through activation of an innate immune receptor, Toll-like receptor 4 (TLR4). Long-term intake of diets high in fats and meats appear to induce chronic systemic low-grade inflammation, endotoxicity, and metabolic diseases. Recent investigations support the idea of the involvement of intestinal bacteria in host metabolism and preventative and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases. Specific intestinal bacteria seem to serve as lipopolysaccharide (LPS) sources through LPS and/or bacterial translocation into the circulation due to a vulnerable microbial barrier and increased intestinal permeability and to play a role in systemic inflammation and progression of metabolic diseases. This review focuses on mechanistic links between metabolic diseases (mainly obesity and type 2 diabetes), chronic systemic low-grade inflammation, intestinal environment, and nutrition and prospective views of probiotic and prebiotic interventions for the diseases.
Metabolic diseases, such as obesity and type 2 diabetes, are world-wide health problems. The prevalence of metabolic diseases is associated with dynamic changes in dietary macronutrient intake during the past decades. Based on national statistics and from a public health viewpoint, traditional approaches, such as diet and physical activity, have been unsuccessful in decreasing the prevalence of metabolic diseases. Since the approaches strongly rely on individual’s behavior and motivation, novel science-based strategies should be considered for prevention and therapy for the diseases. Metabolism and immune system are linked. Both overnutrition and infection result in inflammation through nutrient and pathogen sensing systems which recognize compounds with structural similarities. Dietary macronutrients (fats and sugars) can induce inflammation through activation of an innate immune receptor, Toll-like receptor 4 (TLR4). Long-term intake of diets high in fats and meats appear to induce chronic systemic low-grade inflammation, endotoxicity, and metabolic diseases. Recent investigations support the idea of the involvement of intestinal bacteria in host metabolism and preventative and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases. Specific intestinal bacteria seem to serve as lipopolysaccharide (LPS) sources through LPS and/or bacterial translocation into the circulation due to a vulnerable microbial barrier and increased intestinal permeability and to play a role in systemic inflammation and progression of metabolic diseases. This review focuses on mechanistic links between metabolic diseases (mainly obesity and type 2 diabetes), chronic systemic low-grade inflammation, intestinal environment, and nutrition and prospective views of probiotic and prebiotic interventions for the diseases. PMID:22713169
Bae, Yun Jung; Kim, Mi-Hyun
Previous studies have revealed that magnesium (Mg) plays a significant role in bone health; however, few studies have investigated the effects of Mg supplementation in diets with different calcium (Ca) levels on the bone status and bone metabolism in a growing stage. In this present study, we tested the effects of Mg supplementation on bone status in growing female rats, relative to Ca intake levels. A total of 40 Sprague-Dawley female rats aged 6 weeks were divided into the following four groups and fed for 12 weeks as indicated: (1) LCaAMg: low Ca (Ca, 0.1 % of total diet) and adequate Mg (Mg, 0.05 % of total diet), (2) LCaHMg: low Ca and high Mg ( Mg, 0.1 % of total diet), (3) ACaAMg: adequate Ca (Ca, 0.5 % of total diet) and adequate Mg, and (4) ACaHMg: adequate Ca and high Mg. Our results showed that Mg supplementation with the adequate Ca diet significantly increased the bone mineral contents, bone size (bone area and bone thickness), and bone mineral density of femur or tibia by improving bone metabolism without changing Ca absorption. Mg supplementation significantly increased the serum osteocalcin in the adequate-Ca-diet group (p < 0.05), while the Mg supplementation significantly decreased the serum level of C-telopeptide cross-links of type I collagen in the adequate-Ca-diet group (p < 0.001). This study suggests that Mg supplementation with adequate Ca intake in the growing stage may increase the bone mineral density and bone size by improving bone metabolism.
Denis, I; Cournot, G; Lacroix, H; Colin, C; Zerath, E; Pointillart, A
Vitamin D insufficiency is still a concern in countries where there is no routine food supplementation, such as France. A low vitamin D status is clearly associated with an increased risk of fracture in the elderly, but the long-term consequences of latent vitamin D insufficiency in young people and adults are not known. We fed 26 growing pigs a high calcium diet (1.1%) with a 1000 IU cholecalciferol/kg diet (controls), or without vitamin D (0D) for 4 months. We then analyzed the overall impact of low vitamin D status on osteotropic hormones (calcitriol and immunoreactive parathyroid hormone), plasma markers of bone remodeling (alkaline phosphatase [ALP] activity, carboxyterminal propeptide of type I procollagen [PICP], osteocalcin, hydroxyproline), whole bone parameters (ash content, bending moment), histomorphometry, and the populations of marrow osteoblastic and osteoclastic precursors by ex vivo cultures. The fall in plasma 25-dihydroxyvitamin [25(OH)D] in the 0D pigs indicated severe depletion of their vitamin D stores. However, they remained normocalcemic, were mildly hyperparathyroid after 2 months of vitamin D deprivation, and showed only a slight decrease in plasma calcitriol. The bone mineral content and bending moment of metatarsals decreased and they had increased osteoblastic (+59%, p < 0.05 0D vs. controls) and osteoclastic (+31%, p < 0.1 0D vs. controls) surfaces. This was not paralleled by increased bone turnover, because plasma hydroxyproline and ALP were unchanged and PICP and osteocalcin were decreased. The adherent fraction of bone marrow cells showed a great increase in the number of total stromal colony-forming units (CFU-F; +93%, p < 0.05 0D vs. controls) and in the percent of ALP(+) CFU-F (+58%, p < 0.01 0D vs. controls) in cultures from 0D pigs. More tartrate-resistant acid phosphatase-positive (TRAP(+)) multinucleated cells were generated in cultures of nonadherent marrow cells from 0D pigs, and the area of resorption was 345% greater than
Mizoguchi, Toshihide; Nagasawa, Sakae; Takahashi, Naoyuki; Yagasaki, Hiroshi; Ito, Michio
Dolomite, a mineral composed of calcium magnesium carbonate (CaMg (CO3)2), is used as a food supplement that supplies calcium and magnesium. However, the effect of magnesium supplementation on bone metabolism in patients with osteoporosis is a matter of controversy. We examined the effects of daily supplementation with dolomite on calcium metabolism in ovariectomized (OVX) rats. Dolomite was administered daily to OVX rats for 9 weeks. The same amount of magnesium chloride as that supplied by the dolomite was given to OVX rats as a positive control. Histological examination revealed that ovariectomy decreased trabecular bone and increased adipose tissues in the femoral metaphysis. Dolomite or magnesium supplementation failed to improve these bone histological features. Calcium content in the femora was decreased in OVX rats. Neither calcium nor magnesium content in the femora in OVX rats was significantly increased by dolomite or magnesium administration. Urinary deoxypyridinoline excretion was significantly increased in OVX rats, and was not affected by the magnesium supplementation. Serum concentrations of magnesium were increased, and those of calcium were decreased, in OVX rats supplemented with dolomite or magnesium. However, there was a tendency toward decreased parathyroid hormone secretion and increased calcitonin secretion in OVX rats supplemented with dolomite or magnesium. Serum 1,25-dihydroxyvitamin D(3) and osteocalcin levels were significantly increased in the supplemented OVX rats. These results suggest that increased magnesium intake improves calcium metabolism in favor of increasing bone formation, through the modulation of calcium-regulating hormone secretion.
Yao, J; Zhang, J; Hou, J-F
The effects of ipriflavone on caged layer bone metabolism were examined in vitro and in vivo. Ipriflavone at 10(-8) M stimulated the activity of osteoblasts cultured from embryonic chick calvariae, and 10(-9) to 10(-7) M inhibited osteoclasts from chick tibias and humeri. Ipriflavone concentrations of 10(-4) and 10(-5) M inhibited osteoblast activity. These results suggest that ipriflavone influences bone metabolism by regulating the functional balance between osteoblasts and osteoclasts. Based on these in vitro experiments, in vivo studies were conducted to further clarify the effects of ipriflavone. Five hundred 58-wk-old ISA caged layers were divided into 5 groups that were fed diets containing 0, 15, 25, 50, and 100 ppm of ipriflavone. The experiment lasted 70 d. Egg production increased in hens fed 25 ppm and decreased in hens fed 50 and 100 ppm when compared with the controls and hens fed 15 ppm (P < 0.05). Egg weight, shell quality, BW, and serum P, Ca, estrogen, and bone mineral content were not affected by inclusion of ipriflavone in the diet. Hens consuming 25 ppm of ipriflavone had greater serum alkaline phosphatase and bone gla-protein levels than controls. Adding 25 ppm of ipriflavone to the feed appears to be close to an ideal level for clinical treatment of osteoporosis because of improved egg production while maintaining bone mineral content.
Ibraham, N.G.; Lutton, J.D.; Hoffman, R.; Levere, R.D.
Heme metabolism was examined in developing in vitro erythroid colonies (CFUE) and in bone marrow samples taken directly from four normal donors and four patients with sideroblastic anemia. Maximum activities of delta-aminolevulinic acid synthase (ALAS), ALA dehydratase (ALAD), and /sup 14/C-ALA incorporation into heme were achieved in normal marrow CFUE after 8 days of culture, whereas heme oxygenase progressively decreased to low levels of activity during the same period. Assays on nucleated bone marrow cells taken directly from patients revealed that ALAS activity was considerably reduced in idiopathic sideroblastic anemia (IASA) and X-linked sideroblastic anemia (X-SA) bone marrow specimens, whereas the activity increased more than twofold (normal levels) when cells were assayed from 8-day CFUE. In all cases, ALAD activity appeared to be within normal levels. Measurement of heme synthesis revealed that normal levels of /sup 14/C-ALA incorporation into heme were achieved in IASA cells but were reduced in X-SA cells. In marked contrast to levels in normal cells, heme oxygenase was found to be significantly elevated (two- to fourfold) in bone marrow cells taken directly from patients with IASA and X-SA. Results from this study demonstrate that IASA and X-SA bone marrow cells have disturbances in ALAS and heme metabolism, and that erythropoiesis (CFUE) can be restored to normal levels when cells are cultured in methylcellulose.
Seyfried, Thomas N; Flores, Roberto E; Poff, Angela M; D'Agostino, Dominic P
Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual's unique physiology.
Seyfried, Thomas N.
Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual’s unique physiology. PMID:24343361
Gkiatas, Ioannis; Lykissas, Marios; Kostas-Agnantis, Ioannis; Korompilias, Anastasios; Batistatou, Anna; Beris, Alexandros
Bone growth and development are products of the complex interactions of genetic and environmental factors. Longitudinal bone growth depends on the growth plate. The growth plate has 5 different zones-each with a different functional role-and is the final target organ for longitudinal growth. Bone length is affected by several systemic, local, and mechanical factors. All these regulation systems control the final length of bones in a complicated way. Despite its significance to bone stability, bone growth in width has not been studied as extensively as longitudinal bone growth. Bone growth in width is also controlled by genetic factors, but mechanical loading regulates periosteal apposition. In this article, we review the most recent data regarding bone growth from the embryonic age and analyze the factors that control bone growth. An understanding of this complex system is important in identifying metabolic and developmental bone diseases and fracture risk.
Fluctuations of metabolic reaction fluxes may cause abnormal concentrations of toxic or essential metabolites, possibly leading to metabolic diseases. The mutual binding of enzymatic proteins and ones involving common metabolites enforces distinct coupled reactions, by which local perturbations may spread through the cellular network. Such network effects at the molecular interaction level in human cellular metabolism can reappear in the patterns of disease occurrence. Here we construct the enzyme-reaction network and the metabolite-reaction network, capturing the flux coupling of metabolic reactions caused by the interacting enzymes and the shared metabolites, respectively. Diseases potentially caused by the failure of individual metabolic reactions can be identified by using the known disease-gene association, which allows us to derive the probability of an inactivated reaction causing diseases from the disease records at the population level. We find that the greater the number of proteins that catalyze a reaction, the higher the mean prevalence of its associated diseases. Moreover, the number of connected reactions and the mean size of the avalanches in the networks constructed are also shown to be positively correlated with the disease prevalence. These findings illuminate the impact of the cellular network topology on disease development, suggesting that the global organization of the molecular interaction network should be understood to assist in disease diagnosis, treatment, and drug discovery.
Smith, J.; Botet, J.F.; Yeh, S.D.J.
This is a comprehensive review of 85 patients who had bone sarcoma associated with Paget disease and who were seen at Memorial Sloan-Kettering Cancer Center between 1927 and 1982. There was an almost equal distribution of tumors in the axial and the appendicular skeletons. The pelvis, humerus, femur, and skull were the tumor sites in 80% of cases. The tumors were bulky large soft tissue masses. Lytic lesions were more common than sclerotic lesions. Methylene diphosphonate scans of the bone often showed a cold area that was associated with marked increase in uptake on the gallium scan. Angiography, which was performed in 13 patients, was useful, but CT was much more helpful in showing the soft tissue mass as well as the extent of bony disease. Only three patients in this study survived for five years.
do Nascimento, Cassiane Merigo; Cassol, Tiago; da Silva, Fernanda Soares; Bonfleur, Maria Lucia; Nassar, Carlos Augusto; Nassar, Patricia Oehlmeyer
There is evidence that the lack of metabolic control of obese patients may accelerate periodontitis. The aim of this study was to evaluate radiographically the effect of cafeteria-diet-induced obesity on alveolar bone loss in rats subjected to periodontal disease. Twenty male Wistar rats were randomly divided into four groups: 1) control group, 2) control and ligature group; 3) cafeteria group; and 4) cafeteria and ligature group. The animals were evaluated for obesity and euthanized, and the mandible of each rat was removed to perform a radiographic evaluation of alveolar bone loss and its effect on diet-induced obesity. The results showed greater alveolar bone loss in the mice in Group 4 (P<0.01). Thus, we concluded that obese mice, on average, showed greater radiographic evidence of alveolar bone loss than mice undergoing induction of obesity. PMID:24124386
Fukushi, Ken; Koie, Takuya; Yamamoto, Hayato; Okamoto, Akiko; Imai, Atsushi; Hatakeyama, Shingo; Yoneyama, Takahiro; Hashimoto, Yasuhiro; Ohyama, Chikara
A 61-year-old man was referred to our hospital complaining of elevated serum prostate-specific antigen (PSA) (5.1 ng/ml). Histopathologic diagnosis with trans-rectal prostate biopsy specimen was adenocarcinoma, Gleason score 4+5 = 9. Bone scintigraphy revealed an abnormal uptake on left coxal bone. The patient was diagnosed with prostate cancer with bone metastasis. He received androgen deprivation therapy for two years. Serum PSA decreased to an undetected level. However, the abnormal activity of left coxal bone lesion was not changed on bone scintigraphy. Coxal bone biopsy was performed. The bone lesion was histopathologically diagnosed as Paget's disease of bone.
has passed, is unclear. Understanding the genetics underlying this disease process and how the predisposing mutation interacts with the measles virus...suppressing gene expression in the cell. Then, over the years, a chance genetic event in a single bone cell containing the measles virus results in the...we were able to generate a genetic signature from this comparison of genes that were turned on or turned off in the presence of the measles’ genome
Veldhuijzen, Jean Paul; Vanloon, Jack J. W. A.
