No abstract

Sex and race were associated with maturation-specific differences in cortical BMD and dimensions that were not fully explained by differences in bone length or muscle. No race or sex differences in the functional muscle bone unit were identified.

ABSTRACT:The effect of excess body fat on bone strength accrual is not well understood. Therefore, we assessed bone measures in healthy weight (HW) and overweight (OW) children. Children (9-11 yr) were classified as HW (n ‫ס‬ 302) or OW (n ‫ס‬ 143) based on body mass index. We assessed total (ToD) and cortical (CoD) volumetric BMD and bone area, estimates of bone strength (bone strength index [BSI]; stress-strain index [SSIp]), and muscle cross-sectional area (CSA) at the distal (8%), midshaft (50%), and proximal (66%) tibia by pQCT. We used analysis of covariance to compare bone outcomes at baseline and change over 16 mo. At baseline, all bone measures were significantly greater in OW compared with HW children (+4-15%; p Յ 0.001), with the exception of CoD at the 50% and 66% sites. Over 16 mo, ToA increased more in the OW children, whereas there was no difference for change in BSI or ToD between groups at the distal tibia. At the tibial midshaft, SSIp was similar between groups at baseline when adjusted for muscle CSA, but low when adjusted for body fat in the OW group. At both sites, bone strength increased more in OW because of a greater increase in bone area. Changes in SSIp were associated with changes in lean mass (r ‫ס‬ 0.70, p < 0.001) but not fat mass. In conclusion, although OW children seem to be at an advantage in terms of absolute bone strength, bone strength did not adapt to excess body fat. Rather, bone strength was adapted to the greater muscle area in OW children.

The effect of chronic kidney disease (CKD) on muscle mass in children, independent of poor growth and delayed maturation, is not well understood. We sought to characterize whole body and regional lean mass (LM) and fat mass (FM) in children and adolescents with CKD and to identify correlates of LM deficits in CKD. We estimated LM and FM from dual energy x-ray absorptiometry scans in 143 children with CKD and 958 controls at two pediatric centers. We expressed whole body, trunk, and leg values of LM and FM as Z-scores relative to height, sitting height, and leg length, respectively, using the controls as the reference. We used multivariable regression models to compare Z-scores in CKD and controls, adjusted for age and maturation, and to identify correlates of LM Z-scores in CKD. Greater CKD severity associated with greater leg LM deficits. Compared with controls, leg LM Z-scores were similar in CKD stages 2 to 3 (difference: 0.02 [95% CI: Ϫ0.20, 0.24]; P ϭ 0.8), but were lower in CKD stages 4 to 5 (Ϫ0.41 [Ϫ0.66, Ϫ0.15]; P ϭ 0.002) and dialysis (Ϫ1.03 [Ϫ1.33, Ϫ0.74]; P Ͻ 0.0001). Among CKD participants, growth hormone therapy associated with greater leg LM Z-score (0.58 [0.03, 1.13]; P ϭ 0.04), adjusted for CKD severity. Serum albumin, bicarbonate, and markers of inflammation did not associate with LM Z-scores. CKD associated with greater trunk LM and FM, variable whole body LM, and normal leg FM, compared with controls. In conclusion, advanced CKD associates with significant deficits in leg lean mass, indicating skeletal muscle wasting. These data call for prospective studies of interventions to improve muscle mass among children with CKD.

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.

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. 321 healthy participants (32% black, 47% male), age 5 to 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, mm3), periosteal and endosteal circumference (mm), cortical area (mm2), and volumetric bone mineral density (vBMD, mg/cm3) at the 38% site, and muscle cross-sectional area (CSA, mm2) at the 66% site. Physical activity (average hours /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), R2 = 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 (R2 = 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 R2, muscle size is an adequate surrogate for the mechanical load on bone in healthy participants.

The impact of renal transplantation on trabecular and cortical bone mineral density (BMD) and cortical structure is unknown. We obtained quantitative computed tomography scans of the tibia in pediatric renal transplant recipients at transplantation and 3, 6, and 12 months; 58 recipients completed at least two visits. We used more than 700 reference participants to generate Z-scores for trabecular BMD, cortical BMD, section modulus (a summary measure of cortical dimensions and strength), and muscle and fat area. At baseline, compared with reference participants, renal transplant recipients had significantly lower mean section modulus and muscle area; trabecular BMD was significantly greater than reference participants only in transplant recipients younger than 13 years. After transplantation, trabecular BMD decreased significantly in association with greater glucocorticoid exposure. Cortical BMD increased significantly in association with greater glucocorticoid exposure and greater decreases in parathyroid hormone levels. Muscle and fat area both increased significantly, but section modulus did not improve. At 12 months, transplantation associated with significantly lower section modulus and greater fat area compared with reference participants. Muscle area and cortical BMD did not differ significantly between transplant recipients and reference participants. Trabecular BMD was no longer significantly elevated in younger recipients and was low in older recipients. Pediatric renal transplant associated with persistent deficits in section modulus, despite recovery of muscle, and low trabecular BMD in older recipients. Future studies should determine the implications of these data on fracture risk and identify strategies to improve bone density and structure. During childhood and adolescence, skeletal development is characterized by increases in trabecular and cortical bone mineral density (BMD) and cortical dimensions. 1 Children with CKD have numerous risk factors for impaired bone acquisition, including growth failure, delayed puberty, malnutrition, acidosis, vitamin D deficiency, muscle deficits, and secondary hyperparathyroidism. Successful renal transplantation corrects many of the underlying abnormalities contributing to bone deficits in childhood CKD. However, immunosuppressive therapies and persistent hyperparathyroidism may impair recovery of bone structure and strength. The risk of fracture among adult renal transplant recipients increases in the months after transplantation and then gradually declines. 2 The

Chronic kidney disease (CKD) is associated with increased fracture risk and skeletal deformities. The impact of CKD on volumetric bone mineral density (BMD) and cortical dimensions during growth is unknown. Tibia quantitative computed tomography scans were obtained in 156 children with CKD [69 stage 2–3, 51 stage 4–5, and 36 stage 5D (dialysis)] and 831 healthy participants, ages 5–21 years. Sex-, race-, and age- or tibia length-specific Z-scores were generated for trabecular BMD (TrabBMD), cortical BMD (CortBMD), cortical area (CortArea) and endosteal circumference (EndoC). Greater CKD severity was associated with higher TrabBMD-Z in younger participants (p < 0.001), compared with healthy children; this association was attenuated in older participants (interaction p < 0.001). Mean CortArea-Z was lower (p < 0.01) in CKD 4–5 [−0.49 (95% C.I. −0.80, −0.18)] and 5D [−0.49 (−0.83, −0.15)], compared with healthy children. Among CKD participants, parathyroid hormone (PTH) levels were positively associated with TrabBMD-Z (p < 0.01), and this association was significantly attenuated in older participants (interaction p < 0.05). Higher levels of PTH and biomarkers of bone formation (bone-specific alkaline phosphatase) and resorption (β-CTX) were associated with lower CortBMD-Z and CortArea-Z, and greater EndoC-Z (r = 0.18–0.36; all p ≤ 0.02). CortBMD-Z was significantly lower in CKD participants with PTH levels above vs. below the upper limit of the KDOQI CKD stage-specific target range: −0.46 ± 1.29 vs. 0.12 ± 1.14, p < 0.01. In summary, childhood CKD and secondary hyperparathyroidism were associated with significant reductions in cortical area and CortBMD, and greater TrabBMD in younger children. Future studies are needed to establish the fracture implications of these alterations and to determine if cortical and trabecular abnormalities are reversible.