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Mary L. Bouxsein, PhDCenter for Advanced Orthopedic Studies
Department of Orthopedic Surgery, Harvard Medical School
MIT-Harvard Health Sciences and Technology Program
Boston, MA
16th Annual Osteoporosis Update Meeting
UCSF, July 2019
Denosumab Therapy for Osteoporosis
Disclosures
Consultant / Advisory board:
Agnovos Healthcare, Keros Therapeutics
Research funding:
Radius Health, Amgen
Outline
• Mechanism of action
• Effect on fracture risk
• Effect on bone turnover and BMD
• Long term treatment: BMD and fractures
• Safety & treatment cessation
Excess RANK Ligand Increases Bone Resorption
Bone Formation
Bone Resorption
Activated Osteoclast
CFU-GM PrefusionOsteoclast
MultinucleatedOsteoclast
Osteoblasts
Decreased Estrogen Leads to Increased RANK Ligand
Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.© 2009 Amgen. All rights reserved. Do not copy or distribute.
RANKL
RANK
OPG
RANKL
RANK
OPG
Denosumab
Bone Formation Bone Resorption Inhibited
Osteoclast Formation, Function, and Survival Inhibited
Decreased Osteoclast Number and Function
CFU-GM PrefusionOsteoclast
Osteoblasts
HormonesGrowth FactorsCytokines
© 2009 Amgen. All rights reserved. Do not copy or distribute.
Denosumab Binds RANK Ligand PK and PD properties of Denosumab 60 mg Q 6
Serum denosumab
Serum CTX
Ser
um
co
nce
ntr
atio
n o
f d
eno
sum
ab n
g/m
l
McClung MR, et al. N Engl J Med. 2006;354:821-31 Vasikarin SD. Crit Rev Clin Lab Sci .2008;45:221-258
0
2
4
6
8
0 2 4 6 8 10 12Time (Month)
-80
-60
-40
-20
0
20
Seru
m C
TX
C
han
ge (%
) Fro
m B
aseline
Mean
S
E
Denosumab: fully human IgG2 antibody with very high affinity and specificity for RANK ligand
Denosumab Q 6 Month and Alendronate:
Serum C-telopeptide (Phase II Study)
-100
-80
-60
-40
-20
0
20
0 2 4 6 8 10 12Time (Month)
Placebo, N = 46
60 mg, N = 47
Alendronate 70 mg/wk, N = 45
Ch
ang
e (%
) F
rom
Bas
elin
eM
ean
S
E
McClung MR, et al. N Engl J Med. 2006;354:821-31
Denosumab is a more potent but reversible inhibitor of bone
resorption than is alendronate
Outline
• Mechanism of action
• Effect on fracture risk
Denosumab FREEDOM Trial:Pivotal Phase III Study
Denosumab treatment reduces fracture risk over 3 years Phase 3: The FREEDOM Trial
40%(3%, 63%)P = 0.0362
20%(5%, 33%)P = 0.0106
68%(59%, 74%) P < 0.0001
7.2%
8.0%
1.2%
6.5%
0.7%
2.3%
0
1
2
3
4
5
6
7
8
9
New Vertebral* Nonvertebral† Hip†
Inc
ide
nc
e a
t M
on
th 3
6 (
%)
*Crude incidence†Kaplan-Meier estimate of incidence
(n = 3691)
(n = 3702)
(n = 3906)
(n = 3902)
(n = 3906) (n = 3902)
PlaceboDenosumab
Cummings SR, McClung M et al. New Engl J Med. 2009;361:756-765
ARR = 1.5% over 3 years
Denosumab effective in reducing hip fractures in high risk subgroups Phase 3: The FREEDOM Trial
Incidence represents Kaplan-Meier estimate at month 36
(n = 1406)2.8%
(n = 1384)
47%(8%, 70%)P = 0.0227
1.4%
(n = 1236)2.3%
62%(22%, 82%)P = 0.0065
(n = 1235)0.9%
40%(3%, 63%)P = 0.0362
(n = 3902)0.7%
(n = 3906)1.2%
Inci
den
ce a
t M
on
th 3
6 (%
)
0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
3.0% PlaceboDenosumab
Femoral Neck BMDT-score ≤ -2.5
Age ≥ 75Overall
Boonen S, McClung M et al. J Clin Endocrinol Metab. 2011 Jun;96(6):1727-36.
