Long-term Osteoporosis Therapy What To Do After 5 Years? Developing - - PowerPoint PPT Presentation

Developing a Long-term Management Plan

Long-term Osteoporosis Therapy

What To Do After 5 Years?

OOC OOC Michael R. McClung, MD, FACP

Institute for Health and Ageing, Australian Catholic University, Melbourne, Australia Oregon Osteoporosis Center Portland, Oregon, USA mmcclung.ooc@gmail.com

North American Menopause Society Philadelphia, PA

October 11, 2017

Disclosures

I am disclosing financial relationships as follows: Scientific Advisory Boards: Amgen, Radius Honorarium for speaking: Amgen, Radius OOC OOC 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

OOC OOC

• Several osteoporosis drugs effectively and

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

• steoporosis
• steoporosis
• Osteoporosis is a chronic disease requiring

Osteoporosis is a chronic disease requiring prolonged treatment prolonged treatment

• It is important to develop a strategy for long

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

Images Courtesy of

• Drs. David Dempster & Roger Zebazi

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

Osteoporosis Therapies

OBJECTIVES OBJECTIVES 1,2

1,2

1. 1.

improve bone strength improve bone strength

2. 2.

reduce risk of reduce risk of fracture fracture

3. 3.

prevent rapid bone loss (less commonly) prevent rapid bone loss (less commonly)

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BENEFITS BENEFITS 2

1. 1.

effective protection from fractures effective protection from fractures vertebral fracture by 60 vertebral fracture by 60-70% 70% hip fracture by 40 hip fracture by 40-50% 50% non non-vertebral fracture by 20 vertebral fracture by 20-35% 35%

2. 2.

in general are well tolerated in general are well tolerated

3. 3.

in clinical trials, have in clinical trials, have a favorable safety profile a favorable safety profile

1.

• 1. Seeman

Seeman E et al. Bone 2004;17 E et al. Bone 2004;17 Suppl Suppl 2:23S 2:23S-29S 29S

• 2. McClung M et al.
• 2. McClung M et al. Amer

Amer J Med J Med. 2013;126:13 . 2013;126:13-20 20

Long-term Osteoporosis Therapy

Bisphosphonates and denosumab are the agents considered Bisphosphonates and denosumab are the agents considered for long for long-term use term use Fracture Fracture protection protection

• begins within months of starting therapy

begins within months of starting therapy

• continues with long

continues with long-term therapy term therapy

OOC OOC

continues with long continues with long-term therapy term therapy

• wanes when treatment is

wanes when treatment is stopped stopped

Long Long-term safety term safety

• bisphosphonates: atypical femoral fracture

bisphosphonates: atypical femoral fracture incidence: 1/1000 after 8 incidence: 1/1000 after 8-10 years of therapy 10 years of therapy

• denosumab

denosumab

• ver 10 years, no adverse events increased in frequency with
• ver 10 years, no adverse events increased in frequency with

long long-term therapy term therapy

1. 1. Hanley DA, McClung MR, et al. Hanley DA, McClung MR, et al. Am J Med Am J Med 2017;130:862.e1 2017;130:862.e1-862.e7 862.e7 McClung MR et al. McClung MR et al. Am J Med Am J Med 2013;126:13 2013;126:13-20 20 Bone Bone HG et al. HG et al. Lancet Diabetes Lancet Diabetes Endocrinol Endocrinol 2017 2017;5:513 2017 2017;5:513-23 23

Vertebral Fractures with Zoledronic Acid

ients

10.9% (310/2853) 70%† (62, 76)

ZOL PBO 10 15 P = <0.001 Fracture protection persists with long term therapy Years 1-3

OOC OOC

3.0% (14/469)

% Patient Morphometric Vertebral Fractures

3.3% (92/2822)

5 Years 4-6

4.4% (3/68)

Years 7-9

Core study Extension study

Black DM et al. N Engl J Med 2007;356:1809–22 Black DM et al. J Bone Miner Res 2012;27:243-54 Black DM et al. J Bone Miner Res 2015;30:934-44

