An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol.

INTRODUCTION: Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4. METHODS AND ANALYSIS: BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial.Each subject receives four intravenous doses of 3×106/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover. ETHICS AND DISSEMINATION: The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals. TRIAL REGISTRATION NUMBERS: EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.

[Recommendations for the healthcare of patients with FOP]. / Empfehlungen zur Versorgung von Patient:innen mit FOP.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the type I bone morphogenetic protein (BMP) receptor ACVR1 (activin A receptor-type 1), also known as ALK2 (activin receptor-like kinase-2). It leads to the onset and progression of heterotopic ossification (HO) in soft and connective tissue. HO is often preceded by episodes of soft tissue swelling or flare-ups. Flare-ups, characteristic of FOP, may be induced by trauma, infection, vaccination, or other medications, as well as surgical procedures or may occur spontaneously. As patients age, they develop severe mobility limitations due to progressive HO formation, including immobility, causing a shortened life expectancy. FOP's first characteristic clinical sign is the congenital malformation of one or both big toes with valgus axis deviation, which is present in almost all patients. To confirm the diagnosis, molecular genetic analysis of the ACVR1 gene is possible. AIM OF THE RECOMMENDATIONS: This white paper aims to provide an overview of the necessary prerequisites and conditions for the care of patients with FOP and positively contribute to patients with FOP by improving the overall availability of knowledge. To achieve this, relevant aspects of the care of the very rare disease FOP are presented, from the initial diagnosis to the care in regular care based on the authors' knowledge (German FOP network) and the international FOP Treatment Guidelines. The recommendations presented here are addressed to all actors and decision-makers in the health care system and are also intended to inform patients and the public.

Interaction of body fat percentage and height with appendicular functional muscle-bone unit.

The interaction of body fat percentage and height with appendicular BMC for LBM was analyzed. Only body fat had significant negative correlation with the appendicular BMC for LBM. PURPOSE/INTRODUCTION: For the clinical evaluation of the functional muscle-bone unit, it was proposed to evaluate the adaptation of the bone to the acting forces. A frequently used parameter for this is the total body less head bone mineral content (TBLH-BMC) determined by dual-energy X-ray absorptiometry (DXA) in relation to the total body lean body mass (LBM). Body fat percentage seemed to correlate negatively and height positively with TBLH-BMC for LBM. It was supposed that appendicular BMC for LBM is a more accurate surrogate for the functional muscle-bone unit since appendicular LBM does not incorporate the mass of internal organs. The aim of this study was to analyze the interaction of body fat percentage and height with appendicular BMC for LBM. METHODS: As part of the National Health and Nutrition Examination Survey (NHANES) study, between the years 1999 and 2004, whole-body DXA scans on randomly selected Americans from 8 years of age were carried out. From all eligible DXA scans, three major US ethnic groups were evaluated (non-Hispanic Whites, non-Hispanic Blacks, and Mexican Americans) for further statistical analysis. RESULTS: For the statistical analysis, the DXA scans of 8190 non-Hispanic White children and adults (3903 female), of 4931 non-Hispanic Black children and adults (2250 female), and 5421 of Mexican American children and adults (2424 female) were eligible. Only body fat had a significant negative correlation with the appendicular BMC for LBM. CONCLUSIONS: Only body fat had significant negative correlation with appendicular BMC for LBM, and thus, should be addressed when evaluating functional muscle-bone unit.

Individualized evaluation of lumbar bone mineral density in children with cerebral palsy.

