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Sample records for pth bone anabolism

  1. The Anabolic Effect of PTH on Bone is Attenuated by Simultaneous Glucocorticoid Treatment

    DEFF Research Database (Denmark)

    Oxlund, Hans; Ørtoft, Gitte; Thomsen, Jesper Skovhus;

    2006-01-01

    a pronounced increase in the endocortical bone formation rate (BFR) and a smaller increase in periosteal BFR. The combination of PTH + GC resulted in a partial inhibition of the PTH-induced increase in bone formation. Serum-osteocalcin was increased by 65% in the PTH group and reduced by 39% in the GC group....... The pronounced anabolic effect of PTH injections on the endocortical and trabecular bone surfaces and less pronounced anabolic effect on periosteal surfaces were partially inhibited, but not prevented, by simultaneous GC treatment in old rats. Both cortical and cancellous bone possessed full mechanical...

  2. Protein malnutrition attenuates bone anabolic response to PTH in female rats.

    Science.gov (United States)

    Ammann, P; Zacchetti, G; Gasser, J A; Lavet, C; Rizzoli, R

    2015-02-01

    PTH is indicated for the treatment of severe osteoporosis. Elderly osteoporotic patients frequently suffer from protein malnutrition, which may contribute to bone loss. It is unknown whether this malnutrition may affect the response to PTH. Therefore, the aim of the present study was to assess whether an isocaloric low-protein (LP) diet may influence the bone anabolic response to intermittent PTH in 6-month-old female rats. Six-month-old female rats were either pair fed an isocaloric LP diet (2.5% casein) or a normal-protein (NP) diet (15% casein) for 2 weeks. The rats continued on their respective diet while being treated with 5- or 40-μg/kg recombinant human PTH amino-terminal fragment 1-34 (PTH-[1-34]) daily, or with vehicle for 4 weeks. At the end of this period, areal bone mineral density, bone mineral content, microstructure, and bone strength in axial compression of proximal tibia or 3-point bending for midshaft tibia tests were measured. Blood was collected for the determination of IGF-I and osteocalcin. After 4 weeks of PTH-(1-34), the dose-dependent increase of proximal tibia bone mineral density, trabecular microstructure variables, and bone strength was attenuated in rats fed a LP diet as compared with rats on a NP intake. At the level of midshaft tibia cortical bone, PTH-(1-34) exerted an anabolic effect only in the NP but not in the LP diet group. Protein malnutrition was associated with lower IGF-I levels. Protein malnutrition attenuates the bone anabolic effects of PTH-(1-34) in rats. These results suggest that a sufficient protein intake should be recommended for osteoporotic patients undergoing PTH therapy.

  3. Bone-targeting parathyroid hormone conjugates outperform unmodified PTH in the anabolic treatment of osteoporosis in rats.

    Science.gov (United States)

    Yang, Yang; Aghazadeh-Habashi, Ali; Panahifar, Arash; Wu, Yuchin; Bhandari, Krishna H; Doschak, Michael R

    2017-08-01

    Synthetic parathyroid hormone (PTH) is clinically indicated for the treatment of osteoporosis, through its anabolic effects on parathyroid hormone receptors (PTHRs), located on osteoblast cells. However, the bioavailability of PTH for bone cells is restricted by the short half-life of PTH and the widespread distribution of PTHRs in non-skeletal tissues. To impart affinity for mineralized bone surfaces, bisphosphonate (BP)-mediated PTH analogues were synthesized, characterized, and evaluated in vitro and in vivo. The successful synthesis of PTH-PEG-BP was identified on MALDI-ToF mass spectra; bone-targeting potential was evaluated by hydroxyapatite binding test; and receptor bioactivity was assessed in UMR-106 (rat osteosarcoma) cells that constitutively express PTHRs. Therapeutic efficacy was evaluated using ovariectomized rats that remained untreated for 8 weeks to allow development of osteopenia. Those rats then received daily subcutaneous injections of PTH-PEG-BP, thiol-BP vehicle, or unmodified PTH, and compared to sham-operated healthy rats at 0, 4, 8, 12, and 16 weeks. In vivo micro-CT was conducted on the proximal tibial metaphysis to measure microstructural bone parameters, and new bone formation was detected using dynamic labeling. Bone strength was assessed using three-point bending mechanical testing. Our study determined that PTH-PEG-BP conjugates significantly enhanced PTH targeting to the bone matrix while retaining full PTH bioactivity. Moreover, PTH-PEG-BP conjugates significantly increased trabecular bone quality, anabolic bone formation, and improved bone strength over systemically administered PTH alone. We highlight the promise of a novel class of bone-targeting anabolic compound for the treatment of osteoporosis and related bone disorders.

  4. Maximizing PTH Anabolic Osteoporosis Therapy

    Science.gov (United States)

    2015-09-01

    Medical and Molecular Genetics, IUSM11 5. Center for Computational Biology and Bioinformatics, IUSM12 6. Department of Pediatrics, IUSM13 7. Herman B...67 Hesse , 2012; Yu et al., 2011]. This limits its effectiveness to treat a chronic degenerative disease. Recent 68 advances in bone-forming agents...Seq significance tool. Bioinformatics. 29(15):1922-4. 665 666 Baron R, Hesse E. 2012 Update on bone anabolics in osteoporosis treatment: rationale

  5. Maximizing PTH Anabolic Osteoporosis Therapy. Revision

    Science.gov (United States)

    2016-09-01

    of Pediatrics (Y.H., F.-C.Y.), Indiana University School of Medicine; Herman B Wells Center for Pediatric Research (Y.H., F.-C.Y.); Cellular and...2011;7:647–656. 2. Baron R, Hesse E. Update on bone anabolics in osteoporosis treat- ment: rationale, current status, and perspectives. J Clin

  6. Cyclooxygenase-2 suppresses the anabolic response to PTH infusion in mice.

    Directory of Open Access Journals (Sweden)

    Shilpa Choudhary

    Full Text Available We previously reported that the ability of continuously elevated PTH to stimulate osteoblastic differentiation in bone marrow stromal cell cultures was abrogated by an osteoclastic factor secreted in response to cyclooxygenase-2 (Cox2-produced prostaglandin E2. We now examine the impact of Cox2 (Ptgs2 knockout (KO on the anabolic response to continuously elevated PTH in vivo. PTH (40 μg/kg/d or vehicle was infused for 12 or 21 days in 3-mo-old male wild type (WT and KO mice in the outbred CD-1 background. Changes in bone phenotype were assessed by bone mineral density (BMD, μCT and histomorphometry. PTH infusion for both 12 and 21 days increased femoral BMD in Cox2 KO mice and decreased BMD in WT mice. Femoral and vertebral trabecular bone volume fractions were increased in KO mice, but not in WT mice, by PTH infusion. In the femoral diaphysis, PTH infusion increased cortical area in Cox2 KO, but not WT, femurs. PTH infusion markedly increased trabecular bone formation rate in the femur, serum markers of bone formation, and expression of bone formation-related genes, growth factors, and Wnt target genes in KO mice relative to WT mice, and decreased gene expression of Wnt antagonists only in KO mice. In contrast to the differential effects of PTH on anabolic factors in WT and KO mice, PTH infusion increased serum markers of resorption, expression of resorption-related genes, and the percent bone surface covered by osteoclasts similarly in both WT and KO mice. We conclude that Cox2 inhibits the anabolic, but not the catabolic, effects of continuous PTH. These data suggest that the bone loss with continuously infused PTH in mice is due largely to suppression of bone formation and that this suppression is mediated by Cox2.

  7. Critical Role of Activating Transcription Factor 4 in the Anabolic Actions of Parathyroid Hormone in Bone

    NARCIS (Netherlands)

    Yu, Shibing; Franceschi, Renny T.; Luo, Min; Fan, Jie; Jiang, Di; Cao, Huiling; Kwon, Tae-Geon; Lai, Yumei; Zhang, Jian; Patrene, Kenneth; Hankenson, Kurt; Roodman, G. David; Xiao, Guozhi

    2009-01-01

    Parathyroid hormone (PTH) is a potent anabolic agent for the treatment of osteoporosis. However, its mechanism of action in osteoblast and bone is not well understood. In this study, we show that the anabolic actions of PTH in bone are severely impaired in both growing and adult ovariectomized mice

  8. A Novel Cyclic PTH(1-17) analog with bone anabolic activity and efficacy sufficient to treat established osteopenia in adult ovariectomized rats

    DEFF Research Database (Denmark)

    Morko, Jukka; Peng, ZhiQi; Vääräniemi, Jukka;

    osteopenia was confirmed by peripheral quantitative computed tomography (pQCT). Treatment was started at 7 weeks after the operations and continued for 6 weeks. The osteopenic rats were treated subcutaneously, once a day with ZP2307 at doses of 2.0, 6.0, 20.0, 60.0 and 200.0 µg/kg/d, and with PTH(1-34) used...

  9. Sequential treatment with basic fibroblast growth factor and PTH is more efficacious than treatment with PTH alone for increasing vertebral bone mass and strength in osteopenic ovariectomized rats

    DEFF Research Database (Denmark)

    Iwaniec, U.T.; Mosekilde, Li.; Mitova-Caneva, N.G.

    2002-01-01

    The study was designed 1) to determine whether treatment with basic fibroblast growth factor (bFGF) and PTH is more efficacious than treatment with PTH alone for increasing bone mass and strength and improving trabecular microarchitecture in osteopenic ovariectomized rats, and 2) to assess whether...... prior and concurrent administration of the antiresorptive agents estrogen and risedronate suppresses the bone anabolic response to treatment with bFGF alone and sequential treatment with bFGF and PTH. Three-month-old female Sprague Dawley rats were ovariectomized (OVX) or sham-operated (sham...... of OVX rats with PTH alone increased vertebral cancellous bone mass and strength to the level of vehicle-treated sham rats. Sequential treatment of OVX rats with bFGF and PTH further augmented vertebral bone mass and strength to a level above that observed in OVX rats treated with PTH alone...

  10. PTH prevents the adverse effects of focal radiation on bone architecture in young rats

    Science.gov (United States)

    Chandra, Abhishek; Lan, Shenghui; Zhu, Ji; Lin, Tiao; Zhang, Xianrong; Siclari, Valerie A.; Altman, Allison R.; Cengel, Keith A.; Liu, X. Sherry; Qin, Ling

    2013-01-01

    Radiation therapy is a common treatment regimen for cancer patients. However, its adverse effects on the neighboring bone could lead to fractures with a great impact on quality of life. The underlying mechanism is still elusive and there is no preventive or curative solution for this bone loss. Parathyroid hormone (PTH) is a current therapy for osteoporosis that has potent anabolic effects on bone. In this study, we found that focal radiation from frequent scans of the right tibiae in 1-month-old rats by micro-computed tomography severely decreased trabecular bone mass and deteriorated bone structure. Interestingly, PTH daily injections remarkably improved trabecular bone in the radiated tibiae with increases in trabecular number, thickness, connectivity, structure model index and stiffness, and a decrease in trabecular separation. Histomorphometric analysis revealed that radiation mainly decreased the number of osteoblasts and impaired their mineralization activity but had little effects on osteoclasts. PTH reversed these adverse effects and greatly increased bone formation to a similar level in both radiated and non-radiated bones. Furthermore, PTH protects bone marrow mesenchymal stem cells from radiation-induced damage, including a decrease in number and an increase in adipogenic differentiation. While radiation generated the same amount of free radicals in the bone marrow of vehicle-treated and PTH-treated animals, the percentage of apoptotic bone marrow cells was significantly attenuated in the PTH group. Taken together, our data demonstrate a radioprotective effect of PTH on bone structure and bone marrow and shed new light on a possible clinical application of anabolic treatment in radiotherapy. PMID:23466454

  11. Critical Role of Activating Transcription Factor 4 in the Anabolic Actions of Parathyroid Hormone in Bone

    Science.gov (United States)

    Yu, Shibing; Franceschi, Renny T.; Luo, Min; Fan, Jie; Jiang, Di; Cao, Huiling; Kwon, Tae-Geon; Lai, Yumei; Zhang, Jian; Patrene, Kenneth; Hankenson, Kurt; Roodman, G. David; Xiao, Guozhi

    2009-01-01

    Parathyroid hormone (PTH) is a potent anabolic agent for the treatment of osteoporosis. However, its mechanism of action in osteoblast and bone is not well understood. In this study, we show that the anabolic actions of PTH in bone are severely impaired in both growing and adult ovariectomized mice lacking bone-related activating transcription factor 4 (ATF4). Our study demonstrates that ATF4 deficiency suppresses PTH-stimulated osteoblast proliferation and survival and abolishes PTH-induced osteoblast differentiation, which, together, compromise the anabolic response. We further demonstrate that the PTH-dependent increase in osteoblast differentiation is correlated with ATF4-dependent up-regulation of Osterix. This regulation involves interactions of ATF4 with a specific enhancer sequence in the Osterix promoter. Furthermore, actions of PTH on Osterix require this same element and are associated with increased binding of ATF4 to chromatin. Taken together these experiments establish a fundamental role for ATF4 in the anabolic actions of PTH on the skeleton. PMID:19851510

  12. Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone.

    Directory of Open Access Journals (Sweden)

    Shibing Yu

    Full Text Available Parathyroid hormone (PTH is a potent anabolic agent for the treatment of osteoporosis. However, its mechanism of action in osteoblast and bone is not well understood. In this study, we show that the anabolic actions of PTH in bone are severely impaired in both growing and adult ovariectomized mice lacking bone-related activating transcription factor 4 (ATF4. Our study demonstrates that ATF4 deficiency suppresses PTH-stimulated osteoblast proliferation and survival and abolishes PTH-induced osteoblast differentiation, which, together, compromise the anabolic response. We further demonstrate that the PTH-dependent increase in osteoblast differentiation is correlated with ATF4-dependent up-regulation of Osterix. This regulation involves interactions of ATF4 with a specific enhancer sequence in the Osterix promoter. Furthermore, actions of PTH on Osterix require this same element and are associated with increased binding of ATF4 to chromatin. Taken together these experiments establish a fundamental role for ATF4 in the anabolic actions of PTH on the skeleton.

  13. Disruption of PTH receptor 1 in T cells protects against PTH-induced bone loss.

    Directory of Open Access Journals (Sweden)

    Hesham Tawfeek

    Full Text Available BACKGROUND: Hyperparathyroidism in humans and continuous parathyroid hormone (cPTH treatment in mice cause bone loss by regulating the production of RANKL and OPG by stromal cells (SCs and osteoblasts (OBs. Recently, it has been reported that T cells are required for cPTH to induce bone loss as the binding of the T cell costimulatory molecule CD40L to SC receptor CD40 augments SC sensitivity to cPTH. However it is unknown whether direct PTH stimulation of T cells is required for cPTH to induce bone loss, and whether T cells contribute to the bone catabolic activity of PTH with mechanisms other than induction of CD40 signaling in SCs. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that silencing of PTH receptor 1 (PPR in T cells blocks the bone loss and the osteoclastic expansion induced by cPTH, thus demonstrating that PPR signaling in T cells is central for PTH-induced reduction of bone mass. Mechanistic studies revealed that PTH activation of the T cell PPR stimulates T cell production of the osteoclastogenic cytokine tumor necrosis factor alpha (TNF. Attesting to the relevance of this effect, disruption of T cell TNF production prevents PTH-induced bone loss. We also show that a novel mechanism by which TNF mediates PTH induced osteoclast formation is upregulation of CD40 expression in SCs, which increases their RANKL/OPG production ratio. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that PPR signaling in T cells plays an essential role in PTH induced bone loss by promoting T cell production of TNF. A previously unknown effect of TNF is to increase SC expression of CD40, which in turn increases SC osteoclastogenic activity by upregulating their RANKL/OPG production ratio. PPR-dependent stimulation of TNF production by T cells and the resulting TNF regulation of CD40 signaling in SCs are potential new therapeutic targets for the bone loss of hyperparathyroidism.

  14. Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss

    Science.gov (United States)

    Tawfeek, Hesham; Bedi, Brahmchetna; Li, Jau-Yi; Adams, Jonathan; Kobayashi, Tatsuya; Weitzmann, M. Neale; Kronenberg, Henry M.; Pacifici, Roberto

    2010-01-01

    Background Hyperparathyroidism in humans and continuous parathyroid hormone (cPTH) treatment in mice cause bone loss by regulating the production of RANKL and OPG by stromal cells (SCs) and osteoblasts (OBs). Recently, it has been reported that T cells are required for cPTH to induce bone loss as the binding of the T cell costimulatory molecule CD40L to SC receptor CD40 augments SC sensitivity to cPTH. However it is unknown whether direct PTH stimulation of T cells is required for cPTH to induce bone loss, and whether T cells contribute to the bone catabolic activity of PTH with mechanisms other than induction of CD40 signaling in SCs. Methodology/Principal Findings Here we show that silencing of PTH receptor 1 (PPR) in T cells blocks the bone loss and the osteoclastic expansion induced by cPTH, thus demonstrating that PPR signaling in T cells is central for PTH-induced reduction of bone mass. Mechanistic studies revealed that PTH activation of the T cell PPR stimulates T cell production of the osteoclastogenic cytokine tumor necrosis factor α (TNF). Attesting to the relevance of this effect, disruption of T cell TNF production prevents PTH-induced bone loss. We also show that a novel mechanism by which TNF mediates PTH induced osteoclast formation is upregulation of CD40 expression in SCs, which increases their RANKL/OPG production ratio. Conclusions/Significance These findings demonstrate that PPR signaling in T cells plays an essential role in PTH induced bone loss by promoting T cell production of TNF. A previously unknown effect of TNF is to increase SC expression of CD40, which in turn increases SC osteoclastogenic activity by upregulating their RANKL/OPG production ratio. PPR-dependent stimulation of TNF production by T cells and the resulting TNF regulation of CD40 signaling in SCs are potential new therapeutic targets for the bone loss of hyperparathyroidism. PMID:20808842

  15. Sequential treatment with basic fibroblast growth factor and PTH is more efficacious than treatment with PTH alone for increasing vertebral bone mass and strength in osteopenic ovariectomized rats

    DEFF Research Database (Denmark)

    Iwaniec, U.T.; Mosekilde, Li.; Mitova-Caneva, N.G.

    2002-01-01

    The study was designed 1) to determine whether treatment with basic fibroblast growth factor (bFGF) and PTH is more efficacious than treatment with PTH alone for increasing bone mass and strength and improving trabecular microarchitecture in osteopenic ovariectomized rats, and 2) to assess whether...... prior and concurrent administration of the antiresorptive agents estrogen and risedronate suppresses the bone anabolic response to treatment with bFGF alone and sequential treatment with bFGF and PTH. Three-month-old female Sprague Dawley rats were ovariectomized (OVX) or sham-operated (sham...... into the jugular veins of all rats, and vehicle or bFGF at a dose of 250 microg/kg was injected daily for 14 d. Three groups of rats were killed at the end of bFGF treatment. The remaining rats were continued on their respective antiresorptive therapy and injected sc with vehicle or synthetic human PTH-(1...

  16. Mice lacking bone sialoprotein (BSP) lose bone after ovariectomy and display skeletal site-specific response to intermittent PTH treatment.

    Science.gov (United States)

    Wade-Gueye, Ndéye Marième; Boudiffa, Maya; Laroche, Norbert; Vanden-Bossche, Arnaud; Fournier, Carole; Aubin, Jane E; Vico, Laurence; Lafage-Proust, Marie-Hélène; Malaval, Luc

    2010-11-01

    Bone sialoprotein (BSP) belongs to the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, whose members play multiple and distinct roles in the development, turnover, and mineralization of bone and dentin. The functions of BSP in bone remodeling are not yet well established. We previously showed that BSP knockout (BSP(-/-)) mice exhibit a higher trabecular bone volume, concomitant with lower bone remodeling, than wild-type (BSP(+/+)) mice. To determine whether bone turnover can be stimulated in the absence of BSP, we subjected BSP(+/+) and BSP(-/-) mice to catabolic [ovariectomy (OVX)] or anabolic (intermittent PTH administration) hormonal challenges. BSP(-/-) mice progressively develop hypocalcemia and high serum PTH between 2 and 4 months of age. Fifteen and 30 d after OVX, microtomography analysis showed a significant decrease of trabecular bone volume in tibiae of both genotypes. Histomorphometric parameters of bone formation and resorption were significantly increased by OVX. PTH treatment resulted in an increase of trabecular thickness and both bone formation and resorption parameters at all skeletal sites in both genotypes and a decrease of trabecular bone volume in tibiae of BSP(+/+) but not BSP(-/-) mice. PTH increased cortical thickness and bone area in BSP(+/+) but not BSP(-/-) mice and stimulated the bone formation rate specifically in the endosteum of BSP(+/+) mice and the periosteum of BSP(-/-) mice. PTH enhanced the expression of RANKL, MEPE, and DMP1 in both genotypes but increased OPG and OPN expression only in BSP(-/-) mice. In conclusion, despite the low basal turnover, both catabolic and anabolic challenges increase bone formation and resorption in BSP(-/-) mice, suggesting that compensatory pathways are operative in the skeleton of BSP-deficient mice. Although up-regulation of one or several other SIBLINGs is a possible mechanism, further studies are needed to analyze the interplay and cross-regulation involved in

  17. Short Anabolic Peptides for Bone Growth.

    Science.gov (United States)

    Amso, Zaid; Cornish, Jillian; Brimble, Margaret A

    2016-07-01

    Loss of bone occurs in the age-related skeletal disorder, osteoporosis, leading to bone fragility and increased incidence of fractures, which are associated with enormous costs and substantial morbidity and mortality. Recent data indicate that osteoporotic fractures are more common than other diseases, which usually attract public attention (e.g., heart attack and breast cancer). The prevention and treatment of this skeletal disorder are therefore of paramount importance. Majority of osteoporosis medications restore skeletal balance by reducing osteoclastic activity, thereby reducing bone resorption. These agents, however, do not regenerate damaged bone tissue, leaving limited options for patients once bone loss has occurred. Recently, attention has turned to bone-anabolic agents. Such agents have the ability to increase bone mass and strength, potentially reversing structural damage. To date, only one bone-anabolic drug is available in the market. The discovery of more novel, cost-effective bone anabolic agents is therefore a priority to treat those suffering from this disabling condition. Short peptides offer an important alternative for the development of novel bone-anabolic agents given their high target binding specificity, which translates into potent activity with limited side effects. This review summarizes attempts in the identification of bone-anabolic peptides, and their development for promoting bone growth.

  18. PTH1-34 Alleviates Radiotherapy-induced Local Bone Loss by Improving Osteoblast and Osteocyte Survival

    Science.gov (United States)

    Chandra, Abhishek; Lin, Tiao; Tribble, Mary Beth; Zhu, Ji; Altman, Allison R.; Tseng, Weiju; Zhang, Yejia; Akintoye, Sunday O.; Cengel, Keith; Liu, X. Sherry; Qin, Ling

    2014-01-01

    Cancer radiotherapy is often complicated by a spectrum of changes in the neighboring bone from mild osteopenia to osteoradionecrosis. We previously reported that parathyroid hormone (PTH, 1–34), an anabolic agent for osteoporosis, reversed bone structural deterioration caused by multiple microcomputed tomography (microCT) scans in adolescent rats. To simulate clinical radiotherapy for cancer patients and to search for remedies, we focally irradiated the tibial metaphyseal region of adult rats with a newly available small animal radiation research platform (SARRP) and treated these rats with intermittent injections of PTH1–34. Using a unique 3D image registration method that we recently developed, we traced the local changes of the same trabecular bone before and after treatments, and observed that, while radiation caused a loss of small trabecular elements leading to significant decreases in bone mass and strength, PTH1–34 preserved all trabecular elements in irradiated bone with remarkable increases in bone mass and strength. Histomorphometry demonstrated that SARRP radiation severely reduced osteoblast number and activity, which were impressively reversed by PTH treatment. In contrast, suppressing bone resorption by alendronate failed to rescue radiation-induced bone loss and to block the rescue effect of PTH1–34. Furthermore, histological analyses revealed that PTH1–34 protected osteoblasts and osteocytes from radiation-induced apoptosis and attenuated radiation-induced bone marrow adiposity. Taken together, our data strongly support a robust radioprotective effect of PTH on trabecular bone integrity through preserving bone formation and shed light on further investigations of an anabolic therapy for radiation-induced bone damage. PMID:24998454

  19. Role of paraoxonase-1 in bone anabolic effects of parathyroid hormone in hyperlipidemic mice

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Jinxiu [Department of Physiology, University of California, Los Angeles (United States); Cheng, Henry [Department of Medicine, University of California, Los Angeles (United States); Atti, Elisa [Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California, Los Angeles (United States); Shih, Diana M. [Department of Medicine, University of California, Los Angeles (United States); Demer, Linda L. [Department of Physiology, University of California, Los Angeles (United States); Department of Medicine, University of California, Los Angeles (United States); Department of Bioengineering, University of California, Los Angeles (United States); Tintut, Yin, E-mail: ytintut@mednet.ucla.edu [Department of Medicine, University of California, Los Angeles (United States)

    2013-02-01

    Highlights: ► Anabolic effects of PTH were tested in hyperlipidemic mice overexpressing PON1. ► Expression of antioxidant regulatory genes was induced in PON1 overexpression. ► Bone resorptive activity was reduced in PON1 overexpressing hyperlipidemic mice. ► PON1 restored responsiveness to intermittent PTH in bones of hyperlipidemic mice. -- Abstract: Hyperlipidemia blunts anabolic effects of intermittent parathyroid hormone (PTH) on cortical bone, and the responsiveness to PTH are restored in part by oral administration of the antioxidant ApoA-I mimetic peptide, D-4F. To evaluate the mechanism of this rescue, hyperlipidemic mice overexpressing the high-density lipoprotein-associated antioxidant enzyme, paraoxonase 1 (Ldlr{sup −/−}PON1{sup tg}) were generated, and daily PTH injections were administered to Ldlr{sup −/−}PON1{sup tg} and to littermate Ldlr{sup −/−} mice. Expression of bone regulatory genes was determined by realtime RT-qPCR, and cortical bone parameters of the femoral bones by micro-computed tomographic analyses. PTH-treated Ldlr{sup −/−}PON1{sup tg} mice had significantly greater expression of PTH receptor (PTH1R), activating transcription factor-4 (ATF4), and osteoprotegerin (OPG) in femoral cortical bone, as well as significantly greater cortical bone mineral content, thickness, and area in femoral diaphyses compared with untreated Ldlr{sup −/−}PON1{sup tg} mice. In contrast, in control mice (Ldlr{sup −/−}) without PON1 overexpression, PTH treatment did not induce these markers. Calvarial bone of PTH-treated Ldlr{sup −/−}PON1{sup tg} mice also had significantly greater expression of osteoblastic differentiation marker genes as well as BMP-2-target and Wnt-target genes. Untreated Ldlr{sup −/−}PON1{sup tg} mice had significantly greater expression of PTHR1 than untreated Ldlr{sup −/−} mice, whereas sclerostin expression was reduced. In femoral cortical bones, expression levels of transcription factors, Fox

  20. Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone

    Science.gov (United States)

    Bikle, Daniel D.; Sakata, Takeshi; Leary, Colin; Elalieh, Hashem; Ginzinger, David; Rosen, Clifford J.; Beamer, Wesley; Majumdar, Sharmila; Halloran, Bernard P.

    2002-01-01

    Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 microg/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH.

  1. Intermittent treatment with parathyroid hormone (PTH) as well as a non-peptide small molecule agonist of the PTH1 receptor inhibits adipocyte differentiation in human bone marrow stromal cells.

    Science.gov (United States)

    Rickard, David J; Wang, Fei-Lan; Rodriguez-Rojas, Ana-Maria; Wu, Zining; Trice, Wen J; Hoffman, Sandra J; Votta, Bartholomew; Stroup, George B; Kumar, Sanjay; Nuttall, Mark E

    2006-12-01

    contrast, the MAP kinase inhibitor PD 98059 failed to prevent the anti-adipocytic effect of intermittent PTH, suggesting that the inhibitory effect of PTH on adipocyte differentiation is predominantly cAMP-dependent. These results demonstrate a differential effect of PTH1 receptor agonists on the adipocytic commitment and differentiation of adult human bone marrow mesenchymal stem cells. This response may represent an additional mechanism that contributes to the overall bone anabolic action of intermittent PTH.

  2. Low bone turnover and low BMD in Down syndrome: effect of intermittent PTH treatment.

    Directory of Open Access Journals (Sweden)

    Tristan W Fowler

    Full Text Available Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS. Patterns of differences are now being recognized as patients' age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD has been reported in many studies of males and females with DS yet the specific effects of trisomy 21 on the skeleton remain poorly defined. Therefore we determined the bone phenotype and measured bone turnover markers in the murine DS model Ts65Dn. Male Ts65Dn DS mice are infertile and display a profound low bone mass phenotype that deteriorates with age. The low bone mass was correlated with significantly decreased osteoblast and osteoclast development, decreased bone biochemical markers, a diminished bone formation rate and reduced mechanical strength. The low bone mass observed in 3 month old Ts65Dn mice was significantly increased after 4 weeks of intermittent PTH treatment. These studies provide novel insight into the cause of the profound bone fragility in DS and identify PTH as a potential anabolic agent in the adult low bone mass DS population.

  3. Anabolic actions of Notch on mature bone

    Science.gov (United States)

    Liu, Peng; Ping, Yilin; Ma, Meng; Zhang, Demao; Liu, Connie; Zaidi, Samir; Gao, Song; Ji, Yaoting; Lou, Feng; Yu, Fanyuan; Lu, Ping; Stachnik, Agnes; Bai, Mingru; Wei, Chengguo; Zhang, Liaoran; Wang, Ke; Chen, Rong; New, Maria I.; Rowe, David W.; Yuen, Tony; Sun, Li; Zaidi, Mone

    2016-01-01

    Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response. PMID:27036007

  4. Daily nasal spray of hPTH(1-34) for 3 months increases bone mass in osteoporotic subjects: a pilot study.

    Science.gov (United States)

    Matsumoto, T; Shiraki, M; Hagino, H; Iinuma, H; Nakamura, T

    2006-10-01

    Although intermittent parathyroid hormone (PTH) injection can lead to strong anabolic effects on bone, daily subcutaneous injection is a disadvantage for patient acceptance. We have developed a nasal spray formula of parathyroid peptide [hPTH(1-34)] with peak serum hPTH(1-34) concentrations by nasal spray of 1,000 microg similar to those by subcutaneous injections of 20 microg hPTH(1-34). To determine the clinical efficacy and safety of nasal hPTH(1-34) spray, a randomized, open-labeled clinical trial was conducted in subjects with osteoporosis. Ninety osteoporotic subjects age 52-84 years (mean 66.5 years) were randomly assigned to receive either 250 microg (PTH250, n=31), 500 microg (PTH500, n=30), or 1,000 microg (PTH1000, n=29) of daily nasal hPTH(1-34) spray for 3 months. All received daily supplements of 300 mg calcium and 200 IU vitamin D(3). Daily nasal hPTH(1-34) spray for 3 months increased lumbar bone mineral density (L-BMD) in a dose-dependent manner, and the PTH1000 group showed a 2.4% increase in L-BMD from baseline. Only the 1,000-microg dose produced consistent and statistically significant changes in markers of bone turnover; after 3 months, median serum type I procollagen N-propeptide (PINP) and osteocalcin increased 14.8% and 19.4% from baseline, while urinary type I collagen N-telopeptide (NTX) decreased 16.4%. Seven subjects developed transient hypercalcemia at 3 h after nasal hPTH(1-34) spray, but none of the subjects developed sustained hypercalcemia. These observations demonstrate that nasal hPTH(1-34) spray is safe and well tolerated and can rapidly increase L-BMD. The results warrant further studies to examine its long-term efficacy on bone mass and fractures.

  5. Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses.

    Science.gov (United States)

    Powell, William F; Barry, Kevin J; Tulum, Irena; Kobayashi, Tatsuya; Harris, Stephen E; Bringhurst, F Richard; Pajevic, Paola Divieti

    2011-04-01

    Parathyroid hormone (PTH) is a major physiologic regulator of calcium, phosphorous, and skeletal homeostasis. Cells of the osteoblastic lineage are key targets of PTH action in bone, and recent evidence suggests that osteocytes might be important in the anabolic effects of PTH. To understand the role of PTH signaling through the PTH/PTHrP receptors (PPR) in osteocytes and to determine the role(s) of these cells in mediating the effects of the hormone, we have generated mice in which PPR expression is specifically ablated in osteocytes. Transgenic mice in which the 10 kb-Dmp1 promoter drives a tamoxifen-inducible Cre-recombinase were mated with animals in which exon 1 of PPR is flanked by lox-P sites. In these animals, osteocyte-selective PPR knockout (Ocy-PPR(cKO) mice) could be induced by administration of tamoxifen. Histological analysis revealed a reduction in trabecular bone and mild osteopenia in Ocy-PPR(cKO) mice. Reduction of trabeculae number and thickness was also detected by micro-computed tomography analysis whereas bone volume fraction (BV/TV%) was unchanged. These findings were associated with an increase in Sost and sclerostin expression. When Ocy-PPR(cKO) mice were subjected to a low-calcium diet to induce secondary hyperparathyroidism, their blood calcium levels were significantly lower than littermate controls. Moreover, PTH was unable to suppress Sost and sclerostin expression in the Ocy-PPR(cKO) animals, suggesting an important role of PTH signaling in osteocytes for proper bone remodeling and calcium homeostasis.

  6. Modifications in Bone Matrix of Estrogen-Deficient Rats Treated with Intermittent PTH

    Directory of Open Access Journals (Sweden)

    Rafael Pacheco-Costa

    2015-01-01

    Full Text Available Bone matrix dictates strength, elasticity, and stiffness to the bone. Intermittent parathyroid hormone (iPTH, a bone-forming treatment, is widely used as a therapy for osteoporosis. We investigate whether low doses of intermittent PTH (1-34 change the profile of organic components in the bone matrix after 30 days of treatment. Forty 6-month-old female Wistar rats underwent ovariectomy and after 3 months received low doses of iPTH administered for 30 days: daily at 0.3 µg/kg/day (PTH03 or 5 µg/kg/day (PTH5; or 3 times per week at 0.25 µg/kg/day (PTH025. After euthanasia, distal femora were processed for bone histomorphometry, histochemistry for collagen and glycosaminoglycans, biochemical quantification of sulfated glycosaminoglycans, and hyaluronan by ELISA and TUNEL staining. Whole tibiae were used to estimate the bone mineral density (BMD. Histomorphometric analysis showed that PTH5 increased cancellous bone volume by 6% over vehicle-treated rats. In addition, PTH5 and PTH03 increased cortical thickness by 21% and 20%, respectively. Tibial BMD increased in PTH5-treated rats and this group exhibited lower levels of chondroitin sulfate; on the other hand, hyaluronan expression was increased. Hormonal administration in the PTH5 group led to decreased collagen maturity. Further, TUNEL-positive osteocytes were decreased in the cortical compartment of PTH5 whereas administration of PTH025 increased the osteocyte death. Our findings suggest that daily injections of PTH at low doses alter the pattern of organic components from the bone matrix, favoring the increase of bone mass.

  7. One Year of Abaloparatide, a Selective Activator of the PTH1 Receptor, Increased Bone Formation and Bone Mass in Osteopenic Ovariectomized Rats Without Increasing Bone Resorption.

    Science.gov (United States)

    Varela, Aurore; Chouinard, Luc; Lesage, Elisabeth; Smith, Susan Y; Hattersley, Gary

    2017-01-01

    Abaloparatide is a novel 34-amino acid peptide selected to be a potent and selective activator of the parathyroid hormone receptor (PTH1R) signaling pathway with 41% homology to PTH(1-34) and 76% homology to PTHrP(1-34). A 12-month treatment study was conducted in osteopenic ovariectomized (OVX) rats to characterize the mechanisms by which abaloparatide increases bone mass. Sprague-Dawley (SD) rats were subjected to OVX or sham surgery at age 6 months and left untreated for 3 months to allow OVX-induced bone loss. Ten OVX rats were euthanized after this bone depletion period, and the remaining OVX rats received daily subcutaneous injections of vehicle (n = 18) or abaloparatide at 1, 5, or 25 μg/kg/d (n = 18/dose level) for 12 months. Sham controls (n = 18) received vehicle daily. Bone densitometry and biochemical markers of bone formation and resorption were assessed longitudinally, and L3 vertebra and tibia were collected at necropsy for histomorphometry. Abaloparatide increased biochemical bone formation markers without increasing bone resorption markers or causing hypercalcemia. Abaloparatide increased histomorphometric indices of bone formation on trabecular, endocortical, and periosteal surfaces without increasing osteoclasts or eroded surfaces. Abaloparatide induced substantial increases in trabecular bone volume and density and improvements in trabecular microarchitecture. Abaloparatide stimulated periosteal expansion and endocortical bone apposition at the tibial diaphysis, leading to marked increases in cortical bone volume and density. Whole-body bone mineral density (BMD) remained stable in OVX-Vehicle controls while increasing 25% after 12 months of abaloparatide (25 μg/kg). Histomorphometry and biomarker data suggest that gains in cortical and trabecular bone mass were attributable to selective anabolic effects of abaloparatide, without evidence for stimulated bone resorption. © 2016 American Society for Bone and Mineral Research.

  8. Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice.

    Science.gov (United States)

    Gray, Sarah K; McGee-Lawrence, Meghan E; Sanders, Jennifer L; Condon, Keith W; Tsai, Chung-Jui; Donahue, Seth W

    2012-09-01

    Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28nmol/kg of bbPTH 1-84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6 weeks. Vehicle-treated mdx mice had 44% lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, μCT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic

  9. ANABOLIC BONE WINDOW WITH WEEKLY TERIPARATIDE THERAPY IN POSTMENOPAUSAL OSTEOPOROSIS: A PILOT STUDY.

    Science.gov (United States)

    Gopalaswamy, Vinaya; Dhibar, Deba Prasad; Gupta, Vipin; Arya, Ashutosh Kumar; Khandelwal, Niranjan; Bhansali, Anil; Garg, Sudhir Kumar; Agarwal, Neelam; Rao, Sudhaker D; Bhadada, Sanjay Kumar

    2017-06-01

    Osteoporosis is a major public health problem that reduces bone strength and increases fracture risk. Teriparatide is an established and the only currently available anabolic therapy for the treatment of postmenopausal osteoporosis (PMO) with a recommended daily dose of 20 μg given subcutaneously. However, there are limited data regarding the long-term effect of once-weekly teriparatide therapy on bone mineral density (BMD), bone turnover markers (BTMs), and anabolic bone window. In this prospective observational study, 26 patients with PMO were treated with weekly teriparatide therapy (60 μg) for 2 years. BMD was measured at baseline, 12 months, and 24 months. The bone formation marker type 1 collagen C-terminal propeptide (P1NP) and the bone resorption marker C-terminal telopeptide of type 1 collagen (CTx) were measured at baseline; 6 weeks; and 6, 12, 18, and 24 months. BMDs at the lumbar spine increased by 3.1% and 10.8% after 1 and 2 years of weekly teriparatide therapy, respectively. The T-score increased significantly at the lumbar spine compared to baseline after 2 years of therapy (P = .015). Serum P1NP levels increased significantly at 6 months (P = .024), peaked at 1 year, and remained above the baseline even after 2 years. Serum CTx levels decreased significantly at 6 months (P = .025) and remained below baseline after 2 years of teriparatide therapy. Weekly teriparatide therapy (60 μg) appears to be as effective as daily teriparatide for the treatment of PMO by extending the anabolic bone window. AE = adverse event; BMD = bone mineral density; BTM = bone turnover marker; CTx = C-terminal telopeptide of type 1 collagen; DXA = dual-energy X-ray absorptiometry; iPTH = intact parathyroid hormone; P1NP = type 1 collagen C-terminal propeptide; PMO = postmenopausal osteoporosis.

  10. PTH (1-84) Replacement Therapy in Hypoparathyroidism: Effects on bone metabolism and structure

    DEFF Research Database (Denmark)

    Sikjær, Tanja Tvistholm; Rejnmark, Lars; Tietze, Anna

    , as an add-on therapy. We investigated the changes in bone structure and density using µCT in 44 iliac crest bone biopsies (23 on PTH treatment) obtained after 24-wks of treatment. Trabecular tunnelling was evident in 11 (48%) biopsies from the PTH-group, whereas no tunnelling was detected in the placebo...

  11. PTH (1-84) Replacement Therapy in Hypoparathyroidism: Effects on bone metabolism and structure

    DEFF Research Database (Denmark)

    Sikjær, Tanja Tvistholm; Rejnmark, Lars; Tietze, Anna

    2011-01-01

    , as an add-on therapy. We investigated the changes in bone structure and density using µCT in 44 iliac crest bone biopsies (23 on PTH treatment) obtained after 24-wks of treatment. Trabecular tunnelling was evident in 11 (48%) biopsies from the PTH-group, whereas no tunnelling was detected in the placebo...

  12. PTH对骨代谢双重作用的研究进展%Research progress of the dual effects of PTH on bone metabolism

    Institute of Scientific and Technical Information of China (English)

    万启龙; 王强; 李祖兵

    2011-01-01

    The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts plays a key role in bone remodeling. PTH is one of the important hormones which regulate calcium and phosphate homeostasis. PTH has dual effects on bone metabolism: continuous administration of PTH causes bone resorption, intermittent administration induces bone formation, but the mechanism is unclear. It will be the research focus to identify the mechanism, and this will be helpful to use the anabolic actions of PTH for osteoporosis treatment. In future, using the dual effects of PTH on bone metabolism may be a novel therapy for bone malformation. Supported by National Natural Science Foundation of China (30672341).%成骨细胞参与的骨形成与破骨细胞参与的骨吸收之间的动态平衡,是骨改建过程中的关键.甲状旁腺激素(PTH)是维持机体钙、磷代谢平衡的重要激素.PTH对骨代谢具有双重效应:间歇应用PTH促进骨形成;而持续应用PTH会诱发骨吸收,但其机制仍不明确.明确PTH对骨代谢双重效应的机制,是今后研究的重点,将有助于更好地应用PTH骨合成效应治疗骨质疏松症,并有可能利用其双重效应治疗骨发育畸形.

  13. PTH(1-84) Administration in Hypoparathyroidism Transiently Reduces Bone Matrix Mineralization.

    Science.gov (United States)

    Misof, Barbara M; Roschger, Paul; Dempster, David W; Zhou, Hua; Bilezikian, John P; Klaushofer, Klaus; Rubin, Mishaela R

    2016-01-01

    Patients with hypoparathyroidism have low circulating parathyroid (PTH) levels and higher cancellous bone volume and trabecular thickness. Treatment with PTH(1-84) was shown to increase abnormally low bone remodeling dynamics. In this work, we studied the effect of 1-year or 2-year PTH(1-84) treatment on cancellous and cortical bone mineralization density distribution (Cn.BMDD and Ct.BMDD) based on quantitative backscattered electron imaging (qBEI) in paired transiliac bone biopsy samples. The study cohort comprised 30 adult hypoparathyroid patients (14 treated for 1 year; 16 treated for 2 years). At baseline, Cn.BMDD was shifted to higher mineralization densities in both treatment groups (average degree of mineralization Cn.CaMean +3.9% and +2.7%, p mineralizing surface) was predictive for Cn.BMDD outcomes in the 1-year PTH(1-84) group, but not in the 2-year PTH(1-84) group. Our findings suggest higher baseline bone matrix mineralization consistent with the decreased bone turnover in hypoparathyroidism. PTH(1-84) treatment caused differential effects dependent on treatment duration that were consistent with the histomorphometric bone formation outcomes. The greater increase in bone formation during the first year of treatment was associated with a decrease in bone matrix mineralization, suggesting that PTH(1-84) exposure to the hypoparathyroid skeleton has the greatest effects on BMDD early in treatment.

  14. Bifunctional bisphosphonates for delivering PTH (1-34) to bone mineral with enhanced bioactivity.

    Science.gov (United States)

    Yewle, Jivan N; Puleo, David A; Bachas, Leonidas G

    2013-04-01

    The objective of this work was to demonstrate the bioactivity of parathyroid hormone (1-34) (PTH) delivered through a single molecule of bisphosphonate to improve tissue/cell interactions. Bifunctional hydrazine-bisphosphonates (HBPs) with varying length and lipophilicity were used as a drug delivery vehicle. PTH was oxidized with periodate treatment to obtain an N-terminal aldehyde that was then conjugated to HBPs. The toxicity and apoptotic properties of HBPs and HBP-PTH conjugates were studied with macrophages (RAW 264.7). It was found that one of the HBPs had significant apoptotic characteristics similar to alendronate, which is a widely prescribed drug in the treatment of osteoporosis. The improved binding affinity of PTH following conjugation to HBP was determined using a hydroxyapatite binding assay. The amount of PTH delivered to bone through HBPs was not affected by the length or lipophilicity of the HBPs. Furthermore, the improved bioactivity of PTH delivered to bone through HBPs, in comparison to adsorbed PTH, was demonstrated by quantifying the cAMP produced by pre-osteoblastic (MC3T3-E1) cells in response to PTH. The delivery of bioactive PTH to bone tissue by HBP conjugation demonstrates the potential use of HBPs in delivering therapeutic macromolecules to bone for the treatment of several skeletal diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Anabolic Vitamin D Analogs as Countermeasures to Bone Loss

    Science.gov (United States)

    Li, Wei; Duncan, Randall L.; Karin, Norman J.; Farach-Carson, Mary C.

    1997-01-01

    We demonstrated for the first time that vitamin D3 influences the effect of PTH on bone cell calcium ion levels. This is a rapid effect, taking place within seconds/minutes. This may prove to be a critical contribution to our understanding of bone physiology in that these two hormones are among the most potent regulators of bone calcium content and of systemic calcium homeostasis. Together with the data gathered from the study of astronauts exposed to microgravity for extended periods, these observations suggest the interaction of vitamin D3 and PTH as a possible therapeutic target in the treatment of bone loss disorders such as osteoporosis and disuse atrophy. Chronic exposure of cultured osteoblasts to vitamin D, altered the number of voltage-sensitive Ca(+2) channels expressed. Estrogen treatment yielded a similar result, suggesting that there is overlap in the mechanism by which these hormones elicit long-term effects on bone cell calcium homeostasis.

  16. Phospholipase C signaling via the parathyroid hormone (PTH)/PTH-related peptide receptor is essential for normal bone responses to PTH.

    Science.gov (United States)

    Guo, Jun; Liu, Minlin; Yang, Dehong; Bouxsein, Mary L; Thomas, Clare C; Schipani, Ernestina; Bringhurst, F Richard; Kronenberg, Henry M

    2010-08-01

    We have previously shown that differentiation of hypertrophic chondrocytes is delayed in mice expressing a mutated PTH/PTHrP receptor (PTHR) (called DSEL here) that stimulates adenylyl cyclase normally but fails to activate phospholipase C (PLC). To better understand the role of PLC signaling via the PTHR in skeletal and mineral homeostasis, we examined these mice fed a normal or calcium-deficient diet. On a standard diet, DSEL mice displayed a modest decrease in bone mass. Remarkably, when fed a low-calcium diet or infused with PTH, DSEL mice exhibited strikingly curtailed peritrabecular stromal cell responses and attenuated new bone formation when compared with Wt mice. Attenuated in vitro colony formation was also observed in bone marrow cells derived from DSEL mice fed a low-calcium diet. Furthermore, PTH stimulated proliferation and increased mRNAs encoding cyclin D1 in primary osteoblasts derived from Wt but not from DSEL mice. Our data indicate that PLC signaling through the PTHR is required for skeletal homeostasis.

  17. Bovine parathyroid hormone enhances osteoclast bone resorption by modulating V-ATPase through PTH1R.

    Science.gov (United States)

    Liu, Shuangxin; Zhu, Weiping; Li, Sijia; Ma, Jianchao; Zhang, Huitao; Li, Zhonghe; Zhang, Li; Zhang, Bin; Li, Zhuo; Liang, Xinling; Shi, Wei

    2016-02-01

    The vacuolar-type H+ adenosine triphosphatase (V-ATPase) plays an important role in cellular acidification and bone resorption by osteoclasts. However, the direct effect of bovine parathyroid hormone (bPTH) on V-ATPase has not yet been elucidated. The aim of the present study was to assess the effects of bPTH on V-ATPase and osteoclasts. Osteoclasts from bone marrow (BM)-derived monocytes of C57BL/6 mice were cultured with or without bPTH. The mRNA and protein expression levels of the V-ATPase a3-subunit and d2-subunit (by RT-qPCR and western blot analysis), V-ATPase activity (using the V type ATPase Activity Assay kit) and the bone resorption function of osteoclasts (by bone resorption assay) were examined following treatment with various concentrations of bPTH (0.1, 1.0, 10 and 100 ng/ml) alone or with bPTH and its inhibitor, bafilomycin A1. Furthermore, the expression of parathyroid hormone (PTH) receptors in osteoclasts was also detected. The results revealed that the mRNA and protein expression levels of V-ATPase a3-subunit and d2-subunit increased in a dose‑dependent manner, paralleling the level of bPTH present. In addition, an increase in the concentration of bPTH was accompanied by the increased resorption capability of osteoclasts, whereas bone resorption was inhibited in the presence of bafilomycin A1. In addition, we confirmed the existence of parathyroid hormone 1 receptor (PTH1R) in osteoclasts using three different methods (RT-qPCR, western blot analysis and immunofluorescence staining). We found that bPTH enhanced the bone resorption capability of osteoclasts by modulating the expression of V-ATPase subunits, intracellular acidification and V-ATPase activity. Thus, we propose that PTH has a direct effect on osteoblasts and osteoclasts, and that this effect is mediated through PTH1R, thus contributing to bone remodeling.

  18. Influence of a low calcium and phosphorus diet on the anabolic effect of human parathyroid hormone (1-38) in female rats

    DEFF Research Database (Denmark)

    Steiner, P.D.; Forrer, R.; Kneissel, Michaela;

    2001-01-01

    Parathyroid hormone (PTH) or synthetic N-terminal PTH fragments administered intermittently have been established as anabolic agents in animal and human bones. In the present study, the influence of a low calcium diet on the anabolic effect of human PTH(1-38) [hPTH(1-38)] was investigated. Forty....../-RCa) for an additional 14 days. Total bone mineral density (BMD) values of several bones were determined using quantitative computed tomography and from ratios of ash weight to volume. Biomechanical competence of the fourth lumbar vertebrae and of the right femora was assessed. An anabolic effect could be detected...... in both PTH-treated groups. However, the bones of the +LCa group showed significantly lower BMD and also a diminished increase in maximal breaking force compared with those of the +RCa group. The study demonstrates that the anabolic effect of hPTH(1-38) is blunted by the LCa diet. This suggests that...

  19. Determining Normal Range of Vitamin D Based on PTH and Bone Mineral Density Changes

    Directory of Open Access Journals (Sweden)

    B Larijani

    2004-11-01

    Full Text Available PTH is the most important factor which control calcium homeostasis in the body in this study we tried to determine the normal range of PTH and Vitamin D with examining the relation between PTH and bone density and Vitamin D on the base of bones biological changes. Our subjects were, 20 to 69 years-old men and women of Tehran. Serum volume of PTH and vitamin D in different decades of life had significant difference. Range of serum PTH in osteporotic persons was 29.7-38 pgr/lit (95% SD. This range for non osteporotic persons was 24.33-30.2 pgr/lit. In this study ranges below 18 nmol/lit was considered as severe vitamin D deficiency and 23-36nmol/lit as mild deficiency. So the volume more than 36 nmol/lit volumes was normal range of vitamin D. it seems that biological changes of bones associate more with ranges of vitamin D which causes significant changes in PTH.

  20. Determining Normal Range of Vitamin D Based on PTH and Bone Mineral Density Changes

    Directory of Open Access Journals (Sweden)

    B Larijani

    2004-03-01

    Full Text Available PTH is the most important factor which control calcium homeostasis in the body in this study we tried to determine the normal range of PTH and Vitamin D with examining the relation between PTH and bone density and Vitamin D on the base of bones biological changes. Our subjects were, 20 to 69 years-old men and women of Tehran. Serum volume of PTH and vitamin D in different decades of life had significant difference. Range of serum PTH in osteporotic persons was 29.7-38 pgr/lit (95% SD. This range for non osteporotic persons was 24.33-30.2 pgr/lit. In this study ranges below 18 nmol/lit was considered as severe vitamin D deficiency and 23-36nmol/lit as mild deficiency. So the volume more than 36 nmol/lit volumes was normal range of vitamin D. it seems that biological changes of bones associate more with ranges of vitamin D which causes significant changes in PTH.

  1. Mechanisms for the bone anabolic effect of parathyroid hormone treatment in humans

    DEFF Research Database (Denmark)

    Aslan, Derya; Dahl Andersen, Mille; Gede, Lene Bjerring;

    2012-01-01

    Intermittent low-dose treatment with parathyroid hormone (PTH) analogues has become widely used in the treatment of severe osteoporosis. During normal physiological conditions, PTH stimulates both bone formation and resorption, and in patients with primary hyperparathyroidism, bone loss is frequent...

  2. Mice lacking AMP-activated protein kinase α1 catalytic subunit have increased bone remodelling and modified skeletal responses to hormonal challenges induced by ovariectomy and intermittent PTH treatment

    Science.gov (United States)

    Jeyabalan, J; Shah, M; Viollet, B; Roux, J P; Chavassieux, P; Korbonits, M; Chenu, C

    2012-01-01

    AMP-activated protein kinase (AMPK) is a key regulator of cellular and body energy homeostasis. We previously demonstrated that AMPK activation in osteoblasts increases in vitro bone formation while deletion of the Ampkα1 (Prkaa1) subunit, the dominant catalytic subunit expressed in bone, leads to decreased bone mass in vivo. To investigate the cause of low bone mass in the Ampkα1−/− mice, we analysed bone formation and resorption in the tibia of these mice by dynamic histomorphometry and determined whether bone turnover can be stimulated in the absence of the Ampkα1 subunit. We subjected 12-week-old Ampkα1+/+ and Ampkα1−/− mice to ovariectomy (OVX), intermittent PTH (iPTH) administration (80 μg/kg per day, 5 days/week) or both OVX and iPTH hormonal challenges. Tibiae were harvested from these mice and bone micro-architecture was determined by micro-computed tomography. We show for the first time that Ampkα1−/− mice have a high bone turnover at the basal level in favour of bone resorption. While both Ampkα1+/+ and Ampkα1−/− mice lost bone mass after OVX, the bone loss in Ampkα1−/− mice was lower compared with controls. iPTH increased trabecular and cortical bone indexes in both ovariectomised Ampkα1+/+ and Ampkα1−/− mice. However, ovariectomised Ampkα1−/− mice showed a smaller increase in bone parameters in response to iPTH compared with Ampkα1+/+ mice. By contrast, non-ovariectomised Ampkα1−/− mice responded better to iPTH treatment than non-ovariectomised Ampkα1+/+ mice. Overall, these data demonstrate that Ampkα1−/− mice are less affected by changes in bone turnover induced by OVX but respond better to the anabolic challenge induced by iPTH. These results suggest that AMPKα1 activation may play a role in the hormonal regulation of bone remodelling. PMID:22700192

  3. Glucocorticoid-induced osteoporosis in growing mice is not prevented by simultaneous intermittent PTH treatment

    OpenAIRE

    Postnov, Andrei; Schutter, De, Bob; Sijbers, Jan; Karperien, Marcel; Clerck, De, Luc S.

    2009-01-01

    Abstract: Glucocorticoids (GCs) are widely used in medicine for treatment of chronic diseases. Especially in children, prolonged treatment causes growth retardation and early onset of osteoporosis. Human parathyroid hormone (PTH) has an anabolic effect on bone when administrated intermittently. The aim of the present study was to examine whether a combined therapy of dexamethasone (DEX) and PTH could prevent the detrimental effects of GC on cortical and trabecular bone in the femur and verteb...

  4. Bone Is a Major Target of PTH/PTHrP Receptor Signaling in Regulation of Fetal Blood Calcium Homeostasis.

    Science.gov (United States)

    Hirai, Takao; Kobayashi, Tatsuya; Nishimori, Shigeki; Karaplis, Andrew C; Goltzman, David; Kronenberg, Henry M

    2015-08-01

    The blood calcium concentration during fetal life is tightly regulated within a narrow range by highly interactive homeostatic mechanisms that include transport of calcium across the placenta and fluxes in and out of bone; the mechanisms of this regulation are poorly understood. Our findings that endochondral bone-specific PTH/PTHrP receptor (PPR) knockout (KO) mice showed significant reduction of fetal blood calcium concentration compared with that of control littermates at embryonic day 18.5 led us to focus on bone as a possibly major determinant of fetal calcium homeostasis. We found that the fetal calcium concentration of Runx2 KO mice was significantly higher than that of control littermates, suggesting that calcium flux into bone had a considerable influence on the circulating calcium concentration. Moreover, Runx2:PTH double mutant fetuses showed calcium levels similar to those of Runx2 KO mice, suggesting that part of the fetal hypocalcemia in PTH KO mice was caused by the increment of the mineralized bone mass allowed by the formation of osteoblasts. Finally, Rank:PTH double mutant mice had a blood calcium concentration even lower than that of the either Rank KO or PTH KO mice alone at embryonic day 18.5. These observations in our genetic models suggest that PTH/PTHrP receptor signaling in bones has a significant role of the regulation of fetal blood calcium concentration and that both placental transport and osteoclast activation contribute to PTH's hypercalcemic action. They also show that PTH-independent deposition of calcium in bone is the major controller of fetal blood calcium level.

  5. Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation.

    Science.gov (United States)

    Guo, Jun; Liu, Minlin; Yang, Dehong; Bouxsein, Mary L; Saito, Hiroaki; Galvin, R J Sells; Kuhstoss, Stuart A; Thomas, Clare C; Schipani, Ernestina; Baron, Roland; Bringhurst, F Richard; Kronenberg, Henry M

    2010-02-03

    Parathyroid hormone (PTH) suppresses Dickkopf 1 (Dkk1) expression in osteoblasts. To determine whether this suppression is essential for PTH-mediated Wnt signaling and bone formation, we examined mice that overexpress Dkk1 in osteoblasts (Dkk1 mice). Dkk1 mice were osteopenic due to abnormal osteoblast and osteoclast activity. When fed a low-calcium diet, and in two other models of hyperparathyroidism, these mice failed to develop the peritrabecular stromal cell response ("osteitis fibrosis") and new bone formation seen in wild-type mice. Despite these effects of Dkk1 overexpression, PTH still activated Wnt signaling in Dkk1 mice and in osteoblastic cells cultured from these mice. In cultured MC3T3E1 preosteoblastic cells, PTH dramatically suppressed Dkk1 expression, induced PKA-mediated phosphorylation of beta-catenin, and significantly enhanced Lef1 expression. Our findings indicate that the full actions of PTH require intact Wnt signaling but that PTH can activate the Wnt pathway despite overexpression of Dkk1.

  6. Oxidation inhibits PTH receptor signaling and trafficking.

    Science.gov (United States)

    Ardura, Juan A; Alonso, Verónica; Esbrit, Pedro; Friedman, Peter A

    2017-01-22

    Reactive Oxygen Species (ROS) increase during aging, potentially affecting many tissues including brain, heart, and bone. ROS alter signaling pathways and constitute potential therapeutic targets to limit oxidative damaging effects in aging-associated diseases. Parathyroid hormone receptors (PTHR) are widely expressed and PTH is the only anabolic therapy for osteoporosis. The effects of oxidative stress on PTHR signaling and trafficking have not been elucidated. Here, we used Fluorescence Resonance Energy Transfer (FRET)-based cAMP, ERK, and calcium fluorescent biosensors to analyze the effects of ROS on PTHR signaling and trafficking by live-cell imaging. PTHR internalization and recycling were measured in HEK-293 cells stably transfected with HA-PTHR. PTH increased cAMP production, ERK phosphorylation, and elevated intracellular calcium. Pre-incubation with H2O2 reduced all PTH-dependent signaling pathways. These inhibitory effects were not a result of PTH oxidation since PTH incubated with H2O2 triggered similar responses. PTH promoted internalization and recycling of the PTHR. Both events were significantly reduced by H2O2 pre-incubation. These findings highlight the role of oxidation on PTHR signaling and trafficking, and suggest the relevance of ROS as a putative target in diseases associated with oxidative stress such as age-related osteoporosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. ZP2307, a novel, cyclic PTH(1-17) analog that augments bone mass in ovariectomized rats.

    Science.gov (United States)

    Neerup, Trine S R; Stahlhut, Martin; Petersen, Jørgen S; Daugaard, Jens R; Jensen, Jens-Erik B; Peng, Zhiqi; Morko, Jukka; Thorkildsen, Christian

    2011-06-01

    Daily injections of human parathyroid hormone (1-34), hPTH(1-34), provide a highly effective treatment option for severe osteoporosis. However, PTH analogs shorter than 28 amino acids do not retain any bone augmenting potential. Here, we present ZP2307 ([Ac₅c¹, Aib³, Leu⁸, Gln¹⁰, Har¹¹, Ala¹², Trp¹⁴, Asp¹⁷]PTH(1-17)-NH₂), a novel, chemically modified and cyclized hPTH(1-17) analog, that augments bone mass in ovariectomized, osteopenic rats. Subcutaneous administration of this structurally constrained, K¹³-D¹⁷ side-chain-to-side-chain cyclized peptide reversed bone loss and increased bone mineral density (BMD) up to or above baseline levels in rat long bones and vertebrae. Highly significant effects of ZP2307 were achieved at doses of 40-320 nmol/kg. Micro-CT and histomorphometric analyses showed that ZP2307 improved quantitative and qualitative parameters of bone structure. Biomechanical testing of rat femora confirmed that ZP2307 dramatically increased bone strength. Over a broad maximally effective dose range (40-160 nmol/kg) ZP2307 did not increase serum concentrations of ionized free calcium above normal levels. Only at the highest dose (320 nmol/kg) ZP2307 induced hypercalcemic calcium levels in the ovariectomized rats. To our knowledge ZP2307 is the smallest PTH peptide analog known to exert augmentation of bone. Our findings suggest that ZP2307 has the potential to effectively augment bone mass over a broad dose range without a concomitant increase in the serum concentration of ionized free calcium above the normal range.

  8. ZP2307, a novel, cyclic PTH(1-17) analog that augments bone mass in ovariectomized rats

    DEFF Research Database (Denmark)

    Neerup, Trine Skovlund Ryge; Stahlhut, Martin; Petersen, Jørgen S

    2011-01-01

    Daily injections of human parathyroid hormone (1-34), hPTH(1-34), provide a highly effective treatment option for severe osteoporosis. However, PTH analogs shorter than 28 amino acids do not retain any bone augmenting potential. Here, we present ZP2307 ([Ac₅c¹, Aib³, Leu⁸, Gln¹⁰, Har¹¹, Ala¹², Trp......¹⁴, Asp¹⁷]PTH(1-17)-NH₂), a novel, chemically modified and cyclized hPTH(1-17) analog, that augments bone mass in ovariectomized, osteopenic rats. Subcutaneous administration of this structurally constrained, K¹³-D¹⁷ side-chain-to-side-chain cyclized peptide reversed bone loss and increased bone...... mineral density (BMD) up to or above baseline levels in rat long bones and vertebrae. Highly significant effects of ZP2307 were achieved at doses of 40-320 nmol/kg. Micro-CT and histomorphometric analyses showed that ZP2307 improved quantitative and qualitative parameters of bone structure. Biomechanical...

  9. PTH (1–34), but not strontium ranelate counteract loss of trabecular thickness and bone strength in disuse osteopenic rats

    DEFF Research Database (Denmark)

    Brüel, Annemarie; Vegger, Jens Bay; Raffalt, Anders Christer;

    2013-01-01

    +PTH+SrR (n=12 in each group). PTH was given as injections (SC) at a dosage of 60 μg/kg/d, and SrR as 900 mg/kg/d in the diet. The experiment lasted for 4weeks.BTX resulted in lower trabecular bone formation rate (−68%) and periosteal bone formation rate (−91%), and a higher fraction of osteoclast......) and periosteal (5-fold increase vs. BTX) bone formation rate, trabecular thickness (+25% vs. BTX) and femoral neck strength (+24% vs. BTX). In contrast, SrR did not influence BTX-induced loss of bone formation rate, trabecular bone volume fraction, trabecular thickness, or bone strength. Finally, no additive...

  10. ATF4, A Novel Mediator of the Anabolic Actions of PTH on Bone

    Science.gov (United States)

    2012-01-01

    2007. Accepted December 31, 2007. Address all correspondence and requests for reprints to: Dr. Guozhi Xiao, Division of Hematology /Oncology, Department...www.jbc.org) contains supplemental Figs. S1 and S2. 1 To whom correspondence should be addressed: Division of Hematology / Oncology, Dept of Medicine...Fushiki S, Fliss H, Nakagawa M. 2003. Amlodipine inhibits doxorubicin- induced apoptosis in neonatal rat cardiac myocytes. J Am Coll Cardiol 41:870

  11. ATF4, A Novel Mediator of the Anabolic Actions of PTH on Bone

    Science.gov (United States)

    2009-07-01

    chromatin condensation (early apoptosis) and DNA fragmentation (late apoptosis) were increased greater than 5-fold in Atf4-/- BMSCs compared to wt...TUNEL staining that measures DNA fragmentation in situ. As shown in P1-Fig. 8D-F, the percent apoptotic cells in Atf4- /- BMSCs were increased by 1.6...proteolytically cleave executioner caspases that cause cell death events such as cytoplasm shrinkage, chromatin condensation, and DNA fragmentation . B

  12. Glucocorticoid-Induced Osteoporosis in Growing Mice Is Not Prevented by Simultaneous Intermittent PTH Treatment

    NARCIS (Netherlands)

    Postnov, A.; de Schutter, T.; Sijbers, J.; Karperien, Hermanus Bernardus Johannes; de Clerck, N.

    2009-01-01

    Glucocorticoids (GCs) are widely used in medicine for treatment of chronic diseases. Especially in children, prolonged treatment causes growth retardation and early onset of osteoporosis. Human parathyroid hormone (PTH) has an anabolic effect on bone when administrated intermittently. The aim of the

  13. Maximizing PTH Anabolic Osteoporosis Therapy

    Science.gov (United States)

    2014-09-01

    Mm00435452_m1 Osterix (Sp7 transcription factor) Mm00504574_m1 Pthr1 (parathyroid hormone receptor 1) Mm00441046_m1 Pthrp (parathyroid hormone...peptide ( Pthrp ) in either genotype (Table 7). Our preliminary evaluation of gene expression in the tibia showed that the RNA profiles at 3 weeks of...0.0036 0.4394 Pthr1 0.86 ± 0.23 1.59 ± 0.40 0.68 ± 0.28 1.38 ± 0.68 0.2223 \\0.0001 0.9071 Pthrp 0.75 ± 0.18 1.10 ± 0.44 0.89 ± 0.44 1.00 ± 0.44

  14. Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development

    OpenAIRE

    Lanske, Beate; Amling, Michael; Neff, Lynn; Guiducci, Jennifer; Baron, Roland; Kronenberg, Henry M.

    1999-01-01

    Parathyroid hormone (PTH) and parathyroid hormone–related peptide (PTHrP) bind to and activate the same PTH/PTHrP receptor. Deletion of either the PTHrP gene or the PTH/PTHrP receptor gene leads to acceleration of differentiation of growth plate chondrocytes. To explore further the functional relationships of PTHrP and the PTH/PTHrP receptor, bones of knockout mice were analyzed early in development, and the phenotypes of double-knockout mice were characterized.

  15. Skeletal unloading induces selective resistance to the anabolic actions of growth hormone on bone

    Science.gov (United States)

    Halloran, B. P.; Bikle, D. D.; Harris, J.; Autry, C. P.; Currier, P. A.; Tanner, S.; Patterson-Buckendahl, P.; Morey-Holton, E.

    1995-01-01

    Loss of skeletal weight bearing or physical unloading of bone in the growing animal inhibits bone formation and induces a bone mineral deficit. To determine whether the inhibition of bone formation induced by skeletal unloading in the growing animal is a consequence of diminished sensitivity to growth hormone (GH) we studied the effects of skeletal unloading in young hypophysectomized rats treated with GH (0, 50, 500 micrograms/100 g body weight/day). Skeletal unloading reduced serum osteocalcin, impaired uptake of 3H-proline into bone, decreased proximal tibial mass, and diminished periosteal bone formation at the tibiofibular junction. When compared with animals receiving excipient alone, GH administration increased bone mass in all animals. The responses in serum osteocalcin, uptake of 3H-proline and 45Ca into the proximal tibia, and proximal tibial mass in non-weight bearing animals were equal to those in weight bearing animals. The responses in trabecular bone volume in the proximal tibia and bone formation at the tibiofibular junction to GH, however, were reduced significantly by skeletal unloading. Bone unloading prevented completely the increase in metaphyseal trabecular bone normally induced by GH and severely dampened the stimulatory effect (158% vs. 313%, p bone formation. These results suggest that while GH can stimulate the overall accumulation of bone mineral in both weight bearing and non-weight bearing animals, skeletal unloading selectively impairs the response of trabecular bone and periosteal bone formation to the anabolic actions of GH.

  16. Skeletal unloading induces selective resistance to the anabolic actions of growth hormone on bone

    Science.gov (United States)

    Halloran, B. P.; Bikle, D. D.; Harris, J.; Autry, C. P.; Currier, P. A.; Tanner, S.; Patterson-Buckendahl, P.; Morey-Holton, E.

    1995-01-01

    Loss of skeletal weight bearing or physical unloading of bone in the growing animal inhibits bone formation and induces a bone mineral deficit. To determine whether the inhibition of bone formation induced by skeletal unloading in the growing animal is a consequence of diminished sensitivity to growth hormone (GH) we studied the effects of skeletal unloading in young hypophysectomized rats treated with GH (0, 50, 500 micrograms/100 g body weight/day). Skeletal unloading reduced serum osteocalcin, impaired uptake of 3H-proline into bone, decreased proximal tibial mass, and diminished periosteal bone formation at the tibiofibular junction. When compared with animals receiving excipient alone, GH administration increased bone mass in all animals. The responses in serum osteocalcin, uptake of 3H-proline and 45Ca into the proximal tibia, and proximal tibial mass in non-weight bearing animals were equal to those in weight bearing animals. The responses in trabecular bone volume in the proximal tibia and bone formation at the tibiofibular junction to GH, however, were reduced significantly by skeletal unloading. Bone unloading prevented completely the increase in metaphyseal trabecular bone normally induced by GH and severely dampened the stimulatory effect (158% vs. 313%, p < 0.002) of GH on periosteal bone formation. These results suggest that while GH can stimulate the overall accumulation of bone mineral in both weight bearing and non-weight bearing animals, skeletal unloading selectively impairs the response of trabecular bone and periosteal bone formation to the anabolic actions of GH.

  17. PTH [1-34] induced differentiation and mineralization of mandibular condylar cartilage.

    Science.gov (United States)

    O' Brien, Mara Heather; Dutra, Eliane Hermes; Lima, Alexandro; Nanda, Ravindra; Yadav, Sumit

    2017-06-12

    Intermittent Parathyroid Hormone (I-PTH) is the only FDA approved anabolic drug therapy available for the treatment of osteoporosis in males and postmenopausal females. The effects of I-PTH on the chondrogenic lineage of the mandibular condylar cartilage (MCC) are not well understood. To investigate the role of I-PTH on the MCC and subchondral bone, we carried out our studies using 4 to 5 week old triple transgenic mice (Col1a1XCol2a1XCol10a1). The experimental group was injected with PTH (80 μg/kg) daily for 2 weeks, while control group was injected with saline. Our histology showed that the I-PTH treatment led to an increased number of cells expressing Col1a1, Col2a1 and Col10a1. Additionally, there was an increase in cellular proliferation, increased proteoglycan distribution, increased cartilage thickness, increased TRAP activity, and mineralization. Immunohistochemical staining showed increased expression of pSMAD158 and VEGF in the MCC and subchondral bone. Furthermore our microCT data showed that I-PTH treatment led to an increased bone volume fraction, tissue density and trabecular thickness, with a decrease in trabecular spacing. Morphometric measurements showed increased mandibular length and condyle head length following I-PTH treatment. In conclusion, our study suggests that I-PTH plays a critical role in cellular proliferation, proteoglycan distribution, and mineralization of the MCC.

  18. Dkk1 haploinsufficiency requires expression of Bmp2 for bone anabolic activity.

    Science.gov (United States)

    Intini, Giuseppe; Nyman, Jeffry S

    2015-06-01

    Bone fractures remain a serious health burden and prevention and enhanced healing of fractures have been obtained by augmenting either BMP or Wnt signaling. However, whether BMP and Wnt signaling are both required or are self-sufficient for anabolic and fracture healing activities has never been fully elucidated. Mice haploinsufficient for Dkk1 (Dkk1(+/-)) exhibit a high bone mass phenotype due to an up-regulation of canonical Wnt signaling while mice lacking Bmp2 expression in the limbs (Bmp2(c/c);Prx1::cre) succumb to spontaneous fracture and are unable to initiate fracture healing; combined, these mice offer an opportunity to examine the requirement for activated BMP signaling on the anabolic and fracture healing activity of Wnts. When Dkk1(+/-) mice were crossed with Bmp2(c/c);Prx1::cre mice, the offspring bearing both genetic alterations were unable to increase bone mass and heal fractures, indicating that increased canonical Wnt signaling is unable to exploit its activity in absence of Bmp2. Thus, our data suggest that BMP signaling is required for Wnt-mediated anabolic activity and that therapies aimed at preventing fractures and fostering fracture repair may need to target both pathways for maximal efficacy.

