Prof. Serge Ferrari's presentation from Osteoporosis 2016: Diabetes and bone. Find out more at: https://nos.org.uk/conference

1. Serge Ferrari
Service and Laboratory of Bone Diseases
Geneva University Hospital
and Faculty of Medicine
Switzerland
Diabetes and bone fragility:
challenges and opportunities

2. Diabetes increases with age and longevity
Cornier, Endo Rev 2008; Yach, Nat med 2006

3. Bone fragility in diabetics – A historical perspective
► Decreased skeletal mass and bone development in children with longstanding
diabetes (Morrison LB & Bogan IK. Am J Med Sci 1927)
► Cases of diabetes associated with vertebral crush fractures from the Joslin clinic
(Root HF, White P & Marble A. Arch Intern Med 1934)
► Bone fragility in diabetic patients (Albright F & Reifenstein EC. Parathyroid glands
and metabolic bone disease: selected studies. Baltimore: Williams and Wilkins 1948)
► Osteoporosis in cadaveric bones more severe in young adults with diabetes
(Hernberg CA. Acta Med Scand 1952)
► Diabetes increases fracture risk (Alffram PA. An Epidemiologic Study of Cervical
and Trochanteric Fractures of the Femur in an Urban Population. Analysis of 1,664
Cases with Special Reference to Etiologic Factors. Acta Orthop Scand Suppl 1968)
► Decreased elastic response of bone in vivo by ulnar resonant frequency in
osteoporotic, diabetic and normal subjects (Jurist JM. Phys Med Biol 1970)
► BMD 36-48% lower in insulin-requiring diabetics (Ringe JD, Kuhlencordt F & Kruse
HP. AJR Am J Roentgenol 1976).

4. Diabetes mellitus and Fracture Risk
Type 1 Diabetes Type 2 Diabetes
Any fracture 1.30 (1.16, 1.46) 1.19 (1.11, 1.27)
Hip fracture 1.70 (1.31, 2.21) 1.38 (1.18, 1.60)
Wrist fracture 1.04 (0.76, 1.44) 1.21 (1.01, 1.45)
Spine fracture 2.48 (1.33, 4.62) 1.34 (0.97, 1.86)
Vestergaard et al, Diabetologia 2005, 48: 1292
Case-control study (Denmark)
N=124‘655 cases, n=373‘962 controls (age 43 yrs)
*Adjusted for multiple clinical covariables

5. Type 1 and fractures – meta-analysis
Shah, Diabet Med 2015

6. Life-long increased fracture risk in Type 1 diabetes
in the UK
Weber, Diab Care 2015

7. Low BMD in type 1 diabetes
Bonemass
10 20
yrs
Diabetes
Adapted from Sylvester, Inflamm Bow Dis 2005

8. Decreased bone formation in children with Diabetes
Maggio, JPEM 2010

9. Decreased bone size in children/adolescent T1D -
pQCT
Saha, OI 2009
Bechtold , Diabetes Care 2007
Females
Males

10. MVC: Correlation to microvascular disease
GC: Correlation to glucose control Hough, Ferrari et al., Eur J Endocrinol 2016

11. Microstructural alterations in young adults with
T1D– micro-MRI
Abdalrahaman , JBMR 2015
Mean age 22 yrs
Significantly lower IGF-1
(Increased bone marrow adiposity)

