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B M k i O t i P di ti fBone Markers in Osteoporosis: Prediction of Fractures & Treatment Monitoring
Richard Eastell, MD FRCP FRCPath FMedSci,Professor of Bone Metabolism,
University of Sheffield,Sheffield, UKSheffield, UK
www.shef.ac.uk/bmg
Usefulness of Markers in the Individual PatientO tliOutline
• Bone turnoverBone turnover– Changes at the menopause and with
osteoporosisp• High bone turnover markers
– Association with bone loss and fracture– Association with bone loss and fracture• Effects of treatment on bone turnover
T t t it i• Treatment monitoring• Example
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The Effects of Age and Estrogen Status on Bone Remodelinge ects o ge a d st oge Status o o e e ode g
Activation frequency (#/yr)
1 2
1.4
1.6 A 2-fold increase across the menopause
A 3-fold increase by age 65 yr
0 8
1.0
1.2 A 3 fold increase by age 65 yr.
0 4
0.6
0.8
0 0
0.2
0.4
0.0
www.shef.ac.uk/bmg*Recker R, et al. J Bone Miner Res 2004;19:1628-33
BTMs Reflect Resorption and Formation– Matrix proteins
• osteocalcin (OC)
BTMs Reflect Resorption and Formation
Formation• procollagen type I propeptides
– C-terminal (PICP)
N-terminal (PINP)
Formation
– N-terminal (PINP)
– Enzyme
• bone isoform of alkaline phosphatase (bone ALP)
– Collagen degradation products
• pyridinium cross-links of collagen
(bone ALP) Commercially available assaysSerum: OC, PICP, PINP, bone ALP, NTX, CTX, TRACP 5bUrinary: CTX NTX free DPD– C- and N-telopeptides (CTX, NTX)
– Deoxypyridinoline (DPD)
– Enzyme
ResorptionUrinary: CTX, NTX, free DPD
• tartrate-resistant acid phosphatase (TRACP), type 5b
•Cathepsin K
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•Related factors
•OPG, RANK-L
Levels of Serum βCTX in Women C it b d t d OPUS ( 2780)Community-based study, OPUS (n=2780)
10
1
0 1(ng/
mL)
0.1
βC
TX
0.01
Pre menopausal Post menopausal
20 30 40 50 60 70 800.001
Pre-menopausalMean (SD) 0.16 (0.12) ng/mL
Post-menopausalMean (SD) 0.27 (0.19) ng/mL
www.shef.ac.uk/bmg
Age at visit
Data from Blumsohn A et al, J Bone Miner Res 2003;18:1274-81
High Bone Turnover Markers
www.shef.ac.uk/bmg
Bone Turnover Markers in Relation to Bone Loss and F t Ri kFracture Risk
• A high bone remodelling rate isA high bone remodelling rate is associated with– More rapid bone loss in postmenopausalMore rapid bone loss in postmenopausal
women1
– Increased risk of fractures2
• The association with fracture is variable2
– Hazard ratios of between 1 and 2– Hazard ratios of between 1 and 2– More consistently observed for bone
resorption than bone formation markersresorption than bone formation markers
www.shef.ac.uk/bmg
1. Stepan JJ. Osteoporos Int. 2000; 11 Suppl.6:S45-54;2. Garnero P. Osteoporos Int. 2000; 11 Suppl.6:S55-65.
Bone Turnover and Bone Loss from the SpineBone Turnover and Bone Loss from the Spine
5.0
yr) 5.0
r)
0.0
2.5
n B
MD
(%/y
0.0
2.5
BM
D(%
/yr
-5.0
-2.5
2=0 44
Cha
nge
in
-5.0
-2.5
r= 0 42Cha
nge
in
0 5 10 15 20 25-7.5
Years Since Menopause (YSM)
r2=0.44p=0.0076
4 8 16 32 64 128-7.5
uNTX (nmol BCE/mmol Cr)
r=-0.42p=0.0013
www.shef.ac.uk/bmgRogers A, et al. J Bone Miner Res. 2000;15:1398-1404.
High Bone Resorption Markers May Predict Hip Fracture Ri k i Eld l W th EPIDOS St dRisk in Elderly Women – the EPIDOS Study
EPIDOS = Epidemiologie de l'Osteoporose
5
4
3ratio
3
2
Odd
s r
2
11Low hip
BMDHigh
U-CTXHigh
U-DPDLow BMD Low BMD
+ +High CTX High DPD
www.shef.ac.uk/bmgGarnero P, et al. J Bone Miner Res. 1996;11:1531-38.
