Pauline M. Camacho, MD, FACEProfessor of Medicine

Loyola University Medical CenterImmediate Past President, AACE

AACE Annual Meeting 2018Boston

May 2018

BONE TURNOVER MARKERS: EMERGING TOOLS IN THE MANAGEMENT OF

POSTMENOPAUSAL OSTEOPOROSIS

OBJECTIVES

• To discuss commonly used bone turnover markers

• To discuss advantages and limitations of using bone turnover markers 

• To discuss the role of bone turnover markers in the management of postmenopausal osteoporosis

No conflicts of interest

DISCLOSURES

GUIDELINES FOR DISCUSSION

• Case based: your cases or mine• We can look at the studies, if desired• Discussion will be free flowing but we will follow

the general outline

OUTLINE• What are common biochemical markers of bone turnover

(BTM)?• What management gap can BTM’s fulfill?• What limitations do BTM’s have?• How can BTM’s be used in the initial workup of postmenopausal

osteoporosis?• How can BTM’s be used during the follow up of postmenopausal

osteoporosis?

WHAT ARE COMMON BIOCHEMICAL MARKERS OF BONE TURNOVER (BTM)?

• Illustration of bone turnover *

• Markers of bone formation *

• Markers of bone resorption *

ILLUSTRATION OF BONE TURNOVER

Chronic kidney disease and osteoporosis: evaluation and managementPaul D MillerBoneKEy Reports (2014) 3, Article number: 542 (2014) doi:10.1038/bonekey.2014.37

MARKERS OF BONE FORMATION

• By-products of type 1 collagen synthesis: C-terminal: (P1CP) N-terminal: (P1NP)

• Osteoblast enzymes: Bone specific alkaline phosphatase (BAP)

• Matrix proteins: Osteocalcin (OC)

MARKERS OF BONE RESORPTION• Collagen degradation products:

• Telopeptides of type 1 collagen (C-terminal: CTX-1 and CTX-matrix metalloproteinases [MMP], N-terminal: NTX-1)

• Hydroxyproline• Pyridinium crosslinks (pyridinoline [PYD], deoxypyridinoline [DPD])

• Noncollagenous proteins: Bone sialoprotein• Osteoclastic enzymes:

• Tartrate-resistant acid phosphatase• Cathepsin K

• Osteocyte activity markers:• Receptor activator of nuclear factor kappa-B ligand (RANKL)• Osteoprotegerin (OPG)• Dickkopf-related protein 1• Sclerostin

Shetty S, Kapoor N, Bondu JD, Thomas N, Paul TV. Bone turnover markers: Emerging tool in the management of osteoporosis. Indian Journal of Endocrinology and Metabolism. 2016;20(6):846-852. doi:10.4103/2230-8210.192914.

WHAT BTM’S DO YOU USE?

WHAT MANAGEMENT OR TREATMENT GAP CAN BTM’S FULFILL?

Mrs. Brown, take this medicine and we’’ll see if it works in 2 years !!

Doctor I may not be alive in 2 years !!

WHAT LIMITATIONS DO BTM’S HAVE?

• Diurnal variation *

• Intraindividual variation *

• Lab variation

• Fasting state *

• Specific conditions affecting bone turnover *

DIURNAL VARIATION

Individual subjectMean

Dpd NTx CTx

Ideal specimencollection time

7 10 13 16 19 22 1 4-100

-50

0

50

100

Cha

nge

from

24h

mea

n (%

)

7 10 13 16 19 22 1 4-100

-50

0

50

100

Hour of day7 10 13 16 19 22 1 4

-100

-50

0

50

100

Bollen A-M et al, J Bone Miner Res 1995;10:1885-1890Courtesy of Nelson Watts

INTRAINDIVIDUAL VARIATION

Least significant change

in serial results (mean + SD)

Six serum markers 17.1+4.8%

Five urine markers 38.5+7.7%

Blumsohn A et al, J Bone Mineral Res 1994;9 (suppl 1):S153Courtesy of Nelson Watts

EFFECT OF FOOD ON BTMS• 20 healthy women

• TN-telopeptide cross-link of type I collagen in urine (uNTX) and serum (sNTX), the C-telopeptide in urine (uCTX) and serum (sβCTX), and immunoreactive free deoxypyridinoline (uifDPD) in urine were measured as resorption markers. Procollagen type I N-terminal propeptide (PINP), osteocalcin (OC), and bone alkaline phosphatase (bone ALP) were measured as formation markers

• All bone formation and resorption markers were significantly lower in the fed state with the exception of bone ALP.

