Seminar 28-11-2015 Prof. Dr. W.F. Lems

1. 28 November 2015
Prof Dr Willem F Lems,
Reumatoloog in VUmc en Reade

2. 2

3. Welke Bronnen?
1) Eigen aantekeningen/interpretatie (bias!);
Contacten met Nederlandse/internationale experts;
2)
Website IOF/Sponsored by Eli Lilly
3)

4. • Basale
studies
• Zeldzame
bone
diseases
• Dagelijkse
prak4jk
• Future
developments

5. Congress Highlights ASBMR 5

6. Baron
and
Kneisel,
2013

13. • Basale
studies
• Zeldzame
bone
diseases
• Dagelijkse
prak4jk
• Future
developments

17. Osteogenesis
Imperfecta
• The
effec4veness
of
bisphosphonate
treatment
on
bone
biomarkers
and
fracture
rates
in
Osteogenesis
Imperfecta:
conflic4ng
results
on
fracture
rates,
and
on
bone
markers
(?)
(Shapiro,
Sa
385);
• Muizenmodel,
behandeling
met
an4body
scleros4ne
of
placebo/vehicle:
reduc4e
fracture
rate,
toename
bone
volume,
hoeveelheid
collageen,
toegenomen
sterkte
bij
buigtest
(Kyu
Sang,
1018)
.

18. Intensive
bisphosphonate
therapy
aimed
at
normalising
bone
turnover
on
Paget’s
disease
INCREASES
the
risk
of
fractures
and
requirement
for
orthopedic
procedures
• Aer
tree
years
treatment
with
Zol
or
risedronate
(Langston
JBMR
2010),
longterm
follow-­‐up(
3
years)
in
502
pa4ents
with
Zoledronic
acid:
• a)
symptoma4c
group,
treated
in
case
of
bone
pain
(n=232);
• b)
intensive
treatment,
irrespec4ve
of
bone
pain.
Aim
alkaline
phosphatase
in
normal
range.
(n=270)
• Fractures:
13
versus
26,
orthopedic
procedures:
8
versus
13.
Together,
HR
1.89
(95%
c.i.:
1.04-­‐3.27).
Ralston
1068

19. • Basale
studies
• Zeldzame
bone
diseases
• Dagelijkse
prak7jk
• Future
developments

20. Congress
Highlights
ASBMR
Houston
2014
20
Wie behandelen?
50-plussers met recente fractuur en T-score <-2.5;
Maar ook
- Ouderen met heupfractuur;
- Patienten na een bovenarmsfractuur, klinische wervelfractuur, bekkenfractuur
met een T-score in range van osteopenie.

21. ASBMR/ECTS Clinical Debate “The diagnosis of
osteoporosis should be changed to include patients at high
fracture risk rather than being based on a T-score”
INTRODUCTION
Any one of the above criteria would permit a diagnosis of osteoporosis.
1Low trauma fractures include vertebral, proximal humeral, pelvic, or, in some cases, distal forearm fractures.
Congress Highlights ASBMR 2015 Annual Meeting 21
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22. ASBMR/ECTS Clinical Debate “The diagnosis of
osteoporosis should be changed to include patients at high
fracture risk rather than being based on a T-score”
§ For the motion: Dr Nelson Watts
§ Against the motion: Prof. John Kanis
§ Alternative definition of osteoporosis discussed based on the position
statement of the National Bone Health Alliance (NBHA) Working Group
• T-score ≤ -2.5 (spine or hip)
• Low trauma hip fracture with or without BMD testing
• Low trauma fracture1 with osteopenia
• Individuals with an elevated fracture risk based on the World Health
Organization Fracture Risk Algorithm, FRAX
Siris ES Osteoporos Int. 2014; 25(5): 1439–1443.
INTRODUCTION
Any one of the above criteria would permit a diagnosis of osteoporosis.
1Low trauma fractures include vertebral, proximal humeral, pelvic, or, in some cases, distal forearm fractures.
Congress Highlights ASBMR 2015 Annual Meeting 22
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23. ASBMR/ECTS Clinical Debate “The diagnosis of
osteoporosis should be changed to include patients at high
fracture risk rather than being based on a T-score”
§ The risk of fracture is determined not only by BMD but also by bone quality
and the forces applied to bone, mainly through trauma.
§ Using BMD alone misses these other components of fracture risk
23
§ Points for the motion (Dr Nelson Watts)
Fracture risk is
more than BMD
§ Most individuals who fracture DO NOT have osteoporosis based on the
current definition
§ The NBHA definition would be less prone to this issue
A T score of
≤-2.5 misses
fractures
§ Using a narrow definition of osteoporosis may lead to patients not being
treated appropriately and physicians failing to appreciate fracture risk in
non-osteoporotic patients.
People suffer if
definition is too
narrow
BMD bone mineral density
NELSON WATTS Back to TOC
Congress Highlights ASBMR 2015 Annual Meeting

