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Insights into bone mineral density and bone metabolism in Duchenne muscular dystrophy
Abstracts 2017 / Neuromuscular Disorders 27 (2017) S96–S249 records of boys with DMD on long-term glucocorticoid therapy, who were treated with testosterone for delayed (n = 31) or arrested (n = 2) puberty. Outcomes of interest were endogenous pubertal development; changes in body composition; bone mineral density and content of lumbar spine, whole body and lateral distal femur by dual-energy X-ray absorptiometry; and metabolic laboratory indices. Changes in bone health measures within 2.5 years prior to treatment were compared to changes up to 2.5 years after treatment initiation. Thirty-three male patients (median age 15.0 years, 27% ambulatory) on glucocorticoid therapy (median duration 7.7 years) were treated with testosterone therapy for a median of 37 (range 4.1 to 73.5) months. Endogenous puberty developed in 45% of previously pre-pubertal boys after starting testosterone. We observed increases in spine and whole body absolute bone mineral content (p = 0.03 and 0.0002 respectively), and stabilization of fat mass and percentage of total body fat accrual, when comparing post- to pretestosterone treatment initiation. Although longer-term data are needed, testosterone therapy should be considered in the management of glucocorticoidtreated male patients with DMD who experience delayed puberty. http://dx.doi.org/10.1016/j.nmd.2017.06.044
P.15 Body composition of patients with Duchenne muscular dystrophy B. Wong, S. Hu, P. Horn, I. Rybalsky, K. Shellenbarger, C. Tian, J. Bange, H. Kalkwarf Cincinnati Childrens Hospital Medical Center, Cincinnati, USA Although long-term glucocorticoid therapy slows disease progression for DMD, the disease trajectory is still characterized by declining motor function due to progressive muscle atrophy and loss of lean muscle mass. The rate of loss of lean body mass in DMD has not been reported. To investigate the trajectory of DXA lean body mass of DMD patients compared to healthy population. IRB approved study of longitudinal whole body composition data for lean mass, fat mass and height of Healthy children (HC) from the NICHD “Bone mineral density in childhood study” 2002–2009 and DMD patients. The lean body mass, fat mass, LBMI, FMI and height were analyzed using a repeated measures mixed model. The covariates were disease group and the interaction between disease group and age. For the DMD group and each timed motor test a repeated measures mixed model was analyzed where the covariates were LBMI and Age. Study N: HC 992; DMD 586. Total number of visits with DXA results: HC 5214; DMD 3087. Mean duration of follow up (yrs ±SD [range]: HC 4.3 ± 2.1[0–7.8]; DMD: 4.3 ± 3.3[0–12]. Mean age at last visit: HC 15.8 ± 4.7[5.0–23.4]; DMD: 12.3 ± 4.7[3.3–32.6]. Rate of change: Lean body mass (g/yr): HC – age <10–1732; 10 - ≤ 14–5662; >14–2563; DMD – age <10–1231; 10 - ≤14–786; >14–145. Total fat mass (g/yr): ): HC – age <10–1211; 10 - ≤14–537; >14–435; DMD – age <10–1587; 10 - ≤14–3184; >14–1570. Lean Body Mass Index (LBMI, kg/sq m): HC – age <10-0.19; 10 ≤14-0.85; >14-0.51; DMD – age <10-0.10; 10 - ≤14- -0.28; >14- -0.12. Fat Mass Index (FMI, kg/sq m): HC – age <10-0.36; 10 - ≤14- -0.14; >14-0.06; DMD – age <10-0.79; 10 - ≤14- 1.18; >14- 0.44. LBMI correlated negatively with timed 30 ft run (p=0.02) and Gower rise from the floor (p=0.03); and positively with NSAA (p=0.02). We established the trajectories of lean body mass changes throughout the different stages of DMD. This data is valuable for informing clinical trial designs for DMD. http://dx.doi.org/10.1016/j.nmd.2017.06.045