An experiment using isolated skeletal tissues under microgravity, is reported. Fetal mouse long bones (metatarsals) were cultured for 4 days in the Biorack facility of Spacelab during the IML-1 (International Microgravity Laboratory) mission of the Space Shuttle. Overall growth was not affected, however glucose consumption was significantly reduced under microgravity. Mineralization of the diaphysis was also strongly reduced under microgravity as compared to the on-board 1 g group. In contrast, mineral resorption by osteoclasts was signficantly increased. These results indicate that these fetal mouse long bones are a sensitive and useful model to further study the cellular mechanisms involved in the changed mineral metabolism of skeletal tissues under microgravity.
Soares, Evelise Aline; Novaes, Rômulo Dias; Nakagaki, Wilson Romero; Fernandes, Geraldo José Medeiros; Garcia, José Antônio Dias; Camilli, José Angelo
Simvastatin can modulate lipid and bone metabolism. However, information related to the interaction between diet and simvastatin on bone structure and biomechanics is scarce. Thus, this study evaluated the effects of simvastatin on femoral biomechanics and cortical/trabecular bone structure in wild-type mice nourished with a hyperlipidic diet. Three-month-old male wild-type mice (C57BL6 strain) were divided into four groups: (1) group W, nourished with a standard diet; (2) group WH, fed a hyperlipidic diet; (3) group WS, nourished with a standard diet plus oral simvastatin (20 mg/kg/day); and (4) group WHS, fed a hyperlipidic diet plus oral simvastatin (20 mg/kg/day). All animals received only their specific diet and water for 60 days. Blood samples were collected for the analysis of calcium, triglycerides, total cholesterol (TC) and fraction serum levels. Diet manipulation was able to induce a dyslipidaemic status in mice, characterized by triglyceride and TC rise in WH animals. Simvastatin prevented hypercholesterolaemia and reduced TC and LDL serum levels, but did not prevent hypertriglyceridaemia and HDL serum levels in the WHS group. In the WH mice the hyperlipidaemia was associated with reduction in trabecular bone thickness, femur structural and material property alterations. Simvastatin prevented these morphological alterations and minimized femur biomechanical changes in WHS mice. Taken together, the results indicated that the hyperlipidic diet intake acts as a risk factor for bone integrity, generating bones with reduced resistance and more susceptible to fractures, an effect attenuated by simvastatin that is potentially related to the modulatory action of this drug on lipid and bone metabolism. PMID:26175225
Osteoporosis, a systemic skeletal disease characterized by a low bone mass, is a major public health problem in EC member states because of the high incidence of fragility fractures, especially hip and vertebral fracture. In EC member states the high incidence of osteoporotic fractures leads to considerable mortality, morbidity, reduced mobility and decreased quality of life. In 1995 the number of hip fractures in 15 countries of EC has been 382,000 and the estimated total care cost of about 9 billion of ECUs. Given the magnitude of the problem public health measures are important for preventive intervention. Skeletal bone mass is determined by a combination of endogenous (genetic, hormonal) and exogenous (nutritional, physical activity) factors. Nutrition plays an important role in bone health. The two nutrients essential for bone health are calcium and vitamin D. Reduced supplies of calcium are associated with a reduced bone mass and osteoporosis, whereas a chronic and severe vitamin D deficiency leads to osteomalacia, a metabolic bone disease characterized by a decreased mineralization of bone. Vitamin D insufficiency, the preclinical phase of vitamin D deficiency, is most commonly found in the elderly. The major causes of vitamin D deficiency and insufficiency are decreased renal hydroxylation of vitamin D, poor nutrition, scarce exposition to sunlight and a decline in the synthesis of vitamin D in the skin. The daily average calcium intake in Europe has been evaluated in the SENECA study concerning the diet of elderly people from 19 towns of 10 European countries. In about one third of subjects the dietary calcium intake results were very low, between 300 and 600 mg/day in women, and 350 and 700 mg/day in men. Calcium supplements reduce the rate of bone loss in osteoporotic patients. Some recent studies have reported a significant positive effect of calcium treatment not only on bone mass but also on fracture incidence. The SENECA study, has also shown that
Morgan, Jennifer L. L.; Heer, Martina; Hargens, Alan R.; Macias, Brandon R.; Hudson, Edgar K.; Shackelford, Linda C.; Zwart, Sara R.; Smith, Scott M.
Abstract The purpose of this study was to directly assess sex differences in bone loss, bone biochemistry, and renal stone risk in bed rest. Bed rest simulates some spaceflight effects on human physiology and can be used to address the potential existence of sex‐specific effects on bone metabolism and renal stone risk in space. We combined data from the control subjects in five head‐down‐tilt bed rest studies (combined n = 50 men, 24 women) of differing durations (14–90 days). All subjects were healthy volunteers. Mean age was 35 ± 9 years for women and 33 ± 8 years for men. The main outcome measures were bone density and biochemistry, and renal stone risk chemistry. Before bed rest began, men had higher bone mineral density and content (P < 0.001), and excreted more biomarkers of bone resorption and calcium per day than did women (P < 0.05). These differences remained during bed rest. A number of urine chemistry analytes increased (e.g., calcium) or decreased (e.g., sodium, citrate, and urine volume) significantly for men and women during bed rest. These changes may predispose men to higher stone risk. Men and women do not have substantially different responses to the skeletal unloading of bed rest. PMID:25107989
NAGURA, NANA; KOMATSU, JUN; IWASE, HIDEAKI; HOSODA, HIROSHI; OHBAYASHI, OSAMU; NAGAOKA, ISAO; KANEKO, KAZUO
The purpose of the present study was to evaluate the combined effects of vitamin K (VK) and teriparatide (TPTD) on bone mineral density (BMD), mechanical strength and other parameters for bone metabolism using a rat ovariectomized osteoporosis model. Ovariectomized female Sprague-Dawley rats were administered with VK (an oral dose of 30 mg/kg/day), TPTD (a subcutaneous dose of 30 µg/kg, three times a week) or a combination for 8 weeks. Thereafter, serum levels of γ-carboxylated osteocalcin (Gla-OC) were quantitated by ELISA; BMD and mechanical strength were measured by computed tomography and biomechanical testing, respectively at the femoral metaphysis. Additionally, histomorphometry was performed using the toluidine blue-stained coronal sections of distal femur. The combination of VK and TPTD clearly increased the serum levels of Gla-OC (a specific marker for bone formation) and osteoblast surface (the number of osteoblasts attaching with the surface of cancellous bone), compared to VK or TPTD alone. In addition, the combination of the two agents improved the BMD and bone strength of the femur in the ovariectomized rats, compared to VK or TPTD alone. Taken together, these findings suggest that the treatment with VK and TPTD may have a therapeutic advantage over VK or TPTD monotherapy for postmenopausal osteoporosis, possibly by enhancing the bone formation through the actions on OC and osteoblasts. PMID:26137225
Liu, Guohua; Yue, Ying; Li, Jianke; Zhang, Shu; Cai, Huiyi; Yang, Aijun; Chen, Zhimin
Identifying the metabolic differences in the livers of modern broilers and local chicken breeds is important for understanding their biological characteristics, and many proteomic changes in their livers are not well characterized. We therefore analyzed the hepatic protein profiles of a commercial breed, Arbor Acres (AA) broilers, and a local dual purpose breed, Big Bone chickens, using two-dimensional electrophoresis combined with liquid chromatography-chip/electrospray ionization-quadruple time-of-flight/mass spectrometry (LC-MS/MS). A total of 145 proteins were identified as having differential abundance in the two breeds at three growth stages. Among them, 49, 63 and 54 belonged to 2, 4, and 6 weeks of age, respectively. The higher abundance proteins in AA broilers were related to the energy production pathways suggesting enhanced energy metabolism and lipid biosynthesis. In contrast, the higher abundance proteins in Big Bone chickens showed enhanced lipid degradation, resulting in a reduction in the abdominal fat percentage. Along with the decrease in fat deposition, flavor substance synthesis in the meat of the Big Bone chickens may be improved by enhanced abundance of proteins involved in glycine metabolism. In addition, the identified proteins in nucleotide metabolism, antioxidants, cell structure, protein folding and transporters may be critically important for immune defense, gene transcription and other biological processes in the two breeds. These results indicate that selection pressure may have shaped the two lines differently resulting in different hepatic metabolic capacities and extensive metabolic differences in the liver. The results from this study may help provide the theoretical basis for chicken breeding. PMID:27760160
Zheng, Aijuan; Chang, Wenhuan; Liu, Guohua; Yue, Ying; Li, Jianke; Zhang, Shu; Cai, Huiyi; Yang, Aijun; Chen, Zhimin
Identifying the metabolic differences in the livers of modern broilers and local chicken breeds is important for understanding their biological characteristics, and many proteomic changes in their livers are not well characterized. We therefore analyzed the hepatic protein profiles of a commercial breed, Arbor Acres (AA) broilers, and a local dual purpose breed, Big Bone chickens, using two-dimensional electrophoresis combined with liquid chromatography-chip/electrospray ionization-quadruple time-of-flight/mass spectrometry (LC-MS/MS). A total of 145 proteins were identified as having differential abundance in the two breeds at three growth stages. Among them, 49, 63 and 54 belonged to 2, 4, and 6 weeks of age, respectively. The higher abundance proteins in AA broilers were related to the energy production pathways suggesting enhanced energy metabolism and lipid biosynthesis. In contrast, the higher abundance proteins in Big Bone chickens showed enhanced lipid degradation, resulting in a reduction in the abdominal fat percentage. Along with the decrease in fat deposition, flavor substance synthesis in the meat of the Big Bone chickens may be improved by enhanced abundance of proteins involved in glycine metabolism. In addition, the identified proteins in nucleotide metabolism, antioxidants, cell structure, protein folding and transporters may be critically important for immune defense, gene transcription and other biological processes in the two breeds. These results indicate that selection pressure may have shaped the two lines differently resulting in different hepatic metabolic capacities and extensive metabolic differences in the liver. The results from this study may help provide the theoretical basis for chicken breeding.
Thompson, Wesley K.; McEvoy, Linda K.; Schork, Andrew J.; Zuber, Verena; LeBlanc, Marissa; Bettella, Francesco; Mills, Ian G.; Desikan, Rahul S.; Djurovic, Srdjan; Gautvik, Kaare M.; Dale, Anders M.; Andreassen, Ole A.
Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity. PMID:26695485
Santini, D; Fratto, M E; Vincenzi, B; Napoli, N; Galluzzo, S; Tantardini, M; Abbruzzese, A; Caraglia, M; Tonini, G
This system constituted of the Receptor Activator of nuclear Factor-kB Ligand (RANKL), the Receptor Activator of Nuclear Factor-kB (RANK) and by the decoy Receptor Osteoprotegerin (OPG) plays a central role in bone resorption. Denosumab (AMG 162) is an investigational fully human monoclonal antibody with a high affinity and specificity for RANKL.This review will critically describe and discuss the recent results of clinical trial investigating denosumab in different settings of medical oncology. In particular, we will report the recently published data of clinical trials investigating denosumab in prevention of cancer treatment induced bone loss (CTIBL), in prevention of skeletal related events (SREs) in bone metastatic patients and the ongoing studies in prevention of disease recurrence in the adjuvant setting of solid tumours. The clinical data that will be reported in this review represent the first step in a path that will conduct us to explore new horizons in the field of bone health care in cancer patients.
and Metabolic Disease: Orexin and Modafinil PRINCIPAL INVESTIGATOR: Stephen C. Benoit, Ph.D. CONTRACTING ORGANIZATION: University of...NUMBER Molecular Connections Between Arousal and Metabolic Disease: Orexin and Modafinil 5b. GRANT NUMBER W81XWH-06-2-0019 5c. PROGRAM...the central orexin system may modulate energy balance. Ongoing studies are assessing the effects of treatment on insulin sensitivity and also the
Seifert, Michael E.; Hruska, Keith A.
