Role of bone turnover markersin osteoporosis

Dr N Srinivasan M.S.(ortho),DNB(ortho), M,Ch Neuro

Formerly Prof of ortho Gandhi Medical collegeProfessor & HOD orthopaedics

MIMS,Hyderabad

compromised bone strength>fragility Frs

Bone strength is proportional to bone mass measured with DEXA

Bone quality is depends on bone micro-architecture, bone turnover rate, micro-damage accumulation, calcification, quality of bone matrix

Bone turn over markers indicate the current status of bone quality

Osteoporosis is a silent disease

Bone has 90% type I collagen in organic matrix

Release of Carboxy-peptides and amino-protocollagen molecules during degradation & formation

The same can be detected in blood and urine and are called bone turnover markers

Collagen synthesis

Osteoblastgenes Chr 17 & 7 activation__> à₁ and à₂ polypeptide chains formed on the mRNA

The triple helix is formed by coiling together of two à₁ & one à₂ chains on the ribosome (procollagen)

Hydroxylation of procollagen at lysine & leucine site Extrusion into extracellular fluid Procollagen severed at carboxy C1NPand amino

terminal ends P1NP– remaining helical structure is collagen fibril

collagen fibrils arranged parallelly so that each set over laps two thirds of neighbour and crosslinkage occurs with pyridinium covalent bonds

This forms mature collagen Mature collagen is stable for 3months to few years Osteoclastic resorption causes enzymatic breakage of

mature collagen fibrils into two carboxy telopeptide (CTX or βcrosslaps and amino telopeptide (NTX)

Bone turnover markersClassified as--Bone resorption markers---

↑ osteoclastic activity

Bone formation markers-- increased osteoblastic activity

Bone matrix related protiens

Bone resorption markers

Urinary hydroxyl proline

Urinary total Pyridinoline PYD

Urinary Deoxypyridinoline DPD

Type 1 collagen cross-linked N-telopeptide NTX Serum/urine

Type 1 collagen cross-linked C-telopeptide CTX Serum/plasma/urine

Tartrate-resistant acid phosphatase TRACP-5b Serum/plasma

Bone Sialoprotein (BSP)

Bone formation markers

Serum total alkaline phosphatase

Serum Bone alkaline phosphatase BAP

Osteocalcin OC Serum

Serum Type 1 procollagen-N-propeptide P1NPa

 

Bone matrix-related markers

Undercarboxylated osteocalcin (ucOC Serum)

Homocysteine (HCY)

Diagnosis of osteoporosisDexa scan is still a gold standard for diagnosis of osteoporosis.It has following deficiencies 1. regional examination(hip,wrist,spine) 2. static parameter . 2.variations in serial study is small at short

intervals 3. hence one has to wait till more than one

year for a notable change 4.assessment of fracture risk is not possible

in Osteopaenia group based on DEXA alone

5. BTMS offer dynamic global assessment of skeleton as a whole.

6.have a role in the osteopaenia group regarding fracture risk assessment

7. ↑ BRM s ↑ Fr risk

BTMs in diagnosis of osteoporosis

↑ in BTMs can be an independent risk factor for predicting fragility frs.

serum carboxy terminal telopeptide of collagen type I (s-CTX) as the standard bone resorption marker and serum procollagen type I N-terminal propeptide (s-PINP) as the standard bone formation marker

These two can be utilised in osteopaenia group for assessing fr risk

BTM s in selection of drugsUseful in selection of drugs and changing

drug therapy.↑ BRMs --------- bisphosphonates,SERMS,

No effect in followup PTH, Teriparatide

↑ ucOC in urine vit K↓25-hydroxy vitD -- Vit d₃ supplementation

Evaluation of effectiveness of drug therapy

the change in BMD is small and slow whereas the changes in BTMs are large and occur early after initiation of therapy.

antiresorptive drugs – ↓ in bone resorption markers in 3 months

For anabolic drugs– ↓ in P1NPat 6 months

Only significant change in values should be considered for effectiveness of drugs.

