IWO Bijeenkomst - 11 april - Dr. Lems

Glucocorticoid Induced Osteoporosis
11 April 2018
Prof Willem F Lems,
Location Officer Rheumatology VUmc,
Educational Officer ARC.

Disclosures:
Willem F. Lems.
Company
Speaking Fees/
Advisory Boards
Amgen, Eli Lilly, Merck, UCB, Novartis, Curaphar,
Servier, Will Pharma, Abbott, Pfizer, Roche.

• Epidemiology
• Pathogenesis
• Treatment-Options (drug/non-drug): New Options!
• Glucocorticoïds and RA
• Guidelines
• Summary/Conclusions

Secundary osteoporosis
Mirza & Canalis, EJE 2015
“Glucocorticoid induced Osteoporosis
most common cause of secundary
osteoporosis”

Ranking adverse events
Osteoporosis
CVD
Peptic ulcer
DM / glucose int.
Weight gain
Renal dysfunction
Cataract
Hypertension
Myopathy
Fatigue
Moon face
Glaucoma
Palpitations
Dyspnea
DM / glucose int.
Osteoporosis
Weight gain
Infections
CVD
Atherosclerosis
Peptic ulcer
Cataract
Myopathy
AEs due to interactions
Osteonecrosis
Impaired wound healing
Dyslipidemia
Hypertension
Van der Goes et al. Patients’ and rheumatologists’ perspectives on glucocorticoids. Ann Rheum Dis 2010
Patients
Physicians

How often do we use Glucocorticoids?
• US : 1% (Fardet 2015)
• 3% in 50 years and over, 5.2% in 80 and over (Kanis 2004)
• Global Longitudinal Study of Osteoporosis inWomen (GLOW), in 10
countries: 4,6% of 60 393 postmenopausal women used GC.

How often do we use Glucocorticoids in RA?
Buttgereit, EULAR congress 2016
• In 1996: 55% RA patients prednisolon
• In 2013: 50 % RA patients prednisolon
• But, in 2013, only 5% > 7,5 mg per dag, i.t.t.
15% in 1996!

How often do we use Glucocorticoids in SLE?
• 70% of SLE patients used prednisolon and 10 % methylprednisolon
• Mean dosage 5 mg per day.

Glucocorticoids and vertebral fracture
1.4
1.2
1.0
0.8
0.6
0.4
0.2
van Staa TP et al. JBMR 2000;15:993-1000
WomenMen
High dose
Medium dose
Low dose
Control
Incidence (%)
<35 40 50 60 70 80 >85<35 40 50 60 70 80 >85
Age (yrs)

• Epidemiology
• Pathogenesis
• Treatment-Options (drug/non-drug)
• Glucocorticoïds and RA
• Guidelines
• Summary/Conclusions

Direct Effects of Glucocorticoids on Bone Cells.
Weinstein RS. N Engl J Med 2011;365:62-70 2011, Weinstein S

Glucocorticoids alter the
BMD Fracture Threshold
Steroid users
Nonusers
Femoral neck BMD
Lumbar spine BMD
40
30
20
10
0
40
30
20
10
0
%Fractures
-=4.5 -3.5 -2.5 -1.5 -0.5
-4.5 -3.5 -2.5 -1.5 -0.5 0.5
van Staa. Arthr Rheum 2003; 48: 3224-9

In GIOP:
1. Use the lowest possible dosage of GC;
2. Adequate calcium and vitamin D supply
3. Exercise therapy
4. Optimal treatment Underlying Disease
5. Stop smoking/ limit alcohol intake

Changing Patterns of anti-osteoporotic treatment in
New Glucocorticoid Users (n = 5,471)
9%
14%
41%
23%
33%
62%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Men Women < 50 Women 50+
Rateoftreatment
1995-1998 2001-2003
Curtis JR. Arth Rheum 2005;52:2485

