Seminar 14-10-09 - asbmr 2009

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  • Figure 1. Mean Percent Changes in Areal Bone Mineral Density on Dual-Energy X-Ray Absorptiometry. The vertical lines represent the 95 percent confidence intervals. Negative changes represent decreases.
  • Figure 4. Median Percent Changes in Serum Concentrations of Biochemical Markers of Bone Formation (N-Propeptide of Type I Collagen, Panel A) and Bone Resorption (C-Terminal Telopeptide of Type I Collagen, Panel B). The differences between the combination-therapy group and the parathyroid hormone group at 12 months and between the combination-therapy group and the alendronate group at 12 months were significant (P
  • Denosumab is an investigational, fully human monoclonal antibody that binds with high affinity to, and inhibits the activity of human RANK (receptor activator of nuclear factor kappa B) ligand, a key mediator of osteoclast activity 1 . RANK Ligand is an essential mediator in the formation, activation, and survival of osteoclasts 1,2 . Denosumab does not bind to other TNF receptors, including TRAIL. 1 The pharmacokinetics (SC administration) of denosumab in postmenopausal women were nonlinear with dose. The serum profiles were characterized by three distinct phases: 1) a prolonged absorption phase: maximum serum concentrations increased disproportionately greater (2.6-fold) than the increase in dose and were observed between 5 and 21 days after administration; 2) a prolonged  -phase: half-lives that increased with dose to a maximum of 32 days; and 3) a more rapid terminal phase observed at concentrations <1,000 ng/mL with a half-life that increased from 5 to 10 days as dose increased from 0.01 to 3.0 mg/kg. The mean serum residence time increased with dose from 12 to 46 days. 1 References: 1. Bekker PJ, et al. A single-dose placebo-controlled study of AMG-162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066. 2. Boyle WJ, et al. Osteoclast differentiation and activation. Nature. 2003;423:337-342. 3. Peterson MC, et al. AMG 162 maintains serum concentrations for up to 9 months following a single subcutaneous dose in healthy postmenopausal women. J. Bone Miner. Res. 2003; 18(Suppl 2):S166. Abstract SA393 and poster.
  • Figure 2. Percent Changes in Bone Mineral Density and Biochemical Markers of Bone Turnover. Changes in mean bone mineral density (BMD) at the lumbar spine (Panel A) and total hip (Panel B) are shown for 441 subjects who were included in a substudy of measurements of bone mineral density. As compared with subjects in the placebo group, subjects in the denosumab group had a relative increase of 9.2% in bone mineral density at the lumbar spine and 6.0% at the total hip. Changes in mean values for serum C-telopeptide of type I collagen (CTX) (Panel C) and serum procollagen type I N-terminal propeptide (PINP) (Panel D) are shown for 160 subjects who were included in a substudy of bone-turnover markers. P<0.001 for all between-group comparisons at all time points on the basis of analysis-of-covariance (ANCOVA) models. For bone mineral density, the comparisons were adjusted for study group, baseline bone mineral density, type of machine used to analyze bone mineral density, and interaction between the type of machine and the baseline bone mineral density; for CTX and PINP, the comparisons were calculated with the use of the Wilcoxon rank-sum test.
  • Table 3. Adverse Events.
  • Figure 2. Scores on Measures of Overall Pain, Pain at Night and at Rest, Quality of Life Questionnaire of the European Foundation for Osteoporosis, Assessment of Quality of Life, and Modified Roland-Morris Disability Questionnaire, According to Time and Intervention Group. Pain was assessed on a scale of 0 to 10, with higher numbers indicating more pain and with 1.5 as the minimal clinically important difference (Panel A). Scores on the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) range from 0 to 100, with higher scores indicating worse quality of life; scores on the Assessment of Quality of Life (AQoL) range from −0.04 to 1.0, with 1 indicating perfect health and 0.06 representing the minimal clinically important difference; scores on the Roland-Morris Disability Questionnaire (RDQ) range from 0 to 23, with higher scores indicating worse physical functioning and 2 to 3 points representing the minimal clinically important difference (Panel B). I bars indicate standard deviations.
