Side effects treat opo short

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Nevenwerkingen van medicaties
bij fractuurpreventie:
klinisch relevant?
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Prof Piet Geusens, MD, PhD
Reumatoloog
Maastricht UMC & UHasselt

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Disclosure belangen spreker
(potentiële) belangenverstrengeling
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Voor bijeenkomst mogelijk relevante
relaties met bedrijven


Honorarium of andere (financiële)
vergoeding
Aandeelhouder
Andere relatie, namelijk …
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
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Sponsoring of onderzoeksgeld
Geen
Geen
 Pfizer, Abbott, Lilly, Amgen, MSD,
Will, Roche
 Pfizer, Abbott, Lilly, Amgen, MSD,
UCB, Will, BMS, Novartis
 Geen
 NVT

3. Nevenwerkingen
in RCTs
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CALCIUM
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5. Bolland 2008
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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)
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BMJ 2008;336;262-266;
BMJ 2010;341:c3691

6. n
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Participants 61 433 women (born between
1914 and 1948) followed-up for a median of 19
years (Michaelson, BMJ, 2013)
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RCT 1200 mg calcium vs placebo; women ≥ 70. Base-line dietary intake 950 mg calcium
JBMR, Vol. 25, 2010, pp 2205–2211

8. n
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Adjusted dose-response association between daily calcium
supplement intake and risk for cardiovascular death
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Plos One 2013: e61037

9. Medische behandeling:
calcium en vitamine D
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– Optimalisatie van calcium inname:
• Totaal: 1000-1200 mg calcium/dag
– Vb: geen melkproducten
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– Vb: 1-2 zuivelporties/dag
– Vb: 3-4 zuivelporties/dag
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MUMC&UHasselt
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+ 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. n
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VITAMIN D
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11. Vitamin D supplements
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• 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)
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• Oral cholecalciferol 150,000 IU/3-monthly
– neither beneficial nor adverse effects on falls or physical
function (Glendennig, JBMR, 2012)
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12. Vitamin D supplements in patients
with a recent fracture
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n
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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

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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. Medische behandeling:
calcium en vitamine D
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– Optimalisatie van calcium inname:
• Totaal: 1000-1200 mg calcium/dag
– Vb: geen melkproducten
– Vb: 1-2 zuivelporties/dag
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– Vb: 3-4 zuivelporties/dag
– Vitamine D: 800 E/dag
•
•
•
•
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+ 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
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MUMC&UHasselt
1 zuivelportie =
1 stevig glas melk
1 pot yoghurt
1 schel kaas

15. n
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ANTIRESORPTIEVE MEDICATIES

16. n
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Selected bisphosphonate-associated adverse events of
interest
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Liwiecki, Drugs 2011; 71 (6): 791

17. n
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BISPHOSPHONATE-RELATED
OSTEONECROSIS OF THE JAW
(ONJ, BONJ, BRONJ)

18. n
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Risk factors for bisphosphonate-associated osteonecrosis
of the jaw
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Khosla, J Bone Miner Res, 2007, 1479

19. n
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Differential diagnosis of osteonecrosis of the jaw in
bisphosphonate-treated patients
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Khosla, J Bone Miner Res, 2007, 1479

20. ONJ in cancer patients
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• 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
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Khosla, JCEM, 2012

21. Association between
exposure to oral BPs and ONJ in osteoporosis
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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. ONJ in osteoporosis
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Solomon, Osteoporos Int (2013) 24:237

23. ONJ in osteoporosis
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Solomon, Osteoporos Int (2013) 24:237

24. n
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ATYPICAL FEMUR FRACTURE

25. AFF
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Ng & Png, JBMR, 2013, online

26. n
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Definition of atypical femur fracture, requiring the presence
of each of the listed major features
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Prodromes in >50% of cases
Often bilateral
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Shane, J Bone Miner Res 2010, 2267

27. n
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Case reports in the literature and reports in the FAERS database of
bisphosphonate-associated atypical femoral fractures from January 1996 to
September 2011
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Edwards, Bone Joint Surg Am. 2013;95:297-307

28. n
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Edwards, Bone Joint Surg Am. 2013;95:297-307

29. n
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The risk of subtrochanteric and femoral shaft fractures in
bisphosphonate users from large observational studies
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Saleh, Orthop Clin N Am 44 (2013) 137–151

30. n
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Prasarn, Clin Orthop Relat Res (2012) 470:2295–2301

31. n
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Randomeffects analysis of the studies for the association between bisphosphonate
use and subtrochanteric, femoral shaft, and atypical femur fracture
(AFF),
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Gedmintas, JBMR, 2013, 1729

32. n
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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
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Gedmintas, JBMR, 2013, 1729

33. n
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Random effects analysis of the studies for the association between long‐term
bisphosphonate use (5 years or greater) and subtrochanteric and
femoral shaft fractures
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Gedmintas, JBMR, 2013, 1729

34. AFF
Duration of BPs
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Time to union
Thompson, J Bone Joint Surg Br, 2012;94-B:385–90.