Lumbar spine bone mineral density (LS-BMD) assessed by dual-energy X-ray absorptiometry (DXA) is used in children with cerebral palsy (CP) to evaluate bone health. LS-BMD results in children with CP are influenced significantly by their height, BMI, and mobility level. An adjustment for these parameters might improve the clinical significance of the method. PURPOSE/INTRODUCTION: DXA evaluation is considered useful in children with CP to assess bone health. For this purpose, LS-BMD is often used. The aim of the study was to estimate the effect of height, BMI, and reduced mobility level of children with CP on LS-BMD and to develop a method to adjust individual results of LS-BMD for these factors. METHODS: We conducted a monocentric retrospective analysis of data collected in children and adolescents with CP, who participated in a rehabilitation program and had no history of recurrent fractures. The DXA scan was part of the routine examination for participants older than 4 years of age. The relationship between height and BMI for age Z-scores and age-adjusted LS-BMD Z-scores was analyzed. RESULTS: LS-DXA scans of 500 children and adolescents with CP (Gross Motor Function Classification System levels I-V) were included in the statistical analysis (217 female). The mean age was 9.4 years (± 3.7 years). Children with moderate to severe CP had significantly (p < 0.001) lower LS-BMD Z-scores than children with mild CP. We provided nomograms to adjust individual LS-BMD results to their height, BMI, and mobility level. CONCLUSIONS: LS-BMD results in children with CP were influenced significantly by their height, BMI, and mobility level. An adjustment of the LS-BMD results to height, BMI, and mobility level might improve the clinical significance of an individual result.

Individualized evaluation of lumbar bone mineral density and bone mineral apparent density in children and adolescents.

Lumbar spine bone mineral density (LS-BMD) assessed by dual-energy X-ray absorptiometry (DXA) is used in children to evaluate bone health. LS-BMD results in children are influenced significantly by height and BMI. An adjustment for these parameters may improve the clinical use of the method. PURPOSE/INTRODUCTION: DXA evaluation is considered useful in children to assess bone health. For this purpose, lumbar spine bone mineral density (LS-BMD) and bone mineral apparent density (LS-BMAD) are often used. The aim of the study was to estimate the effect of height and BMI on LS-BMD and LS-BMAD in children and adolescents and to develop a method to adjust individual results for these factors. METHODS: As part of the National Health and Nutrition Examination Survey (NHANES) study, between the years 2005 and 2010 lumbar DXA scans on randomly selected Americans from 8 to 20 years of age were carried out. From all eligible DXA scans, three major US ethnic groups were evaluated (Non-Hispanic Whites, Non-Hispanic Blacks, and Mexican Americans) for further statistical analysis. The relationship between height as well as BMI for age Z-scores and age-adjusted LS-BMD and LS-BMAD Z-scores was analyzed. RESULTS: For the statistical analysis, the DXA scans of 1799 non-Hispanic White children (823 females), of 1696 non-Hispanic Black children (817 females), and of 1839 Mexican American children (884 females) were eligible. The statistical analysis showed that taller and heavier children had significantly (p < 0.001) higher age-adjusted LS-BMD Z-scores than shorter and lighter children. But on LS-BMAD, only BMI and not height had a significant influence. CONCLUSIONS: LS-BMD results in children were influenced significantly by their height and BMI, the LS-BMAD results were only influenced by their BMI. For the first time, the proposed method adjusts LS-BMD and LS-BMAD to BMI. An adjustment of the LS-BMD and LS-BMAD results to these factors might improve the clinical significance of an individual result.

Are there effects of age, gender, height, and body fat on the functional muscle-bone unit in children and adults?

The aim was to describe the effect of age, gender, height, different stages of human life, and body fat on the functional muscle-bone unit. All these factors had a significant effect on the functional muscle-bone unit and should be addressed when assessing functional muscle-bone unit in children and adults. INTRODUCTION: For the clinical evaluation of the functional muscle-bone unit, it was proposed to evaluate the adaptation of the bone to the acting forces. A frequently used parameter for this is the total body less head bone mineral content (TBLH-BMC) determined by dual-energy X-ray absorptiometry (DXA) in relation to the lean body mass (LBM by DXA). LBM correlates highly with muscle mass. Therefore, LBM is a surrogate parameter for the muscular forces acting in everyday life. The aim of the study was to describe the effect of age and gender on the TBLH-BMC for LBM and to evaluate the impact of other factors, such as height, different stages of human life, and of body fat. METHODS: As part of the National Health and Nutrition Examination Survey (NHANES) study, between the years 1999-2006 whole-body DXA scans on randomly selected Americans from 8 years of age were carried out. From all eligible DXA scans (1999-2004), three major US ethnic groups were evaluated (non-Hispanic Whites, non-Hispanic Blacks, and Mexican Americans) for further statistical analysis. RESULTS: For the statistical analysis, the DXA scans of 8190 non-Hispanic White children and adults (3903 female), of 4931 non-Hispanic Black children and adults (2250 female) and 5421 of Mexican-American children and adults (2424 female) were eligible. Age, gender, body height, and especially body fat had a significant effect on the functional muscle-bone unit. CONCLUSIONS: When assessing TBLH-BMC for LBM in children and adults, the effects of age, gender, body fat, and body height should be addressed. These effects were analyzed for the first time in such a large cohort.

