The Use of Bone Turnover Markers in Osteoporosis Therapy Monitoring - PowerPoint Presentation

Slide1

The Use of Bone Turnover Markers in Osteoporosis Therapy Monitoring

in Asia Pacific

Dato’ Dr Lee Joon-Kiong

Deputy Medical Director

HOD, Department of Orthopedic Surgery

Beacon Hospital, Malaysia

Slide2

DisclaimerNo conflict of interest to be declared

Slide3

OutlinePart 1Bone turnover markers (BTM) used in daily clinical practice & what do we need to know?Use of BTM in various therapeutic agentsPart 2Adherence and compliance to bisphosphonates treatmentUse of BTM in bisphosphonate treated patients (TRIO)IOF-IFCC Recommendations (Based on TRIO Study)Part 3Asia Pacific perspective on the use of BTM in clinical practice

Slide4

Bone

Turnover

Markers

Slide5

Bone remodelling / turnoverBSAP, bone-specific alkaline phosphatase; CTX, C-telopeptide

of type I collagen; ICTP, type I collagen degradation product; NTX, N-telopeptide of type I collagen; OC,

osteocalcin; PICP, procollagen type I C-terminal propeptide; PINP, procollagen type I N-terminal propeptide; Pyr, Pyridinoline;

TrAcP, tartrate-resistant acid phosphatase Wheater

et al. J Transl Med 2013;11:201; 2. Leeming et al. Eur J Clin Pharmacol 2006;62:781–792.

1. ResorptionActivated osteoclasts remove the old bone matrix

1

2.

Reversal

Mononuclear cells prepare the bone surface for new bone formation

1

3.

Formation

Osteoblasts

synthesise replacement bone matrix

and fill the cavity with new bone

1

4.

Resting

The bone surface is covered with flattened bone lining cells1

Bone undergoes continual self-renewal, preventing damage and maintaining calcium homeostasis:1

Postmenopausal osteoporosis is due to an increase in bone turnover and an imbalance between formation and resorptionProducts released during resorption or formation can be used as surrogate bone turnover markers

CTXNTXICTPPYR

Phases of the bone modelling cycle(Figure shows biomarkers released at each stage)

RESTING

Activation of

osteoclasts

RESORPTION

REVERSAL

FORMATION

TrAcP

PINP

PICP

OC

BSAP

Lining cells and osteocytes

Osteoblast precursors

Osteoblasts

Osteoclasts

Slide6

Slide7

CTX is released during bone resorptionType I collagen

, the most abundant bone protein (comprising 90% of the matrix), is broken down during bone

resorption

Collagen degradation products include carboxy

- and amino-terminal telopeptides still cross-linked to neighbouring molecules, which are released into the circulation

Serum

C-

telopeptide

cross-links of type I collagen (CTX)

is the

reference bone resorption marker

recommended by the International Federation of Clinical Chemistry

(IFCC)

and the International Osteoporosis Foundation

(IOF)

1

-3

1. IOF website

https://www.iofbonehealth.org/

(last visited 18 September 2018);

2. IFCC website

http://www.ifcc.org/

(last visited 18 September 2018);

3. Vasikaran et al. Osteoporos Int 2011;22:391–420; 4. Garnero

et al. J Bone Miner Res 2003;18:859–867.

Osteoclast-mediated

bone resorption

Type I collagen assembled into fibrils

Collagen degradation

CTX is released from the C-

telopeptide

region

CTX

Cat K

Cat K

Cat K

GPP-SAGFDFSFLPQPPQE

K

AHDGGR



1

C

N

C-TELOPEPTIDE

N-TELOPEPTIDE

CTX,

C-

telopeptide

of type I collagen;

IFCC, International Federation of Clinical Chemistry; IOF, International Osteoporosis Foundation

Slide8

PINP is released during bone formationIFCC, International Federation of Clinical Chemistry; IOF, International Osteoporosis Foundation; PICP, procollagen type I C-terminal propeptide; PINP, procollagen type I N-terminal propeptide

Type I collagen

is synthesised during bone formation

Type I pro-collagen is processed and assembled into cross-linked fibrils

Procollagen type I N-terminal (PINP) and C-terminal (PICP) propeptides are cleaved and released into circulation

Serum PINP

is the

reference bone formation marker

recommended by the

IOF/IFCC

1,2

It is found in the circulation

as a

trimeric

(intact) molecule

and as a monomer

1. IOF website

https://www.iofbonehealth.org/

(last visited 18 September 2018);

2. IFCC website

http://www.ifcc.org/

(last visited 18 September 2018);

3. Vasikaran et al. Osteoporos Int 2011;22:391–420.

Procollagen (triple helix)

Procollagen peptidase

(cleavage of amino

and carboxy

propeptides)

Collagen

monomer

C

C

C

N

N

N

Collagen fibril

Cross-links

Type I collagen synthesis

N

N

N

N

Total PINP

Slide9

Slide10

Biological and Analytical Variability of BTMs Sources of variability may be biological (pre-analytical, relating to patient characteristics) or analytical

(relating to the assay, greatly reduced with automated assays)

1-3Understanding the various sources of variability influencing BTM measurement is essential for the sound interpretation of the data1-3

CTX, C-telopeptide of type I collagen; PINP, procollagen type I N-terminal propeptide

1. Eastell & Szulc. Lancet Diabetes Endocrinol 2017;5:908–923; 2. Wheater et al. J

Transl Med 2013;11:201; 3.Naylor & Eastell. Nat. Rev. Rheumatol 2012;8;379–389; 4.Christgau. Clin Chem 2000;46(3):431; 5.

