Efficacy and Safety of Long-term Denosumab Therapy ... y seguridad del... · OOC • Overall, no...
Transcript of Efficacy and Safety of Long-term Denosumab Therapy ... y seguridad del... · OOC • Overall, no...
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Michael R. McClung, MD, FACP
Professorial Fellow, Institute for Health and AgeingAustralian Catholic University, Melbourne, VIC
Director, Oregon Osteoporosis CenterPortland, Oregon, USA
Santiago de Chile
May 10, 2019
Efficacy and Safety of Long-term
Denosumab Therapy: FREEDOM Study
XXVII Congreso Chileno de Osteología
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Conflict of Interest
I am disclosing financial relationships as follows:
Global Advisory Boards: Amgen, Radius Health
Honorarium for speaking: Amgen, Radius Health
Michael McClung, MD 2019
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Osteoporosis
Definition:
A disorder due to bone loss that damages
skeletal architecture, weakens the skeleton
and predisposes a patient to fracture
• Several osteoporosis drugs effectively and quickly reduce fracture risk in patients with
osteoporosis
• Osteoporosis is a chronic disease requiring prolonged treatment
• It is important to develop a strategy for long-term management
Images Courtesy of
Drs. David Dempster & Roger Zambezi
Black DM and Rosen CJ. N Engl J Med 2016; 374:254-62
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• To review
• the efficacy and safety of long-term denosumab therapy
• effects of discontinuing denosumab
• To discuss the role of denosumab in the long-term management of patients with osteoporosis
Objectives
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RANK Ligand Is an Essential Mediator of
Osteoclast Formation, Function, and Survival
Osteoblasts
Activated
Osteoclast
CFU-GM Prefusion
Osteoclast
Multinucleated
Osteoclast
Hormones
Growth Factors
Cytokines
Bone Formation
Bone ResorptionAdapted from: Boyle WJ, et al. Nature. 2003;423:337-342.© 2009 Amgen. All rights reserved. Do not copy or distribute.
RANKL
RANK
OPG
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RANKL
RANK
OPG
Denosumab
Bone Formation Bone Resorption
Inhibited
Osteoclast Formation, Function,
and Survival Inhibited
Decreases Osteoclast Number
and Activity
CFU-GM Prefusion
Osteoclast
Osteoblasts
Hormones
Growth Factors
Cytokines
© 2009 Amgen. All rights reserved. Do not copy or distribute.
Denosumab Binds RANK Ligand
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Denosumab
• A fully human IgG2 monoclonal antibody that bonds RANK
ligand with very high specificity
• Administered subcutaneously Q 6 months
Serum denosumab
Serum CTX
Seru
m c
on
cen
trati
on
of
den
osu
mab
ng
/ml
0
2
4
6
8
0 2 4 6 8 10 12
Time (Month)
-80
-60
-40
-20
0
20
Seu
m C
TX
Ch
an
ge (%
) Fro
m B
aselin
e
Mean
S
E
1st dose 2nd dose
McClung MR, et al. N Engl J Med 2006;354:821-31
Vasikarin SD. Crit Rev Clin Lab Sci 2008;45:221-58
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International, placebo-controlled study
Study population
▪ 7,808 postmenopausal women
▪ T-score < –2.5 at the lumbar
spine or total hip and
not < –4.0 at either site
▪ Exclusion any severe or > 2
moderate vertebral fractures
Primary endpoint
▪ New vertebral fracture over
36 months
Secondary endpoints
▪ Time to nonvertebral fracture
▪ Time to hip fracture
Study Month
241261Day 1Visit
SCREENING
36
END
OF
STUDY
RANDOMIZATION
Denosumab
60 mg SC Q6M
n = 3,902
Placebo
n = 3,906
Calcium and vitamin D
Denosumab FREEDOM Trial:Pivotal Phase III Study
SC = subcutaneously; Q6M = once every 6 months
Cummings SR, McClung MR et al. N Engl J Med 2009;361:756-65
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Denosumab FREEDOM StudyIncidence of Vertebral and Hip Fracture
