Rita Herskovitz

Longitudinal Assessment of Bone Density and Structure in an Incident Cohort of Children With Crohn's Disease

BACKGROUND & AIMS The impact of childhood Crohns 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.

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.

Long-term inflammation and glucocorticoid therapy impair skeletal modeling during growth in childhood Crohn disease.

CONTEXT Glucocorticoids and inflammation inhibit bone formation; however, the impact on skeletal modeling is unknown. OBJECTIVES The objectives of the study were to examine changes in bone mineral density (BMD) and cortical structure after Crohn disease (CD) diagnosis and identify associations with growth, glucocorticoids, and disease activity. DESIGN/PARTICIPANTS This was a prospective cohort study among 76 CD participants, aged 5-21 years. Tibia quantitative computed tomography trabecular BMD and cortical dimensions were obtained at diagnosis and 6 and 12 and a median of 42 months later; 51 completed the final visit. OUTCOMES Sex, race, and age-specific Z-scores were generated for outcomes based on more than 650 reference participants, and cortical dimension Z-scores were further adjusted for tibia length. Generalized estimating equations were used to model changes in Z-scores. RESULTS Disease activity improved over the study interval (P < .001). Trabecular BMD Z-scores improved over the first 6 months; increases were associated with improved disease activity (P < .001), younger age (P = .005), and increases in vitamin D levels (P = .02). Greater increases in tibia length were associated with greater increases in cortical area Z-scores (P < .001). Greater glucocorticoid doses and disease activity were significantly associated with failure to accrue cortical area and were more pronounced with greater linear growth (interaction P < .05). Mean (±SD) trabecular BMD (-1.0 ± 1.21) and cortical area (-0.57 ± 1.10) Z-scores at the final visit were significantly reduced. CONCLUSIONS CD was associated with persistent deficits in trabecular BMD, although younger participants demonstrated a greater potential for recovery. In addition, greater linear growth was associated with a greater recovery of cortical dimensions, especially among participants with less glucocorticoid exposure and inflammation. These data suggest that younger age and concurrent growth provide a window of opportunity for skeletal recovery.

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.

Improvements in Bone Density and Structure during Anti-TNF-α Therapy in Pediatric Crohn's Disease.

CONTEXT Pediatric Crohns Disease (CD) is associated with deficits in trabecular bone mineral density (BMD) and cortical structure, potentially related to TNF-α effects to decrease bone formation and promote bone resorption. OBJECTIVE This study aimed to examine changes in bone density and structure in children and adolescents with CD following initiation of anti-TNF-α therapy. DESIGN AND PARTICIPANTS Participants (n = 74; age 5-21 years) with CD completed a 12-month prospective cohort study. MAIN OUTCOME MEASURES Tibia peripheral quantitative computed tomography scans were obtained at initiation of anti-TNF-α therapy and 12 months later. Musculoskeletal outcomes were expressed as sex-and race-specific z scores relative to age, based on >650 reference participants. RESULTS At baseline, CD participants had lower height, trabecular BMD, cortical area (due to smaller periosteal and larger endocortical circumferences), and muscle area z scores, compared with reference participants (all P < .01). Pediatric CD activity index decreased during the 10-week induction (P < .001), in association with subsequent gains in height, trabecular BMD, cortical area (due to recovery of endocortical bone), and muscle area z scores over 12 months (height P < .05; others P < .001). Bone-specific alkaline phosphatase levels, a biomarker of bone formation, increased a median of 75% (P < .001) during induction with associated 12-month improvements in trabecular BMD and cortical area z scores (both P < .001). Younger age was associated with greater increases in trabecular BMD z scores (P < .001) and greater linear growth with greater recovery of cortical area (P < .001). CONCLUSIONS Anti-TNF-α therapy was associated with improvements in trabecular BMD and cortical structure. Improvements were greater in younger and growing participants, suggesting a window of opportunity for treatment of bone deficits.

Changes in vitamin D-related mineral metabolism after induction with anti-tumor necrosis factor-α therapy in Crohn's disease.