40%
60%
80%
100%
BONASOL DRANK Tabletten ALN, RIS, IBN
67%
83%

Effect of risedronate on BMD in patients starting with Glucocorticoids
(“ prevention”)
Cohen et al., Arthr Rheum 1999; 42: 2309-
Spine Femoral
Neck
Trochanter-5
-3
-1
1
3
5
# # *#
** *
placebo
risedronate 5 mg
%changeversus
baseline
•p<0,05 vs. baseline
•# p<0,05 vs. controls
Mean starting dose: 21 mg

Effect of risedronate on BMD in patients during chronic GC-treatment
“treatment””
* p<0,05 vs. baseline
# p<0,05 vs. controls
-5
-3
-1
1
3
5
Spine Femoral Neck Trochanter
*#
*#
%changeversusbasline
risedronate 5 mg
Reid et al., J Bone Min Res 2000; 15: 1006-1013
placebo
*
Mean starting dose: 15 mg

0.0
0.5
1.0
1.5
2.0
PMO GIO PMO GIO
RR
N = 9,681 987 14,551 500
Vertebral fracture Non-vertebral fracture
RR= 0.58 0.48 0.81 0.79
Comparison of efficacy of oral bisphosphonates in PMO and GIOP
From Kanis et al, Health Tech Assess 2007;11:1-258

Drugs Approved for GIOP
Spine BMD Hip BMD Vertebral fracture Non-vertebral
fracture
Alendronate ✔ ✔ ✓★ -
Etidronate ✔ ✔ ✔★ -
Risedronate ✔ ✔ ✔★ -
Zoledronate ✔ ✔ - -
Teriparatide ✔ ✔ ✔★ -
Alfacalcidol ✔ ✔§ - -
Calcitriol ✔ ✔§ - -
§ data inconsistent, ★ not a primary end point.
Rizzoli R, Biver E Nat Rev Rheumatol 2015; 11: 98-109

Modern GIOP-studies
New drugs are not tested against placebo, but aginst an active
comparator!

Original Article
Teriparatide or Alendronate in Glucocorticoid-
Induced Osteoporosis
Kenneth G. Saag, M.D., Elizabeth Shane, M.D., Steven Boonen, M.D., Ph.D.,
Fernando Marín, M.D., David W. Donley, Ph.D., Kathleen A. Taylor, Ph.D., Gail P.
Dalsky, Ph.D., and Robert Marcus, M.D.
N Engl J Med
Volume 357(20):2028-2039
November 15, 2007
A three years study!

% of patients with fractures:
teriparatide versus alendronate in GIOP
0
2
4
6
8
10
VF, 18
months
VF, 36
months
non VF, 18 non VF, 36
alendronate
teriparatide
p=0,004
p=0.007
Saag A & R 2009, New Engl J Med 2007

GIO – 36-month Lumbar Spine BMD
Alendronate n= 195 184 173 159 148 131 112 195
Teriparatide n= 198 183 178 170 156 136 123 198
* P<0.05; ‡ P<0.001 Teriparatide vs. Alendronate
Months
0 3 6 12 18 24 36 Endpoint
PercentChangeinBMD
Mean±SE
0
2
4
6
8
10
12
‡
‡
‡
‡
‡
‡
Teriparatide
Alendronate
11.0%
4.2%
8.9%
5.3%
9.8%
5.2%
3.8%
8.0%
*
BMD = bone mineral density, g/cm2
Saag KG et al. Arthritis Rheum 2009;61:November

EuroGIOPS: Study Design
Screening Phase
Visit 1 Visit 2 Visit 4
(6 months)
Visit 6
(18 months)
Baseline
Teriparatide 20 μg/day (injection)
Risedronate 35 mg/week (oral)
4-6 weeks
All
Patients
(Randomization)
Visit 3
3 months 3 months
Visit 5
6 months 6 months
Calcium plus Vitamin D
Active treatment phase
(3 months) (12 months)
T12 (HRQCT) +
L1-3 CT scans
T12 (HRQCT) +
L1-3 CT scans
T12 (HRQCT) +
L1-3 CT scans
CT = computed tomography; HRQCT = high resolution quantitative computed tomography; L1-3 = lumbar vertebrae 1-3;
T12 = 12th thoracic vertebra.
Gluer C, et al. JBMR 2013 .

