Long-term Osteoporosis Therapy: What to Do After 5 Years?

Endocrine Fellows Foundation

2017 Forum on Metabolic Bone Diseases

OOCOOC

Michael R. McClung, MD, FACPOregon Osteoporosis Center

Portland, Oregon, USA

mmcclung.ooc@gmail.com

Denver, CO

September 7, 2017

Disclosures

I am disclosing financial relationships as follows:

Scientific Advisory Boards: Amgen, Radius

Honorarium for speaking: Amgen, Radius

OOCOOC

Michael McClung, MD 2017

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 Several osteoporosis drugs effectively and

OOCOOC

•• Several osteoporosis drugs effectively and Several osteoporosis drugs effectively and quickly reduce fracture risk in patients with quickly reduce fracture risk in patients with osteoporosisosteoporosis

•• Osteoporosis is a chronic disease requiring Osteoporosis is a chronic disease requiring prolonged treatmentprolonged treatment

•• It is important to develop a strategy for longIt is important to develop a strategy for long--term managementterm management

Images Courtesy of Drs. David Dempster & Roger Zebazi

Black DM and Rosen CJ. N Engl J Med 2016; 374:254-62

•• To review To review

•• the benefits and risks of longthe benefits and risks of long--term therapyterm therapy

•• effects of discontinuing bisphosphonate and noneffects of discontinuing bisphosphonate and non--

Objectives

OOCOOC

•• effects of discontinuing bisphosphonate and noneffects of discontinuing bisphosphonate and non--bisphosphonate therapiesbisphosphonate therapies

•• To To consider consider a strategy for longa strategy for long--term management of term management of patients with osteoporosispatients with osteoporosis

Case

• Healthy woman; menopause at age 52

• Age 60: wrist fracture

• Age 67: humerus fracture. BMD T-score -2.6 in lumbar spine and -2.9 at total hip. Begun on alendronate; well tolerated

• Age 72: BMD T-score -1.8 in lumbar spine and -2.6 at total hip.

OOCOOC

• Age 72: BMD T-score -1.8 in lumbar spine and -2.6 at total hip.

• Management choices:

• discontinue alendronate therapy

• continue alendronate therapy

• switch to IV zoledronic acid

• switch to denosumab

• other

Osteoporosis Therapies

OBJECTIVES OBJECTIVES 11

1.1. improve bone strengthimprove bone strength

2.2. reduce risk of fracturereduce risk of fracture

BENEFITS BENEFITS 2

OOCOOC

BENEFITS BENEFITS 2

1.1. effective protection from fractureseffective protection from fractures

vertebral fracture by 60vertebral fracture by 60--70%70%

hip fracture by 40hip fracture by 40--50%50%

nonnon--vertebral fracture by 20vertebral fracture by 20--35%35%

2.2. in general are well toleratedin general are well tolerated

3.3. in clinical trials, have in clinical trials, have a favorable safety profilea favorable safety profile

1. 1. SeemanSeeman E et al. Bone 2004;17 E et al. Bone 2004;17 SupplSuppl 2:23S2:23S--29S29S

2. McClung M et al. 2. McClung M et al. AmerAmer J MedJ Med. 2013;126:13. 2013;126:13--2020

Osteoporosis Therapies

1.1. Fracture protection Fracture protection

•• begins within months of starting therapybegins within months of starting therapy

•• continues with longcontinues with long--term therapyterm therapy

•• wanes when treatment is stoppedwanes when treatment is stopped

OOCOOC

Zoledronic Acid and DenosumabIncidence of Vertebral Fracture

8

9

Inc

ide

nc

e a

t M

on

th 3

6 (

%)

PlaceboDenosumab

RRR 68%P < 0.0001

Vertebral fracture Vertebral fracture protection protection happens within first year of treatmenthappens within first year of treatment