Home-based vibration assisted exercise as a new treatment option for scoliosis - A randomised controlled trial.

OBJECTIVES: The aim of this study was to evaluate the effect of scoliosis specific exercises (SSE) on a side-alternating whole body vibration platform (sWBV) as a home-training program in girls with adolescent idiopathic scoliosis (AIS). METHODS: 40 female AIS patients (10-17 years) wearing a brace were randomly assigned to two groups. The intervention was a six months, home-based, SSE program on a sWBV platform five times per week. Exercises included standing, sitting and kneeling. The control group received regular SSE (treatment as usual). The Cobb angle was measured at start and after six months. Onset of menarche was documented for sub-group analysis. RESULTS: The major curve in the sWBV group decreased significantly by -2.3° (SD±3.8) (95% CI -4.1 to -0.5; P=0.014) compared to the difference in the control group of 0.3° (SD±3.7) (95% CI -1.5 to 2.2; P=0.682) (P=0.035). In the sWBV group 20% (n=4) improved, 75% (n=15) stabilized and 5% (n=1) deteriorated by ≥5°. In the control group 0% (n=0) improved, 89% (n=16) stabilized and 11% (n=2) deteriorated. The clinically largest change was observed in the 'before-menarche' sub-group. CONCLUSIONS: Home-based SSE combined with sWBV for six months counteracts the progression of scoliosis in girls with AIS; the results were more obvious before the onset of the menarche.

Experience with jumping mechanography in children with cerebral palsy.

OBJECTIVES: Jumping mechanography provides robust motor function indicators among healthy children. The aim of the study was to assess the reproducibility and validity of jumping mechanography conducted as single two-legged jump (S2LJ) in children with cerebral palsy (CP). METHODS: 215 S2LJ investigations from a sample of 75 children with CP were eligible for evaluation. For the estimation of the reproducibility, only the baseline set of data per patient were used. Gross motor function was evaluated by the Gross Motor Function Measure (GMFM-66). In 135 S2LJ investigations, GMFM-66 was assessed within a week in the same child. This data was used for validity assessment. RESULTS: Coefficients of variation for the main outcome parameters ranged between 6.15-9.71%, except for jump height (CV%=27.3%). The intraclass correlation coefficients for peak velocity (Vmax) and peak power relative to body weight (Pmax/mass) was 0.927 and 0.931. Vmax and Pmax/mass were also the test parameters with the strongest correlation to the GMFM-66 score (⟩0.7). CONCLUSIONS: S2LJ assessed in the present study provided reproducible outcome measures particularly for Vmax and Pmax/mass in children with CP. Further, Vmax and Pmax/mass showed the strongest correlation with the GMFM-66 score and seem to be the most relevant evaluation criteria.

The functional muscle-bone unit in children with cerebral palsy.

Our results suggest that the prevalence of bone health deficits in children with CP was overestimated, when using only age- and height-adjusted bone mineral content (BMC) and areal bone mineral density (aBMD). When applying the functional muscle-bone unit diagnostic algorithm (FMBU-A), the prevalence of positive results decreased significantly. We recommend applying the FMBU-A when assessing bone health in children with CP. INTRODUCTION: The prevalence of bone health deficits in children with cerebral palsy (CP) might be overestimated because age- and height-adjusted reference percentiles for bone mineral content (BMC) and areal bone mineral density (aBMD) assessed by dual-energy X-ray absorptiometry (DXA) do not consider reduced muscle activity. The aim of this study was to compare the prevalence of positive DXA-based indicators for bone health deficits in children with CP to the prevalence of positive findings after applying a functional muscle-bone unit diagnostic algorithm (FMBU-A) considering reduced muscle activity. METHODS: The present study was a monocentric retrospective analysis of 297 whole body DXA scans of children with CP. The prevalence of positive results of age- and height-adjusted BMC and aBMD defined as BMC and aBMD below the P3 percentile and of the FMBU-A was calculated. RESULTS: In children with CP, the prevalence of positive results of age-adjusted BMC were 33.3% and of aBMD 50.8%. Height-adjusted results for BMC and aBMD were positive in 16.8 and 36.0% of cases. The prevalence of positive results applying the FMBU-A regarding BMC and aBMD were significantly (p < 0.001) lower than using age- and height-adjusted BMC and aBMD (8.8 and 14.8%). CONCLUSIONS: Our results suggest that the prevalence of bone health deficits in children with CP was overestimated, when using age- and height-adjusted BMC and aBMD. When applying the FMBU-A, the prevalence decreased significantly. We recommend applying the FMBU-A when assessing bone health in children with CP.

