Post on 18-Jun-2015
description
Nevenwerkingen van medicaties bij fractuurpreventie:
klinisch relevant?
Prof Piet Geusens, MD, PhD
Reumatoloog
Maastricht UMC & UHasselt
dhr. P. G
eusens
(potentiële) belangenverstrengeling Geen
Voor bijeenkomst mogelijk relevante relaties met bedrijven
Geen
Sponsoring of onderzoeksgeld
Honorarium of andere (financiële) vergoeding
Aandeelhouder Andere relatie, namelijk …
Pfizer, Abbott, Lilly, Amgen, MSD, Will, Roche Pfizer, Abbott, Lilly, Amgen, MSD, UCB, Will, BMS, Novartis Geen NVT
Disclosure belangen spreker
dhr. P. G
eusens
Nevenwerkingen in RCTs
dhr. P. G
eusens
CALCIUM
dhr. P. G
eusens
Bolland 2008
BMJ 2008;336;262-266;
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, 0.69-
1.38)
BMJ 2010;341:c3691 dhr. P. G
eusens
Participants 61 433 women (born between 1914 and 1948) followed-up for a median of 19 years (Michaelson, BMJ, 2013)
dhr. P. G
eusens
RCT 1200 mg calcium vs placebo; women ≥ 70. Base-line dietary intake 950 mg calcium JBMR, Vol. 25, 2010, pp 2205–2211 dhr. P
. Geusens
Adjusted dose-response association between daily calcium supplement intake and risk for cardiovascular death
Plos One 2013: e61037 dhr. P. G
eusens
Medische behandeling: calcium en vitamine D
– Optimalisatie van calcium inname:
• Totaal: 1000-1200 mg calcium/dag – Vb: geen melkproducten + 3-4 zuivelporties of 1000 mg
calcium supplement
– Vb: 1-2 zuivelporties/dag + 1-2 zuivelporties of +500 mg calcium supplement
– Vb: 3-4 zuivelporties/dag geen aanpassing nodig
MUMC&UHasselt
1 zuivelportie = 1 stevig glas melk 1 pot yoghurt 1 schel kaas dhr. P
. Geusens
VITAMIN D
dhr. P. G
eusens
Vitamin D supplements
• 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)
• Oral cholecalciferol 150,000 IU/3-monthly
– neither beneficial nor adverse effects on falls or physical function (Glendennig, JBMR, 2012)
dhr. P. G
eusens
Vitamin D supplements in patients with a recent fracture
Shab-Bidar, European Journal of Endocrinology (2013) 169 597
Before CBO 2011 After CBO 2011 Loading dose according to baseline 25(OH)D Fixed dose of 800IU/d 80% achieved >50 nmol/L 80% achieved >50 nmol/L
dhr. P. G
eusens
Gallagher, AIM, 2012
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
dhr. P. G
eusens
Medische behandeling: calcium en vitamine D
– Optimalisatie van calcium inname: • Totaal: 1000-1200 mg calcium/dag
– Vb: geen melkproducten + 3-4 zuivelporties of 1000 mg calcium supplement
– Vb: 1-2 zuivelporties/dag + 1-2 zuivelporties of +500 mg calcium supplement
– Vb: 3-4 zuivelporties/dag geen aanpassing nodig
– Vitamine D: 800 E/dag • Bij osteoporose behandeling • Bij mensen in verzorgingsinstelling • Hoger indien nodig • Na recente fractuur
MUMC&UHasselt
1 zuivelportie = 1 stevig glas melk 1 pot yoghurt 1 schel kaas dhr. P
. Geusens
ANTIRESORPTIEVE MEDICATIES
dhr. P. G
eusens
Selected bisphosphonate-associated adverse events of interest
Liwiecki, Drugs 2011; 71 (6): 791 dhr. P. G
eusens
BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW (ONJ, BONJ, BRONJ) dhr. P
. Geusens
Risk factors for bisphosphonate-associated osteonecrosis of the jaw
Khosla, J Bone Miner Res, 2007, 1479 dhr. P. G
eusens
Differential diagnosis of osteonecrosis of the jaw in bisphosphonate-treated patients
Khosla, J Bone Miner Res, 2007, 1479 dhr. P. G
eusens
ONJ in cancer patients
• 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
Khosla, JCEM, 2012 dhr. P. G
eusens
Association between exposure to oral BPs and ONJ in osteoporosis
Lapi, Osteoporos Int (2013) 24:697
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 dhr. P
. Geusens
ONJ in osteoporosis
Solomon, Osteoporos Int (2013) 24:237 dhr. P. G
eusens
ONJ in osteoporosis
Solomon, Osteoporos Int (2013) 24:237 dhr. P. G
eusens
ATYPICAL FEMUR FRACTURE
dhr. P. G
eusens
AFF
Ng & Png, JBMR, 2013, online dhr. P. G
eusens
Definition of atypical femur fracture, requiring the presence of each of the listed major features
Shane, J Bone Miner Res 2010, 2267
Prodromes in >50% of cases Often bilateral
dhr. P. G
eusens
Case reports in the literature and reports in the FAERS database of bisphosphonate-associated atypical femoral fractures from January 1996 to
September 2011
Edwards, Bone Joint Surg Am. 2013;95:297-307 dhr. P. G
eusens
Edwards, Bone Joint Surg Am. 2013;95:297-307 dhr. P. G
eusens
The risk of subtrochanteric and femoral shaft fractures in bisphosphonate users from large observational studies
Saleh, Orthop Clin N Am 44 (2013) 137–151 dhr. P. G
eusens
Prasarn, Clin Orthop Relat Res (2012) 470:2295–2301 dhr. P. G
eusens
Randomeffects analysis of the studies for the association between bisphosphonate use and subtrochanteric, femoral shaft, and atypical femur fracture
(AFF),
Gedmintas, JBMR, 2013, 1729 dhr. P. G
eusens
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
Gedmintas, JBMR, 2013, 1729 dhr. P. G
eusens
Random effects analysis of the studies for the association between long‐term bisphosphonate use (5 years or greater) and subtrochanteric and
femoral shaft fractures
Gedmintas, JBMR, 2013, 1729 dhr. P. G
eusens
AFF
Thompson, J Bone Joint Surg Br, 2012;94-B:385–90.
