23/06/2015

1

Risks and Benefits of Long-Term Treatment

Richard Eastell, MD, FRCP, FRCPath, FMedSciProfessor of Bone Metabolism University of Sheffield, Sheffield, UK

12th Annual Osteoporosis: New Insights in Research, Diagnosis, and Clinical Care23rd July 2015

E-mail r.eastell@sheffield.ac.uk

Sheffield, EnglandMore trees per capita than any city in Europe!

23/06/2015

2

Conflicts of Interest

• Research funding, consulting and honoraria fromo Novartis

o Amgen

o AstraZeneca

o Pfizer

o Warner Chilcott

o Sanofi

Overview of Osteoporosis Treatments: Long-term Efficacy Data

23/06/2015

3

Osteoporosis Treatment Extension Studies

0 2 4 6 8 10

Risedronate

Alendronate

Zoledronic acid

ALN = alendronate; DB = double-blind; EXT 1= extension 1; EXT 2= extension 2; FIT = Fracture Intervention Trial; FLEX = FIT Long-term EXtension; HORIZON-PFT = Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly Pivotal Fracture Trial; OL, Open-label; PBO = placebo; RCT = randomized controlled trial; RIS = risedronate; VERT-MN = Vertebral Efficacy with Risedronate Therapy MultiNational; Z3P3 = zoledronic acidtreatment for 3 years followed by placebo for 3 years; Z6 = zoledronic acid treatment for 6 years; ZOL = zoledronic acid. 1. Black DM, et al. N Engl J Med. 2007;356:1809-1822. 2. Black DM, et al. J Bone Miner Res. 2012; 27:243-254. 3. The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis:A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT).Presented at ASBMR 2013 (abstract no. SA0389). 4. Black DM, et al. Lancet. 1996;348:1535-1541. 5. Cummings SR, et al. JAMA. 1998;280:2077–2082. 6. Black DM, et al. JAMA. 2006;296:2927-2938. 7. Reginster J-Y, et al. Osteoporos Int. 2000;11:83–91. 8. Sorensen OH, et al. Bone. 2003;32:120-126. 9. Mellström DD, et al. Calif Tissue Int. 2004;75:462-468.

Time (Years)

FIT4,5

ALN (n = 3236) PBO (n = 3223)

RCT – FLEX6

ALN 5 mg (n = 329) or 10 mg (n = 333) PBO (n = 437)

HORIZON-PFT1

ZOL (n = 3889) PBO (n = 3876)

RCT – EXT12

Z6 (n = 616)Z3P3 (n = 617)

VERT-MN7

RIS 2.5 mg (n = 408) 5 mg (n = 407) PBO (n = 407)

RCT – EXT8

RIS (n=135)PBO (n=130)

OL-EXT9RIS 7 yrs (n = 83)PBO 5 yrs/RIS 2yrs (n = 81)

RCT – EXT23

Z9 (n = 95)Z6P3 (n = 95)

Z6 n= 613 609 608 600 524 450

Z3P3 n= 615 613 606 602 540 467

Effect of Zoledronic Acid on Total Hip BMD over 6 Years: HORIZON PFTEffect of Zoledronic Acid on Total Hip BMD over 6 Years: HORIZON PFT

Time (Years From Core Study Baseline)

Subset of Core Study Population

Z6 Z3P3

0

Core + Extension study

–2.0–1.00.01.02.03.04.0

–3.0

5.0

Start of extension trial

1.4%

3 61 2 4 5

(0.58, 2.15)P = 0.0007**

5.06%*

+4.5% 

+3.1% 

Black DM, et al. JBMR 2012 Feb;27(2):243-54. *p < 0.0001, p value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables**p value computed from 2-way ANOVA with treatment and region as explanatory variables

23/06/2015

4

Effect of Zoledronic Acid on Total Hip BMD over 9 Years: HORIZON PFT

MITT = Modified-intent-to-treat; ITT = Intent-to-treat; BMD = Bone mineral density; Bracketed value is P value, ZOL vs. placebo

0

1

2

3

4

5

6

7

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9

Ch

ang

e fr

om b

asel

ine

(%)

Time (years)

Z9

Z6P3

[0.069] [0.351]

Core Extension-1 Extension-2

Total hip BMD from Core StudyBaseline to Year 9 (ITT)

Parallel results for other BMD sites

-2

-1.5

-1

-0.5

0

Z9 Z6P3

Per

cen

tag

e ch

ang

e (%

)

Year 9 relative to Year 6 (MITT)

P = 0.183

Black DM...Eastell R. J Bone Miner Res. 2015 May;30(5):934-44

0

2

4

6

8

10

12

% P

atie

nts

ZOL PBO Z6 Z3P3 Z9 Z6P3

1010.9%%[310/2853]

3.3%[92/2822]

3.0%[14/469]

6.2%[30/486] 5.3%

[5/95]3.2%[3/95]

Morphometric vertebral fractures

Core Extension-1 Extension-2

Incidence of new Vertebral Morphometric Fractures in the core study, Years 3-6 and Years 6-9 (ITT)

70%*(62, 76) 49%†

(26, 95)

*P < 0.001 vs. placebo†P = 0.035 vs. Z3P3

40% (-144, 85)

p = 0.461

Black DM...Eastell R. J Bone Miner Res. 2015 May;30(5):934-44

23/06/2015

5

* Measured in clinical fracture arm only, ALN = alendronate, BMD = bone mineral density, FIT = Fracture Intervention Trial, FLEX = FIT Long-term Extension, FN = femoral neck, LS = lumbar spine. Black DM, et al. JAMA. 2006;296:2927–2938.