BMD = bone mineral density; U = urinary.
10-year Risk of Hip Fracture10 year Risk of Hip Fracture
• This approach hasThis approach has now been implemented asimplemented as the WHO FRAXTM
scorescore– Doesn’t include
bone markersJohnell O, et al. Osteoporosis Int.
2002;13:523-6.
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Treatment Effects
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Postmenopausal OsteoporosisEffects of Treatments
Quiescence NegativeRemodelling Imbalance
Remodelling Balanceg
Anti-catabolic Drugs•Decrease activation
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Activation Resorptionfrequency•Restore remodelling balance
Changes in Bone Resorption Marker NTX With Alendronate
Time (weeks)
Therapy in Osteoporosis – Mean Decrease 75%
4 8 12 240
Time (weeks)
NTX
iFDPD
OC –25
Bone ALPhang
e
–50% c
h
–75
www.shef.ac.uk/bmgMachado A, et al. J Bone Miner Res. 1999;14:602-8.
ALP = alkaline phosphatase; iFDPD = free deoxypyridinoline; OC = osteocalcin; NTX = N-terminal telopeptide.
Treatment Effects on Telopeptide MarkersCTX d NTXCTX and NTX
• Different responses to treatmentsDifferent responses to treatments– Strontium, calcium, 10 to 20%– Raloxifene 30 to 40%Raloxifene, 30 to 40%– HRT and risedronate, 50 to 60%– Zoledronic acid ibandronate alendronate 70– Zoledronic acid, ibandronate, alendronate, 70
to 80%• All reduce vertebral fractures• All reduce vertebral fractures
– Mechanism may involve effects other than a decrease in bone resorptiondecrease in bone resorption
• The telopeptide response helpful for any particular treatment
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particular treatment
Postmenopausal OsteoporosisEffects of Treatments
Quiescence NegativeRemodelling ImbalancePositiveRemodelling ImbalancegRemodelling Imbalance
Anabolic Drugs•Increase activation frequencyI d iti d lli•Induce positive remodelling
balance
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Activation Resorption
Randomized, Controlled Trial of Alendronate or Teriparatide i P t l O t i
% Change from baseline (Mean ± SE)
in Postmenopausal Osteoporosis
250Teriparatide
250Alendronate
150
200
150
200
0
50
100
0
50
100
-100
-50
0
-100
-50
0
MonthsNTX (Resorption)PINP (Formation)
0 1 3 6 12 0 1 3 6 12
P<0.001bet een gro p difference
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NTX (Resorption) between-group difference teriparatide vs. alendronate
2004Arlot M, et al. J Bone Miner Res. 2005;20:1244-53.
Strontium increases bone formation markers and decreases b ti k b t th ff t ll (<10%)
EE
bone resorption markers, but the effects are small (<10%)
0.8
1.2 ***
* **** **
0.4
0 8 * Bone ALP (ng/mL)
+8%
-300
0
S-CTX (pmol/L)
-600
300
*** *** *** * **
S CTX (pmol/L)
-12%
0 3 6 12 24 36
E E ti t f diff b t t ti d l b i l i
Months***
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E= Estimate of difference between strontium group and placebo group, covariance analysis, baseline adjusted *** p<0.001; ** p<0.01; * p<0.05
Meunier PJ et al, N Engl J Med. 2004 Jan 29;350(5):459-68.
Treatment Monitoring
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The average response to risedronate 5 mg exceeds LSC li f BTM (3 th ) th BMD (18 th )LSC earlier for BTM (3 months) than BMD (18 months)
Spine BMD, % Δ from baseline
Risedronate 5mg
NTX, % Δ from baseline
0
ControlRisedronate 5mg
-25
LSC
-50LSC
-750 6 36
ControlRisedronate 5mg
Time, months Time, months
www.shef.ac.uk/bmg
LSC, least significant change
Using BMD and Bone Turnover Markers in Clinical P ti A ti C t b li Th iPractice: Anti-Catabolic Therapies
100LSC (LSBMD)
10% 17%
0
Urinary NTX, % changeat 6 months
10% 17%
-100
at 6 monthsLSC (NTX)
-20065%8%
-10 0 10 20 30 40
Spine BMD, % change
www.shef.ac.uk/bmg
LSC, least significant changeBMD, bone mineral density
Fracture Incidence Over 3.6 Years of Alendronate, vs 12-Month Bone ALP: % Change From Baseline
• One year change in bone ALP in alendronate-treated
• FIT study3105 in alendronate arm
women– 3105 in alendronate arm– One-year change in bone
ALP (insufficient samples ip
ip
ure
ure
100100101011 for PINP or CTX)
– 3.6 years of follow-up for fracture
OR
Hi
OR
Hi
Frac
tuFr
actu 11
0.10.10.010.01
0.0010.001 fracture
Change in Bone ALP (%)Change in Bone ALP (%)--6060 --4040 --2020 00 2020
10101010
11
Vert
ebra
l Ve
rteb
ral
ract
ure
ract
ure
0.10.1
Ch i B ALP (%)Ch i B ALP (%)--6060 --4040 --2020 00 2020
OR
VO
R V FrFr
www.shef.ac.uk/bmg
OR=Odds ratio.Bauer DC et al. J Bone Mineral Res. 2004;19:1250-1258.
