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Osteoporosis
Training Course in Sexual and Reproductive Health Research
Geneva, February 17 2009
Prof René Rizzoli M.D.
Division of bone diseases
WHO collaborating center for osteoporosis prevention
Department of rehabilitation and geriatrics
Geneva university hospitals and Faculty of medicine
Geneva, Switzerland
A systemic skeletal disease characterized
by low bone mass and
microarchitectural deterioration, with a
consequent increase in bone fragility with
susceptibility to fracture.
Osteoporosis Definition
Consensus Development Conference: Am J Med 1991;90:107-110
Osteoporosis:
a 2-Stage Disease
•With
•Without Fracture
Osteoporosis:
Lecture Content
•Disease Definition
•Epidemiology
•Burden
•Diagnosis
•Pathophysiology
•Management
0
5
10
15
20
25
30
Women Men Women Men Women Men
Age Group (Years)
Minor Fractures
Other Major Fractures
Vertebral Fractures
Proximal Femur Fractures
60–69 70–79 > 80
Center J et al. Lancet. 1999;353:878–882.
Fractures by Age and GenderDubbo Osteoporosis Epidemiology Study, 1989–
1994
Lifetime risk of fragility fracture in the
Swedish population at the age of 50 years (%)
Women Men
• Proximal femur 23 11
• Distal forearm 21 5
•Vertebral (clinical) 15 8
•Proximal Humerus 13 5
• Any 46 % 22 %
From Kanis et al 2000
(Switzerland 51 % 20 %)
1 500 000 *
0
500
1000
1500
2000
Osteoporotic
Fractures
Riggs BL, Melton LJ. Bone. 1995.
Heart and Stroke Facts. 1996. American Heart Association.
Cancer Facts & Figures. 1996. American Cancer Society.
*annual incidence all ages
† annual estimate women 29+
‡annual estimate women 30+
§1996 new cases,all ages
513 000 †
228 000 ‡ 184 300 §750 000vertebral
250 000 other sites
250 000forearm
250 000hip
An
nu
al
incid
en
ce x
1000
Heart
AttackStroke Breast
Cancer
Osteoporotic Fractures in Women:
Comparison With Other Diseases
Projected burden of osteoporotic
hip fractures worldwide
0
200
400
600
800
North
America
Europe Latin
America
Asia
1950
2050
3250
Estimated n°of hip
Fractures (1000s)
Number of hip fractures: 1990: 1.66 million; 2050: 6.26 million
Adapted from Cooper C., Melton U, Osteoporosis Int 2:285-289, 1992
If the prevalence of hip fracture continues
to rise at current rates, it may well be that
in the next few decades, orthopaedists
will do little else but treat this problem.
W. C. Hayes, In: Bone Formation and Repair
(American Academy of Orthopaedic Surgeons) 1994
Burden
Degree of dependence
50 70 80 9060
normal
aging
Forearm
fracture
Vertebral
fracture
Hip fracture
Age (years)
Morbidity After Vertebral Fractures
• Back pain
• Loss of height
• Deformity (kyphosis, protuberant abdomen)
• Reduced pulmonary function
• Diminished quality of life: loss of self-esteem,
distorted body image, dependence on narcotic
analgesics, sleep disorder, depression, loss of
independence
A Fragility Fracture -> Fracture
A dangerous vicious circle
New fracture
First fracture
Inactivity
Social
isolation
DepressionPain
Loss of
autonomy
Low bone mass
Mortality after Major Types of
Osteoporotic Fracture
in Men and Women: an Observational StudyCenter et al, Lancet 1999
5 - Year Prospective Cohort Study
Age-Standardized Mortality Ratio
Fracture Women Men
