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The effect of homozygosity versus heterozygosity for IGFALS gene mutations on growth, bone strength and insulin resistance
S12
Abstracts
O33 The effect of homozygosity versus heterozygosity for IGFALS gene mutations on growth, bone strength and insulin resistance W. Höglera, D. Martinb, N. Crabtreec, T. Barretta, N. Shawa, J. Tomlinsond, R. Rosenfelde, V. Hwae, S. Rosef, J. Walkerg, J. Frystykh a Dept. of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham, UK b University Children's Hospital, Paediatric Endocrinology and Diabetology, Tuebingen, Germany c Dept. of Nuclear Medicine, Birmingham Children's Hospital, Birmingham, UK d University of Birmingham, Centre of Endocrinology, Institute of Biomedical Research, Birmingham, UK e Oregon Health Sciences University, Dept. of Pediatrics, Portland, USA f Dept. of Paediatrics, Heartlands Hospital, Birmingham, UK g Portsmouth Hospital, Dept. of Paediatrics, Portsmouth, UK h University Hospital Aarhus, Medical Research Laboratories, Aarhus, Denmark Abstract: Background: Acid-labile subunit (ALS) deficiency inhibits ternary complex formation leading to primary IGF-I deficiency and short stature. Potential metabolic consequences such as diabetes and low bone mass are not well studied. Objective: This study measured insulin sensitivity, lipid profile, bone density and structure in members of 4 affected families and explore possible gene-dose effects. Methods: 4 patients (7–21 years) with homozygous IGFALS gene mutations and 12 heterozygous carriers had i.v. glucose tolerance tests performed. Dual-energy X-ray absorptiometry of spine, hip and total body, peripheral quantitative computer tomography of the radius and metacarpal (MC) radiogrammetry were performed. Results: Height z-scores in patients (median − 3.75 [range − 4.25 to − 2.62]) were lower compared to carriers (− 1.77 [− 2.21 to + 0.26], p b 0.001), a reflection of their significantly lower IGF-I, ALS and IGFBP3 levels (p b 0.005). Glucose disappearance rate (k), HOMA-IR, fasting insulin, glucose and lipid levels were similar between the two groups. 3 carriers (age 29, 53 and 55 y) had k rates below 1%, and elevated fasting glucose levels, indicating diabetes mellitus. Lumbar spine BMD was lower in patients (Z-score − 2.0 [− 2.6 to − 1.1]) compared to carriers (− 0.7 [− 2.5 to 0.9], p = 0.04), likely influenced by their short stature since size-corrected spine BMAD as well as radial total and trabecular BMD were not different between groups. Structurally, MC bone width (− 2.67 [− 3.5 to − 2.56] vs − 1.28 [− 1.92 to − 0.54], p = 0.004) and length (− 1.72 [− 2.83 to − 0.11] vs 0.33 [− 0.6 to 2.65], p = 0.015) were lower in patients compared to carriers but the MC bone health index was similar. Conclusions: 3/12 IGFALS gene carriers had type 2 diabetes and there was some evidence of insulin resistance in this cohort. ALS deficiency affects bone lengthening and widening (growth). There is sufficient evidence for a gene-dose effect on bone size but insufficient evidence for a true reduction in bone density and strength.
