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