Proximal Femur 2.2 3.2
Vertebral 1.7 2.4
Other Major 1.9 2.2
Other Minor 0.8 1.5
Time after hip fracture (years)
2 4 6 8 10
0.00
0.25
0.50
0.75
1.00
Hip fractured Women
Hip fractured Men
Women
Men
Su
rviv
al p
rob
ab
ilit
y
Expected survival in the the general population
Survival after Hip FractureTrombetti et al, Osteoporos Int 2002
0 1000 2000 3000 4000
Osteoporosis
Ischemic Heart Diseases
Chronic Obstructive Pulmonary Diseases
Osteoarthritis
Alzheimer’s
Cirrhosis
Asthma
Migraine
Hypertensive Heart Disease
Rheumatoid Arthritis
Peptic Ulcer
Parkinson’s
Multiple Sclerosis
Benign Prostatic Hyperplasia
Johnell & Kanis, Osteoporos Int 2006 Disability-Adjusted Life-Years (DALYs) Lost
Disability-Adjusted Life-Years Lost because of
Non-communicable Diseases in Europe
Osteoporosis Results in More Cost than
Many Other Diseases
Number of bed days (men and women)
• 701,000 for osteoporosis
• 891,000 for COPD
• 533,000 for stroke
• 328,000 for myocardial infarction
• 201,000 for breast cancer
Lippuner et al. Osteoporosis Int 1997; 7: 414-25
Osteoporosis
# 1 when
looking at
women only
Diagnosis
X-ray techniques
DXA
pQCT
pDXA
Io
I
DXA: Principle
• Two attenuation profiles:
Low energy X-ray attenuation
High energy X-ray attenuation
• Multiply high energy profile by ‘k’ factor (ratio of soft tissue attenuation at low- & high-energy)
• BMD along scan = Low-energy profile - k-corrected high energy profile
0
2
4
6
8
10
12
I II III IV
BMD & Hip fracture
BP & stroke
Cholesterol & MI
Gradients of risk
Relative risk
Quartile
Noninvasive Measurement
of Bone Mineral Mass
Technique Site Precision Cost Response
to Therapy
SXA Forearm ++ ± ±
Heel
DXA Spine ++ + ++
Hip + + +
Tot. Body ++ + ±
QCT Spine ± ++ +
Forearm ++ +(+) ±
US Heel ± - -
+ Fingers
Medicare Coverage for BMD Tests
Procedure Site Fee Schedule
Medicare *
DXA Axial $ 128
pDXA Appendicular $ 40
RX Absorptiometry Appendicular $ 38
QUS Appendicular $ 53
SXA Appendicular $ 40
QCT Axial $ 185
pQCT Appendicular $ 40
* Medicare Allowable Charge = 80% of the Costs
JAMA 288:1889-1897,2002
Example for T-score = - 2.0, 60 year old
and Z-Score = - 0.5
20 40 60 80 100
1.20
0.96
0.84
0.72
1.08
1.32
BM
D g
/cm
2
Spine: L1-L4
Age
Z
T-Score
0
-1
-2
-3
+1
-4
T
T-score
Normal -1
Osteopenia < -1 and > -2.5
Osteoporosis -2.5
SevereOsteoporosis
-2.5 with Fracture
Diagnosis of Osteoporosis Using Central DXA
WHO-Definition
Mainly for Spine and Hip in Women
Pathophysiology
Osteoporosis Pathogenesis and Management
Fracture
Fracture Treatment
Rehabilitation
-> To Restore Independence
-> To Reduce Disabilities
Prevention Subsequent Fracture
Osteoporosis Pathogenesis and Management
Fracture
Fracture Treatment
Mechanical Incompetence
Osteoporosis
Low Peak Bone Mass
Sex Hormone Deficiency
Age
Nutritional Insufficiency
Rehabilitation
-> To Restore Independence
-> To Reduce Disabilities
Prevention Subsequent Fracture
Osteoporosis Pathogenesis and Management
Fracture
Fracture Treatment
Mechanical Overload Mechanical Incompetence
Falls
Sway
Walking
Muscle Strength
Neuro-muscular Impairment
Osteoporosis
Low Peak Bone Mass
Sex Hormone Deficiency
Age
Nutritional Insufficiency
Rehabilitation
-> To Restore Independence
-> To Reduce Disabilities
Prevention Subsequent Fracture