Duration of BPs Time to union
dhr. P. G
eusens
Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures
in Older Women
ST/D 42 349 204 121 FN/intertroch 817 5587 2438 881
*
* *
Park, JAMA, February 23, 2011—Vol 305, No. 8 783 dhr. P. G
eusens
Bisphosphonate Use and Atypical Fractures of the Femoral Shaft (atypical subtrochanteric fractures, n=56)
0
10
20
30
40
50
60
70
80
0 <1yr 1--2yr >2yr stop BPs
<1yr 1--2yr >2yr
HR
N cases
Natyp 13 3 4 39 42 1 3 Nwomen 1437820 15672 21406 46233 83311 70036 75583
Schilcher, N Engl J Med 2011;364:1728-37. dhr. P. G
eusens
Bone microarchitecture in AFF
Zanchetta, JBMR, 2013, online dhr. P. G
eusens
Microindentation values for the four groups of study subjects. (A) Total indentation distance (Total ID), age-adjusted statistical differences
Guerri, Journal of Bone and Mineral Research, Vol. 28, 2013, pp 162 dhr. P. G
eusens
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).
Chiang, Bone 52 (2013) 360–365 dhr. P. G
eusens
BISFOSFONATEN EN SLOKDARM KANKER
MUMC&UHasselt dhr. P. G
eusens
MUMC&UHasselt Dixon, Nat. Rev. Rheumatol. 2011, 369 dhr. P
. Geusens
MUMC&UHasselt Dixon, Nat. Rev. Rheumatol. 2011, 369 dhr. P
. Geusens
DENOSUMAB AND INFECTIONS
dhr. P. G
eusens
Serious adverse events of cellulitis and erysipelas and relationship to timing of administration
Watts, OI, 2012 dhr. P. G
eusens
Denosumab vs. Placebo Infections
Watts, OI, 2012 dhr. P. G
eusens
Denosumab 6 yrs
dhr. P. G
eusens
FRACTUURHELING
dhr. P. G
eusens
Fracture healing
Claes, NRR, 2012 dhr. P. G
eusens
Fracture healing
• Bisphosphonates
– Increased callus
• Denosumab (Adami, JBJS, 2012)
– No delayed union
• Teriparatide
– Positive effect?
• NSAIDs (Geusens, Curr Opin Rh, 2013)
– Avoid long-term use after recent fracture
dhr. P. G
eusens
ANABOLE MIDDELEN
dhr. P. G
eusens
Teriparatide
• In clinical trials the following reactions were reported at a ≥ 1% difference in frequency from placebo:
– vertigo, nausea, pain in limb, dizziness, depression, dyspnoea
dhr. P. G
eusens
STRONTIUM RANELAAT
dhr. P. G
eusens
Strontium ranelate
• Drug rash with eosinophilia and systemic symptoms (DRESS) (Cacoub, OI, 2012)
– 1/24.000 (France)
• DVT (Osborne, Drug Saf 2010)
– Incidence: 6/1000 patient yrs
• CV events (EMEA 2013)
– 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. dhr. P
. Geusens
Veiligheid
• Bisfosfonaten (JCEM 2012:2272) – Osteonecrose kaak 0.001 – 0.1%
– Atypische femurfracturen 0,0005% - 0,2%
– Atriumfibrillatie associatie in één studie
– Oesofagus carcinoom geen associatie
• Denosumab (JCEM 2013:4483)
– Osteonecrose kaak 8 casus
– Atypische femurfracturen 2 casus
– Infecties / cellulitis 1,4 en <0,1%
dhr. P. G
eusens
J Clin Endocrinol Metab 98: E723–E726, 2013
63-year-old woman with: - rheumatoid arthritis for 30 years - diabetes for 3 years - alendronate 70mg weekly for 7 years
6 months
Baseline: Spinal compression fractures L3 and L4 T-score spine: -2.25
No mention of calcium and vitamin D intake or follow up strategy! dhr. P. G
eusens
Niet-wervel fractuur na 1 jaar therapie
Bij twijfel/vragen
Intolerantie
Follow up tijdens behandeling: gestructureerde monitoring
Teriparatide (2de keuze: PTH), na 3de fractuur waaronder 2 wervelfracturen
Sterk aanbevolen
Kan zinvol zijn
Klinisch vermoeden van nieuwe
wervelfractuur
DXA na 2-3 jaar
Non Compliance
Overleg
Botmarkers
Zo nodig andere medicatie of SC of IV
RX
Gestructureerde klinische monitoring (min. na 3 maanden, nadien jaarlijks) Start
therapie
dhr. P. G
eusens
Conclusies
• 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:
– met een wervel of heupfractuur
– of een BMD T-score <2.5
• Of dit ook het geval is wanneer patiënten geselecteerd worden op basis van FRAX of Garvan, noodzaakt verder onderzoek
dhr. P. G
eusens