Botmarkers (BTM) in de dagelijkse praktijk

Universitair Medisch Centrum Groningen

Dr. E. van der Veer Maastricht, 23 en 24 november 2012

UMCG

  Bone volume   Materials properties

  Mineralization (adverse effects of fluoride)   Organic matrix composition (mutations in type I collagen gene)

  Structure   Size and shape   Internal architecture

  Turnover   Damage accumulation

(microcracks)   Connectivity

Micro-compression of Bone

Ralph Müller

UMCG Seeman et al. NEJM 2006

PINP

BALP

Osteocalcine CTx

Naylor K, Eastell R. Bone Turnover Markers: use in osteoporosis.

Nat Rev Rheumatol. 2012 Jun 5;8(7):379-389

•  BTMs are useful for the management of patients with osteoporosis, –  for initial clinical assessment –  for guiding and monitoring of treatment.

UMCG

–100

–80

–60

–40

–20

0

Baseline 6 12 months

Mea

n ch

ange

(%)

Urine NTx Serum CTx

p<0.001

p<0.001 –40%

–53% –55%

–74% p<0.001

p<0.001

3

p<0.001

Treatment difference 13%

p<0.001

Treatment difference 19%

Alendronate n = 442 429 414 365 449 443 423 382 Risedronate n = 457 449 426 375 459 455 433 387

Alendronate 70 mg OW Risedronate 35 mg OW

–100

–80

–60

–40

–20

0

Baseline 6 12 months 3

BMD (DXA) wordt uitgedrukt in T-score of Z-score. Maat voor de hoeveelheid botmassa

3 2 1 0

-1 -2 -3

BM

D T

-Sco

re

T-score = -2.5 Z-score = -1

20 30 40 50 60 70 80 90

+1 SD 0 -1 SD

Leeftijd (jaren)

UMCG

Lower half of reference interval

Upper half of reference interval

80

NTX/Cr (nmol/mmol creatinine)

Osteoporosis; untreated

NTX/Cr (nmol/mmol creatinine)

Osteoporosis; risedronate

100 10 32 100 10 32

Num

ber o

f pat

ient

s

0

10

20

30

40

50

60

70

Num

ber o

f pat

ient

s 0

10

20

30

40

Eastell JBMR 2005

0 11 62 27% 7 63 28 2%

UMCG

1.  The baseline level of bone resorption is related to subsequent fracture risk,

2.  The reduction in bone resorption explains, in part, the reduction in the risk of fractures with risedronate,

Placebo

Calcium + vitamin D

Risedronate 5 mg

u CTx T-score u NTx T-score

UMCG

Eastell R , Barton I , Hannon RA , Chines A , Garnero P , Delmas PD Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate.

J Bone Miner Res 2003; 18: 1051– 1056.

Eastell R, Hannon RA, Garnero P, Campbell MJ, Delmas PD Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. Review of statistical analysis.

J Bone Miner Res 2007; 22: 1656– 1660.

UMCG

0 5

10 15 20 25 30 35

1 2 3 4 5 6 7 8 9 10

66 patients in each groupe

CTx T-score <-1.7 -1 0 +1 +2 >+2.4

% fr

actu

res

In the context of fracture risk for groups: The appropiate risk is that of the group above a specified limit compared to the risk of the general population e.g. Q4/Q1-4

In the context of fracture risk assessment for an individual: The most appropiate relative risk (assuming a normal distribution) is the risk of the individual compared with the risk in the normal population

BTMs in fracture risk prediction  

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BTM "   OC: osteocalcin "   PINP: product of collagen formation "   BALP: necessary for start of mineralization "   sCTX: product of collagen degradation

"   Z-scores "   (BTM value of individual patient – mean BTM value of the matched 10-year-cohort of

reference group) / SD of matched reference cohort

sCTX in males and females of a healthy reference cohort (n=550)

Healthy reference cohort

UMCG

Bisphosphonate calcium & vitamin D

UMCG

% change after start bisphosphonate Follow-up in Z-scores

LSC

LSC = least significant change

UMCG

???