Outline
• Mechanism of action
• Effect on fracture risk
• Effect on bone turnover and BMD
BMD and bone turnover in Phase III study
Cummings SR, et al NEJM 2009; 361:756
LS BMD TH BMD
sCTX sP1NP
Outline
• Mechanism of action
• Effect on fracture risk
• Effect on bone turnover and BMD
• Long term treatment: BMD and fractures
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
RANDOMIZATION
Denosumab 60 mgSC Q6M
(N = 3902)
PlaceboSC Q6M
(N = 3906)
Long-termDenosumabTreatment
Cross-overDenosumabTreatment
Denosumab 60 mgSC Q6M
(N = 2343)
Denosumab 60 mgSC Q6M
(N = 2207)
Calcium and Vitamin D
FREEDOM Extension Study DesignInternational, multicenter, open-label, single-arm study
5
ExtensionFREEDOM
0
10
20
30
40
50
60
70
80
90
100ExtensionFREEDOM
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Effects of denosumab on bone turnover markers through 10 years
Placebo Cross-over DenosumabLong-term Denosumab
sCTX P1NP
Concentrations of the predose bone turnover markers sCTX and P1NP in subjects included in the BTM substudy. Dashed lines represent the premenopausal reference ranges: 0.20–0.90 ng/mL for sCTX and 17.4–61.6 µg/L for P1NP. Data are medians and interquartile ranges. Time points: baseline, month 1, and years 0.5, 1, 2, 3, 3 (day 10), 3.5, 4, 5, 6, 7, 8, 9, and 10.
ng
/mL
0 1 2 3 4 5 6 7 8 9 10Study Year Study Year
0 1 2 3 4 5 6 7 8 9 10
μg
/L
Bone HG et al. Lancet Diabetes Endocrinol. 2017;27:1677-82
BMD data are LS means and 95% confidence intervals. aP < 0.05 vs FREEDOM baseline. bP < 0.05 vs FREEDOM and Extension baselines. cPercentage change while on denosumab treatment. dAnnualized incidence: (2-year incidence) / 2. Lateral radiographs (lumbar and thoracic) were not obtained at years 4, 7, and 9 (years 1, 4, and 6 of the Extension).
Placebo Cross-over DenosumabLong-term Denosumab
FREEDOM Extension
-2
-1
0
1
2
3
4
5
6
7
8
9
10
b
bb
b
b
b
b
b
a
a
aa
a
a
a
a
9.2%c
7.4%c
b
b
Per
cen
tag
e C
han
ge
Fro
m B
asel
ine
Study Year
1 2 3 4 50 6 7 8 9 10
Total Hip
a
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 Spine
Per
cen
tag
e C
han
ge
Fro
m B
asel
ine
b
b
aa
b
b
Study Year
1 2 3 4 50 6 7 8 9 10
a
Bone HG et al. Lancet Diabetes Endocrinol. 2017;27:1677-82
Effects of denosumab on BMD through 10 yearsEffects of therapy on total hip BMD through 10 years (not head to head studies!)
