Genetic factors contributing to late adverse musculoskeletal effects in childhood acute lymphoblastic leukemia survivors.

BACKGROUND: A substantial number of survivors of childhood acute lymphoblastic leukemia (ALL) suffer from treatment-related late adverse effects. While multiple studies have identified the effects of chemotherapeutics and radiation therapy on musculoskeletal outcomes, few have investigated their associations with genetic factors. METHODS: Here we analyzed musculoskeletal complications in relation to common and rare genetic variants derived through whole-exome sequencing of the PETALE cohort. Top-ranking associations were further assessed through stratified and multivariate analyses. RESULTS: DUOX2 variant was associated with skeletal muscle function deficit, as defined by peak muscle power Z score ≤ -2 SD (P = 4.5 × 10-5 for genotyping model). Upon risk stratification analysis, common variants in the APOL3, COL12A1, and LY75 genes were associated with Z score ≤ -2 SD at the cross-sectional area (CSA) at 4% radial length and lumbar bone mineral density (BMD) in high-risk patients (P ≤ 0.01). The modulation of the effect by risk group was driven by the interaction of the genotype with cumulative glucocorticoid dose. Identified variants remained significant throughout multivariate analyses incorporating non-genetic factors of the studied cohort. CONCLUSION: This exploratory study identified novel genetic variants associated with long-term musculoskeletal impairments in childhood ALL survivors. Replication in an independent cohort is needed to confirm the association found in this study.

Muscle abnormalities in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is mainly characterized by bone fragility but muscle abnormalities have been reported both in OI mouse models and in children with OI. Muscle mass is decreased in OI, even when short stature is taken into account. Dynamic muscle tests aiming at maximal eccentric force production reveal functional deficits that can not be explained by low muscle mass alone. However, it appears that diaphyseal bone mass is normally adapted to muscle force. At present the determinants of muscle mass and function in OI have not been clearly defined. Physiotherapy interventions and bisphosphonate treatment appear to have some effect on muscle function in OI. Interventions targeting muscle mass have shown encouraging results in OI animal models and are an interesting area for further research.

Physical activity in youth with osteogenesis imperfecta type I.

INTRODUCTION: Individuals with Osteogenesis Imperfecta (OI) type I often show muscular weakness. However, it is unclear whether muscular weakness is a consequence of physical inactivity or a result of the disease itself. The aim was to assess muscle function in youth with OI type I and evaluate physical activity (PA). METHODS: Fourteen children with OI type I (mean age [SD]: 12.75 [4.62] years) were compared to 14 age- and gender-matched controls (mean age [SD]: 12.75 [4.59] years). Muscle force and power were determined through mechanography. PA and daily energy expenditure were measured with an accelerometer and a questionnaire. RESULTS: Compared to controls, children with OI type I had lower muscle force and power. OI type I children were as active as their healthy counterparts. CONCLUSIONS: Children and adolescents with OI type I and their healthy counterparts did not reached daily recommendations of PA. Given their muscle function deficit, youth with OI type I would benefit to reach these recommendations to prevent precocious effect of aging on muscles.

Validity of an accelerometer as a vertical ground reaction force measuring device in healthy children and adolescents and in children and adolescents with osteogenesis imperfecta type I.

INTRODUCTION: Vertical ground reaction forces (vGRFs) are closely related to bone strength and development. It is therefore relevant to assess these forces in bone disorders accompanied with muscle weakness such as in osteogenesis imperfecta type I (OI type I). The purpose of the present study was to assess the validity of vGRFs derived from an accelerometer. METHODS: Fourteen children and adolescents with a diagnosis of OI type I (age range: 7 to 21; mean age [SD]: 14.1 [4.8] years; 5 males) and fourteen healthy controls (age range: 6 to 21; mean age [SD]: 12.5 [4.2] years; 5 males) performed three repetitions of five different jump and rise tests on a ground reaction force plate. Jumps and rises outcomes were measured simultaneously with the ground reaction force plate and an accelerometer. RESULTS: Pearson correlation coefficients were over 0.96 (p<0.001) for the five tests. The limits of agreement represented between 17 and 31% of the average peak force measured by both devices. The accelerometer is a promising tool to assess ground reaction forces in everyday life settings and has been shown to be sufficiently sensitive to detect muscular weakness in children and adolescent with OI type I.

Biomechanical analysis of fracture risk associated with tibia deformity in children with osteogenesis imperfecta: a finite element analysis.