  • Figure 2. Secondary Outcome Measures at 1 Month (Intention-to-Treat Analyses). Prespecified secondary outcomes included mean (±SD) scores on the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), version 2, including both the Physical Component Summary (Panel A) and the Mental Component Summary (Panel B), the Pain Frequency Index (Panel C), the Pain Bothersomeness Index (Panel D), the European Quality of Life-5 Dimensions (EQ-5D) scale (Panel E), and the Study of Osteoporotic Fractures-Activities of Daily Living (SOF-ADL) scale (Panel F), as well as the proportion of patients who were taking any opioid analgesics (Panel G). Scores on the SF-36 range from 0 to 100, with lower scores indicating a worse outcome. Scores on the Pain Frequency Index and the Pain Bothersomeness Index range from 0 to 4, with higher scores indicating more severe pain. Scores on the EQ-5D scale range from −0.1 to 1.0, with higher scores indicating a better quality of life. Scores on the SOF-ADL scale range from 0 to 18, with higher scores indicating more back-related disability. For continuous outcome measures, treatments were compared with the use of analysis-of-covariance models with adjustment for study-group assignment, baseline value of the outcome measure, and study center, with all positive numbers favoring vertebroplasty. The treatment effect for opioid use is reported as an odds ratio from a logistic-regression model with adjustment for baseline opioid use and study center. The I bars denote 95% confidence intervals.
  • Figure 3. Scores on Measures of Disability and Pain over a 3-Month Period. Scores on the Roland-Morris Disability Questionnaire (RDQ) range from 0 to 23, with higher scores indicating more severe disability (Panel A). Scores on the pain-intensity rating range from 0 (no pain) to 10 (worst pain) (Panel B). Patients were classified as having adhered to their random study-group assignment if they did not subsequently undergo the alternative procedure before the 3-month follow-up. Patients who underwent the alternative procedure during this period were said to have crossed over to the other study group. At 3 months, 8 patients (12%) in the vertebroplasty group and 27 patients (43%) in the control group had crossed over to the other group and had undergone the alternative procedure (P<0.001). The black vertical lines indicate the time when baseline measures were taken, and the colored vertical lines represent 95% confidence intervals.
  • Each country used their discretion in recruitment of participating physicians who specialised in the treatment of osteoporosis and its complications.
  • During follow-up, 138 (8.8%) women sustained a total of 168 incident fractures, giving an overall fracture rate of 821 fractures/10,000 patient-years. Twenty-three patients (1.5%) sustained two or more new fractures The majority of patients who sustained a fracture while on teriparatide treatment, had already experienced a fracture in the 12 months prior to starting teriparatide treatment (129 [93.4%]). A history of fracture in this prior 12-month period did not have a statistically significant effect on the risk of first fracture that occurred on teriparatide treatment (hazard ratio 1.37 [CI: 0.97, 1.95], p=0.076) Overall, the number of patients who had at least one fracture during teriparatide treatment significantly decreased between the first 6-month period (n=72, 4.6%) and the second 6-month period (n=45; 3.5%) (adjusted model odds ratio [OR]=0.68 [95% CI: 0.47-0.98], p=0.038), and between the first 6-month period and the last 6-month period on treatment (n=33, 2.8%) (OR=0.53 [95% CI: 0.35-0.82], p=0.004) (Table 1). The fracture incidence per 10,000 patient-years of 1113 in the first six months decreased to 583 during the 12-18 month period.