  19. Arsenic may be involved in fluoride-induced bone toxicity through PTH/PKA/AP1 signaling pathway.

    Science.gov (United States)

    Zeng, Qi-bing; Xu, Yu-yan; Yu, Xian; Yang, Jun; Hong, Feng; Zhang, Ai-hua

    2014-01-01

    Chronic exposure to combined fluoride and arsenic continues to be a major public health problem worldwide, affecting thousands of people. In recent years, more and more researchers began to focus on the interaction between the fluorine and the arsenic. In this study, the selected investigation site was located in China. The study group was selected from people living in fluoride-arsenic polluted areas due to burning coal. The total number of participants was 196; including the fluoride-arsenic anomaly group (130) and the fluoride-arsenic normal group (63). By observing the changes in gene and protein expression of PTH/PKA/AP1 signaling pathway, the results show that fluoride can increase the expression levels of PTH, PKA, and AP1, but arsenic can only affect the expression of AP1; fluoride and arsenic have an interaction on the expression of AP1. Further study found that fluoride and arsenic can affect the mRNA expression level of c-fos gene (AP1 family members), and have an interaction on the expression of c-fos, but not c-jun. The results indicate that PTH/PKA/AP1 signaling pathway may play an important role in bone toxicity of fluoride. Arsenic can affect the expression of c-fos, thereby affecting the expression of transcription factor AP1, indirectly involved in fluoride-induced bone toxicity. Copyright © 2013. Published by Elsevier B.V.

  20. [Relationship of pharmacokinetics, changes of bone turnover markers and BMD/fractures efficacy during treatment with anabolic agents;Teriparatide daily and once weekly subcutaneous injections.

    Science.gov (United States)

    Miyauchi, Akimitsu

    Teriparatide(recombinant human PTH1-34, 20 μg daily subcutaneous injection)has been approved for osteoporosis patients at high risk of fracture in many countries including Japan. Teriparatide daily injection therapy has been reported to increase BMD, improve microarchitecture of bone, and reduce the risk of new vertebral fractures and that of non-vertebral fractures. Pharmakokinetic(PK)study after a single Teriparatide injection of the daily dose in healthy Japanese postmenopausal women(n=18)revealed very rapid achievement of peak blood level(median of tmax=0.25 hr)followed by fast disappearance from the blood(mean t1/2=0.708 hr, n=17). Consistent with these PK characteristics, a rapid increase in bone formation marker and later increase in bone resorption marker has previously been observed, which was described as a bone anabolic window. More recently, once weekly subcutaneous injection of teriparatide acetate(56.5 μg)has been reported to reduce the risk of new vertebral fractures compared with placebo and has been approved in Japan. PK study after injection of the higher weekly dose in healthy Japanese postmenopausal women(n=10)revealed a relatively slow achievement of the peak blood level(mean tmax=0.875 hr)compared to daily injections, followed by relatively slow disappearance from the blood(mean t1/2=1.295 hr). Consistent with these PK characteristics, an initial(<24 hr)transient decrease of bone formation markers(serum osteocalcin and P1NP)and transient increase of bone resorption markers(serum NTX and urinary CTX)were observed. However, afterword, the bone formation and resorption markers were increased and decreased, respectively, for longer than 1 week from the baseline levels. The relationship of pharmacokinetics, changes of bone turnover markers and BMD/fractures efficacy during daily versus weekly teriparatide treatment needs to be clarified.

  1. Vitamin D status and PTH in young men: a cross-sectional study on associations with bone mineral density, body composition and glucose metabolism

    DEFF Research Database (Denmark)

    Frost, M; Abrahamsen, B; Nielsen, T L

    2010-01-01

    Although vitamin D and bone metabolism are closely related, few studies have addressed the effects of vitamin D status on bone in men at time of peak bone mass. The objectives of this study were to evaluate the prevalence of vitamin D inadequacy in a cross-sectional study in young men...... and the effects of vitamin D and parathyroid hormone (PTH) on bone mass, bone markers and metabolic function....

  2. Bi-directionally selective bone targeting delivery for anabolic and antiresorptive drugs: a novel combined therapy for osteoporosis?

    NARCIS (Netherlands)

    Liu, J.; Zhang, H.; Dong, Y.; Jin, Y.; Hu, X.; Cai, K.; Ma, J.; Wu, G.

    2014-01-01

    Osteoporosis is a progressive systemic skeletal disease, in which the equilibrium of bone resorption and bone formation is disturbed. The drugs for osteoporosis can be divided into two categories according to their predominant effects: antiresorptive drugs and anabolic drugs. Antiresorptive drugs

  3. Nmp4/CIZ suppresses the response of bone to anabolic parathyroid hormone by regulating both osteoblasts and osteoclasts.

    Science.gov (United States)

    Childress, Paul; Philip, Binu K; Robling, Alexander G; Bruzzaniti, Angela; Kacena, Melissa A; Bivi, Nicoletta; Plotkin, Lilian I; Heller, Aaron; Bidwell, Joseph P

    2011-07-01

    How parathyroid hormone (PTH) increases bone mass is unclear, but understanding this phenomenon is significant to the improvement of osteoporosis therapy. Nmp4/CIZ is a nucleocytoplasmic shuttling transcriptional repressor that suppresses PTH-induced osteoblast gene expression and hormone-stimulated gains in murine femoral trabecular bone. To further characterize Nmp4/CIZ suppression of hormone-mediated bone growth, we treated 10-week-old Nmp4-knockout (KO) and wild-type (WT) mice with intermittent human PTH(1-34) at 30 μg/kg daily or vehicle, 7 days/week, for 2, 3, or 7 weeks. Null mice treated with hormone (7 weeks) gained more vertebral and tibial cancellous bone than WT animals, paralleling the exaggerated response in the femur. Interestingly, Nmp4/CIZ suppression of this hormone-stimulated bone formation was not apparent during the first 2 weeks of treatment. Consistent with the null mice enhanced PTH-stimulated addition of trabecular bone, these animals exhibited an augmented hormone-induced increase in serum osteocalcin 3 weeks into treatment. Unexpectedly, the Nmp4-KO mice displayed an osteoclast phenotype. Serum C-terminal telopeptide, a marker for bone resorption, was elevated in the null mice, irrespective of treatment. Nmp4-KO bone marrow cultures produced more osteoclasts, which exhibited elevated resorbing activity, compared to WT cultures. The expression of several genes critical to the development of both osteoblasts and osteoclasts was elevated in Nmp4-KO mice at 2 weeks, but not 3 weeks, of hormone exposure. We propose that Nmp4/CIZ dampens PTH-induced improvement of trabecular bone throughout the skeleton by transiently suppressing hormone-stimulated increases in the expression of proteins key to the required enhanced activity and number of both osteoblasts and osteoclasts.

  4. Applications of Anabolic Vitamin D Analogs as Countermeasures to Bone Loss

    Science.gov (United States)

    Karin, Norman J.

    1998-01-01

    The experiments in Round 2 were designed to extend the results of our efforts in Round 1 which led us to hypothesize that the seco-steroid, 1,25-dihydroxyvitamin D3[1,25(OH)2D3], acts in synergy with parathyroid hormone (PTH) to regulate bone calcium homeostasis. Our work centered on one particular target of 1,25(OH)2D3 action, the voltage-sensitive calcium channels (VSCC's), which are activated acutely by this steroid within milliseconds of exposure . A second area of research focused on the effects of mechanical strain on VSCC expression in bone. These experiments were performed in collaboration with Dr. Steven Goldstein (Univ. Michigan), who generously provided RNA extracted from dog bones that had been exposed to mechanical strain in vivo. Our results suggest that mechanical loading elevated VSCC expression in the long bones from 3 of the 6 animals tested. A second line of experimentation, carried out in collaboration with Dr. Randall Duncan, a NASA-funded investigator in Indianapolis, centered on RT-PCR analysis of effects of mechanical strain on Ca2(+) channel expression in cultured bone cells. Compared to unstrained controls, the expression of vitamin-D-sensidve Ca2(+) channels is elevated 3- to 5-fold over a 24 hr period.

  5. Epidermal growth factor receptor plays an anabolic role in bone metabolism in vivo.

    Science.gov (United States)

    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

    2011-05-01

    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. Copyright © 2011

  6. Enhanced Bone Morphogenetic Protein-2-Induced Ectopic and Orthotopic Bone Formation by Intermittent Parathyroid Hormone (1-34) Administration

    NARCIS (Netherlands)

    Kempen, Diederik H. R.; Lu, Lichun; Hefferan, Theresa E.; Creemers, Laura B.; Heijink, Andras; Maran, Avudaiappan; Dhert, Wouter J. A.; Yaszemski, Michael J.

    2010-01-01

    Bone morphogenetic proteins (BMPs) play a central role in local bone regeneration strategies, whereas the anabolic features of parathyroid hormone (PTH) are particularly appealing for the systemic treatment of generalized bone loss. The aim of the current study was to investigate whether local BMP-2

  7. PTH has the potential to rescue disturbed bone growth in achondroplasia.

    Science.gov (United States)

    Ueda, Koso; Yamanaka, Yoshitaka; Harada, Daisuke; Yamagami, Emi; Tanaka, Hiroyuki; Seino, Yoshiki

    2007-07-01

    Achondroplasia (Ach), the most common form of short-limb short stature, and related disorders are caused by constitutively active point mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Recent studies have provided a large body of evidence for the role of the proliferation and differentiation of chondrocytes in these disorders. Furthermore, a G380R mutation in FGFR3 (FGFR3(Ach)), which results in achondroplasia, induces apoptosis in the chondrogenic cell line ATDC5. This is associated with a decrease in the expression of PTHrP, which shares the same receptor with PTH, and it is significant that PTHrP rescues these cells from apoptosis. Fetuses derived from transgenic mice expressing FGFR3(Ach) under the control of the type II collagen promoter (AchTG) or from wild-type mice were obtained on the 15th day of pregnancy. The femurs were collected from these specimens and cultured for 4 days with PTH. The effects of PTH treatment were then determined by morphometric and histological analyses, in situ hybridization of type X collagen mRNA, and the TUNEL assay. AchTG femurs showed suppressed growth compared with wild type (0.29+/-0.10 mm vs. 0.46+/-0.06 mm, respectively; ptreatments improved the growth velocity in the femurs of the AchTG (0.50+/-0.06 mm; pachondroplasia.

  8. Parathyroid hormone and bone healing

    DEFF Research Database (Denmark)

    Ellegaard, M; Jørgensen, N R; Schwarz, P

    2010-01-01

    , no pharmacological treatments are available. There is therefore an unmet need for medications that can stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis, and intriguingly a number of animal studies suggest that PTH could be beneficial...... in the treatment of fractures and could thus be a potentially new treatment option for induction of fracture healing in humans. Furthermore, fractures in animals with experimental conditions of impaired healing such as aging, estrogen withdrawal, and malnutrition can heal in an expedited manner after PTH treatment...

  9. Model-based Comparative Prediction of Transcription-Factor Binding Motifs in Anabolic Responses in Bone

    Institute of Scientific and Technical Information of China (English)

    Andy; B.; Chen; Kazunori; Hamamura; Guohua; Wang; Weirong; Xing; Subburaman; Mohan; Hiroki; Yokota; Yunlong; Liu

    2007-01-01

    Understanding the regulatory mechanism that controls the alteration of global gene expression patterns continues to be a challenging task in computational biology. We previously developed an ant algorithm, a biologically-inspired computational technique for microarray data, and predicted putative transcription-factor binding motifs (TFBMs) through mimicking interactive behaviors of natural ants. Here we extended the algorithm into a set of web-based software, Ant Modeler, and applied it to investigate the transcriptional mechanism underlying bone formation. Mechanical loading and administration of bone morphogenic proteins (BMPs) are two known treatments to strengthen bone. We addressed a question: Is there any TFBM that stimulates both "anabolic responses of mechanical loading" and "BMP-mediated osteogenic signaling"? Although there is no significant overlap among genes in the two responses, a comparative model-based analysis suggests that the two independent osteogenic processes employ common TFBMs, such as a stress responsive element and a motif for peroxisome proliferator-activated recep- tor (PPAR). The post-modeling in vitro analysis using mouse osteoblast cells sup- ported involvements of the predicted TFBMs such as PPAR, Ikaros 3, and LMO2 in response to mechanical loading. Taken together, the results would be useful to derive a set of testable hypotheses and examine the role of specific regulators in complex transcriptional control of bone formation.

  10. Early Effects of Single and Low-Frequency Repeated Administration of Teriparatide, hPTH(1-34), on Bone Formation and Resorption in Ovariectomized Rats.

    Science.gov (United States)

    Isogai, Yukihiro; Takao-Kawabata, Ryoko; Takakura, Aya; Sugimoto, Emika; Nakazono, Osamu; Ikegaki, Ichiro; Kuriyama, Hiroshi; Ishizuya, Toshinori

    2015-10-01

    Intermittent repeated administration of teriparatide (TPTD) has potent anabolic effects on bones in vivo. However, TPTD has both anabolic and catabolic effects on osteoblasts in vitro, and the mechanisms underlying its promotion of bone formation are unclear. This study aimed to elucidate the time-dependent changes in bone formation and resorption by examining changes in bone turnover markers and bone tissue over time after TPTD administration with low frequency in ovariectomized rats. The amount of serum osteocalcin, a bone formation marker, was transiently reduced after single TPTD administration, but increased thereafter, remaining increased for several days. In contrast, the amount of excreted urinary C-telopeptide, a bone resorption marker, increased transiently after single TPTD administration, and subsequently returned to control levels on the day after administration. Tissue histomorphometric analyses conducted 8 h after administration showed no changes in bone formation or bone resorption parameters. However, at 48 h, the bone formation parameters OS/BS and Ob.S/BS were increased, while the bone resorption parameter ES/BS was decreased. After repeated TPTD administration for 4 weeks, OS/BS, Ob.S/BS, and MS/BS increased, while Oc.S/BS decreased. Serum osteocalcin at 4 weeks after repeated administration was significantly correlated with OS/BS and Ob.S/BS. These present findings indicate that TPTD has dual, time-dependent effects on bone resorption and bone formation. Immediately after single administration, there was transient promotion of bone resorption and suppression of bone formation. However, sustained stimulation of bone formation occurred thereafter. Furthermore, these data suggest that this sustained bone formation led to anabolic effects with repeated TPTD administration.

  11. Withaferin A: a proteasomal inhibitor promotes healing after injury and exerts anabolic effect on osteoporotic bone.

    Science.gov (United States)

    Khedgikar, V; Kushwaha, P; Gautam, J; Verma, A; Changkija, B; Kumar, A; Sharma, S; Nagar, G K; Singh, D; Trivedi, P K; Sangwan, N S; Mishra, P R; Trivedi, R

    2013-01-01

    supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur, decreased bone turnover markers (osteocalcin and TNFα) and expression of skeletal osteoclastogenic genes. It also increased new bone formation and expression of osteogenic genes in the femur bone as compared with vehicle groups (Sham) and ovariectomy (OVx), Bortezomib (known PI), injectible parathyroid hormone and alendronate (FDA approved drugs). WFA promoted the process of cortical bone regeneration at drill-holes site in the femur mid-diaphysis region and cortical gap was bridged with woven bone within 11 days of both estrogen sufficient and deficient (ovariectomized, Ovx) mice. Together our data suggest that WFA stimulates bone formation by abrogating proteasomal machinery and provides knowledge base for its clinical evaluation as a bone anabolic agent.

  12. Cell Cycle and Apoptosis Regulatory Protein (CARP)-1 is Expressed inOsteoblasts and Regulated by PTH

    Energy Technology Data Exchange (ETDEWEB)

    Sharma, Sonali; Mahalingam, Chandrika D.; Das, Varsha [Department of Internal Medicine/Endocrinology, Wayne State University School of Medicine, Detroit, MI 48201 (United States); Jamal, Shazia [Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201 (United States); Levi, Edi [Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201 (United States); Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201 (United States); Rishi, Arun K. [Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201 (United States); Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201 (United States); VA Medical Center, Wayne State University School of Medicine, Detroit, MI 48201 (United States); Datta, Nabanita S., E-mail: ndatta@med.wayne.edu [Department of Internal Medicine/Endocrinology, Wayne State University School of Medicine, Detroit, MI 48201 (United States); Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201 (United States); Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201 (United States)

    2013-07-12

    suggesting that PTH utilized an Extracellular Signal Regulated Kinase (ERK)-independent but p38 dependent pathway to regulate CARP-1 protein expression in osteoblasts. Immunofluorescence staining of differentiated osteoblasts further revealed nuclear to cytoplasmic translocation of CARP-1 protein following PTH treatment. Collectively, our studies identified CARP-1 for the first time in osteoblasts and suggest its potential role in PTH signaling and bone anabolic action.

  13. PTH Reloaded: A New Evolutionary Perspective

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    Paula Suarez-Bregua

    2017-10-01

    Full Text Available The parathyroid hormone (PTH family is a group of structurally-related secreted peptides involved in bone mineral homeostasis and multitude of developmental processes in vertebrates. These peptides mediate actions through PTH receptors (PTHRs, which belong to the transmembrane G protein-coupled receptor group. To date, genes encoding for PTH and PTHR have only been identified in chordates, suggesting that this signaling pathway may be an evolutionary innovation of our phylum. In vertebrates, we found up to six PTH and three PTHR different paralogs, varying in number between mammals and teleost fishes due to the different rounds of whole-genome duplication and specific gene losses suffered between the two groups of animals. The diversification of the PTH gene family has been accompanied by both functional divergence and convergence, making sometimes difficult the comparison between PTH peptides of teleosts and mammals. Here, we review the roles of all Pth peptides in fishes, and based on the evolutionary history of PTH paralogs, we propose a new and simple nomenclature from PTH1 to PTH4. Moreover, the recent characterization of the Pth4 in zebrafish allows us to consider the prominent role of the brain-to-bone signaling pathway in the regulation of bone development and homeostasis. Finally, comparison between PTH peptides of fish and mammals allows us to discuss an evolutionary model for PTH functions related to bone mineral balance during the vertebrate transition from an aquatic to a terrestrial environment.

  14. The abnormal phenotypes of cartilage and bone in calcium-sensing receptor deficient mice are dependent on the actions of calcium, phosphorus, and PTH.

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    Jingning Liu

    2011-09-01

    Full Text Available Patients with neonatal severe hyperparathyroidism (NSHPT are homozygous for the calcium-sensing receptor (CaR mutation and have very high circulating PTH, abundant parathyroid hyperplasia, and severe life-threatening hypercalcemia. Mice with homozygous deletion of CaR mimic the syndrome of NSHPT. To determine effects of CaR deficiency on skeletal development and interactions between CaR and 1,25(OH(2D(3 or PTH on calcium and skeletal homeostasis, we compared the skeletal phenotypes of homozygous CaR-deficient (CaR(-/- mice to those of double homozygous CaR- and 1α(OHase-deficient [CaR(-/-1α(OHase(-/-] mice or those of double homozygous CaR- and PTH-deficient [CaR(-/-PTH(-/-] mice at 2 weeks of age. Compared to wild-type littermates, CaR(-/- mice had hypercalcemia, hypophosphatemia, hyperparathyroidism, and severe skeletal growth retardation. Chondrocyte proliferation and PTHrP expression in growth plates were reduced significantly, whereas trabecular volume, osteoblast number, osteocalcin-positive areas, expression of the ALP, type I collagen, osteocalcin genes, and serum ALP levels were increased significantly. Deletion of 1α(OHase in CaR(-/- mice resulted in a longer lifespan, normocalcemia, lower serum phosphorus, greater elevation in PTH, slight improvement in skeletal growth with increased chondrocyte proliferation and PTHrP expression, and further increases in indices of osteoblastic bone formation. Deletion of PTH in CaR(-/- mice resulted in rescue of early lethality, normocalcemia, increased serum phosphorus, undetectable serum PTH, normalization in skeletal growth with normal chondrocyte proliferation and enhanced PTHrP expression, and dramatic decreases in indices of osteoblastic bone formation. Our results indicate that reductions in hypercalcemia play a critical role in preventing the early lethality of CaR(-/- mice and that defects in endochondral bone formation in CaR(-/- mice result from effects of the marked elevation in serum

  15. Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength.

    Science.gov (United States)

    Sinder, B P; White, L E; Salemi, J D; Ominsky, M S; Caird, M S; Marini, J C; Kozloff, K M

    2014-08-01

    Treatments to reduce fracture rates in adults with osteogenesis imperfecta are limited. Sclerostin antibody, developed for treating osteoporosis, has not been explored in adults with OI. This study demonstrates that treatment of adult OI mice respond favorably to sclerostin antibody therapy despite retention of the OI-causing defect. Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Antiresorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 month old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly > Cys substitution on Col1a1. Six-month-old WT and Brtl/+ mice were treated with Scl-Ab (25 mg/kg, 2×/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed. Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength. Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI.

  16. PTH-analogs: comparable or different?

    Science.gov (United States)

    Verhaar, H J J; Lems, W F

    2009-01-01

    Because no comparative studies exist, no clear pronouncements can be made about the potential differences in effectiveness and safety between PTH 1-34 and PTH 1-84. As regards the efficacy, a convincing reduction of vertebral fractures was shown in both cases [Neer, R.M., Arnaud, C.D., Zanchetta, J.R., Prince, R., Gaich, G.A., Reginster, J.Y., Hodsman, A.B., Eriksen, E.F., Ish-Shalom, S., Genant, H.K., Wang, O., Mitlak, B.H., 2001. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344, 1434-1441; Greenspan, S.L., Bone, H.G., Ettinger, M.P., Hanley, D.A., Lindsay, R., Zanchetta, J.R., Blosch, C.M., Mathisen, A.L., Morris, S.A., Marriott, T.B., Treatment of Osteoporosis with Parathyroid Hormone Study Group, 2007. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann. Intern. Med. 146, 326-339]. A reduction of non-vertebral fractures was shown in the case of PTH 1-34 only. Another significant resemblance is that both medicines have a strong anabolic action; this mechanism of action is essentially different from the bisphosphonates and strontium ranelate. Both medicines constitute a welcome addition to the therapeutic arsenal for patients with severe osteoporosis. More data from literature (including information on follow-up data and use in men) are available for PTH 1-34 because it has been available for longer. As regards the side effect profile, PTH 1-84 appears to have a higher incidence of hypercalcemia, hypercalciuria and nausea than teriparatide. Here, too, no comparative study exists: the differences may therefore be based on an actual difference in side effects, or it may be ascribed to differences in definitions and/or patient populations.

  17. Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone.

    Directory of Open Access Journals (Sweden)

    Khalid S Mohammad

    Full Text Available During development, growth factors and hormones cooperate to establish the unique sizes, shapes and material properties of individual bones. Among these, TGF-beta has been shown to developmentally regulate bone mass and bone matrix properties. However, the mechanisms that control postnatal skeletal integrity in a dynamic biological and mechanical environment are distinct from those that regulate bone development. In addition, despite advances in understanding the roles of TGF-beta signaling in osteoblasts and osteoclasts, the net effects of altered postnatal TGF-beta signaling on bone remain unclear. To examine the role of TGF-beta in the maintenance of the postnatal skeleton, we evaluated the effects of pharmacological inhibition of the TGF-beta type I receptor (TbetaRI kinase on bone mass, architecture and material properties. Inhibition of TbetaRI function increased bone mass and multiple aspects of bone quality, including trabecular bone architecture and macro-mechanical behavior of vertebral bone. TbetaRI inhibitors achieved these effects by increasing osteoblast differentiation and bone formation, while reducing osteoclast differentiation and bone resorption. Furthermore, they induced the expression of Runx2 and EphB4, which promote osteoblast differentiation, and ephrinB2, which antagonizes osteoclast differentiation. Through these anabolic and anti-catabolic effects, TbetaRI inhibitors coordinate changes in multiple bone parameters, including bone mass, architecture, matrix mineral concentration and material properties, that collectively increase bone fracture resistance. Therefore, TbetaRI inhibitors may be effective in treating conditions of skeletal fragility.

  18. Increased glutamine catabolism mediates bone anabolism in response to WNT signaling.

    Science.gov (United States)

    Karner, Courtney M; Esen, Emel; Okunade, Adewole L; Patterson, Bruce W; Long, Fanxin

    2015-02-01

    WNT signaling stimulates bone formation by increasing both the number of osteoblasts and their protein-synthesis activity. It is not clear how WNT augments the capacity of osteoblast progenitors to meet the increased energetic and synthetic needs associated with mature osteoblasts. Here, in cultured osteoblast progenitors, we determined that WNT stimulates glutamine catabolism through the tricarboxylic acid (TCA) cycle and consequently lowers intracellular glutamine levels. The WNT-induced reduction of glutamine concentration triggered a general control nonderepressible 2-mediated (GCN2-mediated) integrated stress response (ISR) that stimulated expression of genes responsible for amino acid supply, transfer RNA (tRNA) aminoacylation, and protein folding. WNT-induced glutamine catabolism and ISR were β-catenin independent, but required mammalian target of rapamycin complex 1 (mTORC1) activation. In a hyperactive WNT signaling mouse model of human osteosclerosis, inhibition of glutamine catabolism or Gcn2 deletion suppressed excessive bone formation. Together, our data indicate that glutamine is both an energy source and a protein-translation rheostat that is responsive to WNT and suggest that manipulation of the glutamine/GCN2 signaling axis may provide a valuable approach for normalizing deranged protein anabolism associated with human diseases.

  19. Mechanical strain, induced noninvasively in the high-frequency domain, is anabolic to cancellous bone, but not cortical bone.

    Science.gov (United States)

    Rubin, C; Turner, A S; Mallinckrodt, C; Jerome, C; McLeod, K; Bain, S

    2002-03-01

    Departing from the premise that it is the large-amplitude signals inherent to intense functional activity that define bone morphology, we propose that it is the far lower magnitude, high-frequency mechanical signals that continually barrage the skeleton during longer term activities such as standing, which regulate skeletal architecture. To examine this hypothesis, we proposed that brief exposure to slight elevations in these endogenous mechanical signals would suffice to increase bone mass in those bones subject to the stimulus. This was tested by exposing the hind limbs of adult female sheep (n = 9) to 20 min/day of low-level (0.3g), high-frequency (30 Hz) mechanical signals, sufficient to induce a peak of approximately 5 microstrain (micro epsilon) in the tibia. Following euthanasia, peripheral quantitative computed tomography (pQCT) was used to segregate the cortical shell from the trabecular envelope of the proximal femur, revealing a 34.2% increase in bone density in the experimental animals as compared with controls (p = 0.01). Histomorphometric examination of the femur supported these density measurements, with bone volume per total volume increasing by 32% (p = 0.04). This density increase was achieved by two separate strategies: trabecular spacing decreased by 36.1% (p = 0.02), whereas trabecular number increased by 45.6% (p = 0.01), indicating the formation of cancellous bone de novo. There were no significant differences in the radii of animals subject to the stimulus, indicating that the adaptive response was local rather than systemic. The anabolic potential of the signal was evident only in trabecular bone, and there were no differences, as measured by any assay, in the cortical bone. These data suggest that subtle mechanical signals generated during predominant activities such as posture may be potent determinants of skeletal morphology. Given that these strain levels are three orders of magnitude below strains that can damage bone tissue, we

  20. The Bone-Protective Effect of Genistein in the Animal Model of Bilateral Ovariectomy: Roles of Phytoestrogens and PTH/PTHR1 Against Post-Menopausal Osteoporosis

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    Jian-Bo Wang

    2011-12-01

    Full Text Available Genistein, a major phytoestrogen of soy, is considered a potential drug for the prevention and treatment of post-menopausal osteoporosis. Mounting evidence suggested a positive correlation between genistein consumption and bone health both in vivo and in vitro. Earlier studies have revealed that genistein acted as a natural estrogen analogue which activated estrogen receptor and exerted anti-osteoporotic effect. However, it remains unclear whether PTH, the most crucial hormone that regulates mineral homeostasis, participates in the process of genistein-mediated bone protection. In the present study, we compared the therapeutic effects between genistein and nilestriol and investigated whether PTH and its specific receptor PTHR1 altered in response to genistein-containing diet in the animal model of ovariectomy. Our results showed that genistein administration significantly improved femoral mechanical properties and alleviates femoral turnover. Genistein at all doses (4.5 mg/kg, 9.0 mg/kg and 18.0 mg/kg per day, respectively exerted improved bending strength and b-ALP limiting effects than nilestriol in the present study. However, genistein administration did not exert superior effects on bone protection than nilestriol. We also observed circulating PTH restoration in ovariectomized rats receiving genistein at the dose of 18 mg/kg per day. Meanwhile, PTHR1 abnormalities were attenuated in the presence of genistein as confirmed by RT-PCR, Western blot and immunohistochemistry. These findings strongly support the idea that besides serving as an estrogen, genistein could interact with PTH/PTHR1, causing a superior mineral restoring effect than nilestriol on certain circumstance. In conclusion, our study reported for the first time that the anti-osteoporotic effect of genistein is partly PTH/PTHR1-dependent. Genistein might be a potential option in the prevention and treatment of post-menopausal osteoporosis with good tolerance, more clinical benefits

  1. JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats.

    Science.gov (United States)

    Kimura, Shuichi; Nakagawa, Takashi; Matsuo, Yushi; Ishida, Yuji; Okamoto, Yoshihisa; Hayashi, Mikio

    2011-10-01

    Intermittent administration of parathyroid hormone (PTH) has a potent anabolic effect on bone in humans and animals. Calcium-sensing receptor (CaSR) antagonists stimulate endogenous PTH secretion through CaSR on the surface of parathyroid cells and thereby may be anabolic agents for osteoporosis. JTT-305 is a potent oral short-acting CaSR antagonist and transiently stimulates endogenous PTH secretion. The objective of the present study was to investigate the effects of JTT-305 on PTH secretion and bone in ovariectomized rats. Female rats, immediately after ovariectomy (OVX), were orally administered vehicle or JTT-305 (0.3, 1, or 3 mg/kg) for 12 weeks. The serum PTH concentrations were transiently elevated with increasing doses of JTT-305. In the proximal tibia, JTT-305 prevented OVX-induced decreases in both the cancellous and total bone mineral density (BMD) except for the 0.3mg/kg dose. At the 3mg/kg dose, JTT-305 increased the mineralizing surface and bone formation rate in histomorphometry. The efficacy of JTT-305 at the 3mg/kg dose on the BMD corresponded to that of exogenous rat PTH1-84 injection at doses between 3 and 10 μg/kg. In conclusion, JTT-305 stimulated endogenous transient PTH secretion and bone formation, and consequently prevented bone loss in OVX rats. These results suggest that JTT-305 is orally active and has the potential to be an anabolic agent for the treatment of osteoporosis.

  2. Ihh and PTH1R signaling in limb mesenchyme is required for proper segmentation and subsequent formation and growth of digit bones.

    Science.gov (United States)

    Amano, Katsuhiko; Densmore, Michael; Fan, Yi; Lanske, Beate

    2016-02-01

    Digit formation is a process, which requires the proper segmentation, formation and growth of phalangeal bones and is precisely regulated by several important factors. One such factor is Ihh, a gene linked to BDA1 and distal symphalangism in humans. In existing mouse models, mutations in Ihh have been shown to cause multiple synostosis in the digits but lead to perinatal lethality. To better study the exact biological and pathological events which occur in these fused digits, we used a more viable Prx1-Cre;Ihh(fl/fl) model in which Cre recombinase is expressed during mesenchymal condensation in the earliest limb buds at E9.5 dpc and found that mutant digits continuously fuse postnatally until phalanges are finally replaced by an unsegmented "one-stick bone". Mutant mice displayed osteocalcin-positive mature osteoblasts, but had reduced proliferation and abnormal osteogenesis. Because of the close interaction between Ihh and PTHrP during endochondral ossification, we also examined the digits of Prx1-Cre;PTH1R(fl/fl) mice, where the receptor for PTHrP was conditionally deleted. Surprisingly, we found PTH1R deletion caused symphalangism, demonstrating another novel function of PTH1R signaling in digit formation. We characterized the symphalangism process whereby initial cartilaginous fusion prevented epiphyseal growth plate formation, resulting in resorption and replacement of the remaining cartilage by bony tissue. Chondrocyte differentiation displayed abnormal directionality in both mutants. Lastly, Prx1-Cre;Ihh(fl/fl);Jansen Tg mice, in which a constitutively active PTH1R allele was introduced into Ihh mutants, were established to address the possible involvement of PTH1R signaling in Ihh mutant digits. These rescue mice failed to show significantly improved phenotype, suggesting that PTH1R signaling in chondrocytes is not sufficient to restore digit formation. Our results demonstrate that Ihh and PTH1R signaling in limb mesenchyme are both essential to regulate

  3. Time course of 25(OHD3 vitamin D3 as well as PTH (parathyroid hormone during fracture healing of patients with normal and low bone mineral density (BMD

    Directory of Open Access Journals (Sweden)

    Wöfl Christoph

    2013-01-01

    Full Text Available Abstract Background Until now the exact biochemical processes during healing of metaphyseal fractures of healthy and osteoporotic bone remain unclear. Especially the physiological time courses of 25(OHD3 (Vitamin D as well as PTH (Parathyroid Hormone the most important modulators of calcium and bone homeostasis are not yet examined sufficiently. The purpose of this study was to focus on the time course of these parameters during fracture healing. Methods In the presented study, we analyse the time course of 25(OHD3 and PTH during fracture healing of low BMD level fractures versus normal BMD level fractures in a matched pair analysis. Between March 2007 and February 2009 30 patients older than 50 years of age who had suffered a metaphyseal fracture of the proximal humerus, the distal radius or the proximal femur were included in our study. Osteoporosis was verified by DEXA measuring. The time courses of 25(OHD3 and PTH were examined over an eight week period. Friedmann test, the Wilcoxon signed rank test and the Mann-Withney U test were used as post-hoc tests. A p-value ≤ 0.05 was considered significant. Results Serum levels of 25(OHD3 showed no differences in both groups. In the first phase of fracture healing PTH levels in the low BMD level group remained below those of the normal BMD group in absolute figures. Over all no significant differences between low BMD level bone and normal BMD level bone could be detected in our study. Conclusions The time course of 25(OHD3 and PTH during fracture healing of patients with normal and low bone mineral density were examined for the first time in humans in this setting and allowing molecular biological insights into fracture healing in metaphyseal bones on a molecural level. There were no significant differences between patients with normal and low BMD levels. Hence further studies will be necessary to obtain more detailed insight into fracture healing in order to provide reliable decision criteria for

  4. [Cytokines in bone diseases. Genetic defects of PTH/PTHrP receptor in chondrodysplasia].

    Science.gov (United States)

    Ogata, Naoshi

    2010-10-01

    Parathyroid hormone-related protein (PTHrP) signaling plays important roles in regulating the differentiation of chondrocytes in endochondral bone development. PTHrP signaling functions as an inhibitory effect on chondrocyte hypertrophy which is a terminal stage of differentiation at a growth plate. Mutations of the PTH÷PTHrP receptor have been identified in Jansen metaphyseal chondrodysplasia, Blomstrand's lethal chondrodysplasia, and enchondromatosis. Furthermore, genetic manipulations of the PTHrP and its receptor genes in mice have demonstrated the critical roles of these proteins in regulating both the switch between proliferation and differentiation of chondrocytes.

  5. Vitamin D binding protein genotype is associated with serum 25-hydroxyvitamin D and PTH concentrations, as well as bone health in children and adolescents in Finland.

    Science.gov (United States)

    Pekkinen, Minna; Saarnio, Elisa; Viljakainen, Heli T; Kokkonen, Elina; Jakobsen, Jette; Cashman, Kevin; Mäkitie, Outi; Lamberg-Allardt, Christel

    2014-01-01

    Vitamin D binding protein (DBP)/group-specific component (Gc), correlates positively with serum vitamin D metabolites, and phenotype influences serum 25-hydroxyvitamin D (S-25(OH)D) concentration. The protein isoform has been associated with decreased bone mineral density (BMD) and increased fracture risk. We examined the role of GC genotypes in S-25(OH)D status and BMD in 231 Finnish children and adolescents aged 7-19 yr. BMD was measured with DXA from lumbar spine (LS), total hip, and whole body, and for 175 subjects, radial volumetric BMD was measured with pQCT. Background characteristic and total dietary intakes of vitamin D and calcium were collected. The concentrations of 25(OH)D, parathyroid hormone (PTH), calcium and other markers of calcium homeostasis were determined from blood and urine. Genotyping was based on single-nucleotide polymorphism (rs4588) in the GC gene. The genotype distribution was: GC 1/1 68%, GC 1/2 26% and GC 2/2 6%. A significant difference emerged in 25(OH)D and PTH concentrations between the genotypes, (p = 0.001 and 0.028 respectively, ANCOVA). There was also a linear trend in: Gc 2/2 had the lowest 25(OH)D and PTH concentrations (p = 0.025 and 0.012, respectively). Total hip bone mineral content was associated with GC genotype (BMC) (p = 0.05, ANCOVA) in boys. In regression analysis, after adjusting for relevant covariates, GC genotype was associated with LS BMC and strength and strain index (SSI) Z-score in both genders, and LS BMD in boys. In conclusion, the present study demonstrates the association between GC genotypes and S-25(OH)D and PTH concentrations. The results show the influence of DBP genetic variation on bone mass accrual in adolescence.

  6. Vitamin D binding protein genotype is associated with serum 25-hydroxyvitamin D and PTH concentrations, as well as bone health in children and adolescents in Finland.

    Directory of Open Access Journals (Sweden)

    Minna Pekkinen

    Full Text Available Vitamin D binding protein (DBP/group-specific component (Gc, correlates positively with serum vitamin D metabolites, and phenotype influences serum 25-hydroxyvitamin D (S-25(OHD concentration. The protein isoform has been associated with decreased bone mineral density (BMD and increased fracture risk. We examined the role of GC genotypes in S-25(OHD status and BMD in 231 Finnish children and adolescents aged 7-19 yr. BMD was measured with DXA from lumbar spine (LS, total hip, and whole body, and for 175 subjects, radial volumetric BMD was measured with pQCT. Background characteristic and total dietary intakes of vitamin D and calcium were collected. The concentrations of 25(OHD, parathyroid hormone (PTH, calcium and other markers of calcium homeostasis were determined from blood and urine. Genotyping was based on single-nucleotide polymorphism (rs4588 in the GC gene. The genotype distribution was: GC 1/1 68%, GC 1/2 26% and GC 2/2 6%. A significant difference emerged in 25(OHD and PTH concentrations between the genotypes, (p = 0.001 and 0.028 respectively, ANCOVA. There was also a linear trend in: Gc 2/2 had the lowest 25(OHD and PTH concentrations (p = 0.025 and 0.012, respectively. Total hip bone mineral content was associated with GC genotype (BMC (p = 0.05, ANCOVA in boys. In regression analysis, after adjusting for relevant covariates, GC genotype was associated with LS BMC and strength and strain index (SSI Z-score in both genders, and LS BMD in boys. In conclusion, the present study demonstrates the association between GC genotypes and S-25(OHD and PTH concentrations. The results show the influence of DBP genetic variation on bone mass accrual in adolescence.

  7. Local delivery of a selective androgen receptor modulator failed as an anabolic agent in a rat bone marrow ablation model.

    Science.gov (United States)

    Aro, Hannu T; Kulkova, Julia; Moritz, Niko; Kähkönen, Esa; Mattila, Riina H

    2015-01-01

    Selective androgen receptor modulators (SARMs) have been developed to have systemic anabolic effects on bones and muscles without the adverse effects of steroidal androgens. One unexplored therapeutic option is the targeted application of SARMs for the enhancement of local new bone formation. We evaluated the osteogenic efficacy of a locally released SARM (ORM-11984). ORM-11984 was mixed with a copolymer of L-lactide and ɛ-caprolactone (PLCL). An in vitro dissolution test confirmed the sustainable release of ORM-11984 from the matrix. A bone marrow ablation model was used in female Sprague-Dawley rats. Implants containing 10%, 30%, or 50% ORM-11984 by weight or pure PLCL were inserted into the medullary canal of the ablated tibia. At 6 and 12 weeks, the volume of intramedullary new bone and the perimeter of bone-implant contact were measured by micro-computed tomography and histomorphometry. Contrary to our hypothesis, there was a negative correlation between the amount of new bone around the implant and the dose of ORM-11984. There was only a mild (and not statistically significant) enhancement of bone formation in ablated bones subjected to the lowest dose of the SARM (10%). This study suggests that intramedullary/endosteal osteogenesis had a negative, dose-dependent response to locally released SARM. This result highlights the complexity of androgenic effects on bones and also suggests that there are biological limits to the targeted local application of SARMs.

  8. PTH(1-34) and zoledronic acid have differing longitudinal effects on juvenile mouse femur strength and morphology.

    Science.gov (United States)

    Bartlow, Christopher M; Oest, Megan E; Mann, Kenneth A; Zimmerman, Nicholas D; Butt, Bilal B; Damron, Timothy A

    2016-09-21

    Treatment of secondary pediatric osteoporosis-particularly that due to chronic diseases, immobilization, and necessary medical treatments-is currently limited by a poor understanding of the long-term efficacy and safety of skeletal metabolism modifying drugs. This study aimed to characterize longitudinal effects of representative anabolic (parathyroid hormone, PTH) and anti-catabolic (zoledronic acid, ZA) drugs on skeletal morphology, mechanical strength, and growth in juvenile mice. BALB/cJ mice aged 4 weeks were given PTH(1-34) or vehicle (control) daily for 8 weeks, or 4 weekly doses of ZA, and evaluated at time points 0-26 weeks after treatment initiation. There were no enduring differences in body length or mass between treatment groups. ZA increased femur size as early as week 0, including increased distal femur bone volume and diaphyseal cross-sectional area, persisting through week 26. PTH treatment only transiently increased bone size, including distal femur volume at weeks 4-12. ZA decreased diaphyseal cortical tissue mineral density (TMD) at 12-26 weeks versus controls; PTH decreased TMD only at 2 weeks (vs. controls). ZA increased bending strength at 0-12 weeks and flexural strength at week 4 (vs. controls), but decreased flexural strength and modulus at week 26. PTH treatment increased bending strength only at 4 weeks, and did not affect flexural strength. Overall, ZA rapidly and persistently increased femur strength and size, but compromised bone material quality long-term. In healthy juvenile mice, limited-duration PTH treatment did not exert a strong anabolic effect, and had no adverse effects on femur strength, morphology, or growth. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

  9. Comparison of calcium carbonate and aluminium hydroxide as phosphate binders on biochemical bone markers, PTH(1-84), and bone mineral content in dialysis patients

    DEFF Research Database (Denmark)

    Jespersen, B; Jensen, J D; Nielsen, H K;

    1991-01-01

    Bone mineral content, estimated by single-photon absorptiometry of the forearm, serum values of intact parathyroid hormone (PTH(1-84], osteocalcin, alkaline phosphatase, 1,25-dihydroxycholecalciferol (1,25(OH)2D3), and aluminium were determined during treatment with calcium carbonate (CaCO3...... 0.05), osteocalcin decreased (89% versus 117%, P less than 0.01), alkaline phosphatase decreased (92% versus 116%, P less than 0.05), and aluminium decreased (56% versus 189%, P less than 0.05). 1,25(OH)2D3 remained unchanged in both periods. No increase in soft-tissue calcification was demonstrated......) or aluminium hydroxide (Al(OH)3) in 11 dialysis patients participating in a randomised cross-over study. Each treatment period lasted 6 months. Serum phosphorus was maintained in the range 1.5-2.0 mmol/l. During Al(OH)3 treatment bone mineral content (BMC) decreased by 11% per half-year (mean), but only by 3...

  10. Hypoxia-inducible factor-1a restricts the anabolic actions of parathyroid hormone

    Institute of Scientific and Technical Information of China (English)

    Julie L Frey; David P Stonko; Marie-Claude Faugere; Ryan C Riddle

    2014-01-01

    The hypoxia inducible factors (Hifs) are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1a in osteoanabolic signaling, we assessed the effect of Hif-1a loss-of-function on bone formation in response to intermittent parathyroid hormone (PTH). Mice lacking Hif-1a in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1a protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1a-mediated suppression of b-catenin transcriptional activity. Together, these data indicate that Hif-1a functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1a function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.

  11. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis.

    Science.gov (United States)

    Hanada, Keigo; Furuya, Kazuyuki; Yamamoto, Noriko; Nejishima, Hiroaki; Ichikawa, Kiyonoshin; Nakamura, Tsutomu; Miyakawa, Motonori; Amano, Seiji; Sumita, Yuji; Oguro, Nao

    2003-11-01

    A novel nonsteroidal androgen receptor (AR) binder, S-40503, was successfully generated in order to develop selective androgen receptor modulators (SARMs). We evaluated the binding specificity for nuclear receptors (NRs) and osteoanabolic activities of S-40503 in comparison with a natural nonaromatizable steroid, 5alpha-dihydrotestosterone (DHT). The compound preferentially bound to AR with nanomolar affinity among NRs. When S-40503 was administrated into orchiectomized (ORX) rats for 4 weeks, bone mineral density (BMD) of femur and muscle weight of levator ani were increased as markedly as DHT, but prostate weight was not elevated over the normal at any doses tested. In contrast, DHT administration caused about 1.5-fold increase in prostate weight. The reduced virilizing activity was clearly evident from the result that 4-week treatment of normal rats with S-40503 showed no enlargement of prostate. To confirm the bone anabolic effect, S-40503 was given to ovariectomized (OVX) rats for 2 months. The compound significantly increased the BMD and biomechanical strength of femoral cortical bone, whereas estrogen, anti-bone resorptive hormone, did not. The increase in periosteal mineral apposition rate (MAR) of the femur revealed direct bone formation activity of S-40503. It was unlikely that the osteoanabolic effect of the compound was attribute to the enhancement of muscle mass, because immobilized ORX rats treated with S-40503 showed a marked increase in BMD of tibial cortical bone without any actions on the surrounding muscle tissue. Collectively, our novel compound served as a prototype for SARMs, which had unique tissue selectivity with high potency for bone formation and lower impact upon sex accessory tissues.

  12. Does simvastatin stimulate bone formation in vivo?

    Directory of Open Access Journals (Sweden)

    Chorev Michael

    2003-04-01

    Full Text Available Abstract Background Statins, potent compounds that inhibit cholesterol synthesis in the liver have been reported to induce bone formation, both in tissue culture and in rats and mice. To re-examine potential anabolic effects of statins on bone formation, we compared the activity of simvastatin (SVS to the known anabolic effects of PTH in an established model of ovariectomized (OVX Swiss-Webster mice. Methods Mice were ovariectomized at 12 weeks of age (T0, remained untreated for 5 weeks to allow development of osteopenia (T5, followed by treatment for 8 weeks (T13. Whole, trabecular and cortical femoral bone was analyzed by micro-computed tomography (micro CT. Liquid chromatography/mass spectrometry (LC/MS was used to detect the presence of SVS and its active metabolite, simvastatin β-hydroxy acid (SVS-OH in the mouse serum. Results Trabecular BV/TV at T13 was 4.2 fold higher in animals treated with PTH (80 micro-g/kg/day compared to the OVX-vehicle treated group (p in vivo study. Conclusions While PTH demonstrated the expected anabolic effect on bone, SVS failed to stimulate bone formation, despite our verification by LC/MS of the active SVS-OH metabolite in mouse serum. While statins have clear effects on bone formation in vitro, the formulation of existing 'liver-targeted' statins requires further refinement for efficacy in vivo.

  13. Anabolic Steroids

    Science.gov (United States)

    Anabolic steroids are man-made substances related to male sex hormones. Doctors use anabolic steroids to treat some hormone problems in men, delayed ... some diseases. Bodybuilders and athletes often use anabolic steroids to build muscles and improve athletic performance. Using ...

  14. Comparison of Intact PTH and Bio-Intact PTH Assays Among Non-Dialysis Dependent Chronic Kidney Disease Patients.

    Science.gov (United States)

    Einbinder, Yael; Benchetrit, Sydney; Golan, Eliezer; Zitman-Gal, Tali

    2017-09-01

    The third-generation bio-intact parathyroid hormone (PTH) (1-84) assay was designed to overcome problems associated with the detection of C-terminal fragments by the second-generation intact PTH assay. The two assays have been compared primarily among dialysis populations. The present study evaluated the correlations and differences between these two PTH assays among patients with chronic kidney disease (CKD) stages 3 to 5 not yet on dialysis. Blood samples were collected from 98 patients with CKD stages 3 to 5. PTH concentrations were measured simultaneously by using the second-generation - PTH intact-STAT and third-generation bio-intact 1-84 PTH assays. Other serum biomarkers of bone mineral disorders were also assessed. CKD stage was calculated by using the CKD-Epidemiology Collaboration (EPI) formula. Serum bio-intact PTH concentrations were strongly correlated but significantly lower than the intact PTH concentrations (r=0.963, Pbio-intact PTH) positively correlated with urea (r=0.523, r=0.504; P=0.002, respectively), phosphorus (r=0.532, r=0.521; Pbio-intact PTH assay detected significantly lower PTH concentrations compared with intact PTH assay. Additional studies that correlate the diagnosis and management of CKD mineral and bone disorders with bone histomorphometric findings are needed to determine whether bio-intact PTH assay results are better surrogate markers in these early stages of CKD.

  15. Bone marrow oxytocin mediates the anabolic action of estrogen on the skeleton

    Science.gov (United States)

    Estrogen withdrawal in women due to natural or artificial menopause is followed by rapid bone loss, osteoporosis, and a high fracture risk. Replacement with estrogen prevents this bone loss and reduces the risk of fracture. Estrogen uses two mechanisms to exert this effect: it inhibits bone resorpti...

  16. Bone Anabolic Effects of Soluble Si: In Vitro Studies with Human Mesenchymal Stem Cells and CD14+ Osteoclast Precursors.

    Science.gov (United States)

    Costa-Rodrigues, J; Reis, S; Castro, A; Fernandes, M H

    2016-01-01

    Silicon (Si) is indispensable for many cellular processes including bone tissue metabolism. In this work, the effects of Si on human osteogenesis and osteoclastogenesis were characterized. Human mesenchymal stem cells (hMSC) and CD14+ stem cells, as osteoblast and osteoclast precursors, were treated with a wide range of Si concentrations, covering the physiological plasma levels. Si promoted a dose-dependent increase in hMSC proliferation, differentiation, and function, at levels similar to the normal basal plasma levels. Additionally, a decrease in the expression of the osteoclastogenic activators M-CSF and RANKL was observed. Also, Si elicited a decrease in osteoclastogenesis, which became significant at higher concentrations, as those observed after meals. Among the intracellular mechanisms studied, an upregulation of MEK and PKC signalling pathways was observed in both cell types. In conclusion, Si appears to have a direct positive effect on human osteogenesis, at basal plasma levels. On the other hand, it also seemed to be an inhibitor of osteoclastogenesis, but at higher concentrations, though yet in the physiological range. Further, an indirect effect of Si on osteoclastogenesis may also occur, through a downregulation of M-CSF and RANKL expression by osteoblasts. Thus, Si may be an important player in bone anabolic regenerative approaches.

  17. Manipulating the anabolic and catabolic response in bone graft remodeling: synergism by a combination of local BMP-7 and a single systemic dosis of zoledronate.

    Science.gov (United States)

    Harding, Anna Kajsa; Aspenberg, Per; Kataoka, Masashi; Bylski, David; Tägil, Magnus

    2008-09-01

    Remodeling of a bone graft can be influenced both by anabolic substances, such as a bone morphogenic protein (BMP) and by anticatabolic substances, such as the bisphosphonates. BMPs are potent bone anabolic substances, but also boost catabolism and cause resorption. Bisphosphonates inhibit osteoclast function and can be used to postpone resorption. In the present study a combination of both drugs was explored in a rat bone chamber model. Cancellous bone grafts were treated with either BMP-7 or saline and placed in a bone chamber implanted in the proximal tibia. After 2 weeks, an injection of either zoledronate 0.1 mg/kg or saline was given subcutaneously. The rats were killed after 6 weeks, and bone ingrowth distance into the graft and graft resorption were measured by histomorphometry. BMP-7 significantly (p = 0.007) increased new bone ingrowth distance into the graft from 2.0 mm (SD = 0.98 mm) in the controls to 3.1 mm (SD = 0.93 mm). If bisphosphonate was not given, most of the newly formed and old graft bone was resorbed. A single injection of zoledronate significantly (p < 0.001) increased the trabecular volume/total volume to 40% (SD = 9%) compared to 14% (SD = 10%) in the nonbisphosphonate treated. In total, the net amount of bone increased by 400% when BMP-7 and zoledronate combined was compared to saline. A bone graft can be treated with BMP-7 to increase new bone formation and at the same time be protected against premature catabolism by a single dose of a bisphosphonate. This combination might be useful in various conditions in orthopedic reconstruction. (c) 2008 Orthopaedic Research Society

  18. The association between body composition, 25(OH)D, and PTH and bone mineral density in black African and Asian Indian population groups.

    Science.gov (United States)

    George, Jaya A; Micklesfield, L K; Norris, S A; Crowther, N J

    2014-06-01

    There are few data on the contribution of body composition to bone mineral density (BMD) in non-Caucasian populations. We therefore studied the contribution of body composition, and possible confounding of 25-hydroxyvitamin D and PTH, to BMD at various skeletal sites in black African (BA) and Asian Indian (AI) subjects. This was a cross-sectional study in Johannesburg, South Africa. BMD, body fat, and lean mass were measured using dual x-ray absorptiometry and abdominal fat distribution by ultrasound in 714 healthy subjects, aged 18-65 years. Whole-body (subtotal), hip, femoral neck, and lumbar spine (lumbar) BMD were significantly higher in BA than AI subjects (P < .001 for all). Whole-body lean mass positively associated with BMD at all sites in both ethnic groups (P < .001 for all) and partially explained the higher BMD in BA females compared with AI females. Whole-body fat mass correlated positively with lumbar BMD in BA (P = .001) and inversely with subtotal BMD in AI subjects (P < .0001). Visceral adiposity correlated inversely with subtotal BMD in the BA (P = .037) and with lumbar BMD in the AI group (P = .005). No association was found between serum 25-hydroxyvitamin D and BMD. PTH was inversely associated with hip BMD in the BA group (P = .01) and with subtotal (P = .002), hip (P = .001), and femoral BMD (P < .0001) in the AI group. Significant differences in whole-body and site-specific BMD between the BA and AI groups were observed, with lean mass the major contributor to BMD at all sites in both groups. The contribution of other components of body composition differed by site and ethnic group.

  19. Intra-oral PTH administration promotes tooth extraction socket healing.

    Science.gov (United States)

    Kuroshima, S; Kovacic, B L; Kozloff, K M; McCauley, L K; Yamashita, J

    2013-06-01

    Intermittent parathyroid hormone (PTH) administration increases systemic and craniofacial bone mass. However, the effect of PTH therapy on healing of tooth extraction sites is unknown. The aims of this study were to determine the effect of PTH therapy on tooth extraction socket healing and to examine whether PTH intra-oral injection promotes healing. The mandibular first molars were extracted in rats, and subcutaneous PTH was administered intermittently for 7, 14, and 28 days. In a second study, maxillary second molars were extracted, and PTH was administered by either subcutaneous or intra-oral injection to determine the efficacy of intra-oral PTH administration. Healing was assessed by micro-computed tomography and histomorphometric analyses. PTH therapy accelerated the entire healing process and promoted both hard- and soft-tissue healing by increasing bone fill and connective tissue maturation. PTH therapy by intra-oral injection was as effective as subcutaneous injection in promoting tooth extraction socket healing. The findings suggest that PTH therapy promotes tooth extraction socket healing and that intra-oral injections can be used to administer PTH.

  20. The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects

    Science.gov (United States)

    Hurchla, MA; Garcia-Gomez, A; Hornick, MC; Ocio, EM; Li, A; Blanco, JF; Collins, L; Kirk, CJ; Piwnica-Worms, D; Vij, R; Tomasson, MH; Pandiella, A; Miguel, JF San; Garayoa, M; Weilbaecher, KN

    2013-01-01

    Proteasome inhibitors (PIs), namely bortezomib, have become a cornerstone therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting pathologic bone destruction. In clinical trials, carfilzomib, a next generation epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. Interactions between myeloma cells and the bone marrow (BM) microenvironment augment the number and activity of bone-resorbing osteoclasts (OCs) while inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth and osteolytic lesions. At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzomib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM. PMID:22763387

  1. Efficacy and safety of human parathyroid hormone-(1-84) in increasing bone mineral density in postmenopausal osteoporosis.

    Science.gov (United States)

    Hodsman, Anthony B; Hanley, David A; Ettinger, Mark P; Bolognese, Michael A; Fox, John; Metcalfe, Anna J; Lindsay, Robert

    2003-11-01

    Daily sc injections of N-terminal analogs of PTH increase bone mass and decrease fractures in osteoporotic women. We investigated the efficacy and safety of human PTH-(1-84) (full-length PTH) in the treatment of postmenopausal osteoporosis in a double-blind, placebo-controlled study. The women (n = 50-53/group) self-administered PTH (50, 75, or 100 microg) or placebo by daily sc injection for 12 months. PTH treatment induced time- and dose-related increases in lumbar spine bone mineral density (BMD). The 100-microg dose increased BMD significantly at 3 months (+2.0%) and 12 months (+7.8%). BMD underestimated the anabolic effect of PTH in lumbar spine (bone mineral content, +10.0%) because bone area increased significantly (+2.0%). A nonsignificant decrease (-0.9%) in total hip BMD occurred during the first 6 months with the 100-microg dose, but this trend reversed (+1.6%) during the second 6 months. Bone turnover markers increased during the first half of the study and were maintained at elevated levels during the second 6 months. Protocol compliance was excellent (95-98%), and treatment was generally safe and well tolerated. Dose-related incidences of transient hypercalcemia occurred, but only one patient (100-microg group) was withdrawn because of repeated hypercalcemia. Thus, full-length PTH was efficacious and safe over 12 months.

  2. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats

    Science.gov (United States)

    Gowen, Maxine; Stroup, George B.; Dodds, Robert A.; James, Ian E.; Votta, Bart J.; Smith, Brian R.; Bhatnagar, Pradip K.; Lago, Amparo M.; Callahan, James F.; DelMar, Eric G.; Miller, Michael A.; Nemeth, Edward F.; Fox, John

    2000-01-01

    Parathyroid hormone (PTH) is an effective bone anabolic agent, but it must be administered parenterally. An orally active anabolic agent would provide a valuable alternative for treating osteoporosis. NPS 2143 is a novel, selective antagonist (a “calcilytic”) of the parathyroid cell Ca2+ receptor. Daily oral administration of NPS 2143 to osteopenic ovariectomized (OVX) rats caused a sustained increase in plasma PTH levels, provoking a dramatic increase in bone turnover but no net change in bone mineral density. Concurrent oral administration of NPS 2143 and subcutaneous infusion of 17β-estradiol also resulted in increased bone turnover. However, the antiresorptive action of estrogen decreased the extent of bone resorption stimulated by the elevated PTH levels, leading to an increase in bone mass compared with OVX controls or to either treatment alone. Despite the sustained stimulation to the parathyroid gland, parathyroid cells did not undergo hyperplasia. These data demonstrate that an increase in endogenous PTH secretion, induced by antagonism of the parathyroid cell Ca2+ receptor with a small molecule, leads to a dramatic increase in bone turnover, and they suggest a novel approach to the treatment of osteoporosis. PMID:10841518

  3. MKP1-dependent PTH modulation of bone matrix mineralization in female mice is osteoblast maturation stage specific and involves P-ERK and P-p38 MAPKs.

    Science.gov (United States)

    Mahalingam, Chandrika D; Sampathi, Bharat Reddy; Sharma, Sonali; Datta, Tanuka; Das, Varsha; Abou-Samra, Abdul B; Datta, Nabanita S

    2013-03-01

    Limited information is available on the role of MAPK phosphatase 1 (MKP1) signaling in osteoblasts. We have recently reported distinct roles for MKP1 during osteoblast proliferation, differentiation, and skeletal responsiveness to parathyroid hormone (PTH). As MKP1 regulates the phosphorylation status of MAPKs, we investigated the involvement of P-ERK and P-p38 MAPKs in MKP1 knockout (KO) early and mature osteoblasts with respect to mineralization and PTH response. Calvarial osteoblasts from 9-14-week-old WT and MKP1 KO male and female mice were examined. Western blot analysis revealed downregulation and sustained expressions of P-ERK and P-p38 with PTH treatment in differentiated osteoblasts derived from KO males and females respectively. Exposure of early osteoblasts to p38 inhibitor, SB203580 (S), markedly inhibited mineralization in WT and KO osteoblasts from both genders as determined by von Kossa assay. In osteoblasts from males, ERK inhibitor U0126 (U), not p38 inhibitor (S), prevented the inhibitory effects of PTH on mineralization in early or mature osteoblasts. In osteoblasts from KO females, PTH sustained mineralization in early osteoblasts and decreased mineralization in mature cells. This effect of PTH was attenuated by S in early osteoblasts and by U in mature KO cells. Changes in matrix Gla protein expression with PTH in KO osteoblasts did not correlate with mineralization, indicative of MKP1-dependent additional mechanisms essential for PTH action on osteoblast mineralization. We conclude that PTH regulation of osteoblast mineralization in female mice is maturation stage specific and involves MKP1 modulation of P-ERK and P-p38 MAPKs.

  4. The Relationship Among Between Serum Cytokine, Intact PTH, Osteocalcin and Bone Mineral Density Values in Postmenopausal Women

    Directory of Open Access Journals (Sweden)

    M. Yıldız

    2002-06-01

    Full Text Available This study was designed to compare the bone mineral density (BMD in 108 postmenopausal women with laboratory data including osteocalcin, intact parathyroid hormone and serum cytokine values. One hundred eigth postmenopausal women were randomly divided into 3 sub groups according to their BMD and medical treatment. The first group consisting of 18 postmenopausal women had no osteoporosis, mean age and mean duration of postmenopausal period were 52.94± 4.90 and 6.5±4.76 years respectively. The second group consisting of 15 postmenopausal women had osteoporosis and was not treated, mean age and mean duration of postmenopausal period were 53.60±8.84 and 9.73± 6.75 years respectively. The third group consisting of 75 postmenopausal osteoporotic women was under medical treatment, mean age nd mean duration of postmenopausal period were 58.52±8.51 and 13.20±8.41 years respectively. Bone mineral density at femur Ward’s triangle, trochanter and lumbar spine t score values were evaluated by dual X ray absorptiometry (DXA. Serum calcium, phosphorous, C-reactive protein, erythrocyte sedimentation rate, cytokines (interleukin-1, IL-1, interleukin-2, IL-2, interleukin-6, IL-6, interleukin-8, IL-8 and tumor necrosis factor alpha TNF-a, osteocalcin, intact parathyroid hormone were measured. In subjects, no significant correlation was observed between BMD t scores of lumbar spine, trochanter, Ward’s triangle and cytokine values. On the other hand, among these groups significant difference was found between age, treatment duration, t scores of lumbar spine, trochanter, Ward’s triangle and postmenopausal period, but not between IL-1, IL-2, IL-6, IL-8, TNF-a, osteocalcin, intact parathyroid. As a conclusion we think BMD (especially in the early postmenopausal period might be correlating with the levels of cytokines in bone microenvironment rather than serum levels. In the early postmenopausal osteoporosis period serum IL-6 value might be supporting to

  5. Role of p38MAPK in signal transduction of low density ESW and Iow dose intermittent rhPTH1 -34's action on bone formation of cultured rat osteoblasts%p38MAPK在低能ESW和间歇rhPTH1-34促进ROB成骨的信号转导中的作用

    Institute of Scientific and Technical Information of China (English)

    王李; 刘长剑; 罗宗键

    2011-01-01

    [ Objective] To investigate the role of p38MAPK in the signal path way of low density ESW and low dose intermittent rhPTH1 -34 stimulation's action on rat osteoblasts. [ Methods] After stimulations of 0. 18 rmJ/mm2 ESW and 10-11 mol/L intermittent rhPTHI - 34,the specific inhibitor of p38MAPK was added for finding the role of p38MAPK in the intracellular signal path way. The rat osteoblasts were collected, and cultured was detected, proliferation of these cells was observed by MTI and bone formation by measuring ALP activity. The expression of p - p38MAPK was detected by Western blot. [ Results] Enhaning effect on bone formation by ESW can be significantly inhibited by SB203580, a inhibitor of p38MAPK( P <0.05 ). But the enhancement of ROBs' bone formation by intermittent rhPTHI -34 can not be inhibited by SB203580. Suitable ESW stimulation can improve the expression of p38MAPK, but intermittent rhPTH1 - 34 stimulation can not. [ Conclusions] Suitable ESW stimulation can enhance bone formation of ROB by activation of p38MAPK. The enhancement of ROBs' bone formation by intermittent rhlPFH1 -34 stimulation dosen' t depend on activation of p38MAPK.%[目的]探讨低能体外冲击波(ESW)和间歇人重组甲状旁腺素(rhPTH1-34)刺激引起的体外培养大鼠成骨细胞(ROB)成骨的细胞内信号转导中p38MAPK的作用.[方法]分别用有效的低能ESW刺激和间歇rhPTH1-34作用于ROB,并设立加入p38MAPK抑制剂SB203580组,来观察ROB增殖、成骨指标及Western Blot检测的p38MAPK磷酸化激活变化.[结果]p38MAPK抑制剂SB203580能明显抑制120次0.18 mJ/mm2ESW刺激引起的ROB细胞增殖和成骨作用(P0.05).ESW应力刺激可促进P-p38MAPK表达,但间歇rhPTH1-34不能促进P-p38MAPK表达.[结论]适当的ESW应力刺激可通过激活p38MAPK促进体外培养ROB增殖和成骨;但p38MAPK并不参与10-11 mol/L间歇rhPTH1-34刺激引起的ROB细胞增殖和成骨的细胞信号转导.

  6. The levels of bone turnover markers 25(OH)D and PTH and their relationship with bone mineral density in postmenopausal women in a suburban district in China.

    Science.gov (United States)

    Gao, C; Qiao, J; Li, S S; Yu, W J; He, J W; Fu, W Z; Zhang, Z L

    2017-01-01

    This study evaluated the levels of bone turnover markers (BTMs) and investigated relationships between them and bone mineral density (BMD) in postmenopausal women in China suburban district. The prevalence of osteoporosis was 25.03 % at lumbar spine and 6.23 % at femoral neck, and BTMs were negatively correlated with BMDs.

  7. Parathyroid Hormone-Related Protein, Its Regulation of Cartilage and Bone Development, and Role in Treating Bone Diseases.

    Science.gov (United States)

    Martin, T John

    2016-07-01

    Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in many tissues, where its effects are context dependent. Thus its location and action in the vasculature explained decades-long observations that injection of PTH into animals rapidly lowered blood pressure by producing vasodilatation. Its roles have been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodeling, respectively. Although it shares actions with parathyroid hormone (PTH) through the use of their common receptor, PTHR1, PTHrP has other actions mediated by regions within the molecule beyond the amino-terminal sequence that resembles PTH, including the ability to promote placental transfer of calcium from mother to fetus. A striking feature of the physiology of PTHrP is that it possesses structural features that equip it to be transported in and out of the nucleus, and makes use of a specific nuclear import mechanism to do so. Evidence from mouse genetic experiments shows that PTHrP generated locally in bone is essential for normal bone remodeling. Whereas the main physiological function of PTH is the hormonal regulation of calcium metabolism, locally generated PTHrP is the important physiological mediator of bone remodeling postnatally. Thus the use of intermittent injection of PTH as an anabolic therapy for bone appears to be a pharmacological application of the physiological function of PTHrP. There is much current interest in the possibility of developing PTHrP analogs that might enhance the therapeutic anabolic effects. Copyright © 2016 the American Physiological Society.

  8. Deletion of the Distal Tnfsf11 RL-D2 Enhancer That Contributes to PTH-Mediated RANKL Expression in Osteoblast Lineage Cells Results in a High Bone Mass Phenotype in Mice.

    Science.gov (United States)

    Onal, Melda; St John, Hillary C; Danielson, Allison L; Pike, J Wesley

    2016-02-01

    Receptor activator of nuclear factor-κB ligand (RANKL) is a tumor necrosis factor (TNF)-like cytokine that is necessary for osteoclast formation and survival. Elevated RANKL synthesis is associated with both increased osteoclast number and bone resorption. Earlier studies identified an enhancer 76 kb upstream of the Tnfsf11 transcriptional start site (TSS) termed RL-D5 or the distal control region (DCR) that modulates RANKL expression in response to PTH, 1,25(OH)2D3,, and an array of cytokines. Mice lacking RL-D5 exhibit high bone mass associated with decreased RANKL expression in bone, spleen, and thymus. In addition to RL-D5, genome-wide studies have identified 9 additional Tnfsf11 enhancers residing upstream of the gene's TSS, which provide RANKL cell type-specificity and responsiveness to local and systemic factors. ChIP-chip analyses has revealed inducible vitamin D receptor (VDR) and cAMP response element-binding protein (CREB) binding at an enhancer termed RL-D2 23 kb upstream of the Tnfsf11 TSS in osteoblastic ST2 cells. Herein, we use ChIP-seq analyses to confirm this finding and then delete this enhancer from the mouse genome to determine its physiological role in vivo. RL-D2(-/-) primary stromal cells showed decreased RANKL-induction by both forskolin and 1,25(OH)2D3 ex vivo. Consistent with this, the parathyroid hormone (PTH) induction of RANKL expression was significantly blunted in RL-D2(-/-) mice in vivo. In contrast, lack of RL-D2 had no effect on 1,25(OH)2D3 induction of RANKL in vivo. Similar to the results found in RL-D5(-/-) mice, lack of RL-D2 led to decreased skeletal RANKL expression, resulting in decreased osteoclast numbers and a progressive increase in bone mineral density. Lack of RL-D2 increased cancellous bone mass in femur and spine but did not alter femoral cortical bone thickness. These results highlight the role of distal enhancers in the regulation of RANKL expression by PTH and perhaps 1,25(OH)2D3 and suggest that the RL-D2 and

  9. Anabolic Action Of Bovine Parathyroid Hormone In Male Rats ...

    African Journals Online (AJOL)

    Anabolic Action Of Bovine Parathyroid Hormone In Male Rats. ... bovine parathyroid hormone (bPTH) and to throw more lights on the mechanisms of these ... DNA, RNA and activities of some lipogenic enzymes such as ATP-citrate lyase, malic ...

  10. Acute and chronic regulation of circulating PTH: significance in health and in disease.

    Science.gov (United States)

    D'Amour, Pierre

    2012-08-01

    Circulating human parathyroid hormone (PTH) is immunoheterogenous. It is composed of 80% carboxyl-terminal (C) fragments and of 20% PTH(1-84). This composition contrasts with the biological activity of the hormone, which is only related to PTH(1-84), creating a paradox between circulating PTH composition and PTH bioactivity. PTH molecular forms are either secreted by the parathyroid glands or generated by the peripheral metabolism of PTH(1-84) in the liver. The kidney has a major role in the disposal of C-PTH fragments. Secretion of PTH molecular forms by the parathyroid glands is highly regulated under a variety of clinical conditions, suggesting that C-PTH fragments could exert some biological effects of their own. Recent data suggest that C-PTH fragments can exert biological actions opposite to those of PTH(1-84) by acting on a C-PTH receptor not yet cloned. They can decrease calcium concentration, phosphate excretion, bone resorption and 1,25(OH)₂ synthesis. The clinical implications of this new concept are reviewed.

  11. Gene structure, transcripts and calciotropic effects of the PTH family of peptides in Xenopus and chicken

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    Power Deborah M

    2010-12-01

    Full Text Available Abstract Background Parathyroid hormone (PTH and PTH-related peptide (PTHrP belong to a family of endocrine factors that share a highly conserved N-terminal region (amino acids 1-34 and play key roles in calcium homeostasis, bone formation and skeletal development. Recently, PTH-like peptide (PTH-L was identified in teleost fish raising questions about the evolution of these proteins. Although PTH and PTHrP have been intensively studied in mammals their function in other vertebrates is poorly documented. Amphibians and birds occupy unique phylogenetic positions, the former at the transition of aquatic to terrestrial life and the latter at the transition to homeothermy. Moreover, both organisms have characteristics indicative of a complex system in calcium regulation. This study investigated PTH family evolution in vertebrates with special emphasis on Xenopus and chicken. Results The PTH-L gene is present throughout the vertebrates with the exception of placental mammals. Gene structure of PTH and PTH-L seems to be conserved in vertebrates while PTHrP gene structure is divergent and has acquired new exons and alternative promoters. Splice variants of PTHrP and PTH-L are common in Xenopus and chicken and transcripts of the former have a widespread tissue distribution, although PTH-L is more restricted. PTH is widely expressed in fish tissue but from Xenopus to mammals becomes largely restricted to the parathyroid gland. The N-terminal (1-34 region of PTH, PTHrP and PTH-L in Xenopus and chicken share high sequence conservation and the capacity to modify calcium fluxes across epithelia suggesting a conserved role in calcium metabolism possibly via similar receptors. Conclusions The parathyroid hormone family contains 3 principal members, PTH, PTHrP and the recently identified PTH-L. In teleosts there are 5 genes which encode PTHrP (2, PTH (2 and PTH-L and in tetrapods there are 3 genes (PTHrP, PTH and PTH-L, the exception is placental mammals which

  12. Parathyroid hormone administration improves bone marrow microenvironment and partially rescues haematopoietic defects in Bmi1-null mice.

