This study demonstrates significant musculoskeletal deficits in children with CD at diagnosis, with largely persistent deficits over the following year of treatment. The current study advances previous studies in 3 major ways. First, the use of pQCT provides 3-dimensional measures of trabecular and cortical vBMD, as well as measures of cortical dimensions and strength. To our knowledge, this is the first study to use QCT to assess bone outcomes in children or adults with inflammatory bowel disease. DXA is a 2-dimensional projection technique that cannot distinguish between superimposed cortical and trabecular bone and systematically underestimates vBMD in children with reduced height for age.23
Second, the use of an incident cohort allows one to establish the independent musculoskeletal effects of CD prior to initiation of therapy. Three prior studies of children and adolescents with newly diagnosed CD reported decreased DXA measures of lumbar spine or whole body areal BMD24–26
; however, these studies were limited by small numbers of controls (less than 50) and did not address the impact of body composition. Third, the robust control population described here constitutes the largest reference population used in the assessment of CD in children or adults, allowing adjustment for age, sex, race, bone length, pubertal maturation, and body composition.
The baseline data illustrate the substantial musculo-skeletal deficits attributable to the underlying inflammation and malnutrition in CD. The mean TrabBMD z score of −1.32 indicates that the average CD subject had a TrabBMD at the 10th percentile for age, sex, and race. These deficits are consistent with cytokine-mediated reductions in bone formation and potential increases in bone resorption. The decreased cortical bone strength (Zp) at the time of diagnosis was a result of significant reductions in the outer (periosteal) dimension coupled with significant expansion of the inner (endosteal) dimensions of the cortical shell in the diaphysis, relative to age and tibia length. This pattern likely represents the combined effects of decreased biomechanical loading by muscle forces and increased inflammatory cytokines. Whereas other studies have reported trabecular bone loss and cortical thinning in patients with disparate inflammatory diseases, those studies were complicated by concurrent GC therapies in subjects of widely varying disease duration.27,28
Finally, the substantial muscle deficits are consistent with prior reports of inflammatory cachexia in children with CD.29
As muscles increase during growth, bones adapt by increasing dimensions and strength. This capacity of bone to respond to mechanical loading with increased bone strength is greatest during childhood.30
Numerous studies have demonstrated that physical activity during childhood promotes cortical bone acquisition, either because of greater periosteal expansion and/or greater endosteal contraction.31,32
These reports are consistent with our finding in this incident CD cohort that greater increases in muscle mass significantly and independently attenuated decreases in Zp and periosteal circumference z scores following diagnosis.
Given the strong associations between muscle mass and cortical bone strength, investigators have advocated a 2-staged algorithm to assess (1) muscle mass relative to body size and (2) bone outcomes relative to muscle mass.14
This “functional muscle-bone unit” approach is intended to distinguish between primary bone disorders (muscle mass is normal and bone mass is low relative to muscle), as opposed to bone disorders that are secondary to muscle deficits (muscle mass is reduced but bone mass is “adequate” for the reduced muscle mass). Whereas bone and muscle deficits are highly correlated, this does not prove a causal relationship. This close association may be mediated by nutritional, hormonal, or inflammatory factors that directly influence both muscle and bone.33
In the CD cohort described here, baseline Zp and periosteal circumference z scores adjusted for age were significantly lower
in CD compared with controls. However, when these baseline bone outcomes were adjusted for the low muscle CSA z scores, they were significantly higher
in CD compared with controls. Next, mean Zp z scores decreased over the subsequent 6 months while muscle CSA z scores increased, and greater gains in muscle were significantly associated with lesser declines in Zp. At the 6-month visit, Zp z scores adjusted for muscle CSA z scores were significantly lower
in CD compared with controls. There are multiple potential explanations for this apparent overcompensation of bone at baseline and undercompensation at 6 months. First, the baseline muscle deficits may have progressed over a short interval prior to diagnosis, such that the bone loss secondary to decreased biomechanical loading lagged behind the muscle loss observed at baseline. Lag time between changes in muscle and bone adaptation to the changes in muscle loading might also explain why Zp z scores decreased over the first 6 months in the setting of increasing muscle CSA z scores. Second, the direct effects of cytokines, malnutrition, and CD therapies on muscle and bone may differ. For example, the progression of Zp deficits, despite improvements in muscle CSA, may have been due to direct GC effects to suppress bone formation, potentially impairing bone acquisition on the periosteal surface. Third, cytokines and glucocorticoids may directly decrease osteocyte function and survival, thereby impairing the bone cells that promote bone formation in response to mechanical strain.34
Finally, muscle CSA may not fully capture muscle forces in the setting of altered muscle composition or metabolism because of CD and its therapies. Measures of muscle force are needed to fully characterize the relations between bone and muscle in CD and controls. These observations illustrate the limitations of the functional muscle bone unit paradigm in chronic inflammatory disease.
TrabBMD z scores improved significantly over the study interval, despite the use of GC therapy in the majority of subjects. Whereas prior studies suggested that GCs were associated with greater bone deficits in CD, disease severity may have confounded the relationship between GC exposure and bone status. Prepubertal and early pubertal subjects demonstrated greater recovery of TrabBMD, compared with middle to late pubertal subjects. This may represent a window of opportunity to improve TrabBMD in these subjects.
Finally, CortBMD z scores were normal at baseline and increased over the first 6 months of therapy. GC exposure was associated with increases in CortBMD z scores over the first 6 months, and absence of GC therapy was associated with subsequent declines in CortBMD in the second 6 months. We recently reported that CortBMD was significantly greater in children and adolescents with juvenile idiopathic arthritis compared with controls.35
We hypothesized that GCs resulted in reduced bone turnover, resulting in reduced intracortical porosity, greater secondary mineralization, and higher CortBMD. Importantly, high CortBMD may not improve bone quality. Thinner, denser cortical bones may be more brittle and susceptible to damage accumulation.36
Our study was limited by the absence of bone biopsy histomorphometry. The impact of CD and its therapies on bone remodeling cannot be definitively addressed in the absence of dynamic measures of bone formation and resorption. However, this study provides important insight into the effects of CD and its therapies on bone vBMD and structure. An additional limitation is the variability in patterns of GC exposure over the study interval. The summary measure of mg/kg/day may not fully capture differences in intermittent GC exposure.
In summary, this study demonstrated that CD is associated with substantial deficits in TrabBMD, cortical dimensions, and muscle mass at diagnosis. Despite improvements in TrabBMD and muscle mass over the study interval, substantial deficits persisted after 1 year. The failure to fully recover TrabBMD and the sustained deficits in cortical dimensions, despite improvements in muscle CSA, suggest that interventions to improve bone acquisition are indicated. Future studies are needed to determine the associations between these bone deficits and fracture risk and to determine the effects of CD and its therapies on dynamic measures of bone remodeling.