Long-term Denosumab Therapy

Vertebral and Non-vertebral Fractures

Persistent reduction in fracture risk

OOC OOC

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

• Hypocalcemia
• Intolerance
• upper GI symptoms: oral drugs
• acute phase reaction: IV drugs
• bone and muscle pain

Risks and Concerns with Long-term Therapy

Bisphosphonates

No increase with long-term therapy

OOC OOC

• bone and muscle pain
• Inflammatory eye problems
• Atrial fibrillation
• Esophageal cancer: oral drugs
• Osteonecrosis of the jaw
• Atypical fractures
• 1/1000 patients after 8-10 years

Unproven relationship; minimal evidence of increased risk with long-term therapy Concern here of risk of long-term therapy

Atypical Femoral Fracture and Long-term Bisphosphonate Therapy

11,466 patients with femoral fracture 7430 typical hip fracture 142 atypical stress-type fractures

10%occurres in untreated patients d incidence of ,000 pt-years

60 80 100 120

In untreated patients: 0.3/100,000 patient-years

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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 Rapid decrease in risk when treatment is stopped

Schilcher J et al.N Engl J Med. 2014;371:974-6 R Dell: personal communication

Age-adjusted i AFF per 100,0

Years of bisphosphonate therapy

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

Denosumab: Long-term Safety

Exposure-adjusted Subject Incidence of Adverse Events (Rates per 100 Subject-years) No adverse events increased in frequency with long-term therapy

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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 < 0.1 < 0.1 Atypical femoral fracture < 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 Bone HG et al. HG et al. Lancet Diabetes Lancet Diabetes Endocrinol Endocrinol 2017 2017;5:513 2017 2017;5:513-23 23

Osteoporosis Therapies

Fracture protection Fracture protection

• begins within months of starting therapy

begins within months of starting therapy

• persists with long

persists with long-term therapy term therapy

• wanes when treatment is stopped

wanes when treatment is stopped – even with bisphosphonates even with bisphosphonates

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– even with bisphosphonates even with bisphosphonates

Vertebral Fractures with Zoledronic Acid

52%* (10, 74)

ients

10.9% (310/2853) 70%† (62, 76)

Z3P3 Z6 ZOL PBO 10 15 P = 0.0348 P = <0.001 Absolute risk of new vertebral fracture if therapy is stopped = 1%/year No difference in incidence of non- vertebral fractures

OOC OOC

Black DM, et al. N Engl J Med. 2007;356:1809–22 6.2% (30/486) 3.0% (14/469) 52%* (10, 74)

% Patient Morphometric Vertebral Fractures

3.3% (92/2822) Core study1 Extension study

5

Clinical Vertebral Fractures in FLEX Study

ative Incidence ractures (%)

3 4 5 6 ALN 5 years

• Placebo 5 years

Alendronate 10 years

5.4%

RR

• 55%

P = 0.013

2.5%

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1 2 4 5 Cumulat

• f Fra

Years Since FIT

ALN/PLB 437 436 425 412 398 387 ALN/ALN 662 660 646 631 615 597

3

1 2

2.5%

Black DM et al. JAMA. 2006;296:2927-38

Bisphosphonate “Drug Holiday”

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

therapy

• Risk of atypical fracture may decrease when treatment stopped

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• 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

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

OOC OOC

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

Low risk High risk

Bisphosphonate “Drug Holiday”

• An “opportunity” – not a necessity and not mandatory
• There is no “rule” that therapy must be stopped after any interval of time

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That decision has to be made on a case-by-case basis

McClung M. Personal opinion, 2017

Denosumab Drug Holiday?

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Discontinuing Denosumab: BMD

Phase 2 Study in Women With Low BMD

Discontinued Discontinued Treatment Treatment Discontinued Discontinued Treatment Treatment

Lumbar Spine Lumbar Spine Total Hip Total Hip

ange ange SE) SE)

6

8 8

10 10 12 12

14 14

Placebo Placebo 210 mg Q6M 210 mg Q6M Open Open-label alendronate label alendronate

OOC OOC

Adapted from Miller PD, McClung M et al. Adapted from Miller PD, McClung M et al. Bone Bone 2008;43:222 2008;43:222-29 29

