Seminiar 30-11-2013 Side effects treat opo short

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Seminiar 30-11-2013 Side effects treat opo short

  1. 1. n e Nevenwerkingen van medicaties bij fractuurpreventie: klinisch relevant? . r h . P s u e G Prof Piet Geusens, MD, PhD Reumatoloog Maastricht UMC & UHasselt
  2. 2. n e Disclosure belangen spreker (potentiële) belangenverstrengeling s u e G Voor bijeenkomst mogelijk relevante relaties met bedrijven   Honorarium of andere (financiële) vergoeding Aandeelhouder Andere relatie, namelijk … . r h   . P Sponsoring of onderzoeksgeld Geen Geen  Pfizer, Abbott, Lilly, Amgen, MSD, Will, Roche  Pfizer, Abbott, Lilly, Amgen, MSD, UCB, Will, BMS, Novartis  Geen  NVT
  3. 3. Nevenwerkingen in RCTs . r h . P s u e G n e
  4. 4. n e . r h . P CALCIUM s u e G
  5. 5. Bolland 2008 . P n e s u e G Boland 2010 Calcium treatment was associated with: • increased risk of myocardial infarction dietary calcium intake > 805 mg/day (HR 1.85, 1.28-2.67) • no increased risk in those with dietary calcium intake < 805mg/day (HR 0.98, 0.691.38) . r h BMJ 2008;336;262-266; BMJ 2010;341:c3691
  6. 6. n e s u e G Participants 61 433 women (born between 1914 and 1948) followed-up for a median of 19 years (Michaelson, BMJ, 2013) . r h . P
  7. 7. n e . r h . P s u e G RCT 1200 mg calcium vs placebo; women ≥ 70. Base-line dietary intake 950 mg calcium JBMR, Vol. 25, 2010, pp 2205–2211
  8. 8. n e Adjusted dose-response association between daily calcium supplement intake and risk for cardiovascular death . r h . P s u e G Plos One 2013: e61037
  9. 9. Medische behandeling: calcium en vitamine D s u e G – Optimalisatie van calcium inname: • Totaal: 1000-1200 mg calcium/dag – Vb: geen melkproducten . P – Vb: 1-2 zuivelporties/dag – Vb: 3-4 zuivelporties/dag . r h MUMC&UHasselt n e + 3-4 zuivelporties of 1000 mg calcium supplement + 1-2 zuivelporties of +500 mg calcium supplement geen aanpassing nodig 1 zuivelportie = 1 stevig glas melk 1 pot yoghurt 1 schel kaas
  10. 10. n e . r h . P VITAMIN D s u e G
  11. 11. Vitamin D supplements s u e G n e • Toxic dose: >10.000 IU/d • Annual oral 500,000 IU of cholecalciferol – 26% increased risk of fracture and a 15% increased risk of falling compared to placebo (Sanders, JAMA, 2010) . P • Oral cholecalciferol 150,000 IU/3-monthly – neither beneficial nor adverse effects on falls or physical function (Glendennig, JBMR, 2012) . r h
  12. 12. Vitamin D supplements in patients with a recent fracture . r h . P n e s u e G Before CBO 2011 Loading dose according to baseline 25(OH)D 80% achieved >50 nmol/L After CBO 2011 Fixed dose of 800IU/d 80% achieved >50 nmol/L Shab-Bidar, European Journal of Endocrinology (2013) 169 597
  13. 13. n e . r h . P s u e G A vitamin D3 dosage of 800 IU/d increased serum 25-(OH)D levels to greater than 50 nmol/L in 97.5% of women Gallagher, AIM, 2012
  14. 14. Medische behandeling: calcium en vitamine D s u e G – Optimalisatie van calcium inname: • Totaal: 1000-1200 mg calcium/dag – Vb: geen melkproducten – Vb: 1-2 zuivelporties/dag . P – Vb: 3-4 zuivelporties/dag – Vitamine D: 800 E/dag • • • • n e + 3-4 zuivelporties of 1000 mg calcium supplement + 1-2 zuivelporties of +500 mg calcium supplement geen aanpassing nodig Bij osteoporose behandeling Bij mensen in verzorgingsinstelling Hoger indien nodig Na recente fractuur . r h MUMC&UHasselt 1 zuivelportie = 1 stevig glas melk 1 pot yoghurt 1 schel kaas
  15. 15. n e . r h . P s u e G ANTIRESORPTIEVE MEDICATIES