  • The frequency of back pain decreased over the treatment period; at baseline 65.8% of patients reported experiencing back pain every day or almost every day and this decreased to 29.9% of patients after completing 18 months of treatment At every post-baseline visit, there were significantly more patients who reported a decrease in the frequency of back pain compared with baseline, than those reporting an increase in frequency of back pain (sign-test, p<0.001) Once or twice (%) A few times (%) Fairly often (%) Everyday or almost everyday(%) Missing/unknown (%) Baseline 3.8 9.9 18.3 65.8 2.2 3 months 11.3 28.8 18.9 37.3 3.8 6 months 16.1 28.2 15.8 34.8 5.1 12 months 18.1 28.0 15.2 32.9 5.8 18 months 22.2 25.0 17.6 29.9 5.2
  • The limitation on activity also decreased over the course of the study (p<0.001) No limitation (%) Minor (%) Moderate/severe (%) Missing/unknown (%) Baseline 10 15.1 73.8 1.1 3 months 19 26.1 52.8 2.1 6 months 24.6 27.4 44.7 3.2 12 months 27.2 27 42.3 3.5 18 months 31.7 24.3 41.2 2.8
  • Logistic regression analysis with repeated measures showed that the odds of sustaining a fracture decreased over time for each 6-month interval. Compared with the first 6-month interval, the difference in odds of fracture over time was significant from the 12-18 months interval onwards for the total study cohort
  • The results after one year were spectacular: when compared with the sulphasalazine group, the patients in the COBRA group (here in green) had a more rapid decrease in several different disease activity measures, here summarized in a pooled index, and a delay in radiological progression after 1 year follow up.
  • after mean 4.5 years of follow up , the COBRA group still shows persistent benefits in delay of damage progression, despite similar treatment and disease activity in the follow up period.
  • We recently performed the 11 year follow up of the COBRA trial, and showed that the delay in radiological progression in the COBRA group was still detectible.
  • When we do the second analyses, including 3 month follow up measures, we see that this adds to the explained variance of the models, resulting in 46% of explained variance in the CTX2 dataset, with again RANKL:OPG and the 3 month follow up measurement of CTX2 as strong independent predictors of radiological joint progression over 11 years. If we take a closer look at this model that explains 46% of the variance in radiological progression,
  • Seminar 14-10-09 - asbmr 2009

    1. 1. Verslag ASBMR 2009, IWO (14 October, Utrecht) Prof Dr Willem F Lems Vrije Universiteit medisch centrum, afdeling reumatologie, Amsterdam
    2. 2. • Combinatietherapie; • Nieuwe middelen; • Therapietrouw; • Denosumab; • Vertebroplastiek; • Nederlandse Young Investigators Award Winners; • FRAX : pro en contra. • NB Soms korte terugblik op zeer recente literatuur!
    3. 3. Combinatietherapie met PTH en botresorptieremmer zinvol?
    4. 4. Black, D. M. et al. N Engl J Med 2003;349:1207-1215 Mean Percent Changes in Areal Bone Mineral Density on Dual-Energy X-Ray Absorptiometry
    5. 5. Black, D. M. et al. N Engl J Med 2003;349:1207-1215 Changes in Markers of Bone Formation (N-Propeptide of Type I Collagen, Panel A) and Bone Resorption (C-Terminal Telopeptide of Type I Collagen, Panel B)
    6. 6. Effects of Once-Yearly Zoledronic Acid 5mg in Combination with Teriparatide (PTH) on Postmenopausal Women with Osteoporosis • In 412 postmenopausal, osteoporotic, women, the combination of ZOL and PTH increased BMD more than either alone. • “Combination therapy could be considered for patients at high risk for hip fractures or those with very low BMD” F Cosman et al; 1025
    7. 7. New Anti-Osteoporotic Drugs?
    8. 8. Disease and Therapy Mediated by the Calcium-Sensing Receptor
    9. 9. Ronacaleret, A Calcium-Sensing Receptor Antagonist: Results of a 1 Year Double-Blind, Placebo-Controlled, Dose-Ranging Phase II Study • 569 postmenopausal women open-label teriparatide (TER) or placebo or one of 4 doses of ronacaleret (RON) (100, 200, 300 or 400mg daily), or alendronate (ALN) (70mg weekly). • The primary endpoint was the % change in lumbar spine (LS) bone mineral density (BMD) at 12 months. • The trial was terminated early due to lack of efficacy following an interim analysis of % change in LS BMD at 6 months. • Ronacaleret (200, 300, 400mg) Spine BMD was significantly different from placebo (1.4-1.9%), while ALN and TER increased LS BMD 4.7% and 9.2%. • At the total hip, RON caused small but statistically significant decreases in BMD at all dose ronacaleret levels, while ALN and TER showed modest gains (2.8%, 2.6%). • RON (200, 300, 400mg) showed median increases in serum CTx >20% starting at month 6, reaching a maximum of 58% at month 10 as compared to TER
    10. 10. Over therapie-trouw
    11. 11. Netelenbos, ASBMR, Denver, 2009 ? Persistance of anti-osteoporotic drugs in daily practice
    12. 12. Most Non-Persistent Patients with Osteoporosis Do Not Switch to Other Drug Treatments: a 3,5 year market survey of 240,000 patients in the Netherlands • After stopping, follow-up of 18 month: only 20% (95% c.i.: 17-25%) switched to other drugs. • “ major failure to adequately treat patients at high risk for fractures in real clinical practice”
    13. 13. Reasons for stopping anti-osteoporosis medications among postmenopausal women. (GLOW). (Ch Roux, et al, M 352)
    14. 14. • Heel veel data over denosumab!
