Trabecular and cortical bone deficits are present in children and adolescents with cystic fibrosis.

Osteopenia and increased fracture rates are well-recognized in adults with CF, but neither the specific contributions of cortical and trabecular bone deficits to bone fragility nor their presence in youth with CF are well-characterized. This study sought to characterize cortical and trabecular volumetric bone mineral density (vBMD), geometry, and biomechanical competence in children with CF and determine their relationship to growth, body composition, and disease severity. Peripheral quantitative computerized tomography (pQCT) measures of total, cortical, and trabecular vBMD, cortical, muscle, and fat cross-sectional areas (CSA), periosteal and endosteal circumferences, and the polar unweighted section modulus (Zp) of the tibia were converted to age- and tibial length-adjusted Z-scores in 97 CF and 199 healthy children (aged 8-21y). Effects of body composition and pulmonary function (forced expiratory volume in 1s, FEV1) upon pQCT outcomes were determined using linear regression. Children with CF (FEV1%-predicted: 84.4+19.7) had lower weight-, height-, BMI-, and whole body lean mass (LBM)-Z and tibial length. Females with CF had lower (p<0.01) total and trabecular vBMD; cortical, muscle, and fat CSA; Zp and periosteal circumference than females in the healthy reference group. These bone differences persisted after adjustment for BMI-Z and to a great extent following adjustment for muscle CSA. Males with CF had lower (p<0.01) cortical, muscle, and fat CSA and their trabecular vBMD deficit approached significance (p=0.069). Deficits were attenuated by adjustment for BMI-Z and to a greater extent adjustment for muscle CSA-Z. The relationship between FEV1%-predicted and pQCT outcomes persisted only in males following adjustment for age and BMI-Z. The CF cohort had lower tibial muscle CSA than expected for their LBM. In this relatively healthy, young CF cohort, deficits in trabecular and multiple cortical bone parameters were present. In females, deficits were greater at older ages and were not fully explained by alterations in body composition. In males worsening pulmonary function was associated with greater deficits that was not explained by increasing age or compromised nutritional status. The occurrence of these differences in CF youth highlights the importance of instituting measures to optimize peak bone mass early in the course of CF.

Kelly A ，Schall J ，Stallings VA ，Zemel BS ... -  《-》

Bone accrual and structural changes over one year in youth with cystic fibrosis.

Pediatric bone accrual governs peak bone mass and strength. Longitudinal studies of bone health in youth with cystic fibrosis (CF) may provide insight into CF-related bone disease (CFBD), a prevalent co-morbidity in adults with CF. This one-year longitudinal study of youth with pancreatic insufficient CF, enrolled in a nutrition intervention study [n = 62 (36 M/26F)] 1) examined dual-energy x-ray absorptiometry (DXA)-defined lumbar spine (LS) and total body less head (TBLH) bone accrual and 2) compared their changes in peripheral quantitative computed tomography (pQCT) cortical and trabecular tibial bone density and geometry to those of a healthy reference group [n = 143 (68 M/75F)].Main outcome measures were 1) DXA: lumbar spine areal bone mineral density (LSaBMD) and total body less head bone mineral content (TBLH-BMC), sex- and pubertal status-specific, height velocity (HV)-adjusted or HV and lean body mass velocity (HV-LBMV)-adjusted annualized velocity-Z scores and 2) pQCT: age, sex, pubertal status and, when appropriate, tibial length adjusted Z-scores for bone architecture measures.DXA velocity-Z were compared to expected mean of 0 and correlations with clinical parameters (age, BMI-Z and FEV1%-predicted) tested. Within-subject comparisons of HV-adjusted and LBMV-HV-adjusted DXA velocity-Z were conducted in CF.pQCT Z-scores were compared between the two groups over one year using longitudinal models. Longitudinal relationships between measures of bone health and clinical parameters (age, BMI-Z and FEV1%-predicted) were examined in individuals with CF. DXA velocity-Z were higher than normal in females (p < 0.05) but not males with CF. HV-adjusted and LBMV-HV-adjusted velocity-Z did not differ for LSaBMD or TBLH-BMC.In males with CF, both HV-adjusted and LBMV-HV-adjusted LSaBMD velocity-Z scores correlated negatively with age (HV rho: -0.35; p = 0.045 and LBMV-HV rho: -0.47; p = 0.0046). In males with CF BMI-Z correlated positively with HV-adjusted LSaBMD velocity-Z (rho: 0.37; p = 0.034), but this relationship did not persist for LBMV-HV (rho: 0.14; p = 0.42). In females with CF, no correlations between LSaBMD velocity-Z scores and age or BMI-Z were found (all p > 0.05). No correlations between LSaBMD velocity-Z scores and FEV1%-predicted were seen in either sex (all p > 0.12). TBLH-BMC velocity Z-scores were not correlated with clinical parameters in either sex (all p > 0.1).At baseline, multiple pQCT parameters were lower in CF (p < 0.05). pQCT Z-scores did not differ between baseline and one-year in either CF or reference group. In a longitudinal model comparing pQCT-Z changes in CF and reference, multiple pQCT-Z outcomes remained lower in CF, but the changes in parameters did not differ in CF vs reference (all p > 0.26). Lower pQCT outcomes in CF were largely restricted to males (CF group*female sex interaction beta coefficients > 0). In this combined longitudinal model, of both CF and reference, BMI-Z was positively associated with pQCT-Z parameters(p < 0.001).Multiple pQCT-Z outcomes positively correlated with both BMI-Z and FEV1%-predicted in males with CF, and with FEV1%-predicted in females with CF (p < 0.05). Age was negatively associated with section modulus (p = 0.001) in males and with cortical density-Z in females (p < 0.001). With improved longevity, bone health in CF is of increasing importance. On average, bone accrual was preserved in youth with CF, and while deficits in bone geometry and strength were found, these deficits did not worsen over the one-year study. Lower LS bone accrual with increasing age suggests emerging adulthood is a period of vulnerability in CF while the role of LBM in bone health is underscored by the lack of relationship between LBMV-adjusted accrual and BMI. These findings may be useful in targeting screening practices and interventions.