Determinants of Fracture Risk
1.Age
2. Prevalent Fracture
3. Family history of Fracture
4. Glucocorticoid
5. Low BMI
6. Alkohol, Smoking
7. Baseline BMD
8. Baseline Turnover
Type I collagen epitopes and
Cathepsin K cleavage sites
N C
a2 (I) JYDGKGVG GPP-SAGFDFSFLPQPPQ EKAHDGGR a 1
NTX CTXICTP
CK CK CK CK
CK CK
Garnero et al., JBC, 1998
Sassi et al., Bone, 2000
Deoxypyridinoline
Pyridinolines
Age (years)
10 20
Tracking of Bone Mineral MassB
on
e M
inera
l M
ass
50 90
Fracture
Risk
A
B
10 20 40 70Age:
Rizzoli et al.,J Mol Endocrinol 2001
Peak Bone Mass
HeredityGender
Hormones
Nutrition
Risk Factors
Mechanical
Forces
• Resting
• Resorption
• Formation
• Reversal
•Coupled and balanced
•Uncoupled and imbalanced
•Coupled but imbalanced
•Uncoupled but balanced
MALNUTRITION IN ELDERLY
Calcium Deficiency
- > PTH - > Bone Resorption
Vitamin D Deficiency
OSTEOPOROSIS
- > IGF-1
Protein Deficiency - > Bone Formation
- > Sensitivity
to IGF-1
Management
•Indication to treatment
•Treatment possibilities
–4 –3 –2 –1 0 1 2 3
BMD (SD units)
Su
bje
cts
Nu
mb
er
Osteoporosis Preventive Strategies
Present Situation
Whole Population
Modification
Target very
High Risk
Higher Risk
Population
Modfication
0
10
20
30
40
50
60
70
0 -1 -2 -3
T-score
0 -1 -2 -3
None
Prior fracture
+Glucocorticoids
+Family history
Men Women
US Caucasian, no CRF, BMI=24 *Hip, spine, humerus, forearm
Probability of osteoporotic
fracture* at age 65
10-year probability (%)
06ca106 FRAX
Patient
65
65
165
-2.5
23.9
8.0
24
Age
10-Year Risk:
50%
40%
30%
20%
°
°
10%
2
1
General Management
•Treatment of any Disease Causing Bone Loss
•Ensure Dietary Calcium Intake ≥ 1000 mg /d
•Ensure Adequate Dietary Protein Intake
•Correct or Prevent Vitamin D Insufficiency (800 IU/d)
•Promote Weight-Bearing Physical Exercise
•Reduce Falling Risk
•Reduce Fall Consequences (Hip Protectors)
Risk Factors Associated with Falls
1. Impaired Mobility, Disability
2. Impaired Gait and Balance
3. Neuromuscular or Musculoskeletal Disorders
4. Age
5. Impaired Vision
6. Neurological, Heart Disorders
7. History of Falls
8. Medication
9. Cognitive Impairment
After Myers et al., Bone 1996
The Hip Protector
Hip Fracture Prevention
•RCT in Community: No
•RCT in Nursing Homes:
Cluster Random.: Yes
Individual Random.: No
Left vs Right: No
•Problems
Compliance
Persistence
Therapeutic Agents Used in Osteoporosis
Anticatabolic
Agents
Anabolic
Agents
•Estrogens ± Progestagens
•SERMs
•Bisphosphonates
•Calcitonin
•Calcium
•Denosumab
•(Fluoride)
•Parathyroid Hormone
Complex Action•Vitamin D and Derivatives
•Anabolic Steroids
•(Ipriflavone)
•Tibolone
Mixed Action•Strontium Ranelate
H. Bischoff-Ferrrari et al JAMA 2004
Vitamin D and Risk of Falling
WHI Study,
Cauley et al, 2003
Hormone Replacement Therapy and Fracture Risk
Hip
Vertebral
All Fractures
Placebo
HRT
Women’s Health Initiative - First randomized, controlled trial in women
(50-79 years) treated with HRT
6700 women with 5.2 years of follow-up
-37% -34% -34%
+29% +26%+41%
+112%
-80
-40
0
40
80
120
160
Inte
sti
nal can
cer
Dif
fere
nce %
vs. p
laceb
o
Vert
eb
ral fr
actu
re
Hip
fra
ctu
re
Card
iovascu
lar
dis
eases
Str
ok
e
Bre
ast
can
cer
AdvantagesTro
mb
. ven
ou
s
Disadvantages
