Post on 09-Sep-2018
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