EuroGIOPs: % Changes from Baseline to Month 18 in T-12 vBMD and
Bone Microstructure (by HRQCT)
BMD = bone mineral density; BS/TV = bone surface to volume ratio; BV/TV = bone volume fraction; Ct.BMD = cortical BMD;
Ct.Th.DW = density weighted cortical thickness; HRQCT = high resolution quantitative computed tomography; Int.BMD =
integral BMD; Integr. = integral; T12 = 12th thoracic vertebra; LS = least square; SE = standard error; Tb.BMD = trabecular
BMD; Tb.N = trabecular number; Trab. = trabecular.
-10
-5
0
5
10
15
20
25
30
Int.BMD Tb.BMD Ct.BMD Ct.Th.DW Tb.N BV/TV BS/TV
LSmean%Change
fromBaseline(SE)
Risedronate Teriparatide *p<0.05
§ p<0.1
§
Bone mineral density
.
Cortical
T
*
* *
Microstructure

0
10
20
30
40
Month 6 Month 18
LSmean%Change
fromBaseline(SE)
Anterior Bending
Risedronate
Teriparatide *
0
10
20
30
40
Month 6 Month 18
LSmean%Change
fromBaseline(SE)
Axial Torsion
Risedronate
Teriparatide
**
0
10
20
30
40
Month 6 Month 18
LSmean%Change
fromBaseline(SE)
Axial Compression
Risedronate
Teriparatide * *
EuroGIOPs: % Changes from Baseline in Vertebral Strength of T-12
Estimated by FEA
LS = least square; SE = standard error; T-12 = 12th thoracic vertebra * p<0.05 ** p<0.01
torsion
compression
Gluer C, et al. JBMR 2013

Change in PINP at 3, 6, 18 Months vs. that in FE
Strength at 18 Months for Anterior Bending
-50
-25
0
25
50
75
100
125
150
-75 -50 -25 0 25 50 75 100 125 150 175 200 225 250 275 300
18MonthChangeinMaximalTorque
(kNmm)
Change in P1NP (μg/L) at 18 Months
18 Months
Teriparatide:
r = 0.546, p = 0.016
Risedronate: r = -0.141, n.s.
-50
-25
0
25
50
75
100
125
150
-50 0 50 100 150 200 250 300
18MonthChangeinMaximal
Torque(kNmm)
6 Months
Teriparatide:
r = 0.486, p = 0.019
Risedronate: r = -0.023, n.s.
-50
-25
0
25
50
75
100
125
150
-50 -25 0 25 50 75 100 125
18MonthChangeinMaximal
Torque(kNmm)
3 Months
Teriparatide:
r = 0.422, p = 0.045
Risedronate:
r = -0.033, n.s.
Farahmand P. etal. Ost Int 2013

Effect of Denosumab Compared With Risedronate in
Glucocorticoid-treated Individuals: Results From the 12-month
Primary Analysis of a Randomized, Double-blind, Active-controlled Study
K Saag1, RBWagman2, P Geusens3, J Adachi4, O Messina5,R Emkey6,
R Chapurlat7, NS Daizadeh2, N Pannacciulli2, WF Lems8
1University of Alabama, Birmingham, AL, USA; 2Amgen Inc., Thousand Oaks, CA, USA;
3Maastricht University, Maastricht, The Netherlands; 4McMaster

Study Objectives
• Primary
– To demonstrate in GC-C and GC-I subpopulations separately that
denosumab was not inferior to risedronate with respect to percentage
change from baseline in lumbar spine BMD at 12 months
• Secondary
– To compare effects of denosumab with those of risedronate in GC-C
and GC-I subpopulations separately on percentage change from
baseline in:
• Lumbar spine BMD at 12 months
• Total hip BMD at 12 months
• Lumbar spine BMD at 24 months
• Total hip BMD at 24 months