P.16 Relationships between ambulatory function and body composition in patients with Duchenne muscular dystrophy B. Wong 1, J. Signorovitch 2, S. Hu 1, J. Bange 1, I. Rybalsky 1, K. Shellenbarger 1, C. Tian 1, E. Swallow 2, J. Song 2, S. Ward 3 1 Cincinnati Childrens Hospital Medical Center, Cincinnati, USA; 2 Analysis Group, Boston, USA; 3 The TAP Collaboration, Cambridge, USA
S103
Ambulatory function is highly variable in Duchenne muscular dystrophy (DMD), even among boys of the same age. In addition, variations in total body mass and lean body mass are typical, and reflect growth as well as muscle atrophy. We measured the extent to which body composition can explain variability in ambulatory function in boys with DMD aged 5–20 years. Associations were measured at concurrent assessments of total body mass, % lean body mass (measured via DEXA) and ambulatory function using Pearson correlations and multivariable regressions accounting for repeated measures. A total of 327 patients were studied at n = 1453 visits with DEXA scans and ambulatory assessments. Percent lean body mass decreased with age, with means (standard deviations) of 75 (4), 74 (6), 68 (9), 60 (10) and 53 (10) for patients aged <6, 6–8, 8–10, 10–12, and >12 years, respectively. Associations between function and % lean body mass were numerically stronger than associations between function and age, with Pearson correlations of 0.59 and -0.32 for the North Star Ambulatory Assessment (NSAA) total score, −0.45 and 0.33 for the 30-ft walk/run, −0.42 and 0.37 for sit to stand and -0.38 and 0.25 for the 4-stair climb. In multivariable analyses adjusted for age and total body mass, each 10 point decrease in % lean body mass was associated with 5.4 units lower NSAA score, 1.7 seconds longer 30-ft walk/run, 2.5 seconds longer sit to stand and 1.5 seconds longer 4-stair climb (all p < 0.05). Accounting for % lean body mass, in addition to age and total body mass, more than doubled the proportion of explained variation in most functional measures, with levels of explained variation reaching 19–37%. We conclude that lean body mass is an important determinant of multiple components of ambulatory function. These findings can contribute to the interpretation of treatment effects on ambulatory outcomes, especially for treatments that aim to impact muscle mass and/or function. http://dx.doi.org/10.1016/j.nmd.2017.06.046
P.17 Insights into bone mineral density and bone metabolism in Duchenne muscular dystrophy M. Sframeli 1, G. Vita 2, A. Catalano 1, M. Distefano 1, M. La Rosa 1, C. Barcellona 1, C. Bonanno 1, G. Nicocia 1, C. Profazio 2, N. Morabito 1, C. Lunetta 2, G. Vita 1, S. Messina 1 1 Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 2 NEMO SUD Clinical Centre for Neuromuscular Disorders, Messina, Italy Low bone mineral density (BMD) and increased fracture risk are frequently observed in Duchenne muscular dystrophy (DMD). Our aim was to explore BMD and bone turn over and to evaluate their main determinants in a cohort of DMD subjects. BMD at lumbar spine, detected by DXA and expressed as Z-score values, C-terminal telopeptide of procollagen type I (CTX) and osteocalcin (BGP), as bone resorption and formation markers respectively, and sclerostin were assessed. Prevalent fragility fractures were recorded. Left Ventricular Ejection fraction (LVEF%) and Forced Vital Capacity (FVC%) were evaluated. Thirty-one patients [median age 14 (12 to 21.5) yr.] were studied. Ambulant subjects showed significantly higher Z-score values in comparison with not ambulant ones, and subjects with prevalent clinical fractures had significantly lower Z-score values in comparison to subjects without fractures. Z-score values were positively correlated with FVC (r = 0.50; p = 0.01), but not with GCs