Early vibration assisted physiotherapy in toddlers with cerebral palsy - a randomized controlled pilot trial.

OBJECTIVES: to investigate feasibility, safety and efficacy of home-based side-alternating whole body vibration (sWBV) to improve motor function in toddlers with cerebral palsy (CP). METHODS: Randomized controlled trial including 24 toddlers with CP (mean age 19 months (SD±3.1); 13 boys). INTERVENTION: 14 weeks sWBV with ten 9-minute sessions weekly (non-individualized). Group A started with sWBV, followed by 14 weeks without; in group B this order was reversed. Feasibility (≥70% adherence) and adverse events were recorded; efficacy evaluated with the Gross Motor Function Measure (GMFM-66), Pediatric Evaluation of Disability Inventory (PEDI), at baseline (T0), 14 (T1) and 28 weeks (T2). RESULTS: Developmental change between T0 and T1 was similar in both groups; change scores in group A and B: GMFM-66 2.4 (SD±2.1) and 3.3 (SD±2.9) (p=0.412); PEDI mobility 8.4 (SD±6.6) and 3.5 (SD±9.2) (p=0.148), respectively. In two children muscle tone increased post-sWBV. 24 children received between 67 and 140 sWBV sessions, rate of completed sessions ranged from 48 to 100% and no dropouts were observed. CONCLUSION: A 14-week home-based sWBV intervention was feasible and safe in toddlers with CP, but was not associated with improvement in gross motor function.

Safety and efficacy of denosumab in children with osteogenesis imperfect--a first prospective trial.

OBJECTIVES: Osteogenesis imperfecta (OI) is a rare hereditary disease leading to bone fragility. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. Aim of this study was a 48-week, open-label, pilot study of the safety and efficacy of denosumab in 10 children with OI. METHODS: Ten patients (age range: 5.0-11.0 years; at least two years of prior bisphosphonate treatment) with genetically confirmed OI were studied. Denosumab was administered subcutaneously every 12 weeks with 1 mg/kg body weight. Primary endpoint was change of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 48 weeks. Safety was assessed by bone metabolism markers and adverse event reporting. RESULTS: Mean relative change of lumbar aBMD was +19 % (95%-CI: 7-31%). Lumbar spine aBMD Z-Scores increased from -2.23±2.03 (mean±SD) to -1.27±2.37 (p=0.0006). Mobility did not change (GMFM-88 +2.72±4.62% (p=0.16); one-minute walking test +11.00±15.82 m (p=0.15). No severe side effects occurred. CONCLUSIONS: On average, there was a significant increase in lumbar spine aBMD percent change after 48 weeks of denosumab. There was no change in mobility parameters and no serious adverse events. Further trials are necessary to assess long-term side effects and efficacy.

Neuromuscular training based on whole body vibration in children with spina bifida: a retrospective analysis of a new physiotherapy treatment program.

