Determinants of changes in linear growth and body composition in incident pediatric Crohn's disease.

BACKGROUND & AIMS: Pediatric Crohn's disease (CD) is associated with growth, lean mass (LM), and fat mass (FM) deficits. This study assessed and identified determinants of changes in height and body composition in children with CD following. METHODS: Whole-body LM and FM were assessed using dual-energy x-ray absorptiometry in 78 CD subjects at diagnosis, 6, 12, and a median of 43 months (range, 24-63) later. Race- and sex-specific Z scores for lean mass (LM-ht-Z) and fat mass (FM-ht-Z) relative to height were derived using reference data in >900 controls. Serum cytokines and growth factors were measured, and quasi-least squares regression was used to identify determinants of changes in height and body composition. RESULTS: LM-ht-Z and FM-ht-Z (both P<.005) improved significantly after diagnosis; however, female patients had persistent LM deficits vs controls (-0.50+/-1.02, P<.05). Serum interleukin-6, tumor necrosis factor-alpha, and lipopolysaccharide binding protein decreased significantly (all P<.001). Greater increases in LM-ht-Z were associated with infliximab therapy (P<.05), increases in albumin (P<.001) and decreases in erythrocyte sedimentation rate (P<.05), interleukin-6 (P<.005), and lipopolysaccharide binding protein (P<.05). Greater increases in FM-ht-Z were associated with glucocorticoid, methotrexate, and infliximab therapy, and increases in albumin (P<.05) and growth hormone binding protein (P<.05). Overall, height-Z did not improve; however, greater increases in insulin-like growth factor-1 (P<.05) and decreases in tumor necrosis factor-alpha (P<.05), interleukin-6 (P<.05), and lipopolysaccharide binding protein (P<.05) levels were associated with increases in height-Z. CONCLUSIONS: Immune-mediated mechanisms contribute to growth and body composition deficits in CD. Therapies should target these deficits.

Longitudinal assessment of bone density and structure in an incident cohort of children with Crohn's disease.

BACKGROUND & AIMS: The impact of childhood Crohn's disease (CD) on volumetric bone mineral density (vBMD), bone structure, and muscle mass have not been established. The objective of this longitudinal study was to assess musculoskeletal outcomes in an incident cohort of children with CD using peripheral quantitative computed tomography (pQCT). METHODS: Tibia pQCT was performed in 78 CD subjects (ages, 5-18 years) at diagnosis and in 67 over the subsequent year. pQCT outcomes were converted to sex- and race-specific z scores based on reference data in over 650 controls. Multivariable linear regression models identified factors associated with changes in bone outcomes. RESULTS: At diagnosis, CD subjects had significant deficits in trabecular vBMD (z score, -1.32+/-1.32; P< .001), cortical section modulus (a measure of bone geometry and strength) (z score, -0.44+/-1.11; P< .01), and muscle (z score, -0.96+/-1.02; P< .001) compared with controls. Over the first 6 months, trabecular vBMD and muscle z scores improved significantly (both, P< .001); however, section modulus worsened (P= .0001), and all 3 parameters remained low after 1 year. Increases in muscle z scores were associated with less severe declines in cortical section modulus z scores. Improvements in trabecular vBMD z scores were greater in prepubertal subjects. Glucocorticoids were associated with increases in cortical vBMD. CONCLUSIONS: Substantial deficits in trabecular vBMD, cortical bone geometry, and muscle were observed at CD diagnosis. Trabecular vBMD improved incompletely; however, cortical deficits progressed despite improvements in muscle. Glucocorticoids were not associated with bone loss. Therapies to improve bone accrual in childhood CD are needed.

Mechanical loads and cortical bone geometry in healthy children and young adults.

Muscle and bone form a functional unit. While muscle size is a useful surrogate of mechanical load on bone, the independent contributions to bone strength of muscle force, muscle size, gravitational load (body weight), and physical activity have not been assessed. Three hundred twenty-one healthy participants (32% black, 47% male), aged 5-35 years were assessed. Peak dorsiflexion muscle torque (ft-lbs) of the ankle was assessed using isometric dynamometry. Tibia peripheral quantitative computed tomography measures included polar section modulus (Zp; mm(3)), periosteal and endosteal circumference (mm), cortical area (mm(2)), and volumetric bone mineral density (vBMD; mg/cm(3)) at the 38% site, and muscle cross-sectional area (CSA; mm(2)), at the 66% site. Physical activity (average hours per week) was assessed by questionnaire. Log linear regression was used to assess determinants of muscle specific force (MSF; torque relative to muscle CSA) and Zp adjusted for age and tibia length. MSF was greater in blacks than whites (p<0.05) and lower in females than males (p<0.001). Zp was greater in blacks than whites (p=0.002) in Tanner stages 1-4, but the difference was attenuated in Tanner 5 (interaction, p=0.02); R(2)=0.87. Muscle CSA, muscle torque, body weight, and physical activity were added to the model and each load covariate was independently and significantly (all, p<0.02) associated with Zp (R(2)=0.92), periosteal circumference, and cortical area. Inclusion of these measures attenuated but did not eliminate the significant race differences. Only muscle CSA was positively associated with endosteal circumference, while none of the load covariates were associated with vBMD. In conclusion, bone geometry is associated with several factors that define the mechanical load on bone, independent of age, tibia length, maturation, race, and sex. Race differences in Zp were not explained by these measures of mechanical load. Given that inclusion of muscle torque, body weight, and physical activity resulted in a nominal increase in the R(2), muscle size is an adequate surrogate for the mechanical load on bone in healthy participants.

Divergent effects of glucocorticoids on cortical and trabecular compartment BMD in childhood nephrotic syndrome.

Glucocorticoid (GC) effects on skeletal development have not been established. The objective of this pQCT study was to assess volumetric BMD (vBMD) and cortical dimensions in childhood steroid-sensitive nephrotic syndrome (SSNS), a disorder with minimal independent deleterious skeletal effects. Tibia pQCT was used to assess trabecular and cortical vBMD, cortical dimensions, and muscle area in 55 SSNS (age, 5-19 yr) and >650 control participants. Race-, sex-, and age-, or tibia length-specific Z-scores were generated for pQCT outcomes. Bone biomarkers included bone-specific alkaline phosphatase and urinary deoxypyridinoline. SSNS participants had lower height Z-scores (p < 0.0001) compared with controls. In SSNS, Z-scores for cortical area were greater (+0.37; 95% CI = 0.09, 0.66; p = 0.01), for cortical vBMD were greater (+1.17; 95% CI = 0.89, 1.45; p < 0.0001), and for trabecular vBMD were lower (-0.60; 95% CI, = -0.89, -0.31; p < 0.0001) compared with controls. Muscle area (+0.34; 95% CI = 0.08, 0.61; p = 0.01) and fat area (+0.56; 95% CI = 0.27, 0.84; p < 0.001) Z-scores were greater in SSNS, and adjustment for muscle area eliminated the greater cortical area in SSNS. Bone formation and resorption biomarkers were significantly and inversely associated with cortical vBMD in SSNS and controls and were significantly lower in the 34 SSNS participants taking GCs at the time of the study compared with controls. In conclusion, GCs in SSNS were associated with significantly greater cortical vBMD and cortical area and lower trabecular vBMD, with evidence of low bone turnover. Lower bone biomarkers were associated with greater cortical vBMD. Studies are needed to determine the fracture implications of these varied effects.