12. Group A
PA< PROT<
(N=40)
Group B
PA > PROT <
(N=26)
Group C
PA < PROT >
(N=24)
Group D
PA> PROT >
(N=34)
P
Total vBMD (mg HA/cm2
) 245 ± 46 264 ± 54 276 ± 43 267 ± 40 0.747
Cortical vBMD (mg HA/cm2
) 726 ± 56 736 ± 54 739 ± 54 731 ± 56 0.807
Trabecular vBMD (mg HA/cm2
) 199 ± 27 195 ± 31 205 ± 25 205 ± 27 0.413
BV/TV (%) 16.6 ± 2.2 16.3 ± 2.6 17.1 ± 2.1 17.1 ± 2.2 0.415
Tb.N (mm-1
) 2.04 ± 0.23 2.00 ± 0.23 2.10 ± 0.25 2.21 ± 0.35 0.015
Tb.Th (µm) 81.6 ± 10.5 81.6 ± 12.0 82.3 ± 10.9 78.3 ± 10.9 0.474
Tb.Sp (µm) 415 ± 50 424 ± 57 402 ± 61 385 ± 65 0.044
Ct.Th (µm) 798 ± 324 832 ± 367 878 ± 321 814 ± 298 0.809
CSA (mm2
) 833 ± 126 854 ± 120 847 ± 111 955 ± 172 0.001
Impact of Physical Activity and Protein Intake on Bone
Density and Microstructure at Distal Tibia in Healthy
Adolescent Boys
HR-pQCT
Chevalley et al, JBMR 2014
PA : Physical activity
PROT: Protein Intake

13. Low turnover, Higher non-enzymatic collagen
crosslinks and degreee of mineralization in T1D
Farlay, JBMR 2015

14. The Type 2 Diabetic Patient with Bone Fragility
► 74-yr-old
► 98 kg, 162 cm (BMI 37.4)
► 12 yrs of T2DM, Rx
metformin
► HbA1C 7.4%
► Humerus fracture by falling
from chair (standing)
► BMD: LS +0.5 T-sc.,
FN -0.2 T-sc.

15. Fracture Risk in Type 2 Diabetes: WHI
RR (95%CI)*
Any fracture 1.20 (1.11, 1.30)
Hip, pelvis, upper leg 1.46 (1.17, 1.83)
Lower leg, ankle, knee 1.13 (0.95, 1.34)
Foot 1.32 (1.07, 1.62)
Upper arm, shoulder 1.13 (0.90, 1.41)
Lower arm, wrist, hand 1.02 (0.85, 1.22)
Spine 1.27 (1.00, 1.61)
*adjusted for age, ethnicity, weight, height, fall history, previous fracture, history of osteoporosis, smokung, alcohol,
exercise, medication incl. Calcium, vitamin d estrogen and bisphosphonates
Bonds et al, J Clin Endocrinol Metab 2006, 91: 3404
Women‘s Health Initiative Observational Study
(follow-up 7 yrs)
n=93‘676, age at baseline 64 yrs (DM2, n=5285)

16. Linear increase in hip fracture incidence with
increasing HbA1c.
Li et al.
J Bone Miner Res 2015 30:
1338–46.
A1c>10
A1c<6

17. Hip fracture risk in Diabetes:
9 years Cohort study of 35’000 subjects 50+ from
Norway
Forsen, Diabetologia 1999

18. Impact of Antidiabetic Therapy on Bone
Palermo, OI 2015

19. BMD in Type 2 Diabetes: WHI
likely to have used oral steroid hormones. Women with
diabetes were shorter at baseline and heavier (Table 1) and,
for the subset that underwent BMD measurements at base-
line, had a higher hip and spine BMD (Table 2).
After an average of 7 yr of total follow-up, there was a
higher rate of fracture among women with diabetes (Table 3).
When fractures were broken down by location, women with
diabetes had a higher rate of hip/pelvis/upper leg, lower
leg/ankle/knee, foot, upper arm/shoulder/elbow, and
spine/tailbone fractures. There was an equal rate of fracture
of the lower arm/wrist/hand reported by both groups.
Women with diabetes were 29% more likely to have suf
fered a fracture during the follow-up period (Table 4). Thi
increased risk remained after adjustment for other baselin
differences in the multivariate adjusted model, our primar
outcome. When fractures by region were compared, wome
with diabetes had a significantly increased risk of the hip/
pelvis/upper leg, foot, and spine/tailbone fracture (Table 4
There was also an increased risk of lower leg/ankle/kne
and upper arm/shoulder/elbow fractures that did not mee
statistical significance.
In sensitivity analyses, we reran the above analyses usin
TABLE 2. B M D measur ements at spine and hipa
S pine B M D (g/cm2
) H ip B M D (g/cm2
)
Diabetic women (n) Nondiabetic women (n) Diabetic women (n) N ondiabetic women (n)
B aselineb
1.04 0.19 (472) 0.97 0.17 (5922) 0.90 0.16 (469) 0.84 0.14 (5915)
Year 3 1.06 0.20 (331) 0.99 0.17 (4839) 0.89 0.16 (331) 0.84 0.13 (4831)
Year 6 1.07 0.21 (253) 1.00 0.18 (4203) 0.87 0.16 (261) 0.84 0.13 (4262)
Year 9 1.12 0.24 (91) 1.02 0.18 (1608) 0.88 0.17 (92) 0.82 0.13 (1606)
a
All compar isons of diabetic women vs. nondiabetic women wer e P 0.01.
b
Cor r ected for the use of multiple scanner s and the longitudinal natur e of the data.
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Bonds et al, J Clin Endocrinol Metab 2006, 91: 3404
BMD 5-10% higher in diabetics

