Download skeletal fragility and fracture risk in patients with diabetes

SKELETAL FRAGILITY AND FRACTURE RISK
IN PATIENTS WITH DIABETES
Nelson B. Watts, MD
OSTEOPOROSIS AND BONE HEALTH SERVICES
CINCINNATI, OHIO
DISCLOSURES
• Stock options/holdings, company owner, official role:
OsteoDynamics co-founder, shareholder
• Honoraria in the past year: Amgen, Merck, Shire
• Consulting fees in the past year: AbbVie, Amgen, Merck, Radius
DIABETES MELLITUS AND FRACTURE RISK
• “. . . Any reduction of bone mass in diabetics
that is revealed by sophisticated analysis is
of no medical or economic importance. . .
Further extensive studies of bone metabolism
in diabetics are unlikely to yield results of
practical importance. . . ”
Heath HH III et al N Engl J Med 1980;303:567-570
Scientific Committee of the First International Symposium on Diabetes and Bone
Rome, Italy, November 2014
DIABETES MELLITUS AND BONE
• Type 1 diabetes and fracture risk
• Type 2 diabetes and fracture risk
–Prediction of fracture risk
–Predisposing factors
• What to do
BMD AND FRACTURES IN
TYPE 1 DIABETES MELLITUS
•
•
•
•
Lower body weight and lower BMI
If DM onset is before growth spurt, lower peak bone mass
Modest reduction in BMD
Higher hip fracture risk
– RR expected from lower BMD = 1.4
– Meta-analysis: RR = 6.3* (2.6, 15.1)
Clearly, fracture risk is increased, but something more than
reduced BMD is going on
*Risk increased 12-fold in type 1 patients with nephropathy
Vestergaard P et al Osteoporos Int 2007;18:427-444
TYPE 1 DM AND FRACTURE RISK
•
•
In patients with type 1 DM, fractures are more likely in the distal radius,
proximal humerus, hip and spine (OR 2.4)
Mechanisms include
– Deficiency of insulin and IGF-1
– Low peak bone mass
– Increased risk of falling (sarcopenia, retinopathy, cataracts, neuropathy,
gait disturbance, hypoglycemia)
– Decreased bone formation (AGEs, glucose toxicity), amylin, IFG-1, IAPP,
osteocalcin, increased resorption (uncoupling)
– Renal calcium leak, CKD, secondary/tertiary HPTH
– Inflammatory cytokines
– Altered collagen structure and cross linking (AGEs, pentosidine)
– Medications that increase fall risk (sedatives, opiates, anti-epilepsy
drugs, anti-Parkinson’s), also SSRIs, PPIs
– Other autoimmune diseases: celiac disease with calcium malabsorption,
hyperthyroidism, supraphysiologic T4 Rx
Hough FS et al Europ J Endocrinol 2016;174:R127-R138
DUAL ENERGY X-RAY ABSORPTIOMETRY
(DXA)
BMD by DXA is a
powerful predictor
of fracture risk
Relative risk of fracture
35
30
25
20
15
10
2x
5
-1 SD
0
-5
-4
-3
-2
Z-score or T-score
-1
0
BMD IS HIGHER IN PATIENTS
WITH T2DM
BMD (g/cm2)
Study of Osteoporotic Fractures
0.7
0.6
0.5
0.4
Adjusted for age, BMI
All p <0.01 for non-ins tx vs. not DM
All NS for insulin tx vs. non-insulin-tx
0.3
Femoral Neck
Calcaneal
Distal Radius
Insulin Tx
Non-insulin Tx
Non-diabetic
Schwartz AV et al J Clin Endocrinol Metab 2001:86:32-38
FRACTURE RISK IN T2DM BASED ON
BONE MINERAL DENSITY
BMD is higher in T2DM
therefore
fracture risk should be lower
than age-matched controls
FRACTURES ARE MORE COMMON
IN PATIENTS WITH DIABETES
Major osteoporosis-related fracture
Hip fracture
Giangregorio LM et al J Bone Miner Res 2012;27:301-308