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    Ruinan Lu

    Full Text Available The epigenetic regulator Bmi1 is key in haematopoietic stem cells, and its inactivation leads to defects in haematopoiesis. Parathyroid hormone (PTH, an important modulator of bone homeostasis, also regulates haematopoiesis, so we asked whether PTH administration improves bone marrow microenvironment and rescues the haematopoietic defects in Bmi1-null mice. The mice were treated with PTH1-34 (containing the first 34 residues of mature PTH, an anabolic drug currently used for treating osteoporosis, and compared with the vehicle-treated Bmi1-/- and wild-type littermates in terms of skeletal and haematopoietic phenotypes. We found that the administration significantly increased all parameters related to osteoblastic bone formation and significantly reduced the adipocyte number and PPARγ expression. The bone marrow cellularity, numbers of haematopoietic progenitors and stem cells in the femur, and numbers of lymphocytes and other white blood cells in the peripheral blood all increased significantly when compared to vehicle-treated Bmi1-/- mice. Moreover, the number of Jagged1-positive cells and percentage of Notch intracellular domain-positive bone marrow cells and protein expression levels of Jagged1 and NICD in bone tissue were also increased in Bmi1-/- mice upon PTH1-34 administration,whereas the up-regulation of PTH on both Notch1 and Jagged1 gene expression was blocked by the Notch inhibitor DAPT administration. These results thus indicate that PTH administration activates the notch pathway and partially rescues haematopoietic defects in Bmi1-null mice, further suggesting that haematopoietic defects in the animals are not only a result of reduced self-renewal of haematopoietic stem cells but also due to impaired bone marrow microenvironment.

  13. Anabolic steroids.

    Science.gov (United States)

    Brower, K J

    1993-03-01

    Anabolic-androgenic steroids are controlled substances that are taken illicitly to enhance physical appearance and performance. In addition to the desired somatic effects, reasonably good evidence suggests that AASs are capable of influencing mood and behavior. A myriad of adverse effects have been reported. Although many of these effects appear to reverse with cessation of use, fatalities due to suicides, homicides, liver disease, heart attacks, and cancer have been reported infrequently among illicit users. Although studies are needed to quantify more precisely the long-term consequences and risks of using AASs, patterns of illicit use are particularly troublesome. The use of extremely high doses, needles, counterfeit and veterinary drugs, and multiple steroidal and nonsteroidal drugs simultaneously may further enhance the risks of using AASs. The clinician should suspect AAS use in high-risk individuals who manifest any of the possible consequences described in this article. Laboratory tests can be valuable for detection of use and assessment of consequences. Treatment approaches may borrow from proven techniques employed with other substance abusers, but should also address the special value that physical attributes and body image have for the AAS user.

  14. New anabolic therapies for osteoporosis.

    Science.gov (United States)

    Minisola, Salvatore; Cipriani, Cristiana; Occhiuto, Marco; Pepe, Jessica

    2017-08-05

    Osteoporosis is characterized by low bone mass and qualitative structural abnormalities of bone tissue, leading to increased bone fragility that results in fractures. Pharmacological therapy is aimed at decreasing the risk of fracture, mainly correcting the imbalance between bone resorption and formation at the level of bone remodeling units. Anabolic therapy has the capability to increase bone mass to a greater extent than traditional antiresorptive agents. The only currently available drug licensed is parathyroid hormone 1-34 (teriparatide); new drugs are on the horizon, targeting the stimulation of bone formation, and therefore improving bone mass, structure and ultimately skeletal strength. These are represented by abaloparatide (a 34-amino acid peptide which incorporates critical N-terminal residues, shared by parathyroid hormone and parathyroid hormone-related protein, followed by sequences unique to the latter protein) and romosozumab (an antibody to sclerostin). In the future, the availability of new anabolic treatment will allow a more extensive utilization of additive and sequential approach, with the goal of both prolonging the period of treatment and, more importantly, avoiding the side effects consequent to long-term use of traditional drugs.

  15. Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor.

    Science.gov (United States)

    Dean, Thomas; Vilardaga, Jean-Pierre; Potts, John T; Gardella, Thomas J

    2008-01-01

    PTH and PTHrP use the same G protein-coupled receptor, the PTH/PTHrP receptor (PTHR), to mediate their distinct biological actions. The extent to which the mechanisms by which the two ligands bind to the PTHR differ is unclear. We examined this question using several pharmacological and biophysical approaches. Kinetic dissociation and equilibrium binding assays revealed that the binding of [(125)I]PTHrP(1-36) to the PTHR was more sensitive to GTPgammaS (added to functionally uncouple PTHR-G protein complexes) than was the binding of [(125)I]PTH(1-34) ( approximately 75% maximal inhibition vs. approximately 20%). Fluorescence resonance energy transfer-based kinetic analyses revealed that PTHrP(1-36) bound to the PTHR more slowly and dissociated from it more rapidly than did PTH(1-34). The cAMP signaling response capacity of PTHrP(1-36) in cells decayed more rapidly than did that of PTH(1-34) (t(1/2) = approximately 1 vs. approximately 2 h). Divergent residue 5 in the ligand, Ile in PTH and His in PTHrP, was identified as a key determinant of the altered receptor-interaction responses exhibited by the two peptides. We conclude that whereas PTH and PTHrP bind similarly to the G protein-coupled PTHR conformation (RG), PTH has a greater capacity to bind to the G protein-uncoupled conformation (R(0)) and, hence, can produce cumulatively greater signaling responses (via R(0)-->RG isomerization) than can PTHrP. Such conformational selectivity may relate to the distinct modes by which PTH and PTHrP act biologically, endocrine vs. paracrine, and may help explain reported differences in the effects that the ligands have on calcium and bone metabolism when administered to humans.

  16. PTH1 receptor is involved in mediating cellular response to long-chain polyunsaturated fatty acids.

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    Jose Candelario

    Full Text Available The molecular pathways by which long chain polyunsaturated fatty acids (LCPUFA influence skeletal health remain elusive. Both LCPUFA and parathyroid hormone type 1 receptor (PTH1R are known to be involved in bone metabolism while any direct link between the two is yet to be established. Here we report that LCPUFA are capable of direct, PTH1R dependent activation of extracellular ligand-regulated kinases (ERK. From a wide range of fatty acids studied, varying in chain length, saturation, and position of double bonds, eicosapentaenoic (EPA and docosahexaenoic fatty acids (DHA caused the highest ERK phosphorylation. Moreover, EPA potentiated the effect of parathyroid hormone (PTH(1-34 in a superagonistic manner. EPA or DHA dependent ERK phosphorylation was inhibited by the PTH1R antagonist and by knockdown of PTH1R. Inhibition of PTH1R downstream signaling molecules, protein kinases A (PKA and C (PKC, reduced EPA and DHA dependent ERK phosphorylation indicating that fatty acids predominantly activate G-protein pathway and not the β-arrestin pathway. Using picosecond time-resolved fluorescence microscopy and a genetically engineered PTH1R sensor (PTH-CC, we detected conformational responses to EPA similar to those caused by PTH(1-34. PTH1R antagonist blocked the EPA induced conformational response of the PTH-CC. Competitive binding studies using fluorescence anisotropy technique showed that EPA and DHA competitively bind to and alter the affinity of PTH1 receptor to PTH(1-34 leading to a superagonistic response. Finally, we showed that EPA stimulates protein kinase B (Akt phosphorylation in a PTH1R-dependent manner and affects the osteoblast survival pathway, by inhibiting glucocorticoid-induced cell death. Our findings demonstrate for the first time that LCPUFAs, EPA and DHA, can activate PTH1R receptor at nanomolar concentrations and consequently provide a putative molecular mechanism for the action of fatty acids in bone.

  17. Anabolic Effect of Insulin Therapy on the Bone: Osteoprotegerin and Osteocalcin Up-Regulation in Streptozotocin-Induced Diabetic Rats.

    Science.gov (United States)

    Bortolin, Raul Hernandes; Freire Neto, Francisco Paulo; Arcaro, Carlos Alberto; Bezerra, João Felipe; da Silva, Flávio Santos; Ururahy, Marcela Abbott Galvão; Souza, Karla Simone da Costa; Lima, Valeria Morgiana Gualberto Duarte Moreira; Luchessi, André Ducati; Lima, Francisco Pignataro; Lia Fook, Marcus Vinicius; da Silva, Bartolomeu Jorge; Almeida, Maria das Graças; Abreu, Bento João; de Rezende, Luciana Augusto; de Rezende, Adriana Augusto

    2017-03-01

    Type 1 diabetes mellitus (T1DM) is associated with several skeletal alterations, particularly in conditions of poor glycaemic control. Insulin therapy is the major conservative treatment for T1DM; however, the effects of this hormone on bone markers of T1DM rats are limited, and the regulatory mechanisms remain elusive. Therefore, the evaluation of molecular and non-molecular parameters in a chronic animal model of T1DM-induced bone loss, treated with and without insulin, may help in elucidating the insulin mechanisms. Male Wistar rats were assigned into three groups: control, T1DM (T1DM rats induced with streptozotocin [STZ] at 40 mg/kg intravenously) and T1DM plus insulin therapy (T1DMI). After 8 weeks, we evaluated the serum biochemical, tibia histomorphometric and biomechanical parameters, as well as the gene expression of the receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and osteocalcin (OC) of femur mRNA. Compared with T1DM, the T1DMI group showed less bone loss, which was revealed by the increased trabecular width (TbWi, p insulin, which was demonstrated by the maintenance of bone architecture and flexibility. These results suggest that insulin therapy may prevent T1DM-induced bone loss via the effects on the bone formation.

  18. Characterization of a new fish-derived bioactive neuropeptide involved in bone remodelling. Its physiological function and therapeutic potential.

    Directory of Open Access Journals (Sweden)

    Paula Suarez-Bregua

    2014-04-01

    Full Text Available A complex network of autocrine and paracrine signals, hormones and neuronal factors preserve the structural integrity of the skeleton and regulate mineral metabolism in vertebrates. We have characterized a new neuropeptide belonging to parathyroid hormone (PTH family. PTH family members are known to play a key role in maintaining mineral homeostasis, bone remodeling and in regulating embryonic development of skeleton and other tissues. This new neuropeptide is synthesized by two clusters of neurons located in lateral hypothalamus as showed in whole mount in situ hybridization. The functional characterization of the gene using a stable transgenic line revealed its key role in the regulation of bone mineral density. Moreover, phylogenetic analyses and comparative genomics results of conserved synteny reveal that this new neuropeptide is a new ohnolog of the PTH family present in teleosts and some tetrapods like chicken, but absent in mammals . Our findings suggest a new brain to bone pathway, where neuronal factors from hypothalamus signal to receptors on bone cells promoting bone remodeling. Further investigations about this new neuropeptide system would be relevant for developing therapies for bone mineral disorders in humans, since this neuropeptide has a conserved domain similar to other PTH-related peptides which have anabolic effects on bone.

  19. Zinc enhances bone metabolism in ovariectomized rats and exerts anabolic osteoblastic/adipocytic marrow effects ex vivo.

    Science.gov (United States)

    Li, Binbin; Liu, Hao; Jia, Shengnan

    2015-02-01

    Investigations of bone mass and marrow adiposity are critical for defining the role of zinc (Zn) in bone metabolism. Rats used for study were grouped as follows: control (sham), ovariectomy (OVX), ovariectomy + estradiol (OVX-E), ovariectomy + Zn treatment (OVX-Zn). Bone mineral density (BMD) was quantified (microCT); serum osteocalcin, adiponectin, RANKL, and TRAP levels were assayed (ELISA); and biochemical determinations of serum alkaline phosphatase (ALP), calcium (Ca), and phosphorus (P) were done. Cells derived from bone mesenchymal stem cell (BMSC) isolates of respective test groups were compared, identifying primary osteoblasts by MTT assay and adipocytes by Oil Red O stain. Osteocalcin and adiponectin levels in culture supernatants were determined by ELISA. Zn supplementation resulted in a modest increase in BMD, but serum osteocalcin and ALP activity increased significantly (P < 0.01, both). Serum levels of RANKL and TRAP were lower in OVX-Zn (vs OVX) rats (P < 0.01), whereas serum concentrations of adiponectin, Ca, and P did not differ by group. Osteocalcin level was significantly upregulated ex vivo (P < 0.01) in the supernatant of cultured OVX-Zn (vs OVX) cells, accompanied by a slight upturn in osteoblastic differentiation. However, Oil Red O uptake and adiponectin level in supernatant were sharply diminished in cultured OVX-Zn (vs OVX) cells (P < 0.01). Overall, we concluded that Zn contributes to bone mass by marginally stimulating differentiation and proliferation of osteoblasts and by effectively inhibiting osteoclastic and adipocytic differentiation of BMSCs.

  20. One year of abaloparatide, a selective peptide activator of the PTH1 receptor, increased bone mass and strength in ovariectomized rats.

    Science.gov (United States)

    Varela, Aurore; Chouinard, Luc; Lesage, Elisabeth; Guldberg, Robert; Smith, Susan Y; Kostenuik, Paul J; Hattersley, Gary

    2017-02-01

    Abaloparatide is a novel 34 amino acid peptide selected to be a potent and selective activator of the parathyroid hormone receptor 1 (PTHR1) signaling pathway. The effects of 12months of abaloparatide treatment on bone mass, bone strength and bone quality was assessed in osteopenic ovariectomized (OVX) rats. SD rats were subjected to OVX or sham surgery at 6months of age and left untreated for 3months to allow OVX-induced bone loss. Eighteen OVX rats were sacrificed after this bone depletion period, and the remaining OVX rats received daily s.c. injections of vehicle (n=18) or abaloparatide at 1, 5 or 25μg/kg/d (n=18/dose level) for 12months. Sham controls (n=18) received vehicle daily. Bone changes were assessed by DXA and pQCT after 0, 3, 6 or 12months of treatment, and destructive biomechanical testing was conducted at month 12 to assess bone strength and bone quality. Abaloparatide dose-dependently increased bone mass at the lumbar spine and at the proximal and diaphyseal regions of the tibia and femur. pQCT revealed that increased cortical bone volume at the tibia was a result of periosteal expansion and endocortical bone apposition. Abaloparatide dose-dependently increased structural strength of L4-L5 vertebral bodies, the femur diaphysis, and the femur neck. Increments in peak load for lumbar spine and the femur diaphysis of abaloparatide-treated rats persisted even after adjusting for treatment-related increments in BMC, and estimated material properties were maintained or increased at the femur diaphysis with abaloparatide. The abaloparatide groups also exhibited significant and positive correlations between bone mass and bone strength at these sites. These data indicate that gains in cortical and trabecular bone mass with abaloparatide are accompanied by and correlated with improvements in bone strength, resulting in maintenance or improvement in bone quality. Thus, this study demonstrated that long-term daily administration of abaloparatide to

  1. Deletion of PTH rescues skeletal abnormalities and high osteopontin levels in Klotho-/- mice.

    Directory of Open Access Journals (Sweden)

    Quan Yuan

    Full Text Available Maintenance of normal mineral ion homeostasis is crucial for many biological activities, including proper mineralization of the skeleton. Parathyroid hormone (PTH, Klotho, and FGF23 have been shown to act as key regulators of serum calcium and phosphate homeostasis through a complex feedback mechanism. The phenotypes of Fgf23(-/- and Klotho(-/- (Kl(-/- mice are very similar and include hypercalcemia, hyperphosphatemia, hypervitaminosis D, suppressed PTH levels, and severe osteomalacia/osteoidosis. We recently reported that complete ablation of PTH from Fgf23(-/- mice ameliorated the phenotype in Fgf23(-/-/PTH(-/- mice by suppressing serum vitamin D and calcium levels. The severe osteomalacia in Fgf23(-/- mice, however, persisted, suggesting that a different mechanism is responsible for this mineralization defect. In the current study, we demonstrate that deletion of PTH from Kl(-/- (Kl(-/-/PTH(-/- or DKO mice corrects the abnormal skeletal phenotype. Bone turnover markers are restored to wild-type levels; and, more importantly, the skeletal mineralization defect is completely rescued in Kl(-/-/PTH(-/- mice. Interestingly, the correction of the osteomalacia is accompanied by a reduction in the high levels of osteopontin (Opn in bone and serum. Such a reduction in Opn levels could not be observed in Fgf23(-/-/PTH(-/- mice, and these mice showed sustained osteomalacia. This significant in vivo finding is corroborated by in vitro studies using calvarial osteoblast cultures that show normalized Opn expression and rescued mineralization in Kl(-/-/PTH(-/- mice. Moreover, continuous PTH infusion of Kl(-/- mice significantly increased Opn levels and osteoid volume, and decreased trabecular bone volume. In summary, our results demonstrate for the first time that PTH directly impacts the mineralization disorders and skeletal deformities of Kl(-/-, but not of Fgf23(-/- mice, possibly by regulating Opn expression. These are significant new perceptions into

  2. The C-terminal fragment of parathyroid hormone-related peptide promotes bone formation in diabetic mice with low-turnover osteopaenia

    Science.gov (United States)

    Lozano, D; Fernández-de-Castro, L; Portal-Núñez, S; López-Herradón, A; Dapía, S; Gómez-Barrena, E; Esbrit, P

    2011-01-01

    BACKGROUND AND PURPOSE Current data suggest that parathyroid hormone (PTH)-related peptide (PTHrP) domains other than the N-terminal PTH-like domain contribute to its role as an endogenous bone anabolic factor. PTHrP-107-139 inhibits bone resorption, a fact which has precluded an unequivocal demonstration of its possible anabolic action in vivo. We thus sought to characterize the osteogenic effects of this peptide using a mouse model of diabetic low-turnover osteopaenia. EXPERIMENTAL APPROACH PTHrP-107-139 was administered to streptozotocin-induced diabetic mice, with or without bone marrow ablation, for 13 days. Osteopaenia was confirmed by dual-energy X-ray absorptiometry and microcomputed tomography analysis. Histological analysis was performed on paraffin-embedded bone tissue sections by haematoxylin/eosin and Masson's staining, and tartrate-resistent acid phosphatase immunohistochemistry. Mouse bone marrow stromal cells and osteoblastic MC3T3-E1 cells were cultured in normal and/or high glucose (HG) medium. Osteogenic and adipogenic markers were assessed by real-time PCR, and PTHrP and the PTH1 receptor protein expression by Western blot analysis. KEY RESULTS PTHrP-107-139 reversed the alterations in bone structure and osteoblast function, and also promoted bone healing after marrow ablation without affecting the number of osteoclast-like cells in diabetic mice. This peptide also reversed the high-glucose-induced changes in osteogenic differentiation in both bone marrow stromal cells and the more differentiated MC3T3-E1 cells. CONCLUSIONS AND IMPLICATIONS These findings demonstrate that PTHrP-107-139 promotes bone formation in diabetic mice. This mouse model and in vitro cell cultures allowed us to identify various anabolic effects of this peptide in this scenario. PMID:21175568

  3. PTH [1-34]-induced alterations predispose the mandibular condylar cartilage to mineralization.

    Science.gov (United States)

    Dutra, E H; O'Brien, M H; Gutierrez, T; Lima, A; Nanda, R; Yadav, S

    2017-06-01

    To study the effects of intermittent parathyroid hormone (PTH [1-34]) on the mandibular condylar cartilage (MCC) and subchondral bone in adult female mice. Twenty-two, 20-week-old female mice were used for in vivo experiments. The experimental mice (n=11) received daily intraperitoneal injections of PTH [1-34] for 3 weeks, while control mice (n=11) received intraperitoneal injections of 0.9% saline solution. Mice were euthanized and then micro-computed tomography (micro-CT); histology and immunostaining were carried out to assess the response. Intermittent PTH [1-34] led to early MCC breakdown and surface irregularities. Micro-CT analyses indicated that PTH [1-34] treatment led to increased bone volume fraction, tissue density and trabecular thickness, while decreasing the trabecular spacing. Histological analyses showed decreased proteoglycan secretion, increased bone turnover (TRAP staining) and increased mineralization. Furthermore, PTH [1-34] treatment showed increased apoptosis of the cells. Our immunohistochemistry showed increased expression of pSMAD158 in the MCC and subchondral bone with PTH administration, whereas sclerostin (SOST) expression was decreased. Intermittent PTH [1-34] results in early mineralization of the MCC, which may result in cartilage degeneration. Our results identified a novel mechanism by which PTH [1-34] induces alteration in the microarchitecture of the MCC and the subchondral bone. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Effect of Alendronate on Bone Formation during Tooth Extraction Wound Healing.

    Science.gov (United States)

    Tanoue, R; Koi, K; Yamashita, J

    2015-09-01

    Alendronate (ALN) is an antiresorptive agent widely used for the treatment of osteoporosis. Its suppressive effect on osteoclasts has been extensively studied. However, the effect of ALN on bone formation is not as clear as its effect on resorption. The objective was to determine the effect of short-term ALN on bone formation and tooth extraction wound healing. Molar tooth extractions were performed in mice. ALN, parathyroid hormone (PTH), or saline (vehicle control) was administered. PTH was used as the bone anabolic control. Mice were euthanized at 3, 5, 7, 10, and 21 d after extractions. Hard tissue healing was determined histomorphometrically. Neutrophils and lymphatic and blood vessels were quantified to evaluate soft tissue healing. Gene expression in the wounds was assessed at the RNA level. Furthermore, the vossicle bone transplant system was used to verify findings from extraction wound analysis. Alkaline phosphatase (ALP) was visualized in the vossicles to assess osteoblast activity. ALN exhibited no negative effect on bone formation. In intact tibiae, ALN increased bone mass significantly more than PTH did. Consistently, significantly elevated osteoblast numbers were noted. In the extraction sockets, bone fill in the ALN-treated mice was equivalent to the control. Genes associated with bone morphogenetic protein signaling, such as bmp2, nog, and dlx5, were activated in the extraction wounds of the ALN-treated animals. Bone formation in vossicles was significantly enhanced in the ALN versus PTH group. In agreement with this, ALN upregulated ALP activity considerably in vossicles. Neutrophil aggregation and suppressed lymphangiogenesis were evident in the soft tissue at 21 d after extraction, although gross healing of extraction wounds was uneventful. Bone formation was not impeded by short-term ALN treatment. Rather, short-term ALN treatment enhanced bone formation. ALN did not alter bone fill in extraction sockets.

  5. Functional characterization and evolution of PTH/PTHrP receptors: insights from the chicken

    Directory of Open Access Journals (Sweden)

    Pinheiro Pedro LC

    2012-07-01

    Full Text Available Abstract Background The parathyroid hormone (PTH-family consists of a group of structurally related factors that regulate calcium and bone homeostasis and are also involved in development of organs such as the heart, mammary gland and immune system. They interact with specific members of family 2 B1 G-protein coupled receptors (GPCRs, which have been characterised in teleosts and mammals. Two PTH/PTHrP receptors, PTH1R and PTH2R exist in mammals and in teleost fish a further receptor PTH3R has also been identified. Recently in chicken, PTH-family members involved in calcium transport were characterized and specific PTHRs are suggested to exist although they have not yet been isolated or functionally characterized. The aim of this study is to further explore the evolution and function of the vertebrate PTH/PTHrP system through the isolation, phylogenetic analysis and functional characterization of the chicken receptors. Results Two PTHRs were isolated in chicken and sequence comparison and phylogenetic analysis indicate that the chicken receptors correspond to PTH1R and PTH3R, which emerged prior to the teleost/tetrapod divergence since they are present in cartilaginous fish. The vertebrate PTH2R receptor and its ligand TIP39 have been lost from bird genomes. Chicken PTH1R and PTH3R have a divergent and widespread tissue expression and are also evident in very early embryonic stages of development. Receptor stimulation studies using HEK293 cells stably expressing the chicken PTH1R and PTH3R and monitoring cAMP production revealed they are activated by chicken 1–34 N-terminal PTH-family peptides in a dose dependent manner. PTH-L and PTHrP were the most effective peptides in activating PTH1R (EC50 = 7.7 nM and EC50 = 22.7 nM, respectively. In contrast, PTH-L (100 nM produced a small cAMP accumulation on activation of PTH3R but PTHrP and PTH (EC50 = 2.5 nM and EC50 = 22.1 nM, respectively readily activated the receptor. PTHr

  6. Vitamin D Binding Protein Genotype Is Associated with Serum 25-Hydroxyvitamin D and PTH Concentrations, as Well as Bone Health in Children and Adolescents in Finland

    DEFF Research Database (Denmark)

    Pekkinen, Minna; Saarnio, Elisa; Viljakainen, Heli T.

    2014-01-01

    fracture risk. We examined the role of GC genotypes in S-25(OH)D status and BMD in 231 Finnish children and adolescents aged 7-19 yr. BMD was measured with DXA from lumbar spine (LS), total hip, and whole body, and for 175 subjects, radial volumetric BMD was measured with pQCT. Background characteristic.......012, respectively). Total hip bone mineral content was associated with GC genotype (BMC) (p = 0.05, ANCOVA) in boys. In regression analysis, after adjusting for relevant covariates, GC genotype was associated with LS BMC and strength and strain index (SSI) Z-score in both genders, and LS BMD in boys. In conclusion...

  7. Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats

    Energy Technology Data Exchange (ETDEWEB)

    Gilmour, Peter S., E-mail: Peter.Gilmour@astrazeneca.com [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); O' Shea, Patrick J.; Fagura, Malbinder [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Pilling, James E. [Discovery Sciences, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Sanganee, Hitesh [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Wada, Hiroki [R and I IMed, AstraZeneca R and D, Molndal (Sweden); Courtney, Paul F. [DMPK, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Kavanagh, Stefan; Hall, Peter A. [Safety Assessment, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Escott, K. Jane [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom)

    2013-10-15

    Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/μCT imaging. GSK-3 inhibitors caused β-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure in rats. After 7 days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH{sub 1–34} or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/μCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption. - Highlights: • Wnt modulation with 3 novel GSK-3 inhibitors alters bone growth. • Human stem cell osteoblastogenesis

  8. Effects of increasing age, dosage, and duration of PTH treatment on BMD increase--a meta-analysis

    DEFF Research Database (Denmark)

    Schwarz, Peter; Jorgensen, Niklas Rye; Mosekilde, Leif;

    2012-01-01

    We studied the effects of increasing age, dosage, and duration of parathyroid hormone (PTH) treatment on changes in bone mineral density (BMD). Randomized placebo controlled trials on PTH treatment in men or women were retrieved from PubMed (1951 to present), Web of Science (1945 to present...

  9. Acetate free citrate-containing dialysate increase intact-PTH and BAP levels in the patients with low intact-PTH

    Directory of Open Access Journals (Sweden)

    Kuragano Takahiro

    2013-01-01

    Full Text Available Abstract Background Recently, acetate-free citrate containing dialysate (A(−D was developed. We have already reported about the significant effect of A(−D on metabolic acidosis, anemia, and malnutrition in maintenance hemodialysis (MHD patients. In this study, we compared the effect of A(−D and acetate containing dialysate (A(+D on serum calcium and intact-parathyroid hormone (int-PTH levels. Method Single session study: Seventeen patients were treated with A(+D in one session and also treated with A(−D in another session. Serum levels of pH, HCO3-, total (t-calcium, ionized (i-calcium, and int-PTH were evaluated at the beginning and the end of each session. Cross over study: A total of 29 patients with MHD were treated with A(+D for 4 months, switched to A(−D for next 4 months, and returned to A(+D for the final 4 months. Results In single session study, serum i-calcium and t-calcium levels significantly increased, and int-PTH levels decreased after HD with A(+D, whereas HD with A(−D did not affect iCa and int-PTH. In cross over study, if all patients were analyzed, there was no significant difference in serum int-PTH or bone alkaline phosphatase (BAP levels during each study period. In contrast, in the patients with low int-PTH ( Conclusion A(−D containing citrate could affect calcium and PTH levels, and, in 4 month period of crossover study, increased int-PTH levels pararelled with increasing BAP levels, exclusively in MHD patients with low int-PTH levels.

  10. Unfocused extracorporeal shock waves induce anabolic effects in osteoporotic rats

    NARCIS (Netherlands)

    van der Jagt, Olav P.; Waarsing, Jan H.; Kops, Nicole; Schaden, Wolfgang; Jahr, Holger; Verhaar, Jan A. N.; Weinans, Harrie

    2013-01-01

    Unfocused extracorporeal shock waves (UESW) have been shown to have an anabolic effect on bone mass. Therefore we investigated the effects of UESW on bone in osteoporotic rats with and without anti-resorptive treatment. Twenty-week-old rats were ovariectomized (n=27). One group was treated with sali

  11. Mind Over Matter: Anabolic Steroids

    Science.gov (United States)

    ... Medicine Doctors never prescribe anabolic steroids for building muscle in young, healthy people. (Try push-ups instead!) But doctors sometimes prescribe anabolic steroids to treat some types of anemia or disorders in ... don’t build muscles the way that anabolic steroids do, people don’ ...

  12. Pharmacology of anabolic steroids.

    Science.gov (United States)

    Kicman, A T

    2008-06-01

    Athletes and bodybuilders have recognized for several decades that the use of anabolic steroids can promote muscle growth and strength but it is only relatively recently that these agents are being revisited for clinical purposes. Anabolic steroids are being considered for the treatment of cachexia associated with chronic disease states, and to address loss of muscle mass in the elderly, but nevertheless their efficacy still needs to be demonstrated in terms of improved physical function and quality of life. In sport, these agents are performance enhancers, this being particularly apparent in women, although there is a high risk of virilization despite the favourable myotrophic-androgenic dissociation that many xenobiotic steroids confer. Modulation of androgen receptor expression appears to be key to partial dissociation, with consideration of both intracellular steroid metabolism and the topology of the bound androgen receptor interacting with co-activators. An anticatabolic effect, by interfering with glucocorticoid receptor expression, remains an attractive hypothesis. Behavioural changes by non-genomic and genomic pathways probably help motivate training. Anabolic steroids continue to be the most common adverse finding in sport and, although apparently rare, designer steroids have been synthesized in an attempt to circumvent the dope test. Doping with anabolic steroids can result in damage to health, as recorded meticulously in the former German Democratic Republic. Even so, it is important not to exaggerate the medical risks associated with their administration for sporting or bodybuilding purposes but to emphasize to users that an attitude of personal invulnerability to their adverse effects is certainly misguided.

  13. A comparison of parathyroid hormone-related protein (1-36) and parathyroid hormone (1-34) on markers of bone turnover and bone density in postmenopausal women: the PrOP study.

    Science.gov (United States)

    Horwitz, Mara J; Augustine, Marilyn; Khan, Leila; Kahn, Leila; Martin, Emily; Oakley, Christine C; Carneiro, Raquel M; Tedesco, Mary Beth; Laslavic, Angela; Sereika, Susan M; Bisello, Alessandro; Garcia-Ocaña, Adolfo; Gundberg, Caren M; Cauley, Jane A; Stewart, Andrew F

    2013-11-01

    Parathyroid hormone-related protein (PTHrP)(1-36) increases lumbar spine (LS) bone mineral density (BMD), acting as an anabolic agent when injected intermittently, but it has not been directly compared with parathyroid hormone (PTH)(1-34). We performed a 3-month randomized, prospective study in 105 postmenopausal women with low bone density or osteoporosis, comparing daily subcutaneous injections of PTHrP(1-36) to PTH(1-34). Thirty-five women were randomized to each of three groups: PTHrP(1-36) 400 µg/day; PTHrP(1-36) 600 µg/day; and PTH(1-34) 20 µg/day. The primary outcome measures were changes in amino-terminal telopeptides of procollagen 1 (PINP) and carboxy-terminal telopeptides of collagen 1 (CTX). Secondary measures included safety parameters, 1,25(OH)2 vitamin D, and BMD. The increase in bone resorption (CTX) by PTH(1-34) (92%) (p PTHrP(1-36) (30%) (p PTHrP(1-36) (46% and 87%). The increase in PINP was earlier (day 15) and greater than the increase in CTX for all three groups. LS BMD increased equivalently in each group (p PTHrP(1-36) (p PTHrP(1-36) 400 (p PTHrP(1-36) 400 induced mild, transient (day 15) hypercalcemia. PTHrP(1-36) 600 required a dose reduction for hypercalcemia in three subjects. PTH(1-34) was not associated with hypercalcemia. Each peptide induced a marked biphasic increase in 1,25(OH)2 D. Adverse events (AE) were similar among the three groups. This study demonstrates that PTHrP(1-36) and PTH(1-34) cause similar increases in LS BMD. PTHrP(1-36) also increased hip BMD. PTH(1-34) induced greater changes in bone turnover than PTHrP(1-36). PTHrP(1-36) was associated with mild transient hypercalcemia. Longer-term studies using lower doses of PTHrP(1-36) are needed to define both the optimal dose and full clinical benefits of PTHrP. © 2013 American Society for Bone and Mineral Research. © 2013 American Society for Bone and Mineral Research.

  14. Novel parathyroid hormone (PTH) antagonists that bind to the juxtamembrane portion of the PTH/PTH-related protein receptor.

    Science.gov (United States)

    Shimizu, Naoto; Dean, Thomas; Tsang, Janet C; Khatri, Ashok; Potts, John T; Gardella, Thomas J

    2005-01-21

    Current antagonists for the parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PTHR) are N-terminally truncated or N-terminally modified analogs of PTH(1-34) or PTHrP(1-34) and are thought to bind predominantly to the N-terminal extracellular (N) domain of the receptor. We hypothesized that ligands that bind only to PTHR region comprised of the extracellular loops and seven transmembrane helices (the juxtamembrane or J domain) could also antagonize the PTHR. To test this, we started with the J domain-selective agonists [Gln(10),Ala(12),Har(11),Trp(14),Arg(19) (M)]PTH(1-21), [M]PTH(1-15), and [M]PTH(1-14), and introduced substitutions at positions 1-3 that were predicted to dissociate PTHR binding and cAMP signaling activities. Strong dissociation was observed with the tri-residue sequence diethylglycine (Deg)(1)-para-benzoyl-l-phenylalanine (Bpa)(2)-Deg(3). In HKRK-B7 cells, which express the cloned human PTHR, [Deg(1,3),Bpa(2),M]PTH(1-21), [Deg(1,3),Bpa(2),M]PTH(1-15), and [Deg(1,3),Bpa(2),M]PTH(1-14) fully inhibited (IC(50)s = 100-700 nm) the binding of (125)I-[alpha-aminoisobutyric acid(1,3),M]PTH(1-15) and were severely defective for stimulating cAMP accumulation. In ROS 17/2.8 cells, which express the native rat PTHR, [Deg(1,3),Bpa(2),M]PTH(1-21) and [Deg(1,3),Bpa(2),M]PTH(1-15) antagonized the cAMP-agonist action of PTH(1-34), as did PTHrP(5-36) (IC(50)s = 0.7 microm, 2.6 microm, and 36 nm, respectively). In COS-7 cells expressing PTHR-delNt, which lacks the N domain of the receptor, [Deg(1,3),Bpa(2), M]PTH(1-21) and [Deg(1,3),Bpa(2),M]PTH(1-15) inhibited the agonist actions of [alpha-aminoisobutyric acid(1,3)]PTH(1-34) and [M]PTH(1-14) (IC(50)s approximately 1 microm), whereas PTHrP(5-36) failed to inhibit. [Deg(1,3),Bpa(2),M]PTH(1-14) inhibited the constitutive cAMP-signaling activity of PTHR-tether-PTH(1-9), in which the PTH(1-9) sequence is covalently linked to the PTHR J domain, as well as that of PTHR(cam)H223R. Thus, the J

  15. Parathyroid hormone versus bisphosphonate treatment on bone mineral density in osteoporosis therapy: a meta-analysis of randomized controlled trials.

    Directory of Open Access Journals (Sweden)

    Longxiang Shen

    Full Text Available BACKGROUND: Bisphosphonates and parathyroid hormone (PTH represent the antiresorptive and anabolic classes of drugs for osteoporosis treatment. Bone mineral density (BMD is an essential parameter for the evaluation of anti-osteoporotic drugs. The aim of this study was to evaluate the effects of PTH versus bisphosphonates on BMD for the treatment of osteoporosis. METHODS/PRINCIPAL FINDINGS: We performed a literature search to identify studies that investigated the effects of PTH versus bisphosphonates treatment on BMD. A total of 7 articles were included in this study, representing data on 944 subjects. The pooled data showed that the percent change of increased BMD in the spine is higher with PTH compared to bisphosphonates (WMD = 5.90, 95% CI: 3.69-8.10, p<0.01,. In the hip, high dose (40 µg PTH (1-34 showed significantly higher increments of BMD compared to alendronate (femoral neck: WMD = 5.67, 95% CI: 3.47-7.87, p<0.01; total hip: WMD = 2.40, 95%CI: 0.49-4.31, p<0.05. PTH treatment has yielded significantly higher increments than bisphosphonates with a duration of over 12 months (femoral neck: WMD = 5.67, 95% CI: 3.47-7.86, p<0.01; total hip: WMD = 2.40, 95% CI: 0.49-4.31, P<0.05 and significantly lower increments at 12 months (femoral neck: WMD = -1.05, 95% CI: -2.26-0.16, p<0.01; total hip: WMD: -1.69, 95% CI: -3.05-0.34, p<0.05. In the distal radius, a reduction in BMD was significant between PTH and alendronate treatment. (WMD = -3.68, 95% CI: -5.57-1.79, p<0.01. DISCUSSION: Our results demonstrated that PTH significantly increased lumbar spine BMD as compared to treatment with bisphosphonates and PTH treatment induced duration- and dose-dependent increases in hip BMD as compared to bisphosphonates treatment. This study has also disclosed that for the distal radius, BMD was significantly lower from PTH treatment than alendronate treatment.

  16. [Dehydroepiandrosterone [DHEA(S)]: anabolic hormone?].

    Science.gov (United States)

    Luci, Michele; Valenti, Giorgio; Maggio, Marcello

    2010-09-01

    The role of dehydroepiandrosterone (DHEA) and its sulphated form (DHEAS) as anabolic hormones is still debated in the literature. In this review we describe the fundamental steps of DHEA physiological secretion and its peripheral metabolism. Moreover we will list all the observational and intervention studies conducted in humans. Many observational studies have tested the relationship between low DHEA levels and age-related changes in skeletal muscle and bone, while intervention studies underline the positive and significant effects of DHEA treatment on several parameters of body composition. Surprisingly, observational studies are not consistent with different effects in men and women. There is recent evidence of a significant role of DHEA in frailty syndrome and as predictor of mortality. However a more complete approach of the problem suggests the opportunity to not focus only on one single hormonal derangement but to analyze the parallel dysregulation of anabolic hormones including sex steroids, GH-IGF-1 system and other catabolic hormones.

  17. The effect of PTH(1-34) on fracture healing during different loading conditions

    DEFF Research Database (Denmark)

    Ellegaard, Maria; Kringelbach, Tina; Syberg, Susanne

    2013-01-01

    . Five days before fracture, half of the animals received Botulinum Toxin A injections in the muscles of the fractured leg to induce muscle paralysis (unloaded group), whereas the other half received saline injections (control group). For the following 8 weeks, half of the animals in each group received...... and control animals. PTH(1-34) treatment increased ultimate force of the fracture by 63% in both control and unloaded animals and no interaction of the two interventions could be detected. PTH(1-34) was able to stimulate bone formation in normally loaded as well as unloaded intact bone. In conclusion...

  18. 17β-Hydroxyestra-4,9,11-trien-3-one (trenbolone) exhibits tissue selective anabolic activity: effects on muscle, bone, adiposity, hemoglobin, and prostate.

    Science.gov (United States)

    Yarrow, Joshua F; Conover, Christine F; McCoy, Sean C; Lipinska, Judyta A; Santillana, Cesar A; Hance, John M; Cannady, Darryl F; VanPelt, Tisha D; Sanchez, Joshua; Conrad, Bryan P; Pingel, Jennifer E; Wronski, Thomas J; Borst, Stephen E

    2011-04-01

    Selective androgen receptor modulators (SARMs) now under development can protect against muscle and bone loss without causing prostate growth or polycythemia. 17β-Hydroxyestra-4,9,11-trien-3-one (trenbolone), a potent testosterone analog, may have SARM-like actions because, unlike testosterone, trenbolone does not undergo tissue-specific 5α-reduction to form more potent androgens. We tested the hypothesis that trenbolone-enanthate (TREN) might prevent orchiectomy-induced losses in muscle and bone and visceral fat accumulation without increasing prostate mass or resulting in adverse hemoglobin elevations. Male F344 rats aged 3 mo underwent orchiectomy or remained intact and were administered graded doses of TREN, supraphysiological testosterone-enanthate, or vehicle for 29 days. In both intact and orchiectomized animals, all TREN doses and supraphysiological testosterone-enanthate augmented androgen-sensitive levator ani/bulbocavernosus muscle mass by 35-40% above shams (P ≤ 0.001) and produced a dose-dependent partial protection against orchiectomy-induced total and trabecular bone mineral density losses (P testosterone-enanthate and high-dose TREN elevated prostate mass by 84 and 68%, respectively (P muscle and partial protection against orchiectomy-induced bone loss and visceral fat accumulation. Our findings indicate that TREN has advantages over supraphysiological testosterone and supports the need for future preclinical studies examining the viability of TREN as an option for androgen replacement therapy.

  19. A Comparison of Parathyroid Hormone-related Protein (1–36) and Parathyroid Hormone (1–34) on Markers of Bone Turnover and Bone Density in Postmenopausal Women: The PrOP Study

    Science.gov (United States)

    Horwitz, Mara J; Augustine, Marilyn; Kahn, Leila; Martin, Emily; Oakley, Christine C; Carneiro, Raquel M; Tedesco, Mary Beth; Laslavic, Angela; Sereika, Susan M; Bisello, Alessandro; Garcia-Ocaña, Adolfo; Gundberg, Caren M; Cauley, Jane A; Stewart, Andrew F

    2013-01-01

    Parathyroid hormone-related protein (PTHrP)(1–36) increases lumbar spine (LS) bone mineral density (BMD), acting as an anabolic agent when injected intermittently, but has not been directly compared to parathyroid hormone (PTH)(1–34). We performed a three month, randomized, prospective study in 105 postmenopausal women with low bone density or osteoporosis comparing daily subcutaneous injections of PTHrP(1–36) to PTH(1–34). Thirty-five women were randomized to each of three groups: PTHrP(1–36) 400 μg/d; PTHrP(1–36) 600 μg/d; and PTH(1–34) 20 μg/d. The primary outcomes measures were changes in amino-terminal telopeptides of procollagen 1 (PINP) and carboxy-terminal telopeptides of collagen 1 (CTX). Secondary measures included safety parameters, 1,25(OH)2vitamin D and BMD. The increase in bone resorption (CTX) by PTH(1–34) (92%) (pPTHrP(1–36) (30%) (pPTHrP(1–36) (46 & 87%). The increase in PINP was earlier (day 15) and greater than the increase in CTX for all three groups. LS BMD increased equivalently in each group (pPTHrP(1–36) (pPTHrP(1–36) 400 (pPTHrP(1–36) 400 induced mild, transient (day 15) hypercalcemia. PTHrP(1–36) 600 required a dose reduction for hypercalcemia in three subjects. PTH(1–34) was not associated with hypercalcemia. Each peptide induced a marked biphasic increase in 1,25(OH)2D. Adverse events (AE) were similar among the three groups. This study demonstrates that PTHrP(1–36) and PTH(1–34) cause similar increases in LS BMD. PTHrP(1–36) also increased hip BMD. PTH(1–34) induced greater changes in bone turnover than PTHrP(1–36). PTHrP(1–36) was associated with mild transient hypercalcemia. Longer term studies using lower doses of PTHrP(1–36) are needed to define both the optimal dose and full clinical benefits of PTHrP. PMID:23661240

  20. Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients

    DEFF Research Database (Denmark)

    Hocher, Berthold; Oberthür, Dominik; Slowinski, Torsten;

    2013-01-01

    Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies i...

  1. Anabolic Steroids as a Novel Therapeutic Strategy for the Prevention of Bone Loss after Spinal Cord Injury: Animal Model and Molecular Mechanism

    Science.gov (United States)

    2012-10-01

    mFc after SCI”. Ancillary Studies. During the first year and the early second year of the funding period, we discovered an unexpected...wells and cultured in α-MEM supplemented with 15% preselected FCS (Hyclone, Logan , UT, USA) and ascorbic acid-2-phosphate (1 mM). Incubation was...sectional study of bone turnover during bicalutamide monotherapy for prostate cancer. Urology 2003;61(1):127–31. 11 Wimalawansa SM, Chapa MT , Wei JN, Westlund

  2. ANABOLIC ANDROGENIC STEROIDS AND DEPENDENCE

    Directory of Open Access Journals (Sweden)

    IHSAN SARI

    2010-12-01

    Full Text Available Anabolic androgenic steroids are used for sportive, cosmetic, therapeutic and occupational reasons and there are many side effects reported (George, 2005; Nieminen et al., 1996; O'Sullivan et al., 2000. Prevalence of anabolic steroids’ use also indicates the importance of this topic. Moreover, it is now known that use of anabolic steroids could lead to dependence which could be psychological or/and physiological (Copeland et al., 2000. It isimportant to know about all aspects of anabolic steroids including dependence. Therefore, this study has attempted to give an insight into use of anabolic steroids and dependence. The discussion will focus on prevalence, reasons, and side effects of use and physiological and psychological dependence

  3. A semimechanistic model of the time-course of release of PTH into plasma following administration of the calcilytic JTT-305/MK-5442 in humans.

    Science.gov (United States)

    Cabal, Antonio; Mehta, Khamir; Ross, David S; Shrestha, Rajiv P; Comisar, Wendy; Denker, Andrew; Pai, Sudhakar M; Ishikawa, Tomohiro

    2013-08-01

    JTT-305/MK-5442 is a calcium-sensing receptor (CaSR) allosteric antagonist being investigated for the treatment of osteoporosis. JTT-305/MK-5442 binds to CaSRs, thus preventing receptor activation by Ca(2+) . In the parathyroid gland, this results in the release of parathyroid hormone (PTH). Sharp spikes in PTH secretion followed by rapid returns to baseline are associated with bone formation, whereas sustained elevation in PTH is associated with bone resorption. We have developed a semimechanistic, nonpopulation model of the time-course relationship between JTT-305/MK-5442 and whole plasma PTH concentrations to describe both the secretion of PTH and the kinetics of its return to baseline levels. We obtained mean concentration data for JTT-305/MK-5442 and whole PTH from a multiple dose study in U.S. postmenopausal women at doses of 5, 10, 15, and 20 mg. We hypothesized that PTH is released from two separate sources: a reservoir that is released rapidly (within minutes) in response to reduction in Ca(2+) binding, and a second source released more slowly following hours of reduced Ca(2+) binding. We modeled the release rates of these reservoirs as maximum pharmacologic effect (Emax ) functions of JTT-305/MK-5442 concentration. Our model describes both the dose-dependence of PTH time of occurrence for maximum drug concentration (Tmax ) and maximum concentration of drug (Cmax ), and the extent and duration of the observed nonmonotonic return of PTH to baseline levels following JTT-305/MK-5442 administration.

  4. Primary hyperparathyroidism: intraoperative PTH-measurements

    DEFF Research Database (Denmark)

    Rolighed, L; Heickendorff, L; Hessov, I

    2004-01-01

    measurement as a predictor of successful cure. MATERIAL AND METHODS: From September 1999 to April 2002 143 patients with pHPT underwent a parathyroid operation (bilateral neck exploration with identification of all parathyroid glands) with intraoperative measurements of plasma PTH (immediately prior......BACKGROUND: With the development of rapid assays and intraoperative measurement of intact parathyroid hormone (PTH), new strategies in the handling of patients with primary hyperparathyroidism (pHPT) have evolved. AIM: The aim of our study was to illustrate the performance of the intraoperative PTH...... to surgery (T0) and 5 minutes after gland excision (T5)). A positive test result was defined as plasma PTH values at T5 below 20% of T0 or a value in the normal range below 7.6 pmol/l. Hence T5 values above 20% of T0 and above 7.6 pmol/l were considered test negative. RESULTS: 122 patients (85%) were test...

  5. Parathyroid hormone (PTH) blood test

    Science.gov (United States)

    ... excess calcium supplements or certain antacids, that contain calcium carbonate or sodium bicarbonate (baking soda) Parathyroid glands do ... More 25-hydroxy vitamin D test Bone tumor Calcium ... level Malabsorption Milk-alkali syndrome Multiple endocrine neoplasia (MEN) I Multiple ...

  6. [Successive ruptures of patellar and Achilles tendons. Anabolic steroids in competitive sports].

    Science.gov (United States)

    Isenberg, J; Prokop, A; Skouras, E

    2008-01-01

    Derivatives of testosterone or of 19-nor-testosterone are used as anabolics for the purpose of improving performance although the effect of anabolics is known still to be under discussion. The use of anabolic steroids continues among competitive athletes despite increased controls and increasingly frequent dramatic incidents connected with them. Whereas metabolic dysfunction during anabolic use is well documented, ruptures of the large tendons are rarely reported. Within 18 months, a 29-year-old professional footballer needed surgery for rupture of the patellar tendon and of both Achilles tendons. Carefully directed questioning elicited confirmation that he had taken different anabolic steroids regularly for 3 years with the intention of improving his strength. After each operation anabolic steroids were taken again at a high dosage during early convalescence and training. Minimally invasive surgery and open suturing techniques led to complete union of the Achilles tendons in good time. Training and anabolic use (metenolon 300 mg per week) started early after suturing of the patellar tendon including bone tunnels culminated in histologically confirmed rerupture after 8 weeks. After a ligament reconstruction with a semitendinosus tendon graft with subsequent infection, the tendon and reserve traction apparatus were lost. Repeated warnings of impaired healing if anabolic use was continued had been given without success. In view of the high number of unrecorded cases in competitive and athletic sports, we can assume that the use of anabolic steroids is also of quantitative relevance in the operative treatment of tendon ruptures.

  7. Additional weight-bearing during exercise is more important than duration of exercise for anabolic stimulus of bone: a study of running exercise in female rats.

    Science.gov (United States)

    van der Wiel, H E; Lips, P; Graafmans, W C; Danielsen, C C; Nauta, J; van Lingen, A; Mosekilde, L

    1995-01-01

    Mechanical loading is necessary for maintenance of skeletal integrity, but the most effective type, intensity, and duration of exercise are not known. In vivo experiments have indicated that the strain generated by the stimulus is more important than the duration of the stimulus. To elucidate this question, we studied 5-month-old female Wistar rats exercised on a motor-driven exercise belt for 17 weeks, 5 days per week (average velocity 20 m/min). Group 1 served as controls, group 2 was trained for 30 min, group 3 was trained for 30 min with a 50-g backpack, and group 4 was trained for 15 min with a 50-g backpack. Total body bone mineral content (BMC), bone mass of the lower extremities (LEBMC), total body lean soft-tissue mass (LSTM), and total body fat-tissue mass (FTM) were measured by dual-energy absorptiometry (DXA) at 0, 6, and 17 weeks. The BMC increased more in group 4 than in controls (15% vs. 8%, p LSTM after 6 weeks was most pronounced in group 3, at 20%, compared with 10% in the control group (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Utilizing time-lapse micro-CT-correlated bisphosphonate binding kinetics and soft tissue-derived input functions to differentiate site-specific changes in bone metabolism in vivo.

    Science.gov (United States)

    Tower, R J; Campbell, G M; Müller, M; Glüer, C C; Tiwari, S

    2015-05-01

    The turnover of bone is a tightly regulated process between bone formation and resorption to ensure skeletal homeostasis. This process differs between bone types, with trabecular bone often associated with higher turnover than cortical bone. Analyses of bone by micro-computed tomography (micro-CT) reveal changes in structure and mineral content, but are limited in the study of metabolic activity at a single time point, while analyses of serum markers can reveal changes in bone metabolism, but cannot delineate the origin of any aberrant findings. To obtain a site-specific assessment of bone metabolic status, bisphosphonate binding kinetics were utilized. Using a fluorescently-labeled bisphosphonate, we show that early binding kinetics monitored in vivo using fluorescent molecular tomography (FMT) can monitor changes in bone metabolism in response to bone loss, stimulated by ovariectomy (OVX), or bone gain, resulting from treatment with the anabolic bone agent parathyroid hormone (PTH), and is capable of distinguishing different, metabolically distinct skeletal sites. Using time-lapse micro-CT, longitudinal bone turnover was quantified. The spine showed a significantly greater percent resorbing volume and surface in response to OVX, while mice treated with PTH showed significantly greater resorbing volume per bone surface in the spine and significantly greater forming surfaces in the knee. Correlation studies between binding kinetics and micro-CT suggest that forming surfaces, as assessed by time-lapse micro-CT, are preferentially reflected in the rate constant values while forming and resorbing bone volumes primarily affect plateau values. Additionally, we developed a blood pool correction method which now allows for quantitative multi-compartment analyses to be conducted using FMT. These results further expand our understanding of bisphosphonate binding and the use of bisphosphonate binding kinetics as a tool to monitor site-specific changes in bone metabolism in

  9. Anabolic Steroids...What's the Hype?...

    Science.gov (United States)

    Landry, Gregory L.; Wagner, Lauris L.

    This pamphlet uses a question-and-answer format to examine the use and abuse of anabolic steroids. It begins by explaining that all steroids are not anabolic steroids and that anabolic steroids are those used specifically to build muscles quickly. Medical uses of anabolic steroids are reviewed; how people get steroids, how they take them, and…

  10. Gene expression profiles give insight into the molecular pathology of bone in primary hyperparathyroidism

    DEFF Research Database (Denmark)

    Reppe, Sjur; Stilgren, Lis; Olstad, Ole K

    2006-01-01

    of the global transcriptional activity were repeated in a second bone biopsy from the same patient taken one year after surgery and reversal of disease parameters. Real time PCR was carried out on many genes for corroboration of the results. Out of more than 14500 different genes examined, 99 which were related...... to bone and extra-cellular matrix, showed altered expression. Of these were 85 up- and 14 down-regulated before operation. The majority of regulated genes represented structural and adhesion proteins, but included also proteases and protease regulators which promote resorption. Increased expressions...... of collagen type 1 and osteocalcin mRNAs in disease reflecting the PTH anabolic action were paralleled by increased concentrations of these proteins in serum. In addition, genes encoding transcriptional factors and their regulators as well as cellular signal molecules were up-regulated during disease...

  11. Serum parathyroid hormone (PTH) in pregnant women determined by an immunoradiometric assay for intact PTH

    Energy Technology Data Exchange (ETDEWEB)

    Davis, O.K.; Hawkins, D.S.; Rubin, L.P.; Posillico, J.T.; Brown, E.M.; Schiff, I.

    1988-10-01

    Most studies of circulating PTH levels using traditional RIAs have supported the concept of physiological hyperparathyroidism of pregnancy, with pregnant women having serum immunoreactive PTH levels significantly higher than those in nonpregnant subjects. However, such RIAs are insensitive and often detect inactive PTH fragments, so that the correlation between PTH immunoreactivity and bioactivity is poor. Employing a new intact PTH immunoradiometric assay (Allegro-Nichols), we reassessed the effects of pregnancy on parathyroid function. The mean serum PTH level in 81 pregnant women was 14.4 +/- 6.3 (+/- SD) compared to 24.8 +/- 9.0 ng/L in 11 normally cycling nonpregnant women (P less than 0.001). The mean serum total and ionized calcium levels in the 2 groups were similar. In 5 of the pregnant women, serum bioactive PTH, determined by cytochemical bioassay, was slightly lower (7.7 +/- 3.4 ng/L) than in normal individuals (11.1 +/- 1.9 ng/L). Our findings suggest, in contrast with the results of most previous studies, that serum intact PTH may decline during pregnancy.

  12. Anabolic steroids and growth hormone.

    Science.gov (United States)

    Haupt, H A

    1993-01-01

    Athletes are generally well educated regarding substances that they may use as ergogenic aids. This includes anabolic steroids and growth hormone. Fortunately, the abuse of growth hormone is limited by its cost and the fact that anabolic steroids are simply more enticing to the athlete. There are, however, significant potential adverse effects regarding its use that can be best understood by studying known growth hormone excess, as demonstrated in the acromegalic syndrome. Many athletes are unfamiliar with this syndrome and education of the potential consequences of growth hormone excess is important in counseling athletes considering its use. While athletes contemplating the use of anabolic steroids may correctly perceive their risks for significant physiologic effects to be small if they use the steroids for brief periods of time, many of these same athletes are unaware of the potential for habituation to the use of anabolic steroids. The result may be incessant use of steroids by an athlete who previously considered only short-term use. As we see athletes taking anabolic steroids for more prolonged periods, we are likely to see more severe medical consequences. Those who eventually do discontinue the steroids are dismayed to find that the improvements made with the steroids generally disappear and they have little to show for hours or even years of intense training beyond the psychological scars inherent with steroid use. Counseling of these athletes should focus on the potential adverse psychological consequences of anabolic steroid use and the significant risk for habituation.

  13. Enhancement of Lumbar Fusion and Alleviation of Adjacent Segment Disc Degeneration by Intermittent PTH(1-34) in Ovariectomized Rats.

    Science.gov (United States)

    Zhou, Zhuang; Tian, Fa-Ming; Gou, Yu; Wang, Peng; Zhang, Heng; Song, Hui-Ping; Shen, Yong; Zhang, Ying-Ze; Zhang, Liu

    2016-04-01

    Osteoporosis, which is prevalent in postmenopausal or aged populations, is thought to be a contributing factor to adjacent segment disc degeneration (ASDD), and the incidence and extent of ASDD may be augmented by osteopenia. Parathyroid hormone (PTH) (1-34) has already been shown to be beneficial in osteoporosis, lumbar fusion and matrix homeostasis of intervertebral discs. However, whether PTH(1-34) has a reversing or retarding effect on ASDD in osteopenia has not been confirmed. In the present study, we evaluated the effects of intermittent PTH(1-34) on ASDD in an ovariectomized (OVX) rat model. One hundred 3-month-old female Sprague-Dawley rats underwent L4 -L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation 4 weeks after OVX surgery. Control groups were established accordingly. PTH(1-34) was intermittently administered immediately after PLF surgery and lasted for 8 weeks using the following groups (n = 20) (V = vehicle): Sham+V, OVX+V, Sham+PLF+V, OVX+PLF+V, OVX+PLF+PTH. The fused segments showed clear evidence of eliminated motion on the fusion-segment based on manual palpation. Greater new bone formation in histology was observed in PTH-treated animals compared to the control group. The extent of ASDD was significantly increased by ovariotomy. Intermittent PTH(1-34) significantly alleviated ASDD by preserving disc height, microvessel density, relative area of vascular buds, endplate thickness and the relative area of endplate calcification. Moreover, protein expression results showed that PTH(1-34) not only inhibited matrix degradation by decreasing MMP-13, ADAMTS-4 and Col-I, but also promote matrix synthesis by increasing Col-II and Aggrecan. In conclusion, PTH(1-34), which effectively improves lumbar fusion and alleviates ASDD in ovariectomized rats, may be a potential candidate to ameliorate the prognosis of lumbar fusion in osteopenia.

  14. PTH1–34 Blocks Radiation-induced Osteoblast Apoptosis by Enhancing DNA Repair through Canonical Wnt Pathway*

    Science.gov (United States)

    Chandra, Abhishek; Lin, Tiao; Zhu, Ji; Tong, Wei; Huo, Yanying; Jia, Haoruo; Zhang, Yejia; Liu, X. Sherry; Cengel, Keith; Xia, Bing; Qin, Ling

    2015-01-01

    Focal radiotherapy for cancer patients has detrimental effects on bones within the radiation field and the primary clinical signs of bone damage include the loss of functional osteoblasts. We reported previously that daily injection of parathyroid hormone (PTH, 1–34) alleviates radiation-induced osteopenia in a preclinical radiotherapy model by improving osteoblast survival. To elucidate the molecular mechanisms, we irradiated osteoblastic UMR 106-01 cells and calvarial organ culture and demonstrated an anti-apoptosis effect of PTH1–34 on these cultures. Inhibitor assay indicated that PTH exerts its radioprotective action mainly through protein kinase A/β-catenin pathway. γ-H2AX foci staining and comet assay revealed that PTH efficiently promotes the repair of DNA double strand breaks (DSBs) in irradiated osteoblasts via activating the β-catenin pathway. Interestingly, Wnt3a alone also blocked cell death and accelerated DNA repair in primary osteoprogenitors, osteoblastic and osteocytic cells after radiation through the canonical signaling. Further investigations revealed that both Wnt3a and PTH increase the amount of Ku70, a core protein for initiating the assembly of DSB repair machinery, in osteoblasts after radiation. Moreover, down-regulation of Ku70 by siRNA abrogated the prosurvival effect of PTH and Wnt3a on irradiated osteoblasts. In summary, our results identify a novel role of PTH and canonical Wnt signaling in regulating DSB repair machinery and apoptosis in osteoblasts and shed light on using PTH1–34 or Wnt agonist as possible therapy for radiation-induced osteoporosis. PMID:25336648

  15. Primary hyperparathyroidism: intraoperative PTH-measurements

    DEFF Research Database (Denmark)

    Rolighed, L; Heickendorff, L; Hessov, I

    2004-01-01

    measurement as a predictor of successful cure. MATERIAL AND METHODS: From September 1999 to April 2002 143 patients with pHPT underwent a parathyroid operation (bilateral neck exploration with identification of all parathyroid glands) with intraoperative measurements of plasma PTH (immediately prior...

  16. Non-canonical signaling of the PTH receptor

    Science.gov (United States)

    Vilardaga, Jean-Pierre; Gardella, Thomas J.; Wehbi, Vanessa L.; Feinstein, Timothy N.

    2012-01-01

    The classical model of arrestin-mediated desensitization of cell-surface G protein-coupled receptors (GPCRs) is thought to be universal. However, this paradigm is incompatible with recent reports that the parathyroid hormone (PTH) receptor (PTHR), a crucial GPCR for bone and mineral ion metabolism, sustains GS activity and continues to generate cAMP for prolonged periods after ligand-wash-out; during these periods the receptor is observed mainly in endosomes, associated with the bound ligand, GS and β-arrestins. In this review, we discuss possible molecular mechanisms underlying sustained signaling by the PTHR, including modes of signal generation and attenuation within endosomes, as well as the biological relevance of such non-canonical signaling. PMID:22709554

  17. Serum BAP as the clinically useful marker for predicting BMD reduction in diabetic hemodialysis patients with low PTH.

    Science.gov (United States)

    Ueda, Misako; Inaba, Masaaki; Okuno, Senji; Maeno, Yoshifumi; Ishimura, Eiji; Yamakawa, Tomoyuki; Nishizawa, Yoshiki

    2005-07-22

    With decrease of serum PTH in hemodialysis (HD) patients, other factors besides parathyroid hormone (PTH) become important in regulating bone metabolism. We investigated which serum bone metabolic marker is the best to predict the bone mineral density (BMD) reduction in HD patients with serum PTHBAP), intact osteocalcin (OC), and N-terminal propeptide of type I collagen (PINP), and the bone resorption markers, deoxypyridinoline (DPD), pyridinoline (PYD), and beta-crossLaps (beta-CTx) were measured in serum from 137 HD patients. BMD of all patients was measured twice, approximately 1.5 years before and 1.5 years after measurement of their markers of bone metabolism. In all 137 HD patients, serum BAP was the only marker significantly higher in those with BMD reduction than in those without. In 42 diabetes mellitus (DM) HD patients with serum PTHBAP was again the only marker to discriminate those with BMD reduction from those without. At serum PTHBAP retained tendency toward higher value. These findings suggest that serum BAP might be the most sensitive to identify small changes of bone metabolism in low bone turnover state. Retrospective study confirmed the usefulness of serum BAP in clinical practice by significantly higher values in those with bone loss at PTHBAP is a clinically useful bone formation marker to predict the BMD reduction in DM HD patients with low level of PTH.

  18. Exercise and pharmacological countermeasures for bone loss during long-duration space flight

    Science.gov (United States)

    Cavanagh, Peter R.; Licata, Angelo A.; Rice, Andrea J.

    2005-01-01

    Bone loss in the lower extremities and lumbar spine is an established consequence of long-duration human space flight. Astronauts typically lose as much bone mass in the proximal femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic stimulus from exercise has been inadequate to maintain bone mass, due to insufficient load or duration. Attention has therefore been focused on several pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth. Anti-resorptives are the class of drugs most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) and teriparatide (rhPTH [1-34]). Vitamin D and calcium supplementation have also been used. Recent studies of kindreds with abnormally high bone mineral density have provided insight into the genetic regulation of bone mass. This has led to potential therapeutic interventions based on the LRP5, Wnt and BMP2 pathways. Another target is the RANK-L/osteoprotegerin signaling pathway, which influences bone turnover by regulating osteoclast formation and maturation. Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies--all of which may have unique characteristics when the drugs are used in space.

  19. Endocrine aspects of anabolic steroids.

    Science.gov (United States)

    Wu, F C

    1997-07-01

    Understanding of the mechanism of androgen action has been enhanced by advances in knowledge on the molecular basis of activation of the androgen receptor and the importance of tissue conversion of circulating testosterone to dihydrotestosterone and estradiol. New evidence supports the view that supraphysiological doses of anabolic steroids do have a definite, positive effect on muscle size and muscle strength. However, the nature of the anabolic action of androgens on muscle is currently unclear and may involve mechanisms independent of the androgen receptor. The dose-response relationships of anabolic actions vs the potentially serious risk to health of androgenic-anabolic steroids (AAS) use are still unresolved. Most of the adverse effects of AAS are reversible but some are permanent, particularly in women and children. The reported incidence of acute life-threatening events associated with AAS abuse is low, but the actual risk may be underrecognized or underreported; the exact incidence is unknown. The long-term consequences and disease risks of AAS to the sports competitor remain to be properly evaluated.

  20. Feasibility Study of a Standardized Novel Animal Model for Cervical Vertebral Augmentation in Sheep Using a PTH Derivate Bioactive Material

    Directory of Open Access Journals (Sweden)

    Karina Klein

    2014-08-01

    Full Text Available Prophylactic local treatment involving percutaneous vertebral augmentation using bioactive materials is a new treatment strategy in spine surgery in humans for vertebral bodies at risk. Standardized animal models for this procedure are almost non-existent. The purpose of this study was to: (i prove the efficacy of PTH derivate bioactive materials for new bone formation; and (ii create a new, highly standardized cervical vertebral augmentation model in sheep. Three different concentrations of a modified form of parathyroid hormone (PTH covalently bound to a fibrin matrix containing strontium carbonate were used. The same matrix without PTH and shams were used as controls. The bioactive materials were locally injected. Using a ventral surgical approach, a pre-set amount of material was injected under fluoroscopic guidance into the intertrabecular space of three vertebral bodies. Intravital fluorescent dyes were used to demonstrate new bone formation. After an observation period of four months, the animals were sacrificed, and vertebral bodies were processed for µCT, histomorphometry, histology and sequential fluorescence evaluation. Enhanced localized bone activity and new bone formation in the injected area could be determined for all experimental groups in comparison to the matrix alone and sham with the highest values detected for the group with a medium concentration of PTH.

  1. Bone metabolic changes during pregnancy: a period of vulnerability to osteoporosis and fracture.

    Science.gov (United States)

    Sanz-Salvador, Lucía; García-Pérez, Miguel Ángel; Tarín, Juan J; Cano, Antonio

    2015-02-01

    Changes in bone density and bone markers suggest that pregnancy is associated with deterioration of bone mass in the mother. The metabolism of calcium resets to allow for the needs imposed by the building of the fetal skeleton. The fetus contributes to the process through the output of regulators from the placenta. Understanding of the whole process is limited, but some changes are unambiguous. There is an increase in the circulating levels of vitamin D, but its functional impact is unclear. Fetal parathyroid hormone (PTH) and PTH-related peptide (PTHrp) play an indirect role through support of a calcium gradient that creates hypercalcemia in the fetus. Placental GH, which increases up to the end of pregnancy, may exert some anabolic effects, either directly or through the regulation of the IGF1 production. Other key regulators of bone metabolism, such as estrogens or prolactin, are elevated during pregnancy, but their role is uncertain. An increase in the ratio of receptor activator of nuclear factor kappa B ligand (RANKL) to osteoprotegerin (OPG) acts as an additional pro-resorbing factor in bone. The increase in bone resorption may lead to osteoporosis and fragility fracture, which have been diagnosed, although rarely. However, the condition is transitory as long-term studies do not link the number of pregnancies with osteoporosis. Prevention is limited by the lack of identifiable risk factors. When fractures are diagnosed, rest, analgesics, or, when indicated, orthopedic intervention have demonstrated efficacy. Systemic treatment with anti-osteoporotic drugs is effective, but the potential harm to the fetus imposes caution in their use.

  2. Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia.

    Science.gov (United States)

    Xie, Yangli; Su, Nan; Jin, Min; Qi, Huabing; Yang, Junbao; Li, Can; Du, Xiaolan; Luo, Fengtao; Chen, Bo; Shen, Yue; Huang, Haiyang; Xian, Cory J; Deng, Chuxia; Chen, Lin

    2012-09-15

    Achondroplasia (ACH) and thanatophoric dysplasia (TD) are caused by gain-of-function mutations of fibroblast growth factor receptor 3 (FGFR3) and they are the most common forms of dwarfism and lethal dwarfism, respectively. Currently, there are few effective treatments for ACH. For the neonatal lethality of TD patients, no practical effective therapies are available. We here showed that systemic intermittent PTH (1-34) injection can rescue the lethal phenotype of TD type II (TDII) mice and significantly alleviate the retarded skeleton development of ACH mice. PTH-treated ACH mice had longer naso-anal length than ACH control mice, and the bone lengths of humeri and tibiae were rescued to be comparable with those of wild-type control mice. Our study also found that the premature fusion of cranial synchondroses in ACH mice was partially corrected after the PTH (1-34) treatment, suggesting that the PTH treatment may rescue the progressive narrowing of neurocentral synchondroses that cannot be readily corrected by surgery. In addition, we found that the PTH treatment can improve the osteopenia and bone structure of ACH mice. The increased expression of PTHrP and down-regulated FGFR3 level may be responsible for the positive effects of PTH on bone phenotype of ACH and TDII mice.

  3. Why Current PTH Assays Mislead Clinical Decision Making in Patients with Secondary Hyperparathyroidism.

    Science.gov (United States)

    Hocher, Berthold; Yin, Lianghong

    2017-02-10

    Preclinical studies in cell culture systems as well as in whole animal chronic kidney disease (CKD) models showed that parathyroid hormone (PTH), oxidized at the 2 methionine residues (positions 8 and 18), caused a loss of function. This was so far not considered in the development of PTH assays used in current clinical practice. Patients with advanced CKD are subject to oxidative stress, and plasma proteins (including PTH) are targets for oxidants. In patients with CKD, a considerable but variable fraction (about 70 to 90%) of measured PTH appears to be oxidized. Oxidized PTH (oxPTH) does not interact with the PTH receptor resulting in loss of biological activity. Currently used intact PTH (iPTH) assays detect both oxidized and non-oxPTH (n-oxPTH). Clinical studies demonstrated that bioactive, n-oxPTH, but not iPTH nor oxPTH, is associated with mortality in CKD patients.

  4. Anabolic steroids are fool's gold.

    Science.gov (United States)

    Ryan, A J

    1981-10-01

    Since increases in muscle strength are proportional to increases in the cross-sectional diameter of the muscles being trained, the body must convert greater than normal amounts of amino acids available to it to increase size in athletes in training. When androgens became available in the 1930's they were used primarily to restore positive nitrogen balance in victims of starvation. Anabolic steroids, which were developed to avoid unwanted effects of androgens, were first given to weight lifters, but football players and weight throwers were soon using them. From 1965 to 1977, 25 clinical studies were published dealing with the administration of an anabolic-androgenic steroid to adult human males for evaluating changes in strength and, in 10 of these studies, in maximum oxygen consumption. In 12 of these studies, improvements were claimed from the use of these steroids; in the other 13 no improvements were observed. Other studies have shown that in healthy adult males these steroids reduce testosterone and gonadotrophin output, which reduces spermatogenesis. Alterations of normal liver function have been found in up to 80% of persons treated with C17-alkylated testosterone derivatives. Peliosis hepatitis, with liver failure and death, and fatal liver cancer have also been reported in adults so treated. Reliable methods for detecting anabolic steroids in the urine are now used in certain international competitions. Testing, announced bans, and disqualifications have not been effective in controlling the use of the drugs. The best hope for doing so lies in continuing education of athletes and their supervisors.

  5. PTHrP 1-141 and 1-86 Increase In Vitro Bone Formation

    Science.gov (United States)

    Hildreth, Blake Eason; Werbeck, Jillian L.; Thudi, Nandu K.; Deng, Xiyun; Rosol, Thomas J.; Toribio, Ramiro E.

    2010-01-01

    Background Parathyroid hormone-related protein (PTHrP) has anabolic effects in bone, which has led to the clinical use of N-terminal fragments of PTHrP and PTH. Since 10-20% of fractures demonstrate healing complications and osteoporosis continues to be a debilitating disease, the development of bone-forming agents is of utmost importance. Due to evidence that regions of PTHrP other than the N-terminus may have bone-forming effects, this study was designed to compare the effects of full-length PTHrP 1-141 to N-terminal PTHrP 1-86 on in vitro bone formation. Materials and methods MC3T3-E1 pre-osteoblasts were treated once every 6 days for 36 days with 5, 25, and 50 pM of PTHrP 1-141 or 1-86 for 1 or 24 hours. Cells were also treated after blocking the N-terminus, the nuclear localization sequence (NLS), and the C-terminus of PTHrP, individually and in combination. Area of mineralization, alkaline phosphatase (ALP), and osteocalcin (OCN) were measured. Results PTHrP 1-141 and 1-86 increased mineralization after 24-hr treatments, but not 1-hr. PTHrP 1-141 was more potent than 1-86. Treatment with PTHrP 1-141 for 24-hr, but not 1-86, resulted in a concentration-dependent increase in ALP, with no effect after 1-hr. Exposure to both peptides for 1- or 24-hrs induced a concentration-dependent increase in OCN, with 24-hr exceeding 1-hr. Antibody blocking revealed that the NLS and C-terminus are anabolic. Conclusions Both PTHrP 1-141 and 1-86 increased in vitro bone formation; however, PTHrP 1-141 was more effective. The NLS and C-terminus have anabolic effects distinct from the N-terminus. This demonstrates the advantage of PTHrP 1-141 as a skeletal anabolic agent. PMID:20538301

  6. Tissue-specific transcription start sites and alternative splicing of the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor gene: a new PTH/PTHrP receptor splice variant that lacks the signal peptide.

