Denosumab Therapy for Osteoporosis - UCSF CME RANK OPG Denosumab Bone Formation Bone Resorption Inhibited Osteoclast Formation, Function, and Survival Inhibited Decreased Osteoclast

Mary L. Bouxsein, PhDCenter for Advanced Orthopedic Studies

Department of Orthopedic Surgery, Harvard Medical School

MIT-Harvard Health Sciences and Technology Program

Boston, MA

14th Annual Osteoporosis Update Meeting

UCSF, July 2017

Denosumab Therapy for Osteoporosis

Disclosures

Consultant / Advisory board: Agnovos Healthcare, Acceleron Pharma, Radius Health

Research funding: Amgen – for an investigator initiated preclinical study

Outline

• Mechanism of action

• Effect on fracture risk

• Effect on bone turnover and BMD

• Long term treatment: BMD and fractures

• Safety & treatment cessastion

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

Seu

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



Denosumab FREEDOM Trial:Pivotal Phase III Study

FREEDOM Trial: Pivotal Phase III Study

Baseline Characteristics

Cummings SR, McClung M et al. New Engl J Med. 2009;361:756-765

Denosumab 60 mg Q6M

(n=3902)

Placebo

(n=3906)

Mean age - years (SD) 72.3 (5.2) 72.3 (5.2)

Mean body mass index (BMI) (SD) 26.0 (4.1) 26.0 (4.2)

Mean serum 25 OH-vitamin D ng/ml (SD) 23.1 (11.7) 22.9 (11.3)

Mean lumbar spine T-score (SD) -2.82 (0.70) -2.84 (0.69)

Mean total hip T-score (SD) -1.89 (0.81) -1.91 (0.81)

Mean femoral neck T-score (SD) -2.15 (0.72) -2.17 (0.71)

Prevalent vertebral fracture, N (%) 929 (23.8) 915 (23.4)

Completed study, N (%) 3272 (84) 3206 (82)

Received all doses of study medication, N (%) 3093 (80) 2886 (75)

Denosumab treatment reduces fracture risk over 3 years Phase 3: The FREEDOM Trial

40%(3%, 63%)P = 0.0362

20%(5%, 33%)P = 0.010668%

(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†

Inci

den

ce 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


ARR = 1.5% over 3 years

Denosumab Treatment Reduced Vertebral Fracture Risk Phase 3: The FREEDOM Trial

RRR 61%P < 0.0001

2.2% 0.9%0

1

2

3

4

5

6

7

8

9

0-12 Months

Inci

den

ce a

t M

on

th 3

6 (%

)

PlaceboDenosumab

0-24 Months 0-36 Months

5.0% 1.4% 7.2% 2.3%

RRR 71%P < 0.0001

RRR 68%P < 0.0001

ARR 1.4% ARR 3.5% ARR 4.8%


Vertebral fracture risk reduction within 12 months

The Effect of Denosumab on Time to First Hip Fracture Through 36 MonthsPhase 3: The FREEDOM Trial

Placebo, n 3,906 3,799 3,672 3,538 3,430 3,311 3,221

Denosumab, n 3,902 3,796 3,676 3,566 3,477 3,397 3,311

Number of patients at risk

Cu

mu

lati

ve I

nci

den

ce (

%)

Month0 6 12 24

0.018 30 36

0.4

0.8

1.2

0.7%*

1.2%

Placebo

Denosumab 60 mg Q6M

40%†

*P = 0.04


Strong trend in reduction of hip fracture risk within 12 months

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




BMD and bone turnover in Phase III study

Cummings SR, et al NEJM 2009; 361:756

Treatment-naïve

Switching From Bisphosphonates to Denosumab

Data are least-squares means and 95% confidence intervals. *p < 0.0001 denosumab vs BP. 1Recknor C et al. ASBMR Poster FR0388. 2Kendler DL et al. J Bone Miner Res. 2010;25:72-81. 3Brown JP et al. J Bone Miner Res. 2009;24:153-161.