use, and FVC was positively associated with BGP (r = 0.55; p = 0.02). In not ambulant subjects, Z-score values were associated with BMI (r = 0.54; p = 0.02) and sclerostin was associated with age (r = 0.44; p = 0.05). At a stepwise multiple regression analysis, age, BMI, FVC and sclerostin levels were retained in the model as independent predictors of BMD. Our data confirm low BMD values in DMD subjects, especially in not ambulant ones, irrespective of the use of GCs, and identify, for the first time, FVC and sclerostin as main determinants of BMD in this cohort. Therefore, a multidisciplinary setting, focusing on rehabilitative and respiratory care, is warranted to reduce bone complications in DMD. http://dx.doi.org/10.1016/j.nmd.2017.06.047
P.15 Body composition of patients with Duchenne muscular dystrophy B. Wong, S. Hu, P. Horn, I. Rybalsky, K. Shellenbarger, C. Tian, J. Bange, H. Kalkwarf Cincinnati Childrens Hospital Medical Center, Cincinnati, USA Although long-term glucocorticoid therapy slows disease progression for DMD, the disease trajectory is still characterized by declining motor function due to progressive muscle atrophy and loss of lean muscle mass. The rate of loss of lean body mass in DMD has not been reported. To investigate the trajectory of DXA lean body mass of DMD patients compared to healthy population. IRB approved study of longitudinal whole body composition data for lean mass, fat mass and height of Healthy children (HC) from the NICHD “Bone mineral density in childhood study” 2002–2009 and DMD patients. The lean body mass, fat mass, LBMI, FMI and height were analyzed using a repeated measures mixed model. The covariates were disease group and the interaction between disease group and age. For the DMD group and each timed motor test a repeated measures mixed model was analyzed where the covariates were LBMI and Age. Study N: HC 992; DMD 586. Total number of visits with DXA results: HC 5214; DMD 3087. Mean duration of follow up (yrs ±SD [range]: HC 4.3 ± 2.1[0–7.8]; DMD: 4.3 ± 3.3[0–12]. Mean age at last visit: HC 15.8 ± 4.7[5.0–23.4]; DMD: 12.3 ± 4.7[3.3–32.6]. Rate of change: Lean body mass (g/yr): HC – age <10–1732; 10 - ≤ 14–5662; >14–2563; DMD – age <10–1231; 10 - ≤14–786; >14–145. Total fat mass (g/yr): ): HC – age <10–1211; 10 - ≤14–537; >14–435; DMD – age <10–1587; 10 - ≤14–3184; >14–1570. Lean Body Mass Index (LBMI, kg/sq m): HC – age <10-0.19; 10 ≤14-0.85; >14-0.51; DMD – age <10-0.10; 10 - ≤14- -0.28; >14- -0.12. Fat Mass Index (FMI, kg/sq m): HC – age <10-0.36; 10 - ≤14- -0.14; >14-0.06; DMD – age <10-0.79; 10 - ≤14- 1.18; >14- 0.44. LBMI correlated negatively with timed 30 ft run (p=0.02) and Gower rise from the floor (p=0.03); and positively with NSAA (p=0.02). We established the trajectories of lean body mass changes throughout the different stages of DMD. This data is valuable for informing clinical trial designs for DMD. http://dx.doi.org/10.1016/j.nmd.2017.06.045
P.16 Relationships between ambulatory function and body composition in patients with Duchenne muscular dystrophy B. Wong 1, J. Signorovitch 2, S. Hu 1, J. Bange 1, I. Rybalsky 1, K. Shellenbarger 1, C. Tian 1, E. Swallow 2, J. Song 2, S. Ward 3 1 Cincinnati Childrens Hospital Medical Center, Cincinnati, USA; 2 Analysis Group, Boston, USA; 3 The TAP Collaboration, Cambridge, USA
S103
