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.

TAPT1-at the crossroads of extracellular matrix and signaling in Osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a hereditary skeletal disorder primarily affecting collagen type I structure and function, causing bone fragility and occasionally versatile extraskeletal symptoms. This study expands the spectrum of OI-causing TAPT1 mutations and links extracellular matrix changes to signaling regulation.

Effects of Burosumab Treatment on Mineral Metabolism in Children and Adolescents With X-linked Hypophosphatemia.

CONTEXT: Burosumab has been approved for the treatment of children and adults with X-linked hypophosphatemia (XLH). Real-world data and evidence for its efficacy in adolescents are lacking. OBJECTIVE: To assess the effects of 12 months of burosumab treatment on mineral metabolism in children (aged <12 years) and adolescents (aged 12-18 years) with XLH. DESIGN: Prospective national registry. SETTING: Hospital clinics. PATIENTS: A total of 93 patients with XLH (65 children, 28 adolescents). MAIN OUTCOME MEASURES: Z scores for serum phosphate, alkaline phosphatase (ALP), and renal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) at 12 months. RESULTS: At baseline, patients showed hypophosphatemia (-4.4 SD), reduced TmP/GFR (-6.5 SD), and elevated ALP (2.7 SD, each P < .001 vs healthy children) irrespective of age, suggesting active rickets despite prior therapy with oral phosphate and active vitamin D in 88% of patients. Burosumab treatment resulted in comparable increases in serum phosphate and TmP/GFR in children and adolescents with XLH and a steady decline in serum ALP (each P < .001 vs baseline). At 12 months, serum phosphate, TmP/GFR, and ALP levels were within the age-related normal range in approximately 42%, 27%, and 80% of patients in both groups, respectively, with a lower, weight-based final burosumab dose in adolescents compared with children (0.72 vs 1.06 mg/kg, P < .01). CONCLUSIONS: In this real-world setting, 12 months of burosumab treatment was equally effective in normalizing serum ALP in adolescents and children, despite persistent mild hypophosphatemia in one-half of patients, suggesting that complete normalization of serum phosphate is not mandatory for substantial improvement of rickets in these patients. Adolescents appear to require lower weight-based burosumab dosage than children.

Lifetime impact of achondroplasia study in Europe (LIAISE): findings from a multinational observational study.

BACKGROUND: Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults. METHODS: Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes. RESULTS: Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0-84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes. CONCLUSIONS: The findings of this study suggest that, across an individual's lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 - prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368.

The effect of the design of the orthosis on the axial load transmission of two flexion abduction orthoses used in treating congenital hip dysplasia.

Background: With an incidence of 2-4% in all newborns, developmental dysplasia of the hip, DDH, represents the most frequent congenital disorder of the skeletal system in Germany. The therapy options are deduced with the help of a sonography. The conservative therapy approach includes the application of flexion abduction orthoses, which lead to a development of the child's hip through abduction and flexion angle. The overall structure of the orthoses puts a strain on the axial skeleton of the children. The following work is intended to clarify what role the design of the orthoses plays in this respect. Methods: Inclusion criterion for the study was fully developed newborns without an indication of skeletal malformations with Type I hip joints according to Graf verified by ultrasound. A total of 19 newborns were recruited and included in the period 3/2013-01/2015. Two types of orthoses used in treating developmental dysplasia of the hip (Tübinger splint, Otto Bock; hip flexion abduction orthosis (Superior orthosis) according to Mittelmeier-Graf, AIDAMED e.K (Kreuz et al., 2012; Mittelmeier et al., 1998; Schmitz et al., 1999), constructions differ, were used. Force was measured with the help of three force sensors, which were even able to be integrated into these without changing the design of the orthosis. In this closed system, force transmission was measured for the duration of a fixed period of two minutes. Findings: The greatest axial force development (overall force) is in the Tübinger splint with an average force of 15.1 N (min. 0.59 N, max. 53.09 N, mean 15.1, SD 2.46). 4.09 N (min. 0.96 N, max. 20.99 N, mean 4.09, SD 0.65) resulted in the Superior orthosis. Significant correlations between body weight and resulting axial traction - on average during the entire measurement period and in movement - can be taken from the statistical analysis regarding the Tübinger splint. Such a correlation cannot be depicted for the Superior orthosis. Interpretation: The analysis of the load transmission of the examined flexion and abduction orthoses reveals differences between the models. The construct of the orthoses in itself appears to play a significant role. Long-term effects of orthosis therapy on a child's axial skeleton have not been studied to date. Furthermore, it seems reasonable to expand the test series to orthoses, the design of which is configured in a similar matter compared to the examined aids. Conclusion: This study proves that the orthotic design has an influence on the infant's axial load.

