Page 1 Currently Available Biochemical Markers of Bone Turnover - PDF document

Bone Remodeling Sequence Bone Turnover Markers in Clinical Practice: Ready for Prime Time? Douglas C. Bauer, MD University of California San Francisco, CA No disclosures 2 Markers of Bone Resorption: Currently Available Biochemical Markers Type I Collagen Crosslinks of Bone Turnover N Bone matrix • Resorption (urine and serum) Hyl N  1 – Pyridinoline and deoxypyridinoline  1 C Hyl  2 C – N-telopeptides of type 1 collagen (uNTX) Osteoclastic bone resorption – C-telopeptides of type 1 collagen (uCTX, sCTX*) C-telopeptides N-telopeptides COOH NH 2 COOH NH 2 OH COOH NH 2 COOH (OH) NH 2 NH 2 COOH NTX CTX Free PYD and DPD (40%) Crosslinked C and N-telopeptides (60%) PYD = pyridinoline; CTX = C-telopeptides of type I collagen DPD = deoxypyridinoline; NTX = N-telopeptides of type I collagen * Recommended for clinical use by IOF-IFCC Working Group 3 4 Page 1

Currently Available Biochemical Markers of Bone Turnover Markers of Bone Formation: PINP • Formation (serum) Procollagen type I – Osteocalcin (OC) – Bone alkaline phosphatase (Bone ALP) – N-terminal propeptide type I procollagen (PINP)*^ N ‐ Terminal pro ‐ peptid (PINP) C ‐ Terminal pro ‐ peptid (PICP) PINP (monomer – kidneys) + Collagen type I Intact PINP (trimer ‐ liver) * Recommended for clinical use by IOF-IFCC Working Group ^Automated assay platform not FDA approved or available in US 5 6 Possible Clinical Uses of BTMs Predicting Fracture in Biochemical Markers Untreated Individuals • Published studies; some positive and some • Predict fracture risk in untreated individuals negative • Promote compliance among treated • Meta-analysis of 6 prospective cohort studies individuals without adjustment for BMD • Identify non-compliance among treated – PINP per SD increase: RR=1.2 (CI: 1.1-1.4) individuals – sCTX per SD increase: RR=1.2 (CI: 1.1-1.3) • Assess treatment efficacy during and after • Weaker than hip BMD alone (typically RR=2-3 drug therapy per SD decrease) Johansson H et al, Calcif Tissue Int, 2014 7 8 Page 2

Possible Clinical Uses of If BMD Known, Does Marker Help? Biochemical Markers • Fracture risk calculators (e.g. FRAX) do not include • Predict fracture risk in untreated individuals BTMs. Should they? • Promote compliance among treated • Combination of tests best assessed by AUC in ROC individuals analyses • Identify non-compliance among treated • Only one study (EPIDOS) has reported ROC for individuals fracture prediction: – AUC with high uCTX = 0.58 • Assess treatment efficacy during and after – AUC with low BMD = 0.63 drug therapy – AUC with both = 0.66 • Suggests little benefit from BTM if BMD known Garnero P et al. Osteo Int 1998 9 10 Use of Bone Turnover to Enhance Compliance BTM Feedback and Compliance • BMD testing increases likelihood of • 3 RCTs: women starting treatment, randomized medication use to BTM monitoring/feedback or no BTMs • Most medication discontinuation occurs • No improvement in compliance or persistence during the first year with BTM feedback • Does routine use of bone turnover shortly • The good news: clinician visits 3, 6 and 8 mo. after initiation of therapy enhance after initiation increased adherence by 57%! compliance? Silverman S et al, Osteo Int 2012 Delmas P et al, JCEM 2007 Clowes JA et al, JCEM 2004 11 12 Page 3

Possible Clinical Uses of ALN vs. PBO in FIT: Overlap of Biochemical Markers Change in BAP • Predict fracture risk in untreated individuals • Promote compliance among treated individuals • Identify non-compliance among treated individuals (applies to oral agents) • Assess treatment efficacy during and after drug therapy Bauer DC et al, J Bone Miner Res 2004 13 14 Identification of Non-Adherent Possible Clinical Uses of Individuals in IMPACT (Risedraonte) Biochemical Markers • Predict fracture risk in untreated individuals >30% Drop <30% Drop • Promote compliance among treated Adherence in sCTX in sCTX individuals >80% 279 (77%) 84 (23%) • Identify non-compliance among treated individuals • Assess treatment efficacy during and after <80% 1353 (84%) 262 (16%) drug therapy (particularly bisphosphonates) Eastell et al, JBMR 2011 15 16 Page 4