    Science.gov (United States)

    Joun, H; Lanske, B; Karperien, M; Qian, F; Defize, L; Abou-Samra, A

    1997-04-01

    The PTH/PTHrP receptor gene is expressed in bone and kidney as well as in many other tissues. Using primer extension followed by rapid cloning of amplified complementary DNA ends, we have isolated new PTH/PTHrP receptor complementary DNAs with different splicing patterns and have characterized a new upstream transcription start site. Three 5' nontranslated exons, U3, U2 and U1, located 4.8, 2.5, and 1.2 kb upstream of the exon that encodes the putative signal peptide of the classical receptor (exon S), have been characterized. Four types of splicing patterns were recognized. Type I splicing pattern is transcribed from exon U1 and is spliced to exons S and E1; this pattern was found in most tissues tested. Types II, III, and IV splicing patterns are transcribed from exon U3 and have a restricted tissue distribution. Type II splice pattern, containing exons U3, U2, and S and type III splicing pattern, containing exon U3, U2, and E1 (skipping exon S), was found only in kidney. Type IV splice pattern, containing exon U3 and S was found both in kidney and ovary. Because the type III splice variant skips exon S, translation of this splice variant initiates at a different AUG codon. The type III splice variant was weakly expressed on the cell surface of COS-7 cells, as assessed by double antibody binding assay, and no detectable ligand binding was observed on intact cells. The type III splice variant, however, increased cAMP accumulation in COS-7 cells when challenged with PTH(1-34), PTH(1-84) and hPTHrP(1-36) with EC50s that are similar to those observed in COS-7 cells expressing the type I variant but with a maximum stimulation that was lower than that observed in COS-7 cells expressing the type I variant. These data indicate low levels of cell surface expression of the type III splice variant. Treatment of COS-7 cells with tunicamycin decreased the size of the type I splice variant from a broad band of 85 kDa to a compact band of about 60 kDa. The type III splice

  7. Valores de PTH en pacientes bajo tratamiento con bifosfonatos PTH Levels in Patients Treated with Bisphosphonates

    Directory of Open Access Journals (Sweden)

    MS Saavedra

    2012-06-01

    Full Text Available Se han cuestionado los rangos o valores de referencia (VR de PTH definidos en sujetos en los cuales las causas de aumento en los niveles de PTH no hayan sido exhaustivamente excluidas: un VR óptimo debe coexistir con niveles de vitamina D adecuados. En este estudio analizamos el VR en mujeres post-menopáusicas, con niveles adecuados de 25(OH D, bajo tratamiento con bifosfonatos orales. Éstos, por su mecanismo de acción, pueden producir disminución asintomática del calcio sérico y aumento secundario de PTH; por lo cual, el VR de 15 a 65 pg/ml, informado para la medición de PTH molécula intacta por electroquimioluminiscencia, podría no ser el adecuado para esta población en particular. La edad media y la desviación estándar de los sujetos fue de 71,4 ± 8,55 años, con una media para 25(OH D3, de 37,3 ng/ml, calcio iónico: 4,9 mg/dl (VR.4,3-5,3; calcio urinario: 110 mg/24 h (VR: 60-200; fósforo en suero: 3,6 mg% (VR: 2,5-4,5; fósforo en orina: 0,61 g/24hs (VR: 0,3-1,0, creatinina plasmática: 0,80 mg% (VR: 0,5-1,5 y un FGe de 74 ml/min/1,73 m² (V corte >60. Para los fíCTx la media obtenida fue 212 pg/ml, que refleja la acción antirresortiva de los bifosfonatos. El VR de PTH calculado para esta población, según las recomendaciones del CLSI C28-A3 fue de 26,2-87,7 ng/ml. De la regresión lineal múltiple (r²=0,14 de la variable dependiente PTHi con las predictoras pCTx y creatinina, ajustadas por edad, los valores de PTHi dependieron de pCTx (P= -0,024; p=0,022 y de creatinina (P = 22,294; p=0,040. Todos nuestros resultados ponen en evidencia que el aumento de los niveles de PTH en esta población se debería en parte al efecto de la terapia antirresortiva y así como del proceso de envejecimiento fisiológico natural. Conclusión: El VR empleado para la población general no sería aplicable a las mujeres posmenopaúsicas, con niveles suficientes de 25OHD3, suplementadas con calcio, bajo tratamiento con bifosfonatos orales

  8. Parathyroid hormone 1-84 targets bone vascular structure and perfusion in mice: impacts of its administration regimen and of ovariectomy.

    Science.gov (United States)

    Roche, Bernard; Vanden-Bossche, Arnaud; Malaval, Luc; Normand, Myriam; Jannot, Martin; Chaux, Robin; Vico, Laurence; Lafage-Proust, Marie-Hélène

    2014-07-01

    Bone vessel functions during bone remodeling are poorly understood. They depend on both vessel network structure and vasomotor regulation. Parathyroid hormone (PTH) is a systemic vasodilator that may modulate microvascularization. Moreover, although intermittent PTH is anti-osteoporotic, continuous PTH administration can be catabolic for bone. Finally, ovariectomy (OVX) reduces bone perfusion and vessel density in mice. We reasoned that the effects of PTH on bone vascularization might depend on its administration regimen and be impacted by ovariectomy. A 100-µg/kg PTH 1-84 daily dose was administered for 15 days to 4-month-old female C57BL/6 mice, either as daily sc injection (iPTH) or continuously (cPTH; ALZET minipump). Blood pressure (BP) and tibia bone perfusion were measured in vivo with a laser Doppler device. Histomorphometry of bone and barium-contrasted vascular network were performed on the same tibia. Compared with untreated controls, both iPTH and cPTH increased bone formation but had opposite effects on resorption. Both iPTH and cPTH were slightly angiogenic. Intermittent PTH increased microvessel size (+48%, p < 0.001), whereas cPTH decreased it (-29%, p = 0.009). iPTH increased bone perfusion (27%, p < 0.001) with no change in BP, whereas cPTH did not. The vascular effects of a 15-day iPTH treatment were analyzed in OVX mice and compared with sham-operated and OVX untreated controls. Two other anti-osteoporotic drugs, zoledronate (one injection, 70 µg/kg) and propranolol, (5 mg/kg/d) were tested in OVX mice. Although no change in bone mass was observed, iPTH stimulated bone formation and prevented the OVX-induced reduction in bone perfusion and vessel density. Both zoledronate and propranolol strongly lowered bone turnover, but surprisingly, zoledronate prevented OVX-induced reduction in bone perfusion but propranolol did not. Our integrative approach thus demonstrates that the effects of PTH on bone vessel structure and function depend on its

  9. Anabolic steroids for rehabilitation after hip fracture in older people

    Directory of Open Access Journals (Sweden)

    Vaqas Farooqi

    Full Text Available ABSTRACT BACKGROUND: Hip fracture occurs predominantly in older people, many of whom are frail and undernourished. After hip fracture surgery and rehabilitation, most patients experience a decline in mobility and function. Anabolic steroids, the synthetic derivatives of the male hormone testosterone, have been used in combination with exercise to improve muscle mass and strength in athletes. They may have similar effects in older people who are recovering from hip fracture. OBJECTIVES: To examine the effects (primarily in terms of functional outcome and adverse events of anabolic steroids after surgical treatment of hip fracture in older people. METHODS: Search methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialized Register (10 September 2013, the Cochrane Central Register of Controlled Trials (CENTRAL (The Cochrane Library, 2013 Issue 8, MEDLINE (1946 to August Week 4 2013, EMBASE (1974 to 2013 Week 36, trial registers, conference proceedings, and reference lists of relevant articles. The search was run in September 2013. Selection criteria: Randomized controlled trials of anabolic steroids given after hip fracture surgery, in inpatient or outpatient settings, to improve physical functioning in older patients with hip fracture. Data collection and analysis: Two review authors independently selected trials (based on predefined inclusion criteria, extracted data and assessed each study's risk of bias. A third review author moderated disagreements. Only very limited pooling of data was possible. The primary outcomes were function (for example, independence in mobility and activities of daily living and adverse events, including mortality. MAIN RESULTS: We screened 1290 records and found only three trials involving 154 female participants, all of whom were aged above 65 years and had had hip fracture surgery. All studies had methodological shortcomings that placed them at high or unclear risk of bias. Because of this high

  10. Antiresorptives and anabolic therapy in sequence or combination for postmenopausal osteoporosis.

    Science.gov (United States)

    Palacios, S; Mejía, A

    2015-01-01

    Osteoporosis is a chronic disease which may require treatment for many years and requires not only individual management but often sequential or combination treatments. Monotherapy with antiresorptives is usually the first choice. Sometimes, it is necessary to modify this option for therapeutic failure or for the time of use and risk of side-effects. Due to their different mode of action, therapy with anabolic drugs has increased our options in the treatment of osteoporosis. Postmenopausal women and men with severe and progressive osteoporosis despite antiresorptive treatment ('therapeutic failure') should be evaluated for treatment with an anabolic option. Moreover, anabolic agents are indicated for 18-24 months in patients at high risk. Then, sequential antiresorptive therapy is recommended to maintain drug increases in bone mass and support secondary mineralization of the newly formed bone. Combination therapies of antiresorptives and anabolic agents have shown a significant increase in bone mineral density compared to monotherapies. However, none of the combinations have been studied for the prevention of fractures. Combination therapy may not be recommended because of the possible increase in cost.

  11. Anabolic steroid abuse and dependence.

    Science.gov (United States)

    Brower, Kirk J

    2002-10-01

    Anabolic-androgenic steroids (AAS) are mainly used to treat androgen deficiency syndromes and, more recently, catabolic states such as AIDS-associated wasting. There is no evidence in the reviewed literature that AAS abuse or dependence develops from the therapeutic use of AAS. Conversely, 165 instances of AAS dependence have been reported among weightlifters and bodybuilders who, as part of their weight training regimens, chronically administered supraphysiologic doses, often including combinations of injected and oral AAS as well as other drugs of abuse. A new model is proposed in which both the "myoactive" and psychoactive effects of AAS contribute to the development of AAS dependence. The adverse consequences of AAS are reviewed, as well as their assessment by means of a history and physical, mental status examination, and laboratory testing. When patients with AAS use disorders are compared with patients with other substance use disorders, both similarities and differences become apparent and have implications for treatment.

  12. ABUSE OF ANABOLIC ANDROGENIC STEROIDS

    Directory of Open Access Journals (Sweden)

    Abbas Yavari

    2009-09-01

    Full Text Available According to the International Olympic Committee, the abuse of anabolic androgenic steroids (AASS is found in over 50% of positive doping tests. AASS abuse is not restricted to the organized sports andwidespread use. It remains as an unsolved public-health problem.Lower black market price, easier access to AASS, bodybuilding clubs and internet advertising are factors of this increasingly misuse. There is not real data about the prevalence of AASS abuse in various populations or countries, because most of athletes or students, due to their prohibition or ethical aspects do not admit to AASS abuse. Often they are aware of the risks of their choice and yet, are eager to put themselves at risk without deeper consideration. The abusers use them to improve their physical fitness and appearance.Present article has been collected to elucidate the risks and adverse effects of AASS and explanation of mechanisms of these events.

  13. Developmental upregulation of human parathyroid hormone (PTH)/PTH-related peptide receptor gene expression from conserved and human-specific promoters.

    Science.gov (United States)

    Bettoun, J D; Minagawa, M; Hendy, G N; Alpert, L C; Goodyer, C G; Goltzman, D; White, J H

    1998-09-01

    The parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR) functions in skeletal development and mediates an array of other physiological responses modulated by PTH and PTHrP. PTHR gene transcription in mouse is controlled by two promoters: P1, which is highly and selectively active in kidney; and P2, which functions in a variety of tissues. P1 and P2 are conserved in human tissue; however, P1 activity in kidney is weak. We have now identified a third human promoter, P3, which is widely expressed and accounts for approximately 80% of renal PTHR transcripts in the adult. No P3 activity was detected in mouse kidney, indicating that renal PTHR gene expression is controlled by different signals in human and mouse. During development, only P2 is active at midgestation in many human tissues, including calvaria and long bone. This strongly suggests that factors regulating well conserved P2 control PTHR gene expression during skeletal development. Our results indicate that human PTHR gene transcription is upregulated late in development with the induction of both P1 and P3 promoter activities. In addition, P2-specific transcripts are differentially spliced in a number of human cell lines and adult tissues, but not in fetal tissues, giving rise to a shorter and less structured 5' UTR. Thus, our studies show that both human PTHR gene transcription and mRNA splicing are developmentally regulated. Moreover, our data indicate that renal and nonrenal PTHR gene expression are tightly coordinated in humans.

  14. Bone

    Science.gov (United States)

    Helmberger, Thomas K.; Hoffmann, Ralf-Thorsten

    The typical clinical signs in bone tumours are pain, destruction and destabilization, immobilization, neurologic deficits, and finally functional impairment. Primary malignant bone tumours are a rare entity, accounting for about 0.2% of all malignancies. Also benign primary bone tumours are in total rare and mostly asymptomatic. The most common symptomatic benign bone tumour is osteoid osteoma with an incidence of 1:2000.

  15. Anabolic steroids abuse and male infertility

    National Research Council Canada - National Science Library

    El Osta, Rabih; Almont, Thierry; Diligent, Catherine; Hubert, Nicolas; Eschwège, Pascal; Hubert, Jacques

    2016-01-01

    .... Up to date, 3,000,000 anabolic-androgenic steroids (AAS) users have been reported in the United States with an increasing prevalence, making AAS consumption a major public health growing concern...

  16. Supported Liquid Membrane Extraction of Anabolic Androgenic ...

    African Journals Online (AJOL)

    NJD

    performance liquid chromatography coupled to a mass spectrometer operating under positive ion electrospray mode. (LC-PI-ESI-MS) ... for the analysis of anabolic compounds.37–44 However, both GC ..... Table 3 gives a summary of the frag-.

  17. Bone metabolism during pregnancy.

    Science.gov (United States)

    Salles, Jean Pierre

    2016-06-01

    During pregnancy, mineral concentrations, of calcium and phosphorus in particular, are maintained at a high level in fetal blood so that the developing skeleton may accrete adequate mineral content. The placenta actively transports minerals for this purpose. Maternal intestinal absorption increases in order to meet the fetal demand for calcium, which is only partly dependent on calcitriol. Mineral regulation is essentially dependent on parathyroid hormone (PTH) and PTH-related protein (PTHrP). The calcium-sensing receptor (CaSR) regulates PTH and PTHrP production. If calcium intake is insufficient, the maternal skeleton will undergo resorption due to PTHrP. After birth, a switch from fetal to neonatal homeostasis occurs through increase in PTH and calcitriol, and developmental adaptation of the kidneys and intestines with bone turnover contributing additional mineral to the circulation. Calcium absorption becomes progressively active and dependent on calcitriol. The postnatal skeleton can transiently present with osteoposis but adequate mineral diet usually allows full restoration. Cases of primary osteoporosis must be identified. Loss of trabecular mineral content occurs during lactation in order to provide calcium to the newborn. This programmed bone loss is dependent on a "brain-breast-bone" circuit. The physiological bone resorption during reproduction does not normally cause fractures or persistent osteoporosis. Women who experience fracture are likely to have other causes of bone loss. Copyright © 2016. Published by Elsevier Masson SAS.

  18. Update on the efficacy, safety, and adherence to treatment of full length parathyroid hormone, PTH (1-84, in the treatment of postmenopausal osteoporosis

    Directory of Open Access Journals (Sweden)

    Luca Pietrogrande

    2009-11-01

    Full Text Available Luca PietrograndeDipartimento di Medicina Chirurgia e Odontoiatria Polo San Paolo, Università degli Studi di Milano, Milan, ItalyAbstract: Full length (1-84 parathyroid hormone (PTH was introduced in Europe as a treatment for postmenopausal osteoporosis in 2006. The efficacy of PTH (1-84 in the prevention of vertebral fractures is very high, and is similar to that of teriparatide. Its action in the prevention of femoral fractures has yet to be fully demonstrated, but the incidence of such fractures in trials was very low, and a decrease in nonvertebral fractures was seen in high-risk patients. The effect on bone mineral density (BMD was clearly demonstrated in the spine and also in the hip. The effects on BMD were evident and increased progressively with treatment until 36 months. After its discontinuation there was a clear decrease in BMD if no antiresorptive treatment was initiated. Increases in bone volumetric density and bone volume in trabecular sites were also reported. Moreover, a bone volume increase was detected in cortical sites. Hypercalcemia and hypercalciuria are frequent consequences of PTH treatment, but rarely have clinical effects and are usually well controlled by reducing calcium and vitamin D supplementation.Keywords: PTH (1-84, full-length parathyroid hormone, osteoporosis treatment

  19. Effect of intermittent versus continuous parathyroid hormone in the cardiovascular system of rats

    DEFF Research Database (Denmark)

    Smajilovic, Sanela; Schaal-Jensen, Rasmus; Jabbari, Reza

    2010-01-01

    PTH increases ionic calcium concentration in the serum, acting primarily on bone and kidney cells through the type 1 PTH receptor. Interestingly, PTH stimulates bone formation when administrated intermittently but causes severe bone loss with continuous administration. Daily injections of PTH...... are used as the most promising anabolic agent in the treatment of severe osteoporosis. Elevated PTH is reported an independent risk factor for left ventricle hypertrophy....

  20. Altered Selectivity of Parathyroid Hormone (PTH) and PTH-Related Protein (PTHrP) for Distinct Conformations of the PTH/PTHrP Receptor

    OpenAIRE

    Dean, Thomas; Vilardaga, Jean-Pierre; Potts, John T.; Gardella, Thomas J

    2007-01-01

    PTH and PTHrP use the same G protein-coupled receptor, the PTH/PTHrP receptor (PTHR), to mediate their distinct biological actions. The extent to which the mechanisms by which the two ligands bind to the PTHR differ is unclear. We examined this question using several pharmacological and biophysical approaches. Kinetic dissociation and equilibrium binding assays revealed that the binding of [125I]PTHrP(1–36) to the PTHR was more sensitive to GTPγS (added to functionally uncouple PTHR-G protein...

  1. Programmed administration of parathyroid hormone increases bone formation and reduces bone loss in hindlimb-unloaded ovariectomized rats

    Science.gov (United States)

    Turner, R. T.; Evans, G. L.; Cavolina, J. M.; Halloran, B.; Morey-Holton, E.

    1998-01-01

    Gonadal insufficiency and reduced mechanical usage are two important risk factors for osteoporosis. The beneficial effects of PTH therapy to reverse the estrogen deficiency-induced bone loss in the laboratory rat are well known, but the influence of mechanical usage in this response has not been established. In this study, the effects of programed administration of PTH on cancellous bone volume and turnover at the proximal tibial metaphysis were determined in hindlimb-unloaded, ovariectomized (OVX), 3-month-old Sprague-Dawley rats. PTH was administered to weight-bearing and hindlimb-unloaded OVX rats with osmotic pumps programed to deliver 20 microg human PTH (approximately 80 microg/kg x day) during a daily 1-h infusion for 7 days. Compared with sham-operated rats, OVX increased longitudinal and radial bone growth, increased indexes of cancellous bone turnover, and resulted in net resorption of cancellous bone. Hindlimb unloading of OVX rats decreased longitudinal and radial bone growth, decreased osteoblast number, increased osteoclast number, and resulted in a further decrease in cancellous bone volume compared with those in weight-bearing OVX rats. Programed administration of PTH had no effect on either radial or longitudinal bone growth in weight-bearing and hindlimb-unloaded OVX rats. PTH treatment had dramatic effects on selected cancellous bone measurements; PTH maintained cancellous bone volume in OVX weight-bearing rats and greatly reduced cancellous bone loss in OVX hindlimb-unloaded rats. In the latter animals, PTH treatment prevented the hindlimb unloading-induced reduction in trabecular thickness, but the hormone was ineffective in preventing either the increase in osteoclast number or the loss of trabecular plates. Importantly, PTH treatment increased the retention of a baseline flurochrome label, osteoblast number, and bone formation in the proximal tibial metaphysis regardless of the level of mechanical usage. These findings demonstrate that

  2. Distribution of genes for parathyroid hormone (PTH)-related peptide, Indian hedgehog, PTH receptor and patched in the process of experimental spondylosis in mice.

    Science.gov (United States)

    Nakase, Takanobu; Ariga, Kenta; Meng, Wenxiang; Iwasaki, Motoki; Tomita, Tetsuya; Myoui, Akira; Yonenobu, Kazuo; Yoshikawa, Hideki

    2002-07-01

    Little is known about the molecular mechanisms underlying the process of spondylosis. The authors determined the extent of genetic localization of major regulators of chondrogenesis such as Indian hedgehog (Ihh) and parathyroid hormone (PTH)-related peptide (PTHrP) and their receptors during the development of spondylosis in their previously established experimental mouse model. Experimental spondylosis was induced in 5-week-old ICR mice. The cervical spines were chronologically harvested, and histological sections were prepared. Messenger (m) RNA for PTHrP, Ihh, PTH receptor (PTHR; a receptor for PTHrP), patched (Ptc; a receptor for Ihh), bone morphogenetic protein (BMP)-6, and collagen type X (COL10; a marker for mature chondrocyte) was localized in the tissue sections by performing in situ hybridization. In the early stage, mRNA for COL10, Ihh, and BMP-6 was absent; however, mRNA for PTHrP, PTHR, and Ptc was detected in the anterior margin of the cervical discs. In the late stage, evidence of COL10 mRNA began to be detected, and transcripts for Ihh, PTHrP, and BMP-6 were localized in hypertrophic chondrocytes adjacent to the bone-forming area in osteophyte. Messenger RNA for Ptc and PTHR continued to localize at this stage. In control mice, expression of these genes was absent. The localization of PTHrP, Ihh, BMP-6, and the receptors PTHR and Ptc demonstrated in the present experimental model indicates the possible involvement of molecular signaling by PTHrP (through the PTHR), Ihh (through the Ptc), and BMP-6 in the regulation of chondrocyte maturation leading to endochondral ossification in spondylosis.

  3. Endogenous parathyroid hormone-related protein compensates for the absence of parathyroid hormone in promoting bone accrual in vivo in a model of bone marrow ablation.

    Science.gov (United States)

    Zhu, Qi; Zhou, Xichao; Zhu, Min; Wang, Qian; Goltzman, David; Karaplis, Andrew; Miao, Dengshun

    2013-09-01

    To assess the effect of hypoparathyroidism on osteogenesis and bone turnover in vivo, bone marrow ablation (BMXs) were performed in tibias of 8-week-old wild-type and parathyroid hormone-null (PTH(-/-)) mice and newly formed bone tissue was analyzed from 5 days to 3 weeks after BMX. At 1 week after BMX, trabecular bone volume, osteoblast numbers, alkaline phosphatase-positive areas, type I collagen-positive areas, PTH receptor-positive areas, calcium sensing receptor-positive areas, and expression of bone formation-related genes were all decreased significantly in the diaphyseal regions of bones of PTH(-/-) mice compared to wild-type mice. In contrast, by 2 weeks after BMX, all parameters related to osteoblastic bone accrual were increased significantly in PTH(-/-) mice. At 5 days after BMX, active tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts had appeared in wild-type mice but were undetectable in PTH(-/-) mice, Both the ratio of mRNA levels of receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) and TRAP-positive osteoclast surface were still reduced in PTH(-/-) mice at 1 week but were increased by 2 weeks after BMX. The expression levels of parathyroid hormone-related protein (PTHrP) at both mRNA and protein levels were upregulated significantly at 1 week and more dramatically at 2 weeks after BMX in PTH(-/-) mice. To determine whether the increased newly formed bones in PTH(-/-) mice at 2 weeks after BMX resulted from the compensatory action of PTHrP, PTH(-/-) PTHrP(+/-) mice were generated and newly formed bone tissue was compared in these mice with PTH(-/-) and wild-type mice at 2 weeks after BMX. All parameters related to osteoblastic bone formation and osteoclastic bone resorption were reduced significantly in PTH(-/-) PTHrP(+/-) mice compared to PTH(-/-) mice. These results demonstrate that PTH deficiency itself impairs osteogenesis, osteoclastogenesis, and osteoclastic bone resorption, whereas subsequent upregulation of PTHr

  4. Anabolic steroids and cardiovascular risk.

    Science.gov (United States)

    Angell, Peter; Chester, Neil; Green, Danny; Somauroo, John; Whyte, Greg; George, Keith

    2012-02-01

    Recent reports from needle exchange programmes and other public health initiatives have suggested growing use of anabolic steroids (AS) in the UK and other countries. Data indicate that AS use is not confined to body-builders or high-level sportsmen. Use has spread to professionals working in emergency services, casual fitness enthusiasts and subelite sportsmen and women. Although the precise health consequences of AS use is largely undefined, AS use represents a growing public health concern. Data regarding the consequences of AS use on cardiovascular health are limited to case studies and a modest number of small cohort studies. Numerous case studies have linked AS use with a variety of cardiovascular disease (CVD) events or endpoints, including myocardial infarction, stroke and death. Large-scale epidemiological studies to support these links are absent. Consequently, the impact of AS use upon known CVD risk factors has been studied in relatively small, case-series studies. Data relating AS use to elevated blood pressure, altered lipid profiles and ECG abnormalities have been reported, but are often limited in scope, and other studies have often produced equivocal outcomes. The use of AS has been linked to the appearance of concentric left ventricular hypertrophy as well as endothelial dysfunction but the data again remains controversial. The mechanisms responsible for the negative effect of AS on cardiovascular health are poorly understood, especially in humans. Possibilities include direct effects on myocytes and endothelial cells, reduced intracellular Ca2+ levels, increased release of apoptogenic factors, as well as increased collagen crosslinks between myocytes. New data relating AS use to cardiovascular health risks are emerging, as novel technologies are developed (especially in non-invasive imaging) that can assess physiological structure and function. Continued efforts to fully document the cardiovascular health consequences of AS use is important to

  5. Ecdysteroids: A novel class of anabolic agents?

    Directory of Open Access Journals (Sweden)

    MK Parr

    2015-05-01

    Full Text Available Increasing numbers of dietary supplements with ecdysteroids are marketed as “natural anabolic agents”. Results of recent studies suggested that their anabolic effect is mediated by estrogen receptor (ER binding. Within this study the anabolic potency of ecdysterone was compared to well characterized anabolic substances. Effects on the fiber sizes of the soleus muscle in rats as well the diameter of C2C12 derived myotubes were used as biological readouts. Ecdysterone exhibited a strong hypertrophic effect on the fiber size of rat soleus muscle that was found even stronger compared to the test compounds metandienone (dianabol, estradienedione (trenbolox, and SARM S 1, all administered in the same dose (5 mg/kg body weight, for 21 days. In C2C12 myotubes ecdysterone (1 μM induced a significant increase of the diameter comparable to dihydrotestosterone (1 μM and IGF 1 (1.3 nM. Molecular docking experiments supported the ERβ mediated action of ecdysterone. To clarify its status in sports, ecdysterone should be considered to be included in the class “S1.2 Other Anabolic Agents” of the list of prohibited substances of the World Anti-Doping Agency.

  6. Cinacalcet Reduces the Set Point of the PTH-Calcium Curve

    Science.gov (United States)

    Valle, Casimiro; Rodriguez, Mariano; Santamaría, Rafael; Almaden, Yolanda; Rodriguez, Maria E.; Cañadillas, Sagrario; Martin-Malo, Alejandro; Aljama, Pedro

    2008-01-01

    The calcimimetic cinacalcet increases the sensitivity of the parathyroid calcium-sensing receptor to calcium and therefore should produce a decrease in the set point of the parathyroid hormone (PTH)-calcium curve. For investigation of this hypothesis, nine long-term hemodialysis patients with secondary hyperparathyroidism were given cinacalcet for 2 mo, the dosage was titrated per a protocol based on intact PTH and plasma calcium concentrations. Dialysis against low- and high-calcium (0.75 and 1.75 mM) dialysate was used to generate curves describing the relationship between PTH and calcium. Compared with precinacalcet levels, cinacalcet significantly reduced mean serum calcium, intact PTH and whole PTH (wPTH; all P < 0.001). The set points for PTH-calcium curves were significantly reduced, and both maximum and minimum levels of PTH (intact and whole) were significantly decreased. The calcium-mediated inhibition of PTH secretion was more marked after cinacalcet treatment. In addition, cinacalcet shifted the inverse sigmoidal curve of wPTH/non-wPTH ratio versus calcium to the left (i.e., less calcium was required to reduce the wPTH/non-wPTH ratio). In conclusion, cinacalcet increases the sensitivity of the parathyroids to calcium, causing a marked reduction in the set point of the PTH-calcium curve, in hemodialysis patients with secondary hyperparathyroidism. PMID:18632847

  7. Anabolic-androgenic steroids for alcoholic liver disease

    DEFF Research Database (Denmark)

    Rambaldi, Andrea; Iaquinto, Gaetano; Gluud, Christian

    2002-01-01

    The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease.......The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease....

  8. Anabolic steroids: implications for the nurse practitioner.

    Science.gov (United States)

    Duncan, D J; Shaw, E B

    1985-12-01

    Anabolic steroids are being used by athletes in a wide variety of sports in efforts to enhance their athletic performances. Steroid abuse is complex to evaluate due to the highly emotional subject matter and the limitations in researching anabolic steroids. This article has been written to heighten the practitioner's awareness of the problem of "sports doping" with anabolic steroids. It will provide practical information on possible consequences of steroid use and outline essential information to obtain through the history, physical exam and laboratory studies. Intervention strategies based on the three levels of prevention are described. With awareness of the problem of sports doping and knowledge of how to deal with it in primary care, the nurse practitioner can enhance the health care provided to aspiring athletes, athletes and retired athletes.

  9. MicroRNA 874-3p Exerts Skeletal Anabolic Effects Epigenetically during Weaning by Suppressing Hdac1 Expression*

    Science.gov (United States)

    Kushwaha, Priyanka; Khedgikar, Vikram; Sharma, Deepika; Yuen, Tony; Gautam, Jyoti; Ahmad, Naseer; Karvande, Anirudha; Mishra, Prabhat R.; Trivedi, Prabodh K.; Sun, Li; Bhadada, Sanjay K.; Zaidi, Mone; Trivedi, Ritu

    2016-01-01

    Embryonic skeletogenesis and postnatal bone development require the transfer of calcium from the mother to the offspring during pregnancy and lactation. Therefore, bone resorption in the mother becomes elevated during these periods, resulting in significant maternal skeletal loss. There follows an anabolic phase around weaning during which there is a remarkable recovery of the maternal skeleton. However, the mechanism(s) of this anabolic response remain(s) largely unknown. We identified eight differentially expressed miRNAs by array profiling, of which miR-874-3p was highly expressed at weaning, a time when bone loss was noted to recover. We report that this weaning-associated miRNA is an anabolic target. Therefore, an agomir of miR-874-3p induced osteoblast differentiation and mineralization. These actions were mediated through the inhibition of Hdac1 expression and enhanced Runx2 transcriptional activation. When injected in vivo, the agomir significantly increased osteoblastogenesis and mineralization, reversed bone loss caused by ovariectomy, and increased bone strength. We speculate that elevated miR-874-3p expression during weaning enhances bone formation and that this miRNA may become a therapeutic target for conditions of bone loss. PMID:26663087

  10. Using Anabolic Androgenic Steroids in Sport

    Directory of Open Access Journals (Sweden)

    Sefa Lök

    2010-12-01

    Full Text Available It is known that sportsmen especially youngers who engaged in athletism, weight lifting and body building sport have beenusing ‘‘Anabolic Androgenic Steroid’’ (AAS intensively for purpose of doping during world sport history. Used dopingsubstances to increase sport performance differ from sport branches. In some sport branches, it is used to diminish neuralstress while in other sport branches it is used to increase force, endurance and resistance against exhaustion. Today amongsportsmen using ergogenic substances to increase rivalry and physical performance for purpose of doping are increased. Inthis study using anabolic androgenic steroids in sports will be assessed.

  11. Bone pain

    DEFF Research Database (Denmark)

    Frost, Charlotte Ørsted; Hansen, Rikke Rie; Heegaard, Anne-Marie

    2016-01-01

    Skeletal conditions are common causes of chronic pain and there is an unmet medical need for improved treatment options. Bone pain is currently managed with disease modifying agents and/or analgesics depending on the condition. Disease modifying agents affect the underlying pathophysiology...... of the disease and reduce as a secondary effect bone pain. Antiresorptive and anabolic agents, such as bisphosphonates and intermittent parathyroid hormone (1-34), respectively, have proven effective as pain relieving agents. Cathepsin K inhibitors and anti-sclerostin antibodies hold, due to their disease...... modifying effects, promise of a pain relieving effect. NSAIDs and opioids are widely employed in the treatment of bone pain. However, recent preclinical findings demonstrating a unique neuronal innervation of bone tissue and sprouting of sensory nerve fibers open for new treatment possibilities....

  12. Identification of an RNA-binding protein that is phosphorylated by PTH and potentially mediates PTH-induced destabilization of Npt2a mRNA.

    Science.gov (United States)

    Murray, Rebecca D; Merchant, Michael L; Hardin, Ericka; Clark, Barbara; Khundmiri, Syed J; Lederer, Eleanor D

    2016-02-01

    Parathyroid hormone (PTH) is a key regulator of the expression and function of the type IIa sodium-phosphate cotransporter (Npt2a), the protein responsible for regulated renal phosphate reabsorption. We previously showed that PTH induces rapid decay of Npt2a mRNA through posttranscriptional mechanisms. We hypothesized that PTH-induced changes in RNA-binding protein (RBP) activity mediate the degradation of Npt2a mRNA. To address this aim, we treated opossum kidney (OK) cells, a PTH-sensitive proximal tubule cell culture model, with 100 nM PTH for 30 min and 2 h, followed by mass spectrometry characterization of the PTH-stimulated phosphoproteome. We identified 1,182 proteins differentially phosphorylated in response to PTH, including 68 RBPs. Preliminary analysis identified a phospho-RBP, hnRNPK-homology-type-splicing regulatory protein (KSRP), with predicted binding sites for the 3'-untranslated region (UTR) of Npt2a mRNA. Western blot analysis confirmed expression of KSRP in OK cells and showed PTH-dependent translocation to the nucleus. Immunoprecipitation of KSRP from control and PTH-treated cells followed by RNA isolation and RT-quantitative PCR analysis identified Npt2a mRNA from both control and PTH-treated KSRP pulldowns. Knockdown of KSRP followed by PTH treatment showed that KSRP is required for mediating PTH-stimulated reduction in sodium/hydrogen exchanger 3 mRNA, but not Npt2a mRNA. We conclude that 1) PTH is a major regulator of both transcription and translation, and 2) KSRP binds Npt2a mRNA but its role in PTH regulation of Npt2a mRNA is not clear.

  13. Teriparatide (rhPTH) treatment in children with syndromic hypoparathyroidism.

    Science.gov (United States)

    Matarazzo, Patrizia; Tuli, Gerdi; Fiore, Ludovica; Mussa, Alessandro; Feyles, Francesca; Peiretti, Valentina; Lala, Roberto

    2014-01-01

    Subcutaneous recombinant human parathormone [rhPTH (1-34)] has been introduced for hypoparathyroidism treatment, allowing avoidance of vitamin D and calcium side effects. Our objective was to evaluate rhPTH (1-34) safety and efficacy in pediatric patients with genetically proved syndromic hypoparathyroidism. The study was a 2.5-year self-controlled trial on six pediatric patients (four males, two females, age 9.8±5.1 years) with syndromic hypoparathyroidism including three with autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED) syndrome, two with DiGeorge syndrome, and one with hypoparathyroidism-deafness-renal dysplasia syndrome. We compared patients' clinical and biochemical outcome of conventional treatment based on oral administration of calcium (1-1.5 g/day in three doses) plus oral calcitriol (6.5-33 ng/kg per day in two to three doses) with the outcome obtained with rhPTH (1-34) (teriparatide, 12.5 μg bid). Therapy shift was conducted introducing rhPTH (1-34) while progressively withdrawing calcium and vitamin D. Blood calcium, phosphorus, alkaline phosphatase, and urinary calcium-to-creatinine ratio (mg/mg) before and during rhPTH therapy were compared. rhPTH treatment allowed complete calcium and vitamin D withdrawal in two patients, calcium withdrawal in three and reduction of vitamin D dose in two. During rhPTH (1-34), mean blood calcium, phosphorus, and alkaline phosphatase were not significantly modified, whereas significant reduction of the calciuria-to-creatininuria ratio (0.55±0.31 vs. 0.1±0.1, p=0.02) was obtained. The number of tetanic episodes was reduced in four patients during teriparatide treatment compared to conventional treatment. In children with syndromic hypoparathyroidism, substitutive treatment with rhPTH (1-34) maintains adequate blood calcium levels and allows prompt normalization of urinary calcium excretion, through direct action on the kidney and through calcium and vitamin D therapy layoff.

  14. Dialysis membranes and PTH changes during hemodialysis in patients with secondary hyperparathyroidism.

    Science.gov (United States)

    De Francisco, A L; Amado, J A; Prieto, M; Alcalde, G; Sanz de Castro, S; Ruiz, J C; Morales, P; Arias, M

    1994-01-01

    Changes in parathyroid hormone (PTH) during hemodialysis have been explained by the influence of ionized calcium changes on PTH secretion. In this study we have investigated the influence of dialysis membranes of different permeability on PTH changes during hemodialysis. Five chronic renal failure patients underwent three consecutive hemodialysis sessions with cuprophane (CUP) polysulfone (PS) and polyacrylonitrile (PAN). Two hours of isolated ultrafiltration were followed by 3 h dialysis. A significant decrease in carboxy terminal PTH (COOH PTH) was observed with PAN (p < 0.05) but not with CUP or PS. Intact PTH decreased (p < 0.001) with all three membranes, following a significant increase in ionized calcium (p < 0.001). Sieving coefficients for COOH PTH were significantly lower with CUP than with PS (p < 0.05) or PAN (p < 0.001). Intact PTH sieving coefficients were near zero for all three membranes. COOH PTH and intact PTH clearance rates were significantly higher with PAN (p < 0.001) than with PS or CUP, either in isolated ultrafiltration or with dialysis fluid. Thus PTH changes during hemodialysis do not only depend on the increase in calcium but also on the nature of the dialysis membrane. Adsorption of PTH to the PAN membrane surface explain the high PTH clearance rates achieved with this filter.

  15. Anabole Wirkungen auf den Knochen durch pulsatiles exogenes Parathormon - ein wiederentdecktes Therapieprinzip

    Directory of Open Access Journals (Sweden)

    Bernecker PM

    2002-01-01

    Full Text Available Parathormon (PTH wird in den Zellen der Nebenschilddrüse produziert und in enger Abhängigkeit vom Serumspiegel des ionisierten Kalziums in die Zirkulation abgegeben. Ein Abfall des Serum-Kalziums führt zu einem augenblicklichen Ansteigen der PTH-Ausschüttung aus der Nebenschilddrüse, ohne daß "second messenger"-Mechanismen zum Tragen kommen; viel mehr wird die Kalziumkonzentration durch einen auf der Oberfläche der Nebenschilddrüsenzellen befindlichen Kalzium-empfindlichen Rezeptor direkt durch die Zelle erfaßt. PTH wirkt auf verschiedene Weise; Ziel der Wirkung ist in jedem Fall eine Anhebung des Serum-Kalzium-Spiegels. Aus der Extrazellulärflüssigkeit (ECF des Knochens, die durch das Havers'sche Kanalsystem zirkuliert, kann recht rasch Kalzium mobilisiert werden. In der Knochen-ECF sind ca. 1-3 Gramm Kalzium in lockerer Ionenbindung gespeichert; diese können unter dem Einfluß von Parathormon sehr rasch in das Blutkompartment übergeführt werden. Am Knochen stimuliert Parathormon die Knochenresorption, auch hier mit dem physiologischen Ziel, Kalzium freizusetzen. Da der Knochenstoffwechsel jedoch in definierten "Knochenumbaueinheiten" (bone remodelling units = BMU erfolgt, in denen Knochenresorption und Knochenformation eng gekoppelt sind und sequentiell ablaufen, wurde die Steuerung dieser Umbauvorgänge durch PTH schon vor längerer Zeit untersucht. Die Überraschung war groß, als man feststellen mußte, daß die den Knochen abbauenden Osteoklasten keinerlei Rezeptoren für PTH, sondern nur für dessen physiologischen Gegenspieler, das Calcitonin, besitzen. PTH-Rezeptoren wurden dagegen in großer Dichte auf Osteoblasten, also Knochen-aufbauenden Zellen, gefunden. Es wird daher angenommen, daß der initiale Reiz für die Knochenresorption auf die Osteoklasten indirekt übermittelt wird, und zwar über bisher unbekannte second-messaging-Mechanismen; Prostaglandine der E- und F-Serien als auch Interleukin-1 wurden hier als solche

  16. Noncanonical GPCR signaling arising from a PTH receptor–arrestin–Gβγ complex

    Science.gov (United States)

    Wehbi, Vanessa L.; Stevenson, Hilary P.; Feinstein, Timothy N.; Calero, Guillermo; Romero, Guillermo; Vilardaga, Jean-Pierre

    2013-01-01

    G protein-coupled receptors (GPCRs) participate in ubiquitous transmembrane signal transduction processes by activating heterotrimeric G proteins. In the current “canonical” model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor–G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. β-Arrestins prolong G protein (GS)-mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin–PTHR complexes on endosomes and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the current model of arrestin-mediated receptor–G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gβγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of GS activation and increases the steady-state levels of activated GS, leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor. PMID:23297229

  17. Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gβγ complex.

    Science.gov (United States)

    Wehbi, Vanessa L; Stevenson, Hilary P; Feinstein, Timothy N; Calero, Guillermo; Romero, Guillermo; Vilardaga, Jean-Pierre

    2013-01-22

    G protein-coupled receptors (GPCRs) participate in ubiquitous transmembrane signal transduction processes by activating heterotrimeric G proteins. In the current "canonical" model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor-G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. β-Arrestins prolong G protein (G(S))-mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin-PTHR complexes on endosomes and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the current model of arrestin-mediated receptor-G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gβγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of G(S) activation and increases the steady-state levels of activated G(S), leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor.

  18. Review of Androgenic Anabolic Steroid Use

    Energy Technology Data Exchange (ETDEWEB)

    T. Borges; G. Eisele; C. Byrd

    2001-07-31

    An area that has been overlooked within personnel security evaluations is employee use of androgenic-anabolic steroids (AAS). Current drug testing within the federal government does not include testing for anabolic steroids, and the difficulties to implement such testing protocols-not to mention the cost involved-make AAS testing highly improbable. The basis of this report is to bring to the forefront the damage that anabolic steroids can cause from both a physical and a psychological standpoint. Most individuals who use AASs do so to increase their muscle mass because they wish to gain some type of competitive edge during athletic competition or they wish to enhance their physical features for self-satisfaction and self-esteem (i.e., body building). Security officers are one group of men who often take high doses of anabolic steroids, according to the Second Report of the Senate Standing Committee (1990). The negative psychological characteristics for AAS use is extensive and includes prominent hostility, aggressiveness, irritability, euphoria, grandiose beliefs, hyperactivity, reckless behavior, increased sexual appetite, unpredictability, poor impulse control, mood fluctuations, and insomnia. The drug may invoke a sense of power and invincibility (Leckman and Scahill, 1990). Depressive symptoms, such as anhedonia, fatigue, impaired concentration, decreased libido, and even suicidality (Pope and Katz, 1992) have been noted with steroid withdrawal. It appears that long-term users of AAS experience similar characteristics as other substance abusers (i.e., craving, dependence, and withdrawal symptoms).

  19. Targeting Neuropilin-1 in Prostate Cancer Bone Metastasis

    Science.gov (United States)

    2011-04-01

    metastasis. Prostate 2000;44: 91–103. 32. Beier F, LuValle P. The cyclin D1 and cyclin A genes are targets of activated PTH/ PTHrP receptors in Jansen’s...various stimuli, including parathyroid hormone (PTH), PTH related protein ( PTHrP ), calcitriol, tumor necrosis factor- (TNF-), glucocorticoids...Bone Cells Guise303 and Mundy304 presented the concept of a vicious cycle involving TGF produced by bone cells that promotes the production of PTHrP by

  20. In vivo transcription of two promoters, PTH4 and PTH270 involved in regulation of Streptomyces differentiation

    Institute of Scientific and Technical Information of China (English)

    谭华荣; 田宇清; 杨海花; 吴畏; 董可宁; Keith F.Chater

    1997-01-01

    The promoters, PTH4 and P-TH270 involved in the regulation of Streptomyces coelicolor differentiation were subcloned into Streptomyces promoter, i.e. probe plasmid pIJ4083, and the recombinant plasmids, pIJ4470 and pIJ4471, were constructed. Two promoters could drive the expression of reporter gene encoding catechol dioxygenase when pIJ4470 and pIJ4471 were introduced into some white mutants (C85, C70, C71, C17 and C119). The total RNA was isolated from these strains containing recombinant plasmid. Probes were prepared by labelling 5 -ends of PTH4 AND PTH270 DNA fragments using radioisotope. DNA - RNA hybridization was carried out with the probes and RNAs isolated from different strains. The S1 mapping result showed that all RNAs from strains of C85/pIJ4470, C85/4471, C70/pIJ4470, C70/pIJ4471 and C17/pIJ4470 as well as C17/pIJ4471 gave rise to strong positive hy-bridization signal, whereas RNAs from C71/pIJ4470 and C71/pIJ4471 did not give any positive signal. RNAs from C119/pIJ4470 and C119/pIJ4471 gav

  1. Skeletal changes in osteoprotegerin and receptor activator of nuclear factor-kappab ligand mRNA levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism

    DEFF Research Database (Denmark)

    Stilgren, L S; Rettmer, E; Eriksen, E F;

    2004-01-01

    (PHPT), hypersecretion of PTH leads to enhanced bone resorption and formation with increased risk of fracture. Decreasing PTH levels by surgery normalizes bone metabolism, but the effects on skeletal OPG and RANKL production are unknown. In this study, 24 patients referred to our clinic for evaluation...

  2. Effects of add on PTH(1-84) substitution therapy in hypoparathyroidism: results from a double-blind randomised controlled study

    DEFF Research Database (Denmark)

    Sikjær, Tanja Tvistholm; Rejnmark, Lars; Mosekilde, Leif

    -phosphate levels within the physiological range. Compared with placebo, participants randomised to PTH (1-84) reduced their daily dose of calcium supplements by 68 % (pvitamin D dose by 53% (p...Conventional treatment of hypoparathyroidism (hypoPT) with calcium supplements and active vitamin D analoges causes a high renal calcium excretion and over-mineralized bone. We studied 62 patients with known hypoPT randomised to 6 months of treatment with either PTH(1-84) 100 µg/d s.c. or similar...... and 7 were not in need of active vitamin D. With the actual add on therapy there were no change in renal calcium excretion in response to treatment. Compared with placebo, bone mineral density (BMD) decreased significantly at the hip (-1.59 ± 0.57%), lumbar spine (-1.76 ± 1.03%) and whole body (-1...

  3. Consequences of use of anabolic androgenic steroids.

    Science.gov (United States)

    Casavant, Marcel J; Blake, Kathleen; Griffith, Jill; Yates, Andrew; Copley, LaRae M

    2007-08-01

    Whether providing anticipatory guidance to the young adolescent patient, conducting a preparticipation examination on a young athlete, or treating a sick user of anabolic androgenic steroids (AASs), the primary care physician must be familiar with the adverse consequences of the use of these compounds. This article reviews the endocrine, cardiovascular, neuropsychiatric, musculoskeletal, hematologic, hepatic, and miscellaneous effects of AASs, highlighting effects reported in children and adolescents, and relying on consequences in adults when pediatric data is unavailable.

  4. Echocardiographic Finding in Anabolic Steroids Abuser Athletics

    OpenAIRE

    B. Haji Moradi; K. Fatahi

    2006-01-01

    Introduction & Objective: Abuse of anabolic steroids in body builders and competitive sports (doping) is common and prevalent in our country. Due to disagreement about cardiovascular side effects of these drugs and existing controversy in published articles, this study was designed to evaluate the echocardiographic finding in athletics who are current user of these drugs. Materials & Methods: Body builders with continues sport for preceding year and at least twice weekly selected and divided ...

  5. Relationship Between Aldosterone and Parathyroid Hormone, and the Effect of Angiotensin and Aldosterone Inhibition on Bone Health

    DEFF Research Database (Denmark)

    L.S., Bislev; T., Sikjaer; L., Rolighed

    2015-01-01

    Emerging evidence suggests a stimulating effect of parathyroid hormone (PTH) on the reninnullangiotensinnullaldosterone system (RAAS). In primary hyperparathyroidism, chronic-elevated PTH levels seem to stimulate the RAAS which may explain the increased risk of cardiovascular disease (CVD...... hyperparathyroidism due to increased renal calcium excretion. Moreover, the angiotensin II receptor is expressed by human parathyroid tissue, and angiotensin may therefore directly stimulates PTH secretion. An increased bone loss is found in patients with hyperaldosteronism. The angiotensin II receptor seems main...

  6. Alteração do teor de cálcio no banho de DP para 2,5 mEq/L é eficaz no reestabelecimento dos valores preconizados por diretrizes atuais em pacientes com PTH < 150 pg/dL Low-calcium peritoneal dialysis solution is effective in bringing PTH levels to the range recommended by current guidelines in patients with PTH levels < 150 pg/dL

    Directory of Open Access Journals (Sweden)

    Thyago Proença de Moraes

    2010-09-01

    Full Text Available INTRODUÇÃO/OBJETIVO: A doença óssea adinâmica (DOA é um achado comum em diálise peritoneal (PD e é considerada fator de risco para desenvolvimento de fraturas e doença cardiovascular. Dados do BRAZPD apontam as soluções de cálcio a 3,5 mEq/L presentes na maioria das prescrições no país, que possui quase 9.000 pacientes em PD. É comum o balanço positivo de cálcio com concentrações a 3,5 mEq/L contribuindo para o desenvolvimento de DOA. Diretrizes atuais recomendam um PTHi na DRC V em diálise entre 2 e 9 vezes (150-500 pg/mL o valor máximo da normalidade. O objetivo deste estudo foi avaliar a resposta em 6 meses do PTH-i após a conversão para solução de cálcio a 2,5 mEq/L de pacientes que usavam soluções com cálcio a 3,5 mEq/L e com PTH-i basal INTRODUCTION/OBJECTIVE: Adinamic bone disease (ABD is a common finding in peritoneal dialysis (PD and is associated with higher risk of developing cardiovascular and bone disease. Data from BRAZPD indicates that 3.5 mEq/L calcium PD solutions represents the majority of PD prescriptions in the country. A positive calcium balance can contribute to ABD development. Currently guidelines suggest that PTH-i levels in end stage renal disease should be kept from 150-300 pg/mL. The purpose of this study is to evaluate 6 month PTH-i response after conversion to 2.5 mEq/L calcium PD solution in patients with baseline PTH-i levels < 150 pg/mL. METHODS: Prospective, observational study of all prevalent patients (at least 90 days on therapy on PD of a single Brazilian center from January 2008 to May 2009. Inclusion criteria (1 be in use of a PD solution with 3.5mEq/L of calcium; (2 baseline PTH leves < 150 pg/ mL. According to clinical practice patients could be switched to PD solutions with 2.5 mEq/L of calcium. RESULTS: 35 patients (age 62 ± 17 years were included. Of these 22 were converted to 2.5 mEq/L calcium solutions. Diabetic nephropathy (36% was the main cause of renal disease

  7. Impact of parathyroid hormone on bone marrow-derived stem cell mobilization and migration

    Institute of Scientific and Technical Information of China (English)

    Bruno; C; Huber; Ulrich; Grabmaier; Stefan; Brunner

    2014-01-01

    Parathyroid hormone(PTH) is well-known as the principal regulator of calcium homeostasis in the human body and controls bone metabolism via actions on the survival and activation of osteoblasts. The intermittent administration of PTH has been shown to stimulate bone production in mice and men and therefore PTH administration has been recently approved for the treatment of osteoporosis. Besides to its physiological role in bone remodelling PTH has been demonstrated to influence and expand the bone marrow stem cell niche where hematopoietic stem cells, capable of both self-renewal and differentiation, reside. Moreover, intermittent PTH treatment is capable to induce mobilization of progenitor cells from the bone marrow into the bloodstream. This novel function of PTH on modulating the activity of the stem cell niche in the bone marrow as well as on mobilization and regeneration of bone marrow-derived stem cells offers new therapeutic options in bone marrow and stem cell transplantation as well as in the field of ischemic disorders.

  8. Unfocused Extracorporeal Shock Waves Induce Anabolic Effects in Rat Bone

    NARCIS (Netherlands)

    O.P. van der Jagt (Olav); T.M. Piscaer (Tom); W. Schaden (Wolfgang); J. Li; N. Kops (Nicole); H. Jahr (Holger); J.C. van der Linden (Jacqueline); J.H. Waarsing (Jan); J.A.N. Verhaar (Jan); M. de Jong (Marion); H.H. Weinans (Harrie)

    2011-01-01

    textabstractAbstract. BACKGROUND: Extracorporeal shock waves are known to stimulate the differentiation of mesenchymal stem cells toward osteoprogenitors and induce the expression of osteogenic-related growth hormones. The aim of this study was to investigate if and how extracorporeal shock waves af

  9. Unfocused Extracorporeal Shock Waves Induce Anabolic Effects in Rat Bone

    NARCIS (Netherlands)

    O.P. van der Jagt (Olav); T.M. Piscaer (Tom); W. Schaden (Wolfgang); J. Li; N. Kops (Nicole); H. Jahr (Holger); J.C. van der Linden (Jacqueline); J.H. Waarsing (Jan); J.A.N. Verhaar (Jan); M. de Jong (Marion); H.H. Weinans (Harrie)

    2011-01-01

    textabstractAbstract. BACKGROUND: Extracorporeal shock waves are known to stimulate the differentiation of mesenchymal stem cells toward osteoprogenitors and induce the expression of osteogenic-related growth hormones. The aim of this study was to investigate if and how extracorporeal shock waves

  10. ALX 111: ALX1-11, parathyroid hormone (1-84) - NPS Allelix, PREOS, PTH, recombinant human parathyroid hormone, rhPTH (1-84).

    Science.gov (United States)

    2003-01-01

    ALX 111 [parathyroid hormone (1-84) - NPS Allelix, recombinant human parathyroid hormone, rhPTH (1-84), PREOS] is a full-length, recombinant human parathyroid hormone. It has potential as an anti-osteoporotic agent, due to its properties as a bone formation stimulant. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It has been recommended that ALX 111 should be given for 1 to 2 years and may be given in combination with an antiresorptive agent, such as estrogen or a bisphosphonate. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. NPS harmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. Until 1994, Allelix Biopharmaceuticals and Glaxo in Canada were involved in a joint venture to investigate the efficacy of ALX 111 in osteoporosis. Allelix was subsequently, until September 1998, collaborating with Astra of Sweden in developing ALX 111. Astra had acquired exclusive worldwide rights to ALX 111 and was responsible for development of the agent. However, Astra returned all rights to ALX 111 to Allelix as a result of its merger with Zeneca to form AstraZeneca. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. The phase III trial of ALX 111 for the treatment of osteoporosis has completed patient enrolment, and phase II trials have been completed in Canada and the Netherlands. The 18-month, phase III, multicentre, placebo-controlled trial (Treatment of Osteoporosis with

  11. [Rhabdomyolysis in a bodybuilder using anabolic steroids].

    Science.gov (United States)

    Hageloch, W; Appell, H J; Weicker, H

    1988-09-01

    The clinical course and the laboratory findings of a massive rhabdomyolysis in a male bodybuilder is presented. Particularly spectacular are the light- and electron-microscopical pictures of the histological findings. The acute renal failure as the most important and major life-threatening complication of the rhabdomyolysis is considered and the successful therapeutic procedure is described. The probability of a causal relation between anabolic steroids and rhabdomyolysis is discussed as well as the resulting consequences for the care of athletes in sports medicine.

  12. Fluoride inhibits the response of bone cells to mechanical loading

    NARCIS (Netherlands)

    Willems, H.M.E.; van den Heuvel, E.G.H.M.; Castelein, S.; Keverling Buisman, J.; Bronckers, A.L.J.J.; Bakker, A.D.; Klein-Nulend, J.

    2011-01-01

    The response of bone cells to mechanical loading is mediated by the cytoskeleton. Since the bone anabolic agent fluoride disrupts the cytoskeleton, we investigated whether fluoride affects the response of bone cells to mechanical loading, and whether this is cytoskeleton mediated. The mechano-respon

  13. Fluoride inhibits the response of bone cells to mechanical loading

    NARCIS (Netherlands)

    Willems, H.M.E.; van den Heuvel, E.G.H.M.; Castelein, S.; Keverling Buisman, J.; Bronckers, A.L.J.J.; Bakker, A.D.; Klein-Nulend, J.

    2011-01-01

    The response of bone cells to mechanical loading is mediated by the cytoskeleton. Since the bone anabolic agent fluoride disrupts the cytoskeleton, we investigated whether fluoride affects the response of bone cells to mechanical loading, and whether this is cytoskeleton mediated. The

  14. Association between very low PTH levels and poor survival rates in haemodialysis patients: results from the French ARNOS cohort.

    Science.gov (United States)

    Jean, G; Lataillade, D; Genet, L; Legrand, E; Kuentz, F; Moreau-Gaudry, X; Fouque, D

    2011-01-01

    A very low parathyroid hormone (PTH) level (VLPL) is associated with an increased risk of adynamic bone disease, vascular calcification, and mortality in haemodialysis (HD) patients. The aim of the study was to assess the frequency, the associated factors, and the prognosis of non-surgical VLPL in a cohort of prevalent HD patients. In July 2005, a cross-sectional study was performed on the French ARNOS cohort in 1,348 prevalent HD patients from 24 dialysis centres in the Rhône-Alpes area. Patients with a baseline intact PTH level <50 pg/ml (VLPL, Group 1) and ≥ 50 pg/ml (Group 2) were compared and a 42-month survival analysis was performed. Patients with prevalent or incident parathyroidectomy were excluded. We studied 1,138 prevalent HD patients. As compared to patients of Group 2 (n = 1,019), patients with VLPL (Group 1, n = 119) had lower serum albumin levels (34.5 ± 5 vs. 36.4 ± 5 g/l, p < 0.0001), less protein intake (nPCR 0.99 ± 0.28 vs. 1.1 ± 0.28 g/kg/day, p = 0.01), higher calcaemia (2.30 ± 0.2 vs. 2.26 ± 0.2 mmol/l, p = 0.01) and were more frequently treated with calcium carbonate (67 vs. 54%, p < 0.001). Patients with VLPL had a higher mortality rate (HR: 1.4 (1.07-1.8), p = 0.006) after adjustment for age, gender, diabetes, and dialysis vintage. The odds ratios of mortality for patients with VLPL remained higher in all calcaemia and serum albumin quartiles. Only 3/119 patients in Group 1 did not receive any PTH-lowering therapies (i.e. calcium carbonate (67%), alfacalcidol (38%), cinacalcet (10.1%), and dialysate calcium ≥ 1.5 mmol/l (94%)). In this observational French cohort, VLPL was observed in 10% of prevalent HD patients and was associated with poor survival rates. An inadequate therapeutic strategy could be responsible for this observation. The real consequences of this iatrogenic adynamic bone disease remain hypothetical, but it may be related to the risk of developing vascular calcification. It is hypothesized that a more adequate

  15. Acute myocardial infarction in a young man using anabolic steroids.

    Science.gov (United States)

    Wysoczanski, Mariusz; Rachko, Maurice; Bergmann, Steven R

    2008-01-01

    Anabolic-androgenic steroids are used worldwide to help athletes gain muscle mass and strength. Their use and abuse is associated with numerous side effects, including acute myocardial infarction (MI). We report a case of MI in a young 31-year-old bodybuilder. Because of the serious cardiovascular complications of anabolic steroids, physicians should be aware of their abuse and consequences.

  16. Anabolic-androgenic steroids for alcoholic liver disease

    DEFF Research Database (Denmark)

    Rambaldi, A; Gluud, C

    2006-01-01

    Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease.......Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease....

  17. Effect on thyroid function and serum PTH, BGP, CT of small dose of iodine 131 combined with Methimazole in patients with hyperthyroidism

    Institute of Scientific and Technical Information of China (English)

    Jia-Yin Qiu; Yan Zhu; Qing-Hong Xi

    2016-01-01

    Objective:To observe the effect Effect on thyroid function and serum PTH, BGP, CT of small dose of iodine 131 combined with Methimazole in patients with hyperthyroidism. Methods:A total of 104 patients with hyperthyroidism willing be incorporated into the study were randomly divided into the observation group (54 cases) and the control group (50 cases). The control group was treated with Methimazole, and the observation group was given a small dose of iodine 131 the basised on the control group. For 2 months, to observe the changes of thyroid function (TT3, TT4, FT3, FT4 and TSH) and bone metabolism related indexes (PTH, BGP and CT) of the two groups. Results:(1) After treatment, TT3, FT3, TT4 and FT4 of the two groups decreased with before, and the observation group improved more significantly than the control group, with statistical difference;TSH of the two groups had no significant change. (2) After treatment, BGP and CT of the two groups decreased and PTH increased, the observation group improved more significantly than the control group, with statistical difference. Conclusion:small dose of iodine 131 combined with Methimazole can correct thyroid function and bone metabolism quickly in patients with hyperthyroidism.

  18. Mechanisms of ligand binding to the parathyroid hormone (PTH)/PTH-related protein receptor: selectivity of a modified PTH(1-15) radioligand for GalphaS-coupled receptor conformations.

    Science.gov (United States)

    Dean, Thomas; Linglart, Agnes; Mahon, Matthew J; Bastepe, Murat; Jüppner, Harald; Potts, John T; Gardella, Thomas J

    2006-04-01

    Mechanisms of ligand binding to the PTH/PTHrP receptor (PTHR) were explored using PTH fragment analogs as radioligands in binding assays. In particular, the modified amino-terminal fragment analog, (125)I-[Aib(1,3),Nle8,Gln10,homoarginine11,Ala12,Trp14,Tyr15]rPTH(1-15)NH2, (125)I-[Aib(1,3),M]PTH(1-15), was used as a radioligand that we hypothesized to bind solely to the juxtamembrane (J) portion of the PTHR containing the extracellular loops and transmembrane helices. We also employed (125)I-PTH(1-34) as a radioligand that binds to both the amino-terminal extracellular (N) and J domains of the PTHR. Binding was examined in membranes derived from cells expressing either wild-type or mutant PTHRs. We found that the binding of (125)I-[Aib(1,3),M]PTH(1-15) to the wild-type PTHR was strongly (approximately 90%) inhibited by guanosine 5'-O-(3-thio)triphosphate (GTPgammaS), whereas the binding of (125)I-PTH(1-34) was only mildly (approximately 25%) inhibited by GTPgammaS. Of these two radioligands, only (125)I-[Aib(1,3),M]PTH(1-15) bound to PTHR-delNt, which lacks most of the receptor's N domain, and again this binding was strongly inhibited by GTPgammaS. Binding of (125)I-[Aib(1,3),M]PTH(1-15) to the constitutively active receptor, PTHR-H223R, was only mildly (approximately 20%) inhibited by GTPgammaS, as was the binding of (125)I-PTH(1-34). In membranes prepared from cells lacking Galpha(S) via knockout mutation of Gnas, no binding of (125)I-[Aib(1,3),M]PTH(1-15) was observed, but binding of (125)I-[Aib(1,3),M]PTH(1-15) was recovered by virally transducing the cells to heterologously express Galpha(S). (125)I-PTH(1-34) bound to the membranes with or without Galpha(S). The overall findings confirm the hypothesis that (125)I-[Aib(1,3),M]PTH(1-15) binds solely to the J domain of the PTHR. They further show that this binding is strongly dependent on coupling of the receptor to Galpha(S)-containing heterotrimeric G proteins, whereas the binding of (125)I-PTH(1-34) can occur

  19. Mechanisms of Ligand Binding to the Parathyroid Hormone (PTH)/PTH-Related Protein Receptor: Selectivity of a Modified PTH(1–15) Radioligand for GαS-Coupled Receptor Conformations

    Science.gov (United States)

    Dean, Thomas; Linglart, Agnes; Mahon, Matthew J.; Bastepe, Murat; Jüppner, Harald; Potts, John T.; Gardella, Thomas J.

    2011-01-01

    Mechanisms of ligand binding to the PTH/PTHrP receptor (PTHR) were explored using PTH fragment analogs as radioligands in binding assays. In particular, the modified amino-terminal fragment analog, 125I-[Aib1,3,Nle8,Gln 10,homoarginine11,Ala12 Trp14,Tyr15]rPTH(1–15)NH2, 125I-[Aib1,3,M]PTH(1–15), was used as a radioligand that we hypothesized to bind solely to the juxtamembrane (J) portion of the PTHR containing the extracellular loops and transmembrane helices. We also employed 125I-PTH(1– 34) as a radioligand that binds to both the amino-terminal extracellular (N) and J domains of the PTHR. Binding was examined in membranes derived from cells expressing either wild-type or mutant PTHRs. We found that the binding of 125I-[Aib1,3,M]PTH(1–15) to the wild-type PTHR was strongly (∼90%) inhibited by guanosine 5′-O-(3-thio)triphosphate (GTPγS), whereas the binding of 125I-PTH(1–34) was only mildly (∼25%) inhibited by GTPγS. Of these two radioligands, only 125I-[Aib1,3,M]PTH(1–15) bound to PTHR-delNt, which lacks most of the receptor's N domain, and again this binding was strongly inhibited by GTPγS. Binding of 125I-[Aib1,3,M]PTH(1–15) to the constitutively active receptor, PTHR-H223R, was only mildly (∼20%) inhibited by GTPγS, as was the binding of 125I-PTH(1–34). In membranes prepared from cells lacking GαS via knockout mutation of Gnas, no binding of 125I-[Aib1,3,M]PTH(1–15) was observed, but binding of 125I-[Aib1,3,M]PTH(1–15) was recovered by virally transducing the cells to heterologously express GαS. 125I-PTH(1–34) bound to the membranes with or without GαS. The overall findings confirm the hypothesis that 125I-[Aib1,3,M]PTH(1–15) binds solely to the J domain of the PTHR. They further show that this binding is strongly dependent on coupling of the receptor to GαS-containing heterotrimeric G proteins, whereas the binding of 125I-PTH(1–34) can occur in the absence of such coupling. Thus, 125I-[Aib1,3,M]PTH(1–15) appears to

  20. Novel mutations in PTH1R associated with primary failure of eruption and osteoarthritis.

    Science.gov (United States)

    Frazier-Bowers, S A; Hendricks, H M; Wright, J T; Lee, J; Long, K; Dibble, C F; Bencharit, S

    2014-02-01

    Autosomal dominant mutations in PTH1R segregate with primary failure of eruption (PFE), marked by clinical eruption failure of adult teeth without mechanical obstruction. While the diagnosis of PFE conveys a poor dental prognosis, there are no reports of PFE patients who carry PTH1R mutations and exhibit any other skeletal problems. We performed polymerase chain reaction-based mutational analysis of the PTH1R gene to determine the genetic contribution of PTH1R in 10 families with PFE. Sequence analysis of the coding regions and intron-exon boundaries of the PTH1R gene in 10 families (n = 54) and 7 isolated individuals revealed 2 novel autosomal dominant mutations in PTH1R (c.996_997insC and C.572delA) that occur in the coding region and result in a truncated protein. One family showed incomplete penetrance. Of 10 families diagnosed with PFE, 8 did not reveal functional (nonsynonymous) mutations in PTH1R; furthermore, 4 families and 1 sporadic case carried synonymous single-nucleotide polymorphisms. Five PFE patients in 2 families carried PTH1R mutations and presented with osteoarthritis. We propose that the autosomal dominant mutations of PTH1R that cause PFE may also be associated with osteoarthritis; a dose-dependent model may explain isolated PFE and osteoarthritis in the absence of other known symptoms in the skeletal system.

  1. Parathyroid Hormone (1-34 Might Not Improve Early Bone Healing after Sinus Augmentation in Healthy Rabbits

    Directory of Open Access Journals (Sweden)

    Jisun Huh

    2017-01-01

    Full Text Available Purpose. This study evaluated the effect of administering intermittent parathyroid hormone [PTH (1-34, henceforth PTH] on the early-stage bone healing of maxillary sinus augmentation in healthy rabbits. Materials and Methods. Bovine bone mineral was grafted on the sinuses of 20 female New Zealand white rabbits. The animals were randomly divided into two groups, PTH (n=10 or saline (n=10, in which either PTH or saline was injected subcutaneously 5 days a week for 2 weeks. Half of the animals in each group were killed at 2 weeks postoperatively and the other half were killed at 4 weeks postoperatively. The dosage of PTH was 10 μg/kg/day. Radiographic and histomorphometric analyses were performed. Result. The new bone area (NBA did not differ significantly between the PTH and saline groups. The NBA in the PTH group in the total augmented area and in the demarcated window, center, and Schneiderian membrane regions increased significantly from 2 to 4 weeks. The number of osteoclasts decreased significantly from 2 to 4 weeks in both groups, with no difference between the two groups. Conclusion. Intermittent PTH might not stimulate new bone formation in healthy rabbits during the first 4 weeks of healing.

  2. Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators.

    Science.gov (United States)

    Thevis, Mario; Schänzer, Wilhelm

    2010-01-01

    The central role of testosterone in the development of male characteristics, as well as its beneficial effects on physical performance and muscle growth, has led to the search for synthetic alternatives with improved pharmacological profiles. Hundreds of steroidal analogs have been prepared with a superior oral bioavailability, which should also possess reduced undesirable effects. However, only a few entered the pharmaceutical market due to severe toxicological incidences that were mainly attributed to the lack of tissue selectivity. Prominent representatives of anabolic-androgenic steroids (AAS) are for instance methyltestosterone, metandienone and stanozolol, which are discussed as model compounds with regard to general pharmacological aspects of synthetic AAS. Recently, nonsteroidal alternatives to AAS have been developed that selectively activate the androgen receptor in either muscle tissue or bones. These so-called selective androgen receptor modulators (SARMs) are currently undergoing late clinical trials (IIb) and will be prohibited by the World Anti-Doping Agency from January 2008. Their entirely synthetic structures are barely related to steroids, but particular functional groups allow for the tissue-selective activation or inhibition of androgen receptors and, thus, the stimulation of muscle growth without the risk of severe undesirable effects commonly observed in steroid replacement therapies. Hence, these compounds possess a high potential for misuse in sports and will be the subject of future doping control assays.

  3. Synergistic effects of high dietary calcium and exogenous parathyroid hormone in promoting osteoblastic bone formation in mice

    OpenAIRE

    Feng, Yuxu; Zhou, Min; Zhang, Qunhu; Liu, Huan; Xu, Yong; Shu, Lei; Zhang, Jue; Miao, Dengshun; Ren, Yongxin

    2015-01-01

    In the present study, we investigated whether high dietary Ca and exogenous parathyroid hormone 1–34 fragments (PTH 1–34) have synergistic effects on bone formation in adult mice, and explored the related mechanisms. Adult male mice were fed a normal diet, a high-Ca diet, a PTH-treated diet, or a high-Ca diet combined with subcutaneously injected PTH 1–34 (80 μg/kg per d) for 4 weeks. Bone mineral density, trabecular bone volume, osteoblast number, alkaline phosphatase (ALP)- and type I colla...

  4. Anabolic steroids for treating pressure ulcers.

    Science.gov (United States)

    Naing, Cho; Whittaker, Maxine A

    2017-06-20

    Pressure ulcers, also known as bed sores, pressure sores or decubitus ulcers develop as a result of a localised injury to the skin or underlying tissue, or both. The ulcers usually arise over a bony prominence, and are recognised as a common medical problem affecting people confined to a bed or wheelchair for long periods of time. Anabolic steroids are used as off-label drugs (drugs which are used without regulatory approval) and have been used as adjuvants to usual treatment with dressings, debridement, nutritional supplements, systemic antibiotics and antiseptics, which are considered to be supportive in healing of pressure ulcers. Anabolic steroids are considered because of their ability to stimulate protein synthesis and build muscle mass. Comprehensive evidence is required to facilitate decision making, regarding the benefits and harms of using anabolic steroids. To assess the effects of anabolic steroids for treating pressure ulcers. In March 2017 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. Published or unpublished randomised controlled trials (RCTs) comparing the effects of anabolic steroids with alternative treatments or different types of anabolic steroids in the treatment of pressure ulcers. Two review authors independently carried out study selection, data extraction and risk of bias assessment. The review contains only one trial with a total of 212 participants, all with spinal cord injury and open pressure ulcers classed as stage III and IV. The participants were

  5. Echocardiographic Finding in Anabolic Steroids Abuser Athletics

    Directory of Open Access Journals (Sweden)

    B. Haji Moradi

    2006-01-01

    Full Text Available Introduction & Objective: Abuse of anabolic steroids in body builders and competitive sports (doping is common and prevalent in our country. Due to disagreement about cardiovascular side effects of these drugs and existing controversy in published articles, this study was designed to evaluate the echocardiographic finding in athletics who are current user of these drugs. Materials & Methods: Body builders with continues sport for preceding year and at least twice weekly selected and divided into steroid abuser and not abuser and compared with age and BMI matched non athletic healthy volunteers .Results: There was not significant difference in age, body mass index, ejection fraction, ventricular compliance and valve function between three groups. But diastolic size of septum and free wall is significantly thicker in both of athletics in comparison with non athletic volunteer but observed differences were only significant (Pvalue = 0.05 between first and third group. The difference between the above mentioned index was not significant between two groups of athleticConclusion: Observed differences in diastolic size of septum and free wall between first and third group and also absence of difference between two athletic groups is in favor of that long term abuse of anabolic steroid (more than one year results in augmentation of physiologic hypertrophy due to isometric exercise. Furthermore long term abuse and supra pharmacologic dose does not have significant effect in size and left ventricular function.