Cataract in children and adolescents with type 1 diabetes. Insights from the German/Austrian DPV registry.

OBJECTIVE: To study diabetic cataract in type 1 diabetes in a large pediatric cohort. METHODS: The 92,633 patients aged 0.5-21 years from German/Austrian multicenter diabetes registry (DPV) were analyzed. The 235 patients (0.25%) with diabetic cataract were found, 200 could be categorized: 67 with early cataract (3 months before diabetes onset - 12 months afterwards), 133 with late cataract (>12 months after diabetes onset). Regression models adjusted for age and gender were used to compare clinical parameters at diabetes onset. Regression models for patients with late cataract were implemented for the total documentation period and additionally adjusted for diabetes duration. RESULTS: Rate of cataract development shows a peak at diabetes onset and declines with longer diabetes duration. Patients with cataract showed strong female preponderance. Patients developing early cataract were older at diabetes onset (12.8 years [11.8/13.9] vs. 8.9 [8.9/9.0]; p < 0.001) and showed higher HbA1c than patients without cataract (9.0% [8.55/9.38] vs. 7.6% [7.60/7.61]; p < 0.001). They had lower height-SDS, (-0.22 [-0.48/0.04] vs. 0.25 [0.24/0.26]; p < 0.001), lower weight-SDS (-0.31 [-0.55/-0.08] vs. 0.21 [0.20/0.21]; p < 0.001) and lower BMI-SDS (-0.25 [-0.49/-0.02] vs. 0.12 [0.12/0.13); p = 0.002). Patients with late cataract showed higher HbA1c at diabetes onset (8.35% [8.08/8.62] vs. 8.04% [8.03/8.05]; p = 0.023) and higher mean HbA1c during total documentation period (8.00% [7.62/8.34] vs. 7.62% [7.61/7.63]; p = 0.048). CONCLUSIONS: Our data confirm known demographic and clinical characteristics of patients developing early cataract. Hyperglycemia-induced osmotic damage to lens fibers at diabetes onset might be the main pathomechanism. Long term glycemic control is associated with cataract development.

Pediatric Reference Centiles of Bone Mineral Density and Body Composition of Lower Limbs.

Localized neurological diseases such as spina bifida are often accompanied by normal upper limb and spinal bone mineral density (BMD), whereas regional BMD of the lower limbs may be decreased. Therefore, regional BMD measurements may be more accurate to quantify regional bone health. Until now, no pediatric reference centiles of bone mineral density and body composition of the lower extremities are available for Hologic DXA systems. The objective was to generate age-and sex specific reference centiles of DXA scans of lower limbs for Hologic DXA systems. Data from the National Health and Nutrition Examination Survey of the period 1999-2004 (age 8 - 20 years) were used to generate age-specific and sex-specific reference centiles for the non-Hispanic Black, non-Hispanic White and Mexican-American NHANES study population. The LMS method was used to calculate the reference centiles. Data of DXA scans of 2233 non-Hispanic black children (880 females), 1869 non-Hispanic white children (803 females) and 2350 Mexican American children (925 females) were used to create age-specific and sex-specific reference curves. We presented age-and sex-specific reference centiles for regional bone mineral density, bone mineral content, lean body mass and fat mass at the lower limbs for children and adolescents which were ethnicity specific and directly applicable to Hologic QDR-4500A fan-beam densitometer.

Association of muscle mass and fat mass on low-density-lipoprotein cholesterol and triglyceride plasma concentration in children and adolescents.

OBJECTIVES: Obesity has often been associated with high low-density-lipoprotein cholesterol (LDL-C) and triglyceride plasma concentrations, known risk factors for diabetes mellitus and cardiovascular disease. Study objective was to evaluate the association of LDL-C and triglyceride plasma concentration with muscle and fat mass in children and adolescents. METHODS: We analyzed data of the National Health and Nutrition Examination Survey (1999-2004) to estimate lean muscle and fat mass assessed by dual-energy X-ray absorptiometry (DXA) of participants whose lipid profiles had been examined. Fat mass was operationalized by DXA-determined fat mass index (FMI). Muscle mass was assessed by appendicular lean mass index (aLMI). High LDL-C and triglyceride concentration was defined as above 130 mg/dL. RESULTS: For the evaluation of the association of LDL-C and triglyceride plasma concentration with LMI and FMI Z-scores, the data of 2,487 children and adolescents (age 8-19 years) (984 females) were eligible. High aLMI showed no association with LDL-C or triglyceride concentration, but high FMI showed significant association with LDL-C and triglyceride plasma concentration in the bivariate regression analysis. CONCLUSIONS: Isolated muscle mass increase may not be protective against high LDL-C and triglycerides plasma levels in children and adolescents. Thus, exercise may lead to risk factor reduction mainly through fat mass reduction.

