Erik J M van Bommel1, Renate T de Jongh2, Myrte Brands3, Annemieke C Heijboer4, Martin den Heijer2, Mireille J Serlie3, Daniel H van Raalte5. 1. Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. 2. Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands. 3. Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands. 4. Department of Clinical Chemistry, Endocrine Laboratory, VU University Medical Center, Amsterdam, The Netherlands. 5. Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: d.vanraalte@vumc.nl.
Abstract
HYPOTHESIS: Glucocorticoids (GCs) induce osteoporosis predominantly by inhibiting osteoblast activity. We hypothesised that osteoblastic factors could also be linked to GC-induced adverse metabolic effects. METHODS: We performed a post-hoc analysis of a randomised, placebo-controlled, double blind, dose-response intervention study involving 32 healthy males (age: 22 ± 3 years; BMI 22.4 ± 1.7 kg/m2) who were allocated toprednisolone (PRED) 7.5 mg once daily (n = 12), PRED 30 mg once daily (n = 12), or placebo (n = 8) for two weeks using block randomisation. Mean outcomes measures included osteocalcin, N-terminal propeptide of type 1 procollagen (P1NP) and their relation to glucose and lipid metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp. RESULTS:Osteocalcin and P1NP concentrations were dose-dependently decreased by PRED treatment (p < 0.001 both). PRED dosages dose-dependently reduced sensitivity of the liver and skeletal muscle for insulin (p < 0.001 both) and impaired suppression of lipolysis mediated by insulin (p < 0.01). In multivariate analyses, GC-induced changes in osteocalcin concentrations related to reduces hepatic insulin sensitivity (β = -0.315; p = 0.044). In addition, GC-induced changes in P1NP were negatively related to changes in insulin-mediated suppression of hepatic glucose production (r = -0.582; p = 0.001), and were positively related to insulin-stimulated glucose uptake (r = 0.638; p < 0.001). Finally, changes in PN1P were negatively related to changes in fasting hypertriglyceridemia (r = -0.499; p = 0.004) and insulin-induced suppression of lipolysis rates (r = -0.494; p = 0.006). CONCLUSION:GC treatment alters osteoblastic function which is associated with several adverse metabolic effects of GC treatment. Future causal studies are needed to assess the specific mediator(s) by which the osteoblast alters intermediary metabolism. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN83991850.
RCT Entities:
HYPOTHESIS: Glucocorticoids (GCs) induce osteoporosis predominantly by inhibiting osteoblast activity. We hypothesised that osteoblastic factors could also be linked to GC-induced adverse metabolic effects. METHODS: We performed a post-hoc analysis of a randomised, placebo-controlled, double blind, dose-response intervention study involving 32 healthy males (age: 22 ± 3 years; BMI 22.4 ± 1.7 kg/m2) who were allocated to prednisolone (PRED) 7.5 mg once daily (n = 12), PRED 30 mg once daily (n = 12), or placebo (n = 8) for two weeks using block randomisation. Mean outcomes measures included osteocalcin, N-terminal propeptide of type 1 procollagen (P1NP) and their relation to glucose and lipid metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp. RESULTS:Osteocalcin and P1NP concentrations were dose-dependently decreased by PRED treatment (p < 0.001 both). PRED dosages dose-dependently reduced sensitivity of the liver and skeletal muscle for insulin (p < 0.001 both) and impaired suppression of lipolysis mediated by insulin (p < 0.01). In multivariate analyses, GC-induced changes in osteocalcin concentrations related to reduces hepatic insulin sensitivity (β = -0.315; p = 0.044). In addition, GC-induced changes in P1NP were negatively related to changes in insulin-mediated suppression of hepatic glucose production (r = -0.582; p = 0.001), and were positively related to insulin-stimulated glucose uptake (r = 0.638; p < 0.001). Finally, changes in PN1P were negatively related to changes in fasting hypertriglyceridemia (r = -0.499; p = 0.004) and insulin-induced suppression of lipolysis rates (r = -0.494; p = 0.006). CONCLUSION: GC treatment alters osteoblastic function which is associated with several adverse metabolic effects of GC treatment. Future causal studies are needed to assess the specific mediator(s) by which the osteoblast alters intermediary metabolism. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN83991850.