Bone Turnover Markers

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Osteoporosis Therapies Monitoring
AGENDA
• Introduction Prof Richard Eastell
• Presentation “BTM: Initial Evaluation”
– Questions and Answers
• Introduction Prof Erik Fink Eriksen
• Presentation “BTM in Clinical Decision Making”
– Questions and Answers
• Closing
Prof Richard Eastell
•
Professor of Bone Metabolism at the University of Sheffield and Honorary Consultant Physician in
Metabolic Bone Disease at the Northern General Hospital in Sheffield, England, United Kingdom, where he
is also Head of the Academic Unit of the Bone Metabolism Group and Director of the National Institute for
Health Research Bone Biomedical Research Unit.
•
Professor Eastell has an active research group focusing on the pathophysiology, diagnosis, and treatment
of osteoporosis, and he has published more than 300 papers on osteoporosis and related topics. He is on
the editorial boards of Osteoporosis International and Osteoporosis Review and is an Associate Editor of
Bone. He is Past President of the European Calcified Tissue Society and Past Chairman of the National
Osteoporosis Society.
Bone Turnover Markers: Initial
Evaluation
Professor Richard Eastell, Director NIHR BRU Musculoskeletal
Diseases
Academic Unit of Bone Metabolism,
University of Sheffield, Sheffield, UK
09/03/2012
Outline
• What are bone turnover markers (BTMs)?
– How do we measure them?
• Initial evaluation of bone turnover in osteoporosis
–
–
–
–
Sources of variability
Reference Intervals
Medication and disease
Taking variability into account in clinical practice
• Clinical use of bone turnover markers
– Diagnosis of osteoporosis
– Prediction of rates of bone loss
– Prediction of fracture risk
6
Bone Turnover Markers
• Resorption markers
– Type I Collagen Degradation products
• Pyridinium crosslinks (PYD and
DPD)
• C-and N-telopeptides (CTX, ICTP,
NTX)
–Enzymes
• Tartrate resistant acid phosphatase
(TRACP) 5b
• Cathepsin K
• Matrix metallo-proteinases (MMPs)
• Formation markers
– Matrix proteins
• Procollagen type I
propeptides
– C-terminal (PICP)
– N-terminal (PINP)
• Osteocalcin (OC)
– Enzyme
• Bone isoform of alkaline
phosphatase (bone ALP)
8
Adapted from Leeming et al Eur J Clin Pharmacol (2006) 62: 781–792
Position paper of the International Osteoporosis
Foundation and International Federation of
Clinical Chemistry and Laboratory Medicine
Recommended serum CTX and PINP as reference markers
Vasikaran S, et al; IOF-IFCC Bone Marker Standards Working Group.
Osteoporos Int. 2011 Feb;22(2):391-420
9
Measurement of Bone Turnover
Markers
• Bone turnover markers are often measured using
autoanalysers
Roche Cobas e411
INITIAL EVALUATION OF BONE
TURNOVER IN OSTEOPOROSIS
14
Sources of Variability
• Pre-analytical (usually account for 32-75% variability)
– Patient
– Specimen
• Haemolysis
• Storage
• Analytical
– Performance of tests (assay performance, expertise)
• Post-analytical
– Reporting
• Some sources we know about
• Some sources we do not know about
16
Sources of Variability in Bone
Turnover Markers
• Modifiable source
– Circadian rhythm
– Daily, monthly, seasonal
rhythms
– Diet
– Exercise
• Non-modifiable source
– Stages of life
– Growth
– Pregnancy, Pill
– Menopause
– Gender, race
– Geographical location
– Recent fracture
– Immobility
Hannon R, Eastell R. Osteoporos Int. 2000; 11 Suppl 6:S30-44
17
Circadian Rhythm of Serum CTX
Postmenopausal osteoporotic women, n = 15
Arrows indicate meal times
sCTX (ng/ml)
0.75
0.50
0.25
0.00
08:00
12:00
16:00
20:00
Time
Eagleton A, PhD thesis, 2003
18
Figure 4
Effect of Feeding on CTX Circadian
Rhythm
Serum CTX
Serum OC
Qvist P, et al. Bone 2002;31:57-61
Day to Day Variability in PINP
21 Healthy Young Women
Reference Interval
20
Clowes JA, et al. Bone. 2002 Jun;30(6):886-90
Biochemical Markers after
Ankle Fracture
Formation
Resorption
% baseline
% baseline
220
220
PINP
I-Bone ALP
WG-Bone ALP
OC
200
180
180
160
160
140
140
120
120
100
100
80
80
60
60
13 7 14
13 7 14
28
42
90
180
360
Time, days
Ingle BM et al. Osteoporosis Int. 1999;10:408-15
TRAcP
ifDpd
NTx
200
28
42
90
180
Time, days
360
Reference Intervals
Automated
Manual
CTX
PINP
NTX
Bone ALP
• Several studies
• All show similar
reference intervals for
young women
– Manual assays may
produce higher
values than
automated assays
1. de Papp AE, et al. Bone. 2007;
40:1222-30.