Vasikaran et al.

Osteoporos

Int

2011; 22:391–342;

6.Ahmad AM, et al. Bone 2003;32(2):170–179; 7.Blumsohn et al. J Bone Miner Res 2003;18(7):1274–1281; 8. Clowes et al.

Bone

2002;30(6):886–890; 9. Clowes et al. J Clin

Endocrinol

Metab

2002;87:3324–3329

.

Slide11

Biological and Analytical Variability of BTMs A number of pre-analytical factors influencing BTM levels can be controlled

for by the physician directly, for exampletaking samples

for CTX testing in the morning and after fasting4,5 or opting for PINP testing, which is minimally affected by circadian variation6,7

and food intake8,9Other non-controllable factors

, such as patient age and gender can be taken into account when interpreting the result, for example1,3using an appropriate age-based reference intervalallowing for higher than expected values after fracture and using markers that are less influenced by fracture (i.e.

resorption markers)CTX, C-telopeptide of type I collagen;

PINP, procollagen type I N-terminal propeptide

1.

Eastell

&

Szulc

. Lancet Diabetes

Endocrinol

2017;5:908–923; 2.

Wheater

et al. J

Transl

Med 2013;11:201;

3.Naylor &

Eastell

. Nat. Rev.

Rheumatol 2012;8;379–389; 4.Christgau. Clin Chem 2000;46(3):431; 5.Vasikaran et al. Osteoporos Int 2011; 22:391–342; 6.Ahmad AM, et al. Bone 2003;32(2):170–179; 7.Blumsohn et al. J Bone Miner Res 2003;18(7):1274–1281; 8. Clowes et al. Bone

2002;30(6):886–890; 9. Clowes et al. J Clin Endocrinol Metab 2002;87:3324–3329.

Slide12

Sources of Pre-analytical Variability of Bone Markers: Controllable Factors

Source

Nature of effect1-3

Recommendation1-3

Circadian rhythm

Most striking for bone resorption markers; highest values in second half of night and on waking; lowest values in afternoon and evening

Collect samples at the same time of day to

minimise variability, e.g. between 7.30 and 10 am after overnight fast

Feeding

Feeding results in a decrease in BTM; e.g., serum CTX decreases by 20% after breakfast

Collect samples after overnight fast

Exercise

Changes occur but depend on type of exercise and age of subjects

Record physical activity; avoid intense

exercise

the day before sampling

Menstrual

Small decreases in bone

resorption

and increases in bone formation during luteal phase

Collect samples during the first week of cycle

Seasonal

BTMs increase over winter

Consider potential effect in longitudinal studies of Europeans;

Record travel to sunny climatesDiet

Small reduction in BTMs

immediately following calcium supplementationRecord dietary supplements and consider their potential effect on BTM measurements

BTM, bone turnover marker; CTX, C-

telopeptide cross-links of type I collagen1. Naylor and Eastell 2012;2. Eastell

& Szulc. Lancet Diabetes Endocrinol 2017;5:908–923;3. Vasikaran et al. Osteoporos

Int 2011;22:391–420.Note

. Sources of variability are colour-coded according to the importance of the variability in measuring and interpreting BTM levels (very important, moderate, limited importance).

Slide13

Sources of Pre-analytical Variability of Bone Markers: Uncontrollable Factors

Source

Nature of effect1-5

Recommendation1,4

Age

Children: BTMs are highest from birth to 1 year and mid-pubertyAdults: increase with age in men and women

Use appropriate age-based reference interval

Menopausal status

BTMs increase in older women within a few months after the last menstrual period

Confirm menopausal status; use reference interval based on the menopause

Gender

BTMs are higher in older women than older men (>50 years old)

Sex-specific reference interval should be used

Fractures

BTMs increase after a fracture (maximal at 2–12 wks, but effect lasts for up to 52 wks)

Take into account a potential effect

for at 6 months to a year after event

Pregnancy and lactation

BTMs

increased during pregnancy; highest during 3

rd

trimester, even higher postpartum

Take into account

pregnancy stage or lactation in interpretation

Drugs

BTMs may be decreased (glucocorticoids) or increased (anticonvulsants)Record medical and drug history; be aware of effects of the particular

drug on BTMs

Disease

BTMs often increased (thyrotoxicosis, chronic kidney disease)

Take full medical history

Bed rest/immobility

Bone formation markers decrease and resorption markers increase

Consider effect of immobility

Geography

Small changes amongst countries, usually explained by differences in lifestyle

Take lifestyle factors into account; use appropriate reference interval where available

Ethnicity

Small changes, such as lower OC in African Americans vs. CaucasiansUse appropriate reference interval where available

Oral contraception

Lower values for

BTMs

Consider small effect of contraceptive in the interpretation

BTM, bone turnover marker; OC,

osteocalcin

1. Naylor and

Eastell 2012; 2. Walsh et al. Endocrinol Metab 2012;97:3342–3348; 3.

Garnero et al. J Bone Miner Res 1996;11:337–349;

4. Eastell & Szulc. Lancet Diabetes Endocrinol 2017;5:908–923;

5.Vasikaran et al. Osteoporos Int 2011;22:391–420.

