Annual Rheumatology & Therapeutics Review for Organizations & Societies

Annual Rheumatology & Therapeutics Review for Organizations & Societies

Biochemical Markers of Bone Turnover: Definitions and Recommendations for Monitoring Therapy

Learning Objectives for Biochemical Markers of Bone Turnover To understand the pathophysiology of the bone remodeling process To understand the clinical diseases that generate different bone turnover markers To understand how therapy for osteoporosis can alter biochemical markers of bone turnover To understand how to incorporate bone turnover markers into clinical practice of osteoporosis.

The Lifecycle of Bone Activation Resorption Resting Osteoclasts Reversal Apoptotic Osteoclasts Bone lining cells Osteoblasts Formation Osteoblasts Mineralization Osteoid Adapted from: Baron R. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. 2003:1-8; Bringhurst FR, et al.

Bone Cell Lineages Hematopoietic stem cells: monocytes Fibroblasts Stromal stem cells Myocytes Multiple cell lineages Adipocytes Chondrocytes Osteoclasts Osteoblastic lineage Osteocytes come from osteoblasts

Biochemical Markers of Bone Metabolism (Monitors of Bone Loss) Formation Resorption Osteoblasts Osteoclasts AP / BAP (S) Osteocalcin (S) P1CP / P1NP (S) Crosslinks and crosslinked telopeptides NTX, CTX (U, S) Calcium (U) Hydroxyproline (U)

Rapid Change

BTMs Can Respond More Rapidly Than BMD Placebo (500mg Ca/day) Alendronate (10mg/day + 500mg Ca/day) Percentage Change untx/cr 1 Percentage Change LSBMD 2 0-25 -50-75 4 8 12 24 14 12 10 8 6 4 2 0-2 -4-6 -8 12 24 36 Time, Weeks Time, Months Braga de Castro Machado et al JBMR 1999;14:602-8 Liberman et al NEJM 1995:333;1437-43

Resorption Markers Change More Rapidly Than Formation Markers Alendronate CTX (resorption) PINP (formation) 0 Percent Change from Baseline -20-40 -60-80 -100 0 1 3 12 Months of Treatment Black DM et al, N Engl J Med 2003;349:1207-1215

Predictor of Increased Fracture Risk In Untreated Subjects

Population Studies: Elevated Biomarkers Increase Fracture Risk in Untreated Patients A Risk Factor Not Captured in FRAX* * Fracture Risk Assessment Tool

ODDS RATIO BMD and Markers Predict Hip Fracture the Epidos Study For Each 2SD of CTX Above T-score OR for Fracture 2X 6 5 4 4.8 4.1 CTX 3 2 2.7 2.2 1.9 Free DPD 1 0 LOW HIP BMD HIGH MARKER BOTH Garnero P, et al. JBMR 1996;11:1531

Bone Turnover Markers Predict a Higher Risk for Fractures 9 years Later in Elderly (75 yrs +) Untreated Women Baseline sctx Highest tertile 2, 810 pg/ml 9 years later Had HRs (1.32) of all clinical fractures by tertiles not adjusted for age (mean = 75 yrs.) increase adjusted for baseline BMD Population sample size : 1,040 Fracture number : 363 fractures including 116 hip fractures Ivaskaa KK et al JBMR 2010 Malmo, Sweden

Predictor of Increased Fracture Risk In Treated Patients (Groups)

RR of Nonspine Fracture OP Therapies: Greater Decrease in Bone Resorption Predicts Greater Reduction in Non-spine Fracture Risk 1.6 1.4 1.2 1.0 0.8 0.6 0.4 Dashed line = no effect Size of study (person-year) >10,000 500-10,000 500 Regression line 40% risk reduction -60-40 -20 0 20 40 60 RR Reduction (%) 0.2 80 0 100 1 20 40 60 80 Change in Resorption Marker Versus Placebo (%) RR= Relative risk Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586 1592

Fracture Incidence (%) Bone Marker Reduction Correlates to Fracture Risk Reduction CTX reduction after 3-6 months correlates to fracture risk reduction. When 60% reduction is achieved, there is no greater reduction in fracture risk. 0-3 yr Vertebral Fracture Incidence 25 20 15 Ca and Vit D 10 5 0 Risedronate -70-60 -50-40 -30-20 -10 0 5 ß-CTX % Change Source: Eastell et al (2003), J Bone Miner Res.18