INTRODUCTION: Spina bifida is the most common congenital cause of spinal cord lesions resulting in paralysis and secondary conditions like osteoporosis due to immobilization. Physiotherapy is performed for optimizing muscle function and prevention of secondary conditions. Therefore, training of the musculoskeletal system is one of the major aims in the rehabilitation of children with spinal cord lesions. INTERVENTION AND METHODS: The neuromuscular physiotherapy treatment program Auf die Beine combines 6 months of home-based whole body vibration (WBV) with interval blocks at the rehabilitation center: 13 days of intensive therapy at the beginning and 6 days after 3 months. Measurements are taken at the beginning (M0), after 6 months of training (M6), and after a 6-month follow-up period (M12). Gait parameters are assessed by ground reaction force and motor function by the Gross Motor Function Measurement (GMFM-66). Sixty children (mean age 8.71 ± 4.7 years) who participated in the program until February 2014 were retrospectively analyzed. RESULTS: Walking velocity improved significantly by 0.11 m/s (p = 0.0026) and mobility (GMFM-66) by 2.54 points (p = 0.001) after the training. All changes at follow-up were not significant, but significant changes were observed after the training period. Decreased contractures were observed with increased muscle function. CONCLUSION: Significant improvements in motor function were observed after the active training period of the new neuromuscular training concept. This first analysis of the new neuromuscular rehabilitation concept Auf die Beine showed encouraging results for a safe and efficient physiotherapy treatment program which increases motor function in children with spina bifida.

Functional recovery after experimental spinal cord compression and whole body vibration therapy requires a balanced revascularization of the injured site.

PURPOSE: Based on several positive effects of whole-body-vibration (WBV) therapy on recovery after SCI, we looked for correlations between functional (analysis of locomotion), electrophysiological (H-reflex) and morphological (density of functioning capillaries) measurements after SCI and WBV-treatment. METHODS: Severe compression SCI at low-thoracic level (T8) in adult female Wistar rats was followed by WBV twice a day (2 × WBV) over a 12-week post-injury period. Intact rats and rats with SCI but no WBV-therapy ("No-WBV") served as controls. Recovery of locomotion was determined by BBB-locomotor rating, foot stepping angle (FSA), rump-height index (RHI), correct ladder steps (CLS) and H-reflex at 1, 3, 6, 9, and 12 weeks after SCI. Animals were sacrificed by an overdose of Isoflurane (Abbott). One hour later their spinal cords were fixed in 4% PFA for 24 h. Samples from the thoracic cord containing the lesion site and from the lumbar intumescence were cut into 10 µm thick longitudinal frozen sections. RESULTS: All functioning capillaries were unequivocally identified because the endogenous peroxidase of the erythrocytes was clearly visualized with 0.05% diaminobenzidine (DAB). A determination of their absolute (in µm2) and proportional areas (percent of photographed tissue) revealed a significantly denser capillary network in the WBV-treated rats: 1,66 ± 0,41% in the "vibrated" rats versus 0,79 ± 0,19% in the "No-WBV" animals. The portion of the capillary network in intact rats was 1,51 ± 0,69%. Surprisingly, even though the vascularization in the treated animals was significantly increased, this had no beneficial influence on the recovery of functions after SCI. CONCLUSION: The results of this study provide for the first time evidence that intensive WBV-therapy leads to a significantly denser capillary network in the lesioned spinal cord. However, since this higher capillary density is not associated with improved functional recovery (possibly because it exceeded the balance necessary for functional improvements), optional treatments with lower intensity or less time of WBV-therapy should be tested.

A specialized rehabilitation approach improves mobility in children with osteogenesis imperfecta.

OBJECTIVE: Osteogenesis imperfecta (OI) is a rare disease leading to recurrent fractures, hyperlaxicity of ligaments, short stature and muscular weakness. Physiotherapy is one important treatment approach. The objective of our analysis was to evaluate the effect of a new physiotherapy approach including side alternating whole body vibration on motor function in children with OI. METHODS: In a retrospective analysis data of 53 children were analyzed. The 12 months approach included 6 months of side alternating whole body vibration training, concomitant physiotherapy, resistance training, treadmill training and 6 months follow up. Primary outcome parameter was the Gross Motor Function Measure after 12 months (M12). RESULTS: 53 children (male: 32; age (mean±SEM): 9.1±0.61, range 2.54-24.81 years) participated in the treatment approach. A significant increase of motor function (GMFM-66 score 55.47±2.45 to 58.67±2.83; p=0.001) and walking distance (47.04 m±6.52 to 63.36±8.25 m (p<0.01) between M0 and M12 was seen. Total body without head bone mineral density increased significantly at M12 (p=0.0189). CONCLUSIONS: In the cohort of OI children which participated in the specialized treatment approach improvements of motor function were observed. Therefore this program should be considered as additional therapeutic approach for children with severe OI.