CONTEXT Preclinical studies suggest that TNF-α suppresses PTH synthesis, inhibits renal 1α-hydroxylase activity, and impairs fibroblast growth factor 23 (FGF23) degradation. The impact of inflammation on vitamin D and mineral metabolism has not been well-characterized in Crohns disease (CD). OBJECTIVE The objective of the study was to assess short-term changes in vitamin D-related mineral metabolism in CD after anti-TNF-α induction therapy. DESIGN/PARTICIPANTS Eighty-seven CD participants, aged 5-39 years, were assessed at the initiation of anti-TNF-α therapy and 10 weeks later. OUTCOMES Indices of clinical disease activity and serum concentrations of vitamin D metabolites, vitamin D-binding protein (DBP), calcium, PTH, FGF23, IL-6, and TNF-α were measured at each visit. A multivariable generalized estimating equation (GEE) regression analysis was used to examine the correlates of PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations at each visit. RESULTS After anti-TNF-α therapy, cytokines and inflammatory markers [IL-6, TNF-α, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)] concentrations decreased (all P < .0001), and PTH and 1,25(OH)2D concentrations increased (median 21 vs 30 pg/mL, P < .0001, and median 41.7 vs 48.1 pg/mL, P = .014, respectively). Levels of 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D, DBP, and FGF23 did not change. In GEE analyses, higher IL-6, TNF-α, ESR, and CRP were associated with lower PTH concentrations (all P < .001), adjusted for corrected calcium and 25(OH)D levels. Higher PTH was associated with higher 1,25(OH)2D concentrations (P < .001) at each visit, independent of 25(OH)D concentrations. Higher levels of all inflammatory markers were associated with lower 1,25(OH)2D concentrations (all P < .05). However, when PTH was added to these models, the inflammatory markers (with the exception of CRP) were no longer significantly associated with 1,25(OH)2D. CONCLUSIONS Greater inflammation was associated with lower PTH and 1,25(OH)2D concentrations. After anti-TNF-α induction, PTH and 1,25(OH)2D concentrations increased without concomitant changes in 25(OH)D and FGF23, consistent with effects of inflammation on PTH and thereby renal conversion of 25(OH)D to 1,25(OH)2D.

Muscle Torque Relative to Cross-Sectional Area and the Functional Muscle-Bone Unit in Children and Adolescents with Chronic Disease

Measures of muscle mass or size are often used as surrogates of forces acting on bone. However, chronic diseases may be associated with abnormal muscle force relative to muscle size. The muscle‐bone unit was examined in 64 children and adolescents with new‐onset Crohns disease (CD), 54 with chronic kidney disease (CKD), 51 treated with glucocorticoids for nephrotic syndrome (NS), and 264 healthy controls. Muscle torque was assessed by isometric ankle dynamometry. Calf muscle cross‐sectional area (CSA) and tibia cortical section modulus (Zp) were assessed by quantitative CT. Log‐linear regression was used to determine the relations among muscle CSA, muscle torque, and Zp, adjusted for tibia length, age, Tanner stage, sex, and race. Muscle CSA and muscle torque‐relative‐to‐muscle CSA were significantly lower than controls in advanced CKD (CSA −8.7%, p = 0.01; torque −22.9%, p < 0.001) and moderate‐to‐severe CD (CSA −14.1%, p < 0.001; torque −7.6%, p = 0.05), but not in NS. Zp was 11.5% lower in advanced CKD (p = 0.005) compared to controls, and this deficit was attenuated to 6.7% (p = 0.05) with adjustment for muscle CSA. With additional adjustment for muscle torque and body weight, Zp was 5.9% lower and the difference with controls was no longer significant (p = 0.09). In participants with moderate‐to‐severe CD, Zp was 6.8% greater than predicted (p = 0.01) given muscle CSA and torque deficits (R2 = 0.92), likely due to acute muscle loss in newly‐diagnosed patients. Zp did not differ in NS, compared with controls. In conclusion, muscle torque relative to muscle CSA was significantly lower in CKD and CD, compared with controls, and was independently associated with Zp. Future studies are needed to determine if abnormal muscle strength contributes to progressive bone deficits in chronic disease, independent of muscle area.

Effect of Low‐Magnitude Mechanical Stimuli on Bone Density and Structure in Pediatric Crohn's Disease: A Randomized Placebo‐Controlled Trial

Pediatric Crohns Disease (CD) is associated with low trabecular bone mineral density (BMD), cortical area, and muscle mass. Low‐magnitude mechanical stimulation (LMMS) may be anabolic. We conducted a 12‐month randomized double‐blind placebo‐controlled trial of 10 minutes daily exposure to LMMS (30 Hz frequency, 0.3 g peak‐to‐peak acceleration). The primary outcomes were tibia trabecular BMD and cortical area by peripheral quantitative CT (pQCT) and vertebral trabecular BMD by QCT; additional outcomes included dual‐energy X‐ray absorptiometry (DXA) whole body, hip and spine BMD, and leg lean mass. Results were expressed as sex‐specific Z‐scores relative to age. CD participants, ages 8 to 21 years with tibia trabecular BMD <25th percentile for age, were eligible and received daily cholecalciferol (800 IU) and calcium (1000 mg). In total, 138 enrolled (48% male), and 121 (61 active, 60 placebo) completed the 12‐month trial. Median adherence measured with an electronic monitor was 79% and did not differ between arms. By intention‐to‐treat analysis, LMMS had no significant effect on pQCT or DXA outcomes. The mean change in spine QCT trabecular BMD Z‐score was +0.22 in the active arm and –0.02 in the placebo arm (difference in change 0.24 [95% CI 0.04, 0.44]; p = 0.02). Among those with >50% adherence, the effect was 0.38 (95% CI 0.17, 0.58, p < 0.0005). Within the active arm, each 10% greater adherence was associated with a 0.06 (95% CI 0.01, 1.17, p = 0.03) greater increase in spine QCT BMD Z‐score. Treatment response did not vary according to baseline body mass index (BMI) Z‐score, pubertal status, CD severity, or concurrent glucocorticoid or biologic medications. In all participants combined, height, pQCT trabecular BMD, and cortical area and DXA outcomes improved significantly. In conclusion, LMMS was associated with increases in vertebral trabecular BMD by QCT; however, no effects were observed at DXA or pQCT sites.