The last 25 years have been characterized by dramatic improvements in short-term patient and allograft survival after kidney transplantation. Long-term patient and allograft survival remains limited by cardiovascular disease and chronic allograft injury, among other factors. Cardiovascular disease remains a significant contributor to mortality in native chronic kidney disease as well, as cardiovascular mortality in chronic kidney disease more than doubles that of the general population. The chronic kidney disease-mineral bone disorder (CKD-MBD) is a syndrome recently coined to embody the biochemical, skeletal, and cardiovascular pathophysiology that results from disrupting the complex systems biology between the kidney, skeleton, and cardiovascular system in native and transplant kidney disease. The CKD-MBD is a unique kidney disease-specific syndrome containing novel cardiovascular risk factors, with an impact reaching far beyond traditional notions of renal osteodystrophy and hyperparathyroidism. This Overview reviews current knowledge of the pathophysiology of the CKD-MBD, including emerging concepts surrounding the importance of circulating pathogenic factors released from the injured kidney that directly cause cardiovascular disease in native and transplant chronic kidney disease, with potential application to mechanisms of chronic allograft injury and vasculopathy. PMID:26356179
Seifert, Michael E; Hruska, Keith A
The last 25 years have been characterized by dramatic improvements in short-term patient and allograft survival after kidney transplantation. Long-term patient and allograft survival remains limited by cardiovascular disease and chronic allograft injury, among other factors. Cardiovascular disease remains a significant contributor to mortality in native chronic kidney disease as well as cardiovascular mortality in chronic kidney disease more than doubles that of the general population. The chronic kidney disease (CKD)-mineral bone disorder (MBD) is a syndrome recently coined to embody the biochemical, skeletal, and cardiovascular pathophysiology that results from disrupting the complex systems biology between the kidney, skeleton, and cardiovascular system in native and transplant kidney disease. The CKD-MBD is a unique kidney disease-specific syndrome containing novel cardiovascular risk factors, with an impact reaching far beyond traditional notions of renal osteodystrophy and hyperparathyroidism. This overview reviews current knowledge of the pathophysiology of the CKD-MBD, including emerging concepts surrounding the importance of circulating pathogenic factors released from the injured kidney that directly cause cardiovascular disease in native and transplant chronic kidney disease, with potential application to mechanisms of chronic allograft injury and vasculopathy.
... Language Publications (en español) | Asian-Language Publications NIH Osteoporosis and Related Bone Diseases ~ NIH National Resource Center ... Font Size | S S M M L L Bone Basics Osteoporosis Osteogenesis Imperfecta Pagets Disease of Bone Related Topics ...
Spetsieris, Phoebe G; Ko, Ji Hyun; Tang, Chris C; Nazem, Amir; Sako, Wataru; Peng, Shichun; Ma, Yilong; Dhawan, Vijay; Eidelberg, David
The delineation of resting state networks (RSNs) in the human brain relies on the analysis of temporal fluctuations in functional MRI signal, representing a small fraction of total neuronal activity. Here, we used metabolic PET, which maps nonfluctuating signals related to total activity, to identify and validate reproducible RSN topographies in healthy and disease populations. In healthy subjects, the dominant (first component) metabolic RSN was topographically similar to the default mode network (DMN). In contrast, in Parkinson's disease (PD), this RSN was subordinated to an independent disease-related pattern. Network functionality was assessed by quantifying metabolic RSN expression in cerebral blood flow PET scans acquired at rest and during task performance. Consistent task-related deactivation of the "DMN-like" dominant metabolic RSN was observed in healthy subjects and early PD patients; in contrast, the subordinate RSNs were activated during task performance. Network deactivation was reduced in advanced PD; this abnormality was partially corrected by dopaminergic therapy. Time-course comparisons of DMN loss in longitudinal resting metabolic scans from PD and Alzheimer's disease subjects illustrated that significant reductions appeared later for PD, in parallel with the development of cognitive dysfunction. In contrast, in Alzheimer's disease significant reductions in network expression were already present at diagnosis, progressing over time. Metabolic imaging can directly provide useful information regarding the resting organization of the brain in health and disease.
Abou Al-Shaar, H; Shariff, RK; Albakr, A
Abstract Neurodegenerative disorders are commonly encountered in medical practices. Such diseases can lead to major morbidity and mortality among the affected individuals. The molecular pathogenesis of these disorders is not yet clear. Recent literature has revealed that mutations in RNA-binding proteins are a key cause of several human neuronal-based diseases. This review discusses the role of RNA metabolism in neurological diseases with specific emphasis on roles of RNA translation and microRNAs in neurodegeneration, RNA-mediated toxicity, repeat expansion diseases and RNA metabolism, molecular pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia, and neurobiology of survival motor neuron (SMN) and spinal muscular atrophy. PMID:27785391
Krivit, W; Peters, C; Dusenbery, K; Ben-Yoseph, Y; Ramsay, N K; Wagner, J E; Anderson, R
Wolman disease is characterized by severe diarrhea and malnutrition leading to death during infancy. Lysosomal acid lipase deficiency is the cause of the symptoms and signs. It is inherited in an autosomal recessive manner. All Wolman disease patients have adrenal gland calcification. Previous therapeutic attempts have failed to provide remission. We report successful long-term bone marrow engraftment in a patient with Wolman disease resulting in continued normalization of peripheral leukocyte lysosomal acid lipase enzyme activity. Diarrhea is no longer present. Now, at 4 years of age, this patient is gaining developmental milestones. Cholesterol and triglyceride levels are normal. Liver function is normal. This is the first long-term continued remission reported for Wolman disease.
Zhang, Xianrong; Tamasi, Joseph; Lu, Xin; Zhu, Ji; Chen, Haiyan; Tian, Xiaoyan; Lee, Tang-Cheng; Threadgill, David W; Kream, Barbara E; Kang, Yibin; Partridge, Nicola C; Qin, Ling
While the epidermal growth factor receptor (EGFR)-mediated signaling pathway has been shown to have vital roles in many developmental and pathologic processes, its functions in the development and homeostasis of the skeletal system has been poorly defined. To address its in vivo role, we constructed transgenic and pharmacologic mouse models and used peripheral quantitative computed tomography (pQCT), micro-computed tomography (µCT) and histomorphometry to analyze their trabecular and cortical bone phenotypes. We initially deleted the EGFR in preosteoblasts/osteoblasts using a Cre/loxP system (Col-Cre Egfr(f/f)), but no bone phenotype was observed because of incomplete deletion of the Egfr genomic locus. To further reduce the remaining osteoblastic EGFR activity, we introduced an EGFR dominant-negative allele, Wa5, and generated Col-Cre Egfr(Wa5/f) mice. At 3 and 7 months of age, both male and female mice exhibited a remarkable decrease in tibial trabecular bone mass with abnormalities in trabecular number and thickness. Histologic analyses revealed decreases in osteoblast number and mineralization activity and an increase in osteoclast number. Significant increases in trabecular pattern factor and structural model index indicate that trabecular microarchitecture was altered. The femurs of these mice were shorter and smaller with reduced cortical area and periosteal perimeter. Moreover, colony-forming unit-fibroblast (CFU-F) assay indicates that these mice had fewer bone marrow mesenchymal stem cells and committed progenitors. Similarly, administration of an EGFR inhibitor into wild-type mice caused a significant reduction in trabecular bone volume. In contrast, Egfr(Dsk5/+) mice with a constitutively active EGFR allele displayed increases in trabecular and cortical bone content. Taken together, these data demonstrate that the EGFR signaling pathway is an important bone regulator and that it primarily plays an anabolic role in bone metabolism.
Yamamoto, Masahiro; Sugimoto, Toshitsugu
Recent meta-analysis and some studies have shown that patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures despite their elevated bone mineral density, suggesting that poor bone quality deteriorates bone strength in T2DM patients. Bone geometry as well as bone turnover and mineralization are key components of bone quality. Limited studies have indicated that the section area and cortical thickness of diaphyses in T2DM patients are narrower and thinner than those in control subjects and that bone formation as well as mineralization in T2DM group are suppressed as compared to normal subjects. High-resolution peripheral quantitative computed tomography (HR-pQCT) revealed that T2DM patients had higher cortical pore volume in distal radius as compared to control subjects and that bone strength index estimated by finite element analysis was lower than that of control group. These results suggest that these bone quality factors are associated with bone strength in T2DM patients.
Johnson, Mark L
Rare bone diseases, generally defined as monogenic traits with either autosomal recessive or dominant patterns of inheritance, have provided a rich database of genes and associated pathways over the past 2-3 decades. The molecular genetic dissection of these bone diseases has yielded some major surprises in terms of the causal genes and/or involved pathways. The discovery of genes/pathways involved in diseases such as osteopetrosis, osteosclerosis, osteogenesis imperfecta and many other rare bone diseases have all accelerated our understanding of complex traits. Importantly these discoveries have provided either direct validation for a specific gene embedded in a group of genes within an interval identified through a complex trait genome-wide association study (GWAS) or based upon the pathway associated with a monogenic trait gene, provided a means to prioritize a large number of genes for functional validation studies. In some instances GWAS studies have yielded candidate genes that fall within linkage intervals associated with monogenic traits and resulted in the identification of causal mutations in those rare diseases. Driving all of this discovery is a complement of technologies such as genome sequencing, bioinformatics and advanced statistical analysis methods that have accelerated genetic dissection and greatly reduced the cost. Thus, rare bone disorders in partnership with GWAS have brought us to the brink of a new era of personalized genomic medicine in which the prevention and management of complex diseases will be driven by the molecular understanding of each individuals contributing genetic risks for disease.
Brown, Todd T; Hoy, Jennifer; Borderi, Marco; Guaraldi, Giovanni; Renjifo, Boris; Vescini, Fabio; Yin, Michael T; Powderly, William G
Thirty-four human immunodeficiency virus (HIV) specialists from 16 countries contributed to this project, whose primary aim was to provide guidance on the screening, diagnosis, and monitoring of bone disease in HIV-infected patients. Four clinically important questions in bone disease management were identified, and recommendations, based on literature review and expert opinion, were agreed upon. Risk of fragility fracture should be assessed primarily using the Fracture Risk Assessment Tool (FRAX), without dual-energy X-ray absorptiometry (DXA), in all HIV-infected men aged 40-49 years and HIV-infected premenopausal women aged ≥40 years. DXA should be performed in men aged ≥50 years, postmenopausal women, patients with a history of fragility fracture, patients receiving chronic glucocorticoid treatment, and patients at high risk of falls. In resource-limited settings, FRAX without bone mineral density can be substituted for DXA. Guidelines for antiretroviral therapy should be followed; adjustment should avoid tenofovir disoproxil fumarate or boosted protease inhibitors in at-risk patients. Dietary and lifestyle management strategies for high-risk patients should be employed and antiosteoporosis treatment initiated.
An increasing number of women with rare inherited disorders of metabolism are becoming pregnant. Although, in general, outcomes for women and their children are good, there are a number of issues that need to be considered. Currently, limited specific guidance on the management of these conditions in pregnancy is available. Prepregnancy counselling with information on inheritance, options for reproduction, teratogenicity risk, potential impact on maternal health and long-term health of children should be offered. With appropriate specialist management, the teratogenic risk of conditions such as maternal phenylketonuria (PKU) can be eliminated, and the risk of metabolic decompensation in disorders of energy metabolism or intoxication significantly reduced. Multidisciplinary management, and close liaison between obstetricians and other specialists, is required for those women in whom there is cardiac, renal, respiratory, joint or other organ involvement.
Bradley, William D; Zwingelstein, Catherine; Rondinone, Cristina M
The intestine is an important metabolic organ that has gained attention in recent years for the newly identified role that it plays in the pathophysiology of various metabolic diseases including obesity, insulin resistance and diabetes. Recent insights regarding the role of enteroendocrine hormones, such as GIP, GLP-1, and PYY in metabolic diseases, as well as the emerging role of the gut microbial community and gastric bypass bariatric surgeries in modulating metabolic function and dysfunction have sparked a wave of interest in understanding the mechanisms involved, in an effort to identify new therapeutics and novel regulators of metabolism. This review summarizes the current evidence that the gastrointestinal tract has a key role in the development of obesity, inflammation, insulin resistance and diabetes and discusses the possible players that can be targeted for therapeutic intervention.
Li, Tiangang; Chiang, John Y L
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid-activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein-coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver.
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid–activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein–coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. PMID:25073467
Biver, Emmanuel; Hardouin, Pierre; Caverzasio, Joseph
A large body of evidence supports an important role of bone morphogenic proteins (BMPs) pathways in skeletal development in the embryo. BMPs are also involved in skeletal homeostasis and diseases in the adult. They were first identified as major bone anabolic agents and recent advances indicate that they also regulate osteoclastogenesis and joint components via multiple cross-talks with other signaling pathways. This review attempts to integrate these data in the pathogenesis of bone and joints diseases, such as osteoporosis, fracture healing, osteoarthritis, inflammatory arthritis, or bone metastasis. The use of recombinant BMPs in bone tissue engineering and in the treatment of skeletal diseases, or future therapeutic strategies targeting BMPs signal and its regulators, will be discussed based on these considerations.
Johnson, Elizabeth L; Heaver, Stacey L; Walters, William A; Ley, Ruth E
Bacterial species composition in the gut has emerged as an important factor in obesity and its related metabolic diseases such as type 2 diabetes. Out of thousands of bacterial species-level phylotypes inhabiting the human gut, the majority belong to two dominant phyla, the Bacteroidetes and Firmicutes. Members of the Bacteroidetes in particular have been associated with human metabolic diseases. However, their associations with disease are not always consistent between studies. Delving deeper into the diversity within the Bacteroidetes reveals a vast diversity in genomes and capacities, which partly explain how not all members respond equally to similar environmental conditions in their hosts. Here, we discuss the Bacteroidetes phylum, associations of its members with metabolic phenotypes, and efforts to characterize functionally their interactions with their hosts. Harnessing the Bacteroidetes to promote metabolic health will require a nuanced understanding of how specific strains interact with their microbial neighbors and their hosts under various conditions.