Note

. Sources of variability are colour-coded according to the importance of the variability in measuring and interpreting BTM levels (

very important, moderate, limited importance).

Slide14

Circadian Rhythm and Feeding Affect CTX Levels BTM levels follow a circadian rhythm and are influenced by food intake

Bone resorption markers are more strongly affected by circadian fluctuations than formation markers

2CTX levels are highest in the second half of night and on waking, lowest in the afternoon.1 They are highly dependent on food intake.1,2Serum PINP levels are minimally affected by circadian variation3,4

and food intake5,6Urine markers show higher circadian variability than serum markers and require creatinine correction

CTX, C-telopeptide of type I collagen; PINP, procollagen type I N-terminal propeptide

1. Christgau . Clin Chem 2000;46:431; 2. Vasikaran et al. Osteoporos

Int

2011;22:391–420; 3. Ahmad et al. Bone 2003;32:170–179; 4.

Blumsohn

et al. J Bone Miner Res 2003;18:1274–1281; 5. Clowes et al.

Bone

2002;30:886–890;

6. Clowes et al. J Clin

Endocrinol

Metab

2002;87:3324–3329;

7

.

Cosman

et al. Osteoporos Int 2014;25:2359–2381. These intra-individual variables can be controlled for by taking

fasting morning samples or serial measurements at the

same time of the day7 Effects of circadian rhythm and feeding on serum CTX levels1

Overnight fastDeviation from 24-h mean (%)

160140

120

100

80

60

40

05:00

08:00

11:00

14:00

17:00

20:00

23:00

02:00

05:00

08:00

11:00

Time (h)

Fasting

Normal diet

Slide15

Fracture Increases BTMs LevelsFracture results in a large increase in bone turnover markers over the first few weeksPINP

increased by

an average of 52% 4 weeks after forearm fracture1; and 96% 6 weeks after ankle fracture;2 Other formation markers (bone ALP) can increase up to 199% 24 weeks after tibial fracture3

Levels of PINP remain elevated for up to 1 year after fracture1-3ALP, alkaline phosphatase; β-CTX, C-

telopeptide of type I collagen; OC, ostecalcin; PINP, procollagen type I N-terminal peptide; PIIINP, procollagen type III N-terminal peptide; SEM, standard error of the mean1. Ingle et al. Osteoporosis Int

1999;10:399–407;2. Ingle et al. Osteoporosis Int 1999;10:408–415;3. Veitch et al. Osteoporosis Int 2006;17:364–372;

4.

Hashidate

et al. Open

Orthop

J 2011;5:32–36.

Bone markers following

tibial

fracture

3

% Change from baseline for biochemical markers shown.

Lines

represent mean ± SEM (± n=18)

Change from baseline (%)

250

200

150

100

50

0

-50

w2

w8

w16

w24

Time (d, days; w, weeks)

w12

w4

d7

d3

Bone ALP

Serum

β

-CTX

PINP

PIIINP

OC

BTM assessment results may be inconclusive within

1 year after a fracture

Physicians should also consider the possibility of a clinically silent vertebral fracture when interpreting results

4

Slide16

DiseaseEffect

on BTMs1

Primary hyperparathyroidism; thyrotoxicosis Increase in BTM concentrations depend on the severity of underlying disease Paget’s disease of bone Increased BTM concentrations, especially bone resorption

markers in untreated polyostotic forms Bone metastases

Increased BTM concentrations, especially increased bone resorption markers Myeloma Increased bone resorption

markers; bone formation markers not always increased, and might even be decreased in the early untreated phase Inflammation (eg, rheumatoid arthritis) Increased BTMs, especially increased bone

resorption

markers during acute inflammatory stages

Malabsorption

(

eg

,

Crohn’s

disease, coeliac disease, and chronic pancreatitis)

Increased BTMs, especially in patients with secondary hyperparathyroidism

Chronic kidney disease–mineral and bone disorder

Dependent on the type of chronic kidney disease–mineral and bone disorder, BTMs are raised in secondary hyperparathyroidism (bone alkaline phosphatase, intact PINP, and TRAP5b are not excreted or degraded by the kidneys and are valid measures of bone turnover rate; BTMs that are usually degraded or excreted by the kidneys [

eg

,

osteocalcin

, CTX-I, and NTX-I] are strongly affected by the severity of impairment of renal function); BTMs are low in

adynamic

bone disease Liver disease Various BTM trends dependent on the type and stage of disease, eg, increased bone resorption

in early inflammatory stages, and slightly increased PINP in late fibrotic stagesDiseases and Medications Affect BTMs LevelsSeveral diseases can affect BTM levels. The effect is dependent on:1Disease severityMedicationGlucocorticoid therapy has a notable impact on bone turnoverMost common secondary case of osteoporosisSuppression of bone formation (reduction of bone formation markers such as PINP) can lead to accelerated bone loss2BTM, bone turnover marker; CTX-I, C-telopeptide of type I collagen; NTX-I, N-telopeptide of type I collagen; PINP, N-terminal propeptide of type I collagen; TRAP5b, tartrate-resistant acid phosphatase type 51. Eastell & Szulc. Lancet Diabetes Endocrinol 2017;5:908–923;2. Briot & Roux. RMD Open 2015;1:e000014.

Slide17

Reference Bone Turnover Markers1. Vasikaran et al. Osteoporos

Int 2011;22:391–420.

