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bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
bone turnover markers
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bone turnover markers

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  • Osteoporosis is a silent disease. It is a disease of compromised bone strength leading to fragility fractures. Bone strength is measured by DEXA which indicates bone mass. Bone quality indicated by bone micro-architecture, bone turnover rate, micro-damage accumulation, calcification, quality of bone matrix its collagen etc
  • Historically urinary calcium was the first test to assess bone resorption.not effective as it is influenced by intake,absorption, renal threshold etc.Urinary hydroxyproline product of collagen breakdown is also has low specificity & sensitivity as other tissue break down and dietary intake modify the result.The collagen molecules in bone matrix are covalently linked by pyridinoline (Pir) and deoxypyridinoline (Dpir) forming fibrils. The former is also found in cartilage, however, Dpir is more specific for bone. They do not depend on diet, and are not absorbed via the gut. They express both changes of bone metabolism, rising in childhood, menopause, osteomalacia, hyperparathyroidism and hyperthyroidism, and lowering due to estrogen and bisphosphonate treatment.11Other elements released during bone resorption are the carboxyterminal (ICTP, CTX) and amino-terminal (NTX) telopeptides of collagen. They have shown a significant correlation with BMD in postmenopausal women, and both CTX and NTX are considered the most clinically useful markers of bone resorption currentlyTartrate-resistant acid phosphatase 5b (5b Fatra) is a lysosomal enzyme not only involved in osteoclast bone degradation, but is also present in other tissues. It is poorly specific, and together with the methodological difficulty in identifying it, currently makes it of little clinical use.
  • alkaline phosphatase (ALP), is an enzyme that plays an important role in osteoid formation and mineralization. Alkaline phosphatase activity is derived from various tissues such as the liver, bone, placenta, etc. Bone and liver isoforms are the most common (90%. The bone isoform has the advantage of presenting no variation between genders and not influenced by circadian rhythm, so that, despite having low sensitivity and specificity in the study of metabolic bone disease, it is easy to detect in the absence gestation and liver disease Osteocalcin is the most abundant non-collagenous protein of the extracellular matrix. Specific for bone and dentin, it is elevated in situations of increased bone turnover, has a short half-life and is eliminated via the urine, so its levels are increased in situations of renal failure. Its exact role in bone remodeling is not well established. Recent work has analyzed the potential role of infracarboxilatedosteocalcin in predicting bone mass and risk of fracture Because type I collagen is the main product of synthesis of the osteoblast, the amino-terminal carboxypropeptides would, theoretically, be the ideal marker of bone formation. However, the fact that type I collagen appears in other tissues other than bone limits its use in the study of metabolic bone disease
  • . Undercarboxylatedosteocalcin is another marker that indicates VIT K deficiency useful in predicting increased fracture risk.osteocalcin is bone formation marker produced by osteoblasts.Vit K dependent carboxylase acts on GLU acid residue of osteocalcin modifying into carboxyglu residue which binds to hydroxyapatite crystals stabilising it.Undercarboxylation of osteocalcin occurs in VItKdefficiency.Although the exact mechanism is still obscure, many reports indicated that ucOC is an independent predictor for osteoporotic fracture [34, 35].90% ofBone matrix consists of TYPEI COLLAGEN. there are two types collagen cross-link formation 1. Enzymatic 2. Non-enzymatic. Decrease in enzymatic crosslink and /or increase in nonenzymatic crosslink lowers bone strength. Vit D₃ defficiency affects enzymatic crosslinking.Homocysteine is also similarly a negative regulator of enzymatic crosslinking. Furthermore, recentprogress in the risk analysis for fracture has revealed that mild elevation of plasma homocysteine is an independent predictor for future fracture.
  • Diagnosis of osteoporosis is based on dexa scan mainly of hip, wrist, spine which measures bone mass. But dexa measures only certain main areas of the skeleton with regional variation and does not indicate the current metabolic status of bone. Further one can not demonstrate small changes in bone with treatment by dexa at short intervals.Even when osteoporosis is assessed with dexa , there are more no of people in osteopaenia group than in osteoporosis and they also sustain fragility fractures. No risk assessment can be made in this group basing on dexaalone.SoFrax is the tool for fr risk assessment that includes other factors also apart from dexa.
  • Bone resorption markers when they are in increased compared to reference value, is indication for institution of antiresorptive therapy. Alendronates have strong antiresorptive effect compared to oestrogen receptor agonists (raloxifene) ↑ in ucOC in urine indicated Vit K defficiency and need for supplentation. ↓Serum hydroxyvit D₃ levels need for Vit D supplementation.
  • Transcript

    • 1. Dr N Srinivasan M.S.(ortho),DNB(ortho), M,Ch Neuro Formerly Prof of ortho Gandhi Medical college Professor & HOD orthopaedics MIMS,Hyderabad
    • 2.  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
    • 3.  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
    • 4. Collagen synthesis  Osteoblastgenes 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)
    • 5. Bone turnover markers  Classified as--  Bone resorption markers---↑ osteoclastic activity  Bone formation markers-- increased osteoblastic activity  Bone matrix related protiens
    • 6. 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)
    • 7. Bone formation markers  Serum total alkaline phosphatase  Serum Bone alkaline phosphatase BAP  Osteocalcin OC Serum  Serum Type 1 procollagen-N-propeptide P1NPa
    • 8. Bone matrix-related markers  Undercarboxylated osteocalcin (ucOC Serum)  Homocysteine (HCY)
    • 9. Diagnosis of osteoporosis  Dexa 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
    • 10. 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
    • 11. BTM s in selection of drugs  Useful 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
    • 12. 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
    • 13. Specimen sampling  Both 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%
    • 14. Evaluation of effectiveness of drug therapy Drug 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
    • 15. Role in drug complaiance  If 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
    • 16. 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
    • 17.  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   
    • 18. conclusion  BTMS 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.
    • 19. 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

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