IBNALN

ALN

RIS

1.6%*1.4%*

0.9%*

1.0%*

1 2 3

Pre-treated

Pre-treatedPre-treated

Tota

l H

ip P

erce

nt

Ch

ang

e F

rom

Bas

elin

e

0.5% 0.9% 1.1% 2.6%2.0% 2.2% 1.9% 3.5%0.0%

1.0%

2.0%

3.0%

4.0%

vs RIS vs IBN vs ALN vs ALN

Discontinuing Denosumab: BMDPhase 2 Study in Women With Low BMD

Adapted from Miller PD, McClung M et al. Bone. 2008;43:222-229.

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 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

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



Placebo210 mg Q6MOpen-label alendronate

Outline





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


(N = 2343)


(N = 2207)

Calcium and Vitamin D

FREEDOM Extension Study DesignInternational, multicenter, open-label, single-arm study

5

Cross-over DMAb Treatment Extension Subjects

N = 2207

Long-term DMAb Treatment Extension Subjects

N = 2343

FREEDOM Baseline

Extension Baseline

FREEDOM Baseline

ExtensionBaseline

Age (years) 71.8 74.8 71.9 74.9

Age groups (%)

≥ 65 years 93.7% 97.4% 94.3% 97.9%

≥ 75 years 28.3% 52.2% 28.3% 53.7%

Prevalent vertebral fractures (%)

22.0% 25.0% 23.9% 24.5%

LS BMD T-score –2.84 –2.81 –2.83 –2.14

TH BMD T-score –1.85 –1.93 –1.85 –1.50

sCTX* (ng/mL) 0.555 0.568 0.505 0.182

P1NP* (µg/L) 55.81 48.80 46.17 17.25

N = number of subjects enrolled in the Extension. Data are means unless otherwise noted.*Median values; from the BTM substudy.

Baseline Characteristics

Bone HG et al. Lancet Diabetes Endocrinol. 2017;27:1677-82

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 Treatment 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


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).

Effects of Denosumab Treatment on BMD Through 10 Years


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


Effects of Denosumab Therapy on Total Hip BMD Through 10 Years

FREEDOM Extension

-2

-1

0

1

2

3

4

5

6

7

8

9

10 9.2%

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 BMD

Long-term Denosumab


Effects of Therapy on Total Hip BMD Through 10 Years

Long-term DenosumabFREEDOM Extension

-2

-1

0

1

2

3

4

5

6

7

8

9

10 9.2%

6.8%

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 BMD

4.6%

1. Bone HG et al. New Engl J Med. 2004; 350:1189-11992. Black DM et al. New Engl J Med

Zoledronic acid 5 mg/y2

Alendronate 10 mg/d1

Long-term Denosumab

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

Effects of Denosumab Treatment on Lumbar Spine BMD and New Vertebral Fractures Through 10 Years

b

b

FREEDOM Extension

FREEDOM Extension

Years of Denosumab Treatment1/2d 4/5d3

1 2 3 4/5d 7/8d6 9/10d

6/7d

Years of Denosumab Treatment

Yea

rly

Inci

den

ce o

fN

ew V

erte

bra

l Fra

ctu

res

(%)

Yea

rly

Inci

den

ce o

fN

ew V

erte

bra

l Fra

ctu

res

(%)

Study Year

1 2 3 4 50 6 7 8 9 10


a


FREEDOM Extension

-2

-1

0

1

2

3

4

5

6

7

8

9

10

Effects of Denosumab Treatment on Total Hip BMD and Nonvertebral 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

den

ce o

fN

on

vert

ebra

l Fra

ctu

res

(%)

Yea

rly

Inci

den

ce o

fN

on

vert

ebra

l Fra

ctu

res

(%)

1 532 4

1 2 3 4 865 7 9 10

6 7




a


• A simulation method was used to estimate expected fracture rates in a hypothetical cohort of long-term placebo controls (“virtual twins”) since all subjects in the Extension study received denosumab treatment.1

– Models were developed using actual FREEDOM data on BMD, fracture history, BMI, age, and smoking status for subjects who received placebo during the 3 years of FREEDOM and enrolled in the Extension.