CTX, C-telopeptide of type I collagen; IFCC, International Federation of Clinical Chemistry; IOF, International Osteoporosis Foundation; PINP, procollagen type I N-terminal propeptideThe IOF and the IFCC Working Group on Bone Marker Standards (WG-BMS) identified a need for international reference standards

1CTX and PINP were selected as reference BTMs based on the following criteria:1

Adequately characterised and clearly defined, bone-specificPerform well in predicting fracture risk and monitoring treatmentAcceptable biological and analytical variability

, with characteristics that facilitate sample handling and stabilityMeasurements obtainable ideally from blood samples, to help limit individual variation that may otherwise arise from measurement in urineMeasurable in routine clinical laboratories, ideally using automated assaysAssay should be

widely available

and not be the monopoly of a single supplier

Slide18

Clinical Uses of BTMsRisk assessmentPrediction of bone loss

Prediction of fractureIdentification of secondary osteoporosis

TreatmentSelection of treatmentMonitoring of responseIdentification of poor adherenceMonitoring of offset of effect

Eastell

et al.

Eur

J

Endocrinol

2018;178:R19–R31

Slide19

THERAPY MONITORING

Slide20

Therapy Monitoring with BMD vs BTMsBone mineral density

Bone turnover markers

SamplingDual-energy X-ray absorptiometry (DXA)Blood or urine sample collectionRelatively non-invasiveRepeat testing

Repeat BMD measurements are not advocated within 12 months of each other due to the time taken for significant change to be attained1Can be repeated frequently

Cost++++Expected change – timing and size of signal in response to therapy

~6–8% change within a year~20–300% within 3 to 6 monthsStandardised methodology and availability of guidelines+++

+

BMD, bone mineral density;

BTM, bone turnover marker

1.

Kanis et al. Osteoporos Int 2013;24:23–57;

2. Lee &

Vasikaran

. Ann Lab Med 2012;32:105–112; 3. Miller et al. J

Clin

Densitom

1999; 2:323–342;

4.

Delmas

et al. Osteoporosis

Int 2000; Suppl 6: S2–17.

BMD

is widely used to monitor response to treatment; however, treatment-induced increments in BMD are observed only several years after starting treatment1Treatment-induced changes in BTMs are much more rapid and take 3–6 months1

Slide21

Early Therapy Monitoring with BTMsBTMs decrease rapidly under antiresorptive treatment and increase rapidly under anabolic treatment

1-8

BMD, bone minderal density; CTX, C-telopeptide cross-links of type I collagen; PINP, procollagen type I N-terminal propeptide; SEM, standard error of the mean

A reduction in BTM

with antiresorptive therapy predicts a subsequent increase in BMD1

and reduction in fracture risk2–5 The magnitude of BTM decrease is associated with the level of risk reduction

6

An

early increase in BTM levels

following anabolic

therapy with parathyroid hormone

predicts

a subsequent increase in BMD

7

Anabolic therapy

0

-80

-60

-40

-20

0

6

12

Month

% Change

18

24

PIN

P

CTX

0

0

50

150

100

200

250

6

12

Month

% Change

18

24

PIN

P

CTX

Antiresorptive Therapy

Mean % change (SEM) in BTM from baseline to 24 months after treatment with

denosumab

(purple) and

teriparatide

(pink line)

8

1. Greenspan et al. J Bone Miner Res 1998;13:1431–1438; 2. Watts et al. J

Clin

Densitom

2004;7:255–261; 3

. Eastell

et al. J Bone Miner Res 2003;18:1051–1056; 4. Bauer et al. J Bone Miner Res 2004;19:1250–1258; 5.

Sarkar

et al. J Bone Miner Res 2004;19:394–401; 6.

Bouxsein

et al. J Bone Miner Res 2008;23:1155–1167; 7. Chen et al. J Bone Miner Res 2005;20:962–970. 8.

Leder et al. J Clin Endocrinol Metab 2014;99(5):1694–1700.

Slide22

Patients Achieving the Greatest Reduction in BTMs Demonstrate the Largest Improvement in BMD833 postmenopausal women treated with once-weekly bisphosphonates1Women who achieved the greatest reduction in BTMs (highest tertile) at 3 months had the largest mean increase in BMD measured at 24 months

Smaller BTM responses (lowest tertile

) predicted BMD non-response at 24 monthsBMD, bone mineral density; CTX, C-telopeptide of type I collagen; PINP, procollagen type I N-terminal propeptide1. Burnett-Bowie et al.

J Clin Endocrinol Metab 2009;94:1097–1103.

p<0.001 for all sites and both markers (ANOVA)

Lowest

Middle

Highest

Tertile

:

BMD according to

tertile

of CTX

at 3 months

BMD according to

tertile

of PINP

at 3 months

BMD change from baseline at 24 months (%)

6

5

4

3

2

1

0

Trochanter

Total

hip

Femoral

neck

PA lumbar

spine

0

Trochanter

Total

hip

FemoralneckPA lumbar

spine

6

5

4

3

2

1

BMD change from baseline at 24 months (%)

Slide23

Vertebral fracture risk is related to reduction in BTMs: FNIH Bone Quality StudyIn the FNIH bone quality study, a strong relationship was shown

between vertebral fracture risk reduction and treatment-related bone ALP or PINP changes (r2

  = 0.82 [p < 0.001] and r2  = 0.75 [p = 0.011], respectively)ALP, alkaline phosphatase; BTM, bone turnover marker; FNIH, Foundation for the National Institutes of Health;

PINP, procollagen type I N-terminal propeptideBauer et al. J Bone Miner Res 2018;33:634–642.