Percent Chan Percent Chan (LS Mean (LS Mean ± S Months Months

− − − − − − − −6 − − − − − − − −4 − − − − − − − −2 2 4

Months Months

6 12 12 18 18 24 24 36 36 48 48 − − − − − − − −4 4 − − − − − − − −2 2 2 2 4 4 6 6 8 8 10 10 6 12 12 18 18 24 24 36 36 48 48

–6.7% N = 52

Discontinuing Denosumab After 8 Years

Lumbar Spine BMD

Extension Study Parent Study

All on DMAb Treatment 13 15 17 19 21

16.8% N = 52

Observation

• m Baseline

Placebo Denosumab 210 mg Q6M Off-treatment

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–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. ASBMR 2014

Study Month Percentage Change From

Serum Serum CTx CTx BSAP BSAP

1.2 1.2 1.4 1.4 1.6 1.6

(Q1, Q3) (Q1, Q3)

20 20 25 25 1, Q3) 1, Q3)

†

Discontinuing Denosumab: BMD Discontinuing Denosumab: BMD

Phase 2 Study in Women With Low BMD Phase 2 Study in Women With Low BMD

Discontinued Discontinued Treatment Treatment Discontinued Discontinued Treatment Treatment

Placebo Placebo 210 mg Q6M 210 mg Q6M Open Open-label alendronate label alendronate

OOC OOC

*P < 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.

†P = 0.008 at month 36 vs placebo.

= 0.008 at month 36 vs placebo.

0.2 0.2 0.4 0.4 0.6 0.6 0.8 0.8 1.0 .0 1.2 1.2 6 12 12 18 18 24 24 30 30 36 36 42 42 48 48

Median ng/mL (Q Median ng/mL (Q

5 10 10 15 15 20 20 6 12 12 18 18 24 24 30 30 36 36 42 42 48 48 Months Months Months Months Median mcg/L (Q1, Median mcg/L (Q1,

* *

† Adapted from Miller PD, McClung M et al. Adapted from Miller PD, McClung M et al. Bone Bone 2008;43:222 2008;43:222-29 29

Effect of Withdrawing Alendronate or E/P:

Urinary NTx

Mean Percent Change ( Mean Percent Change (± SE) SE)

Stratum 1 Only Stratum 1 Only

nt Change nt Change

• 20

20 OOC OOC Years Years 1 2 3 4 5 6 Mean Percent Mean Percent

• 100

100

• 80

80

• 60

60

• 40

40

PBO/PBO/PBO PBO/PBO/PBO Estrogen/Progestin Estrogen/Progestin

• Off Therapy

Off Therapy

Wasnich, McClung et al. Wasnich, McClung et al. Menopause Menopause 2004;1:622 2004;1:622-

• 630

630

Denosumab “Drug Holiday”?

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)

OOC OOC

• 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 27 2. Heiss G et al. JAMA 299:1036–45 3. McClung MR. Osteoporos Int. 2016;27:1677-82

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

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Vertebral fractures Multiple vertebral fractures Brown JP et al. ASBMR Abstract #1100, 2016

Effect of Withdrawing Hormone Therapy:

Hip Fracture in WHI

• Within first year, of stopping hormone therapy, hip fracture

rates approximate those in placebo group

• No evidence of rebound in fracture risk

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Heiss G et al. JAMA. 2008;299:1036-45

2

s - %

CEE-MPA Treatment (N=8506) CEE-MPA Post-treatment (N-8052) PBO Post-treatment (N=7678) Placebo (N=8102)

Effect of Withdrawing Hormone Therapy:

Fractures in WHI

No rebound or excess fracture risk after stopping estrogen

OOC OOC

0.5 1 1.5

Annualized rates

Heiss G et al. JAMA 2008;299:1036-45

Hip fracture Vertebral fracture Other fractures

6 8

Denosumab and Alendronate (DAPS Trial)

Cross-over Treatment after 12 Months

Baseline

Denosumab Alendronate

Switching from denosumab to alendronate, bone loss did not occur

Lumbar spine

OOC OOC

2 4 6 12 24

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

Percent Change From Months Total hip

• There are very few reasons to consider stopping

denosumab therapy

• intolerance or side effect
• reaching a treatment “target”