Study Design
Month 0
Primary endpoint
12 24
R
A
N
D
O
M
I
Z
A
T
I
O
N
Denosumab 60 mg SC Q6M and
Placebo for Risedronate PO QD
(N = 253)
Risedronate 5 mg PO QD and
Placebo for Denosumab SC Q6M
(N = 252)
Calcium and Vitamin D
Month 0
Primary endpoint
12 24
R
A
N
D
O
M
I
Z
A
T
I
O
N
Denosumab 60 mg SC Q6M and
Placebo for Risedronate PO QD
(N = 145)
Risedronate 5 mg PO QD and
Placebo for Denosumab SC Q6M
(N = 145)
Calcium and Vitamin D
Glucocorticoid-continuing (GC-C) Glucocorticoid-initiating (GC-I)
Key Inclusion Criteria:
• Women and men ≥ 18 years receiving GC therapy at ≥ 7.5 mg prednisone daily or equivalent prior to
screening; stratified for
• ≥ 3 months (Glucocorticoid-continuing [GC-C])
• < 3 months (Glucocorticoid-initiating [GC-I])
• All subjects < 50 years required to have a history of osteoporotic fracture
• GC-C subjects ≥ 50 years required to have LS, TH, or FN BMD T-score ≤ ‒2.0; or T-score ≤ ‒1.0 with
history of osteoporotic fracture

Glucocorticoid-continuing
(GC-C)
Glucocorticoid-initiating
(GC-I)
Risedronate
N = 252
Denosumab
N = 253
Risedronate
N = 145
Denosumab
N = 145
Sex – n (%)
Men 67 (26.6) 68 (26.9) 52 (35.9) 52 (35.9)
Women 185 (73.4) 185 (73.1) 93 (64.1) 93 (64.1)
Age (years) – mean (SD) 61.3 (11.1) 61.5 (11.6) 64.4 (10.0) 67.5 (10.1)
Medical disorders requiring
glucocorticoid use – n (%)
Rheumatoid arthritis 118 (46.8) 96 (37.9) 43 (29.7) 48 (33.1)
Polymyalgia rheumatica 18 (7.1) 20 (7.9) 52 (35.9) 50 (34.5)
Systemic lupus
erythematosus
16 (6.3) 15 (5.9) 4 (2.8) 2 (1.4)
Prednisone-equiv. dose (mg) –
mean (SD)
11.13 (7.69) 12.29 (8.09) 15.61 (10.25) 16.57 (13.01)
25 (OH) vit D (ng/mL) – median
(Q1, Q3)
28.0 (23.6,
36.3)
29.2 (24.2,
37.6)
28.6 (24.2,
36.4)
28.8 (23.6,
36.0)
Lumbar spine BMD T-score –
mean (SD)
‒1.96 (1.38) ‒1.92 (1.39) ‒1.06 (1.57) ‒0.92 (1.86)
Total hip BMD T-score – mean
(SD)
‒1.56 (0.96) ‒1.66 (0.96) ‒0.98 (1.07) ‒1.14 (1.00)
Prior osteoporotic fracture since
age 18 – n (%)
134 (53.2) 136 (53.8) 51 (35.2) 49 (33.8)

-0.5
1.5
3.5
5.5
-0.5
1.5
3.5
5.5
Lumbar Spine BMD Percentage Change From Baseline
at Months 6 and 12
BL 6 12 BL 6 12
BMDPercentageChange
FromBaseline
BMDPercentageChange
FromBaseline
Study Month Study Month
227 211
224 209
128 126
127 119
Risedronate n=
Denosumab n=
n = Number of subjects with observed values at baseline and the time point of interest; *p ≤ 0.002
*
* *
*
Risedronate Denosumab

-1.0
0.0
1.0
2.0
3.0
-0.5
0.5
1.5
2.5
Total Hip BMD Percentage Change From Baseline at
Month 12
* *
BMDPercentageChange
FromBaseline
BMDPercentageChange
FromBaselinen = Number of subjects with observed values at baseline and the time point of interest; *p ≤ 0.001
BL 6 BL 6 12
Risedronate n=
Denosumab n=
12
215
217
128
119