META-ANALYSIS
HIP FRACTURE RISK IN T2DM
12 studies
RR 1.7 (1.3, 2.2)
Janghorbani M et al Am J Epidemiol 2007;166:495-505
META-ANALYSIS
HIP FRACTURE RISK IN DM
21 studies
42 subgroups
Both type 1 and type 2
T1DM
RR 5.76 (3.66, 9.07)
T2DM
RR 1.34 (1.01, 1.51)
RR 2.07 (1.83, 2.33)
Fan Y et al Osteoporos Int 2016;27:219-228
HIP FRACTURE INCIDENCE IN
RECENT ONSET T2DM
58,438 newly-diagnosed T2DM
113,448 controls
Hip fx 2.7 vs 2.1 per 1,000 pt-yrs
HR 1.20 (1.06, 1.35)
Martinez-Laguna D et al Osteoporos Int 2015;26:827-833
NOT JUST HIP FRACTURES
T2DM AND FRACTURE RISK – WHI-OS
Proximal humerus
RR (95% CI)
1.30 (1.07, 1.56)
Foot
1.44 (1.21, 1.71)
Ankle
1.34 (1.16, 1.55)
Clinical spine
1.28 (1.04, 1.56)
Forearm
0.98 (0.84, 1.15)
30-40% increased risk for any clinical fracture
Bonds DE et al J Clin Endocrinol Metab 2006;91:3404-3410
WHY IS FRACTURE RISK INCREASED IN
PATIENTS WITH TYPE 2 DIABETES?
Napoli N et al Nature Rev Endocrinol 2016; epub ahead of print
RISK OF MORE FREQUENT FALLS
Health, Aging and Body Composition Study
Normal
OR*
(95% CI)
1.00
Reference
Impaired glucose metabolism 0.95
T2DM
1.42
(0.82, 1.11)
(1.20, 1.68)
Falls: 0, 1, 2-3, 4-5, 6+ in past year
*Adjusted for age, race, gender
Schwartz AV et al Diab Care 2008:31:391-396
FALL RISK: A1c AND INSULIN USE
FALL PREVENTION IN TYPE 2 DIABETES
• Standard fall prevention measures
• Reducing complications through glycemic
control likely to prevent falls
• Intensive control safer with oral meds, but
caution with insulin use and low A1c
WHAT OTHER FACTORS COULD CONTRIBUTE
TO FRACTURE RISK IN DIABETES?
• Falls
• Biochemical abnormalities
–Renal calcium loss1
–Abnormal PTH levels (high or low)2
–Vitamin D deficiency3
–Decreasing Sirt14,5
1. Gregorio F et al Diabetes Res Clin Pract 23:43-54
2. McNair P et al Dan Med Bull 1988;35:109-121
3. Pittas AG et al Diab Care 2006;29:650-656
4. Iyer S et al J Biol Chem 2014;289;24069-24078
5. Artsi H et al Endocrinol 2014:155:3508-3515
WHAT FACTORS COULD CONTRIBUTE
TO FRACTURE RISK IN DIABETES?
• Falls
• Biochemical abnormalities
– Renal calcium loss
– Abnormal PTH levels (high or low)
– Vitamin D deficiency
– Decreasing Sirt1
• Reduced bone “quality”
– Collagen glycosylation
– Reduced bone formation
– Microarchitectural deterioration
ADVANCED GLYCATION END PRODUCTS
MIGHT DECREASE BONE STRENGTH
Pentosidine
• AGE can reduce pyridinium crosslinks1
• AGE accumulation could impair mechanical
properties of bone2
• In cadaver bone, higher pentosidine is
associated with reduced strength3
1. Dominguez LJ et al Biochem Biophys Res Commun 2005;330:1-4
2. Saito M et al Osteoporos Int 2006;17:1514-1523
3. Viguet-Carrin S et al Bone 2006;39:1073-1079
OSTEOBLAST DYSFUNCTION MIGHT
INCREASE FRACTURE RISK
• Glucose can be toxic to osteoblasts1
• Histomorphometry: low bone formation2
• Osteocalcin, a marker of bone formation, is low
in diabetes (inverse correlation with blood
glucose)3
1. Inaba M et al J Bone Miner Res 1995;10:1050-1056
2. Krakauer JC et al Diabetes 1995;44:775-82
3. Kanazawa et al J Clin Endocrinol Metab 2009;94:3031-3037
BONE STRUCTURE IN
TYPE 2 DIABETES
NORMAL
Melton LJ III et al J Clin Endocrinol Metab 2008;93:4804-4809
BUT…….
