This study is the first to examine trabecular and cortical volumetric BMD and cortical dimensions across the full spectrum of CKD severity in children or adults. These data demonstrated that secondary hyperparathyroidism in CKD was associated with lower cortical BMD, greater endosteal circumference and smaller cortical area, independent of CKD severity. These associations are consistent with known PTH effects to increase cortical porosity and decrease cortical thickness through loss of endocortical bone.(8)
Elevated PTH levels were associated with greater trabecular BMD in younger participants; however, this association was absent in the older adolescents.
To our knowledge, six prior studies used pQCT to examine bone density and structure in children with CKD.(24–29)
Four of these reported significantly greater trabecular BMD in CKD compared with controls; however, the very small sample sizes and sparse reference data precluded assessment of age effects.(24–26,28)
Of note, in a study of 21 children on peritoneal dialysis, trabecular BMD was significantly greater in the children with CKD, compared with adult
controls (p < 0.0001) and trabecular BMD was greater in younger children.(26)
Studies of pQCT trabecular BMD in adults with CKD compared with controls are limited to a recent high-resolution pQCT study in older adults (age > 50 yr) with CKD stages 2–4.(49)
The authors reported that CKD was associated with lower trabecular BMD compared with controls. However, the investigators excluded the 45% of male and 55% of female controls with DXA BMD T-scores < −1.0, effectively excluding controls with normal age-related bone loss. It is not stated if the CKD participants differed from the control sample as a whole.
The etiology of the markedly elevated trabecular BMD Z-scores in our younger CKD participants is unclear, and is unique to CKD. Prior studies by our group in nephrotic syndrome,(39)
and juvenile idiopathic arthritis(46)
demonstrated consistent reductions in trabecular BMD Z-scores associated with systemic inflammation and/or glucocorticoid therapy across the entire pediatric age range. We anticipated that trabecular BMD Z-scores would be elevated in CKD due to an anabolic effect of PTH.(8)
Although this association was present in the younger CKD participants, it was absent in the older adolescents. We hypothesize that the elevated trabecular BMD in the younger children and in prior pediatric pQCT studies (24–26,28)
is due to CKD and PTH effects on the metaphysis. Mehls, et al reported that transformation of metaphyseal spongiosa into diaphyseal spongiosa is disturbed in advanced CKD in children, such that dense metaphyseal spongiosa is encountered further along the shaft of the bone.(45)
We do not believe that the elevated trabecular BMD represents an artifact of the abnormal growth plate morphology in pediatric CKD(50,51)
because the pQCT reference line was positioned at the proximal margin of the distal growth plate in all CKD and control participants. The resolution of pQCT is insufficient to define individual trabeculae.(52)
In the metaphysis, pQCT measures of trabecular volumetric BMD are a function of the bone volume fraction and the material bone mineral density distribution within the individual trabeculae. It is not known if the differences observed here between CKD and reference participants were due to differences in trabecular microarchitecture or material density. Future studies are needed in children with CKD using high-resolution pQCT to assess trabecular microarchitecture and compartment BMD along the entire metaphysis.
It is well-established that hyperparathyroidism results in increased bone turnover with endocortical bone loss and increased cortical porosity.(8,53,54)
The extent of cortical bone loss in adults on maintenance dialysis was demonstrated in a bone biopsy study.(7)
Regardless of the histological classification, the major structural abnormality in the skeleton was generalized thinning of cortical bone due to increased net endocortical resorption. Limited pQCT studies have been conducted in adults on hemodialysis,(55–57)
children on dialysis(26)
and children following transplantation, (24,27)
demonstrating reductions in cortical volumetric BMD and/or cortical thickness. In the study here, the positive association of endosteal circumference Z-scores with PTH levels and bone turnover biomarkers was consistent with PTH effects on endocortical bone, and the association with low serum bicarbonate and high bone resorption markers was consistent with reports that chronic acidosis also contributes to cortical bone loss.(58)
Of note, many of the estimated correlations between laboratory parameters and cortical bone Z-scores were weak (r = 0.18 to 0.36). However, when assessed as a group, the cumulative evidence supported the hypothesis that secondary hyperparathyroidism resulted in increased bone turnover, endocortical bone loss and decreases in cortical BMD in CKD. Secondary analyses adjusted for cortical thickness or limited to subjects with cortical thickness greater than 3 mm confirmed that these observations were not due to partial volume effects.(33)
Given the strong associations between muscle mass and cortical bone strength during growth and development, investigators have advocated a two-staged algorithm to assess (1) muscle mass relative to body size, and (2) bone outcomes relative to muscle mass in children with chronic disease.(59)
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). In this study, we reported that cortical area deficits in CKD stage 5D were no longer significant after adjustment for muscle deficits. However, 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.(60)
The greatest limitation of this study was the cross-sectional design. BMD and cortical dimensions reflect cumulative bone accrual and disease activity throughout growth and development, while the medication and laboratory data presented here represent a snapshot in time. The heterogeneity of the underlying renal diseases is another important limitation. However, this study of 156 children is the largest pediatric pQCT study to date (the largest prior study enrolled 22 children). Importantly, the secondary analyses conducted within the 96 CAKUT participants reduced the heterogeneity and confirmed the key findings. Last, this study is limited by lack of bone biopsy data. Despite these limitations, this study provides important and novel insights into the structural effects of CKD and secondary hyperparathyroidism on bone development.
In summary, this study is the first to examine trabecular and cortical volumetric BMD and cortical dimensions across the full spectrum of CKD severity in children or adults. Furthermore, the healthy reference group constitutes the largest reference population used in the assessment of the skeletal effects of CKD in children and adolescents, facilitating adjustment for age, sex, race, pubertal maturation, and tibia length. This study is the first to provide Z-score estimates of the magnitude of the cortical volumetric BMD and cortical area deficits in the growing skeleton, and the first to identify that the associations of trabecular BMD with CKD severity and PTH levels vary according to age. Future studies are needed to establish the fracture implications of these alterations, to determine if cortical and trabecular abnormalities are reversible, and to identify therapies to improve bone quality in children with CKD.