  6. Lanthanum carbonate stimulates bone formation in a rat model of renal insufficiency with low bone turnover.

    Science.gov (United States)

    Fumoto, Toshio; Ito, Masako; Ikeda, Kyoji

    2014-09-01

    Control of phosphate is important in the management of chronic kidney disease with mineral and bone disorder (CKD-MBD), for which lanthanum carbonate, a non-calcium phosphate-binding agent, has recently been introduced; however, it remains to be determined whether it has any beneficial or deleterious effect on bone remodeling. In the present study, the effects of lanthanum carbonate were examined in an animal model that mimics low turnover bone disease in CKD, i.e., thyroparathyroidectomized (TPTX) and 5/6 nephrectomized (NX) rats undergoing a constant infusion of parathyroid hormone (PTH) and thyroxine injections (TPTX-PTH-5/6NX). Bone histomorphometry at the second lumbar vertebra and tibial metaphysis revealed that both bone formation and resorption were markedly suppressed in the TPTX-PTH-5/6NX model compared with the sham-operated control group, and treatment with lanthanum carbonate was associated with the stimulation of bone formation but not an acceleration of bone resorption. Lanthanum treatment caused a robust stimulation of bone formation with an activation of osteoblasts on the endosteal surface of femoral diaphysis, leading to an increase in cortical bone volume. Thus, lanthanum carbonate has the potential to stimulate bone formation in cases of CKD-MBD with suppressed bone turnover.

  7. Rat parathyroid hormone (rPTH) ELISAs specific for regions (2-7), (22-34) and (40-60) of the rat PTH structure: influence of sex and age.

    Science.gov (United States)

    D'Amour, Pierre; Rousseau, Louise; Hornyak, Stephen; Yang, Zan; Cantor, Tom

    2010-09-15

    Rat (r) PTH ELISAs were used to study the influence of age and sex on rPTH levels and circulating PTH molecular forms separated by HPLC. Standard curves and saturation analysis were undertaken to define epitopes. Rats were sacrificed at approximately 27, 47 and 75days. Relevant biochemical parameters and 25(OH) vitamin D were measured. Differences between sexes were analyzed by Kruskal-Wallis ANOVA, followed by Dunn's test. Epitopes were localized in regions 2-7, 22-34 and 40-60 of rPTH structure for whole (W), total (T) and carboxyl (C) rPTH ELISAs. The W-rPTH assay only detected rPTH(1-84) and N-PTH in circulation while the T-PTH assay further detected large C-rPTH fragments. The C-rPTH assay detected all circulating rPTH molecular forms including smaller C-rPTH fragments. In both sexes, weight (p<0.001), ionized calcium, creatinine, albumin and 25(OH)D values (p<0.001) increased with age, while phosphate and alkaline phosphatase decreased (p<0.001). In male rats, W-rPTH remained unchanged, while T-rPTH rose slightly (p<0.05) and C-rPTH declined by half with time (p<0.001). In female rats, W-rPTH (p<0.05), T-rPTH (p<0.001) and C-rPTH (p<0.01) all increased in older animals. In both sexes, C-rPTH/W-rPTH and C-rPTH/T-rPTH ratios decreased between 25 and 47 days, to rise again between 47 and 75 days. The initial decrease may represent an adaptation to weaning and a change of diet between 25 and 47 days while the rise corresponds to higher calcium and 25(OH)D levels between 47 and 75 days. These changes were more pronounced in female rats, indicating an influence of sex on PTH molecular form secretion or metabolism.

  8. Recreational football improves bone mineral density and bone turnover marker profile in elderly men

    DEFF Research Database (Denmark)

    Helge, E W; Andersen, T R; Schmidt, J F;

    2014-01-01

    This study examined the effect of recreational football and resistance training on bone mineral density (BMD) and bone turnover markers (BTMs) in elderly men. Twenty-six healthy sedentary men (age 68.2 ± 3.2 years) were randomized into three groups: football (F; n = 9) and resistance training (R; n...... training had no effect. The anabolic response may be due to increased bone turnover, especially improved bone formation....

  9. Effect of Deletion of the Prostaglandin EP2 Receptor on the Anabolic Response to Prostaglandin E2 and a Selective EP2 Receptor Agonist

    OpenAIRE

    Choudhary, Shilpa; Alander, Cynthia; Zhan, Peili; Gao, Qi; Pilbeam, Carol; Raisz, Lawrence

    2008-01-01

    Studies using prostaglandin E receptor (EP) agonists indicate that prostaglandin (PG) E2 can have anabolic effects through both EP4 and EP2 receptors. We previously found that the anabolic response to a selective EP4 receptor agonist (EP4A, Ono Pharmaceutical) was substantially greater than to a selective EP2 receptor agonist (EP2A) in cultured murine calvarial osteoblastic cells. To further define the role of the EP2 receptor in PG-mediated effects on bone cells, we examined the effects of E...

  10. 21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are...

  11. PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling

    Science.gov (United States)

    Kollert, Sina; Rukoyatkina, Natalia; Sturm, Julia; Gambaryan, Stepan; Stellzig-Eisenhauer, Angelika; Meyer-Marcotty, Philipp; Eigenthaler, Martin; Wischmeyer, Erhard

    2016-01-01

    Aim Primary failure of tooth eruption (PFE) is causally linked to heterozygous mutations of the parathyroid hormone receptor (PTH1R) gene. The mutants described so far lead to exchange of amino acids or truncation of the protein that may result in structural changes of the expressed PTH1R. However, functional effects of these mutations have not been investigated yet. Materials and Methods In HEK293 cells, PTH1R wild type was co-transfected with selected PTH1R mutants identified in patients with PFE. The effects on activation of PTH-regulated intracellular signaling pathways were analyzed by ELISA and Western immunoblotting. Differential effects of wild type and mutated PTH1R on TRESK ion channel regulation were analyzed by electrophysiological recordings in Xenopus laevis oocytes. Results In HEK293 cells, activation of PTH1R wild type increases cAMP and in response activates cAMP-stimulated protein kinase as detected by phosphorylation of the vasodilator stimulated phosphoprotein (VASP). In contrast, the PTH1R mutants are functionally inactive and mutant PTH1R/Gly452Glu has a dominant negative effect on the signaling of PTH1R wild type. Confocal imaging revealed that wild type PTH1R is expressed on the cell surface, whereas PTH1R/Gly452Glu mutant is mostly retained inside the cell. Furthermore, in contrast to wild type PTH1R which substantially augmented K+ currents of TRESK channels, coupling of mutated PTH1R to TRESK channels was completely abolished. Conclusions PTH1R mutations affect intracellular PTH-regulated signaling in vitro. In patients with primary failure of tooth eruption defective signaling of PTH1R mutations is suggested to occur in dento-alveolar cells and thus may lead to impaired tooth movement. PMID:27898723

  12. A salt bridge between Arg-20 on parathyroid hormone (PTH) and Asp-137 on the PTH1 receptor is essential for full affinity.

    Science.gov (United States)

    Weaver, Richard E; Wigglesworth, Mark J; Donnelly, Dan

    2014-11-01

    Parathyroid hormone (PTH) acts via the receptor PTH1 and plays an important role in calcium homeostasis. PTH's interaction with the N-terminal domain of PTH1 is mediated in part by Arg-20 on the peptide which forms a number of interactions with the receptor: a charge-charge interaction with Asp-137; hydrogen bonds with the backbone of Asp-29 and Met-32; and hydrophobic interactions with Met-32 and Gln-37. The aim of this work was to establish the importance of the charge-charge interaction through the combined use of modified peptide ligands, site-directed mutations of the receptor, and pharmacological assays. The substitution of Arg-20 with norleucine resulted in a 50-fold reduction in potency at PTH1 and Asp-137-Glu while, in contrast, both Asp-137-Asn and Asp-137-Ala receptors were largely insensitive to this ligand modification. The effect of this removal of the positive charge as position 20 could be partially rescued at PTH1 and Asp-137-Glu, but not Asp-137-Asn and Asp-137-Ala, through a substitution of peptide position 20 with ornithine. The latter two receptors, which have no negative charge at position 137, displayed potency for PTH that was reduced by 40- and 117-fold, respectively. These data demonstrate that a negative charge at residue-137 is important for interacting with ligands containing a positive charge at residue-20, and that the Arg-20 interaction with Asp-137, observed in the crystal structure of the isolated N-terminal domain of PTH1, is likely to be present in the full length receptor where it provides an important affinity- and potency-generating interaction through a salt bridge. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Runx1 is critical for PTH-induced onset of mesenchymal progenitor cell chondrogenic differentiation.

    Directory of Open Access Journals (Sweden)

    Jinwu Wang

    Full Text Available Parathyroid hormone (PTH plays a critical role in the regulation of chondrogenesis. In this study, we have found for the first time that Runt-related transcription factor 1 (Runx1 contributes to PTH-induced chondrogenesis. Upon PTH treatment, limb bud mesenchymal progenitor cells in micromass culture showed an enhanced chondrogenesis, which was associated with a significant increase of chondrogenic marker gene expression, such as type II collagen and type X collagen. Runx1 was also exclusively expressed in cells treated with PTH at the onset stage of chondrogenesis. Knockdown of Runx1 completely blunted PTH-mediated chondrogenesis. Furthermore, PTH induced Runx1 expression and chondrogenesis were markedly reduced by inhibition of protein kinase A (PKA signaling. Taken together, our present study indicates that chondrogenesis induced by PTH in mesenchymal progenitor cells is mediated by Runx1, which involves the activation of PKA. These data provide a novel insight into understanding the molecular mechanisms behind PTH-enhanced cartilage regeneration.

  14. Anabolic androgenic steroid-induced hepatotoxicity.

    Science.gov (United States)

    Bond, Peter; Llewellyn, William; Van Mol, Peter

    2016-08-01

    Anabolic androgenic steroids (AAS) have been abused for decades by both professional and amateur athletes in order to improve physical performance or muscle mass. AAS abuse can cause adverse effects, among which are hepatotoxic effects. These effects include cholestatic icterus and possibly peliosis hepatis and hepatocellular carcinoma or adenoma. In particular, 17α-alkylated AAS appear to be hepatotoxic, whereas nonalkylated AAS appear not to be. The 17α-alkyl substitution retards hepatic metabolism of the AAS rendering it orally bioavailable. The mechanism responsible for the hepatotoxicity induced by 17α-alkylated AAS remains poorly understood. However, oxidative stress has been repeatedly shown to be associated with it. In this manuscript we present a hypothesis which describes a potential mechanism responsible for AAS-induced hepatotoxicity, based on several observations from the literature which suggest oxidative stress being a causal factor.

  15. Therapeutic effect of human parathyroid hormone1 - 34 ( rhPTH1 - 34) on osteoporosis of ovariectomized rats%rhPTH(1-34)对骨质疏松大鼠的作用及对sclerostin的影响

    Institute of Scientific and Technical Information of China (English)

    富勇; 唐永亮; 赵承斌; 张军

    2011-01-01

    [目的]探讨人重组甲状旁腺素1 - 34(rhPTH1 - 34)对骨质疏松的治疗作用以及与血钙、磷代谢和生长因子的关系.[方法]用摘除大鼠双侧卵巢的方式制备骨质疏松模型,实验动物分为3个组:模型对照组(OVX组,摘除大鼠双侧卵巢不作任何处理);rhPTH1 - 34治疗组(PTH组,摘除大鼠双侧卵巢12周后用rhPTH1 - 34治疗8周);假手术组(sham组,仅切除卵巢周围的脂肪组织约3 g,术后12周纳入实验).应用第4代双能X线骨密度仪测量大鼠股骨上段骨密度值(BMD);用ELISA法测定血清硬化蛋白(sclerostin)水平及骨钙素(BGP)浓度;用自动生化仪测定血清碱性磷酸酶(ALP).[结果]rhPTH1 - 34治疗组、sham组均较OVX组股骨上段骨密度增高,组间比较差异有显著性(P<0.01).rhPTH1 - 34治疗组血清BGP浓度值升高及sclerostin值降低,与OVX组比较差异有显著性(P<0.01).各组血清钙、磷含量无明显变化,与OVX组比较差异无显著性,ALP值治疗组与OVX组无明显差异.[结论] rhPTHl - 34能够预防股骨上段骨密度丢失,并且血清BGP浓度值升高及sclerostin值降低,但对Ca、P、ALP含量无明显作用.%[Objective] To observe the therapeutic effect of human parathyroid hormonel -34 (rhPTHl -34) on osteoporosis of ovariectomized rats and its relation to blood calcium, phosphorus and growth factors. [Methods] Seventy - four ovariectomized (OVX) rats were divided into model control group (OVX group without any treatment) , rhPTHl -34 treatment group ( PTH group with treatment for 8 weeks) , and sham operation group. BMD of femur were measured with Hologic dual energy X - ray 4500 W bone desitometer in rats. Serum sclerostin levels and BGP concentrations were determined by ELISA. [Results] BMD of the femur in rhPTHl - 34 group and sham group were higher than those in OVX control group ( P < 0. 01) . The serum sclerostin and BGP in rhPTHl -34 group were significantly different with OVX control group (P

  16. [Research progresses of anabolic steroids analysis in doping control].

    Science.gov (United States)

    Long, Yuanyuan; Wang, Dingzhong; Li, Ke'an; Liu, Feng

    2008-07-01

    Anabolic steroids, a kind of physiological active substance, are widely abused to improve athletic performance in human sports. They have been forbidden in sports by the International Olympic Committee since 1983. Since then, many researchers have been focusing their attentions on the establishment of reliable detection methods. In this paper, we review the research progresses of different analytical methods for anabolic steroids since 2002, such as gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry, immunoassay, electrochemistry analysis and mass spectrometry. The developing prospect of anabolic steroids analysis is also discussed.

  17. Multiple arterial thromboses associated with anabolic androgenic steroids.

    Science.gov (United States)

    McCulloch, Neil Arthur; Abbas, Jonathan Raihan; Simms, Malcolm Harold

    2014-03-01

    The use of supraphysiological doses of anabolic androgenic steroids can have serious side effects. This article reports the case of a young man who suffered potentially life-threatening arterial thromboses following the use of these drugs.

  18. Medical issues associated with anabolic steroid use: are they exaggerated?

    Science.gov (United States)

    Hoffman, Jay R; Ratamess, Nicholas A

    2006-01-01

    For the past 50 years anabolic steroids have been at the forefront of the controversy surrounding performance enhancing drugs. For almost half of this time no attempt was made by sports governing bodies to control its use, and only recently have all of the major sports governing bodies in North America agreed to ban from competition and punish athletes who test positive for anabolic steroids. These punitive measures were developed with the primary concern for promotion of fair play and eliminating potential health risks associated with androgenic-anabolic steroids. Yet, controversy exists whether these testing programs deter anabolic steroid use. Although the scope of this paper does not focus on the effectiveness of testing, or the issue of fair play, it is of interest to understand why many athletes underestimate the health risks associated from these drugs. What creates further curiosity is the seemingly well-publicized health hazards that the medical community has depicted concerning anabolic steroidabuse. Is there something that the athletes know, or are they simply naïve regarding the dangers? The focus of this review is to provide a brief history of anabolic steroid use in North America, the prevalence of its use in both athletic and recreational populations and its efficacy. Primary discussion will focus on health issues associated with anabolic steroid use with an examination of the contrasting views held between the medical community and the athletes that are using these ergogenic drugs. Existing data suggest that in certain circumstances the medical risk associated with anabolic steroid use may have been somewhat exaggerated, possibly to dissuade use in athletes. Key PointsFor many years the scientific and medical communities depicted a lack of efficacy and serious adverse effects from anabolic steroid use.Clinical case studies continue to link anabolic steroid administration with myocardial infarct, suicide, and cancer, evidence to support a cause and

  19. Medical Issues Associated with Anabolic Steroid Use: Are They Exaggerated?

    OpenAIRE

    2006-01-01

    For the past 50 years anabolic steroids have been at the forefront of the controversy surrounding performance enhancing drugs. For almost half of this time no attempt was made by sports governing bodies to control its use, and only recently have all of the major sports governing bodies in North America agreed to ban from competition and punish athletes who test positive for anabolic steroids. These punitive measures were developed with the primary concern for promotion of fair play and elimin...

  20. ANABOLIC-ANDROGENIC STEROID DEPENDENCE? INSIGHTS FROM ANIMALS AND HUMANS

    OpenAIRE

    Wood, Ruth I.

    2008-01-01

    Anabolic-androgenic steroids (AAS) are drugs of abuse. They are taken in large quantities by athletes and others to increase performance, with negative health consequences. As a result, in 1991 testosterone and related AAS were declared controlled substances. However, the relative abuse and dependence liability of AAS have not been fully characterized. In humans, it is difficult to separate the direct psychoactive effects of AAS from reinforcement due to their systemic anabolic effects. Howev...

  1. MEDICAL ISSUES ASSOCIATED WITH ANABOLIC STEROID USE: ARE THEY EXAGGERATED?

    Directory of Open Access Journals (Sweden)

    Jay R. Hoffman

    2006-06-01

    Full Text Available For the past 50 years anabolic steroids have been at the forefront of the controversy surrounding performance enhancing drugs. For almost half of this time no attempt was made by sports governing bodies to control its use, and only recently have all of the major sports governing bodies in North America agreed to ban from competition and punish athletes who test positive for anabolic steroids. These punitive measures were developed with the primary concern for promotion of fair play and eliminating potential health risks associated with androgenic-anabolic steroids. Yet, controversy exists whether these testing programs deter anabolic steroid use. Although the scope of this paper does not focus on the effectiveness of testing, or the issue of fair play, it is of interest to understand why many athletes underestimate the health risks associated from these drugs. What creates further curiosity is the seemingly well-publicized health hazards that the medical community has depicted concerning anabolic steroidabuse. Is there something that the athletes know, or are they simply naïve regarding the dangers? The focus of this review is to provide a brief history of anabolic steroid use in North America, the prevalence of its use in both athletic and recreational populations and its efficacy. Primary discussion will focus on health issues associated with anabolic steroid use with an examination of the contrasting views held between the medical community and the athletes that are using these ergogenic drugs. Existing data suggest that in certain circumstances the medical risk associated with anabolic steroid use may have been somewhat exaggerated, possibly to dissuade use in athletes

  2. Anabolic-androgenic steroids for alcoholic liver disease

    DEFF Research Database (Denmark)

    Rambaldi, A; Iaquinto, G; Gluud, C

    2003-01-01

    Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease.......Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease....

  3. The Multifactorial Role of Peripheral Nervous System in Bone Growth

    Directory of Open Access Journals (Sweden)

    Ioannis Gkiatas

    2017-09-01

    Full Text Available Bone alters its metabolic and anabolic activities in response to the variety of systemic and local factors such as hormones and growth factors. Classical observations describing abundance of the nerve fibers in bone also predict a paradigm that the nervous system influences bone metabolism and anabolism. Since 1916 several investigators tried to analyze the effect of peripheral nervous system in bone growth and most of them advocated for the positive effect of innervation in the bones of growing organisms. Moreover, neuronal tissue controls bone formation and remodeling. The purpose of this mini-review is to present the most recent data concerning the influence of innervation on bone growth, the current understanding of the skeletal innervation and their proposed physiological effects on bone metabolism as well as the implication of denervation in human skeletal biology in the developing organism since the peripheral neural trauma as well as peripheral neuropathies are common and they have impact on the growing skeleton.

  4. Serum phosphorus adds to value of serum parathyroid hormone for assessment of bone turnover in renal osteodystrophy.

    Science.gov (United States)

    Gentry, Jimmy; Webb, Jonathan; Davenport, Daniel; Malluche, Hartmut H

    2016-07-01

    It is well-established that parathyroid hormone (PTH) correlates with the level of bone turnover in patients with chronic kidney disease stage 5D (CKD-5D). Hyperphosphatemia is a well-established complication of end-stage renal disease and is usually attributed to dietary intake. This study evaluates the relationship between serum phosphorus levels and bone turnover in patients with CKD-5D. 93 patients with CKD-5D from the Kentucky Bone Registry who had sequentially undergone anterior iliac bone biopsies were reviewed. Undecalcified bone sections were qualitatively assessed for turnover and placed into a group with low turnover and a group with non-low (normal/high) turnover. Results of PTH and phosphorus concentrations in blood drawn at the time of biopsies were compared between the groups. PTH and phosphorus levels were significantly higher in the non-low turnover group compared to the low turnover group. Cutoff levels for PTH and phosphorus were tested for predictive power of bone turnover. Both PTH and phosphorus correlated with turnover. Adding serum phosphorus to serum PTH enhanced predictive power of PTH for low turnover. The vast majority of patients with serum phosphorus levels ≥ 6.0 mg/dL had non-low turnover, while the majority of those with low turnover had phosphorus values 6.2 mg/dL) in patients with PTH 4.55 mg/dL ruled out low turnover bone disease. This suggests that not only dietary intake but also bone affects serum phosphorus levels.

  5. Optical and thermal properties of PTh-co-PANI-Ti random copolymer composite for photovoltaic application

    Directory of Open Access Journals (Sweden)

    Sanjay R. Takpire

    2015-12-01

    Full Text Available In thе present work, a polythiophene (PTh-co-polyaniline (PANI-titanium (Ti copolymer has been synthesized as a novel copolymeric composite material for photovoltaic (PV application. The focus of the study was to evaluate optical and thermal properties of the PTh-co-PANI-Ti copolymer containing different types of monomers. The optical conductivity was determined from the UV–VIS spectra that were used to calculate the extinction coefficients. The structure and morphology of composite was analyzed through field emission-electron microscopy (FESEM. The PTh-co-PANI-Ti copolymer composite exhibited significant photovoltaic (PV response to light intensity. J–V analysis showed an increase in conversion efficiency from 0.21 to 1.5 of PTh-co-PANi-Ti with illumination light intensity. PV properties demonstrated that the PTh-co-PANI-Ti exhibited the highest power conversion efficiency ɳ=1.5, with a short circuit current Isc=0.72mA, an open circuit voltage Voc=0.9V and a fill factor FF=0.51. Thermo-gravimetric (TG and differential thermal (DTA analyses were carried out for the thermal stability of the PTh-co-PANI-Ti copolymer composite. The results obtained from the characterization of PTh-co-PANI-Ti showed that many properties of PV action are present in as-synthesized material.

  6. ASSOCIATION OF PARATHYROID HORMONE GENE POLYMORPHISM WITH BONE MINERAL DENSITY IN CHINESE WOMEN

    Institute of Scientific and Technical Information of China (English)

    李梅; 孟迅吾; 周学瀛; 邢小平; 余卫

    2003-01-01

    Objective. To investigate the distribution frequency of parathyroid hormone(PTH) gene polymorphism in healthy adults from Bejing area and to explore the association of PTH genotypes with bone mineral density (BMD). Methods. PTH gene polymorphism was detected in 270 subjects by polymerase chain reaction (PCR) and PCR/restriction fragment length polymorphism (PCR/RFLP). The digestion products of restriction enzyme Bst B1 were separated on 1% agarose gels. PTH genotypes were confirmed by DNA sequences analysis. BMD was measured by dual-energy X-ray absorptiometry (DEXA, DPX- L, Lunar). Results. Genotype frequencies of BB, Bb, bb were 73.7% , 25.9% and 0.4% respectively in Beijing adults( P0.05). Conclusion. PTH gene polymorphism is not associated with BMD in Chinese women. The further research to explore the genetic risk factors of osteoporosis should be committed.

  7. Relationship between vitamin D, parathyroid hormone, and bone health.

    Science.gov (United States)

    Sai, A J; Walters, R W; Fang, X; Gallagher, J C

    2011-03-01

    There is a controversy regarding the definition of vitamin D insufficiency as it relates to bone health. The objective of the study was to examine the evidence for a threshold value of serum 25-hydroxyvitamin D (25OHD) that defines vitamin D insufficiency as it relates to bone health. This was a cross-sectional analysis of baseline data in 488 elderly Caucasian women, mean age 71 yr, combined with a literature review of 70 studies on the relationship of serum PTH to serum 25OHD. The study was conducted in independent-living women in the midwest United States. The relationship between serum 25OHD, serum PTH, and serum osteocalcin and 24-h urine N-telopeptides was evaluated. Serum PTH was inversely correlated with serum 25OHD (r = -0.256, P bone markers, serum osteocalcin and urine N-telopeptides, that increased only below a serum 25OHD of approximately 18 ng/ml (45 nmol/liter). Calcium absorption was not correlated with serum PTH and serum 25OHD, and no threshold was found. A literature review of 70 studies generally showed a threshold for serum PTH with increasing serum 25OHD, but there was no consistency in the threshold level of serum 25OHD that varied from 10 to 50 ng/ml (25-125 nmol/liter). Vitamin D insufficiency should be defined as serum 25OHD less than 20 ng/ml (50 nmol/liter) as it relates to bone.

  8. Parathyroid hormone and parathyroid hormone-related protein analogs as therapies for osteoporosis.

    Science.gov (United States)

    Augustine, Marilyn; Horwitz, Mara J

    2013-12-01

    Osteoporotic fractures result in significant morbidity and mortality. Anabolic agents reverse the negative skeletal balance that characterizes osteoporosis by stimulating osteoblast-dependent bone formation to a greater degree than osteoclast-dependent bone resorption. Parathyroid hormone (PTH) and parathyroid hormone- related protein (PTHrP) are peptide hormones, which have anabolic actions when administered intermittently. The only FDA-approved anabolic bone agent for the treatment of osteoporosis in the United States is PTH 1-34, or teriparatide, administered by daily subcutaneous injections. However, PTH 1-84 is also available in Europe. Synthetic human PTHrP 1-36 and a PTHrP 1-34 analog, BA058, have also been shown to increase lumbar spine bone density. These agents and several other PTH and PTHrP analogs, including some which are not administered as injections, continue to be investigated as potential anabolic therapies for osteoporosis.

  9. Decrease in the expression of the type 1 PTH/PTHrP receptor (PTH1R on chondrocytes in animals with osteoarthritis

    Directory of Open Access Journals (Sweden)

    Skwara Adrian

    2010-04-01

    Full Text Available Abstract Background To evaluate the expression of the type 1 PTH/PTHrP receptor (PTH1R on chondrocytes from hyaline cartilage over the course of osteoarthritis (OA. Methods In 12 NZW rabbits, the anterior cruciate ligament (ACL was resected to create anterior instability of the knee. In 12 control rabbits, only a sham operation, without resection of the ACL, was performed. Four animals from each group were killed at 3, 6, and 12 weeks. After opening the knee joint, OA was macroscopically graded and hyaline cartilage of the load-bearing area was evaluated histologically according to the Mankin scale and by immunostaining for PTH1R. Results There was a positive linear correlation between the time after surgery and the macroscopic and histologic OA scores. The scores in the control group were constant over the time course. Immunostaining showed significantly less expression of PTH1R in the experimental compared to the control group after 6 (P Conclusions The results show an in vivo decrease in the expression of PTH1R on chondrocytes over the time course of OA. Further studies are needed to evaluate whether new treatment approaches could evolve from this knowledge.

  10. In vitro vitamin K(2) and 1α,25-dihydroxyvitamin D(3) combination enhances osteoblasts anabolism of diabetic mice.

    Science.gov (United States)

    Poon, Christina C W; Li, Rachel W S; Seto, Sai Wang; Kong, Siu Kai; Ho, Ho Pui; Hoi, Maggie P M; Lee, Simon M Y; Ngai, Sai Ming; Chan, Shun Wan; Leung, George P H; Kwan, Yiu Wa

    2015-11-15

    In this study, we evaluated the anabolic effect and the underlying cellular mechanisms involved of vitamin K2 (10 nM) and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) (10 nM), alone and in combination, on primary osteoblasts harvested from the iliac crests of C57BL/KsJ lean (+/+) and obese/diabetic (db/db) mice. A lower alkaline phosphatase (ALP) activity plus a reduced expression of bone anabolic markers and bone formation transcription factors (osteocalcin, Runx2, Dlx5, ATF4 and OSX) were consistently detected in osteoblasts of db/db mice compared to lean mice. A significantly higher calcium deposits formation in osteoblasts was observed in lean mice when compared to db/db mice. Co-administration of vitamin K2 (10 nM) and 1,25(OH)2D3 (10 nM) caused an enhancement of calcium deposits in osteoblasts in both strains of mice. Vitamins K2 and 1,25(OH)2D3 co-administration time-dependently (7, 14 and 21 days) increased the levels of bone anabolic markers and bone formation transcription factors, with a greater magnitude of increase observed in osteoblasts of db/db mice. Combined vitamins K2 plus 1,25(OH)2D3 treatment significantly enhanced migration and the re-appearance of surface microvilli and ruffles of osteoblasts of db/db mice. Thus, our results illustrate that vitamins K2 plus D3 combination could be a novel therapeutic strategy in treating diabetes-associated osteoporosis.

  11. Mechanisms of Bone Mineralization and Effects of Mechanical Loading

    Science.gov (United States)

    Babich, Michael

    1996-01-01

    The data suggest that PTH and PKC inhibit nodule formation, and that alternative energy sources are utilized by osteoblasts in the process of mineralization. The conditions and techniques to grow, fix, photograph, and measure bone mineralization in vitro were defined. The results are presently in preliminary form and require further assessment as follows; quantitate the surface area of nodules + treatments via computer-aided image analysis; use PTH + inhibitors of signaling pathways to determine the mechanism of nodule formation; determine how protein kinase C is involved as a promotor of nodule formation; cell proliferation vs. cell death affected by modulation of signal transduction (i.e., PTH, enzyme inhibitors and activators); identify mRNA induced or decreased in response to PTH and signaling modulators that encode proteins that regulate cell morphology, proliferation, and nodule formation. Therefore, several follow-up studies between the laboratories at NASA-Ames Research Center and my laboratory at the University of Illinois have been initiated.

  12. Parathyroid Hormone Induces Bone Cell Motility and Loss of Mature Osteocyte Phenotype through L-Calcium Channel Dependent and Independent Mechanisms.

    Directory of Open Access Journals (Sweden)

    Matthew Prideaux

    Full Text Available Parathyroid Hormone (PTH can exert both anabolic and catabolic effects on the skeleton, potentially through expression of the PTH type1 receptor (PTH1R, which is highly expressed in osteocytes. To determine the cellular and molecular mechanisms responsible, we examined the effects of PTH on osteoblast to osteocyte differentiation using primary osteocytes and the IDG-SW3 murine cell line, which differentiate from osteoblast to osteocyte-like cells in vitro and express GFP under control of the dentin matrix 1 (Dmp1 promoter. PTH treatment resulted in an increase in some osteoblast and early osteocyte markers and a decrease in mature osteocyte marker expression. The gene expression profile of PTH-treated Day 28 IDG-SW3 cells was similar to PTH treated primary osteocytes. PTH treatment induced striking changes in the morphology of the Dmp1-GFP positive cells in IDG-SW3 cultures and primary cells from Dmp1-GFP transgenic mice. The cells changed from a more dendritic to an elongated morphology and showed increased cell motility. E11/gp38 has been shown to be important for cell migration, however, deletion of the E11/gp38/podoplanin gene had no effect on PTH-induced motility. The effects of PTH on motility were reproduced using cAMP, but not with protein kinase A (PKA, exchange proteins activated by cAMP (Epac, protein kinase C (PKC or phosphatidylinositol-4,5-bisphosphonate 3-kinase (Pi3K agonists nor were they blocked by their antagonists. However, the effects of PTH were mediated through calcium signaling, specifically through L-type channels normally expressed in osteoblasts but decreased in osteocytes. PTH was shown to increase expression of this channel, but decrease the T-type channel that is normally more highly expressed in osteocytes. Inhibition of L-type calcium channel activity attenuated the effects of PTH on cell morphology and motility but did not prevent the downregulation of mature osteocyte marker expression. Taken together, these

  13. A decrease in intact parathyroid hormone (iPTH) levels is associated with higher mortality in prevalent hemodialysis patients.

    Science.gov (United States)

    Villa-Bellosta, Ricardo; Rodriguez-Osorio, Laura; Mas, Sebastian; Abadi, Younes; Rubert, Mercedes; de la Piedra, Concepción; Gracia-Iguacel, Carolina; Mahillo, Ignacio; Ortiz, Alberto; Egido, Jesús; González-Parra, Emilio

    2017-01-01

    The mortality of dialysis patients is 10- to 100-fold higher than in the general population. Baseline serum PTH levels, and more recently, changes in serum PTH levels (ΔPTH) over time, have been associated to mortality in dialysis patients. We explored the relationship between ΔPTH over 1 year with mortality over the next year in a prospective cohort of 115 prevalent hemodialysis patients from a single center that had median baseline iPTH levels within guideline recommendations. Median baseline iPTH levels were 205 (116.5, 400) pg/ml. ΔiPTH between baseline and 1 year was 85.2 ± 57.1 pg/ml. During the second year of follow-up, 27 patients died. ΔiPTH was significantly higher in patients who survived (+157.30 ± 25.82 pg/ml) than in those who died (+39.03 ± 60.95 pg/ml), while baseline iPTH values were not significantly different. The highest mortality (48%) was observed in patients with a decrease in ΔiPTH (ΔiPTH quartile 1, negative ΔiPTH) and the lowest (12%) mortality in quartile 3 ΔiPTH (ΔiPTH increase 101-300 pg/ml). In a logistic regression model, ΔiPTH was associated with mortality with an odds ratio (OR) of 0.998 (95% CI 0.996-0999, p = 0.038). In multivariable analysis, mortality risk was 73% and 88% lower for patients with ΔiPTH 0-100 pg/ml and 101-300 pg/ml, respectively, than for those with a decrease in ΔiPTH. In patients with a decrease in ΔiPTH, the OR for death was 4.131 (1.515-11.27)(p = 0.006). In prevalent hemodialysis patients with median baseline iPTH values within the guideline recommended range, a decrease in ΔiPTH was associated with higher mortality. Further studies are required to understand the mechanisms and therapeutic implications of this observation that challenges current clinical practice.

  14. Anabolic-androgenic steroids and the adolescent.

    Science.gov (United States)

    Rogol, A D; Yesalis, C E

    1992-03-01

    This article has reviewed some of the hormonal and behavioral maturation that occurs during adolescence, which are characterized by remarkable physical changes and behavioral vulnerability. Risk taking of many varieties is common and drugs (including anabolic-androgenic steroids) form a part of the prevailing culture in many places. These steroids probably are not severe health hazards when taken intermittently and in low to moderate doses. The 17-alkylated derivatives are clearly the more likely to cause hepatotoxicity. Thus, the scare tactics formerly used (severe constitutional side effects) are doomed to failure. The tenuous link between these drugs and objective behavioral and addictive effects must be strengthened before health strategies based on this issue can be validated. Clearly, the lack of scientific information has impeded, if not precluded, the formulation of an effective health education strategy. The most potent deterrent to the use of steroid drugs by athletes must be the moral issue of fair play and maintaining a "level playing field." We strongly support directed research in these areas and hope that the credibility of the scientific community can be regained after its faulted "stop steroid use" campaigns based on the lack of steroid efficacy in bringing about desired results or on their dire consequences have been replaced with credible evidence to refute their use on these and other grounds.

  15. Bone mineral density and markers of bone turnover in patients with renal transplantation and regular hemodialysis

    Directory of Open Access Journals (Sweden)

    Samir M. Ibrahim,. Khalid H Abdel-Mageed, Magdi M El-Sharkawy

    2002-09-01

    Full Text Available Background: Decreased bone mineral density (BMD is a known complication for the uremic state antedating dialysis / renal transplantation (RTx. The issue of stabilized versus continued decrease of BMD especially on long-term basis, continues to be unresolved. Patients and Methods: !"#"hemodialysis (HD-#" $% " &'( &'(-group had been evaluated for metabolic bone changes by calcium homeostasis parameters (serum calcium, phosphorus, alkaline phosphatase "ALP" and vitamin D "calcitriol", markers of bone formation (bone alkaline phosphatase "BAP", osteocalcin "OC", N-terminal propeptide of collagen type I "PINP", bone resorption markers (pyridoline "PYL" and deoxypyridoline "DPYL", and intact parathyroid hormone (iPTH. Also, BMD had been assessed by dual energy x-ray absorptiometry (DEXA twice, at inclusion time and * ! "" Results: comparing both groups regarding calcium homeostasis, markers of bone turnover and iPTH showed non significant difference. However, there was a significant drop of BMD (as evidenced by T-score at follow up in the HD group, compared to stabilization of T-score for the RTx-group. Furthermore, annual T-score change was significantly more in HD-group, compared to RTx-group. Results also showed that, the best marker correlating with T-score annual changes and iPTH to be PINP. Irrespective of normal calcium homeostasis parameters, low BMD is a prevalent disorder among patients on regular HD and renal transplants.Conclusion: Follow up for * ! " %+ ,- ." % """"!to continued bone loss in patients on regular HD. This could raise recommendation for calcium and calcitriol supplementation, especially in the predialysis period, early post transplantation period, and continued guided replacement for those on maintenance HD. Serum PINP showed best correlations with BMD changes and iPTH and could be considered a reliable marker reflecting bone formation in those patients. Keywords: hemodialysis, renal transplantation, markers of bone

  16. Oxytocin and bone

    Science.gov (United States)

    Sun, Li; Zaidi, Mone; Zallone, Alberta

    2014-01-01

    One of the most meaningful results recently achieved in bone research has been to reveal that the pituitary hormones have profound effect on bone, so that the pituitary-bone axis has become one of the major topics in skeletal physiology. Here, we discuss the relevant evidence about the posterior pituitary hormone oxytocin (OT), previously thought to exclusively regulate parturition and breastfeeding, which has recently been established to directly regulate bone mass. Both osteoblasts and osteoclasts express OT receptors (OTR), whose stimulation enhances bone mass. Consistent with this, mice deficient in OT or OTR display profoundly impaired bone formation. In contrast, bone resorption remains unaffected in OT deficiency because, even while OT stimulates the genesis of osteoclasts, it inhibits their resorptive function. Furthermore, in addition to its origin from the pituitary, OT is also produced by bone marrow osteoblasts acting as paracrine-autocrine regulator of bone formation modulated by estrogens. In turn, the power of estrogen to increase bone mass is OTR-dependent. Therefore, OTR−/− mice injected with 17β-estradiol do not show any effects on bone formation parameters, while the same treatment increases bone mass in wild-type mice. These findings together provide evidence for an anabolic action of OT in regulating bone mass and suggest that bone marrow OT may enhance the bone-forming action of estrogen through an autocrine circuit. This established new physiological role for OT in the maintenance of skeletal integrity further suggests the potential use of this hormone for the treatment of osteoporosis. PMID:25209411

  17. Estradiol increases hematopoietic stem and progenitor cells independent of its actions on bone

    NARCIS (Netherlands)

    Illing, Anett; Liu, Peng; Ostermay, Susanne; Schilling, Arndt; de Haan, Gerald; Krust, Andree; Amling, Michael; Chambon, Pierre; Schinke, Thorsten; Tuckermann, Jan P.

    2012-01-01

    Hematopoietic stem and progenitor cells reside in vascular and endosteal niches in the bone marrow. Factors affecting bone remodeling were reported to influence numbers and mobilization of hematopoietic stem cells. We therefore analyzed the effects of estradiol acting anabolic on bone integrity. Her

  18. P12 - PTHC1: A Continuing Cell Line Expressing PTH and Genes Involved in Calcium Homeostasis

    OpenAIRE

    Fabbri, S.; Mazzotta, C.; Ciuffi, S.; Mavilia, C; Galli, G; Zonefrati, R.; Strigoli, D.; Cavalli, L.; Cavalli, T.; Brandi, M L

    2010-01-01

    The main organs regulating serum levels of ionised calcium (Ca2+) are the parathyroids, which are composed of two different cell types: chief cells and oxyphil cells. Chief cells, through the calcium sensing receptor (CaSR), are affected by changes in calcium concentration, modifying PTH secretion in proportion to calcium levels. Current understanding of calcium regulation mechanisms connected to PTH and of the signalling pathways involved derive from in vitro studies carried out on primary c...

  19. Androgenic anabolic steroid use among male adolescents in Falkenberg.

    Science.gov (United States)

    Nilsson, S

    1995-01-01

    Recent reports show that androgenic anabolic steroids are used by many teenagers, not as a deliberate attempt to give them strength, better athletic performance, etc., but to improve their looks. The so-called macho cult among young boys tempts them into using androgenic anabolic steroids to give them bigger muscles and a more powerful appearance. This study was undertaken to investigate the prevalence of androgenic anabolic steroid use among teenagers in a small town and to create a platform for future work with the aim of decreasing the misuse of these drugs. In Falkenberg, a town in the county of Halland in the west of Sweden, the pupils at two high schools were investigated by means of an anonymous multiple-choice questionnaire. A total of 1383 students (688 males and 695 females) aged 14-19 years participated in the study, giving a participation rate of 96%. The number of answers completed was 99%. The use of androgenic anabolic steroids is a reality among male teenagers in Falkenberg, with 5.8% of them using the drugs. Among 15- to 16-year-old boys misuse of these drugs is as high as 10%, and of these 50% (5.0% of total) also inject ampoules of the drugs. This prevalence is alarming since the adverse effects of androgenic anabolic steroids are more serious in teenagers. Serious action must be taken to inform teenagers of the consequences of misusing drugs.

  20. Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats.

    Science.gov (United States)

    Curtis, Ryan C; Custis, James T; Ehrhart, Nicole P; Ehrhart, E J; Condon, Keith W; Gookin, Sara E; Donahue, Seth W

    2016-01-01

    Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma.

  1. PTH modulation of NCC activity regulates TRPV5 Ca2+ reabsorption.

    Science.gov (United States)

    Hoover, Robert S; Tomilin, Viktor; Hanson, Lauren; Pochynyuk, Oleh; Ko, Benjamin

    2016-01-15

    Since parathyroid hormone (PTH) is known to increase transient receptor potential vanilloid (TRPV)5 activity and decrease Na(+)-Cl(-) cotransporter (NCC) activity, we hypothesized that decreased NCC-mediated Na(+) reabsorption contributes to the enhanced TRPV5 Ca(2+) reabsorption seen with PTH. To test this, we used mDCT15 cells expressing functional TRPV5 and ruthenium red-sensitive (45)Ca(2+) uptake. PTH increased (45)Ca(2+) uptake to 8.8 ± 0.7 nmol·mg(-1)·min(-1) (n = 4, P NCC activity from 75.4 ± 2.7 to 20.3 ± 1.3 nmol·mg(-1)·min(-1) (n = 4, P NCC is required for RasGRP1 knockdown to impact the PTH effect on TRPV5 activity. Knockdown of with no lysine kinase (WNK)4 resulted in an attenuation of the increase in PTH-mediated TRPV5 activity. TRPV5 activity increased by 36% compared with 45% in control (n = 4, P NCC activity contributes to the response to PTH, implying a role for hormonal modulation of NCC activity in distal Ca(2+) handling.

  2. [Abuse of anabolic steroids and its impact on thyroid function].

    Science.gov (United States)

    Fortunato, Rodrigo S; Rosenthal, Doris; Carvalho, Denise P de

    2007-12-01

    The use of anabolic steroids to increase physical performance and for aesthetic ends has reached alarming indices in the last three decades. Besides the desired actions, several collateral effects have been described in the literature, such as the development of some types of cancer, ginecomasty, peliosis hepatis, renal insufficiency, virilization, amongst others. The most proeminent effect on human thyroid function is the reduction of thyroxine binding globulin (TBG), with consequent reductions of total serum T3 and T4, depending however on the susceptibility of the drug to aromatization and subsequent transformation into estrogen. In rats, anabolic steroids also act in the peripheral metabolism of thyroid hormones and seem to exert an important proliferative effect on thyroid cells. Thus, the aim of the present paper is to review data on the effect of supraphysiological doses of anabolic steroids on thyroid function, showing the danger that indiscriminate use of these drugs can cause to health.

  3. The response of bone to unloading

    Science.gov (United States)

    Bikle, D. D.; Halloran, B. P.

    1999-01-01

    Skeletal unloading leads to decreased bone formation and decreased bone mass. Bone resorption is uncoupled from bone formation, contributing to the bone loss. During spaceflight bone is lost principally from the bones most loaded in the 1-g environment, and some redistribution of bone from the lower extremities to the head appears to take place. Although changes in calcitropic hormones have been demonstrated during skeletal unloading (PTH and 1,25(OH)2D decrease), it remains unclear whether such changes account for or are in response to the changes in bone formation and resorption. Bed rest studies with human volunteers and hindlimb elevation studies with rats have provided useful data to help explain the changes in bone formation during spaceflight. These models of skeletal unloading reproduce a number of the conditions associated with microgravity, and the findings from such studies confirm many of the observations made during spaceflight. Determining the mechanism(s) by which loading of bone is sensed and translated into a signal(s) controlling bone formation remains the holy grail in this field. Such investigations couple biophysics to biochemistry to cell and molecular biology. Although studies with cell cultures have revealed biochemical responses to mechanical loads comparable to that seen in intact bone, it seems likely that matrix-cell interactions underlie much of the mechanocoupling. The role for systemic hormones such as PTH, GH, and 1,25(OH)2D compared to locally produced factors such as IGF-I, PTHrP, BMPs, and TGF-beta in modulating the cellular response to load remains unclear. As the mechanism(s) by which bone responds to mechanical load with increased bone formation are further elucidated, applications of this knowledge to other etiologies of osteoporosis are likely to develop. Skeletal unloading provides a perturbation in bone mineral homeostasis that can be used to understand the mechanisms by which bone mineral homeostasis is maintained, with

  4. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis.

    Science.gov (United States)

    Li, Xiaodong; Ominsky, Michael S; Warmington, Kelly S; Morony, Sean; Gong, Jianhua; Cao, Jin; Gao, Yongming; Shalhoub, Victoria; Tipton, Barbara; Haldankar, Raj; Chen, Qing; Winters, Aaron; Boone, Tom; Geng, Zhaopo; Niu, Qing-Tian; Ke, Hua Zhu; Kostenuik, Paul J; Simonet, W Scott; Lacey, David L; Paszty, Chris

    2009-04-01

    The development of bone-rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin's role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency-induced bone loss, at which point Scl-AbII was administered for 5 wk. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. Taken together, these preclinical results establish sclerostin's role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.

  5. [Bone Cell Biology Assessed by Microscopic Approach. Micro- and nanomechanical analysis of bone].

    Science.gov (United States)

    Saito, Masami; Hongo, Hiromi

    2015-10-01

    For Stiffness, we have several ways, Vicker's, Nano Indentor and NanoIndentation with AFM. Recent study needs several nm, tens of nm scale lateral resolution. For this request, AFM supply new technology, PeakForce QNM®, is only way to measure sub molecular level modulus mapping. In this article, introduce several data and specially talk about bone modulus near osteocytic lacunae treated with PTH which is considering to resolve bone matrix around the osteocytic lacunae.

  6. Evidence of associations between feto-maternal vitamin D status, cord parathyroid hormone and bone-specific alkaline phosphatase, and newborn whole body bone mineral content

    Science.gov (United States)

    In spite of a high prevalence of vitamin D inadequacy in pregnant women and neonates, relationships among vitamin D status [25(OH)D], parathyroid hormone (PTH), bone specific alkaline phosphatase (BALP), and whole body bone mineral content (WBBMC) in the newborn are poorly characterized. The purpose...

  7. On the Free Energy That Drove Primordial Anabolism

    Directory of Open Access Journals (Sweden)

    Michael Kaufmann

    2009-04-01

    Full Text Available A key problem in understanding the origin of life is to explain the mechanism(s that led to the spontaneous assembly of molecular building blocks that ultimately resulted in the appearance of macromolecular structures as they are known in modern biochemistry today. An indispensable thermodynamic prerequisite for such a primordial anabolism is the mechanistic coupling to processes that supplied the free energy required. Here I review different sources of free energy and discuss the potential of each form having been involved in the very first anabolic reactions that were fundamental to increase molecular complexity and thus were essential for life.

  8. [Anabolic androgenic steroids in amateur sports in the Netherlands].

    Science.gov (United States)

    Woerdeman, Jorn; de Hon, Olivier; Levi, Marcel; de Ronde, W Pim

    2010-01-01

    In the Netherlands an estimated 20,000 people use anabolic androgenic steroids (AAS). The use of AAS is particularly common in regular visitors to gyms and fitness centres. AAS are usually synthetic derivatives of testosterone with both an anabolic and an androgenic effect. AAS have many side effects like liver damage (oral use) or infections (intramuscular use), which can be explained partly by the androgenic effect and partly by the manner of use. Many of these side effects are only reported in case studies and have not been systematically investigated.

  9. [Myocardial infarction and anabolic steroid use. A case report].

    Science.gov (United States)

    Godon, P; Bonnefoy, E; Guérard, S; Munet, M; Velon, S; Brion, R; Touboul, P

    2000-07-01

    The potential cardiotoxicity of anabolic steroids is not well known. The authors report the case of a young man who was a top class body builder and who developed severe ischaemic cardiomyopathy presenting with an inferior wall myocardial infarction. The clinical history revealed prolonged and intensive usage of two types of anabolic steroids to be the only risk factor. This cardiotoxicity may be related to several physiopathological mechanisms: accelerated atherogenesis by lipid changes, increased platelet aggregation, coronary spasm or a direct toxic effect on the myocytes. The apparent scarcity of the reported clinical details in the literature is probably an underestimation of the consequences of this usage.

  10. Anabolic steroids: what should the emergency physician know?

    Science.gov (United States)

    Brown, James T

    2005-08-01

    Anabolic steroids have not currently made their way into the daily practice of emergency physicians. The patients that use and abuse them have. In addition, those patients that are suffering from the consequences of illnesses that have excess levels of androgens are commonly evaluated in the emergency department. Clinicians should familiarize themselves with the practices of anabolic steroid users, so they can provide more beneficial council to their patients. As research continues, the emergency physician may find uses for androgens within the emergency department.

  11. Manifestation of severe coronary heart disease after anabolic drug abuse.

    Science.gov (United States)

    Mewis, C; Spyridopoulos, I; Kühlkamp, V; Seipel, L

    1996-02-01

    Anabolic steroids are frequently abused, thus increasing the risk of cardiovascular disease, despite the known unfavorable influence on lipid profiles. We report on a young bodybuilder who presented with ventricular tachycardia as the first manifestation of severe underlying coronary heart disease. Coronary angiogram revealed severe stenotic lesions in the right coronary artery and the left descending coronary artery, and hypokinetic regions corresponded to posterolateral and anterior myocardial infarctions. This young patient had a history without any coronary risk factors, but with a 2-year abuse of the anabolic steroid stanazolol. No report published so far has shown possible atherogenic consequences of long-term abuse of stanazolol.

  12. 21 CFR 1308.25 - Exclusion of a veterinary anabolic steroid implant product; application.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Exclusion of a veterinary anabolic steroid implant... OF JUSTICE SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.25 Exclusion of a veterinary anabolic steroid implant product; application. (a) Any person...

  13. Follicle-stimulating hormone increases bone mass in female mice.

    Science.gov (United States)

    Allan, Charles M; Kalak, Robert; Dunstan, Colin R; McTavish, Kirsten J; Zhou, Hong; Handelsman, David J; Seibel, Markus J

    2010-12-28

    Elevated follicle-stimulating hormone (FSH) activity is proposed to directly cause bone loss independent of estradiol deficiency in aging women. Using transgenic female mice expressing human FSH (TgFSH), we now reveal that TgFSH dose-dependently increased bone mass, markedly elevating tibial and vertebral trabecular bone volume. Furthermore, TgFSH stimulated a striking accrual of bone mass in hypogonadal mice lacking endogenous FSH and luteinizing hormone (LH) function, showing that FSH-induced bone mass occurred independently of background LH or estradiol levels. Higher TgFSH levels increased osteoblast surfaces in trabecular bone and stimulated de novo bone formation, filling marrow spaces with woven rather than lamellar bone, reflective of a strong anabolic stimulus. Trabecular bone volume correlated positively with ovarian-derived serum inhibin A or testosterone levels in TgFSH mice, and ovariectomy abolished TgFSH-induced bone formation, proving that FSH effects on bone require an ovary-dependent pathway. No detectable FSH receptor mRNA in mouse bone or cultured osteoblasts or osteoclasts indicated that FSH did not directly stimulate bone. Therefore, contrary to proposed FSH-induced bone loss, our findings demonstrate that FSH has dose-dependent anabolic effects on bone via an ovary-dependent mechanism, which is independent of LH activity, and does not involve direct FSH actions on bone cells.

  14. Role of amino acid side chains in region 17-31 of parathyroid hormone (PTH) in binding to the PTH receptor.

    Science.gov (United States)

    Dean, Thomas; Khatri, Ashok; Potetinova, Zhanna; Willick, Gordon E; Gardella, Thomas J

    2006-10-27

    The principal receptor-binding domain (Ser(17)-Val(31)) of parathyroid hormone (PTH) is predicted to form an amphiphilic alpha-helix and to interact primarily with the N-terminal extracellular domain (N domain) of the PTH receptor (PTHR). We explored these hypotheses by introducing a variety of substitutions in region 17-31 of PTH-(1-31) and assessing, via competition assays, their effects on binding to the wild-type PTHR and to PTHR-delNt, which lacks most of the N domain. Substitutions at Arg(20) reduced affinity for the intact PTHR by 200-fold or more, but altered affinity for PTHR-delNt by 4-fold or less. Similar effects were observed for Glu substitutions at Trp(23), Leu(24), and Leu(28), which together form the hydrophobic face of the predicted amphiphilic alpha-helix. Glu substitutions at Arg(25), Lys(26), and Lys(27) (which forms the hydrophilic face of the helix) caused 4-10-fold reductions in affinity for both receptors. Thus, the side chains of Arg(20), together with those composing the hydrophobic face of the ligand's putative amphiphilic alpha-helix, contribute strongly to PTHR-binding affinity by interacting specifically with the N domain of the receptor. The side chains projecting from the opposite helical face contribute weakly to binding affinity by different mechanisms, possibly involving interactions with the extracellular loop/transmembrane domain region of the receptor. The data help define the roles that side chains in the binding domain of PTH play in the PTH-PTHR interaction process and provide new clues for understanding the overall topology of the bimolecular complex.

  15. The pleiotropic effects of paricalcitol: Beyond bone-mineral metabolism.

    Science.gov (United States)

    Egido, Jesús; Martínez-Castelao, Alberto; Bover, Jordi; Praga, Manuel; Torregrosa, José Vicente; Fernández-Giráldez, Elvira; Solozábal, Carlos

    2016-01-01

    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. Copyright © 2015 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  16. Small Molecule Binding, Docking, and Characterization of the Interaction between Pth1 and Peptidyl-tRNA

    Directory of Open Access Journals (Sweden)

    Mary C. Hames

    2013-11-01

    Full Text Available Bacterial Pth1 is essential for viability. Pth1 cleaves the ester bond between the peptide and nucleotide of peptidyl-tRNA generated from aborted translation, expression of mini-genes, and short ORFs. We have determined the shape of the Pth1:peptidyl-tRNA complex using small angle neutron scattering. Binding of piperonylpiperazine, a small molecule constituent of a combinatorial synthetic library common to most compounds with inhibitory activity, was mapped to Pth1 via NMR spectroscopy. We also report computational docking results, modeling piperonylpiperazine binding based on chemical shift perturbation mapping. Overall these studies promote Pth1 as a novel antibiotic target, contribute to understanding how Pth1 interacts with its substrate, advance the current model for cleavage, and demonstrate feasibility of small molecule inhibition.

  17. Prevent and cure disuse bone loss

    Science.gov (United States)

    Jee, Webster S. S.

    1994-01-01

    Anabolic agents like parathyroid hormone and postagladin E-like substances were studied in dogs and rats to determine their effectiveness in the prevention and cure of bone loss due to immobilization. It was determined that postagladin E2 administration prevented immobilization while at the same time it added extra bone in a dose responsive manner. Although bone mass returns, poor trabecular architecture remains after normal ambulation recovery from immobilization. Disuse related bone loss and poor trabecular architecture were cured by post-immobilization postagladin E2 treatment.

  18. Experience with a third-generation parathyroid hormone assay (BIO-PTH) in the diagnosis of primary hyperparathyroidism in a Brazilian population.

    Science.gov (United States)

    Bonanséa, Teresa Cristina P; Ohe, Monique Nakayama; Brandão, Cynthia; Ferrer, Cláudia de Francischi; Santos, Lívia Marcela; Lazaretti-Castro, Marise; Vieira, José Gilberto Henriques

    2016-10-01

    To evaluate the usefulness of a third-generation PTH assay in the diagnosis of primary hyperparathyroidism (PHPT). Forty-one PHPT patients (4 men and 37 women) with 61.2 ± 10.9 (mean ± SD) years, were studied and had PTH levels measured with two different methods using the same immunochemiluminescent assay plataform (Elecsys 2010 System, Roche). We compared a second-generation assay (I-PTH) with a third-generation PTH assay (Bio-PTH). Two populations of 423 and 120 healthy adults with serum 25OHD levels above 25 ng/mL were used to define normal values in the I-PTH and Bio-PTH assays respectively. Normal PTH values based in the healthy adults population were 24.2-78.0 pg/mL for the I-PTH assay and 19.9-58.5 pg/mL for Bio-PTH assay. In PHPT patients, PTH values ranged from 67 to 553 pg/mL (median: 168 pg/mL) using the I-PTH assay and from 55 to 328 pg/mL (median: 111 pg/mL) using the Bio-PTH assay. Results obtained with the Bio-PTH assay were significantly lower (p Bio-PTH showed highly significant correlation (r = 0.952, p Bio PTH = 13.44 + 0.59 x intact PTH. PHPT patients had 25OHD levels ranging from 4 to 36 ng/mL (mean 16.2 ng/mL); 35 subjects (85.3%) had values bellow 25 ng/mL. Our results demonstrate that both second and third generation PTH methods are strongly correlated in PHPT patients and control subjects. Lower results with Bio-PTH tests are expected in function of the assay specificity determined by the amino-terminal antibody used.

  19. pthG from Pantoea agglomerans pv. gypsophilae encodes an avirulence effector that determines incompatibility in multiple beet species.

    Science.gov (United States)

    Ezra, David; Barash, Isaac; Weinthal, Dan M; Gaba, Victor; Manulis, Shulamit

    2004-03-01

    SUMMARY Pantoea agglomerans pv. gypsophilae (Pag) causes root and crown gall disease on gypsophila, whereas P. agglomerans pv. betae (Pab) induces the disease on beet as well as gypsophila. Both pathovars harbour a pathogenicity plasmid (pPATH(Pag) or pPATH(Pab)) that determines disease development. We have previously isolated and partially characterized a pleiotropic gene from the pPATH(Pag), designated as pthG, that encodes a virulence factor in gypsophila and an elicitor of a hypersensitive-like response in beet roots. The present study was undertaken to characterize pthG further as an avr gene. The infiltration of beet leaves with strains expressing PthG (i.e. Pag or Pab containing pthG in trans) caused an hypersensitive reaction (HR) response within 48 h, whereas strains lacking intact pthG (i.e. Pab or Pag mutated in pthG) resulted in gall formation after 5 days. A hypersensitive reaction was elicited by PthG on multiple beet species, whereas a marker exchange mutant of Pag in pthG extended its host range on these beet species. A marker exchange mutant of Pag in hrpJ, encoding a component of the Type III secretion system, prevented HR elicitation. Mutations in each of the hrp regulatory genes (hrpY, hrpS and hrpL) substantially reduced the transcriptional activity of pthG in gypsophila cuttings. PthG could only be detected inside Pag cells during over-expression of hrpS or hrpL. Particle bombardment of GFP-PthG fusion caused cell death in beet, but not in non-host (melon) leaves. Present and previous results have established pthG as a broad-host-range avr gene that functions in multiple host plant species and the first functional avr gene in Pantoea spp.

  20. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro.

    Science.gov (United States)

    Slatopolsky, E; Finch, J; Denda, M; Ritter, C; Zhong, M; Dusso, A; MacDonald, P N; Brown, A J

    1996-01-01

    Dietary phosphorus (P) restriction is known to ameliorate secondary hyperparathyroidism in renal failure patients. In early renal failure, this effect may be mediated by an increase in 1,25-(OH)2D3, whereas in advanced renal failure, P restriction can act independent of changes in 1,25-(OH)2D3 and serum ionized calcium (ICa). In this study, we examined the effects of dietary P on serum PTH, PTH mRNA, and parathyroid gland (PTG) hyperplasia in uremic rats. Normal and uremic rats were maintained on a low (0.2%) or high (0.8%) P diet for 2 mo. PTG weight and serum PTH were similar in both groups of normal rats and in uremic rats fed the 0.2% P diet. In contrast, there were significant increases in serum PTH (130 +/- 25 vs. 35 +/- 3.5 pg/ml, P < 0.01), PTG weight (1.80 +/- 0.13 vs. 0.88 +/- 0.06 microg/gram of body weight, P < 0.01), and PTG DNA (1.63 +/- 0.24 vs. 0.94 +/- 0.07 microg DNA/gland, P < 0.01) in the uremic rats fed the 0.8% P diet as compared with uremic rats fed the 0.2% P diet. Serum ICa and 1,25-(OH)2D3 were not altered over this range of dietary P, suggesting a direct effect of P on PTG function. We tested this possibility in organ cultures of rat PTGs. While PTH secretion was acutely (30 min) regulated by medium calcium, the effects of medium P were not evident until 3 h. During a 6-h incubation, PTH accumulation was significantly greater in the 2.8 mM P medium than in the 0.2 mM P medium (1,706 +/- 215 vs. 1,033 +/- 209 pg/microg DNA, P < 0.02); the medium ICa was 1.25 mM in both conditions. Medium P did not alter PTH mRNA in this system, but cycloheximide (10 microg/ml) abolished the effect of P on PTH secretion. Thus, the effect of P is posttranscriptional, affecting PTH at a translational or posttranslational step. Collectively, these in vivo and in vitro results demonstrate a direct action of P on PTG function that is independent of ICa and 1,25-(OH)2D3. PMID:8647946

  1. Psychological and Behavioral Effects of Anabolic-Androgenic Steroids.

    Science.gov (United States)

    Bahrke, Michael S.

    This review of the literature on the psychological and behavioral effects of anabolic-androgenic steroids (AS) first looks at aspects of the history and prevalence of AS use in competitive sports. Research suggests that one-quarter to one-half million adolescents in the United States have used, or are currently using AS. Some effects of androgens…

  2. Investigation of anabolic steroids in two taste aversion paradigms.

    Science.gov (United States)

    Ganesan, R; Rosellini, R A; Svare, B

    1993-02-01

    The aversive effects of estradiol have been studied in two different taste aversion paradigms. A similar investigation was undertaken for the anabolic-androgenic steroids, nandralone and testosterone cypionate, using Rockland-Swiss mice. Experiments 1 and 2 used the brief exposure of a novel saccharin solution as the conditioned stimulus for taste aversion learning, and showed that anabolic steroids (1 mg) do not induce taste aversions. Instead, these hormones induced a small non-contingent increase in saccharin preference. Experiment 3 showed that daily nandralone administration (1 mg/day) had a greater anabolic effect than the same dose of testosterone cypionate. Experiment 4 paired the continuous exposure to a novel diet with daily nandralone injections, and showed that steroid treatment increased intake of the novel diet. When the novel diet was subsequently presented with the familiar diet in a two-choice preference test, there was no indication that an aversion was conditioned to the novel target diet. On the contrary, nandralone treatment significantly increased the preference for the novel diet. These experiments show that anabolic-androgenic steroids do not have aversive effects in mice, and that they may have positive consequences.

  3. Adverse cardiovascular effects of anabolic steroids : pathophysiology imaging

    NARCIS (Netherlands)

    Golestani, Reza; Slart, Riemer H. J. A.; Dullaart, Robin P. F.; Glaudemans, Andor W. J. M.; Zeebregts, Clark J.; Boersma, Hendrikus H.; Tio, Rene A.; Dierckx, Rudi A. J. O.

    2012-01-01

    Eur J Clin Invest 2012; 42 (7): 795803 Abstract Background Anabolic-androgenic steroids (AAS) are widely abused for enhancing muscle mass, strength, growth and improving athletic performance. Materials and methods In recent years, many observational and interventional studies have shown important ad

  4. Hypercholesterolemia in Male Power Lifters Using Anabolic-Androgenic Steroids.

    Science.gov (United States)

    Cohen, Jonathan C.; And Others

    1988-01-01

    Measurement of serum cholesterol concentrations in male power lifters who used anabolic-androgenic steroids for eight weeks, three years, or eight years indicated that mean serum cholesterol levels increased with drug use, but decreased promptly to near pre-steroid levels after steroid use ended. (Author/CB)

  5. Adverse cardiovascular effects of anabolic steroids : pathophysiology imaging

    NARCIS (Netherlands)

    Golestani, Reza; Slart, Riemer H. J. A.; Dullaart, Robin P. F.; Glaudemans, Andor W. J. M.; Zeebregts, Clark J.; Boersma, Hendrikus H.; Tio, Rene A.; Dierckx, Rudi A. J. O.

    2012-01-01

    Eur J Clin Invest 2012; 42 (7): 795803 Abstract Background Anabolic-androgenic steroids (AAS) are widely abused for enhancing muscle mass, strength, growth and improving athletic performance. Materials and methods In recent years, many observational and interventional studies have shown important ad

  6. Anabolic steroid usage in athletics: facts, fiction, and public relations.

    Science.gov (United States)

    Berning, Joseph M; Adams, Kent J; Stamford, Bryant A

    2004-11-01

    Anecdotal evidence suggests the widespread usage of anabolic steroids among athletes (20-90%), particularly at the professional and elite amateur levels. In contrast, scientific studies indicate that usage is rare and no higher than 6%. Conclusions from scientific studies suggest that anabolic steroid usage declines progressively from high school to college and beyond; however, anecdotal evidence claims the opposite trend. In this clash between "hard" scientific data vs. "soft" anecdotal information, it is natural that professionals would gravitate toward scientifically based conclusions. However, in the case of anabolic steroids (a stigmatized and illegal substance), should word-of-mouth testimony from individuals closest to the issues--those who have participated in and coached sports, those who have served as drug-testing overseers, and journalists who relentlessly track leads and verify sources--be set aside as irrelevant? Not if a complete picture is to emerge. In this review, hard scientific evidence is placed on the table side-by-side with soft anecdotal evidence, without weighting or bias. The purpose is to allow the opportunity for each to illuminate the other and, in so doing, potentially bring us a step closer to determining the true extent of anabolic steroid usage in athletics.

  7. Long-Term Cinacalcet HCl Treatment Improved Bone Metabolism in Japanese Hemodialysis Patients with Secondary Hyperparathyroidism

    Science.gov (United States)

    Shigematsu, Takashi; Akizawa, Tadao; Uchida, Eiji; Tsukamoto, Yusuke; Iwasaki, Manabu; Koshikawa, Shouzo

    2009-01-01

    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

  8. Are PTH levels related to oxidative stress and inflammation in chronic kidney disease patients on hemodialysis?

    Directory of Open Access Journals (Sweden)

    Marcel Jaqueto

    Full Text Available Abstract Introduction: Patients at end stage renal disease have higher levels of inflammation and oxidative stress than the general population. Many factors contribute to these issues, and the parathyroid hormone (PTH is also implicated. Objective: The study was conducted in order to assess the relationship between PTH levels and inflammation and oxidative stress in hemodialysis patients. Methods: Cross-sectional study with patients of two hemodialysis facilities in Londrina, Brazil. Patients with other conditions known to generate oxidative stress and inflammation were excluded. Blood levels of PTH and biochemical parameters of inflammation (interleukins 1 and 6, tumor necrosis factor-alpha and oxidative stress (total plasma antioxidant capacity, malonic dialdehyde, lipid hydroperoxidation, advanced oxidation protein products, quantification of nitric oxide metabolites, and 8-isoprostane were measured before a dialysis session. Then, we made correlation analyses between PTH levels - either as the continuous variable or categorized into tertiles-, and inflammatory and oxidative stress biomarkers. Results: PTH did not show any correlation with the tested inflammation and oxidative stress parameters, nor as continuous variable neither as categorical variable. Conclusion: In this descriptive study, the results suggest that the inflammation and oxidative stress of hemodialysis patients probably arise from mechanisms other than secondary hyperparathyroidism.

  9. Mobilization of endogenous bone marrow derived endothelial progenitor cells and therapeutic potential of parathyroid hormone after ischemic stroke in mice.

    Directory of Open Access Journals (Sweden)

    Li-Li Wang

    Full Text Available Stroke is a major neurovascular disorder threatening human life and health. Very limited clinical treatments are currently available for stroke patients. Stem cell transplantation has shown promising potential as a regenerative treatment after ischemic stroke. The present investigation explores a new concept of mobilizing endogenous stem cells/progenitor cells from the bone marrow using a parathyroid hormone (PTH therapy after ischemic stroke in adult mice. PTH 1-34 (80 µg/kg, i.p. was administered 1 hour after focal ischemia and then daily for 6 consecutive days. After 6 days of PTH treatment, there was a significant increase in bone marrow derived CD-34/Fetal liver kinase-1 (Flk-1 positive endothelial progenitor cells (EPCs in the peripheral blood. PTH treatment significantly increased the expression of trophic/regenerative factors including VEGF, SDF-1, BDNF and Tie-1 in the brain peri-infarct region. Angiogenesis, assessed by co-labeled Glut-1 and BrdU vessels, was significantly increased in PTH-treated ischemic brain compared to vehicle controls. PTH treatment also promoted neuroblast migration from the subventricular zone (SVZ and increased the number of newly formed neurons in the peri-infarct cortex. PTH-treated mice showed significantly better sensorimotor functional recovery compared to stroke controls. Our data suggests that PTH therapy improves endogenous repair mechanisms after ischemic stroke with functional benefits. Mobilizing endogenous bone marrow-derived stem cells/progenitor cells using PTH and other mobilizers appears an effective and feasible regenerative treatment after ischemic stroke.

  10. Effects of androgenic-anabolic steroids in athletes.

    Science.gov (United States)

    Hartgens, Fred; Kuipers, Harm

    2004-01-01

    Androgenic-anabolic steroids (AAS) are synthetic derivatives of the male hormone testosterone. They can exert strong effects on the human body that may be beneficial for athletic performance. A review of the literature revealed that most laboratory studies did not investigate the actual doses of AAS currently abused in the field. Therefore, those studies may not reflect the actual (adverse) effects of steroids. The available scientific literature describes that short-term administration of these drugs by athletes can increase strength and bodyweight. Strength gains of about 5-20% of the initial strength and increments of 2-5 kg bodyweight, that may be attributed to an increase of the lean body mass, have been observed. A reduction of fat mass does not seem to occur. Although AAS administration may affect erythropoiesis and blood haemoglobin concentrations, no effect on endurance performance was observed. Little data about the effects of AAS on metabolic responses during exercise training and recovery are available and, therefore, do not allow firm conclusions. The main untoward effects of short- and long-term AAS abuse that male athletes most often self-report are an increase in sexual drive, the occurrence of acne vulgaris, increased body hair and increment of aggressive behaviour. AAS administration will disturb the regular endogenous production of testosterone and gonadotrophins that may persist for months after drug withdrawal. Cardiovascular risk factors may undergo deleterious alterations, including elevation of blood pressure and depression of serum high-density lipoprotein (HDL)-, HDL2- and HDL3-cholesterol levels. In echocardiographic studies in male athletes, AAS did not seem to affect cardiac structure and function, although in animal studies these drugs have been observed to exert hazardous effects on heart structure and function. In studies of athletes, AAS were not found to damage the liver. Psyche and behaviour seem to be strongly affected by AAS

  11. Anabolic steroids after total knee arthroplasty. A double blinded prospective pilot study

    Directory of Open Access Journals (Sweden)

    Hohmann Stefanie

    2010-12-01

    Full Text Available Abstract Background Total knee arthroplasty is reported to improve the patient's quality of life and mobility. However loss of mobility and pain prior to surgery often results in disuse atrophy of muscle. As a consequence the baseline functional state prior to surgery may result in poorer outcome "post surgery" and extended rehabilitation may be required. The use of anabolic steroids for performance enhancement and to influence muscle mass is well established. The positive effects of such treatment on bone and muscle could therefore be beneficial in the rehabilitation of elderly patients. The purpose of this study was to investigate the effects of small doses of Nandrolone decanoate on recovery and muscle strength after total knee replacement and to establish the safety of this drug in multimorbid patients. Methods This study was designed as a prospective double blind randomized investigation. Five patients (treatment group with a mean age of 66.2 (58-72, average BMI of 30.76 (24.3-35.3 received 50 mg nandrolone decanoate intramuscular bi-weekly for 6 months. The control group (five patients; mean age 65.2, range 59-72; average BMI 31.7, range 21.2-35.2 was injected with saline solution. "Pre-operatively" and "post-operatively" (6 weeks, 3,6,9 and 12 months all patients were assessed using the knee society score (KSS, isokinetic strength testing and functional tests (a sit-to-stand and timed walking tests. In addition, a bone density scan was used preoperatively and 6 month postoperatively to assess bone mineral density. Results Whilst the steroid group generally performed better than the placebo group for all of the functional tests, ANOVA failed to reveal any significant differences. The steroid group demonstrated higher levels of quadriceps muscle strength across the postoperative period which reached significance at 3 (p = 0.02, 6 (p = 0.01, and 12 months (p = 0.02. There was a significant difference for the KSS at 6 weeks (p = 0.02, 6 (p

  12. Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

    DEFF Research Database (Denmark)

    Marie, Pierre J; Kassem, Moustapha

    2011-01-01

    Age-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass...