HIGH RESOLUTION pQCT
(Xtreme CT, Scanco Medical AG)
3-D stack of 116 high resolution
CT slices acquired at nondominant
distal radius and tibia
~ 82 µm3 voxel size
~ 3 min scan time, < 4 µSv
Reproducibility:
density: 0.7 to 1.8%
structure: 1.2 - 7.4%
CORTICAL POROSITY IS INCREASED
IN T2DM, WITH AND W/O FRACTURE
HR pQCT
Distal
Tibia
Proximal
Tibia
Mineralized Cortical
Bone
Porosity
Control
T2DM
No fx
T2 DM
w fracture
Images from Burghardt AJ et al J Clin Endocrinol Metab 2010;95:5045-5055
Similar findings by Patsch JM et al J Bone Miner Res 2013;28:313-324
TYPE 2 DIABETES AND HIP FRACTURE RISK
META-ANALYSIS
• Compared with subjects without diabetes, for patients
with T2DM, based on BMD alone, the age-adjusted
RR for hip would be expected to be lower, ~0.8
• But RR for hip fracture is higher, 1.34-1.7
Janghorbani M et al Am J Epidemiol 2007;166:495-505
Fan Y et al Osteoporos Int 2016;27:219-228
BONE DENSITOMETRY,
T2DM AND FRACTURE RISK
• Given that in diabetes mellitus, fractures
occur at higher BMD, compared with ageand weight-matched controls…
• Is BMD still predictive?
– In patients with diabetes, is lower BMD
associated with a higher fracture risk?
LOWER BMD PREDICTS FRACTURE IN T2DM
Baseline BMD
among
participants
with diabetes
in the Health
ABC Study
Total hip BMD
(g/cm2)
Health, Aging and Body Composition Study
*P<0.0001
*
0.967
0.818
Incident
fracture
No fracture
Strotmeyer ES et al Arch Intern Med 2005;165:1612-1617
• What if any effect do treatments for diabetes
have on fracture risk?
PIOGLITAZONE:
INCREASED FRACTURE RISK IN WOMEN
• Meta-analysis of fracture AEs for clinical trials of pioglitazone
• PIO N=8,100
Comparison N=7,400
12,000 person-years per group
• Increased risk in women but not men
Rx
Fx per 100
person-yrs
1.9
Pioglitazone
Placebo or active comp
RR
1.7
1.1
Periscope, April 2008: 543 SUBJECTS
FX 3% PIOGLITAZONE GROUP
0% GLIMEPERIDE
Takeda Letter to Health Care Providers 2007
ADOPT: ROSIGLITAZONE
INCREASED FRACTURE RISK IN WOMEN
10
% with Fracture
9
60
Rosiglitazone
8
7
Metformin
6
Glyburide
*
5
4
3
36
30
32
29 28
*
21
2
22
*
*
8
1
0
*
18
All Fractures
Men
All Fx
Lower limb
10 9
Upper limb
1
1
1
Spine
Women
*P<0.05 vs rosiglitazone (unadjusted, contingency chi-square test)
Kahn SE et al Diabetes Care 2008;31:845-851
TZDs AND FRACTURE RISK
UK GPRD
• Observational study, 1994-2005
• Patients with type 2 diabetes (N=66,696)
• Cases: First low trauma fracture (N=1,020)
• Controls: Matched for age, sex, general practice
attended, index date (N=3,728)
• 58% were 70 years or older at index date
• 68% were women
• 6% of cases used a TZD (PIO and ROSI)
Meier C et al Arch Intern Med 2008;168:820-825
NO EVIDENCE OF INTERACTION
WITH GENDER OR AGE
Fracture Risk: Current TZD ≥8+ Rxs vs Non Use
Women
OR
2.56
95% CI
(1.43-4.58)
Men
2.50
(0.84-7.41)
<70 y.o.