2. Glover SJ, et al. Bone. 2008;
42:623-30.
3. Glover SJ, et al. J Bone Miner
Res. 2009; 24:389-97
Eastell R, et al. Bone 2012 Feb 12 Epub ahead of print.
Diseases and Medications
32
Effects of Disease on BTM
• OPO, osteoporosis
• PHPT, primary
hyperparthyroidism
• PD, Paget’s disease
• MM, multiple myeloma
• BC-, breast cancer without
metastases
• BC+, breast cancer with
metastases
Results expressed as Z scores
Standard deviation units from normal
Mean for normal = 0
Woitge HW, et al. J Bone Miner Res. 1999 May;14(5):792-801
Calcium Supplement Reduces
CTX by 20-40%
CTX
0
*
***
-20
***
**
*
***
***
**
**
*
1
*
**
***
***
-40
-60
0
2
3
*
***
4
***
Group 1 (96 mg); n=7
Group 2 (244 mg); n=9
Group 3 (459 mg); n=7
Group 4 (676 mg); n=6
5
Hours
PTH
0
Percent change
• Young women
received calciumfortified ice cream
• This decreased
CTX and PTH
within a couple of
hours
Percent change
**
-20
-40
*
**
*
***
***
*
***
***
***
***
-60
0
1
2
3
Hours
Ferrar L, et al. Osteoporos Int. 2011 Oct;22(10):2721-31
*
**
**
**
***
* ***
4
5
36
Taking variability into account in clinical practice
37
BTMs Can Respond More Rapidly
than BMD Measurements
Percentage change lumbar spine BMD
Percentage change uNTX/Cr
16
0
12
-25
8
4
-50
0
-4
-8
-75
4
8
12
24
12
24
36
Time, months
Time, weeks
Placebo (500mg Ca/day)
Alendronate (10mg ALN/day + 500mg Ca/day)
Least significant change or critical difference
Machado A, et al. JBMR 1999;14:602-8
Eastell R. N Engl J Med. 1998 Mar 12;338(11):736-46
38
Effect of Lasofoxifene on BTM
100
100
50
0
a
b
Lasofoxifene
% Change Bone ALP
Bone
ALP
% Change Bone Alp
Placebo
-50
-100
-6
0
4
8
12
d
-6
4
12
100
Placebo
50
24
0
a
b
b
-50
0
4
8
12
100
0
d
-6
-50
12
0
4
8
12
100
-100
8
24
Lasofoxifene
50
0
d
-50
d
d
8
12
-6
0
4
Overall P< 0.0001 by repeated measures ANOVA
100
Lasofoxifene
% change U-NTX
Placebo
0
-50
24
Time, weeks
Overall P=0.61 by repeated measures ANOVA
50
d
-100
24
Time, weeks
100
d
Overall P<0.0001 by repeated measures ANOVA
% change sCTX
0
4
d
Time, weeks
50
0
d
-50
-100
24
Placebo
-6
Lasofoxifene
50
Overall P= 0.013 by repeated measures ANOVA
% change sCTX
0
Overall P< 0.0001 by repeated measures ANOVA
Time, weeks
% change U-NTX
8
d
Overall P=<0.01 by repeated measures ANOVA
-6
NTX/Cr
d
Time, weeks
-100
CTX
d
-50
-100
24
% change PINP
% change PINP
0
Time, weeks
100
PINP
50
50
0
d
d
-50
d
d
-100
-100
-6
0
4
8
12
24
Time, weeks
Overall P=0.78 by repeated measures ANOVA
-6
0
4
8
12
24
Time, weeks
Overall P< 0.0001 by repeated measures ANOVA
Rogers A, et al. Bone 45 (2009)
1044–1052
CLINICAL USE OF BONE
TURNOVER MARKERS
40
Clinical Practice
• Identification of secondary osteoporosis
– If bone turnover markers are high, look hard for the cause
• Prediction of accelerated bone loss
• Prediction of fractures
• Monitoring of treatment effect
– Enhancement of adherence
• Monitoring offset of effect
41
Bone Turnover in
Postmenopausal Osteoporosis
May have secondary
osteoporosis
42
BONE LOSS AND BTM
43
High Bone Turnover Markers May
Predict Fracture
EPIDOS, Epidemiologie de l'Osteoporose
5
Odds ratio
4
3
2
1
Low hip
BMD
High
U-CTX
High
U-DPD
Low BMD
+
high CTX
Low BMD
+
high DPD
BMD, bone mineral density; U, urinary
45
Adapted from Garnero P, et al. J Bone Miner Res. 1996;11:1531-38.