The change should exceed MSC

Minimum significant change is twice inter day change for that particular BTM in postmenopausal woman

Specimen samplingBoth blood and urine to

be collected at the same time during every sampling in the morning . Fasting specimen preferred

Diurnal variation for NTX is as much as 20-30%

Evaluation of effectiveness of drug therapyDrug BTM to be monitored

Bisphosphonate, SERM, oestrogen

DPD, NTX, CTX, TRACP-5b, BAP, or P1NP

Vit D₃ NTX, BAP, P1NP

PTH ( Teriparatide) P1NP

Vit K ↑ ucOC in urine

Role in drug complaianceIf there is no significant change in BTMs over

a period , one should check for drug complaiance.

In bisphosphonate administration , one should check whether there is sufficient gap between drug intake and food intake

One should also look into other causes causing secondary osteoporosis for failure of drug therapy

Algorithm for use of BTM in therapy

decision to treat

based on fr risk assessment ↓

Measure baseline BTMS Serum CTx for resorptive

therapy Serum P1NP for anabolic

therapy ↓

3months visit measure BTMs ↓

Significant change in BTMs achieved

change therapy ←no ← review complaiance ← no ↓ y es

other causes for osteoporosis ↓

Yes address problem reassure pateient ↓ ↓

Measure BTM s at 3 months Check BMD at 18-24 months

Jehoon Lee, M.D. and Samuel Vasikaran, M.D.Ann. Lab .Medicine 2012

Table 3 Bone turnover marker reference values and established conditions Type of marker (assay method) Reference values Established conditions (women)   Bone formation markers BAP (CLEIA)a 2.9–14.5 µg/L Premenopausal BAP (EIA)b 7.9–29.0 U/L 30–44 years P1NPc 17.1–64.7 µg/L 30–44 years   Bone resorption markers DPDb 2.8–7.6 nmol/mmol Cr 30–44 years sNTXb 7.5–16.5 nmol BCE/L 40–44 years uNTXb 9.3–54.3 nmol BCE/mmol Cr 30–44 years sCTXc 0.100–0.653 ng/mL 30–44 years uCTXb 40.3–301.4 µg/mmol Cr 30–44 years TRACP-5ba 120–420 mU/dL Young adult mean (YAM 30–44 years)   Bone matrix marker   ucOCa 3.94 ng/mL (not established as reference value) Upper limit in women B44 years 4.5 ng/mL Cut-off value for the determination of Vitamin K insufficiency (more frequent use in clinical setting) 5.5 ng/mL Cut-off value for the risk of fracture   Reference values of bone metabolic markers are within the range of the mean ± 1.96 SD, as established in healthy

premenopausal women      

conclusionBTMS can predict bone loss and fracture

risk in untreated patient when BMD is on borderline.

It is useful in monitoring patients compliance and response to therapy

Can help in selection of drug therapy

With more standardization of laboratory methods, Estimation of BTMS is likely to become more popular.

references 1. Guidelines for the use of bone metabolic markers in the diagnosis and treatment of osteoporosis (2012 edition)------Yoshiki Nishizawa et al: J Bone Miner Metab. 2. Biochemical Markers in Osteoporosis: Usefulness in Clinical Practice Carmen M. Romero Barcon et al : Reumatol Clin. 2012;8(3):149–152 3. Current Recommendations for Laboratory Testing and Use of Bone

Turnover Markers in Management of Osteoporosis-- Jehoon Lee, M.D.1, and Samuel Vasikaran, M.D. Ann Lab Med 2012;32:105-112

4. A Comprehensive Approach to Fragility Fractures.-Brian J. Rebolledo, BA,* Aasis Unnanuntana, MD Journal ortho trauma 2012

5. Role of Common Biochemical Markers for the Assessment of Fracture Union

M. Mukhopadhyay • R. Sinha • M. Pal:Ind J Clin Biochem (July-Sept 2011) 26(3):274–278