24. ASBMR/ECTS Clinical Debate “The diagnosis of
osteoporosis should be changed to include patients at high
fracture risk rather than being based on a T-score”
§ Determining which patients should be treated (intervention threshold) is
entirely different to defining a disease (diagnostic criteria)
24
§ Points against the motion (Prof John Kanis)
Diagnostic
criteria vs
intervention
threshold
§ The NBHA definition diagnoses osteoporosis (a risk factor for fracture)
based on the presence of the endpoint (hip fracture) alone.
§ This is akin to diagnosing hypertension by the presence of a stroke!
Concerns
regarding the
NBHA definition
§ The NBHA definition suggests defining osteoporosis based on a given
FRAX risk. This would not work on a global scale.
§ Fracture risk varies by country as does treatment cost effectiveness by risk.
One size
doesn’t fit all
countries
BMD bone mineral density
JOHN A KANIS Back to TOC
Congress Highlights ASBMR 2015 Annual Meeting

25. Oct
2015

26. Oct
2015

27. Oct
2015

28. LB-1156 The Association of Race Ethnicity and Risk of
Atypical Femur Fracture in Women Treated with Oral
Bisphosphonate Drugs
§ Atypical femoral fracture (AFF), is a transverse, non-comminuted fracture at
the subtrochanteric or femoral shaft region
§ The risk of atypical femoral fracture seems to increase with bisphosphonate
(BP) therapy duration, but such rare events are outweighed by fracture risk
reduction in high risk patients
§ ASBMR AFF Task Force suggests that after 5 years of oral BP or 3 years of
intravenous BP, reassessment of therapy should be considered
§ Greater risk in AFF has been described in Asian patients
INTRODUCTION
AFF atypical femoral fracture • BP biphosphonate
JOAN LO, RITA HUI, CHRISTOPHER GRIMSRUD, MALINI CHANDRA, ROMAIN
NEUGEBAUER, JOEL GONZALEZ, AMER BUDAYR, GENE LAU, BRUCE ETTINGER, KAISER
PERMANENTE, USA
28
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Congress Highlights ASBMR 2015 Annual Meeting

29. LB-1156 The Association of Race Ethnicity and Risk of
Atypical Femur Fracture in Women Treated with Oral
Bisphosphonate Drugs
§ Ethnicity: 65.3% white, 17.1% Asian, 17.6% other races
§ During a median follow-up of 7.7 years
§ 68 women with AFF
§ Rate of AFF 18.7 per 100,000 person-years overall
§ 8x higher in Asian compared to white women (64.2 vs 7.6 per 100,000
person-years, respectively)
§ Median duration of BP use greater in Asian women (3.8 years) vs whites
(2.7 years) and others (2.4 years)
§ In unadjusted analyses, prior fracture, diabetes, RA and baseline
glucocorticoid, aromatase inhibitor and proton pump inhibitor therapy not
associated with AFF
§ Race/ethnicity strongly associated with risk of AFF, with an age-adjusted
relative hazard of 8.5 (95% CI 4.9-14.9) comparing Asian to white women
RESULTS
AFF atypical femoral fracture • BP biphosphonate • RA rheumatoid arthritis • CI confidence Interval
JOAN LO, RITA HUI, CHRISTOPHER GRIMSRUD, MALINI CHANDRA, ROMAIN
NEUGEBAUER, JOEL GONZALEZ, AMER BUDAYR, GENE LAU, BRUCE ETTINGER, KAISER
PERMANENTE, USA
29
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Congress Highlights ASBMR 2015 Annual Meeting