  16. 16. n e Selected bisphosphonate-associated adverse events of interest . r h . P s u e G Liwiecki, Drugs 2011; 71 (6): 791
  17. 17. n e . r h . P s u e G BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW (ONJ, BONJ, BRONJ)
  18. 18. n e Risk factors for bisphosphonate-associated osteonecrosis of the jaw . r h . P s u e G Khosla, J Bone Miner Res, 2007, 1479
  19. 19. n e Differential diagnosis of osteonecrosis of the jaw in bisphosphonate-treated patients . r h . P s u e G Khosla, J Bone Miner Res, 2007, 1479
  20. 20. ONJ in cancer patients n e s u e G • The incidence of bisphosphonate-associated ONJ is highest in patients with underlying malignancies • who receive high doses of iv bisphosphonates (e.g. zoledronic acid, 4mg iv every 3–4 wk) to decrease the risk of skeletal complications of malignancy • 1 and 10% may go on to develop ONJ . r h . P Khosla, JCEM, 2012
  21. 21. Association between exposure to oral BPs and ONJ in osteoporosis . r h . P n e s u e G Italian record linkage claims database with a target population of 6 million over 55 years of age Incidence rate: 36.6 per 100,000 person-years Lapi, Osteoporos Int (2013) 24:697
  22. 22. ONJ in osteoporosis . r h . P n e s u e G Solomon, Osteoporos Int (2013) 24:237
  23. 23. ONJ in osteoporosis . r h . P n e s u e G Solomon, Osteoporos Int (2013) 24:237
  24. 24. n e . r h . P s u e G ATYPICAL FEMUR FRACTURE
  25. 25. AFF . r h . P n e s u e G Ng & Png, JBMR, 2013, online
  26. 26. n e Definition of atypical femur fracture, requiring the presence of each of the listed major features s u e G Prodromes in >50% of cases Often bilateral . r h . P Shane, J Bone Miner Res 2010, 2267
  27. 27. n e Case reports in the literature and reports in the FAERS database of bisphosphonate-associated atypical femoral fractures from January 1996 to September 2011 . r h . P s u e G Edwards, Bone Joint Surg Am. 2013;95:297-307
  28. 28. n e . r h . P s u e G Edwards, Bone Joint Surg Am. 2013;95:297-307
  29. 29. n e The risk of subtrochanteric and femoral shaft fractures in bisphosphonate users from large observational studies . r h . P s u e G Saleh, Orthop Clin N Am 44 (2013) 137–151
  30. 30. n e . r h . P s u e G Prasarn, Clin Orthop Relat Res (2012) 470:2295–2301
  31. 31. n e Randomeffects analysis of the studies for the association between bisphosphonate use and subtrochanteric, femoral shaft, and atypical femur fracture (AFF), . r h . P s u e G Gedmintas, JBMR, 2013, 1729
  32. 32. n e Random effects analysis of the studies for the association between bisphosphonate use and subtrochanteric, femoral shaft, and atypical femur fracture (AFF), stratified by outcome definition . r h . P s u e G Gedmintas, JBMR, 2013, 1729
  33. 33. n e Random effects analysis of the studies for the association between long‐term bisphosphonate use (5 years or greater) and subtrochanteric and femoral shaft fractures . r h . P s u e G Gedmintas, JBMR, 2013, 1729
  34. 34. AFF Duration of BPs . r h . P n e s u e G Time to union Thompson, J Bone Joint Surg Br, 2012;94-B:385–90.
  35. 35. Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women s u e G * . r h ST/D FN/intertroch . P 42 817 n e * 349 5587 204 2438 * 121 881 Park, JAMA, February 23, 2011—Vol 305, No. 8 783
  36. 36. n e Bisphosphonate Use and Atypical Fractures of the Femoral Shaft (atypical subtrochanteric fractures, n=56) 80 70 60 50 40 30 20 . r h 10 0 0 Natyp 13 Nwomen 1437820 . P <1yr 3 15672 1--2yr 4 21406 s u e G >2yr 39 46233 HR N cases stop BPs <1yr 42 83311 1--2yr >2yr 1 3 70036 75583 Schilcher, N Engl J Med 2011;364:1728-37.