  13. ACOG Committee Opinion No. 484: Performance enhancing anabolic steroid abuse in women.

    Science.gov (United States)

    2011-04-01

    Anabolic steroids are composed of testosterone and other substances related to testosterone that promote growth of skeletal muscle, increase hemoglobin concentration, and mediate secondary sexual characteristics. These substances have been in use since the 1930s to promote muscle growth, improve athletic performance, and enhance cosmetic appearance. Although anabolic steroids are controlled substances, only to be prescribed by a physician, it is currently possible to obtain anabolic steroids illegally without a prescription. There are significant negative physical and psychologic effects of anabolic steroid use, which in women can cause significant cosmetic and reproductive changes. Anabolic steroid use can be addictive and, therefore, difficult to stop. Treatment for anabolic steroid abuse generally involves education, counseling, and management of withdrawal symptoms. Health care providers are encouraged to address the use of these substances, encourage cessation, and refer patients to substance abuse treatment centers to prevent the long-term irreversible consequences of anabolic steroid use.

  14. Moderate ingestion of alcohol is associated with acute ethanol-induced suppression of circulating CTX in a PTH-independent fashion.

    Science.gov (United States)

    Sripanyakorn, Supannee; Jugdaohsingh, Ravin; Mander, Adrian; Davidson, Sarah L; Thompson, Richard Ph; Powell, Jonathan J

    2009-08-01

    The "J shape" curve linking the risk of poor bone health to alcohol intake is now well recognized from epidemiological studies. Ethanol and nonethanol components of alcoholic beverages could influence bone remodeling. However, in the absence of a solid underlying mechanism, the positive association between moderate alcoholic intake and BMD remains questionable because of confounding associated social factors. The objective of this work was to characterize the short-term effects of moderate alcohol consumption on circulating bone markers, especially those involved in bone resorption. Two sequential blood-sampling studies were undertaken in fasted healthy volunteers (age, 20-47 yr) over a 6-h period using beer of different alcohol levels (2% ethanol; p 6 h). The early effect on bone resorption is well described after the intake of energy, mediated by glucagon-like peptide-2, but the late effect of moderate alcohol ingestion is novel, seems to be ethanol specific, and is mediated in a non-calcitonin- and a non-PTH-dependent fashion, thus providing a mechanism for the positive association between moderate alcohol ingestion and BMD.

  15. Lower Limb Metaphyseal Bone Is Lost in Men with Coeliac Disease and Does Not Relate to Parathyroid Status

    Directory of Open Access Journals (Sweden)

    Michael W. J. Davie

    2016-01-01

    Full Text Available Aims. To investigate regional lower limb bone density and associations with weight, PTH, and bone breakdown in coeliac men. Methods. From whole body DXA scans bone mineral density (BMD was measured in 28 coeliac men, in the lower limb (subdivided into 6 regions, 3 being metaphyseal (mainly trabecular and 2 diaphyseal (mainly cortical. BMD at femoral neck (FN and lumbar spine L2–4, body weight, height, serum calcium, alkaline phosphatase, parathyroid hormone (PTH, and urinary calcium and NTx/Cr, a measure of bone breakdown, were also measured. Age matched healthy men provided values for BMD calculation of z and T scores and for biochemical measurements. Results. Low BMD z scores were found at metaphyseal regions in the leg (p<0.001 and in the FN (p<0.05. The distal metaphyseal region BMD in the leg was lower than spine or FN (p<0.05. PTH, urinary calcium/creatinine, and urinary NTx/Cr were similar to controls. Both metaphyseal and diaphyseal BMD z scores were associated with body weight (p<0.02, but not with either PTH or urinary NTx/Cr. Conclusions. Low BMD lower limb regions comprising mostly trabecular bone occur early in CD and in the absence of elevated PTH or increased bone resorption. Low BMD is associated with low body weight.

  16. Lower Limb Metaphyseal Bone Is Lost in Men with Coeliac Disease and Does Not Relate to Parathyroid Status

    Science.gov (United States)

    Evans, Sally F.

    2016-01-01

    Aims. To investigate regional lower limb bone density and associations with weight, PTH, and bone breakdown in coeliac men. Methods. From whole body DXA scans bone mineral density (BMD) was measured in 28 coeliac men, in the lower limb (subdivided into 6 regions, 3 being metaphyseal (mainly trabecular) and 2 diaphyseal (mainly cortical)). BMD at femoral neck (FN) and lumbar spine L2–4, body weight, height, serum calcium, alkaline phosphatase, parathyroid hormone (PTH), and urinary calcium and NTx/Cr, a measure of bone breakdown, were also measured. Age matched healthy men provided values for BMD calculation of z and T scores and for biochemical measurements. Results. Low BMD z scores were found at metaphyseal regions in the leg (p < 0.001) and in the FN (p < 0.05). The distal metaphyseal region BMD in the leg was lower than spine or FN (p < 0.05). PTH, urinary calcium/creatinine, and urinary NTx/Cr were similar to controls. Both metaphyseal and diaphyseal BMD z scores were associated with body weight (p < 0.02), but not with either PTH or urinary NTx/Cr. Conclusions. Low BMD lower limb regions comprising mostly trabecular bone occur early in CD and in the absence of elevated PTH or increased bone resorption. Low BMD is associated with low body weight. PMID:27672477

  17. Institutional experience of PTH evaluation on fine-needle washing after aspiration biopsy to locate hyperfunctioning parathyroid tissue

    Institute of Scientific and Technical Information of China (English)

    Massimo GIUSTI; Mara DOLCINO; Lara VERA; Carla GHIARA; Francesca MASSARO; Laura FAZZUOLI; Diego FERONE; Michele MUSSAP; Francesco MINUTO

    2009-01-01

    Assaying parathyroid hormone (PTH) in the washing liquid after fine-needle aspiration biopsy (FNAB) seems to be a valid approach to locate parathyroid tissue. PTH-FNAB was evaluated in 47 patients with a clinical picture of primary hyper-parathyroidism (PHP) and ultrasonography (US) suggestive of parathyroid lesion. The patients were subdivided into two groups on the basis of the absence or presence of US thyroid alterations. The result of PTH-FNAB was compared with those of cytology, scintigraphy and, in 24 patients, surgical outcome. PTH-FNAB samples with a value higher than that recorded in the serum and higher than our institutional cut-off were deemed to be probable samples of parathyroid tissue. Cytology proved diagnostic for benign thyroid lesions, non-diagnostic for thyroid lesions, hyperplastic parathyroid tissue, undetermined or malignant thyroid lesions and other lesions in 45%, 30%, 17%, 4%, and 4% of cases, respectively. In 47% of cases, PTH-FNAB indicated that the sample had been taken in parathyroid tissue. In patients without US alterations, the diagnostic accuracy of PTH-FNAB was greater than that of scintigraphy. After surgery, comparison between the results of PTH-FNAB and scintigraphy, in terms of positive predictive value (PPV), revealed the superiority of PTH-FNAB; PPV was 94% for FNAB and 71% for scintigraphy, while sen-sitivity was 83% and 69%, respectively. PTH-FNAB evaluation after FNAB appears to be more diagnostic than cytology and scintigraphy. Of all the procedures used, PTH-FNAB appears to be the method of choice when the target is US suggestive and reachable. PTH-FNAB appears to be a useful method of guiding surgical intervention.

  18. Bone disease in primary hyperparathyroidism

    Science.gov (United States)

    Bandeira, Francisco; Cusano, Natalie E.; Silva, Barbara C.; Cassibba, Sara; Almeida, Clarissa Beatriz; Machado, Vanessa Caroline Costa; Bilezikian, John P.

    2015-01-01

    Bone disease in severe primary hyperparathyroidism (PHPT) is described classically as osteitis fibrosa cystica (OFC). Bone pain, skeletal deformities and pathological fractures are features of OFC. Bone mineral density is usually extremely low in OFC, but it is reversible after surgical cure. The signs and symptoms of severe bone disease include bone pain, pathologic fractures, proximal muscle weakness with hyperreflexia. Bone involvement is typically characterized as salt-and-pepper appearance in the skull, bone erosions and bone resorption of the phalanges, brown tumors and cysts. In the radiography, diffuse demineralization is observed, along with pathological fractures, particularly in the long bones of the extremities. In severe, symptomatic PHPT, marked elevation of the serum calcium and PTH concentrations are seen and renal involvement is manifested by nephrolithiasis and nephrocalcinosis. A new technology, recently approved for clinical use in the United States and Europe, is likely to become more widely available because it is an adaptation of the lumbar spine DXA image. Trabecular bone score (TBS) is a gray-level textural analysis that provides an indirect index of trabecular microarchitecture. Newer technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have provided further understanding of the microstructural skeletal features in PHPT. PMID:25166047

  19. Dual regulation of the parathyroid hormone (PTH)/PTH-related peptide receptor signaling by protein kinase C and beta-arrestins.

    Science.gov (United States)

    Castro, Marián; Dicker, Frank; Vilardaga, Jean-Pierre; Krasel, Cornelius; Bernhardt, Manfred; Lohse, Martin J

    2002-10-01

    We examined here the role of second messenger-dependent kinases and beta-arrestins in short-term regulation of the PTH receptor (PTHR) signaling. The inhibition of protein kinase C (PKC) in COS-7 cells transiently expressing PTHR, led to an approximately 2-fold increase in PTH-stimulated inositol phosphate (IP) and cAMP production. The inhibition of protein kinase A increased cAMP production 1.5-fold without affecting IP signaling. The effects of PKC inhibition on PTHR-mediated G(q) signaling were strongly decreased for a carboxy-terminally truncated PTHR (T480) that is phosphorylation deficient. PKC inhibition was associated with a decrease in agonist-stimulated PTHR phosphorylation and internalization without blocking PTH-dependent mobilization of beta-arrestin2 to the plasma membrane. Overexpression of beta-arrestins strongly decreased the PTHR-mediated IP signal, whereas cAMP production was impaired to a much lower extent. The regulation of PTH-stimulated signals by beta-arrestins was impaired for the truncated T480 receptor. Our data reveal mechanisms at, and distal to, the receptor regulating PTHR-mediated signaling pathways by second messenger-dependent kinases. We conclude that regulation of PTHR-mediated signaling by PKC and beta-arrestins are separable phenomena that both involve the carboxy terminus of the receptor. A major role for PKC and beta-arrestins in preferential regulation of PTHR-mediated G(q) signaling by independent mechanisms at the receptor level was established.

  20. Pseudohypoparathyroidism type Ib is not caused by mutations in the coding exons of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene

    Energy Technology Data Exchange (ETDEWEB)

    Schipani, E.; Bergwitz, C.; Iida-Klein, A. [Massachusetts General Hospital, Boston, MA (United States)] [and others

    1995-05-01

    Pseudohypoparathyroidism type Ib (PHP-Ib) is thought to be from caused by a PTH/PTH-related peptide (PTHrP) receptor defect. To search for receptor mutations in genomic DNA from 17 PHP-Ib patients, three recently isolated human genomic DNA clones were further characterized by restriction enzyme mapping and nucleotide sequencing across intron/exon borders. Regions including all 14 coding exons and their splice junctions were amplified by polymerase chain reaction, and the products were analyzed by either temperature gradient gel electrophoresis or direct nucleotide sequencing. Silent polymorphisms were identified in exons G (1 of 17), M4 (1 of 17), and M7 (15 of 17). Two base changes were found in introns, 1 at the splice-donor site of the intron between exons E2 and E3 (1 of 17) and the other between exons G and M1 (2 of 17). Total ribonucleic acid from COS-7 cells expressing minigenes with or without the base change between exons E2 and E3 showed no difference by either Northern blot analysis or reverse transcriptase-polymerase chain reaction. Radioligand binding was indistinguishable for both transiently expressed constructs. A missense mutation (E546 to K546) in the receptor`s cytoplamic tail (3 of 17) was also found in 1 of 60 healthy individuals, and PTH/PTHrP receptors with this mutation were functionally indistinguishable from wild-type receptors. PHP-Ib thus appears to be rarely, if ever, caused by mutations in the coding exons of the PTH/PTHrP receptor gene. 58 refs., 4 figs., 4 tabs.

  1. A novel, mild, specific and indirect maleimido-based radioiodolabeling method; Radiolabeling of analogs derived from parathyroid hormone (PTH) and PTH-related protein (PTHrP)

    Energy Technology Data Exchange (ETDEWEB)

    Chorev, M.; Caulfield, M.P.; Roubini, E.; McKee, R.L.; Gibbons, S.W.; Chih-Tai Leu; Levy, J.J.; Rosenblatt, M.

    1992-01-01

    In an effort to design a mild, non-oxidative and site-specific means of radiolabeling bioactive molecules we have employed maleimido-sulfhydryl chemistry to produce bioactive hormone radioligands. We have prepared two novel radioiodolabeled reagents, 3'-maleimidopropanoyl-3-[sup 125]I-tyramide and its retro analog, N-maleoyl-N'-3-(4-hydroxy-3-[sup 125]I-phenyl)propanoyl ethylenediamide, by either oxidative radioiodination of the precursors or radiolabeling of the phenolic component prior to its incorporation into the radiolabeling reagents. These reagents were then used to radiolabel analogs of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) in an efficient way, yielding reaction mixtures which were easily purified. The radioligands obtained are stable upon storage and bind in an reversible manner to a single population of binding sites displaying affinity in the low nanomolar range. The potencies of these analogs are comparable to the non-modified PTH and PTH rP analogs. This study demonstrates the utility of the novel maleimido-based indirect radioiodination approach and highlights some of its advantages over either direct oxidative procedures or acylation using the Bolton-Hunter reagent. (au).

  2. Physiological data including evaluation of immuno-response in relation to anabolic effects on veal calves.

    Science.gov (United States)

    Gropp, J; Herlyn, D; Boehncke, E; Schulz, V; Sandersleben, J V; Hänichen, T; Geisel, O

    1976-01-01

    In a series of experiments with a total of 1480 veal calves, different aspects of treating calves with anabolic steroids were examined. The anabolics used were 17beta-estradiol (E), trenbolone acetate (T), progesterone (P), testosterone (Te), C+T, E+P, E+Te and zeranole (Z). The N-retention was estimated by examining the urea: creatinine ratio in single urine specimens during the course of two feeding trials. Increased gain due to the treatment with E (20 mg implanted/calf) + P (200 mg) and Te (200 mg), respectively, E + T (140 mg) or Z (36 mg) was during the whole experimental period. The extra gain, due to anabolics seems to contain even more protein. This conclusion may be supported by the crude protein content of meat samples. The antibody production of a total of 311 male and female calves was investigated after the application of the following steroids: E (20 mg), T (200 mg), T (200 mg), E + T, P (200 mg), Te (200 mg), E + P, E + Te, and Z. Eleven days after the implantation of the steroids the animals were immunized with alumprecipitated human serumalbumin. Antibody-titres were determined by the Antigen-Binding-Capacity Test on day 14 following immunization. In nearly all groups the antibody-titres of female calves exceeded those of male calves on the average by 75%. The immune response of all experimental groups did not differ significantly from that of the corresponding control groups. However, the results indicate that both E + T and its single components E and T exert an immunodepressive effect in male calves. While the humoral antibody formation in the calf appears not to be influenced by anabolic steroids, it cannot be decided presently whether these substances effect cell-mediated immune reactions and/or unspecific mechanisms of resistance. When estradiol (20, 200, and 500 mg) and trenbolone acetate (140, 1400, 3500 mg) alone and in combination were implanted in female calves, blood glucose, GOT, GPT, alkaline phosphatase, LDH, cholesterine and

  3. MECHANISMS IN ENDOCRINOLOGY: Medical consequences of doping with anabolic androgenic steroids: effects on reproductive functions.

    Science.gov (United States)

    Nieschlag, Eberhard; Vorona, Elena

    2015-08-01

    Anabolic androgenic steroids (AASs) are appearance and performance-enhancing drugs (APEDs) used in competitive athletics, in recreational sports, and by body-builders. The global lifetime prevalence of AASs abuse is 6.4% for males and 1.6% for women. Many AASs, often obtained from the internet and dubious sources, have not undergone proper testing and are consumed at extremely high doses and in irrational combinations, also along with other drugs. Controlled clinical trials investigating undesired side effects are lacking because ethical restrictions prevent exposing volunteers to potentially toxic regimens, obscuring a causal relationship between AASs abuse and possible sequelae. Because of the negative feedback in the regulation of the hypothalamic-pituitary-gonadal axis, in men AASs cause reversible suppression of spermatogenesis, testicular atrophy, infertility, and erectile dysfunction (anabolic steroid-induced hypogonadism). Should spermatogenesis not recover after AASs abuse, a pre-existing fertility disorder may have resurfaced. AASs frequently cause gynecomastia and acne. In women, AASs may disrupt ovarian function. Chronic strenuous physical activity leads to menstrual irregularities and, in severe cases, to the female athlete triad (low energy intake, menstrual disorders and low bone mass), making it difficult to disentangle the effects of sports and AASs. Acne, hirsutism and (irreversible) deepening of the voice are further consequences of AASs misuse. There is no evidence that AASs cause breast carcinoma. Detecting AASs misuse through the control network of the World Anti-Doping Agency (WADA) not only aims to guarantee fair conditions for athletes, but also to protect them from medical sequelae of AASs abuse.

  4. Vitamin D status of 51-75-year-old Irish women: its determinants and impact on biochemical indices of bone turnover

    DEFF Research Database (Denmark)

    Hill, T. R.; O'Brien, M. M.; Lamberg-Allardt, C.

    2006-01-01

    Objectives: To assess the vitamin D status of Irish postmenopausal women during wintertime, and to examine its relationship with serum parathyroid hormone (PTH) and biochemical markers of bone turnover. In addition, the determinants of wintertime serum 25-hydroxyvitamin D (25OH-D) levels...... or calcium/bone metabolism. Results: Forty-eight per cent and 7% of women had serum 25OH-D levels vitamin D-containing supplements (P=0...... of bone turnover, between subjects with serum 25OH-D levels above or below 50 nmol l(-1). Conclusion: A high proportion of Irish postmenopausal women had low vitamin D status (serum PTH but not of bone turnover markers...

  5. Mechanisms of multiple myeloma bone disease

    Science.gov (United States)

    Galson, Deborah L; Silbermann, Rebecca; Roodman, G David

    2012-01-01

    Multiple myeloma is the second most common hematological malignancy and the most frequent cancer to involve the skeleton. Multiple myeloma bone disease (MMBD) is characterized by abnormal bone remodeling with dysfunction of both bone resorption and bone formation, and thus can be used as a paradigm for other inflammatory bone diseases, and the regulation of osteoclasts and osteoblasts in malignancy. Studies of MMBD have identified novel regulators that increase osteoclastogenesis and osteoclast function, repress osteoblast differentiation, increase angiogenesis, or permanently alter stromal cells. This review will discuss the current understanding of mechanisms of osteoclast and osteoblast regulation in MMBD, and therapeutic approaches currently in use and under development that target mediators of bone destruction and blockade of bone formation for myeloma patients, including new anabolic therapies. PMID:23951515

  6. Cell-specific expression of the parathyroid hormone (PTH)/PTH-related peptide receptor gene in kidney from kidney-specific and ubiquitous promoters.

    Science.gov (United States)

    Amizuka, N; Lee, H S; Kwan, M Y; Arazani, A; Warshawsky, H; Hendy, G N; Ozawa, H; White, J H; Goltzman, D

    1997-01-01

    The kidney is the major site of expression of the PTH/PTH-related peptide receptor (PTHR) gene. Previously we have shown that the PTHR gene is expressed from two promoters in kidney, an upstream kidney-specific promoter (P1) and a downstream promoter (P2) that is active in a wide variety of tissues. Here, we have used immunohistochemical and transcript-specific in situ hybridization techniques to map the expression of the PTHR gene and protein and to determine the distribution of P1- and P2-driven messenger RNAs in renal tissue. Immunohistochemical and immunoelectron microscopic analysis showed that PTHR protein is expressed on both basolateral and luminal membranes of proximal tubular epithelial cells, strongly suggesting a bipolar mode of action of PTH. Receptor protein also was detected on the surface of glomerular podocytes. Strikingly, immunoelectron microscopic analysis showed that endothelial cells of the peritubular vasculature, but not the glomerular vasculature, contain high levels of PTHR protein. We found that both P1 and P2 are expressed at moderate levels in both cortical and medullary epithelial cells of nephrons, correlating well with the immunohistochemical localization of PTHR protein. However, although abundant transcripts were detected in peritubular endothelial cells with P1-specific and coding sequence probes, P2-specific expression was not observed in these cells. These results provide evidence that the physiological effects of PTH- and/or PTH-related peptide on renal tubular function may be mediated not only through direct effects on epithelial cells but also indirectly through endothelial cell-based signaling. In addition to expression in vascular endothelial cells, high levels of P1-specific, but not P2-specific, PTHR messenger RNA were detected in vascular smooth muscle. Taken together, these experiments provide evidence for strong PTHR gene expression in renal vascular tissues. Moreover, given that previous studies have shown that P2

  7. PTH levels and not serum phosphorus levels are a predictor of the progression of kidney disease in elderly patients with advanced chronic kidney disease.

    Science.gov (United States)

    Toapanta Gaibor, Néstor Gabriel; Nava Pérez, Nathasha Carolina; Martínez Echevers, Yeleine; Montes Delgado, Rafael; Guerrero Riscos, María Ángeles

    At present, there is a high incidence of elderly patients with advanced chronic kidney disease (CKD) and it is important to know the long term progression and the factors that influence it. To analyse the progression of advanced CKD in elderly patients and the influence of bone-mineral metabolism. Retrospective study of 125 patients ≥70years of age with CKD stages 4-5 who started follow-up from January 1, 2007 to December 31, 2008, showing the progression of CKD (measured by the slope of the regression line of the estimated glomerular filtration rate [eGFR] by MDRD-4) over 5years. Progression in the entire group (median and 25th and 75th percentiles): -1.15 (-2.8/0.17) ml/min/1.73m(2)/year, CKD-4: -1.3 (-2.8/0.03) ml/min/1.73m(2)/year, CKD-5: -1.03 (-3.0/0.8) ml/min/1.73m(2)/year; the slope of the regression line was positive in 35 patients (28%: CKD does not progress) and negative in 90 patients (72%: CKD progresses). Negative correlation (Spearman) (slower progression): PTH, albumin/Cr ratio and daily Na excretion (all baseline measurements). No correlation with eGFR, serum P, urinary P excretion, protein intake and intake of P (all baseline measurements). In the linear regression analysis (dependent variable: slope of progression): albuminuria and PTH (both at baseline measurements) influenced this variable independently. Logistic regression (progresses vs. does not progress): PTH, albuminuria and eGFR (all at baseline measurements) influenced significantly. In our group of elderly patients, impairment of renal function is slow, particularly in CKD-5 patients. Albuminuria and PTH at baseline levels are prognostic factors in the evolution of renal function. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  8. Anabolic steroid abuse causing recurrent hepatic adenomas and hemorrhage

    Institute of Scientific and Technical Information of China (English)

    Nlicole M Martin; Barham K Abu Dayyeh; Raymond T Chung

    2008-01-01

    Anabolic steroid abuse is common among athletes and is associated with a number of medical complications. We describe a case of a 27-year-old male bodybuilder with multiple hepatic adenomas induced by anabolic steroids. He initially presented with tumor hemorrhage and was treated with left lateral hepatic segmentectomy. Regression of the remaining tumors was observed with cessation of steroid use. However, 3 years and a half alter his initial hepatic segmentectomy, he presented with recurrent tumor enlargement and intraperitoneal hemorrhage in the setting of steroid abuse relapse. Given his limited hepatic reserve, he was conservatively managed with embolization of the right accessory hepatic artery.This is the first reported case of hepatic adenoma re-growth with recidivistic steroid abuse, complicated by life-threatening hemorrhage. While athletes and bodybuilders are often aware of the legal and social ramifications of steroid abuse, they should continue to be counseled about its serious medical risks.

  9. Anabolic-androgenic steroid dependence? Insights from animals and humans.

    Science.gov (United States)

    Wood, Ruth I

    2008-10-01

    Anabolic-androgenic steroids (AAS) are drugs of abuse. They are taken in large quantities by athletes and others to increase performance, with negative health consequences. As a result, in 1991 testosterone and related AAS were declared controlled substances. However, the relative abuse and dependence liability of AAS have not been fully characterized. In humans, it is difficult to separate the direct psychoactive effects of AAS from reinforcement due to their systemic anabolic effects. However, using conditioned place preference and self-administration, studies in animals have demonstrated that AAS are reinforcing in a context where athletic performance is irrelevant. Furthermore, AAS share brain sites of action and neurotransmitter systems in common with other drugs of abuse. In particular, recent evidence links AAS with opioids. In humans, AAS abuse is associated with prescription opioid use. In animals, AAS overdose produces symptoms resembling opioid overdose, and AAS modify the activity of the endogenous opioid system.

  10. Stevens-Johnson syndrome and abuse of anabolic steroids

    Science.gov (United States)

    2017-01-01

    Stevens-Johnson syndrome (SJS) is characterized by mucocutaneous tenderness and typical hemorrhagic erosions, erythema and epidermal detachment presenting as blisters and areas of denuded skin. SJS is often observed after drug use as well as after bacterial or viral infections. Several drugs are at high risk of inducing SJS, but there are no cases in the English literature regarding anabolic steroid use triggering SJS. In our paper, we describe a case in which use of anabolic androgenic steroids (AAS) was associated with SJS. The patient participated in competitive body-building and regularly took variable doses of AAS. Initial symptoms (headache, weakness, pharyngodynia, and fever) were ignored. After a week he presented to the Emergency Department with a burning sensation on the mouth, lips, and eyes. Painful, erythematous, maculopapular, and vesicular lesions appeared all over the body, including on the genitals. During hospitalization, he also developed a cardiac complication. The patient had not taken any drugs except AAS.

  11. Anabolic therapy in b-thalassaemia major induced osteoporosis: case report and literature review

    Directory of Open Access Journals (Sweden)

    F.P. Cantatore

    2011-06-01

    Full Text Available Transfusion program and chelating therapy treatment has extended the life expectancy of thalassaemic patient; osteoporosis is considered an important cause of morbidity in adult patients who display increased fracture risk. This is a case report is about a thalassaemic young female with multiple spine fractures (D11, D12 e L2 and lumbar spine DEXA - Tscore = -3,1 and femoral = -3,4. This was in spite of therapy with alendronate 70 mg/week from January 2006 to September 2007. The patient was subsequentently treated for 18 months with 1-34 recombinant human parathyroid hormone and colecalciferol (100.000 U/monthly. After 4 months of therapy, the patient showed a decrease in spinal pain (Roland and Morris Disability Questionnaire and an improvement of quality of life (Qualeffo with normalization of osteocalcin and 25-OHcolecalciferol haematic levels after 6 months. Lumbar spine and femoral DEXA - Tscore, at 18 months, rose respectively to -2,5 and -2,4. Thalassaemia-induced osteoporosis is multifactorial and its management is very difficult. Bone marrow expansion, endocrine dysfunction, iron overload and genetic factors all seem to play important roles in the development of low bone mass in these patients. Bisphosfonates have been used in the management of thalassemia induced osteoporosis but there is no data about fracture risk. Anabolic therapy for thalassemic patients requests additional study on a large scale.

  12. Echocardiographic Findings in Power Athletes Abusing Anabolic Androgenic Steroids

    OpenAIRE

    Hajimoradi, Behzad; Kazerani, Hashem

    2012-01-01

    Purpose Anabolic androgenic steroids (AAS) abuse for improving physical appearance and performance in body builders is common and has been considered responsible for serious cardiovascular effects. Due to disagreement about cardiovascular side effects of these drugs in published articles, this case control study was designed to evaluate the echocardiographic findings in body builder athletes who are current and chronic abusers of these drugs. Methods Body builder athletes with continuous prac...

  13. In silico and functional evaluation of PTH1R mutations found in patients with primary failure of eruption (PFE).

    Science.gov (United States)

    Hendricks, H M; Bencharit, S; Seaman, W; Frazier-Bowers, S A

    2017-06-01

    The genetic basis of PFE (OMIM ID: 125350) was interrogated using molecular functional studies. PFE is a disorder that results in a poor prognosis in the eruption of teeth and by extension, in treatment with a continuous archwire. We tested the hypothesis that PTH1R mutations result in loss of function due to altered protein structure to determine (i) the fate of a functional PTH1R mutation and (ii) the resulting PTH1R protein structure of each functional mutation. We used immunofluorescence assay of COS7 cells that were transfected with either the WT or 1092delG PTH1R mutation sequence to compare the fate of the expressed protein. We also performed in silico analysis of the WT PTH1R and four different functional PTH1R mutations RESULTS: Functional studies (IFA) showed a variation in expression between the WT and mutant PTH1R. Further, in silico analysis showed structural differences between WT and mutant PTH1R proteins, particularly in the regions of the 3rd intracellular loop and the 6th transmembrane domain required for efficient PTH1R function. PTH1R mutations identified in PFE likely result from diminished function due to truncation of the protein, lack of efficient G-protein interactions and putatively attenuated signal transduction. By identifying the mode of protein dysfunction, scientist-clinicians are better prepared to recognize and thereby develop improved methods of treatment, starting at the molecular level. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Monitoring of intermittent PTH(1-34) treatment by serum PINP in adult ovariectomized osteopenic rats

    DEFF Research Database (Denmark)

    Halleen, Jussi; Peng, ZhiQi; Fagerlund, Katja

    , allowing measurement of serum PINP in preclinical rodent osteoporosis models. The purpose of this study was to evaluate the use of serum PINP for monitoring intermittent PTH(1-34) treatment in adult ovariectomized (OVX) osteopenic rats. Study groups included a sham-operated control group and an OVX...

  15. CORRELATION OF PARATHYROID HORMONE-1 RECEPTOR EXPRESSION TO BONE METASTASIS OF BREAST CARCINOMA PATIENTS

    Directory of Open Access Journals (Sweden)

    P. A. Tusta-Adiputra

    2014-01-01

    Full Text Available Background: Bone metastasis is a common complication of metastasis of breast cancer and it is a unique pathobiology process. The Parathyroid Hormone-related Peptide (PTHrP is a protein which has an important role in breast cancer cells to invade and infiltrate bones or bone marrow and accelerate angiogenetic process. The objective of this study is to reveal the relationship of PTHrP receptor named Parathyroid Hormone-1 Receptor (PTH1R expression to bone metastasis in breast cancer patients. Methods: This was an analytical cross-sectional study, applying a non probability consecutive sampling. Samples were divided into two groups, i.e. one group of breast cancer metastasis to bone (+others and another group with non-bone metastasis. Patients were collected from an existed data base (from medical record, cancer register, histopathology, since 2007. The specimen paraffin blocks were re-examined using IHC technique for PTHrP receptor. The data were analyzed and tested with Chi-Square (X2, otherwise it would be tested using Fisher Exact Test. Each group would be allocated minimal of 17 patients/samples. Results: The Chi-Square test failed to show the association between PTH1R expression in breast cancer patients with bone metastasis (p=0.295. The relative prevalence result for positive PTH1R expression was 1.48. There was no proof that positive PTH1R expression was an associated factor for bone metastasis (95% confidence interval. Conclusion: PTH1R expression is not a factor associated with bone metastasis in breast cancer patients. 

  16. Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment.

    Science.gov (United States)

    Sinder, Benjamin P; Salemi, Joseph D; Ominsky, Michael S; Caird, Michelle S; Marini, Joan C; Kozloff, Kenneth M

    2015-02-01

    Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk that presents most severely in children. Anti-resorptive bisphosphonates are frequently used to treat pediatric OI and controlled clinical trials have shown that bisphosphonate therapy improves vertebral outcomes but has little benefit on long bone fracture rate. New treatments which increase bone mass throughout the pediatric OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for pediatric OI and functions by stimulating osteoblastic bone formation via the canonical Wnt signaling pathway. To explore the effect of Scl-Ab on the rapidly growing OI skeleton, we treated rapidly growing 3week old Brtl/+ mice, harboring a typical heterozygous OI-causing Gly→Cys substitution on col1a1, for 5weeks with Scl-Ab. Scl-Ab had anabolic effects in Brtl/+ and led to new cortical bone formation and increased cortical bone mass. This anabolic action resulted in improved mechanical strength to WT Veh levels without altering the underlying brittle nature of the material. While Scl-Ab was anabolic in trabecular bone of the distal femur in both genotypes, the effect was less strong in these rapidly growing Brtl/+ mice compared to WT. In conclusion, Scl-Ab was able to stimulate bone formation in a rapidly growing Brtl/+ murine model of OI, and represents a potential new therapy to improve bone mass and reduce fracture risk in pediatric OI.

  17. Alkaline mineral water lowers bone resorption even in calcium sufficiency: alkaline mineral water and bone metabolism.

    Science.gov (United States)

    Wynn, Emma; Krieg, Marc-Antoine; Aeschlimann, Jean-Marc; Burckhardt, Peter

    2009-01-01

    Dietary acid charge enhances bone loss. Bicarbonate or alkali diet decreases bone resorption in humans. We compared the effect of an alkaline mineral water, rich in bicarbonate, with that of an acid one, rich in calcium only, on bone markers, in young women with a normal calcium intake. This study compared water A (per litre: 520 mg Ca, 291 mg HCO(3)(-), 1160 mg SO(4)(-), Potential Renal Acid load (PRAL) +9.2 mEq) with water B (per litre: 547 mg Ca, 2172 mg HCO(3)(-), 9 mg SO(4)(-), PRAL -11.2 mEq). 30 female dieticians aged 26.3 yrs (SD 7.3) were randomized into two groups, followed an identical weighed, balanced diet (965 mg Ca) and drank 1.5 l/d of the assigned water. Changes in blood and urine electrolytes, C-telopeptides (CTX), urinary pH and bicarbonate, and serum PTH were measured after 2 and 4 weeks. The two groups were not different at baseline, and showed a similar increase in urinary calcium excretion. Urinary pH and bicarbonate excretion increased with water B, but not with water A. PTH (p=0.022) and S-CTX (p=0.023) decreased with water B but not with water A. In calcium sufficiency, the acid calcium-rich water had no effect on bone resorption, while the alkaline water rich in bicarbonate led to a significant decrease of PTH and of S-CTX.

  18. Changes in Vitamin D and PTH Metabolism in Incident Pediatric Crohn Disease

    Science.gov (United States)

    Prosnitz, Aaron R.; Leonard, Mary B.; Shults, Justine; Zemel, Babette S.; Hollis, Bruce W.; Denson, Lee A.; Baldassano, Robert N.; Cohen, Aaron B.; Thayu, Meena

    2015-01-01

    Background and Aims Prior studies of vitamin D metabolism in Crohn disease (CD) did not include controls or examine changes following diagnosis. This study examined associations among 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D] and parathyroid hormone (PTH) levels in incident pediatric CD, compared with controls, and following diagnosis. Methods Serum vitamin D and PTH were measured at diagnosis (n = 78), 6, 12, and a median of 43 months (n = 52) later in CD participants, and once in 221 controls. Multivariate regression was used to examine baseline associations, and quasi-least squares regression to assess subsequent changes. Results At diagnosis, 42% of CD participants were 25(OH)D deficient (<20 ng/mL). The odds ratio for deficiency was 2.1 (95% CI 1.1, 3.9; p<0.05) vs. controls, adjusted for age, race, and season. 1,25(OH)2D was lower in CD vs. controls (p<0.05), adjusted for 25(OH)D, tumor necrosis factor–α (TNF-α) and PTH. TNF-α was associated with lower 1,25(OH)2D (p<0.05), and the positive association between PTH and 1,25(OH)2D in controls was absent in CD (interaction p=0.02). Among participants with 25(OH)D <30 ng/mL, CD was associated with lower PTH (p<0.05) vs. controls. Following diagnosis, 25(OH)D and 1,25(OH)2D improved (p<0.001). At the final visit, 3% were 25(OH)D deficient, PTH was no longer low relative to 25(OH)D, and 1,25(OH)2D was significantly elevated (p<0.001), compared with controls. Conclusions Incident CD was associated with 25(OH)D and 1,25(OH)2D deficiency and a relative hypoparathyroidism that resolved following diagnosis. Inflammatory cytokine suppression of PTH and renal 1-α-hyroxylase may contribute to these alterations. PMID:22488969

  19. Effects of Intermittent Administration of Parathyroid Hormone (1-34 on Bone Differentiation in Stromal Precursor Antigen-1 Positive Human Periodontal Ligament Stem Cells

    Directory of Open Access Journals (Sweden)

    Xiaoxiao Wang

    2016-01-01

    Full Text Available Periodontitis is the most common cause of tooth loss and bone destruction in adults worldwide. Human periodontal ligament stem cells (hPDLSCs may represent promising new therapeutic biomaterials for tissue engineering applications. Stromal precursor antigen-1 (STRO-1 has been shown to have roles in adherence, proliferation, and multipotency. Parathyroid hormone (PTH has been shown to enhance proliferation in osteoblasts. Therefore, in this study, we aimed to compare the functions of STRO-1(+ and STRO-1(− hPDLSCs and to investigate the effects of PTH on the osteogenic capacity of STRO-1(+ hPDLSCs in order to evaluate their potential applications in the treatment of periodontitis. Our data showed that STRO-1(+ hPDLSCs expressed higher levels of the PTH-1 receptor (PTH1R than STRO-1(− hPDLSCs. In addition, intermittent PTH treatment enhanced the expression of PTH1R and osteogenesis-related genes in STRO-1(+ hPDLSCs. PTH-treated cells also exhibited increased alkaline phosphatase activity and mineralization ability. Therefore, STRO-1(+ hPDLSCs represented a more promising cell resource for biomaterials and tissue engineering applications. Intermittent PTH treatment improved the capacity for STRO-1(+ hPDLSCs to repair damaged tissue and ameliorate the symptoms of periodontitis.

  20. Anabolic treatment with GH, IGF-I, or anabolic steroids in patients with HIV-associated wasting.

    Science.gov (United States)

    Mulligan, Kathleen; Schambelan, Morris

    2002-09-01

    Wasting, and particularly loss of metabolically active lean tissue, contributes to increased mortality, accelerated disease progression, and impairment of strength and functional status in patients with HIV infection. A variety of protein anabolic agents, including growth hormone, insulin-like growth factor-I, testosterone, nandrolone decanoate, oxandrolone, and oxymetholone, have been studied in patients with HIV-associated wasting. Overall, these studies have demonstrated that treatment with protein anabolic agents can increase lean body mass (LBM) and in some cases provide functional benefits and improvements in quality of life. Further research is needed to determine whether such treatment prolongs survival or reduces the overall health care burden of HIV infection. The advances in identification of successful treatments for HIV-associated wasting can provide a model for using these therapies in other catabolic states, including end-stage renal disease, cancer, chronic obstructive pulmonary disease, and cardiac cachexia.

  1. Bone healing induced by local delivery of an engineered parathyroid hormone prodrug.

    Science.gov (United States)

    Arrighi, Isabelle; Mark, Silke; Alvisi, Monica; von Rechenberg, Brigitte; Hubbell, Jeffrey A; Schense, Jason C

    2009-03-01

    Regenerative medicine requires innovative therapeutic designs to accommodate high morphogen concentrations in local depots, provide their sustained presence, and enhance cellular invasion and directed differentiation. Here we present an example for inducing local bone regeneration with a matrix-bound engineered active fragment of human parathyroid hormone (PTH(1-34)), linked to a transglutaminase substrate for binding to fibrin as a delivery and cell-invasion matrix with an intervening plasmin-sensitive link (TGplPTH(1-34)). The precursor form displays very little activity and signaling to osteoblasts, whereas the plasmin cleavage product, as it would be induced under the enzymatic influence of cells remodeling the matrix, was highly active. In vivo animal bone-defect experiments showed dose-dependent bone formation using the PTH-fibrin matrix, with evidence of both osteoconductive and osteoinductive bone-healing mechanisms. Results showed that this PTH-derivatized matrix may have potential utility in humans as a replacement for bone grafts or to repair bone defects.

  2. Anabolic androgenic steroids reverse the beneficial effect of exercise on tendon biomechanics: An experimental study

    OpenAIRE

    2014-01-01

    Background\\ud The effect of anabolic androgenic steroids on tendons has not yet been fully elucidated. Aim of the present study was the evaluation of the impact of anabolic androgenic steroids on the biomechanical and histological characteristics of Achilles tendons.\\ud Methods\\ud Twenty-four male Wistar rats were randomized into four groups with exercise and anabolic steroids (nandrolone decanoate) serving as variables. Protocol duration was 12 weeks. Following euthanasia, tendons’ biomechan...

  3. Effects of different dosages of parathyroid hormone-related protein 1-34 on the bone metabolism of the ovariectomized rat model of osteoporosis.

    Science.gov (United States)

    Xu, Jin; Rong, Haiqin; Ji, Hong; Wang, Dong; Wang, Jie; Zhang, Wenwen; Zhang, Yanling

    2013-09-01

    Intermittent and low-dose parathyroid hormone (PTH) injection to stimulate bone formation has been used in the treatment of osteoporosis. The N-terminal fragment 1-34 of PTH is quite similar in structure and function to N-terminal PTH-related protein (PTHrP). PTH(1-34) and PTHrP also share a coreceptor, the PTH/PTHrP receptor. Therefore, some studies have suggested that PTHrP could effectively stimulate bone formation, similar to PTH. We used an ovariectomized (OVX) rat model of osteoporosis to study the effects of PTHrP(1-34) on bone metabolism by measuring bone mineral density (BMD), bone histomorphometrics, and biomechanical parameters. We found that subcutaneous injection of PTHrP(1-34) (40 or 80 μg/kg body weight every day) in OVX rats increased lumbar and femoral BMD, improved bone biomechanical properties, enhanced bone strength, and promoted bone formation. We selected 40 μg/kg as the preferred therapeutic dose of PTHrP(1-34) and investigated the effects of frequency of treatment (per 1, 2, 3, or 7 days) on bone metabolism in OVX rats. We found that injection of PTHrP(1-34) once per day or every other day significantly improved the BMD and strength of OVX rats. Serum calcium and phosphate levels in all treated rats did not vary significantly from control rats. Based on our results, intermittent low-dose PTHrP(1-34) injection promoted bone formation in OVX rats, suggesting a high potential for therapeutic use in osteoporosis patients.

  4. Parathyroid hormone in the treatment of metabolic bone diseases%甲状旁腺激素制剂治疗代谢性骨病

    Institute of Scientific and Technical Information of China (English)

    吕芳; 李梅

    2014-01-01

    甲状旁腺激素(PTH)是调节钙平衡及骨转换的重要内分泌激素.目前已有PTH氨基端1-34片段和PTH 1-84全段两种重组甲状旁腺激素,用于治疗严重原发性及糖皮质激素诱发性骨质疏松.最近研究发现,PTH制剂对甲状旁腺功能减退症、成骨不全症、低磷酸酶症等代谢性骨病也有良好疗效.%Parathyroid hormone (PTH) is an important hormone in maintaining calcium balance and modulating bone remodeling.Now there are two forms of recombinant PTH (PTH 1-34 and PTH 1-84) in the treatment of severe primary osteoporosis and glucocorticoid induced osteoporosis.Recently,PTH has been found to be effective in other metabolic bone diseases,such as hypoparathyroidism,osteogenesis imperfecta and hypophosphatasia.

  5. Influence of orlistat on bone turnover and body composition

    DEFF Research Database (Denmark)

    Gotfredsen, A; Westergren Hendel, H; Andersen, T

    2001-01-01

    of bone mineral and body composition included total bone mineral content (TBMC), total bone mineral density (TBMD), lumbar spine BMC and BMD, forearm BMC and BMD, fat mass (FM), fat free-mass (FFM), percentage fat mass (FM%) as well as a DXA estimate of the body weight. Body composition (FM, FFM and FM...... biochemical variables except s-osteocalcin changed significantly after 1 y in the OLS group, disclosing a pattern of an incipient negative vitamin D balance, a secondary increase in PTH-secretion, and an increase in bone turnover with the emphasis on an increase in resorption parameters (fU-OHpr/creat, f...

  6. Bone tumor

    Science.gov (United States)

    Tumor - bone; Bone cancer; Primary bone tumor; Secondary bone tumor; Bone tumor - benign ... The cause of bone tumors is unknown. They often occur in areas of the bone that grow rapidly. Possible causes include: Genetic defects ...

  7. The regulation and regulatory role of collagenase in bone

    Science.gov (United States)

    Partridge, N. C.; Walling, H. W.; Bloch, S. R.; Omura, T. H.; Chan, P. T.; Pearman, A. T.; Chou, W. Y.

    1996-01-01

    Interstitial collagenase plays an important role in both the normal and pathological remodeling of collagenous extracellular matrices, including skeletal tissues. The enzyme is a member of the family of matrix metalloproteinases. Only one rodent interstitial collagenase has been found but there are two human enzymes, human collagenase-1 and -3, the latter being the homologue of the rat enzyme. In developing rat and mouse bone, collagenase is expressed by hypertrophic chondrocytes, osteoblasts, and osteocytes, a situation that is replicated in a fracture callus. Cultured osteoblasts derived from neonatal rat calvariae show greater amounts of collagenase transcripts late in differentiation. These levels can be regulated by parathyroid hormone (PTH), retinoic acid, and insulin-like growth factors, as well as the degree of matrix mineralization. Much of the work on collagenase in bone has been derived from studies on the rat osteosarcoma cell line, UMR 106-01. All bone-resorbing agents stimulate these cells to produce collagenase mRNA and protein, with PTH being the most potent stimulator. Determination of secreted levels of collagenase has been difficult because UMR cells, normal rat osteoblasts, and rat fibroblasts possess a scavenger receptor that removes the enzyme from the extracellular space, internalizes and degrades it, thus imposing another level of control. PTH can also regulate the abundance of the receptor as well as the expression and synthesis of the enzyme. Regulation of the collagenase gene by PTH appears to involve the cAMP pathway as well as a primary response gene, possibly Fos, which then contributes to induction of the collagenase gene. The rat collagenase gene contains an activator protein-1 sequence that is necessary for basal expression, but other promoter regions may also participate in PTH regulation. Thus, there are many levels of regulation of collagenase in bone perhaps constraining what would otherwise be a rampant enzyme.

  8. Marked increase in bone formation markers after cinacalcet treatment by mechanisms distinct from hungry bone syndrome in a haemodialysis patient

    Science.gov (United States)

    Goto, Shunsuke; Fujii, Hideki; Matsui, Yutaka; Fukagawa, Masafumi

    2010-01-01

    A 59-year-old female who was on dialysis due to diabetic nephropathy was referred to our hospital for severe hyperparathyroidism refractory to intravenous vitamin D receptor activator treatment. With subsequent cinacalcet hydrochloride treatment, parathyroid hormone (PTH) levels were only slightly suppressed. However, progressive increases were observed in serum alkaline phosphatase (ALP) and bone-specific alkaline phosphatase (BAP) levels with mild hypocalcaemia. A bone biopsy, obtained immediately before surgical parathyroidectomy after 3 months of cinacalcet treatment, revealed no disappearance of osteoclasts. These data suggest that cinacalcet hydrochloride treatment may induce a marked promotion of bone formation by mechanisms distinct from hungry bone syndrome that usually develops after parathyroidectomy. PMID:25949410

  9. Brief report: Does PTH increase with age, independent of 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium?

    Science.gov (United States)

    Carrivick, Simon J; Walsh, John P; Brown, Suzanne J; Wardrop, Robert; Hadlow, Narelle C

    2015-05-01

    Circulating PTH concentrations increase with age. It is uncertain whether an age-related PTH increase occurs independent of changes in circulating 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium. The purpose of this article was to analyze the relationship between PTH and age, controlling for 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium. This was a retrospective, cross-sectional study analyzing the relationship between PTH and age in 2 independent datasets (laboratory 1, n = 17 275 and laboratory 2, n = 4878). We further analyzed subgroups after excluding participants with estimated glomerular filtration rate of increase in age was associated with a 5.0% increase in PTH (95% confidence interval [CI], 4.4%-5.6%; P increase in laboratory 2 (95% CI, 3.0%-5.4%; P increase in age was associated with a 6.1% increase in PTH (95% CI, 5.5%-6.8%; P increase (95% CI 3.5%-6.2%; P increase with age, independent of 25-hydroxyvitamin D, ionized calcium, phosphate, and renal function. Further research is required to explore the underlying mechanisms and clinical relevance and to determine whether the use of age-related PTH reference ranges improves diagnostic accuracy, particularly in elderly individuals.

  10. Vitamin C prevents hypogonadal bone loss.

    Directory of Open Access Journals (Sweden)

    Ling-Ling Zhu

    Full Text Available Epidemiologic studies correlate low vitamin C intake with bone loss. The genetic deletion of enzymes involved in de novo vitamin C synthesis in mice, likewise, causes severe osteoporosis. However, very few studies have evaluated a protective role of this dietary supplement on the skeleton. Here, we show that the ingestion of vitamin C prevents the low-turnover bone loss following ovariectomy in mice. We show that this prevention in areal bone mineral density and micro-CT parameters results from the stimulation of bone formation, demonstrable in vivo by histomorphometry, bone marker measurements, and quantitative PCR. Notably, the reductions in the bone formation rate, plasma osteocalcin levels, and ex vivo osteoblast gene expression 8 weeks post-ovariectomy are all returned to levels of sham-operated controls. The study establishes vitamin C as a skeletal anabolic agent.

  11. Correlation of vitamin D, bone mineral density and parathyroid hormone levels in adults with low bone density

    Directory of Open Access Journals (Sweden)

    Sunil Kota

    2013-01-01

    Full Text Available Background: Bone mineral densiy (BMD is known to be affected by serum 25-hydroxyvitamin D (25(OH D levels, intact parathyroid hormone (iPTH levels. Indian data pertinent to above observation is scant. Our study aimed to investigate the relationships between serum 25-hydroxyvitamin D (25(OH D levels, intact parathyroid hormone (iPTH levels and bone mineral density (BMD in a cohort of Indian patients. Materials and Methods: Adults with or without fragility fractures with low BMD at the hip or lumbar spine were evaluated clinically along with laboratory investigations. T-scores of the hip and spine were derived from BMD-DEXA (dual-energy X-ray absorptiometry. Multivariate regression models were used to investigate the relationships between serum 25(OH D, iPTH and BMD. Results: Total of 102 patients (male:female = 38:64 with a mean age of 62.5 ± 6.4 years were included in the study. Forty-four patients had osteopenia. Osteoporosis was present in 58 patients. The mean values for serum 25(OH D and iPTH levels were 21.3 ± 0.5 ng/ml and 53.1 ± 22.3 pg/ml, respectively. In 84.3% of patients, serum 25(OH D levels were below 30 ng/ml (Normal = 30-74 ng/ml, confirming vitamin D deficiency. There was no association between 25(OH D levels and BMD at the hip or lumbar spine (P = 0.473 and 0.353, respectively. Both at the hip and lumbar spine; iPTH levels, male gender, body mass index (BMI and age were found to be significant predictors of BMD. Patients with higher BMI had significantly lower BMD and T-score. At levels <30 ng/ml, 25(OH D was negatively associated with iPTH (P = 0.041. Conclusion: Among our cohort of patients with low BMD, no direct relationship between serum 25(OH D levels and BMD was observed. However, a negative correlation between iPTH and 25(OH D at serum 25(OH D concentrations <30 ng/ml. Serum iPTH levels showed a significant negative association with BMD at the hip and lumbar spine. Our findings underscore the critical role of

  12. BIOCHEMICAL MARKERS OF BONE RESORPTION AND HORMONAL REGULATION OF BONE METABOLISM FOLLOWING LIVER TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    V. P. Buzulina

    2013-01-01

    Full Text Available Aim. Comparative evaluation of two biochemical markers of bone resorption and hormonal regulation of bone metabolism in liver recipients. Methods and results. Bоne densitometry of L2–L4 and neck of femur, serum level of some hormones (PTH, vitamin D3, estradiol, testosterone regulating osteoclastogenesis as well as com- parative analyses of two bone resorption markers β-crosslaps and tartrate-resistant acid phosphatase type 5b (TRAP-5b were fulfilled in patients after orthotopic liver transplantation (OLT. In 1 month after OLT bone density reduction of L2–L4 and neck of femur; decrease of vitamin D3, estradiol in women, testosterone in men and increase levels of bone resorption markers were observed. In 1 and 2 years after OLT the rise of bone density, increased levels of PTH, estradiol, testosterone and decreased β-crosslaps levels were revealed, while vitamin D3 and TRAP-5b levels remained stable. Conclusion. TRAP-5b was found to be a more speciffic marker of bone resorption, independent from collagen metabolism in liver. Osteoporosis defined in long-term period after OLT was associated with higher TRAP-5b and revialed in women with low estradiol level. 

  13. Effects of parathyroid hormone alone or in combination with antiresorptive therapy on bone mineral density and fracture risk--a meta-analysis

    DEFF Research Database (Denmark)

    Vestergaard, P; Jørgensen, Niklas R; Mosekilde, L

    2007-01-01

    AIM: The effects of parathyroid hormone (PTH) alone or in combination with antiresorptive therapy on changes in bone mineral density (BMD) and fracture risk were studied. MATERIALS AND METHODS: Randomised placebo controlled trials were retrieved from the PubMed, Web of Science or Embase databases....... RESULTS: PTH alone or in combination with antiresorptive drugs reduced vertebral [relative risk (RR)=0.36, 95% confidence interval (CI): 0.28-0.47, 2p

  14. [Use and abuse of androgens and anabolic steroids].

    Science.gov (United States)

    Alén, M

    1993-01-01

    At therapeutic dosages, androgen and anabolic steroids enhance neither muscle strength nor competitive performance. Endogenous androgen secretion is inhibited, and the net effect is negligible. The dosages taken by athletes and body-builders are 10-50 fold greater than the therapeutic dosages, and give rise to hyperandrogenic conditions. Although this improves endurance, strength and muscle development, at the same time a manifest hormone disturbance is developed with a variety of consequences. Abusers, who as a rule inject illicit preparations themselves, are also at risk of hepatitis and HIV.

  15. Acute hypotension induced by aortic clamp vs. PTH provokes distinct proximal tubule Na+ transporter redistribution patterns

    DEFF Research Database (Denmark)

    Leong, Patrick K K; Yang, Li E; Lin, Harrison W

    2004-01-01

    clearance. There was, however, no significant change in glomerular filtration rate (GFR) or subcellular distribution of NHE3 and NaPi2. In contrast, high-dose PTH rapidly (blood pressure to 51 +/- 3 mmHg, decreased urine output, and shifted NHE3 and NaPi2 out of the low......-density membranes enriched in apical markers. PTH at much lower doses (blood pressure and was diuretic. In conclusion, acute hypotension per se increases proximal tubule Na(+) reabsorption without changing NHE3 or NaPi2 subcellular distribution, indicating that trafficking...... in renal cortical membranes fractionated on sorbitol density gradients. Aortic clamp-induced acute hypotension (from 100 +/- 3 to 78 +/- 2 mmHg) provoked a 62% decrease in urine output and a significant decrease in volume flow from the proximal tubule detected as a 66% decrease in endogenous lithium...

  16. BONE TURNOVER AND MINERAL DENSITY OF THE LUMBAR VERTEBRAE IN WOMEN WITH PRIMARY BILIARY CIRRHOSIS BEFORE AND AFTER ORTHOTOPIC LIVER TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    I. A. Pronchenko

    2013-01-01

    Full Text Available Aim. To elucidate the role of cholestasis and menopausal status in the development of osteoporosis in women with primary biliary cirrhosis (PBC before and after orthotopic liver transplantation (OLT. Methods and re- sults. There were fulfilled 74 estimations of biochemical markers of bone metabolism, estrogen (E2, parathy- roid hormone (PTH endogenous secretion so as mineral content of lumbar vertebras in 21 women with PBC (10 women before and 17 in different terms after OLT. Bone turnover disturbances were characterized by delay of bone formation associated with hyperbilirubinaemia before OLT while increased bone turnover following OLT. Bone resorption markers correlated inversely with E2 in postmenopausal women and positively with PTH in premenopausal women. Conclusion. Bone wastes degree depended on hard and duration of disease before OLT so as menopausal status after OLT. In postmenopausal women bone wastes were associated with degree of endogenous E2 decreasing, increased bone turnover, and graft dysfunction. 

  17. P-th moment and almost sure stability of stochastic switched nonlinear systems.

    Science.gov (United States)

    Gu, Haibo; Gao, Caixia

    2016-01-01

    This paper mainly tends to utilize [Formula: see text]-type function to investigate p-th moment and almost sure stability for a class of stochastic switched nonlinear systems. Based on the multiple Lyapunov functions approach, some sufficient conditions are derived to check the stability criteria of stochastic switched nonlinear systems. One numerical example is provided to demonstrate the effectiveness of the proposed results.

  18. Solution Structure of Archaeoglobus fulgidis Peptidyl-tRNA Hydrolase(Pth2) Provides Evidence for an Extensive Conserved Family of Pth2 Enzymes in Archaea, Bacteria and Eukaryotes.

    Energy Technology Data Exchange (ETDEWEB)

    Powers, Robert; Mirkovic, Nebojsa; Goldsmith-Fischman, Sharon; Acton, Thomas; Chiang, Yiwen; Huang, Yuanpeng; Ma, LiChung; Rajan, Paranji K.; Cort, John R.; Kennedy, Michael A.; Liu, Jinfeng; Rost, Burkhard; Honig, Barry; Murray, Diana; Montelione, Gaetano

    2005-11-01

    The solution structure of protein AF2095 from the thermophilic archaea Archaeglobus fulgidis, a 123-residue (13.6 kDa) protein, has been determined by NMR methods. The structure of AF2095 is comprised of four a-helices and a mixed b-sheet consisting of four parallel and anti-parallel b-strands, where the a-helices sandwich the b-sheet. Sequence and structural comparison of AF2095 with proteins from Homo sapiens, Methanocaldococcus jannaschii and Sulfolobus solfataricus, reveals that AF2095 is a peptidyl-tRNA hydrolase (Pth2). This structural comparison also identifies putative catalytic residues and a tRNA interaction region for AF2095. The structure of AF2095 is also similar to the structure of protein TA0108 from archaea Thermoplasma acidophilum, which is deposited in the Protein Database but not functionally annotated. The NMR structure of AF2095 has been further leveraged to obtain good quality structural models for 55 other proteins. Although earlier studies have proposed that the Pth2 protein family is restricted to archeal and eukaryotic organisms, the similarity of the AF2095 structure to human Pth2, the conservation of key active-site residues, and the good quality of the resulting homology models demonstrate a large family of homologous Pth2 proteins that are conserved in eukaryotic, archaeal and bacterial organisms, providing novel insights in the evolution of the Pth and Pth2 enzyme families.

  19. Anabolic Steroids: A Threat to Body and Mind. National Institute on Drug Abuse Research Report Series.

    Science.gov (United States)

    National Inst. on Drug Abuse (DHHS/PHS), Rockville, MD.

    This report, based on findings of recent studies on the use of anabolic steroids in the United States, was written to educate the public about these drugs and the dangers of misusing them. It notes that the nonmedical use of anabolic/androgenic steroids among adolescents and young adults is of growing concern, with possibly as many as half a…

  20. Anabolic androgenic steroids, an easily forgotten cause of polycythaemia and cerebral infarction.

    Science.gov (United States)

    Low, M S Y; Vilcassim, S; Fedele, P; Grigoriadis, G

    2016-04-01

    Excessive anabolic androgenic steroids (both exogenous and endogenous) are known causes of polycythaemia and ischaemic cardiovascular events. Despite this, they are commonly forgotten in the workup of patients. We report a case of exogenous anabolic androgenic steroid-induced polycythaemia and stroke and explore possible pitfalls for clinicians. © 2016 Royal Australasian College of Physicians.

  1. Sarcopenia in older mice is characterized by a decreased anabolic response to a protein meal

    NARCIS (Netherlands)

    Dijk, van Miriam; Nagel, Jolanda; Dijk, Francina J.; Salles, Jerôme; Verlaan, Sjors; Walrand, Stephane; Norren, van Klaske; Luiking, Yvette

    2017-01-01

    Ageing is associated with sarcopenia, a progressive decline of skeletal muscle mass, muscle quality and muscle function. Reduced sensitivity of older muscles to respond to anabolic stimuli, i.e. anabolic resistance, is part of the underlying mechanisms. Although, muscle parameters have been studied

  2. PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer.

    Science.gov (United States)

    Kir, Serkan; Komaba, Hirotaka; Garcia, Ana P; Economopoulos, Konstantinos P; Liu, Wei; Lanske, Beate; Hodin, Richard A; Spiegelman, Bruce M

    2016-02-09

    Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.

    Science.gov (United States)

    Akizawa, Tadao; Kurita, Noriaki; Mizobuchi, Masahide; Fukagawa, Masafumi; Onishi, Yoshihiro; Yamaguchi, Takuhiro; Ellis, Alan R; Fukuma, Shingo; Alan Brookhart, M; Hasegawa, Takeshi; Kurokawa, Kiyoshi; Fukuhara, Shunichi

    2016-04-13

    Cinacalcet lowers parathyroid hormone levels. Whether it can prolong survival of people with chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) remains controversial, in part because a recent randomized trial excluded patients with iPTH <300 pg/ml. We examined cinacalcet's effects at different iPTH levels. This was a prospective case-cohort and cohort study involving 8229 patients with CKD stage 5D requiring maintenance hemodialysis who had SHPT. We studied relationships between cinacalcet initiation and important clinical outcomes. To avoid confounding by treatment selection, we used marginal structural models, adjusting for time-dependent confounders. Over a mean of 33 months, cinacalcet was more effective in patients with more severe SHPT. In patients with iPTH ≥ 500 pg/ml, the reduction in the risk of death from any cause was about 50% (Incidence Rate Ratio [IRR] = 0.49; 95% Confidence Interval [95% CI]: 0.29-0.82). For a composite of cardiovascular hospitalization and mortality, the association was not statistically significant, but the IRR was 0.67 (95% CI: 0.43-1.06). These findings indicate that decisions about using cinacalcet should take into account the severity of SHPT.

  4. Structure, morphology and corrosion resistance of Ni–Mo+PTh composite coatings

    Indian Academy of Sciences (India)

    J Niedbała

    2015-06-01

    Ni–Mo+PTh composite coatings were prepared from nickel–molybdenum galvanic bath with the addition of thiophene (Th) and HClO4 as result of two processes: induced Ni–Mo alloy deposition and PTh polymerization. A scanning electron microscope was used for surface morphology characterization of the coatings. The Scanning ElectrochemicalWorkstationM370 was used to the surface map of the tested composite coatings. The chemical composition of the coatings was determined by the energy-dispersive spectroscopy (EDS) method. It was stated that the surface of the coatings are characterized by the presence of Ni–Mo particles and polythiophene agglomerates. Electrochemical corrosion investigations of coatings were carried out in the 5 M KOH solution, using voltammetry and electrochemical impedance spectroscopy (EIS) methods. On the basis of these research works it was found that the composite Ni–Mo+PTh coatings are more corrosion resistant in alkaline solution than Ni–Mo. The reasons for this are the presence of the polymer on the surface of the coatings and a decrease of corrosion active surface area of the coatings.

  5. Bone-Remodeling Transcript Levels Are Independent of Perching in End-of-Lay White Leghorn Chickens

    Directory of Open Access Journals (Sweden)

    Maurice D. Dale

    2015-01-01

    Full Text Available Osteoporosis is a bone disease that commonly results in a 30% incidence of fracture in hens used to produce eggs for human consumption. One of the causes of osteoporosis is the lack of mechanical strain placed on weight-bearing bones. In conventionally-caged hens, there is inadequate space for chickens to exercise and induce mechanical strain on their bones. One approach is to encourage mechanical stress on bones by the addition of perches to conventional cages. Our study focuses on the molecular mechanism of bone remodeling in end-of-lay hens (71 weeks with access to perches. We examined bone-specific transcripts that are actively involved during development and remodeling. Using real-time quantitative PCR, we examined seven transcripts (COL2A1 (collagen, type II, alpha 1, RANKL (receptor activator of nuclear factor kappa-B ligand, OPG (osteoprotegerin, PTHLH (PTH-like hormone, PTH1R (PTH/PTHLH type-1 receptor, PTH3R (PTH/PTHLH type-3 receptor, and SOX9 (Sry-related high mobility group box in phalange, tibia and femur. Our results indicate that the only significant effect was a difference among bones for COL2A1 (femur > phalange. Therefore, we conclude that access to a perch did not alter transcript expression. Furthermore, because hens have been used as a model for human bone metabolism and osteoporosis, the results indicate that bone remodeling due to mechanical loading in chickens may be a product of different pathways than those involved in the mammalian model.

  6. Vitamin D and parathyroid hormone in relation to bone mineral density in postmenopausal women

    Directory of Open Access Journals (Sweden)

    Vučeljić Marina

    2012-01-01

    Full Text Available Background/Aim. Despite vitamin D insufficiency being widely reported, in Serbia the epidemiological data lack information regarding vitamin D status in the sera of postmenopausal women. The aim of this study was to establish the prevalence of inadequate serum 25-hydroxyvitamin D [25(OHD] concentrations in postmenopausal Serbian women with seasonal variations of 25(OHD, in relation to parathyroid hormone (PTH and bone mineral density (BMD. Methods. A total of 95 postmenopausal women, mean age 65.1 ± 9.08 years, were examined. Measurements of 25(OHD and PTH were performed both in the winter and the summer period, using electrochemiluminiscence immunoassays. BMD (g/cm2 was measured by the dualenergy x-Ray absortimetry (DXA method on the spine and hip areas. Results. A decreased value of vitamin D (< 75 nmol/L in 88.4% of postmenopausal women and an elevated level of PTH (> 65 pg/mL in 25.3% of the cases were found. Elevated PTH varied individually, but was mostly increased if 25(OHD was equal or lower than 37.6 nmol/L. 25(OHD insufficiency was found in winter in 94.5% and in summer in 80% of the cases (p < 0.01. The mean of the PTH was higher (p < 0.05 in winter than in summer. A significant negative correlation between 25(OHD and PTH (p < 0.001 was proved. Correlation between 25(OHD and PTH with BMD at lumbar spine was established in the whole group, but at the femoral neck in women aged over 65 years (p < 0.05. Conclusion. Our results showed a high prevalence of vitamin D insufficiency (88.4% among postmenopausal women. The levels of 25(OHD and PTH changed significantly according to the season.

  7. Comparative safety evaluation of selective androgen receptor modulators and anabolic androgenic steroids.

    Science.gov (United States)

    Choi, Seul Min; Lee, Byung-Mu

    2015-01-01

    Anabolic androgenic steroids (AASs) have been in use for decades for the treatment of short stature, severe burns, HIV wasting syndrome, osteoporosis, and anemia. However, their lack of selective effects on certain symptoms and unfavorable pharmacokinetic properties has limited their long-term usage in clinics. Selective androgen receptor modulators (SARMs) have some advantages over AASs; they are highly specific for androgen receptors, are orally available, and, most importantly, act as strong receptor agonists in skeletal muscle and bone, and as weak agonists or antagonists in androgen-responsive tissues such as the prostate and sebaceous glands. The exact molecular mechanism, however, has not been fully elucidated. This article includes a toxicological review of major AASs, and a comparative safety analysis of major AASs and SARMs in clinical trials to evaluate the therapeutic potential of SARMs. Based on the robust tissue selectivity of SARMs over AASs, they are worth considering as a promising therapeutic option for the treatment of various muscle-wasting diseases.

  8. Enhancing Quality of Life for Breast Cancer Patients with Bone Metastases

    Science.gov (United States)

    2008-04-01

    Sellinger, D. S., McBeath, A. A., and Engber, W. D. Metastatic breast cancer in the femur . A search for the lesion at risk of fracture . Clin Orthop...cancer, bone metastasis , animal model, radiation therapy, anabolic agents, bisphosphonates, biomechanical testing, histology 16. SECURITY...Current treatment for osteolytic breast cancer bone metastasis typically involves radiation therapy (RTX) to palliate bone pain and a

  9. [Insulin as an anabolic: hypoglycemia in the bodybuilding world].

    Science.gov (United States)

    Konrad, C; Schüpfer, G; Wietlisbach, M; Gerber, H

    1998-07-01

    Excessive body building may be dangerous. To promote athletic performance and to improve physical appearance many of the body builders abuse anabolic-androgenic steroids and other drugs. The abuse of insulin as an anabolic medication in this athletic community was followed by a case of severe hypoglycaemia in a body builder. A 30-year old male presented with cerebral symptoms of hypoglycaemia. Directly before an international competition he tried to stimulate muscle growth by using the hypoglycaemic stimulus to the growth hormone. To achieve this he injected 70 IE of a short-acting insulin subcutaneously, resulting in severe hypoglycaemia. After the initial administration of intravenous glucose by the paramedics, he lost consciousness and showed signs of convulsions. After orotracheal intubation by an emergency physician, despite of ongoing infusion of glucose the blood glucose concentration remained low as measured in the out-of-hospital setting. Finally administration of additional glucose and glucagon in the intensive care unit was able to stabilize the metabolic system. In any case of severe hypoglycaemia, repetitive measurements of blood glucose even in the prehospital setting should be performed to detect the hypoglycaemia especially if athletes are concerned.

  10. [Body cult and use of anabolic steroids by bodybuilders].

    Science.gov (United States)

    Iriart, Jorge Alberto Bernstein; Chaves, José Carlos; Orleans, Roberto Ghignone de

    2009-04-01

    This study focused on the reasons for practicing bodybuilding and the use of anabolic steroids, as well as the social representations and uses of the body among bodybuilding steroid users. This ethnographic study involved participant observation in middle and lower-class bodybuilding gyms in Salvador, Bahia State, Brazil, and 43 in-depth interviews with steroid users. Aesthetic reasons are the main motivation for bodybuilding and steroid use in both middle and lower-class users. Dissatisfaction with one's real body as compared to the ideal standard flaunted by the mass media, fear of being devalued or shunned by one's peer groups, the symbolic capital associated with a 'pumped-up' body, and the sense of immediacy in obtaining results all contributed to steroid use. Preventive campaigns are needed, targeting young people and combining a critical view and deconstruction of the values assigned to the body by consumer society, counteracted by high-quality information on the health risks associated with anabolic steroid use.

  11. A Review of Maximizing Muscle Building Capabilities with Anabolic Enzymes

    Directory of Open Access Journals (Sweden)

    Elvis Agbons

    2017-07-01

    Full Text Available Building muscle at a rate faster than the human body would under normal circumstances is of great importance in skills and activities that require intense muscular effort. Although physical training stands as the backbone of muscle building, physiological variations make it an unfair yardstick in measuring individual efforts. Other methods of muscle building such as specialised nutrition and the use of digestive enzymes in breaking down proteins for quick absorption are also commonly used together with physical training. The use of anabolic substances, however, has proved more successful than any of the aforementioned methods. Nevertheless, with it comes ethical, legal, and clinical issues especially in sports. In spite of this, athletes still find ways of circumventing test protocols which have been a major issue for the World Anti-Doping Agency. However, advancements in science have opened the doorway for anabolic enzymes which are the ultimate muscle growers to be more or less, directly manipulated. One method is gene doping which involves altering gene expressions. The future of muscle building lies in man’s ability to decisively alter the functioning of these enzymes directly.

  12. Effects of anabolic-androgens on brain reward function

    Directory of Open Access Journals (Sweden)

    Emanuela eMhillaj

    2015-08-01

    Full Text Available Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming the so called androgen anabolic steroids (AAS. These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, the off-label utilization is very wide. Furthermore, combination of different steroids, and doses largely higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. Among the AAS abusers, the frequency of side effects is higher, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because the collection of data is very difficult due to reticent subjects and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in reward process, leading to an increased sensitivity toward opioid narcotics and central stimulants. The aim of this review is to discuss what is present in literature in regard to steroid abuse and alteration of reward system in preclinical and clinical studies.

