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8 Kummer 1965 (Pauwels 1973)

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11 Ultrasound treatment Kristiansen et al. J Bone Joint Surg. 1997;79:961-73

12 Benläkning och läkemedel, den positiva sidan. Per Aspenberg

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15 BMPs J Bone Joint Surg Am. 2002;84-A(12):

16 BMPs P=0.0005

17 BMPs improve fracture repair However. Resorption: spine fracture, morcellized graft (Combine with bisphosphonate?) No proven superiority to cancellous bone graft Non-responders!?

18 However.. Postop 3 months Laursen et al. Eur. Spine J. 1999

19 However.. Postop 3 months Laursen et al. Eur. Spine J. 1999

20 PTH Intermittent PTH ökar benbildning Selye H. Endocrinology 1932;16:547. Osteoporos-behandling! Neer RM et al. N Engl J Med 2001;344(19):1434 P Aspenberg, Linköping

21 PTH Linday et al. Lancet 1997;250:550

22 20 days PTH Andreassen et al. J Bone Min Res 1999; 6: 960

23 PTH Ultimate load (N) 3 weeks 6 weeks Control 76 N Vehicle 60µg 200µg Vehicle 60µg 200µg 0 Data from Andreassen TT et al. J Bone Miner Res 1999

24 PTH Frakturexperiment: Stark effekt, men först efter enkondrala fasen

25 PTH

26 Nybildad vävnad i kammaren efter 6 veckor Control PTH

27 Bone volume density in chamber, lumbar vertebra and distal femur 6 weeks.8 PTH 60µg/KgBW per day.4 Control 0 Chamber Femur Vertebra

28 Bone volume density in chamber, lumbar vertebra and distal femur 6 weeks.8 PTH 60µg/KgBW per day.4 Control 0 Chamber Femur Vertebra

29 Bone volume density in chamber, lumbar vertebra and distal femur 6 weeks.8 PTH 60µg/KgBW per day.4 Control 0 Chamber Femur Vertebra

30 Bone volume density in chamber, lumbar vertebra and distal femur 6 weeks.8 PTH 60µg/KgBW per day.4 Control 0 Chamber Femur Vertebra

31 PTH har starkare effekt på läkning än på remodellering (t ex osteoporos)

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35 Choices: or periosteal + exogenous marrow

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37 PTH Utdragskraft och urvridningsmoment ökade 2 till 3 gånger på 2 veckor

38 PTH Histologisk benkontakt (%) Control PTH W2 W4 0 W2 W4 Cement Steel

39 PTH Implantatförsök: Tidig och dramatisk ökning av inläkningen

40 PTH Effekt på human osteoporos Effekt på frakturläkning i djur och i människa?

41 Effects of Teriparatide on Distal Radial Fracture Healing in Postmenopausal Women: a Randomized Double-blinded Study P. Aspenberg* 1, H. K. Genant 2, T. Johansson 1, A. J. Nino 3, K. See 3, K. Krohn 3, P. Garcia 4, C. P. Recknor 5, T. A. Einhorn 6, G. P. Dalsky 3, M. Lakshmanan 3 Presented at ECTS 2008

42 PTH (1-34) Clinical study on distal radial fractures.

43 PTH (1-34) Clinical study on distal radial fractures. International multicenter Eli Lilly Corp. 105 conservatively treated cases Radiography every 2nd week Central radiographic reading

44 PTH (1-34) Clinical study on distal radial fractures. International multicenter Eli Lilly Corp. 106 conservatively treated fractures Radiography every 2nd week Central radiographic reading 20 µg, 40 µg or placebo. Double-blinded.