31. Maternal
Gesta4onal
Vitamin
D
supple4on
and
Offspring
Bone
Mass
• Zwangere
vrouwen
kregen
1000
IU
vitamin
D
of
placebo;
• Bone
mineral
content
gemeten
bij
655
kinderen,
2
weken
na
geboorte;
• Geen
verschil
in
BMC:
61.6
versus
60.5
g
• Maar:
prespecified
analysis:
BMC
van
kinderen
die
in
de
winter
geboren
zijn:
63.0
versus
57.5,
p=0.004
• Vitamine
D
deficiency
(<
50
nmol/l)reduced:
16.6%
versus
63.5%
C
Cooper,
Fr
0052
(abstract)

32. 1090 A randomized, double-blind, placebo-controlled
clinical trial on the treatment of vitamin D
insufficiency in postmenopausal women
§ RCT, double blind, in postmenopausal women with 25(OH)D levels 14-27
ng/mL
Determine the optimal 25(OH)D levels for musculoskeletal health
DESIGN
§ One-year changes in total fractional Ca absorption, spine, hip and total body BMD and
TBS
§ Timed-Up-and-Go and 5-Sit-to-Stand tests and pain at 0, 30, 60, 120, 240 and 365
days
METHODS
RCT randomized clinical trial • Ca calcium • BMD bone mineral density • TBS trabecular bone score
KAREN HANSEN, R. ERIN JOHNSON, KAITLIN CHAMBERS, MICHAEL G. JOHNSON,
CHRISTINA C. LEMON, TIEN NGUYEN THUY VO, SHEEVA MARVDASHTI, UNIVERSITY OF
WISCONSIN, USA
32
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Congress Highlights ASBMR 2015 Annual Meeting

33. 1090 A randomized, double-blind, placebo-controlled
clinical trial on the treatment of vitamin D
insufficiency in postmenopausal women
IU international unit
KAREN HANSEN, R. ERIN JOHNSON, KAITLIN CHAMBERS, MICHAEL G. JOHNSON,
CHRISTINA C. LEMON, TIEN NGUYEN THUY VO, SHEEVA MARVDASHTI, UNIVERSITY OF
WISCONSIN, USA
33
Postmenopausal women
25 (OH) D levels 14-27 ng/mL
50,000 IU every 15
days for 1 year
800 IU daily and yellow
placebo every 15 days for 1
year
Sham yellow placebo capsule
White placebo daily and
yellow placebo every 15
days
50,000 IU daily
Loading dose of Vit D for 15 days
25 (OH)D > 30 ng/mL
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Congress Highlights ASBMR 2015 Annual Meeting

34. 1090 A randomized, double-blind, placebo-controlled
clinical trial on the treatment of vitamin D
insufficiency in postmenopausal women
§ Changes over 1 year between arm
*significant versus high-dose ns: not significant versus high-dose
RESULTS
Ca calcium • BMD bone mineral density • IU international unit • pbo placebo
KAREN HANSEN, R. ERIN JOHNSON, KAITLIN CHAMBERS, MICHAEL G. JOHNSON,
CHRISTINA C. LEMON, TIEN NGUYEN THUY VO, SHEEVA MARVDASHTI, UNIVERSITY OF
WISCONSIN, USA
34
Vitamin
D
Placebo
High
dose
arm
Low
dose
arm
50,000
IU
800
IU
Total
frac2onal
Ca
absorp2on
+1%
(10
mg/d)
-­‐2%*
-­‐1.3%*
Spine
ns
Total
hip
ns
Mean
femoral
neck
ns
Total
body
BMD
ns
5-­‐sit
to
stand
test
0.4
sec
p=0.02
vs
pbo
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Congress Highlights ASBMR 2015 Annual Meeting