Biochemical Markers of Bone Turnover are What is Optimal Reduction in Decreased by Antiresorptive Therapy* Turnover for Fracture Protection? Years Years • Meta-analyses of RCTs: greater reduction in 0 1 2 3 0 1 2 3 0 0 turnover associated with greater reduction in fracture risk. –10 –10 – May not apply to individual patients –20 –20 Reduction (%) Reduction (%) • Utility for individuals: analysis of change in –30 –30 marker and fracture outcomes in the active –40 –40 treatment group of RCT –50 –50 Placebo Alendronate –60 –60 –70 –70 NTX Bone ALP Hochberg M et al, J Clin Endocrinol Metab *Results from Fracture Intervention Trial (FIT) 17 18 Reduction in uCTX and New Reduction in Bone ALP and Non-spine Vertebral Fracture: Risedronate Fracture: Alendronate 0.20 Risedronate 5 mg Alendronate 5-10 mg 25 non-spine fracture 0-3 year vertebral 0.15 Probability of fracture incidence 15 0–4 year non-spine Incidence % fracture incidence 0.10 10 0.05 5 0 0 -100 -50 0 50 100 -70 -65 -60 -55 -55 -50 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 5 1-year change in bone ALP (%) 3 and 6 month change in a CTX (%) n=358 risedronate-treated postmenopausal women n=3105 alendronate-treated postmenopausal women Eastell R et al. J Bone Miner Res. 2003 Bauer et al. J Bone Miner Res. 2004 19 20 Page 5

Reduction in Bone ALP and New What Threshold Indicates an Vertebral Fracture: Raloxifene Acceptable Clinical Response? 0.30 Risk of new vertebral fracture • Observed change > Least Significant Change? Raloxifene 0.27 – LSC = change unlikely due to chance (p<0.05) 0.24 0-3 year vertebral (risk ± 95% CI) fracture incidence 0.21 – LSC could be less than optimal change for a given 0.18 treatment 0.15 • On-treatment BTM < premenopausal range+2SD? 0.12 – Why not 1SD? 3SD? 0.09 0.06 – Is premenopausal turnover optimal? 0.03 • Base decision on fracture risk among treated 0 -80 -60 -40 -20 0 20 40 60 women at specific marker thresholds… 1-year change in bone ALP (%) n=601 raloxifene-treated post menopausal women Reginster JY et al. Bone. 2004 21 22 Risedronate: Fracture Rate With and Alendronate: Fracture Rates With Without “ Good ” Marker Response and Without “Good” BTM Response FIT Fracture Rates (Mean F/U 3.6 Years) IMPACT Fracture Rates (Mean F/U 1 Year) Placebo ALN Group ALN Group Placebo RIS Group RIS Group  sCTX<30% †  sCTX>30% Group  BAP<30% †  BAP>30% Group Vertebral 7.3% 4.3%* 3.8%* Vertebral NA NA NA Non-spine NA 4.3% 1.7%* Non-spine 9.8% 8.7% 6.8%* Hip NA NA NA Hip 1.0% 0.8% 0.2%* † 17% of RIS-treated women *p=0.002 compared to <30% group † 44% of ALN-treated women *p<0.001 compared to PBO group Eastell et al. J Bone Miner Res. 2011 Bauer DC et al. J Bone Miner Res. 2004 . 23 24 Page 6

What Happens When BTMs Indicate What About BTM Monitoring After Suboptimal Response to Therapy? Bisphosphonate Discontinuation? • Little known about causes of • Drug Holiday: serial changes in BTMs might suboptimal marker response indicate those at greater risk of fracture – Compliance? Absorption? Genetics? 2° causes? • Only trial data is from FLEX placebo group: • What should clinicians do? – 437 postmenopausal women previously treated with alendronate for about 5 years – Reassess compliance? Not likely to help – BTMs measured at time of discontinuation and – Change dosing or treatment? one year later May help but no data – 82 women fractured during next 5 years – Repeat test? Delay tactic, increases anxiety and costs Can sub-optimal response be improved? No data… Bauer DC et al, Jama Intern Med 2014 25 26 Fractures in FLEX Placebo Group by One Other Big Uncertainty: Tertile of 1-year Change in BTM Commercial Lab Reproducibility • Before routine use, BTMs must be reliably measured in clinical practice • Greatly improved: pre-analytic factors (fasting status, etc) and automated assays • Laboratory performance not disseminated • Pooled sera sent to 6 US commercial labs: reproducibility of serum BAP and urine NTX – Same day CV: 2-17% (NTX), 0-15% (BAP) – Longitudinal CV: 5-38% (NTX), 3-24% (BAP) Schafer A et al, Osteo Inter 2009 Bauer DC et al, Jama Intern Med 2014 27 28 Page 7