Long-term Denosumab
FREEDOM Extension
-2-10123456789
109.2%
6.8%Percentage
Change From Baseline
Study Year1 2 3 4 50 6 7 8 9 10
Total Hip BMD
4.6%
1. Bone HG et al. New Engl J Med. 2004; 350:1189-11992. Black DM et al. New Engl J Med, 2007; 2016
ZOL (5 mg/y)2
ALN (10 mg/d)1
Dmab
FREEDOM Extension
-2
-1
0
1
2
3
4
5
6
7
8
9
10
Effects of denosumab on total hip BMD andnonvertebral fractures through 10 years
b
bb
b
b
b
b
b
a
a
aa
a
a
a
a
9.2%c
7.4%c
b
b
Per
cen
tag
e C
han
ge
Fro
m B
asel
ine
Study Year
1 2 3 4 50 6 7 8 9 10
Total HipFREEDOM Extension
FREEDOM Extension
Yea
rly
Inci
de
nce
of
No
nve
rteb
ral F
ract
ure
s (%
)Y
earl
y In
cid
en
ce o
fN
on
vert
ebra
l Fra
ctu
res
(%)
1 532 4
1 2 3 4 865 7 9 10
6 7
Years of Denosumab Treatment
Years of Denosumab Treatment
Placebo Cross-over DenosumabLong-term Denosumab
a
Bone HG et al. Lancet Diabetes Endocrinol. 2017;27:1677-82
Non-vertebral fracture rate significantly lower with longer-term treatmentNon-vertebral fracture rate significantly lower with longer-term treatment
Ferrari et al, JCEM (online May 24, 2019)
Incidence of specific non-vertebral fractures with long-term denosumab treatmentIncidence of specific non-vertebral fractures with long-term denosumab treatment
Ferrari et al, JCEM (online May 24, 2019)
Both Lumbar Spine and Total Hip Only Total Hip
Denosumab treatment over 10 years enables asubstantial proportion of women with osteoporosis toachieve non-osteoporotic T-scores
Denosumab treatment over 10 years enables asubstantial proportion of women with osteoporosis toachieve non-osteoporotic T-scores
Years of Denosumab Treatment
0
20
40
60
80
100
Years of Denosumab Treatment
Pe
rce
nta
ge
of
Su
bje
cts
0
20
40
60
80
100
Ferrari et al JBMR (online March 19, 2019)
Relationship between total hip T-score and non-vertebralfracture risk
Inci
den
ce o
f n
on
-ver
teb
ral
frac
ture
at
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
DMAb (N = 3612)
Age ≥ 75 (N = 1118)
Age < 75 (N = 2494)
Total Hip T-score
Ferrari et al JBMR (online March 19, 2019)
Outline
• Mechanism of action
• Effect on fracture risk
• Effect on bone turnover and BMD
• Long term treatment: BMD and fractures
• Safety & treatment cessation
• Overall, no increased risk of adverse events or serious adverse events in clinical trials
• Increased incidence of • skin rash (3.0% vs 1.7%)• cellulitis (12/3808 vs 1/3805)
• No renal or cardiovascular effects noted
• Deaths: 90 in placebo group; 70 with DMab (p=0.06)
• Less than 1% of patients developed binding antibodies over 2-8 years; none have developed neutralizing antibodies
Denosumab Ph III study: Safety and Tolerability
Cummings SR, McClung MR et al. N Engl J Med. 2009;361:756-65.
• Very few cases of ONJ (13) and AFF (2) were reportedin the FREEDOM Extension trial to 10 years (>50,000patient-years exposure)
• Rare cases of AFF in patients receiving denosumab inclinical practice have been described: most hadreceived previous bisphosphonate therapy
• There are too few cases of ONJ and AFF to knowwhether these events are related to denosumabtherapy or the duration of therapy
• Very few cases of ONJ (13) and AFF (2) were reportedin the FREEDOM Extension trial to 10 years (>50,000patient-years exposure)
• Rare cases of AFF in patients receiving denosumab inclinical practice have been described: most hadreceived previous bisphosphonate therapy
• There are too few cases of ONJ and AFF to knowwhether these events are related to denosumabtherapy or the duration of therapy
Osteonecrosis of the jaw and atypical femur fractures with denosumabOsteonecrosis of the jaw and atypical femur fractures with denosumab
Discontinuing denosumab: BMD changesPhase 2 Study in Women With Low BMD
Discontinuing denosumab: BMD changesPhase 2 Study in Women With Low BMD
Adapted from Miller PD, McClung M et al. Bone. 2008;43:222-229.