    15. 15. Denosumab Binds to RANK Ligand Inhibiting Osteoclast Development, Activation, and Survival Osteoblasts Hormones Growth factors Cytokines Bone Resorption Prevented and Inhibited Osteoclast Precursor Osteoclast Formation Inhibited Osteoclast Function and Survival Inhibited Adapted from Boyle WJ, et al. Nature. 2003;423:337-342. RANK Ligand RANK Denosumab OPG
    16. 16. Original Article Steven R. Cummings, M.D., Javier San Martin, M.D., Michael R. McClung, M.D., Ethel S. Siris, M.D., Richard Eastell, M.D., Ian R. Reid, M.D., Pierre Delmas, M.D., Ph.D., Holly B. Zoog, Ph.D., Matt Austin, M.S., Andrea Wang, M.A., Stepan Kutilek, M.D., Silvano Adami, M.D., Ph.D., Jose Zanchetta, M.D., Cesar Libanati, M.D., Suresh Siddhanti, Ph.D., Claus Christiansen, M.D., for the FREEDOM Trial N Engl J Med Volume 361(8):756-765 August 20, 2009
    17. 17. 17 FREEDOM Study Design • International, multicenter, randomized, double-blind, placebo-controlled study Key Inclusion Criteria: • Postmenopausal women aged 60 to 90 years • T-score < -2.5 and > -4.0 at the lumbar spine or total hip • No severe or > 2 moderate vertebral fractures Primary Endpoint: • New vertebral fractures Secondary Endpoints: • Nonvertebral fractures • Hip fractures R A N D O M I Z A T I O N Placebo n = 3906 Denosumab 60 mg Q6M SC n = 3902 Daily Calcium and Vitamin D Supplementation N = 7808 S C R E E N I N G Months: 0 6 12 18 24 30 36 E N D O F T R E A T M E N T Last dose Cummings S, et al. N Engl J Med. 2009;361:756-765.
    18. 18. Primairy Endpoint: Vertebral Fractures Cummings SR et al. N Engl J Med 2009;361:756-765
    19. 19. RR hip: 0.60; 95% c.i.: 0.37-0.97 RR 0.80; 95% c.i.: 0.67-0.95 Secondairy Outcomes: non-vertebral fractures and hipfractures
    20. 20. Percent Changes in Bone Mineral Density and Biochemical Markers of Bone Turnover Cummings SR et al. N Engl J Med 2009;361:756-765
    21. 21. Cummings SR et al. N Engl J Med 2009;361:756-765Cummings SR et al. N Engl J Med 2009;361:756-765
    22. 22. Freedom-studie, subanalyse (pre-specified) bij high-risk patients: >70 jaar, T<-3, prevalente wervelfractuur (tenminste 2 items) 0 2 4 6 8 10 12 vertebral hip nonvertebral all placebo high risk placebo high risk denosumab -65%, p<0,0001 -48%, p=0,02 NS
    23. 23. Effects of denosumab on bone histology/histomorphometry: FREEDOM and STAND studies • Reid et al; Saturday 1030 hour
    24. 24. Background • Anti-resorptive therapies for postmenopausal osteoporosis reduce bone resorption, increase bone mineral density (BMD), and reduce the risk of fracture. • Whether therapy-associated increases in BMD and reductions in fracture risk are related to the level of bone resorption at baseline is a topic of interest.