Summary
• We have a wide choice of bone turnover markers and can
measure them precisely
• We can use them in the initial evaluation of bone turnover
in osteoporosis if we understand
–
–
–
–
Sources of variability
Reference Intervals
Medication and disease
Taking variability into account in clinical practice
• Bone turnover markers have a number of clinical uses
–
–
–
–
Diagnosis of osteoporosis
Prediction of rates of bone loss
Prediction of fracture risk
Treatment monitoring
46
Prof Erik Fink Eriksen
•
Professor Eriksen is currently professor of Endocrinology at Oslo University Hospital, Aker. In addition to
serving on a number of scientific societies and committees, Dr Eriksen sits on the Board of Directors of the
International Society for Bone Morphometry, and is a member of the Committee of Scientific Advisors,
International Osteoporosis Foundation.
Previously, he served as Chairman Advisory Board, Danish Osteoporosis Society (1994-2000), Chairman,
Danish Bone and Tooth Society (1989-1993) and Board Member, Danish Endocrinology Society (19891993), Scientific Editor of the European Journal Clinical Investigation, Editorial Boards of Bone, Journal of
Bone and Mineral Research, Osteoporosis International and European Journal of Musculoskeletal Research.
He has authored or co-authored 270 publications and 3 books. His work is cited 307 times per year and
each paper has an average citation index of 31.
BONE TURNOVER MARKERS
Erik Fink Eriksen, Oslo University Hospital
48
OVERVIEW
 Validation of bone turnover markers
 Bone remodeling and biochemical markers
 Bone markers in clinical decision making
 Bone markers for therapy monitoring
Antiresorptive therapy
Anabolic therapy
49
BTM AND HISTOMORHOMETRY
Eriksen et al. JBMR 1993
50
BTM AND CALCIUM KINETICS
Eastell et al. JCEM 1988
51
BONE MARKERS IN CLINICAL
DECISION MAKING
52
BONE REMODELING IN
OSTEOPOROSIS
53
BONE STRUCTURE IN
OSTEOPOROSIS
Osteoporotic
Strength of osteoporotic bone is impaired by:
• Loss of bone mass
Young Normal
• Reduction in bone quality:
• Loss of horizontal struts
• Loss of connectivity
• Conversion of trabecular plates to rods
• Resorption pits are “stress concentrators”
• Unfavorable geometry
54
Porosity and antiresorptive therapy
High and low turnover states in cortical bone
Compound osteonal remodeling
Stress riser
High turnover state-scalloping and increased porosity
Low turnover state-reduced endosteal resorption and porosity
RISK FACTORS FOR BONE LOSS
• Anemias hemoglobinopathies
• Chronic respiratory disorders
• Hypogonadism
• Homocystinuria
• Glucocorticoid excess
• Immobilization
• Alcohol, tobacco abuse
• Neoplastic diseases
• GI/hepatic disorders
• Osteogenesis Imperfecta
• Hyperparathyroidism
• Renal insufficiency
• Hypercalciuria