-100
-50
0
50
*
Combined Subpopulations
* * *
100107112111110127 113
89100104106110121 108
P1NP
CTX and P1NP Percentage Change From Baseline (Bone
Marker Sub-study)
n = Number of subjects with observed values at baseline and the time point of interest; *p ≤ 0.05
Risedronate n=
Denosumab n=
-130
-80
-30
20
Combined Subpopulations
* * * **
98106110110107126 111
86100102104109120 107
CTX
CTXPercentageChange
FromBaseline
P1NPPercentageChange
FromBaseline
BL 6 12 BL 6 12

Clinical and New Vertebral Fractures
n = Number of subjects with ≥ 1 fracture
N = Number of subjects randomized
N1 = Number of subjects randomized with a baseline assessment and ≥ 1 post-baseline assessment of vertebral fracture
Clinical fracture – n / N (%) 15 / 397 (3.8) 19 / 398 (4.8)
New vertebral fracture – n / N1 (%) 11 / 342 (3.2) 9 / 333 (2.7)

n (%)
Risedronate
N = 384
Denosumab
N = 394
Adverse events of Interest
Acute pancreatitis 1 (0.3) 0 (0.0)
Atypical femoral fracture (AFF) 0 (0.0) 1 (0.3)
Cardiac disorders 16 (4.2) 20 (5.1)
Eczema 0 (0.0) 2 (0.5)
Hypersensitivity 12 (3.1) 19 (4.8)
Hypocalcemia 0 (0.0) 1 (0.3)
Malignancy 3 (0.8) 5 (1.3)
Musculoskeletal pain 56 (14.6) 54 (13.7)
Osteonecrosis of the jaw (ONJ) 0 (0.0) 0 (0.0)
Serious infections 15 (3.9) 17 (4.3)
Serious skin infections 1 (0.3) 1 (0.3)
Vascular disorders 25 (6.5) 25 (6.3)
N = Number of subjects who received ≥ 1 dose of IP

50
“Not only Glucocorticoids, but also the underlying disease
might have a negative effect on bone strength! (drug/disease
confounding)
RA Disease Activity Bone Strength
Glucocorticoids
Courtesy of Maarten Boers
Secondary Osteoporosis: RA, SLE, Vasculitis, COPD, Inflammatory Bowel
Disease, etc

COBRA-light trial: changes in DAS after 4 years
53Konijn, N. P., van Tuyl, L. H., Boers, M., den Uyl, D., ter Wee, M. M., van der Wijden, L. K., ... & Nurmohamed, M. T. (2017). Similar efficacy and safety of initial COBRA-light and COBRA therapy in
rheumatoid arthritis: 4-year results from the COBRA-light trial. Rheumatology.

Changes in BMD after COBRA (initially 60 mg prednisone/day) and COBRA light
(initially 30 mg prednisone/day), after 4 years, change in BMD lumbar spine
No significant difference in BMD between
COBRA en COBRA-light over 4 years
(p-value: 0.32)
54
Figure 1. Mean changes in BMD over four years at lumbar spine
COBRA
COBRA-light
−0.5%
−1.0%
No significant difference between
baseline and 4 years (p-value: 0.08)
Merel Lucassen, winner ASBMR
Young Investigators Award 2017

56
Guidelines for Management of Glucocorticoid-Induced Osteoporosis.
Weinstein RS. N Engl J Med 2011;365:62-70

GIOP: ECTS - IOF postmenopausal women and
men > 50 years

GlOP: Conclusions
• Glucocorticoids are used to treat a wide variety of diseases and are prescribed by a wide variety of physicians
• Glucocorticoid-induced osteoporosis is the most common type of secondary osteoporosis, affecting men,
premenopausal women, and postmenopausal women
• Glucocorticoid-induced bone loss should be prevented and, if established, should be treated (options include
bisphosphonates and teriparatide ; all with calcium and vit D)
• Denosumab is a new option in GC-treated patients;
• Any therapy to prevent or treat glucocorticoid-induced bone loss should be continued at least as long as the
patient is receiving glucocorticoids
• Risk assessment using FRAX with appropriate country-specific treatment thresholds facilitates clinical
decision-making

IWO Bijeenkomst - 11 april - Dr. Lems

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IWO Bijeenkomst - 11 april - Dr. Lems