Manson JE at al, N Engl J Med, 2003;349:523-534
* with prev vert fracture(s) ** without prev vert fractures *** with or without prev vert fractures
Vertebral Fx
0.6 1.00.2
RLX 60 (MORE)*
RLX 60 (MORE)**
CT 200 (PROOF)*
Teriparatide 20µg*
ALN 5/10 (FIT1)*
ALN 5/10 (FIT2)**
RIS 5 (VERT-NA)*
RIS 5 (VERT-MN)*
Strontium ranelate(SOTI)*
Strontium ranelate
(SOTI +TROPOS)**
Update from Delmas 2002
IBAN 2.5 ***IBAN inter
Anti -fracture efficacy (RR ± 95% CI)
ZOL
* with prev vert fracture(s) ** without prev vert fractures *** with or without prev vert fractures
0.6 1.00.2
Non-Vertebral Fx
RLX 60, 120
(MORE)***
CT 200 (PROOF)*
Teriparatide 20µg*
ALN 5/10 (FIT1)*
ALN 5/10 (FIT2)**
RIS 5 (VERT-NA)*
RIS 5 (VERT-MN)*
RIS 2.5/5 (Hip Study)***
Vertebral Fx
0.6 1.00.2
RLX 60 (MORE)*
RLX 60 (MORE)**
CT 200 (PROOF)*
Teriparatide 20µg*
ALN 5/10 (FIT1)*
ALN 5/10 (FIT2)**
RIS 5 (VERT-NA)*
RIS 5 (VERT-MN)*
Strontium ranelate(SOTI)*
Strontium ranelate
(SOTI +TROPOS)**
Strontium ranelate
(TROPOS)***
Strontium ranelate
(SOTI)*
Update from Delmas 2002
IBANIBAN 2.5 ***
IBAN inter
Anti -fracture efficacy (RR ± 95% CI)
ZOLZOL
* with prev vert *** with or without prev vert fractures
0.6 1.00.2
Hip Fx
RLX 60, 120
(MORE)***
CT 200 (PROOF)*
Teriparatide 20µg*
ALN 5/10 (FIT1)*
ALN 5/10 (FIT2)**
RIS 5 (VERT-NA)*
RIS 5 (VERT-MN)*
RIS 2.5/5 (Hip Study)***
Strontium ranelate
(TROPOS)***
Strontium ranelate
(SOTI)*
IBAN
Anti -fracture efficacy (RR ± 95% CI)
Significant hip fracture risk
Reduction: 3 studies
Only studies with
preplanned analysis:
RIS 2.5/5 (Hip Study)
ZOL 5 mg (Horizon Study)
ZOL
Bisphosphonate New Schedules of Administration
1. Weekly (Alendronate, Risedronate)
-> Monthly Oral Administration - Ibandronate
- Risedronate
2. Trimonthly Intravenous Administration - Ibandronate
3. Annual Intravenous Administration - Zoledronate *
4. Sequential Regimen (PTH -> ALN, RIS or ALN -> PTH)
*: Fracture Data
Mechanism of Action of Denosumab
Activated
Osteoclast
CFU-M
Pre-Fusion
Osteoclast
Multinucleated
Osteoclast
BONE
Growth Factors
Hormones
Cytokines
RANK
Denosumab
RANKL
OPG
ASBMR 2008 - D’après Cummings S.R. et al., San Francisco, États-Unis, abstract 1286,
Placebo
Denosumab
0
0,5
1
1,5
2
2,5
3
3,5
Year 10-1
Year 21-2
Year 32-3
2,2 %
0,9 %0,7 %
3,1 % 3,1 %
1,1 %
Inc
ide
nc
e (
%)
61 %p < 0,0001
78 %p < 0,0001
65 %p < 0,0001
Reduction in vertebral fracture risk
Phase III Trial on the Effects of Denosumab on
Vertebral Fracture Risk in Women with
Postmenopausal Osteoporosis
0 6 12 18 24 30 36
0
0,5
1,0
1,5
2,0
Cu
mu
lati
ve
In
cid
en
ce
(%
)
Months
Placebo
Denosumab
0,7 %
1,2 %
40 %
p = 0,036IC95 : 3-63
Hip Fractures
Hip Fracture : 69
Non-Vertebral Fractures
Placebo
Denosumab 8,0 %
6,5 %
0 6 12 18 24 30 36
Months
0
2
4
6
8
10
20 %
p = 0,011IC95 : 5-33
Cu
mu
lati
ve
In
cid
en
ce
(%
)
ASBMR 2008 - D’après Cummings S.R. et al., San Francisco, États-Unis, abstract 1286,
No-Vertebral Fractures : 531
Phase III Trial on the Effects of Denosumab on
Non-Vertebral Fracture Risk in Women with
Postmenopausal Osteoporosis
Osteoporosis Treatment in 2009
Summary
•HRT: spine fx; hip fx
• SERMS: spine fx; no effect on peripheral fx
•Calcitonin: possible spine fx; no hip data
• Alendronate: spine fx; hip fx
