Diabetes and Bone: the model of GIO Gherardo Mazziotti A.O. Carlo Poma Mantova, Italy

Glucose metabolism and bone Abnormal bone remodelling Hyperglycemia Abnormal bone remodelling Skeletal fragility

Glucose metabolism and bone Abnormal bone remodelling Hyperglycemia Abnormal bone remodelling Skeletal fragility

Background/1 Effects of bone signals on glucose metabolism Mice lacking molecule osteocalcin displayed decrease in β-cell proliferation with glucose intolerance and insulin resistance. Infusion of undercarboxylated osteocalcin reduced diet and chemically-induced insulin resistance in mice. Lee et al., Cell 2007 Ferron et al., PNAS 2008

Background/2 Interplay between glucose metabolism and bone remodelling/1 Insulin signaling in osteoblasts is a significant determinant of whole-body glucose homeostasis by favoring osteocalcin decarboxylation Ferron et al., Cell 2010

Background/3 Interplay between glucose metabolism and bone remodelling: clinical data/1 Serum undercarboxylated osteocalcin negatively correlated with plasma glucose and fat mass in men with type 2 diabetes (Osteopor Int. 2011; Endocrine 2013). Antiresorptive therapy did not have a clinically important effect on fasting glucose, weight, or diabetes risk in postmenopausal women (JCE&M 2013). Exposure to bisphosphonates was associated with a significant 50% reduction in the risk of incident T2DM in older subjects (JCE&M 2015).

Background/4 Interplay between glucose metabolism and bone remodelling: clinical data/2 Serum undercarboxylated osteocalcin negatively correlated with plasma glucose and fat mass in men with type 2 diabetes (Osteopor Int. 2011; Endocrine 2013). Antiresorptive therapy did not have a clinically important effect on fasting glucose, weight, or diabetes risk in postmenopausal women (JCE&M 2013). Exposure to bisphosphonates was associated with a significant 50% reduction in the risk of incident T2DM in older subjects (JCE&M 2015).

Background/5 Interplay between glucose metabolism and bone remodelling: clinical data/3 Serum undercarboxylated osteocalcin negatively correlated with plasma glucose and fat mass in men with type 2 diabetes (Osteopor Int. 2011; Endocrine 2013). Antiresorptive therapy did not have a clinically important effect on fasting glucose, weight, or diabetes risk in postmenopausal women (JCE&M 2013). Exposure to bisphosphonates was associated with a significant 50% reduction in the risk of incident T2DM in older subjects (JCE&M 2015).

Background/7 Interplay between glucose metabolism and bone remodelling: the model of glucocorticoid excess Glucocorticoids induce osteoporosis. Glucocorticoids induce insulin resistance and disorders of glucose homeostasis.

Glucocorticoids and bone remodelling/1 Mazziotti et al., Trends Endocrinol Metab 2006

Glucocorticoids and bone remodelling/2 Osteocalcin is exquisitely sensitive to the action of GCs (↑11-HSD1  ↑GCs activity  ↓ OC production) Cooper et al., JCE&M 2003

Glucocorticoids and glucose metabolism/1 Prevalence of glucose disorders in chronic exposure to GCs Mazziotti et al., Trends Endocrinol Metab 2011

Glucocorticoids and glucose metabolism/2 Traditional pathophysiological paradigm of GC-induced diabetes Mazziotti et al., Trends Endocrinol Metab 2011

Bone remodelling and glucose metabolism/1 Experimental model of GC-induced diabetes/1 Transgenic mouse model in which intracellular glucocorticoid signaling is disrupted in osteoblasts, by expression of 11-HSD2 inactivating enzyme . (Aim: to evaluate the effects of GCs on fuel metabolism after abrogating signals from osteoblasts). Endogenous heterotopic expression (in liver) of osteocalcin by gene therapy in WT mice. (Aim: to determine whether osteocalcin is able to prevent, attenuate, or reverse glucocorticoid-induced metabolic dysfunction). Brennan-Speranza et al., J Clin Invest 2012

Bone remodelling and glucose metabolism/2 Experimental model of GC-induced diabetes/2 “… Targeted disruption of glucocorticoid signaling in osteoblasts partially prevents the GC-induced suppression of osteocalcin production…” Brennan-Speranza et al., J Clin Invest 2012

Bone remodelling and glucose metabolism/3 Experimental model of GC-induced diabetes/3 “…Targeted disruption of glucocorticoid signaling in osteoblasts partially prevents impaired metabolic responses seen in glucocorticoid-treated WT mice…” Brennan-Speranza et al., J Clin Invest 2012

