stephen hough, mediclinic durbanville & endocrine unit ... · stephen hough, mediclinic...
TRANSCRIPT
Stephen Hough,
Mediclinic Durbanville &
Endocrine Unit Stellenbosch University
SASOG 2014
The European (IOF) Effort
The American (ASBMR) Effort
Normal Osteoporotic
Determinants of bone strength
Bone Mass (BMD)
Determinants of Bone Strength
Bone Quantity BMD
Bone Quality
• Macro- architecture
• Micro- architecture
• Bone Turnover
• Material Properties
- Geometry / size
• Cortical – porosity, thickness
• Trabecular – size, number, connectivity
Diagnosis of Osteoporosis: Methodology
Conventional Skeletal Radiology
DXA
Accurate measurement of arial BMD
Epidemiologic data to corroborate BMD data
Adequate assessment of vertebral morphology
QCT
QUS
p QCT; p DXA
Vertebral Fracture Assessment (VFA)
Genant classification of vertebral fractures.
Changes in Bone Density with Age
C 13
0 . 6
0 . 8
1 . 0
1 . 2
1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0
A g e ( Y e a r s )
Spine BMD
(g/cm2)
by DXA
White Women
Increase with adolescence
Peak bone mass
Plateau maintained
Menopausal bone loss (~1%-2% per year)
Age-related bone loss
(0.5% - 1.0% per year)
7
ASSOCIATION BETWEEN BMD AND RISK OF FRACTURE IN PMW
The association is continuous
Low BMD = high risk
0
2
4
6
8
10
-3 -2 -1 0 1
Hip Bone Density (T-score)
Re
lative
Ris
k o
f F
ractu
re
LUMBAR (L1-L4) BMD
FEMORAL BMD
T-Score
T = −2.0 Z = −0.5
0.0
-1.0
-2.0
-3.0
+1.0
T
Z
20 40 60 80 100
1.200
0.960
0.840
-4.0 0.720
1.080
1.320
BMD gm/cm2 Spine: L1-L4
Age
WHO Criteria for Osteoporosis
in Postmenopausal Women
Normal BMD or BMC < 1SD below the young adult reference range
Low bone mass BMD or BMC 1 - 2.5SD below the mean of young healthy women
Osteoporosis BMD or BMC > 2.5SD below the mean of young healthy women
Severe osteoporosis BMD or BMC > 2.5SD below the mean of young healthy women and the presence of one or more fragility fractures
WHO Technical Report Series: B43,1994
Assessment of BMD in Premenopausal
Women
WHO criteria and T-scores do not apply
Only Z-scores should be used: within 1 SD of norm = normal
decreased between 1 and 2 SD below the norm = uncertain or
intermediate
decreased > 2 SD is abnormal but, given the uncertainty re the relationship
between BMD and fracture risk in premenopausal women, is not sufficient
to confirm a diagnosis of osteoporosis.
Therefore, refer to a BMD Z-score of - ≤2SD as a
low BMD - not osteoporosis.
Diagnostic Criteria
Fragility fracture
Significantly low BMD (i.e. Z-score
decreased by ≥ 2 SD) plus one or more
well-known secondary causes of
osteoporosis.
WHO Criteria for Osteoporosis
in Postmenopausal Women
Normal BMD or BMC < 1SD below the young adult reference range
Low bone mass BMD or BMC 1 - 2.5SD below the mean of young healthy women
Osteoporosis BMD or BMC > 2.5SD below the mean of young healthy women
Severe osteoporosis BMD or BMC > 2.5SD below the mean of young healthy women and the presence of one or more fragility fractures
WHO Technical Report Series: B43,1994
WHO criteria based on data from white postmenopausal women employing axial DXA and cannot be extrapolated to other populations or techniques to measure BMD
No general agreement on skeletal sites to measure BMD, nor
most appropriate reference data to uses
Causes of a low BMD other than osteoporosis not considered
Bone quality not assessed Extraskeletal risk factors not addressed
Limitations of Mass-based Definitions of Osteoporosis
WHO criteria based on data from white postmenopausal women
employing axial DXA and cannot be extrapolated to other populations or techniques to measure BMD
No agreement on skeletal sites to measure BMD, nor most appropriate
reference data to use Bone quality not assessed Extraskeletal risk factors not addressed Causes of a low BMD other than osteoporosis not considered
Single BMD measurement lacks sensitivity (± 50%)
Limitations of Mass-based Definitions of Osteoporosis
Fracture Rates, Population BMD Distribution and Number of Fractures
BMD T-scores
60
50
40
30
20
10
0
Fra
ctu
re r
ate
per
1000 p
ers
on
-years
>1.0 1.0 to 0.5
0.5 to 0.0
0.0 to –0.5
–0.5 to –1.0
–1.0 to –1.5
–1.5 to –2.0
–2.0 to –2.5
–2.5 to –3.0
–3.0 to –3.5
–3.5
Siris ES, et al.JAMA. 2001;286:2815-22.