Jemtland, Rune; Holden, Marit; Reppe, Sjur; Olstad, Ole K; Reinholt, Finn P; Gautvik, Vigdis T; Refvem, Hilde; Frigessi, Arnoldo; Houston, Brian; Gautvik, Kaare M
Genome-wide gene expressions in bone biopsies from patients with postmenopausal osteoporosis and healthy controls were profiled, to identify osteoporosis candidate genes. All osteoporotic patients (n = 27) in an unbiased cohort of Norwegian women presented with bone mineral density (BMD) T-scores of less than -2.5 SD and one or more confirmed low-energy fracture(s). A validation group (n = 18) had clinical and laboratory parameters intermediate to the control (n = 39) and osteoporosis groups. RNA from iliac crest bone biopsies were analyzed by Affymetrix microarrays and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Differentially expressed genes in osteoporosis versus control groups were identified using the Bayesian ANOVA for microarrays (BAMarray) method, whereas the R-package Limma (Linear Models for Microarray Data) was used to determine whether these transcripts were explained by disease, age, body mass index (BMI), or combinations thereof. Laboratory tests showed normal ranges for the cohort. A total of 609 transcripts were differentially expressed in osteoporotic patients relative to controls; 256 transcripts were confirmed for disease when controlling for age or BMI. Most of the osteoporosis susceptibility genes (80%) also were confirmed to be regulated in the same direction in the validation group. Furthermore, 217 of 256 transcripts were correlated with BMD (adjusted for age and BMI) at various skeletal sites (|r| > 0.2, p < .05). Among the most distinctly expressed genes were Wnt antagonists DKK1 and SOST, the transcription factor SOX4, and the bone matrix proteins MMP13 and MEPE, all reduced in osteoporosis versus control groups. Our results identify potential osteoporosis susceptibility candidate genes adjusted for confounding factors (ie, age and BMI) with or without a significant correlation with BMD.
Iwasaki, Yoshiko; Yamato, Hideyuki
Chronic kidney disease (CKD) patients have an extremely increased risk of fragility fractures, but the underling pathophysiological mechanisms remain obscure. Recently, the progresses of analysis technology have revealed the changes of bone quality in CKD condition. In particular, we can observe the characteristic changes of bone microarchitecture and bone chemical compositions in both human bone biopsy samples and experimental animal bones. Here, I will provide a short review on these bone quality factors and discuss on the relationship between bone quality and fracture in CKD patients.
Morales Piga, Antonio; Alonso Ferreira, Verónica; Villaverde-Hueso, Ana
Recent years have seen an unprecedented increase in the knowledge and understanding of biochemical disturbances involved on constitutional bone disorders. Recognition of the genetic background as the common cause of these diseases prompted the substitution of the term «constitutional» by «genetic», in referring to them. Understanding physiopathological bases by finding out the altered metabolic pathways as well as their regulatory and control systems, favours an earlier and more accurate diagnosis based on interdisciplinary collaboration. Although clinical and radiological assessment remains crucial in the study of these disorders, ever more often the diagnosis is achieved by molecular and genetic analysis. Elucidation of the damaged underlying molecular mechanisms offers targets potentially useful for therapeutic research in these complex and often disabling diseases.
Scully, C; Langdon, J; Evans, J
The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarises data about Paget disease of bone.
Cai, Huan; Cong, Wei-na; Ji, Sunggoan; Rothman, Sarah; Maudsley, Stuart; Martin, Bronwen
Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.
Smith, S M; Zwart, S R; Heer, M A; Baecker, N; Evans, H J; Feiveson, A H; Shackelford, L C; Leblanc, A D
We report results from a study designed to explore the utility of artificial gravity (AG) as a countermeasure to bone loss induced by microgravity simulation. After baseline testing, 15 male subjects underwent 21 days of 6 degrees head-down bed rest to simulate the deconditioning associated with spaceflight. Eight of the subjects underwent 1 h of centrifugation (AG; 1 G(z) at the heart, 2.5 G(z) at the feet) each day for 21 days, whereas seven of the subjects served as untreated controls (Con). Blood and urine were collected before, during, and after bed rest for bone marker determinations. Bone mineral density (BMD) and bone mineral content (BMC) were determined by dual-energy X-ray absorptiometry and peripheral quantitative computerized tomography before and after bed rest. Urinary excretion of bone resorption markers increased during bed rest, but the AG and Con groups did not differ significantly. The same was true for serum C-telopeptide. During bed rest, bone alkaline phosphatase (ALP) and total ALP tended to be lower in the AG group (P = 0.08, P = 0.09). Neither BMC nor BMD changed significantly from the pre-bed rest period in AG or Con groups, and the two groups were not significantly different. However, when AG and Con data were combined, there was a significant (P < 0.05) effect of time for whole body total BMC and total hip and trochanter BMD. These data failed to demonstrate efficacy of this AG prescription to prevent the changes in bone metabolism observed during 3 wk of bed rest.
Rignell-Hydbom, A.; Skerfving, S.; Lundh, T.; Lindh, C.H.; Elmstahl, S.; Bjellerup, P.; Juensson, B.A.G.; Struemberg, U.; Akesson, A.
Environmental contaminants such as cadmium and persistent organochlorine pollutants have been proposed as risk factors of osteoporosis, and women may be at an increased risk. To assess associations between exposure to cadmium and two different POPs (2,2',4,4',5,5'-hexachlorobiphenyl CB-153, 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene p,p'-DDE), on one hand, and bone effects, on the other, in a population-based study among postmenopausal (60-70 years) Swedish women with biobanked blood samples. The study included 908 women and was designed to have a large contrast of bone mineral densities, measured with a single photon absorptiometry technique in the non-dominant forearm. Biochemical markers related to bone metabolism were analyzed in serum. Exposure assessment was based on cadmium concentrations in erythrocytes and serum concentrations of CB-153 and p,p'-DDE. Cadmium was negatively associated with bone mineral density and parathyroid hormone, positively with the marker of bone resorption. However, this association disappeared after adjustment for smoking. The major DDT metabolite (p,p'-DDE) was positively associated with bone mineral density, an association which remained after adjustment for confounders, but the effect was weak. There was no evidence that the estrogenic congener (CB-153) was associated with any of the bone markers. In conclusion, no convincing associations were observed between cadmium and POPs, on one hand, and bone metabolism markers and BMD, on the other.
Cornall, Lauren M; Mathai, Michael L; Hryciw, Deanne H; McAinch, Andrew J
Obesity, type 2 diabetes mellitus and cardiovascular disease are at epidemic proportions in developed nations globally, representing major causes of ill-health and premature death. The search for drug targets to counter the growing prevalence of metabolic diseases has uncovered G-protein-coupled receptor 120 (GPR120). GPR120 agonism has been shown to improve inflammation and metabolic health on a systemic level via regulation of adiposity, gastrointestinal peptide secretion, taste preference and glucose homeostasis. Therefore, GPR120 agonists present as a novel therapeutic option that could be exploited for the treatment of impaired metabolic health. This review summarizes the current knowledge of GPR120 functionality and the potential applications of GPR120-specific agonists for the treatment of disease states such as obesity, type 2 diabetes mellitus and cardiovascular disease.
Bredesen, Dale E.
The cause of Alzheimer's disease is incompletely defined, and no truly effective therapy exists. However, multiple studies have implicated metabolic abnormalities such as insulin resistance, hormonal deficiencies, and hyperhomocysteinemia. Optimizing metabolic parameters in a comprehensive way has yielded cognitive improvement, both in symptomatic and asymptomatic individuals. Therefore, expanding the standard laboratory evaluation in patients with dementia may be revealing. Here I report that metabolic profiling reveals three Alzheimer's disease subtypes. The first is inflammatory, in which markers such as hs-CRP and globulin:albumin ratio are increased. The second type is non-inflammatory, in which these markers are not increased, but other metabolic abnormalities are present. The third type is a very distinctive clinical entity that affects relatively young individuals, extends beyond the typical Alzheimer's disease initial distribution to affect the cortex widely, is characterized by early non-amnestic features such as dyscalculia and aphasia, is often misdiagnosed or labeled atypical Alzheimer's disease, typically affects ApoE4-negative individuals, and is associated with striking zinc deficiency. Given the involvement of zinc in multiple Alzheimer's-related metabolic processes, such as insulin resistance, chronic inflammation, ADAM10 proteolytic activity, and hormonal signaling, this syndrome of Alzheimer's-plus with low zinc (APLZ) warrants further metabolic, genetic, and epigenetic characterization. PMID:26343025
McCully, Kilmer S
The importance of homocysteine in vascular function and arteriosclerosis was discovered by demonstration of arteriosclerotic plaques in children with homocystinuria caused by inherited enzymatic deficiencies of cystathionine synthase, methionine synthase, or methylene-tetrahydrofolate reductase. According to the homocysteine theory of arteriosclerosis, an elevated blood homocysteine level is an important risk factor for atherosclerosis in subjects without these rare enzymatic abnormalities. The homocysteine theory is supported by demonstration of arterial plaques in experimental animals with hyperhomocysteinemia, by discovery of a pathway for conversion of homocysteine thiolactone to sulfate in cell cultures from children with homocystinuria, and by demonstration of growth promotion by homocysteic acid in normal and hypophysectomized animals. Studies with cultured malignant cells revealed abnormal homocysteine thiolactone metabolism, resulting in homocysteinylation of proteins, nucleic acids, and glycosaminoglycans, explaining the abnormal oxidative metabolism, abnormalities of cellular membranes, and altered genetic expression observed in malignancy. Abnormal homocysteine metabolism in malignant cells is attributed to deficiency of thioretinamide, the amide synthesized from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide combine with cobalamin to form thioretinaco. Based on the molecular structure of thioretinaco, a theory of oxidative phosphorylation was proposed, involving oxidation to a disulfonium derivative by ozone, and binding of oxygen, nicotinamide adenine dinucleotide and phosphate as the active site of adenosine triphosphate synthesis in mitochondria. Obstruction of vasa vasorum by aggregates of microorganisms with homocysteinylated low-density lipoproteins is proposed to cause ischemia of arterial wall and a microabscess of the intima, the vulnerable atherosclerotic plaque.
Hackl, Matthias; Heilmeier, Ursula; Weilner, Sylvia; Grillari, Johannes
Biomarkers are essential tools in clinical research and practice. Useful biomarkers must combine good measurability, validated association with biological processes or outcomes, and should support clinical decision making if used in clinical practice. Several types of validated biomarkers have been reported in the context of bone diseases. However, because these biomarkers face certain limitations there is an interest in the identification of novel biomarkers for bone diseases, specifically in those that are tightly linked to the disease pathology leading to increased fracture-risk. MicroRNAs (miRNAs) are the most abundant RNA species to be found in cell-free blood. Encapsulated within microvesicles or bound to proteins, circulating miRNAs are remarkably stable analytes that can be measured using gold-standard technologies such as quantitative polymerase-chain-reaction (qPCR). Nevertheless, the analysis of circulating miRNAs faces several pre-analytical as well as analytical challenges. From a biological view, there is accumulating evidence that miRNAs play essential roles in the regulation of various biological processes including bone homeostasis. Moreover, specific changes in miRNA transcription levels or miRNA secretory levels have been linked to the development and progression of certain bone diseases. Only recently, results from circulating miRNAs analysis in patients with osteopenia, osteoporosis and fragility fractures have been reported. By comparing these findings to studies on circulating miRNAs in cellular senescence and aging or muscle physiology and sarcopenia, several overlaps were observed. This suggests that signatures observed during osteoporosis might not be specific to the pathophysiology in bone, but rather integrate information from several tissue types. Despite these promising first data, more work remains to be done until circulating miRNAs can serve as established and robust diagnostic tools for bone diseases in clinical research, clinical
Pratap, Jitesh; Lian, Jane B.; Stein, Gary S.
Progression of cancer from the earliest event of cell transformation through stages of tumor growth and metastasis at a distal site involves many complex biological processes. Underlying the numerous responses of cancer cells to the tumor microenvironment which support their survival, migration and metastasis are transcription factors that regulate the expression of genes reflecting properties of the tumor cell. A number of transcription factors have been identified that play key roles in promoting oncogenesis, tumor growth, metastasis and tissue destruction. Relevant to solid tumors and leukemias, tissue specific transcription factors that are deregulated resulting from mutations, being silenced or aberrantly expressed, have been well characterized. These are the master transcription factors of the Runx family of genes, the focus of this review, with emphasis placed on Runx2 that is abnormally expressed at very high levels in cancer cell lines that are metastatic to bone. Recent evidence has identified a correlation of Runx2 levels in advanced stages of prostate and breast cancer and demonstrated that effective depletion of Runx2 by RNA interference inhibits migration and invasive properties of the cells prevents metastatic bone disease. This striking effect is consistent with the broad spectrum of Runx2 properties in activating many genes in tumor cells that have already been established as indicators of bone metastasis in poor prognosis. Potential strategies to translate these findings for therapeutic applications are discussed. PMID:20561908
McDonald, Lindsay T; LaRue, Amanda C
The understanding of bone marrow stem cell plasticity and contribution of bone marrow stem cells to pathophysiology is evolving with the advent of innovative technologies. Recent data has led to new mechanistic insights in the field of mesenchymal stem cell (MSC) research, and an increased appreciation for the plasticity of the hematopoietic stem cell (HSC). In this review, we discuss current research examining the origin of pulmonary cell types from endogenous lung stem and progenitor cells as well as bone marrow-derived stem cells (MSCs and HSCs) and their contributions to lung homeostasis and pathology. We specifically highlight recent findings from our laboratory that demonstrate an HSC origin for pulmonary fibroblasts based on transplantation of a clonal population of cells derived from a single HSC. These findings demonstrate the importance of developing an understanding of the sources of effector cells in disease state. Finally, a perspective is given on the potential clinical implications of these studies and others addressing stem cell contributions to lung tissue homeostasis and pathology. PMID:26798846
The abnormalities in bone and mineral metabolism in chronic kidney disease patients are associated with an increased risk of fractures, vascular calcifications and cardiovascular diseases. A few decades ago hyperphosphatemia and the common development of secondary hyperparathyroidism were thought to be the main problem to deal with. Since dietary phosphate restriction and haemodialysis were not proven to be sufficient measures to reduce phosphorus, phosphate-binding therapy has been widely instituted as a treatment option. Various types of phosphate binders employed over the years have contributed to the changing spectrum of renal osteodystrophy from high to low bone turnover along with the shift from hypocalcemia and negative calcium balance towards hypercalcemia and the positive calcium balance. Thus, hypercalcemia instead of hyperphosphatemia is nowadays associated with the increased risk of vascular calcification, morbidity and mortality in the dialysis population. Besides the very expensive non-calcium based phosphate binders, at least two common tools may be helpful in the treatment of hypercalcemia and adynamic bone. A reduced daily use of calcium carbonate/acetate up to 1g per main meal is an easily manageable and inexpensive tool. The second option for stimulation of parathyroid gland activity and bone turnover is the lowering of the dialysate calcium concentration. In conclusion, an aggressive treatment of hyperphosphatemia and calcium overload might lead towards an opposite effect of hypoparathyroidism and hypercalcemia. Reasonable treatment strategies based on a careful monitoring should be employed in order to prevent related consequences and to contribute to a better long-term quality of life and survival of dialysis patients.