Change in Bone ALP (%)Change in Bone ALP (%)
Surrogates for Fracture Risk ReductionSurrogates for Fracture Risk Reduction
Proportion of 3 year fragility fracture treatment effect explained by surrogatesProportion of 3 year fragility fracture treatment effect explained by surrogates
Surrogate Proportion 95% CISurrogate Proportion explained
95% CI
Femoral neck 14% 7 21%Femoral neck BMD
14% 7, 21%
U i NTX 52% 29 75%Urinary NTX 52% 29, 75%
NTX d 67% 39 100%NTX and FNBMD
67% 39, 100%
www.shef.ac.uk/bmgDelmas PD, et al. ECCEO 2005; abstract P360
We Would Like to Suppress Bone Turnover to Levels Found inH lth Y W (Wh H A T S f 0)
Treatment: Calcium Calcium and risedronate 5 mg
Healthy Young Women (Who Have an Average T-Score of 0)l s
25
Treatment: Calcium Calcium and risedronate 5 mg
Vert
ebra
lo
3 ye
ars
15
20 Reduce absolute vertebral fracture risk by 10%
ence
of V
ures
, 0 to
10
15
Reduce bone resorption by 2 SD
Inci
deFr
actu
0
5
00.0 0.5 1.0 1.5 2.0
(20) (35)-2.0 -1.5 -1.0 -0.5
www.shef.ac.uk/bmg
Urinary NTX, T-score
Eastell R, et al. J Bone Miner Res. 2003;18:1051-1056.
Vertebral Fractures over 3 years and Bone Resorption C bi d T t d d Pl b GCombined Treated and Placebo Groups
Decile Analysis, about 66/decile
Th h ld i t20
25No. women withvertebral fractures
Threshold is atmean for young women (T=0)
15
20
10
0
5
1 2 3 4 5 6 7 8 9 100
Urinary CTX (T-score) at 3 to 6 months, decileT=-1 T=+1
www.shef.ac.uk/bmgEastell R, Hannon RA, Garnero P, Campbell MJ, Delmas PD. JBMR 2007 (letter online 17th September 2007)
Develop Reference Range for Women Based on t l t 150 H lth Y W
Reference Range Graphical Display of the DataNTx/Cr Premenopausal Reference Range (Healthy drug-free subset)
at least 150 Healthy Young Women
LocationMean 47.066Median 42.4079Mode No Mode 0 02
0.025
0.03
AdjR
elativeMode No Mode
SpreadStandard Deviation 24.4041Variance 595.5589Parametric 95% LRL -1 7422
0.01
0.015
0.02 justed e Frequency
Parametric 95% LRL 1.7422Parametric 95% URL 95.8742Non Parametric 2.5th centile 16.3759Non Parametric 97.5th centile 103.5667
-0.005
0
0.005
-50 0 50 100 150 200 250
Minimum 8.03217427Maximum 211.0338478Interquartile Range 25.2433Range 203.0016735
-0.015
-0.01
MiscellaneousN 370CV 0.5185
-0.025
-0.02
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Effect of Risedronate Therapy on Bone Resorption
Lower half ofreference interval
Upper half ofreference interval
O O
80
Osteoporosis, Untreated Osteoporosis, Risedronate
70
400 11 62 27% 7 63 28 2%
atien
ts
50
60
70
tient
s
30
Num
ber o
f Pa
20
30
40
Num
ber o
f Pa
20
0
10
20
0
10
NTX/Cr, nmol/mmol Creatinine NTX/Cr, nmol/mmol Creatinine10010 3210010 32
www.shef.ac.uk/bmgEastell R and Delmas PD. J Bone Miner Res. 2005;20:1261-2
Does monitoring affect adherence?
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Does Monitoring affect Adherence?Does Monitoring affect Adherence?