Long-term Denosumab Therapy

Summary

OOC OOC

• 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

Effects of Therapy on Total Hip BMD Through 10 Years

Long Long-term Denosumab term Denosumab

FREEDOM FREEDOM Extension Extension 6 7 8 9 10 9.2% 9.2% 6.8% 6.8%

• m Baseline
• m Baseline

Alendronate 10 mg/d Alendronate 10 mg/d2 Denosumab Denosumab1

Total Hip BMD Total Hip BMD OOC OOC

• 2
• 1

1 2 3 4 5

Percentage Change From Percentage Change From Study Year Study Year

1 2 3 4 5 6 7 7 8 8 9 9 10 10

4.6% 4.6%

Zoledronic Zoledronic acid 5 mg/y

acid 5 mg/y3

• 1. Bone HG et al.
• 1. Bone HG et al. Lancet Diabetes

Lancet Diabetes Endocrinol Endocrinol 2017 Published Online May 22, 2017 2017 Published Online May 22, 2017 http://dx.doi.org/10.1016/S2213 http://dx.doi.org/10.1016/S2213-8587(17)30138 8587(17)30138-9

• 2. Bone HG et al.
• 2. Bone HG et al. New

New Engl Engl J J Med.2004 Med.2004;350:1189 ;350:1189-99 99

• 3. Black DM et al.
• 3. Black DM et al. New

New Engl Engl J J Med Med 2012;27:243 2012;27:243-54 54

Switching From Bisphosphonates to Denosumab

1.6%* 1.4%* 0.9%* 1.3%* e From Baseline

3.0% 4.0%

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

OOC OOC

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

Total Hip Percent Change

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

0.0% 1.0% 2.0% vs RIS (1) vs IBN (2) vs ALN (3) vs ZOL (4)

FNIH Meta-regression

Change in Total Hip BMD vs Reduction in Hip Fracture

MORE (RAL) FIT II(ALN) HIP(RIS) FREEDOM (DMAB) Clodronate

R2=0.52

The greater the increase in BMD, the greater reduction in NV fractures

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FIT I(ALN) HORIZON(ZOL) FREEDOM (DMAB) WHI

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

Relationship Between On Relationship Between On-Treatment Total Hip Treatment Total Hip BMD T BMD T-score score and Non and Non-vertebral Fracture Risk vertebral Fracture Risk

• n
• n-vertebral

vertebral 1 year (%) 1 year (%) 4.0 4.0 5.0 5.0 6.0 6.0 Treating to a BMD target Treating to a BMD target may now be feasible may now be feasible Current NV fracture risk Current NV fracture risk was strongly correlated was strongly correlated

OOC OOC

Incidence of no Incidence of no fracture at 1 fracture at 1

• 3.0

3.0

• 2.5

2.5

• 2.0

2.0

• 1.5

1.5

• 1.0

1.0

• 0.5

0.5 1.0 1.0 2.0 2.0 3.0 3.0 4.0 4.0 Total Hip T Total Hip T-score score

Ferrari S et al. ASBMR; Seattle, WA Ferrari S et al. ASBMR; Seattle, WA; October ; October 2015 2015

was strongly correlated was strongly correlated with on target hip BMD with on target hip BMD

Treat to Target: An Evolving Concept

OOC OOC

Cummings SR et al. J Bone Miner Res 2017;32:3-10

Osteoporosis: Long-term Treatment Plan

Raloxifene Bisphosphonate

When concerned about hip fracture 3-5 years Low risk Consider drug holiday Re-treat

OOC OOC

Teriparatide/abaloparatide Denosumab

After 12-24 months After 12-24 months 3-5 years High risk Continue therapy?

Denosumab Bisphosphonate

for 1-2 years

If “target” is met

Osteoporosis Therapy:

Long-term Management Plan

• Decisions about starting therapy must be

individualized

• After 3-5 years of bisphosphonates, consider
• drug holiday for patients at modest risk

OOC OOC

• drug holiday for patients at modest risk
• switching to denosumab if hip BMD still low
• 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

Thank you

OOC OOC

Michael R. McClung, MD, FACP

Founding Director Oregon Osteoporosis Center Portland, Oregon, USA mmcclung@orost.com