    25. 25. Subject Incidence of New Vertebral Fracture Through Month 36 by Baseline CTX Quartiles n = Number of subjects with spine x-ray at baseline and ≥ 1 postbaseline visit. Baseline CTX Quartiles (ng/mL) ncidence Through Month 36 (%) 0 2 4 6 8 10 12 14 Cochran-Armitage trend test among denosumab groups; P = 0.01 891 898 895 914n < 0.381 0.381-0.536 0.537-0.717 ≥ 0.718 IncidenceThroughMonth35(%) Placebo Denosumab 86% 884 917 937 887 3.1% P = 0.0002 55% 6.9% 1.4% P < 0.0001 9.9% 4.9% 1.8% P = 0.0002 64% 6.7% 3.2% P = 0.0009 51%
    26. 26. Subject Incidence of New Vertebral Fracture Through Month 36 by Baseline TRACP5b Quartiles n = Number of subjects with spine x-ray at baseline and ≥ 1 postbaseline visit. Placebo Denosumab Baseline TRACP5b Quartiles (IU/L) < 3.424 3.424-4.352 4.353-5.478 ≥ 5.479 0 2 4 6 8 10 881 878 891 940n Cochran-Armitage trend test among denosumab groups; P = 0.16 7.9% 3.2% P < 0.0001 59% 906 919 918 871 6.7% 2.1% P < 0.0001 70% 7.3% 1.7% P < 0.0001 76% 6.5% 2.4% P < 0.0001 62% IncidenceThroughMonth35(%)
    27. 27. Subject Incidence of Nonvertebral Fracture Through Month 36 by Baseline CTX Quartiles n = Number of randomized subjects. Cochran-Armitage trend test among denosumab groups; P = 0.09 Baseline CTX Quartiles (ng/mL)) dence Through Month 36 (%) 0 2 4 6 8 10 11 7.5% P = 0.89 9.7% P = 0.06 7.5% 7.2% P = 0.37 P = 0.06 7.2% 7.3% 6.7% 5.2% 2% 26% 15% 30% 937 944 950 951 938 972 966 936n < 0.381 0.381-0.536 0.537-0.717 ≥ 0.718 IncidenceThroughMonth36(%) Placebo Denosumab
    28. 28. Subject Incidence of Nonvertebral Fracture Through Month 36 by Baseline CTX Quartiles n = Number of randomized subjects. Cochran-Armitage trend test among denosumab groups; P = 0.09 Baseline CTX Quartiles (ng/mL)) dence Through Month 36 (%) 0 2 4 6 8 10 11 7.5% P = 0.89 9.7% P = 0.06 7.5% 7.2% P = 0.37 P = 0.06 7.2% 7.3% 6.7% 5.2% 2% 26% 15% 30% 937 944 950 951 938 972 966 936n < 0.381 0.381-0.536 0.537-0.717 ≥ 0.718 IncidenceThroughMonth36(%) Placebo Denosumab
    29. 29. Subject Incidence of Nonvertebral Fracture Through Month 36 by Baseline TRACP5b Quartiles n = Number of randomized subjects. Cochran-Armitage trend test among denosumab groups; P = 0.43 Baseline TRACP5b Quartiles (IU/L) IncidenceThroughMonth36(%) 0 2 4 6 8 10 11 7.4% P = 0.22 8.1% P = 0.62 6.8% 9.4% P= 0.16 P = 0.01 6.0% 8.9% 5.4% 6.1% 20% 8% 24% 35% 934 959 926 968 939 955 984 910n < 3.424 3.424-4.352 4.353-5.478 ≥ 5.479 Placebo Denosumab
    30. 30. Effects of Denosumab on Bone Mineral Density and Biochemical Markers of Bone Turnover: 6 Year Results of a Phase 2 Clinical Trial P Miller
    31. 31. Was er echt nieuws over vertebro-kyfoplastieken? (Sa -389) • R. Pflugmacher • Background: Excellent clinical and radiological results could be achieved in patients with osteoporotic fractures treated with Balloon- Kyphoplasty. Only a few articles report on the clinical and radiological outcome in comparison to a non surgical treatment. Purpose: To evaluate the long-term outcomes of 126 patients with 239 osteoporotic vertebral fractures, located in the thoracic and lumbar spine, treated with Balloon Kyphoplasty and compared with a conservatively treated control group. Study design: A prospective follow-up was performed in all patients. Patients who refused surgical treatment served as control. Patient