HORIZON Study HORIZON Study 11 FREEDOM Study FREEDOM Study 22

OOCOOC1. Black DM et al. N Engl J Med. 2007;356:1809-22

2. Cummings SR et al. New Engl J Med. 2009;361:756-65

RRR 61%P < 0.0001

2.2% 0.9%0

1

2

3

4

5

6

7

0-12 Months

Inc

ide

nc

e a

t M

on

th 3

6 (

%)

Denosumab

0-24 Months 0-36 Months

5.0% 1.4% 7.2% 2.3%

RRR 71%P < 0.0001

Zoledronic Acid and DenosumabCumulative Incidence of Hip Fracture

HORIZON Study HORIZON Study 11 FREEDOM Study FREEDOM Study 22

Cumulative incidence of hip fractureCumulative incidence of hip fracture

OOCOOC1. Black DM et al. N Engl J Med. 2007;356:1809-22

2. Cummings SR et al. New Engl J Med. 2009;361:756-65

Osteoporosis Therapies

1.1. Fracture protection Fracture protection

•• begins within months of starting therapybegins within months of starting therapy

•• persists with longpersists with long--term therapyterm therapy

•• wanes when treatment is stoppedwanes when treatment is stopped

OOCOOC

Vertebral Fractures with Zoledronic Acid%

Pati

en

ts

10.9%(310/2853)

70%†(62, 76)

ZOL PBO

10

15P = <0.001

Years 4-6

Fracture protection persists with long term therapyYears 1-3

OOCOOC Black DM, et al. N Engl J Med. 2007;356:1809–22

3.0%(14/469)

% P

ati

en

ts

Morphometric Vertebral Fractures

3.3%(92/2822)

Core study1 Extension study

0

5

Years 4-6

Effects of Denosumab Treatment on Vertebral and Non-vertebral Fracture Risk

Vertebral fractureVertebral fracture NonNon--vertebral fracturevertebral fracture

PlaceboPlacebo DenosumabDenosumab

OOCOOC PapapoulosPapapoulos S et al. S et al. OsteoporosOsteoporos IntInt 2015;26:27732015;26:2773––8383

Effects of Therapy on Total Hip BMD Through 10 YearsEffects of Therapy on Total Hip BMD Through 10 Years

LongLong--term Denosumabterm Denosumab

FREEDOMFREEDOM ExtensionExtension

6

7

8

9

10 9.2%9.2%

6.8%6.8%

Perc

en

tag

e C

han

ge F

rom

Baseli

ne

Perc

en

tag

e C

han

ge F

rom

Baseli

ne

Total Hip BMDTotal Hip BMD

Alendronate 10 mg/dAlendronate 10 mg/d22

LongLong--term Denosumabterm Denosumab11

OOCOOC

-2

-1

0

1

2

3

4

5

Perc

en

tag

e C

han

ge F

rom

Baseli

ne

Perc

en

tag

e C

han

ge F

rom

Baseli

ne

Study YearStudy Year

11 22 33 44 5500 66 77 88 99 1010

4.6%4.6%

1. Bone HG et al. ASBMR; Seattle, WA1. Bone HG et al. ASBMR; Seattle, WA; October 12, 2015; #LB; October 12, 2015; #LB--1157 1157 2. Bone HG et al. New 2. Bone HG et al. New EnglEngl J Med. 2004; 350:1189J Med. 2004; 350:1189--11991199

3. Black DM et al. New 3. Black DM et al. New EnglEngl J MedJ Med

Zoledronic acid 5 mg/yZoledronic acid 5 mg/y33

Switching From Bisphosphonates to Denosumab

1.6%*1.4%*

0.9%* 1.3%*

To

tal

Hip

Pe

rce

nt

Ch

an

ge

Fro

m B

as

eli

ne

3.0%

4.0%

Patients who had previously been treated with bisphosphonates randomly assigned to a bisphosphonate or denosumab.

OOCOOCData 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. 3Miller PD et al. J Clin Endo Metab. 2016;101:3163-70.