RRR 61%
P < 0.0001
2.2% 0.9%
0
1
2
3
4
5
6
7
8
9
0-12 Months
Inc
ide
nc
e a
t M
on
th 3
6 (
%)
Placebo
Denosumab
0-24 Months 0-36 Months
5.0% 1.4% 7.2% 2.3%
RRR 71%
P < 0.0001
RRR 68%
P < 0.0001
Cummings SR, McClung MR et al. N Engl J Med 2009;361:756-65
Hip FractureVertebral Fracture
Cu
mu
lati
ve
in
cid
en
ce
-%
Month
Effect of fracture protection seen with in first 12 months of therapy
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• Increased trabecular bone score in lumber spine
• Increased volumetric BMD of cortical and trabecular bone
• Increased cortical thickness, especially at sites of loading in the hip
• Decreased cortical porosity
• Increased estimated bone strength in hip and spine by finite element analysis (FEA) of CT scans
• No abnormalities observed on bone biopsies
Denosumab: Improved Bone QualityPhase 3: The FREEDOM Trial
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• Overall, no increased risk of adverse events or serious adverse events in clinical trials (1)
• In FREEDOM: increased incidence of
• skin rash (3.0% vs 1.7%)
• cellulitis (12/3808 vs 1/3805)
• Numerically more neoplasms and “infections”-- no signal of opportunistic infections
• No renal or cardiovascular effects noted
• Deaths: 90 in placebo group; 70 with DMab (p=0.06)
• No immunological resistance
• No impact on fracture healing (2)
Denosumab: Safety and TolerabilityPhase 3: The FREEDOM Trial
1. Cummings SR, McClung MR et al. N Engl J Med 2009;361:756-65
2. Adami S, et al. J Bone Joint Surg Am 2012;94:2113-9
Usually mild and resolved with
ongoing treatment
Unrelated to site or time of injection
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Key Inclusion Criteria for the Extension:
• Completed the FREEDOM study (completed the 3-year visit, did not
discontinue investigational product, and did not miss > 1 dose)
• Not receiving any other osteoporosis medications
FREEDOM Extension
1 2 3Year 0 5 6 74 8 9 10
1 2 30 6 74Year
R
A
N
D
O
M
I
Z
A
T
I
O
N
Denosumab 60 mg
SC Q6M
(N = 3902)
Placebo
SC Q6M
(N = 3906)
Long-term
Denosumab
Treatment
Cross-over
Denosumab
Treatment
Denosumab 60 mg
SC Q6M
(N = 2343)
Denosumab 60 mg
SC Q6M
(N = 2207)
Calcium and Vitamin D
FREEDOM Extension Study Design
5
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FREEDOM Extension
-2
0
2
4
6
8
10
12
14
16
18
20
22
24
b
21.7%c
b
b
a
a
a
a
b
b
b
16.5%c
Lumbar SpineP
erc
en
tag
e C
ha
ng
e F
rom
Ba
se
lin
e
b
b
aa
Long-term Denosumab TherapyLumbar Spine and Total Hip BMD
b
b
Study Year
1 2 3 4 50 6 7 8 9 10
Placebo Cross-over DenosumabLong-term Denosumab
a
FREEDOM Extension
-2
-1
0
1
2
3
4
5
6
7
8
9
10
b
bb
b
b
b
b
b
a
a
a
a
a
a
a
a
9.2%c
7.4%c
b
b
Pe
rce
nta
ge
Ch
an
ge
Fro
m B
ase
lin
e
Study Year
1 2 3 4 50 6 7 8 9 10
Total Hip
a
Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23
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Long-term Denosumab TherapyVertebral and Non-vertebral Fractures
Persistent or improved reduction in fracture risk
Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23
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FREEDOM Years 1–3 Extension Years 1–7
Rates per 100 subject-yearsPlacebo
(N = 3883)
Cross-over Denosumab (N = 2206)
Long-term Denosumab(N = 2343)
All AEs 156.1 96.8 97.0
Infections 30.7 20.7 19.9
Malignancies 1.6 2.0 2.0
Eczema 0.6 0.9 0.9
Hypocalcemia < 0.1 < 0.1 < 0.1
Pancreatitis < 0.1 < 0.1 < 0.1
Serious AEs 10.4 10.1 10.3
Infections 1.3 1.4 1.5
Cellulitis or erysipelas < 0.1 < 0.1 < 0.1
Fatal AEs 0.8 0.8 0.8
Osteonecrosis of the jaw 0 < 0.1 < 0.1
Atypical femoral fracture 0 < 0.1 < 0.1
N = number of subjects who received ≥ 1 dose of investigational product. AE = adverse event.