35. Bisphosphonate Use and the Risk
of Subtrochanteric or Femoral Shaft Fractures
in Older Women
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*
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ST/D
FN/intertroch
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42
817
n
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*
349
5587
204
2438
*
121
881
Park, JAMA, February 23, 2011—Vol 305, No. 8 783

36. n
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Bisphosphonate Use and Atypical Fractures
of the Femoral Shaft (atypical subtrochanteric fractures, n=56)
80
70
60
50
40
30
20
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10
0
0
Natyp
13
Nwomen 1437820
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P
<1yr
3
15672
1--2yr
4
21406
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>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. Bone microarchitecture in AFF
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Zanchetta, JBMR, 2013, online

38. n
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Microindentation values for the four groups of study subjects. (A)
Total indentation distance (Total ID), age-adjusted statistical differences
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Guerri, Journal of Bone and Mineral Research, Vol. 28, 2013, pp 162

39. n
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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).
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Chiang, Bone 52 (2013) 360–365

40. n
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BISFOSFONATEN EN SLOKDARM
KANKER
MUMC&UHasselt

41. n
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MUMC&UHasselt
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Dixon, Nat. Rev. Rheumatol. 2011, 369

42. n
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MUMC&UHasselt
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Dixon, Nat. Rev. Rheumatol. 2011, 369

43. n
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DENOSUMAB AND INFECTIONS

44. Serious adverse events of cellulitis and erysipelas and
relationship to timing of administration
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Watts, OI, 2012

45. Denosumab vs. Placebo
Infections
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Watts, OI, 2012

46. Denosumab 6 yrs
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FRACTUURHELING

48. Fracture healing
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Claes, NRR, 2012

49. Fracture healing
• Bisphosphonates
– Increased callus
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• Denosumab (Adami, JBJS, 2012)
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– No delayed union
• Teriparatide
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– Positive effect?
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• NSAIDs (Geusens, Curr Opin Rh, 2013)
– Avoid long-term use after recent fracture

50. n
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ANABOLE MIDDELEN

51. Teriparatide
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• In clinical trials the following reactions were
reported at a ≥ 1% difference in frequency
from placebo:
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P
– vertigo, nausea, pain in limb, dizziness,
depression, dyspnoea
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52. n
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STRONTIUM RANELAAT

53. Strontium ranelate
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• Drug rash with eosinophilia and systemic symptoms
(DRESS) (Cacoub, OI, 2012)
– 1/24.000 (France)
• DVT (Osborne, Drug Saf 2010)
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– Incidence: 6/1000 patient yrs
• CV events (EMEA 2013)
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– 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. n
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Veiligheid
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• Bisfosfonaten (JCEM 2012:2272)
–
–
–
–
Osteonecrose kaak
Atypische femurfracturen
Atriumfibrillatie
Oesofagus carcinoom
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P
0.001 – 0.1%
0,0005% - 0,2%
associatie in één studie
geen associatie
• Denosumab (JCEM 2013:4483)
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– Osteonecrose kaak
– Atypische femurfracturen
– Infecties / cellulitis
8 casus
2 casus
1,4 en <0,1%

55. 63-year-old woman with:
- rheumatoid arthritis for 30 years
- diabetes for 3 years
- alendronate 70mg weekly for 7 years
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6 months
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Baseline:
Spinal compression fractures L3 and L4
T-score spine: -2.25
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No mention of calcium and vitamin D intake or follow up strategy!
J Clin Endocrinol Metab 98: E723–E726, 2013

56. Follow up tijdens behandeling:
gestructureerde monitoring
Sterk aanbevolen
Kan zinvol zijn
Start
therapie
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Gestructureerde klinische monitoring (min. na 3 maanden, nadien jaarlijks)
Intolerantie
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Non
Compliance
Niet-wervel fractuur
na 1 jaar therapie
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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. Conclusies
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• 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:
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– met een wervel of heupfractuur
– of een BMD T-score <2.5
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• Of dit ook het geval is wanneer patiënten
geselecteerd worden op basis van FRAX of Garvan,
noodzaakt verder onderzoek