– Models then predicted fracture outcomes for the denosumab-treated women who entered the Extension had they received placebo for 3 years in FREEDOM and 7 years in the Extension (“virtual twins”).

Virtual Twin Placebo

1. Bone HG et al., J Clin Endocrinol Metab 2013;98:4483-4492.

Cumulative Subject Incidence of New Vertebral and Nonvertebral Fractures: Long-term Denosumab Group

Placebo Virtual Twin PlaceboLong-term Denosumab

n 264 86 149N 3691 3702 2116

RR (95% CI) =0.62 (0.47–0.80)

New VertebralRR (95% CI) =

0.54 (0.43–0.68)

Nonvertebral

n 293 238 172N 3606 3902 2343


Yearly Subject Incidence of Nonvertebral Fractures: Long-term Denosumab Group

Long-term DenosumabVirtual Twin Placebo

RR (95% CI) =0.58 (0.35–0.89)

RR (95% CI) =0.44 (0.25–0.71)

RR (95% CI) =0.62 (0.36–1.00)

RR (95% CI) =0.50 (0.26–0.84)

RR (95% CI) =0.27 (0.12–0.52)

Su

bje

ct I

nci

den

ce o

fN

on

vert

ebra

l F

ract

ure

(%

)

n 34 27 34 28 14 16 27N 2343 2244 2067 1867 1743 1585 1451

RR (95% CI) =0.31 (0.13–0.61)

RR (95% CI) =0.55 (0.22–1.17)

1.51.2

1.8 1.6

0.81.1

1.9

ARR 1.1% 1.6% 1.0% 1.5% 2.5% 2.4% 2.0%

ARR in FREEDOM was 1.5% over 3 years


Relationship Between Total Hip T-score and Non-vertebral Fracture 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)

Prior vertebral fracture (N = 1416)

No prior vertebral fracture (N = 2196)

Total Hip T-score

Outline





• 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.

FREEDOM Years 1–3 Extension Years 1–7

Placebo (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. Treatment groups are based on the original randomized treatments received in FREEDOM. AEs coded using MedDRA v13.0. Cumulative osteonecrosis of the jaw cases: 6 cross-over, 7 long-term. Cumulative atypical femoral fracture cases: 1 cross-over, 1 long-term.

Exposure-adjusted Subject Incidence of Adverse Events (Rates per 100 Subject-years)


• Very few cases of ONJ (13) and AFF (2) were reported in theFREEDOM Extension trial to 10 years (>50,000 patient-years exposure)

• Rare cases of AFF in patients receiving denosumab in clinicalpractice have been described: most had received previousbisphosphonate therapy

• There are too few cases of ONJ and AFF to know whether theseevents are related to denosumab therapy or the duration oftherapy

Osteonecrosis of the Jaw and Atypical Fractures with Denosumab

–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

79

11

13

1517

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

Per

cen

tag

e C

han

ge

Fro

m B

asel

ine

Placebo Denosumab 210 mg Q6M Off-treatment

Vertebral Fractures After Discontinuing Denosumab Therapy

• At least 24 patients have been reported who experienced vertebral fractures within 3-18 months after discontinuing denosumab therapy. (1)

• Many or most have had multiple and/or severe fractures

• Raised concern about “rebound” risk of fracture

• Similar to rapid loss of fracture protection when estrogen therapy is discontinued (2,3)

1. Anastasilakis AD et al. J Bone Miner Res. 2017 Feb 272. Heiss G et al. JAMA 299:1036–45

3. McClung MR. Osteoporos Int. 2016;27:1677-82

Case Reports of Clinical Vertebral Fractures Following Denosumab Discontinuation

• Anecdotal Case of Multiple Fractures following discontinuation of denosumab• 51 y.o. PMO 5 yrs. , T score LS -2.5, no vertebral frx

by xray

• 2/2012 Rx Denosumab 60mg q 6 for 3 years., last Rx 8/2014

• 2/2015 T score LS -1.8

• 4/2015 Severe back pain bending to pull drawer of refigerator, 8 months after last dmab Rx

• MRI found 3 incident Vertebral Frxns T12, L1, and L3

Anastasilakis AD, et al OI, (2016): 1929-1930

MRI of the Spine with Incident vertebral fractures and Change in Bone Turnover Markers

Anastasilakis et al, OI 2016, 27:1929-1930

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

Brown JP et al. ASBMR Abstract #1100, 2016

• Bone loss and rise in serum CTX is attenuated in patients who stop denosumab but who took bisphosphonates before denosumab therapy.