Cumulative osteonecrosis of the jaw cases: 6 cross-over, 7 long-term. Cumulative atypical femoral fracture cases: 1 cross-over, 1 long-term.
Long-term Denosumab TherapySafety (Exposure-adjusted Subject Incidence of Adverse Events)
Bone HG et al. Lancet Diabetes Endocrinol 2017;5:513-23
Watts NB, et al. J Bone Miner Res 2017;32:1481-5
No increase in incidence of adverse events with long-term therapy
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• In FREEDOM and its Extension, all oral adverse events were adjudicated by a committee of experts to identify cases consistent with ONJ
• 13 cases in FREEDOM Extension study (5.2 per 10,000 subject-years)
• 45% of responders to questionnaire during Extension reported at least one invasive oral procedures or event (OPE)
• ONJ incidence was higher in those reporting an OPE (0.68%) than not (0.05%)
• 212 patients had dental implants – no ONJ
• 6 of the 13 patients with ONJ had ill-fitting dentures
• Most cases resolved with conservative therapy or surgery while denosumab therapy was continued
• No literature found exploring use of denosumab after ONJ has healed
Denosumab and Osteonecrosis of the Jaw
Bone HG et al. Lancet Diabetes Endocrinol 2017;5:513-23
Watts NB et al. J Clin Endocrinol Metab 2019 Feb 13. doi: 10.1210/jc.2018-01965. [Epub ahead of print]
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• RANK ligand is expressed in some lymphocytes
• What roles RANKL play in the immune system is unknown
• Adults with genetic syndromes of RANKL deficiency do not have immune dysfunction
• No laboratory signal of immune dysfunction on Phase 2 or 3 denosumab studies
• In FREEDOM study, numerically more serious adverse events related to infection in the denosumab arm (4.12%) vs the placebo group (3.45%)
• No imbalance in rates of opportunistic infections
Denosumab and Immune Dysfunction
Watts NB et al. Osteoporos Int 2012;23:327-37
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FREEDOM Extension StudySafety
• In neither the long-term treatment group or the cross-over group
was there an increase in rate of infection
Watts NB et al. J Bone Miner Res 2017;32:1481-5
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• No evidence of increased risk of infection in the studies with denosumab treatment (120 mg/month) in patients with skeletal
metastases (1, 2)
• Denosumab was well tolerated in 63 patients with solid organ transplant (3)
• No studies about the use of denosumab in patients with HIV
Denosumab and Immune Dysfunction
1. Xgeva prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf.
Accessed April 2, 2019
2. 2. Sun L et al. Am J Clin Oncol 2013;36:399-403
3. Brunova J et al. Front Endocrinol (Lausanne). 2018;17;9:162. doi: 10.3389/fendo.2018.00162. eCollection 2018
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf
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• The rate of hospitalized infection among patients (average age 72 years) with rheumatoid arthritis (RA) receiving denosumab for
osteoporosis (n=1340) concurrently with biologic agents for RA was
not increased compared to matched patients those receiving
zoledronic acid (n=4460).