sample: 90 patients (37 males and 53 females) with 187 osteoporotic vertebral fractures were treated with Balloon Kyphoplasty, 36 (12 males and 24 females) with 52 vertebral fractures served as controls. We were able to have a 2 year follow up in 78 patients with 168 vertebrae treated with Balloon Kyphoplasty and 32 patients with 45 vertebral fractures treated conservatively. Outcome measures: Clinical and radiological results were measured prospectively in all patients. Methods: Symptomatic levels were identified by correlating the clinical presentation with conventional radiographs, CT and / or MRI. During the 2 year follow-up reduction in pain was determined. The effects on pain symptoms were measured on a self-reported Visual analog Scale (VAS) and the Oswestry score was documented to assess disability. Radiographic scans were performed pre- and postoperatively and after 3, 6, 12 and 24 months. The vertebral height and kyphosis angle were measured to assess the restoration of the sagittal alignment. Results: The median pain scores (VAS) improved significantly from pre- to post-intervention as did the Oswestry Disability Score (p<0.001), in the conservative group no significant changes could be documented. Balloon Kyphoplasty led to a significantly vertebral height restoration and correction of kyphotic deformity in the long-term (p<0.05), in the conservative group significant further height loss and increase of kyphosis could be documented (p<0.001). There were significantly fewer patients with new vertebral fractures of the thoracic and lumbar spine, after 24-months, in the kyphoplasty group (15 patients, 4 male, 11 female, 19.2%) than in the control group (13 patients, 3 male, 9 female, 40.6%). Conclusion: Balloon Kyphoplasty as an addition to medical treatment leads to a statistically significant reduction of pain status and improvement of physical function. Further, Balloon Kyphoplasty reduces occurrence of new vertebral fractures and prevents a height loss and increase of kyphotic deformity in the long term. Disclosures: None
    32. 32. Original Article A Randomized Trial of Vertebroplasty for Painful Osteoporotic Vertebral Fractures Rachelle Buchbinder, Ph.D., Richard H. Osborne, Ph.D., Peter R. Ebeling, M.D., John D. Wark, Ph.D., Peter Mitchell, M.Med., Chris Wriedt, M.B., B.S., Stephen Graves, D. Phil., Margaret P. Staples, Ph.D., and Bridie Murphy, B.Sc. N Engl J Med Volume 361(6):557-568 August 6, 2009
    33. 33. Buchbinder R et al. N Engl J Med 2009;361:557-568
    34. 34. Original Article A Randomized Trial of Vertebroplasty for Osteoporotic Spinal Fractures David F. Kallmes, M.D., Bryan A. Comstock, M.S., Patrick J. Heagerty, Ph.D., Judith A. Turner, Ph.D., David J. Wilson, F.R.C.R., Terry H. Diamond, F.R.A.C.P., Richard Edwards, F.R.C.R., Leigh A. Gray, M.S., Lydia Stout, B.S., Sara Owen, M.Sc., William Hollingworth, Ph.D., Basavaraj Ghdoke, M.D., Deborah J. Annesley-Williams, F.R.C.R., Stuart H. Ralston, F.R.C.P., and Jeffrey G. Jarvik, M.D., M.P.H. N Engl J Med Volume 361(6):569-579 August 6, 2009
    35. 35. Secondary Outcome Measures at 1 Month (Intention-to-Treat Analyses) Kallmes DF et al. N Engl J Med 2009;361:569-579
    36. 36. Scores on Measures of Disability and Pain over a 3-Month Period Kallmes DF et al. N Engl J Med 2009;361:569-579