• Bone loss after stopping denosumab is attenuated in patients who then receive anti-remodeling agents

Discontinuing DenosumabOther Information

Ferrari S et al. ECTS 2016


Recommendations• If treatment with denosumab is discontinued, there may be

an increase in bone turnover, bone mass loss and increased risk of vertebral fracture. Therefore

• Consider switching to another anti‐resorptive agent like a bisphosponate

• Studies with less potent antiresorptive agents may work ( SERM, calcitonin, estrogen) however need to be tested.

• Discuss with the potent patients the risk of increased fracture with discontinuation of treatment

Conclusions

• Mechanism of action• Rapid and potent effect

• Effect on fracture risk• Reduction in fracture risk, greatest effect at the spine

• Effect on bone turnover and density• Greater than oral alendronate

• Long-term effect on bone density• 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- consider treatment with another anti-resorptive agent for a few years.

• Denosumab treatment for up to 10 years was associated with:

– persistent reduction of bone turnover

– continued increases in BMD without therapeutic plateau

– low incidence of new vertebral and nonvertebral (including hip) fracture

– no evidence of resistance to therapy

– no new adverse events with long-term therapy

Summary

• Long-term therapy to treat patients with osteoporosis is necessary and important for many patients

• Discontinuing therapy results in rapid loss of gains

• There is rarely a need to discontinue denosumab therapy

– Certainly no need for a “drug holiday”

• Denosumab is effective in elderly patients

• The benefit/risk profile for denosumab in an aging population of postmenopausal women remains favorable

Conclusions

risk of Incident Fracture after Discontinuation

• Discontinuation of Dmab was not associated with an increase in incident osteoporotic fractures in Phase 2 and 3 studies. However, they were short term and underpowered for incident fractures

• Studies on increased hip fracture risk have been reported after estrogen treatment in an observational study ( Yates) Odds Ratio: 1.65

• No reports of increased incident fracture risk after discontinuation of Bisphosphonates

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

Per

cen

t C

han

ge

Fro

m B

asel

ine

Months

Denosumab Alendronate

Switching from denosumab to alendronate, bone loss did not occur

Lumbar spine

Total hip

Discontinuing DenosumabChange in Prescribing Information

• A new caution has been added to Prolia label:

• Multiple vertebral fractures have been reported following Prolia discontinuation.

• Consider transitioning to another antiresorptive agent if Prolia is discontinued.

• There are very few reasons to consider stopping denosumab therapy• intolerance or side effect• reaching a treatment “target”

• 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 1-2 years, re-evaluating the patient at regular intervals

Long-term Denosumab TherapySummary

McClung MR. Cancel the denosumab holiday. Osteoporos Int. 2016;27:1677-82

Camacho PM et al. Endocr Pract. 2016;22(Suppl 4):1-42

AACE Osteoporosis Treatment Guidelines - 2016

Effects of Therapy on Total Hip BMD Through 10 Years

Long-term Denosumab

1. Bone HG et al. ASBMR; Seattle, WA; October 12, 2015; #LB-1157

FREEDOM Extension

-2

0

2

4

6

8

109.2%

Per

cen

tag

e C

han

ge

Fro

m B

asel

ine

Study Year

1 2 3 4 50 6 7 8 9 10

4.6%

2. Black DM et al. New Engl J Med 2012;27:243-54

Zoledronic acid 5 mg/y2

Denosumab 60 mg Q6M1

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.