Reference Centiles to Monitor the 6-minute-walk Test in Ambulant Children with Cerebral Palsy and Identification of Effects after Rehabilitation Utilizing Whole-body Vibration.

Background: Children with cerebral palsy present age-driven development in gross motor skills and walking capacity. Aims: To precisely monitor the 6-minute walk test (6MWT) in children with CP, GMFCS levels 1 and 2 over 6 months and to assess the effect of a 6-month rehabilitation program including whole-body vibration. Methods: Retrospective analysis of data of 157 children with CP who received standardized rehabilitation (DRKS00011331). 6MWT was assessed at the start (M0) and end of the training (M6), as well as at a 6-month follow-up (M12). Centiles were created using the lambda-mu-sigma (LMS) method. Results: We created 6MWT percentiles using data of all 157 children (M0 data). A medium treatment effect size (Cohen's d = 0.69) was found (M6 and M12 data). Conclusions: The generated centiles may help monitor 6MWT changes over 6 months. Combining WBV and conventional physiotherapy can significantly improve 6MWT in children with CP. Abbreviations: 6MWT: 6-Minute Walk Test; CP: Cerebral palsy; ES: effect size; GMFCS: Gross Motor Function Classification System; GMFM-66: Gross Motor Function Measure 66; LOESS: locally weighted scatterplot smoothing; LMS: lambda-mu-sigma; MCID: minimal clinical important difference; SD: standard deviation; SRM: standardized response mean; WBV: whole-body vibration.

Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2.

Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.

Signaling pathways affected by mutations causing osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility and skeletal deformity. To maintain skeletal strength and integrity, bone undergoes constant remodeling of its extracellular matrix (ECM) tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. There are at least 20 recognized OI-forms caused by mutations in the two collagen type I-encoding genes or genes implicated in collagen folding, posttranslational modifications or secretion of collagen, osteoblast differentiation and function, or bone mineralization. The underlying disease mechanisms of non-classical forms of OI that are not caused by collagen type I mutations are not yet completely understood, but an altered ECM structure as well as disturbed intracellular homeostasis seem to be the main defects. The ECM orchestrates local cell behavior in part by regulating bioavailability of signaling molecules through sequestration, release and activation during the constant bone remodeling process. Here, we provide an overview of signaling pathways that are associated with known OI-causing genes and discuss the impact of these genes on signal transduction. These pathways include WNT-, RANK/RANKL-, TGFß-, MAPK- and integrin-mediated signaling as well as the unfolded protein response.

Osteogenesis imperfecta-pathophysiology and therapeutic options.

Osteogenesis imperfecta (OI) is a rare congenital disease with a wide spectrum of severity characterized by skeletal deformity and increased bone fragility as well as additional, variable extraskeletal symptoms. Here, we present an overview of the genetic heterogeneity and pathophysiological background of OI as well as OI-related bone fragility disorders and highlight current therapeutic options.The most common form of OI is caused by mutations in the two collagen type I genes. Stop mutations usually lead to reduced collagen amount resulting in a mild phenotype, while missense mutations mainly provoke structural alterations in the collagen protein and entail a more severe phenotype. Numerous other causal genes have been identified during the last decade that are involved in collagen biosynthesis, modification and secretion, the differentiation and function of osteoblasts, and the maintenance of bone homeostasis.Management of patients with OI involves medical treatment by bisphosphonates as the most promising therapy to inhibit bone resorption and thereby facilitate bone formation. Surgical treatment ensures pain reduction and healing without an increase of deformities. Timely remobilization and regular strengthening of the muscles by physiotherapy are crucial to improve mobility, prevent muscle wasting and avoid bone resorption caused by immobilization. Identification of the pathomechanism for SERPINF1 mutations led to the development of a tailored mechanism-based therapy using denosumab, and unraveling further pathomechanisms will likely open new avenues for innovative treatment approaches.