IBNALN

ZOLRIS

1 2 3To

tal

Hip

Pe

rce

nt

Ch

an

ge

Fro

m B

as

eli

ne

0.5% 0.9% 1.1% 0.6%2.0% 2.2% 1.9% 1.9%0.0%

1.0%

2.0%

vs RIS vs IBN vs ALN vs ZOL

FNIH Meta-regressionChange in Total Hip BMD vs Reduction in Hip Fracture

MORE (RAL)

FIT II(ALN)

HIP(RIS)

FREEDOM (DMAB)

Clodronate

R2=0.52

OOCOOC

FIT I(ALN)

HORIZON(ZOL)

FREEDOM (DMAB)

WHI

*Bubble size ~ to n fractures in study Courtesy of Dr D Black et al, ASBMR 2015

Relationship Between OnRelationship Between On--Treatment Total Hip Treatment Total Hip BMD TBMD T--score score and Nonand Non--vertebral Fracture Riskvertebral Fracture Risk

Incid

en

ce o

f n

on

Incid

en

ce o

f n

on

--vert

eb

ral

vert

eb

ral

fractu

re a

t 1 y

ear

(%)

fractu

re a

t 1 y

ear

(%)

4.04.0

5.05.0

6.06.0

Treating to a BMD target Treating to a BMD target may now be feasiblemay now be feasible

OOCOOC

Incid

en

ce o

f n

on

Incid

en

ce o

f n

on

fractu

re a

t 1 y

ear

(%)

fractu

re a

t 1 y

ear

(%)

--3.03.0 --2.52.5 --2.02.0 --1.51.5 --1.01.0 --0.50.5

1.01.0

2.02.0

3.03.0

4.04.0

Total Hip TTotal Hip T--scorescore

Ferrari S et al. ASBMR; Seattle, WAFerrari S et al. ASBMR; Seattle, WA; October ; October 20152015

Treat to Target: An Evolving Concept

OOCOOC

Osteoporosis Therapies

1.1. Fracture protection Fracture protection

•• begins within months of starting therapybegins within months of starting therapy

•• persists with longpersists with long--term therapyterm therapy

•• wanes when treatment is stopped wanes when treatment is stopped

–– even with bisphosphonateseven with bisphosphonates

OOCOOC

–– even with bisphosphonateseven with bisphosphonates

Vertebral Fractures with Zoledronic Acid

52%*(10, 74)

% P

ati

en

ts

10.9%(310/2853)

70%†(62, 76)

Z3P3 Z6

ZOL PBO

10

15

P = 0.0348

P = <0.001Absolute risk of new vertebral fracture

if therapy is stopped = 1%/year

OOCOOC Black DM, et al. N Engl J Med. 2007;356:1809–22

6.2%(30/486)

3.0%(14/469)

52%*(10, 74)

% P

ati

en

ts

Morphometric Vertebral Fractures

3.3%(92/2822)

Core study1 Extension study

0

5

Osteoporosis Therapies: Safety of Long-term Therapy

OOCOOC

Atypical Femoral Fracture and Long-term Bisphosphonate Therapy

11,466 patients with femoral fracture

7430 typical hip fracture

142 atypical stress-type fractures10% occur in untreated patients

ad

jus

ted

in

cid

en

ce

of

AF

F p

er

10

0,0

00

pt-

ye

ars

60

80

100

120In untreated patients:

0.3/100,000 patient-years

OOCOOC Dell RM et al. J Bone Miner Res. 2012;27:2544-50

Duration-dependent risk of AFF:

1.78/100,000 patient-years in first 2 yr

113/100,000 patient-years in years 8-9.9

May be a decrease in risk if treatment is stopped

R Dell: personal communication

Schilcher J et al. N Engl J Med. 2014;371:974-6

Ag

e-a

dju

ste

d i

nc

ide

nc

e o

f A

FF

pe

r 1

00

,00

0 p

tYears of

bisphosphonate therapy

0

20

40

60

2 5 8-9.9

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

Denosumab: Long-term SafetyExposure-adjusted Subject Incidence of Adverse Events (Rates per 100 Subject-years)

OOCOOC

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.