Percent change in BTM (treatment-placebo difference)

Alendronate

Lasofoxifene

Arzoxifene

Raloxifene

Ibandronate IV

Risedronate

Ibandronate oral

Zoledronic acid

Odds ratio

1.6

1.4

1.2

0.6

0.2

0

-10

-25

-30

Bone ALP

-15

0.8

Vertebral fracture

1.0

0.4

-20

Percent change in BTM (treatment-placebo difference)

PINP

Odds ratio

1.6

1.4

1.2

0.6

0.2

0

-15

-45

-55

-25

0.8

1.0

0.4

-35

Larger circles indicate studies with more fractures. Line represents log relative risk plotted against

percent

change

Slide24

CTX Levels Rapidly Decrease Following Intravenous Infusion of Zoledronic Acid

833 patients with glucocorticoid-induced osteoporosis were classified into prevention and treatment subpopulations according to the duration of pre-study glucocorticoid therapy (≤3 months or >3 months, respectively)

Significantly greater reductions in the concentrations of serum CTX and PINP in subjects receiving once-yearly i.v. zoledronic acid compared with daily oral risedronate

CTX decreased as early as 10 days following zoledronic acid treatment

CTX, C-telopeptide cross-links of type I collagen; GC, glucocorticoid; i.v, intravenous; PINP, procollagen type I N-terminal propeptide;

RIS, risedronate; ZOL, zoledronic acid

Treatment subpopulation (

>3 months pre-study glucocorticoid therapy, n=511)

*

p<0.05

Median (95% CI) (ng/mL)

10 days

3 months

6 months

12 months

0

0.1

0.2

0.3

0.4

0.5

Serum CTX

*

*

*

*

Median (95% CI) (ng/mL)

10 days

3 months

6 months

12 months

Serum PINP

*

*

*

0

10

20

30

40

50

ZOL (male)

ZOL (female)

RIS (male)

RIS (female)

*p<0.05

Devogelaer

et al. Rheumatology 2013;52:1058–1069.

Slide25

PINP and CTX Levels Decrease Rapidly Following Raloxifene Treatment50 postmenopausal women with osteopenia were randomised to raloxifene

or no treatment for 2 years

The least significant change (LSC) was calculated for PINP and CTX based on results from the untreated group; the reference interval (RI) was derived from healthy premenopausal women.PINP and CTX levels decreased rapidly within 12 weeksThe percentage of women identified as responders using the LSC method was 38% for CTX

and 52% for PINP at 12 weeksUsing the RI method

, 38% of women were identified as responders for both CTX and PINPCTX, C-telopeptide of type I collagen; LSC, least significant change; PINP, procollagen type I N-terminal propeptide; SEM, standard error of the mean

Naylor et al. Osteoporos Int 2016;27(8):2585–2592.

PINP

Percentage change (mean and SEM) in CTX and PINP over 48 weeks in women treated with

raloxifene

and women receiving no treatment

Lumbar spine mean percent change

4

0

3

0

2

0

0

−10

−20

−40

−50

0

12

36

48

Week

24

2

4

8

−30

10

Lumbar spine mean percent change

CTX

0

Week

4

0

3

0

2

0

0

−10

−20

−40

−50

−30

10

12

36

48

24

2

4

8

Raloxifene

No treatment

Slide26

The FREEDOM BTM Substudy: Reduced Levels of CTX and PINP Following Denosumab Treatment160 postmenopausal women were randomised to subcutaneous

denosumab 60 mg or placebo injection every 6 months

One month after injection, CTX levels decreased to levels below the premenopausal reference interval in all denosumab-treated women CTX and PINP remained below the premenopausal reference interval at all time points (6 through 36 months) in 46% and 31%

denosumab-treated subjects, respectivelyWith denosumab, but not placebo, there were significant correlations between CTX reduction and BMD increase

(r = -0.24 to -0.44)BMD, bone mineral density; CTX, C-telopeptide of type I collagen; PINP, procollagen type I N-terminal propeptide

Eastell et al. J Bone Miner Res 2011;26:530–537.Absolute values of serum CTX and PINP. The horizontal lines show the premenopausal reference interval.

Serum CTX (ng/mL)

1.5

1.0

0.0

Month

1

Month

24

Month

36

CTX

Month

6

Baseline

0.5

Month

12

Serum PINP (ng/mL)

180

120

0

Month

1

Month

24

Month

36

PINP

Month

6

Baseline

20

Month

12

40

140

100

80

60

320

Placebo

Denosumab

Slide27

Treatment Discontinuation is Rapidly Detected by BTMsChanges in BTM levels may be a sensitive indicator of treatment discontinuationAfter stopping oral biphosphonates BTMs increase, however, even after

2 years, they did not return to pre-treatment baseline values

1After stopping denosumab treatment BTMs rapidly increase, even above baseline levels2

CTX, C-telopeptide cross-links of type I collagen; PINP, procollagen

type I N-terminal propeptide1. Naylor et al. Osteoporos

Int 2018;29:1407–1417;2. Bone et al. J Clin Endocrinol

Metab

2011;96:972–980.