doi:10.1016/j.bone.2012.08.034
O34 Treatment with the cathepsin K inhibitor odanacatib in postmenopausal women with low BMD: 5 year results of a phase 2 trial H. Rescha, N. Binkleyb, H. Bonec, J.A. Eismand, N. Gilchriste, B. Langdahlf, J. Rodriguez Portalesg, A. Denkerh, A. Lombardih, C. Le Bailly De Tilleghemi, C. DaSilvah, E. Rosenbergh, A. Leungh a KH Barmherzige Schwestern, Vienna, Austria b University of Wisconsin, Madison, WI, USA c Michigan Bone and Mineral Clinic, Detroit, MI, USA d Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia e Princess Margaret Hospital, Christchurch, New Zealand f Aarhus University Hospital, Aarhus, Denmark g Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile h Merck, Sharp, and Dohme, Whitehouse Station, NJ, USA i Merck, Sharp, and Dohme, Brussels, Belgium Abstract: The selective cathepsin K inhibitor odanacatib progressively increased spine and hip BMD over 4 years. Here we report results of 5 years and of cessation. Women (mean age 63 yrs, BMD T-scores − 2.0 to − 3.5) received weekly placebo or odanacatib 3, 10, 25, or 50 mg for 2 years, plus vitamin D3 and calcium. In year 3,
women were re-randomized to odanacatib 50 mg or placebo. For years 4–5, women receiving placebo or odanacatib 3 mg in years 1–2 and placebo in year 3 switched to odanacatib 50 mg; others continued year-3 treatments. Assessments were BMD at lumbar spine (primary endpoint) and hip sub-regions, bone turnover markers (BTM), and safety. Women who received odanacatib 50 mg continuously years 1–5 (n = 13) had mean % BMD changes (SE) from baseline of lumbar spine 11.9 (2.1), femoral neck 9.8 (1.9), and total hip 8.5 (1.0). In women switched from odanacatib 50 mg to placebo after 2 years (n = 14), BMD mean % changes (SE) from baseline were: lumbar spine − 0.4 (1.3), femoral neck − 1.6 (1.0) and total hip − 1.8 (0.8). BTM had geometric mean % changes from baseline (SE): urine NTX/creatinine − 67.4 (10.1) and serum BSAP − 15.3 (5.9) in women continuously receiving odanacatib 50 mg (n = 9–10), and 6.0 (7.6) and − 11.9 (3.9) in women switched to placebo after 2 yrs (n = 10). Odanacatib was well tolerated. Women who received odanacatib 50 mg for 5 years had progressive gains in mean spine and hip BMD and sustained reduction in NTX, with smaller reduction in BSAP. Discontinuation resulted in reversal of BMD gains.
doi:10.1016/j.bone.2012.08.035
O35 Vitamin D supports the efficiency of decitabine for induction of differentiation, apoptosis and osteocalcin expression in leukemia and mastocytosis H. Karlica,b, R. Reitermaiera,b, R. Thalerc, J. Vargaa,b,c, S. Spitzerc, M. Pfeilstöckera,b,d, P. Valenta,e, K. Klaushoferc, F. Vargac a Ludwig Boltzmann Cluster Oncology, Vienna, Austria b Ludwig Boltzmann Institute for Leukemia Research and Hematology, Hanusch Hospital, Vienna, Austria c Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling and 1st Medical Department, Hanusch Hospital, Vienna, Austria d 3rd Medical Department, Hanusch Hospital, Vienna Austria e Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria Abstract: Novel treatments for leukemias and mastocytosis with agents such as vitamin D (VD), that induce myelomonocytic differentiation may re-establish functional hematopoiesis in patients. This is associated with induction of osteoblastic markers such as osteocalcin. Similar effects on gene regulation are also observed with demethylating drugs such as Decitabine (5-aza-desoxycytidine, DAC). The aim of this study was to define possible epigenetic mechanisms, which are responsible for the supportive activity of VD on efficiency of DAC. HMC-1 mast cell leukemia cells or HL-60 promyelocytic leukemia cells were treated with vitamin D3 (VD, 10 nM) and/or DAC (5 μM) for 3 days. RNA and DNA were isolated and gene expression (by RT-PCR and Affymetrix human gene 1.0 arrays) as well as promoter methylation was analyzed. Co-treatment of HMC-1 mast cell leukemia cells resulted in a significant stimulation of myelomonocytic differentiation markers such as CD11b, CD14 and CD52 as well as apoptosis markers such as FAS and FAS-ligand. This was accompanied by synergistic stimulation of osteocalcin expression. Down-regulation of DNAmethyltransferases as well as a decrease in promoter methylation indicated that the additive effects of VD on these genes are above all based on DNA demethylation. Results of this study underline the impact of epigenetic mechanisms in the differentiating activity of VD. The observed synergistic activity of VD with DAC suggests that combined application of lower dosages from each agent would support efficiency and reduce side effects for patients. This work was supported by the Medical Scientific Fund of the Mayor of the City of Vienna.