• The magnitude of the decrease ranged from 3.8 ± 0.9% for PINP (p < 0.0001) to 17.8 ± 2.6% (p < 0.0001) for sβCTX

Effect of feeding on bone turnover markers and its impact on biological variability of measurementsClowes, J.A et al. Bone , 2002, Volume 30 , Issue 6 , 886 – 890

SOME CONDITIONS THAT AFFECT BTM’S• Recent fracture• Chronic kidney disease• Vitamin D deficiency• Hyperparathyroidism• Hyperthyroidism• Cushing’s syndrome• Drugs- corticosteroids, aromatase inhibitors

HOW CAN BTM’S BE USED IN THE INITIAL WORKUP OF POSTMENOPAUSAL

OSTEOPOROSIS?

CASE: 58 YEAR OLD WITH CELIAC DISEASE• 58 year old Caucasian female who has a history of celiac disease• On a gluten free diet since diagnosis in her 30’s• Currently vitamin D/Calcium replete and no evidence of malabsorption• No prior fractures and other high risk features for fractures• DXA scan showed lumbar spine T score of -2.4, femoral neck T score

of -1.9• Bone specific alkaline phosphatase - 7.5 ugl/l (7-22.4)• Serum CTX – 230 pg/ml

CASE: 45 YEAR OLD WITH BREAST CANCER• 45 year old Caucasian woman recently diagnosed to have breast CA• Treated with chemotherapy, and now on aromatase inhibitor- letrozole• Also received goserelin• Takes 1200 mg of calcium daily and 2000 IU of vitamin D• No prior fractures or other high risk features• DXA scan showed lumbar spine T score of -2.4, femoral neck T score

of -1.9• Bone specific alkaline phosphatase – 21 ug/L ( 7-22.4)• Serum CTX – 450 pg/ml

WILL YOU MANAGE THESE WOMEN DIFFERENTLY BASED ON THEIR BTM’S?

ROLE OF BTM’S• BTM’s in predicting fracture risk *• BTM’s in predicting future bone loss *• BTM’s in choosing initial agent

PROSPECTIVE STUDIES: RESORPTION MARKERS AND FRACTURE RISK

Study (patient subgroup)

Fracture type

Marker of bone

resorption

Odds ratio or relative risk

(95% CI)

EPIDOS1 (>2SD above premenopausal mean)

Hip uCTX uNTX uDPD

2.2 (1.3, 3.6) 1.4 (0.9, 2.2) 1.9 (1.1, 3.2)

Rotterdam2 (above median) Hip uDPD 3.4 (1.1, 10.6)

OFELY3 (upper quartile) Non-spine uCTX 2.4 (1.1, 5.0)

1Garnero P, et al. J Bone Miner Res 1996;11:1531–82Van Daele PL, et al. Br Med J 1996;312:482–33Garnero P, et al. J Bone Miner Res 2000;15:1526–36

PROSPECTIVE STUDIES: FORMATION MARKERS AND FRACTURE RISK

Study (patient subgroup)

Fracture type

Marker of bone

resorption

Odds ratio or relative risk

(95% CI)

EPIDOS1 (>2SD above premenopausal mean) Hip

OC Bone ALP

1.0 (0.7, 1.6) 1.1 (0.7, 1.7)

Rotterdam2 (above median) Hip

OC Bone ALP

0.3 (0.1, 1.0) 1.0 (0.4, 2.5)

OFELY3 (upper quartile) Non-spine Bone ALP 2.4 (1.1, 4.9)

1Garnero P, et al. J Bone Miner Res 1996;11:1531–82Van Daele PL, et al. Br Med J 1996;312:482–33Garnero P, et al. J Bone Miner Res 2000;15:1526–36

HIGH CTX AND DPD ARERISK FACTORS FOR HIP FRACTURE

0

1

2

3

4

5

6 CTXFree DPD

LOW HIGH BOTHHIP BMD MARKER

Garnero P et al, J Bone Miner Res 1996;11:1531

2.72.2 1.9

4.84.1

URINE NTX AND RATE OF BONE LOSS

-3.5-3.0-2.5-2.0-1.5-1.0-0.50.00.5

1 2 3 4Low NTx High NTx

Quartiles

Chesnut C et al, Am J Med 1997;102:29

Recently menopausalwomen given

calciumsupplements and followed

for 1 year

BTMS AND BONE LOSS

Adapted from Ross PD, Knowlton W. Rapid bone loss is associated with increased levels of biochemical markers. (DPD stands for deoxypyridinoline.) J Bone Miner Res 1998 Feb; 13(2): 297-302 https://emedicine.medscape.com/article/128567-overview

HOW CAN BTM’S BE USED DURING THE FOLLOW UP OF POSTMENOPAUSAL

OSTEOPOROSIS?