25

0

-25

0

1

4

Years

PINP

1

2

-100

-75

3

-50

*

*

On treatment

Off treatment

*

Alendronate

Ibandronate IV

Risedronate

25

0

-25

0

1

4

CTX

1

2

-100

-75

3

-50

**

**

On treatment

Off treatment

Change from baseline (%)

Change from baseline (%)

120

0

14

48

CTX

2

24

-100

-40

36

0

-80

-60

-20

20

40

60

100

80

42

30

27

18

12

10

6

0

On treatment

Off treatment

Placebo

Denosumab

120

0

14

48

Study month

PINP

2

24

-100

-40

36

0

-80

-60

-20

20

40

60

100

80

42

30

27

18

12

10

6

0

On treatment

Off treatment

BISPHOSPHONATES

DENOSUMAB

Slide28

PATIENT ADHERENCE

Slide29

The Challenge of Patient Compliance & AdherenceBisphosphonates (BPs) are considered a first-line treatment for osteoporosisOral bisphosphonate treatment needs to be taken regularly over a period of ≥ 5 years, in compliance with the following instructions:

1First thing in the morningAt least 30 minutes before any food or drink

Swallowed whole with a large glass of waterThe patient must remain upright for ≥ 30 minutesAny calcium-containing supplements must be delayed for 3 hoursThe patient must be calcium and vitamin D replete1. Adronat® Summary of Product Characterisitics 2005 (2018 revision);

Frequent dosing

Side effects and fear of side effects

Osteoporosis eclipsed by other chronic conditions

Lack of positive reinforcement

Complex dosing

Poor patient education

POOR COMPLIANCE &

ADHERENCE

Slide30

POOR COMPLIANCE AND ADHERENCEAdherence to BPs has been reported at 50% or below after one year1-3Low adherence results in lack of efficacy (no or limited decrease in fracture risk) and reduced cost effectiveness4,5

Cramer JA, et al (2007).

Osteoporos

Int 18(8):1023–1031;

Kothawala

P, et al (2007). Mayo Clin Proc 82(12):1493–1501;

Kanis

JA, et al (2012).

Osteoporos

Int 23(1):213–221;

Hiligsmann

M et al (2010). Calcif Tissue Int 86(3):202–210

Olsen et al Osteoporos Int. 2013;24(10):2639-47

Slide31

Recommendations for the Screening of Adherence to Oral Bisphosphonates

International Osteoporosis Foundation and

European Calcified Tissue Society

Working Group

www.iofbonehealth.org

Slide32

Richard Eastell & Adolfo Diez-Perez (co-chairs)

KE Naylor, B

Abrahamsen, D Agnusdei, ML Brandi, C Cooper, E Dennison, EF Eriksen, DT Gold, N Guañabens, P Hadji, M Hiligsmann, R Horne, R Josse, JA

Kanis, B Obermayer-Pietsch, D Prieto-Alhambra, JY Reginster

, R Rizzoli, S Silverman, MC ZillikensIOF-ECTS Working Group

Slide33

Slide34

Slide35

MethodsAn open, controlled trial comprising 172 postmenopausal osteoporotic women (age 53–84 years)Randomised to alendronate, ibandronate or risedronate, plus calcium and vitamin D supplementation for 2 years. Biochemical responses to three oral bisphosphonates were assessed.

The LSC for each marker was derived within the study populationReference Intervals (RIs) were obtained from a control group of healthy premenopausal women (age 35–40 years).

Slide36

Fig. 1 The percentage change from baseline (mean and standard error of the mean) for (a) bone resorption markers for the three bisphosphonate treatments (ibandronate, alendronate, risedronate) over 2 years

Slide37

Fig. 1 The percentage change from baseline (mean and standard error of the mean) for (b) bone formation markers for the three bisphosphonate treatments (ibandronate, alendronate, risedronate) over 2 years

Slide38

Fig. 1 Change from baseline after 3 months of treatment with the three tested bisphosphonates (ibandronate, alendronate, and risedronate) in CTX (left panel) and PINP (right panel). Shadowed zone indicates change > least significant change for the marker

Slide39

The TRIO Study: BTMs Are a Useful Tool to Evaluate Patient Response to Bisphosphonate TherapyCTX, C-telopeptide cross-links of type I collagen; PINP, procollagen type I N-terminal

propeptide; RI, reference interval

Naylor et al. Osteoporos Int 2016;27:21–31.

Ibandronate

Alendronate

Risedronate

Geometric mean

Premenopausal RI

12.0

10.0

6.0

2.0

0.0

-1 week

12 weeks

48 weeks

PINP

μ

g/L

4.0

8.0

2.0

1.5

1.0

0.5

0.0

CTX

μ

g/L

-1 week

12 weeks

48 weeks

Slide40

The average decrease for CTX ranged from 68 to 81% and for PINP between 48 and 63% for the different treatment arms. (Table 1)

Slide41

Table 1 Values of biochemical markers at baseline and after 3 months of treatment and percentage of decrease for each of the treatment groups

Slide42

For the different bisphosphonates, the percentage of individuals with a decrease beyond the LSC ranged from 78 to 98% for CTX and between 75 and 94% for PINP (Table 1)

Slide43

Table 1 Values of biochemical markers at baseline and after 3 months of treatment and percentage of decrease for each of the treatment groups

Slide44

Based on these results, a screening strategy is proposed. After measuring bone turnover markers before initiating medication, a second measurement is performed at 3 months. If the decrease does not exceed the LSC, the clinician should reassess the treatment, mainly the adherence and, eventually, if an underlying cause of secondary osteoporosis or low response to the drug has not been previously detected.

