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

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

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

4. 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

5. 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

6. 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).

7. 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).

8. 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).

9. 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.

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

11. 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

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

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

14. 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

15. 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

16. 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

17. 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

18. 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

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

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

21. 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).

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

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

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

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

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

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

28. 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 ≤ 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):

29. 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 ≤ 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):

30. 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 ≤ 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):

31. 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 ≤ 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):