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Effects of histamine H1, H2 and H3 receptor antagonists on bone mechanical properties in female rats
Abstracts / Bone 48 (2011) S187–S203
S193
PP295-S Effects of histamine H1, H2 and H3 receptor antagonists on bone mechanical properties in female rats J. Folwarczna ⁎, L. Śliwiński, M. Pytlik, A. Janas Department of Pharmacology, Medical University of Silesia, Katowice, Sosnowiec, Poland
PP297-T The impact of normal pregnancy and uteroplacental insufficiency on trabecular and cortical bone in rat mothers J. Wark a, ⁎, T. Romano a, b, M. Wlodek b a Medicine, University of Melbourne, Parkville, Australia b Physiology, University of Melbourne, Parkville, Australia
Abstract: Histamine H1 and H2 receptor antagonists are widely used in the treatment of allergic and upper gastrointestinal diseases, respectively. Histamine receptors are expressed in bone cells and histamine may be involved in regulation of bone metabolism. The aim of the present study was to investigate the effects of loratadine (an H1 receptor antagonist), ranitidine (an H2 receptor antagonist) and betahistine (an H3 receptor antagonist and H1 receptor partial agonist) on bone mechanical properties in female rats. Loratadine (5 mg/kg/day, p.o.), ranitidine (50 mg/kg/day, p.o.), or betahistine dihydrochloride (5 mg/kg/day, p.o.), were administered for 4 weeks to non-ovariectomized (NOVX) and bilaterally ovariectomized (OVX) 3-month-old Wistar rats (n = 9 per group), and their effects were compared with appropriate controls (n= 18 per group). The ovariectomy was performed 7 days before the start of drug administration. Serum levels of type I collagen fragments released during bone resorption (RatLaps), tartrate-resistant acid phosphatase 5b and osteocalcin, bone mass, mass of bone mineral, mechanical properties of tibial metaphysis and femoral diaphysis (in three-point bending tests) and femoral neck (in a compression test) were studied. In rats with normal estrogen level (NOVX), administration of loratadine improved parameters of compact bone, increasing the strength of the femoral neck and diaphysis, and increasing the bone mineral mass to bone mass ratio in the femur. There was no effect of loratadine on cancellous bone (tibial metaphyses). Ranitidine did not significantly affect the investigated parameters in NOVX rats. Betahistine decreased the strength of tibial metaphyses. Loratadine, ranitidine and betahistine did not affect serum bone turnover markers. Estrogen deficiency induced significant worsening of the mechanical properties of tibial metaphyses and characteristic changes in bone turnover markers. Loratadine and betahistine did not affect the investigated parameters of the skeletal system in the OVX rats. Ranitidine tended to improve the strength of tibial metaphyses in OVX rats, but did not affect serum bone turnover markers. In conclusion, the effects of histamine H1, H2 and H3 receptor antagonists on the skeletal system in rats were differential and strongly dependent on estrogen status. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.
Abstract: Pregnancy and lactation affect maternal bone which provides offspring with calcium for growth. Uteroplacental insufficiency complicates 10% of human pregnancies causing intrauterine growth restriction, lower offspring body calcium content and programming of bone deficits. Little is known about the impact of uteroplacental insufficiency on maternal bone. Therefore we used an established rat model to investigate the skeletal phenotype of mothers exposed to uteroplacental insufficiency. Bilateral uterine vessel ligation (Restricted) or sham surgery (Control) was performed on gestational day 18 (term=22 days). Post mortem of Restricted and Control mothers was performed on prenatal day 20, postnatal day 1 and 7, weeks 5, 7 and 9 and in non-pregnant rats. Right femur dimensions, mineral content and density were measured (peripheral quantitative computed tomography). Femur length increased over time and did not differ between Control and Restricted mothers. Trabecular content and density (5% site) were lower on postnatal day 1 (p < 0.05) in Control compared to Restricted by 54% and 15.8% respectively. However, by day 7 post partum and thereafter, no significant trabecular bone differences were observed between Control and Restricted mothers. In Controls only, cortical bone content and density (50% site) increased as expected by prenatal day 20 compared with non-pregnant rats, to support fetal skeletal mineralisation, with content falling below non-pregnant rats by postnatal day 1 (p < 0.05). These deficits in trabecular and cortical bone content and density did not occur in Restricted mothers. The bone stress strain index decreased in Control rats only from prenatal day 20 to postnatal day 1 (p < 0.05). By postnatal day 7, bone parameters in both groups were not different from non-pregnant rats, with complete restoration of bone measures occurring after weaning. There was marked transient bone loss early post partum in Control rats which did not occur in mothers suffering uteroplacental insufficiency. Presumably calcium supply from maternal bone to offspring was reduced during pregnancy and lactation in Restricted mothers, contributing to the limitation in offspring skeletal growth. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: J. Wark Grant / Research Support from Gardiner Foundation, T. Romano Grant / Research Support from Gardiner Foundation, M. Wlodek Grant / Research Support from Gardiner Foundation.