Slide45

Slide46

IOF/ECTS Recommendations for Bisphosphonate Adherence ScreeningDiez-Perez et al. Osteoporosis Int 2017;28:767-774.

The findings of the TRIO study were used as the basis for testing the strategy

Authors identified the proportion of patients receiving oral bisphosphonates who showed a decrease in CTX and/or PINP after 3 monthsDetection rates for a single marker or for both markers were reportedDetection rate for the measurement of PINP=84%

and for CTX=87% If variation in at least one marker was considered when measuring both CTX and PINP, the level of detection was

94.5%Baseline BTM

(PINP, CTX)

3-months BTM

(PINP, CTX)

BTM decrease >LSC

BTM decrease <LSC

Good response

Continue treatment and encourage continued compliance

Suboptimal response

Evaluate and either

correct reason for poor response or change treatment

Treatment initiation

Recommended algorithm for the assessment of adherence based on the measurement of CTX and/or PINP

BTM, bone turnover marker; CTX, C-

telopeptide

cross-links of type I collagen; ECTS, European Calcified Tissue Society; IOF, International Osteoporosis Foundation; LSC, least significant change; PINP, procollagen type I N-terminal

propeptide

Slide47

Asia Pacific Perspective

Slide48

Slide49

The Royal Australian College of General Practitioners/Clinical guideline for the prevention and treatment of osteoporosis in postmenopausal women and older menThe International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine recommend one serum bone formation marker (procollagen type I amino-terminal propeptide, or

PINP) and one bone resorption marker (C-terminal telopeptide, or CTX) to be used as reference markers.These should be measured by standardized assays in observational and intervention studies in order to compare the performance of alternatives and to enlarge the international experience of the application of markers to clinical medicine.

Reimbursement by National Health Care Insurance - Yes

Slide50

Chinese Society of Osteoporosis and Bone Mineral Research, Chinese Medical Association/Guidelines forprimary osteoporosis diagnosis and management (2017) Bone turn over markers help clinicians identify the Primary and Secondary Osteoporosis condition and predict speed of bone loss, evaluate risk of bone fracture and choose medication

as well as enhance patient’s compliance. Recommends PINP and CTX as a standard bone resorption and bone formation markers.Reimbursement by National Health Care Insurance -

Yes

Slide51

Japan Osteoporosis Society Guidelines for the use of bone metabolic markers in the diagnosis and treatment of osteoporosis (2012 edition) These proposed guidelines for the appropriate use of bone metabolic markers take into consideration current health insurance regulations in Japan.However, in order to achieve a more appropriate use of bone metabolic markers, it is now recognized that periodic repeated measurement for monitoring after treatment is also effective.

Reimbursement by National Health Care Insurance - Yes

Slide52

Biochemical markers of bone turnover (BTMs) are not recommended for diagnosis of osteoporosis because there are many confounding factors. BTMs can also change in several non-osteoporosis associated conditions.However, BTMs can be used along with BMD for risk assessment for fracture. BTMs, however, can be useful for follow-up. It is recommended that BTMs should be tested at 3 months and 1 year.These markers can prove to be accurate and efficient in monitoring drug response.

Reimbursement by National Health Care Insurance - Yes

Thai Osteoporosis Foundation/Thai Osteoporosis Foundation (TOPF) position statements on management of osteoporosis

Slide53

The Osteoporosis Society of Hong Kong (OSHK)/2013 OSHK Guideline for Clinical Management of Postmenopausal Osteoporosis in Hong KongChanges in BTMs are much more rapid than the changes in BMD.With most effective anti-resorptive therapies, BTMs decrease rapidly and reach a drug- and dose-dependent plateau within a few months.

Short-term reduction in BTMs have also been shown to correlate with the longer-term BMD response to therapy and reduction in fracture risk.There is emerging support

for their use in monitoring treatment response, especially within the first 3-6 months of initiation of antiresorptive therapy when BMD changes are too small to be detected clinically.Reimbursement by National Health Care Insurance - No

Slide54

Indian Rheumatology Association guidelines for management of glucocorticoid-induced osteoporosis (GIOP) (2011)Bone resorption markers (N-telopeptide, C-telopeptide of type I collagen) can be used in addition to a BMD assessment to identify high risk patients for future fracture and monitoring of response to treatmentBone resorption markers (N-telopeptide, C-telopeptide of type I collagen)

along with DXA can be used to monitor treatment response if feasible. Two separate baseline values followed by repeat measurement at 3 months after starting GC should be done.

Bone resorption markers can be repeated every year if neededReimbursement by National Health Care Insurance - No

Slide55

Summary of Indonesian Guidelines for Diagnosis and Management of OsteoporosisIndication for bone biochemical markers measurement is to identify patient with osteoporosis risk, rapid bone loss, predict femoral fracture risk, to monitor patient with long-term steroid treatment, to evaluate treatment responses and study the pathogenesis of osteoporosis.Treatment with anti-resorptive agents will rapidly decrease bone remodeling, thus it can be detected using bone marker tests.