  13. Hormone Treatment and Muscle Anabolism during Aging: Androgens

    Science.gov (United States)

    Dillon, E. Lichar; Durham, William J.; Urban, Randall J.; Sheffield-Moore, Melinda

    2010-01-01

    Aging is associated with a gradual decline in circulating testosterone concentrations and decreased musculature in men. While testosterone administration is often considered when symptoms of hypogonadism are presented, the long-term effects of androgen use on muscle physiology are not yet fully understood. The definition of hypogonadism in men remains obscure but is generally indicated by total testosterone concentrations less than a threshold value of 300-500 ng/dL. Androgen replacement therapy is generally safe in men and women with low endogenous testosterone concentrations. The development of selective androgen receptor modulators (SARMs) may provide additional options in treatment of hypogonadism while lowering the potential of side effects often associated with long-term androgen use. Androgen administration, either alone or in combination with other treatments, can be successful in improving muscle mass by increasing protein anabolism and reducing protein catabolism in men and women. Further research is necessary to optimize the anabolic and anticatabolic properties of androgens for treatment and prevention of muscle loss in men and women. PMID:20452103

  14. Bone Mineral Status in Children and Adolescents with Klinefelter Syndrome

    Directory of Open Access Journals (Sweden)

    Stefano Stagi

    2016-01-01

    Full Text Available Objective. Klinefelter syndrome (KS has long-term consequences on bone health. However, studies regarding bone status and metabolism during childhood and adolescence are very rare. Patients. This cross-sectional study involved 40 (mean age: 13.7±3.8 years KS children and adolescents and 80 age-matched healthy subjects. For both patient and control groups, we evaluated serum levels of ionised and total calcium, phosphate, total testosterone, luteinising hormone, follicle stimulating hormone, parathyroid hormone (PTH, 25-hydroxyvitamin D (25(OHD, 1,25-dihydroxyvitamin D, osteocalcin, bone alkaline phosphatase, and urinary deoxypyridinoline concentrations. We also calculated the z-scores of the phalangeal amplitude-dependent speed of sound (AD-SoS and the bone transmission time (BTT. Results. KS children and adolescents showed significantly reduced AD-SoS (p<0.005 and BTT (p<0.0005 z-scores compared to the controls. However, KS patients presented significantly higher PTH (p<0.0001 and significantly lower 25(OHD (p<0.0001, osteocalcin (p<0.05, and bone alkaline phosphatase levels (p<0.005. Interestingly, these metabolic bone disorders were already present in the prepubertal subjects. Conclusions. KS children and adolescents exhibited impaired bone mineral status and metabolism with higher PTH levels and a significant reduction of 25-OH-D and bone formation markers. Interestingly, this impairment was already evident in prepubertal KS patients. Follow-ups should be scheduled with KS patients to investigate and ameliorate bone mineral status and metabolism until the prepubertal ages.

  15. Bone Mineral Status in Children and Adolescents with Klinefelter Syndrome

    Science.gov (United States)

    Stagi, Stefano; Di Tommaso, Mariarosaria; Manoni, Cristina; Scalini, Perla; Chiarelli, Francesco; Verrotti, Alberto; Lapi, Elisabetta; Giglio, Sabrina; Dosa, Laura; de Martino, Maurizio

    2016-01-01

    Objective. Klinefelter syndrome (KS) has long-term consequences on bone health. However, studies regarding bone status and metabolism during childhood and adolescence are very rare. Patients. This cross-sectional study involved 40 (mean age: 13.7 ± 3.8 years) KS children and adolescents and 80 age-matched healthy subjects. For both patient and control groups, we evaluated serum levels of ionised and total calcium, phosphate, total testosterone, luteinising hormone, follicle stimulating hormone, parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D, osteocalcin, bone alkaline phosphatase, and urinary deoxypyridinoline concentrations. We also calculated the z-scores of the phalangeal amplitude-dependent speed of sound (AD-SoS) and the bone transmission time (BTT). Results. KS children and adolescents showed significantly reduced AD-SoS (p < 0.005) and BTT (p < 0.0005) z-scores compared to the controls. However, KS patients presented significantly higher PTH (p < 0.0001) and significantly lower 25(OH)D (p < 0.0001), osteocalcin (p < 0.05), and bone alkaline phosphatase levels (p < 0.005). Interestingly, these metabolic bone disorders were already present in the prepubertal subjects. Conclusions. KS children and adolescents exhibited impaired bone mineral status and metabolism with higher PTH levels and a significant reduction of 25-OH-D and bone formation markers. Interestingly, this impairment was already evident in prepubertal KS patients. Follow-ups should be scheduled with KS patients to investigate and ameliorate bone mineral status and metabolism until the prepubertal ages. PMID:27413371

  16. Identification of Anabolic Selective Androgen Receptor Modulators with Reduced Activities in Reproductive Tissues and Sebaceous Glands

    Science.gov (United States)

    Schmidt, Azriel; Harada, Shun-Ichi; Kimmel, Donald B.; Bai, Chang; Chen, Fang; Rutledge, Su Jane; Vogel, Robert L.; Scafonas, Angela; Gentile, Michael A.; Nantermet, Pascale V.; McElwee-Witmer, Sheila; Pennypacker, Brenda; Masarachia, Patricia; Sahoo, Soumya P.; Kim, Yuntae; Meissner, Robert S.; Hartman, George D.; Duggan, Mark E.; Rodan, Gideon A.; Towler, Dwight A.; Ray, William J.

    2009-01-01

    Androgen replacement therapy is a promising strategy for the treatment of frailty; however, androgens pose risks for unwanted effects including virilization and hypertrophy of reproductive organs. Selective Androgen Receptor Modulators (SARMs) retain the anabolic properties of androgens in bone and muscle while having reduced effects in other tissues. We describe two structurally similar 4-aza-steroidal androgen receptor (AR) ligands, Cl-4AS-1, a full agonist, and TFM-4AS-1, which is a SARM. TFM-4AS-1 is a potent AR ligand (IC50, 38 nm) that partially activates an AR-dependent MMTV promoter (55% of maximal response) while antagonizing the N-terminal/C-terminal interaction within AR that is required for full receptor activation. Microarray analyses of MDA-MB-453 cells show that whereas Cl-4AS-1 behaves like 5α-dihydrotestosterone (DHT), TFM-4AS-1 acts as a gene-selective agonist, inducing some genes as effectively as DHT and others to a lesser extent or not at all. This gene-selective agonism manifests as tissue-selectivity: in ovariectomized rats, Cl-4AS-1 mimics DHT while TFM-4AS-1 promotes the accrual of bone and muscle mass while having reduced effects on reproductive organs and sebaceous glands. Moreover, TFM-4AS-1 does not promote prostate growth and antagonizes DHT in seminal vesicles. To confirm that the biochemical properties of TFM-4AS-1 confer tissue selectivity, we identified a structurally unrelated compound, FTBU-1, with partial agonist activity coupled with antagonism of the N-terminal/C-terminal interaction and found that it also behaves as a SARM. TFM-4AS-1 and FTBU-1 represent two new classes of SARMs and will allow for comparative studies aimed at understanding the biophysical and physiological basis of tissue-selective effects of nuclear receptor ligands. PMID:19846549

  17. Identification of anabolic selective androgen receptor modulators with reduced activities in reproductive tissues and sebaceous glands.

    Science.gov (United States)

    Schmidt, Azriel; Harada, Shun-Ichi; Kimmel, Donald B; Bai, Chang; Chen, Fang; Rutledge, Su Jane; Vogel, Robert L; Scafonas, Angela; Gentile, Michael A; Nantermet, Pascale V; McElwee-Witmer, Sheila; Pennypacker, Brenda; Masarachia, Patricia; Sahoo, Soumya P; Kim, Yuntae; Meissner, Robert S; Hartman, George D; Duggan, Mark E; Rodan, Gideon A; Towler, Dwight A; Ray, William J

    2009-12-25

    Androgen replacement therapy is a promising strategy for the treatment of frailty; however, androgens pose risks for unwanted effects including virilization and hypertrophy of reproductive organs. Selective Androgen Receptor Modulators (SARMs) retain the anabolic properties of androgens in bone and muscle while having reduced effects in other tissues. We describe two structurally similar 4-aza-steroidal androgen receptor (AR) ligands, Cl-4AS-1, a full agonist, and TFM-4AS-1, which is a SARM. TFM-4AS-1 is a potent AR ligand (IC(50), 38 nm) that partially activates an AR-dependent MMTV promoter (55% of maximal response) while antagonizing the N-terminal/C-terminal interaction within AR that is required for full receptor activation. Microarray analyses of MDA-MB-453 cells show that whereas Cl-4AS-1 behaves like 5alpha-dihydrotestosterone (DHT), TFM-4AS-1 acts as a gene-selective agonist, inducing some genes as effectively as DHT and others to a lesser extent or not at all. This gene-selective agonism manifests as tissue-selectivity: in ovariectomized rats, Cl-4AS-1 mimics DHT while TFM-4AS-1 promotes the accrual of bone and muscle mass while having reduced effects on reproductive organs and sebaceous glands. Moreover, TFM-4AS-1 does not promote prostate growth and antagonizes DHT in seminal vesicles. To confirm that the biochemical properties of TFM-4AS-1 confer tissue selectivity, we identified a structurally unrelated compound, FTBU-1, with partial agonist activity coupled with antagonism of the N-terminal/C-terminal interaction and found that it also behaves as a SARM. TFM-4AS-1 and FTBU-1 represent two new classes of SARMs and will allow for comparative studies aimed at understanding the biophysical and physiological basis of tissue-selective effects of nuclear receptor ligands.

  18. Increasing dietary phosphorus intake from food additives: potential for negative impact on bone health.

    Science.gov (United States)

    Takeda, Eiji; Yamamoto, Hironori; Yamanaka-Okumura, Hisami; Taketani, Yutaka

    2014-01-01

    It is important to consider whether habitual high phosphorus intake adversely affects bone health, because phosphorus intake has been increasing, whereas calcium intake has been decreasing in dietary patterns. A higher total habitual dietary phosphorus intake has been associated with higher serum parathyroid hormone (PTH) and lower serum calcium concentrations in healthy individuals. Higher serum PTH concentrations have been shown in those who consume foods with phosphorus additives. These findings suggest that long-term dietary phosphorus loads and long-term hyperphosphatemia may have important negative effects on bone health. In contrast, PTH concentrations did not increase as a result of high dietary phosphorus intake when phosphorus was provided with adequate amounts of calcium. Intake of foods with a ratio of calcium to phosphorus close to that found in dairy products led to positive effects on bone health. Several randomized controlled trials have shown positive relations between dairy intake and bone mineral density. In our loading test with a low-calcium, high-phosphorus lunch provided to healthy young men, serum PTH concentrations showed peaks at 1 and 6 h, and serum fibroblast growth factor 23 (FGF23) concentrations increased significantly at 8 h after the meal. In contrast, the high-calcium, high-phosphorus meal suppressed the second PTH and FGF23 elevations until 8 h after the meal. This implies that adequate dietary calcium intake is needed to overcome the interfering effects of high phosphorus intake on PTH and FGF23 secretion. FGF23 acts on the parathyroid gland to decrease PTH mRNA and PTH secretion in rats with normal kidney function. However, increased serum FGF23 is an early alteration of mineral metabolism in chronic kidney disease, causing secondary hyperthyroidism, and implying resistance of the parathyroid gland to the action of FGF23 in chronic kidney disease. These findings suggest that long-term high-phosphorus diets may impair bone health

  19. Bone Canopies in Pediatric Renal Osteodystrophy

    DEFF Research Database (Denmark)

    Pereira, Renata C; Levin Andersen, Thomas; Friedman, Peter A;

    2016-01-01

    Pediatric renal osteodystrophy (ROD) is characterized by changes in bone turnover, mineralization, and volume that are brought about by alterations in bone resorption and formation. The resorptive and formative surfaces on the cancellous bone are separated from the marrow cavity by canopies...... and their association with biochemical and bone histomorphometric parameters in 106 pediatric chronic kidney disease (CKD) patients (stage 2-5) across the spectrum of ROD. Canopies in CKD patients often appeared as thickened multilayered canopies, similar to previous reports in patients with primary hyperparathyroidism....... This finding contrasts with the thin appearance reported in healthy individuals with normal kidney function. Furthermore, canopies in pediatric CKD patients showed immunoreactivity to the PTH receptor (PTHR1) as well as to the receptor activator of nuclear factor kappa-B ligand (RANKL). The number of surfaces...

  20. [Bone involvement in idiopathic calcium lithiasis].

    Science.gov (United States)

    Ghazali, A; Bataille, P; Solal, M C; Marié, A; Brazier, M; Sebert, J L; Prin, L; Fournier, A

    1995-01-01

    Bone involvement in idiopathic calcium nephrolithiasis is characterized by the following abnormalities: a) the bone density is decreased, the severity of bone loss being dependent upon the existence of hypercalciuria and upon the pathophysiology of this latter: it is inconsistent in the absence of hypercalciuria or when hypercalciuria is of the absorptive type I or II, whereas it is almost constant in fasting hypercalciuria without secondary hyperparathyroidism and constant and severe in the rare true renal hypercalciuria. b) The bone histology (which has been evaluated only in idiopathic hypercalciuric patients) mainly shows a defect in bone formation at the exception of the rare renal hypercalciuria. Osteoclastic hyperresorption is only seen in this latter type of hypercalciuria whereas in the other types of hypercalciuria only an increase of the total or inactive resorption surface is observed. This phenomenon is possibly explained only by a delayed refilling of the resorption lacunae secondary to the decreased bone formation. The osteoid thickness is either normal or decreased despite decrease in mineralization apposition rate which seems therefore to be secondary to the decreased bone formation. c) Symptomatic bone disease in hypercalciuric stone formers is exceptional and always related to a severe long term calcium restriction. d) The biochemical markers of bone resorption tend to be increased in idiopathic hypercalciuria. Hydroxyprolinuria is more often elevated than pyridinolinuria. However pyridinolinuria is negatively correlated to bone density. The contrast between the increase of these bone resorption markers and the usual normality of plasma PTH and of the osteoclastic resorptive surfaces, suggest the role of meat induced acid load which may favor inactive resorption by dissolution of bone buffers. A disturbed profile synthesis of cytokines which induce differentiation and proliferation of the osteoclasts and which modulate the osteoblastic

  1. Cytokines and growth factors which regulate bone cell function

    Science.gov (United States)

    Seino, Yoshiki

    Everybody knows that growth factors are most important in making bone. Hormones enhance bone formation from a long distance. Growth factors promote bone formation as an autocrine or paracrine factor in nearby bone. BMP-2 through BMP-8 are in the TGF-β family. BMP makes bone by enchondral ossification. In bone, IGF-II is most abundant, second, TGF-β, and third IGF-I. TGF-β enhances bone formation mainly by intramembranous ossification in vivo. TGF-β affects both cell proliferation and differentiation, however, TGF-β mainly enhances bone formation by intramembranous ossification. Interestingly, TGF-β is increased by estrogen(E 2), androgen, vitamin D, TGF-β and FGF. IGF-I and IGF-II also enhance bone formation. At present it remains unclear why IGF-I is more active in bone formation than IGF-II, although IGF-II is more abundant in bone compared to IGF-I. However, if only type I receptor signal transduction promotes bone formation, the strong activity of IGF-I in bone formation is understandable. GH, PTH and E 2 promotes IGF-I production. Recent data suggest that hormones containing vitamin D or E 2 enhance bone formation through growth factors. Therefore, growth factors are the key to clarifying the mechanism of bone formation.

  2. La proteína PthB de Xanthomonas axonopodis pv. manihotis es autoactiva en ensayos de doble hibrido

    Directory of Open Access Journals (Sweden)

    Gil Juliana

    2011-04-01

    Full Text Available La bacteriosis vascular de yuca producida por la bacteria Xanthomonas axonopodis pv. manihotis (Xam es uno de los factores limitantes para la producción de yuca. Dentro de los primeros factores de patogenicidad identificados en esta bacteria se encuentra el gen pthB. La proteína PthB pertenece a la familia de efectores PthA/AvrBs3, que se caracterizan por presentar dominios NLS (Nuclear Localization Signal y un dominio AAD (Acidic Activation Domain, lo cual sugiere que estas proteínas actúan como factores de transcripción. La identificación de las proteínas de yuca que interactúan con PthB permitiría dar luces sobre la función de esta proteína en la patogenicidad de esta bacteria. En este trabajo se clonó pthB en una fusión traduccional con el BD (Binding Domain del factor de transcripción GAL4. Después de transformar este constructo en una cepa de levadura, se observó autoactivación de los genes reporteros, incluso a concentraciones altas de 3-AT. La eliminación del primer, segundo o de los dos NLS y del AAD no eliminaron la capacidad de autoactivación de los genes reporteros mediada por PthB. Estos resultados indican la imposibilidad de su utilización en un tamizaje de una librería de ADNc de yuca para identificar las proteínas que interactúan con PthB.

  3. Blood-pressure-independent wall thickening of intramyocardial arterioles in experimental uraemia: evidence for a permissive action of PTH.

    Science.gov (United States)

    Amann, K; Törnig, J; Flechtenmacher, C; Nabokov, A; Mall, G; Ritz, E

    1995-11-01

    Abnormalities in cardiovascular structures, e.g. LV hypertrophy and thickening of vessels (arteries, arterioles, veins) are hallmarks of renal failure. They are in part independent of elevated blood pressure. Parathyroid hormone (PTH) has been shown to affect cardiac function and has also been identified as a permissive factor in the genesis of cardiac fibrosis. The present study in rats with experimental renal failure was designed to examine whether PTH was permissive for wall thickening of intramyocardial arterioles as well. Male SD rats were sham operated or subtotally nephrectomized and maintained for 2 weeks. Subgroups of subtotally nephrectomized (SNX) rats were parathyroidectomized (PTX). Saline or rat 1, 34 PTH was administered by osmotic minipump. Eucalcaemia was maintained in PTX animals by a high-calcium diet (3%). Serum calcium was not statistically different between the groups. After perfusion fixation, intramyocardial arterioles were assessed using stereological techniques (wall thickness; wall/lumen ratio; minimal lumen diameter; length density). In random samples of the left ventricle, wall thickness of arterioles was 2.2 +/- 0.25 microns in sham-op controls and 2.76 +/- 0.41 in SNX (n = at least 8 animals per group). SNX-PTX animals+solvent did not differ significantly from sham-op controls (2.08 +/- 0.42 microns), while SNX-PTX animals+PTH had values not significantly different from SNX (2.59 +/- 0.54 microns). Differences in wall thickness were not paralleled by differences in systolic blood pressure (sham-op 110 +/- 13.3 mmHg; SNX 138 +/- 8.4 mmHg, SNX-PTX+solvent 142 +/- 5.2 mmHg; SNX-PTX+PTH 148 +/- 5.7 mmHg). PTH treated animals showed signs of marked vascular smooth-muscle cell and endothelial-cell activation. The data suggest that wall thickening of intramyocardial arterioles in short-term experimental uraemia is dependent upon the presence of PTH (permissive effect).

  4. Relative and combined effects of ethanol and protein deficiency on bone manganese and copper.

    Science.gov (United States)

    González-Pérez, José M; González-Reimers, Emilio; DeLaVega-Prieto, María José; Durán-Castellón, María del Carmen; Viña-Rodríguez, José; Galindo-Martín, Luis; Alvisa-Negrín, Julio; Santolaria-Fernández, Francisco

    2012-06-01

    Both manganese and copper may affect bone synthesis. Bone content of both metals can be altered in alcoholics, although controversy exists regarding this matter. To analyse the relative and combined effects of ethanol and a low protein diet on bone copper and manganese, and their relationships with bone structure and metabolism, including trabecular bone mass (TBM), osteoid area (OA), osteocalcin (OCN), insulin-like growth factor-1 (IGF-1), parathyroid hormone (PTH), urinary hydroxyproline (uHP) and vitamin D. Adult male Sprague-Dawley rats were divided into four groups. The control rats received a 18% protein-containing diet; a second group, an isocaloric, 2% protein-containing diet; a third one, an isocaloric, 36% ethanol-containing diet and a fourth, an isocaloric diet containing 2% protein and 36% ethanol. After sacrifice, TBM and OA were histomorphometrically assessed; bone and serum manganese and copper were determined by atomic absorption spectrophotometry, and serum OCN, IGF-1, PTH, uHP and vitamin D by radioimmunoassay. Ethanol-fed rats showed decreased TBM and bone manganese. Significant relationships existed between bone manganese and TBM, serum IGF-1 and OCN. Ethanol leads to a decrease in bone manganese, related to decreased bone mass and bone synthesis. No alterations were found in bone copper.

  5. Activation of a Non-cAMP/PKA Signaling Pathway Downstream of the PTH/PTHrP Receptor Is Essential for a Sustained Hypophosphatemic Response to PTH Infusion in Male Mice

    Science.gov (United States)

    Song, Lige; Liu, Minlin; Segawa, Hiroko; Miyamoto, Ken-Ichi; Bringhurst, F. Richard; Kronenberg, Henry M.; Jüppner, Harald

    2013-01-01

    PTH increases urinary Pi excretion by reducing expression of two renal cotransporters [NaPi-IIa (Npt2a) and NaPi-IIc (Npt2c)]. In contrast to acute transporter regulation that is cAMP/protein kinase A dependent, long-term effects require phospholipase C (PLC) signaling by the PTH/PTHrP receptor (PPR). To determine whether the latter pathway regulates Pi through Npt2a and/or Npt2c, wild-type mice (Wt) and animals expressing a mutant PPR incapable of PLC activation (DD) were tested in the absence of one (Npt2a−/− or Npt2c−/−) or both phosphate transporters (2a/2c-dko). PTH infusion for 8 days caused a rapid and persistent decrease in serum Pi in Wt mice, whereas serum Pi in DD mice fell only transiently for the first 2 days. Consistent with these findings, fractional Pi excretion index was increased initially in both animals, but this increase persisted only when the PPR Wt was present. The hypophosphatemic response to PTH infusion was impaired only slightly in PPR Wt/Npt2c−/− or DD/Npt2c−/− mice. Despite lower baselines, PTH infusion in PPR Wt/Npt2a−/− mice decreased serum Pi further, an effect that was attenuated in DD/Npt2a−/− mice. Continuous PTH had no effect on serum Pi in 2a/2c-dko mice. PTH administration increased serum 1,25 dihydroxyvitamin D3 levels in Wt and DD mice and increased levels above the elevated baseline with ablation of either but not of both transporters. Continuous PTH elevated serum fibroblast growth factor 23 and blood Ca2+ equivalently in all groups of mice. Our data indicate that PLC signaling at the PPR contributes to the long-term effect of PTH on Pi homeostasis but not to the regulation of 1,25 dihydroxyvitamin D3, fibroblast growth factor 23, or blood Ca2+. PMID:23515284

  6. Evidence for a role of intracellular stored parathyroid hormone in producing hysteresis of the PTH-calcium relationship in normal humans

    DEFF Research Database (Denmark)

    Schwarz, Peter; Madsen, J C; Rasmussen, A Q

    1998-01-01

    OBJECTIVE: Despite the clear recognition that extracellular ionized calcium controls PTH secretion, there have been suggestions of hysteresis in the relationship between extracellular ionized calcium and PTH during recovery from induced hypo- and hypercalcaemia in vivo in humans. In this study, we...... examined the possibility that release of intracellular stored PTH during induced hypocalcaemia may explain hysteresis. VOLUNTEERS: Eleven volunteers, five women and six men, were recruited to participate in the study. DESIGN: A series of three protocols of repeated induction of hypocalcaemia or sequential...... of PTH or a markedly blunted peak. Thus, the PTH response during the initial induction of and the first recovery from hypocalcaemia in our protocol 3 showed significant hysteresis in the relationship between blood ionized calcium and PTH (P

  7. Epigenetic Regulation of Chondrocyte Catabolism and Anabolism in Osteoarthritis.

    Science.gov (United States)

    Kim, Hyeonkyeong; Kang, Donghyun; Cho, Yongsik; Kim, Jin-Hong

    2015-08-01

    Osteoarthritis (OA) is one of the most prevalent forms of joint disorder, associated with a tremendous socioeconomic burden worldwide. Various non-genetic and lifestyle-related factors such as aging and obesity have been recognized as major risk factors for OA, underscoring the potential role for epigenetic regulation in the pathogenesis of the disease. OA-associated epigenetic aberrations have been noted at the level of DNA methylation and histone modification in chondrocytes. These epigenetic regulations are implicated in driving an imbalance between the expression of catabolic and anabolic factors, leading eventually to osteoarthritic cartilage destruction. Cellular senescence and metabolic abnormalities driven by OA-associated risk factors appear to accompany epigenetic drifts in chondrocytes. Notably, molecular events associated with metabolic disorders influence epigenetic regulation in chondrocytes, supporting the notion that OA is a metabolic disease. Here, we review accumulating evidence supporting a role for epigenetics in the regulation of cartilage homeostasis and OA pathogenesis.

  8. Anabolic steroid abuse and dependence in clinical practice.

    Science.gov (United States)

    Brower, Kirk J

    2009-12-01

    The nonmedical use of anabolic-androgenic steroids (AAS) appeals to athletes across several sports, particularly those whose activity makes muscle size and strength advantageous, and in individuals (usually men) with body dysmorphic disorder. Patterns of nonmedical use, including supratherapeutic doses of illicitly obtained drugs, increase the risk for adverse psychiatric and other medical consequences. Although AAS users may be more likely to consult physicians for nonpsychiatric medical consequences than changes in their mental status, it is argued that the motivation for persistent use despite adverse consequences is sustained in large part by psychological variables. Therefore, all physicians who treat nonmedical AAS users will benefit from an understanding of these psychological variables, including the potential for AAS to cause dependence. This article aims to aid such understanding, and guidelines are suggested for assessment and treatment of nonmedical AAS users.

  9. Hepatic neoplasms associated with contraceptive and anabolic steroids.

    Science.gov (United States)

    Ishak, K G

    1979-01-01

    This paper evaluates the differences between HCA (hepatocellular adenoma) and FNH (focal nodular hyperplasia) and the association of HCA and FNH with OC (oral contraceptives). FNH occurs at least twice as frequent in females as in males. A study conducted by the author revealed that only 20% of patients with FNH had symptoms and signs related to their neoplasms; in the rest, FNH was accidentally discovered during surgery for diseases of the gallbladder or at necropsy. The highly characteristic gross appearance of FNH is discribed in detail. The etiologic relationship between FNH and OC was cited in the light of frequent findings of FNH in infants and children, and of suggestions by other authors that FNH could be a direct result on OC therapy or that contraceptive steroids or conjugated estrogens accelerate the growth of FNH, a very slow growing neoplasm. Simple excision is the treatment of choice for FNH; in some cases, hepatic artery ligation is indicated. In the case of HCA, statistics show that the incidence of HCA has been increasing since 1960. Majority of patients with HCA have normal tests of hepatic function. Radiographic studies and hepatic scans may reveal HCA, but the best diagnostic method so far is angiography. Although gross appearance of HCA is variable, the features are clearly distinguishable from that of FNH. Other topics discussed include the occasional occurence of nodular regenerative hyperplasia in patients on OC or anabolic steroids (AS), and malignant liver tumors in patients using OC or AS. Further research should be done to clarify the etiologic relationship between androgenic-anabolic steroids and hepatocellular tumors and tumorlike lesions.

  10. Anabolic steroids and male infertility: a comprehensive review.

    Science.gov (United States)

    de Souza, Guilherme Leme; Hallak, Jorge

    2011-12-01

    What's known on the subject? and What does the study add? The negative impact of AAS abuse on male fertility is well known by urologists. The secondary hypogonadotropic hypogonadism is often highlighted when AAS and fertility are being discussed. On the other hand, the patterns of use, mechanisms of action and direct effects over the testicle are usually overseen. The present study reviews the vast formal and "underground" culture of AAS, as well as their overall implications. Specific considerations about their impact on the male reproductive system are made, with special attention to the recent data on direct damage to the testicle. To our knowledge this kind of overview is absolutely unique, offering a distinguished set of information to the day-by-day urologists. For several decades, testosterone and its synthetic derivatives have been used with anabolic and androgenic purposes. Initially, these substances were restricted to professional bodybuilders, becoming gradually more popular among recreational power athletes. Currently, as many as 3 million anabolic-androgenic steroids (AAS) users have been reported in the United States, and considering its increasing prevalence, it has become an issue of major concern. Infertility is defined as the failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse, with male factor being present in up to 50% of all infertile couples. Several conditions may be related to male infertility. Substance abuse, including AAS, is commonly associated to transient or persistent impairment on male reproductive function, through different pathways. Herein, a brief overview on AAS, specially oriented to urologists, is offered. Steroids biochemistry, patterns of use, physiological and clinical issues are enlightened. A further review about fertility outcomes among male AAS abusers is also presented, including the classic reports on transient axial inhibition, and the more recent experimental reports

  11. Endothelial function in male body builders taking anabolic androgenic steroids

    Directory of Open Access Journals (Sweden)

    H Hashemi

    2005-11-01

    Full Text Available Background: Adverse cardiovascular events have been reported in body builders taking anabolic steroids. Adverse effects of AAS on endothelial function can initiate atherosclerosis. This study evaluates endothelial function in body builders using AAS, compared with non-steroids using athletes as controls. Methods: We recruited 30 nonsmoking male body builders taking AAS, 14 in build up phase, 8 in work out phase, and 8 in post steroid phase, and 30 nonsmoking male athletes who denied ever using steroids. Serum lipids and fasting plasma glucose were measured to exclude dyslipidemia and diabetes. Brachial artery diameter was measured by ultrasound at rest, after cuff inflation, and after sublingual glyceriltrinitrate (GTN to determine flow mediated dilation (FMD, nitro mediated dilation (NMD and ratio of FMD to NMD (index of endothelial function. Result: Use of AAS was associated with higher body mass index (BMI and low density lipoprotein–cholesterol (LDL-C. Mean ratio of flow mediated dilatation after cuff deflation to post GTN dilatation of brachial artery (index of endothelial function in body builders taking AAS was significantly lower than control group (0.96(0.05 versus 1(0.08; p=0.03. After adjusting BMI, age and weight, no significant difference was seen in index of endothelial function between two groups (p=0 .21. Conclusion: Our study indicates that taking AAS in body builders doesn’t have direct effect on endothelial function. Future study with bigger sample size and measurement of AAS metabolites is recommended. Key words: endothelium, lipids, anabolic steroids, body builders

  12. The carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen in serum as a marker of bone resorption

    DEFF Research Database (Denmark)

    Hassager, C; Jensen, L T; Pødenphant, J

    1994-01-01

    in postmenopausal women with mild osteoporosis, and assessed the effect of hormone replacement therapy (HRT) (2 mg 17 beta-estradiol plus 1 mg norethisterone daily) and anabolic steroid therapy (50 mg nandrolone decanoate (ND) i.m. every 3 weeks) on serum ICTP in two double-blind placebo-controlled studies with 55...... conclude that serum ICTP does reflect bone metabolism in postmenopausal osteoporosis, but it is not a sensitive marker of the changes in bone resorption induced by hormone replacement therapy, and it does not correspond with other measures of bone resorption during anabolic steroid therapy....

  13. Characteristics and outcome of patients with heart failure due to anabolic-androgenic steroids

    DEFF Research Database (Denmark)

    Søndergaard, Eva Bjerre; Thune, Jens Jakob; Gustafsson, Finn

    2014-01-01

    OBJECTIVES: The objective of the study was to analyse the outcome of patients with advanced heart failure due to abuse of anabolic-androgenic steroids. DESIGN: A retrospective chart review of patients admitted or referred for advanced heart failure, due to anabolic-androgenic steroid abuse...... with angiotensin-converting enzyme inhibitors and beta-blockers. The remaining 3 patients required implantation of a LV assist device (LVAD) and were listed for heart transplantation. No recovery of LV function in the patients treated with assist device was seen. CONCLUSION: Anabolic-androgenic steroid...

  14. PTH Test

    Science.gov (United States)

    Advertisement Proceeds from website advertising help sustain Lab Tests Online. AACC is a not-for-profit organization and does not endorse non-AACC products and services. Advertising & Sponsorship: Policy | Opportunities ...

  15. Bone Biopsy

    Science.gov (United States)

    ... News Physician Resources Professions Site Index A-Z Bone Biopsy Bone biopsy uses a needle and imaging ... the limitations of Bone Biopsy? What is a Bone Biopsy? A bone biopsy is an image-guided ...

  16. Bone mineral density and bone markers in patients with a recent low-energy fracture: effect of 1 y of treatment with calcium and vitamin D

    DEFF Research Database (Denmark)

    Hitz, Mette F; Jensen, Jens-Erik B; Eskildsen, Peter C

    2007-01-01

    BACKGROUND: Low-energy fractures of the hip, forearm, shoulder, and spine are known consequences of osteoporosis. OBJECTIVE: We evaluated the effect of 1 y of treatment with calcium and vitamin D on bone mineral density (BMD) and bone markers in patients with a recent low-energy fracture. DESIGN...... significantly related to physical performance. CONCLUSIONS: A 1-y intervention with calcium and vitamin D reduced bone turnover, significantly increased BMD in patients younger than 70 y, and decreased bone loss in older patients. The effect of treatment was related to physical performance....... with 0.848 +/- 0.194 (Pbone turnover. PTH was significantly lower in the intervention group (P

  17. Nuclear localization of the type 1 PTH/PTHrP receptor in rat tissues.

    Science.gov (United States)

    Watson, P H; Fraher, L J; Hendy, G N; Chung, U I; Kisiel, M; Natale, B V; Hodsman, A B

    2000-06-01

    The localization of PTH/PTH-related peptide (PTHrP) receptor (PTHR) has traditionally been performed by autoradiography. Specific polyclonal antibodies to peptides unique to the PTHR are now available, which allow a more precise localization of the receptor in cells and tissues. We optimized the IHC procedure for the rat PTHR using 5-microm sections of paraffin-embedded rat kidney, liver, small intestine, uterus, and ovary. Adjacent sections were analyzed for the presence of PTHR mRNA (by in situ hybridization) and PTHrP peptide. A typical pattern of staining for both receptor protein and mRNA was observed in kidney in cells lining the proximal tubules and collecting ducts. In uterus and gut, the receptor and its mRNA are present in smooth muscle layers (PTHrP target) and in glandular cuboidal cells and surface columnar epithelium. This suggests that PTH, or more likely PTHrP, plays a role in surface/secretory epithelia that is as yet undefined. In the ovary, PTHR was readily detectable in the thecal layer of large antral follicles and oocytes, and was present in the cytoplasm and/or nucleus of granulosa cells, regions that also contained receptor transcripts. PTHR protein and mRNA were found in the liver in large hepatocytes radiating outward from central veins. Immunoreactive cells were also present around the periphery of the liver but not within two or three cell layers of the surface. Clear nuclear localization of the receptor protein was present in liver cells in addition to the expected cytoplasmic/peripheral staining. PTHR immunoreactivity was present in the nucleus of some cells in every tissue examined. RT-PCR confirmed the presence of PTHR transcripts in these same tissues. Examination of the hindlimbs of PTHR gene-ablated mice showed no reaction to this antibody, whereas hindlimbs from their wild-type littermates stained positively. The results emphasize that the PTHR is highly expressed in diverse tissues and, in addition, show that the receptor

  18. All-atom simulation study of protein PTH(1-34) by using the Wang-Landau sampling method

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Seung-Yeon [Korea National University of Transportation, Chungju (Korea, Republic of); Kwak, Woo-Seop [Chosun University, Gwangju (Korea, Republic of)

    2014-12-15

    We perform simulations of the N-terminal 34-residue protein fragment PTH(1-34), consisting of 581 atoms, of the 84-residue human parathyroid hormone by using the all-atom ECEPP/3 force field and the Wang-Landau sampling method. Through a massive high-performance computation, the density of states and the partition function Z(T), as a continuous function of T, are obtained for PTH(1-34). From the continuous partition function Z(T), the partition function zeros of PTH(1-34) are evaluated for the first time. From both the specific heat and the partition function zeros, two characteristic transition temperatures are obtained for the all-atom protein PTH(1-34). The higher transition temperature T{sub 1} and the lower transition temperature T{sub 2} of PTH(1-34) can be interpreted as the collapse temperature T{sub θ} and the folding temperature T{sub f} , respectively.

  19. Expedited isolation of natural product peptidyl-tRNA hydrolase inhibitors from a Pth1 affinity column

    Directory of Open Access Journals (Sweden)

    Harkirat S. Sethi

    2017-05-01

    Full Text Available New antibiotics and new antibiotic targets are needed to counter the development of bacterial drug resistance that threatens to return the human population to the pre-antibiotic era. Bacterial peptidyl-tRNA hydrolase (Pth1 is a promising new antibiotic target in the early stages of development. While inhibitory activity has been observed in a variety of natural products, bioactive fractionation has been a bottleneck for inhibitor isolation. To expedite the isolation of inhibitory compounds from complex mixtures, we constructed a Pth1 affinity column and used it to isolate inhibitory compounds from crude natural products. Recombinantly produced S. typhimurium Pth1 was covalently attached to a column matrix and the inhibitory activity isolated from ethanol extracts of Salvinia minima. The procedure reported here demonstrates that isolation of Pth1 inhibitory compounds from complex natural product extracts can be greatly expedited over traditional bioactive fractionation, decreasing time and expense. The approach is generally applicable to Pth1s from other bacterial species and opens an avenue to advance and accelerate inhibitor development against this promising antimicrobial target.

  20. Bone mineral disorder in chronic kidney disease: Klotho and FGF23; cardiovascular implications.

    Science.gov (United States)

    Salanova Villanueva, Laura; Sánchez González, Carmen; Sánchez Tomero, José Antonio; Aguilera, Abelardo; Ortega Junco, Esther

    2016-01-01

    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.

  1. Genetic and environmental factors affecting peak bone mass in premenopausal Japanese women

    OpenAIRE

    Hayakawa, Yoshika; Yanagi, Hisako; Hara, Shuichi; Amagai, Hitoshi; Endo, Kazue; Hamaguchi, Hideo; Tomura, Shigeo

    2001-01-01

    The purpose of this study was to examine the relationships between peak bone mass and genetic and environmental factors. We measured whole-body bone mineral density (BMD), lumbar spine BMD, and radius BMD with dual-energy X-ray absorptiometry (DXA) and analyzed eight genetic factors: vitamin D receptor (VDR)-3′, VDR-5′, estrogen receptor (ER), calcitonin receptor (CTR), parathyroid hormone (PTH), osteocalcin (OC), apolipoprotein E (ApoE), and fatty acid binding protein 2 (FABP2) allelic polym...

  2. Transforming Growth Factor Beta Signaling in Growth of Estrogen-Insensitive Metastatic Bone Lesions

    Science.gov (United States)

    2012-01-01

    global inhibition of AREG signaling, or to specifically reduce cancer cell EGFR signaling during osteolytic lesion growth within the bone, female...the role of EGFR in bone resulted from a study of global changes in osteoblast gene expression induced by the main serum calcium regulator, PTH...suggest that EGFR is xpressed in 18–35% of breast cancers but is not overexpressed elative to the normal breast epithelia [49]. Of course, because

  3. The Relationship of Blood Pressure with Intra- Or extracellular and Bone Calcium Merabolisms in the Elderly

    OpenAIRE

    Sugihara, Nobuyuki; Matsuzaki, Masunori

    1994-01-01

    We investigated the correlations of blood pressure with intra- or extracellular and bone calcium matabolisms in the elderly. We measured serum calcium (Ca), inorganic phosphorus (Pi), C-terminal parathyroid hormone fragment (PTH-C), and calcitonin. Intracellular free calcium ([Ca2+]I) in platelet and erythrocyte was measured by fura- 2/AM from dual excitation wavelength using a fluorescence spectrophotometer. We calculated bone mineral content (BMC) of lumbar vertebral body using a calibratio...

  4. The roles of exercise in bone remodeling and in prevention and treatment of osteoporosis.

    Science.gov (United States)

    Yuan, Yu; Chen, Xi; Zhang, Lingli; Wu, Juanni; Guo, Jianming; Zou, Dongchen; Chen, Binglin; Sun, Zhongguang; Shen, Chao; Zou, Jun

    2016-11-01

    With a rapid increase in the aging population, osteoporosis has become a global health problem. Although anti-resorption and anabolic drugs are available, osteoporosis cannot be completely cured. Exercise is an economical, efficacious, and safe way to prevent the development of osteoporosis. Recent studies have investigated the mechanisms by which exercise affects bone remodeling. Here we update the progress made on the effects of exercise on bone cells, including bone marrow mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts, as well as on bone mass, bone strength, and geometry, hoping to provide a theoretical basis to improve osteoporosis prevention and treatment with exercise.

  5. Effect of Bone Mineral Density on Rotator Cuff Tear: An Osteoporotic Rabbit Model.

    Directory of Open Access Journals (Sweden)

    Xiaobin Chen

    Full Text Available An increased bone mineral density (BMD in the proximity to tendon insertion can improve rotator cuff repair and healing. However, how a decrease of BMD in the humeral head affects the biomechanical properties of the rotator cuff tendon is still unclear. Previous studies have demonstrated ovariectomy in animals to lead to osteoporosis and decreased BMD, and Teriparatide (PTH administration to improve BMD and strength of bone. This study aimed to explore the correlation between humeral head BMD and infraspinatus (ISP tendon insertion strength, and if an increase in bone quantity of the humeral head can improve the strength of the rotator cuff.Eighteen New England white rabbits were divided into the 3 groups: Control, Ovariectomy-Saline (OVX-Saline, and Ovariectomy-PTH (OVX-PTH. The OVX-Saline group and the OVX-PTH were administered daily saline and Teriparatide injections for 8 weeks starting at 17 weeks of OVX. BMD of the humeral head was measured, the ISP tendon failure load was tested and the failure stress was calculated. One specimen from each group was used for histological analysis. Linear regression analysis was used to derive equations for the BMD and failure stress.Significant differences were observed in the measured humeral head BMD of the Control and OVX-PTH groups compared to the OVX-Saline group (P = 0.0004 and P = 0.0024, respectively. No significant difference was found in failure stress among the three groups, but an expected trend with the control group and OVX-PTH group presenting higher failure strength compared to the OVX-Saline group. BMD at the humeral head showed a positive linear correlation with stress (r2 = 0.54. Histology results showed the superiority in OVX-PTH group ISP enthesis compared to the OVX-Saline group.Bone loss of the humeral head leads to decreased tendon/bone insertion strength of the infraspinatus tendon enthesis. Teriparatide administration can increase bone density of the humeral head and may improve

  6. Effect of Bone Mineral Density on Rotator Cuff Tear: An Osteoporotic Rabbit Model.

    Science.gov (United States)

    Chen, Xiaobin; Giambini, Hugo; Ben-Abraham, Ephraim; An, Kai-Nan; Nassr, Ahmad; Zhao, Chunfeng

    2015-01-01

    An increased bone mineral density (BMD) in the proximity to tendon insertion can improve rotator cuff repair and healing. However, how a decrease of BMD in the humeral head affects the biomechanical properties of the rotator cuff tendon is still unclear. Previous studies have demonstrated ovariectomy in animals to lead to osteoporosis and decreased BMD, and Teriparatide (PTH) administration to improve BMD and strength of bone. This study aimed to explore the correlation between humeral head BMD and infraspinatus (ISP) tendon insertion strength, and if an increase in bone quantity of the humeral head can improve the strength of the rotator cuff. Eighteen New England white rabbits were divided into the 3 groups: Control, Ovariectomy-Saline (OVX-Saline), and Ovariectomy-PTH (OVX-PTH). The OVX-Saline group and the OVX-PTH were administered daily saline and Teriparatide injections for 8 weeks starting at 17 weeks of OVX. BMD of the humeral head was measured, the ISP tendon failure load was tested and the failure stress was calculated. One specimen from each group was used for histological analysis. Linear regression analysis was used to derive equations for the BMD and failure stress. Significant differences were observed in the measured humeral head BMD of the Control and OVX-PTH groups compared to the OVX-Saline group (P = 0.0004 and P = 0.0024, respectively). No significant difference was found in failure stress among the three groups, but an expected trend with the control group and OVX-PTH group presenting higher failure strength compared to the OVX-Saline group. BMD at the humeral head showed a positive linear correlation with stress (r2 = 0.54). Histology results showed the superiority in OVX-PTH group ISP enthesis compared to the OVX-Saline group. Bone loss of the humeral head leads to decreased tendon/bone insertion strength of the infraspinatus tendon enthesis. Teriparatide administration can increase bone density of the humeral head and may improve the

  7. Bone Densitometry (Bone Density Scan)

    Science.gov (United States)

    ... News Physician Resources Professions Site Index A-Z Bone Densitometry (DEXA) Bone densitometry, also called dual-energy ... limitations of DEXA Bone Densitometry? What is a Bone Density Scan (DEXA)? Bone density scanning, also called ...

  8. Anabolic Steroids: Metabolism, Doping and Detection in Human and Equestrian Sports

    Science.gov (United States)

    Kicman, A. T.; Houghton, E.; Gower, D. B.

    This chapter highlights the important aspects of detection of doping with synthetic anabolic steroids and discusses some of the problems with, and solutions to, the detection of misuse of the naturally occurring ones.

  9. [Effect of an anabolic steroid on the cellular immunity and postoperative evaluation of uterine cervical cancer].

    Science.gov (United States)

    Ooshika, Y; Umesaki, N; Sako, H; Kawabata, M; Sugana, T

    1984-10-01

    The effects of an anabolic steroid on the immune activity and clinical condition of patients with cancer of the uterine cervix were studied. The effects of the steroid on tumor growth were also studied in animals. The results obtained demonstrated that the anabolic steroid (1) enhanced the activity of macrophages and cell-mediated immune activity, (2) reduced the incidence of post-operative infection, (3) reduced pose-operative loss of weight of patients due to the intrinsic anabolic activity of the steroid, and (4) did not exert any influence on tumor growth. Judging from these results, administration of the anabolic steroid would appear to be effective for the improvement of the general condition of cancer patients following surgery or in terminal cases.

  10. Separation and purification of several anabolics present in bovine urine by isocratic high performance liquid chromatography

    NARCIS (Netherlands)

    Jansen EHJM; Both-Miedema R; van Blitterswijk H; Stephany RW

    1984-01-01

    Een eenvoudig isocratisch hoge druk vloeistofchromatografisch systeem wordt beschreven voor de scheiding en zuivering van verschillende typen laag moleculaire anabole verbindingen en enige van hun metabolieten. Voor dit doel worden de verbindingen gechromatografeerd over een "reversed phase" C18 ko

  11. Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells.

    Science.gov (United States)

    Schmidt, Azriel; Meissner, Robert S; Gentile, Michael A; Chisamore, Michael J; Opas, Evan E; Scafonas, Angela; Cusick, Tara E; Gambone, Carlo; Pennypacker, Brenda; Hodor, Paul; Perkins, James J; Bai, Chang; Ferraro, Damien; Bettoun, David J; Wilkinson, Hilary A; Alves, Stephen E; Flores, Osvaldo; Ray, William J

    2014-09-01

    Prostate cancer (PCa) initially responds to inhibition of androgen receptor (AR) signaling, but inevitably progresses to hormone ablation-resistant disease. Much effort is focused on optimizing this androgen deprivation strategy by improving hormone depletion and AR antagonism. However we found that bicalutamide, a clinically used antiandrogen, actually resembles a selective AR modulator (SARM), as it partially regulates 24% of endogenously 5α-dihydrotestosterone (DHT)-responsive genes in AR(+) MDA-MB-453 breast cancer cells. These data suggested that passive blocking of all AR functions is not required for PCa therapy. Hence, we adopted an active strategy that calls for the development of novel SARMs, which induce a unique gene expression profile that is intolerable to PCa cells. Therefore, we screened 3000 SARMs for the ability to arrest the androgen-independent growth of AR(+) 22Rv1 and LNCaP PCa cells but not AR(-) PC3 or DU145 cells. We identified only one such compound; the 4-aza-steroid, MK-4541, a potent and selective SARM. MK-4541 induces caspase-3 activity and cell death in both androgen-independent, AR(+) PCa cell lines but spares AR(-) cells or AR(+) non-PCa cells. This activity correlates with its promoter context- and cell-type dependent transcriptional effects. In rats, MK-4541 inhibits the trophic effects of DHT on the prostate, but not the levator ani muscle, and triggers an anabolic response in the periosteal compartment of bone. Therefore, MK-4541 has the potential to effectively manage prostatic hypertrophic diseases owing to its antitumor SARM-like mechanism, while simultaneously maintaining the anabolic benefits of natural androgens.

  12. The spectrum of bone disease in end-stage renal failure--an evolving disorder.

    Science.gov (United States)

    Sherrard, D J; Hercz, G; Pei, Y; Maloney, N A; Greenwood, C; Manuel, A; Saiphoo, C; Fenton, S S; Segre, G V

    1993-02-01

    We have assessed the bone histology in 259 chronic dialysis patients, all of whom were in the same dialysis program. All patients had bone biopsies with quantitative histomorphometry, intact parathyroid hormone (PTH) measurements, basal and deferoxamine stimulated serum aluminum levels. Results demonstrate the increased incidence of the recently described aplastic bone lesion, particularly in patients treated with peritoneal dialysis (PD). Aluminum-related bone disease is much less common than previously described, perhaps in relation to the declining use of aluminum as a phosphate binder. A different pattern of bone lesions is seen in PD as compared with hemodialysis (HD), with low turnover disorders comprising 66% of the lesions seen in PD and high turnover lesions accounting for 62% of the bone histologic findings in HD. The difference in these patterns may relate to alterations in PTH levels, as mean PTH levels in HD patients were 2-1/2 times the levels found in PD patients (P < 0.0005), while older age, higher prevalence of diabetes and a shorter duration of dialysis may also have contributed to the findings in the PD patients. We suggest that PD, perhaps by maintaining calcium at higher levels, may more effectively suppress the parathyroid gland.

  13. The salutary effect of dietary calcium on bone mass in a rat model of simulated weightlessness

    Science.gov (United States)

    Bikle, D. D.; Globus, R.; Halloran, B. P.; Morey-Holton, E.

    1985-01-01

    Whether supplementation of dietary calcium reduces the differences in bone mass of unweighed limbs and normally weighted limbs, and whether parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25(OH)2D) respond differently to dietary calcium in unweighted animals in comparison with pair-fed controls was studied. The hind limbs of rats were unweighted by a tail suspension method and diets containing 0.1% to 2.4% calcium. After 2 weeks serum calcium, phosphorus, PTH and 1,25(OH)2D intestinal calcium transport were determined and bone mass, ash weight, and calcium in the tibia, L-1 vertebra, and humerus were measured. No significant differences in body weights were observed among the various groups. Suspended rats maintained constant levels of serum calcium and phosphate over the wide range of dietary calcium. Serum PTH and 1,25(OH)2D and intestinal calcium transport fell as dietary calcium was increased. Bone calcium in the tibia and vertebra from suspended rats remained less than that from pair-fed control. It is suggested that although no striking difference between suspended and control animals was observed in response to dieteary calcium, increasing dietary calcium may reduce the negative impact of unloading on the calcium content of the unweighted bones. The salutary effect of high dietary calcium appears to be due to inhibition of bone resorption rather than to stimulation of bone formation.

  14. Collagen synthesis in postmenopausal women during therapy with anabolic steroid or female sex hormones

    DEFF Research Database (Denmark)

    Hassager, C; Jensen, L T; Pødenphant, J;

    1990-01-01

    The effect of anabolic steroid therapy and estrogen-progestogen substitution therapy on serum concentration of procollagen type III aminoterminal peptide (PIIINP), a measure of collagen synthesis, in postmenopausal women was studied in two double-blind studies: (1) 39 women allocated to treatment....... We conclude that anabolic steroids stimulate type III collagen synthesis in postmenopausal women, while estrogen-progestogen therapy may have such an effect, but only to a lesser degree....

  15. Cardiotoxic effects of cocaine and anabolic-androgenic steroids in the athlete.

    Science.gov (United States)

    Welder, A A; Melchert, R B

    1993-04-01

    Cocaine and anabolic-androgenic steroid abuse have become major drug problems in the United States. Cocaine has been designated as "the drug of greatest national health concern" while as many as 1 million Americans have used or are currently using anabolic-androgenic steroids to promote athletic performance and/or improve physical appearance. Unfavorable cardiovascular events have been linked to both cocaine and anabolic-androgenic steroid abuse in healthy, physically active individuals. Deaths of several United States athletes in 1986 focused attention on the life-threatening cardiovascular consequences of cocaine abuse. Reports of myocardial injury with anabolic-androgenic steroid abuse are anecdotal. Nevertheless, case reports have illustrated the alarming cardiotoxic potential of these steroids in athletes. Anabolic-androgenic steroids were correlated to myocardial infarction in weight lifters and cardiomyopathy in a former professional football player. From the total emergency room episodes where cocaine was mentioned in 1990, approximately 66% of these episodes occurred in young individuals 18-29 years of age. Over 500,000 of the individuals currently taking anabolic-androgenic steroids for nonmedical purposes are high-school children. Because cocaine and anabolic-androgenic steroids are used improperly, more focus needs to be paid to the toxic mechanisms of their adverse effects. Therefore, the purpose of this review is to discuss mechanisms whereby exercise and/or exercise training may alter the cardiovascular responses to these drugs. Furthermore, we would like to illustrate that contrary to the popular belief, acute and chronic abuse of cocaine and anabolic-androgenic steroids have a negative impact on exercise performance.

  16. Growth Hormone and Anabolic Androgenic Steroids : Effects on Neurochemistry and Cognition

    OpenAIRE

    2013-01-01

    Growth hormone (GH) stimulates growth and metabolism but also displays profound effects on the central nervous system (CNS). GH affects neurogenesis and neuroprotection, and has been shown to counteract drug-induced apoptosis in the brain. Anabolic androgenic steroids (AAS), mainly abused for their anabolic and performance-enhancing properties, can cause several adverse effects, such as cardiovascular complications, sterility, depression, and aggression. GH and AAS are both believed to intera...

  17. PYOMYOSITIS IN ATHLETES AFTER THE USE OF ANABOLIC STEROIDS - CASE REPORTS

    OpenAIRE

    Filho, Nivaldo Souza Cardozo; Gaspar,Eric Figueirido; Siqueira, Karina Levy [UNIFESP; Monteiro, Gustavo Cará; Andreoli, Carlos Vicente; Ejnisman, Benno; Cohen, Moisés

    2015-01-01

    Objective: To report on the management of five cases of pyomyositis in athletes after the use of anabolic steroids. Method: Over the past 10 years, five cases of athletes who developed pyomyositis after using anabolic steroids were attended at the Sports Trauma Center (CETE), EPM-UNIFESP. Results: All the patients were diagnosed clinically and through laboratory and imaging tests. Surgical treatment was carried out (with collection of material for culturing) and antibiotic therapy was adminis...

  18. Influence of anabolic agents on protein synthesis and degradation in muscle cells grown in culture

    Energy Technology Data Exchange (ETDEWEB)

    Roeder, R.A.; Thorpe, S.D.; Byers, F.M.; Schelling, G.T.; Gunn, J.M.

    Muscle cell culture (L/sub 6/) studies were conducted to determine whether anabolic agents have a direct effect on the muscle cell. The effect of zeranol, testosterone propionate, estradiol benzoate, progesterone, dexamethasone and anabolic agent-dexamethasone combinations on protein synthesis and degradation were measured. Myoblast and myotube cultures were pretreated with 1 ..mu..M compounds for 12, 24 and 48 h before a 6-h synthesis or degradation measuring period. Protein synthesis was determined as cpm of (/sup 3/H) leucine incorporated per mg cell protein. Protein degradation was measured by a pulse-chase procedure using (/sup 3/H) leucine and expressed as the percentage labeled protein degraded in 6 h. Progesterone slightly increased protein synthesis in myoblast cultures. Testosterone propionate had no effect on synthesis. Protein synthesis was decreased by estradiol benzoate in myotube cultures. Protein degradation was not altered appreciably by anabolic agents. Protein synthesis was initially inhibited in myotubes by dexamethasone, but increased in myoblasts and myotubes in the extended incubation time. Dexamethasone also consistently increased protein degradation, but this required several hours to be expressed. Anabolic agents did not interfere with dexamethasone-induced increases in protein synthesis and degradation. The magnitude of response and sensitivity were similar for both the myoblast and the more fully differentiated myotube for all compounds tested. These results indicate that anabolic agents at the 1 ..mu..M level do not have a direct anabolic effect on muscle or alter glucocorticoid-induced catabolic response in muscle.

  19. Simultaneous control of PTH and CaxP Is sustained over three years of treatment with cinacalcet HCl.

    Science.gov (United States)

    Sprague, Stuart M; Evenepoel, Pieter; Curzi, Mario P; González, Maria Teresa; Husserl, Fred E; Kopyt, Nelson; Sterling, Lulu Ren; Mix, Chris; Wong, Gordon

    2009-09-01

    Chronic kidney disease (CKD) is commonly complicated by secondary hyperparathyroidism (SHPT), leading to increased risk of morbidity and mortality. SHPT is a progressive disease often requiring long-term therapy to control parathyroid hormone (PTH) and mineral imbalances. Vitamin D sterols and phosphate binders, used as traditional therapies to lower PTH and phosphorus, may provide inadequate long-term control for many dialysis patients. Cinacalcet, by simultaneously lowering PTH, calcium, phosphorus, and calcium-phosphorus levels, may maintain PTH and mineral balance in these individuals. However, as with traditional therapies, long-term data are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENT: Dialysis subjects from at least one of five lead-in studies (double-blind placebo-controlled, including one extension trial) completing up to 52 wk of either cinacalcet or placebo were eligible for this open-label extension study, including an 8-wk dose titration (initiated at 30 mg/d), followed by 24-wk maintenance and up to 132 wk of follow-up. Final efficacy analysis was at week 180. Three hundred thirty-four of 589 enrolled subjects received cinacalcet from the beginning of the lead-in study. Weekly median PTH values were < or =300 pg/ml (weeks 16 through 180) and median CaxP values were < or =55 mg(2)/dl(2) (weeks 4 through 180). Similar results were exhibited in the 255 subjects who initially received placebo. Among the patients exposed to cinacalcet from the beginning of the lead-in study, 3% of subjects exhibited treatment-related serious adverse events. Cinacalcet effectively maintained PTH, Ca and P reductions in dialysis subjects for up to 180 wk.

  20. Simultaneous Control of PTH and Ca×P Is Sustained over Three Years of Treatment with Cinacalcet HCl

    Science.gov (United States)

    Evenepoel, Pieter; Curzi, Mario P.; González, Maria Teresa; Husserl, Fred E.; Kopyt, Nelson; Sterling, Lulu Ren; Mix, Chris; Wong, Gordon

    2009-01-01

    Background & objectives: Chronic kidney disease (CKD) is commonly complicated by secondary hyperparathyroidism (SHPT), leading to increased risk of morbidity and mortality. SHPT is a progressive disease often requiring long-term therapy to control parathyroid hormone (PTH) and mineral imbalances. Vitamin D sterols and phosphate binders, used as traditional therapies to lower PTH and phosphorus, may provide inadequate long-term control for many dialysis patients. Cinacalcet, by simultaneously lowering PTH, calcium, phosphorus, and calcium-phosphorus levels, may maintain PTH and mineral balance in these individuals. However, as with traditional therapies, long-term data are limited. Design, setting, participants, & measurement: Dialysis subjects from at least one of five lead-in studies (double-blind placebo-controlled, including one extension trial) completing up to 52 wk of either cinacalcet or placebo were eligible for this open-label extension study, including an 8-wk dose titration (initiated at 30 mg/d), followed by 24-wk maintenance and up to 132 wk of follow-up. Final efficacy analysis was at week 180. Results: Three hundred thirty-four of 589 enrolled subjects received cinacalcet from the beginning of the lead-in study. Weekly median PTH values were ≤300 pg/ml (weeks 16 through 180) and median Ca×P values were ≤55 mg2/dl2 (weeks 4 through 180). Similar results were exhibited in the 255 subjects who initially received placebo. Among the patients exposed to cinacalcet from the beginning of the lead-in study, 3% of subjects exhibited treatment-related serious adverse events. Conclusions: Cinacalcet effectively maintained PTH, Ca and P reductions in dialysis subjects for up to 180 wk. PMID:19696213

  1. [Specific toxicological considerations on anabolic agents; transmitted toxicity].

    Science.gov (United States)

    Ferrando, R; Truhaut, R

    1976-01-01

    The growth of populations and the spread of urbanization, resulting in new agricultural structures, have entailed a concentration of livestock production and recourse to new techniques. Of some importance among these techniques is the enteric or parenteral administration of substances in very low doses. These substances include anabolic agents, some of which, like many natural feeds, exhibit hormonal activity. They may be divided into two classes: --those of the DES type, synthetic compounds non-existent in the natural state, --natural agents, which are normally distributed throughout the animal and human organism, and hence in food of animal origin---milk, meat, eggs. The compounds belonging to the second class may also be synthesized and the main toxicological consideration is that they then have to meet clear-cut standards of identity and purity. A compound belonging to the first class, diethylstilbestrol (DES), administered to rats in doses as small as 60 mug/kg of feed or even smaller, causes in general lower growth rates as well as alterations in the genital system and reproductive functions. In long-term experiments (12 months) using rats and mice and applying so-called toxicity "de relais" tests, developed and described by the authors, it also appeared that meat from calves in which DES pellets were implanted under normal rearing conditions, inhibits growth and reproduction in mice and rats fed a diet containing 20% of this meat. Studies in which the livers from treated calves constituted 6% of the diet of these two rodent species also led to the conclusion that fertility was impaired in the second reproduction test. The authors also recall cases of vaginal cancer observed in young girls whose mothers had been treated with DES during pregnancy. Compounds belonging to the second class (estradiol-progesterone and estradiol-testosterone) gave no evidence of harmful effects upon rats when mixed with their rations during short and medium-term trials. Similar

  2. ZP2307, a novel cyclic PTH(1-17) analog, reversed established osteopenia in adult ovariectomized rats

    DEFF Research Database (Denmark)

    Vääräniemi, Jukka; Morko, Jukka; Peng, ZhiQi

    -17) analog, ZP2307, with a high efficacy and potency on the human PTH receptor in vitro. This study characterized the effects of intermittent treatment with ZP2307 on established osteopenia in adult ovariectomized (OVX) rats. Female Sprague-Dawley rats were ovariectomized at 6 months of age. After 6 weeks......-34). This study demonstrated that the intermittent treatment with ZP2307, the novel cyclic PTH(1-17) analog, is effective in reversing the established osteopenia in adult OVX rats to normal conditions. Due to its broad dose response relationship, ZP2307 may have a wider therapeutic window and a better safety...

  3. Myeloma bone disease: Pathophysiology and management

    Science.gov (United States)

    Silbermann, Rebecca; Roodman, G. David

    2013-01-01

    Multiple myeloma bone disease is marked by severe dysfunction of both bone formation and resorption and serves as a model for understanding the regulation of osteoblasts (OBL) and osteoclasts (OCL) in cancer. Myeloma bone lesions are purely osteolytic and are associated with severe and debilitating bone pain, pathologic fractures, hypercalcemia, and spinal cord compression, as well as increased mortality. Interactions within the bone marrow microenvironment in myeloma are responsible for the abnormal bone remodeling in myeloma bone disease. Myeloma cells drive bone destruction that increases tumor growth, directly stimulates the OCL formation, and induces cells in the marrow microenvironment to produce factors that drive OCL formation and suppress OBL formation. Factors produced by marrow stromal cells and OCL promote tumor growth through direct action on myeloma cells and by increasing angiogenesis. Current therapies targeting MMBD focus on preventing osteoclastic bone destruction; however regulators of OBL inhibition in MMBD have also been identified, and targeted agents with a potential anabolic effect in MMBD are under investigation. This review will discuss the mechanisms responsible for MMBD and therapeutic approaches currently in use and in development for the management of MMBD. PMID:26909272

  4. Parathyroid hormone and calcitonin interactions in bone: Irradiation-induced inhibition of escape in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Krieger, N.S.; Tashjian, A.H. Jr.; Feldman, R.S.

    1982-01-01

    Calcitonin (CT) inhibits hormonally stimulated bone resorption only transiently in vitro. This phenomenon has been termed ''escape,'' but the mechanism for the effect is not understood. One possible explanation is that bone cell differentiation and recruitment of specific precursor cells, in response to stimulators of resorption, lead to the appearance of osteoclasts that are unresponsive to CT. To test this hypothesis, cell proliferation in neonatal mouse calvaria in organ culture was inhibited by irradiation from a cobalt-60 source. At a dose of 6000 R, (/sup 3/H)thymidine incorporation into intact calvaria was inhibited approximately 90%. Irradiation had no effect on the resorptive response to 0.1 U/ml parathyroid hormone (PTH). However, irradiation induced a dose-dependent inhibition of the escape response which was maximal at 6000 R. A dose of 6000 R did not affect the binding of /sup 125/I-salmon CT to calvaria and decreased PTH stimulation of cyclic AMP release from bone without affecting the cyclic AMP response to CT. Although irradiation caused a dose-dependent inhibition of DNA synthesis, the dose-response curves for that effect and inhibition of escape were not superimposable. A morphologic study of hormonally treated calvaria demonstrated that irradiation prevented the early increase in number of osteoclasts in PTH-treated calvaria that had been observed previously in unirradiated bones. Autoradiography showed that irradiation also prevented the PTH-stimulated recruitment of newly divided mononuclear cell precursors into osteoclasts. This may be correlated with the effect of irradiation to prevent the loss of responsiveness to CT in the presence of PTH.

  5. Higher circulating parathormone is associated with smaller and weaker bones in obese children.

    Science.gov (United States)

    Radetti, Giorgio; Franceschi, Roberto; Adami, Silvano; Longhi, Silvia; Rossini, Maurizio; Gatti, Davide

    2014-07-01

    Obese children have disadvantageous bone geometry, bone of low quality, and reduced strength at non-weight-bearing skeletal sites. The aim of our study was to investigate the role of parathormone (PTH) and the Wnt/β-catenin signaling pathway and its inhibitors, sclerostin and Dickkopf-1 (DKK1), as negative modulators of fat mass on bone. This was a cross-sectional observational study performed in 44 (26 males and 18 females) obese subjects, aged 11.41 ± 2.61 years. Thirty-seven normal-weight, healthy children (22 males and 15 females) of the same chronological age served as controls for the biochemical parameters and bone markers, while the data on bone geometry were evaluated according to our normative data obtained previously in a group of 325 control children. Digitalized X-rays were evaluated at the level of the second metacarpal bone for the determination of bone geometry: total cross-sectional area (TCSA), cortical area (CA), medullary area (MA), and bone strength (bending breaking resistance index [BBRI]). Serum bone markers (intact procollagen-1N-terminal propeptide [P1NP] and serum carboxy-terminal telopeptide of collagen-1 [CTX]), sclerostin, DKK1, PTH, 25-hydroxyvitamin D and were also measured. Data for TCSA, CA, MA, and BBRI are expressed as a standard deviation score in order to normalize them for age and sex. TCSA (mean ± SD, -2.92 ± 2.71), CA (-0.60 ± 0.82), MA (-0.45 ± 1.14), and BBRI (-2.65 ± 2.31) were all significantly smaller than in controls (p Bone turnover is higher in obese children than in controls, and this is associated with smaller and apparently weaker bones. Higher PTH and lower sclerostin levels may be responsible for these findings.

  6. Role of purinergic receptor polymorphisms in human bone

    DEFF Research Database (Denmark)

    Wesselius, Anke; Bours, Martijn J L; Agrawal, Ankita

    2011-01-01

    in the mechanotransductory process, where mechanical stimulation on bone leads to anabolic responses in the skeleton. A number of single nucleotide polymorphisms have been identified in the P2 receptor genes, where especially the P2X7 subtype has been the focus of extensive investigation where several polymorphisms have......Osteoporosis is a multifactorial disease with a strong genetic component. Variations in a number of genes have been shown to associate with bone turnover and risk of osteoporosis. P2 purinergic receptors are proteins that have ATP or other nucleotides as their natural ligands. Various P2Y and P2X...... receptor subtypes have been identified on bone cells. Several cellular functions in bone tissue are coupled to P2-receptor activation, including bone resorption, cytokine release, apoptosis, bone formation, and mineral deposition. Furthermore, ATP release and P2 purinergic signalling is a key pathway...

  7. Sex steroids and bone.

    Science.gov (United States)

    Manolagas, S C; Kousteni, S; Jilka, R L

    2002-01-01

    , in sex steroid deficiency, loss of transcriptional effects may be responsible for the increased osteoclastogenesis and osteoblastogenesis and thereby the increased rate of bone remodeling. Loss of nongenotropic anti-apoptotic effects on mature osteoblasts and osteocytes, in combination with an opposite effect on the lifespan of mature osteoclasts, may be responsible for the imbalance between formation and resorption and the progressive loss of bone mass and strength. Elucidation of the dual function of sex steroid receptors has important pathophysiologic and pharmacologic implications. Specifically, synthetic ligands of the ER that can evoke the nongenotropic but not the genotropic signal may be bone anabolic agents, as opposed to natural estrogens or selective estrogen receptor modulators that are antiresorptive agents. The same ligands may also circumvent the side effects associated with conventional hormone replacement therapy.

  8. Dual-phase (99m)Tc-MIBI scintigraphy with delayed neck and thorax SPECT/CT and bone scintigraphy in patients with primary hyperparathyroidism: correlation with clinical or pathological variables.

    Science.gov (United States)

    Qiu, Zhong-Ling; Wu, Bo; Shen, Chen-Tian; Zhu, Rui-Sen; Luo, Quan-Yong

    2014-10-01

    The purpose of this study was to assess the relationship between (99m)Tc-MIBI and (99m)Tc-MDP bone scintigraphy and clinical or pathological variables, including preoperative serum PTH levels and tumor diameter, in patients with newly diagnosed PHPT. Dual-phase (99m)Tc-MIBI planar scintigraphy was performed in 244 patients with PHPT. Of these patients, 155 underwent (99m)Tc-MDP bone scintigraphy to detect bone changes before parathyroidectomy. Factors influencing (99m)Tc-MIBI scintigraphy and (99m)Tc-MDP bone scintigraphy detection rate were assessed using univariate and multivariate logistic regression analysis; optimal cutoff values for predicting positive (99m)Tc-MIBI and (99m)Tc-MDP bone scintigraphy were evaluated using ROC analysis. Among 244 patients, 174 (71.31 %) patients with 181 foci had a positive (99m)Tc-MIBI planar scintigraphy; delayed neck and thorax SPECT/CT could identify and locate the (99m)Tc-MIBI lesions but could not find more lesions than planar scintigraphy. 70 (28.69 %) patients had a negative (99m)Tc-MIBI planar scintigraphy. Tumor diameter, serum PTH level and symptoms were statistically significant predictive factors in predicting positive (9m)Tc-MIBI scintigraphy both univariate and multivariate logistic regression analyses. The optimal thresholds for tumor diameter and serum PTH by ROC analysis were 1.03 cm and 127.60 ng/L, respectively. Among 155 patients with bone scintigraphy, (99m)Tc-MDP bone scintigraphy showed positive finding in 80 (51.61 %) patients and negative finding in 75 patients. Univariate logistic regression analysis showed that patient age, sex, tumor diameter and PTH level (≥150 ng/L) were statistically significant in predicting positive (99m)Tc-MDP bone scintigraphy. Multivariate logistic regression analysis showed both tumor diameter and PTH ≥ 150 ng/L were statistically significant in predicting positive (99m)Tc-MDP bone scintigraphy. The optimal thresholds for tumor diameter and serum PTH by ROC analysis were

  9. Evidence of associations between feto-maternal vitamin D status, cord parathyroid hormone and bone-specific alkaline phosphatase, and newborn whole body bone mineral content.

    Science.gov (United States)

    Dror, Daphna K; King, Janet C; Fung, Ellen B; Van Loan, Marta D; Gertz, Erik R; Allen, Lindsay H

    2012-02-01

    In spite of a high prevalence of vitamin D inadequacy in pregnant women and neonates, relationships among vitamin D status (25(OH)D), parathyroid hormone (PTH), bone specific alkaline phosphatase (BALP), and whole body bone mineral content (WBBMC) in the newborn are poorly characterized. The purpose of the present study was to investigate the relationships between maternal and cord 25(OH)D, PTH, BALP, and WBBMC in newborns in a multiethnic population in Oakland, California and to evaluate the predictive value of the biochemical indices as indicators of WBBMC. Maternal and cord blood were collected from 80 mother-infant pairs and infant WBBMC was measured by dual energy X-ray absorptiometry 8-21 days post-birth. Cord PTH and BALP were each inversely correlated with infant WBBMC (r = -0.28, p = 0.01 and r = -0.26, p = 0.02) and with cord 25(OH)D (r = -0.24, p = 0.03 and r = -0.34, p = 0.002), while cord 25(OH)D and unadjusted or weight-adjusted WBBMC were not significantly correlated with one other. In multivariate regression modeling, infant WBBMC was most strongly predicted by infant weight (p feto-maternal 25(OH)D, cord PTH and BALP, and early infant WBBMC, though neither feto-maternal 25(OH)D nor the measured biochemical indices were suitable indicators of WBBMC.

  10. Geochemical Energy for Catabolism and Anabolism in Hydrothermal Systems

    Science.gov (United States)

    Amend, J. P.; McCollom, T. M.; Bach, W.

    2008-12-01

    Chemically reduced deep-sea vent fluids mixed with oxidized seawater can generate redox disequilibria that serve as energy sources for chemolithoautotrophic (catabolism) and biomass synthesis (anabolism) reactions. Numerical models can be used to evaluate Gibbs energies of such processes on the early Earth and in present-day systems. Here, geochemical data from compositionally diverse vent fluids (Lost City, Rainbow, Logatchev, TAG, 21 °N EPR) are combined with several seawater chemistries to yield a wide range of mixed hydrothermal solutions; this is the starting point for our thermodynamic calculations. In ultramafic-hosted hydrothermal systems, such as Rainbow or Lost City, aerobic chemolithotrophic catabolisms (oxidation of H2, FeII, CH4) are the most energy-yielding at low temperatures (catabolic reaction energetics can then be used to put constraints on the amount of primary biomass production. Under putative early Earth conditions, for example, the net chemoautotrophic synthesis of cellular building blocks is thermodynamically most favorable at moderate temperatures (~50°C), where the energy contributions from HCO3- and H+ in cool seawater coupled to the reducing power in hot vent fluid are optimized. At these conditions, and counter to conventional wisdom, the synthesis of amino acids may even yield small amounts of energy.