Liao, Hung-Wei; Hung, Peir-Haur; Hsiao, Chih-Yen; Liou, Hung-Hsiang; Lin, Hsin-Shih; Huang, Tsang-Hai; Jou, I-Ming; Tsai, Kuen-Jer
Background Phosphate burden in chronic kidney disease (CKD) leads to elevated serum fibroblast factor-23 (FGF-23) levels, secondary hyperparathyroidism and chronic kidney disease-mineral bone disorder (CKD-MBD). However dissociated hyperphosphatemia and low serum FGF-23 concentrations have been observed in experimentally parathyoridectomized rats. The relationships between serum mineral, hormone, and bone metabolism may be altered in the presence of CKD. The aim of our study was to investigate whether a consistent relationship existed between serum FGF-23 levels, specific serum biochemical markers, and histomorphometric parameters of bone metabolism in a parathyroidectomized CKD animal model. Results Sprague Dawley rats were divided into 3 groups: parathyroidectomy (PTX) and CKD (PTX+CKD, 9 rats), CKD without PTX (CKD, 9 rats), and neither PTX nor CKD (sham-operated control, 8 rats); CKD was induced by partial nephrectomy. At 8 weeks after partial nephrectomy, serum biomarkers were measured. Bone histomorphometries of the distal femoral metaphyseal bone were analyzed. The mean serum FGF-23 levels and mean bone formation rate were the highest in the CKD group and the lowest in the PTX+CKD group. Bone volume parameters increased significantly in the PTX+CKD group. Pearson’s correlation revealed that serum FGF-23 levels associated with those of intact parathyroid hormone, phosphate, collagen type I C-telopeptide, and calcium. Univariate linear regression showed that serum FGF-23 values correlated with bone formation rate, bone volume, and osteoid parameters. Stepwise multivariate regression analysis revealed that circulating FGF-23 values were independently associated with bone volume and thickness (β = -0.737; p < 0.001 and β = -0.526; p = 0.006, respectively). Serum parathyroid hormone levels independently correlated with bone formation rate (β = 0.714; p < 0.001) while collagen type I C-telopeptide levels correlated with osteoid parameter. Conclusion Serum FGF
... Disease of Bone Paget’s Disease Basics Facts a New Patient Needs to Know About Paget’s Disease of ... geographical areas, including England, the United States, Australia, New Zealand, and Western Europe. It is not common ...
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone and works by binding to Klotho-FGF receptor complex. Excessive and deficient actions of FGF23 result in hypophosphatemic and hyperphosphatemic diseases, respectively. Therefore, it is reasonable to think that modulating FGF23 activities may be a novel therapeutic measure for these diseases. Several preclinical reports indicate that the inhibition of FGF23 activities ameliorates hypophosphatemic rickets/osteomalacia caused by excessive actions of FGF23. In addition, phase I-II clinical trials of anti-FGF23 antibody in adult patients with X-linked hypophosphatemia rickets, the most prevalent cause of genetic FGF23-related hypophosphatemic rickets, indicated that the antibody enhances renal tubular phosphate reabsorption and increases serum phosphate. However, it is not known whether the inhibition of FGF23 activities actually brings clinical improvement of rickets and osteomalacia. Available data indicate that FGF23-FGF receptor/Klotho pathway can be a new drug target for disorders of phosphate and bone metabolism.
Mignon-Grasteau, Sandrine; Chantry-Darmon, Céline; Boscher, Marie-Yvonne; Sellier, Nadine; Chabault-Dhuit, Marie; Le Bihan-Duval, Elisabeth; Narcy, Agnès
Skeletal integrity in meat-type chickens is affected by many factors including rapid growth rate, nutrition and genetics. To investigate the genetic basis of bone and mineral metabolism, a QTL detection study was conducted in an intercross between two lines of meat-type chickens divergently selected for their high (D +) or low (D -) digestive efficiency. Tibia size (length, diameter, volume) and ash content were determined at 3 weeks of age as well as phosphorus (P) retention and plasma concentration. Heritability of these traits and their genetic correlations with digestive efficiency were estimated. A QTL mapping study was performed using 3379 SNP markers. Tibia size, weight, ash content and breaking strength were highly heritable (0.42 to 0.61). Relative tibia diameter and volume as well as P retention were strongly and positively genetically correlated with digestive efficiency (0.57 to 0.80). A total of 35 QTL were identified (9 for tibia weight, 13 for tibia size, 5 for bone strength, 5 for bone mineralization, 2 for plasma P concentration and 1 for P retention). Six QTL were genome-wide significant, and 3 QTL for tibia relative volume, weight and ash weight on chromosome 6 were fixed, the positive allele coming from the D-line. For two QTL for ash content on chromosome 18 and relative tibia length on chromosome 26, the confidence intervals were small enough to identify potential candidate genes. These findings support the evidence of multiple genetic loci controlling bone and mineral metabolism. The identification of candidate genes may provide new perspectives in the understanding of bone regulation, even beyond avian species.
Cho, Sang Soo; Aminian, Kelly; Li, Crystal; Lang, Anthony E; Houle, Sylvain; Strafella, Antonio P
Fatigue is a common and disabling non-motor symptom in Parkinson's disease associated with a feeling of overwhelming lack of energy. The aim of this study was to identify the neural substrates that may contribute to the development of fatigue in Parkinson's disease. Twenty-three Parkinson's disease patients meeting UK Brain Bank criteria for the diagnosis of idiopathic Parkinson's disease were recruited and completed the 2-[(18) F]fluoro-2-deoxy-D-glucose (FDG)-PET scan. The metabolic activities of Parkinson's disease patients with fatigue were compared to those without fatigue using statistical parametric mapping analysis. The Parkinson's disease group exhibiting higher level of fatigue showed anti-correlated metabolic changes in cortical regions associated with the salience (i.e., right insular region) and default (i.e., bilateral posterior cingulate cortex) networks. The metabolic abnormalities detected in these brain regions displayed a significant correlation with level of fatigue and were associated with a disruption of the functional correlations with different cortical areas. These observations suggest that fatigue in Parkinson's disease may be the expression of metabolic abnormalities and impaired functional interactions between brain regions linked to the salience network and other neural networks. Hum Brain Mapp 38:283-292, 2017. © 2016 Wiley Periodicals, Inc.
Jamal, Sophie A; Nickolas, Thomas L
Fractures are more common and are associated with greater morbidity and morality in patients with kidney disease than in members of the general population. Thus, it is troubling that in chronic kidney disease (CKD) patients there has been a paradoxical increase in fracture rates over the past 20 years compared to the general population. Increased fracture incidence in CKD patients may be driven in part by the lack of screening for fracture risk. In the general population, dual energy X-ray absorptiometry (DXA) is the clinical standard to stratify fracture risk, and its use has contributed to decreases in fracture incidence. In contrast, in CKD, fracture risk screening with DXA has been uncommon due to its unclear efficacy in predicting fracture and its inability to predict type of renal osteodystrophy. Recently, several prospective studies conducted in patients across the spectrum of kidney disease have demonstrated that bone mineral density measured by DXA predicts future fracture risk and that clinically relevant information regarding fracture risk is provided by application of the World Health Organization cutoffs for osteopenia and osteoporosis to DXA measures. Furthermore, novel high-resolution imaging tools, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have been used to elucidate the effects of kidney disease on cortical and trabecular microarchitecture and bone strength and to identify potential targets for strategies that protect against fractures. This review will discuss the updated epidemiology of fractures in CKD, fracture risk screening by DXA, and the utility of state-of-the art imaging methods to uncover the effects of kidney disease on the skeleton.
Mirás, Alicia; Bóveda, M Dolores; Leis, María R; Mera, Antonio; Aldámiz-Echevarría, Luís; Fernández-Lorenzo, José R; Fraga, José M; Couce, María L
There is a compromised bone mass in phenylketonuria patients compared with normal population, but the mechanisms responsible are still a matter of investigation. In addition, tetrahydrobiopterin therapy is a new option for a significant proportion of these patients and the prevalence of mineral bone disease (MBD) in these patients is unknown. We conducted a cross-sectional observational study including 43 phenylketonuric patients. Bone densitometry, nutritional assessment, physical activity questionnaire, biochemical parameters, and molecular study were performed in all patients. Patients were stratified by phenotype, age and type of treatment. The MBD prevalence in phenylketonuria was 14%. Osteopenic and osteoporotic (n=6 patients) had an average daily natural protein intake significantly lower than the remaining (n=37) patients with PKU (14.33 ± 8.95 g vs 21.25 ± 20.85 g). Besides, a lower body mass index was found. There were no statistical differences in physical activity level, calcium, phosphorus and fat intake, and in phenylalanine, vitamin D, paratohormone, docosahexaenoic and eicosapentaenoic acid blood levels. Mutational spectrum was found in up to 30 different PAH genotypes and no relationship was established among genotype and development of MBD. None of the twelve phenylketonuric patients treated with tetrahydrobiopterin (27.9%), for an average of 7.1 years, developed MBD. Natural protein intake and blood levels of eicosapentaenoic acid were significantly higher while calcium intake was lower in these patients. This study shows that the decrease in natural protein intake can play an important role in MBD development in phenylketonuric patients. Therapy with tetrahydrobiopterin allows a more relaxed protein diet, which is associated with better bone mass.
Drake, Matthew T; Collins, Michael T; Hsiao, Edward C
A working group on rare bone diseases was held in Atlanta, Georgia as part of the 2016 annual meeting of the American Society for Bone and Mineral Research. The meeting was organized by Matthew Drake. Given recent advances in our understanding of fibrodysplasia ossificans progressiva (FOP), the initial portion of the program was devoted to basic, translational, and clinical aspects of FOP. The remainder of the program was divided into updates on an array of rare bone diseases as detailed below. In total, there were more than 120 scientists from academia and industry in attendance.
Paschos, P; Paletas, K
Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic entity increasingly recognized as a major health burden in developed countries. It includes a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and rarely, progression to cirrhosis. Recent studies emphasize the role of insulin resistance, oxidative stress and subsequent lipid peroxidation, proinflammatory cytokines, adipokines and mitochondrial dysfunction in the development and progression of NAFLD. Furthermore, accumulating evidence supports an association between NAFLD and metabolic syndrome. Although the data are mainly epidemiological, the pathogenesis of NAFLD and metabolic syndrome seems to have common pathophysiological mechanisms, with focus on insulin resistance as a key factor. This review summarizes the current knowledge on the epidemiology, pathophysiology and diagnosis of both NAFLD and metabolic syndrome and the findings that strongly support the association of nonalcoholic fatty liver disease as a possible component in the cluster of metabolic syndrome. PMID:19240815
Loots, Gabriela G.; Kneissel, Michaela; Keller, Hansjoerg; Baptist, Myma; Chang, Jessie; Collette, Nicole M.; Ovcharenko, Dmitriy; Plajzer-Frick, Ingrid; Rubin, Edward M.
Mutations in distant regulatory elements can negatively impact human development and health, yet due to the difficulty of detecting these critical sequences we predominantly focus on coding sequences for diagnostic purposes. We have undertaken a comparative sequence-based approach to characterize a large noncoding region deleted in patients affected by Van Buchem disease (VB), a severe sclerosing bone dysplasia. Using BAC recombination and transgenesis we characterized the expression of human sclerostin (sost) from normal (hSOSTwt) or Van Buchem(hSOSTvb D) alleles. Only the hSOSTwt allele faithfully expressed high levels of human sost in the adult bone and impacted bone metabolism, consistent with the model that the VB noncoding deletion removes a sost specific regulatory element. By exploiting cross-species sequence comparisons with in vitro and in vivo enhancer assays we were able to identify a candidate enhancer element that drives human sost expression in osteoblast-like cell lines in vitro and in the skeletal anlage of the E14.5 mouse embryo, and discovered a novel function for sclerostin during limb development. Our approach represents a framework for characterizing distant regulatory elements associated with abnormal human phenotypes.
Robertson, J. D.; Samudralwar, D. L.; Markesbery, W. R.
It has been hypothesized that perturbations in element metabolism play a role in the etiology and/or pathogenesis of Alzheimer's disease (AD). No conclusion regarding this hypothesis has been reached, however, as results for central nervous system tissues from different research groups are contradictory. We are currently utilizing external-beam thick-target FIXE and PIGE analyses to investigate the elemental concentrations in the bone tissue of AD patients. Because bone acts as a "repository" for many trace elements, these measurements should provide information on the long-term trace-element status of AD patients. With the simultaneous PIXE/PIGE measurements, we are able to instrumentally determine the concentrations of oxygen, phosphorus, calcium, and 12-15 minor and trace elements in a single 30 min irradiation. Initial results obtained from the IBA measurements of both cortical and trabecular bone autopsy samples from four AD patients and twelve age-matched controls indicate a possible imbalance in Zn, Br and Rb.
Kim, M K; Chon, S J; Noe, E B; Roh, Y H; Yun, B H; Cho, S; Choi, Y S; Lee, B S; Seo, S K
Excessive amount of calcium intake increased risk for metabolic syndrome in men. However, modest amount decreased the risk of metabolic syndrome and osteoporosis in postmenopausal women. Modest amount of calcium also increased bone mineral density (BMD) in both men and postmenopausal women.