35. Vitamin
K
treatment
prevents
postmenopausal
bone
loss
and
microarchitectural
deteriora4on
of
bone
loss,
a
RCT
(1)
• Vitamine
K
van
belang
bij
carboxylering
osteocalcine;
• 142
postmenopausale
vrouwen
(60-­‐80
jaar)
met
osteopenie
kregen
Vit
K2
(375
ųg)
of
placebo;
allen
kregen
calcium
(800
mg)
en
vitamine
D
(38
ųg);
• Geen
effect
op
BMD
van
LWK;
• Daling
BMD
heup
in
placebo-­‐groep
(-­‐0.64%,
p<0.01),
geen
daling
in
verum-­‐groep;
Geen
verschil
in
verandering
tussen
de
groepen.
Sofie
Hertz,
Bente
Langdahl.
1051

36. Vitamin
K
treatment
prevents
postmenopausal
bone
loss
and
microarchitectural
deteriora4on
of
bone
loss,
a
RCT
(2)
• pQCT:
daling
aantal
trabekels
in
placebo-­‐groep,
(-­‐3,5%,
p<0,01),
geen
verschil
in
vitamine
K-­‐groep.
Verschil
in
veranderingen
tussen
groepen:
-­‐3.4%
p=0.02
• Trebeculaire
dikte
nam
toe
in
placebogroep
(4%,
p<0.01),
geen
verschil
in
vitamine
K
groep.
• Totale
BMD
radius:
-­‐1.7%
(placebo)
en
-­‐1.2%
(Vitamine
K);
geen
verschil
tussen
de
veranderingen
in
de
groepen.
Sofie
Hertz,
Bente
Langdahl.
1051

37. What
about
secondary
osteoporosis?

38. 1138 FRAX underestimates hip fracture risk in older
men with CKD
§ Veterans Aging Cohort Study Virtual Cohort (VACSVC), prospective study
§ 13,668 men age 50-70 years
Test whether FRAX® can predict 10-year risk of MOP and hip fractures in patients with
eGFR<30 mL/minute
PARTICIPANTS
§ Comparison of the calibration of FRAX® without BMD across ranges of
kidney functionDESIGN
§ Accuracy of the modified-FRAX calculation compared by observed/
estimated (O/E) ratios of fracture.
§ eGFR estimated by CKD-EPI formula
§ CKD stage defined by National Kidney Foundation criteria (normal kidney
function≥60mL/min)
OUTCOMES
AND ANALYSIS
CKD chronic kidney disease • MOP major osteoporotic • GFR glomerular filtration rate • BMD bone mineral density
THOMAS NICKOLAS, STEPHANIE SHIAU, KYLE NISHIYAMA, NATALIA CORTEZ, ELIZABETH
SHANE, MARIA RODRIQUEZ-BARRADAS, DAVID RIMLAND, CYNTHIA GIBERT, ROGER
BEDIMO, AMY JUSTICE, JULIE WOMACK, MICHAEL YIN, COLUMBIA UNIVERSITY, USA
38
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Congress Highlights ASBMR 2015 Annual Meeting

39. 1138 FRAX underestimates hip fracture risk in older
men with CKD
RESULTS
CKD chronic kidney disease • CI confidence interval • O/E observed/expected
THOMAS NICKOLAS, STEPHANIE SHIAU, KYLE NISHIYAMA, NATALIA CORTEZ, ELIZABETH
SHANE, MARIA RODRIQUEZ-BARRADAS, DAVID RIMLAND, CYNTHIA GIBERT, ROGER
BEDIMO, AMY JUSTICE, JULIE WOMACK, MICHAEL YIN, COLUMBIA UNIVERSITY, USA
39
Reproduced with permission from the American Society for Bone and Mineral Research
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Congress Highlights ASBMR 2015 Annual Meeting