Fracture Rate
<-3.5
Fracture Rates, Population BMD Distribution and Number of Fractures
# Fractures
BMD T-scores
60
50
40
30
20
10
0
450
350
300
250
200
100
0
150
50
400
Fra
ctu
re r
ate
pe
r 1
00
0 p
ers
on
-ye
ars
# F
rac
ture
s
>1.0 1.0 to 0.5
0.5 to 0.0
0.0 to –0.5
–0.5 to –1.0
–1.0 to –1.5
–1.5 to –2.0
–2.0 to –2.5
–2.5 to –3.0
–3.0 to –3.5 < –3.5
BMD distribution
Siris ES, et al. JAMA. 2001
Fracture Rate
50 60 70 70 80 age
- 2.5 SD - 2.5 SD
- 1.0 SD - 1.0 SD
BMD
T score
BMD T-scores
OSTEOPOROTIC FRACTURES
Fx/1000 p-yrs Women with Fxs
0
5
10
15
20
25
30
35
40
45
50
1 0.5 0 -0.5 -1 -1.5 -2 -2.5 -3 -3.5 0
50
100
150
200
250
300
350
400
450
Fracture Rate
Women with Fxs
25%
75% 16% normal
57% osteopenia
FRACTURE RISK ASSESSMENT
Diagnosis of osteoporosis: low BMD or #
Only 10 – 44% of women with an osteoporotic fracture has a BMD T-score ≤ - 2.5
Sensitivity can be improved by:
lowering BMD threshold (e.g. T- score ≤ -2.0)
combining BMD + other risk factors
These other risk factors could include:
Clinical risk factors (CRFs)
Bone turnover (Biomarkers; Bx)
Others (QUS; Genetic markers)
CLINICAL RISK FACTORS (CRFs)
Advanced age, prior #, low BMI, family
history
Life style (e.g. alcohol, smoking, exercise)
Secondary osteoporoses (hypogonadism, GIOP)
Inadequate calcium / vitamin D nutrition; Falls
Generally lack sensitivity; may differ among patient populations. CRFs are additive in the prediction of fractures Local research necessary
INTEGRATED APPROACH TO FRACTURE RISK ASSESSMENT
Diagnostic Criteria vs Intervention Thresholds
Consider treatment in those with prior fragility fractures
Consider treatment when the DXA T-score is ≤ -2.5
Also consider treatment in subjects in whom a diagnosis of osteoporosis has not been confirmed, by employing an appropriate fracture risk assessment tool like SCORE, SOF fracture risk score, QFracture Score, FRAX etc
The FRAX® Tool
This large study (>60,000 subjects / > 12 study populations) identified a number of robust CRFs for the development of osteoporosis
Assessed the relative importance of the CRFs and their interactive and additive nature
Model output is the estimated 10-year probability of a hip and/or major osteoporotic fracture
Can be utilised ± BMD data
Major clinical risk factors identified
The FRAX® Tool
Major clinical risk factors identified:
Prior osteoporotic fracture
Advanced age
Family history of hip #
≥ 3/12 use of systemic GCs
Alcohol ≥ 3 drinks / day
Smoking
Low BMI
RA and other secondary osteoporoses
INTEGRATED APPROACH TO FRACTURE RISK ASSESSMENT
Diagnostic Criteria vs Intervention Thresholds
Consider treatment in those with prior fragility fractures
Consider treatment when the DXA T-score is ≤ -2.5
Also consider treatment in subjects in whom a diagnosis of osteoporosis has not been confirmed
Local incidence of osteoporosis in different populations needs to be assessed, following which a health economic strategy for the treatment of the disease needs to be formulated
NOFSA Recommendations
NON-PHARMACOLOGICAL MANAGEMENT
Adequate calcium (1200mg/d) and vitamin D (800IU/d)
Additional calcium and vitamin D (2,000 IU/d) during pregnancy/lactation
Serum 25(OH)D levels
Walking 30 - 40 min 3x/week
Limit alcohol < 3 units per day
Stop smoking
Avoid bone toxins
Prevent falls
PREVENTING FALLS
Medication – sedatives, hypnotics, etc.