Effect of an interval rehabilitation program with home-based, vibration-assisted training on the development of muscle and bone in children with cerebral palsy - an observational study.

Objectives In children with cerebral palsy (CP), the most common cause of physical impairment in childhood, less muscle and bone growth has been reported, when compared with typically developing children. The aim of this study was to evaluate the effect of an intensive rehabilitation program including physiotherapy in combination with 6 months of home-based, vibration-assisted training on muscle and bone growth in children with CP. Methods We included children with CP, who participated in a rehabilitation program utilizing whole-body vibration (WBV). Muscle mass was quantified by appendicular lean mass index (App-LMI) and bone mass by total-body-less-head bone mineral content (TBLH-BMC) assessed by Dual-energy X-ray absorptiometry (DXA) at the beginning of rehabilitation and one year later. To assess the functional muscle-bone unit, the relation of TBLH-BMC to TBLH lean body mass (TBLH-LBM) was used. Results The study population included 128 children (52 females, mean age 11.9 ± 2.7). App-LMI assessed in kg/m2 increased significantly after rehabilitation. The age-adjusted Z-score for App-LMI showed no significant change. TBLH-BMC assessed in gram increased significantly. The Z-scores for TBLH-BMC decreased lesser than expected by the evaluation of the cross-sectional data at the beginning of rehabilitation. The parameter T B L H - B M C T B L H - L B M $\frac{TBLH-BMC}{TBLH-LBM}$ did not change relevantly after 12 months. Conclusions Muscle growth and to a lesser extent bone growth could be increased in children with CP. The intensive rehabilitation program including WBV seemed to have no direct effect on the bone, but the observed anabolic effect on the bone, may only been mediated through the muscle.

Bone Microarchitecture Assessed by Trabecular Bone Score Is Independent of Mobility Level or Height in Pediatric Patients with Cerebral Palsy.

Bone strength and fracture risk do not only depend on bone density, but also on bone structure. The trabecular bone score (TBS) evaluates homogeneity of bone microarchitecture indirectly by measuring gray-level variations of two-dimensional (2D) DXA images. Although TBS is well-established for adults, there have been only few publications in pediatrics. In this monocentric retrospective analysis, we investigated TBS in children and adolescents with cerebral palsy (CP), a patient group vulnerable to low bone mineral mass due to impaired mobility. The influence of different parameters on TBS and areal BMD (aBMD) were evaluated, as well as the relationship between TBS and aBMD. We compared TBS values of our study population to a reference population. A total of 472 lumbar spine-dual-energy X-ray absorptiometry (LS-DXA) scans of children and adolescents with CP (205 female), aged between 4 and 18 years, were analyzed. The DXA-scans were part of the routine examination. The children had no records of fractures or specific bone diseases. Our study population with CP had similar TBS as the reference population. TBS did not increase with age until an inflection point at 10 years in females, and 12 years in males. Girls had significantly higher TBS than boys (p = .049) and pubertal girls aged 8 to 13 years had significantly higher TBS than prepubertal girls (p = .009). TBS standard deviation score for age (SDS-TBS) and aBMD Z-scores correlated weakly (p < .001; R = 0.276 [males], R = 0.284 [females]). Other than for aBMD Z-scores, SDS-TBS was not influenced by age-adjusted height Z-scores and there was no significant difference in SDS-TBS when grouped by mobility levels, using the Gross Motor Function Classification System (GMFCS). Our results indicate that children with CP have a similar homogeneous distribution of trabecular microarchitecture as controls. Puberty initiation appears to be essential for increase of TBS with age and for sex differences. TBS seems less influenced by body composition, height, and mobility than aBMD. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Reference Centiles for the Evaluation of Nutritional Status in Children using Body Fat Percentage, Fat Mass and Lean Body Mass Index.

