Higher Glucocorticoid Secretion in the Physiological Range Is Associated With Lower Bone Strength at the Proximal Radius in Healthy Children: Importance of Protein Intake Adjustment

Abstract

Whether higher production of glucocorticoids (GCs) within the physiological range may already be affecting bone status in healthy children is unknown. Because dietary protein intake affects both bone and GCs, we examined the association of urinary measures of glucocorticoid status and cortical bone in healthy non-obese children, after particularly controlling for protein intake. Proximal forearm bone parameters were measured by peripheral quantitative computed tomography (pQCT). Subjects studied (n = 175, 87 males, aged 6 to 18 years) had two 24-hour urine samples collected: the first sample at 1 year before bone measurement, and the second sample at the time of bone measurement. Major urinary GC metabolites were measured by mass spectrometry and summed to assess daily adrenal GC secretion (∑C21). Urinary free cortisol (UFF) and cortisone (UFE) were summed to assess potentially bioactive free GCs (UFF + UFE). After controlling for several covariates and especially urinary nitrogen (the biomarker of protein intake) cortisol secretion ∑C21 was inversely associated with all analyzed pQCT measures of bone quality. ∑C21 also predicted a higher endosteal and lower periosteal circumference, explaining both a smaller cortical area and (together with lower BMD) a lower strength-strain-index (SSI). UFF + UFE, UFE itself, and a urinary metabolite-estimate of 11beta-hydroxysteroid dehydrogenase type1 (11beta-HSD1) activity showed corresponding reciprocal associations (p < 0.05) with BMD and bone mineral content, but not with SSI and bone geometry variables. In conclusion, higher GC levels, even within the physiological range, appear to exert negative influences on bone modeling and remodeling already during growth. Our physiological data also suggest a relevant role of cortisone as the direct source for intracrine-generated cortisol by bone cell 11beta-HSD1.

Severe Phenotype of APECED (APS1) Increases Risk for Structural Bone Alterations

“…Reduced bone formation at trabecular bone sites and increased endocortical resorption are the most consistent pathological findings of glucocorticoid excess (12). In healthy children, higher adrenal glucocorticoid secretion within the normal hormonal range has been associated with smaller cortical area resulting from larger endosteal and lower periosteal circumference (13). Half of our patients had current daily hydrocortisone equivalent dose above 20 mg/day (0.32 mg/kg), although the presently recommended hydrocortisone dose is between 0.2-0.3 mg/kg (14).…”

High salt intake: detrimental not only for blood pressure, but also for bone health?

“…Only recently we could show in healthy children that moderately elevated cortisol and cortisone metabolitesstill fully within the normal physiological range-are independently associated with lower BMD and bone strength parameters at the proximal radius [19]. The proof of such subtle long-term effects does usually require a number of sophisticated methodological efforts regarding sample collection (e.g., 24-h urines), dietary recording (e.g., 3-day weighed dietary records), and specific biomarker and hormone metabolite measurements (e.g., gas chromatographymass spectrometry steroid profiling) which can explain that not every study will uncover corresponding physiological relationships between bone status and moderate elevations of glucocorticoids or other biomarkers.…”

“…The mere quantification of cortisol (in blood, urine, or saliva) may not always suffice to appropriately identify functional hypercortisolism. For this, the additional measurement of cortisone can be particularly useful, since cortisone is efficiently activated to cortisol in many tissues and it increasingly emerges as an important player in glucocorticoid-mediated endocrine effects [17][18][19].…”

Untangling the complex relationship between dietary acid load and glucocorticoid metabolism

“…3 A previous report from the Dortmund Nutritional and Anthropometric Longitudinally Designed Study showed significant correlation between higher glucocorticoid hormone levels and impaired bone characteristics in children. 6 Thus, one possible extrapolation is that higher dietary acid loads lead to impaired bone formation in children. However, higher dietary protein intake, a major component of PRAL, actually correlates with greater bone mineral content and bone strength.…”

“…7 It was only after controlling for protein intake, that is, for the major component of PRAL, that higher glucocorticoid hormone levels correlated with impaired bone characteristics in children. 6 Thus, increased dietary protein intake appears to correlate with improved bone characteristics, but “excessive” glucocorticoid hormone response may blunt these benefits. Also, increases in NAE are important in the response to higher PRAL.…”