20. 10-yrs fracture risk higher at every BMD level in
diabetics
A Schwartz et al.,
JAMA 2011

21. MOF – FRAX with BMD
Age 40+, 6455 Diabetic vs 55,958 Non-diabetic
Without diabetes With diabetes
MODEL 1 HR (95% CI) HR (95% CI) p-interaction
Age (per 10 y) 1.43 (1.38-1.47) 1.39 (1.27-1.53) 0.781
Sex (male vs female) 0.90 (0.79-1.02) 1.04 (0.78-1.39) 0.407
BMI (per 5 kg/m2) 0.98 (0.95-1.02) 0.90 (0.83-0.98) 0.080
Current smoking 1.31 (1.06-1.64) 1.75 (1.06-2.87) 0.392
Parental hip fracture 0.82 (0.64-1.04) 0.69 (0.37-1.29) 0.584
Glucocorticoid use 1.30 (1.14-1.48) 1.13 (0.83-1.54) 0.398
Rheumatoid arthritis 1.43 (1.24-1.64) 1.74 (1.21-2.49) 0.325
High alcohol use 2.02 (1.70-2.41) 1.98 (1.27-3.09) 0.941
Any prior fracture 1.62 (1.51-1.74) 1.72 (1.42-2.07) 0.588
Femoral neck T-score 1.68 (1.61-1.75) 1.60 (1.44-1.79) 0.456
omnibus test of all interactions: p-value 0.140
Leslie WD. Osteoporos Int. 2014; 25:2817

22. FRAX estimated vs observed hip fracture risk in
T2DM
Schwartz, JAMA 2011 Giangregorio , JBMR 2012

23. Clinical Implications
► Fracture prediction tools in diabetes can still use
conventional risk factors:
– Lower BMD increases risk for fracture in DM
– Higher BMI protective for fracture in DM
► Diabetes was a risk factor for fracture:
– MOF adjusted HR 1.32 [95% CI 1.20-1.46]
Leslie WD. Osteoporos Int. 2014; 25:2817

24. Is TBS Helpful in Diabetes?
29,407 women ≥50 years with baseline DXA
BMD (g/cm2
)
Diabetes – No diabetes
Mean (95% CI)
Lumbar spine
+0.031
(+0.024 : +0.038)
Femoral neck
+0.012
(+0.007 : +0.016)
Trochanter
+0.008
(+0.003 : +0.013)
Total hip
+0.019
(+0.014 : +0.025)
TBS
-0.051
(-0.056 : -0.046)
* Adjusted for age, BMI, glucocorticoids, prior major fracture, rheumatoid
arthritis, COPD, alcohol abuse and osteoporosis therapy.
Leslie WD et al. JCEM 2013.
TBS predicted incident
major OP fractures
- With DM: aHR 1.27
- Without DM: aHR 1.31
- No interaction