• Rheumatoid arthritis
• Anticonvulsants
• Systemic mastocytosis
• Thyrotoxicosis
• Vitamin D deficiency
BTM - OTHER CLINICAL USES
Bone involvement in metabolic bone disease
Primary hyperparathyroidism
Thyrotoxicosis
Adverse drug effects on bone
Aromatase inhibitors
GIO
Osteogenesis imperfecta
Low levels of PINP and CTX
Stress fractures
Risk assessment
57
BONE TURNOVER
BONE QUALITY CONCEPT
Bone Mass
Bone architecture
Distribution of Mass
Geometry
Architecture
Material Properties
Mineralization
Matrix Quality
Microdamage
BONE
STRENGTH
MONITORING
ANTIRESORPTIVE THERAPY
USING BTM
59
Demographics
Image
Results T- &
Z-scores
Graph
Graph
60
BTM DURING ANTIRESORPTIVE
AND ANABOLIC THERAPY
Formation (PINP)
Resorption (CTx)
Antiresorptive therapy
Alendronate
Anabolic therapy
Teriparatide
TPTD - Bone Formation Resorption Markers
*
250
250
200
200
150
Mean % change with SE
Mean % change with SE
ALN - bone formation and resorption markers
100
50
0
-50
*
-100
150
100
50
0
-50
-100
0 1
3
6
Months
PINP
NTx
OC
OB
Bal
12
0 1
PINP
NTx
3
6
12
Months
OC
OB
Bal
61
Mean (± SE) Urinary NTX
(nmol BCE/mmol creatinine)
KINETICS OF IV. VS. ORAL
BISPHOSPHONATES
50
ALN 70 mg QW
(n = 59)
40
ZOL 5 mg x 1
(n = 69)
30
20
0
*
** *
10
0
2
4
6
*
*
8 10 12 14 16 18 20 22 24 26
Week
*P < .05 for ZOL vs ALN at all postbaseline time points.
ALN = alendronate; NTX = N-telopeptide of type 1 collagen; ZOL = zoledronic acid.
Saag K, et al. Poster presented at: ECCEO6; March 15-18, 2006; Vienna, Austria.
62
Patients Showing a Decrease
from Baseline (%)
RESPONSE RATE DURING IV. BP
THERAPY
100
90
80
70
β-CTx
60
50
PINP
40
Bone ALP
30
20
10
0
N/A
Placebo ZOL 5mg Placebo
6 months
Response rate for
β-CTx (ZOL patients)
assuming LSC of 60%:
LSC, least significant change
Data on file, Novartis
N/A = data not
available
N/A
72.7%
ZOL 5
mg
Placebo
ZOL 5
mg
12 months
24 months
52.5%
46.6%
Placebo ZOL 5mg
36 months
33.9%
63
Differences Between Histomorphometric
and Biochemical Estimations of Bone Turnover
RIS1
ZOL2
IBN3,4
ALN5
DEN6
0
% Suppression
−10
−20
−30
−40
−50
−60
−70
−80
−90
−100
Histomorphometric
Biochemical
1. Eriksen EF, et al. J Bone Miner Res. 2001;16(suppl 1):S218; 2. Reid IR, et al. N Engl J Med. 2002;346-653-661;
3. Recker RR, et al. Osteoporos Int. 2004;15:231-237; 4. Delmas PD, et al. Osteoporos Int. 2004;15:792-798;
5. Chavassieux PM, et al. J Clin Invest. 1997;100:1475-1480.
BTM AND ANTIFRACTURE EFFICACY
ALENDRONATE
Hip
It takes more than 30% reduction of
BAP to achieve non-vert fx. reduction
Spine
Bauer et al. JBMR 2004;19:1250
65
BTM AND ANTIFRACTURE EFFICACY
RISEDRONATE
Incidence %
15
0-1 yr vertebral fracture incidence
Control
Risedronate 5mg
10
5
0
-65 -60 -55 -50 -45 -40 -35 -30 -25 -20 -15 -10 -5
NTX % Change
Eastell et al. JBMR 2001; 16 (Suppl 1): S163.