Vertebral Fractures After Discontinuing Denosumab or Placebo in FREEDOM Study

Brown JP et al. ASBMR Abstract #1100, 2016

• 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

• Prevalent vertebral fracture was main risk factor for vertebral fracture after stopping therapy

Single fracture

Multiple fractures

Pe

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ith v

ert

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ral f

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ure

s

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, 2017

• Bone loss and rise in serum CTX is attenuated in patients who stop denosumab but who took bisphosphonates before denosumab therapy.

• Bone loss after stopping denosumab is attenuated in patients who then receive anti-remodeling agents

Discontinuing DenosumabOther Information

Ferrari S et al. ECTS 2016


Long-term Denosumab TherapySafety


Long-term Denosumab TherapyBone Mineral Density

Persistent inhibition of turnover; no evidence of loss of effect with therapy to 10 years


Long-term Denosumab TherapyBone Mineral Density



Long-term Denosumab TherapyBone Turnover Markers



Long-term Denosumab TherapyVertebral Fractures

Persistent reduction in vertebral fracture risk


Long-term Denosumab TherapyNon-vertebral Fractures


Persistent reduction in non-vertebral fracture risk

Long-term Denosumab TherapyHip Fractures


Persistent reduction in hip fracture risk

Long-term Denosumab TherapyFractures: Virtual Twin Placebo Comparison

Virtual twin matched for age, BMD and baseline fracture history


Effects of Denosumab on Total HipIntegral and Cortical BMD

Data are LS means and 95% CIs.†P < 0.02 for denosumab compared with baseline and placebo.

–4

–2

0

2

4

6

8

10†

†

††

Placebo Denosumab

–4

–2

0

2

4

6

8

10

MIAF Total Hip Integral BMD MIAF Total Hip Cortical BMD

≥ 75 years< 75 years ≥ 75 years< 75 years

Per

cen

tag

e C

han

ge

Fro

mB

asel

ine

at 3

6 M

on

ths

n = 14n = 26 n = 12 n = 10 n = 14n = 26 n = 12 n = 10

MIAF

Effects of Denosumab on Total Hip Cortical Thickness and Cortical Mass

Data are LS means and 95% CIs. †P < 0.02 for denosumab compared with baseline and placebo. ‡One subject had a non-evaluable scan.

† †

–4

–2

0

2

4

6

8

10

††

–4

–2

0

2

4

6

8

10

Total Hip Cortical Thickness Total Hip Cortical Mass

Placebo Denosumab

Per

cen

tag

e C

han

ge

Fro

mB

asel

ine

at 3

6 M

on

ths


n=14 n=26 n=11‡ n=10 n=14 n=26 n=11‡ n=10

Bone Mapping

Data are LS means and 95% CIs. *P < 0.02 for denosumab compared with baseline. †P < 0.02 for denosumab compared with placebo.

Effects of Denosumab on Total HipIntegral and Cortical Strength

Placebo Denosumab

* *

**

Per

cen

tag

e C

han

ge

Fro

mB

asel

ine

at 3

6 M

on

ths

–12–8

–40

4

8

12

16

–16

FEA Total Hip Integral Strength FEA Total Hip Cortical Strength

–12–8

–40

4

8

12

16

–16

† †

†


n=14 n=26 n=12 n=10 n=14 n=26 n=12 n=10

FEA

Porosity Throughout the Hip Cortex% Change From Baseline at 36 Months

1.7%1.2%

-0.3%

0.6%

-3.6%

-6.7%-5.9%

-1.1%

-10.0%

-8.0%

-6.0%

-4.0%

-2.0%

0.0%

2.0%

4.0%

6.0%

Cortex Compact Cortex Outer TransitionalZone

Inner TransitionalZone

Per

cen

tag

e C

han

ge

Fro

m B

asel

ine

(LS

Mea

ns

and

95%

CIs

)

Placebo (n=22) DMAb (n=28)

p=0.0001 p=0.0009 p=0.0008 p=0.0002

n=number of subjects with available data at baseline and 36 months.

Documents

Denosumab Therapy for Osteoporosis - UCSF CME RANK OPG Denosumab Bone Formation Bone Resorption Inhibited Osteoclast Formation, Function, and Survival Inhibited Decreased Osteoclast