Bone metabolism markers can also be used to evaluate treatment responses, and can detect the changes earlier, within 3-4 months.Reimbursement by National Health Care Insurance -

No

Slide56

Malaysian Osteoporosis Society/Clinical Practice Guidelines on Management of Osteoporosis BTMBTM are useful to identify patients at high risk of future fractures. It can also be used to evaluate treatment efficacy and compliance to therapy.They should not be used for the diagnosis of osteoporosis. Changes

in level of BTM can be seen within 3-6 months after initiation of drug therapy.Reimbursement by National Health Care Insurance -

No

Slide57

Guidance on the Diagnosis and Management of Osteoporosis in New ZealandSerum procollagen type I N-terminal propeptide (PINP) measurement:Bisphosphonates reduce bone turnover, which can be assessed by measuring serum PINP. With effective bisphosphonate therapy, PINP levels will decrease to

<35 mg/L.If PINP levels remain 35 mg/L after 6 months of oral bisphosphonate treatment, this indicates suboptimal adherence

to the bisphosphonate or poor absorption of the bisphosphonate. Switching to an IV bisphosphonate should be considered.PINP measurement can be organized through the local laboratory, with no time-of-day restrictions for obtaining blood samples.PINP levels do not usually need to be assessed in patients treated with IV bisphosphonate.Reimbursement by National Health Care Insurance - No

Slide58

OSPFI & POA/Consensus statements on osteoporosis diagnosis, prevention, and management in the PhilippinesBone turnover markers should not be used in the diagnosis of osteoporosis.Biochemical markers of bone turnover in clinical practice can be used for assessing adherence to and effectiveness of therapy.

Reimbursement by National Health Care Insurance - No

Slide59

Singapore Ministry of Health/Singapore Ministry of Health: Clinical Practice Guidelines for OsteoporosisAlternative method for monitoring therapeutic response is evaluating bone turnover markers at baseline and at 3-6 months intervals.The use of most effective osteoporosis drugs has been associated with reductions from baseline of between 20% and 40% for bone formation markers such as osteocalcin and bone alkaline phosphatase, and 30-60% for bone resorption markers such as N telopeptide, C telopeptide and deoxypyridinoline.

Not a diagnostic tool for bone fracture prediction but an aid in fracture risk assessment, the prediction of rates of bone loss, as well as in monitoring response to treatment.Reimbursement by National Health Care Insurance -

No

Slide60

Taiwanese Guidelines for the Prevention and Treatment of Osteoporosis (2014)CTX and P1NP can be utilized as a monitoring tool in osteoporosis treatment, but not diagnostic tool of osteoporosis.Reimbursement by National Health Care Insurance - No

Slide61

Summaries of Consensus StatementEndorse the use of BTMs, especially CTX and P1NP, as short-term monitoring tools for osteoporosis treatment, consistent with recommendations of the AACE/ACE, IOF, IFCC, JOS, NOF, TOA, and associated organizations.

Slide62

Summaries of Consensus StatementBTMs can be used to differentiate patients with relatively higher or lower bone turnover rates and thereafter, helping clinicians to choose an appropriate anti-osteoporosis treatment regimen.

Slide63

Summaries of Consensus StatementBTMs can reflect the therapeutic responses to antiosteoporosis therapies earlier than BMD and are therefore of help both in selecting osteoporosis treatment and in assessing its responses to therapies.

Slide64

Summaries of Consensus StatementAbsolute values or the degree of change from baseline for BTMs can be used to monitor the efficacy of osteoporosis therapies clinically.

Slide65

Summaries of Consensus StatementCTX and/or P1NP can be used to evaluate patient adherence and drug responses to anti-resorptive agents, with measurements suggested at baseline, 3 months, 6 months, and 12 months after starting treatment.

Slide66

Summaries of Consensus StatementP1NP can be used to evaluate patient adherence and drug responses to anabolic agents, with measurements at baseline, 13 months, 6 months, and 12 months after starting anabolic treatment.

Slide67

Summaries of Consensus StatementEncourage reimbursement of BTMs by different health insurance programs in the Asia-Pacific to improve patient adherence and treatment outcomes.

Slide68

Summaries of Consensus StatementRecommend appropriate use of BTMs as a short term monitoring tool for improving the use of therapeutic regimens in osteoporosis care programs, such as fracture liaison service (FLS).

Slide69

ConclusionsThe use of BTMs can be incorporated in treatment algorithms of osteoporosis care programs to improve patient adherence and treatment outcomes.Encouraging sufficient reimbursement from health care systems may facilitate more widespread use of BTMs in clinical practice in the AP region.

Slide70

Raloxifene Treated Patients

Slide71

Risedronate Treated Patients

Slide72

Alendronate Treated Patients

Slide73

Price Range for BTM Test in Asia Pacific Countries

COUNTRY

CTX (USD)P1NP (USD)OC (USD)ReimbursementDXA (USD) HIP & SPINEMalaysia20/30 - 8530 - 4525 - 40NO30 - 60Singapore

NOThailandYES

PhilippineNOIndonesiaNOTaiwan

NOIndiaNOJapan

YES

China

YES

Australia

YES

New Zealand

NO

Hong Kong

NO

Slide74

Thank You

osteoporosis_jklee@yahoo.com

Slide75

Q & A

Slide76

THANK YOUOn

behalf of IOF, we

thank you for your participation in this webinar

This webinar was supported by