0
66
BTM AND ANTIFRACTURE EFFICACY
ZOLEDRONIC ACID
Risk and 95% CI
0.40
ZOL 5 mg
Placebo
0.30
0.20
0.10
0.00
-3
-2
-1
0
1
2
3
4
5
T-score PINP at 1 year
PINP at 1 year ng/mL
6
10 30
60 80 100 130
Due to the non-linearity of the relationship, a quadratic model best explains the association
Data on file, Novartis
67
BTM AND ANTIFRACTURE EFFICACY
BTM VS. BMD
Association1 between a 1 SD
decrease in PINP level at 1 year
and incidence of fractures
HR (95% CI) at 1
year
P value
Association1 between a 1 SD
increase in BMD at 3 years and
incidence of fractures
HR (95% CI) at 3
years
P value
All clinical fractures
0.75
(0.59–0.91)
<0.05
0.78
(0.62–0.99)
0.09
Nonvertebral fractures
0.73
(0.56–0.94)
<0.05
0.76
(0.60–0.97)
0.03
Vertebral fractures
0.60
(0.38–0.95)
<0.05
0.69
(0.49–0.99)
0.05
Data on file, Novartis
1. Li Z et al; Stat Med 2001;20:317−88
68
CLINCIAL EXPERIENCE
ALENDRONATE - OSTEOCALCIN
2
1.5
1
0.5
0
2005
2006
2007
2008
2009
2010
2011
69
CLINICAL EXPERIENCE
CTX - ALENDRONATE
0.7
0.6
0.5
0.4
Series1
Series2
0.3
Series3
0.2
0.1
0
1
2
3
70
CLINICAL EXPERIENCE
BAP - ALENDRONATE
50
45
40
35
30
25
20
15
10
5
0
2005
2006
2007
2008
2009
2010
2011
71
MONITORING ANABOLIC
THERAPY USING BTM
72
EFFFECTS OF PTH ON ARCHITECTURE
Patient treated with 20µg
Female, age 65
Duration of therapy: 637 days (approx 21 mos)
BMD Change:
Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%)
Total Hip:
+5.2% (group mean = 2.6 ± 4.9%)
73
BTM FOR MONITORING
ANABOLIC THERAPY
mean
% change
(mean +- SE)
% change
Bone Markers
- TPTD/ALN
†
ALN10
250
*
TPTD20
200
†
150
†
†
100
*
*
50
*
0
-50
-100
McClung, et al, ASBMR 2003
*
*
PICP
PINP
*
BSAP
*
NTx
*P<0.01 Within treatment
†P<0.01
ALN10 vs TPTD20
74
Early changes in bone structure predicts
structural change after PTH
75
PINP DURING ANABOLIC THERAPY
PINP had the highest signal-to-noise ratio of all BTMs
PINP responses > 10 µg/L after 3 mo.
in 77–97% of teriparatide
in 6% of placebo-treated patients
Mean lumbar spine BMD increases after 12 months
PINP changes > 10 µg/L: 8.3-9.5%
PINP changes ≤ 10 µg/L: 5.9-7.6%.
Eastell er al. Curr Med Op 2006; 2006, Vol. 22;1:61-66
76
MONITORING ANABOLIC THERAPY
USING BTM - PINP
300
250
200
150
100
50
0
Q1
Q2
q4
q8
PINP increases over 10 ug/l associated with significant changes in BMD in
92% of patients trested (Tsujimoto et al. Bone 2011)
77
CONCLUSION
• High bone turnover is an independent risk factor for
bone loss and osteoporotic fracture
• Serum based BTMs reflecting collagen metabolism, in
particular CTX and PINP, are the most specific and
precise markers available, and they are related to the
amount of bone turned over
• The response to oral vs. iv bisphosphonates is
different
• Treatment goals with antiresorptives are BTM levels
at the lower limit of the premenopausal range
78
CONCLUSIONS
• The variation during reduction of bone turnover is
much less than seen in untreated patients
• The dynamic range for PINP responses during
anabolic therapy is way beyond the LSC – and
changes correlate to structural and BMD improvement
• BTMs are useful tools for early monitoring of both
antiresorptive and anabolic osteoporosis therapies,
and can be used to optimize treatment
79
Questions and Answers
If you have any questions following the close
of the webinar, please contact:
Dagmar Kasper
International Business Manager,
Life Science
[email protected]
www.idsplc.com