Zietek, Tamara; Rath, Eva
Chronic diseases, such as obesity and diabetes, cardiovascular, and inflammatory bowel diseases (IBD) share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways, such as the unfolded protein response (UPR), alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC) have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular, the L-cell-derived incretin hormone glucagon-like peptide 1 (GLP-1) has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D). Yet, accumulating data indicate a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment, including the microbiota via receptors and transporters. Subsequently, mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling. This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity, and disease. PMID:27148273
Feigerlova, Eva; Demarquet, Lea; Guéant, Jean-Louis
Homocysteine (HCY) is a degradation product of the methionine pathway. The B vitamins, in particular vitamin B12 and folate, are the primary nutritional determinant of HCY levels and therefore their deficiencies result in hyperhomocysteinaemia (HHCY). Prevalence of hyperhomocysteinemia (HHCY) and related dietary deficiencies in B vitamins and folate increase with age and have been related to osteoporosis and abnormal development of epiphyseal cartilage and bone in rodents. Here we provide a review of experimental and population studies. The negative effects of HHCY and/or B vitamins and folate deficiencies on bone formation and remodeling are documented by cell models, including primary osteoblasts, osteoclast and bone progenitor cells as well as by animal and human studies. However, underlying pathophysiological mechanisms are complex and remain poorly understood. Whether these associations are the direct consequences of impaired one carbon metabolism is not clarified and more studies are still needed to translate these findings to human population. To date, the evidence is limited and somewhat conflicting, however further trials in groups most vulnerable to impaired one carbon metabolism are required.
Chassaing, Benoit; Aitken, Jesse D; Gewirtz, Andrew T; Vijay-Kumar, Matam
The mammalian intestine harbors trillions of microbes collectively known as the microbiota, which can be viewed as an anaerobic metabolic organ that benefits the host in a number of ways. The homeostasis of this large microbial biomass is a prerequisite to maintaining host health by maximizing symbiotic interrelations and minimizing the risk of living in a close relationship. The cooperation between the innate and adaptive immune systems of the host maintains homeostasis of the microbiota. The dysregulation/alteration of microbiota in various immunodeficiency states including both innate and adaptive deficiency results in metabolic disease. This review examines the influence of microbiota on host metabolic health in immunologically altered mice. Accumulated data from a variety of immune-deficient murine models indicate that altered microbiota can play a key role in origination of metabolic diseases through the following potential mechanisms: (i) increasing calorie extraction resulting in adiposity, (ii) inducing low-grade chronic inflammation in the gut directly or increasing systemic loads of microbial ligands via leaky guts, (iii) generating toxic metabolites from dietary components, and (iv) inducing a switch from pro-metabolic to pro-immune phenotype that drives malabsorption of lipids resulting in muscle wastage and weight loss-particularly upon states of adaptive immune deficiency. Further, these murine models demonstrate that altered microbiota is not purely a consequence of metabolic disease but plays a key role in driving this disorder.
Nucleoside receptors are known to be important targets for a variety of brain diseases. However, the therapeutic modulation of their endogenous agonists by inhibitors of nucleoside metabolism represents an alternative therapeutic strategy that has gained increasing attention in recent years. Deficiency in endogenous nucleosides, in particular of adenosine, may causally be linked to a variety of neurological diseases and neuropsychiatric conditions ranging from epilepsy and chronic pain to schizophrenia. Consequently, augmentation of nucleoside function by inhibiting their metabolism appears to be a rational therapeutic strategy with distinct advantages: (i) in contrast to specific receptor modulation, the increase (or decrease) of the amount of a nucleoside will affect several signal transduction pathways simultaneously and therefore have the unique potential to modify complex neurochemical networks; (ii) by acting on the network level, inhibitors of nucleoside metabolism are highly suited to fine-tune, restore, or amplify physiological functions of nucleosides; (iii) therefore inhibitors of nucleoside metabolism have promise for the “soft and smart” therapy of neurological diseases with the added advantage of reduced systemic side effects. This review will first highlight the role of nucleoside function and dysfunction in physiological and pathophysiological situations with a particular emphasis on the anticonvulsant, neuroprotective, and antinociceptive roles of adenosine. The second part of this review will cover pharmacological approaches to use inhibitors of nucleoside metabolism, with a special emphasis on adenosine kinase, the key regulator of endogenous adenosine. Finally, novel gene-based therapeutic strategies to inhibit nucleoside metabolism and focal treatment approaches will be discussed. PMID:21401494
Lean, Mike EJ
The metabolic syndrome is a condition characterized by a special constellation of reversible major risk factors for cardiovascular disease and type 2 diabetes. The main, diagnostic, components are reduced HDL-cholesterol, raised triglycerides, blood pressure and fasting plasma glucose, all of which are related to weight gain, specifically intra-abdominal/ectopic fat accumulation and a large waist circumference. Using internationally adopted arbitrary cut-off values for waist circumference, having metabolic syndrome doubles the risk of cardiovascular disease, but offers an effective treatment approach through weight management. Metabolic syndrome now affects 30–40% of people by age 65, driven mainly by adult weight gain, and by a genetic or epigenetic predisposition to intra-abdominal/ectopic fat accumulation related to poor intra-uterine growth. Metabolic syndrome is also promoted by a lack of subcutaneous adipose tissue, low skeletal muscle mass and anti-retroviral drugs. Reducing weight by 5–10%, by diet and exercise, with or without, anti-obesity drugs, substantially lowers all metabolic syndrome components, and risk of type 2 diabetes and cardiovascular disease. Other cardiovascular disease risk factors such as smoking should be corrected as a priority. Anti-diabetic agents which improve insulin resistance and reduce blood pressure, lipids and weight should be preferred for diabetic patients with metabolic syndrome. Bariatric surgery offers an alternative treatment for those with BMI ≥ 40 or 35–40 kg/m2 with other significant co-morbidity. The prevalence of the metabolic syndrome and cardiovascular disease is expected to rise along with the global obesity epidemic: greater emphasis should be given to effective early weight-management to reduce risk in pre-symptomatic individuals with large waists. PMID:26998259
Han, Thang S; Lean, Mike Ej
The metabolic syndrome is a condition characterized by a special constellation of reversible major risk factors for cardiovascular disease and type 2 diabetes. The main, diagnostic, components are reduced HDL-cholesterol, raised triglycerides, blood pressure and fasting plasma glucose, all of which are related to weight gain, specifically intra-abdominal/ectopic fat accumulation and a large waist circumference. Using internationally adopted arbitrary cut-off values for waist circumference, having metabolic syndrome doubles the risk of cardiovascular disease, but offers an effective treatment approach through weight management. Metabolic syndrome now affects 30-40% of people by age 65, driven mainly by adult weight gain, and by a genetic or epigenetic predisposition to intra-abdominal/ectopic fat accumulation related to poor intra-uterine growth. Metabolic syndrome is also promoted by a lack of subcutaneous adipose tissue, low skeletal muscle mass and anti-retroviral drugs. Reducing weight by 5-10%, by diet and exercise, with or without, anti-obesity drugs, substantially lowers all metabolic syndrome components, and risk of type 2 diabetes and cardiovascular disease. Other cardiovascular disease risk factors such as smoking should be corrected as a priority. Anti-diabetic agents which improve insulin resistance and reduce blood pressure, lipids and weight should be preferred for diabetic patients with metabolic syndrome. Bariatric surgery offers an alternative treatment for those with BMI ≥ 40 or 35-40 kg/m(2) with other significant co-morbidity. The prevalence of the metabolic syndrome and cardiovascular disease is expected to rise along with the global obesity epidemic: greater emphasis should be given to effective early weight-management to reduce risk in pre-symptomatic individuals with large waists.
Cho, Sun Wook; Bae, Jae Hyun; Noh, Gyeong Woon; Kim, Ye An; Moon, Min Kyong; Park, Kyoung Un; Song, Junghan; Yi, Ka Hee; Park, Do Joon; Chung, June-Key; Cho, Bo Youn; Park, Young Joo
Osteoporosis-related fractures are one of the complications of Graves’ disease. This study hypothesized that the different actions of thyroid-stimulating hormone receptor (TSHR) antibodies, both stimulating and blocking activities in Graves’ disease patients might oppositely impact bone turnover. Newly diagnosed premenopausal Graves’ disease patients were enrolled (n = 93) and divided into two groups: patients with TSHR antibodies with thyroid-stimulating activity (stimulating activity group, n = 83) and patients with TSHR antibodies with thyroid-stimulating activity combined with blocking activity (blocking activity group, n = 10). From the stimulating activity group, patients who had matched values for free T4 and TSH binding inhibitor immunoglobulin (TBII) to the blocking activity group were further classified as stimulating activity-matched control (n = 11). Bone turnover markers BS-ALP, Osteocalcin, and C-telopeptide were significantly lower in the blocking activity group than in the stimulating activity or stimulating activity-matched control groups. The TBII level showed positive correlations with BS-ALP and osteocalcin levels in the stimulating activity group, while it had a negative correlation with the osteocalcin level in the blocking activity group. In conclusion, the activation of TSHR antibody-activated TSH signaling contributes to high bone turnover, independent of the actions of thyroid hormone, and thyroid-stimulation blocking antibody has protective effects against bone metabolism in Graves’ disease. PMID:26650844
Wang, Cunchuan; Gao, Zhiguang
The U. S. A. president Obama called for a new initiative to fund precision medicine during his State of Union Address on January 20th, 2015, which meant that the human medicine enters a new era. The meaning of "precision medicine" is significantly similar to the concept of precision obesity and metabolic disease surgery, which was proposed by the author in early August 2011. Nowadays, obesity and metabolic disease surgery has been transformed from open surgery to laparoscopic surgery, the extensive mode to the precision mode. The key value concept is to minimize postoperative complication, minimize postoperative hospital stay and obtain the best effect of weight loss by accurate preoperative assessment, delicate operation, excellent postoperative management and scientific follow-up. The precision obesity and metabolic disease surgery has more development space in the future.
Bridges, Kayla M; Pereira-da-Silva, Luis; Tou, Janet C; Ziegler, Jane; Brunetti, Luigi
Very preterm infants (<32 weeks' gestation) are at high risk for impaired skeletal development because of factors that limit the provision of extrauterine nutrients. Cumulative net deficiencies of calcium, phosphorus, docosahexaenoic acid (DHA), and arachidonic acid (ARA) are evident in these infants after prolonged administration of total parenteral nutrition (TPN). This is significant because minerals as well as metabolites of DHA and ARA are important modulators of bone cell differentiation, lengthening of bone, and bone matrix deposition. Furthermore, diets containing only precursors of DHA and ARA result in suboptimal skeletal growth. With the emergence of new intravenous lipid emulsions, it is important to understand the impact of fatty acids on bone metabolism in the third trimester in order to optimize the provision of TPN in very preterm infants. The purpose of this review is to evaluate current evidence regarding intravenous lipid emulsions and bone metabolism in very preterm infants receiving prolonged TPN and to identify areas of research needed.
Bodé, S; Hassager, C; Gudmand-Høyer, E; Christiansen, C
Twenty two treated adult patients with coeliac disease (aged 20-70 years) were examined. Body composition was assessed from anthropometry and directly measured by dual photon absorptiometry. Bone mineral content was measured in the spine (dual photon absorptiometry) and at two forearm sites (single photon absorptiometry). Compared with age matched healthy subjects, treated coeliac patients had lower body mass index (-5%, p less than 0.05) and lower directly measured total body fat mass (-30%, p less than 0.001). They also had decreased bone mineral content (-9 to -13%, p less than 0.01) in the spine and in the forearms. The serum concentrations of albumin, D vitamin binding protein, and iron were reduced (-6 to -22%, p less than 0.01), but otherwise blood and urine analyses were normal. We conclude that this group of treated adult coeliac patients had a reduced fat mass and bone mineral content compared with the general population. PMID:1752465
Alexander, I E; Cunningham, S C; Logan, G J; Christodoulou, J
Inborn errors of metabolism are collectively common, frequently severe and in many instances difficult or impossible to treat. Accordingly, there is a compelling need to explore novel therapeutic modalities, including gene therapy, and examine multiple phenotypes where the risks of experimental therapy are outweighed by potential benefits to trial participants. Among available gene delivery systems recombinant AAV shows special promise for the treatment of metabolic disease given the unprecedented efficiencies achieved in transducing key target tissues, such as liver and muscle, in small animal models. To date over 30 metabolic disease phenotypes have been investigated in small animal studies with complete phenotype correction being achieved in a substantial proportion. Achieving adequately widespread transduction within the central nervous system, however, remains a major challenge, and will be critical to realization of the therapeutic potential of gene therapy for many of the most clinically troubling metabolic disease phenotypes. Despite the relatively low immunogenicity of AAV vectors, immune responses are also emerging as a factor requiring special attention as efforts accelerate toward human clinical translation. Four metabolic disease phenotypes have reached phase I or I/II trials with one, targeting lipoprotein lipase deficiency, showing exciting early evidence of efficacy.
Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino
Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD. PMID:27610012
Papacleovoulou, Georgia; Abu-Hayyeh, Shadi; Nikolopoulou, Evanthia; Briz, Oscar; Owen, Bryn M; Nikolova, Vanya; Ovadia, Caroline; Huang, Xiao; Vaarasmaki, Marja; Baumann, Marc; Jansen, Eugene; Albrecht, Christiane; Jarvelin, Marjo-Riitta; Marin, Jose J G; Knisely, A S; Williamson, Catherine
The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.