[Secondary forms of osteoporosis. Special features of diagnostics in childhood and adolescence]. / Sekundäre Formen der Osteoporose. Besonderheiten der Diagnostik im Kindes- und Jugendalter.

Rheumatic diseases in childhood and adolescence can lead to secondary osteoporosis based on various pathophysiologies. The underlying disease, medication and immobility resulting in a reduced osteoanabolic stimulus contribute to the development of a fragile skeletal system. For diagnostic purposes dual-energy X-ray absorptiometry (DXA) is the most frequently used technology. For interpretation of the areal bone mineral density, age and gender matched reference data have to be used. Particularly in the pediatric field, body height must additionally be taken into consideration. Further techniques which can provide detailed information are peripheral quantitative computed tomography and high resolution magnetic resonance imaging. Nowadays, skeletal assessments have to be interpreted in the context of the muscular system. The concept of the functional muscle-bone unit is widely accepted and uses the muscles as the dominating factor. In a second step the adaptation of the skeletal system to the applied muscle force is evaluated. This allows a differentiation between primary and secondary skeletal diseases depending on the ratio of muscles to bone. Therapeutic options for secondary osteoporosis include reduction of the causative medication, treatment of the underlying disease, antiresorptive treatment with bisphosphonates and different programs to activate the muscles. A multimodal interval rehabilitation program including alternating side vibration shows positive effects on mobility, muscle function and bone mass in children and adolescents.

Measuring procedures to determine the Cobb angle in idiopathic scoliosis: a systematic review.

BACKGROUND: Scoliosis of the vertebral column can be assessed with the Cobb angle (Cobb 1948). This examination is performed manually by measuring the angle on radiographs and is considered the gold standard. However, studies evaluating the reproducibility of this procedure have shown high variability in intra- and inter-observer agreement. Because of technical advancements, interests in new procedures to determine the Cobb angle has been renewed. This review aims to systematically investigate the reproducibility of various new techniques to determine the Cobb angle in idiopathic scoliosis and to assess whether new technical procedures are reasonable alternatives when compared to manual measurement of the Cobb angle. METHOD: Systematic review. Studies examining procedures used to determine the Cobb angle were selected. Two review authors independently selected studies for inclusion, extracted data and assessed risk of bias. Statistical results of reliability and agreement were summarised and described. RESULTS: Eleven studies of new measuring procedures were included, all reporting the reproducibility. The new procedures can be divided into computer-assisted procedures, automatic procedures and smartphone apps. CONCLUSIONS: All investigated measuring procedures showed high degrees of reliability. In general, digital procedures tend to be slightly better than manual ones. For all other measurement procedures (automatic or smartphone), results varied. Studies implementing vertebral pre-selection and observer training achieved better agreement.

First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI.

UNLABELLED: Osteogenesis imperfecta (OI) is a genetically heterogeneous disease leading to bone fragility. OI-VI is an autosomal-recessive form caused by mutations in SERPINF1. There is experimental evidence suggesting that loss of functional SERPINF1 leads to an activation of osteoclasts via the RANK/RANKL pathway. Patients with OI-VI show a poor response to bisphosphonates. We report on four children with OI-VI who had shown continuously elevated urinary bone resorption markers during a previous treatment with bisphosphonates. We treated these children with the RANKL antibody denosumab to reduce bone resorption. INTERVENTION AND RESULTS: Denosumab (1 mg/kg body weight) was injected s.c. every 3 months. There were no severe side effects. Markers of bone resorption decreased to the normal range after each injection. N-terminal Propeptide of collagen 1 was measured in the serum during the first treatment cycle and decreased also. Urinary deoxypyridinoline/creatinine was monitored in a total of seven treatment cycles and indicated that bone resorption reached the pre-treatment level after 6-8 weeks. CONCLUSION: This was the first use of denosumab in children with OI-VI. Denosumab was well tolerated, and laboratory parameters provided evidence that the treatment reversibly reduced bone resorption. Therefore, denosumab may be a new therapeutic option for patients with OI-VI.

Introduction of a new standardized assessment score of spine morphology in osteogenesis imperfecta.