• 75 women with osteopenia75 women with osteopenia• Treated with Raloxifene and randomised
Repeat prescriptions (no medical contact)– Repeat prescriptions (no medical contact)– Visit nurse every 3 months
Visit nurse and monitor BTM every 3 months– Visit nurse and monitor BTM every 3 months• Measured compliance using MEMS caps
www.shef.ac.uk/bmgClowes JA et al, J Clin Endocrinol Metab 2004;89:1117-23
Monitoring improves adherence to treatment with R l ifRaloxifene
Proportion of patients who remained adherent
Cumulative adherence >75 %
Proportion of patients who remained adherent1.2
1 0 %– Proportion of adherent
subjects increased by 57%
1.0
0.8
in those monitored– P = 0.04
0.6
0 40.4
0.2
Monitored
Not monitored
Days4003002001000
0.0
www.shef.ac.uk/bmgClowes JA et al, J Clin Endocrinol Metab 2004;89:1117-23
Days
Greater adherence is associated with greater biological response
% Change uNTX% Change Hip BMD40
20
0
6
4 0
- 20
- 402
- 60
- 80
0
- 2
120100806040200
- 100
- 120120100806040200
- 4
r = - 0.46P 0 0001
r = 0.34P 0 003
% Adherence% Adherence
www.shef.ac.uk/bmg
P = 0.0001P = 0.003Clowes JA et al, J Clin Endocrinol Metab 2004;89:1117-23
Case PresentationCase Presentation
• Woman (71) develops ( ) pacute onset back pain
• There are no clear risk factors for osteoporosis from the questionnaire or the -3 2 -2 8questionnaire or the biochemical workup
• Bone turnover marker
3.2 2.8T-score
• Bone turnover marker– NTX T-score +4 (150
nmol BCE/mmol Cr)– Bone alkaline
phosphatase T-score +3 (90 ug/L)
www.shef.ac.uk/bmg
+3 (90 ug/L)
What does a high bone turnover marker mean in t i ?osteoporosis?
• Could it just be a spurious result?Ho can e se the information?• How can we use the information?• Is the patients more likely than average to have
rapid bone loss or an increased risk ofrapid bone loss or an increased risk of fracture?
• Does this high result mean she might have• Does this high result mean she might have secondary osteoporosis?
• What do we expect to happen to the resultWhat do we expect to happen to the result when we treat her? What is the goal of our treatment?
www.shef.ac.uk/bmg
Could it just be a spurious result?
www.shef.ac.uk/bmg
Bone resorption markers do vary from day to day, b t it i lik l th t h i i hi h t t tbut it is very likely that she is in a high turnover state
Data from Clowes JA, et al. J Bone. 2002;30:886-90.
Fasting NTx
13
g
58
1012
ject
12141618
Subj
1820
0 40 80 120 160 200 240
www.shef.ac.uk/bmg
If we know why bone turnover markers vary, ll f itwe can allow for it
• Controllable source– Circadian
• Uncontrollable source– GrowthCircadian
– Day to day– Diet
Growth– Age and gender– FracturesDiet
– ExerciseFractures
– Diseases and drugs
• Consequence– Morning, fasting
• Consequence– Establish age and g, g
samples– Take average of more
ggender-specific reference range
www.shef.ac.uk/bmg
than one measurementHannon RA, Eastell R. Osteoporosis Int. 2000;11 (Suppl.6):S30-44.
Circadian Rhythm of Serum CTXCircadian Rhythm of Serum CTX
Eagleton A, PhD thesis, 2003.
sCTX0.75
)
0.50
TX (n
g/m
l
0.25
sCT
08:00 12:00 16:00 20:000.00
Time
www.shef.ac.uk/bmg
TimeArrows indicate meal timesUntreated osteoporosis, n = 15Osteoporosis treated with risedronate for 3 months, n = 15
Biochemical Markers following Ankle FractureBiochemical Markers following Ankle Fracture
Formation Resorption
220% baseline % baseline
Formation Resorption
220
160
180
200 TRAcPifDpdNTx
PINPI-Bone ALP
WG-Bone ALPOC
160
180
200
100
120
140
100
120
140
137 14 2860
80
100
42 90 180 360137 14 2860
80
100
42 90 180 360
Time, days Time, days137 14 28 42 90 180 360
www.shef.ac.uk/bmgIngle BM et al. Osteoporosis Int. 1999;10:408-15.
I h i lik l h hIs the patients more likely than average to have rapid bone loss or an increased risk of fracture?
www.shef.ac.uk/bmg
She is likely to be a ‘fast bone loser’W ld h ll l 5% ?Would she really lose 5% per year?