• After adjustment, the HR of hospitalized infection for denosumab users was noninferior to that for ZA users (HR 0.89 [95% CI 0.69-1.15])
Denosumab and Immune Dysfunction
Curtis JR et al. Arthritis Rheumatol 2015;67:1456-64
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• Summary: No effect of denosumab on immune function has been demonstrated – and no adverse effect has been observed with
denosumab therapy in patients with immune dysfunction
• But caution should be exercised when considering denosumab use in patients with known immune-related diseases
Denosumab and Immune Dysfunction
McClung MR. Personal opinion. 2019
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Long-term Denosumab TherapyTotal Hip BMD
Perc
en
tag
e C
han
ge F
rom
Baselin
e
Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23
-2
-1
0
1
2
3
4
5
6
7
8
9
10
Study Year
1 2 3 4 50 6 7 8 9 10
Filling remodeling space
Secondary mineralization
Gradual decrease in cortical porosity
Persistent periosteal apposition
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Effects of Denosumab on Remodeling and
Modeling in Cynomolgus Monkeys
OVX + Veh OVX + DMab
Remodeling was decreased but modeling-based formation
on perisoteum was maintained at the rib cortical bone in
cynomolgus monkeys treated with denosumab
Drugs may have
different effects on
different skeletal
surfaces
intracortical bone formation
(remodeling)
periosteal bone formation
(modeling)
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Effects of Long-term Therapy on Total Hip BMD
1. Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23
2. Bone HG et al. New Engl J Med 2004; 350:1189-1199
3. Black DM et al. J Bone Miner Res 2015;30:934-44
Long-term Denosumab
FREEDOM Extension
-2
-1
0
1
2
3
4
5
6
7
8
9
10 9.2%P
erc
en
tag
e C
ha
ng
e F
rom
Baseli
ne
Study Year
1 2 3 4 50 6 7 8 9 10
4.6%
Zoledronic acid 5 mg/y3
Denosumab1
Progressive increase with
denosumab vs plateau
after 5 years with
bisphosphonates
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BMD: Denosumab vs AlendronateTotal Hip BMD; Phase 2 Study
McClung MR, et al. N Engl J Med 2006;354:821-31
Placebo, N=46
Denosumab 60 mg Q6M, N=46
Alendronate 70 mg/wk, N=46
Time (Month)
-2
-1
0
1
2
3
0 2 4 6 8 10 12
% C
han
ge f
rom
Baselin
em
ea
n
SE
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Switching From Bisphosphonates to Denosumab
Data are least-squares means and 95% confidence intervals. *p < 0.0001 denosumab vs BP.
(1) Roux C et al. Bone. 2014;58:48-54. (2) Recknor C et al. Obstet Gynec 2013;121:1291-9. (3) Kendler DL et
al. J Bone Miner Res. 2010;25:72-81. (4) Miller PD et al. J Clin Endo Metab. 2016;101:3163-70.
IBN
ALN
ZOL
RIS
1.6%*1.4%*
0.9%* 1.3%*
To
tal
Hip
Perc
en
t C
ha
ng
e F
rom
Baseli
ne
0.5% 0.9% 1.1% 0.6%2.0% 2.2% 1.9% 1.9%0.0%
1.0%
2.0%
3.0%
4.0%
vs RIS (1) vs IBN (2) vs ALN (3) vs ZOL (4)
Patients who had previously been treated with bisphosphonates
randomly assigned to a bisphosphonate or denosumab.
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Denosumab Following Teriparatide
After 2 years of teriparatide, therapy was switched to denosumab
for 2 additional years
Progressive increases in BMD at spine and hip
Leder BZ et al. Lancet. 2015. pii: S0140-6736_61120-5
Shown in BLUE
Teriparatide Denosumab
Teriparatide Denosumab
Total HIP BMDLumbar Spine BMD
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FNIH Meta-regressionChange in Total Hip BMD vs Reduction in Hip Fracture
MORE (RAL)
FIT II(ALN)
FIT I(ALN)
HORIZON(ZOL)
HIP(RIS)
FREEDOM (DMAB)
WHI
Clodronate
*Bubble size ~ to n fractures in study
R2=0.52
Bouxsein M et al. J Bone Miner Res 2019 Jan23. doi: 10.1002/jbmr.3641
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Relationship Between On-Treatment Total Hip
BMD T-score and Non-vertebral Fracture Risk
Inc
ide
nc
e o
f n
on
-ve
rteb
ral
fra
ctu
re a
t 1
ye
ar
(%)
-3.0 -2.5 -2.0 -1.5 -1.0 -0.5
1.0
2.0
3.0
4.0
5.0
6.0