  37. 37. Bone microarchitecture in AFF . r h . P n e s u e G Zanchetta, JBMR, 2013, online
  38. 38. n e Microindentation values for the four groups of study subjects. (A) Total indentation distance (Total ID), age-adjusted statistical differences . r h . P s u e G Guerri, Journal of Bone and Mineral Research, Vol. 28, 2013, pp 162
  39. 39. n e Reduction in bone scan uptake post-teriparatide treatment. Bone scintigraphy scans pre- and post-teriparatide treatment showing reduction in the intensity of isotope uptake (n=4). . r h . P s u e G Chiang, Bone 52 (2013) 360–365
  40. 40. n e . r h . P s u e G BISFOSFONATEN EN SLOKDARM KANKER MUMC&UHasselt
  41. 41. n e . r h MUMC&UHasselt . P s u e G Dixon, Nat. Rev. Rheumatol. 2011, 369
  42. 42. n e . r h MUMC&UHasselt . P s u e G Dixon, Nat. Rev. Rheumatol. 2011, 369
  43. 43. n e . r h . P s u e G DENOSUMAB AND INFECTIONS
  44. 44. Serious adverse events of cellulitis and erysipelas and relationship to timing of administration . r h . P n e s u e G Watts, OI, 2012
  45. 45. Denosumab vs. Placebo Infections . r h . P n e s u e G Watts, OI, 2012
  46. 46. Denosumab 6 yrs . r h . P s u e G n e
  47. 47. n e . r h . P s u e G FRACTUURHELING
  48. 48. Fracture healing . r h . P n e s u e G Claes, NRR, 2012
  49. 49. Fracture healing • Bisphosphonates – Increased callus s u e G • Denosumab (Adami, JBJS, 2012) . P – No delayed union • Teriparatide . r h – Positive effect? n e • NSAIDs (Geusens, Curr Opin Rh, 2013) – Avoid long-term use after recent fracture
  50. 50. n e . r h . P s u e G ANABOLE MIDDELEN
  51. 51. Teriparatide s u e G n e • In clinical trials the following reactions were reported at a ≥ 1% difference in frequency from placebo: . P – vertigo, nausea, pain in limb, dizziness, depression, dyspnoea . r h
  52. 52. n e . r h . P s u e G STRONTIUM RANELAAT
  53. 53. Strontium ranelate s u e G n e • Drug rash with eosinophilia and systemic symptoms (DRESS) (Cacoub, OI, 2012) – 1/24.000 (France) • DVT (Osborne, Drug Saf 2010) . P – Incidence: 6/1000 patient yrs • CV events (EMEA 2013) . r h – Protelos/Osseor should not be used in patients with current or past history of ischaemic heart disease (such as angina or a heart attack), peripheral arterial disease (obstruction of large blood vessels, often in the legs) or cerebrovascular disease (diseases affecting the blood vessels supplying the brain, such as stroke). – Protelos/Osseor should not be used in patients with hypertension (high blood pressure) that is not adequately controlled by treatment.
  54. 54. n e Veiligheid s u e G • Bisfosfonaten (JCEM 2012:2272) – – – – Osteonecrose kaak Atypische femurfracturen Atriumfibrillatie Oesofagus carcinoom . P 0.001 – 0.1% 0,0005% - 0,2% associatie in één studie geen associatie • Denosumab (JCEM 2013:4483) . r h – Osteonecrose kaak – Atypische femurfracturen – Infecties / cellulitis 8 casus 2 casus 1,4 en <0,1%
  55. 55. 63-year-old woman with: - rheumatoid arthritis for 30 years - diabetes for 3 years - alendronate 70mg weekly for 7 years . P 6 months . r h Baseline: Spinal compression fractures L3 and L4 T-score spine: -2.25 n e s u e G No mention of calcium and vitamin D intake or follow up strategy! J Clin Endocrinol Metab 98: E723–E726, 2013
  56. 56. Follow up tijdens behandeling: gestructureerde monitoring Sterk aanbevolen Kan zinvol zijn Start therapie n e s u e G Gestructureerde klinische monitoring (min. na 3 maanden, nadien jaarlijks) Intolerantie . r h Non Compliance Niet-wervel fractuur na 1 jaar therapie . P Botmarkers Zo nodig andere medicatie of SC of IV Klinisch vermoeden van nieuwe wervelfractuur Bij twijfel/vragen RX DXA na 2-3 jaar Overleg Teriparatide (2de keuze: PTH), na 3de fractuur waaronder 2 wervelfracturen
  57. 57. Conclusies n e s u e G • Gezien de zeer lage incidentie van ONJ en AFF versus de belangrijke fractuurreductie met bisfosfonaten en denosumab, is de risico/benefit verhouding duidelijk in het voordeel van behandeling van patiënten met een hoog fractuurrisico: . P – met een wervel of heupfractuur – of een BMD T-score <2.5 . r h • Of dit ook het geval is wanneer patiënten geselecteerd worden op basis van FRAX of Garvan, noodzaakt verder onderzoek

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