45 PTH (1-34) 80% completed follow-up 27 placebo 29 teriparatide 20 µg 26 teriparatide 40 µg 84

46 PTH (1-34) Statistical analysis Gehan-Wilcoxon test and bootstrap method (median healing time) Hypothesis 1: teriparatide 40 µg > placebo If so: Hypothesis 2: teriparatide 20 µg > placebo

47 N = 84

48 N = 84

49 Post - hoc P-values Overall 0.01 PTH 40 µg vs placebo 0.4 PTH 20 µg vs placebo 0.003

50 Incorrectly included Volar dislocation 3 No dislocation 5 Previous fracture 1

51 placebo 20 µg 40 µg

52 Median healing time (weeks) Placebo 9.2 PTH 20 µg 7.1 PTH 40 µg 8.8 P-values Overall <0.001 PTH 40 µg vs placebo 0.13 PTH 20 µg vs placebo <0.001 PTH 20 µg vs PTH

53 PTH(1-34) appears to moderately shorten the time to radiographic healing in distal radial fractures, but with an unclear dose response Special feature of distal radius? Bad luck?? Further studies needed

54 EP-2 agonist Proc Natl Acad Sci U S A May 27;100(11):

55 EP-2 agonist Prostaglandin E2 Receptors EP1, EP2, EP3, EP4

56 Fig. 3. X-rays of canine ulnar critical defect treated with 1.0 ml of PLGH matrix show no healing/ rebridging sequence at 2 (A), 12 (B), and 24 (C) weeks after surgery Paralkar, V. M. et al. (2003) Proc. Natl. Acad. Sci. USA 100, Copyright 2003 by the National Academy of Sciences

57 EP-2 agonist Radiologisk läkning efter 24 veckor Läkt PLGA EP2 agonist* Helt Delvis Icke Totalt *10 mg of CP-533, ml of PLGH Data from Paralkar et al 2003

58 Statiner?

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62 Brottkraft, 14 dagar N (n= 12) 10 (n= 11) 5 0 Control Simvastatin

63 Simvastatin, lokal minipump 0.1 mg/kg /day 14 days (n = ) Transverse area (mm 2 ) Force at failure (N) Energy uptake (Nmm) Control P=0.24 Simva Control P=0.003 Simva Control P=0.002 Simva

64 Rat From Garret,,, Mundy. JOR. 2007;25:1351

65 Rat From Garret,,, Mundy. JOR. 2007;25:1351 Narrow dose range?

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74 Protesfixation Vi tror att fixationen är resultatet av en tävling mellan bennedbrytning eller benbildning

75 Protesfixation Vi tror att fixationen är resultatet av en tävling mellan bennedbrytning eller benbildning I så fall borde minskad nedbrytning förbättra fixationen

76 Protesfixation Vi tror att fixationen är resultatet av en tävling mellan bennedbrytning eller benbildning I så fall borde minskad nedbrytning förbättra fixationen BIFOSFONATER!!

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78 Clodronate prevents prosthetic migration. 50 TKA Clodronate vs placebo 6 months Double-blinded Migration (RSA)

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80 degrees 2,00 Clodronate Placebo 1,50 1,00 0,50 0,00-0,50 6 v 6 m 1 y 2 y 4 y Time

81 Bisphosphonates Local peroperative ibandronate 1 mg (1mL) direct to tibial resection surface before cementing Prospective randomized double-blinded NexGen Knee prosthesis RSA 0, 0.5, 1 and 2 years 50 pat. Lost to follow-up: 1 dead, 1 refused

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83 1,9,8,7,6,5,4,3,2,1 0 MTPM (mm) 6 mo 1 y 2 y Ibandronate Placebo Rep meas Anova p=0.006

84 Placebo Ibandronat

85 .90 Systemic clodronate Control Bisphosphonate

86 .90 Systemic clodronate.90 Local ibandronate Control Bisphosphonate months

87 Placebo 2 år Bifosfonat 2 år Dikotomin för kontrollgruppen är signifikant (p=0.03).

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89 Bisphos coating Acid etching

90 Pull-out Force (N) Weeks

91 Pull-out Energy (Nmm) Weeks

92 But, This can not be explained by decreased removal of dead bone!

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94 Control 1 week

95 Control 8 weeks

96 Control 8 weeks Bisphos 8 weeks

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98 8 weeks

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100 80 ISQ at 6 months pat1 pat2 Pat 3 Pat 4 Pat

101 20 Change in ISQ pat1 pat2 Pat 3 Pat 4 Pat

102 Ja, vi kan påskynda frakturläkning (och därmed implantatfixation) med mekanisk stimulering och flera läkemedel.

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