Total Hip T-score
Treating to a BMD target
may now be feasible
Ferrari S et al. J Bone Miner Res 2019 Mar 28
Current NV fracture risk
was strongly correlated
with on target hip BMD
Similar findings have been
reported with romosozumab and
alendronate (Cosman F. ASBMR
2018)
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Treat to Target: An Evolving Concept
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Long-term Denosumab TherapySummary
Over 10 years of denosumab therapy
• BMD at spine and hip increases progressively
• Improved mechanical strength in cortical and trabecular bone
• Fracture protection occurs early and persists
• No increasing incidence of adverse events
• The level of total hip BMD achieved on denosumab therapy correlates with current fracture risk
• Switching from bisphosphonates to denosumab produces progressive gains in BMD
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Denosumab
Fracture protection
• begins within months of starting therapy
• persists with long-term therapy
• wanes when treatment is stopped
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Discontinuing Denosumab: Phase 2 Study in Women With Low BMD
Adapted from Miller PD, McClung M et al. Bone 2008;43:222-29
PlaceboDmab 210 mg Q6MOpen-label alendronate
Discontinued
TreatmentLumbar Spine BMD
Perc
en
t C
ha
ng
e
(LS
Mean
±S
E)
Months
−4
−2
0
2
4
6
8
10
12
14
0 6 12 18 24 36 48
Serum CTx
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
0 6 12 18 24 30 36 42 48
Med
ian
ng
/mL
(Q1,
Q3)
Months
Discontinued
Treatment
Rapid loss of BMD to baseline due to
rebound in bone remodeling
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*P < 0.001 at month 36 and = 0.05 at month 48 vs placebo.†P = 0.008 at month 36 vs placebo.
Adapted from Miller PD, et al. Bone. 2008;43:222-229.
Serum CTx BSAP
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
0 6 12 18 24 30 36 42 48
Me
dia
n n
g/m
L (
Q1
, Q
3)
0
5
10
15
20
25
0 6 12 18 24 30 36 42 48
Months Months
Med
ian
mcg
/L (
Q1,
Q3)
*
*
†
Adapted from Miller PD, McClung M et al. Bone. 2008;43:222-229.
Discontinuing Denosumab: BMDPhase 2 Study in Women With Low BMD
Discontinued
Treatment
Discontinued
Treatment
Placebo210 mg Q6MOpen-label alendronate
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–6.7%
–5.1%
N = 10
N = 52
Discontinuing Denosumab After 8 YearsLumbar Spine BMD
Extension StudyParent Study
All on DMAb Treatment
–7
–5
–3
–1
1
3
5
7
9
11
13
15
17
19
21
01 3 6 12 18 24 36 48 60 72 84 961 108
16.8%
8.1%
N = 52
N = 10
McClung M et al. Osteoporos Int 2017;28:1723-32.
Observation
Study Month
Perc
en
tag
e C
ha
ng
e F
rom
Baseli
ne
Placebo Denosumab 60 mg Q6M Off-treatment
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Vertebral Fractures After Discontinuing
Denosumab Therapy
• Several case series of patients have been reported who
experienced multiple and/or severe vertebral fractures within
3-18 months after discontinuing denosumab therapy. (1)
• Raised concern about “rebound” risk of fracture
Anastasilakis AD et al. J Bone Miner Res 2017;32:1291-6
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Fracture Risk after Stopping Denosumab
• Subgroup of 797 subjects (470 placebo, 327 denosumab), who discontinued
study drug in FREEDOM after 2-5 doses.
• During the off-treatment period (median 0.8 years per subject), 42% versus
28% of placebo- and denosumab-treated subjects, respectively, initiated other
therapy.
Brown J.P et al. J Bone Miner Res 2013;28:746-52
Following discontinuation, similar percentages of
subjects in both groups sustained a new fracture
(9% placebo, 7% denosumab)
Fracture rate per 100 subject-years of 13.5 for
placebo and 9.7 for denosumab
Hazard ratio [HR] 0.82; 95% confidence interval
[CI], 0.49–1.38, adjusted for age and total hip BMD
T-score at baseline.
There was no apparent difference in fracture
occurrence pattern between the groups during
the off-treatment period.