Ambulatory function is highly variable in Duchenne muscular dystrophy (DMD), even among boys of the same age. In addition, variations in total body mass and lean body mass are typical, and reflect growth as well as muscle atrophy. We measured the extent to which body composition can explain variability in ambulatory function in boys with DMD aged 5–20 years. Associations were measured at concurrent assessments of total body mass, % lean body mass (measured via DEXA) and ambulatory function using Pearson correlations and multivariable regressions accounting for repeated measures. A total of 327 patients were studied at n = 1453 visits with DEXA scans and ambulatory assessments. Percent lean body mass decreased with age, with means (standard deviations) of 75 (4), 74 (6), 68 (9), 60 (10) and 53 (10) for patients aged <6, 6–8, 8–10, 10–12, and >12 years, respectively. Associations between function and % lean body mass were numerically stronger than associations between function and age, with Pearson correlations of 0.59 and -0.32 for the North Star Ambulatory Assessment (NSAA) total score, −0.45 and 0.33 for the 30-ft walk/run, −0.42 and 0.37 for sit to stand and -0.38 and 0.25 for the 4-stair climb. In multivariable analyses adjusted for age and total body mass, each 10 point decrease in % lean body mass was associated with 5.4 units lower NSAA score, 1.7 seconds longer 30-ft walk/run, 2.5 seconds longer sit to stand and 1.5 seconds longer 4-stair climb (all p < 0.05). Accounting for % lean body mass, in addition to age and total body mass, more than doubled the proportion of explained variation in most functional measures, with levels of explained variation reaching 19–37%. We conclude that lean body mass is an important determinant of multiple components of ambulatory function. These findings can contribute to the interpretation of treatment effects on ambulatory outcomes, especially for treatments that aim to impact muscle mass and/or function. http://dx.doi.org/10.1016/j.nmd.2017.06.046
P.17 Insights into bone mineral density and bone metabolism in Duchenne muscular dystrophy M. Sframeli 1, G. Vita 2, A. Catalano 1, M. Distefano 1, M. La Rosa 1, C. Barcellona 1, C. Bonanno 1, G. Nicocia 1, C. Profazio 2, N. Morabito 1, C. Lunetta 2, G. Vita 1, S. Messina 1 1 Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 2 NEMO SUD Clinical Centre for Neuromuscular Disorders, Messina, Italy Low bone mineral density (BMD) and increased fracture risk are frequently observed in Duchenne muscular dystrophy (DMD). Our aim was to explore BMD and bone turn over and to evaluate their main determinants in a cohort of DMD subjects. BMD at lumbar spine, detected by DXA and expressed as Z-score values, C-terminal telopeptide of procollagen type I (CTX) and osteocalcin (BGP), as bone resorption and formation markers respectively, and sclerostin were assessed. Prevalent fragility fractures were recorded. Left Ventricular Ejection fraction (LVEF%) and Forced Vital Capacity (FVC%) were evaluated. Thirty-one patients [median age 14 (12 to 21.5) yr.] were studied. Ambulant subjects showed significantly higher Z-score values in comparison with not ambulant ones, and subjects with prevalent clinical fractures had significantly lower Z-score values in comparison to subjects without fractures. Z-score values were positively correlated with FVC (r = 0.50; p = 0.01), but not with GCs use, and FVC was positively associated with BGP (r = 0.55; p = 0.02). In not ambulant subjects, Z-score values were associated with BMI (r = 0.54; p = 0.02) and sclerostin was associated with age (r = 0.44; p = 0.05). At a stepwise multiple regression analysis, age, BMI, FVC and sclerostin levels were retained in the model as independent predictors of BMD. Our data confirm low BMD values in DMD subjects, especially in not ambulant ones, irrespective of the use of GCs, and identify, for the first time, FVC and sclerostin as main determinants of BMD in this cohort. Therefore, a multidisciplinary setting, focusing on rehabilitative and respiratory care, is warranted to reduce bone complications in DMD. http://dx.doi.org/10.1016/j.nmd.2017.06.047