    37. 37. 397/23/03 EFOS participants Enrolment 8 European countries Austria Denmark France Germany Greece Ireland Netherlands Sweden
    38. 38. Incident fractures during teriparatide treatment 40 n=72 (4.6%) n=45 (3.5%) n=33 (2.8%) n=138 (8.8%) OR 0.68 (95% CI 0.47, 0.98)a** OR 0.53 (95% CI 0.35, 0.82)a* a Adjusted model by age, prior bisphosphonate use, and a history of fracture in the last 12 months before starting teriparatide *p<0.05, **p<0.005 Langdahl et al. CTI [in press]
    39. 39. Frequency of back pain 41 Langdahl et al. CTI [in press] * *** *p<0.001 compared to baseline (sign test)
    40. 40. Limitation of activities 42 Langdahl et al. CTI [in press] * *** *p<0.001 compared to baseline (sign test)
    41. 41. Incidence of fractures during and after teriparatide treatment 51 (3.5%) 76 (4.8%) 34 (2.7%) 41 (3.0%) 18 (1.6%) 13 (1.3%) OR 0.71 (95% CI: 0.50, 1.00; p=0.051) OR 0.61 (95% CI: 0.41, 0.90; p=0.012) OR 0.54 (95% CI: 0.36, 0.82; p=0.004) OR 0.33 (95% CI: 0.19, 0.55; p<0.001) OR 0.26 (95% CI: 0.14, 0.47; p<0.001) 43
    42. 42. About Fractures
    43. 43. Effects of antiresorptive treatment of various non-vertebral fracture outcomes (1242, Mackey D, Cummings S). • Achtergrond: verschillende definities voor non- vertebral fractures in RCTs; • Data van FIT (alendronaat), HORIZON (zoledronaat), PEARL (lasoxifen); • 17.098 postmenopausal osteoporotic women, 1.892 non-vertebral fractures;
    44. 44. Effects of antiresorptive treatment of various non-vertebral fracture outcomes (1242, Mackey D, Cummings S). • Treatment effect vergelijkbaar voor high-trauma versus low trauma: 0.70 (0.52-0.96) versus 0.76 (0.69-0.84); • Non vertebral 6 versus all nonvertebral fractures: 0.69 (0.61-0.77) versus 0.78 (0.69- 0.89); • Excluding finger and toe fractures versus all nonvertebral fractures: 0.73 (0.67-0.81) versus 0.75 (0.68-0.82)
    45. 45. Effects of antiresorptive treatment of various non-vertebral fracture outcomes (1242, Mackey D, Cummings S).
    46. 46. Time Since Prior Fracture is a Risk Modifier for Ten Year Osteoporotic Fractures: The Manitoba Bone Density Program(Leslie, 1093)
    47. 47. Risico voor nieuwe fractuur clusteren in de tijd Maastricht UMC & UHasselt --- First fracture Subsequent fracture from menopause on from 1st fracture on Van Geel, ARD, 2009
    48. 48. • Twee Young Investigators Award! • Tineke van Geel (Maastricht) en Lilian van Tuyl (Amsterdam)
    49. 49. 5- EN 10-JAARS FRACTUURRISICO: EEN NOMOGRAM (1022, Van Geel) • 2372 postmenopausal women, 3 years follow- up; • 382 fractures (16,1%); • Age: 1,09 per 5 years; • Low BMD: 1,23 per SD; • Prior Fracture 3.27 for fracture within last 5 years; • Prior Fracture 1.97 for fracture > 5 years ago;
    50. 50. 1 Lancet 1997 COBRA trial results: 1 year Change in disease activity
    51. 51. Arthritis & Rheumatism 2004 COBRA trial results: 4.5 years P =0.008 0 10 20 30 40 0 1 2 3 4 5 Damage progression (Sharp/van der Heijde) Years COBRACOBRA SSZSSZ
    52. 52. Annals of Rheumatic Diseases 2009 COBRA trial results: 11 years
    53. 53. CTX-1 dataset CTX-2 dataset RANKL:OPG RANKL:OPG CTX1 CTX2 at 3 mo ESR at 3 mo ESR at 3 mo Baseline damage Baseline damage RF R2 = 42% R2 = 46% Best prediction models based on baseline AND follow-up measurements
    54. 54. • Dank voor Uw aandacht!