42. 1073 Change in Fracture Risk After Bariatric Surgery from a
Pattern Associated with Obesity to a Pattern Typical of
Osteoporosis: A Study Using Healthcare Administrative
Databases
§ 10 662 patients who underwent bariatric surgery between 2001-2012
(72.6% women; mean(SD) age of 42(11) years)
§ 3:1 age and sex-matched non-bariatric obese controls (n = 31 986)
§ 3:1 age and sex-matched non-obese controls (n = 31 986)
Investigate whether fracture risk by site changes before and after bariatric surgery
PARTICIPANTS
§ Retrospective, population-based cohort study in the province of Quebec,
Canada, using healthcare administrative databases
§ Followed for mean of 4.2 years (range <1-12 years)
DESIGN
§ Multivariate conditional Poisson regression models adjusted for past
fracture, comorbidities, material and social deprivation and area of
residence
OUTCOMES
CATHERINE ROUSSEAU, SONIA JEAN, PHILIPPE GAMACHE, STEFANE LEBEL, FABRICE
MAC-WAY, LAËTITIA MICHOU, CLAUDIA GAGNON, CHU DE QUEBEC RESEARCH CENTRE;
DEPARTMENT OF MEDICINE, LAVAL UNIVERSITY, CANADA
42
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Congress Highlights ASBMR 2015 Annual Meeting

43. 1073 Change in Fracture Risk After Bariatric Surgery from a
Pattern Associated with Obesity to a Pattern Typical of
Osteoporosis: A Study Using Healthcare Administrative
Databases
Data are presented as relative risks (95% CI). 1 Includes fractures of the knee, foot, ankle, tibia and fibula. 2 Includes fractures
of the shoulder, humerus, elbow, forearm and wrist. 3 Relative risk adjusted for material and social deprivation, area of
residence, and number of comorbidities using multivariate conditional Poisson regression model.
RESULTS
CATHERINE ROUSSEAU, SONIA JEAN, PHILIPPE GAMACHE, STEFANE LEBEL, FABRICE
MAC-WAY, LAËTITIA MICHOU, CLAUDIA GAGNON, CHU DE QUEBEC RESEARCH CENTRE;
DEPARTMENT OF MEDICINE, LAVAL UNIVERSITY, CANADA
43
Bariatric group
(n=10,662)
Obese controls
(n=31986)
Non-obese controls
(n=31986)
Adjusted RR3 Adjusted RR3 Adjusted RR3
Before Surgery or Index date
Lower extremity1 1.60 (1.44,1.78) 1.37 (1.26,1.49) Reference
Upper extremity2 0.85 (0.74,0.98) 0.90 (0.83,0.99) Reference
Spine 1.06 (0.68,1.66) 1.01 (0.73,1.41) Reference
Hip, femur, pelvis 0.99 (0.69,1.25) 0.93 (0.69,1.25) Reference
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Congress Highlights ASBMR 2015 Annual Meeting
Adapted from table and reproduced with permission from the American Society for Bone and Mineral Research

44. 1073 Change in Fracture Risk After Bariatric Surgery from a
Pattern Associated with Obesity to a Pattern Typical of
Osteoporosis: A Study Using Healthcare Administrative
Databases
Data are presented as relative risks (95% CI). 1 Includes fractures of the knee, foot, ankle, tibia and fibula. 2 Includes fractures
of the shoulder, humerus, elbow, forearm and wrist. 3 Relative risk adjusted for material and social deprivation, area of
residence, and number of comorbidities using multivariate conditional Poisson regression model.
RESULTS
CATHERINE ROUSSEAU, SONIA JEAN, PHILIPPE GAMACHE, STEFANE LEBEL, FABRICE
MAC-WAY, LAËTITIA MICHOU, CLAUDIA GAGNON, CHU DE QUEBEC RESEARCH CENTRE;
DEPARTMENT OF MEDICINE, LAVAL UNIVERSITY, CANADA
44
Bariatric group
(n=10,662)
Obese controls
(n=31986)
Non-obese controls
(n=31986)
Adjusted RR3 Adjusted RR3 Adjusted RR3
After Surgery or Index date
Lower extremity1 1.18 (0.96,1.44) 1.29 (1.11,1.49) Reference
Upper extremity2 1.57 (1.30,1.89) 0.88 (0.76,1.03) Reference
Spine 1.67 (0.85,3.27) 0.98 (0.59,1.63) Reference
Hip, femur, pelvis 2.45 (1.58,3.79) 0.94 (0.62,1.45) Reference
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Congress Highlights ASBMR 2015 Annual Meeting
Adapted from table and reproduced with permission from the American Society for Bone and Mineral Research