Zimmermann, Elizabeth A; Busse, Björn; Ritchie, Robert O
Aging and bone diseases are associated with increased fracture risk. It is therefore pertinent to seek an understanding of the origins of such disease-related deterioration in bone's mechanical properties. The mechanical integrity of bone derives from its hierarchical structure, which in healthy tissue is able to resist complex physiological loading patterns and tolerate damage. Indeed, the mechanisms through which bone derives its mechanical properties make fracture mechanics an ideal framework to study bone's mechanical resistance, where crack-growth resistance curves give a measure of the intrinsic resistance to the initiation of cracks and the extrinsic resistance to the growth of cracks. Recent research on healthy cortical bone has demonstrated how this hierarchical structure can develop intrinsic toughness at the collagen fibril scale mainly through sliding and sacrificial bonding mechanisms that promote plasticity. Furthermore, the bone-matrix structure develops extrinsic toughness at much larger micrometer length-scales, where the structural features are large enough to resist crack growth through crack-tip shielding mechanisms. Although healthy bone tissue can generally resist physiological loading environments, certain conditions such as aging and disease can significantly increase fracture risk. In simple terms, the reduced mechanical integrity originates from alterations to the hierarchical structure. Here, we review how human cortical bone resists fracture in healthy bone and how changes to the bone structure due to aging, osteoporosis, vitamin D deficiency and Paget's disease can affect the mechanical integrity of bone tissue. PMID:26380080
Guimaro, Maria C.; Alves, Rozeneide M.; Rose, Ester; Sousa, Alessandro O.; de Cássia Rosa, Ana; Hecht, Mariana M.; Sousa, Marcelo V.; Andrade, Rafael R.; Vital, Tamires; Plachy, Jiří; Nitz, Nadjar; Hejnar, Jiří; Gomes, Clever C.; L. Teixeira, Antonio R.
Background Infection with the protozoan Trypanosoma cruzi manifests in mammals as Chagas heart disease. The treatment available for chagasic cardiomyopathy is unsatisfactory. Methods/Principal Findings To study the disease pathology and its inhibition, we employed a syngeneic chicken model refractory to T. cruzi in which chickens hatched from T. cruzi inoculated eggs retained parasite kDNA (1.4 kb) minicircles. Southern blotting with EcoRI genomic DNA digests revealed main 18 and 20 kb bands by hybridization with a radiolabeled minicircle sequence. Breeding these chickens generated kDNA-mutated F1, F2, and F3 progeny. A targeted-primer TAIL-PCR (tpTAIL-PCR) technique was employed to detect the kDNA integrations. Histocompatible reporter heart grafts were used to detect ongoing inflammatory cardiomyopathy in kDNA-mutated chickens. Fluorochromes were used to label bone marrow CD3+, CD28+, and CD45+ precursors of the thymus-dependent CD8α+ and CD8β+ effector cells that expressed TCRγδ, vβ1 and vβ2 receptors, which infiltrated the adult hearts and the reporter heart grafts. Conclusions/Significance Genome modifications in kDNA-mutated chickens can be associated with disruption of immune tolerance to compatible heart grafts and with rejection of the adult host's heart and reporter graft, as well as tissue destruction by effector lymphocytes. Autoimmune heart rejection was largely observed in chickens with kDNA mutations in retrotransposons and in coding genes with roles in cell structure, metabolism, growth, and differentiation. Moreover, killing the sick kDNA-mutated bone marrow cells with cytostatic and anti-folate drugs and transplanting healthy marrow cells inhibited heart rejection. We report here for the first time that healthy bone marrow cells inhibited heart pathology in kDNA+ chickens and thus prevented the genetically driven clinical manifestations of the disease. PMID:25521296
Campistol, Josep M; Holt, David W; Epstein, Solomon; Gioud-Paquet, Martine; Rutault, Karine; Burke, James T
Sirolimus is a new immunosuppressive agent used as treatment to prevent acute renal allograft rejection. One of the complications of renal transplantation and subsequent long-term immunosuppression is bone loss associated with osteoporosis and consequent fracture. Two open-label, randomized, phase 2 studies comparing sirolimus versus cyclosporine (CsA) included indices of bone metabolism as secondary end-points. Markers of bone turnover, serum osteocalcin and urinary N-telopeptides, were measured over a 1-year period in 115 patients receiving either CsA or sirolimus as a primary therapy in combination with azathioprine and glucocorticoids (study A) or mycophenolate mofetil (MMF) and glucocorticoids (study B). Urinary excretion of N-telopeptides and the concentrations of serum osteocalcin were consistently higher in the CsA-treated patients and significantly different at week 24 for N-telopeptides and at weeks 12, 24, and 52 for osteocalcin. In conclusion, future trials are warranted to test whether a sirolimus-based regimen conserves bone mineral density compared with a CsA-based regimen.
Tatekoshi, Ayumi; Sato, Tsutomu; Ibata, Soushi; Hashimoto, Akari; Kamihara, Yusuke; Horiguchi, Hiroto; Ono, Kaoru; Takada, Kohichi; Iyama, Satoshi; Takimoto, Rishu; Kobune, Masayoshi; Kato, Junji
To date, intravenous drip infusion of zoledronic acid (ZA) has mainly been used for the treatment and prevention of skeletal-related events (SRE) in patients with multiple myeloma (MM). Recently, denosumab, a fully humanized monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL), has also become available for the same purpose, but little is known about the impact of switching from ZA to denosumab. Herein, we present a retrospective study on bone metabolic markers in 10 MM patients initially treated with ZA and then switched to denosumab. Consequently, the levels of bone resorption markers, tartrate-resistant acid phosphatase 5b (TRACP-5b) and serum type-I collagen crosslinked N-telopeptide (sNTX), significantly decreased after denosumab treatment, while the levels of bone formation markers, osteocalcin (OC) and bone-specific alkaline phosphatase (BAP), showed no apparent changes. No patient developed severe hypocalcemia with denosumab treatment. In one patient not given chemotherapy, the M-protein level increased after switching from ZA to denosumab and plateaued when ZA was restarted. Based on this finding, we anticipate that switching from ZA to denosumab would exert a stronger suppressive effect on osteoclasts, but the anti-myeloma activity of ZA must be taken into consideration.
Silva, Viviam de Oliveira; Lobato, Raquel Vieira; Andrade, Eric Francelino; de Macedo, Cristina Gomes; Napimoga, Juliana Trindade Clemente; Napimoga, Marcelo Henrique; Messora, Michel Reis; Murata, Ramiro Mendonça; Pereira, Luciano José
The objective of this study was to assess the effects of oral ingestion of β-glucans isolated from Saccharomyces cereviseae on the metabolic profile, expression of gingival inflammatory markers and amount of alveolar bone loss in diabetic rats with periodontal disease. Diabetes mellitus was induced in 48 Wistar rats by intraperitoneal injection of streptozotocin (80 mg/kg). After confirming the diabetes diagnosis, the animals were treated with β-glucans (by gavage) for 28 days. On the 14th day of this period, periodontal disease was induced using a ligature protocol. β-glucans reduced the amount of alveolar bone loss in animals with periodontal disease in both the diabetic and non-diabetic groups (p < 0.05). β-glucans reduced blood glucose, cholesterol and triacylglycerol levels in diabetic animals, both with and without periodontal disease (p < 0.05). Furthermore, treatment with β-glucans reduced the expression of cyclooxygenase-2 and receptor activator of nuclear factor kappa-B ligand and increased osteoprotegerin expression in animals with diabetes and periodontal disease (p < 0.05). It was concluded that treatment with β-glucans has beneficial metabolic and periodontal effects in diabetic rats with periodontal disease.
The objective of this study was to assess the effects of oral ingestion of β-glucans isolated from Saccharomyces cereviseae on the metabolic profile, expression of gingival inflammatory markers and amount of alveolar bone loss in diabetic rats with periodontal disease. Diabetes mellitus was induced in 48 Wistar rats by intraperitoneal injection of streptozotocin (80 mg/kg). After confirming the diabetes diagnosis, the animals were treated with β-glucans (by gavage) for 28 days. On the 14th day of this period, periodontal disease was induced using a ligature protocol. β-glucans reduced the amount of alveolar bone loss in animals with periodontal disease in both the diabetic and non-diabetic groups (p < 0.05). β-glucans reduced blood glucose, cholesterol and triacylglycerol levels in diabetic animals, both with and without periodontal disease (p < 0.05). Furthermore, treatment with β-glucans reduced the expression of cyclooxygenase-2 and receptor activator of nuclear factor kappa-B ligand and increased osteoprotegerin expression in animals with diabetes and periodontal disease (p < 0.05). It was concluded that treatment with β-glucans has beneficial metabolic and periodontal effects in diabetic rats with periodontal disease. PMID:26291983
Belenky, Peter; Bogan, Katrina L; Brenner, Charles
Nicotinamide adenine dinucleotide (NAD(+)) is both a coenzyme for hydride-transfer enzymes and a substrate for NAD(+)-consuming enzymes, which include ADP-ribose transferases, poly(ADP-ribose) polymerases, cADP-ribose synthases and sirtuins. Recent results establish protective roles for NAD(+) that might be applicable therapeutically to prevent neurodegenerative conditions and to fight Candida glabrata infection. In addition, the contribution that NAD(+) metabolism makes to lifespan extension in model systems indicates that therapies to boost NAD(+) might promote some of the beneficial effects of calorie restriction. Nicotinamide riboside, the recently discovered nucleoside precursor of NAD(+) in eukaryotic systems, might have advantages as a therapy to elevate NAD(+) without inhibiting sirtuins, which is associated with high-dose nicotinamide, or incurring the unpleasant side-effects of high-dose nicotinic acid.
Barnea, Dana; Raghunathan, Nirupa; Friedman, Danielle Novetsky; Tonorezos, Emily S.
As care for the childhood cancer patient has improved significantly, there is an increasing incidence of treatment-related late effects. Obesity and type 2 diabetes mellitus are common and significant metabolic conditions in some populations of adult survivors of childhood cancer. Results from the Childhood Cancer Survivor Study and other large cohorts of childhood cancer survivors reveal that long-term survivors of acute lymphoblastic leukemia and those who received total body irradiation or abdominal radiotherapy are at highest risk. The potential mechanisms for the observed increase in risk, including alterations in leptin and adiponectin, pancreatic insufficiency, poor dietary habits, sedentary lifestyle, and perhaps changes in the composition of the gut microbiota, are reviewed. Discussion of exercise and diet intervention studies shows that further research about the barriers to a healthy lifestyle and other interventions in childhood cancer survivors is warranted. PMID:26568532
Baker, Rebecca G; Hayden, Matthew S; Ghosh, Sankar
Metabolic disorders including obesity, type 2 diabetes, and atherosclerosis have been viewed historically as lipid storage disorders brought about by overnutrition. It is now widely appreciated that chronic low-grade inflammation plays a key role in the initiation, propagation, and development of metabolic diseases. Consistent with its central role in coordinating inflammatory responses, numerous recent studies have implicated the transcription factor NF-κB in the development of such diseases, thereby further establishing inflammation as a critical factor in their etiology and offering hope for the development of new therapeutic approaches for their treatment.
Block, Robert C.; Dorsey, E. Ray; Beck, Christopher A.; Brenna, J. Thomas; Shoulson, Ira
Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease. PMID:20802793
Block, Robert C; Dorsey, E Ray; Beck, Christopher A; Brenna, J Thomas; Shoulson, Ira
Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.
Rowe, Peter S
The beginning of the millennium saw the discovery of a new bone-matrix protein, Matrix Extracellular PhosphoglycoprotEin (MEPE) and an associated C-terminal motif called ASARM. This motif and other distinguishing features occur in a group of proteins called SIBLINGs. These proteins include dentin matrix protein 1 (DMP1), osteopontin, dentin-sialophosphoprotein (DSPP), statherin, bone sialoprotein (BSP) and MEPE. MEPE, DMP1 and ASARM-motifs regulate expression of a phosphate regulating cytokine FGF23. Further, a trimeric interaction between phosphate regulating endopeptidase homolog X-linked (PHEX), DMP1, and α5β3-integrin that occurs on the plasma-membrane of the osteocyte mediates FGF23 regulation (FAP pathway). ASARM-peptides competitively inhibit the trimeric complex and increase FGF23. A second pathway involves specialized structures, matrix vesicles pathway (MVP). This review will discuss the FAP and MVP pathways and present a unified model for mineral and energy metabolism.