•Risedronate: spine fx; hip fx
• Ibandronate: spine fx; no effect on hip
• Zoledronate: spine fx; hip fx
• PTH: spine fx
• Strontium Ranelate: spine fx; hip fx
•Denosumab: spine fx; hip fx
BISPHOSPHONATES
CALCIUM
Vit D (if deficient)
•Advancing age
•Lower BMD
•Presence of Fracture
•Risk factors or disease
causing continued
bone loss
•Leanness
•Family history
Factors Influencing
Treatment
DecisionHRT
RALOXIFENE
50 55 60 65 70 75
No Normal
Treatment
Yes, if fx
OsteoporosisIncreasing
need to
treat
Older
Lower
BMD
80
Osteopenia- 2.5 SD
- 1.0 SD
BMD
T score
Yes
Adapted from
E. Seeman
(2004)
PTH
STRONTIUM RANELATE
≠ Treatment of
Osteoporosis
= Treatment of Patients
with Osteoporosis
1. Aim of Therapy
2. Never Too Late
Fractures are not Unavoidable Expenses to Pay
as a Consequence of Increased Life-Expectancy
Because of
•Better Identification of Risk Factors for Osteoporosis
•Early Diagnosis, before the First Fracture
•A Larger Use of Preventive and Therapeutical Strategies,
whose Efficacy has been Demonstrated in Randomized
Controled Trials, with Fracture Incidence as Primary End-
Point
Bazedoxifene significantly reduces the risk of new vertebral fracture in postmenopausal women with osteoporosis
ASBMR 2007 – From Silverman SL et al., Beverly Hills, USA, abstract 1206, updated
Incidence of new vertebral fracture (intent-to-treat population 0-36 months)
0 6 12 18 24 30 36 42
Months
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Kapla
n-M
eie
r (K
-M)
fra
ctu
re r
ate
(%
)
Bazedoxifene 20 mgBazedoxifene 40 mgRaloxifene 60 mgPlacebo
*
* p < 0.05 for any active group versus placebo
• Results
– the reduction in the incidence of new
vertebral fractures was (as compared to
placebo)
• - 42% in group I
• - 37% in group II
• - 42% in group III
– there was no treatment effect on NVF
– there was no difference between the
different groups with regard to adverse
effects
Effect of Bazedoxifene on Vertebral Fracture in Postmenopausal Women with Osteoporosis
Long-Term Vertebral and Non-vertebral FractureRisk Reduction with Strontium Ranelate
Favors Strontium ranelate
RELATIVE RISKS AND 95% CI
RR
Over 5 years
0 0.5 1 1.5
- 24% P<0.001Vertebral fractures
- 15%
P=0.025- 18%
Non vertebral fractures P=0.032
Major non vertebral fractures
P=0.010- 31% Vertebral fractures, 80 years
P=0.019- 26% Non-vertebral fractures, 80 years
Reginster et al 2007
Pathogenesis of Osteoporotic Fracture
LOW PEAK
BONE MASSAGE-RELATED
BONE LOSS
POSTMENOPAUSAL
BONE LOSS
LOW BONE
MASSOther risk
factors
Nonskeletal factors
(propensity to fall) FRACTUREPoor bone quality
(architecture)
Boonen, Lips et al., unpublished observations
Hip Fracture Risk – Vitamin D & CalciumVersus Placebo/No Treatment
Source
Pooled Estimate
Dawson-Hughes et al. 1997
Chapuy et al. 2002
Porthouse et al. 2005
0.36 (0.02-8.78)
0.62 (0.36-1.07)
1.14 (0.76-1.73)
0.71 (0.31-1.64)
0.82 (0.71-0.94)
FavorsTreatment
FavorsPlacebo
Weight(%)
Relative Risk
(95% CI)
0.1 0.5 1.0 1.5 2.0
0.2%
6.5%
2.8%
10.9%
100.0%
Relative Risk (95% CI) of Hip
Fracture
RECORD Trial Group 2005
0.88 (0.72-1.07)40.7%
Chapuy et al. 1994 0.74 (0.60-0.91)38.9%
WHI Trial Group, 2006
P=0.0005
Bo
ne M
inera
l M
ass
Age (years)
10 20
Tracking of Bone Mineral Mass Accrual