Bone HG et al. Lancet Diabetes Endocrinol 2017;5:513-23

Case

• Healthy woman; menopause at age 52

• Age 60: wrist fracture

• Age 67: humerus fracture. BMD T-score -2.6 in lumbar spine and -2.9 at total hip. Begun on alendronate; well tolerated

• Age 72: BMD T-score -1.8 in lumbar spine and -2.6 at total hip.

OOCOOC

• Age 72: BMD T-score -1.8 in lumbar spine and -2.6 at total hip.

• Management choices:

• discontinue alendronate therapy

• continue alendronate therapy

• switch to IV zoledronic acid

• switch to denosumab

• other

OOCOOC Adler R et al. J Bone Miner Res 2016; 31:16–35

Bisphosphonate “Drug Holiday”

• An “opportunity” – not a necessity

• Protection from fragility fracture persists 1-2 years upon stopping therapy

• Risk of atypical fracture may decrease when treatment stopped

OOCOOC

• After 3-5 years of therapy:

• Patients at moderate fracture risk: consider a “holiday”

• Patients at high risk (low BMD, prior vertebral fracture, elderly): continue to treat and follow to 10 years

NOTE:

No evidence that a “drug holiday” reduces risk of any complication of therapy

Whitaker et al. N Engl J Med 2012;366:2048-51

Discontinuing Denosumab: BMDPhase 2 Study in Women With Low BMD

Discontinued Discontinued TreatmentTreatment

Discontinued Discontinued TreatmentTreatment

Lumbar SpineLumbar Spine Total HipTotal Hip

Perc

en

t C

han

ge

Perc

en

t C

han

ge

SE

)S

E) 66

88

1010

1212

1414

PlaceboPlacebo210 mg Q6M210 mg Q6MOpenOpen--label alendronate label alendronate

OOCOOC Adapted from Miller PD, McClung M et al. Adapted from Miller PD, McClung M et al. BoneBone 2008;43:2222008;43:222--2929

Perc

en

t C

han

ge

Perc

en

t C

han

ge

(LS

Mean

(L

S M

ean

±±S

E)

SE

)

MonthsMonths

−−−−−−−−66

−−−−−−−−44

−−−−−−−−22

00

22

44

MonthsMonths

00 66 1212 1818 2424 3636 4848−−−−−−−−44

−−−−−−−−22

00

22

44

66

88

1010

00 66 1212 1818 2424 3636 4848

Serum Serum CTxCTx BSAPBSAP

1.21.2

1.41.4

1.61.6

Med

ian

ng

/mL

(Q

1,

Q3)

Med

ian

ng

/mL

(Q

1,

Q3)

2020

2525

Med

ian

mcg

/L (

Q1, Q

3)

Med

ian

mcg

/L (

Q1, Q

3)

**††

Discontinuing Denosumab: BMDDiscontinuing Denosumab: BMDPhase 2 Study in Women With Low BMDPhase 2 Study in Women With Low BMD

Discontinued Discontinued TreatmentTreatment

Discontinued Discontinued TreatmentTreatment

PlaceboPlacebo210 mg Q6M210 mg Q6MOpenOpen--label alendronate label alendronate

OOCOOC

**PP < 0.001 at month 36 and = 0.05 at month 48 vs placebo.< 0.001 at month 36 and = 0.05 at month 48 vs placebo.††PP = 0.008 at month 36 vs placebo.= 0.008 at month 36 vs placebo.