doi:10.1016/j.bone.2012.08.036
O36 Update osteocalcin biology G. Karsenty Department of Genetics & Development, Columbia University, New York, USA Abstract: In the last 15 years the biology of the osteoblasts has been profoundly modified through two complementary lines of research. The first one has been to the identification and characterization of novel organs, hormones and neuromediators regulating bone formation, the classical function of these cells. The second one has been the demonstration that osteoblasts are endocrine cells affecting through at least
Abstracts
O33 The effect of homozygosity versus heterozygosity for IGFALS gene mutations on growth, bone strength and insulin resistance W. Höglera, D. Martinb, N. Crabtreec, T. Barretta, N. Shawa, J. Tomlinsond, R. Rosenfelde, V. Hwae, S. Rosef, J. Walkerg, J. Frystykh a Dept. of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham, UK b University Children's Hospital, Paediatric Endocrinology and Diabetology, Tuebingen, Germany c Dept. of Nuclear Medicine, Birmingham Children's Hospital, Birmingham, UK d University of Birmingham, Centre of Endocrinology, Institute of Biomedical Research, Birmingham, UK e Oregon Health Sciences University, Dept. of Pediatrics, Portland, USA f Dept. of Paediatrics, Heartlands Hospital, Birmingham, UK g Portsmouth Hospital, Dept. of Paediatrics, Portsmouth, UK h University Hospital Aarhus, Medical Research Laboratories, Aarhus, Denmark Abstract: Background: Acid-labile subunit (ALS) deficiency inhibits ternary complex formation leading to primary IGF-I deficiency and short stature. Potential metabolic consequences such as diabetes and low bone mass are not well studied. Objective: This study measured insulin sensitivity, lipid profile, bone density and structure in members of 4 affected families and explore possible gene-dose effects. Methods: 4 patients (7–21 years) with homozygous IGFALS gene mutations and 12 heterozygous carriers had i.v. glucose tolerance tests performed. Dual-energy X-ray absorptiometry of spine, hip and total body, peripheral quantitative computer tomography of the radius and metacarpal (MC) radiogrammetry were performed. Results: Height z-scores in patients (median − 3.75 [range − 4.25 to − 2.62]) were lower compared to carriers (− 1.77 [− 2.21 to + 0.26], p b 0.001), a reflection of their significantly lower IGF-I, ALS and IGFBP3 levels (p b 0.005). Glucose disappearance rate (k), HOMA-IR, fasting insulin, glucose and lipid levels were similar between the two groups. 3 carriers (age 29, 53 and 55 y) had k rates below 1%, and elevated fasting glucose levels, indicating diabetes mellitus. Lumbar spine BMD was lower in patients (Z-score − 2.0 [− 2.6 to − 1.1]) compared to carriers (− 0.7 [− 2.5 to 0.9], p = 0.04), likely influenced by their short stature since size-corrected spine BMAD as well as radial total and trabecular BMD were not different between groups. Structurally, MC bone width (− 2.67 [− 3.5 to − 2.56] vs − 1.28 [− 1.92 to − 0.54], p = 0.004) and length (− 1.72 [− 2.83 to − 0.11] vs 0.33 [− 0.6 to 2.65], p = 0.015) were lower in patients compared to carriers but the MC bone health index was similar. Conclusions: 3/12 IGFALS gene carriers had type 2 diabetes and there was some evidence of insulin resistance in this cohort. ALS deficiency affects bone lengthening and widening (growth). There is sufficient evidence for a gene-dose effect on bone size but insufficient evidence for a true reduction in bone density and strength.