Effect of Alendronate on Femoral Neck BMD over 10 Years: FIT and FLEXEffect of Alendronate on Femoral Neck BMD over 10 Years: FIT and FLEX

ALN = alendronate, BMD = bone mineral density, FIT = Fracture Intervention Trial, FLEX = FIT Long-term Extension, LS = lumbar spineBlack DM, et al. JAMA. 2006;296:2927–2938.

Placebo 437 428 429 421 417 414Alendronate 662 659 657 654 650 646

No. at Risk

0

5

10

15

20

0 1 2 3 4 5 6

Time to First Fracture, Years

Cu

mu

lati

veIn

cid

ence

(%

)

RR, 0.45 (95% CI, 0.24–0.86)

Incidence of new Clinical Vertebral Fractures during FLEX

Alendronate (Pooled)Placebo

FIT

FLEX

All patients received ALN

23/06/2015

6

ALN = alendronate, BMD = bone mineral density, FIT = Fracture Intervention Trial, FLEX = FIT Long-term Extension, LS = lumbar spineBlack DM, et al. JAMA. 2006;296:2927–2938.

Incidence of new Non-vertebral Fractures during FLEX

Placebo 437 421 410 396 373 355Alendronate 662 642 619 585 565 537

No. at Risk

360

5

10

15

20

0 12 24 48 60 72

Time to First Fracture, months

Cu

mu

lati

veIn

cid

ence

(%

)

RR, 1.00 (95% CI, 0.76–1.32)

Alendronate (Pooled)Placebo

FIT

FLEX

All patients received ALN

RISEDRONATE: LS BMD Increased Over 7-Year Treatment Period1

BLN 1 2 3 5 6 7

Mea

n C

han

ge

in L

S B

MD

(%

)

4

-1

2

8

10

13

10

345

76

9

1112

*#

**

*

Ris 7 yrs (n=83)

Placebo 5 yrs

Ris 2 yrs (n=81)

Years

*#

*#*#

*#

*#

*#

* P<0.05 vs. baseline, # P<0.05 vs. placebo; BLN = baseline, Ris = risedronate1. Mellström DD, et al. Calcif Tissue Int. 2004;75:462–468.

23/06/2015

7

Continuous Risedronate: Antifracture Efficacy for Radiographic Vertebral Fractures Sustained Over 7 Years1

An

nu

aliz

ed I

nci

den

ce o

f N

ew V

erte

bra

l Fr

actu

res

1. Mellström DD, et al. Calcif Tissue Int. 2004;75:462–468.

Placebo 407 130 81Risedronate 407 130 83

7.6%

4.7%5.2%

3.8%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

Years 0-3 Years 4-5 Years 6-7

Placebo 5mg risedronate

Patients switched to risedronate 5 mg at start of year 6

12.3%

Bisphosphonates Reduce Fracture Risk

Khosla S, et al. J Clin Endocrinol Metab. 97: 2272–2282, 2012

23/06/2015

8

Safety and Long-Term Treatment with Bisphosphonates

Amino-bisphosphonates for Osteoporosis

• Widely used

o In 2008, four million women prescribed oral bisphosphonates in USA

• Safety evaluation for license based on clinical trials

o Only 50,000 treated for up to 3 years

• Thus, in long-term use, when these drugs are used in many more people with co-existents diseases, rare adverse events might become apparent

23/06/2015

9

Safety and Long-Term Treatment with Bisphosphonates - Outline

• Benefits of Bisphosphonates

• Safety issues

o Atypical femur fracture

o Osteonecrosis of the jaw

o Atrial fibrillation

o Oesophageal cancer

o Others

−Oesophagitis

−Chronic kidney disease

− Iritis

• Minimising safety concerns

• Recent references

o Khosla S, et al. J Clin Endocrinol Metab 97: 2272–2282, 2012

o McClung M, et al. Am J Med. 2013 Jan;126(1):13-20.

Atypical femur fracture

23/06/2015

10

What is an atypical fracture of the femur?

• Fracture of the subtrochanteric region or femoral shaft

• Transverse of short oblique orientation

• Minimal trauma

• Medial spike

• No comminution

Shane E, et al. J Bone Miner Res. 2014;29(1):1-23Neviaser AS, et al. J Orthop Trauma. 2008 May-Jun;22(5):346-50.