BACKGROUND: Body fat percentage (BF%), fat mass index (FMI), and lean body mass index (LBMI) are often used to evaluate the nutritional status of children. Until now, no pediatric FMI reference centiles are applicable for GE Healthcare Lunar DXA systems. The aim of the study was to generate age-specific BF%, FMI, and LBMI references centiles for GE Healthcare Lunar DXA systems. METHODOLOGY: Published values from the National Health and Nutrition Examination Survey 1999-2004 (age 8-20 years) were used to generate the reference centiles for the non-Hispanic black, non-Hispanic white, and Mexican American NHANES population. The LMS and LMSP methods were used to generate the reference centiles. RESULTS: Data of 2433 non-Hispanic black children (972 females), 2026 non-Hispanic white children (873 females), and 2547 Mexican American children (1010 females) were eligible. CONCLUSIONS: We presented age-specific reference centiles for BF%, FMI, and LBMI for children and adolescents which were ethnicity specific (non-Hispanic black, non-Hispanic white, and Mexican American) and directly applicable to Prodigy and iDXA GE Healthcare Lunar systems with software version 14.0. We proposed the use of BF%, FMI, and LBMI together to evaluate nutritional status in children.

One-Minute Walk Test in Children with Cerebral Palsy GMFCS Level 1 and 2: Reference Values to Identify Therapeutic Effects after Rehabilitation.

Background: Children with cerebral palsy (CP) show age-driven development and individual fluctuations in walking capacity.Aim: 1. To precisely quantify 1MWT changes in children with CP, GMFCS level 1 and 2, generating 1MWT percentiles, depicting expected development over 6 months; 2. to assess the effect of a 6-month rehabilitation using whole-body vibration (WBV).Methods: Retrospective data analysis in 210 children with CP, GMFCS 1 and 2 who received standardized rehabilitation (DRKS00011331). 1MWT was assessed before (M0) and after treatment (M6), and at a 6-month follow-up (M12). Centiles were created using the lambda-mu-sigma method. Cohen's d was used to assess effect size.Results: We created 1MWT percentiles using data of all 210 children (M0 data). A small treatment effect size (d = 0.46) was found (M6 and M12 data).Conclusions: Using the generated centiles clinicians may monitor 1MWT changes over 6 months. Combining WBV and conventional physiotherapy may improve 1MWT in children with CP.Abbreviations: 1MWT: One-Minute Walk Test; 6MWT: Six-Minute Walk Test; CP: Cerebral palsy; ES: effect size; GMFCS: Gross Motor Function Classification System; GMFM-66: Gross Motor Function Measure 66; LOESS: Locally Estimated Scatterplot Smoothing; LMS: lambda-mu-sigma; SD: standard deviation; WBV: whole-body-vibration.

Individualized treatment with denosumab in children with osteogenesis imperfecta - follow up of a trial cohort.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare disease leading to hereditary bone fragility. Nearly 90% of cases are caused by mutations in the collagen genes COL1A1/A2 (classical OI) leading to multiple fractures, scoliosis, short stature and nonskeletal findings as blue sclera, hypermobility of joints, bone pain and delayed motor function development. Bisphosphonates are used in most moderate and severely affected patients assuming that an increase of bone mineral density might reduce fractures and bone pain in patients with OI. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. First data from small clinical trials promised a high efficacy of Denosumab in children with OI. Aim of this analysis was a retrospective evaluation of an individualized biomarker-associated treatment regime with Denosumab in 10 children with classical OI which were followed for 1 year after their participation in a pilot trial with Denosumab. Therefore urinary deoxypyridinoline levels were evaluated frequently as an osteoclastic activity marker and depending on that levels Denosumab injections were scheduled individually. METHODS: Ten patients (age range: 6.16-12.13 years; all participated in the former OI-AK phase 2 trial (NCT01799798)) were included in the follow-up period. Denosumab was administered subcutaneously depending on the individual urinary excretion course of deoxypyridinoline (DPD/Crea) as osteoclastic activity marker with 1 mg/kg body weight. DPD/Crea levels were evaluated before denosumab administration and afterwards. If patients present after an initial decrease after injection with a re-increase up to the DPD/crea level before Denosumab injection next dosage was planned. Changes of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 12 month was evaluated. Safety was assessed by bone metabolism markers and side effect reporting. RESULTS: During follow-up mean relative change of lumbar aBMD was - 6.4%. Lumbar spine aBMD z-Scores decreased from - 1.01 ± 2.61 (mean ± SD) to - 1.91 ± 2.12 (p = 0.015). Mobility changed not significantly (GMFM-88 -6.49 ± 8.85% (p = 0.08). No severe side effects occurred. Dose intervals could be extended in the mean from 12 weeks previously to 20.3 weeks. CONCLUSIONS: On average, it was possible to prolong the intervals between drug administrations and to reduce the total dose about by 25% without a decrease of mobility or change of vertebral shape despite a reduction of lumbar aBMD during 1 year of biomarker-directed Denosumab treatment. Further trials are necessary to balance side effects and highest efficacy in children.