Bass RM ，Zemel BS ，Stallings VA ，Leonard MB ，Tsao J ，Kelly A ... -  《-》

Cystic fibrosis-related bone disease in children: Examination of peripheral quantitative computed tomography (pQCT) data.

The investigation of skeletal health data beyond dual X-ray absorptiometry (DXA) is limited in young individuals with CF. We assessed volumetric bone mineral densities (BMD), and bone and muscle parameters using peripheral quantitative computed tomography (pQCT) in individuals with CF and controls, 7.00-17.99 years. Peripheral QCT (XCT 3000, Stratec) measurements were made in 53 individuals with CF and 53 controls. Bone mineral content (BMC), total volumetric BMD (vBMD) and cross sectional area (CSA) of the bone were measured at the 4% and 66% sites of the non-dominant tibia and radius. Additionally, trabecular vBMD and bone strength index (BSIc) were measured at the 4% sites, and cortical vBMD, muscle CSA (mCSA) and strength strain index (SSI) were measured at the 66% sites. Pre-pubertal males with CF had greater trabecular vBMD (p=0.01) and total vBMD (p=0.00) at 4% tibia, and greater total vBMD (p=0.02) at 4% radius. Pre-pubertal females with CF had greater total vBMD at 66% tibia (p=0.02) and radius (p=0.04), and cortical vBMD (p=0.04) at the radius. At puberty, the CF cohort had less BMC at 4% tibia (males, p=0.02; females, p=0.01), and smaller mCSA at 66% tibia (males, p=0.02; females, p=0.01). Pubertal CF females had a smaller bone CSA (p=0.01) at 4% tibia, and lower bone strength (SSI) at the tibia (p=0.00) and radius (p=0.05) sites. Bone strength parameters were not compromised prior to puberty in this CF cohort. At puberty, the bone phenotype changed for this CF cohort, showing several deficits compared to the controls. However, bone strength was adapting to the mechanical demands of the muscle. Altered bone parameters and their implications for lowered bone strength with increased age may be greatly influenced by: the CF cohort remaining smaller for age and/or a reduced bone strain, secondary to reduced muscle force.

Brookes DS ，Briody JN ，Munns CF ，Davies PS ，Hill RJ ... -  《-》

Adults with cystic fibrosis have deficits in bone structure and strength at the distal tibia despite similar size and measuring standard and relative sites.