47. LB-1157 Ten Years of Denosumab Treatment in
Postmenopausal Women With Osteoporosis: Results
From the FREEDOM Extension Trial
HG BONE, ML BRANDI, JP BROWN, R CHAPURLAT, SR CUMMINGS, E CZERWINSKI, A
FAHRLEITNER-PAMMER, DL KENDLER, K LIPPUNER, J-Y REGINSTER, C ROUX, E
VITTINGHOFF, NS DAIZADEH, A WANG, P DAKIN, RB WAGMAN, S PAPAPOULOS, MICHIGAN
BONE AND MINERAL CLINIC, USA
47
FREEDOM Extension
2,2
3,1 3,1
0,9
1,5
1,9
1,6
0
1
2
3
4
1/2 3 4/5 6/7
Yearlyincidenceofnewvertebral
fractures(%)
Years of Denosumab treatment
FREEDOM Extension
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Congress Highlights ASBMR 2015 Annual Meeting
Reproduced with permission from the Authors

51. Arthri4s
Rheum
June
2015
Hazard
ra4o:
0.89,
95%
c.i.
0.64-­‐1.15

54. • Basale
studies
• Zeldzame
bone
diseases
• Dagelijkse
prak4jk
• Future
Developments
(treatment)

55. Cathepsine K
Osteoclast
Odanacatib
Collageen degradatie
RANK
Osteoblast
Wnt signalering
LRP Frizzeld
Wnt
DKK
Osteocyt
RANKL
Denosumab Anti-sclerostin
rhPTH (1-34) and (1-84)
Sclerostine
pre-­‐
osteoclast
pre-­‐
osteoblast
RANKL Sclerostine
Lems, Geusens, Current Opinion
Rheumatology, 2014

56. • Cathepsin
k

59. 1143 Romosozumab Improves Strength at the
Lumbar Spine and Hip in Postmenopausal Women
With Low Bone Mass Compared With Teriparatide
§ Postmenopausal women with lumbar spine, total hip, or femoral neck T-
scores ≤–2.0 and ≥–3.5
Investigate the effects of romosozumab on bone strength by FEA
PARTICIPANTS
§ Randomised to
• Romosozumab 210mg SC monthly (n=24)
• Teriparatide 20µg daily (open label) (n=27)
• Placebo (n=31)
DESIGN
§ QCT: L1 & L2 lumbar vertebrae & proximal femur - baseline & 12months
§ Bone strength by 3D FEA (VirtuOst, O.N. Diagnostics)
OUTCOMES
AND ANALYSIS
FEA finite element analysis • sc sub cutaneous • L lumbar • QCT quantitative computer tomography
TONY KEAVENY, DB CRITTENDEN, MA BOLOGNESE, HK GENANT, K ENGELKE, B OLIVERI,
JP BROWN, BL LANGDAHL, YC YANG, A GRAUER, C LIBANATI, UNIVERSITY OF
CALIFORNIA, BERKELEY, USA
59
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60. Percentage Change from Baseline in Bone Mineral Density.
McClung MR et al. N Engl J Med 2014;370:412-420

63. 1053 Effects of Abaloparatide on Major Osteoporotic
Fracture Incidence in Postmenopausal Women with
Osteoporosis - Results of the Phase 3 ACTIVE Trial
§ ACTIVE double-blind, placebo-controlled Phase 3 fracture prevention trial
§ Postmenopausal osteoporotic women randomized:
- Placebo (PBO) SC for 18 months
- Daily ABL 80 µg SC
- Open label teriparatide (TPTD) 20 µg SC
+ Calcium and vitamin D supplements
§ Incidence of major osteoporotic fractures: upper arm, forearm (+ wrist), hip,
shoulder +/- vertebral spine (spine +/- tailbone)
Measure the effects of Abaloparatide on Major Osteoporotic Fracture Incidence in
Postmenopausal Women with Osteoporosis
DESIGN
PBO placebo • TPTD teriparatide • ABL abaloparatide • SC sub-cutaneous
LORRAINE FITZPATRICK, GREG WILLIAMS, WILLARD DERE, ALAN HARRIS, MING-YI
(TRISTAN) HU, KATE BANKS, GARY HATTERSLEY, RADIUS HEALTH INC, USA
,
63
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69. DANK VOOR UW AANDACHT