OBJECTIVES: Osteogenesis imperfecta (OI) frequently leads to long-bone bowing requiring a surgical intervention in severe cases to avoid subsequent fractures. However, there are no objective criteria to decide when to perform such intervention. The objective is to develop a finite element model to predict the risk of tibial fracture associated with tibia deformity in patients with OI. METHODS: A comprehensive FE model of the tibia was adapted to match bi-planar radiographs of a 7 year-old girl with OI. Ten additional models with different deformed geometries (from 2° to 24°) were created and the elasto-plastic mechanical properties were adapted to reflect OI conditions. Loads were obtained from mechanography of two-legged hopping. Two additional impact cases (lateral and torsion) were also simulated. Principal strain levels were used to define a risk criterion. RESULTS: Fracture risks for the two-legged hopping load case remained low and constant until tibia bowing reached 15° and 16° in sagittal and coronal planes respectively. Fracture risks for lateral and torsion impact were equivalent whatever the level of tibial bowing. CONCLUSIONS: The finite element model of OI tibia provides an objective means of assessing the necessity of surgical intervention for a given level of tibia bowing in OI-affected children.

Agreement between vertical ground reaction force and ground reaction force vector in five common clinical tests.

Mechanography is an innovative method to evaluate lower-limb dynamic muscle function. This technique is generally performed on force platforms that measure only the vertical component of ground reaction force (GRF). The underlying assumption is that medio-lateral and antero-posterior forces do not contribute significantly to the GRF in jumping and rising tests. The goal of this study was to establish the validity of this assumption. Fifteen healthy adults (mean age [SD]: 30 [11] years; mean height [SD]: 1.68 [0.12] m; mean body mass: 70 [18] kg) performed three repetitions of five different tests in the following order: multiple two-legged hopping, multiple one-legged hopping, single two-legged jump, heel-rise test and chair-rise test. An excellent agreement was found between peak GRF and peak vertical GRF. In each of the five tests, peak vertical GRF represented more than 99% of peak GRF. Moreover, the limits of agreement ranged between 0.05% (multiple two-legged hopping test) and 0.4% (heel-rise test) of the averaged peak force measurements. Therefore measuring only the vertical component of ground reaction force in healthy participants is appropriate for the five tests used in the present study.

Muscle force and power in obese and overweight children.

The study investigated differences in skeletal muscle function between obese and non-obese children using a force platform. Forty obese children and adolescents (age range 8 to 18 years; 21 girls) and 40 age- and sex-matched controls performed two tests: (1) single two-legged jump, a countermovement jump for maximal height; (2) multiple one-legged hopping on the forefoot, a test of maximal force. In the single two-legged jump, obese subjects had higher absolute peak force (1.62 kN vs 1.09 kN) and peak power (2.46 kW vs 2.06 kW), but lower body weight-related peak force (2.10 vs 2.33) and lower peak power per body mass (30.9 W/kg vs 41.6 W/kg). Jump height (29.3 cm vs 37.5 cm) and maximal vertical velocity (1.92 ms(-1) vs 2.31 ms(-1)) were reduced in obese children. In multiple one-legged hopping, obese subjects had 72% and 84% higher absolute peak force on the left and right foot, respectively. However, forces relative to body weight were 24% and 23% lower in the obese group than in the control group. In conclusion, obese children and adolescents have increased muscle force and power. This partly compensates for the effect of high body weight on muscle performance.

Gait analysis using a force-measuring gangway: intrasession repeatability in healthy adults.

OBJECTIVES: The goal of the present study was to determine the repeatability of gait parameters measured by a force plate gait analysis system (Leonardo Mechanograph® GW). METHODS: Fifteen healthy adult participants walked at a self-selected speed on a 10 m long walkway. Vertical ground reaction forces were measured in the central 6 m of the walkway. Each participant performed three trials while walking barefoot and three trials while wearing shoes, each trial consisting of three 10 m walks. RESULTS: There were minimal differences between trials at each condition. All primary force, time, distance and velocity parameters had intraclass correlation coefficients above 0.90 and coefficients of variation in the order of 2% to 4%. Compared to walking barefoot, walking in shoes resulted in 14% lower maximal vertical ground reaction force, 5% longer step length and 2% higher average velocity and caused less lateral translation of the center of force. CONCLUSIONS: In this group of healthy adults, gait analysis with a force plate system produced repeatable intra-day results. The observation that barefoot and shod walking yield different results indicates that it is important to standardize test conditions.

Reproducibility of jumping mechanography in healthy children and adults.

OBJECTIVES: To describe mechanographic tests that can be performed by patients with a range of functional abilities and to assess the reproducibility of test results in healthy adults and children. METHODS: Fifteen adults and 13 children underwent two separate sessions, one week apart. Participants performed five different tests in both sessions: Multiple one-legged hopping, multiple two-legged hopping, single two-legged jump, heel-rise test, chair-rise test. All measurements were recorded with a portable force platform. RESULTS: The main outcome measures of each test (peak force relative to body weight or peak power relative to body weight, depending on the test) showed no systematic differences between Session 1 and 2 for any of the test results. Coefficients of variation for the suggested main outcome parameters ranged between 3.4% and 7.5% for multiple one-legged hopping, multiple two-legged hopping, single two-legged jump and the heel-rise test, but were higher for the chair-rise test (8.0% in adults, 15.6% in children). CONCLUSIONS: The five mechanographic tests assessed in the present study yield reproducible outcome measures in healthy subjects. It is justified to evaluate the usefulness of these tests in different patient populations.