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Vertebral Fractures After Discontinuing
Denosumab or Placebo in FREEDOM Study
• Vertebral fracture risk was assessed in patients who discontinued either
placebo or denosumab in the FREEDOM study or who stopped
denosumab in the FREEDOM Extension study and who had a follow-up at
least 7 months after their last dose
• Fracture risk increased upon stopping denosumab but not to levels
greater than seen in those who stopped placebo
Vertebral fractures Multiple vertebral fractures
Cummings SR et al. J Bone Miner Res 2018;33:190-8
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Fracture Risk after Stopping Denosumab
• Protection from vertebral fractures is quickly lost upon stopping denosumab
BUT
• There is no apparent excess or rebound in vertebral fracture risk upon stopping
therapy
McClung M. Personal opinion, 2019
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0
2
4
6
8
0 12 24
Denosumab and Alendronate (DAPS Trial)Cross-over Treatment after 12 Months
Freemantle N et al. Osteoporos Int. 2012;23:317-26
Perc
en
t C
ha
ng
e F
rom
Baseli
ne
Months
Denosumab Alendronate
Switching from denosumab to alendronate, bone loss did not occur
Lumbar spine
Total hip
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Discontinuing DenosumabChange in Prescribing Information
• A new caution has been added to Prolia label in USA and
several other countries
• Multiple vertebral fractures have been
reported following Prolia discontinuation.
• Consider transitioning to another
antiresorptive agent if Prolia is discontinued.
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• There are very few reasons to consider stopping denosumab therapy
• If therapy is stopped after a year or more, consider options to prevent rapid bone loss and fracture risk
• At present, the most appealing strategy would be to treat with a bisphosphonate for 2 years and to then re-evaluate the patient. (1)
1. McClung MR. Cancel the denosumab holiday. Osteoporos Int. 2016;27:1677-82
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OOCCamacho PM et al. Endocr Pract. 2016;22(Suppl 4):1-42
AACE Osteoporosis Treatment Guidelines - 2016
No prior fragility fractures or
moderate fracture risk
Alendronate, denosumab,
risedronate, zoledronic acid
Alternative: raloxifene
Prior fragility fractures or indicators of
higher fracture risk
Denosumab, teriparatide, zoledronic acid
Alternatives: alendronate, risedronate
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Osteoporosis: Long-term Treatment Plan
Raloxifene
Bisphosphonate
Teriparatide
Denosumab
When concerned
about hip fracture
After 18-24 months
After 18-24 months
3-5 years
Low risk
High risk
Consider drug holiday
Re-treat
Denosumab Bisphosphonate1 dose ZOL
2 years ALNIf “target”
is met
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Denosumab TherapyOther Indications
• Treatment to increase bone mass in men with osteoporosis at high
risk of fracture
• Treatment to increase bone mass in men and women at high risk of
fracture who are receiving hormone deprivation therapy for non-
metastatic prostate or breast cancer
• Treatment of glucocorticoid-induced osteoporosis in men and
women at high risk of fracture
PROLIA Prescribing Information, 2019
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Denosumab TherapySummary
• Therapy with denosumab rapidly and effectively reduces the risk of
serious fragility fractures in women with postmenopausal
osteoporosis at risk of fracture
• effectiveness continues through at least 10 years of therapy
• No increase in incidence of adverse events with long-term therapy
• BMD increases progressively over at least 10 years of therapy
• Total hip BMD achieved on therapy correlates with current fracture
risk
• Switching from bisphosphonates or teriparatide to denosumab
results in progressive gain in BMD
• Upon discontinuing therapy, protection from vertebral fracture is
quickly lost
McClung M. Personal opinion, 2019
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Denosumab TherapySummary
• Contraindications
• hypocalcemia
• pregnancy
• hypersenstivity
• as with other potent inhibitors of bone resorption, ensuring
adequate intakes of calcium and vitamin D is important
• Not contraindicated in patients with impaired renal function
• extra care to optimize calcium and vitamin D status is required in
these patients to avoid hypocalcemia
McClung M. Personal opinion, 2019
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Denosumab TherapySummary
• Denosumab is
• an attractive first line agent for treating postmenopausal
osteoporosis
• the best current choice for long-term management of
osteoporosis
McClung M. Personal opinion, 2019
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Thank you
Michael R. McClung, MD, FACP, FASBMR
Oregon Osteoporosis CenterPortland, Oregon, USA
Mt Hood, Oregon
mailto:[email protected]