doi:10.1016/j.bone.2011.03.456
doi:10.1016/j.bone.2011.03.458
PP296-M Effects of morphine, buprenorphine and naloxone on bone mechanical properties in ovariectomized and non-ovariectomized rats A. Janas, J. Folwarczna ⁎ Department of Pharmacology, Medical University of Silesia, Katowice, Sosnowiec, Poland Abstract: Opioid receptors were reported to be expressed in osteoblasts. Endogenous opioids may take part in regulation of bone metabolism. Population-based data indicate that morphine may increase fracture risk. The sparse experimental data on the effects of opioid receptor agonists and antagonists on the skeletal system also suggest the possible unfavorable effect of morphine. The aim of the present study was to investigate the effects of morphine (the opioid receptor agonist), buprenorphine (the mi opioid receptor partial agonist and kappa opioid receptor antagonist) and naloxone (the opioid receptor antagonist) on bone mechanical properties in female rats. Morphine hydrochloride (20 mg/kg/day, s.c.), buprenorphine (0.05 mg/kg/day, s.c.) or naloxone hydrochloride dihydrate (2 mg/kg/day, s.c.) were administered for 4 weeks to nonovariectomized (NOVX) and bilaterally ovariectomized (OVX) 3-month-old Wistar rats (n=10 per group), and their effects were compared with appropriate controls (n=18 per group). The ovariectomy was performed 7 days before the start of drug administration. Serum levels of type I collagen fragments released during bone resorption (RatLaps), tartrate-resistant acid phosphatase 5b and osteocalcin, bone mass, mass of bone mineral, mechanical properties of tibial metaphysis and femoral diaphysis (three-point bending tests) and femoral neck (a compression test) were studied. Morphine, buprenorphine and naloxone did not affect the mechanical properties and bone turnover markers in the NOVX rats. However, in the OVX rats, morphine and buprenorphine significantly improved the strength of tibial metaphyses, worsened due to estrogen deficiency, and counteracted the increases in the bone turnover markers (osteocalcin and type I collagen fragments). Naloxone did not induce significant changes in the investigated skeletal parameters of the OVX rats, with the exception of a slight increase in the strength of tibial metaphyses. In conclusion, opioid receptor agonists exerted favorable effects on the skeletal system in estrogen-deficient rats. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared. doi:10.1016/j.bone.2011.03.457
PP298-S The negative effect of increased 2-hydroxylation of estrogen on femur geometry K.M. Kim a, ⁎, K.J. Kim a, M.H. Choi b, Y. Rhee a, S.-K. Lim a a Endocrinology, Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea b Life/Health Division, Korea Institute of Science and Technology, Seoul, Republic of Korea Abstract: Not only bone density, but also bone geometry is a major determinant factor for bone strength. To evaluate the effect of estrogen metabolism on bone strength in postmenopausal women, we measured femoral bone mineral densities and femoral geometry by using quantitative computed tomography and 14 types of urinary metabolites of estrogen by a gas chromatography-mass spectrometry assay system in 67 old postmenopausal women (mean age 70.2 ± 2.7 years). Among the 14 urinary metabolites of estrogen, the 2-hydroxyestrone showed negative correlations with both areal and volumetric hip BMD. Interestingly, total and cortical BMDs were significantly associated with 2-hydroxyestrone. Unlike cortical BMD, trabecular BMD did not show any significant relationship with 2-hydroxyestrone. The urinary 2-hydroxyestrone level and 2-hydroxyestrone/estrone (E1) ratio also revealed negative correlations with femur neck cortical thickness(r = − 0.415, p < 0.05 for 2-hydroxyestrone, r = − 0.366, p < 0.05 for 2-hydroxyestrone/estrone ratio), but a positive correlation with femur neck buckling ratio (r = 0.389, p < 0.05 for 2-hydroxyestrone, r = 0.432, p < 0.05 for 2hydroxyestrone/estrone ratio). Women with a previous history of osteoporotic fracture had a higher values of 2-hydroxyestrone and 2-hydroxyestrone/estrone ratio compared with women without fracture history, but statistically no significance. Femur neck angle, femur neck width and hip axis length were not related with urinary metabolites of estrogen. In multiple linear regression analysis, waist/hip ratio was an independent determinant for level of 2-hydroxyestrone. In conclusion, the increased activity of estrogen 2-hydroxylase could accelerate the loss of bone strength, and central obesity in postmenopausal women is one of major risk factor for this derangement of estrogen metabolism. This article is part of a Special Issue entitled ECTS 2011.