2.96
(1.40-6.25)
70+ y.o.
2.57
(1.22-5.40)
Meier C et al Arch Intern Med 2008;168:820-825
TZDS AND FRACTURE RISK BY SKELETAL SITES
All Fx Sites
Hip / Femur
No Rx
1-7 Rx
8-14
>1
5
1-7
>8
1.0
0.9
1.85
2.86
1.0
1.40
4.54
Humerus
1.0
0.28
1-7
>8
2.12
Wrist / Forearm
1.0
1-7
>8
0.74
2.90
0.01
0.1
1
Too few vertebral or rib fractures to include
10
Adjusted RR
Meier C et al Arch Intern Med 2008;168:820-825
100
TZDs AND THE DECISION PATHWAYS FOR
OSTEOBLAST AND ADIPOCYTE DEVELOPMENT
GOOD FOR BONE
Runx2
Mesenchymal
progenitor cells
in bone marrow
TZDs
PPARg
BAD FOR BONE
Adipocytes
(fat cells)
Osteoblasts
(bone-forming cells)
Rzonca SO et al Endocrinology 2004;145:401-406
Akune T et al J Clin Invest 2004;113:846-855
Pei L, Tontonoz P J Clin Invest 2004;113:805-806
Lecka-Czernik B et al Endocrinology 2007;148:903-911
MICRO-COMPUTED TOMOGRAPHY
(MICROCT) OF PROXIMAL TIBIA
Mouse Model
vehicle
rosiglitazone
% difference rosiglitazone vs. control
Bone
volume
*
- 24.1
Trabecular
thickness
*
- 10.6
* p < 0.05 rosiglitazone vs. control
Trabecular
number
- 21.2
*
Trabecular
spacing
17.4
*
Connectivity
- 24.4
Rzonca SO et al Endocrinology 2004;145:401-406
SGLT2 INHIBITION
SGLT1 found in
kidney, intestine
SGLT2 mainly in
the kidney
Neither are
expressed in
bone
In rats, treatment with canagliflozin leads to carbohydrate malabsorption, skeletal
hyperostosis, absorptive hypercalciuria, decreased PTH and 1,25 D
Not seen in mice, dogs or humans
EFFECT OF CANAGLIFLOZIN ON
BONE TURNOVER MARKERS AND BMD
Bilezikian JP et al J Clin Endocrinol Metab 2016:101:44-51
BTM CHANGE WITH CANAGLIFLOZIN
C-telopeptide
Osteocalcin
Bilezikian JP et al J Clin Endocrinol Metab 2016:101:44-51
CHANGE IN WEIGHT AND CHANGE IN CTX
Week 26
Bilezikian JP et al J Clin Endocrinol Metab 2016:101:44-51
BMD CHANGE WITH CANAGLIFLOZIN
Total hip
Lumbar spine
Distal radius
Femoral neck
Bilezikian JP et al J Clin Endocrinol Metab 2016:101:44-51
FRACTURES WITH CANAGLIFLOZIN
Watts NB et al J Clin Endocrinol Metab 2016:101:157-166
FRACTURES WITH CANAGLIFLOZIN
Watts NB et al J Clin Endocrinol Metab 2016:101:157-166
FRACTURES IN CANVAS
4.0%
2.6%
Watts NB et al J Clin Endocrinol Metab 2016:101:157-166
FRACTURES IN CANVAS
Watts NB et al J Clin Endocrinol Metab 2016:101:157-166
FRACTURES IN CANVAS
Total
Upper limb
Lower limb
PBO
2.6%
CANA
4.0%
1.2%
1.1%
1.7%
1.6%
Watts NB et al J Clin Endocrinol Metab 2016:101:157-166
FRACTURES IN CANVAS
Rate per 1000 patient years
Site
Placebo
All CANA
4.6
6.5
Hand
0.3
0.6
Wrist
0.5
0.5
Humerus
0.1
0.3
4.9
6.8
Foot
0.3
0.7
Ankle
0.3
0.5
Upper limb
Lower limb
Watts NB et al J Clin Endocrinol Metab 2016:101:157-166
CLINICAL IMPLICATIONS
• Fracture risk is increased in patients with diabetes,
both type 1 and type 2
• Peripheral fractures are increased; hip and spine
fractures appear to be increased as well
• TZDs appear to increase the risk for hip and other
fractures further, especially in postmenopausal women,
more risk with longer treatment
• Canagliflozin slightly increases the risk of upper and
lower limb fractures in older, higher-risk subjects. The
increased risk is seen early, too soon to be due to
changes in BMD or bone turnover; possibly related to
increased risk of falling
DIABETES MELLITUS AND FRACTURE RISK
• “. . . Any reduction of bone mass in
diabetics that is revealed by
sophisticated analysis is of no medical
or economic importance. . . Further
extensive studies of bone metabolism
in diabetics are unlikely to yield results
of practical importance. . . ”
•
Heath HH III et al, N Engl J Med 1980;303:567-570
• Until more is known, it is not
unreasonable to consider
diabetes as a risk factor for
fracture; patients with type 2
diabetes are certainly not
protected from fracture and
deserve at least the same
screening for osteoporosis that is
recommended for nondiabetic
subjects.