Discontinued Treatment
Discontinued Treatment
Lumbar Spine Total Hip
Per
cen
t C
han
ge
(LS
Mea
n ±
SE
)
Months
6
4
2
0
2
4
6
8
Months
0 6 12 18 24 36 484
2
0
2
4
6
8
10
12
14
0 6 12 18 24 36 48
Placebo210 mg dmab Q6MOpen-label alendronate
*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
Med
ian
ng
/mL
(Q
1, Q
3)
0
5
10
15
20
25
0 6 12 18 24 30 36 42 48
Months Months
Me
dia
n m
cg
/L (
Q1
, Q
3)
*
*
†
Adapted from Miller PD, McClung M et al. Bone. 2008;43:222-229.
Discontinuing denosumab: Bone Turnover MarkersPhase 2 Study in Women With Low BMD
Discontinued Treatment
Discontinued Treatment
Placebo210 mg Q6MOpen-label alendronate
–6.7%
–5.1%
N = 10
N = 52
Discontinuing denosumab after 8 yearsLumbar Spine BMD 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
Pe
rce
nta
ge
Ch
an
ge
Fro
m B
as
elin
e
Placebo Denosumab 210 mg Q6M Off-treatment
BMD declines after long-term denosumabcessation
BMD declines after long-term denosumabcessation
• 10 yrs dmab (n=9)
• 3 yrs PBO -> 7 yrs dmab (n=3)
• BMD measured 12 mo later
Popp et al, Osteop Int, 2018
Vertebral fractures after discontinuing denosumab therapyVertebral fractures after discontinuing denosumab therapy
• Many case studies and case series report vertebral fractures within 3-18 months after discontinuing denosumab therapy.1
• Many or most have had multiple and/or severe VFx
• Raised concern about risk of “rebound” VFx
• Similar to rapid loss of fracture protection when estrogen therapy is discontinued2
1) Anastasilakis et al, Osteop Int 2016; Aubry-Rozier et al, Osteop Int 2016; Popp et al, Osteop Int 2016; Lamy et al, JCEM 2017; Anastasilakis et al. JBMR 2017; Polyzos et al, Endocrin 2016; Tripto-Schkolnik et al Calcif Tissue Int 20182) Heiss G et al. JAMA 299:1036–45; McClung MR. Osteoporos Int. 2016;27:1677-82
Vertebral fractures increase after discontinuing denosumab or placebo in FREEDOM studyVertebral fractures increase after discontinuing denosumab or placebo in FREEDOM study
• Fracture risk increased upon stopping denosumab but not to levels greater than seen in those who stopped placebo
Vertebral Fracture Multiple Vertebral Fractures
Cummings et al, JBMR 2018
• Treat forever.
• Stop denosumab, follow with other anti-resorptivetherapy to consolidate BMD gains
-- Which therapy?-- When to give it?
Zoledronate after denosumab cessation Zoledronate after denosumab cessation
• 6 postmenopausal women with 7 years denosumab rx
• ZOL given 6 months after last dmab injection -> BMD measured 18-23 mo later
Reid et al, Osteop Int 2017
Denosumab discontinuation: known & unknown
KNOWN UNKNOWN
Persistence with Rx ~50% at 36 mo1 True incidence of VFx after discontinuation
Fast reversal of BMD gain & rapid increase in BTM’s
Whether treatment duration influences BMD loss, BTM risk and
risk of VFx after cessation
Increased risk of VFx after discontinuation, higher in those with
prevalent VFx
Optimal “consolidation” therapy: what, when & for how long?
10 yrs of treatment associated with continued BMD gain, low BTM, low fracture incidence and acceptable
safety profile
Whether prior rx with bisphosphonates attenuates
response to dmab discontinuation
1) Borek et al, Osteop Int 2019
ConclusionsConclusions• Mechanism of action
• Rapid and potent effect
• Effect on fracture risk• Reduction in fracture risk at all sites
• Effect on bone turnover and density• Greater than oral alendronate
• Long-term effect on bone density and non-vert fractures• Continued effects to 10 years
• Safety• Cellulitis; a few cases of ONJ, AFF; transient hypocalcaemia
(avoided by administration of calcium and vitamin D supplements), and if discontinuing denosumab- strongly consider treatment with another anti-resorptive agent for a few years.
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