Bone remodelling and glucose metabolism/4 Experimental model of GC-induced diabetes/4 Transgenic mouse model in which intracellular glucocorticoid signaling is disrupted in osteoblasts, by expression of 11-HSD2 inactivating enzyme . (Aim: to evaluate the effects of GCs on fuel metabolism after abrogating signals from osteoblasts). Endogenous heterotopic expression (in liver) of osteocalcin by gene therapy in WT mice. (Aim: to determine whether osteocalcin is able to prevent, attenuate, or reverse glucocorticoid-induced metabolic dysfunction). Brennan-Speranza et al., J Clin Invest 2012

Bone remodelling and glucose metabolism/5 Experimental model of GC-induced diabetes/5 “…Heterotopic expression of wtOCN improves glucocorticoid-induced glucose tolerance…” Brennan-Speranza et al., J Clin Invest 2012

Bone remodelling and glucose metabolism/6 A new experimental paradigm Ferris & Kahn, J Clin Invest 2012

Modulation of bone remodeling in GIO Saag et al., Arthritis Rheum 2009

Bone remodelling and glucose metabolism/7 Clinical model of GIO/1 The aim of this 12-month prospective study was to investigate whether treatment of glucocorticoid-induced osteoporosis (GIO) with bipshosphonates or teriparatide may influence serum glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG).

Bone remodelling and glucose metabolism/8 Clinical model of GIO/2

Bone remodelling and glucose metabolism/9 Clinical model of GIO/3

Bone remodelling and glucose metabolism/10 Clinical model of GIO/4

Bone remodelling and glucose metabolism/11 Clinical model of GIO/5

Bone remodelling and glucose metabolism/12 Clinical model of GIO/6

Bone remodelling and glucose metabolism/13 Clinical model of GIO/7

Conclusions Chronic glucocorticoid excess provides an unique clinical model to study the interplay between skeleton and glucose metabolism. Under chronic glucocorticoid exposure, there is experimental evidence that osteoblasts signals (i.e., low osteocalcin production) may be involved in the pathogenesis of glucocorticoid-induced diabetes. There is a suggestion from clinical data that teriparatide may induce some improvements in glucose homeostasis in patients with GIO and glucocorticoid-induced diabetes. Placebo Denosumab 60 mg Denosumab 180 mg *p ≤ 0.001 vs placebo. p values are based on a repeated-measures model adjusting for treatment, baseline use of steroids, previous use of biologics, and baseline BMD value. Adapted from: Dore RK, et al. J Bone Miner Res. 2007;22(suppl 1):S59. Abstract 1208 and oral presentation. Adapted from from Cohen SB, et al. Arthritis Rheum. 2008;58(5):1299-1309

Open issues Detailed molecular mechanisms of osteocalcin action on pancreas and peripheral tissues are lacking. It is unclear whether teriparatide may exert direct clinically relevant effects on insulin secretion (pancreatic cells harbor receptor for parathyroid hormone). Placebo Denosumab 60 mg Denosumab 180 mg *p ≤ 0.001 vs placebo. p values are based on a repeated-measures model adjusting for treatment, baseline use of steroids, previous use of biologics, and baseline BMD value. Adapted from: Dore RK, et al. J Bone Miner Res. 2007;22(suppl 1):S59. Abstract 1208 and oral presentation. Adapted from from Cohen SB, et al. Arthritis Rheum. 2008;58(5):1299-1309

Skeletal fragility in diabetes Antiosteoporotic drugs Traditional paradigm Antidiabetic drugs Placebo Denosumab 60 mg Denosumab 180 mg Positive/Negative effects Diabetes Skeletal fragility Antiosteoporotic drugs *p ≤ 0.001 vs placebo. p values are based on a repeated-measures model adjusting for treatment, baseline use of steroids, previous use of biologics, and baseline BMD value. Adapted from: Dore RK, et al. J Bone Miner Res. 2007;22(suppl 1):S59. Abstract 1208 and oral presentation. Adapted from from Cohen SB, et al. Arthritis Rheum. 2008;58(5):1299-1309

Skeletal fragility in diabetes Antiosteoporotic drugs New paradigm Antidiabetic drugs Placebo Denosumab 60 mg Denosumab 180 mg Positive/Negative effects Diabetes Skeletal fragility Positive effects Antiosteoporotic drugs *p ≤ 0.001 vs placebo. p values are based on a repeated-measures model adjusting for treatment, baseline use of steroids, previous use of biologics, and baseline BMD value. Adapted from: Dore RK, et al. J Bone Miner Res. 2007;22(suppl 1):S59. Abstract 1208 and oral presentation. Adapted from from Cohen SB, et al. Arthritis Rheum. 2008;58(5):1299-1309