doi:10.1016/j.bone.2012.08.034
O34 Treatment with the cathepsin K inhibitor odanacatib in postmenopausal women with low BMD: 5 year results of a phase 2 trial H. Rescha, N. Binkleyb, H. Bonec, J.A. Eismand, N. Gilchriste, B. Langdahlf, J. Rodriguez Portalesg, A. Denkerh, A. Lombardih, C. Le Bailly De Tilleghemi, C. DaSilvah, E. Rosenbergh, A. Leungh a KH Barmherzige Schwestern, Vienna, Austria b University of Wisconsin, Madison, WI, USA c Michigan Bone and Mineral Clinic, Detroit, MI, USA d Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia e Princess Margaret Hospital, Christchurch, New Zealand f Aarhus University Hospital, Aarhus, Denmark g Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile h Merck, Sharp, and Dohme, Whitehouse Station, NJ, USA i Merck, Sharp, and Dohme, Brussels, Belgium Abstract: The selective cathepsin K inhibitor odanacatib progressively increased spine and hip BMD over 4 years. Here we report results of 5 years and of cessation. Women (mean age 63 yrs, BMD T-scores − 2.0 to − 3.5) received weekly placebo or odanacatib 3, 10, 25, or 50 mg for 2 years, plus vitamin D3 and calcium. In year 3,
women were re-randomized to odanacatib 50 mg or placebo. For years 4–5, women receiving placebo or odanacatib 3 mg in years 1–2 and placebo in year 3 switched to odanacatib 50 mg; others continued year-3 treatments. Assessments were BMD at lumbar spine (primary endpoint) and hip sub-regions, bone turnover markers (BTM), and safety. Women who received odanacatib 50 mg continuously years 1–5 (n = 13) had mean % BMD changes (SE) from baseline of lumbar spine 11.9 (2.1), femoral neck 9.8 (1.9), and total hip 8.5 (1.0). In women switched from odanacatib 50 mg to placebo after 2 years (n = 14), BMD mean % changes (SE) from baseline were: lumbar spine − 0.4 (1.3), femoral neck − 1.6 (1.0) and total hip − 1.8 (0.8). BTM had geometric mean % changes from baseline (SE): urine NTX/creatinine − 67.4 (10.1) and serum BSAP − 15.3 (5.9) in women continuously receiving odanacatib 50 mg (n = 9–10), and 6.0 (7.6) and − 11.9 (3.9) in women switched to placebo after 2 yrs (n = 10). Odanacatib was well tolerated. Women who received odanacatib 50 mg for 5 years had progressive gains in mean spine and hip BMD and sustained reduction in NTX, with smaller reduction in BSAP. Discontinuation resulted in reversal of BMD gains.
doi:10.1016/j.bone.2012.08.035
O35 Vitamin D supports the efficiency of decitabine for induction of differentiation, apoptosis and osteocalcin expression in leukemia and mastocytosis H. Karlica,b, R. Reitermaiera,b, R. Thalerc, J. Vargaa,b,c, S. Spitzerc, M. Pfeilstöckera,b,d, P. Valenta,e, K. Klaushoferc, F. Vargac a Ludwig Boltzmann Cluster Oncology, Vienna, Austria b Ludwig Boltzmann Institute for Leukemia Research and Hematology, Hanusch Hospital, Vienna, Austria c Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling and 1st Medical Department, Hanusch Hospital, Vienna, Austria d 3rd Medical Department, Hanusch Hospital, Vienna Austria e Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria Abstract: Novel treatments for leukemias and mastocytosis with agents such as vitamin D (VD), that induce myelomonocytic differentiation may re-establish functional hematopoiesis in patients. This is associated with induction of osteoblastic markers such as osteocalcin. Similar effects on gene regulation are also observed with demethylating drugs such as Decitabine (5-aza-desoxycytidine, DAC). The aim of this study was to define possible epigenetic mechanisms, which are responsible for the supportive activity of VD on efficiency of DAC. HMC-1 mast cell leukemia cells or HL-60 promyelocytic leukemia cells were treated with vitamin D3 (VD, 10 nM) and/or DAC (5 μM) for 3 days. RNA and DNA were isolated and gene expression (by RT-PCR and Affymetrix human gene 1.0 arrays) as well as promoter methylation was analyzed. Co-treatment of HMC-1 mast cell leukemia cells resulted in a significant stimulation of myelomonocytic differentiation markers such as CD11b, CD14 and CD52 as well as apoptosis markers such as FAS and FAS-ligand. This was accompanied by synergistic stimulation of osteocalcin expression. Down-regulation of DNAmethyltransferases as well as a decrease in promoter methylation indicated that the additive effects of VD on these genes are above all based on DNA demethylation. Results of this study underline the impact of epigenetic mechanisms in the differentiating activity of VD. The observed synergistic activity of VD with DAC suggests that combined application of lower dosages from each agent would support efficiency and reduce side effects for patients. This work was supported by the Medical Scientific Fund of the Mayor of the City of Vienna.
doi:10.1016/j.bone.2012.08.036
O36 Update osteocalcin biology G. Karsenty Department of Genetics & Development, Columbia University, New York, USA Abstract: In the last 15 years the biology of the osteoblasts has been profoundly modified through two complementary lines of research. The first one has been to the identification and characterization of novel organs, hormones and neuromediators regulating bone formation, the classical function of these cells. The second one has been the demonstration that osteoblasts are endocrine cells affecting through at least