S193
PP295-S Effects of histamine H1, H2 and H3 receptor antagonists on bone mechanical properties in female rats J. Folwarczna ⁎, L. Śliwiński, M. Pytlik, A. Janas Department of Pharmacology, Medical University of Silesia, Katowice, Sosnowiec, Poland
PP297-T The impact of normal pregnancy and uteroplacental insufficiency on trabecular and cortical bone in rat mothers J. Wark a, ⁎, T. Romano a, b, M. Wlodek b a Medicine, University of Melbourne, Parkville, Australia b Physiology, University of Melbourne, Parkville, Australia
Abstract: Histamine H1 and H2 receptor antagonists are widely used in the treatment of allergic and upper gastrointestinal diseases, respectively. Histamine receptors are expressed in bone cells and histamine may be involved in regulation of bone metabolism. The aim of the present study was to investigate the effects of loratadine (an H1 receptor antagonist), ranitidine (an H2 receptor antagonist) and betahistine (an H3 receptor antagonist and H1 receptor partial agonist) on bone mechanical properties in female rats. Loratadine (5 mg/kg/day, p.o.), ranitidine (50 mg/kg/day, p.o.), or betahistine dihydrochloride (5 mg/kg/day, p.o.), were administered for 4 weeks to non-ovariectomized (NOVX) and bilaterally ovariectomized (OVX) 3-month-old Wistar rats (n = 9 per group), and their effects were compared with appropriate controls (n= 18 per group). The ovariectomy was performed 7 days before the start of drug administration. Serum levels of type I collagen fragments released during bone resorption (RatLaps), tartrate-resistant acid phosphatase 5b and osteocalcin, bone mass, mass of bone mineral, mechanical properties of tibial metaphysis and femoral diaphysis (in three-point bending tests) and femoral neck (in a compression test) were studied. In rats with normal estrogen level (NOVX), administration of loratadine improved parameters of compact bone, increasing the strength of the femoral neck and diaphysis, and increasing the bone mineral mass to bone mass ratio in the femur. There was no effect of loratadine on cancellous bone (tibial metaphyses). Ranitidine did not significantly affect the investigated parameters in NOVX rats. Betahistine decreased the strength of tibial metaphyses. Loratadine, ranitidine and betahistine did not affect serum bone turnover markers. Estrogen deficiency induced significant worsening of the mechanical properties of tibial metaphyses and characteristic changes in bone turnover markers. Loratadine and betahistine did not affect the investigated parameters of the skeletal system in the OVX rats. Ranitidine tended to improve the strength of tibial metaphyses in OVX rats, but did not affect serum bone turnover markers. In conclusion, the effects of histamine H1, H2 and H3 receptor antagonists on the skeletal system in rats were differential and strongly dependent on estrogen status. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.
Abstract: Pregnancy and lactation affect maternal bone which provides offspring with calcium for growth. Uteroplacental insufficiency complicates 10% of human pregnancies causing intrauterine growth restriction, lower offspring body calcium content and programming of bone deficits. Little is known about the impact of uteroplacental insufficiency on maternal bone. Therefore we used an established rat model to investigate the skeletal phenotype of mothers exposed to uteroplacental insufficiency. Bilateral uterine vessel ligation (Restricted) or sham surgery (Control) was performed on gestational day 18 (term=22 days). Post mortem of Restricted and Control mothers was performed on prenatal day 20, postnatal day 1 and 7, weeks 5, 7 and 9 and in non-pregnant rats. Right femur dimensions, mineral content and density were measured (peripheral quantitative computed tomography). Femur length increased over time and did not differ between Control and Restricted mothers. Trabecular content and density (5% site) were lower on postnatal day 1 (p < 0.05) in Control compared to Restricted by 54% and 15.8% respectively. However, by day 7 post partum and thereafter, no significant trabecular bone differences were observed between Control and Restricted mothers. In Controls only, cortical bone content and density (50% site) increased as expected by prenatal day 20 compared with non-pregnant rats, to support fetal skeletal mineralisation, with content falling below non-pregnant rats by postnatal day 1 (p < 0.05). These deficits in trabecular and cortical bone content and density did not occur in Restricted mothers. The bone stress strain index decreased in Control rats only from prenatal day 20 to postnatal day 1 (p < 0.05). By postnatal day 7, bone parameters in both groups were not different from non-pregnant rats, with complete restoration of bone measures occurring after weaning. There was marked transient bone loss early post partum in Control rats which did not occur in mothers suffering uteroplacental insufficiency. Presumably calcium supply from maternal bone to offspring was reduced during pregnancy and lactation in Restricted mothers, contributing to the limitation in offspring skeletal growth. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: J. Wark Grant / Research Support from Gardiner Foundation, T. Romano Grant / Research Support from Gardiner Foundation, M. Wlodek Grant / Research Support from Gardiner Foundation.