    55. 55. About FRAX: case finding by the web www.shef.ac.uk/FRAX/ Kanis, Osteoporosis Int, 2008
    56. 56. Doelstellingen van FRAX • Berekening van het 10-jaars fractuurrisico – op basis van gewogen bijdragen van klinische risicofactoren voor osteoporose en fracturen – met en zonder resultaten van botdichtheidmeting • Bijdrage tot het bepalen van afkappunten voor: – indicatie voor botmeting – starten van medicamenteuze behandeling – Wat is de plaatsbepaling in de dagelijkse praktijk?
    57. 57. Voordelen van FRAX • Wereldwijd bruikbaar, en gratis beschikbaar via web • Zinvol voor: –klinische opsporing van fractuurrisico –geeft patient en arts inzicht in absoluut fractuurrisico; –kan belangrijk zijn bij beslissing omtrent behandeling.
    58. 58. Beperkingen van FRAX (1) • Houdt geen rekening met dosiseffect van risico’s – dosis glucocorticoïden – tijdstip van en aantal voorafgaande fracturen • Wervelfracturen tellen niet mee; • Valrisico niet meegenomen; • Enkel toepasbaar bij onbehandelde patiënten; • BMD: enkel femurhals • Geen consensus/recommendation omtrent indicaties therapie – wel beschikbaar via rechtstreekse link met NOGG (UK)
    59. 59. Beperkingen/aandachtspunten FRAX (2): – vitamine D deficiëntie – lichamelijke (in)activiteit – botmarkers – medicatie zoals anti-epileptica, aromatase remmers en androgeen deprivatie therapie – Het lijkt logisch met betrouwbaarheidsintervallen te werken wanneer fractuurrisico wordt berekend op basis van risicofactoren, dit is echter niet in het model geïmplementeerd.
    60. 60. • Het is niet mogelijk om in het model meerdere secundaire risicofactoren in te voeren, terwijl soms ook sprake is van meer dan een oorzaken van secundaire osteoporose; Bij de FRAX calculator veranderd het fractuurrisico niet wanneer secundaire osteoporose wordt aangevinkt, en ook een BMD waarde wordt ingevuld. “dit wordt verklaard doordat BMD het risico van secundaire osteoporose teniet doet” • FRAX geeft alleen de mogelijkheid om heuphals BMD in te voeren, terwijl met name een lage BMD in de lumbale wervelkolom geassocieerd is met een verhoogd risico op wervelfracturen. Enkele beperkingen/aandachtspunten FRAX (3):
    61. 61. UK: Strategie voor interventie in FRAX-NOGG • (elderly) women with a prior fragility fracture should be considered for treatment without the need for further assessment • In men with or without a fragility fracture and in women without a previous fragility fracture, management strategy should be based on the assessment of the ten year probability of a major osteoporotic fracture (clinical spine, hip, forearm or humerus).
    62. 62. NOF richtlijn (VS) interventie – Postmenopauzale vrouwen en mannen van 50 jaar en ouder met de volgende criteria: • Zelf gerapporteerde heup of wervelfractuur na het 20e levensjaar • Heuphals of wervel T-score ≤−2.5 • Heuphals T-score tussen −1 en −2.5 SD met een 10-jaars heup fractuur risico ≥3% of 4-fractuur risico ≥20% Dawson-Hughes B et al., Osteoporos Int 2009. webfirst
    63. 63. Case finding Risicoscore ≥ 4 DEXA (VFA) T-score ≥ -1 T-score tussen -1 en -2,5 T-score ≤ -2,5 of wervelinzakking Geen behandeling Bereken FRAX risico indien geen VFA of Wervelfoto VFA of Wervelfoto Behandelen Wervelinzakking Nee Ja Behandelen Bereken FRAX risico NOGG Geen behandeling NOGG Behandelen
    64. 64. • Dank voor Uw aandacht!

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