The Association of Marker Changes (ALP and P1NP) after 1 Year and Fracture Risk Reduction with Alendronate Treatment for 3 years. Cutpoint (% of women) Spine fracture (N=118) OR (95% CI)* Non-spine fracture (N=225) RH (95% CI)* >15% reduction bone ALP 0.63 (0.42,0.95) 0.79 (0.58,1.08) >30% reduction bone ALP 0.90 (0.62,1.33) 0.72 (0.55,0.92) >50% reduction bone ALP 0.52 (0.29,0.94) 0.84 (0.60,1.19) >30% reduction in P1NP 0.45 (0.30,0.70) 1.02 (0.70,1.49) >50% reduction in P1NP 0.66 (0.49,0.99) 0.86 (0.65,1.15) >70% reduction in P1NP 0.79 (0.50,1.25) 0.63 (0.46,0.88) *OR or RH for fracture among alendronate-treated women with specified 1-year reduction in marker compared with women without specified reduction in marker Bauer DC et al. J Bone Miner Res. 2004;19:1250-1259.

Short-term Changes in Bone Turnover Markers and Bone Mineral Density Response to PTH in PMOP Baseline and Follow-up BTM Among 119 Subjects Variable 0 mth 1 mth 3 mth 1 yr P1NP (bg/ml) 58.0 ± 35 111.9±77 171.6±147.5 180.5±143 Bone ALP 18.1 ±8 23.2±13.3 29.0±21.1 sctx 392 ±203 400 ± 252 722 ± 550 32.2± 19.6 (ng/ml) 882 ± 559 (pg/ml) Bauer DC et al. J Bone Miner Res. 2004;19:1250-1259.

Anabolic Data

% Change from Baseline Changes in P1NP and BALP with Teriparatide 180 167.8% 160 140 120 100 80 60 77.4% P1NP BALP 40 20 10.9% 46.5% 0 0 1 2 3 4 5 6 Months Blumsohn A, et al. Osteoporos Int 2011;22:1935-1946.

Bone Turnover Markers Bone turnover markers Predict bone loss and fracture risk in untreated patients With treatment Change sooner than BMD Identify more responders than BMD Explain a greater proportion of fracture reduction than change in BMD Can be useful in monitoring the response to treatment

Drug Holidays

Mean Percent Change from FLEX Baseline Change in Urinary ntx: Creatinine Ratio From Flex Baseline to Flex Month 60 in Women Receiving Alendronate or Placebo 40 ALN/PBO ALN/ALN 30 20 10 32% p < 0.001 0-10 0 12 36 60 Month Black DM et al, J Bone Miner Res 2004; 19 (suppl 1): 1174 Ensrud K et al, J Bone Miner Res 2004;19:1259-1269

Median Serum CTX (μg/ml) Median BSAP (ng/ml) Effect of Denosumab on Serum CTX and BSAP Discontinued Treatment Placebo 60 mg Q6M Pooled Alendronate 6 mg Q3M 14 mg Q3M 14 mg Q6M 100 mg Q6M 30 mg Q3M 210 mg Q6M 1.2 1.0 Serum CTX Discontinued Treatment BSAP 18 Discontinued Treatment 1.0 16 15.8 14.0 14 0.8 0.6 0.4 0.2 0 0.6 0.6 0.6 0.6 0.4 0.2 0.4 0.1 0 3 6 12 18 24 36 48 Months 12 10 8 6 4 2 0 11.6 6.2 4.8 11.2 8.3 11.3 9.8 0 3 6 12 18 24 36 48 Months

FDA NEJM Perspective Recommend treatment with bisphosphonates for 3-5 years and consider discontinuation in lower risk patients but consider continuation in higher risk patients (prior fracture, older, BMD criteria for osteoporosis). Weak and inconclusive recommendations on what to do when discontinuation is begun. Whitaker M et al; Bisphosphontes for OP; NEJM 2012; 366:2048-2051

Bisphosphonate (BP) Drug Holidays: A Perspective from a Clinician 1. Most patients don t stay on therapy very long. 2. In USA, patients stop on their own; Docs are afraid to treat. 3. The legal threat is there if a patient fractures on or off a bisphosphonate. 4. The skeletal load of BP may differ greatly from patient to patient on the same BP or among different BPs. 5. If BPs are stopped, serial BMD and BTM are the only clinical tools we have to monitor. Khosla S et al JCEM 2012 Boonen S et al JBMR 2012

How I Use Markers 1. In untreated patients with high baseline valuesthink beyond PMO rapid losers. 2. In untreated patients high values may tip the scale in those with borderline risk. 3. In treated patients-values above clinical trial treatment group suggests poor compliance, poor absorption or poor bone biological effect 4. In treated patients a change (decline with antiresorptive or increase with anabolic) from baseline is encouraging (me and the patient) 5. Holiday or retirement?