• Assessment of drug efficacy• Prediction of fracture risk reduction while

on therapy• Assessment of patient compliance• Patient reassurance that drug is working

EXPECTED CHANGES IN BTM’S

• 20-30% decrease in bone formation markers with antiresorptive therapy

• 50-60% decrease in resorption markers and more when denosumab is sed

• 30-50% increase in bone formation markers with anabolic therapy, resorption markers also increase

BAP CHANGE IN ONE YEAR AND FRACTURE RISK

Baseline BMD, change in bone ALP, and spine fracture risk. Age‐adjusted risk of morphometric spine fracture by tertile of baseline spine BMD and tertile of percent change in bone ALP after 1 year of ALN therapy. Referent group (OR = 1.0) is those women in both the tertile with lowest baseline BMD and tertile with least reduction in bone ALP

Change in Bone Turnover and Hip, Non‐Spine, and Vertebral Fracture in Alendronate‐Treated Women: The Fracture Intervention Trial, Volume: 19, Issue: 8, Pages: 1250-1258, First published: 02 December 2009, DOI: (10.1359/JBMR.040512)

ZOLEDRONIC ACID AND SERUM CTX

Effects of Yearly Zoledronic Acid 5 mg on Bone Turnover Markers and Relation of PINP With Fracture Reduction in Postmenopausal Women With Osteoporosis, Volume: 24, Issue: 9, Pages: 1544-1551, First published: 04 December 2009, DOI: (10.1359/jbmr.090310)

Effects of Yearly Zoledronic Acid 5 mg on Bone Turnover Markers and Relation of PINP With Fracture Reduction in Postmenopausal Women With Osteoporosis, Volume: 24, Issue: 9, Pages: 1544-1551, First published: 04 December 2009, DOI: (10.1359/jbmr.090310)

The premenopausal reference interval for PINP was 16.3–78.2 ng/ml

DENOSUMAB AND BTM’S

Effects of denosumab on bone turnover markers in postmenopausal osteoporosis, Volume: 26, Issue: 3, Pages: 530-537, First published: 13 September 2010, DOI: (10.1002/jbmr.251)

WHAT HAPPENS TO BTM’S DURING BISPHOSPHONATE HOLIDAYS?

CHANGE IN NTX/CREAT AFTER ALENDRONATEDISCONTINUATION

-10

0

10

20

30

40

0 12 36 60

Month

Mea

n Pe

rcen

t Cha

nge

from

FL

EX B

asel

ine

Placebo Alendronate

32%p < 0.001

Based on data from Ensrud et al publication and Black et al abstract

Black DM et al, J Bone Miner Res 2004; 19 (suppl 1): 1174Courtesy of Nelson Watts

-60

-40

-20

0

0 1 2 3 4Years

RIS 5 mgPlacebo

Urine NTX

Perc

ent C

hang

e fr

om B

asel

ine

-40

-20

0

0 1 2 3 4Years

RIS 5 mgPlacebo

BAP

Perc

ent C

hang

e fr

om B

asel

ine

*# *#

*

*# *#

*#

*p<0.05 vs baseline#p<0.05 vs placebo Watts NB et al. ISCD Annual Meeting 2004

Courtesy of Nelson Watts

CHANGE IN NTX AND BAP AFTER RISEDRONATE DISCONTINATION

CHANGE IN BTM’S AFTER ZOLEDRONIC ACID DISCONTINUATION

Black DM, Reid IR, Boonen S, et al. The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment of Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT). Journal of Bone and Mineral Research. 2012;27(2):243-254. doi:10.1002/jbmr.1494.

CHANGE IN BTM’S AFTER ZOLEDRONIC ACID DISCONTINUATION

The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Second Extension to the HORIZON‐Pivotal Fracture Trial (PFT), Volume: 30, Issue: 5, Pages: 934-944, First published: 26 December 2014, DOI: (10.1002/jbmr.2442)

CONCLUSIONS• BTM’s can play a major role in the management of

postmenopausal osteoporosis• With declining use of DXA scans and increasing patient anxiety

over osteoporosis drugs, they can play a crucial role in assessing drug efficacy and patient compliance

• LSC is high but the expected changes from medications are much higher

• Clinicians should become familiar with using BTM’s in the management of osteoporosis as a supplement to DXA scans

THANK YOU