Atypical femur fractures

• There is prodromal pain in 75% of cases

• The fracture is bilateral in 25-50% of cases

• There is delayed healing in 25% of cases

• More likely if

o Use of glucocorticoids

o Use of proton pump inhibitors

• In series with radiographs

o Atypical fractures in about 10% of all subtrochanteric fractures

o These are more likely with increased duration of treatment

DM Black has estimated that for every 1000 hip fractures, we might expect 5 atypical fractures

23/06/2015

11

Meta-analysis of atypical femur fracture studies - 2

Gedmintas L, et al. J Bone Miner Res. 2013;28(8):1729-37.

Atypical femur fractures against time on treatment (years)

Dell R, et al. J Bone Miner Res. 2012; 27(12),2544–50

23/06/2015

12

Osteonecrosis of the jaw

Osteonecrosis of the jaw - case definitionfrom several societies (AAOMS, ASBMR, ESCEO)

• Exposed bone in the mouth

• Unhealed for >8 weeks

• No history of radiation therapy to the craniofacial region

Khan AA, et al. J Bone Miner Res. 2015 Jan;30(1):3-23

23/06/2015

13

Reported incidence estimates of osteonecrosis of the jaw coincident with the use of bisphosphonates (1,2)

Malignant conditions

Nonmalignant conditions

IV1 to 10 per 100

patientsRate not published

PO Rate not published1/1,000 to

1/300,000 patient-treatment years

1. Khosla S, et al. J Clin Endocrinol Metab. 97: 2272–2282, 2012, 2. Lee SH, et al. Osteoporos Int 2014 Mar;25(3):1131-9

Meta-analysis of12 studies of osteoporosis:OR=2.91 (95 % CI 1.62–5.22)

Risk factors for ONJ

• Dental surgery

o Extraction

• Intravenous bisphosphonates for oncology indication

o 97% of all cases

• Drugs

o Glucocorticoids

o Chemotherapy

• Co-existent diseases

o Diabetes mellitus

o Alcohol excess

23/06/2015

14

Atrial fibrillation

Atrial FibrillationMeta-analysis of trials

Relative risk with intravenous bisphosphonates is 1.4

Relative risk with Oral bisphosphonates is 1.2

Sharma A, et al. Am J Cardiol. 2014 Jun 1;113(11):1815-21

23/06/2015

15

Oesophageal cancer

FDA Letter to the Journal

• The US Food and Drug Administration recently reported 23 cases of esophageal cancer (between 1995 and 2008) in patients using the bisphosphonate alendronate

o and a further 31 cases in patients using bisphosphonates in Europe and Japan

• This could indicate increased risk of malignancy associated with bisphosphonate use

Wysowski DK. N Engl J Med. 2009;360(1):89–90.

23/06/2015

16

Meta-analysis of oesophageal cancer and oral bisphosphonates

Sun K, et al. Osteoporos Int. 2013;24:279–286

Closing Thoughts

23/06/2015

17

Adverse Publicity: Effect on Oral Bisphosphonate Use in USA

Wysowski DK, Greene P. Bone. 2013;57:423-428

Summary of benefits vs. risks for bisphosphonate treatment as a function of time

BenefitsHip, non-vertebral and spine reductions

Risks

Treatment 3-4 years

Benefits:Only spine reductions

Risks

Treatment Beyond 3-4 yrs

Benefitsunproven

Risks uncertain

Treatment Beyond 6 yrs with ZOL or 10

years with ALN

23/06/2015

18

Thanks to Dennis Black for Discussions

Which patients should be continued on treatment?

• Primary benefit is in reduction of vertebral fractures

• Therefore, logical to continue those at highest risk of vertebral fractures

• Continue treatment in those with highest risk of vertebral fractureo Strongest risk factors in treatment naïve patients are BMD and existing vertebral

fractures (also age)

23/06/2015

19

37

FLEX vertebral fracture benefit:

Who to continue?

Femoral Neck BMD T-Score (start FLEX)

5 Yr risk (%) Clinical Vert. Fx. In PBO

Number Needed to

Treat

All women in study

All BMD values 5.5 34

≤ -2.5 9.3 21

-2.5 to -2 5.8 33

≥ -2 2.3 81

No prevalent vert. fracture (start of FLEX)

≤ -2.5 8.0 24

-2.5 to -2 3.0 63

≥ -2 1.8 102

Prevalent vertebral fracture (start of FLEX)

≤ -2.5 11.1 17

-2.5 to -2 11.1 17

≥ -2 3.7 51Black, et al. NEJM. 2012 May 31;366(22):2051-3

Continue ZOL after 3 years?Summary

- Many women can be discontinued after 3 years of ZOL

- Those at highest risk for vertebral fracture will most likely benefit from continuation- Hip BMD T-score below -2.5

- Existing vertebral fracture (after initial therapy)

- A fracture during initial therapy

- After 6 years, almost all women can take a drug holiday for at least 3 years

Cosman F...Eastell R, Black DM. J Clin Endocrinol Metab. 2014 Dec;99(12):4546-54