5.0
yr) 5.0
r)
0.0
2.5
n B
MD
(%/y
0.0
2.5
BM
D(%
/yr
-5.0
-2.5
2=0 44
Cha
nge
in
-5.0
-2.5
r= 0 42Cha
nge
in
*0 5 10 15 20 25
-7.5
Years Since Menopause (YSM)
r2=0.44p=0.0076
4 8 16 32 64 128-7.5
uNTX (nmol BCE/mmol Cr)
r=-0.42p=0.0013 *
www.shef.ac.uk/bmg
Rogers A, et al. J Bone Miner Res. 2000;15:1398-1404.
10-year Risk of Hip Fracture10 year Risk of Hip Fracture
With l BMD i f t dWith low BMD, prior fracture and high bone turnover marker shehas a 30% 10-year risk of fracturing, better do something soon!better do something soon!
Johnell O, et al. Osteoporosis Int.2002;13:523-6.
www.shef.ac.uk/bmg
Use in Decision-MakingUse in Decision Making
• Does this help us diagnose osteoporosis?Does this help us diagnose osteoporosis?• Does this help us select the best
treatment?treatment?• Does the result make us suspect
secondary osteoporosis?secondary osteoporosis?
www.shef.ac.uk/bmg
The high turnover doesn’t allow us to diagnose osteoporosis, or choose the best t t t it i ht i t t d t itreatment; it might point us to secondary osteoporosis
• Bone turnover markers are increased in b t 25% f ith iabout 25% of women with primary
osteoporosisB t k h t t• Bone turnover markers have not yet proven useful in the selection of treatment
Bisphosphonates are effective at all levels of– Bisphosphonates are effective at all levels of bone turnover1 or only with high turnover2
– Teriparatide most effective if bone turnover isTeriparatide most effective if bone turnover is high!3
• A high level of bone turnover may indicate g ythe presence of secondary osteoporosis
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1. Seibel MJ, et al. J Bone Miner Res. 2004;19:323-3292. Bauer DC, et al. J Bone Miner Res. 2006;21:292-2993. Ettinger B, et al. J Bone Miner Res. 2004;19:745-751
What are the causes of high bone turnover? Watch outgparticularly for endocrine or other bone diseases
HIGH LOW• Metabolic bone diseases
– Paget’s diseaseSecondary
• Cushing’s syndrome– Secondary
hyperparathyroidism • osteomalacia
– low osteocalcin• Osteogenesis imperfecta
l PICP• renal osteodystrophy• malabsorption syndrome
• Endocrine diseases
– low PICP• Hypophosphatasia
low alkaline phosphatase• Endocrine diseases– Primary
hyperparathyroidism
– low alkaline phosphatase
yp p y– Thyrotoxicosis– Hypogonadism
www.shef.ac.uk/bmg
• Malignancy, e.g. myeloma• Recent fracture
Wh t d t t h t th lt hWhat do we expect to happen to the result when we treat her? What is the goal of our treatment?
www.shef.ac.uk/bmg
After starting antiresorptive therapy, should we make follow-up measurements of bone turnover?
• Identify poor response that can be causedIdentify poor response that can be caused by– Poor compliancePoor compliance– Secondary osteoporosis– Ineffective therapiesIneffective therapies
• Take action to improve response Advise on correct dosing instructions– Advise on correct dosing instructions
– Investigate for secondary osteoporosis– Consider larger dose or different treatmentg
• Encourage compliance– No immediate symptomatic benefit to patient
www.shef.ac.uk/bmg
No immediate symptomatic benefit to patient
Our patient was treated with alendronate 70 mg once k d t b th f t ta week, and met both of our targets
NTX/Cr, nmol BCE/mmol Goals
150Decrease to levels in the
50
100 lower half of the reference range for young women, <35 nmol/mmol Cr
B1 B2 mB1B2 V1 V2 V30
NTX, % change
100
200
Decrease by more than the least
200
-100
0 significant change, 50%
www.shef.ac.uk/bmg
B2 mB1B2 V1 V2 V3-200
BMD increase of 5.3% at lumbar spine at 1 year
Usefulness of Markers in the Individual Patient SSummary
• Bone turnover– Increases at the menopause and
increases further in osteoporosis• High bone turnover markers
– Associated with higher risk of bone l d f tloss and fractures
• Treatments for osteoporosis– Result in changes in bone turnover
markers• Treatment monitoring• Treatment monitoring
– Goal is to decrease bone turnover markers beyond least significant
www.shef.ac.uk/bmg
markers beyond least significant change and into pre-menopausal range