Suzuki, Takao; Izawa, Hiromi; Satoh, Atsuko
Background In this study, we examined the influence of exercise loading characteristics on bone metabolic responses and bone morphology in the growth phase and adulthood. Methods Running exercise (RUN) and jumping exercise (JUM) were used for the exercise loading in 28-day-old male Wistar rats. Bone metabolism was measured by blood osteocalcin (OC) and tartrate-resistant acid phosphatase (TRACP) levels. For bone morphology, the maximum bone length, bone weight, and bone strength of the femur and tibia were measured. Results A pre- and post-exercise loading comparison in the growth phase showed significantly increased OC levels in the RUN and JUM groups and significantly decreased TRACP levels in the JUM group. On the other hand, a pre- and post-exercise loading comparison in adulthood showed significantly decreased TRACP levels in the RUN and JUM groups. Femur lengths were significantly shorter in the RUN and JUM groups than in the control (CON) group, while bone weight was significantly greater in the JUM group than in the CON group. Conclusions Exercise loading activates OC levels in the growth phase and suppresses TRACP levels in adulthood. On the other hand, these results suggest that excessive exercise loading may suppress bone length. PMID:27622180
Zhou, Shuanhu; LeBoff, Meryl S.; Glowacki, Julie
Vitamin D metabolites are important effectors of bone and mineral homeostasis. Extrarenal conversion of 25-hydroxyvitamin D (25OHD) to the biologically active form of vitamin D, 1α,25-dihydroxyvitamin D [1,25(OH)2D] is catalyzed in several cell types by the 1α-hydroxylase (CYP27B1), but little is known about the expression or regulation of CYP27B1 in human bones. We examined whether human bone marrow stromal cells (hMSCs, also known as mesenchymal stem cells) participate in vitamin D metabolism and whether vitamin D hydroxylases in hMSCs are influenced by the vitamin D status of the individual from whom the hMSCs were obtained. We also investigated the effects of vitamin D metabolites on osteoblast differentiation and the role of IGF-I in the regulation of CYP27B1. In a series of 27 subjects, vitamin D hydroxylases in hMSCs were expressed at different levels and were correlated with serum 25OHD, 1,25(OH)2D, and PTH. In vitro treatment with 25OHD up-regulated CYP27B1 and IGF-I in hMSCs; IGF-I also up-regulated CY27B1 expression and stimulated osteoblast differentiation. When hydroxylation of 25OHD was blocked by ketoconazole, a cytochrome P450 inhibitor, 25OHD was no longer able to induce CYP27B1 expression. In summary, these findings show that human bone marrow stromal cells have the molecular machinery both to metabolize and respond to vitamin D. We propose that circulating 25OHD, by virtue of its local conversion to 1,25(OH)2D catalyzed by basal CYP27B1 in hMSCs, amplifies vitamin D signaling through IGF-I up-regulation, which in turn induces CYP27B1 in a feed-forward mechanism to potentiate osteoblast differentiation initiated by IGF-I. PMID:19966181
Petrescu, Pompiliu HoraŢiu; Izvernariu, Dragoş Andrei; Iancu, Cătălina; Dinu, Gabriel Ovidiu; Berceanu-Văduva, Marcel Mihai; Crişan, Dan; Iacob, Mihaela; Bucur, Venera Margareta; RăuŢia, Ion Călin; Prejbeanu, Ion Radu; Dema, Sorin; DuŢă, Ciprian Constantin
Paget's disease of bone is a benign disease characterized by exaggerated remodeling of the bone matrix after osteoclast-mediated bone destruction. Its etiology is still unknown, despite the fact that it was discovered and described in 1877, but genetic factors and environmental triggers were shown to play their part in the pathogenesis of the disease. The main clinical presentations of the disease are related to bone pain and deformities. Radiological diagnosis is the main detection tool, though many monostotic Paget's disease cases may remain undiagnosed. We present the case of an 81-year-old male patient admitted to the Clinic of Orthopedics, Emergency County Hospital, Timisoara, Romania, with intense pain and deformity of the upper left thigh. Radiological examination performed shows a complete fracture of the upper third diaphysis of the left femur with suggestive signs for Paget's disease of the bone therefore a biopsy was taken and the patient was treated by surgical realignment with favorable evolution. He was discharged 13 days after surgery. The biopsy of the bone revealed extensive bone remodeling with numerous osteoclasts and extensive bone matrix deposition, unevenly stained and unevenly mineralized and reverse cement lines, which are consistent with the diagnosis of Paget's disease of the bone. Histomorphometric analysis show intense matrix deposition with a highly active remodeling process. Computed tomography (CT) scans were performed three years later and show the extension of the disease into the lower half of the left femur.
This paper reviews recent advances in the studies of various biochemical factors (biomarkers) involved in bone metabolism and remodeling. The collected data in this area suggest the existence of complex and multilevel relationships between calciotropic hormones, various cytokines and growth factors. The paper summarizes the data on the magnitude of the familial and genetic effects on the interindividual variation in circulating levels of many of these biomarkers. The majority of the cited heritability estimates are well above 20%, reaching up to 80% for some cytokines (e.g., TNFalpha and VEGF). These estimates point to potential targets for the identification of novel quantitative trait loci involved in the control of the respective molecules variation. This information is of particular importance, because the available data on the association between specific genes/polymorphisms and the respective circulating molecules variation is still very limited. The paper also provides recent findings on the genetics of co-variation between the circulating levels of various biomarkers. It shows that only in a few instances, such as for example, between IGF-I and IGFBP-3, and IGFBP-1 and leptin, significant and substantial genetic (and environmental) correlations were found. It appears that despite the prominent strong genetic effects on variation of each of the numerous biomarkers, the pleiotropic effects are rather limited. We consider briefly some important new data obtained using the gene expression approach and microarray technique. The data, for instance, indicate that the genetic effects on bone metabolism appear to be an open system, which can be activated or modulated by external factors such as drugs, e.g., PTH. Extensive molecular genetic studies in this area are both timely and imperative to detect the specific genes affecting variation (and co-variation) of the circulating factors associated with bone metabolism.
Ota, Satoshi; Hirose, Masayo; Izumiya, Yoshiaki; Ishida, Yoichi
Effects of switch from sevelamer hydrochloride (Sev) to lanthanum carbonate (La) on serum potassium (K) and bone metabolic markers in maintenance dialysis patients were examined. A switch from Sev to La was made for 14 dialysis patients (mean dialysis period and age: 65.3 months and 58.5 years old) to examine changes of biochemical and bone metabolic markers after 8 weeks. The Sev dosage immediately before the switch was 1857 ± 1325 mg/day, and the La dosage 8 weeks after the switch was 821 ± 301 mg/day. The serum calcium (Ca) level, which was 8.9 mg/dL before the switch, increased to 9.5 mg/dL after the switch (P < 0.05) whereas there was no change in the serum phosphorus level (P levels) or the calcium × phosphorus product. A decrease in the serum K level (4.6 vs. 4.4 mEq/L, P < 0.05), an increase in the total cholesterol level (131 vs. 142 mg/dL, P < 0.05), and a decrease in the serum ALP level (334.5 vs. 282 IU/L, P < 0.05) were observed, but there was no change in the intact parathyroid hormone (PTH) level. A significant negative correlation between the HCO3 level and the serum K level before dialysis was observed. These results suggest that a switch from Sev to La provided a decrease in the serum K level and normalization of bone metabolic markers, which was not mediated by PTH.
Kanis, J. A.; Johnell, O.; Gullberg, B.; Allander, E.; Dilşen, G.; Gennari, C.; Lopes Vaz, A. A.; Lyritis, G. P.; Mazzuoli, G.; Miravet, L.
OBJECTIVE--To examine the effects of taking drugs affecting bone metabolism on the risk of hip fracture in women aged over 50 years. DESIGN--Retrospective, population based, case-control study by questionnaire. SETTING--14 centres in six countries in southern Europe. SUBJECTS--2086 women with hip fracture and 3532 control women matched for age. MAIN OUTCOME MEASURES--Number of drugs affecting bone metabolism taken and length taken for. RESULTS--Women taking drugs affecting bone metabolism had a significantly decreased risk of hip fracture. After adjustment for differences in other risk factors, the relative risk of hip fractures was 0.55 (95% confidence interval 0.31 to 0.85) in women taking oestrogens, 0.75 (0.60 to 0.94) in those taking calcium, and 0.69 (0.51 to 0.92) in those taking calcitonin. The fall in risk was not significant for anabolic steroids (0.6 (0.29 to 1.22)). Neither vitamin D nor fluorides were associated with a significant decrease in the risk of hip fracture. The effect on hip fracture risk increased significantly with increasing duration of exposure (risk ratio 0.8 (0.61 to 1.05) for less than median exposure v 0.66 (0.5 to 0.88) for greater than median exposure). Drugs were equally effective in older and younger women, with the exception of oestrogen. CONCLUSIONS--Oestrogen, calcium, and calcitonins significantly decrease the risk of hip fracture. Short term intervention late in the natural course of osteoporosis may have significant effects on the incidence of hip fracture. PMID:1463947
Kasperk, C H; Wakley, G K; Hierl, T; Ziegler, R
Androgens stimulate bone formation and play an important role in the maintenance of bone mass. Clinical observations suggest that both gonadal and adrenal androgens contribute to the positive impact of androgenic steroids on bone metabolism. We investigated the mechanism of action of the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfated compound dehydroepiandrosterone sulfate (DHEAS) on human osteoblastic cells (HOCs) in vitro. The DHEA- and DHEAS-induced effects were analyzed in parallel with the actions elicited by the gonadal androgen dihydrotestosterone (DHT). There was no qualitative difference between the effects of gonadal and adrenal androgens on HOC metabolism in vitro. Both were stimulatory as regards cell proliferation and differentiated functions, but the gonadal androgen DHT was significantly more potent than DHEA. The actions of DHT and DHEA on HOC proliferation and alkaline phosphatase (ALP) production could be prevented by the androgen receptor antagonist hydroxyflutamide and inhibitory transforming growth factor beta antibodies (TGF-beta ab), respectively, but were not affected by the presence of the 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) and 5-alpha-reductase (5-AR) inhibitor 17 beta-N,N-diethylcarbamoyl-4-methyl- 4aza-5 alpha-androstan-3-one (4-MA). This indicates that DHT and DHEA (1) exert their mitogenic effects by androgen receptor-mediated mechanisms, (2) stimulate ALP production by increased TGF-beta expression, (3) that the action of DHT is not affected by the presence of 4-MA, and that (4) DHEA does not need to be metabolized by 3 beta HSD or 5-AR first to exert its effects on HOCs in vitro.
Keshtkar, Abbasali; Shirani, Shapour; Mounesan, Leila
Background Since 1991 many studies evaluated the link between cardiovascular diseases and osteoporosis, two age-related conditions, but the main common pathologic pathway has not been determined yet. The histological similarity between arterial calcified plaque and bone matrix and involvement of similar cells and mediators provide a special field of research. Therefore in the present study, we aimed to evaluate the relationship between coronary artery calcium score (CACS) as a surrogate marker of atherosclerosis and bone mediators and parameters in postmenopausal women. Methods Eleven postmenopausal women who had CACS higher than 80 were enrolled into the study and underwent bone densitometry. In addition, their serum and urine samples were taken for measuring osteoprotegerin, osteocalcin, and β cross laps. Patients' 10-year probability of fracture was calculated by the World Health Organization fracture-risk assessment tool (FRAX). Results The regression analysis of our results showed the association between CACS and OC (std β=0.66, 95% confidence interval [CI] 5.47-72.27, P=0.027), femoral bone density (std β=−0.6, 95% CI -6864.34-14.27, P=0.05) and T-score (std β=−0.6, 95% CI −773.08-1.28, P=0.05) which remained significant after adjustment for age, weight, years since menopause and body mass index. No association was found between CACS and osteoprotegerin, spinal bone density and FRAX score. Conclusions In conclusion, this pilot study with small sample size showed the potential association between CACS and osteocalcin, femoral bone density and T-score. However, the relationship between CACS and osteoprotegerin, receptor activator of nuclear factor-kappa B ligand, FRAX score and other bone parameters remain to be clarified in larger sample size studies. PMID:28326297
Jin, Ling; Nonaka, Yosuke; Miyakawa, Shin; Fujiwara, Masatoshi; Nakamura, Yoshikazu
Fibroblast growth factor 2 (FGF2) plays a crucial role in bone remodeling and disease progression. However, the potential of FGF2 antagonists for treatment of patients with bone diseases has not yet been explored. Therefore, we generated a novel RNA aptamer, APT-F2, specific for human FGF2 and characterized its properties in vitro and in vivo. APT-F2 blocked binding of FGF2 to each of its four cellular receptors, inhibited FGF2-induced downstream signaling and cells proliferation, and restored osteoblast differentiation blocked by FGF2. APT-F2P, a PEGylated form of APT-F2, effectively blocked the bone disruption in mouse and rat models of arthritis and osteoporosis. Treatment with APT-F2P also exerted a strong analgesic effect, equivalent to morphine, in a mouse model of bone cancer pain. These findings demonstrated dual therapeutic action of APT-F2P in bone diseases and pain, providing a promising approach to the treatment of bone diseases. PMID:27506449
Peinado, Juan R; Diaz-Ruiz, Alberto; Frühbeck, Gema; Malagon, Maria M
Mitochondria play a key role as major regulators of cellular energy homeostasis, but in the context of mitochondrial dysfunction, mitochondria may generate reactive oxidative species and induce cellular apoptosis. Indeed, altered mitochondrial status has been linked to the pathogenesis of several metabolic disorders and specially disorders related to insulin resistance, such as obesity, type 2 diabetes, and other comorbidities comprising the metabolic syndrome. In the present review, we summarize information from various mitochondrial proteomic studies of insulin-sensitive tissues under different metabolic states. To that end, we first focus our attention on the pancreas, as mitochondrial malfunction has been shown to contribute to beta cell failure and impaired insulin release. Furthermore, proteomic studies of mitochondria obtained from liver, muscle, and adipose tissue are summarized, as these tissues constitute the primary insulin target metabolic tissues. Since recent advances in proteomic techniques have exposed the importance of PTMs in the development of metabolic disease, we also present information on specific PTMs that may directly affect mitochondria during the pathogenesis of metabolic disease. Specifically, mitochondrial protein acetylation, phosphorylation, and other PTMs related to oxidative damage, such as nitrosylation and carbonylation, are discussed.
Tokumoto, Tadahiko; Tanabe, Kazunari; Toma, Hiroshi; Akiba, Takashi
The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) provides evidence based clinical practice guidelines developed for all phases of kidney disease and related complications, from diagnosis to monitoring and management. Bone disease sets in during the early stages of Chronic Kidney Disease (CKD). Bone disease is observed in almost patients with chronic renal failure and after renal transplantation. Hyperparathyroid (high turnover) bone disease in patients with chronic renal failure is found most frequently followed by mixed osteodystrophy, low-turn over bone disease, and osteomalasia. Ninety to one hundred percent of kidney transplant patients have histological evidence of osteodystrophy and osteopenia (reduction of bone mass) following renal transplantation. Furthermore, osteoporosis is also appeared in many renal transplant recipients. After renal transplantation, renal osteodystrophy generally improves but bone mineral density (BMD) often worsens. When renal bone disease is assessed using a combination of biochemical markers, histology and bone densitometry, early intervention and carefully effective therapies might be reduced the morbidity associated with these common problems.
Montgomery, Jana E; Brown, Jeremiah R
Cardiac and peripheral vascular biomarkers are increasingly becoming targets of both research and clinical practice. As of 2008, cardiovascular-related medical care accounts for greater than 20% of all the economic costs of illness in the United States. In the age of burgeoning financial pressures on the entire health care system, never has it been more important to try to understand who is at risk for cardiovascular disease in order to prevent new events. In this paper, we will