CKD and Low Cortical Bone Mineral Density Increase Fracture Risk

Chronic kidney disease (CKD) poses multiple threats to bone accrual during growth. A recent study from The Children’s Hospital of Philadelphia, published in the Journal of Endocrinology and Metabolism, sought to clarify if children with CKD and low peripheral quantitative computed tomography (pQCT) measures of cortical volumetric bone mineral density (CortBMD) would be uniquely vulnerable to impaired mineralization and at a higher risk for fractures.

Cortical bone comprises 80% of skeletal mass, and even healthy children are more likely to fracture the cortical-rich appendicular skeleton. In this groundbreaking study, led by Michelle R. Denburg, MD, and Mary Leonard, MD, MSCE, CHOP researchers demonstrated that calcium, iPTH, and 1,25(OH)2D are important and independent correlates of CortBMD. Additionally, this study demonstrated that lower cortical density is associated with an increased risk of fracture in CKD, making it an important therapeutic target. This study is the first to show this in the pediatric CKD population.

This prospective cohort study is also the first to examine associations between CortBMD and serum calcium, phosphorus, PTH, FGF-23, and vitamin D concentrations in a large cohort (171 participants from CHOP and Cincinnati Children’s Hospital Medical Center) of children, adolescents, and young adults with CKD. CortBMD reference data were generated in 675 concurrent healthy participants. We identified the determinants of baseline CortBMD Z-scores and tracked changes in CortBMD Z-scores in childhood CKD. Then we compared the associations of total, free, and bioavailable 25(OH)D concentrations with CortBMD and assessed whether the baseline CortBMD Z-score was associated with a subsequent fracture.

Disease characteristics and medications

Medical charts were reviewed for disease and treatment characteristics. Information on current medications and sources of vitamin D supplementation was obtained by questionnaire and confirmed in the medical record. Participants/guardians were interviewed at all study visits regarding details of new fractures, and all fractures that occurred after the baseline visit were confirmed by review of radiology reports.

Changes in CortBMD Z

The median time between visits was 1 year. The median change in CortBMD Z-score was 0.07. Although the magnitude of the median changes was small, there were participants who had both substantial increases and decreases in all measures of mineral metabolism, facilitating our ability to detect associations with change in CortBMD Z-score. Given the strong positive association between CortBMD Z-score and calcium both cross-sectionally and longitudinally, we hypothesized that calcium may have a greater impact on the growing skeleton. We confirmed that the change in serum calcium was significantly associated with the change in CortBMD Z-score among participants with greater growth.

Fracture

Eleven of 170 participants (6.5%) sustained a fracture after their baseline visit (incidence of 556 per 10,000 person-years). Cox regression analysis adjusted for age and sex demonstrated that lower baseline CortBMD Z-score was associated with fracture. The mean CortBMD Z-score was -0.93 in those who subsequently fractured, compared with 0.08 in those who did not (P = .02).

Discussion

This is the first study to assess the independent relations between comprehensive measures of mineral metabolism and volumetric cortical BMD in CKD, and the first to assess whether lower CortBMD was associated with subsequent fractures. In cross-sectional and longitudinal analyses, lower calcium and greater iPTH and 1,25(OH)2D were the main determinants of CortBMD Z-score deficits.

Furthermore, lower baseline CortBMD Z-score was associated with an increased risk of subsequent fracture. The incidence of fracture in our cohort was 4-fold higher than that reported in a large population-based study of fracture epidemiology in children and adolescents (133 per 10 000 person-years).

The strong positive association between serum calcium and CortBMD Z-score is a novel finding with potentially important clinical implications. We demonstrated an interaction between changes in calcium and linear growth, ie, that increases in serum calcium were strongly associated with increases in CortBMD Z-score, but only among children who were growing.

Our findings of an inverse association between 1,25(OH)2D levels and CortBMD Z-score, independent of PTH, are consistent with a resorptive effect. This supports the compelling clinical finding that the increased fracture risk observed after yearly high-dose oral vitamin D3 in an adult study was associated with the 1,25(OH)2D level 3 months after its administration. After adjustment for its strong positive association with 1,25(OH)2D (as its substrate), greater 25(OH)D concentrations were associated with higher CortBMD Z-scores cross-sectionally, and this was partially explained by iPTH and calcium.

Another important finding was the comparable relations between CortBMD Z-score and total vs free and bioavailable 25(OH)D. Recently a study in healthy young adults reported that free and bioavailable 25(OH)D were more strongly correlated with DXA spine BMD than total 25(OH)D. Using the same DBP assay and formulae to estimate free and bioavailable 25(OH)D, we found no significant difference in the correlation coefficients between CortBMD Z-score and total, free, and bioavailable 25(OH) D, suggesting that at least in terms of CortBMD, total 25(OH)D provides an adequate assessment of nutritional vitamin D status in CKD.

This study is the largest longitudinal study of bone structure and mineral metabolism in childhood CKD. Unlike DXA, the volumetric outcome of CortBMD generated by pQCT is not confounded by bone size; this is critical in pediatric CKD, given the burden of short stature. The large sample of healthy reference participants allowed for the generation of age-, sex-, and race-specific Z-scores. This study is unique in its comprehensive assessment of mineral metabolism with simultaneous and longitudinal measures of vitamin D metabolites, iPTH, FGF-23, calcium, and phosphorus.

References

Mineral metabolism and cortical volumetric bone mineral density in childhood chronic kidney disease. Denburg MR, Tsampalieros AK, de Boer IH, Shults J, Kalkwarf HJ, Zemel BS, Foerster D, Stokes D, Leonard MB. J Clin Endocrinol Metab. 2013;98(5):1930-1938.

Epidemiology of childhood fractures in Britain: a study using the general practice research database. Cooper C, Dennison EM, Leufkens HG, Bishop N, van Staa TP. J Bone Miner Res. 2004;19(12):1976-1981.

The efficacy of high-dose oral vitamin D3 administered once a year: increased fracture risk is associated with 1,25 vitamin D level at 3-months post dose. Sanders K, Duque G, Ebeling P, et al. J Bone Miner Res. 2012;27(suppl 1).

Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship. Powe CE, Ricciardi C, Berg AH, et al. J Bone Miner Res. 2011;26(7):1609-1616.