Rachel J. Wetzsteon

Effects of Sex, Race, and Puberty on Cortical Bone and the Functional Muscle Bone Unit in Children, Adolescents, and Young Adults

CONTEXT Sex and race differences in bone development are associated with differences in growth, maturation, and body composition. OBJECTIVE The aim of the study was to determine the independent effects of sex, race, and puberty on cortical bone development and muscle-bone relations in children and young adults. DESIGN AND PARTICIPANTS We conducted a cross-sectional study of 665 healthy participants (310 male, 306 black) ages 5-35 yr. OUTCOMES Tibia peripheral quantitative computed tomography measures were made of cortical bone mineral content (BMC) and bone mineral density (BMD), periosteal (Peri) and endosteal circumferences, section modulus (Zp), and muscle area. Regression models were adjusted for tibia length, age, race, sex, and Tanner stage. RESULTS All cortical measures were greater in blacks than whites (all P < or = 0.001) in Tanner stages 1-4; however, differences in BMC, Peri, and Zp were negligible in Tanner stage 5 (all interactions, P < 0.01). Cortical BMC, Peri, and Zp were lower in females than males in all Tanner stages (all P < 0.001), and the sex differences in Peri and Zp were greater in Tanner stage 5 (interaction, P < 0.02). Cortical BMD was greater (P < 0.0001) and endosteal circumference was lower (P < 0.01) in Tanner 3-5 females, compared with males. Adjustment for muscle area attenuated but did not eliminate sex and race differences in cortical dimensions. Associations between muscle and bone outcomes did not differ according to sex or race. CONCLUSION 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.

Bone Structure and Volumetric BMD in Overweight Children: A Longitudinal Study†

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 = 302) or OW (n = 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 ≤ 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 = 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.

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.

Association of Chronic Kidney Disease with Muscle Deficits in 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: -0.20, 0.24]; P = 0.8), but were lower in CKD stages 4 to 5 (-0.41 [-0.66, -0.15]; P = 0.002) and dialysis (-1.03 [-1.33, -0.74]; P < 0.0001). Among CKD participants, growth hormone therapy associated with greater leg LM Z-score (0.58 [0.03, 1.13]; P = 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.

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.

Volumetric bone mineral density and bone structure in childhood chronic kidney disease

Chronic kidney disease (CKD) is associated with increased fracture risk and skeletal deformities. The impact of CKD on volumetric bone mineral density (vBMD) and cortical dimensions during growth is unknown. Tibia quantitative computed tomographic scans were obtained in 156 children with CKD [69 stages 2 to 3, 51 stages 4 to 5, and 36 stage 5D (dialysis)] and 831 healthy participants aged 5 to 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 a higher TrabBMD Z‐score in younger participants (p < .001) compared with healthy children; this association was attenuated in older participants (interaction p < .001). Mean CortArea Z‐score was lower (p < .01) in CKD 4–5 [−0.49, 95% confidence interval (CI) −0.80, −0.18)] and CKD 5D (−0.49, 95% CI −0.83, −0.15) compared with healthy children. Among CKD participants, parathyroid hormone (PTH) levels were positively associated with TrabBMD Z‐score (p < .01), and this association was significantly attenuated in older participants (interaction p < .05). Higher levels of PTH and biomarkers of bone formation (bone‐specific alkaline phosphatase) and resorption (serum C‐terminal telopeptide of type 1 collagen) were associated with lower CortBMD and CortArea Z‐scores and greater EndoC Z‐score (r = 0.18–0.36, all p ≤ .02). CortBMD Z‐score was significantly lower in CKD participants with PTH levels above versus below the upper limit of the Kidney Disease Outcome Quality Initiative (KDOQI) CKD stage‐specific target range: −0.46 ± 1.29 versus 0.12 ± 1.14 (p < .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.