Serum Infliximab, Antidrug Antibodies, and Tumor Necrosis Factor Predict Sustained Response in Pediatric Crohn's Disease.

Background:Serum infliximab (s-IFX) levels, antibodies to IFX (ATI), and inflammatory markers are important in predicting clinical outcomes in adults, but their roles in pediatric Crohns disease (CD) require further study. The primary aim of this study was to determine the association between serologic parameters during induction and ongoing IFX therapy at 12 months in pediatric CD. Methods:S-IFX, ATI, serum tumor necrosis factor alpha (s-TNF-&agr;), and C-reactive protein were measured at IFX initiation, 10 weeks, 6 months, and 12 months in a prospective cohort study of children with CD at a single tertiary care center. Results:At 12 months, 60 of 77 participants (78%) remained on IFX. Participants who completed 12 months of IFX had higher 10-week median s-IFX levels (20.40 &mgr;g/mL; interquartile range [IQR], 11.20–35.00] versus 8.70 &mgr;g/mL; IQR 0.90–16.90; P = 0.01), a greater proportion with undetectable 10-week ATI (P = 0.008), and a greater median change in s-TNF-&agr; between baseline and week 10 (−5.96 pg/mL; IQR, −8.73 to −4.17 versus −1.76 pg/mL; IQR, −5.60 to 0.30; P = 0.006). Receiver operating characteristic analysis to predict ongoing IFX at 12 months showed area under the curve (95% confidence interval) for 10-week s-IFX and change in s-TNF-&agr; from baseline to 10 weeks to be 0.71 (0.54–0.88) and 0.74 (0.58–0.91), respectively. C-reactive protein was not associated with ongoing therapy. Conclusions:ATI, s-IFX, and s-TNF-&agr; during IFX induction are associated with 12-month clinical outcomes in pediatric CD. Future studies are needed to further define the clinical role of s-TNF-&agr; measurement and to compare the clinical utility of 10 and 14-week ATI and s-IFX levels.

Bone Mineral Accrual Is Associated With Parathyroid Hormone and 1,25-Dihydroxyvitamin D Levels in Children and Adolescents.

CONTEXT Rapid bone accrual and calcium demands during puberty may result in compensatory increases in PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels; however, these relations have not been established in longitudinal studies. OBJECTIVE To determine whether greater bone accrual velocity is associated with greater PTH and 1,25(OH)2D levels in healthy children and adolescents. DESIGN Prospective cohort study with baseline PTH, 25-hydroxyvitamin D [25(OH)D], and 1,25(OH)2D levels and dual-energy x-ray absorptiometry whole-body bone mineral content (BMC) accrual over 12 months. Secondary analyses examined bone biomarkers and tibia quantitative computed tomography midshaft cortical-BMC. PARTICIPANTS A total of 594 healthy participants, ages 5-21 years, with longitudinal measures in a subset of 145 participants. MAIN OUTCOME MEASURES PTH and 1,25(OH)2D levels. RESULTS PTH levels were higher during Tanner stages 3 and 4 compared to Tanner 1 (P < .05) in males and females and were inversely and significantly associated with 25(OH)D levels and dietary calcium intake. In multivariable analyses, greater bone accrual [measured directly as change in dual-energy x-ray absorptiometry-BMC (P < .001) or quantitative computed tomography-BMC (P < .05), or indirectly as growth velocity (P < .05) or greater bone-formation biomarker level (P < .01)] was associated with higher PTH levels, independent of 25(OH)D level and dietary calcium intake. Similar associations were observed between these direct and indirect indices of bone accrual and 1,25(OH)2D levels. CONCLUSIONS PTH levels rise in midpuberty, in association with multiple measures of bone accrual. This is consistent with compensatory increases in PTH to drive 1,25(OH)2D production and calcium absorption during periods of increased calcium demands. Additional studies are needed to address PTH effects on bone modeling and remodeling during growth and development.