PURPOSE: Osteogenesis imperfecta (OI) is a rare hereditary disease leading to multiple bone deformities and fractures. In the absence of causal therapy, a symptomatic approach is based on treatment with bisphosphonates and physiotherapy. The clinical and radiological manifestations vary. Therefore, standardization and quantification for an objective comparison, especially during therapy, are required. In this paper, radiological changes of the spine are quantified according to their clinical relevance to define a scoring system that transfers the morphological changes into a single value representing the severity of the disease. MATERIALS AND METHODS: 268 lateral spine X-rays of 95 patients with OI (median age 5.6 years) were assessed. The findings were classified based on their clinical relevance. RESULTS: The three criteria, vertebral compression, thoracolumbar kyphosis and deformity type, were quantified in a new grading system. Based on this, a "severity classification" (1 to 5) was defined with implications for diagnostics and treatment. A mathematical formula that takes into account the three criteria and their correlations to clinical relevance, resulting in a "severity score", was developed. CONCLUSION: "Severity classification" and "severity score" introduce a new concept for a standardized evaluation of spine X-rays in patients with OI. For both scientific and routine purposes, it provides the user with a simple and easy-to-handle tool for assessing and comparing different stages of severity prior to and during therapy with detailed accuracy.

Functional deficits and morphological changes in the neurogenic bladder match the severity of spinal cord compression.

UNLABELLED: Following spinal cord injury (SCI), loss of spinal and supraspinal control results in desynchronisation of detrusor vesicae (parasympathicus) and external urethral sphincter (sympathicus) activity. Despite recovery of lower urinary tract function being a high priority in patients with SCI, effective treatment options are unavailable largely because mechanisms are poorly understood. PURPOSE AND METHODS: We used a clinically relevant model of thoracic SCI compression injury in adult female Wistar rats and confirmed that lesion volumes following severe injuries were significantly greater compared to moderate injuries (p < 0.05). Between 1-9 weeks, we assessed recovery of bladder function as well as return of locomotor function using the Basso, Beattie and Bresnahan (BBB) score. Bladder morphometrics and overall intramural innervation patterns, as assessed with ß-III tubulin immunohistochemistry, were also examined. RESULTS: Despite variability, bladder function was significantly worse following severe compared to moderate compression injury (p < 0.05); furthermore, the degree of bladder and locomotor dysfunction were significantly correlated (r = 0.59; p < 0.05). In addition, at 9 weeks after SCI we saw significantly greater increases in bladder dry weight (p < 0.05) and wall thickness following severe compared to moderate injury as well as increases in intramural axon density (moderate: 3× normal values; severe 5×; both p < 0.05) that also correlated with injury severity (r = 0.89). CONCLUSION: The moderate and severe compression models show consistent and correlated deficits in bladder and locomotor function, as well as in gross anatomical and histopathological changes. Increased intramural innervation may contribute to neurogenic detrusor overactivity and suggests the use of therapeutic agents which block visceromotoric efferents.

Reshaping of vertebrae during treatment with neridronate or pamidronate in children with osteogenesis imperfecta.

BACKGROUND/AIMS: Osteogenesis imperfecta (OI) is a hereditary disease causing increased bone fragility. Pamidronate (PAM), which has to be administered as a 3-day course according to the original protocol by Glorieux, is the most frequently used therapy. Other bisphosphonates like neridronate (NER), which can be infused during an outpatient visit, have also proven to be effective. This is the first analysis comparing the effect of PAM and NER using vertebral morphometry. METHODS: 28 patients with OI type III and IV were retrospectively analyzed by matched pairs. RESULTS: No differences were detected between patients treated with PAM or NER at the start of therapy: mean age 4.4 years (p = 0.730), mean height 86.8 cm/85.3 cm (p = 0.854), lumbar vertebral area 208.9 mm(2)/206.0 mm(2) (p = 0.555), and in all vertebral indices. After 1 year of treatment (mean 1.16 years; p = 0.854) both groups showed a significant increase in the vertebral area and improved vertebral indices. Again there were no differences between the groups in the vertebral area (p = 0.590). CONCLUSION: In this study there was no difference between patients treated with PAM or NER regarding vertebral morphometry during the first year of therapy. Because of the possibility of an outpatient setting, NER is convenient for these children.