00

0.20.2

0.40.4

0.60.6

0.80.8

11.0.0

1.21.2

00 66 1212 1818 2424 3030 3636 4242 4848

Med

ian

ng

/mL

(Q

1,

Q3)

Med

ian

ng

/mL

(Q

1,

Q3)

00

55

1010

1515

2020

00 66 1212 1818 2424 3030 3636 4242 4848

MonthsMonths MonthsMonths

Med

ian

mcg

/L (

Q1, Q

3)

Med

ian

mcg

/L (

Q1, Q

3)

**

**

††

Adapted from Miller PD, McClung M et al. Adapted from Miller PD, McClung M et al. BoneBone 2008;43:2222008;43:222--2929

–6.7%

N = 52

Discontinuing Denosumab After 8 YearsLumbar Spine BMD

Extension StudyParent Study

All on DMAb Treatment

13

15

17

19

21

16.8%N = 52

Observation

Pe

rce

nta

ge

Ch

an

ge

Fro

m B

as

eli

ne

Placebo Denosumab 210 mg Q6M Off-treatment

OOCOOC

–6.7%

–5.1%

N = 10

–7

–5

–3

–1

1

3

5

7

9

11

01 3 6 12 18 24 36 48 60 72 84 961 108

8.1%

N = 10

McClung M et al. Osteoporos Int. 2017;28:1723-32

Study Month

Pe

rce

nta

ge

Ch

an

ge

Fro

m B

as

eli

ne

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

OOCOOC

• 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 27

2. Heiss G et al. JAMA 299:1036–45

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

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.

Following discontinuation, similar percentages of

OOCOOC 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

• 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

OOCOOC

Vertebral fractures

On study drug

Off study drug

Multiple vertebral fractures

Brown JP et al. ASBMR Abstract #1100, 2016

Fracture Risk after Stopping Denosumab

• Protection from vertebral fractures is quickly lost upon stopping denosumab

BUT

OOCOOC

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

Discontinuing DenosumabOther Information

Ferrari S et al. ECTS 2016

OOCOOC

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

McClung M et al. Osteoporos Int. 2017;28:1723-32

6

8

Denosumab and Alendronate (DAPS Trial)

Cross-over Treatment after 12 Months

Pe

rce

nt

Ch

an

ge

Fro

m B

as

eli

ne Denosumab Alendronate

Switching from denosumab to alendronate, bone loss did not occur

Lumbar spine

OOCOOC

0

2

4

6

0 12 24

Freemantle N et al. Osteoporos Int. 2012;23:317-26

Pe

rce

nt

Ch

an

ge

Fro

m

Months

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

OOCOOC

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

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

OOCOOC

• 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”

Long-term Denosumab TherapySummary

OOCOOC

• 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

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

Osteoporosis Therapy After 5 YearsSummary

• Bisphosphonates: Consider

• drug holiday for patients at modest risk

• switching to denosumab if hip BMD still low

Denosumab

OOCOOC

• Denosumab

• very rarely a reason to stop therapy

• if denosumab therapy is to be stopped, consider an alternative anti-resorptive (e.g. bisphosphonate) to prevent rapid bone loss

McClung M. Personal opinion, 2017

Photo courtesy of Betsy Love McClung, RN, MN

Case: Management

• Healthy woman; menopause at age 52

• Age 60: wrist fracture

• Age 67: humerus fracture. BMD T-score -2.6 in lumbar spine and -2.9 at total hip. Begun on alendronate; well tolerated

• Age 72: BMD T-score -1.8 in lumbar spine and -2.6 at total hip.

OOCOOC

• Age 72: BMD T-score -1.8 in lumbar spine and -2.6 at total hip.

• Management choices:

• discontinue alendronate therapy

• continue alendronate therapy

• switch to IV zoledronic acid

• switch to denosumab

• other

Osteoporosis: Long-term Treatment Plan

Raloxifene

Bisphosphonate

When concerned about hip fracture

3-5 years

Low risk Consider drug holiday

Re-treat

OOCOOC

Teriparatide

Denosumab

After 18-24 months

After 18-24 months

3-5 years

High risk

Denosumab Bisphosphonate1 dose ZOL2 years ALNIf “target”

is met

Thank you

OOCOOC

Michael R. McClung, MD, FACPOregon Osteoporosis Center

Portland, Oregon, USA

mmcclung.ooc@gmail.com