UMCG

UMCG

UMCG

Osteoporose

25OHvitD en Botmarkers meten

3 – 6 mnd botmarkers herhalen

Daling tot onder gemiddelde waarde gezonde vrouwen, 25OHvitD en botmarkers jaarlijks meten

Geen goede daling, compliantie navragen evt dosering aanpassen? ander geneesmiddel overwegen?

Start behandeling

Na 5 jaar evaluatie behandeling

Behandeling stoppen

Botmarkers meten

Behandeling voortzetten

Botmarkers jaarlijks meten

UMCG

#

6

Ca+D

* p<0.05 from baseline # p<0.05 from placebo Watts et al, OI, 2007

#

#

UMCG

Ca+D

* p<0.05 from baseline # p<0.05 from placebo Watts et al, OI, 2007

#

# # #

UMCG

Alendronate

Urine NTx Mean Percentage Change

Bone NEJM 2004

UMCG

Alendronate

BALP Mean Percentage Change

Bone NEJM 2004

Naylor K, Eastell R. Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol. 2012 Jun 5;8(7):379-389

•  BTMs are useful for the management of patients with osteoporosis, –  for initial clinical assessment –  for guiding and monitoring of treatment.

•  BTM levels respond rapidly to both anabolic and antiresorptive treatments

BTMs in monitoring of osteoporosis treatment

Vasikaran 2011

BTMs in monitoring of osteoporosis treatment

Naylor K, Eastell R. Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol. 2012 Jun 5;8(7):379-389

•  BTMs are useful for the management of patients with osteoporosis, –  for initial clinical assessment –  for guiding and monitoring of treatment.

•  BTM levels respond rapidly to both anabolic and antiresorptive treatments

•  BTMs  are  also  poten.ally  useful  as  surrogate  biomarkers  for  fracture.    

UMCG

0 5

10 15 20 25 30 35

1 2 3 4 5 6 7 8 9 10

66 patients in each groupe

CTx T-score <-1.7 -1 0 +1 +2 >+2.4

% fr

actu

res

BTMs in fracture risk prediction  

uCTX T-score > 2.0 SD

BMD T-score < -2.5 SD

Naylor K, Eastell R. Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol. 2012 Jun 5;8(7):379-389

•  BTMs are useful for the management of patients with osteoporosis, –  for initial clinical assessment –  for guiding and monitoring of treatment.

•  BTM levels respond rapidly to both anabolic and antiresorptive treatments

•  BTMs are also potentially useful as surrogate biomarkers for fracture.

•  BTMs can indentify patients with high bone turnover and rapid bone loss –  to determine possible causes of secondary osteoporosis

BTM in secondary osteoporosis  

Disease Specific BTM findings

Primary Hyperparathyroidism increased BTM (depend disease severity) Thyroid disease Diabetes Paget disease of bone high BTM Myeloma high BTM Rheum Arthritis increased BTM (depend disease severity) Bechterew disease increased BTM (depend disease severity)

Crohn's disease Malabsorption vit D and Ca2+ , increased BTM

Chronic Kidney disease impaired renal function, increased BTM

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Ankylosing Spondylitis

"   Increased bone formation "   Syndesmophytes "   Joint ankylosis

"   Increased bone resorption "   Osteoporosis "   Vertebral fractures

NORMAL

OSTEOPOROSIS

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Ankylosing Spondylitis

"  AS "  bone formation "  bone resorption

"  Detection of osteoporosis is difficult in patients with advanced AS "  overestimation of lumbar spine BMD by the

presence of syndesmophytes, ligament calcifications, and fusion of facet joints

Naylor K, Eastell R. Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol. 2012 Jun 5;8(7):379-389

•  BTMs are useful for the management of patients with osteoporosis, –  for initial clinical assessment –  for guiding and monitoring of treatment.

•  BTM levels respond rapidly to both anabolic and antiresorptive treatments

•  BTMs are also potentially useful as surrogate biomarkers for fracture.

•  BTMs can indentify patients with high bone turnover and rapid bone loss –  to determine possible causes of secondary osteoporosis

•  BTM changes can also be used for understanding the mechanism of action of drugs in development and identifying the correct dose.

•  Appropriate reference intervals should be used for the optimum interpretation of results.