Vitamin D deficiency is common in children and adolescents with chronic kidney disease

Here we determined if vitamin D deficiency is more common in children with chronic kidney disease compared to healthy children. In addition, we sought to identify disease-specific risk factors for this deficiency, as well as its metabolic consequences. We found that nearly half of 182 patients (ages 5 to 21) with kidney disease (stages 2 to 5) and a third of age-matched 276 healthy children were 25-hydroxyvitamin D deficient (<20 ng/ml). The risk of deficiency was significantly greater in advanced disease. Focal segmental glomerulosclerosis and low albumin were significantly associated with lower 25-hydroxyvitamin D, which, in turn, was associated with significantly higher intact parathyroid hormone levels. We found that 25-hydroxyvitamin D levels were positively associated with 1,25-dihydroxyvitamin D, the relationship being greatest in advanced disease (significant interaction), and inversely related to those of inflammatory markers C-reactive protein and IL-6. The association with C-reactive protein persisted when adjusted for the severity of kidney disease. Thus, lower 25-hydroxyvitamin D may contribute to hyperparathyroidism, inflammation, and lower 1,25-dihydroxyvitamin D in children and adolescents, especially those with advanced kidney disease.

Glucocorticoid effects on changes in bone mineral density and cortical structure in childhood nephrotic syndrome.

The impact of glucocorticoids (GC) on skeletal development has not been established. The objective of this study was to examine changes in volumetric bone mineral density (vBMD) and cortical structure over 1 year in childhood nephrotic syndrome (NS) and to identify associations with concurrent GC exposure and growth. Fifty‐six NS participants, aged 5 to 21 years, were enrolled a median of 4.3 (0.5 to 8.1) years after diagnosis. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained at enrollment and 6 and 12 months later. Sex, race, and age‐specific Z‐scores were generated for trabecular vBMD (TrabBMD‐Z), cortical vBMD (CortBMD‐Z), and cortical area (CortArea‐Z) based on >650 reference participants. CortArea‐Z was further adjusted for tibia length‐for‐age Z‐score. Quasi‐least squares regression was used to identify determinants of changes in pQCT Z‐scores. At enrollment, mean TrabBMD‐Z (−0.54 ± 1.32) was significantly lower (p = 0.0001) and CortBMD‐Z (0.73 ± 1.16, p < 0.0001) and CortArea‐Z (0.27 ± 0.91, p = 0.03) significantly greater in NS versus reference participants, as previously described. Forty‐eight (86%) participants were treated with GC over the study interval (median dose 0.29 mg/kg/day). On average, TrabBMD‐Z and CortBMD‐Z did not change significantly over the study interval; however, CortArea‐Z decreased (p = 0.003). Greater GC dose (p < 0.001), lesser increases in tibia length (p < 0.001), and lesser increases in CortArea‐Z (p = 0.003) were independently associated with greater increases in CortBMD‐Z. Greater increases in tibia length were associated with greater declines in CortArea‐Z (p < 0.01); this association was absent in reference participants (interaction p < 0.02). In conclusion, GC therapy was associated with increases in CortBMD‐Z, potentially related to suppressed bone formation and greater secondary mineralization. Conversely, greater growth and expansion of CortArea‐Z (ie, new bone formation) were associated with declines in CortBMD‐Z. Greater linear growth was associated with impaired expansion of cortical area in NS. Studies are needed to determine the fracture implications of these findings.

Changes in bone structure and the muscle–bone unit in children with chronic kidney disease

The impact of pediatric chronic kidney disease (CKD) on acquisition of volumetric bone mineral density (BMD) and cortical dimensions is lacking. To address this issue we obtained tibia quantitative computed tomography scans from 103 patients age 5-21 years with CKD (26 on dialysis) at baseline and 12 months later. Gender, ethnicity, tibia length and/or age-specific Z-scores were generated for trabecular and cortical BMD, cortical area, periosteal and endosteal circumference, and muscle area based on over 700 reference subjects. Muscle area, cortical area, and periosteal and endosteal Z-scores were significantly lower at baseline compared to the reference cohort. Cortical BMD, cortical area and periosteal Z-scores all exhibited a significant further decrease over 12 months. Higher parathyroid hormone levels were associated with significantly greater increases in trabecular BMD and decreases in cortical BMD in younger patients (significant interaction terms for trabecular BMD and cortical BMD). The estimated GFR was not associated with changes in BMD Z-scores independent of parathyroid hormone. Changes in muscle and cortical area were significantly and positively associated in control subjects but not in CKD patients. Thus, children and adolescents with CKD have progressive cortical bone deficits related to secondary hyperparathyroidism and potential impairment of the functional muscle-bone unit. Interventions are needed to enhance bone accrual in childhood-onset CKD.

Bone Density and Cortical Structure after Pediatric Renal Transplantation

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.