Watts NB and D’Alessio DA J Clin Endocrinol Metab 2006:91;3276-3278
FRAX UNDERESTIMATES FRACTURE RISK
IN PATIENTS WITH DIABETES
Schcter GI and Leslie WD, Calcif Tiss Int 2016; epub ahead of print
USING FRAX WITHOUT BMD
NO ADJUSTMENT FOR DIABETES
USING FRAX WITHOUT BMD
TYPE 2 DM
RR 1.7 FOR HIP FX, 1.4 FOR MAJOR FX
CHECK OFF “SECONDARY OSTEOPOROSIS”
7.9
x 1.4
0.9
x 1.7
USING FRAX WITH BMD
NO ADJUSTMENT FOR DIABETES
USING FRAX WITH BMD
NO ADJUSTMENT FOR DIABETES
USING FRAX WITH BMD
TYPE 2 DM
RR 1.7 FOR HIP FX, 1.4 FOR MAJOR FX
REDUCE T-SCORE BY -0.5
x 1.4
11
15.4
1.7
2.9
x 1.7
TYPE 2 DM INCREASES FRACTURE RISK
• RR ~1.4 for clinical fractures
• RR ~1.7 for hip fracture
• FRAX without BMD
– Secondary osteoporosis = DM risk
• FRAX with BMD
– Reduce T-score by 0.5
• Glucocorticoid Rx = TZD risk
TRABECULAR BONE SCORE (TBS)
Silva et al. JBMR 2014; Epub.
TRABECULAR BONE SCORE (TBS)
TBS is a texture analysis parameter
which correlates with micro-architecture parameters
Roux JP et al. ASBMR 2012
Hans et al. JCD 2012
Resch et al. ASBMR 2012
Bilezikian JCEM 2013
BMD OR TRABECULAR BONE SCORE
(TBS) TO PREDICT FRACTURE IN T2DM?
29,407 women age 50 and older
2356 with DM, median f/u 4.7 yr
Leslie WD et al J Clin Endocrinol Metab 2013:98:602-609
ANTI-RESORPTIVE DRUGS DO NOT
AFFECT THE RISK FOR GETTING DIABETES
Risk of incident diabetes
Schwartz AV et al J Bone Miner Res 2013;28;1348-1354
Bonnet N Calcif Tiss Int 2017;100:174-183
Bonnet N Calcif Tiss Int 2017; 100:174-183
SKELETAL FRAGILITY AND FRACTURE RISK
IN PATIENTS WITH DIABETES
• Fracture risk is increased in patients with diabetes
• The causes are multiple: increased skeletal fragility and
increased risk of falling
• TZDs increase fracture risk further; effects of
canagliflozin are minor
• Fracture risk should be assessed in patients with T2DM
– Adjustments are needed for accurate use of FRAX
• For patients at high risk of fracture, pharmacologic and
other measures to reduce fracture risk should be
considered but no agents have proven efficacy
Thank you
for your
attention
[email protected]