Gait & balance
Cognition & affect
Weakness & mobility
Vision & depth perception
Environmental safety
Recurrent falls
Drug Therapy for Osteoporosis
• Anti- Resorptive Agents
- Calcium
- Vitamin D / Metabolites
- Sex Hormones / SERMS
- Calcitonins
- Bisphosphonates
• Formation Stimulating Agents
- Fluoride
- Anabolic Steroids
- Low-Dose Intermittent PTH
• Dual-/ Complex Action Drugs
- Strontium Salts
- Denosumab
Monitoring Therapy
• Clinical
– Disease progression
– Patient compliance
– Drug side effects
• Vertebral Imaging
• Biomarkers
• Routine BMD
– Techniques: DEXA
– Principles: The debate
Hormone Therapy (HT) for Osteoporosis
Initiate for specific indications, when not contra-indicated. For example the 50 - 60 yr woman with vasomotor or urogenital symptoms who is at risk of fracture
HT not recommended > age 60 yr.
Use doses known to provide fracture protection
Use most suitable therapeutic regimen
Monitor response to treatment, since 10 – 20% may lose BMD despite HT. Additional therapy required after D/C.
Current SERMS – use in selected cases
Tibolone – use limited by its safety profile
Phyto-oestrogens, progestins and testosterone cannot be recommended in women
Bisphosphonates (BPs) for Osteoporosis
One of the first-line treatments for osteoporosis in PMW, men and
GIOP
Antifracture efficacy largely limited to patients at high risk – i.e.
those with T-scores ≤ -2.5
Precautions: empty stomach, water only, do not recline, not with
creatinine clearance < 30 ml/min
Osteonecrosis of the jaw (ONJ)
Duration of treatment, atypical fragility fractures, drug holidays
Antifracture efficacy of BP preparations – generic BPs
Drug Therapy for Osteoporosis
• Anti- Resorptive Agents
- Calcium
- Vitamin D / Metabolites
- Sex Hormones / SERMS
- Calcitonins
- Bisphosphonates
• Formation Stimulating Agents
- Fluoride
- Anabolic Steroids
- Low-Dose Intermittent PTH
• Dual-Action Drugs
- Strontium Salts
J Med 2007;357:905-916
The Anabolic Window
The Anabolic Window
Canalis et al 2007
Teriparatide (PTH 1-34) for Osteoporosis
To be used only per specific indication, when not contra-indicated.
20 μg/d sc, for 18 months. Monitor serum and urine calcium
If taking HT or SERM, merely add the teriparatide. Less clear
whether to add or switch to teriparatide when taking a BP
Preserve bone mass gained when completing 18/12 course of
teriparatide
Drug Therapy for Osteoporosis
• Anti- Resorptive Agents
- Calcium
- Vitamin D / Metabolites
- Sex Hormones / SERMS
- Calcitonins
- Bisphosphonates
• Formation Stimulating Agents
- Fluoride
- Anabolic Steroids
- Low-Dose Intermittent PTH
• Dual-Action Drugs
- Strontium Salts
Strontium Ranelate for Osteoporosis
One of the first-line treatments for postmenopausal osteoporosis
Long-term antifracture data available
Effective in patients with osteoporosis, as well as those with
osteopenia
Effective in the very old (>80yr)
Contra-indicated in those with uncontrolled hypertension, known
CVD or at risk of VTE
DRESS syndrome
Rational Choice of Therapy
• Nature of the Osteoporosis - Severity of the osteopenia
- Presence of fractures
- Skeletal sites
- Specific circumstances
Rational Choice of Therapy
• Nature of the Osteoporosis - Severity of the osteopenia
- Presence of fractures
- Skeletal sites
- Response to therapy
• The Patient - Healthy, requiring a bone-specific drug
- Menopausal symptoms
- Risk of breast cancer
- Frail elderly / Life expectancy
- Personal preferences / Willingness
Rational Choice of Therapy
• Nature of the Osteoporosis - Severity of the osteopenia
- Presence of fractures
- Skeletal sites
- Response to therapy
• The Patient - Healthy, requiring a bone-specific drug
- Menopausal symptoms
- Risk of breast cancer
- Frail elderly / Life expectancy
- Personal references / Willingness
• Cost-Effectiveness / Side-Effects
• Availability
Monitoring Therapy
• Clinical
– Disease progression
– Patient compliance
– Drug side effects
• Vertebral Imaging
• Biomarkers
• Routine BMD
– Techniques: DEXA
– Principles: The debate