Inverse Association of High-Density Lipoprotein Cholesterol Concentration with Muscle Mass in Children.

Background: Obesity was often associated with low high-density lipoprotein (HDL) cholesterol concentration, which is an established cardiovascular risk factor. Objectives: To evaluate the association of HDL-cholesterol concentration with fat and muscle mass in children and adolescents. Methods: Data of the National Health and Nutrition Examination Survey (1999-2004) were used to estimate fat and muscle mass by dual-energy X-ray absorptiometry (DXA) of the participants who had also an examination of their lipid profiles. Fat mass was assessed by DXA-determined fat mass index (FMI). Muscle mass was operationalized by appendicular lean mass index (LMI). Low HDL-cholesterol concentration was defined as <40 mg/dL. Results: For the evaluation of the association of HDL-cholesterol concentration with FMI and LMI Z-scores, the data of 6288 children and adolescents (age 8-19 years) (2535 females) were eligible. In the study population, the prevalence of low HDL-cholesterol concentration increased with rising FMI and appendicular LMI Z-scores. Conclusions: The study results suggested that there is a counterintuitive, inverse association of muscle mass and HDL-cholesterol concentration.

The Appendicular Lean Mass Index Is a Suitable Surrogate for Muscle Mass in Children with Cerebral Palsy.

BACKGROUND: Densitometrically measured lean body mass (LBM) is often used to quantify skeletal muscle mass in children with cerebral palsy (CP). Since LBM depends on the individual's height, the evaluation of $\frac{{{\rm{LBM}}}}{{heigh{t^2}}}\ $ (lean BMI) is often recommended. However, LBM includes not only skeletal muscle mass but also the mass of skin, internal organs, tendons, and other components. This limitation applies to a far lesser extent to the appendicular lean mass index (LMIapp). OBJECTIVES: The aim of the study was to evaluate skeletal muscle mass in children with CP using total lean BMI (LMItot) and LMIapp. METHODS: The present study was a monocentric retrospective analysis of prospectively collected data among children and adolescents with CP participating in a rehabilitation program. In total, 329 children with CP [148 females; Gross Motor Function Classification Scale (GMFCS) I, 32 children; GMFCS II, 73 children; GMFCS III, 133 children; GMFCS IV, 78 children; and GMFCS V, 13 children] were eligible for analysis. The mean age was 12.3 ± 2.75 y. Pediatric reference centiles for age-adjusted LMIapp were generated using data from NHANES 1999-2004. Low skeletal muscle mass was defined as a z score for DXA determined LMItot and LMIapp less than or equal to -2.0. RESULTS: The z scores for LMIapp were significantly lower than LMItot in children with CP, GMFCS levels II-V (P < 0.001), with the exception of GMFCS level I (P = 0.121), where no significant difference was found. The prevalence of low LMItot (16.1%; 95% CI: 16.1, 20.1%) was significantly lower (P < 0.001) than the prevalence of LMIapp (42.2%; 95% CI: 36.9, 47.9%) in the study population. CONCLUSIONS: The prevalence of low skeletal muscle mass in children with CP might be underestimated by LMItot. LMIapp is more suitable for the evaluation of skeletal muscle mass in children with CP.

Current and Emerging Therapeutic Options for the Management of Rare Skeletal Diseases.

Increasing knowledge in the field of rare diseases has led to new therapeutic approaches in the last decade. Treatment strategies have been developed after elucidation of the underlying genetic alterations and pathophysiology of certain diseases (e.g., in osteogenesis imperfecta, achondroplasia, hypophosphatemic rickets, hypophosphatasia and fibrodysplasia ossificans progressiva). Most of the drugs developed are specifically designed agents interacting with the disease-specific cascade of enzymes and proteins involved. While some are approved (asfotase alfa, burosumab), others are currently being investigated in phase III trials (denosumab, vosoritide, palovarotene). To offer a multi-disciplinary therapeutic approach, it is recommended that patients with rare skeletal disorders are treated and monitored in highly specialized centers. This guarantees the greatest safety for the individual patient and offers the possibility of collecting data to further improve treatment strategies for these rare conditions. Additionally, new therapeutic options could be achieved through increased awareness, not only in the field of pediatrics but also in prenatal and obstetric specialties. Presenting new therapeutic options might influence families in their decision of whether or not to terminate a pregnancy with a child with a skeletal disease.