  11. Brain connectivity aberrations in anabolic-androgenic steroid users

    Directory of Open Access Journals (Sweden)

    Lars T. Westlye

    2017-01-01

    Full Text Available Sustained anabolic-androgenic steroid (AAS use has adverse behavioral consequences, including aggression, violence and impulsivity. Candidate mechanisms include disruptions of brain networks with high concentrations of androgen receptors and critically involved in emotional and cognitive regulation. Here, we tested the effects of AAS on resting-state functional brain connectivity in the largest sample of AAS-users to date. We collected resting-state functional magnetic resonance imaging (fMRI data from 151 males engaged in heavy resistance strength training. 50 users tested positive for AAS based on the testosterone to epitestosterone (T/E ratio and doping substances in urine. 16 previous users and 59 controls tested negative. We estimated brain network nodes and their time-series using ICA and dual regression and defined connectivity matrices as the between-node partial correlations. In line with the emotional and behavioral consequences of AAS, current users exhibited reduced functional connectivity between key nodes involved in emotional and cognitive regulation, in particular reduced connectivity between the amygdala and default-mode network (DMN and between the dorsal attention network (DAN and a frontal node encompassing the superior and inferior frontal gyri (SFG/IFG and the anterior cingulate cortex (ACC, with further reductions as a function of dependency, lifetime exposure, and cycle state (on/off.

  12. Risk factors for anabolic-androgenic steroid use in men.

    Science.gov (United States)

    Brower, K J; Blow, F C; Hill, E M

    1994-01-01

    The illicit use of anabolic steroids to enhance athletic performance and physical appearance can cause numerous psychiatric and other adverse effects. In order to prevent steroid use and its negative consequences, knowledge of risk factors is needed. We conducted an anonymous survey of 404 male weight lifters from community gymnasiums who completed a 20-min, self-administered questionnaire. The sample for this study included all 35 men who were thinking about using steroids ("high-risk" nonusers), 50 randomly selected nonusers who were not thinking about using steroids ("low-risk" nonusers) and all 49 steroid users. The three groups differed in age, training characteristics, other performance-enhancers tried, body image, acquaintance with steroid users, and perception of negative consequences. When groups were compared along a continuum from low risk to high risk and from high risk to actual use, we found increasing amounts of competitive bodybuilding, performance-enhancers tried, and steroid-using acquaintances. Groups did not differ in their use of addictive substances. Nearly three-fourths of the high-risk group felt "not big enough," compared to 21% of the low-risk group and 38% of the steroid users (p steroids do work to increase satisfaction with body size, and that dissatisfaction with body size may contribute to the risk of using steroids.

  13. Brain connectivity aberrations in anabolic-androgenic steroid users.

    Science.gov (United States)

    Westlye, Lars T; Kaufmann, Tobias; Alnæs, Dag; Hullstein, Ingunn R; Bjørnebekk, Astrid

    2017-01-01

    Sustained anabolic-androgenic steroid (AAS) use has adverse behavioral consequences, including aggression, violence and impulsivity. Candidate mechanisms include disruptions of brain networks with high concentrations of androgen receptors and critically involved in emotional and cognitive regulation. Here, we tested the effects of AAS on resting-state functional brain connectivity in the largest sample of AAS-users to date. We collected resting-state functional magnetic resonance imaging (fMRI) data from 151 males engaged in heavy resistance strength training. 50 users tested positive for AAS based on the testosterone to epitestosterone (T/E) ratio and doping substances in urine. 16 previous users and 59 controls tested negative. We estimated brain network nodes and their time-series using ICA and dual regression and defined connectivity matrices as the between-node partial correlations. In line with the emotional and behavioral consequences of AAS, current users exhibited reduced functional connectivity between key nodes involved in emotional and cognitive regulation, in particular reduced connectivity between the amygdala and default-mode network (DMN) and between the dorsal attention network (DAN) and a frontal node encompassing the superior and inferior frontal gyri (SFG/IFG) and the anterior cingulate cortex (ACC), with further reductions as a function of dependency, lifetime exposure, and cycle state (on/off).

  14. Impaired post exercise heart rate recovery in anabolic steroid users.

    Science.gov (United States)

    dos Santos, M R; Dias, R G; Laterza, M C; Rondon, M U P B; Braga, A M F W; de Moraes Moreau, R L; Negrão, C E; Alves, M-J N N

    2013-10-01

    Previous study showed that muscle sympathetic nerve activity (MSNA) was augmented in anabolic steroids users (AASU). In the present study, we tested the hypothesis that the heart rate (HR) responses after maximal exercise testing would be reduced in AASU. 10 male AASU and 10 AAS nonusers (AASNU) were studied. Cardiopulmonary exercise was performed to assess the functional capacity and heart rate recovery. MSNA was recorded directly from the peroneal nerve by microneurography technique. Peak oxygen consumption (VO₂) was lower in AASU compared to AASNU (43.66±2.24 vs. 52.70±1.68 ml/kg/min, P=0.005). HR recovery (HRR) at first and second minute was lower in AASU than AASNU (21±2 vs. 27±2 bpm, P=0.02 and 37±4 vs. 45±2 bpm, P=0.05, respectively). MSNA was higher in AASU than AASNU (29±3 vs. 20±1 bursts/min, P=0.01). Further analysis showed a correlation between HRR and MSNA (r=- 0.64, P=0.02), HRR at first minute and peak VO₂ (r=0.70, P=0.01) and HRR at second minute and peak VO₂ (r=0.62, P=0.02). The exacerbated sympathetic outflow associated with a lower parasympathetic activation after maximal exercise, which impairs heart rate recovery, strengthens the idea of autonomic imbalance in AASU. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Effects of anabolic androgenic steroids on chylomicron metabolism.

    Science.gov (United States)

    Morikawa, Aleksandra T; Maranhão, Raul C; Alves, Maria-Janieire N N; Negrão, Carlos E; da Silva, Jeferson L; Vinagre, Carmen G C

    2012-11-01

    To evaluate the effects of anabolic androgenic steroids (AAS) on chylomicron metabolism. An artificial lipid emulsion labeled with radioactive cholesteryl ester (CE) and triglycerides (TG) mimicking chylomicrons was intravenously injected into individuals who regularly weight trained and made regular use of AAS (WT+AAS group), normolipidemic sedentary individuals (SDT group) and individuals who also regularly weight trained but did not use AAS (WT group). Fractional clearance rates (FCR) were determined by compartmental analysis for emulsion plasma decay curves. FCR-CE for the WT+AAS group was reduced (0.0073 ± 0.0079 min(-1), 0.0155 ± 0.0100 min(-1), 0.0149 ± 0.0160 min(-1), respectively; p<0.05), FCR-TG was similar for both the WT and SDT groups. HDL-C plasma concentrations were lower in the WT+AAS group when compared to the WT and SDT groups (22 ± 13; 41 ± 7; 38 ± 13 mg/dL, respectively; p<0.001). Hepatic triglyceride lipase activity was greater in the WT+AAS group when compared to the WT and SDT groups (7243 ± 1822; 3898 ± 1232; 2058 ± 749, respectively; p<0.001). However, no difference was observed for lipoprotein lipase activity. Data strongly suggest that AAS may reduce the removal from the plasma of chylomicron remnants, which are known atherogenic factors. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Bigger, Faster, Stronger! An Overview of Anabolic Androgenic Steroids and their Use and Impact on the Sport Industry

    OpenAIRE

    O'Hagan, A.; Walton, H

    2015-01-01

    The use of anabolic androgenic steroids (AAS) in sport is no longer confined to the power disciplines and has become a wide-spread issue throughout the general population. AAS are synthetic versions of the male hormone testosterone and display both anabolic and androgenic properties. It is the anabolic properties that are responsible for the muscle binding characteristics and are the main attraction for users. The primary purpose of this review was to provide an overview of the use of AAS in ...

  17. The myokine irisin increases cortical bone mass

    Science.gov (United States)

    Colaianni, Graziana; Cuscito, Concetta; Mongelli, Teresa; Pignataro, Paolo; Buccoliero, Cinzia; Liu, Peng; Lu, Ping; Sartini, Loris; Di Comite, Mariasevera; Mori, Giorgio; Di Benedetto, Adriana; Brunetti, Giacomina; Yuen, Tony; Sun, Li; Reseland, Janne E.; Colucci, Silvia; New, Maria I.; Zaidi, Mone; Cinti, Saverio; Grano, Maria

    2015-01-01

    It is unclear how physical activity stimulates new bone synthesis. We explored whether irisin, a newly discovered myokine released upon physical activity, displays anabolic actions on the skeleton. Young male mice were injected with vehicle or recombinant irisin (r-irisin) at a low cumulative weekly dose of 100 µg kg−1. We observed significant increases in cortical bone mass and strength, notably in cortical tissue mineral density, periosteal circumference, polar moment of inertia, and bending strength. This anabolic action was mediated primarily through the stimulation of bone formation, but with parallel notable reductions in osteoclast numbers. The trabecular compartment of the same bones was spared, as were vertebrae from the same mice. Higher irisin doses (3,500 µg kg−1 per week) cause browning of adipose tissue; this was not seen with low-dose r-irisin. Expectedly, low-dose r-irisin modulated the skeletal genes, Opn and Sost, but not Ucp1 or Pparγ expression in white adipose tissue. In bone marrow stromal cell cultures, r-irisin rapidly phosphorylated Erk, and up-regulated Atf4, Runx2, Osx, Lrp5, β-catenin, Alp, and Col1a1; this is consistent with a direct receptor-mediated action to stimulate osteogenesis. We also noted that, although the irisin precursor Fndc5 was expressed abundantly in skeletal muscle, other sites, such as bone and brain, also expressed Fndc5, albeit at low levels. Furthermore, muscle fibers from r-irisin–injected mice displayed enhanced Fndc5 positivity, and irisin induced Fdnc5 mRNA expression in cultured myoblasts. Our data therefore highlight a previously unknown action of the myokine irisin, which may be the molecular entity responsible for muscle–bone connectivity. PMID:26374841

  18. Temporal changes in tissue 1α,25-dihydroxyvitamin D3, vitamin D receptor target genes, and calcium and PTH levels after 1,25(OH)2D3 treatment in mice.

    Science.gov (United States)

    Chow, Edwin C Y; Quach, Holly P; Vieth, Reinhold; Pang, K Sandy

    2013-05-01

    The vitamin D receptor (VDR) maintains a balance of plasma calcium and 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], its natural active ligand, by directly regulating the calcium ion channel (TRPV6) and degradation enzyme (CYP24A1), and indirectly regulating the parathyroid hormone (PTH) for feedback regulation of the synthetic enzyme CYP27B1. Studies that examined the intricate relationships between plasma and tissue 1,25(OH)2D3 levels and changes in VDR target genes and plasma calcium and PTH are virtually nonexistent. In this study, we investigated temporal correlations between tissue 1,25(OH)2D3 concentrations and VDR target genes in ileum and kidney and plasma calcium and PTH concentrations in response to 1,25(OH)2D3 treatment in mice (2.5 μg/kg ip, singly or q2d × 4). After a single ip dose, plasma 1,25(OH)2D3 peaked at ∼0.5 h and then decayed biexponentially, falling below basal levels after 24 h and then returning to baseline after 8 days. Upon repetitive ip dosing, plasma, ileal, renal, and bone 1,25(OH)2D3 concentrations rose and decayed in unison. Temporal profiles showed increased expressions of ileal Cyp24a1 and renal Cyp24a1, Mdr1/P-gp, and VDR but decreased renal Cyp27b1 mRNA after a time delay in VDR activation. Increased plasma calcium and attenuated PTH levels and increased ileal and renal Trpv6 expression paralleled the changes in tissue 1,25(OH)2D3 concentrations. Gene changes in the kidney were more sustained than those in intestine, but the magnitudes of change for Cyp24a1 and Trpv6 were lower than those in intestine. The data revealed that 1,25(OH)2D3 equilibrates with tissues rapidly, and VDR target genes respond quickly to exogenously administered 1,25(OH)2D3.

  19. The effect of osteoporosis treatments on fatigue properties of cortical bone tissue

    Directory of Open Access Journals (Sweden)

    Garry R. Brock

    2015-06-01

    Full Text Available Bisphosphonates are commonly prescribed for treatment of osteoporosis. Long-term use of bisphosphonates has been correlated to atypical femoral fractures (AFFs. AFFs arise from fatigue damage to bone tissue that cannot be repaired due to pharmacologic treatments. Despite fatigue being the primary damage mechanism of AFFs, the effects of osteoporosis treatments on fatigue properties of cortical bone are unknown. To examine if fatigue-life differences occur in bone tissue after different pharmacologic treatments for osteoporosis, we tested bone tissue from the femurs of sheep given a metabolic acidosis diet to induce osteoporosis, followed by treatment with a selective estrogen reception modulator (raloxifene, a bisphosphonate (alendronate or zoledronate, or parathyroid hormone (teriparatide, PTH. Beams of cortical bone tissue were created and tested in four-point bending fatigue to failure. Tissue treated with alendronate had reduced fatigue life and less modulus loss at failure compared with other treatments, while tissue treated with PTH had a prolonged fatigue life. No loss of fatigue life occurred with zoledronate treatment despite its greater binding affinity and potency compared with alendronate. Tissue mineralization measured by microCT did not explain the differences seen in fatigue behavior. Increased fatigue life with PTH suggests that current treatment methods for AFF could have beneficial effects for restoring fatigue life. These results indicate that fatigue life differs with each type of osteoporosis treatment.

  20. Self-Perceived Weight and Anabolic Steroid Misuse Among US Adolescent Boys

    Science.gov (United States)

    Jampel, Jonathan D.; Murray, Stuart B.; Griffiths, Scott; Blashill, Aaron J.

    2016-01-01

    Purpose Anabolic steroid misuse is a growing concern among adolescent boys, and chronic misuse is associated with multisystemic health consequences. However, little is known about weight related predictors of anabolic steroid misuse. We examined the prediction of lifetime anabolic steroid misuse as a function of self-perceived weight status among US adolescent boys. Methods Analysis was undertaken using the 2013 Youth Risk Behavior Survey, a nationally representative data set sampling public and private high school students throughout the United States. Data from a total of 6,000 US adolescent boys were used in the present study. Results The prevalence of ever misusing anabolic androgenic steroids was 12.6% among boys who viewed themselves as very underweight, 11.9% for boys who viewed themselves as very overweight, compared with 3.8% for boys who viewed themselves as about the right weight. Compared to boys who viewed themselves as about the right weight, boys who self-perceived themselves as very underweight (adjusted odds ratio = 6.9, 95% confidence interval: 2.7–17.7, p < .001) and very overweight (adjusted odds ratio = 3.8, 95% confidence interval: 1.8–7.7, p < .001) were significantly associated with increased risk of anabolic androgenic steroid misuse. Conclusions Large effect size estimates were revealed, suggesting that anabolic androgenic steroid misuse is not solely a function of boys desiring increased mass; boys who desire leanness are also likely to misuse anabolic androgenic steroids. Future prevention efforts should target not only boys who view themselves as underweight but also those who perceive themselves as overweight. PMID:26598061

  1. Bone within a bone

    Energy Technology Data Exchange (ETDEWEB)

    Williams, H.J.; Davies, A.M. E-mail: wendy.turner@roh.nhs.uk; Chapman, S

    2004-02-01

    The 'bone within a bone' appearance is a well-recognized radiological term with a variety of causes. It is important to recognize this appearance and also to be aware of the differential diagnosis. A number of common conditions infrequently cause this appearance. Other causes are rare and some remain primarily of historical interest, as they are no longer encountered in clinical practice. In this review we illustrate some of the conditions that can give the bone within a bone appearance and discuss the physiological and pathological aetiology of each where known.

  2. Relationship between fasting glucose, vitamin D and PTH in early postmenopausal women

    DEFF Research Database (Denmark)

    við Streym, Susanna; Rejnmark, Lars; Vestergaard, Peter;

    2010-01-01

      Abstract Relationship between fasting glucose, vitamin D and PTH in early postmenopausal women Súsanna við Streym Thomsen (1), Lars Rejnmark (1), Peter Vestergaard (1), Christine Brot (2), Pia Eiken (3), Pernille Hermann (4) Leif Mosekilde (1). (1) Department of Medicine and Endocrinology C...... postmenopausal Caucasian women (n=2016) aged 45 to 58 years old. Measurements: Fasting blood glucose was measured after an overnight fast by standard laboratory methods. Serum levels of 25OHD were measured by a competitive assay using rachitic rat binding protein. The fat and lean mass was measured by DXA...... between fasting blood glucose and 25OHD and all studied indices. In a multivariate linear regression analyzing fasting blood glucose was significantly associated with BMI (b=0.038 ±0.007 (SE), 2p

  3. The Crystal Structure of TAL Effector PthXo1 Bound to Its DNA Target

    Energy Technology Data Exchange (ETDEWEB)

    Mak, Amanda Nga-Sze; Bradley, Philip; Cernadas, Raul A.; Bogdanove, Adam J.; Stoddard, Barry L. (FHCRC); (Iowa State)

    2012-02-10

    DNA recognition by TAL effectors is mediated by tandem repeats, each 33 to 35 residues in length, that specify nucleotides via unique repeat-variable diresidues (RVDs). The crystal structure of PthXo1 bound to its DNA target was determined by high-throughput computational structure prediction and validated by heavy-atom derivatization. Each repeat forms a left-handed, two-helix bundle that presents an RVD-containing loop to the DNA. The repeats self-associate to form a right-handed superhelix wrapped around the DNA major groove. The first RVD residue forms a stabilizing contact with the protein backbone, while the second makes a base-specific contact to the DNA sense strand. Two degenerate amino-terminal repeats also interact with the DNA. Containing several RVDs and noncanonical associations, the structure illustrates the basis of TAL effector-DNA recognition.

  4. Gene controlled by promoter--PTH4 depending on whiG of Streptomyces coelicolor

    Institute of Scientific and Technical Information of China (English)

    谭华荣; 杨海花; 田宇清; 吴畏; 董可宁; K.F.Chater

    1996-01-01

    The downstream gene controlled by promoter--PTH4 which is related to Streptomycesdifferentiation was cloned, and its sequence was determined by the dideoxy chain termination method. The results indicated that the 1597 bp of DNA fragment conferred a complete open reading frame (ORF). In searches of databases, the deduced product of the ORF was not homologous with any known proteins; it may be a new protein. The function of the gene was studied using the strategy of gene disruption; the actinorhodin could not be produced when this gene was disrupted. Therefore, this gene may be related to actinorhodin biosynthesis in Streptomyces coelicolor, and the result also shows that this gene may play a role in multiple level regulation of differentiation genes in Streptomyces.

  5. Effects of treatment with glucagon-like peptide-2 on bone resorption in colectomized patients with distal ileostomy or jejunostomy and short-bowel syndrome

    DEFF Research Database (Denmark)

    Gottschalck, I.B.; Jeppesen, Palle Bekker; Hartmann, B.;

    2008-01-01

    OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome (...... and therefore precludes treatment of their osteopenia with GLP-2. The anti-resorptive response to GLP-2 seems to require an intact small intestine and may involve suppression of PTH secretion Udgivelsesdato: 2008......OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome...... (SBS) and they have reduced bone mineral density (BMD). The aim of the study was to investigate the anti-resorptive effect (assessed by s-CTX) of 14 days of GLP-2 treatment in these patients and to determine whether 56 days of treatment would improve BMD. PTH secretion in response to GLP-2 was also...

  6. Effects of treatment with glucagon-like peptide-2 on bone resorption in colectomized patients with distal ileostomy or jejunostomy and short-bowel syndrome

    DEFF Research Database (Denmark)

    Gottschalck, Ida B; Jeppesen, Palle B; Hartmann, Bolette;

    2008-01-01

    OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome (...... and therefore precludes treatment of their osteopenia with GLP-2. The anti-resorptive response to GLP-2 seems to require an intact small intestine and may involve suppression of PTH secretion.......OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome...... (SBS) and they have reduced bone mineral density (BMD). The aim of the study was to investigate the anti-resorptive effect (assessed by s-CTX) of 14 days of GLP-2 treatment in these patients and to determine whether 56 days of treatment would improve BMD. PTH secretion in response to GLP-2 was also...

  7. Stretching dependence of the vibration modes of a single-molecule Pt-H-2-Pt bridge

    DEFF Research Database (Denmark)

    Djukic, D.; Thygesen, Kristian Sommer; Untiedt, C.

    2005-01-01

    isotope substitution is obtained. The stretching dependence for each of the modes allows uniquely classifying them as longitudinal or transversal modes. The interpretation of the experiment in terms of a Pt-H-2-Pt bridge is verified by density-functional theory calculations for the stability, vibrational...

  8. Identification of Six Novel PTH1R Mutations in Families with a History of Primary Failure of Tooth Eruption

    DEFF Research Database (Denmark)

    Risom, Lotte; Christoffersen, Line Borck; Daugaard-Jensen, Jette

    2013-01-01

    Primary Failure of tooth Eruption (PFE) is a non-syndromic disorder which can be caused by mutations in the parathyroid hormone receptor 1 gene (PTH1R). Traditionally, the disorder has been identified clinically based on post-emergent failure of eruption of permanent molars. However, patients wit...

  9. In vivo PTH provokes apical NHE3 and NaPi2 redistribution and Na-K-ATPase inhibition

    DEFF Research Database (Denmark)

    Zhang, Y; Norian, J M; Magyar, C E

    1999-01-01

    The aim of this study was to test the hypothesis that in vivo administration of parathyroid hormone (PTH) provokes diuresis/natriuresis through redistribution of proximal tubule apical sodium cotransporters (NHE3 and NaPi2) to internal stores and inhibition of basolateral Na-K-ATPase activity...

  10. Serum levels of parathyroid hormone and markers of bone metabolism in patients with rheumatoid arthritis. Relationship to disease activity and glucocorticoid treatment

    DEFF Research Database (Denmark)

    Jensen, Tonny Joran; Hansen, M; Madsen, J C;

    2001-01-01

    OBJECTIVE: To evaluate the influence of inflammatory activity and glucocorticoid (GC) treatment on serum parathyroid hormone (s-PTH) and bone metabolism in patients with rheumatoid arthritis (RA). Furthermore, in patients with active RA, to examine the PTH secretion and Ca2+ set point before...... and after treatment with GC. METHODS: A range of biochemical markers of bone metabolism and calcium homeostasis were measured in 95 patients with definite RA stratified into groups according to disease activity and GC treatment. In a subgroup of 12 patients with active disease, initiating slow...... groups. The levels of urine pyridinoline (Pyr) and s-albumin-corrected calcium (s-AlbCorrCa2+) were elevated in patients with active disease and patients treated with GC. S-PTH and s-phosphate were within normal ranges. S-TAP, s-ICTP, Pyr and s-AlbCorrCa2+ correlated positively with indices of disease...

  11. Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology.

    Science.gov (United States)

    Schmidt, Azriel; Kimmel, Donald B; Bai, Chang; Scafonas, Angela; Rutledge, Sujane; Vogel, Robert L; McElwee-Witmer, Sheila; Chen, Fang; Nantermet, Pascale V; Kasparcova, Viera; Leu, Chih-Tai; Zhang, Hai-Zhuan; Duggan, Mark E; Gentile, Michael A; Hodor, Paul; Pennypacker, Brenda; Masarachia, Patricia; Opas, Evan E; Adamski, Sharon A; Cusick, Tara E; Wang, Jiabing; Mitchell, Helen J; Kim, Yuntae; Prueksaritanont, Thomayant; Perkins, James J; Meissner, Robert S; Hartman, George D; Freedman, Leonard P; Harada, Shun-ichi; Ray, William J

    2010-05-28

    Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.

  12. Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology*

    Science.gov (United States)

    Schmidt, Azriel; Kimmel, Donald B.; Bai, Chang; Scafonas, Angela; Rutledge, SuJane; Vogel, Robert L.; McElwee-Witmer, Sheila; Chen, Fang; Nantermet, Pascale V.; Kasparcova, Viera; Leu, Chih-tai; Zhang, Hai-Zhuan; Duggan, Mark E.; Gentile, Michael A.; Hodor, Paul; Pennypacker, Brenda; Masarachia, Patricia; Opas, Evan E.; Adamski, Sharon A.; Cusick, Tara E.; Wang, Jiabing; Mitchell, Helen J.; Kim, Yuntae; Prueksaritanont, Thomayant; Perkins, James J.; Meissner, Robert S.; Hartman, George D.; Freedman, Leonard P.; Harada, Shun-ichi; Ray, William J.

    2010-01-01

    Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40–80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs. PMID:20356837

  13. Impact of anabolic androgenic steroids on adolescent males.

    Science.gov (United States)

    Lumia, Augustus R; McGinnis, Marilyn Y

    2010-06-01

    Anabolic androgenic steroid (AAS) use increased dramatically among adolescent males. This review focuses on studies using animal models of AAS exposure during adolescence which is a hormonally sensitive developmental period. AAS exposure during this critical period has wide-ranging consequences, including increased dendritic spine density, altered brain serotonin levels and escalated aggression in response to physical provocation. Human data suggest that AAS induces indiscriminate and unprovoked aggression often described as "'roid rage". However, animal studies indicate that the behavioral impact of AAS is modulated by experiential and social contingencies, a perceived provocation, and the chemical composition of the AAS. The AAS, testosterone increases aggression in juvenile and adult male rats when physically provoked. In contrast, stanzolol, inhibits aggression in both juvenile and adult male rats, even when physically provoked. Nandrolone has minimal effects on aggression, unless preceded by attack training. Exposure to AAS during adolescence may have a host of unintended bio-behavioral consequences. Yet, the perception of harmlessness surrounds AAS use. The perception of harmlessness is promoted by the availability of AAS especially through internet pharmacies. The perception of acceptability is reflected in current cultural ethics that no longer condemn cheating to obtain personal achievement or success. A prevailing conviction is that although AAS are illegal they are not really bad. Reduction of the availability of AAS to adolescents requires ardent legislative and legal intervention. The problem of acceptability can be addressed by educating adolescents about the short-term and long-term effects of AAS on brain and behavior, to increase awareness of the potential consequences of AAS use that apply directly to them.

  14. Identification of serum biomarkers for aging and anabolic response

    Directory of Open Access Journals (Sweden)

    Urban Randall J

    2011-06-01

    Full Text Available Abstract Objective With the progressive aging of the human population, there is an inexorable decline in muscle mass, strength and function. Anabolic supplementation with testosterone has been shown to effectively restore muscle mass in both young and elderly men. In this study, we were interested in identifying serum factors that change with age in two distinct age groups of healthy men, and whether these factors were affected by testosterone supplementation. Methods We measured the protein levels of a number of serum biomarkers using a combination of banked serum samples from older men (60 to 75 years and younger men (ages 18 to 35, as well as new serum specimens obtained through collaboration. We compared baseline levels of all biomarkers between young and older men. In addition, we evaluated potential changes in these biomarker levels in association with testosterone dose (low dose defined as 125 mg per week or below compared to high dose defined as 300 mg per week or above in our banked specimens. Results We identified nine serum biomarkers that differed between the young and older subjects. These age-associated biomarkers included: insulin-like growth factor (IGF1, N-terminal propeptide of type III collagen (PIIINP, monokine induced by gamma interferon (MIG, epithelial-derived neutrophil-activating peptide 78 (ENA78, interleukin 7 (IL-7, p40 subunit of interleukin 12 (IL-12p40, macrophage inflammatory protein 1β (MIP-1β, platelet derived growth factor β (PDGFβ and interferon-inducible protein 10 (IP-10. We further observed testosterone dose-associated changes in some but not all age related markers: IGF1, PIIINP, leptin, MIG and ENA78. Gains in lean mass were confirmed by dual energy X-ray absorptiometry (DEXA. Conclusions Results from this study suggest that there are potential phenotypic biomarkers in serum that can be associated with healthy aging and that some but not all of these biomarkers reflect gains in muscle mass upon

  15. Modulation of follistatin and myostatin propeptide by anabolic steroids and gender.

    Science.gov (United States)

    Mosler, S; Geisler, S; Hengevoss, J; Schiffer, T; Piechotta, M; Adler, M; Diel, P

    2013-07-01

    The purpose of this pilot study was to investigate the impact of training, anabolic steroids and endogenous hormones on myostatin-interacting proteins in order to identify manipulations of myostatin signalling. To identify whether analysis of the myostatin interacting proteins follistatin and myostatin propeptide is suitable to detect the abuse of anabolic steroids, their serum concentrations were monitored in untrained males, bodybuilders using anabolic steroids and natural bodybuilders. In addition, we analysed follistatin and myostatin propeptide serum proteins in females during menstrual cycle. Our results showed increased follistatin concentrations in response to anabolic steroids. Furthermore, variations of sex steroid levels during the menstrual cycle had no impact on the expression of follistatin and myostatin propetide. In addition, we identified gender differences in the basal expression of the investigated proteins. In general, follistatin and myostatin propeptide concentrations were relatively stable within the same individual both in males and females. In conclusion, the current findings provide an insight into gender differences in myostatin-interacting proteins and their regulation in response to anabolic steroids and endogenous hormones. Therefore our data provide new aspects for the development of doping prevention strategies.

  16. Aging related ER stress is not responsible for anabolic resistance in mouse skeletal muscle.

    Science.gov (United States)

    Chalil, Sreeda; Pierre, Nicolas; Bakker, Astrid D; Manders, Ralph J; Pletsers, Annelies; Francaux, Marc; Klein-Nulend, Jenneke; Jaspers, Richard T; Deldicque, Louise

    2015-12-25

    Anabolic resistance reflects the inability of skeletal muscle to maintain protein mass by appropriate stimulation of protein synthesis. We hypothesized that endoplasmic reticulum (ER) stress contributes to anabolic resistance in skeletal muscle with aging. Muscles were isolated from adult (8 mo) and old (26 mo) mice and weighed. ER stress markers in each muscle were quantified, and the anabolic response to leucine was assessed by measuring the phosphorylation state of S6K1 in soleus and EDL using an ex vivo muscle model. Aging reduced the muscle-to-body weight ratio in soleus, gastrocnemius, and plantaris, but not in EDL and tibialis anterior. Compared to adult mice, the expression of ER stress markers BiP and IRE1α was higher in EDL, and phospho-eIF2α was higher in soleus and EDL of old mice. S6K1 response to leucine was impaired in soleus, but not in EDL, suggesting that anabolic resistance contributes to soleus weight loss in old mice. Pre-incubation with ER stress inducer tunicamycin before leucine stimulation increased S6K1 phosphorylation beyond the level reached by leucine alone. Since tunicamycin did not impair leucine-induced S6K1 response, and based on the different ER stress marker regulation patterns, ER stress is probably not involved in anabolic resistance in skeletal muscle with aging.

  17. Chronic Drought Decreases Anabolic and Catabolic BVOC Emissions of Quercus pubescens in a Mediterranean Forest

    Science.gov (United States)

    Saunier, Amélie; Ormeño, Elena; Wortham, Henri; Temime-Roussel, Brice; Lecareux, Caroline; Boissard, Christophe; Fernandez, Catherine

    2017-01-01

    Biogenic volatile organic compounds (BVOC) emitted by plants can originate from both anabolism (metabolite production through anabolic processes) and catabolism (metabolite degradation by oxidative reactions). Drought can favor leaf oxidation by increasing the oxidative pressure in plant cells. Thus, under the precipitation decline predicted for the Mediterranean region, it can be expected both strong oxidation of anabolic BVOC within leaves and, as a result, enhanced catabolic BVOC emissions. Using an experimental rain exclusion device in a natural forest, we compared the seasonal course of the emissions of the main anabolic BVOC released by Q. pubescens (isoprene and methanol) and their catabolic products (MACR+MVK+ISOPOOH and formaldehyde, respectively) after 3 years of precipitation restriction (−30% of rain). Thus, we assume that this repetitive amplified drought promoted a chronic drought. BVOC emissions were monitored, on-line, with a PTR-ToF-MS. Amplified drought decreased all BVOC emissions rates in spring and summer by around 40–50 %, especially through stomatal closure, with no effect in autumn. Moreover, ratios between catabolic and anabolic BVOC remained unchanged with amplified drought, suggesting a relative stable oxidative pressure in Q. pubescens under the water stress applied. Moreover, these results suggest a quite good resilience of this species under the most severe climate change scenario in the Mediterranean region. PMID:28228762

  18. Cardiovascular manifestations of anabolic steroids in association with demographic variables in body building athletes

    Directory of Open Access Journals (Sweden)

    Farzad Gheshlaghi

    2015-01-01

    Full Text Available Background: The most common drug abuse among athletes is anabolic steroids which lead to the development of cardiovascular diseases and sudden death. Thus, the aim of this study was to evaluate cardiovascular outcomes of anabolic consumption in body building athletes. Materials and Methods: Totally, 267 male athletes at the range of 20-45 years old with the regular consumption of anabolic steroids for >2 months with at least once weekly. High-density lipoprotein (HDL, low-density lipoprotein (LDL, triglyceride (TG, and hematocrit (Hct levels were measured after 10 h of fasting. Data analysis was performed using K2, t-test, ANOVA and correlation coefficient through SPSS 17. Results: There was a nonsignificant difference between groups regarding HDL, TG, and total cholesterol. There was a significant decrease in the total and categorized LDL and Hct levels in consumers of anabolic steroid versus nonusers (P = 0.01 and P = 0.041, respectively. Results showed a significant increase in systolic and diastolic blood pressure (SBP and DBP in anabolic steroid users which associates with duration of abuse (P = 0.02 and P = 0.03, respectively. No significant electrocardiography changes were found within the follow-up period. Conclusion: Increase in SBP or DBP is a common complication of these drugs which can lead serious vascular disorders. The lower LDL cholesterol level might be due to the higher amounts of lipid consumption in these athletes.

  19. Overview of calpain-mediated regulation of bone and fat mass in osteoblasts.

    Science.gov (United States)

    Shimada, Masako

    2013-05-01

    The receptor for parathyroid hormone (PTH) and PTH-related peptide (PTH1R) belongs to the class II G protein-coupled receptor superfamily. The calpain small subunit encoded by the gene Capns1 is the second protein and the first enzyme identified by a yeast two-hybrid screen using the intracellular C-terminal tail of the rat PTH1R. The calpain regulatory small subunit forms a heterodimer with the calpain large catalytic subunit and modulates various cellular functions as a cysteine protease. To investigate a physiological role of the calpain small subunit in cells of the osteoblast lineage, we generated osteoblast-specific Capns1 knockout mouse models and characterized their bone phenotype. Molecular mechanisms by which calpain modulates cell proliferation of the osteoblast lineage were further examined in vitro. Moreover, we utilized the mutant mice as a disease model of osteoporosis accompanied with impaired bone resorptive function and suggested a possible clinical translation of our basic research finding.

  20. Dried plum's unique capacity to reverse bone loss and alter bone metabolism in postmenopausal osteoporosis model.

    Science.gov (United States)

    Rendina, Elizabeth; Hembree, Kelsey D; Davis, McKale R; Marlow, Denver; Clarke, Stephen L; Halloran, Bernard P; Lucas, Edralin A; Smith, Brenda J

    2013-01-01

    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.

  1. Bone mineral measurements of subchondral and trabecular bone in healthy and osteoporotic rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Castaneda, S [Universidad Autonoma, Rheumatology Department, Hospital de la Princesa, Madrid (Spain); Largo, R.; Marcos, M.E.; Herrero-Beaumont, G. [Universidad Autonoma, Inflammation Research Unit, Rheumatology Department, Fundacion Jimenez Diaz, Madrid (Spain); Calvo, E. [Universidad Autonoma, Inflammation Research Unit, Rheumatology Department, Fundacion Jimenez Diaz, Madrid (Spain); Universidad Autonoma, Department of Orthopaedic Surgery, Fundacion Jimenez Diaz, Madrid (Spain); Rodriguez-Salvanes, F. [Universidad Autonoma, Clinical Epidemiology Unit, Hospital de la Princesa, Madrid (Spain); Diaz-Curiel, M. [Universidad Autonoma, Department of Internal Medicine, Fundacion Jimenez Diaz, Madrid (Spain)

    2006-01-01

    Experimental models of osteoporosis in rabbits are useful to investigate anabolic agents because this animal has a fast bone turnover with predominant remodelling over the modelling processes. For that purpose, it is necessary to characterize the densitometric values of each type of bony tissue. To determine areal bone mass measurement in the spine and in trabecular, cortical and subchondral bone of the knee in healthy and osteoporotic rabbits. Bone mineral content and bone mineral density were measured in lumbar spine, global knee, and subchondral and cortical bone of the knee with dual energy X-ray absorptiometry using a Hologic QDR-1000/W densitometer in 29 skeletally mature female healthy New Zealand rabbits. Ten rabbits underwent triplicate scans for evaluation of the effect of repositioning. Osteoporosis was experimentally induced in 15 rabbits by bilateral ovariectomy and postoperative corticosteroid treatment for 4 weeks. Identical dual energy X-ray absorptiometry (DXA) studies were performed thereafter. Mean values of bone mineral content at the lumbar spine, global knee, subchondral bone and cortical tibial metaphysis were: 1934{+-}217 mg, 878{+-}83 mg, 149{+-}14 mg and 29{+-}7.0 mg, respectively. The mean values of bone mineral density at the same regions were: 298{+-}24 mg/cm{sup 2}, 455{+-}32 mg/cm{sup 2}, 617{+-}60 mg/cm{sup 2} and 678{+-}163 mg/cm{sup 2}, respectively. (orig.)

  2. Rescuing loading induced bone formation at senescence.

    Directory of Open Access Journals (Sweden)

    Sundar Srinivasan

    Full Text Available The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca(2+/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential.

  3. [Increased bone mineral density in patients with tertiary hyperparathyroidism after total parathyroidectomy and autotransplantation of the parathyroid gland].

    Science.gov (United States)

    Robin-Lersundi, Alvaro; Sánchez-Pernaute, Andrés; Ochagavía Cámara, Santiago; Díez-Valladares, Luis; Torres García, Antonio

    2012-01-01

    Changes in bone metabolism and bone mineral density are observed in renal transplant patients with tertiary hyperparathyroidism. The objective of this work was to analyse the increase in bone mineral density, as well the laboratory results, after total parathyroidectomy and autotransplantation in renal transplant patients with tertiary hyperparathyroidism. A retrospective study was conducted in which the bone mineral density values at femoral and lumbar level were analysed, together with the serum levels of calcium, phosphorous, parathyroid hormone (PTH), and alkaline phosphatase in 13 renal transplant patients with tertiary hyperparathyroidism before and after total parathyroidectomy and autotransplantation of the parathyroid glands. Parathyroidectomy is associated with an increase in bone mineral density at femoral and lumbar level, with an increase of 8.6 ± 6.7% at lumbar level, and 4 ± 16.1% at femoral level. The decrease in calcium after the parathyroidectomy was 2.8 mg/dL (95% CI; 1.9-4). The decrease in PTH was 172 pg/mL (95% CI; 98-354) and the decrease in alkaline phosphatase was 229 U/L (95% CI; 70-371). Total parathyroidectomy and autotransplantation of the parathyroid glands in renal transplant patients with tertiary hyperparathyroidism increases the bone mineral density. Furthermore, the calcium, PTH and alkaline phosphatase returned to normal in the long-term. Copyright © 2011 AEC. Published by Elsevier Espana. All rights reserved.

  4. Anabolic Steroid Use: Federal Efforts to Prevent and Reduce Anabolic Steroid Abuse among Teenagers. Report to the Committee on Oversight and Government Reform, House of Representatives. GAO-08-15

    Science.gov (United States)

    Government Accountability Office, 2007

    2007-01-01

    The abuse of anabolic steroids by teenagers--that is, their use without a prescription--is a health concern. Anabolic steroids are synthetic forms of the hormone testosterone that can be taken orally, injected, or rubbed on the skin. Although a 2006 survey funded by the National Institute on Drug Abuse (NIDA) found that less than 3 percent of 12th…

  5. Effects of anti-osteoporosis medications on fracture healing

    DEFF Research Database (Denmark)

    Jørgensen, Niklas R; Schwarz, Peter

    2011-01-01

    A number of fractures are complicated by impaired healing. This is prevalent in certain risk groups such as elderly, osteoporotics, postmenopausal women, and in people with malnutrition. At present, no pharmacologic treatments are available. Thus, there is an unmet need for medications that can...... stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis and, intriguingly, a number of animal studies prove the ability of PTH to induce fracture healing. PTH may therefore be a potential novel treatment option in humans with impaired...

  6. Parathyroid Hormone-Related Protein Analogs as Osteoporosis Therapies.

    Science.gov (United States)

    Esbrit, Pedro; Herrera, Sabina; Portal-Núñez, Sergio; Nogués, Xavier; Díez-Pérez, Adolfo

    2016-04-01

    The only bone anabolic agent currently available for osteoporosis treatment is parathyroid hormone (PTH)-either its N-terminal 1-34 fragment or the whole molecule of 1-84 aminoacids-whose intermittent administration stimulates new bone formation by targeting osteoblastogenesis and osteoblast survival. PTH-related protein (PTHrP) is an abundant factor in bone which shows N-terminal homology with PTH and thus exhibits high affinity for the same PTH type 1 receptor in osteoblasts. Therefore, it is not surprising that intermittently administered N-terminal PTHrP peptides induce bone anabolism in animals and humans. Furthermore, the C-terminal region of PTHrP also elicits osteogenic features in vitro in osteoblastic cells and in various animal models of osteoporosis. In this review, we discuss the current concepts about the cellular and molecular mechanisms whereby PTHrP may induce anabolic actions in bone. Pre-clinical studies and clinical data using N-terminal PTHrP analogs are also summarized, pointing to PTHrP as a promising alternative to current bone anabolic therapies.

  7. Hormonal Relationships to Bone Mass in Elderly Spanish Men as Influenced by Dietary Calcium and Vitamin D

    Directory of Open Access Journals (Sweden)

    Jose M. Moran

    2013-12-01

    Full Text Available We aim to evaluate whether calcium and vitamin D intake is associated with 25-hydroxyvitamin D (25-OH-Vitamin D3 and parathyroid hormone (PTH serum concentrations or is associated with either the phalangeal dual energy X-ray absorptiometry (pDXA or the quantitative bone ultrasound (QUS in independent elderly men. Serum PTH and 25-OH-Vitamin D3 were measured in 195 healthy elderly men (mean age: 73.31 ± 5.10 year. Food intake was quantified using a dietetic scale. Participants with 25-OH-Vitamin D3 levels ≥ 30 ng/mL (75 nmol/L and a calcium intake of 800–1200 mg/day exhibited the lowest PTH levels (41.49 ± 16.72 ng/mL. The highest PTH levels (75.60 ± 14.16 ng/mL were observed in the <30 ng/mL group 25-OH-Vitamin D3 with a calcium intake >1200 mg/day. No significant differences in the serum PTH levels based on the serum 25-OH-Vitamin D3 levels were observed among participants with a calcium intake of 800–1200 mg/day. Serum PTH was inversely correlated with serum 25-OH-Vitamin D3 in the entire patient sample (r = −0.288, p = 0.019. No differences in any of the three densitometry techniques were observed between any of the age groups in the 800–1200 mg/day and >1200 mg/day calcium intake groups. PTH levels correlate negatively with serum 25-OH-Vitamin D3 levels, and neither calcium nor vitamin D intake exert a strong influence on either of the two parameters.

  8. A New Data Analysis System to Quantify Associations between Biochemical Parameters of Chronic Kidney Disease-Mineral Bone Disease.

    Directory of Open Access Journals (Sweden)

    Mariano Rodriguez

    Full Text Available In hemodialysis patients, deviations from KDIGO recommended values of individual parameters, phosphate, calcium or parathyroid hormone (PTH, are associated with increased mortality. However, it is widely accepted that these parameters are not regulated independently of each other and that therapy aimed to correct one parameter often modifies the others. The aim of the present study is to quantify the degree of association between parameters of chronic kidney disease and mineral bone disease (CKD-MBD.Data was extracted from a cohort of 1758 adult HD patients between January 2000 and June 2013 obtaining a total of 46.141 records (10 year follow-up. We used an advanced data analysis system called Random Forest (RF which is based on self-learning procedure with similar axioms to those utilized for the development of artificial intelligence. This new approach is particularly useful when the variables analyzed are closely dependent to each other.The analysis revealed a strong association between PTH and phosphate that was superior to that of PTH and Calcium. The classical linear regression analysis between PTH and phosphate shows a correlation coefficient is 0.27, p<0.001, the possibility to predict PTH changes from phosphate modification is marginal. Alternatively, RF assumes that changes in phosphate will cause modifications in other associated variables (calcium and others that may also affect PTH values. Using RF the correlation coefficient between changes in serum PTH and phosphate is 0.77, p<0.001; thus, the power of prediction is markedly increased. The effect of therapy on biochemical variables was also analyzed using this RF.Our results suggest that the analysis of the complex interactions between mineral metabolism parameters in CKD-MBD may demand a more advanced data analysis system such as RF.

  9. Skeletal unloading causes resistance of osteoprogenitor cells to parathyroid hormone and to insulin-like growth factor-I

    Science.gov (United States)

    Kostenuik, P. J.; Harris, J.; Halloran, B. P.; Turner, R. T.; Morey-Holton, E. R.; Bikle, D. D.

    1999-01-01

    Skeletal unloading decreases bone formation and osteoblast number in vivo and decreases the number and proliferation of bone marrow osteoprogenitor (BMOp) cells in vitro. We tested the ability of parathyroid hormone (PTH) to stimulate BMOp cells in vivo by treating Sprague Dawley rats (n = 32) with intermittent PTH(1-34) (1 h/day at 8 microg/100 g of body weight), or with vehicle via osmotic minipumps during 7 days of normal weight bearing or hind limb unloading. Marrow cells were flushed from the femur and cultured at the same initial density for up to 21 days. PTH treatment of normally loaded rats caused a 2.5-fold increase in the number of BMOp cells, with similar increases in alkaline phosphatase (ALP) activity and mineralization, compared with cultures from vehicle-treated rats. PTH treatment of hind limb unloaded rats failed to stimulate BMOp cell number, ALP activity, or mineralization. Hind limb unloading had no significant effect on PTH receptor mRNA or protein levels in the tibia. Direct in vitro PTH challenge of BMOp cells isolated from normally loaded bone failed to stimulate their proliferation and inhibited their differentiation, suggesting that the in vivo anabolic effect of intermittent PTH on BMOp cells was mediated indirectly by a PTH-induced factor. We hypothesize that this factor is insulin-like growth factor-I (IGF-I), which stimulated the in vitro proliferation and differentiation of BMOp cells isolated from normally loaded bone, but not from unloaded bone. These results suggest that IGF-I mediates the ability of PTH to stimulate BMOp cell proliferation in normally loaded bone, and that BMOp cells in unloaded bone are resistant to the anabolic effect of intermittent PTH therapy due to their resistance to IGF-I.

  10. 1,25 (OH)2D3 enhances PTH-induced Ca2+ transients in preosteoblasts by activating L-type Ca2+ channels

    Science.gov (United States)

    Li, W.; Duncan, R. L.; Karin, N. J.; Farach-Carson, M. C.

    1997-01-01

    We previously demonstrated electrophysiologically that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] shifts the activation threshold of L-type Ca2+ channels in osteoblasts toward the resting potential and prolongs mean open time. Presently, we used single-cell Ca2+ imaging to study the combined effects of 1,25(OH)2D3 and parathyroid hormone (PTH) during generation of Ca2+ transients in fura 2-loaded MC3T3-E1 cells. Pretreatment with 1,25(OH)2D3 concentrations, which alone did not produce Ca2+ transients, consistently enhanced Ca2+ responses to PTH. Enhancement was dose dependent over the range of 1 to 10 nM and was blocked by pretreatment with 5 microM nitrendipine during pretreatment. A 1,25(OH)2D3 analog that activates L-type channels and shifts their activation threshold also enhanced PTH responses. In contrast, an analog devoid of membrane Ca2+ effects did not enhance PTH-induced Ca2+ transients. The PTH-induced Ca2+ transient involved activation of a dihydropyridine-insensitive cation channel that was inhibited by Gd3+. Together, these data suggest that 1,25(OH)2D3 increases osteoblast responsiveness to PTH through rapid modification of L-type Ca2+ channel gating properties, whose activation enhances Ca2+ entry through other channels such as the PTH-responsive, Gd(3+)-sensitive cation channel.

  11. Anabolic steroid-induced cardiomyopathy underlying acute liver failure in a young bodybuilder

    Institute of Scientific and Technical Information of China (English)

    Miguel Bispo; Ana Valente; Rosário Maldonado; Rui Palma; Helena Glória; Jo(a)o Nóbrega; Paula Alexandrino

    2009-01-01

    Heart failure may lead to subclinical circulatory disturbances and remain an unrecognized cause of ischemic liver injury. We present the case of a previously healthy 40-year-old bodybuilder, referred to our Intensive-Care Unit of Hepatology for treatment of severe acute liver failure, with the suspicion of toxic hepatitis associated with anabolic steroid abuse. Despite the absence of symptoms and signs of congestive heart failure at admission, an anabolic steroid-induced dilated cardiomyopathy with a large thrombus in both ventricles was found to be the underlying cause of the liver injury. Treatment for the initially unrecognized heart failure rapidly restored liver function to normal. To our knowledge, this is the first reported case of severe acute liver failure due to an unrecognized anabolic steroid-induced cardiomyopathy. Awareness of this unique presentation will allow for prompt treatment of this potentially fatal cause of liver failure.

  12. Imitation of phase I oxidative metabolism of anabolic steroids by titanium dioxide photocatalysis.

    Science.gov (United States)

    Ruokolainen, Miina; Valkonen, Minna; Sikanen, Tiina; Kotiaho, Tapio; Kostiainen, Risto

    2014-12-18

    The aim of this study was to investigate the feasibility of titanium dioxide (TiO2) photocatalysis for oxidation of anabolic steroids and for imitation of their phase I metabolism. The photocatalytic reaction products of five anabolic steroids were compared to their phase I in vitro metabolites produced by human liver microsomes (HLM). The same main reaction types - hydroxylation, dehydrogenation and combination of these two - were observed both in TiO2 photocatalysis and in microsomal incubations. Several isomers of each product type were formed in both systems. Based on the same mass, retention time and similarity of the product ion spectra, many of the products observed in HLM reactions were also formed in TiO2 photocatalytic reactions. However, products characteristic to only either one of the systems were also formed. In conclusion, TiO2 photocatalysis is a rapid, simple and inexpensive method for imitation of phase I metabolism of anabolic steroids and production of metabolite standards.

  13. Anabolic Steroid Misuse Among US Adolescent Boys: Disparities by Sexual Orientation and Race/Ethnicity.

    Science.gov (United States)

    Blashill, Aaron J; Calzo, Jerel P; Griffiths, Scott; Murray, Stuart B

    2017-02-01

    To examine the prevalence of anabolic steroid misuse among US adolescent boys as a function of sexual orientation and race/ethnicity. We analyzed boys from the 2015 Youth Risk Behavior Survey (n = 6248; mean age = 16), a representative sample of US high school students. Lifetime prevalence of anabolic steroid misuse was dichotomized as never versus 1 or more times. Sexual minority boys reported elevated misuse compared with heterosexual boys, within each level of race/ethnicity. Black, Hispanic, and White sexual minority boys reported misuse at approximately 25%, 20%, and 9%, respectively. Sexual orientation health disparities in anabolic steroid misuse disproportionally affect Black and Hispanic sexual minority adolescent boys, but more research is needed to understand the mechanisms driving these disparities.

  14. All five host-range variants of Xanthomonas citri carry one pthA homolog with 17.5 repeats that determines pathogenicity on citrus, but none determine host-range variation.

    Science.gov (United States)

    Al-Saadi, Abdulwahid; Reddy, Joseph D; Duan, Yong P; Brunings, Asha M; Yuan, Qiaoping; Gabriel, Dean W

    2007-08-01

    Citrus canker disease is caused by five groups of Xanthomonas citri strains that are distinguished primarily by host range: three from Asia (A, A*, and A(w)) and two that form a phylogenetically distinct clade and originated in South America (B and C). Every X. citri strain carries multiple DNA fragments that hybridize with pthA, which is essential for the pathogenicity of wide-host-range X. citri group A strain 3213. DNA fragments that hybridized with pthA were cloned from a representative strain from all five groups. Each strain carried one and only one pthA homolog that functionally complemented a knockout mutation of pthA in 3213. Every complementing homolog was of identical size to pthA and carried 17.5 nearly identical, direct tandem repeats, including three new genes from narrow-host-range groups C (pthC), A(w) (pthAW), and A* (pthA*). Every noncomplementing paralog was of a different size; one of these was sequenced from group A* (pthA*-2) and was found to have an intact promoter and full-length reading frame but with 15.5 repeats. None of the complementing homologs nor any of the noncomplementing paralogs conferred avirulence to 3213 on grapefruit or suppressed avirulence of a group A* strain on grapefruit. A knockout mutation of pthC in a group C strain resulted in loss of pathogenicity on lime, but the strain was unaffected in ability to elicit an HR on grapefruit. This pthC- mutant was fully complemented by pthA, pthB, or pthC. Analysis of the predicted amino-acid sequences of all functional pthA homologs and nonfunctional paralogs indicated that the specific sequence of the 17th repeat may be essential for pathogenicity of X. citri on citrus.

  15. The Effect of Skeletal Unloading on Bone Formation: Role of IGF-I

    Science.gov (United States)

    Bikle, D. D.; Kostenuik, P.; Holton, E. M.; Halloran, B. P.

    1999-01-01

    skeletal unloading. We have focussed on the role of IGF- 1 as the local factor mediating the effects of skeletal unloading on bone formation. IGF-I is produced by bone cells and chondrocytes; these cells have receptors for IGF-I, and respond to IGF-I with an increase in proliferation and function (e.g. collagen, and glycosaminoglycan production, respectively). IGF-I production by bone is under hormonal control, principally by GH and PTH, and IGF-I is thought to mediate some if not all of the effects of GH and PTH on bone growth. Thus, systemic changes in hormones such as GH and PTH may still have effects which vary from bone to bone depending on the loading history.

  16. The anabolic steroid nandrolone alters cannabinoid self-administration and brain CB1 receptor density and function

    NARCIS (Netherlands)

    Struik, Dicky; Fadda, Paola; Zara, Tamara; Zamberletti, Erica; Rubino, Tiziana; Parolaro, Daniela; Fratta, Walter; Fattore, Liana

    2017-01-01

    Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CBI rec

  17. Deltoid compartment syndrome as a complication of lateral decubitus positioning for contralateral elbow surgery in an anabolic steroid abuser.

    Science.gov (United States)

    Wijesuriya, Julian D; Cowling, Paul D; Izod, Christopher; Burton, David Jc

    2014-07-01

    Compartment syndrome as a result of patient positioning for surgery is a rare but serious complication. Compartment syndrome as a result of anabolic steroid use is more rare. We present a unique case of compartment syndrome related to anabolic steroid use and patient positioning for complex distal humerus fracture fixation and also provide a review of the literature related to this topic.

  18. Deltoid compartment syndrome as a complication of lateral decubitus positioning for contralateral elbow surgery in an anabolic steroid abuser

    OpenAIRE

    2014-01-01

    Compartment syndrome as a result of patient positioning for surgery is a rare but serious complication. Compartment syndrome as a result of anabolic steroid use is more rare. We present a unique case of compartment syndrome related to anabolic steroid use and patient positioning for complex distal humerus fracture fixation and also provide a review of the literature related to this topic.

  19. Sarcopenia in older mice is characterized by a decreased anabolic response to a protein meal.

    Science.gov (United States)

    van Dijk, Miriam; Nagel, Jolanda; Dijk, Francina J; Salles, Jerôme; Verlaan, Sjors; Walrand, Stephane; van Norren, Klaske; Luiking, Yvette

    Ageing is associated with sarcopenia, a progressive decline of skeletal muscle mass, muscle quality and muscle function. Reduced sensitivity of older muscles to respond to anabolic stimuli, i.e. anabolic resistance, is part of the underlying mechanisms. Although, muscle parameters have been studied in mice of various ages/strains; the aim was to study if mice display similar deteriorating processes as human ageing. Therefore, 10,16,21 and 25 months-old C57BL6/6J male mice were studied to measure parameters of sarcopenia and factors contributing to its pathophysiology, with the aim of characterizing sarcopenia in old mice. Muscle mass of the hind limb was lower in 25 as compared to 10 month-old mice. A significant decrease in physical daily activity, muscle grip strength and ex vivo muscle maximal force production was observed in 25 compared to 10 month-old mice. The muscle anabolic response to a single protein meal showed increased muscle protein synthesis in young, but not in old mice, indicative to anabolic resistance. However, by increasing the protein content in meals, anabolic resistance could be overcome, similar as in human elderly. Additionally, aged mice showed higher fasted insulin and hepatic malondialdehyde (MDA) levels (=marker oxidative stress). This study shows clear characteristics of sarcopenia that coincide with anabolic resistance, insulin resistance and oxidative stress in 25 month-old C57/BL6 male mice, similar to human ageing. Furthermore, similar decline in muscle mass, strength and function was observed in this aged-mice-model. These observations offer potential for the future to explore in old mice the effects of interventions targeting sarcopenia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Correlation of serum parathyroid hormone with mineral bone disease in chronic kidney disease patients

    Directory of Open Access Journals (Sweden)

    Rajeshwari S Vhora

    2015-01-01

    Full Text Available Background: Mineral bone disease (MBD is a systemic disorder of mineral and bone metabolism due to chronic kidney disease (CKD. Bone disease in CKD is due to secondary hyperparathyroidism. Serum intact parathyroid hormone (iPTH level estimation is a potential noninvasive method for the diagnosis of MBD at early stage. Aim: Treating renal bone disease should be one of the primary aims of therapy for CKD. Evaluation of the biochemical parameters of CKD-MBD (primarily phosphorus, calcium, parathyroid hormone, and Vitamin D levels as early as CKD stage 3, and an assessment of bone status (by the best means available, should be used to guide treatment decisions. The adverse effects of high phosphorus intake relative to renal clearance (including stimulation of hyperparathyroidism precede hyperphosphatemia, which presents late in CKD. Early reduction of phosphorus load may ameliorate these adverse effects. Evidence that calcium load may influence progression of vascular calcification with effects on mortality, should also be considered when choosing the type and dose of phosphate binder to be used. MBD in CKD has high morbidity and mortality and hence it is important to detect it at an early stage. iPTH levels can be highly sensitive and it is one of the useful noninvasive biochemical parameters to detect MBD in CKD. Materials and Methods: This was an observational study carried out in a tertiary care teaching hospital. The study involved 60 patients of CKD. Detailed history, physical examination, and biochemical parameters were assessed in all of them. Results: There was a significant association between hypertension, diabetes with nephropathy, and highly significant association between serum iPTH and raised blood urea levels in MBD group, however there was no significant association between duration of CKD, hemoglobin, creatinine, uric acid, phosphorous, calcium, and alkaline phosphatase with MBD. Conclusions: MBD in CKD can be detected at early

  1. Calcium and Bone Turnover Markers in Acromegaly: A Prospective, Controlled Study.

    Science.gov (United States)

    Constantin, Tina; Tangpricha, Vin; Shah, Reshma; Oyesiku, Nelson M; Ioachimescu, Octavian C; Ritchie, James; Ioachimescu, Adriana G

    2017-07-01

    Acromegaly has been associated with calcium-phosphate and bone turnover alterations. Controlled studies of these interactions are sparse. To evaluate calcium and bone metabolism in active and treated acromegaly. We conducted a controlled, prospective study at a tertiary referral center. We studied 22 patients with acromegaly referred for surgical or medical therapy (ACM) and 22 with nonfunctioning pituitary adenomas referred for surgery (control). Calcium (serum and urine), phosphorus, parathyroid hormone (PTH), 25-hydroxy- and 1,25-dihydroxy-vitamin D, bone turnover markers [serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP)], and cytokines [receptor activator of nuclear factor κB ligand (RANK-L) and osteoprotegerin (OPG)] at baseline and 3 to 6 months after treatment. At baseline, the ACM group had lower PTH levels than controls (36.3 ± 13.9 pg/mL vs 56.0 ± 19.9 pg/mL) and higher phosphorus (4.34 ± 0.71 mg/dL vs 3.55 ± 0.50 mg/dL) (P acromegaly, serum calcium (9.52 ± 0.43 mg/dL to 9.26 ± 0.28 mg/dL), phosphorus (4.34 ± 0.71 mg/dL to 3.90 ± 0.80 mg/dL), and CTX (0.91 ± 0.75 ng/mL to 0.63 ± 0.68 ng/mL) decreased, while PTH increased (36.3 ± 13.9 pg/mL to 48.9 ± 16.7 pg/mL) (P Acromegaly patients exhibited PTH-independent calcium-phosphate alterations and enhanced coupled bone formation and resorption. Within 6 months of treatment, bone resorption decreased, whereas RANK-L/OPG changes were inconsistent.

  2. Wernicke's encephalopathy and anabolic steroid drug abuse. Is there any possible relation?

    Science.gov (United States)

    Christopoulos, P; Katsanoulas, C; Timplalexi, G; Lathyris, D; Vasiliagkou, S; Antoniadou, E

    2012-10-01

    Wernicke's encephalopathy is a reversible, neurologic disorder due to thiamine deficiency which is mainly related to chronic alcohol abuse. We report a case of a young male patient, who was bodybuilder and anabolic drug user, in whom encephalopathy was diagnosed after a short medical course in the ICU after a major upper gastrointestinal bleeding (Mallory-Weiss syndrome) and hypovolemic shock. His clinical condition was typical for Wernicke's encephalopathy and although neuroimaging tests were not indicative, the patient received thiamine supplement therapy, which resulted in rapid clinical improvement. The diagnosis was based only on clinical sings and anabolic drug abuse was considered as a possible predisposing factor for the manifestation of the syndrome.

  3. Prolonged intrahepatic cholestasis and renal failure secondary to anabolic androgenic steroid-enriched dietary supplements.

    Science.gov (United States)

    Krishnan, Prashant V; Feng, Zhen-Zhou; Gordon, Stuart C

    2009-08-01

    The illegal enrichment of anabolic androgenic steroids in over-the-counter dietary supplements is well documented, but the health consequences have not been widely recognized. Three recent reports document cholestatic jaundice and nephropathy due to these compounds. We present 3 additional cases of anabolic androgenic steroid-enriched dietary supplement-induced hepatotoxicity and 1 case of renal failure, and we review the literature and the relevant features of this growing health concern. Recognition of this entity could obviate the need for invasive diagnostic testing and hospitalization and facilitate diagnosis and appropriate counseling.

  4. Invasive fungal sinusitis in a healthy athlete due to long-term anabolic steroid use.

    Science.gov (United States)

    Kim, Irene A; Thompson, Christopher F; Kedeshian, Paul A; Palma-Diaz, Fernando; Suh, Jeffrey D

    2014-08-01

    Invasive fungal rhinosinusitis is a potentially fatal infection that affects immunocompromised patients. Prognosis is generally poor despite aggressive medical and surgical treatments. We present the first reported case of invasive fungal sinusitis in a healthy 18-year-old male athlete who was taking anabolic androgenic steroids (AAS). The effects of excessive AAS use on the immune system are not fully understood, but there may be consequences at supraphysiological concentrations. This case demonstrates potential immunomodulatory effects of anabolic steroids and highlights a previously unknown cause of invasive fungal sinusitis.

  5. Short QT interval is unreliable marker of anabolic androgenic steroid abuse in competitive athletes

    Directory of Open Access Journals (Sweden)

    Đorđević Vitomir

    2012-01-01

    Full Text Available Introduction. Previous animal and human studies provided the evidence that testosterone may affect ventricular repolarization by shortening of the QT interval. Synthetic derivatives of testosterone, modified to enhance its anabolic properties, are occasionally abused by some competitive athletes. Objective. We assessed whether the QT interval duration could discriminate androgenic anabolic steroids (AAS-using strength athletes (SA from drug-free endurance athletes (EA, by comparing 25 formulas for QT interval correction. Methods. We recruited 22 elite male athletes involved in long-term strength or endurance training and 20 sedentary controls. All elite

  6. Biochemical Assessment of Bone Health in Working Obese Egyptian Females with Metabolic Syndrome; the Effect of Weight Loss by Natural Dietary Therapies

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    Maha I.A. Moaty

    2015-12-01

    CONCLUSION: These results confirm the benefit of doum in improving bone health parameter [25 (OH D/PTH axis] in the MetS patients, beside the MetS criteria. So, we can conclude that natural effective supplements lead towards the optimization of biochemical parameters in favor of a healthy outcome.

  7. Treatment of idiopathic short stature: effects of gonadotropin-releasing hormone analogs, aromatase inhibitors and anabolic steroids.

    Science.gov (United States)

    Dunkel, Leo

    2011-01-01

    Modulation of sex steroid action on the growth plate can, at least theoretically, increase adult height in children and adolescents with idiopathic short stature. Gonadotropin-releasing hormone (GnRH) analog therapy during adolescence has been shown effective in a placebo-controlled study, but to obtain clinically significant increases in adult height, the treatment duration must be lengthy (several years). Furthermore, such treatment seems to compromise bone health and, because of the resulting delay in pubertal development, likely has psychosocial consequences. Therefore, GnRH analogs are no longer recommended to augment height in adolescents with short stature and normally timed puberty. Aromatase inhibitors are probably more effective than GnRH analogs in promoting increased adult height in children with short stature and, unlike GnRH analogs, do not delay pubertal development in males. However, due to a dearth of safety data with aromatase inhibitors for the treatment of short stature, their use outside a research setting is currently not recommended. Positive effects of anabolic steroids on adult height have not been documented.

  8. Anabolic steroid use: patterns of use and detection of doping.

    Science.gov (United States)

    Graham, Michael R; Davies, Bruce; Grace, Fergal M; Kicman, Andrew; Baker, Julien S

    2008-01-01

    Anabolic-androgenic steroids (AAS) were the first identified doping agents that have ergogenic effects and are being used to increase muscle mass and strength in adult males. Consequently, athletes are still using them to increase physical performance and bodybuilders are using them to improve size and cosmetic appearance. The prevalence of AAS use has risen dramatically over the last two decades and filtered into all aspects of society. Support for AAS users has increased, but not by the medical profession, who will not accept that AAS use dependency is a psychiatric condition. The adverse effects and potential dangers of AAS use have been well documented. AAS are used in sport by individuals who have acquired knowledge of the half-lives of specific drugs and the dosages and cycles required to avoid detection. Conversely, they are used by bodybuilders in extreme dosages with the intention of gaining muscle mass and size, with little or no regard for the consequences. Polypharmacy by self-prescription is prevalent in this sector. Most recently, AAS use has filtered through to 'recreational street drug' users and is the largest growth of drugs in this subdivision. They are taken to counteract the anorexic and cachectic effects of the illegal psychotropic street drugs. Screening procedures for AAS in World Anti-Doping Agency accredited laboratories are comprehensive and sensitive and are based mainly on gas chromatography-mass spectrometry, although liquid chromatography-mass spectrometry is becoming increasingly more valuable. The use of carbon isotope mass spectrometry is also of increasing importance in the detection of natural androgen administration, particularly to detect testosterone administration. There is a degree of contentiousness in the scenario of AAS drug use, both within and outside sport. AAS and associated doping agents are not illegal per se. Possession is not an offence, despite contravening sporting regulations and moral codes. Until AAS are

  9. Anabolic steroids affect human periodontal health and microbiota.

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    Brusca, María Isabel; Verdugo, Fernando; Amighini, Celeste; Albaina, Olatz; Moragues, María D

    2014-07-01

    This study aims to evaluate periodontal microbiological differences between systemically healthy nonsmoker males taking anabolic androgenic steroids (AASs) and non-AAS users and to find associations between disease severity and AAS use. Ninety-two men practicing bodybuilding were included in the study. They were divided into AAS users and a matched control nonuser group and subgrouped based on their most severe periodontal condition. Pooled subgingival samples from each individual were cultured to evaluate specific periodontopathogen infection. AAS users had significantly higher prevalence of severe periodontitis. AAS users had greater gingival inflammation and clinical attachment loss of ≥ 3 mm than nonusers (odds ratio (OR) = 2.4; p = 0.09; 95 % confidence interval (CI) 0.8-6.4). AAS users were 4.9 times more likely to be infected with Prevotella intermedia than AAS nonusers (OR = 4.9; p = 0.003; 95 % CI 1.6-14.7). The OR of presenting subgingival Aggregatibacter actinomycetemcomitans was 8.2 times higher in AAS users (OR = 8.2; p = 0.03; 95 % CI 0.9-70.8). AAS users were 5.6 times more likely to present subgingival Candida spp. than nonusers (OR = 5.6; p = 0.02; 95 % CI 1.1-27.1). AAS users were 14.8 times more likely to present subgingival Candida parapsilosis than nonusers (OR = 14.8; p < 0.0001; 95 % CI 3.1-69.2). The likelihood of AAS users presenting subgingival Candida tropicalis was 4.3 times higher than nonusers (OR = 4.3; p = 0.03; 95 % CI 1.1-16.9). A. actinomycetemcomitans was mostly isolated in individuals with severe periodontitis and was associated with subgingival Porphyromonas gingivalis, P. intermedia, and Candida spp. AAS use may increase the risk for severe periodontitis and may cause a subgingival selection of certain Candida species. Specific periodontopathogens, such as Candida dubliniensis and Candida albicans, seem to be negatively affected by AAS use. The higher risk for disease progression in AAS users may be explained by the

  10. Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone.

    Science.gov (United States)

    Saito, Mitsuru; Grynpas, Marc D; Burr, David B; Allen, Matthew R; Smith, Susan Y; Doyle, Nancy; Amizuka, Norio; Hasegawa, Tomoka; Kida, Yoshikuni; Marumo, Keishi; Saito, Hitoshi

    2015-04-01

    Eldecalcitol (ELD), an active form of vitamin D analog approved for the treatment of osteoporosis in Japan, increases lumbar spine bone mineral density (BMD), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. We have previously reported that treatment with ELD for 6 months improved the mechanical properties of the lumbar spine in ovariectomized (OVX) cynomolgus monkeys. ELD treatment increased lumbar BMD, suppressed bone turnover markers, and reduced histomorphometric parameters of both bone formation and resorption in vertebral trabecular bone. In this study, we elucidated the effects of ELD on bone quality (namely, mineralization, microarchitecture, microdamage, and bone collagen crosslinks) in OVX cynomolgus monkeys in comparison with OVX-vehicle control monkeys. Density fractionation of bone powder prepared from lumbar vertebrae revealed that ELD treatment shifted the distribution profile of bone mineralization to a higher density, and backscattered electron microscopic imaging showed improved trabecular bone connectivity in the ELD-treated groups. Higher doses of ELD more significantly reduced the amount of microdamage compared to OVX-vehicle controls. The fractionated bone powder samples were divided according to their density, and analyzed for collagen crosslinks. Enzymatic crosslinks were higher in both the high-density (≥2.0 mg/mL) and low-density (mineralization, but prevented non-enzymatic reaction of collagen crosslinks and accumulation of bone microdamage. Bone anti-resorptive agents such as bisphosphonates slow down bone remodeling so that bone mineralization, bone microdamage, and non-enzymatic collagen crosslinks all increase. Bone anabolic agents such as parathyroid hormone decrease bone mineralization and bone microdamage by stimulating bone remodeling. ELD did not fit into either category. Histological analysis indicated that the ELD treatment strongly suppressed bone resorption by reducing the number of

  11. Effects of calcium-fortified ice cream on markers of bone health.

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    Ferrar, L; van der Hee, R M; Berry, M; Watson, C; Miret, S; Wilkinson, J; Bradburn, M; Eastell, R

    2011-10-01

    Premenopausal women with low calcium intakes consumed calcium-fortified ice cream daily for 28 days. Bone markers, NTX, CTX and PTH decreased significantly by 7 days, with some evidence of a calcium dose-dependent effect. Bone marker responses were observed within 1 h of consuming ice cream. Body weight remained constant over 28 days. Dietary calcium is important for lifelong bone health. Milk is a good source of bioavailable calcium, but consumption has declined among young adults. The aims were to determine whether calcium-fortified ice cream, a palatable source of calcium, produces significant, sustainable changes in bone turnover markers and parathyroid hormone (PTH) in premenopausal women with calcium intake below recommended UK levels. Eighty women, ages 20-39 years (calcium intake ice cream containing 96, 244, 459 or 676 mg calcium daily for 28 days. Urinary NTX/Cr, serum CTX, PINP, 1,25D and PTH were measured (baseline, days 1, 7 and 28). Acute changes in CTX and PTH were measured over 5 h (n = 29 women). There were significant mean decreases by 7 days in NTX/Cr, CTX, PTH and 1,25D and increases in PINP (one sample t tests), with a significant dose-dependent effect on CTX analysis of covariance. Only CTX remained suppressed at 28 days. Serum CTX and PTH decreased within 1 h. Body weight did not change significantly between baseline and 28 days. Daily consumption of calcium-fortified ice cream by premenopausal women may significantly reduce levels of the bone resorption marker serum CTX, without stimulating weight gain. The ice cream could be incorporated into the diet to replace low-calcium snacks and thus help individuals with habitually low calcium intakes to meet recommended intakes. The 244 mg calcium preparation would provide more than a quarter of the UK daily recommended nutrient intake for premenopausal women.

  12. Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis

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    Vittorio Locatelli

    2014-01-01

    Full Text Available 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.

  13. Bone scan

    Science.gov (United States)

    ... legs, or spine fractures) Diagnose a bone infection (osteomyelitis) Diagnose or determine the cause of bone pain, ... 2015:chap 43. Read More Broken bone Metabolism Osteomyelitis Review Date 12/10/2015 Updated by: Jatin ...

  14. Bone Cancer

    Science.gov (United States)

    Cancer that starts in a bone is uncommon. Cancer that has spread to the bone from another ... more co