doi:10.1016/j.bone.2011.03.456
doi:10.1016/j.bone.2011.03.458
PP296-M Effects of morphine, buprenorphine and naloxone on bone mechanical properties in ovariectomized and non-ovariectomized rats A. Janas, J. Folwarczna ⁎ Department of Pharmacology, Medical University of Silesia, Katowice, Sosnowiec, Poland Abstract: Opioid receptors were reported to be expressed in osteoblasts. Endogenous opioids may take part in regulation of bone metabolism. Population-based data indicate that morphine may increase fracture risk. The sparse experimental data on the effects of opioid receptor agonists and antagonists on the skeletal system also suggest the possible unfavorable effect of morphine. The aim of the present study was to investigate the effects of morphine (the opioid receptor agonist), buprenorphine (the mi opioid receptor partial agonist and kappa opioid receptor antagonist) and naloxone (the opioid receptor antagonist) on bone mechanical properties in female rats. Morphine hydrochloride (20 mg/kg/day, s.c.), buprenorphine (0.05 mg/kg/day, s.c.) or naloxone hydrochloride dihydrate (2 mg/kg/day, s.c.) were administered for 4 weeks to nonovariectomized (NOVX) and bilaterally ovariectomized (OVX) 3-month-old Wistar rats (n=10 per group), and their effects were compared with appropriate controls (n=18 per group). The ovariectomy was performed 7 days before the start of drug administration. Serum levels of type I collagen fragments released during bone resorption (RatLaps), tartrate-resistant acid phosphatase 5b and osteocalcin, bone mass, mass of bone mineral, mechanical properties of tibial metaphysis and femoral diaphysis (three-point bending tests) and femoral neck (a compression test) were studied. Morphine, buprenorphine and naloxone did not affect the mechanical properties and bone turnover markers in the NOVX rats. However, in the OVX rats, morphine and buprenorphine significantly improved the strength of tibial metaphyses, worsened due to estrogen deficiency, and counteracted the increases in the bone turnover markers (osteocalcin and type I collagen fragments). Naloxone did not induce significant changes in the investigated skeletal parameters of the OVX rats, with the exception of a slight increase in the strength of tibial metaphyses. In conclusion, opioid receptor agonists exerted favorable effects on the skeletal system in estrogen-deficient rats. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared. doi:10.1016/j.bone.2011.03.457
PP298-S The negative effect of increased 2-hydroxylation of estrogen on femur geometry K.M. Kim a, ⁎, K.J. Kim a, M.H. Choi b, Y. Rhee a, S.-K. Lim a a Endocrinology, Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea b Life/Health Division, Korea Institute of Science and Technology, Seoul, Republic of Korea Abstract: Not only bone density, but also bone geometry is a major determinant factor for bone strength. To evaluate the effect of estrogen metabolism on bone strength in postmenopausal women, we measured femoral bone mineral densities and femoral geometry by using quantitative computed tomography and 14 types of urinary metabolites of estrogen by a gas chromatography-mass spectrometry assay system in 67 old postmenopausal women (mean age 70.2 ± 2.7 years). Among the 14 urinary metabolites of estrogen, the 2-hydroxyestrone showed negative correlations with both areal and volumetric hip BMD. Interestingly, total and cortical BMDs were significantly associated with 2-hydroxyestrone. Unlike cortical BMD, trabecular BMD did not show any significant relationship with 2-hydroxyestrone. The urinary 2-hydroxyestrone level and 2-hydroxyestrone/estrone (E1) ratio also revealed negative correlations with femur neck cortical thickness(r = − 0.415, p < 0.05 for 2-hydroxyestrone, r = − 0.366, p < 0.05 for 2-hydroxyestrone/estrone ratio), but a positive correlation with femur neck buckling ratio (r = 0.389, p < 0.05 for 2-hydroxyestrone, r = 0.432, p < 0.05 for 2hydroxyestrone/estrone ratio). Women with a previous history of osteoporotic fracture had a higher values of 2-hydroxyestrone and 2-hydroxyestrone/estrone ratio compared with women without fracture history, but statistically no significance. Femur neck angle, femur neck width and hip axis length were not related with urinary metabolites of estrogen. In multiple linear regression analysis, waist/hip ratio was an independent determinant for level of 2-hydroxyestrone. In conclusion, the increased activity of estrogen 2-hydroxylase could accelerate the loss of bone strength, and central obesity in postmenopausal women is one of major risk factor for this derangement of estrogen metabolism. This article is part of a Special Issue entitled ECTS 2011.