25. FRAX ± TBS in T2D
With TBS 1.15, fracture probability 16% (hip 1%)
Country: Switzerland Name/ID:
1. Age (between 40 and 90 years) or Date of Birth
Age:
69 Y: M: D:
Date of Birth:
2. Sex Male Female
3. Weight (kg) 88
4. Height (cm) 162
5. Previous Fracture No Yes
6. Parent Fractured Hip No Yes
7. Current Smoking No Yes
8. Glucocorticoids No Yes
9. Rheumatoid arthritis No Yes
Questionnaire: 10. Secondary osteoporosis No Yes
11. Alcohol 3 or more units/day No Yes
12. Femoral neck BMD (g/cm2
)
T-Score -0.2
If you have a TBS value, click here: Adjust with TBS
Clear Calculate
Calculation Tool
Please answer the questions below to calculate the ten year probability of fracture with BMD.
Risk factors
w ith BMD
BMI: 33.5
The ten year probability of fracture (%)
Major osteoporotic 13
Hip Fracture 0.7

26. Influence of fat
on TBS
Amnuaywattakom et al., BMC Musculoskel Dis 2016

27. Trunk fat mass and TBS in GERICO
(n=738 post-menopausal women)

28. Conceptual framework for diabetes and
fractures
-6 -5 -4 -3 -2 -1 0 1
RelativeriskMOF
BMD T-score
No DM DM
DIO=diabetes
induced
osteoporosis
Osteoporosis
unrelated
to DM
DBD=diabetic
bone
disease
Adapted from Leslie WD. Osteoporos Int. 2014; 25:2817

29. Increased cortical porosity in T2DM with fractures
(HR-pQCT)
Patsch, JBMR 2013urghardt, JCEM 2010

30. Increased cortical porosity in T2DM is associated
with microvascular disease
Radius (HR-pQCT)
Shanbhogue, Eur J Endocrinol 2016

31. Altered bone material strength in diabetes
Farr, JBMR 2014
Merlotti 2010

32. Algorithm for Management of Osteoporosis in Postmenopausal women and
men over 50 years with T 2DM IOF/CSA Working Group-in preparation
Rapid BMD loss on follow-up
Adjusted Frax probability (TBS?) / Lower intervention
thresholds
New Markers ?
Women & men
with T2DM
No
Measure BMD (T-score
Typical osteoporotic fracture*
> -2.5
Consider specific anti-fracture medication Life-style measures onlyYes
Yes
≤ -2.5
NoIGF-1
AGEs
?
*Fracture of spine,
hip, pelvis or
humerus
# CRFs, substitute RA with T2DM
•Advanced age
•Prior #
•F/H of hip #
•Alcohol, smoking
•GCs, hypogonadism
•High fall propensity
•Insulin therapy
?

33. Conclusions
► Diabetes increases the risk of fragility fractures (T1D > T2D)
► Bone fragility in diabetes is characterized by predominant alterations
of bone quality (microarchitecture, material properties) with or without
reductions of BMD (T1D < T2D)
– In T2D bone quality alterations overcome the higher BMD
► Bone fragility increases with poor glucose control, diabetes duration,
microvascular complications, need of insulin and some antidiabetics
(glitazones, ? Canaglifozin,..)
► New markers of fracture risk in diabetes, specially type 2, which reflect
alterations in « bone quality » need to be developed and evaluated
► The effects of osteoporosis drugs on reducing bone fragility in
diabetes remain to be prospectively evaluated

34. Acknowledgements
IOF Diabetes & Bone WG:
Stephen Hough (co-chair)
Bo Abrahamsen
Mohammed-Salleh Ardawi
Massimo Benedetti
Manju Chandran
Cyrus Cooper
Richard Eastell
Ghada Eli Hajj Fullheihan
Bob Josse
David Kendler
Marius Kraenzlin
Bill Leslie
Nicola Napoli
Dominique Pierroz
Atsushi Suzuki
Ann Schwartz
Geneva Bone Diseases
Clinical Research group:
Emmanuel Biver
Thierry Chevalley
René Rizzoli
Fanny Merminod
Anne Sigaud
Magaly Hars
Chantal Genet
Julio Conicella