Individuals with cystic fibrosis (CF) have lower bone mineral density (BMD) by DXA and are at higher risk of fracture than healthy controls. However, the 2-dimensional measurement of areal BMD (aBMD) provided by DXA is influenced by bone size and the true extent of the bone deficit is unclear. Our objective was to use high-resolution peripheral quantitative computed tomography (HR-pQCT) and individual trabecula segmentation (ITS) analysis to compare volumetric BMD (vBMD), microarchitecture and estimated strength at the distal radius and tibia in 26 young adults with CF and 26 controls matched for age, gender, and race. To assess the effect of limb length and minimize the confounding effects of size on HR-pQCT outcomes, we scanned participants at both the standard fixed HR-pQCT measurement sites and at a subject-specific relative site that varied according to limb length. CF participants did not differ significantly in age, height, weight, or BMI from controls. Ulnar and tibial lengths were 9mm shorter in CF patients, though differences were not significant. CF patients had significantly lower BMI-adjusted aBMD by DXA at the lumbar spine (8.9%, p<0.01), total hip (11.5%, p<0.01) and femoral neck (14.5%, p<0.01), but not at the forearm. At the fixed radius site, thickness of trabecular plates and torsional stiffness were significantly lower in CF participants than controls. At the relative radius site, only torsional stiffness was significantly lower in CF participants. At the tibia, total, trabecular and cortical vBMD were significantly lower at both fixed and relative sites in CF participants, with fewer, more widely-spaced trabecular plates, lower trabecular connectivity, and lower axial and torsional stiffness. Our results confirm that aBMD is lower at the spine and hip in young adults with CF, independent of BMI and body size. We also conclude that vBMD and stiffness are lower at the weight-bearing tibia. The pathogenesis of these differences in bone density and strength at the tibia appear to be related to trabecular drop-out and reduced trabecular connectivity and to be independent of differences in limb length, as assessed by scanning participants at both standard and relative sites. We concluded that significant deficits in bone structure and strength persist in young adults with CF, despite advances in care that permit them to attain relatively normal height and weight.

Nishiyama KK ，Agarwal S ，Kepley A ，Rosete F ，Hu Y ，Guo XE ，Keating CL ，DiMango EA ，Shane E ... -  《-》

Development of musculoskeletal deficits in children with cystic fibrosis in later childhood.

Cystic fibrosis (CF) is a genetic condition primarily affecting the respiratory system, with the associated progressive lung damage and loss of function resulting in reduced lifespan. Bone health is also impaired in individuals with CF, leading to much higher fracture risk even in adolescence. However, the development of these deficits during growth and the relative contributions of puberty, body size and muscular loading remain somewhat unexplored. We therefore recruited 25 children with CF (10 girls, mean age 11.3 ± 2.9y) and 147 children without CF (75 girls, mean age 12.4 ± 2.6y). Bone characteristics were assessed using peripheral quantitative computed tomography (pQCT) at 4 % and 66 % distal-proximal tibia. Muscle cross-sectional area (CSA) and density (an indicator of muscle quality) were also assessed at the latter site. Tibial bone microstructure was assessed using high-resolution pQCT (HR-pQCT) at 8 % distal-proximal tibial length. In addition, peak jump power and hop force were measured using jumping mechanography. Group-by-age interactions and group differences in bone and muscle characteristics were examined using multiple linear regression, adjusted for age, sex and pubertal status and in additional models, height and muscle force. In initial models group-by-age interactions were evident for distal tibial total bone mineral content (BMC) and trabecular volumetric bone mineral density (vBMD), with a lower rate of age-related accrual evident in children with CF. In assessments of distal tibial microstructure, similar patterns were observed for trabecular number and thickness, and cortical CSA. In the tibial shaft, group-by-age interactions indicating slower growth in CF were evident for total BMC and cortical CSA, whilst age-independent deficits in CF were observed for several other variables. Peak jump power and hop force also exhibited similar interactions. Group-by-age interactions for bone were partially attenuated at the distal tibia and fully attenuated at the tibial shaft by adjustment for muscle force. These results suggest that bone and muscle deficits in children with CF develop throughout later childhood, independent of differences in pubertal stage and body size. These diverging growth patterns appear to be mediated by differences in muscle function, particularly for bone characteristics in the tibial shaft. Given the high fracture risk in this population from childhood onwards, development of interventions to improve bone health would be of substantial clinical value.

Ireland A ，Riddell A ，Colombo A ，Ross-Russell R ，Prentice A ，Ward KA ... -  《-》